WO1999061432A1 - Fumagillin analogs and their use as angiogenesis inhibitors - Google Patents

Abstract

The present invention relates to angiogenesis-inhibiting compounds represented by formula (I) wherein R1 through R5 are as defined herein. Compounds of the invention are analogs of fumagillin and are useful in therapy and prophylaxis of disease states associated with angiogenesis such as cancer, diabetic retinopathy and inflammatory diseases (rheumatism, psoriasis etc.).

Description

FUMAGILLIN ANALOGS AND THEIR USE AS ANGIOGENESIS INHIBITORS

FIELD OF THE INVENTION

The present invention relates to angiogenesis-inhibiting compounds, and more particularly, to analogs of fumagillin and their use in therapy and prophylaxis of disease states associated with angiogenesis.

BACKGROUND OF THE INVENTION

Under normal physiological conditions, humans or animals undergo angiogenesis only in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development and formation of the corpus luteum, endometrium and placenta.

Both controlled and uncontrolled angiogenesis are thought to proceed in a similar manner. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels . Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a "sprout" off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. Endothelial sprouts merge with each other to form capillary loops, creating the new blood vessel.

Persistent, unregulated angiogenesis occurs in a multiplicity of disease states such as diabetic retinopathy, inflammatory diseases (rheumatism, psoriasis etc.) cancer and tumor metastasis and supports the pathological damage seen in these conditions.

The link between tumor growth and angiogenesis has been established as early as 1971. Increases in tumor cell population beyond a critical volume must be preceded by an increase in new capillaries converging on the tumor (Folkman, N. Engl . Jour. Med. , 1971, 285:1182). In a prevascular phase of growth, a population of tumor cells occupy a volume of a few cubic millimeters or a few million cells surviving on existing host microvessels . Growth beyond this phase requires an induction of new capillary blood vessels.

It would therefore be desirable to prevent angiogenesis as a means for treating or preventing disease states in which it is implicated.

SUMMARY OF THE INVENTION

The present invention provides angiogenesis inhibiting compounds. According to one embodiment of the invention, the compounds are defined by formula (I) and pharmaceutically acceptable salts and derivatives thereof :

(I)

According to this embodiment of the present invention, the substituents of the invention are defined as follows: j is H or straight or branched

alkyl. R₂ is H, C_1-4 alkyl, aryl, aryl-C^.,, alkyl, cycloalkyl, cycloalkyl-C^,, alkyl. R₃ is a C_1-4 alkyl-C₅._β aryl that is optionally substituted with one or more halogen (F, Cl, I, Br),a C_1-4 alkoxy and/or a C_1-4 alkyl. Additionally, R₄ is H, OH or C_1-4 alkoxy. R_s is selected from the group consisting of H; a substituted alkanoyl group; a substituted aroyl group having at least one substituent selected from the group consisting of C₂.₆ alkyl, amino, halogen, hydroxyl , lower alkoxy, cyano, carbamoyl and carboxyl ; an aromatic heterocycle-carbonyl which may optionally be substituted; a carbamoyl group, which may optionally be substituted; an alkyl group, which may optionally be substituted; a benzenesulfonyl group, which may optionally be substituted; an alkylsulfonyl group, which may optionally be substituted; a sulfamoyl group, which may optionally be substituted; an alkoxycarbonyl group, which may optionally be substituted; a phenoxycarbonyl group, which may optionally be substituted; or C (0 ) -NH-C ( 0) -CH₂-C1.

In another aspect of the invention, there is provided angiogenesis inhibiting compositions comprising a pharmaceutically acceptable carrier, diluent or adjuvant and an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In yet another aspect of the invention, there is provided a method of inhibiting or preventing angiogenesis in a mammal, comprising administering to said mammal an effective amount of a compound of formula (I) or a composition thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to angiogenesis inhibiting compounds which are analogues of fumagillin according to formula (I) :

(I) wherein R_: to R₅ are as previously defined.

The term "alkyl," unless otherwise specified, is defined as a straight, saturated carbon chain optionally incorporating a heteroatom or carbonyl group.

The term "alkenyl," unless otherwise specified, is defined as a straight unsaturated carbon chain optionally incorporating a heteroatom or carbonyl group.

By "heteroatom" is meant N, 0, S, SO and S0₂.

The term "cycloalkyl" is defined as a cyclic alkyl group optionally incorporating a heteroatom or a carbonyl group and optionally incorporates unsaturated bonds. Substituted cycloalkyl groups are alkyl groups that are substituted with halogen (i.e. F, Cl , Br, I); OH, C_1-4 alkyl or C₁._i alkoxy. Cycloalkyl groups, according to one embodiment, preferably are 5 to 10-membered rings, in particular cyclopentyl, cyclohexyl and cycloheptyl as well as pyrrolidine, thiophene, furan, thiazole, imidazole and piperidine. According to one embodiment, cyclohexyl groups are preferred cycloalkyls .

The term "aryl" is defined as a substituted or unsubstituted aromatic or heteroaromatic ring. Susbtituted aryl are substituted by halogen (i.e. F, Cl , Br; I), OH, C_1-4 alkyl, or C^ alkoxy. Non heterocylic aromatic groups, according to some embodiments of the present invention, are preferably 5 to 10-membered aromatic rings and include by way of example and not by limitation, phenyl or naphthyl . Heteroaromatic rings, according to certain embodiments of the present invention incorporate heteroatoms selected from N, 0 and S, and include but are not limited to pyridine, pyrazine and quinoline. According to other embodiments of the present invention, aryl groups preferably are phenyl and pyridine and most preferably are phenyl .

Other terms not specifically defined herin and that pertain to substituents of the R₅ group of Formula I are defined in European Patent No. 0 682 020 published

November 15, 1995 by Takeda Chemical Industries Limited which has been incorporated by reference herein.

Another embodiment of the present invention provides angiogenesis inhibiting compounds of formula I wherein R_x is H or straight or branched C₁.₈ alkyl, _λ__g alkenyl, C₄._β aryl-C_1-8 alkyl, C₄._B aryl-C_1-8 alkenyl. According to this embodiment, R₂ is H, C_1-4 alkyl, aryl, aryl-C^ alkyl, cycloalkyl, cycloalkyl-C^ alkyl or the group

R₃, according to this embodiment, is H or C_x_₄ alkyl, aryl, aryl-C_1-4 alkyl, cycloalkyl or cycloalkyl -C_1-4 alkyl ; and R₄ is H, OH or C^₄ alkoxy.

In a particular embodiment, R_λ is H or C_1-4 alkyl. In an alternative embodiment R_x is methyl. In another embodiment R_x is methylbutyl .

In a particular embodiment, R₂ is H or C_x_₄ alkyl.

According to this embodiment, R₂ is, more preferably, H or methyl and most preferably R₂ is H.

In another embodiment R₂ is aryl, aryl-C^ alkyl, cycloalkyl or cycloalkyl-C^ alkyl. According to this embodiment, R₂ is more preferably aryl-C_x_₄ alkyl and most preferably benzyl .

In yet another embodiment R₃ is H or C_1-4 alkyl

In still another embodiment, R₂ is the group

wherein each R₃ is independently as previously defined and preferably H or C_1-4 alkyl; more preferably H or methyl and most preferably are both methyl.

In another embodiment, R₄ is H. In yet another embodiment, R₄ is OH or methoxy and more preferably methoxy.

In another embodiment, R₅ is H or C (0) -NH-C (0) -CH₂C1.

In still another embodiment:, R₅ is C (0) -NH-C (0) -CH₂C1.

In yet another embodiment, R₅ is H.

According to another embodiment, the invention is a compound of formula (I) and pharmaceutically acceptable salts and derivatives thereof wherein R_x to R₄ are defined as follows:

R_x is H or straight or branched C^ alkyl. R₂ is H,

C_1-4 alkyl, aryl, aryl -C_x_₄ alkyl, cycloalkyl, cycloalkyl-C_x_₄ alkyl. R₃ is a C_1-4 alkyl-C₅_₈ aryl that is optionally substituted with one or more halogen (F, Cl , I, Br) , C_x_₄ alkoxy and/or a C_1-4 alkyl. Furthermore, R₄ is H, OH or C_x_₄ alkoxy. R_s is selected from the group consisting of H; a substituted alkanoyl group; a substituted aroyl group having at least one substituent selected from the group consisting of C₂.₆ alkyl, amino, halogen, hydroxyl , lower alkoxy, cyano, carbamoyl and carboxyl ; an aromatic heterocycle-carbonyl which may optionally be substituted; a carbamoyl group, which may optionally be substituted; an alkyl group, which may optionally be substituted; a benzenesulfonyl group, which may optionally be substituted; an alkylsulfonyl group, which may optionally be substituted; a sulfamoyl group, which may optionally be substituted; an alkoxycarbonyl group, which may optionally be substituted; a phenoxycarbonyl group, which may optionally be substituted; or C (0) -NH-C (0) -CH₂-C1.

In another embodiment, R₅ is H or C (0) -NH-C (0) -CH₂C1.

In still another embodiment, R₅ is C (0) -NH-C (0) -CH₂C1.

In yet another embodiment, R₅ is H.

In another embodiment, the invention is a compound of formula I as previously defined except Ri and R₂ are independently selected from the group consisting of H or C_1-4 alkyl .

In another embodiment, the invention is a compound of formula I as previously defined except R_x and R₂ are independently either H or methyl .

In another embodiment, the invention is a compound of formula I as previously defined except R₂ is aryl, aryl-C_x_₄ alkyl, cycloalkyl or cycloalkyl-C_1-4 alkyl and R₃ is C_x.₄ alkyl-phenyl that is optionally substituted with one or more halogen (F, Cl, I, Br) and/or a C₁__i alkyl.

In another embodiment, the invention is a compound of formula I as previously defined except R₃ is a C_x_₂ alkyl- phenyl .

In another embodiment, the invention is a compound of formula I as previously defined except R₃ is a benzyl and R₂ is H .

In another embodiment, the invention is a compound of formula I as previously defined except R₄ is a Cι-₄ alkoxy.

In another embodiment, the invention is a compound of formula I as previously defined except R₄ is a methoxy.

In another embodiment, the invention is a compound of formula I as previously defined except R_x is H.

Compounds according to one embodiment of the invention include :

(i) (3R,4R,6R,2'R) and (3S, 4S, 6S, 2 ' S ) chloroacetyl carbamic acid-4- (3' , 3' -dimethyl-oxiranyl) -1-oxa- spiro [2.5] oct-6-yl ester;

(ii) (3R, 4R, 6S,2'S) and (3S, 4S, 6R, 2' R) chloroacetyl carbamic acid-4- (3' , 3' -dimethyl-oxiranyl) -1-oxa- spiro [2.5] oct-6-yl ester; (iii) (3R,4S,6S,2'R,3'R) and (3S, 4R, 6R, 2' R, 3'S) chloroacetyl carbamic acid-4- (3' -benzyl, 2' -methyl- oxiranyl) -1-oxa-spiro [2.5] oct-6-yl ester;

(iv) (3R,4S,6S,2'S,3'S) and ( 3S, 4R, 6R, 2' R, 3'R) chloroacetyl carbamic acid-4- (3' -benzyl, 2' -methyl- oxiranyl) -1-oxa-spiro [2.5] oct-6-yl ester;

(v) (3R,4S,6R,2'R,3'R) and (3S, 4R, 6S, 2' S, 3' S) chloroacetyl carbamic acid-4- (3' -benzyl, 2 ' -methyl-oxi anyl) -1-oxa- spiro[2.5] oct-6-yl ester;

(vi) (3R,4S,6R,2'S,3'S) and (3S, 4R, 6S, 2' R, 3' R) - chloroacetyl carbamic acid-4- (2' , 3' -dimethyl-oxiranyl) -1- oxa-spiro- [2.5]-oct-6-yl ester);

(vii) (3R,4S, 6-S,2'R,3'R) and (3S , 4R, 6R, 2' S , 3' S ) - chloroacetyl carbamic acid-4- (2' , 3' -dimethyl-oxiranyl) -1- oxa-spiro- [2.5] -oct-6-yl ester) ; (viii) (2'R,3'R,3R,4S,5S, 6R) and (2 ' S, 3' S, 3S, 4R, 5R, 6S) chloroacetyl-carbamic acid 4- (2' , 3' -dimethyl-oxiranyl) -5- methoxy-1-oxa-spiro [2.5] oct-6-yl ester;

(ix) (2'S,3'S,3R,4S,5S,6R) and (2' R, 3' R, 3S, 4R, 5R, 6S)

(chloroacetyl-carbamic acid 4- (2' , 3' -dimethyl-oxiranyl) -5- methoxy-1-oxaspiro [2.5] oct-6-yl ester; (xi) (3R,4S,6S,2'R,3'R) , ( 3R, 4S, 6S, 2 ' S, 3' S) and

(3R, S, 6R,2'R,3'R) chloroacetyl-carbamic acid 4-[2',3'- bis- (3"-methylbutyl) ] -1-oxaspiro- [2.5] oct-6-yl ester;

(xii) racemic (2S, 3S) -2 , 4 , -trimethoxy-3- (1 'methyl-3 ' - phenyl-propenyl) -cyclohexanonephenyl-propenyl) - eye1ohexanone ;

(xiii) racemic (1R, 2S, 3S) -Benzoic acid-2-methoxy-3 - (1 ' - methyl-3 ' -phenyl propenyl) -4-oxo-cyclohexyl ester;

(xiv) racemic (3R, 4S, 5S, 6R) -Benzoic acid-5-methoxy-4- (1 ' - methyl-3 ' -phenyl-propenyl) -1-oxa- spiro [2.5] oct-6-yl ester;

(xv) racemic (3R, 4S , 5S, 6R, 2 ' S, 3 ' S) -Benzoic acid-4- (2¹- methyl-3 ' -phenyl-oxiranyl) -5-methoxy-l-oxa-spiro [2.5] oct- 6-yl ester;

(xvi) (3R,4S,5S, 6R,2 'R,3 'R) -Benzoic acid-4- (2 ' -methyl-3 ' - phenyl-oxiranyl) -5-methoxy-l-oxa-spiro [2.5] oct-6-yl ester;

(xvii) racemic (3R, S, 5S , 6R, 2 ' S, 3 ' S) 4- (3-benzyl-2- methyl-oxiranyl) -5-methoxy-l-oxa-spiro [2.5] oct-6-ol;

(xviii) racemic (3R, 4S, 5S , 6R, 2 ' S, 3 ' S) chloroacetyl- carbamic acid 4- (3 -benzyl-2 -methyl-oxiranyl) -5-methoxy-l- oxa-spiro [2.5] oct-6-yl ester;

(xix) racemic (3R, 4S, 5S , 6R, 2 ' R, 3 ' R) -4- (2 ' -methyl-3 ' - benzyl-oxiranyl) -5-methoxy -1-oxa-spiro [2.5] oct-6-ol ; and

(xx) racemic (3R, 4S, 5S, 6R, 2 ' R, 3 ' R) -Chloroacetylcarbamic acid-4- (3 ' -benzyl-2 ' methyl-oxiranyl) -5-methoxy-l-oxa- spiro [2.5] oct-6-yl;

According to one embodiment of the invention, more preferred compounds include :

(i) (3R,4R, 6R,2'R) and (3S, 4S, 6S, 2' S) chloroacetyl carbamic acid-4- (3' , 3' -dimethyl-oxiranyl) -1-oxa- spiro [2.5] oct-6-yl ester;

(ii) (3R,4R, 6S,2'S) and (3S, 4S, 6R, 2' R) chloroacetyl carbamic acid-4- (3' ,3' -dimethyl-oxiranyl) -1-oxa- spiro [2.5] oct-6-yl ester;

(vi) (3R, 4S, 6R,2'S,3'S) and (3S, 4R, 6S, 2' R, 3' R) - chloroacetyl carbamic acid-4- (2' , 3' -dimethyl-oxiranyl) -1- oxa-spiro- [2.5] -oct-6-yl ester);

(vii) (3R,4S, 6S,2'R,3'R) and (3S, 4R, 6R, 2' S , 3' S) - chloroacetyl carbamic acid-4- (2' , 3' -dimethyl-oxiranyl) -1- oxa-spiro- [2.5]-oct-6-yl ester) ; (xvii) racemic (3R, 4S, 5S, 6R, 2 ' S, 3 ' S) 4- (3-benzyl-2- methyl-oxiranyl) -5-methoxy-l-oxa-spiro [2.5] oct-6-ol ; (xviii) racemic (3R, 4S, 5S, 6R, 2 ' S, 3 ' S) chloroacetyl- carbamic acid 4- ( -benzyl-2 -methyl -oxiranyl) -5-methoxy-l- oxa-spiro [2.5] oct-6-yl ester; (xix) racemic (3R, 4S, 5S, 6R, 2 ' R, 3 ' R) -4- (2 ' -methyl-3 ' - benzyl-oxiranyl) -5-methoxy -1-oxa-spiro [2.5] oct-6-ol ;

(xx) racemic (3R, S, 5S, 6R, 2 ' R, 3 ' R) -Chloroacetylcarbamic acid-4- (3 ' -benzyl-2 'methyl-oxiranyl) -5-methoxy-l-oxa- spiro [2.5] oct-6-yl ;

According to one embodiment of the invention, preferred compounds include :

(viii) (2'R,3'R,3R,4S,5S,6R) and (2' S, 3' S, 3S, 4R, 5R, 6S) chloroacetyl-carbamic acid 4- (2' , 3' -dimethyl-oxiranyl) -5- methoxy-1-oxa-spiro [2.5] oct-6-yl ester; (ix) (2'S,3'S,3R,4S,5S,6R) and ( 2' R, 3' R, 3S , 4R, 5R, 6S )

(chloroacetyl-carbamic acid 4- (2' , 3' -dimethyl-oxiranyl) -5- methoxy-1-oxaspiro [2.5] oct-6-yl ester; (xviii) racemic (3R, 4S, 5S, 6R, 2 ' S, 3 ' S) chloroacetyl- carbamic acid 4- (3 -benzyl-2-methyl-oxiranyl) -5-methoxy-l- ^■ oxa-spiro [2.5] oct-6-yl ester; and

(xx) racemic (3R, 4S, 5S, 6R, 2 ' R, 3 ' R) -Chloroacetylcarbamic acid-4- (3 ' -benzyl-2 'methyl-oxiranyl) -5-methoxy-l-oxa- spiro [2.5] oct-€-yl .

According to an embodiment of the invention preferred compounds include : (iii) (3R,4S, 6S,2'R,3'R) and ( 3S , 4R, 6R, 2 ' R, 3'S) chloroacetyl carbamic acid-4- ( 3 ' -benzyl, 2 ' -methyl- oxiranyl) -1-oxa-spiro [2.5] oct-6-yl ester; (iv) (3R,4S, 6S,2'S,3'S) and (3S, 4R, 6R, 2' R, 3'R) chloroacetyl carbamic acid-4- (3' -benzyl, 2' -methyl- oxiranyl) -1-oxa-spiro [2.5] oct-6-yl ester; and

(v) (3R,4S,6R,2'R,3'R) and ( 3S, 4R, 6S, 2' S , 3' S ) chloroacetyl carbamic acid-4- (3' -benzyl, 2' -methyl-oxiranyl) -1-oxa- spiro[2.5] oct-6-yl ester.

According to yet another embodiment or the invention, preferred compounds include:

(xvii) racemic (3R, 4S, 5S, 6R, 2 ' S, 3 ' S) 4 - (3 -benzyls- methyl-oxiranyl) -5-methoxy-l-oxa-spiro [2.5] oct-6-ol; (xviii) racemic (3R, 4S, 5S, 6R, 2 ' S , 3 ' S) chloroacetylcarbamic acid 4- (3-benzyl-2-methyl-oxiranyl) - 5-methoxy-l-oxa-spiro [2.5] oct-6-yl ester; (xix) racemic (3R, 4S, 5S, 6R, 2 ' R, 3 ' R) -4- (2 ' -methyl-3 ' - benzyl-oxiranyl) -5-methoxy -1-oxa-spiro [2.5] oct-6-ol ; and (xx) racemic (3R, S, 5S, 6R, 2 ' R, 3 ' R) -Chloroacetylcarbamic acid-4- (3 ' -benzyl-2 'methyl-oxiranyl) -5-methoxy-l-oxa- spiro [2.5] oct-6-yl .

One embodiment of the invention includes as preferred compounds, the following: (xviii) racemic (3R, 4S, 5S, 6R, 2 ' S , 3 ' S) chloroacetylcarbamic acid 4- (3-benzyl-2-methyl-oxiranyl) -5-methoxy-l- oxa-spiro [2.5] oct-6-yl ester; and

(xx) racemic (3R, 4S, 5S, 6R, 2 'R, 3 ' R) -Chlorocarbamic acid-4- (3 ' -benzyl-2 'methyl-oxiranyl) -5 -methoxy-1-oxa- spiro [2.5] oct-6-yl .

According to another embodiment, a more preferred compound of the invention is (x) (3R, 4S, 6R, 2' R, 3' R, 2' ' R) and (3S, 4R, 6S,2' S, 3' S,2' ' S) chloroacetyl carbamic acid-4-[3'- (3' ' , 3' ' -dimethyl-oxiranylmethyl) -2' -methyl-oxiranyl] -1- oxa-spiro [2.5] oct-6-yl ester. According to another embodiment, a preferred compound of the invention is (ii) (3R, 4R, 6S, 2' S) and (3S, 4S, 6R, 2' R) chloroacetyl carbamic acid-4- (3' , 3' -dimethyl-oxiranyl) -1- oxa-spiro [2.5] oct-6-yl ester.

Compounds of the present invention can be synthesised using conventional preparative steps and recovery methods known to those skilled in the art of organic synthesis .

Referring to scheme 1, a synthetic route of one embodiment of the invention involves reacting commercially available starting reagent (a) 4 , 4-dimethoxy-2 , 5-cyclohexadienone with a desired Grignard reagent (1) or organo-lithium reagent (2) in the presence of a suitable 1,4 -addition inducing agent such as MAD (methylaluminum bis- (2 , 6-di-t- butyl-4-methylphenoxide) to yield intermediate (b) . Intermediate (b) undergoes 1, 4-reduction with a suitable reducing agent such as L-selectride in the presence of MAD to give (c) . In particular embodiments wherein R4 is hydroxy or alkoxy, said groups may be incorporated at the 5-position of intermediate (b) prior to its reduction to (c) . Intermediate (c) is 1,2-reduced, followed by deprotection of the ketal and spiro epoxidation with a suitable ylide such as trimethylsulfoxonium iodide to yield (d) . This intermediate undergoes side chain epoxidation with a suitable oxidizing agent such as MCPBA to give the alcohol (e) . Finally, the alcohol is reacted with chloroacetyl-isocyanate to give the final compound.

SCHEME 1

As shown in Scheme I, R_x to R₄ are as defined in this disclosure.

Starting material (a) and reagents employed in the processes described herein may be obtained from commercial sources or alternatively may be prepared according to established synthetic techniques from commercially available reagents .

Other groups defined in R₅ can be made according to the teaching of in European Patent No. 0 682 020 published November 15, 1995 by Takeda Chemical Industries Limited which has been incorporated by reference herein. It will be appreciated that certain substituents require protection during the course of the synthesis and subsequent deprotection. Protective groups for various substituents are described in Protective Groups in Organic Synthesis, 2nd ed., Greene and Wuts, John Wiley & Sons, New York, 1991.

It will be appreciated by those skilled in the art that the compounds of formula (I), depending on the substituents, may contain one or more chiral centers and thus exist in the form of many different isomers, geometric and optical isomers (i.e. enantiomers) and mixtures thereof including racemic mixtures. All such individual isomers, enantiomers and mixtures thereof including racemic mixtures are included within the scope of the present invention.

The present invention also provides methods of inhibiting angiogenesis in a mammal, comprising administering to said mammal an effective amount of a compound according to formula (I) . An "effective amount" or "angiogenesis inhibiting amount" is the amount of active compound required to reduce or eliminate the rate of angiogenesis that would otherwise occur at a site of therapeutic interest absent the administration of said compound. The methods of the invention include inhibiting tumor growth and/or tumor metastasis, preventing or treating diabetic retinophathy and preventing or treating inflammatory diseases such as rheumatism and psoriasis.

The present invention also provides angiogenesis inhibiting compositions which comprise a pharmaceutically acceptable carrier or adjuvant and an amount of a compound of formula (I) effective to inhibit angiogenesis in a mammal. The proportion of each carrier, diluent or adjuvant is determined by the solubility and chemical nature of the particular compound and the route of administration according to standard pharmaceutical practice .

Therapeutic and prophylactic methods of this invention comprise the step of treating patients in a pharmaceutically acceptable manner with those compounds or compositions. Such compositions may be in the form of tablets, capsules, caplets, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions. Compounds of the invention may also be administered via a polymer based implant which will release a compound at a site of interest, for example, near a tumor.

In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. The unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients. For example, binding agents, such as acacia, gelatin, sorbitol, or' polyvinylpyrrolidone; fillers, such as lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tableting lubricants such as magnesium stearate; disintegrants, such as starch, polyvinylpyrrolidone, sodium starch glycollate or macrocrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.

The compounds may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously . For parenteral administration, the compound may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The amount of active ingredient administered parenterally will be approximately 0.1 to 5000 mg/kg/day, preferably about 1 to 200 mg/kg/day, more preferably about 10 to 100 mg/kg/day, and more most preferably about 30 to 60 mg/kg/day.

The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may be administered orally in the form of solutions which may contain coloring and/or flavoring agents. The compounds may also be administered sublingually in the form of tracheas or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The amount of active ingredient administered orally will depend on bioavailability of the specific compound.

The solid oral compositions may be prepared by conventional methods of blending, filling, tableting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art. The tablets may be coated according to methods well known in pharmaceutical practice, in particular with an enteric coating.

Oral liquid preparations may be in the form of emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may or may not contain conventional additives . For example suspending agents, such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats; emulsifying agents, such as sorbitan monooleate or acaci; non-aqueous vehicles (which may include edible oils) , such as almond oil, fractionated coconut oil, oily esters selected from the group consisting of glycerine, propylene glycol, ethylene glycol, and ethyl alcohol; preservatives, for instance methyl para-hydroxybenzoate, ethyl para- hydroxybenzoate, n-propyl parahydroxybenzoate, or n-butyl parahydroxybenzoate of sorbic acid; and, if desired, conventional flavoring or coloring agents .

For parenteral administration, fluid unit dosage forms may be prepared by utilising the compound and a sterile vehicle, and, depending on the concentration employed, may be either suspended or dissolved in the vehicle. Once in solution, the compound may be injected and filter sterilised before filling a suitable vial or ampoule and subsequently sealing the carrier or storage package. Adjuvants, such as a local anaesthetic, a preservative or a buffering agent, may be dissolved in the vehicle prior to use. Stability of the pharmaceutical composition may be enhanced by freezing the composition after 'filling the vial and removing the water under vacuum, (e.g., freeze drying the composition) . Parenteral suspensions may be prepared in substantially the same manner, except that the compound should be suspended in the vehicle rather than being dissolved, and, further, sterilisation is not achievable by filtration. The compound may be sterilised, however, by exposing it to ethylene oxide before suspending it in the sterile vehicle. A surfactant or wetting solution may be advantageously included in the composition to facilitate uniform distribution of the compound .

The pharmaceutical compositions of this invention comprise an angiogenesis inhibiting amount of a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or adjuvant. Typically, they contain from about 0.1% to about 99% by weight of active compound, and preferably from about 10% to about 60% by weight depending on which method of administration is employed.

Physicians will determine the dosage of the present therapeutic agents which will be most suitable. Dosages may vary with the mode of administration and the particular compound chosen. In addition, the dosage may vary with the particular patient under treatment. The dosage of the compound used in the treatment will vary, depending on the weight of the patient, the relative efficacy of the compound and the judgement of the treating physician. Such therapy may extend for several weeks or months, in an intermittent or uninterrupted manner.

To further assist in understanding the present invention, the following non-limiting examples are provided.

EXAMPLE 1 Synthesis of compounds i and ii

ua

Step 1: racemic 4, 4-dimethoxy-5- (2-methyl-propenyl) - cyclohex-2-enone To a mixture of BHT (2, 6-di-tert-butyl-4-methylphenol) (2.86g, 13.0 mmol) and TMA (trimethylaluminium) (2M in toluene) (2.9 ml, 5.8 mmol) in CH₂C1₂ (55 ml) at -78°C and under nitrogen atmosphere, was added a solution of 4,4- dimethoxy-2, 5-cyclohexadienone (500 mg, 3.2 mmol, Aldrich) in CH₂C1₂ (5 ml) . The reaction mixture was stirred for 15 minutes . A solution of 2-methyl-propenyl magnesium bromide (0.37 M in THF) (26.3 ml, 9.7 mmol, prepared from the bromide, Aldrich) in CH₂C1₂ (5 ml) was added one drop at a time. The reaction mixture was stirred at -78°C for 1 hour. After the reaction was completed, a solution of H₂0:NaHC0₃ (sat.) (1:1) (5 ml) was added. The resulting mixture was brought to room temperature, filtered on filter aid and the solvent was evaporated. The crude product was purified by flash chromatography (70:30 hex:AcOEt with a drop of Et₃N) to give the desired product as a colorless oil (443 mg, 65%). R_f 0.29 (hexane : ethyl acetate, 9:1).

Step 2: racemic 4 , 4-dimethoxy-3- (2-methyl-propenyl) - cyclohexanone

To a mixture of BHT (2, 6-di-tert-butyl-4-methylphenol) (1.84 g, 8.4 mmol) and TMA (tri ethylaluminium) (2 M in toluene) (1.9 ml, 3.8 mmol) in toluene (30 ml) at -78°C, was added a solution of 4 , 4-dimethoxy-5- (2-methyl- propenyl) -cyclohex-2-enone (439 mg, 2.1 mmol) in toluene (5 ml) . The reaction mixture was stirred for 25 minutes. A solution of L-selectride (2.3mmol) in 5 mL of toluene was prepared by removing the solvent in vacuo from a commercially available IN solution (2.3mL) in THF and redissolving the residue in toluene. This solution was added one drop at a time to the reaction mixture. The reaction mixture was stirred at -78°C for 45 minutes. After the reaction was completed, a mixture of saturated NH₄C1 (20 ml) and toluene : ether (1:1) (40 ml) was added. The organic layer was separated and the aqueous layer was extracted further with toluene :ether (1:1) (2x40 ml). The combined organic layers were washed with brine (40 ml), dried (Na₂S0₄) and evaporated. The crude was purified by flash chromatography (85:15 hex:AcOEt) to give the desired product as a colorless oil (339 mg, .76%). Rf 0.34 (hexane :ethyl acetate, 8.5:1.5).

Step 3: racemic (3R,4R,6R)- and (3R, 4R, 6S) -4- (2-methyl- propenyl) -1-oxa-spiro [2.5] octan-6-ol To a cooled (-78°C) solution of 4 , 4-Dimethoxy-3- (2-methyl- propenyl) -cyclohexanone (5.604g, 26.434mmol) in dry toluene (25 ml) was added, one drop at a time and under nitrogen atmosphere, 29 ml of a 1 DIBAL-H (diisobutylaluminum hydride, Aldrich) solution in toluene. The mixture was stirred for 30 minutes and quenched with NH4CI sat. After stirring for an additional 45 minutes at room temperature the mixture was extracted with dichloromethane (3x) . The combined organic layers were washed with water and dried (Na₂S0₄) . The solvent was evaporated, the residue (colorless oil) was dried under vacuum and dissolved in 250 ml of acetone and 25 ml of water. To this mixture was added 10.0 mg of pyridinium p-toluene sulfonate. After stirring for 1,5 hour, the mixture was diluted with dichloromethane, washed with NaHC0₃ sat., water and dried (MgS0₄) . After removal of the solvent, the crude product was dissolved in 25 ml of anhydrous DMSO and added to a trimethylsulfoxonium ylide mixture (the ylide was obtained by addition of NaH 60% (2.643g, 66.085 mmol) to trimethylsulfoxonium iodide (17.452 g, 79.302 mmol) in anhydrous DMSO (75 ml) at room temperature and stirring for 2 hours) . The resulting mixture was stirred for 3 hours at room temperature, quenched with water, diluted with brine and extracted with an ether : hexane; 1:2 mixture. The combined organic layers were washed with brine and dried (Na₂S0₄) . Flash chromatography (Hexane—Hexane : Ethyl Acetate; 8:2) gave 3.621g (75% yield for 3 steps) of a separable (3R, 4R, 6R) : (3R,4R, 6S) (1:2) isomers mixture.

Step 4: racemic (3R, 4R, 6R, 2' R) and (3R, 4R, 6R, 2' S) -4-

(3' ,3' -dimethyl-oxiranyl) -1-oxa-spiro [2.5] octan- 6-0I To a solution of racemic (3R, 4R, 6R) -4- (2-methyl- propenyl) 1-oxa-spiro [2, 5] octan-6-ol (15 mg, 0.08 mmol) in CH₂C1₂ (2.3 ml) at room temperature, was added MCPBA (metachloroperoxybenzoic acid, Aldrich) (18 mg, 0.10 mmol) . The reaction mixture was stirred at room temperature and after 45 minutes additional MCPBA (2.8 mg, 0.02 mmol) was added. Stirring was continued and after 45 more minutes, MCPBA (7.0 mg, 0.04 mmol) was added again to complete the reaction. A mixture of saturated Na₂S0₃ (10 ml) and CH₂C1₂ (15 ml) was added. The organic layer was separated and the aqueous layer was extracted further with CH₂C1₂ (2x15 ml) . The combined organic layers were washed with saturated NaHC0₃ (10 ml), dried (Na₂S0₄) and evaporated. The crude residue was purified by flash chromatography (8:2 toluene : acetone) to give the separated desired products (total yield: 14.4 mg, 89%) in a 2:1 (2'R:2'S) ratio.

Step 5: (ia) racemic (3R, 4R, 6R, 2' S) chloroacetyl carbamic acid-4- (3' , 3' -dimethyl-oxiranyl) -1-oxa- spiro [2.5] oct-6-yl ester To a solution of racemic (3R, 4R, 6R, 2 ' S) -4- (3' , 3' -dimethyl-oxiranyl) -1-oxa- spiro [2, 5] octan-6-ol (5.7 mg, 0.03 mmol) in CH₂C1₂ (388 μ 1), was added DMAP (dimethylaminopyridine) (5.2 mg, 0.04 mmol) in one portion. The mixture was cooled to 0°C and was stirred for 15 minutes. Chloroacetylisocyanate (10.9 μl, 0.13 mmol) was added. The reaction mixture was stirred at 0°C for 10 minutes. After the reaction was completed, a mixture of H₂0 (5 ml) and CH₂C1₂ (15 ml) was added. The organic layer was separated and the aqueous layer was back extracted with CH₂C1₂ (2x15 ml) . The combined organic layers were dried (Na₂S0₄) and solvent was evaporated. The crude product was purified by flash chromatography (2:1 hex:AcOEt) to give the desired product (2.3 mg, 25%) .

^XH NMR (400 MHz, CDC1₃) δ 1.28 (d, J = 9.2 Hz, 6H) , 1.83- 2.03 ( , 6H) , 2.19 (td, J = 8.9 Hz and 4.8 Hz, IH) , 2.48 (d, J = 8.9 Hz, IH) , 2.68 (d, J = 4.3 Hz, IH) , 3.18 (d, J = 4.3 Hz, IH) , 4.46 (s, 2H) , 5.25-5.26 (m, IH) , 7.92 (s, IH) . Step 6: (i) racemic (3R, 4R, 6R, 2' R) chloroacetyl carbamic acid-4- (3' , 3' -dimethyl-oxiranyl) -1-oxa- spiro [2.5] oct-6-yl ester Following the procedure described in step 5, 6.7 mg (0.034 mmol) of racemic (3R, 4R, 6R, 2 ' R) -4- (3, 3-dimethyl oxiranyl) - 1-oxaspiro [2,5] octan-6-ol afforded 4.9 mg (46% yield) of desired pure product. ^lH NMR (400 MHz, CDC1₃) δ 1.29 (d, J = 3.7 Hz, 6H) , 1.94- 2.23 (m, 7H), 2.48 (d, J = 8.5 Hz, IH) , 2.67 (d, J = 4.3 Hz, IH) , 2.77 (d, J = 4.2 Hz, IH) , 4.49 (s, 2H) , 5.30 (m, IH) , 7.95 (s, IH) .

Step 7: racemic (3R, 4R, 6S, 2' R) and (3R, 4R, 6S, 2' S) -4- (3' , 3' -dimethyl-oxiranyl) -1-oxa-spiro [2.5] octan-

6-ol) Following the procedure described step 4, 31.6 mg (0.17 mmol) of racemic (3R, 4R, 6S) -4- (2-methyl-propenyl) -1-oxa- spiro [2, 5] octan-6-ol afforded crude material which was purified by flash chromatography (8:2 benzene : acetone) to give the separated desired products (total yield: 34.4 mg, 88%) in a 54:46 (2'R:2'S) ratio.

Step 8: (ii) racemic (3R, 4R, 6S, 2' S) chloroacetyl carbamic acid-4- (3' , 3' -dimethyl-oxiranyl) -1-oxa- spiro [2.5] oct-6-yl ester Following the procedure described in step 5, 6.2 mg (0.031 mmol) of racemic (3R, 4R, 6S, 2' S) -4- (3' , 3' -dimethyl- oxiranyl) -1-oxa-spiro [2.5] octan-6-ol afforded 8.4 mg (85% yield) of desired pure product.

^XH NMR (400 MHz, CDCl₃)δ: 1.28 and 1.30 (2s, 2x3H) , 1.43 (broad d, J = 14 Hz, IH) , 1.68 (t, J = 11.7 Hz, IH) , 1.75- 1.88 (m, 2H) , 1.97-2.05 (m, 2H) , 2.08-2.12 (m, IH) , 2.51 (d, J = 8.6 Hz, IH) , 2.72 and 3.20 (2d, J = 4.3 Hz, 2H) , 4.47 (s, 2H) , 4.83-4.92 (m, IH) , 8.13 (broad s, IH) . ¹³CNMR (100 MHz, CDCl₃)δ: 17.86, 23.87, 27.74, 30.48, 30.63, 37.34, 42.64, 51.31, 55.79, 56.79, 60.56, 73.17, 149.55, 165.51.

IR (film) v_max: 3272, 3200, 2961, 1790, 1756, 1724, 1500, 1206, 912, 732 cm^-1.

Step 9: (iia) racemic (3R, 4R, 6S, 2' R) chloroacetyl carbamic acid-4- (3', 3' -dimethyl-oxiranyl) -1-oxa- spiro [2.5] oct-6-yl ester

Following the procedure described in step 5, 8.6 mg (0.043 mmol) of racemic (3R, 4R, 6S, 2 ' R) -4- (3' , 3' -dimethyl- oxiranyl) -1-oxa-spiro [2.5] octan-6-ol afforded 8.5 mg (62% yield) of desired pure product. ^lR NMR (400 MHz, CDC1₃) δ 1.26 and 1.29 (2S, 2x3H) , 1.45

(broad d, J = 13.9 Hz, IH) , 1.73-1.85 ( , 3H) , 1.98 (td, J = 13.6 Hz and 3.7 Hz, IH) , 2.08-2.15 (m, IH) , 2.25-2.33 (m, IH) , 2.49 (d, J = 8.6 Hz, IH) , 2.72 and 2.77 (2d, J = 4.2 Hz, 2xlH) , 4.51 (s, 2H) , 4.85-4.93 (m, IH) , 8.15 (broad s, IH) .

EXAMPLE 2 Synthesis of compounds iii, iv and v

IV

Step 1: racemic 4 , 4-Dimethoxy-5- (l-methyl-3-phenyl- propenyl) -cyclohex-2-enone

To a -78° C solution of t-butyllithium (1.7 M in toluene)

(11.1 mmol, 6.6 ml) in ether (3 ml) was added one drop at a time a solution of the l-methyl-3-phenyl-propenyl bromide in the- same solvent (3ml) . The bromide was prepared as follows:

To a mixture of acetone-2 , 4 , 6-tri-isopropylbenzene- sulphonyl hydrazone (5.000g, 14.79 mmol) in anhydrous DMF (40 mL) at -78°C was added one drop at a time n- butyllithium 2.5M(12.4mL, 31.06 mmol). The mixture was stirred for one hour and benzyl bromide (2.1 mL, 17.75 mmol) was added one drop at a time. The mixture was stirred for another hour and 8 mL of TMEDA was added one drop at a time. The mixture was stirred for 15 minutes and 5.9 mL of n-butyllithium (14.79 mmol) was added. The resulting mixture was stirred at -40°C for one hour, cooled to -78°C and transferred by canulation to a solution of tetrabromodifluoroethane in the- same solvent with stirring. The reaction mixture was warmed to room temperature and filtered on celite. Solvents were evaporated and the residue was filtered over Si0₂ eluting with pentane to give 2.344g of the desired product (50-60% purity) which was used as such.

The bromide mixture was stirred for 45 minutes. During this period, a MAD solution was prepared by one drop at a time addition of a 2M trimethylaluminium in toluene (5.4 ml, 10.8 mmol) to a mixture of 2, 6-Di-tert-butyl-4- methylphenol (5.289g, 24.0 mmol) in toluene (100 ml). The reaction mixture was stirred for 10 minutes, cooled down to -78°C and a solution of the 4 , 4-dimethoxy-2, 5- cyclohexadienone (925 mg, 6.0mmol) in toluene- (10 ml) was added one drop at a time. After 10 minutes of stirring, the lithio-compound solution was added one drop at a time. The mixture was stirred for 20 minutes and quenched with 3 ml of a (1:1) water- sat. sodium bicarbonate mixture. After stirring for 1 hour at room temperature, the mixture was filtered in vacuo through celite and the solvent was evaporated. Flash chromatography (Hexane—»Hexane : Ethyl Acetate; 9:1) gave 320 mg (24% yield) of desired product.

Step 2: racemic 4 , 4-dimethoxy-5- ( l-methyl-3-phenyl- propenyl) -cyclohexanone To a mixture of 2, 6-Di-tert-butyl-4-methylphenol (1.302g, 5.91mmol) in dry toluene (20 ml) was added one drop at a time a 2M solution of trimethylaluminum in toluene (1,4 ml, 2.70 mmol) . The mixture was stirred for 20 minutes and cooled down to -78° C. A solution of 4,4- Dimethoxy-5- (l-methyl-3-phenyl-propenyl) -cyclohex-2-enone (423 mg, 1.5 mmol) in dry toluene (5 ml) was added one drop at a time (the mixture turned orange) . The mixture was stirred for 5 minutes and a solution of L-selectride (1.7 mL, 1.65 mmol) in dry toluene was added one drop at a time (the mixture became progressively colorless) . After stirring for 20 minutes, the reaction was quenched with sat. NH₄C1, warmed up to room temperature (1 hour) and extracted with dichloromethane. The combined organic layers were washed with water and dried (Na₂S0₄) . Flash chromatography (Hexane—»Hexane : Ethyl Acetate; 9:1) gave 312 mg (72% yield) of desired product.

Step 3: racemic (3R,4S,6R)- and (3R, 4S, 6S) -4- (1-methyl-

3-phenyl-propenyl) -1-oxa-spiro [2.5] octan-6-ol To a -78° C mixture of 4 , 4-Dimethoxy-5- (l-methyl-3-phenyl- propenyl) -cyclohexanone (228 mg, 0.971 mmol) in dry toluene (10 ml) was added, one drop at a time and under nitrogen atmosphere, 1.0 ml (1.069 mmol) of a 1M DIBAL-H solution in toluene. The mixture was stirred -for 30 minutes and quenched with sat. NH₄C1. After stirring for an additional 45 minutes at room temperature the mixture was extracted with dichloromethane. The combined organic layers were washed with water and dried (Na₂S0₄) . The solvent was chased, the residue (colorless oil) was dried under vacuum and dissolved in 250 ml of acetone and 25 ml of water. To this mixture was added 2.0 mg of pyridinium p-toluene sulfonate. After stirring for 1,5 hour, the mixture was diluted with dichloromethane, washed with NaHS0₃ sat., water and dried (MgS0₄) . After removal of the solvent, the crude product was dried in vacuo (pump) , dissolved in 10 ml of anhydrous DMSO and added to an ylide mixture previously obtained by an overnight stirring of NaH 60% (97 mg, 2.428 mmol) with trimethylsulfoxonium iodide (641 mg, 2.913 mmol) in anhydrous DMSO. The mixture was stirred for 3 hours at room temperature, quenched with water, diluted with brine and extracted with a 1:2 ether: hexane mixture. The combined organic layers were washed with brine and dried (Na₂S0₄). Flash chromatography (Hexane—^Hexane : Ethyl Acetate; 7:3) gave first the less polar (3R,4S,6R) (trans) isomer (39 mg: 16%) followed by^" the more polar (3R,4S,6S) cis isomer (147mg, 59%) .

Step 4: racemic (3R, 4S, 6S, 2' R, 3' R) and (3R, 4S, 6S, 2' S, 3' S) -4- (3' -benzyl, 2 ' -methyl-oxiranyl) -1-oxa- spiro [2.5]octan-6-ol To a mixture of (3R,4S,6S) 4- ( l-methyl-3-phenyl-propenyl) - 1-oxa-spiro [2.5] octan-6-ol (72 mg, 0.279 mmol) in dry dichloromethane (30 ml) was added in one portion 96 mg (0.334 mmol) of m-chloro-perbenzoic acid (considered at 60%) . The mixture was stirred for 1.5 hour at room temperature and under nitrogen atmosphere, quenched with saturated sodium sulfite solution and diluted with dichloromethane. The organic layer was washed with sodium bicarbonate and dried (Na₂S0₄) . Purification by flash chromatography (Hex → Hexane:Ethyl Acetate; 6:4) gave the separated desired pure products (total yield: 83 %) in a 6:1 (2'R,3'R:2'S,3'S) ratio.

Step 5: (iii) racemic (3R, 4S, 6S, 2' R, 3' R) chloroacetyl carbamic acid-4- (3' -benzyl, 2' -methyl-oxiranyl) - 1-oxa-spiro [2.5] oct-6-yl ester

To a 0°C mixture of (3R, 4S, 6S, 2 ' R, 3' R) 4- (3' -benzyl-2' - methyl-oxiranyl) -1-oxa-spiro [2.5] octan-6-ol (30 mg, 0.109 mmol) in dry dichloromethane (2 ml) was added in one portion 20 mg (0.164 mmol) of 4-dimethylaminopyridine (DMAP) followed by chloroacetyl isocyanate (37μl, 0.436 mmol) . The mixture was stirred for 15 minutes under nitrogen atmosphere, quenched with water and diluted with dichloromethane. The organic layer was washed back with water and dried (Na₂S0₄) . Flash chromatography (Hexane —> Hexane : ether; 7:3) gave 31 mg of pure desired product (72% yield) .

^XHNMR (400 MHz, CDC1₃) δ: 1.19-1.25 (m, IH) , 1.27 (s, 3H) , 1.45-1.49 (dd, J=13.2 Hz and 3.3 Hz, IH) , 1.73-1.86 (m, IH) , 1.89-1.95 (m, 2H) , 2107-2.09 (dm, J=11.8 Hz, IH) , 2.28-2.32 (dm, J=11.7 Hz, IH) , 2.39 (s, 2H) , 2.72- 2.77 (dd, J=13.4 Hz and 6.8 Hz, IH) , 2.89-2.92 (t, J=6.1 Hz, IH) , 2.99-3.04 (dd, J=14.0 Hz and 5.8 Hz, IH) , 4.50 (s, 2H) , 4.79-4.84 (m, IH) , 7.24-7.29 ( , 3H) , 7.33- 7.37 (m, 2H) , 8.27 (broad s, IH) . ¹³CNMR (75 MHz, CDC1₃) δ: 12.74, 28.08, 30.32, 31.36, 34.05, 42.86, 45.68, 49.54, 57.12, 59.21, 64.40, 73.64, 125.96, 127.90 (2C) , 127.98 (2C) , 136.03, 149.71, 165.90. IR (filπ Vβ_ax. 3300 (broad), 2957, 1756, 1725, 1496, 1206, 1073, 1029, 736, 701 cm^"1.

Step 6: (iv) racemic (3R, 4S, 6S, 2' S, 3' S) chloroacetyl carbamic acid-4- (3' -benzyl, 2' -methyl-oxiranyl) - 1-oxa-spiro [2.5] oct-6-yl ester Following the procedure described in step 5, 3.0 mg (0.0011 mmol) of (3R, 4S, 6S, 2' S, 3' S) 4- (3' -benzyl-2' - methyl-oxiranyl) -1-oxa-spiro [2.5] octan-6-ol afforded after flash chromatography (Hexane→Hexane : ether; 8:2) 1.4 mg (33% yield) of pure desired product. *HNMR (400 MHz, CDC1₃) δ: 1.30-1.34 (dt, J=13.5 Hz and

2.8 Hz, IH) , 1.36 (s, 3H) , 1.59-1.63 (m, IH) , 1.69-1.96 (m, 3H) , 1.99-2.02 (m, IH) , 2.06-2.09 (m, IH) , 2.67 (d, J=4.3 Hz, IH) , 2.74-2.91 (m, 3H) , 3.19-3.20 (d, J=4.3 Hz , IH) , 4.47 (s, 2H) , 4.78-4.85 (m, IH) , 7.22-7.27 (m, 3H) , 7.32-7.35 (m, 2H) , 7.81 (broad s, IH) . Step 7: racemic (3R, 4S, 6R, 2' R, 3' R) -4- (3' -benzyl, 2' - methyl-oxiranyl) -1-oxa-spiro [2.5] octan-6-ol Following the procedure described in step 4, 30 mg (0.116 mmol) of (3R,4R,6R) 4- ( 1' -methyl-3' -phenyl-propenyl) -1- oxa-spiro [2.5] octan-6-ol afforded 24.2 mg of a 7:1 mixture of epoxide isomers (76% yield) favoring the 2'R,3'R . After flash chromatography (Hex — > Hex: acetone; 9:1) only the major isomer could be obtained in a pure form.

Step 8: (v) racemic (3R, 4S, 6R, 2' R, 3' R) chloroacetyl carbamic acid-4- (3' -benzyl, 2' -methyl-oxiranyl) - 1-oxa-spiro [2.5] oct-6-yl ester Following the procedure described in step 5, 11.0 mg

(0.040 mmol) of (3R, 4S, 6R, 2' R, 3' R) 4- (3' -benzyl-2' -methyl- oxiranyl) -1-oxa-spiro [2.5] octan-6-ol afforded 8.1 mg (51% yield) of pure desired product. Flash chromatography (Hexane→Hexane: ether; 8 : 2-6 : 4 ) ^HNMR (400 MHz, CDC1₃) δ: 1.11-1.15 (dt, J=13.4 Hz and 3.5 Hz, IH) , 1.27 (s, 3H) , 1.73-1.77 (dd, J= 12.5 and 3.9 Hz, IH) , 1.94-1.97 (m, 2H) , 2.02-2.10 (m, 2H) , 2.36 and 2.44 (2d, J=4.1 Hz, 2xlH), 2.76-2.79 (dd, J=12.2 Hz and 4.6 Hz, IH) , 2.93- 3.00 ( , 2H) , 4.46 (s, IH) , 5.29-5.31 (m, IH) , 7.24- 7.29 (m,3H), 7.33-7.37 (m,2H), 7.91 (broad s, IH) . ¹³CNMR (75 MHz, CDC1₃) δ: 12.78, 26.62, 28.59, 29.00, 34.06, 42.15, 42.61, 50.05, 57.80, 59.43, 64.14, 71.45, 125.90, 127.87 (2C) , 127.96 (2C), 136.21, 149.50, 165.35. IR (film)v_max: 3350 (broad), 2961, 2927, 1353, 1719, 1201, 1074, 1040, 1023 cm^"1. EXAMPLE 3 Synthesis of compounds vi and vii

VI, VI Step S

VII, VII

Step 1: racemic 4 , 4-Dimethoxy-5- (E-1' -methyl-propenyl) - cyclohex-2-enone Following the procedure described step 1 of example 2, (1.000 g, 6.486 mmol) of 4 , 4-dimethoxy-2, 5- cyclohexadienone afforded 1.022 g (75 % yield) of pure desired product.

Step 2: racemic 4 , 4-Dimethoxy-5- (E-1' -methyl-propenyl) - cyclohexanone Following the procedure described in step 2 of example 2, (280 mg, 1.331 mmol) of 4, 4-dimethoxy-5- (E-1' -methyl- propenyl) -cyclohex-2-enone afforded 208 mg (74 % yield) of pure desired product.

Step 3: racemic- (3R, 4R, 6R) and ( 3R, 4R, 6S) -4- (E-1' - methyl-propenyl) -1-oxa-spiro- [2.5] -octan-6-ol

Following the procedure described in step 3 of example 1, 4 , 4-Dimethoxy-5- (E-1' -methyl-propenyl) -cyclohexanone (200 mg ; 0.942 mmol) afforded the desired 6R and 6S isomers in a 1:3.3 ratio (160 mg crude). Purification by column chromatography using a 2:1 hexane: ethyl acetate mixture as eluent gave 2 fractions, the less polar 6R isomer and the more polar 6S isomer.

Step 4: racemic (3R, 4S, 6R, 2' R, 3' R) and racemic

(3R, 4S, 6R,2' S, 3'S) -chloroacetyl carbamic acid- 4- (2' , 3' -dimethyl-oxiranyl) -1-oxa-spiro- [2.5]- oct-6-yl ester) To a solution of racemic (3R, 4R, 6R) -4- (E-1' -methyl- propenyl) -1-oxa-spiro- [2.5] -octan-6-ol (15 mg; 0.082 mmol) in dichloromethane (2 ml) at 0°C was added MCPBA (23 mg; 1.4 eq based on 86% purity). The resulting mixture was stirred at 0°C for 1 hour. It was then diluted with sat. sodium sulfite solution and extracted with dichloromethane. The combined organic layers were washed with sat. sodium bicarbonate solution (3X) and dried over sodium sulfate. Evaporation of the solvent gave a crude mixture of diepoxyalcohols which was filtered on a pad of silica gel using a 2:1 hexane: ethyl acetate mixture as eluent to give 15.5 mg (.078 mmol) of purified material of which 8 mg (.040 mmol) was treated with chloroacetyl isocyanate according to the procedure described in step 5 of example 1. Purification of the reaction products by column chromatography on silica gel using a 2:1 mixture of hexane: ethyl acetate as eluent afforded as less polar isomer (vi) (0.6 mg; 5% overall) (white gummy solid): ^XHNMR (400 MHz, CDC1₃) δ: 1.22 (s, 3H) , 1.25 (d, J=5.5 Hz, 3H) , 1.30 (m, IH) , 1.80-2.10 (m, 6H) , 2.67 (d, J=4.5 Hz, IH) , 2.81 (q, ^"J=5.5 Hz, IH) , 3.13 (d, J=4.5 Hz, IH) , 4.47 (br s, 2H) , 5.27 (br s, IH) , 7.86 (br s, IH) followed by the more polar isomer (via) (6 mg; 45% overall) (white gummy solid): ^XHNMR (400 MHz, CDC1₃) δ: 1.12 (s, 3H) , 1.20 (m, IH) , 1.30 (d, J=5.5 Hz, 3H) , 1.77 (dd, J=4 and 12.5 Hz, IH) , 1.95-2.25 (m, 5H) , 2.63 (d, J=4.5 Hz, IH) , 2.79 (d, J=4.5 Hz, IH) , 2.83 (q, J=5.5 Hz, IH) , 4.48 (br s, 2H) , 5.31 (br s, IH) , 8.01 (br s, IH) .

Step 5: (viia) racemic (3R, 4S, 6S, 2' S, 3' S) and (vii) racemic (3R, 4S, 6S, 2' R, 3' R) -chloroacetyl carbamic acid-4- (2' ,3' -dimethyl-oxiranyl) -1-oxa- spiro- [2.5] -oct-6-yl ester) Following the procedure described in step 4 of example 1 (3R, 4R, 6S) -4- (E-1' -methyl-propenyl) -1-oxa-spiro- [2.5] - octan-6-ol (23 mg; 0.126 mmol) afforded after flash chromatography using a 1:1 mixture of hexane: ethyl acetate a mixture of two isomeric epoxides (17.5 mg) . Of this mixture, 9 mg (.045 mmol) were treated following the procedure described in step 5 of example 1. Purification of the reaction products by column chromatography on silica gel using a 9:1 mixture of toluene: ethyl acetate as eluent afforded as less polar isomer (viia) (0.8 mg; 4% overall) (white gummy solid) : ^XHNMR (400 MHz, CDC1₃) δ: 1.22 (s, 3H) , 1.20-1.30 (m, IH) , 1.24 (d, J= 5.5 Hz, 3H) , 1.55-1.65 (m, IH) , 1.68-1.98 ( , 4H) , 2.06-2.11 ( , 2H) , 2.71 (d, J= 4.5 Hz, IH) , 2.77 (q, J= 5.5 Hz, IH) , 3.22 (d, J= 4.5 Hz, IH) , 4.22-4.88 (m, IH) , 4.48 ( s ,^• 2H) , 7.84 ( broad m, IH). followed by the more polar isomer (vii) (5.1 mg; 25% overall) (white gummy solid) : ^XHNMR (400 MHz, CDC1₃) δ: 1.12 (s, 3H) , 1.30 (d, J= 5,5 Hz, 3H) , 1.31-136 (m, IH) , 1.48-1.52 (dd, J=15.1 and 3.5 Hz, IH) , 1.74-2.00 (m, 3H) , 2.10-2.14 (m, IH) , 2.28-2.37 (m, IH) , 2.67 (d, J= 4.0 Hz, IH) , 2.77-2.81 (m, 2H) , 4.51 (s, 2H) , 4.85-4.89 (m, Is), 7.89 ( broad s, IH) .

In a like manner were prepared the compounds (xi) (3R,4S,6S,2'R,3'R) , (3R,4S,6S,2'S,3'S) and

(3R, 4S, 6R,2'R,3'R) chloroacetyl-carbamic acid 4-[2',3'- bis- (3"-methylbutyl) ] -1-oxaspiro- [2.5] oct-6-yl ester. EXAMPLE 4 Synthesis of compounds xiii and ix

III IX

Step 1: racemic (5S, 6R) 6-hydroxy-4 , 4-dimethoxy-5- (1' - methyl-propenyl) -cyclohex-2-enone Method A:

4, 4-Dimethoxy-5- (1' -methyl-propenyl) -cyclohex-2-enone (4.0 g, 0.019 mol) was dissolved in 200 mL of freshly distilled THF (ketyl radical) . At -78 °C, NaHMDS (sodium bis- trimethylsilylamide, Aldrich) (24.7 L, 0.024 mol of IM in THF) was added to this solution and the reaction mixture was left stirring for another 15 min. 2- (Phenylsulfonyl) - 3-phenyloxaziridine (7.44 g, 0.029 mol, prepared according to Davis et al, J. Org. Chem., 1982, 47:1775) dissolved in 8 mL of anhydrous THF was slowly added to this stirring mixture and then left at this temperature for 5 minutes before it was worked-up with sodium bicarbonate saturated solution and extracted with dichloromethane. The organic layer was separated, washed with brine, then dried over anhydrous magnesium sulfate. The organic phase was filtrated then evaporated. Chromatography of the residue (10% ethylacetate : 90% hexane) gave 1.6 g of a yellow oil which crystallized in the freezer into a low melting solid. Method B:

4 , 4-Dimethoxy-5- (1' -methyl-propenyl) -cyclohex-2-enone (2.5 g, 0.012 mol) was dissolved in lOOmL of freshly distilled THF (ketyl radical). At -78 °C NaHMDSK (12 mL, 0.012 mol of IM in THF) was added to this solution and the reaction mixture was left stirring for another 30 min. It was then transferred via a canula to a 0.1 M dimethyldioxirane solution in acetone (180 mL, 0.018 mol) maintained at -78 °C . This solution was left stirring 30 min. then the excess oxidizing agent was quenched with a sat. aqueous sodium sulfite solution. The reaction mixture was slowly warmed up to room temperature and the acetone was evaporated under reduced pressure. The desired product was extracted with dichloromethane (2x100 mL) and the organic layers were combined, dried over anhydrous magnesium sulfate then filtrated. The solvents were evaporated to give 2.6 g (96%) of yellow oil which did not need further purification.

Step 2 : racemic ( 5S , 6R) 4 , 4 , 6-trimethoxy-5- ( 1 ' -methyl- propenyl) -cyclohex-2-enone 6-Hydroxy-4 , 4-dimethoxy-5- ( 1' -methyl-propenyl) -cyclohex-2- enone (2.5g, 11.0 mmol) was dissolved with iodomethane (30.0 g, 20.0 mmol) in 25 mL of anhydrous DMF. Sodium hydride (0.48g, 12.0 mmol) was added to this mixture maintained at room temperature. The reaction was left stirring for 8 min. (no more than 10 min. total) then transferred to a NaHC0₃ sat. solution. The desired compound was extracted 3x with 100 mL of dichloromethane, the organic layers were separated, combined then dried over anhydrous magnesium sulfate. After filtration, the solvents were evaporated and the residue was chromatographed on silica gel (previously treated, with hexane containing triethylamine) using a 5%ethyl acetate: 90% hexane eluent mixture, 1.34 g (51%) of the desired product was isolated as a yellow oil. Some starting material (0.27 g) was also recuperated.

Step 3: racemic (2R,3S) 2, 4 , 4-Trimethoxy-3- (1' -methyl- propenyl) -cyclohexanone

2, 6-Di-tert-butyl-4-methyl phenol (1.47 g, 6.68 mmol) was dissolved in 25.0 mL of anhydrous toluene. A solution of trimethylaluminium 2.0 M in toluene (1.5 mL, 3.0 mmol) was added to this solution at room temperature under a flow of nitrogen, the reaction mixture was stirred for 30 min. then cooled to -78 C with a dry ice acetone bath. 4,4,6- trimethoxy-5- ( 1-methyl-propenyl) -cyclohex-2-enone (400 mg, 1.67 mmol) dissolved in 1.0 mL of toluene was added to the aluminum complex. The reaction mixture was stirred at -78C for 20 min. then L-selectride, 1.0 M in toluene, ( approx. 1.9 mL, 1.9 mmol) was slowly added until the reaction mixture paled from dark orange to clear yellow. The reaction mixture was quenched with 5.0 mL of sodium carbonate sat. solution and left stirring at room temperature for 1 hour it was then filtrated over celite. The solvents were evaporated under vacuum and the residue was chromatographed on triethylamine treated silica gel using a 5% ethylacetate 95% hexane eluent mixture. This gave 246 mg (61%) of a yellow oil.

Step 4: racemic (1R,2S,3S) 2, 4, 4-Trimethoxy-3- ( 1' - methyl-propenyl) -cyclohexanol 2,4, 4-trimethoxy-3- ( 1' -methyl-propenyl) -cyclohexanone (246 mg, 1.02 mmol) was dissolved in 31 mL of anhydrous THF, this solution was cooled to -78C and L-selectride (1.22 mL, 1.22 mmol of IM in THF) was added to this solution (over a 4 minutes period) . After stirring at this temperature for 10 min. a saturated ammonium chloride solution was added to the reaction mixture. The desired compound was extracted with dichloromethane then dried over anhydrous magnesium sulfate then filtered. The solvents were evaporated under reduced pressure leaving 400 mg of a yellow oil which was used without further purification in the next step.

Step 5: racemic (2S,3S,4R) 4-hydroxy-3-methoxy-2- (1' - methyl-propenyl) -cyclohexanone The crude product from step 4 (400 mg, 1.02 mmol) was dissolved in 10 mL of acetone and 5.0 of distilled water. This solution was stirred at 0 C for 5 min. then pyridinium p-toluenesulfonate (4.0 mg, 10% eq.) was added to this solution. The reaction mixture was warmed-up to room temperature then left stirring for 2.5 hrs . The reaction mixture was then extracted with dichloromethane, then organic phases were combined washed with brine then dried over anhydrous magnesium sulfate. Evaporation of the solvents followed by chromatography of the residue gave 138.9 mg of the desired compound (69% overall) as a clear oil.

Step 6: racemic (2S,3S,4R) Benzoic acid 2-methoxy-3- (1' - methyl-propenyl) -4-oxo-cyclohexyl ester At 0°C, 4-dimethylaminopyridine (1.45 g, 12.12 mmol) was dissolved in 15 mL of anhydrous methylene chloride along with benzoyl chloride (0.85 g, 6.06 mmol). 4-Hydroxy-3- methoxy-2- (-1' -methyl-propenyl) -cyclohexanone (600 mg, 3.03 mmol) dissolved in 5.0 mL of anhydrous dichloromethane was slowly added to the solution described above. The reaction mixture was warmed-up to room temperature and stirred for 90 min., worked-up with dichloromethane :water . The solvents were evaporated and the residue was chromatographed using 5% ethyl acetate: 95% hexane as the mixture of eluent. In this manner we isolated 627 mg (68%) of a clear oil.

Step 7: racemic (2S,3S,4R) Benzoic acid 5-methoxy-4- ( 1' - methyl-propenyl) -1-oxo-spiro [2.5] oct-6-yl ester

Trimethyl oxosulfonium (250 mg, 1.2 mmol) was grounded then dried under vacuuum and dissolved in 5.0 L of DMSO. Under a nitrogen atmosphere , sodium hydride 60% in oil (25 mg, 0.625 mmol) was added to the resulting reaction mixture was stirred at room temperature for another 24 hrs . Benzoic acid 2-methoxy-3- (1' -methyl-propenyl) -4-oxo- cyclohexyl ester (50.0 mg, 0.165 mmol) was added dissolved in 0.1 mL of DMSO. After stirring 20 min. at -room temperature the reaction mixture was quenched with NH₄C1 sat. and the product was extracted with chloroform. The organic phase was separated, dried over anhydrous MgS0 then filtrated. The solvents were evaporated under reduced pressure and the residue was chromatographed using a 90% hexane: 10%ethyl acetate eluent mixture to give 47.2 mg (90%) of a clear yellow oil.

Step 8: racemic (2' R, 3' R, 3R, 4S, 5S, 6R) and - (2', S, 3' S, 3R, 4S,5S,6R) Benzoic acid 4- (2' , 3' -methyl-oxiranyl) -5-methoxy-l-oxa-spiro [2.5] oct-6-yl ester Benzoic acid 5-methoxy-4- (1' -methyl-propenyl) -1-oxo- spiro [2.5] oct-6-yl ester (45 mg, 0.142 mmol) was dissolved in .5 mL of chloroform at room temperature and m- Chloroperoxybenzoic acid (43 mg, 0.253 mmol) was added to this solution. The reaction mixture was left stirring at room temperature for .5 hour and was then diluted with sat. sodium bicarbonate. The products were extracted with chloroform and the organic layer was dried over magnesium sulfate. Filtration and evaporation of the solvent gave an oily residue which was chromatographed on silica gel using a 9:1 hexane: ethyl acetate eluent mixture to give 8 mg (17%) of the less polar (2' S, 3' S, 3R, 4S, 5S, 6R) isomer as a clear oil follwed by the more polar (2'R,3'R,3R,4S,5S,6R) isomer (39mg, 83%) as a clear oil.

Step 9: racemic (2' R, 3' R, 3R, 4S, 5S, 6R) 4- (2' , 3' -dimethyl- oxiranyl) -5-methoxy-l-oxa-spiro [2.5] octan-6-ol

Benzoic acid 4- (2' , 3' -methyl-oxiranyl) -5-methoxy-l-oxa- spiro [2.5] oct-6-yl ester. (34 mg, 0.1 mmol) was dissolved in 2 mL of THF at room temperature. 0.1 N NaOH (2.5 mL, .25 mmol) was added to this solution. The reaction mixture was left stirring at room temperature for 24 hrs, the desired product was extracted with dichloromethane (2x 10 mL) , the organic phase was separated, dried over anhydrous magnesium sulfate, filtered and the -solvents were evaporated under vacuum. The residue was chromatographed on silica gel using a 1:1 hexane: ethyl acetate eluent mixture to give 14.0 mg (60%) of the desired product as a white powder (m.p. 84.6-86.9 °C) along with 6 mg of starting material.

Step 10: (viii) racemic (2' R, 3' R, 3R, 4S, 5S, 6R) chloroacetyl-carbamic acid 4- (2' , 3' -dimethyl- oxiranyl) -5-methoxy-l-oxa-spiro [2.5] oct-6-yl ester 4- (2' , 3' -dimethyl-oxiranyl) -5-methoxy-l-oxa-spiro [2.5] octan-6-ol (100 mg, 0.438 mmol) was dissolved in 5 mL of anhydrous dichloromethane at 0°C under nitrogen atmosphere. Chloroacetyl isocyanate (104 μL) was syringed in and the reaction mixture was stirred at this temperature for 20 min. The reaction mixture was warmed to room temperature and transferred directly to a column of silica gel. The desired product was eluted with 100 mL of hexane followed by 9:1 hexane : acetone eluent mixture to give 98.7 mg of pure desired product along with 46.9 of slightly impure material which was repurified under the same conditions to give 35 additional mg of pure product (total yield: 88%) as a white powder (m.p. 184-185.5 °C) . ^XH NMR (400 Mhz, CDC1₃) δ 1.15 (m, IH) , 1.18 (s, 3H) , 1.31 (d, J=5.5 Hz, 3H) , 1.93 (d, J=11.0 Hz, IH) , 1.95 (m, IH) , 2.05 (m, 2H) , 2.65 (d, J=4.5 Hz, IH) , 2.71 (q, J=5.5 Hz, IH) , 2.84 (d, J= 4.5 Hz, IH) , 3.48 (s, 3H) , 3.70 (dd, J=11.0, 2.5 Hz, IH) , 4.42 (m, 2H) , 5.62 (m, IH) , 7.98 (bs, IH) .

¹³C NMR (100 Mhz, CDCl₃)δ 13.3, 13.5, 25.5, 29.0, 43.5, 48.3, 51.2, 57.0, 58.1, 59.4, 69.6, 79.1, 150.5, 166.0. IR(film) 3281, 3227, 2996, 1789, 1756, 1725, 1197 cm^"1

Step 11: racemic (2' S, 3' S, 3R, S, 5S, 6R) , 4-(2',3'- dimethy1-oxiranyl) -5-methoxy-l-oxa- spiro [2.5] octan-6-ol Benzoic acid 4- (2' , 3' -dimethyl-oxiranyl) -5-methoxy-l-oxa- spiro [2.5] oct-6-yl ester (8.8 mg, 0.027 mmol) was hydrolyzed using the procedure described in step 9, to give 3.0 mg of the desired alcohol (50%) along with 1.0 mg of starting material.

Step 12: (ix) racemic chloroacetyl-carbamic acid 4-

(2' ,3' -dimethyl-oxiranyl) -5-methoxy-l-oxaspiro [2.5]oct-6-yl ester 4- (2' , 3' -dimethyl-oxiranyl) -5-methoxy-l-oxa- spiro [2.5] octan-6-ol (3.0 mg, 0.013 mmol) was reacted with chloroacetyl isocyanate according to the procedure described in step 5 of example 1 and isolated 1.0 mg of the desired material.

^XH NMR (400 Mhz, CDCl₃)δ 1.15 (m, IH) , 1.21 (s, 3H) , 1.24 (d, J=5.5 Hz, 3H) , 1.87 (d, J=11.5 Hz, IH) , 2.0 ( , 3H) , 2.67 (d, J=4.5 Hz, IH) , 2.76 (q, J=5.5 Hz, IH) , 3.31 (d, J= 4.5 Hz, IH) , 3.41 (s, 3H) , 3.55 (dd, J=11.5, 3.0 Hz, IH) , 4.47 (s, 2H) , 5.59 (m, IH) , 7.89 (s, IH) . ¹³C NMR (100 Mhz, CDCl₃)δ 13.2, 13.4, 25.7, 29.2, 43.7, 48.0, 52.2, 57.4, 58.8, 59.5, 60.4, 69.9, 79.6, 150.7, 166.3.

IR(fil ) 3280, 3230, 2950, 1785, 1758, 1725, 1195 cm^"1

In a similar manner as described in examples 1 to 4 , compound (x) ( 3R, 4S, 6R, 2' R, 3' R, 2"R) and (3S, 4R, 6S,2' S, 3' S,2"S) chloroacetyl carbamic acid-4- [3'- (3", 3"-dimethyl-oxiranylmethyl) -2' -methyl-oxiranyl] -1-oxa- spiro [2.5] oct-6-yl ester was prepared.

EXAMPLE 5 Preparation of Compounds xii through xx

Step S Step 7

Step 1: racemic (2S, 3S) -2 , , 4-trimethoxy-3

(l¹ methyl-3 ' -phenyl-propenyl) -cyclohexanone (Compound xxi)

To a -78°C solution of 4 , 4-dimethoxy-5- (1 ' -methyl-3 'phenyl- propenyl) -cyclohexanone (3.000g, 10.475 mmol) in 120ml of anhydrous THF was added, dropwise, a IM solution of NaHMDS (10.5 ml, 10.475 mmol) in the same solvent. The mixture was stirred for 1.5 hour and transferred through a canula in 157 ml of a -78°C solution of dioxiran (0.1 M) in acetone. The mixture was stirred for 3 minutes, quenched with a (1:1) mixture of NaHC0₃ sat. and Na₂S₂0₃ (10 %) and extracted with dichloromethane (3x) . The combined organic layers were dried with MgS0₄ and the solvent was chased. The crude (3.335g, 11.028 mmol) was dissolved in 30 ml of DMF anhydrous and iodomethane (13.7 ml, 220.569 mmol) was added followed by NaH 60% (485 mg, 12,130 mmol) . The mixture was stirred for 10 minutes, dropped in a funnel containing NaHC0₃ sat . and extracted with dichloromethane (3x) . The combined organic layers were dried with MgS0₄, rotovaped and dried under vacuum.

To a mixture of 2 , 6-di-tert-butyl-4-methylphenol (9.233g, 41.900 mmol) in 150 ml of anhydrous toluene was added dropwise, a 2M solution of trimethylaluminium in toluene (9.4 ml, 18.855 mmol). The mixture was stirred for 15 minutes and cooled down to -78°C. A solution of the crude (3.362 g, 10.475 mmol) obtained earlier dissolved in 25 ml of anhydrous toluene was added dropwise and the mixture was stirred for 5 minutes. Than a solution of L- selectride (11.523 mmol) (the L-selectride was a IN solution in THF. The solvent was chased and replaced by toluene anhydrous) in anhydrous toluene (25 ml) was added drop-wise. The mixture was stirred for 15 minutes, quenched with NH„C1 sat . and extracted with dichloromethane (3x) . The combined organic layers were washed with water and dried (MgSO . Flash chromatography (hexane —> hexane : ethyl acetate ;9 -.1) of the crude gave 1.753 g (53% yield) of desired product.

^XHNMR (400 MHz,^" CDC1₃) δ: 1,85-1.93 (m, 3H) , 1.89 (s, 3H) , 2.22-2.26 (m, IH) , 2.35-2.50 (m, 2H) , 2.74 (d,

J=11.0 Hz, IH) , 3.24-3.30 (2s, 2x3H) , 3.41-3.45 (m, 2H) ,

3.43 (s,3H), 4.07 (d, J=11.0 Hz, IH) , 5.54-5.58 (m, IH) , 7.17- 7.29 (m, 5H) . Step 2: racemic (1R, 2S, 3S) -Benzoic acid-2-methoxy-3-

1 ' -methyl-3 ' -phenyl-propenyl) -4-oxo-cyclohexyl ester (Compound xiii)

To a -78°C solution of racemic (2S, 3S) -2 , 4 , 4-trimethoxy-3- (1 'methyl-3 ' -phenyl-propenyl) -cyclohexanone (1.028 g, 3.228 mmol) in anhydrous THF (70 ml) was added, under nitrogen, 3.6 ml of a IM L-selectride solution in THF (drop-wise) . The mixture was stirred for 15 minutes, quenched with NH₄C1 sat., stirred to room temperature and extracted with dichloromethane (3x) . The combined organic layers were dried with MgS0₄. The solvent was chased and the crude was dissolved in 40 ml of acetone and 20 ml of water. PPTS (catalytic) was added and the mixture was stirred at room temperature for 1 hour, diluted with water and extracted with dichloromethane (3x) . The combined organic layers were dried (MgSOj to give a crude which was dissolved in anhydrous dichloromethane (10 ml) . Benzoyl chloride (0.8 ml, 6.456 mmol) was added followed by pyridine (5 ml) . After 15 minutes of stirring a white precipitate appeared. The mixture was stirred for 30 minutes, diluted with water and extracted with dichloromethane (3x) . The combined organic layers were washed with water, NaHC0₃ sat. and dried (MgSOj . Flash chromatography (hexane—>hexane : ethyl acetate; 9:1) gave 640 mg (54% yield) of desired product.

'HNMR (400 MHz, CDCl₃) δ: 1.76 (s, 3H) , 1.85-1.95 (m, IH) , 2.34-2.47 (m,2H), 2.70 (td, J=18.5 Hz and 6.0 Hz, IH) , 3.45 (s, 3H) , 3.48 and 3.52 (2d, J=7.0 Hz, 2xlH) , 5.47 (t, J=11.0 Hz, IH) , 3.70 (dd, J=ll .0 Hz and 2.5 Hz, IH) , 5.47 (t, J=7.0 Hz, IH) , 5.94-5.95 (m, IH) . 7.16-7.20 (m, IH) , 7.24-7.31 (m, IH) , 7.45-7.49 (m, 2H) , 7.58-7.61 (m, IH) , 8.06-8.09 (m, 2H) .

"CNMR ( 75 MHz , CDC1₃ ) δ : 13 . 38 , 24 . 21 , 33 . 19 , 35 . 14 , 56 .74 , 61 .70 , 65 . 77 , 79 .46 , 124 . 91 , 127 . 44 (2C) , 127 . 53 (2C) , 127.60 (2C) , 128.06, 128.79 (2C) , 129.11, 129.65, 132.36, 139.84, 164.88, 206.56.

Step 3: racemic (3R, 4S, 5S , 6R) -Benzoic acid-5-methoxy-4- (1 ' -methyl-3 ' -phenyl-propenyl) -1-oxa- spiro [2.5] oct-6-yl ester (Compound xiv)

To a mixture of trimethylsulfoxonium iodide (416 mg, 1.891 mmol) in anhydrous DMSO (5 ml) was added, the sodium hydride 60% (43 mg, 1,080 mmol). The mixture was stirred at room temperature overnight. A solution of racemic (1R, 2S, 3S) -Benzoic acid-2-methoxy-3- (1 ' -methyl-3 ' -phenyl- propenyl) -4-oxo-cyclohexyl ester (99.0 mg, 0.270 mmol) in 1 ml of the same solvent, was added dropwise, and the mixture was stirred for 3 hours, quenched with water and extracted with ether: hexane; 1:2 (3x) . The combined organic layer were washed with brine and dried (Na₂S0₄) . Flash chromatography (hexane→hexane : ethyl acetate; 9:1) of the crude (105 mg) gave 76 mg (72% yield) of desired product .

'HNMR (400 MHz, CDCl₃) δ: 1.24 (broad d, J= 14,0 Hz, IH) , 1.76 (s, 3H) , 1.99-2.044 (m, IH) , 2.11-2.16 (m, IH) , 2.32 (td, J= 14.0 Hz and 4.5 Hz, IH) , 2.52 (d, J= 5.0 Hz, IH) , 2.74 (d, J= 5.0 Hz, IH) , 3.09 (d, 12.0 Hz, IH) , 3.37 (dd, J= 16.0 Hz and 6.0 Hz, IH) , 3.44 (s, 3H) , 3.52 (dd, J= 15.5 Hz and 8.5 Hz, IH) , 3.74 (dd, 15.5 Hz and 2.5 Hz, IH) , 5.53 (m, IH) , 5.93 ( broad s, IH) , 7.18-7.22 (m, 3H) , 7.27-7.32 (m, 2H) , 7.44-7.48 (m, 2H) , 7.56-7.60 (m,lH) , 8.08-8.10 (m,2H) .

¹³CNMR (75 MHz, CDCl₃) δ: 24.99, 28.02, 33.30, 48.74, 50.42, 56.17, 59.57, 66.36, 78.48, 124.88 (2C) , 127.46 (4C) , 127.48 (4C) , 128.30, 128.77, 129.61, 131.27, 132.04, 140.26, 164.71. Step 4: racemic (3R, 4S, 5S, 6R, 2 ' S, 3 ' S) -Benzoic acid -4- (2 ' -methyl-3 ' -phenyl-oxiranyl) -5-methoxy -1-oxa-spiro [2.5] oct-6-yl ester (Compound xv)

To a mixture of racemic (3R, 4S, 5S, 6R) -Benzoic acid-5- methoxy-4- (l¹ -methyl-3 ' -phenyl-propenyl) -1-oxa- spiro [2.5] oct-6-yl ester (316 mg, 0.805 mmol) in anhydrous THF (16 ml) was added in one portion the MCPBA (considered at 70%) (397 mg) . The mixture was stirred under nitrogen for 30 minutes and quenched with Na₂S₂0₃ 10 %. Extractions were done with dichloromethane (3x) . The combined organic layers were washed with NaHC0₃ and dried (Na₂S0₄) . Flash chromatography (hexane—hexane :ethylacetate ; 9 :1) of the crude gave 46 mg (14% yield) of desired isomer.

^XHNMR (400 MHz, CDC1₃) δ: 1.15 (broad d, J= 14,0 Hz, IH) , 1.40 (s, 3H) , 2.07-2.22 (m, 4H) , 2.71 (d, J= 4.5 Hz, IH) , 2.82-2.85 (m,lH), 2.92- 2.95 (m, IH) , 3.31 (s, 3H) , 3.41 (d, J= 4.5 Hz, IH) , 3.63 (dd, J= 11.5 Hz and 2.5 Hz, IH) , 5.86 (s, IH) , 7.20- 7.22 (m, IH) , 7.28-7.29 (m, 4H) , 7.42- 7.46 (m, 2H) , 7.55-7.57 (m, IH) , 8.01- 8.02 (m, 2H) .

¹³CNMR (75 MHz, CDC1₃) δ:12.59, 25.04, 28.68, 33.71, 47.39, 51.08, 55.77, 58.80, 58.90, 64.13, 65.80, 78.66, 125.37, 127.49, 127.95, 128.68, 129.46, 132.09, 136.98, 164.78.

Also isolated was 226 mg (69% yield) of another more polar isomer: (3R, 4S, 5S, 6R, 2 ' R, 3 ' R) -Benzoic acid-4- (2 ' -methyl- 3 ' -phenyl-oxiranyl) -5-methoxy-l-oxa-spiro [2.5] oct-6-yl ester (Compound xvi) .

'HNMR (400 MHz, CDCl₃) δ: 1.10 (broad d, J= 12.9 Hz, IH) , 1.36 (s, 3H) , 1.94- 1.97 (m, IH) , 1.98- 2.16 (m, 3H) , 2.39 (d, J= 4.0 Hz, IH) , 2.56 (d, J=4.2 Hz,lH), 2.80-2.89 (m, 2H) , 2.95-2.99 (dd, J=13.5Hz and 6.0 Hz, IH) , 5.90 (d, J= 2.0 Hz, IH) , 2.24-7.36 (m, 5H) , 7.39-7.43 (m, 2H) , 7.52-7.56 (m, IH) , 8.01-8.02 (m, 2H) . ¹³CNMR (75 MHz, CDC1₃) δ: 13.27, 24.92, 28.61, 34.01, 47.74, 49.92, 55.86, 57.73, 58.47, 61.10, 66.00, 78.42, 125.80, 127.37, 127.79, 128.10, 128.79, 129.46, 132.03, 136.66, 164.97.

Step 5: racemic (3R, 4S, 5S, 6R, 2 ' S, 3 ' S) 4- (3-benzyl-2- methyl-oxiranyl) -5-methoxy-1-oxa- spiro [2.5] oct-6-ol (Compound xvii)

Racemic (3R, 4S, 5S, 6R, 2 ' S, 3 ' S) Benzoic acid 4- (3-benzyl-2- methyl -oxiranyl) -5-methoxy-l-oxa-spiro [2.5] oct-6-yl ester (82.1 mg, 0.201 mmol) was dissolved in tetrahydrofuran (5.0 ml) then a 0.5 N sodium hydroxide in water was added to this solution. The reaction mixture was stirred 24h at room temperature. The reaction mixture was then extracted with dichloromethane (3 x 50 ml) , the organic phases were combined, dried over anhydrous MgS0₄, filtered then the solvents were evaporated under reduced pressure, flash chromatography on silica gel (5% acetone: 95% dichloromethane) of the resulting residue gave 39. Ig (64%) of a clear oil. Rf=0.1 (30% EtOAc : 70% hexane)

^XH NMR (400 MHz, CDCl₃)d 1 (dd, IH) , 1.35 (s, 3H) , 1.8 (m, IH) , 1.9 (d, IH) , 2.0 (dm, IH) , 2.15 (ddd, IH) , 2.20 (s,lH), 2.60 (d, IH) , 2.8 (m, IH) , 2.9 (m, 2H) , 3.2 (s, 3H) , 3.3 (d, IH) , 3.45 (dd, IH) , 4.3 (s, IH) , 7.15-7.25 (m, 5H) .

¹³C NMR (100 MHz, CDCl₃)d 13.8, 26.7, 28.4, 34.7, 46.5, 51.9, 56.2, 59.6, 60.0, 63.8, 64.7, 81.0, 126.3, 128.4, 128.9, 137.7.

Step 6: racemic (3R, 4S, 5S, 6R, 2 ' S, 3 ' S) chloroacetylcarbamic acid 4- (3-benzyl-2-methyl-oxiranyl) -5-methoxy-l-oxa-spiro [2.5] oct-6-yl ester (Compounds xviii) To 4- (3 -benzyl-2-methyl-oxiranyl) -5-methoxy-l-oxa- spiro [2.5] oct-6-ol (14 mg, 0.046 mmol) dissolved in 1 ml of dichloromethane at OC, was added chloroacetyl isocyanate (6 mg, 0.046 mmol) via a syringe this reaction mixture was then warmed-up to room temperature over 2H00. The solvents were then evaporated under reduced pressure and the resulting solid was purified by flash chromatography (10% acetone :90% dichloromethane) then with (30% EtoAc : 70% hexane) to give 11 mg ( 56%) of a clear oil. rf=0.23 (30%EtoAc :70% hexane)

*H NMR (400 MHz, CDC1₃) d 1.1 (dd, IH) , 1.35 (s, 3H) , 1.9-

2.1 (m, 4H) , 2.65 (d, IH) , 2.85 (s+d, 2H) , 2.95 (m, IH) , 3.25 (s, 3H) , 3.35 (d, IH) , 3.55 (dd, IH) , 4.45 (s, 2H) , 5.55 (s, IH) , 7.15-7.35 (m, 5 H) , 8 (s, IH) .

¹³C NMR (100 MHz, CDC1₃) d 13.6, 25.6, 29.2, 34.6, 43.6, 47.8, 52.1, 56.9, 59.4, 59.5, 64.7, 69.6, 79.2, 126.4, 128.4, 128.9, 137.8, 150.6.

Step 7: racemic (3R, 4S, 5S, 6R, 2 'R, 3 ^TR) -4- (2 ' -methyl-3 ' - benzyl -oxiranyl) -5-methoxy -1-oxa- spiro [2.5] oct-6-ol (Compound xix)

(3R,4S,5S, 6R,2 'R,3 'R) -Benzoicacid-4- (2 ' -methyl-3 ' -phenyl- oxiranyl) -5-methoxy-l-oxa-spiro [2.5] oct-6-yl ester (226 mg, 0.553 mmol) was reacted according to the procedure outlined in step 5 to give 149 mg (89%) of the desired product which was used without further purification in the next reaction.

^XE NMR (400 MHz, CDCl₃)d 0.9 (dd, IH) , 1.25 (s, 3H) , 1.7 (m, IH) , 1.95 -(m, 2H) , 2.1 (td, IH) , 2.3 (d, IH) , 2.45 (m,lH), 2.8 (m, 2H) , 2.9 (q, 2H) , 3.5 (s, 3H) , 3.6 (d, IH) , 4.35 (s, IH) , 7.2-7.4 (m, 5H) .

¹³C NMR (100 MHz, CDCl₃)d 13.3, 25.6, 27.5, 34, 46.1, 49.7, 55.5, 57.8, 58.8, 61.2, 63, 80, 126, 127.7, 128, 136.

Step 8: racemic (3R, 4S, 5S, 6R, 2 ' R, 3 ' R) -Chlorocarbamic acid-4- (3 ' -benzyl-2 'methyl-oxiranyl) -5- methoxy-1-oxa-spiro [2.5] oct-6-yl

(Compound xx)

To the crude product 4- (2 ' -methyl-3 ' -benzyl-oxiranyl) -5 - methoxy-1-oxa-spiro [2.5] oct-6-ol (0.646 mmol) in dry dichloromethane (6ml) at 0 °C was added drop-wise chloroacetylisocyanate (0.695 mmol, 59 μl) . The mixture was stirred 15 minutes, and flash chromatography (hexane→ hexane : ethyl acetate ; 7 :3) to gave 204 mg (75 % 2 steps) of pure desired product.

^XHNMR (400 MHz, CDC1₃) : 1.07 (broad d, J= 12.0 Hz,

IH) , 1.28 (broad s, IH) , 1.32 (s, 3H) , 1.90-1.94 (m, 2H) , 2.00-2.04 (m, 2H) , 2.37 (d, J= 4.0 Hz, IH) , 2.59 (d, J= 4.0 Hz, IH) , 2.80-2.84 (m, 2H) , 2.94- 2.98 (m, IH) , 3.49 (s, 3H) , 3.68-3.72 (dd, J=11.5 Hz and 2.5 Hz, IH) , 4.41 s, IH) , 5.63 (s, IH) , 7.25-7.36 (m, 5H) , 7.96 (broad s, IH) .

¹³CNMR (75 MHz, CDC1₃) : 13.08, 24.56, 28.09, 33.87,

42.76, 47.18, 49.78, 56.04, 57.74, 58.30, 61.09, 68.47, 78.21, 125.83, 127.79 (2C) , 127.99 (2C) , 136.40, 149.93, 165.77.

EXAMPLE 6 Angiogenesis Inhibition assay

Angiogenesis inhibiting activity was tested using a CAM (chorioallantoic membrane) assay according to the procedures described in Langer and Folkman (Nature, 1976, 263:797), Jakabson et al (Pharmacology and Toxicology, 1989, 64:193) and Dugan et al (The Anatomical Record, 1991, 229:125) .

Briefly, chick embryos of 4 days old were explanted into glass cups and incubated at 37°C, 3% C0₂ for 3 days. Pellets were made by dissolving the test compound in methylene chloride solvent and then added to ethylene- vinyl acetate (EVA) copolymer 5% w/v. Pellets of lOμL (3- 4mm diameter) were left to air dry and then gently transferred on to the periphery of the CAM (chorioallantoic membrane) . After 2 days of incubation, observations for avascular zones were made with a stereoscope. Results are summarized in table I.

Table I

Table I ( continued )

CAM

Compound Name dose inhib/

⁽ μg ⁾ total and 10 6/10

VI mic thyl- iro- er)

(3R,4S,6S,2'R,3'R) and 10 4/8 vii (3S,4R,6R,2'S,3'S)- chloroacetyl carbamic acid-4- (2' , 3' -dimethyl- ^l oxiranyl) -1-oxa-spiro-

[2.5] -oct-6-yl ester)

nd 10 3/12 viii

(2'S,3'S,3R,4S,5S, 6R) and 10 2/13

IX (2'R,3'R,3S,4R,5R,6S) chloroacetyl-carbamic acid 4- (2' , 3' -dimethyl- oxiranyl) -5-methoxy-l-

oxaspiro [2.5] oct-6-yl ester

Table I (continued)

note: inhib/total is the number of eggs exhibiting avascular zones compared to the total number of eggs tested at a particular dose.

EXAMPLE VI: HUVEC CELL ASSAY

HUVEC cells (primary cultures p.5-8) from liquid Nitrogen tank are thawed, washed twice in HUVEC culture medium, counted and plated at a concentration of 10,000 cells per well in 96 well flat bottom plates. A 100 μls of medium alone is first added to each well then 100 μls of 1 x 10⁵ cells is added on top such that the total volume is 200 μls per well. This is done on Monday.

Next day the medium in the wells is gently removed by using pipette tip suction and 200 μls of fresh medium is added and the cells are allowed to continue growth for another day.

Next day the medium is removed and 100 μl of fresh medium is added to the wells. Afterwards a ten fold serial dilutions of angiogenesis inhibitor cpds (stored frozen at 2 x 10^"3M in DMSO in 0.1 ml volume) is prepared in HUVEC medium starting from 2 x 10^"6M till 2 x 10^"12M._ A 100 μls of each of this dilution starting from lowest to highest concentration (against concentration gradient) is then added to the wells in triplicates and the plates are incubated at 37°C in the C0₂ incubator for 48 hrs till Friday. The first row of the plate contains medium alone with no cpds and Fumagillin is used as a golden standard, positive control.

At 18 hrs before the end of the 48 hr incubation time on Thursday at 4.00 pm [³H] -Thymidine is added to the wells at 1 μCi/well in a 10 μl volume diluted in HUVEC medium.

The plates are harvested on Friday at 10.00 a.m.. The medium is removed and a 100 μl PBS is added, then PBS is removed and 50 μl Trypsin-EDTA is added and the plates are incubated for 4 mins . The plates are checked under the microscope to ensure detachment from the wells.

Finally harvested plates are counted in the beta-counter and the results are plotted as % of control (Y-axis) versus concentration (X-axis, log scale).

Compounds of the present invention were evaluated for their ability to inhibit human umbilical vein endothelial cell growth according to the general procedure described below. These compounds were found to inhibit HUVE cell growth with IC₅o ranging from .043 to >10 μM. Specifically, Compounds xviii and xx had IC₅0 results of 2 μM and 0.043 μM respectively.

Claims

What is claimed is:

1. A compound of formula (I) and pharmaceutically acceptable salts and derivatives thereof:

(I) wherein Rj_. is H or straight or branched C_1-8 alkyl;

R₂ is H, C_x.₄ alkyl, aryl, aryl-C_j^.,, alkyl, cycloalkyl, cycloalkyl-C_1-4 alkyl; and

R₃ is a C_1-4 alkyl-C₅.₈ aryl that is optionally substituted with a one or more halogen (F, Cl, I, Br) , a C_1-4 alkoxy or a C_1-4 alkyl;

R₄ is H, OH or C_1-4 alkoxy; and

R₅ is selected from the group consisting of

H; a substituted alkanoyl group; a substituted aroyl group having at least one substituent selected from the group consisting of C₂.₆ alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, carbamoyl and carboxyl ; an aromatic heterocycle-carbonyl which may optionally be substituted; a carbamoyl group, which may optionally be substituted; an alkyl group, which may optionally be substituted; a benzenesulfonyl group, which may optionally be substituted; an alkylsulfonyl group, which may optionally be substituted; a sulfamoyl group, which may optionally be substituted; an alkoxycarbonyl group, which may optionally be substituted- a phenoxycarbonyl group, which may optionally be substituted; or C (0) -NH-C (0) -CH₂-C1.

2. The compound of claim 1, wherein Ri and R₂ are independently selected from the group consisting of H or C_1-4 alkyl .

3. The compound of claim 2, wherein R_x and R₂ are independently either H or methyl .

4. The compound of claim 1, wherein R₂ is aryl, aryl-C^,, alkyl, cycloalkyl or cycloalkyl-C^ alkyl and R₃ is C_x.₄ alkyl-phenyl that is optionally substituted with one or more halogen (F, Cl, I, Br) or a C_1-4 alkyl.

5. The compound of claim 4, wherein R₃ is a C^ alkyl-phenyl.

6. The compound of claim 5, wherein R₃ is a benzyl and R₂ is H.

7. The compound of claim 1, wherein R is a C╬╣_₄ alkoxy.

8. The compound of claim 1, wherein R₄ is a methoxy.

9. The compound of claim 1, wherein Ri is H.

10. The compound of claim 1, wherein R₅ is H or C(O)- NH-C(0)-CH₂C1.

11. The compound of claim 1, wherein R₅ is C(0)-NH- C(0)-CH₂C1.

12. The compound of claim 1, wherein R₅ is H.

13. The compound of claim 1, selected from the group consisting of:

(xviii) racemic (3R, 4S, 5S, 6R, 2 ' S, 3 ' S) chloroacetyl-carbamic acid 4- (3-benzyl-2-methyl-oxiranyl) - 5-methoxy-l-oxa-spiro [2.5] oct-6-yl ester; (xix) racemic (3R, 4S, 5S, 6R, 2 ' R, 3 'R) -4- (2 ΓÇó - methyl-3 ' -benzyl-oxiranyl) -5-methoxy -1-oxa-spiro [2.5] oct- 6-ol; and

(xx) racemic (3R, 4S, 5S, 6R, 2 'R, 3 'R) - Chloroacetylcarbamic acid-4- (3 ' -benzyl-2 'methyl-oxiranyl) - 5-methoxy-l-oxa-spiro [2.5] oct-6-yl;

14. The compound of claim 1, selected from the group consisting of: (xviii) racemic (3R, 4S, 5S, 6R, 2 ' S, 3 ' S) chloroacetyl-carbamic acid 4- (3-benzyl-2-methyl-oxiranyl) - 5-methoxy-l-oxa-spiro [2.5] oct-6-yl ester; and (xx) racemic (3R, 4S, 5S, 6R, 2 'R, 3 'R) - Chlorocarbamic acid-4- (3 ' -benzyl-2 'methyl-oxiranyl) -5- methoxy-1-oxa-spiro [2.5] oct-6-yl .

15. A method of inhibiting angiogenesis in a mammal, comprising administering to said mammal an effective amount of a compound of claim 1.

16. A method of inhibiting tumor growth in a mammal, comprising administering to said mammal an effective amount of a compound of claim 1.

17. A method of inhibiting tumor metastasis in a mammal, comprising administering to said mammal an effective amount of a compound of claim 1.