CYCLOALKYL-HYDROXYL COMPOUNDS AND COMPOSITIONS FOR CHOLESTEROL MANAGEMENT AND RELATED USES

Abstract

The present invention relates to novel cycloalkyl-hydroxyl compounds, compositions comprising hydroxyl compounds, and methods useful for treating and preventing a variety of diseases and conditions such as, but not limited to aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder. Compounds and methods of the invention can also be used to modulate C reactive protein or enhance bile production in a patient. In certain embodiments, the compounds, compositions, and methods of the invention are useful in combination therapy with other therapeutics, such as hypocholesterolemic and hypoglycemic agents.

Claims

1-57. (canceled)

58. A method for treating a cancer, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I: ##STR00026## or a pharmaceutically acceptable salt, hydrate, solvate or a mixture thereof, wherein: (a) each occurrence of m is independently an integer ranging from 0 to 5; (b) each occurrence of n is independently an integer ranging from 3 to 7; (c) X is (CH.sub.2).sub.z or Ph, wherein z is an integer from 0 to 4; (d) R.sup.1 and R.sup.2 and the carbon to which they are both attached are taken together to form a (C.sub.3-C.sub.7)cycloalkyl group; (e) each occurrence of R.sup.11 and R.sup.12 and the carbon to which they are both attached are taken together to form a (C.sub.3-C.sub.7)cycloalkyl group; and ##STR00027## (f) each occurrence of Y.sup.1 and Y.sup.2 is independently COOH, COOR.sup.3, SO.sub.3H, wherein: (i) R.sup.3 is (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C.sub.1-C.sub.6)alkoxy, or phenyl groups, and (ii) each occurrence of R.sup.4 is independently H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or (C.sub.2-C.sub.6)alkynyl and is unsubstituted or substituted with one or two halo, OH, C.sub.1-C.sub.6 alkoxy, or phenyl groups.

59. The method claim 58, wherein each occurrence of Y.sup.1 and Y.sup.2 is independently COOR.sup.3 or COOH.

60. The method of claim 59, wherein m is 0.

61. The method of claim 59, wherein m is 1.

62. The method of claim 59, wherein n is 4.

63. The method of claim 59, wherein n is 5.

64. The method of claim 59, wherein X is (CH2).sub.z and z is 0.

65. The method of claim 58, wherein the compound is ##STR00028##

66. The method of claim 58, wherein the compound is ##STR00029## or a pharmaceutically acceptable salt thereof.

67. The method of claim 58, the method further comprising administering to a patient in need of such treatment a therapeutically effective amount of a second therapeutic agent.

68. The method of claim 67, wherein the second therapeutic agent is selected from the group consisting of a chemotherapeutic agent, an alkylating agent, a plant alkaloid, a DNA topoisomerase inhibitor, a mitomycin, an anti-folate, a pyrimidine analog, a purine analog, a hormonal therapy, a retinoid, a deltoid, a vitamin D3 analog, a photodynamic therapy, a cytokine, a isoprenylation inhibitor, a dopaminergic neurotoxin, a cell cycle inhibitor, an actinomycine, a bleomycin, an anthracycline, a MDR inhibitor, and a Ca.sup.2+ ATPase inhibitor.

69. The method of claim 58, wherein the cancer is selected from group consisting of a solid tumor cancer, a blood-borne cancer, a leukemia, and a lymphoma.

70. The method of claim 69, wherein the solid tumor cancer is selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophogeal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, and retinoblastoma.

71. The method of claim 69, wherein the blood-borne cancer is selected from the group consisting of acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, and multiple myeloma.

72. The method of claim 69, wherein the leukemia is an acute leukemia or a chronic leukemia.

73. The method of claim 72, wherein the acute leukemia or chronic leukemia is selected from the group consisting of lymphoblastic leukemia, myelogenous leukemia, lymphocytic leukemia, and a myelocytic leukemia.

74. The method of claim 69, wherein the lymphoma is selected from the group consisting of Hodgkin's disease, non-Hodgkin's Lymphoma, multiple myeloma, Waldenstr?m's macroglobulinemia, heavy chain disease, and polycythemia vera.

Description

6. SYNTHETIC EXAMPLES

[0254] ##STR00018##

6.1 Tertbutyl 1-(4-bromo-butyl)-cyclopropanecarboxylate

[0255] Under a N.sub.2 atmosphere at ?60? C., a solution of tert-butyl cyclopropanecarboxylate (80.05 g, 0.507 mol) and 1,4-dibromobutane (219.3 g, 1.01 mol) in dry THF (800 mL) was added drop wise to a solution of LDA (2 M in THF/heptane/ethylbenzene, 380 mL, 0.76 mol) in 1.5 h. Stirring was continued for 5 h, during which the reaction mixture was allowed to slowly reach it. After that, the reaction mixture was poured into saturated aqueous NH.sub.4Cl (1 L). The organic layer was separated and concentrated in vacuo to a smaller volume. The aqueous layer was extracted with Et.sub.2O (3?200 mL). The combined organic layers were washed with saturated aqueous NH.sub.4Cl (2?400 mL) and brine (400 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining residue was purified by fractional distillation under reduced pressure to give tert-Butyl 1-(4-bromo-butyl)-cyclopropanecarboxylate (51.4 g, 94% pure by GC, 34%) as a slightly yellow oil. bp: T=93-96 OC (p=0.075-0.087 Torr). .sup.1H NMR (CDCl.sub.3): ?=3.40 (t, J=6.8 Hz, 2H), 1.85 (quintet, J=7.1 Hz, 2H), 1.65-1.46 (m, 4H), 1.43 (s, 9H), 1.12 (q, J=3.5 Hz, 2H), 0.60 (q, J=3.5 Hz, 2H). .sup.13C NMR (CDCl.sub.3): ?=174.0, 79.8, 33.6, 33.2, 32.8, 27.9 (3?), 26.3, 23.9, 15.1 (2?). HRMS calcd for C.sub.12H.sub.21BrO.sub.2 (MH.sup.+): 277.0803, found: 277.0807.

6.2 Tertbutyl 1-[9-[1-(tert-butoxycarbonyl)cyclopronyl]-5-oxononyl]-1-cyclopropanecarboxylate

[0256] Under a N.sub.2 atmosphere, NaH (60% (w/w) in mineral oil, 2.91 g, 72.8 mmol) was added portion wise to a solution of TosMIC (5.85 g, 30.0 mmol) and Bu.sub.4NI (1.10 g, 2.98 mmol) in dry DMSO (100 mL) while stirring vigorously and cooling with a water bath. After 10 min, tert-Butyl 1-(4-bromo-butyl)-cyclopropanecarboxylate (16.56 g, 94% pure by GC, 56.2 mmol) was added drop wise in 20 min and stirring was continued for 1 h and 50 min. Then, H.sub.2O (100 mL) was added drop wise and the resulting mixture was extracted with Et.sub.2O (3?100 mL). The combined organic layers were washed with brine (2?100 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining oil was purified by column chromatography (silica, heptane:EtOAc=6:1) to give tert-butyl 1-{9-[1-(tert-butoxycarbonyl)cyclopropyl]-5-isocyano-5-[(4-methylphenyl)sulfonyl]nonyl}-1-cyclopropanecarboxylate (10.00 g) as a slightly yellow oil. The above mentioned oil (10.00 g) was dissolved in CH.sub.2Cl.sub.2 (200 mL) and conc aqueous HCl (4 mL) was added. After stirring vigorously for 1 h, H.sub.2O (100 mL) was added and the layers were separated. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (100 mL) and the combined organic layers were washed with saturated aqueous NaHCO.sub.3 (3?100 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining residue was purified by column chromatography (silica, heptane:EtOAc=10:1) to give tert-butyl 1-[9-[1-(tert-butoxycarbonyl)cyclopropyl]-5-oxononyl]-1-cyclopropanecarboxylate (5.80 g, 49%) as a colorless oil. .sup.1H NMR (CDCl.sub.3): ?=2.39 (t, J=7.3 Hz, 4H), 1.63-1.38 (m, 30H), 1.10 (dd, J=6.6, 3.9 Hz, 4H), 0.59 (dd, J=6.7, 3.9 Hz, 4H). .sup.13C NMR (CDCl.sub.3): ?=211.1, 174.4 (2?), 79.9 (2?), 42.7 (2?), 33.9 (2?), 28.0 (6?), 27.4 (2?), 24.1 (2?), 24.0 (2?), 15.2 (4?). HRMS calcd for C.sub.25H.sub.43O.sub.5 (MH.sup.+): 423.3111, found: 423.3111.

6.3 1-[9-(1-Carboxycyclopropyl-5-oxononyl]-1-cyclopropanecarboxylic acid

[0257] A solution of tert-butyl 1-[9-[1-(tert-butoxycarbonyl)cyclopropyl]-5-oxononyl]-1-cyclopropanecarboxylate (5.31 g, 12.6 mmol) in HCO.sub.2H (50 mL) was stirred for 3 h, evaporated in vacuo and coevaporated from toluene (3?25 mL) to give 1-[9-(1-carboxycyclopropyl)-5-oxononyl]-1-cyclopropanecarboxylic acid (3.89 g, 99%) as a white solid. An analytical sample was obtained after recrystallization from iPr.sub.2O/heptane. mp: 132-134 OC. .sup.1H NMR (CD.sub.3OD): ?=2.45 (t, J=6.9 Hz, 4H), 1.58-1.39 (m, 12H), 1.14 (dd, J=6.6, 3.7 Hz, 4H), 0.70 (dd, J=6.8, 3.9 Hz, 4H). .sup.13C NMR (CD.sub.3OD): ?=214.4, 179.4 (2?), 43.5 (2?), 34.9 (2?), 28.5 (2?), 25.1 (2?), 24.2 (2?), 16.2 (4?). Anal. calcd for C.sub.17H.sub.26O.sub.5: C, 65.78; H, 8.44, found: C, 65.40; H, 8.37.

6.4 1-[9-(1-Carboxycyclopropyl)-5-hydroxynonyl]-1-cyclopropanecarboxylic acid

[0258] To a suspension of 1-[9-(1-carboxycyclopropyl)-5-oxononyl]-1-cyclopropanecarboxylic acid (6.95 g, 22.4 mmol) in iPrOH (40 mL) and H.sub.2O (40 mL) was added NaOH (1.80 g, 45.0 mmol). After 30 min of stirring, NaBH.sub.4 (0.45 g, 11.8 mmol) was added to the resulting clear solution. After 3 h and 15 min, the mixture was acidified to pH?1 with aqueous HCl (IM) and extracted with Et.sub.2O (3?100 mL). The combined organic phases were dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give 1-[9-(1-carboxycyclopropyl)-5-hydroxynonyl]-1-cyclopropanecarboxylic acid (6.02 g, 86%) as a slightly yellow oil. .sup.1H NMR (CD.sub.3OD): ?=3.49 (br s, 1H), 1.57-1.25 (m, 16H), 1.14 (dd, J=3.6, 6.3, 4H), 0.70 (dd, J=3.3, 6.3, 4H). .sup.13C NMR (CD.sub.3OD): ?=178.9 (2?), 72.2, 38.4 (2?), 35.1 (2?), 28.9 (2?), 27.0 (2?), 24.3 (2?), 16.3 (2?), 16.2 (2?).

##STR00019##

6.5 Tert-butyl 1-(5-chloropentyl-1-cyclopropanecarboxylate

[0259] Under an Ar atmosphere at 0? C., BuLi (2.5M in hexanes, 80 mL, 0.20 mol) was added dropwise to a solution of iPr.sub.2NH (27.2 mL, 194 mmol, distilled from NaOH) in dry THF (200 mL) in 30 min. The reaction mixture was stirred for 30 min, cooled to ?70? C. and then, tert-butyl cyclopropanecarboxylate (prepared according to Kohlrausch, K. W. F.; Skrabal, R., Z. Elektrochem. Angew. Phys. Chem, 1937, 43, 282-285, 25.0 g, 176 mmol) was added dropwise in 30 min. The resultant mixture was allowed to warm up to ?35? C., cooled again to ?70? C. and then l-bromo-5-chloropentane (36 mL, 50.7 g, 273 mmol) was added dropwise in 15 min. The reaction mixture was allowed to reach ?5? C., stirred for 3 h, poured into a mixture of ice (100 mL), H.sub.2O (100 mL), brine (200 mL) and aqueous HCl (2M, 200 mL) and extracted with Et.sub.2O (2?300 mL). The combined organic layers were washed with a mixture of brine and saturated aqueous NaHCO.sub.3 (10:1,300 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining oil was purified by fractional distillation under reduced pressure to give tert-butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate (31.5 g 73%) as a colorless liquid. bp: T=67-74? C. (p=0.001 mbar). .sup.1H NMR (CDCl.sub.3): ?=3.52 (t, J=6.6 Hz, 2H), 1.77 (quintet, J=6.8 Hz, 2H), 1.48-1.38 (m, 6H), 1.42 (s, 9H), 1.10 (dd, J=6.5 Hz, 3.8 Hz, 2H), 0.59 (dd, J=6.6, 3.9 Hz, 2H). .sup.13C NMR (CDCl.sub.3): ?=174.1, 79.9, 45.2, 34.2, 32.7, 28.2 (3?), 27.20, 27.17, 24.3, 15.4 (2?). HRMS calcd for C.sub.13H.sub.24ClO.sub.2 (MH.sup.+): 247.1465, found: 247.1465.

6.6 Tert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate

[0260] To a solution of tert-butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate (31.5 g, 128 mmol) in 2-butanone (150 mL) was added NaI (24.9 g, 166 mmol). The reaction mixture was stirred under reflux for 24 h, diluted with heptane (220 mL) and filtered through a layer of silica (2 cm) in a glassfilter. The residue was eluted with a mixture of heptane and EtOAc (3:1, 5?100 mL). The combined filtrate and elutes were evaporated in vacuo to give tert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate (42.3 g, 99%) as a slightly yellow liquid. .sup.1H NMR (CDCl.sub.3): ?=3.18 (t, J=7.1 Hz, 2H), 1.82 (quintet, J=7.1 Hz, 2H), 1.48-1.33 (m, 6H), 1.42 (s, 9H), 1.10 (dd, J=6.8 Hz, Hz, 2H), 0.58 (dd, J=6.6, 3.9 Hz, 2H). .sup.13C NMR (CDCl.sub.3): ?=174.0, 79.9, 34.1, 33.6, 30.8, 28.2 (3?), 26.8, 24.3, 15.4 (2?), 7.4. HRMS calcd for C.sub.13H.sub.23IO.sub.2 (M.sup.+): 338.0743, found: 338.0743.

6.7 Tert-butyl 1-11-[1-(tert-butoxycarbonyl)cyclopropyl]-6-oxoundecyl-1-cyclopropanecarboxylate

[0261] Under a N.sub.2 atmosphere at 0? C., KOtBu (8.35 g, 74.6 mmol) was added to a solution of TosMIC (13.84 g, 70.9 mmol) in DMAc (100 mL). Then tert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate (24.0 g, 71.0 mmol) was added dropwise in 15 min and the reaction mixture was allowed to warm to rt, stirred for 0.5 h and cooled again to 0? C. Another portion of KOtBu (8.35 g, 74.6 mmol) and tert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate (24 g, 71 mmol, in 15 min) were added and the resultant mixture was allowed to warm to rt. After 2 h, the reaction mixture was poured into an ice/H.sub.2O (300 mL) mixture and extracted with Et.sub.2O (3?150 mL). To the combined organic layers was added EtOAc (100 mL) and the resultant solution was washed with a mixture of brine (100 mL), H.sub.2O (100 mL) and aqueous Na.sub.2SO.sub.3 (10%, 50 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining residue was taken up in EtOAc (100 mL) and filtered through a layer of silica in a glassfilter (elute:heptane:EtOAc=1:1, 5?80 mL). The combined filtrate and washings were evaporated in vacuo. The remaining oil was dissolved in CH.sub.2C.sub.2 (400 mL) and cone aqueous HCl (11.4 mL) was added. After 0.5 h, the reaction mixture was treated with saturated aqueous NaHCO.sub.3 (250 mL) and stirred for 0.5 h. The layers were separated and the aqueous phase was extracted with CH.sub.2C.sub.12 (200 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining residue was dissolved in heptane and set aside for 3 d upon which precipitation occurred. The residue was separated by decantation and washed with heptane (3?75 mL). The combined heptane layers were evaporated in vacuo and the resultant oil was purified by column chromatography (silica, heptane:EtOAc=12:1) to give tert-butyl 1-11-[1-(tert-butoxycarbonyl)cyclopropyl]-6-oxoundecyl-1-cyclopropanecarboxylate (16.3 g, >90% pure by .sup.1H NMR, 46%) as a colorless oil. .sup.1H NMR (CDCl.sub.3): ?=2.37 (t, J=7.4 Hz, 4H), 1.62-1.49 (quintet, J=7.4 Hz, 4H), 1.48-1.36 (m, 8H), 1.41 (s, 18H), 1.33-1.20 (m, 4H) 1.09 (dd, J=6.5, 3.8 Hz, 4H), 0.58 (dd, J=6.6, 3.9 Hz, 4H). .sup.13C NMR (CDCl.sub.3): ?=210.9, 174.1 (2?), 79.8 (2?), 42.9 (2?), 34.1 (2?), 29.6 (2?), 28.2 (6?), 27.7 (2?), 24.4 (2?), 24.0 (2?), 15.4 (4?). HRMS calcd for C.sub.27H.sub.46O.sub.5Na (MNa.sup.+): 473.3243, found 473.3233.

6.8 Tertbutyl 1-11-[1-(tert-butoxycarbonyl)cyclopropyl]-6-hydroxyundecyl-1-cyclopropanecarboxylate

[0262] A solution of tert-butyl 1-11-[1-(tert-butoxycarbonyl)cyclopropyl]-6-oxoundecyl-1-cyclopropanecarboxylate (7.87 g, 17.4 mmol) in EtOH (40 mL) was treated portion wise with NaBH.sub.4 (0.726 g, 19.2 mmol) in ?2 min at 0? C. The reaction mixture was stirred at rt for 1.5 h, and then poured into a mixture of H.sub.2O and ice (200 mL). The resultant mixture was extracted with Et.sub.2O (2?200 mL), and the combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The remaining residue was purified by column chromatography (silica, heptane:EtOAc=8:1) to give tert-butyl 1-11-[1-(tert-butoxycarbonyl)cyclopropyl]-6-hydroxyundecyl-1-cyclopropanecarboxylate (7.00 g, 89%) as a colorless oil. .sup.1H NMR (CDCl.sub.3) ?=3.61-3.51 (m, 1H), 1.49-1.21 (m, 39H) 1.09 (dd, J=6.5, 3.8 Hz, 41H), 0.58 (dd, J=6.5, 3.8 Hz, 4H). .sup.13C NMR (CDCl.sub.3) ?=174.2 (2?), 79.7 (2?), 71.9, 37.6 (2?), 34.2 (2?), 30.0 (2?), 28.2 (6?), 27.9 (2?), 25.8 (2?), 24.4 (2?), 15.4 (2?), 15.3 (2?). HRMS calcd for C.sub.2H.sub.49O.sub.5(M+H)+: 453.3580, found 453.3550.

6.9 1-[11-(1-Carboxycyclopropyl)-6-hydroxyundecyl]-1-cyclopropanecarboxylic acid

[0263] A solution of tert-butyl 1-11-[1-(tert-butoxycarbonyl)cyclopropyl]-6-hydroxyundecyl-1-cyclopropanecarboxylate (6.49 g, 14.4 mmol) in 1,4-dioxane (70 mL) was treated with conc HCl (70 mL) and stirred overnight. Then the mixture was treated with a mixture of ice and H.sub.2O (1:1,300 mL), and extracted with EtOAc (3?100 mL). The combined organic layers were washed with brine (3?100 mL), dried (Na.sub.2SO.sub.4), and concentrated in vacuo. The remaining oil was coevaporated in vacuo from toluene (2?50 mL), CH.sub.2Cl.sub.2 (50 mL) and Et.sub.2O (3?50 mL), and finally further concentrated in vacuo at 65? C. for 3 h, to give 1-[11-(1-carboxycyclopropyl)-6-hydroxyundecyl]-1-cyclopropanecarboxylic acid (5.08 g, 100%) as a slightly yellow oil, contaminated with Et.sub.2O (4% (w/w)) and toluene (0.5% (w/w)). The thick oil started to crystallize spontaneously after 10 d, after which H.sub.2O (100 mL) was added. The resulting mixture was left standing for 3 d, and the so obtained crystalline material was filtered and air dried to give 1-[11-(1-carboxycyclopropyl)-6-hydroxyundecyl]-1-cyclopropanecarboxylic acid (4.64 g, 95%) as colorless crystals. mp: 87-91? C. .sup.1H NMR (CDCl.sub.3) ?=5.50 (br s, 3H), 3.58, (br s, 1H), 1.53-1.22 (m, 20H) 1.25 (dd, J=6.6, 3.9 Hz, 4H), 0.74 (dd, J=6.9, 3.9 Hz, 4H). .sup.13C NMR (CDCl.sub.3) ?=181.6 (2?), 72.0, 37.3 (2?), 33.7 (2?), 29.9 (2?), 27.6 (2?), 25.6 (2?), 23.5 (2?), 16.7 (2?), 16.6 (2?). Anal. calcd for C.sub.19H.sub.32O.sub.5: C, 67.03; H, 9.47. Found: C, 66.83; H, 9.24.

##STR00020##

6.10 {7-Ethoxy-6,6-dimethyl-1-[(4-methylphenyl)sulfonyl]-7-oxoheptyl}(methylidyne)ammonium

[0264] To a mixture of K.sub.2CO.sub.3 (13.18 g, 95.6 mmol) and Bu.sub.4NI (2.35 g, 6.36 mmol) in dry DMF (50 mL) was added a solution of ethyl 2,2-dimethyl-6-bromohexanoate (prepared according to Ackerley, N.; Brewster, A. G.; Brown, G. R.; Clarke, D. S.; Foubister, A. J., Griffin, S. J.; Hudson, J. A.; Smithers, M. J.; Whittamore, P. R. O., J. Med Chem., 1995, 38, 1608-1628, 24.00 g, 95.6 mmol) and TosMIC (12.41 g, 63.7 mmol) in dry DMF (50 mL) in 20 min under a N.sub.2 atmosphere while stirring vigorously. After 4 d, H.sub.2O (100 mL) was added drop wise while keeping the temperature below 25? C. by cooling with an ice-bath. The resulting mixture was extracted with Et.sub.2O (3?200 mL). The combined organic layers were washed with saturated aqueous NaHCO.sub.3 (2?200 mL), dried (Na.sub.2SO.sub.4), and evaporated in vacuo. The remaining residue was purified by column chromatography (silica; heptane:EtOAc=6:1; a layer of NaHCO.sub.3 was put on the base of the column) to give {7-ethoxy-6,6-dimethyl-1-[(4-methylphenyl)sulfonyl]-7-oxoheptyl}(methylidyne) ammonium (15.68 & 42.8 mmol, 67%) as a slightly yellow oil which slowly solidified on standing. An analytical sample was obtained after recrystallization (0.43 g) from iPr.sub.2O/heptane at ?4? C. to give {7-ethoxy-6,6-dimethyl-1-[(4-methylphenyl)sulfonyl]-7-oxoheptyl}(methylidyne)ammonium (0.30 g) as a white solid. mp: 38-39? C. .sup.1H NMR (CDCl.sub.3): ?=7.84 (d, J=8.4 Hz, 2H), 7.40 (d, J=7.8 Hz, 2H), 4.43 (dd, J=3.3, 10.8 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 2.48 (s, 3H), 2.23-2.12 (m, 1H), 1.90-1.77 (m, 1H), 1.66-40 (m, 4H), 1.38-1.22 (m, 2H), 1.24 (t, J=7.1 Hz, 3H), 1.15 (s, 6H). 13C NMR (CDCl.sub.3): ?=177.3, 164.6, 146.3, 131.0, 129.93 (2?), 129.87 (2?), 72.8, 60.4, 42.2, 40.2, 28.4, 26.0, 25.35, 25.30, 24.2, 22.0, 14.5. Anal. calcd for C.sub.19H.sub.27NO.sub.4S: C, 62.44; H, 7.45; N, 3.83, found: C, 62.57; H, 7.57; N, 3.96.

6.11 Tert-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate

[0265] Under an Ar atmosphere at 0? C., BuLi (2.5M in hexanes, 37 mL, 92.5 mmol) was added drop wise to a solution of iPr.sub.2NH (12.3 mL, 88 mmol, distilled from NaOH) in dry THF (150 mL) in 10 min. The reaction mixture was stirred for 20 min, cooled to ?70? C. and then, tert-butyl cyclopropanecarboxylate (prepared according to Kohlrausch, K. W. F.; Skrabal, R., Z. Elektrochem. Angew. Phys. Chem, 1937, 43, 282-285, 12.5 g, 88 mmol) was added drop wise in 20 min. After 3 min, l-bromo-4-chlorobutane (13.7 mL, 20.1 g, 117 mmol) was added drop wise in 15 min. The reaction mixture was allowed to reach rt, poured into a mixture of aqueous saturated NH.sub.4Cl (200 mL) and ice (50 mL) and extracted with Et.sub.2O (1?200 mL, 1?100 mL). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining oil, was purified by fractional distillation to give tert-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate (10.73 g, 52%) as a colorless oil. bp: T=57-61? C. (p=0.001 mbar). .sup.1H NMR (CDCl.sub.3): ?=3.52 (t, J=6.6 Hz, 2H), 1.76 (quintet, J=6.8 Hz, 2H), 1.64-1.54 (m, 2H), 1.51-1.46 (m, 2H), 1.42 (s, 9H), 1.12 (dd, J=6.6, 3.9 Hz, 2H), 0.60 (dd, J=6.6, 3.9 Hz, 2H). .sup.13C NMR (CDCl.sub.3): ?=173.9, 80.0, 45.1, 33.6, 32.9, 28.2 (3?), 25.3, 24.2, 15.4 (2?). HRMS calcd for C.sub.12H.sub.22ClO.sub.2 (MH.sup.+): 233.1308, found: 233.1308.

6.12 Tert-butyl 1-(4-iodobutyl-1-cyclopropanecarboxylate

[0266] To a solution of tert-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate (10.6 & 45.7 mmol) in 2-butanone (50 mL) was added NaI (8.23 g, 54.5 mmol). The reaction mixture was stirred under reflux overnight, diluted with Et.sub.2O (100 mL), washed with a mixture of H.sub.2O (100 mL) and aqueous Na.sub.2S.sub.2O.sub.4 (0.5 M, 10 mL) and brine (50 mL). The organic phase was dried (Na.sub.2SO.sub.4) and evaporate in vacuo to give tert-butyl 1-(4-iodobutyl)-1-cyclopropanecarboxylate (14.8 g, 94% pure by GC, 94%) as a slightly yellow liquid. .sup.1H NMR (CDCl.sub.3): S=3.18 (t, J=6.9 Hz, 2H), 1.76 (quintet, J=7.1 Hz, 2H), 1.62-1.45 (m, 4H), 1.43 (s, 9H), 1.12 (dd, J=6.7 Hz, 3.8 Hz, 2H), 0.60 (dd, J=6.6 Hz, 3.9 Hz, 2H). .sup.13C NMR (CDCl.sub.3): ?=173.9, 80.0, 33.8, 33.3, 28.9, 28.2 (3?), 24.2, 15.5 (2?), 7.2. HRMS calcd for C.sub.12H.sub.21IO.sub.2 (M.sup.+): 324.0587, found: 324.0587.

6.13 Ethyl 11-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-7-oxoundecanoate

[0267] Under a N.sub.2 atmosphere at 0? C., a solution of {7-ethoxy-6,6-dimethyl-1-[(4-methylphenyl)sulfonyl]-7-oxoheptyl}(methylidyne)ammonium (20.5 g, 55.9 mmol) in N,N-dimethylacetamide (DMAc, 125 mL) followed by a solution of tert-butyl 1-(4-iodobutyl)-1-cyclopropanecarboxylate (18.11 g, 55.9 mmol) in DMAc (125 mL) were added drop wise in 30 and 20 min, respectively to a solution of KOtBu (6.57 g, 58.7 mmol) in DMAc (250 mL). The mixture was allowed to reach rt and stirring was continued for 100 min. Then, the reaction mixture was quenched by the drop wise addition of H.sub.2O (250 mL) while cooling with an ice-bath. The resulting mixture was extracted with Et.sub.2O (3?250 mL) and the combined organic layers were washed with brine (2?250 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give a yellow oil (31.79 g). Part of this oil (30.63 g) was dissolved in CH.sub.2Cl.sub.2 (300 mL) and conc aqueous HCl (23 mL) was added. After 2 h of vigorous stirring, H.sub.2O (250 mL) was added. The layers were separated and the aqueous phase was extracted with CH.sub.2Cl.sub.2 (3?250 mL). The combined organic phases were washed with saturated aqueous NaHCO.sub.3 (250 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. To the remaining suspension of a yellow oil with a white solid was added heptane (?50 mL) and the white solid was filtered off and washed with heptane (?50 mL). The filtrate was stored at it for 2 d and more white solid was formed, which was filtered off through a layer of silica (?1 cm) and washed with heptane (?50 mL). The combined filtrates were evaporated in vacuo to give impure ethyl 11-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-7-oxoundecanoate (17.90 g) as a colorless oil. This batch was further purified by column chromatography (silica, heptane:EtOAc=40:1) to give ethyl 11-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-7-oxoundecanoate (9.83 g, >90% pure by NMR, 43%) as a colorless oil. .sup.1H NMR (CDCl.sub.3): ?=4.09 (q, J=7.2 Hz, 2H), 2.38 (t, J=7.2 Hz, 4H), 1.62-1.35 (m, 10H), 1.41 (s, 9H), 1.26-1.17 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.14 (s, 6H), 1.09 (dd, J=6.9, 4.2 Hz, 2H), 0.59 (dd, J=6.3, 3.6 Hz, 2H). .sup.13C NMR: ? 210.5, 177.4, 174.0, 79.8, 60.2, 42.8, 42.6, 42.1, 40.5, 34.0, 28.2 (3?), 27.5, 25.2 (2?), 24.7, 24.3, 24.2, 24.1, 15.3 (2?), 14.4. HRMS calcd for C.sub.23H.sub.41O.sub.5 (MH.sup.+): 397.2954, found: 397.2956.

6.14 11-(1-Carboxycyclopropyl)-2,2-dimethyl-7-oxoundecanoic acid

[0268] A solution of ethyl 11-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-7-oxoundecanoate (9.27 g, >90% pure by NMR, 21.0 mmol) in HCO.sub.2H (50 mL) was stirred for 1.5 h, evaporated in vacuo and coevaporated from toluene (10 mL). The remaining residue was dissolved in a mixture of EtOH and H.sub.2O (2:1, 100 mL) and NaOH (5.33 g, 132 mmol) was added. The resulting clear solution was warmed to 80? C. and after 5 h EtOH was evaporated in vacuo. The remaining solution was diluted with H.sub.2O to ?100 mL, extracted with Et.sub.2O (3?100 mL), acidified to pH ?1 with conc aqueous HCl (?9 mL) and extracted with Et.sub.2O (3?100 mL). The latter organic layers were combined, dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining residue was purified by column chromatography (silica, heptane:EtOAc=2:1 (containing 1% (v/v) HOAc)) to give 11-(1-carboxycyclopropyl)-2,2-dimethyl-7-oxoundecanoic acid (5.83 g, >90% pure by .sup.1H NMR, 80%) as a slightly yellow oil which turns solid when stored at ?18? C. for several days. mp: 49-52? C. .sup.1H NMR (CD.sub.3OD): ?=2.44 (t, J=7.2 Hz, 4H), 1.57-1.42 (m, 10H), 1.30-1.19 (m, 2H), 1.17-1.07 (m, 2H), 1.14 (s, 6H), 0.59 (dd, J=6.6, 3.9 Hz, 2H). .sup.3C NMR (CD.sub.3OD): ?=213.5, 181.4, 178.9, 43.5, 43.4, 43.0, 41.7, 34.9, 28.5, 25.9 (3?), 25.5, 25.2, 24.3, 16.4 (2?). Anal. calcd for C.sub.17H.sub.28O.sub.5: C, 65.36; H, 9.03, found: C, 65.06; H, 9.02.

6.15 11-(1-Carboxycyclopropyl)-7-hydroxy-2,2-dimethylundecanoic acid

[0269] To a mixture of 1-(1-carboxycyclopropyl)-2,2-dimethyl-7-oxoundecanoic acid (3.63 g, >90% pure by NMR, 10.4 mmol) in iPrOH (20 mL) and H.sub.2O (20 mL) was added NaOH (0.94 g, 23.5 mmol). After 5 min of stirring, NaBH.sub.4 (0.24 g, 6.3 mmol) was added to the resulting clear solution. After 19 h, the mixture was acidified to pH?1 with aqueous HCl (2M) and extracted with Et.sub.2O (3?50 mL). The combined organic phases were washed with brine (1?50 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining residue was coevaporated in vacuo from EtOAc to give 11-(1-carboxycyclopropyl)-7-hydroxy-2,2-dimethylundecanoic acid (3.43 g, 93%, contains 8% (w/w) EtOAc and 3% (w/w) iPrOH) as a viscous colorless oil. .sup.1H NMR (CD.sub.3OD): ?=3.5 (br s, 1H), 1.56-1.27 (m, 16H), 1.16 (s, 6H), 1.16-1.14 (m, 2H), 0.72 (dd, J=3.4, 6.6 Hz, 2H). .sup.13C NMR (CD.sub.3OD): ?=181.6, 179.1, 72.3, 43.1, 42.0, 38.5, 38.4, 35.2, 29.0, 27.5, 27.1, 26.4, 26.0, 25.9, 24.4, 16.43, 16.38. HRMS calcd for C.sub.17H.sub.31O.sub.5(M+H.sup.+): 315.2171, found 315.2175.

##STR00021##

6.16 Ethyl 7-bromo-2,2-dimethylheptanoate

[0270] Under Ar atmosphere at ?78? C., to a solution of ethyl isobutyrate (124.0 g, 1.06 mol) and DMPU (5 mL) in THF (160 mL) was added LDA (750 mL, 2M). After 30 min, 1,5-dibromopentane (313 g, 1.32 mol) was added in a single portion. The reaction mixture was allowed to stir overnight, gradually warming to rt. The mixture was hydrolyzed with ice (500 g), saturated NH.sub.4Cl (400 mL) and aqueous HCl (6M, 400 mL), and the solution was extracted with Et.sub.2O (3?300 mL). The organic layers were washed with half saturated NaCl (2?300 mL), dried (MgSO.sub.4) and evaporated in vacuo. The remaining residue was purified by distillation under reduced pressure to give ethyl 7-bromo-2,2-dimethylheptanoate (97.4 g, 32%) as a colorless oil. bp: T=109-110? C. (p=1.5-2 Torr). .sup.1H NMR (CDCl.sub.3): 5=4.15 (q, J=7.2 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 1.90-1.83 (m, 2H), 1.55-1.37 (m, 4H), 1.25 (t, J=6.9 Hz, 3H), 1.30-1.22 (m, 2H), 1.16 (s, 6H). .sup.13C NMR (CDCl.sub.3): ?=177.9, 60.3, 42.2, 40.5, 33.7, 32.7, 28.6, 25.2, 24.2, 14.3. HRMS calcd for C.sub.11H.sub.22BrO.sub.2 (MH.sup.+): 265.0803, found: 265.0816.

6.17 {8-Ethoxy-7,7-dimethyl-1-[(4-methylphenyl)sulfonyl]-8-xooctyl}(methylidyne)ammonium

[0271] Under a N.sub.2 atmosphere, TosMIC (10.01 g, 51.3 mmol) and ethyl 7-bromo-2,2-dimethylheptanoate (20.41 g, 77.0 mmol) were dissolved in dry DMF (100 mL) and Bu.sub.4NI (1.89 g, 5.12 mmol) and K.sub.2CO.sub.3 (10.62 g, 76.8 mmol) were added while stirring vigorously. After 5 d, the reaction mixture was poured in an ice/H.sub.2O mixture (500 mL), extracted with Et.sub.2O (1?200 mL, 2?100 mL) The combined organic layers were washed with brine (2?50 mL), dried (Na.sub.2SO.sub.4), and evaporated in vacuo. The remaining residue was purified by column chromatography (silica, heptane:EtOAc=3:1) to give in order of elution ethyl 7-bromo-2,2-dimethylheptanoate (5.67 g, 90% pure by GC), an impure batch of (8-ethoxy-7,7-dimethyl-1-[(4-methylphenyl)sulfonyl]-8-oxooctyl)(methylidyne)ammonium (0.94 g), and pure {8-ethoxy-7,7-dimethyl-1-[(4-methylphenyl)sulfonyl]-8-oxooctyl}(methylidyne)ammonium (11.83 g, 61%) as a colorless oil. .sup.1H NMR (CDCl.sub.3): ?=7.86 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 4.45 (dd, J=10.9, 3.5 Hz, 1H), 4.11 (q, J=7.2 Hz, 2H), 2.49 (s, 3H), 2.22-2.11 (m, 1H), 1.90-1.77 (m, 1H), 1.67-1.57 (m, 1H), 1.53-1.42 (m, 3H), 1.24 (t, J=7.2 Hz, 3H), 1.39-1.20 (m, 4H), 1.15 (s, 6H). .sup.13C NMR (CDCl.sub.3): ?=177.8, 164.8, 146.5, 131.1, 130.1 (2?), 130.0 (2?), 72.8, 60.2, 42.0, 40.3, 29.0, 28.3, 25.12, 25.06 (2?), 24.5, 21.7, 14.2. HRMS calcd for C.sub.20H.sub.29NNaO.sub.4S (MNa.sup.+): 402.1715, found: 402.1736.

6.18 Ethyl 13-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-8-oxotridecanoate

[0272] Under a N.sub.2 atmosphere at 0? C., a solution of {8-ethoxy-7,7-dimethyl-1-[(4-methylphenyl)sulfonyl]-8-oxooctyl)}(methylidyne)ammonium (28.4 g, 75.0 mmol) in N,N-dimethylacetamide (DMAc, 125 mL) followed by a solution of tert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate (B3, 25.4 g, 75.0 mmol) in DMAc (125 mL) were added dropwise in 60 and 30 min, respectively to a solution of KOtBu (8.83 g, 79.0 mmol) in DMAc (250 mL). The mixture was allowed to reach rt and stirring was continued for 2 h. Then, the reaction mixture was quenched by the dropwise addition of H.sub.2O (250 mL) while cooling with an ice-bath. The resulting mixture was extracted with Et.sub.2O (3?250 mL) and the combined organic layers were washed with brine (2?250 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give a yellow oil (43.02 g). Part of this oil (42.50 g) was dissolved in CH.sub.2Cl.sub.2 (250 mL) and cone aqueous HCl (34 mL) was added. After 1.5 h of vigorous stirring, H.sub.2O (250 mL) was added. The layers were separated and the aqueous phase was extracted with CH.sub.2Cl.sub.2 (3?250 mL). The combined organic phases were washed with saturated aqueous NaHCO.sub.3 (250 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. To the remaining residue was purified by column chromatography (silica, heptane:EtOAc=8:1) to give ethyl 13-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-8-oxotridecanoate (19.0 g, 95% pure by .sup.1H NMR, 57%) as a slightly yellow oil. .sup.1H NMR (CDCl.sub.3): ?=4.09 (q, J=7.2 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 2.36 (t, J=7.2 Hz, 2H), 1.62-1.35 (m, 10H), 1.41 (s, 9H), 1.30-1.21 (m, 6H), 1.24 (t, J=7.2 Hz, 3H), 1.14 (s, 6H), 1.09 (dd, J=6.6, 3.9 Hz, 2H), 0.58 (dd, J=6.3, 3.6 Hz, 2H). .sup.13C NMR (CDCl.sub.3): ?=210.8, 177.6, 174.1, 79.8, 60.2, 42.9. 42.8, 42.2, 40.6, 34.1, 29.8, 29.6, 28.2 (3?), 27.6, 25.3 (2?), 24.9, 24.3, 23.9, 23.8, 15.3 (2?), 14.4. HRMS calcd for C.sub.25H.sub.45O.sub.5(MH.sup.+): 425.3267, found: 425.3267.

6.19 13-(1-Carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid

[0273] A solution of ethyl 13-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-8-oxotridecanoate (18.34 g, 43.3 mmol) in HCO.sub.2H (50 mL) was stirred for 1.5 h, evaporated in vacuo and coevaporated in vacuo from toluene (10 mL). The remaining residue was dissolved in a mixture of EtOH and H.sub.2O (2:1,250 mL) and NaOH (9.68 g, 241 mmol) was added. The resulting clear solution was warmed to 80? C. and after 5 h EtOH was evaporated in vacuo. The remaining solution was diluted with H.sub.2O to ?250 mL, extracted with Et.sub.2O (3?250 mL), acidified to pH ?1 with conc aqueous HCl (?18 mL) and extracted with Et.sub.2O (3?250 mL). The latter organic layers were combined, dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give a yellow oil which solidified overnight. The remaining residue was recrystallized from iPr.sub.2O/heptane to give 13-(1-carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid (9.47 g, 57%) as a white solid. The mother liquor was evaporated in vacuo and the remaining residue was purified by column chromatography (heptane:EtOAc=2:1 (containing 1% (v/v) HOAc)) and recrystallization from iPr.sub.2O/heptane to give a second batch 13-(1-carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid (2.23 g, 14%) as a white solid. mp=65-66? C. .sup.1H NMR: (CD.sub.3OD): ?=2.43 (t, J=7.2 Hz, 4H), 1.58-1.42 (m, 10H), 1.35-1.20 (m, 6H), 1.14 (s, 6H), 1.15-1.06 (m, 2H), 0.70 (dd, J=6.6, 3.9 Hz, 2H). .sup.13C NMR: (CD.sub.3OD): ?=213.8, 181.6, 179.0, 43.6, 43.5, 43.1, 41.9, 35.1, 31.0, 30.6, 28.7, 26.2, 25.9 (2?), 25.02, 24.96, 24.4, 16.4 (2?). Anal. calcd for C.sub.1H.sub.32O.sub.5: C, 67.03; H, 9.47, found: C, 66.86; H, 9.50.

6.20 13-(1-Carboxycyclopropyl)-8-hydroxy-2,2-dimethyltridecanoic acid

[0274] To a mixture of 13-(1-carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid (3.67 g, 10.8 mmol) in iPrOH (20 mL) and H.sub.2O (20 mL) was added NaOH (0.90 g, 22.5 mmol). After 5 min of stirring, NaBH.sub.4 (0.20 g, 5.3 mmol) was added to the resulting clear solution. Additional NaBH.sub.4 (0.10 g) was added after 100 min of stirring. After 16 h, the mixture was acidified to pH?1 with aqueous HCl (IM) and extracted with Et.sub.2O (3?50 mL). The combined organic phases were washed with brine (2?50 mL), dried (Na.sub.2SO.sub.4), evaporated in vacuo and coevaporated in vacuo from EtOAc (2?15 mL) to give 13-(1-carboxycyclopropyl)-8-hydroxy-2,2-dimethyltridecanoic acid (3.99 g, 97%, contains 10% (w/w) EtOAc) as a viscous colorless oil. .sup.1H NMR (CD.sub.3OD): ?=3.48 (m, 1H), 1.50-1.21 (m, 20H), 1.14 (s, 6H), 1.14-1.12 (m, 2H), 0.70 (dd, J=3.9, 6.3 Hz, 2H). .sup.13C NMR (CD.sub.3OD): ?=181.6, 179.0, 72.4, 43.2, 42.0, 38.6, 38.5, 35.2, 31.5, 31.2, 28.9, 26.94, 26.87, 26.3, 25.94, 25.92, 24.4, 13.67, 16.36. HRMS calcd for C.sub.19H.sub.33O.sub.5(M+H).sup.+: 343.2484, found 343.2487.

##STR00022##

6.21 Ethyl 1 4-chlorobutyl)-1-cyclobutanecarboxylate

[0275] Under an N.sub.z atmosphere at ?7? C., BuLi (2.5M in hexanes, 52.8 mL, 132 mmol) was added drop wise to a solution of iPr.sub.2NH (18.52 mL, 132 mmol, distilled from NaOH) in dry THF (70 mL) in 10 min. The reaction mixture was allowed to warm to rt, stirred for 0.5 h, cooled to ?60? C. and then, ethyl 1-cyclobutanecarboxylate (prepared according to T?r?k, B.; Moln?r, ?., J. Chem. Soc. Perkin Trans. 1, 1993, 7, 801-804, 14.05 g, 110 mmol) in dry THF (30 mL) was added dropwise in 20 min. The resulting mixture was allowed to warm to 0? C. in 20 min., cooled again to ?60? C. and then, a solution of 1-bromo-4-chlorobutane (19.1 mL, 165 mmol) in dry THF (30 mL) was added dropwise in 20 min, after which the temperature was raised to ?20? C. in 15 min. After 1.5 h, the temperature was raised to ?10? C. and stirring was continued for 1 h. The reaction mixture was allowed to reach rt, poured into a mixture of aqueous saturated NH.sub.4Cl (200 mL) and ice (50 mL) and extracted with Et.sub.2O (500 mL). The organic layer was washed with brine (250 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining oil was purified by fractional distillation under reduced pressure to give ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (20.53 g, 86%) as a thin, colorless oil. .sup.1H NMR (CDCl.sub.3): ?=4.13 (q, J=7.1 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.50-2.32 (m, 2H), 1.96-1.70 (m, 8H), 1.40-1.20 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). .sup.13C NMR (CDCl.sub.3): ?=176.6, 60.3, 47.6, 44.8, 37.3, 32.8, 30.1 (2?), 22.4, 15.8, 14.4. HRMS calcd for C.sub.11H.sub.20(.sup.37Cl)O.sub.2 (MH.sup.+): 221.1122, found: 221.1116.

6.22 Ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate

[0276] To a solution of ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (21.21 g, 97.0 mmol) in 2-butanone (125 mL) was added NaI (19.07 g, 127 mmol). The reaction mixture was stirred under reflux for 20 h and diluted with Et.sub.2O (500 mL). The resulting mixture was washed with aqueous Na.sub.2S.sub.2O.sub.3 (10% (w/w), 250 mL), brine (250 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (29.91 g, 99%) as a slightly yellow oil. .sup.1H NMR (CDCl.sub.3): ?6=4.14 (q, J=7.1 Hz, 2H), 3.17 (t, J=6.9 Hz, 2H), 2.49-2.32 (m, 2H), 1.98-1.69 (m, 8H), 1.37-1.19 (m, 2H), 1.27 (t, J=7.1 Hz, 3H). .sup.13C NMR (CDCl.sub.3): ?=176.5, 60.3, 47.5, 36.9, 33.7, 30.1 (2?), 26.0, 15.7, 14.5, 6.8. HRMS calcd for C.sub.11H.sub.20IO.sub.2 (MH.sup.+): 311.0508, found: 311.0511.

6.23 Ethyl 1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-oxononyl-1-cyclobutanecarboxylate

[0277] Under a N.sub.2 atmosphere at 0? C., KOtBu (8.61 g, 76.7 mmol) was added portion wise to a solution of ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (24.83 g, 80.1 mmol) and TosMIC (7.26 g, 36.4 mmol) in DMAc (150 mL). After 30 min, the reaction mixture was allowed to warm to rt, stirred for 1.5 h and diluted with DMAc (10 mL). Then, ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (2.01 g, 6.5 mmol) and KOtBu (0.81 g, 7.2 mmol) were added followed by another portion of ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (1.00 g, 3.2 mmol) and KOtBu (0.86 g, 7.7 mmol) after 1 h. After 1 h, the reaction mixture was poured into a mixture of Et.sub.2O (700 mL) and aqueous NaCl (10%, 500 mL) and the layers were separated. The organic layer was washed with brine (1?500 mL, 1?300 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining residue was purified by column chromatography (silica, heptane:EtOAc=6:1) to give ethyl 1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-isocyano-5-[(4-methylphenyl)sulfonyl]nonyl-1-cyclobutanecarboxylate (18.35 g) as a slightly yellow oil. Part of this oil (15.62 g, 27.9 mmol) was dissolved in CH.sub.2Cl.sub.2 (200 mL) and cone aqueous HCl (75 mL) was added. After stirring vigorously for 2 h, H.sub.2O (300 mL) was added and the layers were separated. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (2?100 mL) and the combined CH.sub.2Cl.sub.2 layers were washed with saturated aqueous NaHCO.sub.3 (2?250 mL) and brine (250 mL). All aqueous layers were combined and extracted with Et.sub.2O (2?200 mL). The combined Et.sub.2O layers were washed with saturated aqueous NaHCO.sub.3 (200 mL) and brine (200 mL). The CH.sub.2Cl.sub.2 layers and Et.sub.2O layers were combined, dried (Na.sub.2SO.sub.4) and evaporated in vacuo. To the remaining residue heptane (150 mL) was added, and the mixture was filtered through two stacked folded filter papers. The hazy filtrate was filtered again to give a clear filtrate, which was evaporated in vacuo. The remaining residue was purified by column chromatography (silica, heptane:EtOAc=6:1) to give ethyl 1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-oxononyl-1-cyclobutanecarboxylate (9.99 g, 82%) as a slightly yellow liquid, after evaporation from CH.sub.2Cl.sub.2 (100 mL). .sup.1H NMR (CDCl.sub.3): ?=4.12 (q, J=7.1 Hz, 4H), 2.44-2.32 (m, 8H), 1.93-1.79 (m, 8H), 1.77-1.72 (m, 4H), 1.55 (quintet, J=7.5 Hz, 4H), 1.25 (t, J=7.1 Hz, 6H), 1.21-1.10 (m, 4H). .sup.3C NMR (CDCl.sub.3): ?=210.2, 176.7 (2?), 60.2 (2?), 47.6 (2?), 42.6 (2?), 37.9 (2?), 30.1 (4?), 24.7 (2?), 24.1 (2?), 15.7 (2?), 14.4 (2?). HRMS calcd for C.sub.23H.sub.38O.sub.5 (M.sup.+): 394.2719, found: 394.2703.

6.24 1-[9-(1-(Carboxycyclobutyl-1-oxononyl]-1-cyclo-butanecarboxylic acid

[0278] LiOH.H.sub.2O (3.94 g, 93.9 mmol) and H.sub.2O (30 mL) were added to a solution of ethyl 1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-oxononyl-1-cyclobutanecarboxylate (9.20 g, 23.3 mmol) in EtOH (90 mL) and the resulting mixture was stirred at reflux temperature for 17 h, allowed to cool to rt and concentrated in vacuo to a smaller volume. H.sub.2O (150 mL) was added and the resulting mixture was extracted with Et.sub.2O (50 mL), acidified with aqueous HCl (6 M, 25 mL) and extracted with Et.sub.2O (1?100 mL, 2?50 mL). The latter organic layers were combined, washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining residue was recrystallized from a mixture of iPr.sub.2O and heptane to give 1-[9-(1-carboxycyclobutyl)-5-oxononyl]-1-cyclo-butanecarboxylic acid (4.41 g, 56%) as small, white granules. mp 69-70? C. .sup.1H NMR (CDCl.sub.3): ?=11.2 (br s, 2H), 2.50-2.37 (m, 4H), 2.39 (t, J=7.2 Hz, 4H), 1.96-1.84 (m, 8H), 1.81-1.75 (m, 4H), 1.57 (quintet, J=7.4 Hz, 4H), 1.26-1.12 (m, 4H). .sup.13C NMR (CDCl.sub.3): ?=210.6, 183.4 (2?), 47.6 (2?), 42.7 (2?), 37.8 (2?), 30.1 (4?). 24.7 (2?), 24.1 (2?), 15.7 (2?). Anal. calcd for C.sub.19H.sub.30O.sub.5: C, 67.43; H, 8.93, found: C, 67.19; H, 8.97.

6.25 1-[9-(1-Carboxycyclobutyl)-5-hydroxynonyl]-1-cyclobutanecarboxylic acid

[0279] To a solution of 1-[9-(1-carboxycyclobutyl)-5-oxononyl]-1-cyclo-butanecarboxylic acid (7.83 g, 23.1 mmol) in aqueous NaOH (IM, 70 mL) and i-PrOH (70 mL) was added NaBH.sub.4 (0.659 g, 17.3 mmol). After stirring for 3.5 h, the reaction mixture was acidified to pH-1 with conc HCl and extracted with Et.sub.2O (1?250 mL, 2?150 mL). The combined organic layers were washed with brine (250 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The remaining residue was dried under high vacuum to give 1-[9-(1-carboxycyclobutyl)-5-hydroxynonyl]-1-cyclobutanecarboxylic acid (8.17 g, 97%, contains 7% (w/w) Et.sub.2O) as a thick, colorless oil. .sup.1H NMR (CDCl.sub.3): ?=8.56 (br s, 3H), 3.58 (br s, 1H), 2.55-2.30 (m, 4H), 2.00-1.80 (m, 8H), 1.78 (t, J=7.7 Hz, 4H), 1.52-1.15 (m, 12H). .sup.13C NMR (CDCl.sub.3): =183.0 (2?), 71.7, 47.7 (2?), 38.0 (2?), 37.1 (2?), 30.2 (2?), 30.1 (2?), 25.9 (2?), 25.0 (2?), 15.7 (2?).

##STR00023##

6.26 Butyl 1-(4-bromo-butyl-cyclopentanecarboxylate

[0280] Under a N.sub.2 atmosphere at ?60? C., a solution of butyl cyclopentanecarboxylate (prepared according to Payne, G. B.; Smith, C. W., J. Org. Chem., 1957, 22, 1680-1682, 80.0 g, 0.42 mol) and 1,4-dibromobutane (183.3 g, 0.84 mol) in dry THF (700 mL) was added drop wise to a mixture of LDA (2M in THF/heptane/ethylbenzene, 250 mL, 0.50 mol) and dry THF (250 mL) in 1.5 h. After that, the reaction mixture was allowed to slowly reach rt during 3.5 h. Then, the reaction mixture was poured into ice-cold saturated aqueous NH.sub.4Cl (1 L). The organic layer was decanted and concentrated in vacuo to a smaller volume. The aqueous layer was extracted with Et.sub.2O (3?250 mL). The combined organic layers were washed with saturated aqueous NH.sub.4Cl (250 mL) and brine (2?250 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining residue was purified by fractional distillation to give butyl 1-(4-bromo-butyl)-cyclopentanecarboxylate (62.8 g, 49%) as a light yellow liquid. bp: T=116-117? C. (p=0.040-0.051 Torr). .sup.1H NMR (CDCl.sub.3): ?=4.07 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H), 2.16-2.10 (m, 2H), 1.83 (quintet, J=7.1 Hz, 2H), 1.65-1.59 (m, 8H), 1.50-1.31 (m, 6H), 0.94 (t, J=7.2 Hz, 3H). .sup.13C NMR (CDCl.sub.3): ?=177.6, 64.1, 53.9, 38.2, 36.0 (2?), 33.3, 33.0, 30.6, 24.8 (2?), 24.6, 19.1, 13.6. HRMS calcd for C.sub.14H.sub.25BrO.sub.2 (M.sup.+): 304.1038, found: 304.1042.

6.27 Butyl 1-9-[1-(butoxycarbonyl)cyclopentyl]-5-oxononyl-1-cyclopentanecarboxylate

[0281] Under a N.sub.2 atmosphere, NaH (60% (w/w) in mineral oil, 3.20 g, 80.0 mmol) was added portion wise to a solution of TosMIC (6.58 g, 33.0 mmol) and Bu.sub.4NI (1.31 g, 3.55 mmol) in dry DMSO (100 mL) while stirring vigorously and cooling with a water bath. After 30 min, butyl 1-(4-bromo-butyl)-cyclopentanecarboxylate (21.59 g, 67.2 mmol) was added drop wise to the mixture in 20 min and after 1 h of stirring, another portion of NaH (60% (w/w) in mineral oil, 0.56 g, 14 mmol) was added. After 20 min, H.sub.2O (250 mL, ice-cold) was added drop wise while cooling with a water bath and the resulting mixture was extracted with Et.sub.2O (3?100 mL). The combined organic layers were washed with brine (2?100 mL), dried (Na.sub.2SO.sub.4) and filtered through a layer of silica. The residue was washed with Et.sub.2O (200 mL) and the combined filtrate and washings were evaporated in vacuo. The remaining oil was purified by column chromatography (silica, heptane/EtOAc=8:1) to give butyl 1-{9-[1-(butoxycarbonyl)cyclopentyl]-5-isocyano-5-[(4-methylphenyl)sulfonyl]nonyl}-1-cyclopentanecarboxylate as a yellow oil (13.38 g). This oil (13.38 g) was dissolved in CH.sub.2Cl.sub.2 (250 mL), and cone aqueous HCl (75 mL) was added. After stirring vigorously for 18 h, H.sub.2O (300 mL) was added and the layers were separated. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (2?100 mL) and the combined organic layers were washed with saturated aqueous NaHCO.sub.3 (2?250 mL) and brine (250 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining residue was suspended in heptane (100 mL) and filtered. The filtrate was evaporated in vacuo. The remaining residue was purified by column chromatography (silica, heptane/EtOAc=6:1) to give butyl 1-9-[l-(butoxycarbonyl)cyclopentyl]-5-oxononyl-1-cyclopentanecarboxylate (9.05 g, 56%) as a slightly yellow liquid. .sup.1H NMR (CDCl.sub.3): ?=4.05 (t, J=6.5 Hz, 4H), 2.36 (t, J=7.5 Hz, 4H), 2.14-2.05 (m, 4H), 1.65-1.32 (m, 28H), 1.24-1.16 (m, 4H), 0.96 (t, J=7.2 Hz, 6H). .sup.13C NMR (CDCl.sub.3): ?=210.8, 177.8 (2?), 64.1 (2?), 54.0 (2?), 42.6 (2?), 39.0 (2?), 36.0 (4?), 30.7 (2?), 25.6 (2?), 24.9 (4?), 24.1 (2?), 19.1 (2?), 13.6 (2?). HRMS calcd for C.sub.29H.sub.50O.sub.5 (M.sup.+): 478.3658, found 478.3663.

6.28-[9-(1-Carboxycyclopentyl)-5-oxononyl]-1-cyclopentanecarboxylic acid

[0282] LiOH.H.sub.2O (3.21 g, 76.4 mmol) and H.sub.2O (40 mL) were added to a solution of butyl 1-9-[1-(butoxycarbonyl)cyclopentyl]-5-oxononyl-1-cyclopentanecarboxylate (7.25 g, 15.0 mmol) in EtOH (120 mL) and the resulting mixture was stirred at reflux temperature for 25 h, allowed to cool to rt and concentrated in vacuo to a smaller volume. H.sub.2O (100 mL) was added and the resulting mixture was extracted with Et.sub.2O (25 mL), acidified with aqueous HCl (6 M, 15 mL) and extracted with Et.sub.2O (3?50 mL). The latter organic layers were combined, dried (Na.sub.2SO.sub.4, to avoid loss of material, a minimal amount of Na.sub.2SO.sub.4 was used, with the desiccant becoming a white, oily paste. The organic layer was decanted from the desiccant.) and evaporated in vacuo to give 1-[9-(1-carboxycyclopentyl)-5-oxononyl]-1-cyclopentanecarboxylic acid (5.46 g, 95% pure by .sup.1H NMR, 94%, mp=99-103? C.) as a white solid. An analytical sample was obtained after recrystallization from iPr.sub.2O/heptane. mp=104-106 OC. .sup.1H NMR (CDCl.sub.3): ?=2.39 (t, J=6.9 Hz, 4H), 2.18-2.10 (m, 4H), 1.69-141 (m, 20H), 1.27-1.14 (m, 4H). .sup.13C NMR (CDCl.sub.3): ?=211.1, 184.6 (2?), 53.9 (2?), 42.5 (2?), 39.0 (2?), 35.9 (4?), 25.7 (2?), 24.9 (4?), 24.0 (2?). Anal. calcd for C.sub.21H.sub.34O.sub.5: C, 68.82; H, 9.35, found: C, 68.78; H, 9.47.

6.29 1-[9-(1-Carboxycyclopentyl)-5-hydroxyonyl]-1-cyclo-pentanecarboxylic acid

[0283] To a mixture of 1-[9-(1-carboxycyclopentyl)-5-oxononyl]-1-cyclopentanecarboxylic acid (4.70 g, 11.5 mmol) in iPrOH (30 mL) and H.sub.2O (30 mL) was added NaOH (1.10 g, 27 mmol). To the resulting clear solution, NaBH.sub.4 (0.242 g, 6.4 mmol) was added. After 23 h, TLC analysis revealed the reaction to be incomplete, and an additional portion of NaBH.sub.4 (0.036 g, 0.95 mmol) was added. Stirring was continued for 17 h and then, the reaction mixture was concentrated in vacuo. The remaining residue was dissolved in H.sub.2O (80 mL) and washed with Et.sub.2O (20 mL). The aqueous layer was acidified with aqueous HCl (6M, 15 mL) and then extracted with Et.sub.2O (3?50 mL). The combined organic layers were washed with brine (2?50 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give 1-[9-(1-carboxycyclopentyl)-5-hydroxynonyl]-1-cyclo-pentanecarboxylic acid (4.45 g, 98%, contains 7% (w/w) Et.sub.2O) as a thick, slightly hazy, light yellow oil. .sup.1H NMR (CDCl.sub.3): ?=3.56 (br s, 1H), 2.16-2.10 (m, 4H), 1.65-1.60 (m, 12H), 1.51-1.18 (m, 16H). .sup.13C NMR (CDCl.sub.3): ?=184.1 (2?), 71.1, 54.2 (2?), 39.4 (2?), 37.1 (2?), 36.1 (2?), 35.7 (2?), 26.0 (2?), 25.8 (2?), 25.03 (2?), 25.00 (2?).

##STR00024##

6.30 Butyl 1-(5-bromo-pentyl-cyclopentanecarboxylate

[0284] Under a N.sub.2 atmosphere at ?60? C., a solution of butyl cyclopentanecarboxylate (prepared according to Payne, G. B.; Smith, C. W., J. Org. Chem., 1957, 22, 1680-1682, 40.2 g, 0.236 mol) and 1,5-dibromopentane (64 mL, 0.45 mol) in dry THF (400 mL) was added drop wise to a solution of LDA (2M in THF/heptane/ethylbenzene, 200 mL, 0.40 mol) in 30 min. After 3 h, the reaction mixture was allowed to reach rt in 30 min. Then the reaction mixture was poured out into ice-cold saturated aqueous NH.sub.4Cl (1 L). The organic layer was decanted and concentrated in vacuo to a smaller volume. The aqueous layer was extracted with Et.sub.2O (3?150 mL). The combined organic layers were washed with saturated aqueous NH.sub.4Cl (3?150 mL), brine (150 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining residue was purified by fractional distillation to give butyl 1-(5-bromo-pentyl)-cyclopentanecarboxylate (49.1 g, >90% pure by GC, 59%) as a bright yellow liquid. bp: T=123? C. (p=0.001 Torr). .sup.1H NMR (CDCl.sub.3): ?=4.06 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.9 Hz, 2H), 2.15-2.07 (m, 2H), 1.89-1.79 (quintet, J=7.1 Hz, 2H), 1.69-1.56 (m, 8H), 1.49-1.32 (m, 6H), 1.28-1.17 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). .sup.13C NMR (CDCl.sub.3): ?=177.7, 64.0, 54.0, 39.0, 36.0 (2?), 33.6, 32.5, 30.7, 28.5, 25.1, 24.8 (2?), 19.1, 13.6. HRMS calcd for C.sub.15H.sub.27BrO.sub.2 (M.sup.+): 318.1195, found: 318.1192.

6.31 Butyl 1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-oxoundecyl}-1-cyclopentanecarboxylate

[0285] Under a N.sub.2 atmosphere, NaH (60% (w/w) in mineral oil, 7.55 g, 189 mmol) was added portion wise to a solution of TosMIC (12.48 g, 62.6 mmol) and Bu.sub.4NI (2.56 g, 6.93 mmol) in dry DMSO (200 mL) while stirring vigorously and cooling with a water bath. After 30 min, butyl 1-(5-bromo-pentyl)-cyclopentanecarboxylate (44.46 g, >90%/o pure by GC, 125 mmol) was added drop wise to the mixture in 20 min and after 1 h of stirring, another portion of NaH (60% (w/w) in mineral oil, 1.20 g, 30.0 mmol) was added. After 1 h, the reaction mixture was slowly poured into ice-cold H.sub.2O (500 mL) and the resulting mixture was extracted with Et.sub.2O (3?250 mL). The combined organic layers were washed with aqueous NaCl (10%, 250 mL) and brine (2?200 mL), dried (Na.sub.2SO.sub.4) and filtered through a layer of silica (150 g). The residue was washed with Et.sub.2O (250 mL) and the combined filtrate and washings were evaporated in vacuo. The remaining oil was purified by column chromatography (silica, heptane:EtOAc=8:1) to give butyl 1-{1-[1-(butoxycarbonyl)cyclopentyl]-6-isocyano-6-[(4-methylphenyl)sulfonyl]undecyl}-1-cyclopentanecarboxylate as a yellow oil (32.79 g). This oil (32.79 g) was dissolved in CH.sub.2Cl.sub.2 (400 mL), and cone aqueous HCl (150 mL) was added. After stirring vigorously for 4.5 h, H.sub.2O (500 mL) was added and the layers were separated. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (2?100 mL) and the combined organic layers were washed with saturated H.sub.2O (200 mL), saturated aqueous NaHCO.sub.3 (500 mL) and brine (500 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The remaining residue was purified by column chromatography (silica, heptane:EtOAc=6:1) to give butyl 1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-oxoundecyl}-1-cyclopentanecarboxylate (24.11 g, 90% pure by .sup.1H NMR, 69%) as a slightly yellow liquid. .sup.1H NMR (CDCl.sub.3): ?=4.06 (t, J=6.6 Hz, 4H), 2.36 (t, J=7.4 Hz, 4H), 2.15-2.06 (m, 4H), 1.65-1.52 (m, 20H), 1.49-1.32 (m, 8H), 1.27-1.19 (m, 8H), 0.94 (t, J=7.4 Hz, 6H). .sup.13C NMR (CDCl.sub.3): ?=210.9, 177.6 (2?), 63.8 (2?), 54.0 (2?), 42.5 (2?), 38.9 (2?), 35.8 (4?), 30.6 (2?), 29.5 (2?), 25.6 (2?), 24.7 (4?), 23.4 (2?), 19.0 (2?), 13.5 (2?). HRMS calcd for C.sub.31H.sub.54O.sub.5 (M.sup.+): 506.3971, found: 506.3981.

6.32 1-[11-(1-Carboxycyclopentyl)-6-oxondecyl]-1-cyclopentanecarboxylic acid

[0286] LiOH.H.sub.2O (7.83 g, 187 mmol) and H.sub.2O (100 mL) were added to a solution of butyl 1-{11-[l-(butoxycarbonyl)cyclopentyl]-6-oxoundecyl}-1-cyclopentanecarboxylate (21.03 g, 90% pure by .sup.1H NMR, 37.3 mmol) in EtOH (300 mL) and the resulting mixture was stirred at reflux temperature for 2 d, allowed to cool to rt and concentrated in vacuo to a smaller volume. H.sub.2O (100 mL) was added and the resulting mixture was extracted with Et.sub.2O (100 mL), acidified with conc aqueous HCl (25 mL) and extracted with Et.sub.2O (3?150 mL). The latter organic layers were combined, dried (Na.sub.2SO.sub.4; To avoid loss of material, a minimal amount of Na.sub.2SO.sub.4 was used, with the desiccant becoming a white, oily paste. The organic layer was decanted from the desiccant.) and evaporated in vacuo. The remaining residue was purified by recrystallization from a mixture of iPr.sub.2O and heptane to give 1-[11-(1-carboxycyclopentyl)-6-oxoundecyl]-1-cyclopentanecarboxylic acid (12.15 g, 83%) as white granules. mp=78-85? C. .sup.1H NMR (CDCl.sub.3): ?=2.37 (t, J=7.4 Hz, 4H), 2.18-2.10 (m, 4H), 1.65-1.45 (m, 20H), 1.29-1.25 (m, 8H). .sup.13C NMR (CDCl.sub.3): ?=211.5, 184.8 (2?), 54.0 (2?), 42.4 (2?), 38.9 (2?), 35.9 (4?), 29.2 (2?), 25.5 (2?), 24.9 (4?), 23.5 (2?). Anal. calcd for C.sub.23H.sub.38O.sub.5: C, 70.02; H, 9.71, found: C, 70.37; H, 9.72.

6.33 1-[11-(1-Carboxycyclopentyl)-6-hydroxyundecyl]-1-cyclopentanecarboxylic

[0287] To a mixture of 1-[11-(1-carboxycyclopentyl)-6-oxoundecyl]-1-cyclopentanecarboxylic acid (5.00 g, 12.7 mmol) in iPrOH (30 mL) and H.sub.2O (30 mL) was added NaOH (1.07 g. 26.3 mmol). To the resulting clear solution, NaBH (0.38 g, 10.0 mmol) was added. After 19 h, the reaction mixture was concentrated in vacuo. The remaining residue was dissolved in H.sub.2O (50 mL) and acidified with aqueous HCl (6M, 15 mL). The resulting mixture was extracted with Et.sub.2O (100 mL, 2?50 mL), and the combined organic layers were washed with brine (2?50 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give 1-[11-(1-carboxycyclopentyl)-6-hydroxyundecyl]-1-cyclopentanecarboxylic acid (5.18 g, 99%, contains 4% (w/w) Et.sub.2O) as a thick, light yellow oil that slowly crystallized on standing. mp=: 76-77? C. .sup.1H NMR (CDCl.sub.3); ?=3.56 (br s, 1H), 2.16-2.11 (m, 4H), 1.64-1.61 (m, 12H), 1.51-1.18 (m, 20H). .sup.13C NMR (CDCl.sub.3): ?=184.3 (2?), 71.4, 54.2 (2?), 39.2 (2?), 36.9 (2?), 36.2 (2?), 35.7 (2?), 29.5 (2?), 25.9 (2?), 25.2 (2?), 25.1 (2?), 25.0 (2?).

7. BIOLOGICAL ASSAYS

7.1 Effects of Illustrative Compounds of the Invention on NonHDL Cholesterol, HDL Cholesterol, Triglyceride Levels, Glycemic Control Indicators and Body Weight Control in Obese Female Zucker Rats

[0288] In a number of different experiments, illustrative compounds of the invention are administered daily at a dose of up to 100 mg/kg to chow fed obese female Zucker rats for fourteen days in the morning by oral gavage in 1.5% carboxymethylcellulose/0.2% Tween 20 or 20% ethanol/80% polyethylene glycol (dosing vehicles). Animals are weighed daily. Animals are allowed free access to rodent chow and water throughout the study except on days of blood sampling where food is restricted for six hours prior to blood sampling. Blood glucose is determined after the 6 hour fast in the afternoon without anesthesia from a tail vein. Serum is also prepared from pretreatment blood samples subsequently obtained from the orbital venous plexus (with O.sub.2/CO.sub.2 anesthesia) and following the fourteenth dose at sacrifice from the heart following O.sub.2/CO.sub.2 anesthesia. Serums are assayed for lipoprotein cholesterol profiles, triglycerides, total cholesterol, Non-HDL cholesterol, HDL cholesterol, the ratio of HDL cholesterol to that of Non-HDL cholesterol, insulin, non-esterified fatty acids, and beta-hydroxy butyric acid. The percent body weight gain and the ratio of liver to body weight is also determined. These are shown as absolute values or as a percent change of the pretreatment values in Table 1.

##STR00025##

TABLE-US-00003 TABLE 1 Examples of effects of oral daily treatment of obese female Zucker rats with illustrative compounds of the invention for fourteen days Percent of Pre-treatment Expt. Dose % wt. HDL-C/ Non- Compound # n (mg/kg/day) gain non-HDL-C TG TC HDL-C HDL-C Glucose Insulin NEFA BHA Vehicle LR132 4 10.50% 4 3 5 ?8 10 ?2 42 ?3 78 A 4 30 12.3 4 ?23 37 ?20 76 ?1 ?8 ?30 150 Vehicle LR132 4 10.5 4 3 5 ?8 10 ?2 42 ?3 78 B 4 100 4.2 153 ?91 13 ?94 54 ?24 ?51 ?23 254 Vehicle LR132 4 10.5 4 3 5 ?8 10 ?2 42 ?3 78 D 4 100 ?1.7 785 ?97 ?11 ?98 15 ?13 ?70 ?44 195 Vehicle LR132 4 10.5 4 3 5 ?8 10 ?2 42 ?3 78 E 3 100 10.4 5 ?34 101 1 162 ?2 2 ?24 223 n is number of animals per experiment

7.2 Effects of Illustrative Compounds of the Invention on the is Vitro Lipid Synthesis in Isolated Hepatocytes

[0289] Compounds were tested for inhibition of lipid synthesis in primary cultures of rat hepatocytes. Male Sprague-Dawley rats were anesthetized with intraperitoneal injection of sodium pentobarbital (80 mg/kg). Rat hepatocytes were isolated essentially as described by the method of Seglen (Seglen, P. O. Hepatocyte suspensions and cultures as tools in experimental carcinogenesis. J. Toxicol. Environ. Health 1979, 5, 551-560). Hepatocytes were suspended in Dulbecco's Modified Eagles Medium containing 25 mM D-glucose, 14 mM HEPES, 5 mM L-glutamine, 5 mM leucine, 5 mM alanine, 10 mM lactate, 1 mM pyruvate, 0.2% bovine serum albumin, 17.4 mM non-essential amino acids, 20% fetal bovine serum, 100 nM insulin and 20 ?g/mL gentamycin) and plated at a density of 1.5?10.sup.5 cells/cm.sup.2 on collagen-coated 96-well plates. Four hours after plating, media was replaced with the same media without serum. Cells were grown overnight to allow formation of monolayer cultures. Lipid synthesis incubation conditions were initially assessed to ensure the linearity of [1-.sup.14C]-acetate incorporation into hepatocyte lipids for up to 4 hours. Hepatocyte lipid synthesis inhibitory activity was assessed during incubations in the presence of 0.25 ?Ci [1-.sup.14C]-acetate/well (final radiospecific activity in assay is 1 Ci/mol) and 0, 1, 3, 10, 30, 100 or 300 ?M of compounds for 4 hours. At the end of the 4-hour incubation period, medium was discarded and cells were washed twice with ice-cold phosphate buffered saline and stored frozen prior to analysis. To determine total lipid synthesis, 170 ?l of MicroScint-E? and 50 ?l water was added to each well to extract and partition the lipid soluble products to the upper organic phase containing the scintillant. Lipid radioactivity was assessed by scintillation spectroscopy in a Packard TopCount NXT. Lipid synthesis rates were used to determine the IC.sub.50s of the compounds that are presented in Table 2.

TABLE-US-00004 TABLE 2 Effect of Illustrative Compounds A, B, and D-F on Lipid Synthesis in Primary Rat Hepatocytes. 95% Confidence Interval Compound IC.sub.50 (?M) Lower Upper r.sup.2 A 12.0 5.4 26.3 0.98 B 0.9 0.8 1.1 0.99 D 1.4 1.2 1.6 0.99 E 3.0 2.6 3.4 0.98 F 1.8 1.4 2.3 0.96

[0290] The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments which are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the appended claims.