JPH10506096A - Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders - Google Patents

Abstract

  (57) [Summary] Tetrahydrofuran, tetrahydrothiophene, pyrrolidine and cyclopentane have been disclosed that reduce chemotaxis and respiratory bursts during inflammatory or immune reactions leading to the formation of noxious oxygen radicals in polymorphonuclear leucocytes. These compounds act by acting as PAF receptor antagonists, by inhibiting the enzyme 5-lipoxygenase, or by exhibiting dual activity, i.e., acting as both PAF receptor antagonists and 5-lipoxygenase inhibitors This demonstrates this biological activity. It has been determined that 5-lipoxygenase activity, oral availability, and in vivo stability (eg, glucuronidation rates) can vary widely between the optical isomers of the disclosed compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION   Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders                             Field of the invention   The present invention relates to 2,5-disubstituted tetrahydrothiophene, tetrahydrofuran, Gin and 1,3-disubstituted cyclopentanes. These compounds Inhibits 5-lipoxygenase, an enzyme that acts as a PAF receptor antagonist Or by exhibiting dual activity, i.e., PAF receptor antagonist By acting as both an antidrug and an inhibitor of 5-lipoxygenase, It shows biological activity.                             Background of the Invention   Leukotrienes are inflammatory and inflammatory, including arthritis, asthma, psoriasis and thrombosis. A potent local mediator that plays a major role in allergic reactions You. Leukotriene is produced by the oxidation of arachidonic acid by lipoxygenase. It is a linear eicosanoid produced. Arachidonic acid is produced by 5-lipoxygenase. 5-hydroperoxy-eicosatetrae, which is oxidized to hydroperoxide Acid (5-HPETE), which is leukotriene B_Four, C_FourOr D_FourCan be converted to Leukotriene A_FourIs converted to Currently all potent bronchoconstrictors Leukotrien C_Four, D_FourAnd E_FourIs a slow-reacting substance of anaphylaxis It is known that there is. Specific receptor antagonist or leukotriene synthesis Research efforts to develop growth inhibitors have reduced the pathogenic inflammatory response mediated by these compounds. It has been done to prevent or minimize.   European Patent Application Nos. 90117171.0 and 90170171.0 are indole, benzofura And benzothiophene lipoxygenase inhibiting compounds are disclosed.   In recent years, trans-2,5-bis- (a tetrahydrothiphene derivative of L-652,731) 3,4,5-trimethoxyphenyl) tetrahydrothiophene (L-653, 150) is effective Is a PAF antagonist and a mild inhibitor of 5-lipoxygenase. Was. Certain 2,5-diaryltetrahydrothiophenes are PAF antagonists and leuco It has been disclosed that it is a triene synthesis inhibitor. Biftu et al. Abstr. of 6th Int. Conf. on Prostaglandins and Related Compounds, June 3 -6, 1986, Florence, Italy; Biftu U.S. Patent No. 4,757,084); WO 92/15294; WO 94/01430; WO 94/04537; and WO 94/06790.   WO 92/13848 discloses certain racemic lipoxygenase-inhibiting hydroxamic acids and And structure: (Where R¹Is hydrogen, alkyl, alkenyl, amino or substituted amino, R^FourIs water Element, pharmaceutically acceptable cation, aroyl or alcoyl, A is alkylene Or alkenylene, X is oxygen or sulfur, each Y is hydrogen, halo, cyano, hydride Roxy, alkyl, alkoxy, alkylthio, alkenyl, alkoxyalkyl , Cycloalkyl, aryl, aryloxy, arylalkyl, aryla Alkenyl, arylalkoxy or substituted aryl, Z is oxygen or sulfur, m Represents 0 or 1, n represents 1 to 5, and p represents 2 to 6. ) N-Hydroxyurea derivatives having the motif, which inhibit the enzyme lipoxygenase Is disclosed.   Very high pathogenic immune and inflammatory responses mediated by 5-lipoxygenase Given this, it is necessary to identify new compounds and compositions that inhibit this enzyme. The need remains.   Platelet activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycerol-3-phos Is a potent inflammatory phospholipid with a wide variety of biological activities Vector. PAF was first converted to immunoglobulin E (IgE) -sensitized rabbit basophils. It was confirmed to be a water-soluble compound which was released more. PAF is a suitable immunological and Monocytes, macrophages, polymorphonuclear leukocytes (PMNs), eosinophils Spheres, neutrophils, natural bactericidal lymphocytes, platelets and endothelial cells, and kidney and And is also produced and released by heart tissue Have been. Hwang's "Specific receptor for platelet activating factor, receptor disparity Specific receptors of platelet-activating factor , Receptor heterogeneity, and signal transduction mechanism) ”, Journal of Lipid Mediators, Vol. 2, 123 (1990)). PAF is a very low concentration of platelets Causes agglomeration and devulcanization. PAF efficacy (10^-12~Ten^-9Active in M), Tissue levels (picomoles) and short plasma half-life (2-4 minutes) were determined by thromboxane A_Two Of other lipid mediators such as, prostaglandins and leukotrienes Similar to them.   PAF is a specific PAF receptor found in a wide variety of cells and tissues Mediates biological reactions by binding to About PAF and its analogs Studies of the structure activity of PAFs show that the ability of PAF to bind to these receptors is structure-specific. It indicates that it is stereospecific. Shen et al., `` The Chemical and Biological P roperties of PAF Agonists, Antagonists, and Biosynthetic Inhibitors ", Pl atelet-Activating Factor and Related Lipid Mediators, F. Synder, Plenum Press, New York, New York, 153 (1987)).   PAF mediates essential biological responses, but may cause pathogenic immune and inflammatory responses Seems to play a role. Many published studies have found that arthritis, acute inflammation, Asthma, endotoxin shock, pain, psoriasis, ophthalmitis, ischemia, gastrointestinal ulceration, myocardial infarction, inflammation PAF is involved in human illnesses, including inflammatory bowel disease and acute respiratory distress syndrome Provide evidence of that. Animal models have also been developed for PAFs in certain pathogenic conditions. Or increased.   Involvement of PAF in pathogenic inflammatory and immune states is a PAF receptor antagonist Stimulating substantial research efforts to confirm. In 1983, CV-3988 (rac-3- (N-n- Kutadecyl-carbamoyloxy-ω-methoxypropyl-2-thiazolioethylphosph Phospholipid analogs called PAEs) have PAF receptor antagonist properties Reported Terashita et al., Life Sciences, 32, 1975 (1983)). This field In another early study of Shen et al. (Proc. Natl. Acad. Sci. (U.S.A.), 82 Vol. 672 (1985)) Non (kadsurenone), i.e., Piper futokadsura Sieb et Zu cc) A neolignan derivative isolated from a Chinese herb at the receptor level Have been reported to be potent, specific and competitive inhibitors of PAF activity.   Hwang et al. Reported that the binding of tritium-containing PAF to the PAF receptor site was trans-2,5- Bis- (3,4,5-trimethoxyphenyl) tetrahydrofuran (L-652, 731) inhibits (1985) (Hwang et al., Trans-2,5-bis- (3,4,5-trimethoxy). Cyphenyl) tetrahydrofuran ", Journal of Bioloical Chemistry, 260 15639 (1985)). L-652, 731 is oral activity, administered at 30 mg / kg body weight The amount was found to inhibit PAF-induced rat skin vascular permeability. This compound It was found that the enzyme 5-lipoxygenase had no effect. Hwang et al. 652, 731 (Aryl groups at positions 2 and 5 are opposite to the plane of the tetrahydrofuran ring. Cis-L-652,731 (where the aryl substituent at positions 2 and 5 is tet) On the same side of the plane of the lahydrofuran ring). Was.   In 1988, Hwang et al. Reported that L-659, 989 (trans-2- (3-methoxy-4-propoxy). Phenyl-5-methylsulfonyl) -5- (3,4,5-trimethoxyphenyl) tetrahi Is an orally active, potent and competitive PAF receptor antagonist. Lance-L-652, reported to have an equilibrium inhibition constant 10 times greater than 731 (Hwang J. et al. Pharmacol. Ther., 246, 534 (1988)).   U.S. Pat. Nos. 4,996,203, 5,001,123 and 4,539,332 to Biftsu et al. The description and European patent applications Nos. 89202593.3, 90306235.4 and 90306234.7 Certain classes of 2,5-diaryltetrahydrofurans are PAF receptor antagonists It is disclosed that.   Blowles et al., Synlett, 1993, page 111, describe the limitations that can have PAF receptor antagonism. A number of substituted tetrahydrofurans are disclosed.   Chem. Danyoshi et al. Pharm. Bull., 1989, p. 1969 shows that PAF-induced rabbit blood A 2-substituted-N-alkoxycarbonylpyrrolidine that suppresses plate aggregation has been disclosed .   Therefore, the object of the present invention is to reduce the harmful oxygen radicals during inflammatory or immune reactions. To reduce chemotaxis and respiratory burst that lead to formation of To provide a compound. Another object of the present invention is to provide 5-lipoxygenase Pharmaceutical combinations for the treatment of pathogenic immune or inflammatory diseases mediated by products It is to provide a product.   Another object of the invention is a disease mediated by the product of 5-lipoxygenase. It is an object of the present invention to provide a method for the treatment of an immunogenic or inflammatory disease.   Yet another object of the present invention is to provide a pathogenic immunity or Is to provide a pharmaceutical composition for the treatment of inflammatory diseases.   Another object of the present invention is to provide a pathogenic immunity or inflammation mediated by PAF. It is to provide a method for the treatment of sexually transmitted diseases.                             Summary of the Invention   There is provided a compound of formula (I): (Where:   Ar is preferably halo (including but not limited to fluoro), lower alkoxy ( Methoxy), lower aryloxy (including phenoxy), W, cyano or Is R<sup>Three</sup>An aryl or heteroaryl group optionally substituted by;   m is 0 or 1;   q is 0 or 1;   n is 0 to 6;   W is independently -AN (OM) C (O) N (R<sup>Three</sup>) R<sup>Four</sup>, -N (OM) C (O) N (R<sup>Three</sup>) R<sup>Four</sup>, -AN (R<sup>Three</sup>) C (O) N (OM) R<sup>Four</sup>, -N (R<sup>Three</sup>) C (O) N (OM) R<sup>Four</sup>, -AN (OM) C (O) R<sup>Four</sup>, -N (OM) C (O) R<sup>Four</sup>-, AC (O) N (OM) R<sup>Four</sup>, -C (O) N (OM) R<sup>Four</sup>, -C (O) NHA or -A-B;   A represents lower alkyl, lower alkenyl, lower alkynyl, alkylaryl, Or an arylalkyl group, wherein one or more carbons are O, N or S (valency is required Complete with hydrogen or oxygen, as the case may be). -, -A- or -AW- are two adjacent heteroatoms (ie, -O-O-, -S-S-, -O-S- , Etc.) (In one embodiment, lower alkyl is-(CH<sub>Two</sub>)<sub>n</sub>C (low Secondary alkyl) H- (where n is 1 to 5), particularly-(CH<sub>Two</sub>)<sub>Two</sub>C (CH<sub>Three</sub>Branched alky such as)- Group, or -C≡C-CH (CH<sub>Three</sub>)-Containing the formula -C≡C-CH (lower alkyl)- Grade alkynyl. );   B is selected from the group consisting of pyridylimidazole and benzimidazole Each of them is R<sub>Three</sub>Optionally substituted with pyridyl imidazole or Is benzimidazole preferably attached to A via a nitrogen atom;   M is hydrogen, a pharmaceutically acceptable cation or a metabolically cleavable leaving group;   X is O, S, S (O), S (O)<sub>Two</sub>, NR<sup>Three</sup>Or CHR<sup>Five</sup>;   Y is O, S, S (O), S (O)<sub>Two</sub>, NR<sup>Three</sup>Or CHR<sup>Five</sup>;   Z is O, S, S (O), S (O)<sub>Two</sub>, NR<sup>Three</sup>;   R<sup>1</sup>And R<sup>Two</sup>Is independently hydrogen; methyl, cyclopropylmethyl, ethyl, iso Propyl, butyl, pentyl, hexyl and C<sub>3-8</sub>Cycloalkyl (eg Lower alkyls, including halo-lower alkyls, such as trifluoromethyl Halo, such as fluoro; and -COOH;   R<sup>Three</sup>And R<sup>Four</sup>Is independently hydrogen or alkyl, alkenyl, alkynyl, , Arylalkyl, alkylaryl, C<sub>1-6</sub>Alkoxy-C<sub>1-10</sub>Alkyl, C<sub>1-6</sub>Alkylthio-C<sub>1-10</sub>Alkyl, heteroaryl or heteroarylalkyl Le;   R<sup>Five</sup>Is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl Kill, alkylaryl, -AN (OM) C (O) N (R<sup>Three</sup>) R<sup>Four</sup>, -AN (R<sup>Three</sup>) C (O) N (OM) R<sup>Four</sup>, -AN (OM) C (O) R<sup>Four</sup>, AC (O) N (OM) R<sup>Four</sup>, -AS (O)<sub>x</sub>R<sup>Three</sup>, -AS (O)<sub>n</sub>CH<sub>Two</sub>C (O) R<sup>Three</sup>, -AS (O)<sub>n</sub> CH<sub>Two</sub>CH (OH) R<sup>Three</sup>Or -AC (O) NHR<sub>Three</sub>Where x represents 0 to 2. ).   In one embodiment, the Ar group is phenyl, trimethoxyphenyl, dimethoxy Phenyl, fluorophenyl (especially 4-fluorophenyl), difluorophenyl , Pyridyl, dimethoxypyridyl, quinolinyl, furyl, imidazolyl and thi Selected from the group consisting of enyl groups.   In one embodiment, -A-B is Wherein Ar is an optionally substituted aryl or heteroaryl group And further details are described in section IA below.   Non-limiting examples of preferred compounds are: (Where R<sup>Ten</sup>Is halogen, -CN, hydrogen, lower alkyl, lower alkenyl, lower It is ruquinyl, lower alkoxy or lower aryloxy. ) It is.   These compounds usually produce polymorphonuclear leuco, which is harmful during inflammatory or immune reactions. Chemotaxis and respiratory retriever leading to the formation of oxygen radicals on site Lower the cost. These compounds act as PAF receptor antagonists By inhibiting 5-lipoxygenase to be used or exhibit dual activity That is, both PAF receptor antagonists and 5-lipoxygenase inhibitors This biological activity is exhibited by acting as   Another embodiment of the present invention is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof. Combines an effective amount of the resulting salt or derivative with a pharmaceutically acceptable carrier Or a pharmaceutical composition for any of the diseases described herein.   In a preferred embodiment, said compound or a pharmaceutically acceptable salt thereof or If one or more effective amounts of the derivative are required, a pharmaceutically acceptable carrier Treats diseases mediated by 5-lipoxygenase by administering These compounds are used to perform   Surprisingly, the activity of the compound, for example, 5-lipoxygenase activity, oral use Of compounds disclosed for their solubility and in vivo stability (eg glucuronidation rate) It was determined that it could vary greatly between isomers. Therefore, in one embodiment of the present invention, In this case, the compounds are administered enantiomerically enriched.   Immune, allergic cardiovascular diseases, normal inflammation, heart blood including high blood pressure Duct disease, skeletal muscle disease, osteoarthritis, gout, asthma, pulmonary edema, adult respiratory distress syndrome , Pain, platelet aggregation, shock, rheumatoid arthritis, juvenile rheumatoid joints Inflammation, psoriatic arthritis, psoriasis, autoimmune uveitis, allergic encephalomyelitis, whole body Lupus erythematosus, acute necrotizing hemorrhagic encephalopathy, idiopathic thrombocytopenia, polychondritis, chronic Active hepatitis, idiopathic sprue, Crohn's disease, Graves' eye disorder, primary biliary Cirrhosis, posterior uveitis, interstitial pulmonary fibrosis; allergic asthma; atopic skin Including poison ivy, pollen, insect stings and certain foods, including flame and contact dermatitis Inappropriate allergic response to environmental stimuli such as   The compounds disclosed herein include leukotrienes or PAFs as appropriate. It can also be used as a research tool for studying biological pathways including.   The following are non-limiting examples of compounds defined by formula (I). These examples Are merely examples and are not intended to limit the scope of the invention.   Trans-2- (3,4,5-trimethoxyphenoxymethyl) -5- [4-N'-methyl-N ' -Hydroxyureidyl) butyl] tetrahydrofuran,   Trans-2- (3,4,5-trimethoxyphenoxymethyl) -5- [4-N'-methyl-N ' -Hydroxyureidyl) but-1-ynyl] tetrahydrofuran,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-methyl-N'-hydroxy Siureidyl) butyl] tetrahydrofuran,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-methyl-N'-hydroxy Siureidyl) but-1-ynyl] tetrahydrofuran,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-butyl-N'-hydroxy Siureidyl) butyl] tetrahydrofuran,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-butyl-N'-hydroxy Siureidyl) but-1-ynyl] tetrahydrofuran,   Trans-2- (3,4,5-trimethoxyphenoxymethyl) -5- [4-N'-methyl-N -Hydroxyureidyl) butyl] tetrahydrofuran,   Trans-2- (3,4,5-trimethoxyphenoxymethyl) -5- [4-N'-methyl-N -Hydroxyureidyl) but-1-ynyl] tetrahydrofuran,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-methyl-N-hydroxy Siureidyl) butyl] tetrahydrofuran,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-methyl-N-hydroxy Siureidyl) but-1-ynyl] tetrahydrofuran,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-butyl-N-hydroxy Siureidyl) butyl] tetrahydrofuran,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-butyl-N-hydroxy Siureidyl) but-1-ynyl] tetrahydrofuran,   Trans-2- (3,4,5-trimethoxyphenoxymethyl) -5- [4-N'-methyl-N ' -Hydroxyureidyl) butyl] tetrahydrothiophene,   Trans-2- (3,4,5-trimethoxyphenoxymethyl) -5- [4-N'-methyl-N ' -Hydroxyureidyl) but-1-ynyl] tetrahydrothiophene,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-methyl-N'-hydroxy Siureidyl) butyl] tetrahydrothiophene,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-methyl-N'-hydr Roxyureidyl) but-1-ynyl] tetrahydrothiophene,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-butyl-N'-hydroxy Siureidyl) butyl] tetrahydrothiophene,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-butyl-N'-hydroxy Siureidyl) but-1-ynyl] tetrahydrothiophene,   Trans-2- (3,4,5-trimethoxyphenoxymethyl) -5- [4-N'-methyl-N -Hydroxyureidyl) butyl] tetrahydrothiophene,   Trans-2- (3,4,5-trimethoxyphenoxymethyl) -5- [4-N'-methyl-N -Hydroxyureidyl) but-1-ynyl] tetrahydrothiophene,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-methyl-N-hydroxy Ureidyl) butyl] tetrahydrothiophene,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-methyl-N-hydroxy Ureil) but-1-ynyl] tetrahydrofuran,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-butyl-N-hydroxy Ureidyl) butyl] tetrahydrothiophene,   Trans-2- (4-fluorophenoxymethyl) -5- [4-N'-butyl-N-hydroxy Ureidyl) but-1-ynyl] tetrahydrothiophene,   2- (3,4,5-trimethoxyphenyl) -5- [3- (N'-methyl-N'-hydroxyuree Idyl) propoxy] tetrahydrofuran,   2- (4-fluorophenyl) -5- [3- (N'-methyl-N'-hydroxyureidyl) p Loxy] tetrahydrofuran,   2- (3,4,5-trimethoxyphenyl) -5- [3- (N'-n-butyl-N'-hydroxy Ureil) propoxy] tetrahydrofuran,   2- (4-fluorophenyl) -5- [3- (N'-n-butyl-N'-hydroxyureidyl) Propoxy] tetrahydrofuran,   2- (3 ', 4'-dimethoxyphenyl) -5- [3- (N-butyl-N-hydroxyurei Jill)] propoxytetrahydrofuran,   2- (3 ', 4'-dimethoxyphenyl) -5- [3- (N-methyl-N-hydroxyurei Jill)] propoxytetrahydrofuran,   2- (2,4,5-trimethoxyphenyl) -5- (3-hydroxyureidylpropoxy C) tetrahydrofuran,   2- (4-fluorophenyl) -5- (3-hydroxyureidylpropoxy) tetra Hydrofuran, 2- (4-fluorophenyl) -5- [3- (N'-methyl-N'-hydroxy Reilyl) propoxy] tetrahydrothiophene, and   2- (4-fluorophenyl) -5- (3-hydroxyureidylpropoxy) tetra Hydrothiophene.   Further non-limiting examples of other compounds defined by formula (I) are set forth in Tables 1, 2 and 1 and 3 and FIGS. 1a and 1b.                           BRIEF DESCRIPTION OF THE FIGURES   1a and 1b show the chemical structure of the selected active compound with the indicated stereochemistry Is shown.   FIG. 2 shows racemic compound 202 and its enantiomers, compounds 216, 217, 234. And 236 glucuronidation rates.   FIG. 3 shows the glucuronidation rates of the following enantiomers.   FIG. 4 shows 2S, 5S-trans-2- (4-fluorophenoxymethyl) -5- (4-N-hydrido Roxyureidyl-1-butynyl) tetrahydrofuran (Compound 401) and 2S, 5R -Trans-2- (4-fluorophenoxymethyl) -5- (4-N-hydroxyureidyl Butyl) tetrahydrofuran (compound 402) Show.   FIG. 5 shows compounds 401, 403, 404, measured in% metabolites versus time (hours). 5 is a graph of the glucuronidation rates of and 406 (shown in Table 4).                           Detailed description of the invention I. Description and synthesis of compounds   A. Compound   As used herein, the term "enantiomerically enriched" refers to the single At least about 95%, preferably about 97%, 98%, 99% or 10% of the enantiomers of Mean 0% state of the compound.   As used herein, the term alkyl, unless otherwise specified, refers to a saturated linear, branched, Or cyclic C<sub>1</sub>~ C<sub>Ten</sub>Hydrocarbon means especially methyl, ethyl, propyl, i Isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, i Sopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methyl Including rupentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. Alkyl The group is R<sup>Three</sup>Any suitable group, including, but not limited to, or halo, hydroxyl, Amino, alkylamino, arylamino, alkoxy, aryloxy, nitro , Cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phospho Such as "Protective Groups in Organic Synthesis" by Greene et al. Skilled in the art as taught in John Wiley & Sons, 2nd Edition, 1991. Is protected or unprotected as needed as known to Optionally substituted by one or more groups selected from:   The term "halo" as used herein refers to chloro, fluoro, iodo or bromo. Means   As used herein, the term “halo” refers to C<sub>1</sub>~ C<sub>6</sub>Saturated straight chain , Branched or cyclic (C<sub>Five</sub>-<sub>6</sub>Means hydrocarbons, especially methyl, ethyl , Propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cycle Lopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl Xyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl And those optionally substituted by an alkyl group as described above.   As used herein, the term “alkenyl” includes at least one Having a double bond, optionally substituted as described above.<sub>Two</sub>~ C<sub>Ten</sub>Linear, Branched or cyclic (C<sub>Five</sub>-<sub>6</sub>Means hydrocarbon).   As used herein, the term "lower alkenyl" refers to C<sub>Two</sub>~ C<sub>6</sub>No Means a alkenyl group, especially including vinyl and allyl.   The term "lower alkylamino" has one or two lower alkyl substituents. Amino group.   As used herein, the term "alkynyl" shall include at least one C having a triple bond and optionally substituted as described above<sub>Two</sub>~ C<sub>Ten</sub>Linear or Means a branched hydrocarbon. As used herein, the term "lower alkynyl" Unless otherwise specified, C<sub>Two</sub>~ C<sub>6</sub>Means alkynyl group, especially acetylenyl, propynyl And -C≡C-CH (CH<sub>Three</sub>)-Including -C≡C-CH (alkyl)-.   As used herein, the term “aryl” refers to phenyl, biphenyl, unless otherwise specified. Nyl or naphthyl, preferably phenyl. Aryl groups are halo, ar Droxyl, amino, alkylamino, arylamino, alkoxy, arylo Xy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate Or phosphonates such as Greene et al., Protective Groups in Organic  Synthesis ", taught by John Wiley and Sons, 2nd Edition, 1991 Protected or protected as necessary as known to those skilled in the art. (Including but not limited to, one or more groups selected from the group consisting of ) May be optionally substituted with any suitable group, preferably halo (limited) Not specified, but containing fluoro), lower alkoxy (including methoxy), lower ant -Roxy (including phenoxy), W, cyano or R<sup>Three</sup>Can be replaced by   The term "haloalkyl, haloalkenyl or haloalkynyl" A kill, alkenyl or alkynyl group, wherein at least one hydrogen atom in the group is One is substituted with a halogen atom.   As used herein, "heteroaryl, heterocyclic or heteroaromatic" The term is an aromatic group containing at least one sulfur, oxygen or nitrogen in the aromatic ring. Means that the aryl group can be optionally substituted as described above. Limited Some examples are pyryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl , Thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyri Midyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazo Lil, indolyl, prenyl, carbazolyl, benzimidazoli And isoxazolyl.   The term "aralkyl" refers to an aryl group having an alkyl substituent. You.   The term "alkaryl" refers to an alkyl group having an aryl substituent. You.   The term "organic or inorganic anion" refers to the negatively charged moiety of a salt having a negative charge. Means an organic or inorganic group that can be used as   The term "pharmaceutically acceptable cation" refers to a positively charged drug administered with a drug. Can mean, for example, an organic or inorganic group as a counter cation in a salt You. Pharmaceutically acceptable cations are known to those of skill in the art and include, but are not limited to, Including lium, potassium and quaternary amines.   The term "metabolically cleavable leaving group" refers to the binding molecule Means a group that can be cleaved, including, but not limited to, an organic or inorganic anion, Pharmaceutically acceptable cations, acyl (eg, acetyl, propionyl and (Alkyl) C (O) containing tyryl), alkyl, phosphate, sulfate and And sulfonates.   The term “PAF receptor antagonist” refers to a PAF receptor with a binding constant of 30 μM or less. Means a compound that binds to   The term "5-lipoxygenase inhibitor" refers to 30 μl in a disrupted cell line. A compound that inhibits the enzyme at M or less is meant.   The term "pharmaceutically active derivative" refers to a compound disclosed herein when administered to a patient. Any compound capable of providing a substance directly or indirectly.   2,5-disubstituted tetrahydroofen, tetrahydrofuran and pyrrolidine, And the 1,3-disubstituted cyclopentanes disclosed herein have PAF receptor antagonist activity Or inhibits the enzyme 5-lipoxygenase, or has dual activity, PAF or Or allergic or cardiac mediated by 5-lipoxygenase products Useful for treating people with vascular disease.   B. Stereochemistry   Surprisingly, 5-lipoxygenase activity, oral availability and biostability The activity and properties of the active compounds, including (eg, the rate of glucuronidation) are disclosed It was determined that the compound could vary greatly between the optical isomers of the compounds. Therefore, preferred In an embodiment, the active compound or precursor thereof is enantiomerically enriched That is, administered in a substantially single isomer. Preferred enantiomer Can be used in selected biological assays, such as those described in detail herein. And can be readily determined by evaluating the various possible enantiomers.   2,5-disubstituted tetrahydrofuran, tetrahydrothiophene and pyrrolidine Shows many stereochemical structures. Carbon atoms 2 and 5 in the central ring are chiral; That is, the central ring exists as at least one diastereomer pair. each Diastereomers exist as pairs of enantiomers. Therefore, chiral C<sub>Two</sub>You And C<sub>Five</sub>The compound is a mixture of four enantiomers, based on the atom alone.   When a non-hydrogen substituent is present at carbon atoms 3 and 4 of the central ring, C<sub>Three</sub>and C<sub>Four</sub>Diastereomers whose atoms are chiral and which are also mixtures of four enantiomers -It can exist as a pair.   The 1,3-cyclopentanes disclosed herein also exhibit a number of stereochemical structures. Central ring Carbon atoms 1 and 3 are chiral, that is, the central ring has at least one Exists as a stereomeric pair. Each diastereomer is a set of enantiomers Exist. Therefore, chiral C<sub>1</sub>And C<sub>Three</sub>4 compounds based on atoms alone Is a mixture of the enantiomers of   When non-hydrogen substituents are present at carbon atoms 4 and 5 of the central ring, C<sub>Four</sub>and C<sub>Five</sub>Diastereomers whose atoms are chiral and which are also mixtures of four enantiomers -It can exist as a pair.   One of ordinary skill in the art disclosed by using chiral reagents and known procedures Enantiomers of the compounds obtained can be easily synthesized and separated, Enantiomers isolated by using disclosed or other known techniques Can be assessed for biological activity. Chiral NMR shift reagent, polarimeter or Determining the optical bias of a compound by using chiral HPLC Can be.   Classical decomposition methods involve various physical and chemical techniques. Often the simplest The purest and most efficient technique is repetitive recrystallization. Recrystallization depends on the compound or final energy It can be performed at any stage of the preparation of the enantiomeric product. Fine line In many cases, this simple technique represents the method of choice.   If recrystallization fails to provide material of acceptable optical purity, evaluate other methods be able to. If the compound is basic, it may have very different solubility characteristics Chiral acids that form teleomeric derivatives can be used. Chiral acid limitation Some examples are malic acid, mandelic acid, dibenzoyltartaric acid, 3-bromocamphor Contains -8-sulfonic acid, 10-camphorsulfonic acid and di-p-toluoyltartaric acid . Similarly, acylation of free hydroxyl groups with chiral acids can also separate physical properties. It forms some degree of diastereomeric derivatives that can be sufficiently different.   Enantiomerically pure or enantiomerically enriched compounds are racemic mixtures Through a chromatography column designed for chiral separation Or by enzymatic degradation of a suitably modified substance.   C. Synthesis of active compounds   2,5-disubstituted tetrahydrofuran, tetrahydrothiophene disclosed herein And pyrrolidine are described in Whittaker et al., Synlet, 1993, p. 111, Biorg. Med. Lett ., 1993, p. 1499; Achiwa et al., Chem. Pharm. Bull., 1989, including 1969 pages. It can be prepared by various methods known to those skilled in the art.   For example, one method for synthesizing enantiomer-rich materials is described in Scheme I below. Shown in In this method, the synthesis of enantiomers is based on the chiral reduction of ketones. Begin. Affects diastereomeric degradation after ring closure and -OH group reaction Separation of cis and trans isomers by standard methods known to those skilled in the art. Can be. Additional chiral centers will be known to those skilled in the art, including those shown in the examples below. Can be broken down using known techniques.   Graham et al. Procedure (1,3-diarycyclopentane: A New Class of Potent PAF)  Receptor Antagonists, 197th ACS National Meeting, Dallas, Texas State, April 9-14, 1989, Division of Medicinal Chemistr, poster no. Prepare 1,3-disubstituted cyclopentanes using 25 (abstract) or other known methods can do.   The general procedure for preparing hydroxyurea is shown in Scheme 1 below. Scheme 1 Preparation of hydroxyurea   The general procedure for preparing reverse hydroxyurea is shown in Scheme 2 below. Scheme 2 Preparation of Reverse Hydroxyurea   The general procedure for preparing hydroxamic acid is shown in Scheme 3 below. Scheme 3 Preparation of hydroxamic acid   The general procedure for preparing reverse hydroxamic acid is shown in Scheme 4 below. Scheme 4 Preparation of reverse hydroxamic acid   Scheme 5 shows 2- (3,4,5-trimethoxyphenyl) -5- [3- (N′-substituted-N′-hydro Xyureidyl) propoxy] tetrahydrofuran (1-4) and 2- (4-fluoro Phenyl) -5- [3- (N'-substituted-N'-hydroxyureidyl) propoxy] tetrahi 2 shows the synthesis of drofuran (9-12).   Scheme 6 shows 2- (2,4,5-trimethoxyphenyl) -5- (3-hydroxyureidine Rupropoxy) tetrahydrofuran (13) and 2- (4-fluorophenyl) -5- (3 Shows the synthesis of (-hydroxyureidylpropoxy) tetrahydrofuran (14,15) .   Scheme 7 shows 2- (3,4-dimethoxyphenyl) -5- [3-N'-substituted-N'-hydroxyl 1 shows the synthesis of [Reidylpropoxy] tetrahydrofuran (5-8).   The following examples are merely illustrative and are intended to limit the scope of the present invention. Not. Example 1   2- (3,4,5-trimethoxyphenyl) -5- [3- (N'-substituted-N'-hydroxyurei Jill) propoxy] tetrahydrofuran (1-4) and 2- (4-fluorophenyl)- 5- [3- (N'-substituted-N'-hydroxyureidyl) propoxy] tetrahydrofuran (9-12) adjustment   (a): tert-butyl 4- (3,4,5-trimethoxyphenyl) -4-ketone-butyrate Preparation of Compound (Compound 101)   3,4,5 trimethoxybenzaldehyde (8.0 g, 0.77 mmol), t-butyl acrylate (5.29 g, 41.29 mmol) and the catalyst 3-ethyl-5- (2-hydroxyethyl) -4-methyl Thiazolium bromide (3.52 g, 13.95 mmol) in 50 mL of dimethylformamide (DMF) Dissolved. To this solution, 5.86 mL of triethylamine was added. Reaction mixture at 60 ° C For 16 h, cool to room temperature and quench by adding 10% HCl (pH 1-2). Cooled and extracted with dichloromethane. The organic layer was washed with water and saturated NaCl solution,<sub>Four</sub> , Filtered and evaporated under reduced pressure to give an oil. Column chromatographic product Purified by chromatography (silica, 3: 1 hexane / ethyl acetate) (4.5 g, 34%).<sup>1</sup> H NMR (CDCl<sub>Three</sub>): 1.46 (2,9H); 2.70 (t, 2H); 3.24 (t, 2H); 3.92 (s, 9H); 7.25 (s , 2H).   (b): 4- (4-fluorophenyl) -4-ketone-t-butyl ether butyrate (compound 119 Preparation of   This compound is converted to 3,4,5-trimethoxy-benzaldehyde with 4-fluorobenz Prepared using a method similar to that described in Example 1 (a), replacing the aldehyde. .<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.45 (s, 9H); 2.70 (t, 2H); 3.23 (t, 2H); 7.12 (m, 2H); 8.0 2 (m, 2H).   (c): t-butyl 4- (3,4,5-trimethoxyphenyl) -4-hydroxy-butyrate Preparation of Ter (Compound 102)   Ketone ester 101 (1.09 g, 3.36 mmol) in 10 mL THF and 20 mL methanol Dissolved. To this mixture, add NaBH<sub>Four</sub>Aqueous solution (127.3 mg, 3.36 mmol in 5 ml of water) C. was added dropwise. The reaction mixture was stirred at room temperature for 4 hours, quenched with water and ethyl acetate Extracted. The organic layer was washed with water and saturated NaCl solution,<sub>Four</sub>And filtered Evaporated under reduced pressure to give the product (1.13 g, 103%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.46 (s, 9 H); 2.02 (m, 2H); 2.37 (t, 2H); 3.84 (s, 3H); 3.88 (s, 6H); 4.70 (m, 1H); 6.5 8 (s, 2H).   (d): 4- (4-fluorophenyl) -4-hydroxy-butyric acid t-butyl ether (compound Preparation of thing 120)   This compound was analogous to the procedure described in Example 1 (c), substituting compound 101 for compound 119. Prepared from 119 using a similar procedure.<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.44 (s, 9H); 2.00 (m, 2 H); 2.32 (m, 2H); 4.72 (m, 1H); 7.01 (m, 2H); 7.30 (m, 2H).   (e): Preparation of 4- (3,4,5-trimethoxyphenyl) -δ-lactone (compound 104)   Hydroxyester 102 (1.13 g, 1.47 mmol) was added to 4 mL of methanol, 1.5 mL of water and 5 mL of water. It was added to 4.5 mL of M sodium hydroxide aqueous solution. The reaction mixture was stirred at room temperature for 30 minutes, Then saturated NaHCO<sub>Three</sub>12 mL of an aqueous solution was added. Wash the aqueous phase with ether and add concentrated HCl And extracted with benzene (2 × 30 mL). Benzene layer TLC indicated that a small amount of lactone had formed. Benzene extraction PPTS (10 mg) was added to the liquid and the mixture was refluxed for 1 hour to remove water. The reaction mixture Wash with saturated NaHCO3 solution and evaporate under reduced pressure to give the desired lactone as a solid (700 mg, 80 mg %).<sup>1</sup>H NMR (CDCl<sub>Three</sub>); 2.20 (m, 1H); 2.68 (m, 3H); 3.85 (s, 3H); 3.88 (s , 6H); 5.46 (m, 1H); 6.55 (s, 2H).   (f): Preparation of 4- (4-fluorophenyl) -δ-lactone (compound 122)   This compound was analogous to the procedure described in Example 1 (e), substituting compound 120 for compound 102. Prepared from 120 using a similar procedure.<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 2.20 (m, 1H); 2.68 (m, 3 H); 5.50 (m, 1H); 7.10 (t, 2H); 7.32 (m, 2H).   (g): 2- (3,4,5-trimethoxyphenyl) -5-hydroxytetrahydrofuran Preparation of (Compound 105)   Lactone 104 (6.86 g, 27.22 mmol) was dissolved in 100 mL of dry toluene and the solution was- Cooled to 70 ° C. 28 mL of a 1.5 M solution of DIBALH in toluene was added dropwise to this solution. The reaction mixture was stirred at -70 ° C for 1 hour. Keep the reaction below -60 ° C. The mixture was quenched by adding 11 mL of methanol. Warm the mixture to -20 ° C, then 96m of saturated aqueous potassium sodium tartrate solution while maintaining the reaction temperature between -10 ° C and 0 ° C l was added. The reaction mixture was stirred at 0 ° C. for 3 hours, then the two phases were separated. water The layers were extracted with ethyl acetate. Wash the combined organic layers with water and saturated NaCl solution, then Concentration under reduced pressure gave the product (6.51 g, 94%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.82 to 2.48 (m, 4H); 3.84 (s, 3H); 3.88 (s, 6H); 4.97, 5.20 (m, 1H); 5.65, 5.79 (m, 1H); 6.5 6, 6.70 (s, 2H).   (h): 2- (4-fluorophenyl) -5-hydroxytetrahydrofuran (compound 12 3) Preparation of this compound as described in Example 1 (g), substituting compound 122 for compound 104 Prepared from 122 using a procedure similar to the procedure.<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.79 (m, 1H); 1 .95-2.10 (m, 1H); 2.20-2.32 (m, 1H); 2.48 (m, 1H); 5.00 and 5.22 (m, 1H); 5.63 and 5.78 (m, 1H); 7.04 (m, 2H); 7.30 and 7.41 (m, 2H).   (i): trans and cis 2- (3,4,5-trimethoxyphenyl) -5- (3-phthalic Preparation of (imidylpropyl) tetrahydrofuran (compounds 107 and 108)   Compound 105 (1.14 g, 4.49 mmol) was dissolved in 4 ml of dichloromethane. To this solution Liethylamine (681.4 mg, 6.73 mmol) was added. The reaction mixture was cooled in an ice bath, Trifluoroacetic anhydride (1.41 g, 6.73 mmol) was added dropwise. Reaction mixture at 0 ° C For 30 minutes, then add 3-phthalimidylpropanol (106) (2.4 g, 13.26 mmol). Was added. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction solution was washed with saturated Na HCO<sub>Three</sub>The mixture was quenched with an aqueous solution and extracted with ethyl acetate. Organic layer with water and saturated NaCl solution Wash, MgSO<sub>Four</sub>, Filtered and evaporated under reduced pressure to give an oil, which is Purification by chromatography (silica, 2: 1 hexane / ethyl acetate) (107: 522) mg (trans); 108: 271 mg (cis); 1: 1 mixture of 107 and 108: 110 mg; total yield 46%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>: 107: 1070 (m, 1H); 1.82 (m, 1H); 2.00 (m, 2H); 2.02 (m, 1H); 2.28 (m, 1H); 3.46 (m, 1H); 3.83 (s, 3H); 3.84 (m, 3H); 3.88 (s, 6H); 4. 99 (t, 1H); 5.30 (dd, 1H); 6.56 (s, 2H); 7.72 (m, 2H); 7.85 (m, 2H). 108: 1.95 (m, 3H); 2.00 (m, 2H); 2.20 (m , 1H); 3.51 (m, 1H); 3.83 (s, 3H); 3.85 (m, 2H); 3.88 (s, 6H); 3.92 (m, 1H); 4.90 (m, 1H); 5.16 (dd, 1H); 6.60 (s, 2H); 7.72 (m, 2H); 7.84 (m, 2H).   To determine the stereochemistry of this molecule, a NOE difference experiment was performed.   Trans isomer (107): In this experiment, non-triplet at 4.99 ppm Always emit low specific frequency decoupling pulses and measure only the presence of signal increase In order to do this, data was collected. This represents a positive NOE effect, Represents a close spatial relationship between In this experiment, the furan ring proton, 2.25 NOEs were found for multiplets at ~ 2.39 ppm. About aromatic protons And another NOE, which shows that this triplet represents a benzylic proton. It indicates that NOE observed for doublet at 5.30 ppm Not, which indicates that this is the trans isomer.   Cis isomer (108): NOE difference experiment was performed to determine the stereochemistry of this molecule . In this experiment, the multiplet at 4.88-4.93 ppm showed very low specific Irradiate a wavenumber decoupling pulse and decode to measure only the presence of an increase in signal. Data was collected. This represents a positive NOE effect, and the close vacancies of these protons Represents the interrelationship. In this experiment, another methine furan proton, 5.16 ppm NOE has been discovered for the doublet. Another N for aromatic protons OE was also seen, indicating that this triplet represents a benzylic proton. I have. Multiplex between 1.93 and 2.90 ppm for another furamethylene proton NOE was also observed for the kit.   (j): 2- (4-fluorophenyl) -5- (3-phthalimidylpropoxy) tetrahi Preparation of Drofuran (Compounds 124 and 125)   These compounds were prepared by following the procedure described in Example 1 (i) by substituting compound 123 for compound 105. Prepared from 123 using a procedure similar to<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 124 (trans): 1 .65 (m, 1H); 1.80 (m, 1H); 2.00 (m, 2H); 2.12 (m, 1H); 2.31 (m, 1H); 3.48 (m, 1H); 3.82 (m, 3H); 5.02 (t, 1H); 5.28 (dd, 1H); 7.00 (t, 2H); 7.29 (m, 2H); 7.71 (m, 2H); 7.82 (m, 2H). 125 (cis): 1.90 (m, 2H); 1. 99 (m, 4H); 2.19 (m, 1H); 3.48 (m, 1H); 3.82 (m, 2H); 3.88 (m, 1H); 4.94 (m, 1H ); 5.15 (dd, 1H); 7.00 (t, 2H); 7.30 (m, 2H); 7.71 (m, 2H); 7.84 (m, 2H).   (k): Preparation of 3-phthalimidylpropanol (compound 106)   3-bromopropanol (4.0 g, 28.78 mmol), potassium phthalimide (8.0 g, 43.1 7 mmol) and potassium carbonate (4.0 g, 28.78 mmol) were added to 20 mL of DMF. This reaction The mixture was stirred at 70 ° C. for 4 hours, quenched with water and extracted with ethyl acetate. Organic layer with water And washed with saturated NaCl solution and evaporated under reduced pressure to give a solid, which is ethyl acetate (3.5 g, 67%).   (l): cis 2- (3,4,5-trimethoxyphenyl) -5- (3-aminopropoxy) te Preparation of Trahydrofuran (Compounds 109 and 110)   Compound 107 (455 mg, 1.03 mmol) and hydrazine monohydrate (165.3 mg, 5.16 mmol) Was added to 2 mL of ethanol. The reaction mixture was refluxed for 2 hours, quenched with water, Extracted with dichloromethane. The organic layer was washed with water and saturated NaCl solution,<sub>Four</sub>Dried in Filtration and evaporation under reduced pressure gave the trans product 109 (225 mg, 70%).<sup>1</sup>H NMR (C DCl<sub>Three</sub>): 1.75 (m, 2H); 1.78 (m, 1H); 1.96 (m, 1H); 2.20 (m, 1H); 2.40 (m, 1H); 2.82 (t, 2H); 3.55 (m, 1H); 3.81 (m, 1H); 3.83 (s, 3H); 3.87 (s, 6H); 5.00 (t , 1H); 5.34 (dd, 1H); 6.56 (s, 2H).   The cis isomer 110 was purified using a procedure similar to that described for compound 109. Prepared from 8.<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.76 (M, 2H); 2.08 (M, 3H); 2.27 (M, 1H); 2.8 2 (t, 2H); 3.55 (m, 1H); 3.84 (s, 3H); 3.88 (s, 6H); 3.92 (m, 1H); 4.95 (m, 1H ); 5.20 (m, 1HO; 6.64 (s, 2H).   (m): 2- (4-fluorophenyl) -5- (3-aminopropoxy) tetrahydrofura Preparation of Compounds (Compounds 126 and 127)   Examples of these compounds, replacing compounds 107 and 108 with compounds 124 and 125 Prepared from 124 and 125 using a procedure similar to that described in 1 (l).<sup>1</sup>H NMR ( CDCl<sub>Three</sub>): 124 (trans): 1.75 (m, 31H); 1.96 (m, 1H); 2.20 (m, 1H); 2.40 (m , 1H); 2.82 (t, 2H); 3.54 (m, 1H); 3.83 (m, 1H); 5.05 (t, 1H); 5.32 (dd, 1H); 7.01 (t, 2H); 7.30 (m, 2H). 125 (cis): 1.74 (m, 2H ); 1.97 (m, 1H); 2.05 (m, 2H); 2.25 (m, 1H); 2.77 (t, 2H); 3.47 (m, 1H); 3.85 (m, 1H); 4.95 (m, 1H); 5.15 (dd, 1H); 7.00 (t, 2H); 7.34 (m, 2H).   (n): trans and cis 2- (3,4,5-trimethoxyphenyl) -5- [3- (N'-meth Tyl-N′-hydroxyureidyl) propoxy] tetrahydrofuran (compound 1, Preparation of 3)   Compound 109 (60 mg, 0.19 mmol) and triphosgene (23 mg, 0.078 mmol) Dissolved in 3 mL of methane. Add triethylamine (29.3 mg, 0.29 mmol) to this solution did. The reaction mixture was refluxed for 2 hours and cooled in an ice bath. Add triethyl alcohol to the cooling solution. Min (34.0 mg, 0.34 mmol) and methylhydroxyamine hydrochloride (32.2 mg, 0.39 mmol) l) was added. The reaction was stirred at room temperature for 16 hours, quenched with water, and extracted with dichloromethane. Issued. The organic layer was washed with saturated NaCl solution and evaporated under reduced pressure to give an oil, which was Purification by preparative TLC (silica, ethyl acetate) gave trans product 1 (51 mg, 69%). Obtained.<sup>1</sup>H NNR (CDCl<sub>Three</sub>): 1.82 (m, 3H); 1.95 (m, 1H); 2.22 (m, 1H); 2.40 (m, 1H);  3.15 (s, 3H); 3.40 (m, 2H); 3.58 (m, 1H); 3.84 (s, 3H); 3.85 (m, 1H); 3.88 (s 5.00 (t, 1H); 5.33 (m, 1H); 6.32 (m, 1H); 6.56 (s, 2H); 7.37 (s, 1H).   The cis isomer 3 was converted to 110 using a procedure similar to that described for compound 1. Prepared from<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.83 (m, 2H); 2.07 (m, 3H); 2.28 (m, 1H); 3.13 ( 3.35 (m, 2H); 3.55 (m, 1H); 3.84 (s, 3H); 3.87 (s, 6H); 3.88 (m, 1H);  4.97 (m, 1H); 5.20 (m, 1H); 6.22 (m, 1H); 6.63 (s, 2H); 7.37 (s, 1H).   (o): 2- (4-fluorophenyl) -5- [3- (N′-methyl-N′-hydroxyureido) Preparation of propoxy] tetrahydrofuran (compounds 9, 11)   Examples of these compounds, replacing compounds 109 and 110 with compounds 126 and 127 Prepared from 126 and 127 using a procedure similar to that described in 1 (n).<sup>1</sup>H NMR ( CDCl<sub>Three</sub>): 9 (trans): 1.70 (m, 1H); 1.78 (m, 2H); 1.96 (m, 1H); 2.19 (m, 1 H); 2.40 (m, 1H); 3.10 (s, 3H); 3.31 (m, 2H); 3.51 (m, 1H); 3.83 (m, 1H); 5.05 (t, 1H); 5.30 (dd, 1H); 6.38 (t, 1H); 7.01 (t , 2H); 7.28 (m, 2H). 11 (cis): 1.80 (m, 2H); 2.05 (m, 3H); 2.24 (m, 1H); 3. 06 (s, 3H); 3.30 (m, 2H); 3.48 (m, 1H); 3.86 (m, 1H); 4.98 (m, 1H); 5.16 (dd, 1H); 6.30 (t, 1H); 7.02 (t, 2H); 7.31 (m, 2H); 8.08 (bs, 1H).   (p): trans and cis 2- (3,4,5-trimethoxyphenyl) -5- [3- (N′-n -Butyl-N'-hydroxyureidyl) propoxy] tetrahydrofuran (compound Preparation of 2, 4)   Compound 109 (60 mg, 0.19 mmol) and triphosgene (23 mg, 0.078 mmol) Dissolved in 3 mL of methane. To this solution was added triethylamine (29.3 mg, 0.29 mmol). Added. The reaction mixture was refluxed for 2 hours and cooled in an ice bath. Butyl hydride in the cooling solution Roxyamine (51.4 mg, 0.29 mmol) was added. The reaction was stirred at room temperature for 16 hours, And quenched with dichloromethane. Wash the organic layer with saturated NaCl solution and Evaporation gave an oil. Trans product 2 was purified by preparative TLC (silica, ethyl acetate ) (46.9 mg, 54.7%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 0.93 (t, 3H); 1.35 (m, 2H); 1 .58 (m, 2H); 1.81 (m, 3H); 1.96 (m, 1H); 2.21 (m, 1H); 2.40 (m, 1H); 3.38 (m, 2 H); 3.50 (m, 2H); 3.57 (m, 1H); 3.83 (s, 3H); 3.85 (m, 1H); 3.88 (s, 6H); 5.00 (t, 1H); 5.32 (m, 1H); 6.32 (m, 1H); 6.56 (s, 2H).   The cis isomer 4 was converted to 110 using a procedure similar to that described for compound 2. Prepared from<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 0.92 (t, 3H); 1.32 (m, 2H); 1.58 (m, 2H); 1.81 (m, 2H); 2.08 (m, 3H); 2.28 (m, 1H); 3.35 (m, 2H); 3.47 (m, 2H); 3.54 (m, 1H) 3.84 (s, 3H); 3.87 (s, 6H); 3.88 (m, 1H); 4.97 (m, 1H); 5.20 (m, 1H); 6.22 ( m, 1H); 6.63 (s, 2H).   (q): 2- (4-fluorophenyl) -5- [3- (N'-n-butyl-N'-hydroxyurea Preparation of [zil) propoxy] tetrahydrofuran (compounds 10, 12)   Examples of these compounds, replacing compounds 109 and 110 with compounds 126 and 127 Prepared from 126 and 127 using a procedure similar to that described in 1 (p) 4.<sup>1</sup>H NMR ( CDCl<sub>Three</sub>): 10 (trans): 0.90 (t, 3H); 1.30 (m, 2H); 1.55 (m, 2H); 1.70 (m, 1H); 1.78 (m, 2H); 1.96 (m, 1H); 2.19 (m, 1H); 2.40 (m, 1H);  3.31 (m, 2H); 3.44 (m, 2H); 3.52 (m, 1H); 3.82 (m, 1H); 5.05 (t, 1H); 5.30 (dd , 1H); 6.32 (t, 1H); 7.00 (t, 2H); 7.28 (m, 2H); 7.55 (bs, 1H). 12 (cis): 0.90 (t, 3H); 1.30 (m, 2H); 1.52 (m, 2H); 1.80 (m, 2H); 2.04 (m, 3H); 2.24 (m , 1H); 3.30 (m, 2H); 3.40 (m, 2H); 3.48 (m, 1H); 3.85 (m, 1H); 4.98 (t, 1H); 5.16 (dd, 1H); 6.27 (t, 1H); 7.03 (t, 2H); 7.32 (m, 2H); 7.53 (bs, 1H). Example 2   2- (3,4-dimethoxyphenyl) -5- [3-N'-substituted-N'-hydroxyureidylp Preparation of [ropoxy] tetrahydrofuran (5-8)   (a): Preparation of 4- (3 ′, 4′-dimethoxyphenyl) -4-oxobutyronitrile (111)   Pure acrylonitrile (3.2 ml, 0.048 mol) and triethylamine (5 ml, 0.11 mol) And a single portion of 3,4-dimethoxybenzaldehyde under an argon atmosphere with stirring. Hyde (7.8 g, 0.047 mol) and 3-benzyl-5- (2-hydroxyethyl) -4-methylthio Azolium chloride (5.3g, 0.02mol) in dry dimethylformamide (25ml) Added to the mixture. The mixture was left at room temperature overnight. Dilute the reaction solution with water and add ethyl acetate (3 × 100 ml). The organic layer is washed with water (3 x 100ml), brine (3 x 100ml) And the solvent was removed under reduced pressure to give an amber oil. TLC (silica gel; acetic acid Analysis by ethyl: hexane = 1: 1) revealed that Rf 0.80 (starting aldehyde), 0.50 A mixture of three spots of (compound 1) and 0.30 (unknown by-product) was shown. . The sample is applied to a column (flash) on silica gel 60 (230-400 mesh). Purify by chromatography, eluting with ethyl acetate: hexane (= 1: 1) The desired compound (2.26 g, 22%) was obtained as a yellow solid.<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 2.78 (t , 2H, J = 8Hz), 3.33 (t, 2H, J = 8Nz), 3.96 (s, 3H), 3.98 (s, 3H), 6.90 (d, 1H, J = 8.5Hz), 7.52 (d, J = 2Hz, 2H), 7.58 (dd, J = 2 and 8Hz, 2H).   (b): Preparation of 4- (3 ′, 4′-dimethoxyphenyl) -4-oxobutyric acid (112)   4- (3 ′, 4′-dimethoxyphenyl) -4-oxobutyronitrile (111) (2.26 g, A solution of (0.01 mol) in acetic acid (15 ml) and hydrochloric acid (12 N, 40 ml) is heated under reflux for 1.5 hours with stirring. And cooled to room temperature. The solvent was removed under reduced pressure to give a brown solid. Reunited from water Crystallization afforded 112 as light and pale brown crystals (1.57 g, 66%).<sup>1</sup>H HMR (CDCl<sub>Three</sub> ): 2.80 (t, J = 7.5Hz, 2H), 3.30 (t, J = 7.5Hz, 2H), 3.94 (s, 3H), 3.96 (s, 3H) , 6.89 (d, 1H, J = 9 Hz), 7.55 (d, 1H, J = 1 Hz) and 7.64 (dd, 1H, 1 and 9 Hz) .   (c): Preparation of 4- (3 ′, 4′-dimethoxyphenyl) butyrolactone (113)   A solution of sodium borohydride (0.89 g, 0.023 mol) in water (4 ml) was placed under an argon atmosphere. In the air, with stirring, 112 (2.8 g, 0.012 mol) of freshly distilled dry tetrahydrofura (40 ml) and a solution in methanol (20 ml) were added dropwise over 5 minutes. . The reaction was left overnight at room temperature. TLC (silica gel; ethyl acetate: methanol: Analysis with acetic acid = 9.5: 0.5: few drops) indicated the presence of starting material. Sarana Sodium borohydride (0.5 g, 0.013 mol) in water (2 ml). The reaction was left at room temperature for 3 hours. Minutes by TLC (same system as above) Analysis showed the absence of starting material. The reaction solution was quenched with hydrochloric acid (6N, 25 ml), Leave for 15 minutes at warm. The mixture was extracted with ethyl acetate (3x75ml). Organic extract Wash with water (3 × 75 ml), brine (3 × 75 ml) and remove the solvent under reduced pressure to give a light brown solid. (2.0 g, 75%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 2.18 to 2.25 (m, 1H), 2.59 to 2.70 (m , 3H), 3.89 (s, 3H), 3.90 (s, 3H), 5.44 to 5.49 (m, 1H) and 6.82 to 6.87 (m, 3H ).   (d): Preparation of 4- (3 ′, 4′-dimethoxyphenyl) butyrolactol (114)   A solution of diisobutylaluminum hydride (1.5 M, 9 ml, 13.5 mmol) was dried. Dry 113 (2.0 g, 9 mmol) in an argon atmosphere cooled by a chair-acetone bath. To the solution in dry toluene (40 ml) was added dropwise under stirring over 30 minutes. reaction The liquid was stirred at -78 ° C for 1 hour. TLC (silica gel; ethyl acetate: hexane = 1: 1) ) Shows the absence of starting material and a new spot at Rf 0.38 Indicated. The reaction was quenched with methanol (20ml) and slowly warmed to 0 ° C. Liquor A saturated solution of sodium potassium citrate (50 ml) was added and stirred at 0 ° C. for 45 minutes. Mixed The compound was extracted with ethyl acetate (3 × 100 ml) and the organic extract Was washed with water (3 × 75 ml), brine (3 × 75 ml). The solvent was removed under reduced pressure and the dark An amber oil (1.7 g, 84%) was obtained.<sup>1</sup>H NMR (CDCl<sub>Three</sub>) (Cis isomer and trans isomer 1.71 to 2.49 (m, 8H), 2.91 (br s, 1H), 3.09 (br s, 1H), 3.89 (s, 6H) , 3.90 (s, 6H), 4.97 (m, 1H), 5.19 (t, J = 7 Hz, 1H), 5.62 (m, 1H), 5.77 (m, 1H) And 6.82 to 7.28 (m, 6H).   (e): Preparation of N- (3-hydroxypropyl) phthalimide (106)   3-bromopropanol (4 g, 0.029 mmol), potassium phthalate (8 g, 0.043 mmol) And a mixture of potassium carbonate (4 g, 0.029 mmol) in dry DMF (50 ml) was stirred at 70 ° C. Heat for 4 hours. The mixture was diluted with water (100ml) and extracted with ethyl acetate (3x75ml) . Wash the organic layer with water (3 × 100 ml) and dry (Na<sub>Two</sub>SO<sub>Four</sub>)did. The solvent is removed under reduced pressure To give a white solid which was extracted with benzene. Evaporate the benzene extract to white A color solid was obtained, which was recrystallized from ethyl acetate-hexane to give white crystals (1.27 g, 2 4%).   (f): trans and cis 2- (3 ′, 4′-dimethoxyphenyl) -5- [3- (N-phthalo Yl)] Preparation of propoxytetrahydrofuran (115 and 116)   Triflic an Hydride (0.68 ml, 4.8 mmol) as a single part Of 114 (0.72 g, 3.2 mmol) in an argon atmosphere cooled using an ice bath A solution in dichloromethane (20 ml) and triethylamine (0.68 ml, 4.9 mmol) was added with stirring. Added. The reaction was stirred at 0 ° C. for 30 minutes. N- (3-hydroxypropyl) phthal Imide (106) (1.27 g, 7 mmol) is added to the reaction mixture and the solution is allowed to warm to room temperature. It was left at this temperature for 2 hours. The solution was diluted with aqueous sodium bicarbonate (saturated, 25 ml), extract with ethyl acetate (3 x 50 ml), brine (3 x 50 ml), dry (sulfur Acid). The solvent was removed under reduced pressure, leaving an amber oil (2.02 g) . The oil was analyzed by TLC (silica gel; ethyl acetate: hexane = 1: 1) to give Rf 0. The presence of four spots at 80, 0.60, 0.50 and 0.35 was indicated. Rf0.60 and The spot ratio at 0.50 was 2: 1. Samples were run on silica gel (230-40 Purified by column chromatography (flash) on 0 mesh) Eluting with ethyl: hexane (= 3: 7) first gave a clear, colorless oil at Rf 0.60 ( 0.40 g, 30%). It is trans 2- (3 ', 4'-dimethoxyphenyl) -5- [3- (N-phthaloyl)] It was identified as ropoxytetrahydrofuran (115) (0.40 g, 30%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>) 1 .34 to 1.94 (m, 2H), 1.96 to 2.05 (m, 2H), 2.09 to 2.20 (m, 1H), 2.25 to 2.36 (m, 1H ), 3.46 to 3.53 (m, 1H), 3.84 (t, 9Hz, 2H), one proton multi hidden here 3.88 (s, 3H), 3.91 (s, 3H), 5.01 (t, 7.3Hz, 1H), 5.30 (dd, J = 2 and 5Hz, 1Hz), 6.82 to 6.90 (m, 3H), 7.71 to 7.74 (m, 2H) and 7.84 to 7.88 ( m, 2H).   To determine the stereochemistry of this molecule, a NOE difference experiment was performed. In this experiment Very low specific frequency decoupling pulse to the triplet at 5.01 ppm And data collection was performed to determine only the presence of an increase in signal. this Represents the positive NOE effect and represents the close spatial relationship of these protons. This experiment Of the multiplet at 2.25 to 2.36 ppm which is a furan ring proton NOE was discovered. Another NOE was also found for aromatic protons, Indicates that this triplet represents a benzylic proton. 5.30ppm NOE was not observed for the doublet in It is shown that it is a isomer.   Successive elution with the same solvent system gave the R as a colorless oil (0.21 g, 15%). A spot was given at f0.50, which was cis 2- (3 ', 4'-dimethoxyphenyl) -5- [3- (N-phthaloyl)] propoxytetrahydrofuran (116).<sup>1</sup>H NMR ( CDCl<sub>Three</sub>) 1.92 to 2.12 (m, 6H), 3.44 to 3.52 (m, 1H), 3.86 (s, 3H), 3.88 (s, 3H), 3. 76 to 3.93 (m, 3H), 4.89 to 4.94 (m, 1H), 5.35 (d, J = 4 Hz), 6.89 (d, J = 8 Hz), 6.87 (dd, J = 2 and 8 Hz), 6.92 (d, J = 2 Hz), 7.69 to 7.72 (m, 2H) and 7.82 to 7.85 (m , 2H).   To determine the stereochemistry of this molecule, a NOE difference experiment was performed. In this experiment Very low specific frequency decoupling for multiplets at 4.89 to 4.94 ppm Irradiate a pulse and collect data to measure only the presence of an increase in signal Was. This represents a positive NOE effect and a close spatial relationship of these protons. In this experiment, a doublet at 5.35 ppm, another methine furan proton, was used. NOE was discovered for This means that this molecule is a cis isomer Is shown. Another NOE is seen for aromatic protons, It indicates that this triplet represents a benzylic proton. Other N also for multiplets at 1.92 to 2.12 ppm containing ramethylene protons OE was present.   Chromatography also yielded a mixture of 115 and 116 (0.342 g, 26%) .   (g): trans 2- (3 ', 4'-dimethoxyphenyl) -5- (3-aminopropoxy) Preparation of tetrahydrofuran (117)   Pure hydrazine hydrate (150 μL, 3.2 mmol) was stirred with 115 (253 mg, 0.62 mm ol) in a solution of absolute ethanol (1.5 ml). Heat the solution to reflux for 5 minutes, A white solid precipitated from the solution. The mixture was heated at reflux for 2 hours. TLC (silica gel Analysis; ethyl acetate: hexane = 1: 1) showed the absence of starting material and Spots in the first part were shown. The reaction was quenched with water (10 ml) and Extracted with methane (5 × 10 ml). Wash the organic phase with water (2 × 10 ml), brine (2 × 10 ml) And dried (sodium sulfate). Removal of the solvent under reduced pressure gave a colorless oil (150 mg, 86%) remained.<sup>1</sup>H NMR (CDCl<sub>Three</sub>) 1.25 (brs, 2H), 1.68-1.78 (m, 3H), 1.81-1.98 (m, 1H), 2.14 to 2.2 (m, 1H), 2.3 to 2.36 (m, 1H), 2.80 (t, J = 6.5Hz, 2H), 3.47 ~ 3.55 (m, 1H), 3.78 ~ 3.87 (m, partially hidden, 1H), 3.86 (s, 3H), 3.88 ( s, 3H), 4.99 (t, J = 7 Hz, 1H), 5.31 (dd, J = 2 and 6 Hz, 1H), 6.80-6.88 (m, 3H ).   (h): cis 2- (3 ', 4'-dimethoxyphenyl) -5- (3-aminopropoxy) tetra Preparation of lahydrofuran (118)   Pure hydrazine hydrate (125 μl, 2.57 mmol) was stirred with 116 (210 mg, 0.51 m mol) in anhydrous ethanol (3.0 ml). When the solution is heated to reflux for 5 minutes A white solid precipitated from the solution. The mixture was heated at reflux for 2 hours. TLC (silica Gel; ethyl acetate: hexane = 1: 1) showed no starting material And spots in the first part. The reaction solution was quenched with water (10 ml), Extracted with dichloromethane (5 × 10 ml). Wash the organic phase with water (2 × 10 ml), brine (1 × 10 ml) And dried (sodium sulfate). Remove solvent under reduced pressure A hard oil (105 mg, 73%) remained.<sup>1</sup>H NMR (CDCl<sub>Three</sub>) 1.45 (b rs, 2H), 1.7 3 to 1.78 (m, 2H), 2.01 to 2.12 (m, 3H), 2.19 to 2.29 (m, 1H), 2.81 (t, J = 7 Hz, 2H) , 3.48 to 3.53 (m, 1H), 3.85 to 3.93 (m, partially hidden, 1H), 3.88 (s, 3H) , 3.90 (s, 3H), 4.96 to 5.01 (m, 1H), 5.17 (dd, J = 3 and 6 Hz, 1H), 6.83 (d, J = 8.89 (dd, J = 2 and 8 Hz, 1H) and 6.96 (d, J = 2 Hz, 1H).   (i): trans 2- (3 ′, 4′-dimethoxyphenyl) -5- [3- (N-butyl-N-hydro Preparation of [xiureidyl) propoxy] tetrahydrofuran (5)   A solution of 117 (53 mg, 0.19 mmol) in dry dichloromethane (3 ml) was added under argon atmosphere. Under stirring, triethylamine (32 μl, 0.22 mmol) and then triphosgene (19 mg, 0.06 mmol) was added. The solution was heated at reflux for 30 minutes and cooled to room temperature. In this solution , Solid n-butylhydroxylamine (34 mg, 0.38 mmol) was added in one portion and it was Left overnight at warm. Quench the reaction with water (10 ml) and extract with dichloromethane (3 × 10 ml). Issued. Wash the combined organic phases with aqueous sodium bicarbonate solution (saturated, 3 × 10 ml) and dry Dry (sodium sulfate). Analysis by TLC (silica gel; ethyl acetate) , Rf 0.90, 0.50, 0.25 and 0.00. Samples should be silica By column (flash) chromatography on gel 60 (230-400 mesh) And purified by elution with ethyl acetate to a milky oil (8 mg, 11%) at Rf 0.50. Got the spot.<sup>1</sup>H NMR (CDCl<sub>Three</sub>) 0.92 (t, J = 7Hz, 3H), 1.27 ~ 1.39 (m, 2H), 1.51 to 1.61 (m, 2H), 1.71 to 1.86 (m, 3H), 1.88 to 2.15 (m, 1H), 2.17 to 2.29 (m, 1 H), 2.32 to 2.42 (m, 1H), 3.28 to 3.58 (m, 4H), 3.81 to 3.94 (m, partially hidden Yes, 2H), 3.87 (s, 3H), 3.90 (s, 3H), 5.49 to 5.05 (m, 1H), 5.31 to 5.38 (m, 1H ), 6.28 to 6.34 (m, 1H) and 6.81 to 6.86 (m, 3H), IR (film) 3407, 3193, 2 933,1640,1516,1263,1029cm<sup>-1</sup>.   (j): trans 2- (3 ′, 4′-dimethoxyphenyl) -5- [3- (N-methyl-N-hydro Preparation of [xiureidyl) propoxy] tetrahydrofuran (6)   A solution of 117 (32 mg, 0.11 mmol) in dry dichloromethane (3 ml) under an argon atmosphere, Under stirring, triphosgene (12 mg, 0.04 mmol) is immediately followed by triethyl alcohol. Min (17 μl, 0.12 mmol) was added. The solution was heated at reflux for 2 hours, cooled to room temperature, Placed in ice bath. To this reaction mixture, add pure triethylamine (32 μl, 0.23 mmol) Was added followed by methylhydroxylamine hydrochloride (19 mg, 0.23 mmol). Reaction liquid Was left overnight at room temperature. The reaction was quenched with water (10 ml) and dichloromethane (3 × 10 ml) Extracted. Wash the organic extract with water (3 × 10 ml), brine (3 × 10 ml) and remove the solvent under reduced pressure. Removed below to give an amber oil. For analysis by TLC (silica gel; ethyl acetate) Thus, only one new spot at Rf 0.30 was shown. Sample For column (flash) chromatography on Kagel 60 (230-400 mesh) Purify more and elute the desired compound with an amber oil (12 mg, 3 0%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>) 1.73 to 1.84 (m, 2H), 1.90 to 2.01 (m, 1H), 2.03 ~ 2.13 (m, 1H), 2.18 ~ 2.29 (m, 1H), 2.32 ~ 2.43 (m, 1H), 3.13 (s, 3H), 3.30 ~ 3.44 (m, 2H), 3.49 to 3.59 (m, 1H), 3.82 to 3.92 (m, partially hidden, 3H), 3 .88 (s, 3H), 3.91 (m, 3H), 4.96 to 5.04 (m, 1H), 5.34 (dd, J = 2 and 5Hz, 1H), 6.34 (brt, 5 Hz, 1H) and 6.82 to 6.68 (m, 3H), IR (film) 3407, 3229, 29 35, 1636, 1516, 1263 and 1029cm<sup>-1</sup>.   (k): cis 2- (3 ′, 4′-dimethoxyphenyl) -5- [3- (N-butyl-N-hydroxy Preparation of ureidyl) propoxy] tetrahydrofuran (7)   A solution of 118 (50 mg, 0.18 mmol) in dry dichloromethane (3 ml) was added under argon atmosphere. Under stirring, triphosgene (18 mg, 0.06 mmol) is immediately followed by triethylamine (80 μl, 0.57 mmol) was added. The solution was heated at reflux for 2 hours, cooled to room temperature and placed in an ice bath. placed. To this reaction mixture was added neat triethylamine (50 μl, 0.35 mmol) followed by Solid n-butylhydroxylamine (32 mg, 0.36 mmol) was added. Reaction solution at room temperature And left overnight. Quench the reaction with water (10 ml) and extract with dichloromethane (3 × 10 ml) did. Wash the organic extract with water (3 × 10 ml), brine (3 × 10 ml) and remove the solvent under reduced pressure. Leave to give an amber oil. Analysis by TLC (silica gel; ethyl acetate) revealed that R Substantially equivalent two new spots at f0.85 and 0.45 were shown. sample Column (flash) chromatography on silica gel 60 (230-400 mesh) Purified by fee, ethyl acetate First spot at Rf 0.85 as an amber oil (26 mg) Obtained. Elution of the title compound with an amber oil (2. (5 mg, 35%).<sup>1</sup>H NMR (CDCl<sub>Three</sub> 1.1 (t, J = 7Hz, 3H), 1.25 to 1.37 (m, 2H) , 1.49 to 1.59 (m, 2H), 1.76 to 1.84 (m, 2H), 1.99 to 2.1 (m, 3H), 2.19 to 2.26 (m, 1H), 3.26 to 3.54 (m, 5H), 3.84 to 3.92 (m, partially hidden, 1H), 3.87 (s, 3 H), 3.88 (s, 3H), 4.96 to 5.02 (m, 1H), 5.17 (d, J = 4 Hz, 1H), 6.24 (t, J = 4 Hz, 1 H), 6.52 (br s, 1H), 6.83 (d, J = 8 Hz, 1H) and 6.89 to 95 (m, 2H), IR (fill 2913, 1640, 1570, 1463, 1262, 1139 and 1031 cm<sup>-1</sup>.   (l): cis 2- (3 ′, 4′-dimethoxyphenyl) -5- [3- (N-methyl-N-hydroxy Preparation of ureidyl) propoxy] tetrahydrofuran (8)   118 (56 mg, 0.2 mmol) in dry dichloromethane (3 ml) Under stirring, triphosgene (20 mg, 0.07 mmol) is immediately followed by triethylamine (80 mg μl, 0.57 mmol) was added. The solution was heated at reflux for 2 hours, cooled to room temperature and placed in an ice bath. placed. To the reaction mixture was added neat triethylamine (80 μl, 0.57 mmol) followed by Solid methylhydroxylamine hydrochloride (32 mg, 0.39 mmol) was added. Reaction chamber Left overnight at warm. Quench the reaction with water (10 ml) and extract with dichloromethane (3 × 10 ml). Issued. Wash the organic extract with water (3 × 10 ml), brine (3 × 10 ml) and remove the solvent under reduced pressure Removal gave an amber oil. Analysis by TLC (silica gel; ethyl acetate) One spot at Rf 0.30 and a little material at the first position are shown Was. Run the sample on a column (flash) on silica gel 60 (230-400 mesh) Purify by chromatography, eluting with ethyl acetate to give the title compound as an amber Obtained as a colored oil (30 mg, 42%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>) 1.76 (m, 2H), 1.98-2.10 (m , 3H), 2.18 to 2.26 (m, 1H), 3.07 (s, 3H), 3.25 to 3.37 (m, 2H), 3.46 to 3.54 (m, 1H), 3.85 to 3.90 (m, partially hidden, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 4.93 to 5.00 (m, 1H), 5.16 (d, J = 4 Hz, 1H), 6.27 (t, J = 5 Hz, 1H), 6.83 (d, J = 8 Hz , 1H) and 6.88 to 6.93 (m, 2H), IR (pure) 2933, 1643, 1518, 1261 and 1029 cm<sup>-1</sup>. Example 3   2- (2,4,5-trimethoxyphenyl) -5- (3-hydroxyureidylpropoxy B) tetrahydrofuran (13) and 2- (4-fluorophenyl) 5- (3-hydroxy Preparation of (Siureidylpropoxy) tetrahydrofuran (14,15)   (a): 2- (3,4,5-trimethoxyphenyl) -5- (3-bromopropoxy) tetra Preparation of hydrofuran (compound 128)   Compound 105 (1.0 g, 3.94 mmol) was dissolved in 4 ml of dichloromethane. To this solution Liethylamine (597 mg, 5.90 mmol) was added. The reaction mixture was cooled in an ice bath and Fluoroacetic anhydride (1.24 g, 5.90 mmol) was added dropwise. Reaction mixing Stir at 0 ° C. for 30 min, then add 3-bromopropanol (1.84 g, 13.27 mmol) did. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction solution was saturated NaHCO<sub>Three</sub> The mixture was quenched with an aqueous solution and extracted with ethyl acetate. Wash the organic layer with water and saturated NaCl solution , MgSO<sub>Four</sub>, Filtered and evaporated under reduced pressure to give an oil, which is Purified by chromatography (silica, 4: 1 hexane / ethyl acetate) (128: 430 m g and its cis isomer 250 mg; total yield 46%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 128 (Transformer ): 1.77 (m, 1H); 1.98 (m, 1H); 2.15 (m, 2H); 2.20 (m, 1H); 2.40 (m, 1H); 3.5 3 (t, 2H); 3.60 (m, 1H); 3.83 (s, 3H); 3.87 (m, 1H); 3.89 (s, 6H); 5.01 (t, 1H ); 5.35 (dd, 1H); 6.57 (s, 2H).   (b): 2- (4-fluorophenyl) -5- (3-bromopropoxy) tetrahydrofura Preparation of Compounds (Compounds 129 and 130)   These compounds are described in Example 3 (a) by substituting compound 105 for compound 105. Prepared from 123 using a procedure similar to the procedure.<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 129 (trans) : 1.72 (m, 1H); 1.98 (m, 1H); 2.14 (m, 2H); 2.20 (m, 1H); 2.40 (m, 1H); 3.53 ( 3.60 (m, 1H); 3.89 (m, 1H); 5.06 (t, 1H); 5.34 (m, 1H); 7.02 (t, 2H);  7.30 (m, 2H). 130 (cis): 1.98 (m, 1H); 2.07 (m, 2H); 2.14 (m, 2H); 2.26 (m 3.52 (t, 2H); 3.58 (m, 1H); 3.93 (m, 1H); 5.00 (m, 1H); 5.20 (dd, 1H);  7.03 (t, 2H); 7.35 (m, 2H).   (c): 2- (3,4,5-trimethoxyphenyl) -5- (3-O-benzylhydroxy Preparation of (Silaminopropoxy) tetrahydrofuran (Compound 131)   Compound 128 (260 mg, 0.69 mmol) was treated with 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1 H) -Pyrimidinone (DMPU) was dissolved in 2 ml. Add sodium carbonate (220.4 mg, 2 .08 mmol) and benzylhydroxylamine hydrochloride (166 mg, 1.04 mmol). Was. The reaction was stirred at 80 ° C. for 16 hours, quenched with water and extracted with ethyl acetate. Organic layer Is washed with water and saturated sodium chloride solution,<sub>Four</sub>Dried, filtered and evaporated An oil was obtained, and the column was flashed using ethyl acetate (114 mg, 40%) as solvent. G) Purification by chromatography.<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.72 (m, 1H); 1.82 (m , 2H); 1.92 (m, 1H); 2.18 (m, 1H); 2.36 (m, 1H); 3.06 (t, 2H); 3.52 (m, 1H); 3.81 (m, 1H); 3.83 (s, 3H); 3.87 (s, 6H); 4.71 (s, 2H); 4.98 (t, 1H). 530 (dd , (Dd, 1H); 6.55 (s, 2H); 7.35 (m, 5H).   (d): 2- (4-fluorophenyl) -5- (3-O-benzylhydroxylaminopropo Preparation of xy) tetrahydrofuran (compounds 132 and 133)   These compounds were prepared in Example 3 (c) by replacing Compound 128 with Compounds 129 and 130. Prepared from 129 and 130 using procedures similar to those described.<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1 32 (trans): 1.70 (m, 1H); 1.83 (m, 2H); 1.94 (m, 1H); 2.17 (m, 1H); 2.38 (m, 1H); 3.07 (t, 2H); 3.52 (m, 1H); 3.82 (m, 2H); 4.71 (s, 2H); 5.02 (t, 1H) 5.30 (ss, 1H); 7.02 (t, 2H); 7.30 (m, 2H); 7.36 (m, 5H). 133 (cis): 1.85 (m, 2H); 1.96 (m, 1H); 2.05 (m, 2H); 2.26 (m, 1H); 3.05 (t, 2H); 3.50 (m, 1H) ; 3.88 (m, 2H); 4.70 (s, 2H); 4.99 (m, 1H); 5.17 (dd, 1H); 5.50 (bs, 1H); 7.0 0 (t, 2H); 7.35 (m, 7H).   (e): 2- (3,4,5-trimethoxyphenyl) -5- (3-O-benzylhydroxyl Preparation of Reidylpropoxy) tetrahydrofuran (Compound 134)   Compound 131 (114 mg, 0.27 mmol) was dissolved in 3 ml of dichloromethane. To this solution Limethylsilyl isocyanate (47.6 mg, 0.41 mmol) was added. Reaction at room temperature Stirred for 16 hours and then refluxed for 4 hours. The reaction was quenched with saturated ammonium chloride solution. Cooled, extracted with ethyl acetate and evaporated to an oil. The product is vinegar Isolated by preparative TLC using ethyl acid as solvent.<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.72 (m, 1H); 1.94 (m, 3H); 2.16 (m, 1H); 2.38 (m, 1H); 3.50 (m, 1H); 3.62 (m, 2H); 3. 80 (m, 1H); 3.82 (s, 3H); 3.84 (s, 6H); 4.81 (s, 2H); 4.99 (t, 1H); 5.30 (m, 3 H); 6.54 (s, 2H); 7.37 (s, 5H).   (f): 2- (4-fluorophenyl) -5- (3-O-benzylhydroxyureidylpro Preparation of (Poxy) tetrahydrofuran (Compounds 135 and 136)   These compounds were prepared in Example 3 (e) by substituting compound 131 for compounds 132 and 133. Prepared from 132 and 133 using procedures similar to those described.<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1 35 (trans): 1.70 (m, 1H); 1.93 (m, 3H); 2.16 (m, 1H); 2.39 (m, 1H); 3.50 (m, 1H); 3.62 (m, 2H); 3.80 (m, 1H); 4.82 (s, 2H); 5.04 (t, 1H); 5.30 (dd, 1H ); 5.35 (bs, 2H); 7.00 (t, 2H); 7.29 (m, 2H); 7.38 (s, 5H). 136 (cis): 1.9 8 (m, 4H); 2.08 (m, 1H); 2.25 (m, 1H); 3.48 (m, 1H); 3.62 (m, 2H); 3.83 (m, 1H ); 4.81 (s, 2H); 4.98 (m, 1H); 5.17 (dd, 1H); 5.42 (bs, 1H); 7.00 (t, 2H); 7. 33 (m, 2H); 7.38 (s, 5H).   (g): 2- (3,4,5-trimethoxyphenyl) -5- (3-hydroxyureidilp Preparation of (ropoxy) tetrahydrofuran (compound 13)   Compound 134 (90 mg, 0.19 mmol) was dissolved in 2 ml of ethyl acetate and then Pd / C (10%) (18 mg ) Was added. The reaction mixture was hydrogenated at balloon pressure for 16 hours. Filter the reaction, The filtrate was concentrated. Product is isolated by preparative TLC using ethyl acetate as solvent (68 mg).<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.75 (m, 1H); 1.91 (m, 2H); 1.95 (m, 1H); 2.20 (m , 1H); 2.37 (m, 1H); 3.58 (m, 1H); 3.66 (m, 2H); 3.81 (s, 3H); 3.85 (m, 1H); 3.87 (s, 6H); 5.00 (t, 1H); 5.35 (dd, 1H); 5.41 (bs, 2H); 6.35 (s, 2H); 8.39 ( s, 1H).   (h): 2- (4-fluorophenyl) -5- (3-hydroxyureidylpropoxy) Preparation of tetrahydrofuran (compounds 14, 15)   Example 3 (g) Compounds 14 and 15 were replaced by compounds 135 and 136 instead of compound 134 Prepared from 135 and 136 using a procedure similar to that described in<sup>1</sup>H NMR (CDCl<sub>Three</sub>):  14 (trans): 1.72 (m, 1H); 1.93 (m, 3H); 2.20 (m, 1H); 2.38 (m, 1H); 3.58 (m, 1H); 3.67 (m, 2H); 3.85 (m, 1H); 5.05 (t, 1H); 5. 33 (dd, 1H); 5.48 (bs, 2H); 7.00 (t, 2H); 7.28 (m, 2H); 8.48 (bs, 1H). 15 ( S): 1.92 (m, 2H); 2.01 (m, 1H); 2.10 (m, 2H); 2.26 (m, 1H); 3.53 (m, 1H); 3 .64 (m, 2H); 3.87 (m, 1H); 4.98 (m, 1H); 5.20 (dd, 1H); 5.43 (bs, 2H); 7.01 (m , 2H); 7.31 (m, 2H); 8.43 (bs, 1H). Example 4   Trans-2- {3- (N-hydroxyureidyl) -but-1-ynyl} -5- (4-fluoro (Rophenyl) tetrahydrofuran (207)   A synthetic scheme for preparing compound 207 is shown in Scheme 8.   (a): 2- (t-butyldimethylsilyloxy) -5- (4-fluorophenyl) tetrahi Preparation of Drofuran (Compound 202):   2-hydroxy-5- (4-fluorophenyl) tetrahydrofuran (550 mg, 3.0 mmol ), T-butyldimethylsilyl chloride (498 mg, 3.3 mmol) and imidazole (45 (0 mg, 6.6 mmol) was dissolved in 2 ml of dry DMF. Put this solution under a dry argon atmosphere Stir overnight, pour into 200 ml of water and mix 2: 1 mixture of ethyl acetate and hexane (3 × 100 m Extracted in l). Wash the combined organic extracts with water (4 × 200 ml) and brine (100 ml) , Dried over sodium sulfate and evaporated to give 2- (t-butyldimethylsilyloxy) -5- (4-fluorophenyl) tetrahydrofuran (compound 202, cis isomer and trans 830 mg (93%) as a colorless oil that does not require any purification I got it.<sup>1</sup>H-NMR (CDCl<sub>Three</sub>) δ 7.40-7.50 (2H, m, minor isomer), 7.25-7.35 (2 H, m, major isomer), 7.00 to 7.10 (2H, m, both major and minor isomers), 5 .71-5.75 (1H, m, major isomer), 5.59-5.62 (1H, m, minor isomer), 5.12-5 .20 (1H, m, major isomer), 4.90 to 4.98 (1H, m, minor isomer), 2.40 to 2.55 (1 H, m, both major and minor isomers), 2.05 to 2.17 (1H, m, major and minor isomers) 1.87 to 2.00 (1H, m, both major and minor isomers), 1.6 7 to 1.70 (1H, m, both major and minor isomers), 0.92 (s, 9H, major isomer) And both minor isomers), 0.16 (s, 6H, both major and minor isomers).   (b): trans-2- (3-tetrahydropyranyloxy-but-1-ynyl) -5- (4-fur Preparation of (Orophenyl) tetrahydrofuran (Compound 204):   2- (t-butyldimethylsilyloxy) -5- (4-fluorophenyl) tetrahydro Furan (202, 593 mg, 2.0 mmol) was mixed into 10 ml of dry methylene chloride. It was degassed by blowing Lugon). This solution was cooled to -70 ° C. Dry While stirring at the same temperature in an argon atmosphere, trimethylsilyl bromide (290 μl 1, 2.2 mmol) was added dropwise. Stirring is continued for a further 1.5 hours and the 2-bromo -5- (4-Fluorophenyl) tetrahydrofuran (203) was prepared and isolated. And used for subsequent chemical treatments without further purification (see below).   In a separate flask, 3-tetrahydropyraniloxy-but-1-yne (370 mg, 2.4 mmol) Was dissolved in dry THF (5 ml). Cool the solution to -60 ° C and in a dry argon atmosphere While stirring at the same temperature, n-butyllithium (1.0 ml, 2.4 mmol) was added dropwise. More added. Stirring was continued for another 0.5 hour. Remove the resulting solution with a syringe and add 2 Add dropwise to the solution of -bromotetrahydrofuran (prepared) at -70 ° C with stirring Added by Stirring was continued at -78 ° C for an additional 1.5 hours. Reaction flask in refrigerator (-78 ° C) overnight (TLC did not show any changes). Anti The reaction mixture was poured into a 2 M solution of ammonium chloride (50 ml) and methylene chloride (3 × 50 ml) was added. ). The solution was dried over sodium sulfate and the solvent was removed under reduced pressure. Residue By flash column chromatography (eluent, 10% ethyl acetate in hexane) To give two components. Proton NMR analysis shows less polar components Is trans-2- (3-tetrahydropyraniloxy-but-1-ynyl) -5- (4-fluoro Rophenyl) tetrahydrofuran (compound 204, 280 mg, 45%) Found that the more polar component (230 mg) was a mixture of two or more compounds Was. This mixture was discarded.<sup>1</sup>H-NMR (CDCl<sub>Three</sub>) δ 7.27 to 7.30 (2H, m), 7.01 (2H, t , J = 8.7 Hz), 5.09 (1H, t, J = 7.1 Hz), 4.91 to 4.95 (2H, m), 4.57 to 4.64 (1H, m), 3.78 to 3.90 (1H, m), 3.50 to 3.60 (1H, m), 2.30 to 2.50 (2H, m), 2.05 to 2.17 ( 1H, m), 1.70 to 1.90 (3H, m), 1.50 to 1.65 (4H, m), 1.48 (3H, d, J = 6.6Hz).   (c): trans-2- (3-hydroxy-but-1-ynyl) -5- (4-fluorophenyl ) Preparation of tetrahydrofuran (compound 205):   Trans-2- (3-tetrahydropyraniloxy-but-1-ynyl) -5- (4-fluoro Phenyl) tetrahydrofuran (compound 204, 280 mg, 0.9 mmol) in methanol (15 ml ). 50 mg of p-toluenesulfonic acid) is added to this solution, The solution was stirred for 45 minutes. Saturated sodium bicarbonate solution (10 ml) was added. 5 minutes of agitation After stirring, the solution was added to 10 ml of water, diluted with 15 ml of brine, and methylene chloride (3 × 30 ml) Extracted. The combined organic extracts are dried over sodium sulfate and the solvent is removed on a rotary evaporator. To remove the trans-2- (3-hydroxy-but-1-ynyl) -5- (4-fluorophenyl Le) tetrahydrofuran (compound 205) 212 mg (100 %).<sup>1</sup>H-NMR (CDCl<sub>Three</sub>) δ 7.29 (2H, dd, J = 8.7,5.2Hz), 7.01 (2H, t, J = 8 .7Hz), 5.09 (1H, t, J = 7.4Hz), 4.92 (1H, t, J = 7.4Hz), 4.59 (1H, q, J = 6.6H) z), 2.30 to 2.50 (2H, m), 2.05 to 2.15 (1H, m), 2.00 (1H, brs), 1.75 to 1.88 (1H , M), 1.47 (3H, d, J = 6.6 Hz).   (d): trans-2- ｛3- (N-phenoxycarbonyloxy-N-phenoxycarboni Ru-amino) -but-1-ynyl} -5- (4-fluorophenyl) tetrahydrofuran ( Preparation of compound 206): trans-2- (3-hydroxy-but-1-ynyl) -5- (4-f (Fluorophenyl) tetrahydrofuran (compound 205, 210 mg, 0.89 mmol), Nylphosphine (288 mg, 1.1 mmol) and N, O-bis (phenoxycarbonyl) Droxylamine (283 mg, 1.1 mmol) was dissolved in dry THF (5 ml). Argon solution Cool to 0 ° C under an atmosphere and diisopropyl azodicarboxylate (216 ml, 1.1 μm ol) was added dropwise. Stirring was continued at the same temperature for 1 hour. Evaporate solvent Flash column chromatography (eluent, 30% vinegar in hexane) Ethyl acid) to give trans-2- ｛3- (N-phenoxycarbonyloxy-N-pheno (Xycarbonyl-amino) -but-1-ynyl-5- (4-fluorophenyl) tetrahi 250 mg (57%) of drofuran (compound 206) were obtained.<sup>1</sup>H-NMR (CDCl<sub>Three</sub>) Δ 7.15 ~ 7.45 (12H, m), 7.02 (2H, t, J = 8.6Hz), 5.32 (1H, q, J = 7.0Hz), 5.07 (1H, t, J = 6 .8Hz), 4.96 (1H, t, J = 5.7Hz), 2.25 to 2.50 (2H, m), 2.05 to 2.20 (1H, m), 1.70 ~ 1.85 (1H, m), 1.66 (3H, d, J = 7.0Hz).   (e): trans-2- {3- (N-hydroxyureidyl) -but-1-ynyl} -5- (4- Preparation of (fluorophenyl) tetrahydrofuran (compound 207):   Trans-2- ｛3- (N-phenoxycarbonyloxy-N-phenoxycarbonyl-a Mino) -but-1-ynyl) -5- (4-fluorophenyl) tetrahydrofuran (206, 2 00 mg, 0.41 mmol) as a solution in methylene chloride in a high pressure tube. Solvent Evaporated using a stream of gon and the residue was cooled to -78 ° C. Ammonium in this tube (8 ml) was concentrated, and 4 ml of t-butanol was added. Seal the tube and slowly warm to room temperature The mixture was left warm and stirred at room temperature for 18 hours. Release pressure very slowly, The tube was left open for one hour. Transfer the residue to a flask and add Twenty rotavapped with toluene. Flash column residue Purify by chromatography (eluent, 3% methanol in ethyl acetate) and separate Purification by preparative TLC (solvent, 5% methanol in methylene chloride) yielded trans-2- ｛3- (N- (Hyoxyureidyl) -but-1-ynyl-5- (4-fluorophenyl) tetrahydride 93 mg (78%) of lofran (compound 207) was obtained. IR (film) 3481, 3269, 2985, 2 877, 2249, 1662, 1670, 1510, 1444, 1224, 1172, 1037 cm-<sup>1</sup>;<sup>1</sup>H-NMR (CDCl<sub>Three</sub>) δ 8.10 (1H, br s), 7.26 (2H, dd, J = 8.6, 5.4Hz), 7.00 (2H, t, J = 8.6Hz), 5 .80 (1H, br, s), 5.00 to 5.20 (2H, m), 4.80 to 5.00 (1H, m), 2.20 to 2.50 (2H, m) , 2.00 to 2.20 (1H, m), 1.70 to 1.90 (1H, m), 1.37 (3H, dd, J = 6.9, 1.9Hz). Example 5   Trans-2- {3- (N-hydroxyureidyl) -but-1-ynyl} -5- (4-fluoro S, S, S- and S, S of (rophenyl) tetrahydrofuran (compounds 216 and 217) Of R, R-isomer   Trans-2- {3- (N-hydroxyureidyl) -but-1-ynyl} -5- (4-fluoro To prepare the S, S, R- and S, S, S-isomers of (phenyl) tetrahydrofuran One method for this is shown in Scheme 9 below.   (a): Preparation of methyl 3- (4-fluorobenzoyl) propionate (compound 209) Made   3- (4-Fluorobenzoyl) propionic acid (1.98 g, 10.0 mmol) in methanol (25 0.5 ml of concentrated sulfuric acid was added to the solution. The resulting solution is placed in an argon atmosphere for 2 hours While stirring. Neutralize the reaction mixture with saturated sodium bicarbonate and rotate methanol It was removed using an evaporator and the residue was dissolved in 50 ml of ethyl acetate. Saturate the resulting solution Wash with sodium bicarbonate (3 × 50 ml) and brine (50 ml) and dry over sodium sulfate After drying, the solvent is removed under reduced pressure and methyl 3- (4-fluorobenzoyl) propione is removed. (2 g, 94%). IR (film) 3448, 3111, 3076, 3003, 3958, 1734, 1678, 1601, 1423, 1300, 1240, 1155, 1099cm<sup>-1</sup>;<sup>1</sup>H-NMR (CDCl<sub>Three</sub>) Δ 7.97 (2H , Dd, J = 9.0, 5.5 Hz), 7.10 (2H, T, J = 8.9 Hz), 3.67 (3H, s), 3.25 (2H, t, J = 6 .6Hz), 2.73 (2H, t, J = 6.6Hz); 13C-NMR (CDCl<sub>Three</sub>) Δ 196.50, 173.34, 167.54, 164.17, 132.98, 130.77, 115.91, 115.62, 51.91, 33.31, 28.00.   (b): Preparation of (S) -5- (4-fluorophenyl) -γ-butyrolactone (Compound 210)   Methyl 3- (4-fluorobenzoyl) propionate (Compound 209, 780 mg, 3.67 (mmol) in dry THF (2 ml) was previously cooled (0 ° C) with stirring under an argon atmosphere. (-)-DIP-chloride (2.02 g, 6.25 mmol) in THF (2 ml) by dropwise addition. Added. The resulting solution was stirred at the same temperature for 2 hours and left overnight at 0-5 ° C. While maintaining the temperature at 0 ° C., water (2 ml) is stirred, followed by methanol (5 ml) and NaOH A 5M solution of (5 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours. , Cooled and added 15 ml of saturated sodium bicarbonate solution. Ate the resulting mixture (3 × 50 ml) and acidified with 6N HCl. Acidic mixture with toluene (3 × 50 ml) Extracted. Wash the combined toluene extract with Brion (50 ml) and wash with sodium sulfate. Dry and remove the solvent under reduced pressure. Resuspend the residue in 50 ml of toluene and add PPTS (10 mg) was added. The resulting solution is transferred to a Dean-Stark trap (15 ml of distillate first). (Discharged) and refluxed for 2 hours. Cool the solution and wash with saturated bicarbonate solution (2 × 50 ml) Dried over sodium sulfate and dissolved The medium was removed under reduced pressure, and 620 mg of (S) -5- (4-fluorophenyl) -γ-butyrolactone ( 94%). 1H-NMR (CDCl<sub>Three</sub>) Δ 7.33 (2H, dd, J = 8.8,5.3Hz), 7.09 (2H, t, J = 8.7Hz), 5.50 (1H, dd, J = 8.4, 5.9Hz), 2.64 to 2.71 (3H, m), 2.17 to 2.22 (1H, m ).   (c): (5S) -2-hydroxy-5- (4-fluorophenyl) tetrahydrofuran Preparation of Compound 211) (S) -5- (4-Fluorophenyl) -γ-butyrolactone (Compound 210 , 620 mg, 3.44 mmol) were dried azeotropically (with hexane) and dried methylene chloride (25 m l) dissolved in The solution was cooled to -78 ° C under stirring in an argon atmosphere, and DIBALH (Torr 3.5 ml of a 1.5 M solution in ene, 5.16 mmol) were added dropwise. Stirring at -78 ° C Continuing for 2 hours, then a saturated solution of potassium sodium tartrate (25 ml) was added. cooling The bath was removed and stirring continued for another 2 hours. Dilute the reaction mixture with methylene chloride (25 ml). I shouted. Separate the organic layer, wash with water (2 × 50 ml) and brine (50 ml), and add sodium sulfate Dry with ium and remove the solvent under reduced pressure to remove 2-hydroxy-5- (4-fluorophenyl L) Tetrahydrofuran (620 mg, 100%) was obtained.<sup>1</sup>H-NMR (CDCl<sub>Three</sub>) Δ 7.30 ~ 7.41 (m, 2H), 7.04 (m, 2H), 5.63 to 5.78 (m, 1H), 5.00 to 5.22 (m, 1H), 2.48 (m, 1H) , 2.20 to 2.32 (m, 1H), 1.95 to 2.10 (m, 1H), 1.79 (m, 1H).   (d): (5S) -2- (t-butyldimethylsilyloxy) -5- (4-fluorophenyl) te Preparation of Trahydrofuran (Compound 212)   (5S) -2-hydroxy-5- (4-fluorophenyl) tetrahydrofuran (compound 21 1,620 mg, 3.5 mmol), t-butyldimethylsilyl chloride (700 mg, 5.25 mmol) and And imidazole (595 mg, 8.75 mmol) were dissolved in 2 ml of dry DMF. The resulting solution Was stirred overnight in a dry argon atmosphere, poured into 200 ml of water, And extracted with a 2: 1 mixture (3 × 100 ml). The combined organic layers were combined with water (4 × 200 ml) and Wash with brine (100 ml), dry over sodium sulfate, remove the solvent under reduced pressure (5S ) -2- (t-Butyldimethylsilyloxy) -5- (4-fluorophenyl) tetrahydro 1 g (96%) of furan (compound 212, a mixture of cis and trans isomers) Obtained as a colorless oil that did not require further purification.<sup>1</sup>H-NMR (CDCl<sub>Three</sub>) Δ 7.40-7.50 ( 2H, m, minor isomer), 7.25 to 7.35 (2H, m, major isomer), 7.00-7.10 (2H, m, both major and minor isomers), 5.71 -5.75 (1H, m, major isomer), 5.59-5.62 (1H, m, minor isomer), 5.12-5.20 (1H, m, major isomer), 4.90 to 4.98 (1H, m, minor isomer), 2.40 to 2.55 (1H, m, both major and minor isomers), 2.05 to 2.17 (1H, m, minor and minor isomers) 1.87 to 2.00 (1H, m, both major and minor isomers), 1.67 to 1. .70 (1H, m, both major and minor isomers), 0.92 (s, 9H, major and minor isomers) 0.16 (s, 6H, both major and minor isomers).   (e): (2S, 5S) -trans-2- (3-t-butyldimethylsilyloxy-but-1-ynyl Preparation of) -5- (4-Fluorophenyl) tetrahydrofuran (Compound 213)   (5S) -2- (t-butyldimethylsilyloxy) -5- (4-fluorophenyl) tetrahi Drofuran (Compound 212, 1 g, 3.4 mmol) was added to dry methylene chloride (argon before use). Degassed by blowing. ) Dissolved in 10 ml. Cool the solution to -70 ° C Trimethylsilyl bromide (550 μl , 4.1 mmol) were added dropwise. Stirring was continued for an additional 1.5 hours. Obtaining lomo-5- (4-fluorophenyl) tetrahydrofuran and isolating it Used (see below). In a separate flask, add 3-t-butyldimethylsilyloxy- But-1-yne (840 mg, 4.5 mmol) was dissolved in dry THF (10 ml). Cool solution to -60 ° C And n-butyllithium (in hexane) at the same temperature and with stirring in an argon atmosphere. A 2.5 M solution (1.8 ml, 4.5 mmol) was added dropwise. Stir for another 0.5 hours Continued. The resulting solution is passed through a cannula and stirred at -70 ° C with 2-bromote. A solution of trahydrofuran (prepared earlier) was added dropwise. Stirring, -7 Continued at 8 ° C. for another 1.5 hours. The reaction flask was left in the refrigerator (-78 ° C) overnight (TLC did not show any changes.) The reaction mixture was treated with 2M ammonium chloride. Poured into the solution (100 ml) and extracted with methylene chloride (3 × 75 ml). Add sodium sulfate solution The solvent was removed under reduced pressure. Flash residue chromatography Purification on a feed (eluent, 10% ethyl acetate in hexane) yielded two components. Step By Roton NMR analysis Component with a lower polarity is (2S, 5S) -trans-2- (3-t-butyldimethylsilyl Xy-but-1-ynyl) -5- (4-fluorophenyl) tetrahydrofuran (compound 2 13,765 mg, 65%).<sup>1</sup>H-NMR (CDCl<sub>Three</sub>) Δ 7.29 (2H, m), 7.01  (2H, t, J = 8.7Hz), 5.09 (1H, t, J = 7.1HZ), 4.91 ~ 4.97 (2H, m), 4.55 ~ 4.62 (1 H, m), 2.26 to 2.50 (2H, m), 2.05 to 2.17 (1H, m), 1.75 to 1.88 (1H, m), 1.38 (3H , D, J = 6.6 Hz), 0.90 (9H, s), 0.12 (6H, s). The more polar components are (2R, 5S) -Cis-2- (3-t-butyldimethylsilyloxy-but-1-ynyl) -5- (4-fluorophenyl Enyl) tetrahydrofuran (Compound 214, 190 mg, 16%).   (f): (2S, 5S) -trans-2- (3-hydroxy-but-1-ynyl) -5- (4-fluoro Preparation of (rophenyl) tetrahydrofuran (compound 215)   (2S, 5S) -trans-2- (3-t-butyldimethylsilyloxy-but-1-ynyl) -5- (4-Fluorophenyl) tetrahydrofuran (compound 213, 765 mg, 2.2 mmol) in THF  Dissolved in 20 ml. The solution was cooled to 0 ° C., and TBAF (6.6 ml of a 1M solution in THF) was added thereto. Was added. The resulting solution was stirred at 0 ° C. for 2 hours and the solvent was removed under reduced pressure. Residue In ethyl acetate (100 ml) and water (3 × 100 ml, in each case 5 ml) and then with brine (50 ml), washed with sodium sulfate and dissolved. The medium is removed under reduced pressure to give (2S, 5S) -trans-2- (3-hydroxy-but-1-ynyl) -5 500 mg (97%) of-(4-fluorophenyl) tetrahydrofuran (compound 215) were obtained. . 1H-NMR (CDCl3) δ 7.29 (2H, dd, J = 8.7, 5.2 Hz), 7.01 (2H, t, J = 8.7 Hz), 5.09 (1H, t, J = 7.4Hz), 4.92 (1H, t, J = 7.4Hz), 4.59 (1H, q, J = 6Hz), 2.30 to 2. 50 (2H, m), 2.05 to 2.15 (1H, m), 1.75 to 1.88 (1H, m), 1.72 (1H, brs), 1.47 (3H , D, J = 6.6 Hz).   (2S, 5S) -trans-2- (3-hydroxy-but-1-ynyl) -5- (4-fluorophen Nyl) tetrahydrofuran (compound 215, 500 mg, 2.13 mmol), (R) -α-methoxy- Phenylacetic acid (1.06 g, 6.4 mmol) and DMAP (86 mg, 0.7 mmol) were dried in methyl chloride (3 ml). DCC (1.5 g, 7.24 mmol) was added and the resulting solution was allowed to cool at room temperature. The mixture was stirred for 3 hours in a gon atmosphere (many white solids precipitated in a few minutes). Solid After filtration, the filtrate was concentrated under reduced pressure. Flush residue Purify by column chromatography (eluent, 8% ethyl acetate in hexane) Two diastereomeric esters were obtained. Those with smaller polarity are (2S, 5S)- -2- {3- (S) -hydroxy-but-1-ynyl} -5- (4-fluorophenyl) tetra Hydrofuran (compound 216, 250 mg, 30%,<sup>1</sup>More than 95% from H-NMR) Was.<sup>1</sup>H-NMR (CDCl<sub>Three</sub>) Δ 7.25 to 7.50 (7H, m), 7.02 (2H, t, J = 8.5Hz), 5.52 to 5.60 (1H, m), 5.06 (1H, t, J = 6.8 Hz), 4.88 to 4.94 (1H, m), 4.78 (1H, s), 3.43 (3H, s), 2.25 to 2.47 (2H, m), 2.00 to 2.13 (1H, m), 1.75 to 1.88 (1H, m), 1.37 (3 H, d, J = 6.7 Hz). Those with higher polarity are (2S, 5S) -trans-2--3- (R) -hydrid Roxy-but-1-ynyl-5- (4-fluorophenyl) tetrahydrofuran (compound 217, 230mg, 29%,<sup>1</sup>(H-NMR: 72%).<sup>1</sup>H-NMR (CDCl<sub>Three</sub>) Δ 7.22 ~ 7.50 (7H, m), 7.01 (2H, t, J = 8.7Hz), 5.50 ~ 5.60 (1H, m), 4.98 (1H, t, J = 7.2Hz), 4.79 to 4.85 (1H, m), 4.79 (1H, s), 3.44 (3H, s), 2.20 to 2.40 (2H, m) , 1.88 to 1.98 (1H, m), 1.72 to 1.80 (1H, m), 1.51 (3H, d, J = 6.7 Hz). These two The two esters are subjected to basic hydrolysis (3 KOH in 10 ml of a 1 M ethanol solution at 50 ° C.). After stirring for 0 minutes and performing the usual treatment), each alcohol (2S, 5S) -trans-2- {3- (S) -hydroxy-but-1-ynyl} -5- (4-fur Orophenyl) tetrahydrofuran (compound 218, 150 mg, 98%) and its dia Stereomer (2S, 5S) -trans-2- {3- (R) -hydroxy-but-1-ynyl} -5- (4 (-Fluorophenyl) tetrahydrofuran (compound 221, 50 mg, 100%) was obtained. Of both these alcohols<sup>1</sup>The H-NMR spectrum was identical to that of 218.   (g): (2S, 5S) -trans-2- ｛3- (R)-(N-phenoxycarbonyloxy-N-pheno (Xycarbonyl-amino) -but-1-ynyl-5- (4-fluorophenyl) tetrahi Preparation of Drofuran (Compound 219)   (2S, 5S) -trans-2- {3- (S) -hydroxy-but-1-ynyl} -5- (4-fluoro Phenyl) tetrahydrofuran (compound 218, 150 mg, 0.64 mmol), triphenyl Phosphine (200 mg, 0.77 mmol) and N, O-bis (phenoxycarbonyl) hydro Xylamine (200 mg, 0.77 mmol) was dissolved in dry THF (3 ml). The solution was cooled to 0 ° C., and diisopropyl alcohol was added thereto under stirring in a dry argon atmosphere. Zodicarboxylate (142 μl, 0.77 mmol) was added dropwise. Stirring Continued at the same temperature for 1 hour. The solvent is evaporated on a rotary evaporator and the residue is flash Purify by ram chromatography (eluent, 30% ethyl acetate in hexane) (2S , 5S) -trans-2- ｛3- (R)-(N-phenoxycarbonyloxy-N-phenoxycarbo Nyl-amino) -but-1-ynyl) -5- (4-fluorophenyl) tetrahydrofuran 225 mg (72%) of (219) were obtained.<sup>1</sup>H-NMR (CDCl<sub>Three</sub>) Δ 7.15 to 7.45 (12H, m), 7.02 (2H, t , J = 8.6 Hz), 5.32 (1H, q J = 7.0 Hz), 5.07 (1H, t, J = 6.8 Hz), 4.96 (1H, t, J = 5.7Hz), 2.25 to 2.50 (2H, m), 2.05 to 2.20 (1H, m), 1.70 to 1.85 (1H, m), 1.66 ( 3H, d, J = 7.0Hz).   (h): (2S, 5S) -trans-2- ｛3- (S)-(N-phenoxycarbonyloxy-N-pheno (Xycarbonyl-amino) -but-1-ynyl-5- (4-fluorophenyl) tetrahi Preparation of Drofuran (Compound 222)   (2S, 5S) -trans-2- {3- (R) -hydroxy-but-1-ynyl} -5- (4-fluoro Phenyl) tetrahydrofuran (compound 221, 150 mg, 0.64 mmol) According to a procedure similar to 218, (2S, 5S) -trans-2- ｛3- (S)-(N-phenoxy Boniloxy-N-phenoxycarbonyl-amino) -but-1-ynyl｝ -5- (4-fluoro (Phenyl) tetrahydrofuran (compound 222) was obtained. 1H-NMR is identical to 219 Was.   (i): (2S, 5S) -trans-2- ｛3- (R)-(N-hydroxyureidyl) -but-1-i Nyl｝ -5- (4-fluorophenyl) tetrahydrofuran (CMI-947) (Compound 220 Preparation of:   (2S, 5S) -trans-2- ｛3- (R)-(N-phenoxycarbonyloxy-N-phenoxy Carbonyl-amino) -but-1-ynyl-5- (4-fluorophenyl) tetrahydro Furan (Compound 219, 225 mg) was dissolved in a high pressure tube as a solution in methylene chloride. The solvent was evaporated with a stream of argon and the residue was cooled to -78 ° C. Ammonium in this tube 10 ml was concentrated and 2 ml of t-butanol was added. Seal the tube and slowly reach room temperature It was left warm. It was allowed to stir at room temperature for 18 hours. Pressure very slowly And left the tube open for one hour. Transfer the residue to a flask, Toluene was added and the mixture was concentrated twice under reduced pressure. The residue was separated by preparative TLC (eluent, methyl chloride (2S, 5S) -trans-2- ｛3- (R)-(N-hydroxy Siureidyl) -but-1-ynyl-5-5- (4-fluorophenyl) tetrahydrofura (CMI-947, 220) 120 mg (90%) was obtained. IR (film) 3209, 2985, 2874, 165 3,1510,1449,1336,1224,1157,1037cm<sup>-1</sup>,<sup>1</sup>H-NMR (CD3 OD) δ 7.34 (2H, dd , J = 8.7, 5.4 Hz), 7.04 (2H, t, J = 8.8 Hz), 5.00 to 5.10 (2H, m), 4.85 to 4.95 (1 H, m), 2.25 to 2.50 (2H, m), 2.00 to 2.15 (1H, m), 1.78 to 1.85 (1H, m), 1.38 (3H , D, J = 7.0 Hz).   (j): (2S, 5S) -trans-2- ｛3- (S)-(N-hydroxyureidyl) -but-1-i Nyl｝ -5- (4-fluorophenyl) tetrahydrofuran (CMI-948) (compound 223) Preparation:   (2S, 5S) -trans-2- ｛3- (S)-(N-phenoxycarbonyloxy-N-phenoxy Carbonyl-amino) -but-1-ynyl-5- (4-fluorophenyl) tetrahydro Starting from furan (compound 222, 225 mg), following the same procedure as for 219, (2S, 5S ) -Trans-2- {3- (S)-(N-hydroxyureidyl) -but-1-ynyl} -5- (4-f 110 mg (83%) of (fluorophenyl) tetrahydrofuran (CMI-948,223) were obtained. I R (film) 3200, 2985, 2881, 1643, 1510, 1442, 1222, 1035cm<sup>-1</sup>; 1H-NMR (CD3 OD) δ 7.34 (2H, dd, J = 8.7, 5.5 Hz), 7.04 (2H, t, J = 8.9 Hz), 5.00 to 5. 10 (2H, m), 4.85 to 4.95 (1H, m), 2.25 to 2.50 (2H, m), 2.00 to 2.15 (1H, m), 1.70 ~ 1.85 (1H, m), 1.38 (3H, d, J = 7.0Hz). Example 6   Trans-2- {3- (N-hydroxyureidyl) -but-1-ynyl} -5- (4-fluoro R, R, S- and R, R, R-isomers of (rophenyl) tetrahydrofuran (compound 234 And 236)   Trans-2- {3- (N-hydroxyureidyl) -but-1-ynyl} -5- (4-fluoro S, S, R- and S, S ,. Prepare S-isomer One method for this is shown in Scheme 10 below.   (a) of 4- (4-fluorophenyl) -4-oxo-methylbutanoate (compound 209) Preparation   To a solution of 3- (4-benzoyl) propionic acid (208) (5.0 g) in methanol (20 ml), Under stirring, a few drops of sulfuric acid were added. After stirring overnight (19 hours), the reaction was Neutralized with aqueous sodium carbonate and the methanol was removed under reduced pressure. The residue was treated with acetate Dissolved in chill (50 ml), saturated aqueous sodium bicarbonate solution (3 x 15 ml), water (2 x 15 ml) and And brine (2 x 15 ml), dry (Na<sub>Two</sub>SO<sub>Four</sub>), Filtered and concentrated to a pale crystalline A solid (5.3 g, 98%) was obtained.<sup>1</sup>H-NMR: 2.79 (t, 2H), 3.30 (T, 2H), 3.71 (S, 3H) , 7.14 (T, 2H), 8.02 (m, 2H).   (b): Preparation of R-4- (4-fluorophenyl) -γ-butyrolactone (compound 224)   Cooled (0 ° C.) solution of (+)-DIP chloride (25 g, 77.9 mmol) in dry THF (20 ml) The keto-ester 209 (10.07 g, 48.0 mmol) was dried in an argon atmosphere with stirring. A solution in dry THF (20 ml) was added slowly. Place the reaction mixture in a refrigerator (4 ° C) for 30 hours Then return to the ice bath and stir with water (10 ml), methanol (30 ml) and 10% aqueous NaOH The liquid (60 ml) was added. The ice bath was removed. When all of the esters are hydrolyzed, An aqueous solution of sodium bicarbonate (80 ml) was added. Extract the aqueous solution with ether (2 × 100 ml) Discharged, then acidified to pH 2 and extracted with benzene (2 × 180 ml). Combined benzene layer Pyridinium-p-toluenesulfonate (60 ml) was added to The mixture was heated to reflux using a work trap. When the reaction is completed, the benzene solution is Wash with saturated aqueous sodium bicarbonate (150 ml) and brine (2 × 50 ml) and dry (Na<sub>Two</sub> SO<sub>Four</sub>), Filtered and concentrated to give a white crystalline solid (7.92 g, 91%), which was It was confirmed to be an R structure based on the literature.<sup>1</sup>H-NMR: 2.10 to 2.25 (m, 1H), 2.68 (m, 3H), 5.50 (m, 1H), 7.08 (t, 2H), 7.30 (m, 2H).   (c): cis and trans-5R-5- (4-fluorophenyl) -2-hydroxytetra Preparation of hydrofuran (compound 225)   Drying of lactone 224 (7.25 g, 40.3 mmol) cooled in a dry ice / acetone bath Diisobutylaluminum hydride in a solution in dry toluene (50 ml) under stirring (1.5 M solution in toluene) (1.5 eq, 40 ml) was added. When the reaction is complete , Methanol (10 ml) was added slowly, then saturated sodium L-tartrate potassium Aqueous solution (60 ml) was added and the ice bath was removed. This solution was stored overnight (16 hours), The layers were separated and the aqueous fraction was extracted with ethyl acetate (2x50ml). Combined organic The layers were washed with water (3 × 30 ml) and brine (3 × 30 ml) and dried (Na<sub>Two</sub>SO<sub>Four</sub>), Filter and concentrate Shrunk. The product is a colorless oil (6/50) which is a mixture of two diastereomers (50/50). .32g, 86%).<sup>1</sup>H-NMR: 1.7 (m, 1H), 1.9 to 2.3 (m, 2H), 2.42 (m, 1H), 3 .60 (bs, 0.5H), 3.72 (bs, 0.5H), 4.98 (t, 0.5H), 5.20 (t, 0.5H), 5.60 (bs, 0. 5H), 5.72 (m, 0.5H), 7.00 (t, 2H), 7.25 (m, 1H), 7.40 (m, 1H).   (d): cis and trans-5R-5- (4-fluorophenyl) -2-t-butyldimethyl Preparation of Siloxytetrahydrofuran (Compound 226):   To a solution of lactol 225 (6.32 g, 34.7 mmol) in methylene chloride (140 ml) under stirring , Imidazole (1.1 equivalents, 38.2 mmol, 2.60 g)) and TBD <S chloride (5.77 g) Was added. After stirring overnight, the reaction was filtered and concentrated. The crude product is A colorless oil which is filtered through a plug and is a mixture of two diastereomers (2: 1) (9.61 g, 93%).<sup>1</sup>H-NMR: 0.14 (s, 6H), 0.92 (s, 9H), 1.7 (m, 1H) , 1.9 to 2.2 (m, 2H), 2.4 to 2.5 (m, 1H), 4.9 (m, 0.33H), 5.16 (t, 0.66H), 5.59 ( m, 0.33H), 5.71 (dd, 0.66H), 7.00 (m, 2H), 7.25 (m, 1.33H), 7.40 (m, 0.66H) .   For a sample of this compound having a racemic mixture and a 5-position modification, The presence of each structure in the heart is determined by the use of a chiral solvating agent [2,2,2-trifluoro-1- (9-an Thrill) ethanol, 2.2 mg base, 40 mg CSA]. This These conditions indicated that compound 226 had no detectable amount of the 5S isomer.   As a control, a 2: 1 diastereomer mixture of compound 226, which is a racemic mixture at position 5, The compound (2.2 mg) was treated with CSA (40 mg). 4.86 to 4.92 ppm (0.33H) multiplet Resulted in two multiplets at 4.64 to 4.72 and 4.78 to 4.84 ppm. For other diastereomers (same spectrum), 5.66- The doublet at 5.70 ppm was doubled at 5.64-5.68 and 5.70-5.74 ppm. Became a pair of dd. For compounds with reduced chiral, small at 4.62 to 4.70 Multiplet (W / CSA) appears, double doublet at 5.68-5.70 ppm It is. No evidence of other isomers was found.   (e): 2R, 5R-trans-5- (4-fluorophenyl) -2- (3-t-butyldimethylsi Preparation of (roxy-1-butynyl) tetrahydrofuran (compound 227):   Dissolve 226 (500 mg, 1.69 mmol) in dry degassed methylene chloride (10 ml) cooled to -78 ° C. To the solution was added TMS bromide (0.25 ml, 1.86 mmol). This was stirred for 4 hours. 3-t Another solution containing -butyldimethylsiloxy-1-butyne (0.31, 1.68 mmol) and THF (5 ml) To the flask was added n-butyllithium (1.6 M in hexane, 1.26 ml, 2.02 mmol) . After 30 minutes, the solution was transferred to the solution by cannula. After 2 hours, the reaction solution was Pour into aqueous ammonium chloride (25 ml), extract into methylene chloride (3 × 25 ml), Dry (Na<sub>Two</sub>SO<sub>Four</sub>), Filtered and concentrated. Flash chromatography (hexane (5% ethyl acetate in) to give the trans product as a clear oil (280 mg, 48%). Was.<sup>1</sup>H NMR: 0.17 (d, 6H), 0.91 (s, 9H), 1.42 (d, 3H), 1.8 (m, 1H), 2.25 to 2.5 0 (m, 2H), 4.58 (m, 1H), 4.91 (m, 1H), 5.09 (m, 1H), 7.0 (t, 2H), 7.30 (m, 2H) .   (f): 2R, 5R-trans-5- (4-fluorophenyl) -2- (3-hydroxy-1-butyi Preparation of nyl) tetrahydrofuran (compound 228):   With stirring of a solution of 227 (0.38 g, 1.1 mmol) in THF (5 ml) cooled in an ice bath, Labutylammonium fluoride (0.86 g, 3.3 mmol) was added. Remove the ice bath Was. After 30 minutes, the solvent is removed and the product is flash chromatographed (hex (25% ethyl acetate in toluene). The product is a colorless oil (170 mg, 67%). Was.<sup>1</sup>H NMR: 1.48 (d, 3H), 1.8 (m, 1H), 2.1 (m, 1H), 2.3 to 2.5 (m, 2H), 4.58 (m, 1H), 4.91 (t, 1H), 5.1 (t, 1H), 7.0 (t, 2H), 7.29 (m, 2H).   The hydroxy function of 228 was converted to R-alpha-methoxyphenylacetic acid (DDC, DMAP, CH<sub>Two</sub> Cl<sub>Two</sub>, 55%) after esterification to give the diastere Separation (flash chromatography) of the rheomers (229 + 230) The R and S isomers at the carbitol carbon were isolated. Ester to base Removal by digestion (KOH, 78%) provided carbinols 231 and 232. MosHeR model And the complete structure was confirmed.   (g): 2R, 5R-trans-5- (4-fluorophenyl) -2- (3R-3-N, O-bispheno Xycarbonylhydroxylamino-1-butynyl) tetrahydrofuran (compound Preparation of compound 233):   Cooled (ice bath) 2R, 5R-trans-5- (4-fluorophenyl) -2- (3S-3-H (Droxy-1-butynyl) tetrahydrofuran (231) (29 mg, 0.12 mmol), triphenyl Luphosphine (39 mg, 0.15 mmol) and N, O-bisphenoxycarbonyl hydro Diisopropyl azodica was added to a solution of xylamine (37 mg, 0.14 mmol) in THF (3 ml). Ruboxylate (0.029 ml, 0.15 mmol) was added slowly. Remove the ice bath and anti Upon completion of the reaction (several minutes), the solvent was removed. Product is flash column chromatographed Chromatography (15% ethyl acetate in hexane) gave a colorless oil (32 mg, 53%). I got it.<sup>1</sup>H NMR: 1.65 (d, 3H), 1.8 (m, 1H), 2.1 (m, 1H), 2.4 (m, 2H), 4.94 ( m, 1H), 5.08 (m, 1H), 5.30 (m, 1H), 7.0 (t, 2H), 7.15 to 7.40 (m, 2H).   (h): 2R, 5R-trans-5- (fluorophenyl) -2- (3R-3-N-hydroxyuree Preparation of (idyl-1-butynyl) tetrahydrofuran (compound 234):   Compound 233 (32 mg) at −78 ° C. in a screw-capped vessel equipped with a stir bar , Condensed ammonia (about 3 ml) and t-butanol (about 2 ml). Close the container Sealed and removed cooling bath. After stirring at room temperature overnight, the pressure was released and the solvent was removed . Triturate the product (25% ethyl acetate in hexane) to give a white solid (14mg, 74%) Was. 1H NMR: 1.41 (d, 3H), 1.8 (m, 1H), 2.1 (m, 1H), 2.3 to 2.5 (m, 2H), 4.93 (t , 1H), 5.08 (t, 1H), 5.20 (m, 1H), 5.38 (bs, 1H), 7.0 (t, 2H), 7.29 (m, 2H). Electric spray MS: M + 1 = 293   Synthesis of the RRS isomer from ester 230 (CMI-957) was performed using the RRR isomer from ester 29. The synthesis was performed in the same manner as in the synthesis of (CMI-954). Example 7   2S, 5S-trans-2- (4-fluorophenoxymethyl) -5- (4-N-hydroxy Reidyl-1-butynyl) tetrahydrofuran (Compound 1, Fig. 4) and 2S, 5R-Tora 2- (4-fluorophenoxymethyl) -5- (4-N-hydroxyureidylbutyl) ) Preparation of tetrahydrofuran (compound 402, Fig. 4)   4S- (4-fluorophenoxymethyl) -γ-butyrolactone (Compound 301, Fig. 4) Preparation of (S) -γ-butyrolactone (1.0 g, 8.61 mmol), 4-fluorophenol (1.16 g , 10.35 mmol) and triphenylphosphine (2.49 g, 9.49 mmol) in THF (10 ml). The solution was stirred with diisopropoxyl azodicarboxylate (1.87 μl, 9.46 mmol ) Was added dropwise. After the addition, the reaction mixture was stirred at 80 ° C. for 16 hours . The solvent was removed and the product was flash chromatographed (silica, 2: 1 hex). (Sun / ethyl acetate) (1.38 g, 76.3%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 2.27 (m, 1H); 2.42 (m, 1H); 2.60 (m, 1H); 4.04 (m, 1H); 4.15 (m, 1H); 4.85 (m, 1H); 6. 84 (m, 2H); 6.98 (m, 2H).   2S- (4-fluorophenoxymethyl) -5-hydroxy-tetrahydrofuran Preparation of compound 302, Fig. 4)   A solution of lactone 301 (1.38 g, 27.22 mmol) in dry toluene (24 ml) was stirred with -78 At 1.5 ° C, a 1.5 M solution of DIBALKH in toluene (6.76 ml, 10.13 mmol) was added dropwise. I got it. The reaction mixture was stirred at -78 ° C for 2 hours. Keep the reaction below -60 ° C. While quenching, the mixture was quenched by the addition of additional methanol (1.7 ml). Cool mixture to -20 ° C And saturated sodium potassium tartrate while maintaining the reaction temperature at -10 to 0 ° C. Aqueous solution (10 ml) was added. The reaction mixture is stirred overnight at room temperature, then the two phases are separated. Released. The aqueous layer was extracted with ethyl acetate. Wash the combined organic layers with water and saturated NaCl solution And then concentrated under reduced pressure to give an oil, which was purified by flash column chromatography. -(Silica, 1: 1 hexane / ethyl acetate) (1.41 g, 101%).<sup>1</sup>H NM R (CDCl<sub>Three</sub>): 1.80 (m, 1H); 2.05 (m, 2H); 2.26 (m, 1H); 3.93 (m, 2H); 4.04 (m, 2H) ); 4.47 (m, 0.5H); 4.61 (m, 0.5H); 5.57 (m, 0.5H); 5.66 (m, 0.5H); 6.88 (m, 2H ); 6.98 (m, 2H) .   2S- (4-fluorophenoxymethyl) -5- (t-butyldimethylsiloxy) tetrahi Preparation of Drofuran (Compound 303, Fig. 4)   A solution of lactol 302 (1.41 g, 6.65 mmol) in methylene chloride (25 ml) was stirred under stirring. Add midazole (498.1 mg, 7.32 mmol) and TBDMS chloride (1.10 g, 7.32 mmol). Added. The reaction mixture was stirred at room temperature overnight, then the reaction was filtered and the filtrate was concentrated. Was. Flash color the crude product using 9: 1 hexane / ethyl acetate as solvent. Of the two diastereomers (approximately 2: 1) A colorless oil (1.22 g, 56.2%) was obtained as a mixture.<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 0.11 (s, 6H);  0.90 (s, 9H); 1.80 to 2.10 (m, 3H); 2.22 (m, 1H); 3.91 (m, 2H); 4.38 (m, 0.33H ); 4.50 (m, 0.67H); 5.52 (m, 0.33H); 5.59 (m, 0.67H); 6.86 (m, 2H); 6.96 (m, 2H).   2S, 5S-trans-2- (4-fluorophenoxymethyl) -5- (4-t-butyldimethylene Lucyloxy-1-butynyl) tetrahydrofuran (compound 304, FIG. 4) and 2S, 5R -Cis-2- (4-fluorophenoxymethyl) -5- (4-t-butyldimethylsiloxy-1- Preparation of (butynyl) tetrahydrofuran (compound 305, FIG. 4)   To a solution of 303 (720 mg, 2.21 mmol) in dry methylene chloride (10 ml) cooled to -78 ° C Under stirring, TMS bromide (349.8 μl, 2.65 mmol) was added. The reaction mixture was cooled to -78 ° C. For 4 hours. 4-t-butyldimethylsiloxy-1-butyne (812.8 mg, 4.42 mmol) And another flask containing THF (10 ml), n-butyllithium (2.5 M in hexane, 2. 65 ml, 6.63 mmnol) was added. After 30 minutes, transfer the solution to the solution by cannula. Was. Two hours later, the reaction solution was added with a saturated aqueous solution of ammonium chloride, and then added with methylene chloride. Extracted, dried over mgSO4, filtered and concentrated. Flash column chromatograph (Silica, 95: 5 hexane / ethyl acetate) to give two products: Lance compound 304 (210 mg) and cis compound 305 (160 mg) and the combination of these two compounds A mixture (50 mg) was obtained. The total yield is 48.5%.<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 304: 0.10 (s, 6H); 0.91 (s, 9H); 1.87 (m, 1H); 2.01 (m, 1H); 2.22 (m, 2H); 2.43 (t, 2H); 3. 72 (t, 2H); 3.92 (d, 2H); 4.47 (m, 1H); 4.73 (m, 1H); 6.86 (m, 2H); 6.95 (t, 2 H) .305: 0.09 (s, 6H); 0.90 (s, 9H); 1.92 to 2.20 (m, 4H); 2.42 (m, 2H); 3.70 (t, 2H); 3.92 ( m, 1H); 4.07 (m, 1H); 4.29 (m, 1H); 4.62 (m, 1H); 6.86 (m, 2H); 6.96 (t, 2H) .   In preparing compounds 304 and 305, one skilled in the art will be aware of other than 4-t-butyldimethylsilyl. Oxygen protecting groups known to those skilled in the art can be used if desired.   To determine the stereochemistry of this molecule, NOE difference experiments were performed on both 304 and 305. went. In 304 NOE difference experiment, multiplet at 4.73 ppm To emit a low specific frequency decoupling pulse and measure the presence of an increase in signal Data was collected only for. This represents a positive NOE effect and the parent of these protons. Show close spatial relationships. In this experiment, to 2.22 ppm which is a furan ring proton NOE was discovered about multiplets in Where the multi at 4.47 ppm Irradiate the applet with a very low specific frequency decoupling pulse to increase the signal. Data was collected only to determine location. 2.22pp which is a furan ring proton A NOE was found for the multiplet at m. Also, this multiplet The proton at 3.92 ppm, which is a proton on methylene close to One NOE was discovered, indicating that this multiplet had It indicates that it represents Roton.   Very low specificity for triplets at 4.62 ppm in 305 NOE difference experiments Irradiate a wavenumber decoupling pulse and decouple only to determine the presence of an increase in signal. Data was collected. This represents a positive NOE effect, the intimate space of these protons Show the relationship. In this experiment, the other methine furan proton, 4.29 ppm, NOE was discovered about multiplets in It is also furan proton 2 Another NOE was seen for the multiplet at .17 ppm. Where 4.29p irradiates the multiplet at pm with a very low specific frequency decoupling pulse Data collection was performed only to determine the presence of an increase in signal. Other methinefs NOE was found for a triplet at 4.62 ppm, which is a run proton. Ma 3.92 and 4.07, the protons on methylene adjacent to this multiplet Another NOE was found for protons in ppm, which indicates Proto with pret close to methylene Indicates that the In addition, the malon at 2.11 ppm which is furan proton Another NOE was seen for chiplets.   2S, 5S-trans-2- (4-fluorophenoxymethyl) -5- (4-t-hydroxy-1- Preparation of (butyl) tetrahydrofuran (compound 306, Fig. 4)   A solution of 304 (210 mg, 0.54 mmol) in THF (1.4 ml) cooled in an ice bath was stirred while stirring. Trabutylammonium fluoride (420.3 mg, 1.61 mmol) was added. Ice bath Removed and the reaction was stirred at room temperature for 1 hour. Remove solvent and flash Separation by chromatography (silica, 1: 1 hexane / ethyl acetate) (124 m g, 83.2%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.88 (m, 1H); 2.02 (m, 1H); 2.25 (m, 2H); 2.50 (m , 2H); 3.72 (t, 2H); 3.93 (d, 2H); 4.48 (m, 1H); 4.76 (m, 1H); 6.84 (m, 2H); 6.96 (t, 2H).   2S, 5S-trans-2- (4-fluorophenoxymethyl) -5- (4-N, O-bispheno Xycarbonylhydroxylamino-1-butynyl) tetrahydrofuran (Compound 3 07, Preparation of FIG. 4)   Compound 306 (124.0 mg, 0.45 mmol) cooled (ice bath), triphenylphosphine (128.9 mg, 0.49 mmol) and N, O-bisphenoxycarbonyl hydroxylamido (147.3 mg, 0.54 mmol) in THF (5 ml) was added to diisopropoxyl-azodicarbo. Xylate (94.1 μl, 0.48 mmol) was added. Remove the ice bath and allow the reaction to reach room temperature. Warmed and stirred at room temperature for 30 minutes. Remove solvent and purify product by flash column chromatography Purification by chromatography (silica, 4: 1 hexane / ethyl acetate) (195 mg, 8 2.0%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.85 (m, 1H); 2.03 (m, 1H); 2.22 (m, 2H); 2.75 (m, 2H ); 3.92 (d, 2H); 4.05 (m, 2H); 4.47 (m, 1H); 4.76 (m, 1H); 6.84 (m, 2H); 6.95 (m, 2H); 7.26 (m, 5H); 7.41 (m, 5H).   2S, 5S-trans-2- (4-fluorophenoxymethyl) -5- (4-N-hydroxy Preparation of Reidyl-1-butynyl) tetrahydrofuran (Compound 401, FIG. 4)   NH at -78 ° C in a container with a head screw<sub>Three</sub>(About 1-2 ml). Methaneau Compound 307 (195.0 mg, 0.37 mmol) previously dissolved in 20 ml Added to cold liquid nitrogen. The vessel was sealed and the dry ice bath was removed. Reaction mixture The mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled again in a dry ice bath and Pulled out. The container was opened and the solvent was removed. Using ethyl acetate as the solvent for the product Solid by flash column chromatography (108 mg, 91.7%) I got<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.84 (m, 1H); 2.01 (m, 1H); 2.22 (m, 2H); 2.55 (t, 2H) 3.75 (t, 2H); 3.94 (m, 2H); 4.48 (m, 1H); 4.74 (t, 1H); 5.25 (bs, 2H); 6.86 (m, 2H); 6.98 (m, 2H).   2S, 5S-trans-2- (4-fluorophenoxymethyl) -5- (4-N-hydroxy Preparation of Reidyl-1-butynyl) tetrahydrofuran (Compound 402)   Compound 1 (75 mg, 0.23 mmol) was dissolved in 2 ml of ethyl acetate and then Pd / C (10%) (15 mg) Was added and hydrogenated at balloon pressure for 16 hours. The reaction was filtered and the filtrate was concentrated. Flash column chromatography using ethyl acetate as the solvent More isolated (70 mg, 92.2%).<sup>1</sup>H NMR (CDCl<sub>Three</sub>): 1.50 to 1.70 (m, 8H); 2.10 (m, 2H ); 3.58 (m, 2H); 3.91 (m, 2H); 4.08 (m, 1H); 4.40 (m, 1H); 5.15 (bs, 2H); 6.8 7 (m, 2H); 6.97 (t, 2H); 7.40 (bs, 1H). II. Pharmaceutical composition   Inflammatory diseases, especially those mediated by PAF or 5-lipoxygenase products Humans, horses, dogs, cattle and other animals, particularly mammals, suffering from oxygen In a pharmaceutically acceptable carrier or diluent that reduces the formation of dikar One or more of the above compounds, pharmaceutically acceptable derivatives or salts thereof Can be treated by administering to these patients an effective amount of Active material Liquid, cream, gel or solid or aerosol, any suitable By route, for example, oral, parenteral, intravenous, intradermal, subcutaneous or topical be able to.   As used herein, the term "pharmaceutically acceptable salt or complex" Retains the desired biological activity of the compound and minimizes the undesirable toxicological effects. Means the salt or complex shown. Non-limiting examples of such salts include (a) inorganic acids (eg, For example, acid formed with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid Addition salts and acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoate Perfume acid, tannic acid, pamoic acid, arginic acid, polyglutamic acid, naphthalene Sulfonic acid, naphthalenedisulfonic acid and polygalacturonic acid (polygalactu (b) zinc, calcium, bismuth , Barium, magnesium, aluminum, copper, cobalt, nickel, cadmium Metal cations such as sodium, potassium and the like, or ammonia, N , N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium Base addition salts formed with cations formed from ethylene or diamine; Or (c) a combination of (a) and (b), such as zinc tannate. Compound The products may also be pharmaceutically acceptable quaternary salts known to those skilled in the art, in particular, of the formula -NR<sub>Three</sub> <sup>+</sup> Wherein R is alkyl or benzyl, and Z is chloride, bromide, Azide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfone Phosphate, phosphate or carboxylate (eg, benzoate, succinate Salt, acetate, glycolate, maleate, malate, citrate, tarta Rate, ascorbate, benzoate, cinnamoate, manderoate, And diphenyl acetate). ) Can also be administered as quaternary ammonium salts, including:   The active compound does not cause severe toxic effects in the treated patient A pharmaceutically acceptable carrier in an amount sufficient to be dispensed to the patient in a therapeutically effective amount. Layer or diluent. Preferred active compounds for all of the above symptoms The dosage is about 10 ng / kg to 300 mg / kg per day, preferably 0.1 to 100 mg / kg, more generally Specifically, it is 0.5 to about 25 mg / kg of the patient's body weight per day. Cardiovascular indications The preferred dosage for is 10 ng / kg to 20 mg / kg. Typical topical dosages are appropriate It is 0.01-3% by weight / weight in the carrier. Pharmaceutically acceptable derivatives Effective dose ranges can be calculated based on the weight of the parent compound to be administered. You. If the derivative is active itself, the effective dose is determined using the weight of the derivative. Estimate as described above or use other means known to those skilled in the art. Can be.   The compound may be, but is not limited to, 1 to 3000 mg, preferably 5 to 3 mg per unit dosage form. Conveniently administered in any suitable unit dosage form, including those containing 500 mg of active ingredient. It is. It is usually convenient for oral dosages to be between 25 and 250 mg.   Preferably, the active ingredient has an activation of about 0.00001-30 mM, preferably about 0.1-30 μM Administered to achieve peak plasma concentration of the compound. This is, for example, if necessary By intravenous infusion of a solution or composition of the active ingredient contained in saline or aqueous media. Alternatively, it may be achieved by administration of the active ingredient as a bolus.   The concentration of the active compound in the drug composition determines the absorption, distribution, inactivation and secretion of the drug. It depends on speed, as well as other factors known to those skilled in the art. Severe symptoms to be alleviated It should be noted that the dosage also varies with this. In addition, any special Also the professional judgment and personal judgment of the person who controls or supervises the administration of the composition. That specific doses should be adjusted over time according to human needs, and The concentration ranges disclosed herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions. It is to be understood that no restrictions are intended. Active ingredient is administered at once Or split into many smaller doses to be administered at varying time intervals Can be.   Oral compositions will usually be included in an inert diluent or an edible carrier. Those Can be enclosed in gelatin capsules or compressed into tablets. Oral cure For the purpose of therapeutic administration, the active compound can be incorporated with excipients, tablets, troches or lozenges. It can be used in capsule form. Pharmaceutically compatible binders and / or An adjuvant material can be included as part of the composition.   Tablets, pills, capsules and troches etc. are similar in any of the following properties: Or compounds may be included: microcrystalline cellulose, gum tragacanth or Or a binder such as gelatin; an excipient such as starch or lactose; algin Dispersing agents such as acid, Primogel or corn starch; magnesium stearate or Or a lubricant such as Sterotes; a lubricant such as colloidal silicon dioxide; Sweeteners such as sugar or saccharin; or peppermint, methyl salicylate Flavors such as orange or orange flavors. If the dosage unit form is a capsule, Liquid carriers such as fatty oils in addition to Can be taken. In addition, dosage unit forms are species that modify the physical form of the dosage unit. Can contain various other materials, such as sugar coatings, shellac or enteric agents .   The active compound or a pharmaceutically acceptable salt or derivative thereof is elixir, May be administered as a component such as a suspension, syrup, wafer or chewing gum it can. Syrup contains, in addition to the active ingredient, sucrose as a sweetening agent and Certain preservatives, dyes and colorings and flavoring may be included.   The active compound or a pharmaceutically acceptable salt or derivative thereof has the desired effect. Other active materials that do not impair, or antibiotics, antifungals, other anti-inflammatory or anti- It can also be used in admixture with materials that supplement the desired effect, such as irritating compounds. You.   Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical application are: The following components can be included: water for injection, saline solution, fixed oil, poly Of ethylene glycol, glycerin, propylene glycol or other synthetic solvents A sterilizing diluent such as; a bactericide such as benzyl alcohol or methyl paraben; Antioxidants such as ascorbic acid or sodium bisulfite; ethylene dia Chelating agents such as mintetraacetic acid; acetate, citrate or phosphate Adjust buffer and tonicity like sodium chloride or dextrose Drugs to do. Parenteral preparations can be taken in ampoules, disposable syringes or glass or It may be enclosed in a plastic multidose vial.   When administered intravenously, preferred carriers are saline or phosphate Buffered saline (PBS).   In one embodiment, the active compound is administered to an implanted and microencapsulated administration system. Carriers that protect compounds against rapid elimination from the body, such as controlled release formulations It is prepared using a layer. Ethylene vinyl acetate, polyanhydride, polyglycolic acid Biodegradable and biocompatible, such as collagen, polyorthoester and polylactic acid Polymers can be used. Methods for preparing such formulations are known to those skilled in the art. it is obvious. The materials are from Alza (California) and Scios Nova (Baltimore, Maryland) it can.   Liposomal suspensions can also be pharmaceutically acceptable carriers. These are described, for example, in US Pat. No. 4,522,811 (herein incorporated by reference in its entirety). Prepared by methods known to those skilled in the art as disclosed in US Pat. be able to. For example, liposome preparations can be prepared using appropriate lipids (eg, stearoylphos). Sphatidylethanolamine, stearoyl phosphatidylcholine, aracad Phosphatidylcholine and cholesterol) in an inorganic solvent. By evaporating the inorganic solvent to leave a thin film of dry lipid on the surface of the container Can be prepared. Active compound or its monophosphate, diphosphate And / or triphosphate derivatives are then introduced into the container. Next Rotate the vessel by hand to remove the lipid material from the sides of the container, disperse the lipid aggregates, and This forms a suspension of liposomes. III. Biological activity   Compounds that include the ability of compounds to bind to PAF receptors To evaluate the ability to act and the effect of compounds on various PAF-mediated pathways A wide variety of biological assays have been used. What are these known assays Some also evaluated the ability of the compounds disclosed herein to act as PAF receptor antagonists. Can be used to evaluate   For example, PAF induces hemoconcentration and increased permeability of microcirculation, Is known to lead to a decrease in PAF-mediated acute circulatory collapse By analyzing the effect of compounds on PAF-induced reduced plasma volume in a product model Basis of an Assay to Evaluate the Performance of a Compound as a PAF Antagonist Can be used as   Various including fever, hypotension, leukocytosis, and disturbance of glucose and lipid metabolism Contains eicosanoids, PAF and ulcer necrosis factor (TNF) that stimulate the physiological response of Endotoxemia causes the release of chemical mediators. Endotoxemia is severe Can lead to death and death. Endotoxin-induced mouse mortality To assess the pharmacological effects of compounds on inflammatory shock Animal model.   Used to evaluate the ability of a compound to act as a PAF receptor antagonist Two other common assays are platelet aggregation in vitro and in rats. Shen et al., `` The Chemical and Biological Properties of PAF Ago nists, Antagonists, and Biosynthetic Inhibitors ", Platelet-Activating Fa Edited by ctor and Related Lipid Mediators, F. Snyder, Plenum Press New York State 153 (1987).   Also widely used to evaluate the ability of compounds to inhibit the enzyme 5-lipoxygenase Various biological assays have been used. For example, for leukotriene biosynthesis In this study, cytosolic 5-liposome of rat Xygenase has been widely used. Compounds that inhibit 5-lipoxygenase Decrease the level of ukotriene.   Used to evaluate the ability of compounds to inhibit the enzyme 5-lipoxygenase Another biological assay is LTB from ionophore-stimulated human whole blood._FourCurb Based on classic pharmacological models of inflammation induced by Example 5   The ability of compounds to bind to PAF receptors (A) Preparation of human platelet thin film   Blood samples obtained from the American Red Cross Blood Service (Dedham, Mass.) Prepare human platelet thin film from plate concentrate. Platelet wash solution (150 mM NaCl, 10 mM MTr and 2 mM EDTA, pH 7.5) after washing several times, the platelet pellet was washed with 5 mM MgCl_Two, 10 mM Tris, and 2 mM EDTA at pH 7.0. Then put the cells in a liquid Freeze quickly with nitrogen and slowly thaw at room temperature. Fewer freezing and thawing procedures Repeat three times. Dissolved thin film suspension to further separate thin film fragments With 10 mM MgCl_Two, 10 mM Tris, and 0.25, 1.0 prepared in 2 mM EDTA (pH 7.0). The layers were separated on top of a discontinuous sucrose concentration gradient of 3 and 1.5 M sucrose, 63,50 Centrifuge at 0xg for 2 hours. 0.25 to 1.03M thin film fraction (thin film A) and 1 Separate thin film fraction (thin film B) of .03-1.5M Collected. The protein concentration of the thin film preparation was determined using bovine serum albumin (BSA) as a standard. Is determined by the Lowry's method. Next, remove the thin film (4 ml each), store at -80 ° C and thaw before use. (B) [^ThreeH] PAF binding suppression   [^ThreeThe ability of H] PAF to bind to specific receptors on human platelet_Two Under the optimum condition of pH 7.0 in the presence of. 10mM MgCl_Two, 10 mM Tris, and 0.25 % In BAS (pH 7.0)^ThreeH] PAF 0.15 pmol (0.3 nM concentration) and known amount of unlabeled PAF Alternatively, in a final 0.5 ml solution containing a PAF receptor antagonist, add g) is added. After incubation at 0 ° C. for 4 hours, binding and non-binding [^ThreeH] PAF under reduced pressure Through Whatman GF / C glass fiber. Under the assay conditions In the filter combination [^ThreeH] PAF degradation should not be detected. Non-specific Binding is based on high concentrations of unlabeled PFA, PAF analogs or PAF receptor antagonists. Total binding in the presence of excess unlabeled PAF (1 mM) without displacement It is determined as a match. Specific binding is defined as the difference between total binding and non-specific binding. It is.   Total binding in the absence of inhibitor to determine relative potency of test compound 0% inhibition and 100% total binding in the presence of 1 mM unlabeled PAF Allows for [in the presence of an inhibitor^Three[H] PAF binding is normalized as% inhibition. Compound The percent inhibition depending on the product can be calculated by the following equation.   % Inhibition = [(total binding-total binding in presence of compound) / non-specific binding] × 100%   I c₅₀Is specific^ThreeThe concentration of inhibitor required to achieve 50% inhibition of H] PAF binding Calculated, non-linear regression computer software program, GraphPadInplot , Version 3.0 (Graph Pad Software, San Diego, CA) A). Example 6   Effects of compounds on PAF-induced hemoconcentration (A) Animals   From Charles River Laboratory (Wilmington, MA) To obtain female CD-1 mice weighing 16-20 g. Tap water and rodent laboratory tea Provide voluntarily (5001, Purina Mills, St. Louis, MO). Mau The animals are kept in the breeding room for an average of 4 days before use. (B) Hematocrit measurement   PAF (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, Sigma C chemical) in 0.25% bovine serum albumin (BAS) in 0.9% NaCl solution I do. Except for dose-response studies, 10 μg of PAF solution (10 ml / kg) was injected into the tail vein I do. Dissolve all test compounds in 0.5 DMSO salt solution and add 3 mg 15 min before PAF trial / kg body weight intravenous injection. 15 min after PAF administration 30-50 μl by cutting the tail end into a matcrit tube (OD 1.50 mm) Collect blood. All test compounds were tested in mice with PAF (10 μg / kg, iv) It is given intravenously in a dose of 3 mg / kg 15 minutes before AA (0.5 mg / ear) or AA (0.5 mg / ear). Example 7   Effects of compounds on cytosolic 5-lipoxygenase in rat basophil leukemia cells. Fruit (A) Enzyme preparation   The washed rat RBL cells (4 × 108) were mixed with 10% ethylene glycol / 1 mM EDTA (buffer A ) Was suspended in 20 ml of 50M potassium phosphate buffer at pH 7.4. 20 cell suspensions Sonicate at KHz for 30 seconds, centrifuge the sonicate at 10,000 xg for 10 minutes, followed by Further, the mixture was centrifuged at 105,000 × g for 1 hour. Supernatant solution containing 5-lipoxygenase (Cytosol fraction) was stored at -70 ° C. Bovine serum albumin as standard Using the Bradford procedure (Bradford Dye Reagent)). (B) Enzyme assay   In a typical assay for 5-lipoxygenase, the mixture is phosphate phosphate at pH 7.4. Lium buffer 50mM, 2mM CaCl_Two, 2 mM ATP, 25 M larachidonic acid (0.1 Ci) and And enzymes (50-100 mg of protein) were included in a final volume of 200 liters. Reaction Performed at 24 ° C. for 3 minutes. The mixture was treated with ethyl ether: methanol: 0.2M citric acid (= The mixture was extracted with 0.2 ml of an ice-cold mixture of 30: 4: 1). Extract the petroleum ether: ethyl ether : Thin layer chromatography at -10 ° C in a solvent system of acetic acid (= 15: 85: 0.1). did. Cut off the silica gel region corresponding to authentic arachidonic acid and its metabolites Placed in scintillation vials for counting. Enzyme activity is oxidized in 3 minutes Expressed as arachidonic acid. In this assay, the representative Compounds 9, 11, 14, and 15 showed activity. Example 8   Inhibition of soluble 5-lipoxygenase in RBL-1 cell extracts   RBL-1 cells were grown in rotating flasks according to specifications from the ATCC (2 × 1 0⁶/ ml). Cells were harvested and incubated in calcium-free and magnesium-free PBS. Washed times. Transfer cells to 50 mM K_TwoHPO_Four pH 7.4, 10% PEG-8000, 1mM EDTA, 1mM PMSF 2 × 10⁷/ ml, then sonicate. Dissolve the lysate at 100,000 xg 4 Centrifuge at ℃ for 1 hour, remove supernatant (cytosol) and store at -70 ℃ I do.   The 5-L0 activity in the RBL-1 cytosol is determined as follows: 5 mM CaCl_Two, 2mM ATP, 50mM K_TwoHPO_Four pH 7.4, varying concentrations of test compound (dissolved in DMSO From 10 ml of the compound), and 50% [¹⁴C] Arachidonic acid base is converted to oxygenated products (each site) From the RBL-1 cytosol at a concentration that converts Incubate 0.2 ml of the reaction solution at room temperature for 10 minutes. From the ethanol store [¹⁴C] Araki The reaction is started by adding 5 ml of donic acid (final concentration = 9.5 mM) and allowed to proceed for 3 minutes. Let go. The reaction was run in cold ethyl ether: methanol: 0.2 M citric acid (= 30: 4: 1 ) And centrifuged at 10,000 xg for 1 minute. Organic layer 5 Take out 0 ml, put it in a glass capillary pipette, and play silica gel 60A TLC D (Whatman # LK6D). Plate with petroleum ether: ethyl Develop in ether: acetic acid (= 15: 85: 0.1) for 30 minutes at room temperature. Kodak XA Plate Exposure to R-5 film for 24 hours. Film Develop and scan with densitometer to detect arachidonic acid and its product peaks. Calculate the work area. The% inhibition is relative to the control sample (not the test compound) Converted to oxygenated products in the sample containing the test compound [¹⁴C] Arachidone Determine from the amount of acid.   Table 5 shows that racemic compound 202 and its enantiomers, compounds 216, 217, 234 And 236 inhibit the inhibition of soluble 5-lipoxygenase in RBL-1 cell extracts Provide data. Example 9   Leukotriene B in human whole blood stimulated with ionophore_FourProduction restraint   Take out human blood, put it in a blood collection tube with heparin, and add 1 ml to 1.5 ml Place in a microfuge tube. 5 ml of different concentrations of test compound dissolved in DMSO Add to blood sample and incubate at 37 ° C for 30 minutes. Calcium ionophore in DMSO (5 ml) (A23187) was added to a final concentration of 50 mM, and the sample was incubated at 37 ° C for 15 minutes. Nourish. Next, the sample was centrifuged at 1100 × g (2500 rpm, H1000B rotor, Sorvall centrifugation). Centrifuge at 4 ° C for 10 minutes. Transfer 100 ml of supernatant to a 1.5 ml microtube, Add 400 ml of cold ethanol and precipitate the protein on ice for 30 minutes. sample Was centrifuged at 110 × g at 4 ° C. for 10 minutes, and the supernatant was used as a commercially available EIA kit (Cayma LTB according to the manufacturer's instructions_FourTest for   Table 5 shows that racemic compound 202 and its enantiomers, compounds 216, 217, 234 B and leukotriene B in human whole blood stimulated with ionophore_FourManufacturing Shown is data on suppression. Example 9   Evaluation of premature death (ex-vivo) mouse and rat whole blood 5-lipoxygenase   CD-1 female mice weighed 18-25 g from Charles River Laboratory And CD female rats weighing 150-230 g were obtained. Compound was administered to mice (0.5 mg / ml Dissolve in 0.5% DMSO in 0.9% NaCl to use in rats (5 mg / ml) for alcoholic medium (benzyl alcohol 2%, ethanol 1%, PE G300 40%, propylene glycol 10%, DiH_Two5% dextrose in O + 3.5% pl uronic F-68 (47%). Fifteen minutes before killing by decapitation, animals receive compound (5 mg / ml) or the corresponding vehicle (0.5% DMSO in saline, 10 ml / kg for mice; al Call vehicle, 1.ml/kg for rats) was injected. Whole blood with heparin (0.3 ml) was added to 3 ml of 2 mM calcium ionophore A23187 (final concentration of A23187 was 20 mM). Was added to a 1.5 ml Eppendorf centrifuge tube containing Samples were placed in a 37 ° C water bath for 30 minutes. Incubate for 2 minutes and then centrifuge for 2 minutes. Dilute the plasma (x120) and LTB using EIA_Four Was tested.   Table 5 shows that racemic compound 202 and its enantiomers, compounds 216, 217, 234 5-lipoxygenase levels in mouse and rat whole blood of premature death after administration of 236 and 236 Provide data for Example 10   Glucuronidation rate   Glucuronidation rate is a measure of the metabolic stability of the compounds disclosed herein in vivo. .   Human microsomal protein 2mg / ml, 5mM magnesium chloride, 100mM Tris HCl ( pH = 7.4), using a reaction mixture containing 0.1-1.0 mM base and 3 mM UDP-glucuronic acid. An in vitro glucuronidation reaction was performed. 0 (control), 15, 30, 45, 60, at 37 ° C After culturing for 90, 120, 180, and 240 minutes, 40 μl of the reaction mixture is mixed with 80 μl of acetonitrile. And centrifuged to remove the precipitated protein. Aliens in the supernatant by reverse phase HPLC Coats were analyzed to determine parent compound disappearance and metabolite formation.   Table 5 shows that racemic compound 202 and its enantiomers, compounds 216, 217, 234 And 236 glucuronidation rate data are provided, and FIG. 2 shows it.   FIG. 3 shows the glucuronidation rates of the indicated enantiomers. Example 11   Effects of compounds on cytosolic 5-lipoxygenase in rat basophil leukemia cells.   RBL-2H3 cells were purified from Carter et al. (J Pharm Exp Ther 256 (3); 929-937, 1991). Grown in tissue culture flasks. Harvest cells, calcium and mug Washed 5 times in nesium-free D-PBS. Cells were treated with 10 mM BES, 10 mM PIPES pH 6.8, 2 × 10 in 1 mM EDTA⁷/ ml, then sonicate. Sonic crushed material , 20,000 xg for 20 minutes at 4 ° C. Next, the supernatant liquid (cytosol ) And store at -70 ° C.   The 5-L0 activity in the RBL-2H3 formulation is determined as follows: 0.7 mM CaCl_Two, 100m M NaCl, 1mM EDTA, 10mM BES, 10MM PIPES pH7.4, dissolved in varying concentrations of DMSO Test compound (finally 7.5% DMSO in the assay) and 15% arachi The oxygenated product of the donic acid base mixture (determined experimentally for each RBL-2H3 formulation ) Is incubated at room temperature for 20 minutes. 5 μl arachidonic acid base mixture (0.028% NH per assay)_FourIn OH [¹⁴C] arachidonic acid 0.94 The reaction is started by adding 4 nmol and 6.06 nmol of arachidonic acid) and Let go for 5 minutes. The reaction was carried out by (i) triphenylphosphine in ethyl ether 1. 0.1 mg of a mixture of 66 mg / ml; (ii) methanol; and (iii) 0.2 M citric acid (= 30: 4: 1) And centrifuged at 1000 × g for 1 minute. Organic layer 50 μl Take out and place in a glass capillary pipette, silica gel 60A TLC plate (Whatman # 6KDF). Plates were washed with ethyl ether: acetic acid (= 10 0: 0.1) for 25 minutes at room temperature. Plate on Kodak X-OMA TAR film 40 Expose for a time. Develop the film, scan with densitometer, and add arachidonic acid And the peak area of the product is calculated. The% inhibition was compared to the control sample (test compound). To the oxygenated products in the sample containing the test compound did[¹⁴C] Determined from the amount of arachidonic acid.   Table 4 shows the results. Example 12   Leukotriene B in human whole blood stimulated with ionophore_FourProduction restraint   Take out human blood, put it in a blood collection tube with heparin, and add 1 ml to 1.5 ml Put in a microtube. Different concentrations of test compounds (5 ml) dissolved in DMSO were And incubate at 37 ° C for 15 minutes. Calcium ionophore in DMSO (5 ml, A231 87) is added to a final concentration of 50 mM, and the sample is incubated at 37 ° C. for 30 minutes. Next At 40 ° C. at 1100 × g (2500 rpm, H1000B rotor, Sorvall centrifuge). And centrifuge for 10 minutes. Transfer the supernatant (100 ml) to a 1.5 ml microtube and add cold ethanol. 400 ml of knol are added and the protein is precipitated on ice for 30 minutes. Sample at 110 × g After centrifugation at 4 ° C. for 10 minutes, the supernatant is separated from a commercially available EIA kit (Cayman Chemical LTB according to the manufacturer's specifications_FourTest for   Table 5 shows the results. Example 4   Evaluation of 5-lipoxygenase from whole blood of prematurely dead mice   CD-1 female mice weighed 18-25 g from Charles River Laboratory And CD female rats weighing 150-230 g were obtained. Compound was administered to mice (0.5 mg / ml Dissolve in 0.5% DMSO in 0.9% NaCl to use in rats (5 mg / ml) Alcohol medium (benzyl alcohol 2%, ethanol 1%, PEG300 40%, Propylene glycol 10%, DiH_Two5% dextrose in O + 3.5% Pluronic F- (47% of 68). Fifteen minutes before killing by decapitation, animals receive compound (5 mg / ml) or Corresponding vehicle (0.5% DMSO in saline, 10 ml / kg for mice; alcohol vehicle) 1 ml / kg) was injected into rats and rats. Heparinized whole blood (0.3 ml) 1, containing 3 ml of 2 mM calcium ionophore A23187 (final concentration of A23187 is 20 mM) 1. Added into 5 ml Eppendorf centrifuge tubes. Samples in a 37 ° C water bath for 30 minutes Culture and then centrifuged for 2 minutes. Dilute the plasma (x120) and LTB using EIA_FourNitsu And tested.   Table 5 shows the results. Example 5   Glucuronidation research   Glucuronidation rate is a measure of the metabolic stability of the compounds disclosed herein in vivo. .   Human microsomal protein 2mg / ml, 5mM magnesium chloride, 100mM Tris HCl ( pH = 7.4), using a reaction mixture containing 0.1-1.0 mM base and 3 mM UDP-glucuronic acid. An in vitro glucuronidation reaction was performed. 0 (control), 15, 30, 45, 60, at 37 ° C After culturing for 90, 120, 180, and 240 minutes, 40 μl of the reaction mixture is mixed with 80 μl of acetonitrile. And centrifuged to remove the precipitated protein. Aliens in the supernatant by reverse phase HPLC Coats were analyzed to determine parent compound disappearance and metabolite formation.   Table 5 shows the results. Example 6   Eosinophil infiltration assay   Accumulation of inflammatory cells in the lungs is one of the etiologic features of asthma. That to the patient After Rugen is aspirated, an increase in white blood cells in blood and lung lavage fluids, especially An increase in spheres was observed. Eosinophils are a small form of granular protein in allergic inflammation. An important effector cell with a cytotoxic properties and the effect of releasing inflammatory mediators It seems. Prevention of allergen-induced eosinophil influx into the lungs is a potential new antiasthmatic drug It is considered to be a compelling goal.   Leukotriene is a product of the arachidonic acid 5-lipoxygenase (5-LO) pathway. You. Lipoxygenase metabolites (LTB_Four, 5-oxo-15-hydroxy-eicosatetrae Acid) was identified as having potent activity on supplemented eosinophils. Acute bronchi It can block contractions and produce favorable effects on lung cells as a result of the effects of allergens. 5-LO inhibitors, which can reduce subsequent accumulation of eosinophils, prevent asthma and May be beneficial for treatment.   Eosinophil infiltration into the lungs is caused by allergen-induced bronchial It can be measured by counting the number of cells in the alveolar lavage fluid (BALF).   Guinea pig model: Female Hartley guinea pig weighing 400-500 g, 0.9% NaCl 0.5 20 μg of OVA and Al (OH) in ml_Three100 mg intraperitoneal injection on day 1 and 2 Sensitized to ovalbumin (OVA). Animals are 0.5% OVA (in 0.9% NaCl) Treatment with aerosol on days 15 and 16. Compound 10% PEG200 or 0.5% Prepared in carboxymethylcellulose and orally administered 3 times (1 hour before each treatment And between the two treatments). 15 treatments to prevent histamine release-induced death One minute prior to receiving pyrilamine (3 mg / kg, ip). 24 hours after the first treatment At (or 4 hours after the last treatment), the animals were bled from the carotid artery under anesthesia. OPBS (w / o Ca²⁺, Mg²⁺)) At 37 ° C with 0.5 ml of A BAL was performed by insertion. The total cell count in the BAL fluid is determined by Sysmex microcell counting. The number of cells that differed in the cytospin preparation was counted by a cell count (F-800). % Inhibition for total cell or eosinophil accumulation = [(vehicle-sham)-(treatment Physical-fake)] / (vehicle-fake) Object) x 100.   Mouse model: Male C57 BL / 6 male mice weighing 21-23 g in 0.2 ml of 0.9% NaCl OVA 10 μg and Al (OH)_ThreeSensitized to OVA by administering 1 mg on day 1 did. Aerosolized 1% OVA or saline is aspirated for 30 minutes daily from day 14 to day 21 After that, hypersensitivity developed. Compound 10% PEG200 or 0.5% carboxymethyl Prepared in cellulose and orally administered at a dose of 20 mg / kg twice daily on days 18-22 Was. Four hours after the last OVA aspiration, animals were anesthetized and blood was drawn from the carotid artery. 0 DPBS containing 5 mM sodium EDTA (w / o Ca²⁺, Mg²⁺) Using 2 x 1 ml, at 37 ° C BAL was performed by tracheal cannulation. Determine the total number of cells in the BAL fluid It was measured using a microcell counter (F-800). Sysmex microcell counter (F- 800), differential cells in BAL fluid were counted. Cytospin formulation and white Differential cells were counted on Giemsa dye. Whole cell or eosinophil accumulation % Inhibition = [(vehicle-fake)-(treated-fake)] / (vehicle-fake) ) X 100. (Yeadon et al., Agents Actions, 38, 8-17, 1993; Brusselle  G.G. et al., ALA'94, A754; Schwenk U. et al., J. Biol. Biochem. 267: 12482-1248. 8, 1992; and Clinic M. et al., Cur. Poin. Immunol. Volume 6, pages 860-864, 19 94)   For compounds that reduce the formation of oxygen radicals during inflammatory or immune reactions Modifications and variations of the present invention will be apparent to those skilled in the art from the foregoing detailed description of the invention. . Such modifications and variations are intended to fall within the scope of the appended claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 307/16 C07D 307/16 333/28 333/28 333/32 333/32 401/04 401/04 405/04 405/04 409/04 409/04 471/04 107 471/04 107Z // C07D 207/04 207/04 (31) Priority claim number 08 / 454,748 (32) Priority date May 31, 1995 (33) Priority Claimed States United States (US) (81) Designated States EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA ( BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, MW, SD, SZ, UG), AM, AU, BB, BG, BR, BY, CA, CN, CZ, EE, FI, GE, U, IS, JP, KG, KP, KR, KZ, LK, LR, LT, LV, MD, MG, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, TJ, TM Fuller, Avera United States 02139 Massachusetts, Cambridge, Memorial Drive 812, Apartment No. 1707 (72) Inventor Scannel, Ralph United States 01748 Massachusetts, Hopkinton, Cedar Mill Road 6 (72) 72) Inventor Bifts, Tesfey United States 07090 New Jersey, Westfield, High Slip Street 108 (72) Inventor Kian, Changgen United States 01778 Massachusetts, Wayland, East Plainstree 29

Claims (1)

[Claims] 1. A compound represented by the following formula: (Where:   Ar is halo (including but not limited to fluoro), lower alkoxy (methoxy) Lower) aryloxy (including phenoxy), W, cyano or R^ThreeFrom A group optionally substituted by at least one group selected from the group consisting of A reel or heteroaryl group;   m is 0;   W is independently -AN (OM) C (O) N (R^Three) R^Four, -AN (R^Three) C (O) N (OM) R^Four, -AN (OM) C (O) R^Four,- AC (O) N (OM) R^Four, -C (O) N (OM) R^Four, -C (O) NHA or -A-B;   A is a lower alkynyl, alkaryl or aralkyl group, wherein one or more Carbon is optionally substituted with O, N or S;   B is selected from the group consisting of pyridylimidazole and benzimidazole And they are all R^ThreeMay be substituted with   M is hydrogen, a pharmaceutically acceptable cation or a metabolically cleavable leaving group;   X is O, S, S (O), NR^FiveOr CHR^Five;   Y is O, S, S (O), NR^FiveOr CHR^Five;   R¹And R^TwoIs independently hydrogen; methyl, cyclopropylmethyl, ethyl, iso Propyl, butyl, pentyl, hexyl and C_3-8Cycloalkyl (eg Lower alkyls, including halo-lower alkyls, such as trifluoromethyl Le; halo; and -COOH;   R^ThreeAnd R^FourIs independently hydrogen or alkyl, alkenyl, alkynyl, a Reel, Aralkil, Alkal, C_1-6Alkoxy-C_1-10Alkyl, C_1-6A Lucircio-C_1-10Alkyl, heteroaryl or heteroarylalkyl;   R^FiveIs hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkaryl , -AN (OM) C (O) N (R^Three) R^Four, -AN (R^Three) C (O) N (OM) R^Four, -AN (OM) C (O) R^Four, -AC (O) N (OM) R^Four, -AC (O) N (OM) R^Four, -AS (O)_nR^Three, -AS (O)_nCH_TwoC (O) R^Three, -AS (O)_nCH_TwoCH (OH) R^Three, -AC (O) NH R^ThreeHere, n represents 0 to 2. ). 2. Ar group is phenyl, trimethoxyphenyl, dimethoxyphenyl, fluoro Phenyl, especially 4-fluorophenyl, difluorophenyl, pyridyl, dimethoxy From the group consisting of cypyridyl, quinolinyl, furyl, imidazolyl and thienyl A compound according to claim 1, which is selected. 3. -A-B, Wherein Ar is W, halo, hydroxyl, amino, alkylamino, aryl Mino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate , At least one selected from phosphonic acids, formates and phosphonates 2. The compound according to claim 1, which is an aryl or heteroaryl substituted with a group Compound. 6. A compound or pharmaceutically acceptable according to claim 1, 2, 3, 4, 5, 9 or 10. A medicament comprising an effective amount of a salt thereof and a pharmaceutically acceptable carrier Composition. 7. A compound or pharmaceutically acceptable according to claim 1, 2, 3, 4, 5, 9 or 10. Inflammatory disease in the host comprising administering an effective amount of a salt thereof. How to treat the case. 8. The method according to claim 7, wherein the animal is selected from humans, mammals, horses, dogs and cattle. The method described. 9. A compound represented by the following formula: (Where:   Ar is halo (including but not limited to fluoro), lower alkoxy (methoxy) Lower) aryloxy (including phenoxy), W, cyano or R^ThreeFrom A group optionally substituted by at least one group selected from the group consisting of A reel or heteroaryl group;   m is 0;   W is independently -AN (R^Three) C (O) N (OM) R^Four, -AN (OM) C (O) R^Four, -AC (O) N (OM) R^Four, -C (O) N (OM) R^Four, -C (O) NHA or -A-B;   A is lower alkynyl, lower alkenyl, lower alkynyl, alkaryl or Is an aralkyl group, where one or more carbons can be replaced by O, N or S Can be;   B is selected from the group consisting of pyridylimidazole and benzimidazole All of which are optionally R_ThreeMay be substituted with   M is hydrogen, a pharmaceutically acceptable cation or a metabolically cleavable leaving group;   X is O, S, S (O), NR^FiveOr CHR^Five;   Y is O, S, S (O), NR^FiveOr CHR^Five;   R¹And R^TwoIs independently hydrogen; methyl, cyclopropylmethyl, ethyl, iso Propyl, butyl, pentyl, hexyl and C_3-8Cycloalkyl (eg Lower alkyls, including halo-lower alkyls, such as trifluoromethyl Le; halo; and -COOH;   R^ThreeAnd R^FourIs independently hydrogen or alkyl, alkenyl, alkynyl, , Aralkyl, alkaryl, C_1-6Alkoxy-C_1-10Alkyl, C_1-6Al Kircio-C_1-10Alkyl, heteroaryl or heteroarylalkyl Le;   R^FiveIs hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkaryl , -AN (OM) C (O) N (R^Three) R^Four, -AN (R^Three) C (O) N (OM) R^Four, -AN (OM) C (O) R^Four, -AC (O) N (OM) R^Four, -AC (O) N (OM) R^Four, -AS (O)_nR^Three, -AS (O)_nCH_TwoC (O) R^Three, -AS (O)_nCH_TwoCH (OH) R^Three, -AC (O) NH R^ThreeHere, n represents 0 to 2. ). Ten. A compound represented by the following formula: (Where:   Ar is halo (including but not limited to fluoro), lower alkoxy (methoxy) Lower) aryloxy (including phenoxy), W, cyano or R^ThreeFrom A group optionally substituted by at least one group selected from the group consisting of A reel or heteroaryl group;   m is 1;   W is independently -AN (OM) C (O) N (R^Three) R^Four, -AN (R^Three) C (O) N (OM) R^Four, -AN (OM) C (O) R^Four,- AC (O) N (OM) R^Four, -C (O) N (OM) R^Four, -C (O) NHA or -A-B;   A is lower alkyl, lower alkenyl, lower alkynyl, alkaryl or An aralkyl group, wherein one or more carbons are optionally substituted with O, N or S May be;   B is selected from the group consisting of pyridylimidazole and benzimidazole All of which are optionally R_ThreeMay be substituted with   M is hydrogen, a pharmaceutically acceptable cation or a metabolically cleavable leaving group;   X is O, S, S (O) or NR^Five;   Y is O, S, S (O), NR^FiveOr CHR^Five;   R¹And R^TwoIs independently hydrogen; methyl, cyclopropylmethyl, ethyl, i Sopropyl, butyl, pentyl, hexyl and C_3-8Cycloalkyl (eg, Lower alkyls, including halo-lower alkyls such as trifluoromethyl Chill; halo; and -COOH;   R^ThreeAnd R^FourIs independently hydrogen or alkyl, alkenyl, alkynyl, , Aralkyl, alkaryl, C_1-6Alkoxy-C_1-10Alkyl, C_1-6Al Kircio-C_1-10Alkyl, heteroaryl or heteroarylalkyl;   R^FiveIs hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkaryl , -AN (OM) C (O) N (R^Three) R^Four, -AN (R^Three) C (O) N (OM) R^Four, -AN (OM) C (O) R^Four, -AC (O) N (OM) R^Four, -AC (O) N (OM) R^Four, -AS (O)_nR^Three, -AS (O)_nCH_TwoC (O) R^Three, -AS (O)_nCH_TwoCH (OH) R^Three, -AC (O) NH R^ThreeHere, n represents 0 to 2. ). 11． A compound represented by the following formula: (Where:   Ar is halo (including but not limited to fluoro), lower alkoxy (methoxy) Lower) aryloxy (including phenoxy), W, cyano or R^ThreeFrom A group optionally substituted by at least one group selected from the group consisting of A reel or heteroaryl group;   m is 0 or 1;   W is independently -AN (OM) C (O) N (R^Three) R^Four, -AN (R^Three) C (O) N (OM) R^Four, -AN (OM) C (O) R^Four,- AC (O) N (OM) R^Four, -C (O) N (OM) R^Four, -C (O) NHA or -A-B;   A is lower alkyl, lower alkenyl, lower alkynyl, alkaryl or An aralkyl group, wherein one or more carbons are optionally substituted with O, N or S May be;   B is selected from the group consisting of pyridyl imidazole and benzimidazole All of which are optionally R^ThreeMay be substituted with   M is hydrogen, a pharmaceutically acceptable cation or a metabolically cleavable leaving group;   X is O, S, S (O), NR^FiveOr CHR^Five;   Y is O, S, S (O), NR^FiveOr CHR^Five;   R¹And R^TwoIs independently hydrogen; methyl, cyclopropylmethyl, ethyl, iso Propyl, butyl, pentyl, hexyl and C_3-8Cycloalkyl, such as_Four Lower alkyl, including lopentyl; halo lower alkyl, for example, trifluoromethyl Halo; and -COOH;   R^ThreeAnd R^FourIs independently hydrogen or alkyl, alkenyl, alkynyl, , Aralkyl, alkaryl, C_1-6Alkoxy-C_1-10Alkyl, C_1-6Al Kircio-C_1-10Alkyl, heteroaryl or heteroarylalkyl;   R^FiveIs hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkaryl , -AN (OM) C (O) N (R^Three) R^Four, -AN (R^Three) C (O) N (OM) R^Four, -AN (OM) C (O) R^Four, -AC (O) N (OM) R^Four, -AC (O) N (OM) R^Four, -AS (O)_nR^Three, -AS (O)_nCH_TwoC (O) R^Three, -AS (O)_nCH_TwoCH (OH) R^Three, -AC (O) NH R^ThreeHere, n represents 0 to 2. ). 12． A compound according to claim 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising an effective amount of an acceptable carrier. 13. Administering an effective amount of the compound of claim 11 or a pharmaceutically acceptable salt thereof. A method of treating an inflammatory disease in a host comprising administering to the subject. 14. The compound according to claim 1, 9 or 10, wherein X is O. 15． The compound according to claim 1, 9 or 10, wherein the aryl group has a halogen substituent. . 16． W is AN (OM) C (O) NR^ThreeR^FourThe compound according to claim 1, which is: 17． R^ThreeAnd R^Four17. The compound according to claim 16, wherein is hydrogen. 18． R¹And R^TwoIs a compound according to claim 1, 9 or 10; 19. The compound according to claim 1, wherein A is lower alkyl. 20. 2. The compound according to claim 1, wherein M is H. twenty one. 12. The compound according to claim 11, wherein M is O. twenty two. 12. The compound according to claim 11, wherein the alkyl group has a halogen substituent. twenty three. 23. The compound according to claim 22, wherein the halogen is fluorine. twenty four. 24. The compound according to claim 23, wherein the fluorine is in the para position. twenty five. W is AN (OM) C (O) NR^ThreeR^Four12. The compound according to claim 11, which is 26. R^ThreeAnd R^Four26. The compound according to claim 25, wherein is hydrogen. 27. R¹And R^Two12. The compound according to claim 11, wherein is hydrogen. 28. The compound according to claim 5, wherein A is lower alkyl. 29. 29. The compound according to claim 28, wherein the lower alkyl group is butyl. 30. 12. The compound according to claim 11, wherein the lower alkyl group is isopentyl. 31. 2. The compound according to claim 1, wherein M is H. 32. A compound represented by the following formula: (Where:   Ar is halo, lower alkoxy, lower aryloxy, W, cyano or R^ThreeBy An optionally substituted aryl or heteroaryl group;   m is 0 or 1;   n is 1 to 6;   W is independently -AN (OM) C (O) N (R^Three) R^Four, -N (OM) C (O) N (R^Three) R^Four, -AN (R^Three) C (O) N (OM) R^Four , -N (R^Three) C (O) N (OM) R^Four, -AN (OM) C (O) R^Four, -N (OM) C (O) R^Four, -AC (O) N (OM) R^Four, -C (O) N (OM) R^Four, -C (O) NHA;   A represents lower alkyl, lower alkenyl, lower alkynyl, alkylaryl, Or an arylalkyl group wherein one or more carbons are O, N or S (valency required Complete with hydrogen or oxygen, depending on Is -Y-A-, -A- or -AW- is two adjacent heteroatoms (ie -O-O-, -S-S-, -O-S- etc.);   M is hydrogen, a pharmaceutically acceptable cation or a metabolically cleavable leaving group;   X is O, S, S (O), S (O)_Two, NR^ThreeOr CHR^Five;   Y is O, S, S (O), S (O)_Two, NR^ThreeOr CHR^Five;   Z is O, S, S (O), S (O)_Two, NR^Three;   R¹And R^TwoIs independently hydrogen, lower alkyl, cyclopropylmethyl, ethyl , Isopropyl, butyl, pentyl, hexyl, and C_3-8Cycloalkyl, example For example, cyclopentyl; halo-lower alkyl, halo, or -COOH;   R^ThreeAnd R^FourIs independently hydrogen or alkyl, alkenyl, alkynyl, , Arylalkyl, alkylaryl, C_1-6Alkoxy-C_1-10Alkyl, C_1-6Alkylthio-C_1-10Alkyl, heteroaryl or heteroarylalkyl And;   R^FiveIs hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl Kill, alkylaryl, -AN (OM) C (O) N (R^Three) R^Four, -AN (R^Three) C (O) N (OM) R^Four, -AN (OM) C (O) R^Four, AC (O) N (OM) R^Four, -AS (O)_xR^Three, -AS (O)_nCH_TwoC (O) R^Three, -AS (O)_nCH_TwoCH (OH) R^ThreeAlso Is -AC (O) NHR^ThreeWhere x represents 0 to 2. ). 33. Ar group is phenyl, trimethoxyphenyl, dimethoxyphenyl, fluoro Phenyl, difluorophenyl, pyridyl, dimethoxypyridyl, quinolinyl, 33. The composition of claim 32, wherein the composition is selected from the group consisting of furyl, imidazolyl and thienyl Compound. 34. 33. The compound according to claim 32, wherein Ar is 4-fluorophenyl. 35. 33. The compound according to claim 32, wherein Z is O. 36. 33. The compound according to claim 32, wherein Z is S. 37. -(Y)_m33. The compound of claim 32, wherein W is selected from the group consisting of: 38. -(Y)_m3. The compound according to claim 2, wherein W is selected from the group consisting of: 39. Claims 32, 33, 34, 35, 36, which are at least 97% enantiomeric rich 39. The compound according to 37 or 38. 40. 2S, 5S-trans-2- (4-fluorophenoxymethyl) -5- (4-protected oxo Ci-1-butynyl) tetrahydrofuran and 2S, 5R-cis-2- (4-fluorophenoxy) From the group consisting of (cimethyl) -5- (4-protected oxy-1-butynyl) tetrahydrofuran The compound to be selected. 41.2S, 5R-trans-2- (4-fluorophenoxymethyl) -5- (4-N-hydroxy 33. The compound according to claim 32, which is (ureidyl-1-butynyl) tetrahydrofuran. 42.2S, 5S-trans-2- (4-fluorophenoxymethyl) -5- (4-N-hydroxy 33. The compound according to claim 32, which is (ureidyl-1-butynyl) tetrahydrofuran. 43.2R, 5S-trans-2- (4-fluorophenoxymethyl) -5- (4-N-hydroxy 33. The compound according to claim 32, which is (ureidyl-1-butynyl) tetrahydrofuran. 44.2R, 5R-trans-2- (4-fluorophenoxymethyl) -5- (4-N-hydroxy 33. The compound according to claim 32, which is (ureidyl-1-butynyl) tetrahydrofuran. 45. An effective anti-inflammatory amount of a compound of claims 32-34 or a pharmaceutically acceptable salt thereof. And a pharmaceutically acceptable carrier. 46. Before any medical treatment, for example for the treatment or prevention of inflammatory diseases A compound according to the preceding claim. 47. A method according to any preceding claim, in the manufacture of a medicament for the treatment of an inflammatory disease. Use of the compounds and pharmaceutically acceptable derivatives and salts thereof. 48. A compound of any preceding claim in combination with a pharmaceutically acceptable carrier .