MXPA00009628A - C11 - Google Patents

Abstract

The invention provides novel prostaglandin analogs. In particular, the present invention relates to compounds having a structure according to formula (I) wherein R1, R2, R3, R4, R5, R6, W, X, Z, a, b, p and q are defined below. This invention also includes optical isomers, diastereomers and enantiomers of formula (I), and pharmaceutically-acceptable salts, biohydrolyzable amides, esters, and imides thereof. The compounds of the present invention are useful for the treatment of a variety of diseases and conditions, such as bone disorders and glaucoma. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for bone disorders and glaucoma using these compounds or the compositions containing them.

Description

QXIMILQ PRQSTAGLANDINES OF CNE HIDRQXILAMINQ USEFUL AS PROSTAGLANDIN AGONISTS F TECHNICAL FIELD The invention in question relates to certain novel analogues of the natural prostaglandins. Specifically, the invention in question relates to novel analogs of prostaglandin F. The invention in question, further relates to methods for using said novel analogues of prostaglandin F. Preferred uses include methods for treating bone disorders and glaucoma.

BACKGROUND OF THE INVENTION Natural prostaglandins (PGA, PGB, PGE, PGF, and PGI) are unsaturated fatty acids of C-20. PGF a, natural prostaglandin F in humans, is characterized by hydroxyl groups in the Cg and Cu positions in the alicyclic ring, a cis double bond between C and Ce and a trans double bond between C13 and C. Thus, PGF2a has the following formula: Natural prostaglandin F analogues have been described in the art. For example, see US Patent No. 4,024,179 published for Bindra and Johnson on May 17, 1977, German Patent No. DT-002,460,990 published for Beck, Lerch, Seeger and Teufel in July 1 , 1976, US Patent No. 4,128,720 published for Hayashi, Kop, and Miyake on December 5, 1978, US Patent No. 4,011, 262 published for Hess, Johnson, Bindra, and Schaaf on March 8, 1977, US Patent No. 3,776,938 published for Bergstrom and Sjovall on December 4, 1973, PW Collins and SW Djupc, Synthesis of Therapeutically Useful Prostaglandin and Prostacychn Analogs, Chem Rev Vol 93 (1993), pp 1533-1564, GL Bundy and FH Lincoln, Synthesis of 17-Phenyl- 18,19,20-Tr? Norprostagland? Ns I The Gi Series, Prostaqlandms, Vol 9 No 1 (1975), pp 1-4, W Bartman, G Beck, U Lerch, H Teufel, and B Scholkens, 'Luteolytic Prostaglandins Synthesis and Biological Activity ", Prostaalandins Vol 17 No 2 (1979), pp 301-311, C Liljebns, G Sel in B Resul, J Sternschantz, and U Hacksell, 'Denvatives of 17-phenyl-18,19,20-tr? norprostagland? n F2a Isopropyl Ester Potential Antiglaucoma Agents, Journal of Medicinal Chemistry, Vol 38 No 2 (1995), pp 289-304 It is known that natural prostaglandins have a wide range of pharmacological properties. For example, prostagladins have shown: relax smooth muscle, which results in vasodilation and bronchodilation, inhibit gastric acid secretion, inhibit platelet aggregation, reduce intraocular pressure and induce labor. Although natural prostagladins are characterized by their activity against a particular prostaglandin receptor, they are generally not specific for any prostaglandin receptor. Therefore, it is known that natural prostaglandins cause side effects such as inflammation, as well as superficial irritation when administered systemically. In general, it is believed that the rapid metabolism of natural prostaglandins after their release in the body limits the effects of prostaglandin to a local area. This effectively prevents the prostaglandin from stimulating prostaglandin receptors throughout the body and causing the effects appreciated with the systemic administration of natural prostaglandins. Prostaglandins, especially E-series prostaglandins (PGE), are known to be potent stimulators of bone resorption. PGF2a has also been shown to be a bone resorption stimulator but not as potent as PGE2. In addition, PGF2a has been shown to have a small effect on bone formation as compared to PGF2. It has been suggested that some of the effects of PGF2a on bone resorption, cell formation and replication can be mediated by an increase in the endogenous production of PGE2.

In view of the wide range of pharmacological properties of natural prostaglandins and the side effects appreciated with the systemic administration of these natural prostaglandins, attempts have been made to prepare analogues of natural prostaglandins that are selective for a specific receptor or receptors. A number of such analogs have been described in the art. Although a variety of prostaglandin analogs have been described, there is a continuing need for potent and selective prostaglandin analogues for the treatment of a variety of diseases and conditions.

BRIEF DESCRIPTION OF THE INVENTION The invention provides novel analogs of PGF. In particular, the present invention relates to compounds having a structure according to the following formula: where Ri, R2, R3, R4, R, Re, W, X, Z, a, b, p and q are defined below.

This invention further includes optical isomers, diastereomers and enantiomers of the above formula and pharmaceutically acceptable salts, biohydrolyzable amides, esters and imides thereof. The compounds of the present invention are useful for the treatment of a variety of diseases and conditions, such as disorders. Bones and Glaucoma Accordingly, the invention further provides pharmaceutical compositions comprising these compounds The invention further provides methods of treatment for bone disorders and glaucoma using these compounds or compositions containing them DETAILED DESCRIPTION OF THE INVENTION Terms and definitions "Acyl" is a group suitable for acylating a nitrogen atom to form an amide or carbamate or an oxygen atom to form an ester group. Preferred acyl groups include benzoyl, acetyl, terbutylacetyl, para-phenylbenzoyl and tpfluroacetyl. most preferred acyl include acetyl and benzoyl The most preferred acyl group is acetyl "Alkyl" is a saturated or unsaturated hydrocarbon chain having 1 to 18 carbon atoms, preferably 1 to 12, preferably 1 to 6, greater preference 1 to 4 carbon atoms The alkyl chains they may be straight or branched Preferred branched alkyl have one or two branches, preferably a branching Preferred alkyls are saturated Unsaturated alkyls have one or more double bonds and / or one more triple bonds Preferred unsaturated alkyls have one or two double bonds or a triple bond, preferably a double bond Alkyl chains can be unsubstituted or substituted by 1 to 4 substituents Preferred substituted alkyls are mono, di or tpsubstituted Substituents can be lower alkyl, halogen, hydroxy, aploxy (by example, phenoxy), acyloxy (eg, acetoxy), carboxy, monocyclic aromatic ring (eg, phenyl), monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic fatic ring and "lower alkyl" amino is an alkyl chain consisting of 1 to 6, preferably 1 to 4 carbon atoms "Ring aromatic" is a ring system of aromatic hydrocarbon Aromatic rings are fused monocyclic or bicyclic ring systems Monicic aromatic rings contain from about 10 carbon atoms, preferably from 5 to 7 carbon atoms and preferably from 5 to 6 carbon atoms in the ring The bicyclic aromatic rings contain from 8 to 12 carbon atoms, preferably 9 or 10 carbon atoms in the ring. The aromatic rings can be substituted or unsubstituted with 1 to 4 substituents in the ring. Substituents can be halogen, cyano, alkyl , heteroalkyl, halogenalkyl, phenyl, phenoxy or any combination thereof Preferred substituents include halogen and halogenalkyl Preferred aromatic rings include naphthyl and phenyl The most preferred aromatic ring is phenyl "Bone disorder" means the need for bone repair or replacement The conditions in the that the need for bone repair or replacement may arise include osteoporosis (which includes post-menopausal osteoporosis, senile osteoporosis in men and women and corticosteroid-induced osteoporosis), osteoartptis, Paget's disease, osteomalacia, multiple myeloma and other forms of cancer, rest in prolonged bed, chronic disuse of a limb, anorexia, microgravity, exogenous and endogenous gonadal insufficiency, bone fracture, non-union, defect, implantation of prosthesis and the like "carbocyclic aliphatic ring" is a saturated or unsaturated hydrocarbon ring The aliphatic rings carbocycles are not aromatic icos The carbocyclic aliphatic rings are monocyclic or are bicyclic ring systems fused, spiral or linked Monocyclic carbocyclic ring rings contain from about 4 to about 10 carbon atoms, preferably from 4 to 7 carbon atoms, and preferably from 5 to 6 carbon atoms in the ring The bicyclic carbocyclic aliphatic rings contain 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in the ring Carbonated cyclic rings can be unsubstituted or substituted with 1 to 4 substituents in the ring Substituents may be halogen, cyano, heteroalkyl, haloalkyl, phenyl, phenoxy, or any combination thereof Preferred substituents include halogen and halogenalkyl Preferred carbocyclic fatigue rings include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl Carbocyclic most preferred aliphatic rings include cyclohexyl, cycloheptyl and cyclooctyl "halogen" is fluorine, chlorine, bromine or iodine halogens preferred are fluoro, chloro and bromo, the most preferred are chloro and fluoro, especially fluoro "Haloalkyl" is a straight hydrocarbon, branched or cyclic substituted with one or more halogen substituents the haloalkyls preferred are C? -C? 2 are preferably C1-C6, more preferably are C1-C3 substituents preferred halogens are fluoro and chloro The most preferred halogenoalkyl is trifluoromethyl "Heteroalkyl" is a saturated or unsaturated chain ada containing carbon and at least one heteroatom, wherein neither of the two heteroatoms are adjacent. The heteroalkyl chains contain from 1 to 18 element atoms (carbon and heteroatoms) in the chain, preferably 1 to 12, preferably 1 to 6, most preferably 1 to 4 heteroalkyl chains may be straight or branched preferred branched heteroalkyl have one or two branches, preferably one branch preferred heteroalkyl are saturated unsaturated heteroalkyl have one or more double bonds and / or one or more triple links The heteroalkyl unsaturated preferred have one or two double bonds or one triple bond, preferably a double bond Heteroalkyl chains may be unsubstituted or substituted with 1 to 4 substituents Substituted heteroalkyl preferred are mono-, di-, or tpsustituidos Substituents may be lower alkyl, halogen, hydroxy, aploxy (e.g., phenoxy), acyloxy (e.g., acetoxy), carboxy, monocyclic aromatic ring (e.g., phenyl), monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic and amino heterocyclic aliphatic ring "Heteroaromatic ring" is an aromatic ring system containing carbon and from 1 to about 4 heteroatoms in the ring. The heteroaromatic rings are monocyclic or bicyclic ring systems fused. Monocyclic heteroaromatic rings contain from about 5 to about 10 element atoms ( carbon and heteroatoms), preferably 5 7, and preferably 5 to 6 ring Bicyclic heteroaromatic rings contain from 8 to 12 carbon atoms element, preferably 9 to 10 ring Heteroaromatic rings may be unsubstituted or substituted with 1 to 4 substituents on the ring Substituents can be halogen, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof Preferred substituents include halogen, haloalkyl and phenyl Preferred heteroaromatic rings include thienyl, tlazole, pupnyl, pipmidyl, pindyl, and furanyl The most preferred heteroaromatic rings include thienyl, furanyl and pindyl The most preferred heteroaromatic ring is thienyl "Heteroatom" is a nitrogen, sulfur or oxygen atom Groups containing more than one heteroatom may contain different heteroatoms "Heterocyclic aliphatic ring" is a saturated or unsaturated ring that contains carbon and from 1 to about 4 heteroatoms in the ring, where neither of the two heteroatoms are adjacent to the ring and no carbon in the ring having a heteroatom attached thereto further has a hydroxyl, amino or thiol group attached thereto The heterocyclic aliphatic rings are not aromatic The heterocyclic aliphatic rings are monocyclic, or they are bicyclic ring systems fused or bonded The monocyclic heterocyclic aliphatic rings contain from about 4 to about 10 element atoms (carbon and heteroatom), preferably from 4 to 7 and more preferably from 5 to 6 in the ring The heterocyclic bicyclic aliphatic rings contain from 8 to 12 element atoms, preferably 9 or 10 in the ring. The heterocyclic aliphatic rings can be unsubstituted or substituted with 1 to 4 substituents on the ring. The substituents can be halogen, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halogen and haloalkyl. heterocyclic aliphatics, preferably include pipepzil, morpholimide, tetrahydrofuranyl, tetrahydropyranyl and piperdyl "Phenyl is a monochromatic aromatic ring which may or may not be substituted with 1 to about 4 substituents. Substituents may be fused but not linked and may be substituted in the ortho, meta or para position on the phenyl ring or some combination of the The substituents can be halogen, cyano, alkyl, heteroalkyl, haloalkyl, femlo, phenoxy or any combination thereof. Preferred substituents on the phenyl ring include halogen and halogenoalkyl. The most preferred substituents is halogen. The preferred substitution pattern in the ring Phenyl is ortho or meta The most preferred substitution pattern in the phenyl ring is meta Compounds The present invention involves compounds having the following structure in the antepor structure, R, is C02H, C (0) NHOH, C02R7, CH2OH, S (0) 2R7, C (0) NHR7, C (0) NHS (0) 2R7, or tetrazole wherein R7 is alkyl, heteroalkyl, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring or heteroaromatic ring monocyclic Preferably, R is methyl, ethyl and isopropyl Preferably R? is C02H, C (0) NHOH, C02R7, C (0) NHS (0) 2R7, and tetrazole More preferably, R1 is C02H, and C02R7 In the above structure W is O, NH, S, S (O), S (0) 2 or (CH2) m, where m is an integer from 0 to about 3 Preferably, W is O and (CH2) m Preferably, W is (CH2)! In the above structure R, is H and R3 is H or lower alkyl or R2 and R3 together form a covalent bond In the above structure, R4 is H, heteroalkyl alkyl, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring or monocyclic heteroaromatic ring Preferably, R4 ßs H and lower alkyl Preferably, R4 is H In the above structure, each 5 is independently selected from the group consisting of H, CH3 and C2H5 Preferably, R is H and CH3 Preferably In the above structure, X is NHRβ or ORβ wherein each Re is independently selected from the group consisting of H, acyl, alkyl, heteroalkyl, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic fatic ring, monocyclic aromatic ring and monocyclic heteroaromatic ring Preferably, RB is H Preferably, X is OR8 Preferably X is OH In the above structure each Re is independently selected from the group consisting of H, CH3, C2H5, OR8, NHR8. Preferably R6 is H, CH, C2H5 OR8. Preferably R6 is H and CH. In the above structure, Y is O, NHR8, S, S (O), or S (0) 2, with the proviso that no carbon has more than one heteroatom attached thereto. Preferably, Y is O, NHR8, and S. Preferably Y is O. In the above structure, Z is H, methyl, carbocyclic monocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring or monocyclic heteroaromatic ring, bicyclic carbocyclic aliphatic ring , bicyclic heterocyclic aliphatic ring, bicyclic aromatic ring or bicyclic heteroatom ring, with the proviso that when Y is S, S (O), or S (0) 2 YZ is H, q is at least 1. Preferably Z is ring monocyclic aromatic and monocyclic heteroaromatic ring. Preferably Z is thienyl and phenyl. In the above structure, a and b are independently selected from the group consisting of single bond, double cis bond and double trans bond. Preferably, a is a single bond or double bond cls and preferably, b is single bond or double trans link. In the above structure, p is an integer from 1 to 5, q is an integer from 0 to 5 and p + q is from 1 to 5. The invention also includes optical isomers, diastereomers and enantiomers of the above structure. The preferred sterochemical in all the stereocenters of the compounds of the invention resemble those of natural PGF2a. It has been discovered that novel analogs of PGF of the present invention are useful for treating bone disorders, especially those that require a significant increase in bone mass, bone volume or bone strength. Surprisingly, it has been found that the compounds of the present invention provide the following advantages over known therapies of bone disorders: (1) an increased trabecular number through the formation of new trabeculae; (2) an increase in bone mass and bone volume while maintaining a more normal rate of bone turnover; and / or (3) an increase in bone formation in the endosteal surface without increasing cortical porosity. In order to determine and evaluate the pharmacological activity, the test of the subject compounds in animals is performed using various tests known to those skilled in the art. For example, the bone activity of the compounds in question can be favorably demonstrated using a test designed to analyze the ability of the compounds in question to increase the volume, mass or bone density. An example of such tests is the ovariectom rat test. In the ovariectom rat test, six-month-old rats are ovariectom, and after two months, a subcutaneous dose is applied once a day with a test compound. At the end of the study, the mass and / or bone density can be measured by absorptometry by dual energy X-ray (DXA) or peripheral quantitative computer tomography (pQCT), or computerized microtomography (mCT). Alternatively, static and dynamic histomorphometry can be used to measure the increase in volume or bone formation. The pharmacological activity for glaucoma can be demonstrated using tests designed to analyze the ability of the compounds in question to decrease intraocular pressure. Examples of such tests are described in the following reference, incorporated herein: C. hljebris, G. Selen, B. Resul, J. Stemschantz, and U. Hacksell, "Derivatives of 17-Phenyl-18,19,20 -tpnorprostaglandin F2a Isopropyl Ester: Potential Antiglaucoma Agents, "Journal of Medicinal Chemistry, vol.38 No. 2 (1995), pp. 289-304. The compounds useful in the present invention can be made using conventional organic synthesis. Particularly preferred syntheses are the following two general reaction schemes: SCHEME 1 In Scheme 1, Ri R2 R3 R4 R5 R6, X, Y, p, q, and Z are as defined above, unless otherwise defined, Methyl 7- [3- (R) - heptanoate - H? drox? -5-oxo-1-c? clopent-1-? lo] (S1 a) described as starting material for scheme 1 is commercially available (as for example from Sumitomo Chemical or Cayman Chemical) In the scheme 1 antepor, heptanoate of met? L-7 [3- (R) -h? Drox? -5-oxo-1 -c? Clopent-1-1I0] (S1a) reacts with a base and silylating agent in a solvent that The preferred silylating agents will include terbutyldimethylsilyl chloride and tert-butyldimethylsilyl tpfluoromethanesulfonate. The most preferred agent is terbutyldimethylsilyl trifluoromethanesulfonate. Preferred bases include tetylamine, t-methylamine, and 2,6-lut? d? na Most preferred bases include tet- ylamine and 2,6-lut? d? na The most preferred base is 2,6-lutidine Preferred solvents include halogencarbon solvents with dichloromet The most preferred solvent is the reaction. The reaction is allowed to proceed at a temperature preferably between -100 ° C and 100 ° C, preferably between -80 ° C and 80 ° C, and preferably between -70 ° C and 23 ° C. The resulting Sihlated compound is isolated by methods known to those skilled in the art. Such methods include but are not limited to extraction, solvent evaporation, distillation and crystallization. Preferably, the silyl ether is purified after isolation by vacuum distillation.

The silylated compound is then reacted with the cuprate generated through the Grignard formation of the suitable alkenyl bromide, as described, for example, in the references: H.O. House et al., "The Chemistry of Carbanions: A Convenient Precursor for the Generation of Lithium Organocuprates", J, Orq. Chem. Vol. 40 (1975) pp. 1460-69; and P. Knochel et. al., "Zinc and Copper Carbenoids as Efficient and Selective to '/ d' Multicoupling Reaaents". J. Amer. Chem. Soc. Vol. 111 (1989) p. 6474-76. Preferred alkenyl bromides include 4-bromo-1-butene, 4-bromo-1-butyne, 4-bromo-2-methyl-1-butene, and 4-bromo-2-ethyl-1-butene. The most preferred alkenyl bromide is 4-bromo-1-butene. Preferred solvents include ether solvents of which diethyl ether and tetrahydrofuran are preferred. The most preferred solvent is tetrahydrofuran. The Grignard reagent is allowed to form at a temperature between 100 ° C and 23 ° C, preferably between 85 ° C and 30 ° C and preferably between 75 ° C and 65 ° C. The preferred reaction time is between 1 hour and 6 hours, with a preferred reaction time between 2 hours and 5 hours and the most preferred reaction time being between 3 hours and 4 hours. Once the Grignard reagent is formed, cuprate is generated from alkenylmagnesium species. The temperature scale for cuprate formation is between -100 ° C and 0 ° C. The preferred temperature scale is between -80 ° C and -20 ° C. The most preferred temperature scale is between -75 ° C and -50 ° C. The preferred reaction time is between 30 minutes and 6 hours. The most preferred reaction time is between 45 minutes and 3 hours The most preferred reaction time is between 1 hour and 1 5 hours. The compound described as S1 b is isolated by methods known to the person skilled in the art. Such methods include, but are not limited to extraction, evaporation of solvent, distillation and crystallization Preferably, S1 b is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 10% EtOAc / hexanes as the eluent S1 b is then reacted with a hydride reducing agent and a polar protic solvent to give the alcohol Cg Preferred reducing agents include lithium-aluminum hydride, sodium borohydride and L-selectpdo The most preferred reducing agents include sodium borohydride and L selectpdo The most preferred reducing agent is borohydride. Sodium Preferred solvents include methanol, ethanol and butanol The most preferred solvent is methanol The reduction is carried out at a temperature between -10 0 ° C and 23 ° C The preferred temperature scale is between -60 ° C and 0 ° C The most preferred temperature scale is between -45 ° C and -20 ° C The resulting alcohol of S1 b is isolated by methods known to the person skilled in the art Such methods include, but are not limited to extraction, solvent evaporation, distillation and crystallization. Preferably, the alcohol is purified by flash chromatography on a silica (Merck, 230-400 mesh) using 20% EtOAc / hexanes as the eluent. The alcohol can be protected as described hereinabove. The protected or unprotected alcohol is then treated with meta-chloroperbenzoic acid in a halogencarbon solvent to provide the novel epoxide intermediate described as S1c. Preferred halogenocarbon solvents include dichloromethane, dichloroethane and chloroform. The most preferred halogenocarbon solvents are dichloromethane and dichloroethane. The preferred halogencarbon solvent is dichloromethane. The compound described as S1c is isolated by methods known to the person skilled in the art. Such methods include, but are not limited to extraction, solvent evaporation, distillation and crystallization. Preferably, S1c is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 20% EtOAc / hexanes as the eluent. The intermediate epoxide described as S1c can be reacted with a variety of nucleophiles containing oxygen, sulfur and nitrogen as described for example in J.G. Smith, "Synthetically Useful Reactants of Expoxides", Svnthesis (1984) p. 629-656, to provide the derivatives of 13, 14-dihydro-15-substituted-16-tetranor prostaglandin F1a Cn-protected. With sulfur nucleophiles, the reaction is preferably carried out between 150 ° C and 0 ° C, preferably between 120 ° C and 20 ° C and preferably between 80 ° C and 50 ° C. Preferred bases for the reaction include triethylamine, N, N diisopropylethylamine and trimethylamine. The most preferred base is triethylamine. Preferred solvents for the reaction are aromatic hydrocarbon solvents. Preferred solvents include xylenes, toluene and benzene. The most preferred solvent is benzene. With nitrogen and oxygen nucleophiles, preferred solvents include ether solvents and polar protic solvents. The most preferred ether solvents include diethyl ether, dibutyl ether and tetrahydrofuran. The most preferred ether solvent is tetrahydrofuran. The most preferred polar protic solvents include ethyl alcohol, methyl alcohol and tert-butyl alcohol. The most preferred polar protic solvent is ethyl alcohol. The ring opening process with nitrogen and oxygen nucleophiles can be catalyzed with Lewis acids. Preferred Lewis acids include magnesium perchlorate, trimethylsilyl trifluoromethanesulfonate and trimethylammonium. The most preferred Lewis acid is magnesium perchlorate. The reaction is carried out at a temperature between 150 ° C and 23 ° C, preferably between 125 ° C and 40 °, preferably between 100 ° C and 75 ° C.

The selective protection of C-9 and C-15 can be carried out by methods known to the person skilled in the art. Preferred protecting groups include, but are not limited to, acylating agents, alkylating agent and carbonate forming agents. The most preferred protective group is acetyl. Preferred solvents include halogenhydrocarbon and amine solvents. The most preferred is pyridine. The Preferred reagents include acetyl alkenes and acetic anhydride. The most preferred is acetic anhydride. The temperature scale for the reaction is -100 ° C to 100 ° C. The preferred scale is -10 ° C to 40 ° C. The most preferred scale is -5 ° C to 30 ° C The preferred reaction time is from 1 hour to 48 hours. The preferred time is from 6 hours to 24 hours. The compound described as S1d is isolated by methods known to the person skilled in the art. Such methods include , but are not limited to extraction, solvent evaporation, distillation and crystallization. Preferably, S1d is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 10% EtOAc / hexanes as the eluent. The ether of C- 11 resulting in compound S1d is deprotected using an equivalent of fluoride. The deprotection reagents include tetrabutylammonium fluoride, hydrogen fluoride in pipdin, potassium fluoride and treatment with strong acid. HF / pipdin The temperature scale is -100 ° C to 50 ° C The preferred temperature scale is -50 ° C to 30 ° C The most preferred is -20 ° C to 10 ° C Preferred solvents are THF, Acetonitoplo and Et20 Most preferred is acetonitoplo The compound is isolated by methods known to those skilled in the art. Such methods include, but are not limited to extraction, solvent evaporation, distillation and crystallization. Preferably, the compound is purified by flash chromatography. on silica gel (Merck, 230-400 mesh) using 20% EtOAc / hexanes as the eluent Compound S1e is produced by the oxidation of the C-11 alcohol to the ketone. Oxidation can be carried out by, but not limited to, Swern, Jones, PCC, PDC. PCC is preferred. The most preferred solvent is dichloromethane. The reaction temperature Preferred is -30 ° C to 100 ° C 0 ° C to 50 ° C is preferred The compound S1e is isolated by methods known to the person skilled in the art Such methods include, but are not limited to extraction, solvent evaporation, distillation and crystallization Preferably, the compound is purified by filtration through Floral and solvent evaporation Compound S1f is formed by the reaction of NH2OR4 in solvent-regulated pH solution. The preferred pH regulator is sodium acetate. The preferred solvent ratio is 3 1 1 (methanol dioxane water) The preferred temperature scale is -20 ° C to 100 ° C The compound described as S1f is isolated by methods known to the person skilled in the art. Such methods in cluyen, but not limited to extraction, evaporation of solvent, distillation and crystallization Preferably S1f is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 10% EtOAc / hexanes as the eluent The deprotection of S1f is performed by methods known to the person skilled in the art and produces the compounds of formula I The compounds described by formula I are shown in examples 1-15 The reduction of the oxime of S1f gives the compound S1h as hydroxylamine The reduction is carried out by treatment with cyanoborohydride sodium. The preferred solvent is MeOH. The preferred temperature scale is -100 ° C to 100 ° C. The deprotection of S1 h is carried out by methods known to those skilled in the art and produces compounds of formula II. The compounds described by formula II are shown in examples 29-34.

SCHEME 2 XRI In scheme 2, R-i, R2, R3, R, R5, R6 W, X, Z and P are as defined above, unless defined otherwise. The aldehyde of Corey (S2a) described as starting material for scheme 2 is commercially available (as for example from Aldrich Chemical or Cayman Chemical). In Scheme 2 above, Corey's aldehyde is commercially available with either a silyl group (Pi) or an ester group (Pi) attached to the alcohol. Preferred protecting groups include tert-butyldimethylsilyl, acetate, benzoate and para-phenylbenzoate. The most preferred protecting group is terbutyldimethylsilyl. The Corey aldehyde (S2a) is first reacted with an aldehyde protecting group to make a ketal or acetal. Examples of this type of protection are found in Greene and Wuts, Protectinq Groups in Orqanic Svnthesis, 2d ed., Wiley & Sons, N.Y. 1991. In this case, acetals and cyclic ketals are especially preferred. The aldehyde (S2a) is reacted with the appropriate 1, 2-diol and a suitable acidic catalyst. The solvent may be the diol and an anhydrous solvent, such as ether or dichloromethane. 1, 2-bis-TMS ethylene glycol is particularly useful for effecting this transformation in ether at room temperature. The ketal-protected S2a can then be subjected to protection / deprotection routine if desired, to exchange the Pi group for a more suitable one, using procedures known in the art. Particularly useful is the exchange of a silyl group by an acyl group and vice versa. It is also useful to exchange a silyl or acyl group with an o-bromo-benzyl ether group. The compound (S2b) is then subjected to a reduction of DIBAL to make the hemiacetal. This intermediate is not isolated but is reacted as soon as possible with a vVitting salt to form an alkene (S2c) Particularly preferred Witting salts are derived from straight chain carboxylic acids of 4 to 5 carbons omega bromine and 3- acids oxo-carboxylic These combine favorably with triphenylphosphine in a suitable solvent to form the Witting reactive salts. Other preferred reagents include straight-chain omega-bromine tetrazoles and primary nitriles. The compound (S2c) is not isolated, but is reacted in crude with diazomethane in diethyl ether or preferably with TMS diazomethane in methanol to give S2d. In addition, a suitable protective group can be placed in the Cg alcohol at this time. The compound S2d is isolated by methods known to the person skilled in the art. Such methods include, but are not limited to extraction, solvent evaporation, distillation and crystallization. Preferably, it is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 10% EtOAc / hexanes as the eluent. The compound (S2d) is then optionally reduced to C-5, 6 to give the saturated alpha chain of prostangladine, if desired, or taken without reduction. The cyclic ketal is removed with acid or exchange resin acidic ion in a suitable solvent to give the free aldehyde Preferred solvents include mixtures of THF / water The resulting aldehyde (S2e) is not isolated but is reacted with phosphonium salts stabilized with ketone These salts are generally referred to as "Wadsworth" reagents -Homer-Emmons "This reaction requires a soft base. Suitable base examples include sodium carbonate or tetylamine. The product ketone (S2f) is purified by methods known to the person skilled in the art. Such methods include, but are not limited to extraction. , solvent evaporation, distillation and crystallization Preferably, the ketone (S2f) is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 20% EtOAc / hexanes as the eluent As seen in Scheme 2 above, the ketone (S2f) can be reacted in three ways The reduction of the ketone with a reducing agent such as the Luche reagent, effects an alcohol in C-15 , as illustrated in S2g. At this point, the alcohols of S2g at C-9 and C-15 may be protected, if needed or desired. If so, the alcohols may be protected as described above in the present compound. S2g containing protected or unprotected alcohols is then treated with a deprotection agent to selectively liberate Pt at C-11. Examples of such selective deprotection reactions are presented in Greene and Wuts Alternatively, when Pi is the o-bromobenzyl ether, reduction of the bromine with a radical reducing agent such as (n-Bu) 3SnH will cause the oxidation induced by the C-11 radical for the ketone. no need for protection Compounds of the S2h type can be converted to compounds of formula III and formula IV The compounds described in formula III are shown in examples 16-28 The compounds described in formula IV are shown in examples 35-40 Ketone ( S2f) can also be converted to compounds of the S2I type This occurs by the addition of suitable nucleophile to the ketone (S2f) Examples of nucleophiles include methylmagnesium bromide By using substantially the same techniques as described above, compounds of the S2I type can be converted in compounds of formula V and the compounds of formula V can be converted into compounds of formula VI. The compounds described in formula V are shown in examples 41-43 and the compounds described in formula VI are shown in example 44 Compounds of type S2f can also be reacted to give compounds of the S2m type by reacting the ketone in C -15 with an active amine Examples of reactive amines include methylamine and ethylamine The products can be reduced or reacted with nucleophiles using standard techniques and the reduction can also be extended to reduce the alkenes, if desired, using such a reagent as hydrogen gas on palladium on carbon So Alternatively, sodium cyanoborohydride will selectively reduce the mine without dissolving the alkenes. Finally, a suitable nucleophile, preferably such as an ethyl-reactive reagent, may be added to the mine. The addition of the methylceryl nucleophile (-1.5 equiv.) Is described in T. Imamoto, et al., "Carbon-Carbon Bond Forming Reactions Using Cerium Metal or Organocerium (III) Reagents", J. Orq. Chem. Vol. 49 (1984) p. 3904-12; T. Imamoto, et al., "Reactions of Carbonyl Compounds with Grignard Reagents in the Presence of Cerium Chloride," J. Am. Chem. Soc. Vol. 111 (1989) p. 4392-98; and references cited therein, giving the aminomethyl derivative. In that case, R5 in the compound S1 n would be a methyl group. By using the reactions described above for compounds of the S2h type, the compounds of formula VII can be made from S2n. The compounds described in formula VII are shown in example 45. Thus, compounds of formula VIII can be made from compounds of formula VII. The compounds described in formula VII are shown in example 46. The compounds of formula IX can be made from sulfonation or hydroxylation of compounds of formula III. The compounds described in formula IX are shown in examples 47-48. These compounds are isolated by methods known to the person skilled in the art. Such methods include, but are not limited to extraction, solvent evaporation, distillation and crystallization.

The following non-limiting examples illustrate the compounds, compositions and uses of the present invention.

EXAMPLES The compounds are analyzed using 1 H and 13 C NMR, elemental analysis, mass spectra, high resolution mass spectra and / or IR spectra as necessary. Normally, inert solvents are preferably used in dry form. For example, tetrahydrofuran (THF) is distilled from sodium and benzophenone, diisopropylamine is distilled from calcium hydride and all other solvents are purchased in the proper degree. Chromatography is performed on silica gel (70-230 mesh, Aldrich) or (230-400 mesh, Merck) as necessary. A thin layer chromatography analysis is performed on glass gel silica gel plates (200-300 mesh, JT Baker) and visualized using uv light, 5% phosphomolybdic acid in EtOH, or ammonium molybdate / cerium sulfate in 10% aqueous H2S0.

EXAMPLE 1 Preparation of 11-oximethyl-13,14-dihydro-16-phenyltio-16-tetranor PGDIadi) * - "-» a.- Heptanoate of methyl-7- (2-oxo-4- (1,1, 2,2-tetramethyl-1-silapropoxy) cyclopent-1-enyl) (1a): To a solution of heptanoate of methyl-7- [ 3- (R) -hydroxy-5-oxo-1-cyclopenten-1-yl] (1 equiv.) In CH 2 Cl 2 at -70 ° C is added dropwise 2.6 lutidine (1.3 equiv.) For 15 minutes. The solution is maintained at -78 ° C and TBDMS Triflate (1.2 equiv.) In CH2Cl2 is added dropwise over 15 minutes. The reaction is gradually warmed to room temperature and stirred at room temperature for 15 hours. 10% aqueous HCL is added and the layers separated. The water layer is extracted with CH2Cl2 and the organic layers are combined. The organic layer is washed with brine, dried (Na2SO) and concentrated. The residue is distilled under vacuum (10 mm Hg) to provide the silyl ether 1 a as a yellow liquid. b.- Methyl-7- (5-but-3-enyl-2-hydroxy-4- (1,1,1,2-tetramethyl-1-silapropoxy) cyclopentyl heptane) (1 c): To a suspension of Mg ° powder (2 equiv.) In THF at room temperature is added dropwise a crystal of l2 and 1-bromobutene (2 equiv.) For 10 minutes. The reaction proceeds to produce an exotherm as the addition continues. After the addition is complete, the reaction is refluxed for 3 hours and cooled to room temperature. The Grignard is diluted with THF and added through a probe to a 3-neck flask equipped with mechanical agitation and loaded with CuBr.DMS (2 equiv.) In a 1: 1 solution of THF / DMS at -78 ° C. .

After the addition of the Grignard (-20 min), the reaction is stirred for 1 hour at -78 ° C. the color of the reaction is dark red at this point. Then a solution of the ketone 1a (1 equiv.) In THF is added dropwise over 25 minutes. The reaction is stirred at -78 ° C for 15 minutes, then allowed to warm slowly to room temperature for 2 hours. The reaction is quenched with aqueous NH CI and the excess DMS is allowed to evaporate overnight. The reaction is partitioned between brine / CH2Cl2 and the layers are separated. The aqueous layer is extracted again with CH 2 Cl 2 and the organic layers are combined and dried (Na 2 SO 4). The solvent is removed in vacuo and the residue is chromatographed on Si02 (10% hexane / EtOAc) to give the ketone 1b as a clear oil. Ketone 1b (1 equiv.) Is dissolved in MeOH and cooled to -40 ° C. Sodium borohydride (0.9 equiv.) Is added in portions for 10 minutes. After the addition is complete, the reaction is stirred for 13 hours at -40 ° C and then for 12 hours at -78 ° C. The reaction is quenched with water, divided between brine and CH2Cl2 and the layers separated. The aqueous layer is extracted again with CH 2 Cl 2 and the organic layers are combined and dried (Na 2 SO). The solvent is removed in vacuo and the residue is chromatographed on Si02 (30% EtOAc / hexanes) to give the alcohol 1c as a colorless oil. c - Metho-7- (2- (2-ox aranyl) heptanoate et? -1-4- (1.1, 2,2-tetramet? l-1 -s? lapropox?) c? clopent? lo) (1d) Alcohol 1c (1 equiv) is dissolved in CH2CI2 and cooled to -0 ° C Sodium bicarbonate is added in portions, followed by m-CPBA (57% -85% purity) (3 equiv) during 15 minutes After the addition is complete, the reaction is stirred for 20 hours at room temperature The reaction is poured into water, divided between brine and CH2Cl2 and the layers are separated The aqueous layer is extracted again with CH2Cl2 and the organic layers combine and dry (Na2SO4). The solvent is removed in vacuo and the residue is subjected to chromatography on S02 (20% EtOAc / hexanes) to give the diastereomers epoxides 1d as a colorless oil. d-13,14-d? h? dro-16-phen? lt? tetranor PGF? "(1e) In a 5 ml round base flask, 1d epoxide (1 equiv.) and 100 .mu.l dry benzene are added. The flask is cooled to 0 ° C, then treated with 60 μl of thiophenol (1.2 eq) and 78 μl of tetylamine (1.2 eq) as described in JG Smith, "Synthetically Useful Reactants of Epoxides", Svnthesis (1984). p 629-656, and references cited therein The ice bath is removed and the reaction is stirred at room temperature under nitrogen overnight. TLC is used to monitor the reaction. Thiophenol is added in excess if necessary. The reaction is quenched with Brine and extract with methylene chloride. The organic layer is washed three times with IN HCl, brine, dried over sodium sulfate and concentrated to produce 1e. and. Methyl 9.15-acetyl 3,14-dihydro-16-phenylthio tetranor PGF? "(1q): Diol 1e (1 equiv.) And acetic anhydride (2 ml) in pyridine (10 ml) are stirred in a 25 ml round bottom flask. mi) during the night. The reaction is concentrated under reduced pressure. The residue is dissolved in dichloromethane (40 ml) and washed twice with 1 N HCl. The organic layer is dried with MgSO 4 and the solvent is removed in vacuo leaving the crude (1f). Crude 1f is treated with HF / pyridine (6 equiv.) In dry acetonitrile (10 ml). The mixture is stirred at 0 ° C for 2 hours and concentrated under reduced pressure. The crude material is subjected to flash chromatography on a column of silica gel using 30% ethyl acetate in hexane. The appropriate fractions are mixed and concentrated giving (1g) as a colorless oil.

F. Methyl 9.15-acetyl 13.14-dihydro-16-phenylthio tetranor PGF? "(1 h): In a 50 ml round bottom flask, 1 g alcohol (1 equiv.) Is added to dichloromethane (20 ml) with 10 grams of molecular sieves. powdered. Then PCC (3 equiv.) Is added and the solution is stirred overnight. The mixture is filtered through Floracil and concentrated to a yellow oil (1 h). g Methyl 9,15-acet? l 11-ox? m? l-13,14-d? h? dro-16-phen? lt? o tetranor Into a 25 ml round base flask is added ketone 1 h (1 equiv), sodium acetate (9 equiv) and hydroxylamine (2 equiv), in 3 1 1 (MeOH dioxane water) (5 ml) The solution is stirred overnight and ether (50 mL) is added. The organic layer is then washed with 1 N HCl and brine. The organic layer is dried with MgSO 4 and concentrated under reduced pressure. The crude matepal is subjected to flash chromatography on silica gel using 30% ethyl acetate in hexane. The appropriate fractions were collected and concentrated to a yellow liquid (1?) h-11-ox? m? l-13.14-d? h? dro-16-phen? lt? o-16-tetranor PGF? "(1?) In a 15 ml round base flask is added 1? (1 equiv) and LiOH (3 equiv) in 3 1 (THF water) The mixture is stirred overnight and concentrated under reduced pressure. The residue is subjected to flash chromatography on a column of silica gel in 5% MeOH dichloromethane with 0 1% acetic acid The appropriate fractions were combined and concentrated to give a colorless oil (1j) EXAMPLES 2-15 Examples 2-15 are prepared using substantially the same procedures as those described in example 1, substituting the suitable starting materials. The person skilled in the art can change temperature, pressure, atmosphere, solvents or the order of reactions as necessary. In addition, one skilled in the art can use protecting groups to block side reactions or increase yields as needed. The person skilled in the art of organic chemistry can easily perform all modifications and thus is within the scope of the invention.

EXAMPLE 2 11-Oximyl-13.1-dihydro-16- (2,4-difluorophenolyl) -16- tetranor-PGDi methyl ester EXAMPLE 3 11-oximil-13,14-dihydro-16- (2,4-difluorophenoxy) -16-tetranor-PGD? EXAMPLE 4 11-Oximil-13.14-dihydro-16-aza-17-'2.4-fluorophenyl) -17-trinor-PGDi methyl ester EXAMPLE 5 Ethyl ester of 11-oximethyl-13,14-dihydro-16- (4-fluorophenylthio) -16-tetranor- EXAMPLE 6 11-oximl-13.14-dihydro-16- (4-fluorophenoxy-16-tetranor-PGD? EXAMPLE 7 11-Oximyl-13.14-dihydro-16- (3-chlorophenoxy) -16-tetranor-PGD? EXAMPLE 8-Oximyl-13,14-dihydro-16-methyl-16- (3-chlorophenoxy) -16-tetranor-PGD? EXAMPLE 9 11-Oximyl-13.14-dihydro-16- (2-methoxy-phenylthio) -16-tetranor-PGD? EXAMPLE 10 11-Oximyl-13,14-dihydro-16- (3-methoxyphenylthio) -16-tetranor-PGDi isopropyl ester EXAMPLE 11 11-Oximyl-13.14-dihydro-16- (thiomethyl- (2-thienyl)) - methyl ester tetranor-PGDi EXAMPLE 12 11-Oxymethyl-13.14-dihydro-16 - ((3-trifluoromethyl) phenoxy) -1 methyl ester (tetranor PGDi) EXAMPLE 13 11-Oximyl-13,14-dihydro-16- (2-methylphenoxy) -16-tetranor qlyceryl ester EXAMPLE 14 11-Oximyl-13,14-dihydro-16- (3-methyl) phenylthioH6-tetranor PGDi EXAMPLE 15 11-Oximyl-13,14-dihydro-16-phenylthio-16-tetranor methyl ester PGDi EXAMPLE 16 Preparation of 11-oximyl-16- (2-fluorophenoxy) -16-tetranor-PGD2? T (1 n): to. 7-benzoyloxy-6- (2,5-dioxolanyl) -2-oxabicyclo3.3.01octan-3-one I16b] In a round-bottomed flask equipped with a magnetic stirring bar, 1, 2-&is placed. 's (trimethylsilyloxy) ethane in methylene chloride at -78 ° C. To this is added, in the next 20 minutes, a solution of 16a in CH2Cl2. The reaction is stirred for 1 hour at -78 ° C and then slowly warmed to 25 ° C for 1 hour. The reaction is quenched at 0 ° C with water, extracted with methylene chloride, dried over MgSO, and concentrated in vacuo to give crude 16b (FW = 318.32 g / mol). b. 6- (2,5-dioxolanyl) -7-hydroxy-2-oxabicyclo3.3.01octan-3-one (16c) To a well-stirred solution of crude 16b (63.85 g, 201 mmoles, 1 eq) in methanol (786 mL) at 0 ° C is added a suspension of sodium methoxide (13.27 g, 246 mmol, 1.2 eq) in MeOH (98.3 mL). The reaction is stirred at 0 ° C for 1 hour then heated at 25 ° C for 1 hour. The reaction is neutralized with acid ion exchange resin that has been thoroughly washed with MeOH (5 x 100 mL). The filtrate is concentrated in vacuo to give a syrup which is subjected to flash chromatography on silica gel eluting with 4: 1 hexane: ethyl acetate and 2% MeOH in CH 2 Cl 2 to give 16c as a yellow syrup. c 6- (2,5-d? oxolan?) -2-oxa-7-p-bromobenzyl?) bicyclo 1 * 3 3 01 octan-3-one (16d) In a round bottom flask with a magnetic stirring bar, a solution of 16c in CH2Cl2 is stirred. A suspension of NaH is added dropwise to this solution at -78 ° C. The reaction is stirred for 30 minutes at -78 ° C and then ortho-bromide is added. bromine benzyl and the reaction is heated at 25 ° C overnight The reaction is quenched with water (100 mL) The organic layer is washed with water (3 x 100 mL), dried over MgSO4 and concentrated in vacuo to give a yellow oil which is subjected to flash chromatography on silica gel eluting with hexanes then 1% MeOH in CH 2 Cl 2. The product is then washed with 1 N HCl, 0 1 N HCl, water and brine to give 16d d Hept-5-enoate of met? l-7- (5- (2,5-d? oxolan? l) -2-h? drox? -4- (o-bromobenzyloxy) cyclopentyl (16f) In a round bottom flask with a magnetic stirring bar, a solution of 16d in dry toluene is stirred. This solution, at -78 ° C, is slowly added DIBAL in hexane. The reaction mixture is stirred for 2 hours and then heated to 0 ° C. Diluted with water (100 mL), the more soluble precipitate is removed by suction filtration and the solid is washed with EtOAc (2 x 25 mL). The liquid phase is extracted with EtOAc (3 x 50 mL) and the combined organic phase is dried over MgSO4. and it is concentrated in vacuo to give a yellow syrup. The product, 16e, must be immediately or store at -70 ° C overnight. To a suspension of (4-carboxybutyl) tpfen? lphosphon? in THF at 0 ° C under nitrogen a solution of KHMDS in toluene is added dropwise. The resulting dark orange reaction mixture is stirred for 1 hour at 25 ° C. The above reaction mixture at -78 ° C is added a solution of 16e in THF. The reaction mixture is allowed to warm to 25 ° C overnight The reaction is quenched with water at 0 ° C and the pH is adjusted to 3.5-4.0 with 1 N HCl The water phase is extracted with EtOAc and the combined organic phase is dried over MgSO4 and concentrated m vacuo to give a syrup containing crude acid To a well stirred solution of acid in and MeOH at 0 ° C add TMS diazomethane until the reaction mixture maintains a light yellow color The addition of a drop of acetic acid, glacial and thin-layer chromatography verify that the reaction has been completed The reaction solution is concentrated in vacuum and purify by flash chromatography on silica gel eluting with 30% EtOAc in hexanes yielding 16f e Hept-5-enoate of met-l-7- (2-h? drox? -4- (o-bromobenz? lox?) - 5-formyl-cyclopentyl (16q) In a round bottom flask with a bar Magnetic stirring is placed a quantity of the ketal, 16f To this flask is added a sufficient quantity of a mixture of two parts of acetone to one part of 1 N HCl to bring the ketal completely into the solution This material is stirred until, by TLC, the initial matepal is consumed, typically overnight The crude mixture, which contains the product 16g, is extracted with ether, and the ether extract is reestepfica in situ, preferably, TMS-diazomethane The extracts were concentrated under reduced pressure at 0 ° C and used immediately without further purification f d-Mether-3- (2-fluorophenoxy?) - 2-oxo-butyl (16?) phosphonate In a flame-dried round bottom flask equipped with a stir bar and thermometer, phosphonate is placed of dimethylmethyl (1.0 equiv.) in anhydrous THF The solution is cooled to -78 ° C and treated with p-butyl-thio (1 05 equiv). The reaction mixture is allowed to stir for 15 minutes. To this solution is added propionate. methanol-2- (2-fluorophenoxy?) (11 equiv) in anhydrous THF The mixture is allowed to warm to room temperature over the next 6 hours. The mixture is treated with a saturated solution of ammonium chloride and extracted with CH 2 Cl 2. The organic layer is washed with water followed by brine. The combined aqueous layers are extracted again with CH 2 Cl 2 and the combined organic layers are dried over anhydrous MgSO 4, filtered, and concentrated under reduced pressure. The purification is carried out by column chromatography. of silica gel (hexane / ethyl acetate / 2-propanol 45/50/5 to hexane / acetate of et? lo / 2-propanol 40/50/10) to produce 1 34 g (70%) of d? met? l-4- (2-fluorophen? l) -2-oxo-butyl phosphonate ( 16j) as an oil q 11-O-bromobenzyl loxyl ester -16- (2-fluorofenox?) - 17- tpnor-15-oxo-PGF? a (16k) In a round-bottomed, flame-dried flask equipped with a bar of magnetic stirring is placed phosphonate of d? met? l-4- (2-5 fluorofen? l) -2-oxo-but? lo (16j) (1 43 equiv) in DME and water To this solution is added bromide of lithium (1 65 equiv), tetylamine (1 65 equiv), and (16g) (1 0 equiv) The solution is stirred at room temperature for 48 hours. At this point additional tetylamine and water are added and the solution is stirred for 1 additional hour The solution is poured into brine and extracted with 3 portions of ethyl acetate The organic layers are combined, dried over anhydrous MgSO 4, filtered, and concentrated under reduced pressure. Purification is carried out by silica gel column chromatography (dichloromethane / methanol 19/1) give the methyl ester of 11-o-bromobenz? lox? -17- (2-fluorophen? l) -17-tr? nor-15-oxo-PGF2a (1 k) as an oil h 11-o-bromobenzyl? -x- methyl ester (R, S) -16- (2-fluorofenox?) - 17-tpnor-PGF? A (161) In a round-bottomed flask, flame-dried equipped with a stirring bar is placed 17- (2-fluorophenyl) -17-tpnor-20 15-oxo-PGF2a (16k) methyl ester (10 equiv), centenic chloride (1 05 equiv) in methanol The solution is stirred at room temperature for 5 minutes The solution is cooled to -10 ° C and sodium borohydride (1.02 equiv) in methanol is added The solution is stirred at -10 ° C for 3 hours The mixture is treated with water and the pH is brought to 6-7 with 1N hydrochloric acid. The mixture is extracted twice with ethyl acetate, and the organic layers are combined, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The purification is carried out. by silica gel column chromatography (3% methanol in dichloromethane to 5% methanol in dichloromethane) start to give the epimer 15 (R) and the epimer 15 (S) as colorless oils i Methyl ester of 9.15-? > s-tert-but? ld? met? ls? l? lox? -13,14-d? h? dro-16- (2-fluorofenox?) - 17-tpnor-PGD2 (16m) In a round bottom flask equipped with a magnetic stirring bar, a solution of 161 (1 equiv) in CH 2 Cl 2 is stirred. To this solution is added dropwise at -78 ° C 2,6-lut? d? na (2 9 equiv) followed by TBDMSOTf (2 8 equiv) The reaction is stirred for 30 minutes at -78 ° C and then warmed to 25 ° C overnight The reaction is quenched with water The organic layer is washed with water, dried over MgSO 4, and Concentrate in vacuo to give a yellow oil which is subjected to flash chromatography on silica gel eluting with hexanes then 1% MeOH in CH 2 Cl 2 Then the product is washed with 1 N HCl, 0 1 N HCl, water, and brine to give the protected intermediate. This intermediate is placed in a flame-dried round bottom flask equipped with a stir bar. Tp-p-butyltin hydride is added to the flask. ether and the reaction is stirred for 24 hours. It is quenched with 1 N HCl and then the organic products 2 are washed again with brine. It is dried over MgSO4 and the Organic is concentrated under reduced pressure and is chromatographed to produce the PGD 16m analogue. i. 11-oximyl-13,14-dihydro-16- (2-fluorophenoxy) -17-trinor-PGD; Í16n) A round bottom flask equipped with a stir bar is cooled to 0 ° C and the methyl ester (16m) and a solution of HF in pyridine are added. The solution is allowed to warm to room temperature and followed by TLC. When the starting materials are consumed, the solution is concentrated and divided between ethyl acetate and 0.1% aqueous sodium carbonate. The organic extracts are combined and chromatographed and the crude product is stirred overnight with hydroxylamine and sodium acetate (1: 9) in 1: 1: 3 p-dioxane: water: methanol. The mixture is concentrated under reduced pressure and lithium hydroxide monohydrate (1.8 equiv) is added in a 50/50 THF / water solution. The mixture is stirred at room temperature for 6 hours and then diluted with water and acidified to pH 2-3 with 1 N HCl. The aqueous phase is extracted 3 times with ethyl acetate and the organic layers are combined. The combined organic layers were dried over anhydrous MgSO 4, filtered and concentrated under reduced pressure to yield the crude acid. The purification is carried out by means of HPLC to produce an analytical sample of 16n.

EXAMPLES 17-28 Examples 17-28 are prepared using substantially the same procedures as those described in Example 16, substituting the appropriate starting materials. The person skilled in the art can change the temperature, pressure, atmosphere, solvents or the order of the reactions as appropriate. Additionally, one skilled in the art can use protecting groups to block side reactions or increase performances as appropriate. Such modifications can easily be made by the person skilled in the art of organic chemistry, and are therefore within the scope of the invention.

EXAMPLE 17 11-Oximyl-16- (2,4-difluorophenylthio) -17-trinor-PGD methyl ester • * - * * • - • * - ~ EXAMPLE 18 11-Oximyl-16-aza- (3,5-difluorophenyl) -17-trinor-PGD2 EXAMPLE 19 11-Oximyl-16- (2-fluorophenylthio) -17-trinor-PGD methyl ester EXAMPLE 20 Methyl ester of 11-oximyl-16- (4-fluorophenoxy) -16-tetranor-PGD? EXAMPLE 21 11-oximid-16- (4-fluorophenylthio) -16-tetranor-PGD: > EXAMPLE 22 11-Oximyl-16- (2-methoxyphenoxy) -16-tetranor PGD? EXAMPLE 23 11-Oximyl-16- (3-methoxyphenoxy) -16-tetranor PGD isopropyl ester - '- -' --- EXAMPLE 24 11-Oximyl-17-oxo- (2-methyl-tiepil) -18-dinor methyl ester PGD? EXAMPLE 25 11-Oximyl-16 - ((3-trifluoromethyl) phenoxy) -16-tetranor PGD methyl ester EXAMPLE 26 11-Oximyl-16- (2-methylphenoxy) -16-tetranor PGD methyl ester -Hbti ^ -lii ».

EXAMPLE 27 -oximil-16- (3-methyl-phenoxy) -16-tetra by PGD2 EXAMPLE 28 11-Oximyl-16-phenoxy-16-tetranor PGD? EXAMPLE 29 Preparation of 11-oximyl-13,14-dihydro-16-phenylthio-16-tetranor PGD? " Compound 1 i of Example 1 is treated with sodium cyanoborohydride in THF: acetic acid (1: 1) and allowed to react for 2 hours. The mixture is quenched with 1 N HCl and washed with brine twice. The organic layer is dried over magnesium sulfate and reduced under pressure. The resulting oil is chromatographed using 30% ethyl acetate: hexane. The appropriate fractions were combined and reduced to a yellow oil, yielding 29a. Deprotection is carried out by methods described above, yielding 29b.

EXAMPLES 30-34 Examples 30-34 are prepared using substantially the same procedures as those described in Example 29, substituting the appropriate starting materials. The person skilled in the art can change the temperature, pressure, atmosphere, solvents or the order of the reactions as appropriate. Additionally, one skilled in the art can use protecting groups to block side reactions or increase performances as appropriate. Such modifications can easily be made by the person skilled in the art of organic chemistry, and are therefore within the scope of the invention.

EXAMPLE 30 11-hydroxylamino-13.14-dihydro-16- (3-chlorophenoxy) -16-tetranor-PGD? EXAMPLE 31 11-Hydroxylamino-13.14-dihydro-16- (2,4-difluorophenylthio) -16-tetranor PGD methyl ester.

EXAMPLE 32 11-Hydroxylamino-13.14-dihydro-16-aminophenyl-16-tetranor-PGDi methyl ester EXAMPLE 33 Ethyl ester of 11-hydroxylamino-13.14-dihydro-16- (4-fluorophenitol) -16- tetranor PGDi EXAMPLE 34 11-hydroxylamino-13,14-dihydro-16- (4-flurofenoxi) -16-tetranor PGD? EXAMPLE 35 11-Hydroxylamine-16-phenoxy-16-tetranor-1-tetrazole PGD? 35a 35b 11-Ox? M-16-phenoxy? -16-tetranor-1-tetrazole? PGD2 is prepared using substantially the same procedures as those described in example 16, substituting the tetrazoylphosphonium salt for the carboxylate and phenyl o-fluorophenone To this compound (35a) is added 1 5 equiv of sodium cyanoborohydride in a mixture of 1 1 acetic acid and tetrahydrofuran The reaction is monitored by TLC After the initial matepal has been consumed completely, the reaction is diluted with water and exhaustively extracted with EtOAc, yielding hydroxylamine EXAMPLES 36-40 Examples 36-40 are prepared using substantially the same procedures as described in Example 35, substituting the appropriate starting materials. The person skilled in the art can change the temperature, pressure, atmosphere, solvents or the order of the reactions as be appropriate Aditionally, one skilled in the art can use protecting groups to block side reactions or increase performances as appropriate. Such modifications can easily be carried out by the person skilled in the art of organic chemistry, and are therefore within the scope of the invention.

EXAMPLE 36 11-Hydroxylamine-16-phenylthio-16-tetranor-PGD2a EXAMPLE 37 11-Hydroxylamino-20-ethoxy-PGD? A Bía? D - ou! -l-¿l- (l! Ue-n! L-e) -9l-oiJ! IU1, |! Xa | P! H-U ee opdi iara 01 B £ a? D JOUBjjat-g 1, -ixouajo.? On wp-g 'j-g? .- ou ?; uiB |?; xo} a | / \ | - .. ee oidi? iara V9 EXAMPLE 40 11-Hydroxylamino-16 - ((3-trifluoromethyl) phenoxy) -17-trinor methyl ester.

EXAMPLE 41 Methyl ester of 11-oximyl-15-methyl-16-2-fluorophenoxy-17-trinor-PGD? Compound 16k of example 16 is dissolved in dry THF and 1 2 equiv of TBDMSOTf and 1 equiv of 2,6 lutidine are added. The standard treatment produces the TBDMS protected version of 16k, which is dissolved in THF The addition of the nucleophile of metilcepo (~ 1 5 equi) (for examples of nucleophilic addition mediated by chloride of ceno see T Imamoto, et al, "Carbon-Carbon Bond Forming Reacrtions Using Cerium Metal or Orgapocepum (III) Reagents', J Orq Chem Vol 49 ( 1984) p 3904-12, Imamoto T, et al, "Reactions of Carbopyl Compounds with Gpgnard Reagents in the Presence of Cerium Chlopde," J Am Chem Soc Vol 111 (1989) p 4392-1098, and references referenced in the same) gives the product S41c, which after the purification is dissolved in liquid ammonia and a sufficient amount of lithium metal is added to carry out the deprotection of the benzyl ether. After purification, the deprotected S41c is condensed with hydroxylamine. as described in the Example 1 and deprotected to produce the title compound, S41d EXAMPLES 42-43 Examples 42-43 are prepared using substantially the The same procedures as those which are deciphered in Example 41, substituting the appropriate starting materials. The person skilled in the art can change the temperature, pressure, atmosphere, solvents or the order of the reactions as appropriate.

You can use protective groups to block side reactions or increase yields as appropriate. Such modifications can easily be carried out by the person skilled in the art of organic chemistry, and therefore are within the scope of the invention.

EXAMPLE 42 11-Quximyl-15-ethyl-17-phenoxy-18-dinor-PGD? EXAMPLE 43 3- xo-1-oximyl-13,14-d-hydroxy-15-methyl-16-phenoxy-16-tetranor-PGD? P EXAMPLE 44 3-Qxo-l 1 -hydroxylammon-13,14-dihydro-15-methyl-16-phenoxy-16-tetranor-PGD ?.

To a 50 mL round bottom flask is added 3-oxo-11-oximyl-13,14-dihydro-15-methyl-16-phenoxy-17-trinor-PGD2 (Example 43) and 1.5 equiv. of sodium cyanoborohydride in a 1: 1 mixture of acetic acid and tetrahydrofuran. The reaction is monitored by TLC. After the starting material has been completely consumed, the reaction is diluted with water, the pH is adjusted to 3.0, and exhaustively extracted with EtOAc, yielding the PGF analog containing the hydroxylamine of the title.

EXAMPLE 45 Methyl ester of 11-oximethyl-15-methyl-15-deoxy-15-metamino-16-2-fluorophenoxy-16-tetranor-PGD? Compound 16k of Example 16 is dissolved in dry THF and 1 2 equiv of TBDMSTf and 1 equiv of 2.6 lutidine are added. The standard treatment produces the 16K TBDMS protected version, which is dissolved in THF and condensed with methylamine to produce the intermediate imine The addition of the nucleophile of methylcepo (-1 5 equiv) (for examples of nucleophilic addition mediated by chloride of ceno see T Imamoto, et al, "Carbon-Carbon Bond Fopning Reacrtions Using Cerium Metal or Organocepum (lll ) Reagents ", J Orq Chem Vol 49 (1984) p 3904-12, T Imamoto, et al," Reactions of Carbonyl Compounds with Gpgnard Reagents in the Presence of Cerium Chlopde ", J Am Chem Soc Vol 111 (1989) p 4392 -98, and references mentioned therein) gives the product S45b, which after the purification is dissolved in THF and a sufficient amount of tp-n-butyltin hydride is added to carry out the oxidative removal of the benzyl ether. purification, S45c is condensed with hydroxylamine as deciphered in example 16 and deprotected to yield the title compound, S45d EXAMPLE 46 11-Hydroxylamino-15-methyl-15-deoxy-15-methylamino-16-2-fluorophenoxy-16-tetranor-PGF? OH OH To a 50 mL round bottom flask is charged methyl ester of 11-ox? M? L-15-met? L-15-deox? -15-metam? No-16-o-fluorofenox? -17-tpnor- PGD2 (example 45) and 1 5 equiv of sodium cyanoborohydride in a mixture of 1 1 acetic acid and tetrahydrofuran. The reaction is monitored by TLC. After the starting material has been completely consumed, the reaction is diluted with water and Extract exhaustively with EtOAc, yielding the PGF analog containing the hydroxylamine of the title EXAMPLE 47 Preparation of the acid 11-oximyl-13,14-dihydro-16 - ((3-trifluoromethyl) phenoxy) -16-tetranor-PDG? 1-hydroxamic In a flame-dried, 25 mL round-bottom flask equipped with a magnetic stir bar, 1-O-methyl-IS.M-dihydro-i-S-tpfluoromethyl-phenoxy-1-tpnor-PGD methyl ester is placed ( example 12) (10 equiv) in methanol To this solution is added hydroxylamine in methanol (1 25 equiv) The solution is stirred for 18 hours then the solution is treated with 1 N hydrochloric acid and extracted three times with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride, dried over gS? 4, filter and concentrate under reduced pressure. The residue is purified by chromatography to give 11-ox? M? L-13,14-d? -hydroxy-20- ((3-tpfluoromet? L) phenoxy acid? ) -16-tetranor-PGD? 1-h? Droxam? Co "" * - "-" * - • •• EXAMPLE 48 Example 48 is prepared using substantially the same procedures as described in Example 47, substituting the appropriate starting materials. The person skilled in the art can change the temperature, pressure, atmosphere, solvents or the order of the reactions as appropriate. Additionally, one skilled in the art can use protecting groups to block side reactions or increase yields as appropriate. Such modifications can easily be made by the person skilled in the art of organic chemistry, and are therefore within the scope of the invention.

EXAMPLE 48 11-Quximyl-16-phenoxy-17-trinor-PGD? 1-N-methanesulfonamide Compositions The compositions of the present invention comprise a safe and effective amount of the compounds herein, and a pharmaceutically acceptable carrier. As used herein, "safe and effective amount" means an amount of a compound sufficient to induce significantly a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit / risk ratio), within the scope of sound medical judgment A safe and effective amount of a compound will go with the condition in particular that is being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of the concurrent therapy, the particular pharmaceutically acceptable vehicle used, and similar factors within the knowledge and experience of the attending physician In addition to the compound, the ions of the present invention contain a pharmaceutically acceptable carrier The term "pharmaceutically acceptable carrier", as used herein, means one or more solid or liquid compatible filler diluents or encapsulating substances that are suitable for administration to a subject. The term " "compatible", as used herein, means that the components of the composition are capable of mixing with the compound, and with each other, in a manner such that there is no interaction that would substantially reduce the pharmaceutical efficacy of the composition under of ordinary use The pharmaceutically acceptable carriers should, of course, be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the subject being treated. Some examples of substances which can serve as pharmaceutically acceptable carriers or components thereof are sugars , such as lactose, glucose and sucrose, starches, such as corn starch and potato, cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragacanth, malt, gelatin, talc, solid lubricants, such as stearic acid, magnesium stearate, calcium sulfate, vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, oil of corn and theobroma oil, polyols such as propylene glycol, ghupna, sorbitol, mannitol, and po ethileng col, alginic acid; emulsifiers, such as Tweens®, wetting agents such as sodium lauplsulfate, coloring agents, sabotagers, excipients, tabletting agents, stabilizers, antioxidants, preservatives, pyrogen-free water, isotonic saline, and pH regulator solutions of Phosphate The choice of a pharmaceutically acceptable carrier to be used in conjunction with a compound is basically determined by the manner in which the compound is to be administered. The compounds of the present invention can be administered systemically. The routes of administration include transdermal, oral, parenteral, including subcutaneous or intravenous, topical, and / or intranasal injection The appropriate amount of the compound to be used can be determined by routine experimentation with animal models. Such models include, but are not limited to, models of rat intact ovapectomized, the ferret, canine, and non-human primate models as well as disused models Preferred unit dosage forms for injection include sterile water solutions, physiological saline, or mixtures thereof The pH of said solutions it should be adjusted to approximately 74 Suitable carriers for injection or surgical implants include hydrogels, controlled or sustained release devices, polylactic acid, and collagen matrices. Pharmaceutically acceptable carriers suitable for topical application include those suitable for use in lotions., creams, gels and the like. If the compound is to be administered in peroral form, the preferred unit dosage form is tablets, capsules and the like. Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Their selection will depend on secondary considerations such as flavor, cost, and stability on the shelf, which are not decisive for the purposes of the present invention, and those skilled in the art can do so without difficulty Methods of use The compounds of the present invention are useful for treating many medical disorders, including for example, eye disorders, hypertension, fertility control, nasal congestion, neurogenic bladder disorder, gastrointestinal disorders, dermatological disorders, and osteoporosis. present invention are useful for increasing (1) bone volume and trabecular number by forming new trabeculae, (2) bone mass while maintaining a normalized bone turnover rate, and / or (3) endosteum surface formation without Remove the bone from the existing cortex. Accordingly, these compounds are useful in the treatment and prevention of bone disorders. The preferred routes of administration for treating bone disorders are transdermal and intranasal. Other preferred routes of administration include rectal, sublingual, and oral. dose of the compound for systemic administration is from about 0.01 to about 1000 μg / kg of body weight, preferably from about 0-1 to about 100 μg / kg per body weight, most preferably from about 1 to about 50 μg / kg of body weight per day. Transdermal doses will be designed to achieve similar serum or plasma levels, based on techniques known to those skilled in the art of pharmacokinetics and transdermal formulations. Plasma levels are expected to systematic administration are on the scale of O 01 to 100 nanograms / ml, preferably from 005 to 50 ng / ml, and most preferably from 0 1 to 10 ng / ml Although these doses are based on a target administration rate, cumulative doses can be used weekly or monthly to calculate clinical requirements. Doses can be varied based on the patient being treated, the condition being treated, the severity of the condition being treated, the route of administration, etc., to obtain the desired effect The compounds of the present composition are also useful for decreasing infraocular pressure. Therefore, these compounds are useful in the treatment of glaucoma. The preferred administration route for treating glaucoma is topical.

EXAMPLES OF COMPOSITIONS AND METHODS The following non-limiting examples illustrate the present invention The following examples of compositions and methods do not limit the invention, but provide guidance to one skilled in the art to prepare and use the compounds, compositions and methods of the invention. case other compounds within the invention can be substituted for the example compound shown below with similar results. The skilled physician will understand that the examples provide guidance and can be varied based on the condition being treated and the patient EXAMPLE A Pharmaceutical compositions are prepared in the form of tablets by conventional methods, such as mixing and direct compaction, formulated as follows: Ingredient Amount (mq per tablet) Compound of example 1 5 Microcrystalline cellulose 100 Sodium starch glycolate 30 Magnesium stearate 3 When orally administered once a day, the above composition substantially increases bone volume in a patient suffering from osteoporosis.

EXAMPLE B Pharmaceutical compositions are prepared in liquid form by conventional methods, formulated as shown below: Ingredient Quantity Compound of Example 32 1 mg Physiological saline pH regulated 10 ml with phosphate Methylparaben 0.05 ml When 1.0 ml of the above composition is administered subcutaneously once a day, the above composition substantially increases bone volume in a patient suffering from osteoporosis.

EXAMPLE C Topical pharmaceutical compositions for reducing ocular pressure are prepared by conventional methods and formulated as follows: Ingredient Quantity (% by weight) Compound of example 1 0.004 Dextran 70 0.1 Hydroxypropylmethylceulose 0.3 Sodium chloride 0.77 Potassium chloride 0.12 Disodium EDTA (Edetato of disodium) 0.05 Benzalkonium chloride 0.01 HCL and / or NaOH pH 7.2-7.5 Purified water qs to 100% Although the particular embodiments of the present invention have been described, it will be obvious to those skilled in the art that various changes and modifications can be made to the compositions described herein without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, such modifications that are within the scope of this invention.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the structure: characterized in that (a) Ri is C02H, C (0) NHOH, C02R7, CH2OH, S (0) 2R7, C (0) NHR7, C (0) NHS (0) 2R7, or tetrazole; characterized by R is alkyl, heteroalkyl, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; (b) W is O, NH, S, S (O), S (0) 2, or (CH2) m, characterized in that m is an integer from 0 to about 3; (c) R2 is H and R3 is H or lower alkyl, or R2 and R3 together form a covalent bond; (d) R 4 is H, alkyl, heteroalkyl, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; (e) each R5 is independently selected from the group consisting of H, CH3, and C2H5; (f) X is NHR8 or ORß, characterized in that each Re is independently selected from the group consisting of

H, acyl, alkyl, heteroalkyl, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring, and monocyclic heteroaromatic ring; (g) each R6 is independently selected from the group consisting of H, CH3, C2H5, OR8, and NHR8; (h) Y is O, NHR8, S, S (O), or S (0) 2, provided that no carbon has more than one heteroatom attached to it; (i) Z is H, methyl, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring, monocyclic heteroaromatic ring, bicyclic carbocyclic aliphatic ring, heterocyclic and bicyclic aliphatic ring, bicyclic aromatic ring, or bicyclic heteroaromatic ring, provided that when Y is S, S (O), or S (0) 2 and Z is H, q is at least 1; (j) a and b are independently selected from the group consisting of single bond, double cis bond, and double trans bond; (k) p is an integer from 1 to 5, q is an integer from 0 to 5, and p + q is 1 to 5; and any optical isomer, diastereomer, enantiomer, of the above structure or a pharmaceutically acceptable salt, or biohydrolyzable amide, ester, or imide thereof. 2. The compound according to claim 1, further characterized in that Ri is C02H, C (0) NHOH, C02R, C (0) NHS (0) 2R7, or tetrazole.

3. The compound according to claim 1 or 2, further characterized in that R and R5 are each H and X is OH.

4. The compound according to any of the preceding claims, further characterized in that p + q is 1 or 2 and Z is monocyclic aromatic ring or monocyclic heteroaromatic ring.

5. The compound according to claim 1, 2 or 3, further characterized in that p + q is 3 to 5 and Z is H or methyl.

6. The compound according to any of the preceding claims, further characterized in that W is (CH2) ?.

7. The compound according to any of the preceding claims, further characterized in that a is a double bond cis and b is a trans double bond.

8. The use of a compound according to any of the preceding claims in the manufacture of a medicament for treating a bone disorder in a human or other mammal.

9. The use of claim 8, further characterized in that said bone disorder is osteoporosis.

10. The use of a compound according to any of the preceding claims in the manufacture of a medicament for treating glaucoma in a human or other mammal.