AU2012200514B2 - Treatment of inflammatory bowel disease - Google Patents

Abstract

Abstract Disclosed herein is a method comprising administering a compound to a mammal suffering from an inflammatory bowel disease for the treatment of said disease, said compound having a structure according to Formula I wherein X, Y, B, R2, R3, R4, R5, R6 and n have the meanings found herein. C:\NRPortbI\DCC\TZM\4119443_ .DOC . 30/1/12

Description

Australian Patents Act 1990 - Regulation 3.2 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Treatment of inflammatory bowel disease The following statement is a full description of this invention, including the best method of performing it known to me: P/00/011 5951 TREATMENT OF INFLAMMATORY BOWEL DISEASE By Inventors 5 Varly Donde, Jeremiah H. Nguyen, Karen M. Kedzie, Daniel W. Gil, John E. Donello and Wha-Bin Im 10 15 Description of Related Art Prostaglandins can be described as derivatives of prostanoic acid which have the following structural formula: 20 7 5 3 9 8 6 4 2 COOH 10 14 16 18 1 -220 117 13 i5 17 19 Various types of prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side 25 chain indicated by numerical subscripts after the generic type of prostaglandin [e.g. prostaglandin El (PGE1), prostaglandin E2 (PGE2)], and on the configuration of the substituents on the alicyclic ring indicated by a or p [e.g. prostaglandin F2a (PGF2Q)].

WO 2006/101867 PCT/US2006/009222 2 Prostaglandins are useful for the long-term medical management of glaucoma (see, for example, Bito, L.Z. Biological Protection with Prostaglandins, Cohen, M.M., ed., Boca Raton, Fla, CRC Press Inc., 1985, pp. 231-252; and Bito, L.Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, 5 S.M. and Neufeld, A.H. eds., New York, Grune & Stratton, 1984, pp. 477-505. Such prostaglandins include PGF2a, PGFia, PGE2, and certain lipid-soluble esters, such as Ci to C2 alkyl esters, e.g. 1-isopropyl ester, of such compounds. Certain 15,15-dimethyl prostaglandins with antihypertensive, gastric acid secretion inhibition, and smooth muscle stimulant properties, are known to have 10 improved metabolic stability. These are described in documents such as the following: Pernet et al in US Patent 4,117,014 (filed 23 December 1976); Pernet, Andre G. et al., Prostaglandin analogs modified at the 10 and 11 positions, Tetrahedron Letters, (41), 1979, pp. 3933-3936; 15 Plantema, Otto G. et al., Synthesis of (.+-.)-10.10-dimethylprostaglandin El methyl ester and its 15-epimer, Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-organic Chemistry (1972-1999), (3), 1978, pp. 304-308; Plantena, 0. G. et al., Synthesis of 10,10-dimethylprostaglandin El, Tetrahedron 20 Letters, (51), 1975, 4039; Hamon, A., et al., Synthesis of (+-)- and 15-EPI(+-)-10,10-Dimthylprostaglandin El, Tetrahedron Letters, Elsevier Science Publishers, Amsterdam, NL, no. 3, January 1976, pp. 211-214; and Patent Abstracts of Japan, Vol. 0082, no. 18 (C-503), June 10, 1988 & JP 63 25 002972 A (Nippon Iyakuhin Kogyo KK), 7 January 1988; the disclosure of these documents are hereby expressly incorporated by reference. Inflammatory bowel disease (IBD) is a group of disease characterized by inflammation in the large or small intestines and is manifest in symptoms such as diarrhea, pain, and weight loss. Nonsteroidal anti-inflammatory drugs have 30 been shown to be associated with the risk of developing IBD, and recently Kabashima and colleagues have disclosed that "EP4 works to keep mucosal integrity, to suppress the innate immunity, and to downregulate the proliferation WO 2006/101867 PCT/US2006/009222 3 and activation of CD4+ T cells. These findings have not only elucidated the mechanisms of IBD by NSAIDs, but also indicated the therapeutic potential of EP4-selective agonists in prevention and treatment of IBD." (Kabashima, et. al., The Journal of Clinical Investigation, April 2002, Vol. 9, 883-893) 5 Summary of the Invention Disclosed herein is a method comprising administering a compound to a mammal suffering from an inflammatory bowel disease for the treatment of said 10 disease, said compound having a structure according to Formula I 0 R2 r\X BXY R3 n R6 R40 R' OH Formula I wherein the dashed line indicates the presence or absence of a bond, the hatched 15 wedge indicates the a (down) configuration, and the solid triangle indicates the 0 (up) configuration; B is a single, double, or triple covalent bond; n is 0-6; X is CH 2 , S or 0; 20 Y is any pharmaceutically acceptable salt of CO 2 H, or CO 2 R, CONR 2 ,

CONHCH

2

CH

2 OH, CON(CH 2

CH

2

OH)

2 , CH 2 OR, P(O)(OR) 2 , CONRSO 2 R,

SONR

2 , or

N

7

A

H :\cdl\Interwoven\NRPortbl\DCC\CDL\59320571.doc-14/01/2014 4 R is H, C 1 -6 alkyl or C 2

-

6 alkenyl;

R

2 and R 3 are C1- 6 linear alkyl which may be the same or different, and may be bonded to each other such that they form a ring incorporating the carbon to which they are commonly attached; 5 R is hydrogen, R, C(=O)R, or any group that is easily removed under physiological conditions such that R 4 is effectively hydrogen;

R

5 is hydrogen or R; R6is i) hydrogen; 10 ii) a linear or branched hydrocarbon containing between 1 and 8 carbon atoms, which may contain one or more double or triple bonds, or oxygen or halogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogen atoms may be substituted by 0 or a halogen; or iii) aryloxy, heteroaryloxy, C 3

.

8 cycloalkyloxy, C 3

.

8 cycloalkyl, C 6

.

1 0 15 aryl or C 3

.

1 0 heteroaryl, wherein one or more carbons is substituted with N, 0, or S; and which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 6

.

10 aryl, C 3

-

10 heteroaryl, aryloxy, heteroaryloxy, C1.

6 alkyl, OR, SR, and SO 2 R. 20 Compositions and medicaments related thereto are also disclosed. In a first aspect the present invention provides a method for the treatment of an inflammatory bowel disease comprising administering a compound having a structure according to Formula III 0Y X B X -- y RS 25 HO OH Formula III H:\cdl\Interwoven\NRPortbl\DCC\CDL\5932057_1.doc-14/0 1/2014 4A wherein B is a single, double, or triple covalent bond; n is 0-6; R6is i) hydrogen; 5 ii) a linear or branched hydrocarbon containing between 1 and 8 carbon atoms, which may contain one or more double or triple bonds, or oxygen or halogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogen atoms may be substituted by 0 or a halogen; or iii) aryloxy, heteroaryloxy, C 3

.

8 cycloalkyloxy, C 3

.

8 cycloalkyl, C 6

-

1 0 aryl or C 3 .. 10 1o heteroaryl, wherein one or more carbons is substituted with N, 0, or S; and which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 6

.

10 aryl, C 3 .1o heteroaryl, aryloxy, heteroaryloxy, C 1

.

6 alkyl, OR, SR, and SO 2 R; Y is CO 2 R; 15 X is CH 2 , S or 0; and R is H, C 1 .6 alkyl or C 2

-

6 alkenyl, or any pharmaceutically acceptable salt of CO 2 H to a mammal in need thereof. 20 In a second aspect the present invention provides a use of a compound having a structure according to Formula III xB - " X y R 6 HO OH Formula III wherein B is a single, double, or triple covalent bond; 25 n is 0-6; R is i) hydrogen; H:\cdl\Interwoven\NRPortbl\DCC\CDL\5932057_1.doc-14/01/2014 4B ii) a linear or branched hydrocarbon containing between 1 and 8 carbon atoms, which may contain one or more double or triple bonds, or oxygen or halogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogen atoms may be substituted by 0 or a halogen; or 5 iii) aryloxy, heteroaryloxy, C 3

-

8 cycloalkyloxy, C 3 .8 cycloalkyl, C 6

.

10 aryl or C3. 10 heteroaryl, wherein one or more carbons is substituted with N, 0, or S; and which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 6

-

10 aryl, C 3 .1o heteroaryl, aryloxy, heteroaryloxy, C 1

.

6 alkyl, OR, SR, and SO 2 R; 10 Y is CO 2 R; X is CH 2 , S or 0; and R is H, C 1 -6 alkyl or C 2

.

6 alkenyl, or any pharmaceutically acceptable salt of CO 2 H, in the manufacture of a medicament for the treatment of an inflammatory bowel disease in 15 a mammal. Brief Description of the Drawing Figures Figures 1-9 illustrate possible ways to prepare compounds of the 20 invention. Detailed Description of the Invention Treatment of inflammatory bowel disease may be accomplished by the 25 administration of the compounds described herein to the suffering mammal. Inflammatory bowel disease describes a variety of diseases characterized by inflammation of the bowels including, but not limited to, ulcerative colitis and WO 2006/101867 PCT/US2006/009222 5 Crohn's disease. Treatment may be accomplished by oral administration, by suppository, or parenteral administration, or some other suitable method. The compounds used in the treatment described herein have a structure according to Formula I OO - RG R 40 R5 OH. 5 Formula I A preferred group of the compounds of the present invention includes compounds that do not have the following structural formula H: 0A E JO G OH Formula H 10 wherein A is CO 2 H, CO 2 Me, or CO 2 Et; D is a single, double, or triple covalent bond; E is a linear, branched, or cycloalkyl chain of 3 to 7 carbons, trifluoromethylbutyl, hydroxylalkyl, or CH 2

R

7 wherein R 7 is phenyl, cyclopentyl, phenoxy, chlorophenoxy, propoxy, or -CH 2

SCH

2

CH

3 ; 15 J is hydrogen, R, C(=0)R, or any group that is easily removed under physiological conditions such that R 4 is effectively hydrogen; and G is H or CH 3

.

WO 2006/101867 PCTIUS2006/009222 6 As used herein, the symbols "Me" and "Et" refer to the moieties commonly referred to as "methyl" and "ethyl" by those of ordinary skill in the art. In other compounds related to Formula I and Formula II, A is C0 2

R

8 , 5 wherein R 8 is any linear, branched, or cyclic alkyl group having from 3 to 6 carbons. Another preferred group includes compounds having formula III: Y HO OH Formula III 10 Another preferred group includes compounds having formula IV: 0 Re HO OH Formula IV Another preferred group includes compounds having formula V: WO 2006/101867 PCT/US2006/009222 7 0 R X -' R6 H6 R 5 OH Formula V wherein at least one of R 2 and R 3 is not methyl. In the above formulae, the substituents and symbols are as hereinabove defined. 5 In the above formulae: Preferably Y is any pharmaceutically acceptable salt of CO 2 H or CO 2 R. More preferably Y is C02H or CO 2 Me. Preferably n is 2. Preferably, R 6 is C6-10 aryl or C 3

..

1 o heteroaryl, which may contain one or 10 more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 1 .6 alkyl, OR, SR, and SO 2 R. More preferably

R

6 is phenyl, napthyl, benzofuranyl, or benzothienyl, which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 1 .6 alkyl, OR, SR, and SO 2 R. Most preferred is 15 3-chlorobenzothien-2-yl. Another preferred group includes compounds having formula XIII: O .H R6 HO Formula XIII wherein B represents a single or double bond; WO 2006/101867 PCT/US2006/009222 8 and R 6 is napthyl, benzofuranyl, or benzothienyl, which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 1 -6 alkyl, OR, SR, and SO 2 R. Compounds useful for the methods described herein may be prepared by 5 methods known to those skilled in the art. The synthesis of several of these compounds is illustrated in Schemes 2-7. These Schemes that are included herein are merely illustrative and are not intended to limit the scope of the invention in any way. Although there are several ways the reduction of compounds of Formula VI to Formula VII could be incorporated into the 10 synthesis of these compounds, one convenient way to this is shown in Scheme 2. In this Scheme, compound 2 is a compound of Formula VI and compound 3 is a compound of formula VII. However, those skilled in the art will recognize that there are many ways in which the reduction could be used to prepare compounds of this invention. 15 Table 1 Structure Low Rf High Rf diastereomer diastereomer 0

.

21 22 HOOH 23 24 0 s 34 35 0 36 37 0O 38 39 H.C 0 .. 40 41 >~j coa 42 0 43 a 0H WO 2006/101867 PCT/US2006/009222 9 Co.H 44 om 45 HO OH 0 46 47 10 CoaCM 0 48 49 HO H 0 50 51 HO OH 0 52 53 8 54 55 HO 0C 56 57 Ho H 0 58 59 O H 0 60 61 H OH 0 >6 62 63 OH 0 O 64 65 -NN o 66 67 CONII > 68 69 HO oH 0 a 70 71 H0OH 0 4 9 72 73

HOH

WO 2006/101867 PCTIUS2006/009222 10 0 5 74 75 HOOH The compounds named below, and illustrated in Table 1, are especially preferred representatives of the compounds of the present invention: 5 (3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-acetic acid methyl ester (21, 22); (3- { (1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-acetic acid 10 (23, 24); (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent 1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl)-hept-5-ynoic acid methyl ester (34, 35); (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent 15 1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoic acid (36,37); (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent 1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl I -hept-5-enoic acid methyl ester (38,39); (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent 20 1-enyl]-4-hydroxy-3,3-dimethyl:-2-oxo-cyclopentyl}-hept-5-enoic acid (40,41); 7-[(1R,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2 oxo-cyclopentyl]-hept-5-ynoic acid methyl ester (42) 7-[(1R,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2 oxo-cyclopentyl]-hept-5-ynoic acid (43) 25 (Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2 oxo-cyclopentyl]-hept-5-enoic acid (44) (Z)-7-[(IR,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2 oxo-cyclopentyl]-hept-5-enoic acid methyl ester (45) (Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-4-phenyl-but-1-enyl)-3,3 30 dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (46, 47) WO 2006/101867 PCT/US2006/009222 11 (Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-4-phenyl-but-1-enyl)-3,3 dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid methyl ester (48,49) (Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-3,3 dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid methyl ester (50,51) 5 (Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-3,3 dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (52,53) (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (54,55) 7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4 10 hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-heptanoic acid (56,57) (Z)-7-[(IR,4S,5R)-5-(4-Benzo[b]thiophen-2-yl-3-hydroxy-butyl)-4-hydroxy-3,3 dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (58,59) (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid ethylamide (60,61) 15 (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[bjthiophen-2-yl-3-hydroxy-but-1-enyl)-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid diethylamide (62,63) (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (2-hydroxy-ethyl) 20 amide (64,65) (3S,4R,5R)-4-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-3-hydroxy 2,2-dimethyl-5-[(Z)-6-(l-H-tetrazol-5-yl)-hex-2-enyl]-cyclopentanone (66,67) (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid amide (68,69) 25 (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid methyl ester (70,71) 7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy 3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-ynoic acid methyl ester (72,73) 7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy 30 3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-ynoic acid (74,75) Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the WO 2006/101867 PCT/US2006/009222 12 present invention, or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.0001 and about 5 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations. For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 6.5 and 7.2 with an appropriate buffer system. The formulations may also contain conventional, 10 pharmaceutically acceptable preservatives, stabilizers and surfactants. Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. 15 Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water. Tonicity adjustors may be added as needed or convenient. They include, 20 but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor. Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include 25 acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed. In a similar vein, an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated 30 hydroxytoluene. Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate WO 2006/101867 PCTIUS2006/009222 13 disodium, although other chelating agents may also be used in place or in conjunction with it. The ingredients are usually used in the following amounts: Ingredient Amount (% w/v) 5 active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 10 pH adjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purified water as needed to make 100% 15 The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan. The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers 20 equipped with a dropper, to facilitate the application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution. Synthetic Examples 25 The methods of preparing compounds of this invention are further illustrated by the following non-limiting Examples, which are summarized in the reaction schemes of Figures 1-7 wherein the compounds are identified by the same designator in both the Examples and the Figures. 2-Alkyl-cyclopentane-1,3-dione (la). A mixture of 1,3 30 cyclopentanedione (89.4 mmol, Aldrich), I-R 2 (96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in H20 (25 mL)/ dioxane (75 mL) is heated at reflux. After 5 h, a solution of KOH (2 g) and I-R 2 (2 mmol) in H20 (5 mL)/ dioxane (15 mL) is added and after another 3 h at reflux the solution is allowed to stir at room temperature overnight. In the morning, the reaction is continued by WO 2006/101867 PCT/US2006/009222 14 addition of a solution of KOH (2 g) and I-R 2 (2.4 mmol) in H 2 0 (5 mL)/ dioxane (15 mL) and heating at reflux. After 4 h, the mixture is allowed to cool to room temperature and is extracted with ether (1 x 100mL, 3 x 75 mL). The combined ether extracts are evaporated, the residue is combined with HCI (50 5 mL 10%), and the resulting mixture is placed in a 120 *C oil bath until boiling is observed (ca. 15 min.). The mixture is then allowed to cool to room temperature, is neutralized by addition of NaHCO 3 solution (150 mL, saturated) and the resulting mixture is then extracted with CH 2 C1 2 (4 x 75 mL). The combined CH 2 C1 2 solution is dried (MgSO 4 ), filtered and evaporated to leave a 10 brown oil which is used directly in the next step. 2-Alkyl-2-methyl-cyclopentane-1,3-dione (2a). A mixture of 2 methyl-1,3-cyclopentanedione (10.025 g, 89.4 mmol, Aldrich), I-R 2 (96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in H20 (25 mL)/ dioxane (75 mL) is heated at reflux. After 5 h, a solution of KOH (2 g) and I-R 2 (2 mmol) in H 2 0 (5 15 mL)/ dioxane (15 mL) is added and after another 3 h at reflux the solution is allowed to stir at room temperature overnight. In the morning, the reaction is continued by addition of a solution of KOH (2 g) and I-R 2 (2.4 mmol) in H 2 0 (5 mL)/ dioxane (15 mL) and heating at reflux. After 4 h, the mixture is allowed to cool to room temperature and is extracted with ether (1 x 100mL, 3 x 75 mL). 20 The combined ether extracts are evaporated, the residue is combined with HCI (50 mL 10%), and the resulting mixture is placed in a 120 *C oil bath until boiling is observed (ca. 15 min.). The mixture is then allowed to cool to room temperature, is neutralized by addition of NaHCO 3 solution (150 mL, saturated) and the resulting mixture is then extracted with CH 2 Cl 2 (4 x 75 m). The 25 combined CH 2

C

2 solution is dried (MgSO 4 ), filtered and evaporated to leave a brown oil which is used directly in the next step. 2,2-Dialkyl-methyl-cyclopentane-1,3-dione (2b). A mixture of 2 alkyl-1,3-cyclopentanedione la (89.4 mmol, Aldrich), I-R 3 (96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in H 2 0 (25 mL)/ dioxane (75 mL) is 30 heated at reflux. After 5 h, a solution of KOH (2 g) and I-R 3 (2 mmol) in H20 (5 mL)/ dioxane (15 mL) is added and after another 3 h at reflux the solution is allowed to stir at room temperature overnight. In the morning, the reaction is WO 2006/101867 PCT/US2006/009222 15 continued by addition of a solution of KOH (2 g) and I-R 3 (2.4 mmol) in H20 (5 mL)/ dioxane (15 mL) and heating at reflux. After 4 h, the mixture is allowed to cool to room temperature and is extracted with ether (1 x 100 mL, 3 x 75 mL). The combined ether extracts are evaporated, the residue is combined with HCl 5 (50 mL 10%), and the resulting mixture is placed in a 120 *C oil bath until boiling is observed (ca. 15 min.). The mixture is then allowed to cool to room temperature, is neutralized by addition of NaHCO 3 solution (150 mL, saturated) and the resulting mixture is then extracted with CH 2 Cl 2 (4 x 75 mL). The combined CH 2 C1 2 solution is dried (MgSO 4 ), filtered and evaporated to leave a 10 brown oil which is used directly in the next step. Spiro[2.4]heptane-4,7-dione (2c). A mixture of 2-alkyl-1,3 cyclopentanedione la (89.4 mmol, Aldrich), 1,2-dibromoethane (120 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in H 2 0 (25 mL)/ dioxane (75 mL) is heated at reflux for 24 hours. The mixture is allowed to cool, and the crude 15 product is extracted with ether (1 x 1OOmL, 3 x 75 mL). The combined ether extracts are evaporated, the residue is combined with HCl (50 mL 10%), and the resulting mixture is placed in a 120 *C oil bath until boiling is observed (ca. 15 min.). The mixture is then allowed to cool to room temperature, is neutralized by addition of NaHCO 3 solution (150 mL, saturated) and the resulting mixture 20 is then extracted with CH 2

CI

2 (4 x 75 mL). The combined CH 2

CI

2 solution is dried (MgSO 4 ), filtered and evaporated to leave a brown oil which is used directly in the next step. 2,2-Dimethyl-cyclopentane-1,3-dione (2). The published procedure was followed. (Agosta, W.C.; Smith, A.B. J.Org.Chem. 1970,35, 3856) A 25 mixture of 2-methyl-1,3-cyclopentanedione (10.025 g, 89.4 mmol, Aldrich), methyl iodide (6.0 mL, 96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in H20 (25 mL)/ dioxane (75 mL) was heated at reflux. After 5 h, a solution of KOH (2 g) and Mel (2.4 mL) in H20 (5 mL)/ dioxane (15 mL) was added and after another 3 h at reflux the solution was allowed to stir at room temperature 30 overnight. In the morning, the reaction was continued by addition of a solution of KOH (2 g) and MeI (2.4 mL) in H20 (5 mL)/ dioxane (15 mL) and heating at reflux. After 4 h, the mixture was allowed to cool to room temperature and was WO 2006/101867 PCT/US2006/009222 16 extracted with ether (1 x 100mL, 3 x 75 mL). The combined ether extracts were evaporated, the residue combined with HCI (50 mL 10%), and the resulting mixture was placed in a 120 *C oil bath until boiling was observed (ca. 15 min.). The mixture was then allowed to cool to room temperature, was 5 neutralized by addition of NaHCO 3 solution (150 mL, saturated) and the resulting mixture then extracted with CH 2

CI

2 (4 x 75 mL). The combined

CH

2 Cl 2 solution was dried (MgSO 4 ), filtered and evaporated to leave a brown oil (10.474 g, 83 mmol, 93%) which was used directly in the next step. (S)-3-Hydroxy-2,2-dimethyl-cyclopentanone (3). The published procedure 10 was followed. (Brooks, D.W.; Hormoz, M.; Grothaus, P.G. J.Org.Chem. 1987, 52, 3223) A 35 *C (internal temperature) solution of D-glucose (106.73 g, 592 mmol, Aldrich) in H 2 0 (690 mL) in a 4 L Erlenmeyer was treated with baker's yeast (71.065 g, Fleischmann's). The mixture was allowed to ferment for 2 h, then 2,2-dimethyl-cyclopentane-1,3-dione (2) (7.316 g, 58 mmol) was added. 15 The mixture was stired for 48 h and then filtered through celite, washing with about 1 L CH 2 Cl 2 . The filtration was difficult due to the thick consistency of the yeast and it helped to continually add CH 2 Cl 2 to the mixture and scrape the top of the celite layer with a spatula. The filtrate was transferred to a separators funnel, and 100 mL brine was added and the layers were 20 separated. Brine (400 mL) was added to the aqueous layer and the resulting solution extracted further with CH 2 Cl 2 (3 x 500 mL). The combined CH 2

CI

2 solution was dried (MgSO 4 ), filtered and evaporated to leave a yellow oil. Flash chromatography (11 x 5 cm, 20% EtOAc/hexs 4 25% - 30% - 40% - 50%) gave alcohol 3 (2.435 g, 19 mmol, 33%). 25 The enantiomeric excess of 3 was assayed by 1 H NMR of the corresponding Mosher's ester which was prepared by treatment of alcohol 3 (11 mg, 0.09 mmol) in dichloroethane (0.3 mL, Aldrich) with pyridine (27 pL, 0.33 mmol, Aldrich) and (R)-ax-methoxy-a-trifluoromethyphenylacetic acid chloride (58 pL, 0.31 mmol, Fluka). The mixture was stirred overnight and then 30 partitioned between water (10 mL) and ether (10 mL). The ether layer was washed with 1 M HC] (10 mL) and saturated NaHCO 3 solution and then was WO 2006/101867 PCT/US2006/009222 17 dried (MgSO 4 ), filtered and evaporated. 'H NMR analysis was done on the crude ester. (S)-3-(tert)-Butyl-dimethyl-silanyloxy-2,2-dimethyl-cyclopentanone (4). A solution of alcohol 3 (520 mg, 4.1 mmol) and 2,6-lutidine (0.56 mL, 4.8 mmol, 5 Aldrich) in CH 2 C1 2 (8.0 mL, Aldrich) was treated with TBSOTf (1.0 mL, 4.3 mmol, Aldrich). After 5.5 h, saturated NaHCO 3 solution (20 mL) was added and the mixture extracted with CH 2

C

2 (20 mL). The CH 2

CI

2 solution was washed with 20 mL each of 1 M HCl, saturated NaHCO 3 solution, and brine and then was dried (MgSO 4 ), filtered and evaporated. Flash chromatography (5 x 5 cm, 10 10% Et 2 0/pentane) gave TBS ether 4 (698 mg, 2.9 mmol, 70%). (S)-3-(tert)-Butyl-dimethyl-silanyloxy-2,2-dimethyl-5-phenylselanyl cyclopentanone (5). A solution of TBS ether 4 (1.496 g, 6.2 mmol) in THF (2 mL, Aldrich) was added dropwise to a -78 *C solution of LDA (4.9 mL, 7.3 mmol, 1.5 M/cyclohexane, Aldrich) in THF (22 mL, Aldrich), rinsing with 2 15 mL THF. After 15 min., a solution of PhSeCl (1.424 g, 7.4 mmol, Aldrich) in THF (2 mL) was quickly added by cannula, rinsing with 2 mL THF. The solution was stirred for 10 min. and then partitioned between 50 mL 0.5 M HCl and 75 mL ether. The ether layer was washed with 30 mL each of water, saturated NaHCO 3 solution, and brine and then was dried (MgSO 4 ), filtered and 20 evaporated. Flash chromatography (2% EtOAc/hexs -> 4%) gave phenylselenide 5 (1.641 g, 4.1 mmol, 67%) along with 476 mg of mixed fractions containing a lower Rf impurity. (S)-4-(tert)-Butyl-dimethyl-silanyloxy-5,5-dimethyl-cyclopent-2-enone(6). A solution of selenide 5 (1.641 g, 4.1 mmol) and pyridine (0.62 mL, 7.7 mmol, 25 Aldrich) in CH 2 Cl 2 (13 mL, Aldrich) was treated with H20 (1 mL) and 30%

H

2 0 2 (1.1 mL, Aldrich). The mixture was stirred for 30 min. and then was partitioned between 25 mL CH 2 Cl 2 and 25 mL saturated NaHCO 3 solution. The aqueous layer was extracted with 25 mL CH 2

C]

2 and the combined CH 2 Cl 2 solution washed with 1 M HCI (2 x 25 mL) and brine (50 mL). The solution was 30 then dried (MgSO 4 ), filtered and evaporated to leave an orange oil. Flash chromatography (6 x 4 cm, 10% ether/pentane) gave enone 6 (572 mg, 2.4 mmol, 59%).

WO 2006/101867 PCT/US2006/009222 18 (3-Mercapto-propylsulfanyl)-acetic acid methyl ester (8). An ice-cold solution of 1,3-dithiane (2.0 mL, 19.9 mmol) in THF (40 mL) was treated with NaH (819 mg, 20.5 mmol). After 30 min., methyl bromoacetate (1.9 mL, 20.0 mmol) was added and the mixture stirred for 3.5 h at room temperature. The 5 reaction was quenched by addition of MeOH and then 50 mL 1 M HCl. The mixture was extracted with ether (2 x 50 mL) and the combined ether solution washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL) and then was dried (MgSO 4 ), filtered and evaporated. Purification by flash chromatography on silica gel (10-15% ethyl acetate/hexanes) gave 971 mg (5.38 10 mmol, 27 %) of the thiol. {3-[(S)-3-(tert)-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-5-oxo-cyclopent-l enylsulfanyl]-propylsulfanyl}-acetic acid methyl ester (10). A solution of enone 6 (156 mg, 0.65 mmol) in MeOH (4.3 mL) was treated with 30 % H202 (0.21 mL) and 1 M NaOH (32 IAL). After 4 h, 20 mL saturated ammonium 15 chloride solution was added and the mixture was extracted with dichloromethane (3 x 10 mL). The combined dichloromethane solution was dried (Na 2

SO

4 ), filtered and evaporated in vacuo. A solution of thiol 8 (110 mg, 0.61 mmol) in dichloromethane (3 mL) was added to the crude epoxide (9) by cannula, rinsing with 1.2 mL. Basic 20 alumina (628 mg) was added and the mixture stirred for 16 h. The solvent was evaporated and purification of the residue by flash chromatography on silica gel (15% ethyl acetate/hexanes) gave 129 mg (0.31 mmol, 48 %) of the coupled enone (10). (3-Chloro-benzo[b]thiophen-2-yl)-methanol (12). To an ice cold solution of 25 10.0 g (47.0 mmol) of 3-chloro-benzo[b]thiophene-2-carboxylic acid (11) in 200 mL of THF was added 47 mL of LiAlH 4 (47 mmol, 1 M/THF). After 3 h, the reaction was quenched by addition of MeOH (ca. 40 mL). The volatiles were evaporated and the residue was treated with 50 mL 1 M HCL. After stirring for 10 min., the mixture was extracted with CH 2

C

2 ( 3 x 150 mL). The combined 30 CH 2

CI

2 solution was dried (MgSO 4 ), filtered and evaporated. Purification by flash chromatography on silica gel (10-20% ethyl acetate/hexane) gave 4.32 g (21.6 mmol, 46 %) of the alcohol (12).

WO 2006/101867 PCT/US2006/009222 19 3-Chloro-benzo[b]thiophene-2-carbaldehyde (13). A solution of alcohol 12 (4.32 g, 21.6 mmol) in 40 mL of CH 2 Cl 2 was treated with 4A molecular sieves, NMO (3.81 g, 32.5 mmol), and TPAP (381 mg, 1.08 mmol). The reaction was stirred for 10 min. and then was evaporated to dryness. Purification by flash 5 chromatography on silica gel (2% ethyl acetate/hexane) gave 3.52 g (18.3 mmol, 84%) of the aldehyde (13). (E)-3-(3-Chloro-benzo[b]thiophen-2-yl)-acrylic acid methyl ester (14). A solution of 3.52 g (18.3 mmol) of 13 in 50 mL toluene was treated with methyl(triphenylphosphoranylidene)acetate (7.48 g, 21.9 mmol). After 4 h, 10 saturated NaHCO 3 solution (50 mL) was added and the mixture extracted with ethyl acetate (2 x 75 mL). The combined ethyl acetate solution was washed with brine (50 mL), dried (Na 2

SO

4 ), filtered and evaporated. Purification by flash chromatography on silica gel (5% ethyl acetate/hexane) provided 3.60 g (14.6 mmol, 80%) of the enoate (14). 15 3-(3-Chloro-benzo[b]thiophen-2-yl)-propionic acid methyl ester (15). A solution of 3.60 g (14.6 mmol) of 14 in 50 mL THF was treated with Wilkinson's catalyst (3.35 g, 3.62 mmol). The mixture was stirred under 1 atm

H

2 for 18 h and then was filtered through celite. The solvent was evaporated and the residue purified by flash chromatography on silica gel (0-2% ethyl 20 acetate/hexane) to give 3.63 g (14.3 mmol, 99%) of the saturated ester (15). 3-(3-Chloro-benzo[b]thiophen-2-yl)-propan-1-ol (16). An ice cold solution of 3.63 g (14.3 mmol) of 15 in 60 mL of ether was treated with LiBH 4 (621 mg, 28.5 mmol) and methanol (2 nL). After 30 min., 30 mL of 0.5 M NaOH solution was added. The mixture was extracted with ethyl acetate (2 x 25 mL) 25 and the combined ethyl acetate solution washed with brine (50 mL), dried (MgSO 4 ), filtered and evaporated. The residue was purified by flash chromatography on silica gel (5-20% ethyl acetate/hexane) to give 2.57 g (11.3 mmol, 79%) of the alcohol (16). 3-(3-Chloro-benzo[b]thiophen-2-yl)-propionaldehyde (17). A -78 *C 30 solution of oxalyl chloride (1.73 g, 13.6 mmol) in dichloromethane (20 mL) was treated with DMSO (20 mL). After 5 min., a solution of alcohol 16 (2.57g, 11.3 mmol) in dichloromethane (20 mL) was added. After another 15 min., WO 2006/101867 PCT/US2006/009222 20 triethylamine (7.1 mL, 50.6 mmol) was added. The reaction was stirred at -78 *C for 5 min., and then allowed to warm to room temperature. After 30 min., 100 mL water was added and the mixture extracted with dichloromethane (3 x 60 mL). The combined dichloromethane solution was dried (Na 2

SO

4 ), filtered 5 and evaporated. Purification by flash chromatography on silica gel (10% ethyl acetate/hexane) gave 2.11 g (9.4 mmol, 83%) of the aldehyde (17). 5-(3-Chloro-benzo[b]thiophen-2-yl)-pent-1-yn-3-o (18). A solution of aldehyde 17 (2.11 g, 9.4 minol) in 15 mL THF was added to a solution of ethynylmagnesium bromide (28.2 mL, 14.1 mmol, 0.5 M THF) at 0 *C. After 10 1.5 h, saturated NH 4 C] solution (75mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate solution was washed with brine (50 mL) and then was dried (Na 2

SO

4 ), filtered and evaporated. Purification by flash chromatography (5-20% ethyl acetate/hexane) gave 2.20 g (8.78 mmol, 93%) of the alcohol (18). 15 tert-Butyl-{1-[2-(3-chloro-benzo[b]thiophen-2-yl)-ethyl]-prop-2-ynyloxy dimethyl-silane (19). A solution of alcohol 18 (2.20 g, 8.78 mmol) in dichloromethane (15 mL) was treated with DMAP (215 mg, 1.8 mmol), TBSCI (1.59 g, 10.5 mmol), and triethylamine (1.8 mL, 13.2 mmol). The reaction was stirred for 24 h and then saturated sodium bicarbonate solution (50 mL) was 20 added. The mixture was extracted with dichloromethane (2 x 50 mL) and the combined dichloromethane solution dried (Na 2

SO

4 ), filtered and evaporated. Purification by flash chromatography (4% ethyl acetate/hexane) gave 3.06 g (6.4 mmol, 73%) of the protected alcohol (19). (3-{(1R,4S,5S)-4-(tert-Butyl-dimethyl-silanyloxy)-5-[(E)-3-(tert-butyl 25 dimethyl-silanyloxy)-5-(3-chloro-benzo[b]thiophen-2-y)-pent-1-enyl]-3,3 dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-acetic acid methyl ester (20). A solution of alkyne 19 (105 mg, 0.28 mmol) in THF (1.2 mL) was treated with bis(cyclopentadienyl)zirconium chloride hydride (91 mg, 0.35 mmol). The reaction was stirred for 30 min., then was cooled to -78 *C and 30 treated with methyllithium (0.46 mL, 0.64 mmol, 1.4 M in ether). After 10 min., a precooled (-78 *C) solution of lithium 2-thienylcyanocuprate (1.3 mL, 0.33 mmol, 0.25 M in THF) was added by cannula. The reaction was stirred for 45 WO 2006/101867 PCT/US2006/009222 21 min. and then enone 10 (61 mg, 0.15 mmol) in 0.2 mL THF was added by cannula, rinsing with 0.2 mL THE. After 1 h, The reaction was quenched by addition of 20 mL 1:1 saturated ammonium chloride solution/concentrated ammonium hydroxide. The mixture was stirred for 45 min. and then was 5 extracted with ethyl acetate (3 x 20 mL). The combined ethyl acetate solution was dried (Na 2

SO

4 ), filtered and evaporated. Purification by flash chromatography on silica gel (10 % ethyl acetate/hexanes) gave 51 ng (0.064 mmol, 43%) of the coupled product (20). (3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl] 10 4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-acetic acid methyl ester (21, 22). A solution of 20 (51 mg, 0.064 mmol) in CH 3 CN (1.6 mL) was treated with HF-pyridine (0.26 mL). The reaction was stirred for 24 h and then was quenched by addition of 15 mL saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 x 10 mL) and the 15 combined dichloromethane solution was dried (Na 2

SO

4 ), filtered and evaporated. Purification by preparative thin layer chromatography on silica gel (40% ethyl acetate/hexanes) gave 12 mg (0.023 mmol, 71%) of each diastereomer. (3-{(1R,4S,5S)--(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl] 20 4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-acetic acid (23, 24). Rabbit liver esterase (9 mg) was added to a solution of the lower Rf ester 21 (11 mg, 0.021 mmol) in pH 7.2 phosphate buffer (0.5 mL)/CH 3 CN (0.1 mL). The mixture was stirred overnight and then 10 mL 0.5 M HCl was added along with a few mL's of brine. The mixture was extracted with ethyl 25 acetate (3 x 10 mL) and the combined ethyl acetate solution dried (Na 2

SO

4 ), filtered and evaporated. Purification by flash chromatography on silica gel (3 5% MeOH/CH 2 Cl 2 ) gave 4 ng (0.0078 mmol, 37%) of the acid (23). 300 MHz 'H NMR (CDC 3 , ppm) 8 7.73 (2 H, d, J = 8.4 Hz) 7.4-7.3 (2 H, m) 5.9-5.8 (1 H, n) 5.8-5.7 (1 H, m) 4.4-4.3 (1 H, n) 3.63 (1 H, d, J = 9.7 Hz) 3.21 (2 H, s) 30 3.1-2.4 (11 H, overlapping m) 2.1-1.7 (4 H, overlapping m) 1.12 (3 H, s) 1.03 (3 H, s).

WO 2006/101867 PCT/US2006/009222 22 The higher Rf ester was hydrolyzed similarly except a solution of rabbit liver esterase (10 mg) in 0.5 mL of pH 7.2 phosphate buffer was added to a solution of the ester (10 mg, 0.019 mnol) in CH 3 CN (0.2 mL). The reaction was stirred for 22 h and then worked up and purified as above. This gave 7 mg 5 (0.013 mmol, 71%) of the acid (24). 300 MHz 'H NMR (CDC 3 , ppm) 8 7.73 (2 H, d, J = 8.8 Hz) 7.44-7.31 (2 H, m) 5.9-5.8 (1 H, m) 5.8-5.7 (1 H, n) 4.4-4.3 (1 H, m) 3.64 (1 H, d, J= 9.7 Hz) 3.3-2.3 (13 H, overlapping m) 2.1-1.7 (4 H, overlapping m) 1.12 (3 H, s) 1.03 (3 H, s). tert-Butyl-hex-5-ynyloxy-dimethyl-silane (26). 10 7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn--o (27). Acetic acid 7 -(tert-butyl-dimethyl-silanyloxy)-hept-2-ynyl ester (28). A solution of 7 -(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol 27 (4.507 g, 21 mmol) in pyridine (20 mL) was treated with acetic anhydride (3.0 mL, 31.8 mmol). After 18 h, the solvent was evaporated and the residue co-evaporated 15 with toluene. The residue was used directly in the next step. 7-Acetoxy-hept-5-ynoic acid (29). A solution of crude 28 in acetone (100 mL) was treated with Jones Reagent (18.0 mL, 41.4 mmol, 2.3 M). The mixture became warm and so was cooled with an ice bath. After 1 h at room temperature, 10 mL isopropyl alcohol was added and the mixture stirred further 20 for 15 min. The mixture still had a brown color so another 10 niL isopropyl alcohol was added. After another 15 min., the color had not changed so the mixture was filtered through celite and the filtrate evaporated in vacuo. The residue was partitioned between 100 mL ether and 100 mL saturated ammonium chloride solution. The aqueous layer was extracted with 100 mL ether and the 25 combined ether solution washed with brine and then was dried (MgSO 4 ), filtered and evaporated to leave a yellow oil (6.333 g) that was used directly in the next step. 7-Hydroxy-hept-5-ynoic acid methyl ester (30). The crude acid 29 (6.333 g) was treated with a 1% solution of acetyl chloride in methanol (60 mL). After 16 30 h, sodium bicarbonate (1.966 g, 23.4 mmol) was added. The mixture was dried (MgSO 4 ), filtered through celite and evaporated in vacuo. Purification by flash chromatography on silica gel (30-40% ethyl acetate/hexanes) gave 7-Hydroxy- WO 2006/101867 PCT/US2006/009222 23 hept-5-ynoic acid methyl ester 30 (3.022 g, 19.3 mmol, 92% from 7-(tert-Butyl dimethyl-silanyloxy)-hept-2-yn- 1 -ol 27). 7-Iodo-hept-5-ynoic acid methyl ester (31). A solution of 30 (1.347 g, 8.6 mmol) in 5 mL dichloromethane was added to a mixture of triphenylphosphine 5 (2.725 g, 10.4 mmol), imidazole (726 mg, 10.7 mmol), and iodine (2.602 g, 10.3 mmol) in 34 mL dichloromethane, rinsing with 5 mL dichloromethane. After 40 min., the dichloromethane was evaporated in vacuo to a few mL's and the resulting mixture filtered through basic alumina, washing with 10% ethyl acetate/hexanes. Purification by flash chromatography on silica gel (10% ethyl 10 acetate/hexanes) gave 1.878 g (7.1 mmol, 83%) of the propargyl iodide. tert-Butyl-{(E)-1-[2-(3-chloro-benzo[b]thiophen-2-yl)-ethyl]-3-iodo allyloxy}-dimethyl-silane (32). A solution of alkyne 19 (5.547 g, 15.2 mmol) in dichloromethane (50 mL) was treated with Cp 2 ZrHCl (5.794 g, 22.5 mmol). The reaction was stirred for 45 min. and then N-iodosuccinimide (4.966 g, 22.1 . 15 mmol) was added. After 15 min., saturated sodium bicarbonate solution (200 mL) was added and the mixture was extracted with dichloromethane (2 x 100 mL). The combined dichloromethane solution was dried (MgSO 4 ), filtered and evaporated. Purification by flash chromatography on silica gel (0-5% ethyl acetate/hexanes) gave 6.608 g (13.1 mmol, 86%) of the vinyl iodide (32). 20 7 -{(lR, 4

SSR)-

4 -(tert-Butyl-dimethyl-slanyloxy)-5-[(E)-3-(tert-butyl dimethyl-silanyloxy)-5-(3-chloro-benzo[b]thiophen-2-yl)-pent-1-enyl]-3,3 dimethyl-2-oxo-cyclopentyl-hept-5-ynoic acid methyl ester (33). A -78 *C solution of iodide 32 (675 mg, 1.34 mmol) in THF (2.0 mL) was treated with tert-butyllithium (1.73 mL, 2.94 mL, 1.7 M/pentane). The dark red mixture was 25 stirred for 25 min. and then dimethylzinc (0.80 mL, 1.6 mmol, 2 M/toluene) was added. The solution was stirred at 0 *C for 15 min. and then recooled to -78 *C. At this time, a solution of enone 6 (208 mg, 0.87 mmol) in THF (1.0 mL) was added over 2 h by syringe pump, rinsing with 0.5 mL THF. After 30 min., HMPA (1.34 mL, distilled from CaH2) was added followed by a solution of 30 propargyl iodide 31 (1.286 g, 4.83 mmol) in THF (1.0 mL). The solution was stirred in a -40 *C bath overnight and then 20 mL saturated ammonium chloride solution and 10 mL water were added. The mixture was extracted with WO 2006/101867 PCTIUS2006/009222 24 dichloromethane (20 mL) and ethyl acetate (2 x 20 mL). The combined organic extracts were dried (MgSO 4 ), filtered and evaporated. Purification by flash chromatography on silica gel (5-10% ethyl acetate/hexanes) gave 198 mg (0.27 mmol, 31%) of 33. 5 (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl)-hept-5-ynoic acid methyl ester (34, 35). A solution of 33 (198 mg, 0.27 mmol) in CH 3 CN (6.5 mL) was treated with HF-pyridine (1.2 mL). The solution was stirred for 3 h and saturated sodium bicarbonate solution (120 mL) was added. The mixture was 10 extracted with dichloromethane (3 x 50 mL) and the combined dichloromethane solution dried (Na2SO 4 ), filtered and evaporated. Purification by flash chromatography (50% ethyl acetate/hexane) followed by preparative TLC (55% ethyl acetate/hexane) gave 55 mg (0.11 mmol, 41%) of the less polar diastereomer (34) and 51 mg (0.10 mmol, 37%) of the more polar diastereomer 15 (35). (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl)-hept-5-ynoic acid (low Rr diastereomer, 36). A solution of 34 (9 mg, 0.017 mmol) and rabbit liver esterase (1 mg) in pH 7.2 phosphate buffer (2 mL)/CH 3 CN (0.1 mL) was 20 stirred for 17 h. The mixture was then coevaporated with CH 3 CN to remove water and the residue purified by flash chromatography on silica gel (3-7% MeOH/CH 2 Cl 2 ) to give 8 mg (0.016 mmol, 93%) of the acid (36). (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoic acid 25 (high Rr diastereomer, 37). A solution of 35 (12 mg, 0.023 mmol) and rabbit liver esterase (1 mg) in pH 7.2 phosphate buffer (2 mL)/CH 3 CN (0.1 mL) was stirred for 17 h. TLC showed the presence of starting material, so another 2 mg of the esterase was added. After stirring for another 24 h, the reaction was complete. Work up and purification as above for 36 gave 8 mg (0.016 mmol, 30 69%) of the acid (37). (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoic acid WO 2006/101867 PCT/US2006/009222 25 methyl ester (low Rf diastereomer, 38). Ethanol (95%, 2.5 mL) was added to NiCl 2 (50 mg, 0.39 mmol) and NaBH 4 (7 mg, 0.19 mmol). The resulting black mixture was stirred for 5 min. and then ethylenediamine (41 pL, 0.61 mmol) was added. After 15 min., a solution of alkyne 34 (40 mg, 0.077 mmol) in 0.5 5 mL 95% ethanol was added, rinsing with 0.5 mL ethanol. The flask was purged with H 2 and allowed to stir under 1 atm H 2 for 22 h. The mixture was then filtered through celite and purified by flash chromatography on silica gel (55% ethyl acetate/hexanes) to give 17 mg (0.032 mmol, 43%) of the alkene (38). (Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy 10 pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoic acid methyl ester (high Rr diastereomer 39). The same procedure as for 36 was followed to give 17 mg (0.032 mmol, 41%) of 39. (Z)-7-{(lR,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoic acid 15 (low Rr diastereomer, 40). The same procedure as above for 36 was used to give 9 mg (0.018 mmol, 85%) of acid 40. 300 MHz 'H NMR (CDC 3 , ppm) 8 7.73 (2 H, d, J = 8.4 Hz) 7.45-7.30 (2 H, m) 5.8-5.6 (2 H, m) 5.4-5.3 (2 H, m) 4.3-4.1 (1 H, m) 3.57 (1 H, d, J = 9.7 Hz) 3.1-2.9 (2 H, m) 2.5-1.9 (10 H, m) 1.7-1.6 (2 H, m) 1.09 (3 H, s) 0.89 (3 H, s). 20 (Z)-7-((1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-S-enoic acid (high Rr diastereomer, 41). The same procedure as above for the 36 was used to give 9mg (0.018 mmol, 85%) of acid 41. 300 MHz 1H NMR (CDCl 3 , ppm) 0 7.73 (2 H, d, J = 8.8 Hz) 7.45-7.30 (2 H, m) 5.8-5.6 (2 H, m) 5.45-5.30 (2 H, m) 25 4.3-4.2 (1 H, m) 3.61 (1 H, d, J = 9.7 Hz) 3.1-3.0 (2 H, m) 2.5-1.9 (10 H, m) 1.7-1.6 (2 H, m) 1.10 (3 H, s) 0.90 (3 H, s). 2-Benzo[b]thiophen-2-yl-ethanol (9-2, Fig. 9). n-BuLi (100 mL, 160 mmol, 1.6M/hexanes) was added to a -78 *C mixture of thianaphthene (17.31 g, 129 mmol) in THF (70 mL)/ether (30 mL). The mixture was stirred at -78 *C for 2 h 30 and then a solution of ethylene oxide (42.86 g, 1,071 mmol) in THF (70 mL)/ether (30 mL) was added by cannula over 15 min. The resulting mixture was stirred for 2 h at -78 *C and then at room temperature for 15 h. At this time, WO 2006/101867 PCT/US2006/009222 26 the mixture was evaporated, 200 mL H 2 0 was added, and the resulting mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic solution was washed with brine and then was dried (Na 2

SO

4 ), filtered, and evaporated. Purificaion by flash chromatography on silica gel (20% ethyl acetate/hexanes) 5 gave 8-2 (13.61 g, 78 mmol, 60%). Benzo[b]thiophen-2-yl-acetaldehyde (9-3). A 0 C mixture of 9-2 (8.019 g, 44.9 mmol) in 100 mL dichloromethane was treated with Dess-Martin reagent (20g, 47.2 mmol). The mixture was stirred at 0 *C for 10 min. and at room temperature for 40 min. Saturated NaHCO 3 solution (200 mL) and 0.1 M 10 NaHSO 3 solution were added and the resulting mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic solution was dried (Na 2 SO4), filtered and evaporated to give 9-3 (8.77 g). The aldehyde was taken on crude for the next reaction. 1-Benzo[b]thiophen-2-yl-but-3-yn-2-oI (9-4). A solution of crude 9-3 (8.77 g) 15 in THF (100 mL) was added to a solution of ethynylmagnesium bromide (450 mL, 225 mmol, 0.5 M/THF) at 0 C by cannula. The mixture was stirred for 1 h at 0 C and for 1 h at room temperature. The reaction was then queched by addition of 200 nL saturated NH 4 Cl solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined 20 organic solution was washed with brine and then was dried (Na 2 SO4), filtered and evaporated. Purification by flash chromatography on silica gel (10% -> 20% ethyl acetate/hexanes) gave 8-4 (7.67 g, 37.9 mmol, 84% from 9-2). (1-Benzo[b]thiophen-2-ylmethyl-prop-2-ynyloxy)-tert-butyl-dimethyl-silane (9-5). DMAP (2.306 g, 18.9 mmol), TBSCl (11.502 g, 76.3 mmol) and 25 triethylamine (5.25 mL, 37.7 mmol) were added to a solution of 9-4 (7.67 g, 37.9 mmol) in dichloromethane (120 mL). After 17 h, 150 mL of saturated

NH

4 Cl solution was added and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 100 mL) and the combined organic solution was dried (Na 2

SO

4 ), filtered and evaporated. Purification by flash 30 chromatography on silica gel (4% ethyl acetate/hexanes) gave 9-5 (8.38 g, 26.5 mmol, 70%).

WO 2006/101867 PCTIUS2006/009222 27 ((E)-1-Benzo[b]thiophen-2-ylmethyl-3-iodo-allyloxy)-tert-butyl-dimethyl silane (9-6). Cp 2 ZrHCI (1.719 g, 6.67 mmol) was added to a solution of 9-5 (1.372 g, 4.34 mmol) in dichloromethane (30 mL). The reaction was stirred for 30 min. at room temperature and N-iodosuccinimide (1.997 g, 8.88 mmol) was 5 added. After 1 h, the reaction was poured into 100 mL of saturated NaHCO 3 solution. The resulting mixture was extracted with dichloromethane (3 x 75 mL) and the combined organic extracts were dried (Na 2

SO

4 ), filtered and evaporated. Purification by flash chromatography on silica gel (2% ethyl acetate/hexanes) gave 9-6 (1.7484 g, 91%). 10 (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (2-hydroxy ethyl)-anide (65)-General procedure for synthesis of secondary and tertiary aides. A solution of acid 55 (7 mg, 0.015 mmol) in DMF (0.5 mL) was treated with N-hydroxysuccinimide (6.9 mg, 0.056 mmol). The mixture 15 was stirred for 5 minutes and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI,20.7 mg, 0.11 mmol) was added. After stirring for 7 h, 2 aminoethanol (5 OL, 0.083 mmol) was added and the mixture stirred further for 16 h. Ethyl acetate (50 mL) was added and the mixture was washed with water (3 x 50 mL) and brine (50 mL). The organic layer was dried (Na 2

SO

4 ), filtered 20 and evaporated. Purification by flash chromatography on silica gel (5% methanol/dichloromethane) followed by preparative thin layer chromatography (10% methanol/dichloromethane) gave amide 65 (5 mg, 0.010 mmol, 65%). Amides 60-63 were prepared in a similar manner. (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4 25 hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid aide (69). A solution of acid 55 (9 mg, 0.02 mmol) in dichloromethane (0.2 mL) was treated with triethylamine (15 OL, 0.11 mmol). The solution was cooled to O 0C and after 10 minutes, ethyl chloroformate (7 OL, 0.073 mmol) was added. The solution was stirred further for 1 h at 0 0C and then concentrated aqueous 30 ammonium hydroxide solution was added (10 OL, 0.26 mmol). The reaction was allowed to stir at room temperature overnight and then was quenched by addition of 0.5 M HCI (7 mL). The mixture was extracted with ethyl acetate (3 x WO 2006/101867 PCT/US2006/009222 28 30 mL) and the combined ethyl acetate solution was washed with saturated NaHCO 3 solution (20 mL) and brine (20 mL) and then was dried (Na 2

SO

4 ), filtered and evaporated. Purification by flash chromatography on silica gel (2% 6% methanol/dichloromethane) gave the title aide (2.6 mg, 28 %). 5 The methods of screening the compounds of this invention for the desired biological activity are illustrated in the following non-limiting examples. Results for example compounds of this invention are included in Table 2. These results are presented purely for illustrative purposes and are not intended to limit the scope of the invention in any way. 10 Radioligand Binding Cells Stably Expressing EP. EP. EP, EP 4 and FP Receptors IEK-293 cells stably expressing the human or feline FP receptor, or EPI, EP 2 , EP 3 , or EP 4 receptors were washed with TME buffer, scraped from the 15 bottom of the flasks, and homogenized for 30 sec using a Brinkman PT 10/35 polytron. TME buffer was added to achieve a final 40 ml volume in the centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mM MgCl2, 2M EDTA; ION HCl is added to achieve a pH of 7.4). The cell homogenate was centrifuged at 19000 r.p.m. for 20 min at 4" C 20 using a Beckman Ti-60 rotor. The resultant pellet was resuspended in TME buffer to give a final 1 mg/ml protein concentration, as determined by Biorad assay. Radioligand binding competition assays vs. [ 3 H-]17 -phenyl PGF 2 a (5 nM) were performed in a 100pl volume for 60 min. Binding reactions were started by adding plasma membrane fraction. The reaction was terminated by 25 the addition of 4 ml ice-cold TRIS-HCI buffer and rapid filtration through glass fiber GF/B filters using a Brandel cell harvester. The filters were washed 3 times with ice-cold buffer and oven dried for one hour. Non-specific binding was determined with 10 uM unlabeled 17 -phenyl PGF 2 a.

[

3 H-] PGE 2 (5 nM; specific activity 180 Ci mmol) was used as the 30 radioligand for EP receptors. Binding studies employing EPI, EP 2 , EP 3

,EP

4 were performed in duplicate in at least three separate experiments. A 200tl assay volume was used. Incubations were for 60 min at 25*C and were WO 2006/101867 PCT/US2006/009222 29 terminated by the addition of 4 ml of ice-cold 50 mM TRIS-HCl, followed by rapid filtration through Whatman GF/B filters and three additional 4 ml washes in a cell harvester (Brandel). Non-specific binding determined with 10~ 5 M of unlabeled PGE 2 ,. 5 METHODS FOR FLIPRTm STUDIES (a) CELL CULTURE HEK-293(EBNA) cells, stably expressing one type or subtype of recombinant human prostaglandin receptors (prostaglandin receptors expressed: hDP/Gqs5; hEPI; hEP2/Gqs5; hEP3A/Gqi5; hEP4/Gqs5; hFP; hIP; hTP), were 10 cultured in 100 mm culture dishes in high-glucose DMvEM medium containing 10% fetal bovine serum, 2 mM l-glutamine, 250 sg/ml geneticin (G418) and 200 pg/ml hygromycin B as selection markers, and 100 units/ml penicillin G, 100 pg/ml streptomycin and 0.25 pg/ml amphotericin B. (b) CALCIUM SIGNAL STUDIES ON THE FLIPRTm 15 Cells were seeded at a density of 5x10 4 cells per well in Biocoat@ Poly D-lysine-coated black-wall, clear-bottom 96-well plates (Becton-Dickinson) and allowed to attach overnight in an incubator at 37 "C. Cells were then washed two times with HBSS-HEPES buffer (Hanks Balanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES, pH 7.4) using a Denley Cellwash 20 plate washer (Labsystems). After 45 minutes of dye-loading in the dark, using the calcium-sensitive dye Fluo-4 AM at a final concentration of 2 pM plates were washed four times with HBSS-HEPES buffer to remove excess dye leaving 100 s1 in each well. Plates were re-equilibrated to 37 *C for a few minutes. 25 Cells were excited with an Argon laser at 488 nm, and emission was measured through a 510-570 nm bandwidth emission filter (FLIPRTM, Molecular Devices, Sunnyvale, CA). Drug solution was added in a 50 01 volume to each well to give the desired final concentration. The peak increase in fluorescence intensity was recorded for each well. On each plate, four wells 30 each served as negative (HBSS-HEPES buffer) and positive controls (standard agonists: BW245C (hDP); PGE 2 (hEP 1 ; hEP 2 /Gqs5; hEP 3 A/Gqi5; hEP 4 /Gqs5);

PGF

20 (hFP); carbacyclin (hIP); U-46619 (hTP), depending on receptor). The WO 2006/101867 PCT/US2006/009222 30 peak fluorescence change in each drug-containing well was then expressed relative to the controls. Compounds were tested in a high-throughput (HTS) or concentration response (CoRe) format. In the HTS format, forty-four compounds per plate 5 were examined in duplicates at a concentration of 10-5 M. To generate concentration-response curves, four compounds per plate were tested in duplicates in a concentration range between 10-5 and 1011 M. The duplicate values were averaged. In either, HTS or CoRe format each compound was tested on at least 3 separate plates using cells from different passages to give an n > 3.

WO 2006/101867 PCT/US2006/009222 31 Table 2 Compound hFP hEP 1 hEP 2 hEP3D hEP4 hDP hIP hTP hEP3A 21 NA NA >10K NA 98 NA NA NA 22 NA NA 300 NA NA NA NA 30 NA NA NA 23 NA >10K 44 NA NA NA NA 0.1 NA NA >10K NA >>1OK 26 NA NA NA NA 0.1 NA NA NA 34 NA >10K NA NA >10K NA NA 35 NA NA 2455 NA NA 36 NA 200 37 NA NA NA 66 >10K NA 38 NA 100 ..-.-. A NA NA 32 >0K NA 38 NA2700 _____ A NA NA 269 ___ NA NA 39 NA 2300 NA NA 141 NA NA 40 NA 200 NA NA NA 0.3 ___ NA >10K 41 NA >10K NA 20 NA >10K 42 NA >10 >10' ____ NA NA NA 559 NA NA NA NA NA 1700 400 43 NA >104 NA 11 63 3981 18 1500 300 5.5 NA 782 944 4.6 0.2 >10 K 284 18 45 NA >10 400 NA 631 NA NA NA 531 51 NA NA NA 46 >10K >10K 4 NA 290 589 0.4 NA NA 47 NA 963 NA >10K 76 NA NA 45 49 NA 1400 50 NA 6607 2400 NA 638 >10K 3162 NA >10K 51 NA 700 NA NA NA 52 NA72 52 NA 27 NA 60 18 NA 53 59 NA 1020 NA 1862 6.4 NA WO 2006/101867 PCT/US2006/009222 32 Compound hFP hEPi hEP 2 hEP3D hEP 4 hDP hIP hTP hEP3A 54 NA 4700 20 NA 308 NA 0.3 NA NA 55 NA >10K 310 NA 758 NA 38 NA NA 60 NA NA NA NA >10K NA NA NA 61 NA NA NA NA NA NA NA NA 62 NA NA NA NA 832 NA NA NA 63 NA >10K NA NA 478 NA NA NA 64 NA NA NA NA 4154 NA NA NA 65 NA NA NA NA NA NA NA NA 68 NA NA NA NA 678 NA NA >NK 69 NA NA NA NA 5000 NA NA >10K 70 NA NA NA >10K 219 NA NA 71 NA NA NA NA 10000 NA NA 72 NA NA NA NA >10K NA NA NA 73 NA NA NA NA NA NA NA NA 74 NA 2376 NA 256 NA NA 75_ 1NA 2050 NA I >10K NA NA >10K The top numbers are the radioligand binding IC50 values(nM) The bottom numbers are the functional EC50 data (nM) While not intending to limit the scope of the invention in any way, the 5 results presented in Table 2 suggest that the compounds described herein are selective EP4 agonists, and will thus be useful for the treatment of inflammatory bowel disease. The compounds disclosed herein are also useful in combination with other drugs useful for the treatment of glaucoma or other conditions. 10 For the treatment of glaucoma, combination treatment with the following classes of drugs are contemplated: p-Blockers (or p-adrenergic antagonists) including carteolol, levobunolol, metiparanolol, timolol hemihydrate, timolol maleate, 01-selective antagonists WO 2006/101867 PCTIUS2006/009222 33 such as betaxolol, and the like, or pharmaceutically acceptable salts or prodrugs thereof; Adrenergic Agonists including non-selective adrenergic agonists such as epinephrine borate, epinephrine 5 hydrochloride, and dipivefrin, and the like, or pharmaceutically acceptable salts or prodrugs thereof; and a2-selective adrenergic agonists such as apraclonidine, brimonidine, and the like, or pharmaceutically acceptable salts or prodrugs thereof; Carbonic Anhydrase Inhibitors including acetazolanide, dichlorphenamide, 10 methazolamide, brinzolamide, dorzolamide, and the like, or pharmaceutically acceptable salts or prodrugs thereof; Cholinergic Agonists including direct acting cholinergic agonists such as carbachol, pilocarpine hydrochloride, pilocarbine nitrate, pilocarpine, and the like, or pharmaceutically acceptable 15 salts or prodrugs thereof; cholinesterase inhibitors such as demecarium, echothiophate, physostigmine, and the like, or pharmaceutically acceptable salts or prodrugs thereof; Glutamate Antagonists and other neuroprotective agents such as Ca 2 ' channel blockers such as memantine, amantadine, rimantadine, nitroglycerin, 20 dextrophan, detromethorphan, CGS-19755, dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil, diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related drugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine, 2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine, barnidipine, verapamil, lidoflazine, prenylamine 25 lactate, amiloride, and the like, or pharmaceutically acceptable salts or prodrugs thereof; Prostamides such as bimatoprost, or pharmaceutically acceptable salts or prodrugs thereof; and Prostaglandins including travoprost, UFO-21, chloprostenol, fluprostenol, 30 13,14-dihydro-chloprostenol, isopropyl unoprostone, latanoprost and the like. Cannabinoids including CB1 agonists such as WIN-55212-2 and CP-55940 and the like, or pharmaceutically acceptable salts or prodrugs thereof.

H:\cdl\Interwoven\NRPortbl\DCC\CDL\5932057_1.doc-14/01/2014 34 For treatment of diseases affecting the eye including glaucoma, these compounds can be administered topically, periocularly, intraocularly, or by any other effective means known in the art. 5 The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode contemplated. However, it is apparent for one of ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the disclosed compounds can also be obtained 10 from different starting compounds via different chemical reactions. Similarly, different pharmaceutical compositions may be prepared and used with substantially the same result. Thus, however detailed the foregoing may appear in text, it should not be construed as limiting the overall scope hereof; rather, the ambit of the present invention is to be governed only by the lawful construction 15 of the appended claims. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group 20 of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an 25 acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (18)

1. A method for the treatment of an inflammatory bowel disease comprising administering a compound having a structure according to Formula III X B X - Y R6 5 HO OH Formula III wherein B is a single, double, or triple covalent bond; n is 0-6; R6is 10 i) hydrogen; ii) a linear or branched hydrocarbon containing between 1 and 8 carbon atoms, which may contain one or more double or triple bonds, or oxygen or halogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogen atoms may be substituted by 0 or a halogen; or 15 iii) aryloxy, heteroaryloxy, C 3 . 8 cycloalkyloxy, C 3 . 8 cycloalkyl, C 6 - 10 aryl or C 3 . 10 heteroaryl, wherein one or more carbons is substituted with N, 0, or S; and which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 6 . 10 aryl, C 3 - 10 heteroaryl, aryloxy, heteroaryloxy, C 1 . 6 alkyl, OR, SR, and SO 2 R; 20 Y is CO 2 R; X is CH 2 , S or 0; and R is H, C 1 - 6 alkyl or C 2 - 6 alkenyl, or any pharmaceutically acceptable salt of CO 2 H to a mammal in need thereof. 25

2. The method of claim 1, wherein R6 is C 6 -1o aryl or C 3 . 1 o heteroaryl, wherein one or more carbons is substituted with N, 0, or S; and which may contain one or more CkNRPortb\DCC\TZM\453906Xl .DOC-16A0/2012 36 substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 1 . 6 alkyl, OR, SR, and SO 2 R.

3. The method of claim 2, wherein R 6 is napthyl, benzofuranyl, or benzothienyl, 5 which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 1 . 6 alkyl, OR, SR, and SO 2 R.

4. The method of any one of claims 1 to 3, wherein Y is CO 2 H or CO 2 Me. 10

5. The method of claim 4, wherein R 6 is 3-chlorobenzothien-2-yl.

6. The method of any one of claims I to 5, wherein n is 2.

7. The method of any one of claims I to 6, wherein B is a single bond. 15

8. The method of claim 1 wherein the compound of Formula III is further represented by Formula IV B Y Re HO OH Formula IV wherein Y is CO 2 R, or any pharmaceutically acceptable salt of CO 2 H; and R 6 is C 6 . 10 aryl 20 or C 3 . 1 0 heteroaryl, wherein one or more carbons is substituted with N, 0, or S; and which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 1 - 6 alkyl, OR, SR, and SO 2 R.

9. The method of claim 8, wherein Y is CO 2 H or CO 2 Me. 25

10. The method of claim 8 or claim 9, wherein R 6 is phenyl. C:NRPonbI\DCC\T7\4519(j6X_ 1.DOC-16/)K/2012 37

11. The method of claim 8 or claim 9, wherein R 6 is napthyl, benzofuranyl, or benzothienyl, which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, CI- 6 alkyl, OR, SR, and 5 SO 2 R.

12. The method of claim 11, wherein R 6 is 3-chlorobenzothien-2-yl.

13. The method of any one of claims 8 to 12, wherein B is a double bond. 10

14. The method of any one of claims 8 to 12, wherein B is a double or triple bond.

15. The method of claim 1, wherein said compound is selected from the group consisting of: (3-{ (1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl)-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-acetic acid methyl ester; (3-{ (1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-I-enyl]-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl }-propylsulfanyl)-acetic acid; (Z)-7- { (1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent 1 -enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl } -hept-5-ynoic acid methyl ester; (Z)-7-{ (1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent 1 -enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl)-hept-5-ynoic acid; (2)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent 1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoic acid methyl ester; (Z)-7-{ (1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent 1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl)-hept-5-enoic acid; 7-[(lR,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2 oxo-cyclopentyl]-hept-5-ynoic acid methyl ester; 7-[(1R,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2 15 oxo-cyclopentyl]-hept-5-ynoic acid; 38 (Z)-7-[( 1R,4S ,5R)-4-IHydroxy-5-((E)-(S)-3-hydroxy-oct-1 -enyl)-3 ,3-dimethyl-2 oxo-cyclopentyl]-hept-5-enoic acid; (Z)-7-[( 1R,4S ,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-lI-enyl)-3 ,3-dimethyl-2 oxo-cyclopentyl]-hept-5-enoic acid methyl ester; (Z)-7-[II(1R,4S ,5R)-4-Hydroxy-5-((E)-3-hydroxy-4-phenyl-but-l1-enyl)-3 ,3 dimethyl-2-oxo-cyclopentyl)-hept-5-enoic acid; (Z)-7-[( 1R,4S ,5R)-4-H}ydroxy-5-((E)-3-hyclroxy-4-phenyl-but-l1-enyl)-3 ,3 dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid methyl ester; (Z)-7-[( 1R,4S ,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent- 1-enyl)-3 ,3 dimethyl-2-oxo-cyclopentylll-hept-5-enoic acid methyl ester; (Z)-7-[(l1R,4S ,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-l1-enyl)-3 ,3 dimethyl-2-oxo-cyclopentyl] -hept-5-enoic acid; (Z)-7-[( 1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yI-3-hydroxy-but-1 -enyl)-4 hydroxy-3 ,3-dimethyl-2-oxo-cyclopentyll-hept-5-enoic acid; 7-[( 1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-l1-enyl)-4 hydroxy-3 ,3-dimethyl-2-oxo-cyclopentyllj-heptanoic acid; (Z)-7-[( 1R,4S,5R)-5-(4-Benzo[b]thiophen-2-yl-3-hydroxy-butyl)-4-hydroxy-3 ,3 dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid; (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo [b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4 hydroxy-3 ,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid ethylamide; (Z)-7-[( 1R,4S,5R)-5-((fl-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1 -enyl)-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid diethylarnide; (Z)-7-[( 1R,4S,5R)-5-((E)-4-Benzolb]thiophen-2-yl-3-hydroxy-but-l1-enyl)-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid (2-hydroxy-ethyl) amide; (3S,4R,5R)-4-((E)-4-Benzolb]thiophen-2-yl-3-hydroxy-but- 1-enyl)-3-hydroxy 2,2-dimethyl-5-[(Z)-6-(1-H-tetrazol-5-yl)-hex-2-enyl]-cyclopentanone; (2)-7-[( 1R,4S,5R)-5-((E)-4-Benzollb]thiophen-2-yl-3-hydroxy-but-1 -enyl)-4 hydroxy-3 ,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid amide; H:\cdl\Interwoven\NRPortbl\DCC\CDL\5932057_1.doc-14/01/2014 39 (Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4 hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoic acid methyl ester, 7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy 3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-ynoic acid methyl ester, and 7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy 3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-ynoic acid.

16. The method of claim 1, wherein said inflammatory bowel disease is ulcerative colitis. 5

17. The method of claim 1, wherein said inflammatory bowel disease is Crohn's disease.

18. Use of a compound having a structure according to Formula III O BX Xy R 6 10 HO OH Formula III wherein B is a single, double, or triple covalent bond; n is 0-6; R 6 is 15 i) hydrogen; ii) a linear or branched hydrocarbon containing between 1 and 8 carbon atoms, which may contain one or more double or triple bonds, or oxygen or halogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogen atoms may be substituted by 0 or a halogen; or 20 iii) aryloxy, heteroaryloxy, C 3 . 8 cycloalkyloxy, C 3 . 8 cycloalkyl, C 6 . 10 aryl or C 3 .. 1o heteroaryl, wherein one or more carbons is substituted with N, 0, or S; and which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 6 . 10 aryl, C 3 . 10 heteroaryl, H:\cdl\Interwoven\NRPortbl\DCC\CDL\5932057_1.doc-14/01/2014 40 aryloxy, heteroaryloxy, C 1 - 6 alkyl, OR, SR, and SO 2 R; Y is CO 2 R; X is CH 2 , S or 0; and R is H, C 1 -6 alkyl or C 2 - 6 alkenyl, 5 or any pharmaceutically acceptable salt of CO 2 H, in the manufacture of a medicament for the treatment of an inflammatory bowel disease in a mammal.