Pgd2 receptor antagonistic pharmaceutical compositions

TECHNICAL FIELD

[0001] This invention relates to a bicyclic amide derivative, an antagonist against PGD2 receptor, and a pharmaceutical composition comprising the same.

BACKGROUND ART

[0002] As a pharmaceutical composition comprising an antagonist against PGD2 receptor, a compound of the formula:

[0003] wherein Y is bicyclic ring and R is phenyl etc., was described in WO 97/00853 (International publication date: Jan. 1, 1997).

[0004] On the other hand, it was disclosed that 3-oxa-derivatives were prepared as metabolically stable TXA2/PGH2 receptor antagonists in Bioorganic & Medicinal Chemistry Letters, Vol.2, No.9, pp.1069-1072, 1992. The active value of the compound was only described but the metabolic stability has not been described in the literature.

[0005] wherein, Z is p-fluorophenyl; Rω is benzenesulfonamino and the like.

[0006] Furthermore, it was reported in PROSTAGLANDINS, 1986, 31, 95 that ILOPROST, PGI2 mimetics was stabilized metabolically by converting to the 3-oxa-derivative. But, remaining activity of each compound was only compared under a presence of the metabolic enzyme of a rat and the metabolic stability did not mentioned.

DISCLOSURE OF INVENTION

[0007] The present inventors have carried out the structure modification research on α chain of a pharmaceutical composition comprising an antagonist against PGD2 receptor described in WO97/00853, found out a metabolically stable antagonist against PGD2 receptor and have completed the present invention.

[0008] The present invention provides:

[0009] (1) a compound represented by the formula (I):

[0010] wherein

[0011] R1 is optionally substituted heteroaryl;

[0012] R2 is hydrogen or alkyl;

[0013] R3 is —CH2—CH2—CH2—CH2—CH═CH—COOR4, —CH2—CH2—CH2—CH2—X1—CH2—COOR4, —CH2—CH═CH—CH2—X1—CH2—COOR4 or —CH2—CH2—CH2—CH2—COOR4;

[0014] R4 is hydrogen or alkyl;

[0015] X1 is —O— or —S—,

[0016] a prodrug, a pharmaceutically acceptable salt or a solvate thereof,

[0017] (2) a compound as described in (1), wherein

[0018] a prodrug, a pharmaceutically acceptable salt or a solvate thereof,

[0019] (3) a compound as described in (1) or (2), wherein R1 is optionally substituted thienyl, optionally substituted benzothienyl, optionally substituted furyl, optionally substituted benzofuryl, optionally substituted pyrrolyl, optionally substituted thienopyrrolyl or optionally substituted indolyl, a prodrug, a pharmaceutically acceptable salt or a solvate thereof,

[0020] (4) a compound as described in (1) or (2), wherein R1 is heteroaryl which may be substituted with a group of the formula: -Z1-Z2 wherein Z1 is a bond, —O—, —S—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—SO2—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —SO2—, —CH2—O—, —CH2—NH—C(═O)—, —CH2—NH—C(═O)—O—, —CH2—NH—SO2— or —CH2—C(═O)— and Z2 is alkyl or optionally substituted amino; carboxy; halogen; hydroxy; or nitro, a prodrug, a pharmaceutically acceptable salt or a solvate thereof,

[0021] (5) a compound as described in any one of (1) to (4), wherein R3 is —CH2—CH2—CH2—CH2—CH═CH—COOR4, —CH2—CH2—CH2—CH2—X1—CH2—COOR4, —CH2—CH═CH—CH2—X1—CH2—COOR4 or —CH2—CH2—CH2—CH2—COOR4; R4 is hydrogen; and X1 is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvate thereof,

[0022] (6) a compound as described in (5), wherein R3 is —CH2—CH2—CH2—CH2—CH═CH—COOR4 or —CH2—CH2—CH2—CH2—X1—CH2—COOR4; R4 is hydrogen; and X1 is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvate thereof,

[0023] (7) a pharmaceutical composition containing a compound, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof as described in any one of (1) to (6),

[0024] (8) a pharmaceutical composition having an antagonistic activity against PGD2 receptor as described in (7),

[0025] (9) a pharmaceutical composition as described in (7), which is used for the treatment of nasal,

[0026] (10) a pharmaceutical composition as described in (7), which is used for the treatment of allergic conjunctivitis,

[0027] (11) a pharmaceutical composition as described in (7), which is used for the treatment of allergic rhinitis,

[0028] (12) a method for treating nasal blockage, allergic conjunctivitis or allergic rhinitis, which comprises administrating a composition as described in (7), and

[0029] (13) use of the compound as described in any one of (1) to (6) for the preparation of a pharmaceutical composition for treating nasal blockage, allergic conjunctivitis or allergic rhinitis.

[0030] The terms used herein is explained below. Each term used herein is defined to have meanings below in either case of a single or a joint use with other terms.

[0031] The term “heteroaryl” includes a 5- to 7-membered aromatic heterocycle containing one or more oxygen atom, sulfur atom and/or nitrogen atom in the ring, or such an aromatic heterocycle as fused with one or more carbocycle or other aromatic heterocycle, which has a bond at any substitutable. Any one of aromatic heterocycle and aromatic carbocycle may have a bond.

[0032] Examples of “heteroaryl” include pyrrolyl (e.g., 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazolyl (e.g., 3-pyrazolyl, 4pyrazolyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), carbazolyl (e.g., 1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), benzimidazolyl (e.g., 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), indazolyl (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), furyl (e.g., 2-furyl, 3-furyl), benzofuryl (e.g., 2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5-benzofuryl, 6-benzofuryl, 7-benzofuryl), thienyl (e.g., 2-thienyl, 3-thienyl), benzothienyl (e.g., benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl), dibenzothienyl (e.g., 2-dibenzothienyl, 3-dibenzothienyl), dibenzofuryl (e.g., 2-dibenzofuryl, 3-dibenzofuryl), naphthothienyl (e.g., naphtho[2,3-b]thiophen-2-yl, naphtho[2,3-b]thiophen-3-yl, naphtho[1.2-b]thiophen-2-yl, naphtho[1.2-b]thiophen-3-yl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), imidazothiazolyl (e.g., imidazo[2.1-b]thiazol-2-yl, imidazo[2.1-b]thiazol-3-yl), benzoisoxazolyl (e.g., benzo[d]isoxazol-3-yl), benzothiazolyl (e.g., benzo[d]thiazol-2-yl), thienopyrrolyl (e.g., thieno[2,3-b]pyrrole-2-yl, thieno[2,3-b]pyrrole-3-yl, thieno[2,3-b]pyrrole-5-yl, thieno[2,3-c]pyrrole-2-yl, thieno[2,3-c]pyrrole-4-yl, thieno[3,2-b]pyrrole-2-yl, thieno[3,2-b]pyrrole-3-yl, thieno[3,2-b]pyrrole-5-yl), and the like.

[0033] Thienyl, benzothienyl, furyl, benzofuryl, pyrrolyl, are indolyl preferred.

[0034] The term of “aromatic carbocycle or other aromatic heterocycle” which may fuse the above “heteroaryl” includes 5- to 7-membered aromatic cycle which may contains one or more oxygen atom, sulfur atom and/or nitrogen atom in the ring, or such an aromatic ring as fused with one or more other aromatic rings.

[0035] The above “heteroaryl” may be fused 4- to 7-membered cycloalkane or 4- to 7-membered non-aromatic heterocycle. Examples of cycloalkane include cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Examples of non-aromatic heterocycle include pyrrolidine, piperazine, oxorane, 1,3-dioxorane, 1,4-dioxane, thiorane, or the like. The above “cycloalkane” and “non-aromatic heterocycle” may be fused with other aromatic carbocycle such as benzene or aromatic heterocycle such as thiophene or furan. Examples of heteroaryl fused with 4- to 7-membered cycloalkane or 4- to 7-membered non-aromatic heterocycle are illustrated below.

[0036] Examples of the substituent on “optionally substituted heteroaryl” include a group of the formula: -Z1-Z2 wherein Z1 is a bond, —O—, —S—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—SO2—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —SO2—, —CH2—O—, —CH2—NH—C(═O)—, —CH2—NH—C(═O)—O—, —CH2—NH—SO2—, or —CH2—C(═O)—, and Z2 is alkyl, haloalkyl, alkenyl, alkynyl, or optionally substituted amino; carboxy; halogen (F, Cl, Br, I); hydroxyalkyl; hydroxy; nitro; cyano; mercapto; thioformyl; thioacetyl; thiocarboxy; dithiocarboxy; thiocarbamoyl; sulfino; sulfo; sulfamoyl; sulfoamino and the like. A group of the formula: -Z1-Z2 wherein Z1 is a bond, —O—, —S—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—SO2—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —SO2—, —CH2—O—, —CH2—NH—C(═O)—, —CH2—NH—C(═O)—O—, —CH2—NH—SO2—, or —CH2—C(═O)—, and Z2 is alkyl or optionally substituted amino; carboxy; halogen; hydroxy; and nitro are preferred. Further, A group of the formula: -Z1-Z2 wherein Z1 is a bond, —O—, —NH—C(═O)—, or —C(═O)—, and Z2 is alkyl or optionally substituted amino; halogen; and hydroxy are preferred. One to three of the above substituents may be at any suitable position on the above heteroaryl.

[0037] “Alkyl” includes a straight or branched C1 to C8 alkyl group or a C3 to C8 cycloalkyl group. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A straight or branched C1 to C3 alkyl group is preferred.

[0038] “Haloalkyl” includes the above alkyl substituted with one to three halogen(s). A straight or branched C1 to C3 haloalkyl is preferred. Trifluoromethyl, 2,2,2-trifluoroethyl and the like are exemplified.

[0039] “Alkenyl” includes the above alkyl having one to three double bond(s). A straight or branched C2 to C3 alkenyl is preferred. Vinyl, allyl, 1-propenyl, isopropenyl and the like are exemplified.

[0040] “Alkynyl” includes the above alkyl having one to three triple bond(s). A straight C2 to C3 alkynyl is preferred. Ethynyl and the like are preferred.

[0041] Examples of the substituent of “optionally substituted amino” include alkyl, alkyloxy, alkylsulfonyl, hydroxy, and the like. It may be mono- or di-substituted with these substituents.

[0042] “Hydroxy alkyl” includes the above alkyl substituted with one to three hydroxy. A straight or branched C1 to C3 hydroxyalkyl is preferred. Hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and the like are exemplified.

[0043] “Halogen” includes fluoro, chloro, bromo, and iodo.

[0044] A compound of the present invention has the following [2.2.1] and [3.1.1] bicyclic skeleton.

[0045] A compound of the present invention can be any of the following stereo isomers of [2.2.1] and [3.1.1] bicyclic skeleton.

[0046] In a case of

[0047] In a case of

[0048] In a case of

[0049] In these stereo isomers, preferable is a compound having the skeleton of the formula:

[0050] The present invention includes all stereo isomers of them and the optional mixtures thereof. Namely, the bond binding to the bicyclic ring is in R configuration or S configuration, and all of the stereo isomers (diastereomer, epimer, enantiomer and the like), racemates, and optional mixture thereof are included in the present invention.

[0051] Moreover, the a chain of the compound of the present invention can be in Z configuration or E configuration, thus a compound having any of the configurations and the mixture thereof are included in the present invention.

[0052] Further, as the α chain (R3) of the compound of the present invention, —CH2—CH2—CH2—CH2—CH═CH—COOR4, —CH2—CH2—CH2—CH2—X1—CH2—COOR4, —CH2—CH═CH—CH2—X1—CH2—COOR4 and —CH2—CH2—CH2—CH2—COOR4 (R4 is hydrogen or alkyl; X1 is —O— or —S—) are exemplified. Especially, —CH2—CH2—CH2—CH2—CH═CH—COOR4, —CH2—CH2—CH2—CH2—X1—CH2—COOR4, —CH2—CH═CH—CH2—X1—CH2—COOR4 and —CH2—CH2—CH2—CH2—COOR4 (R4 is hydrogen; X1 is —O— or —S—) are preferred. Further, —CH2—CH2—CH2—CH2—CH═CH—COOR4 and —CH2—CH2—CH2—CH2—X1—CH2—COOR4 (R4 is hydrogen; X1 is —O— or —S—) are preferred.

[0053] This invention includes not only a compound represented by the formula (I), but also a prodrug, a pharmaceutically acceptable salt or a solvate thereof.

[0054] A prodrug of a compound of the formula (I) is a derivative of the compound of the present invention having a group which can be decomposed chemically or metabolically, and such prodrug is converted to a pharmaceutically active compound of the present invention by means of solvolysis or by placing the compound in vivo under a physiological condition. Method for the selection and process of an appropriate prodrug derivative are described in the literature such as Design of Prodrugs, Elsevier, Amsterdam 1985.

[0055] When the compound of the formula (I) has a carboxyl group, an ester derivative prepared by reacting a basal acid compound with a suitable alcohol or an amide derivative prepared by reacting a basal acid compound with a suitable amine is exemplified as a prodrug. A particularly preferred ester derivative as an prodrug is an optionally substituted alkyl ester derivative (e.g., methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester), an arylalkyl ester derivative (e.g., benzyl ester, phenethyl ester, benzhydryl ester), or the like. A particularly preferred amide derivative as a prodrug is alkyl amide derivative (e.g., N-methyl amide, N-ethyl amide, N-(n-propyl)amide, N-isopropyl amide, N-(n-butyl)amide, N-isobutyl amide, N-(tert-butyl)amide), aryl alkyl amide (e.g., N-benzyl amide, N-phenethyl amide, benzhydryl amide), or the like.

[0056] When the compound of the formula (I) has a hydroxy group, an acyloxy derivative prepared by reacting with a suitable acyl halide or a suitable acid anhydride is exemplified as a prodrug. A particularly preferred acyloxy derivative as a prodrug is a derivative substituted with optionally substituted alkylcarbonyloxy (e.g., —OCOC2H5, —OCO(tert-Bu), —OCOC15H31, —OCOCH2CH2COONa, —OCOCH(NH2)CH3, —OCOCH2N(CH3)2—), optionally substituted arylcarbonyloxy (e.g., —OCO(m-COONa-Ph) or the like.

[0057] When the compound of the formula (I) has an amino group, an amide derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride is exemplified as a prodrug. A particularly preferred amide derivative as a prodrug is a derivative substituted with optionally substituted alkylcarbonyl (e.g., —NHCO(CH2)20CH3, —NHCOCH(NH2)CH3) or the like.

[0058] Examples of a salt of the compound of the formula (I) or its prodrug include alkali metal salts such as lithium salts, sodium salts or potassium salts, alkaline-earth metal salts such as calcium salts, salts with organic bases such as tromethamine, trimethylamine, triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexylamine, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthylene methylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthorathene, 2-aminoanthorathene, dehydroabiethylamine, N-methylmorpholine, pyridine), basic amino acid salts such as arginine salts or lysine salts.

[0059] A solvate means a solvate with an organic solvent, a hydrate and the like of the compound of the formula (I), its prodrug or its pharmaceutically acceptable salt, for example, monohydrate, dihydrate or the like.

[0060] “A pharmaceutical composition having an antagonistic activity against PGD2 receptor” means a pharmaceutical composition comprising at least one compound of the formula (I) having an antagonistic activity against a PGD2 receptor. In addition to a compound of the formula (I), the other active agents (e.g. antiinflammatory agents, antiallergy agents and the like) and pharmaceutically acceptable admixtures (e.g., binding agent, filler and the like) may be included.

[0061] A PGD2 antagonist is useful in the improvement of conditions due to excessive production of PGD2, particularly as a composition for treating diseases in which mast cell dysfunction is involved, for example, systemic mastocytosis and disorder of systemic mast cell activation as well as for nasal blockage, allergic conjunctivitis, allergic rhinitis, airway contraction, asthma, urticaria, ischemic reperfusion injury, inflammation, and atopic dermatitis.

[0062] This invention includes a method for treating a condition due to excessive production of PGD2 such as nasal blockage, allergic conjunctivitis, allergic rhinitis, and the like, which comprises administrating a compound represented by the formula (I). In addition, this invention includes use of the compound represented by the formula (I) for the preparation of a pharmaceutical composition for treating a condition due to excessive production of PGD2 such as nasal blockage, allergic conjunctivitis or allergic rhinitis.

BEST MODE FOR CARRYING OUT THE INVENTION

[0063] The compound represented by the formula (I) can be prepared in accordance with the following method.

[0064] R1 is optionally substituted heteroaryl;

[0065] R2 is hydrogen or alkyl;

[0066] R3 is —CH2—CH2—CH2—CH2—CH═CH—COOR4, —CH2—CH2—CH2—CH2—X1—CH2—COOR4, —CH2—CH═CH—CH2—X1—CH2—COOR4 or —CH2—CH2—CH2—CH2—COOR4;

[0067] R4 is hydrogen or alkyl; and

[0068] X1 is —O— or —S—.

[0069] As shown in the above process, the compound of the formula (I) can be prepared by reacting a carboxylic acid of the formula (M-2) or its reactive derivative with an amino compound of the formula (M-1).

[0070] The reactive derivatives of carboxylic acid of the formula (M-2) mean the corresponding acid halides (e.g., chloride, bromide, iodide), anhydrides (e.g., mixed anhydride with formic acid or acetic acid), active esters (e.g., N-hydroxysuccinimide ester), and the like, and include acylating agents used for the usual acylation of amino group.

[0071] For example, an acid halide is obtained by reacting the compound (M-2) with a thionyl halide (e.g., thionyl chloride), phosphorous halide (e.g., phosphorous trichloride, phosphorous pentachloride), oxalyl halide (e.g., oxalyl chloride), and the like, in accordance with known methods as described in the literatures.

[0072] The reaction can be conducted under a condition generally used for the acylation of amino group. For example, in the case of condensation with the acid halide, the reaction is carried out in a solvent such as an ether solvent (e.g., diethyl ether, tetrahydrofuran, dioxane), benzene solvent (e.g., benzene, toluene, xylene), halogenated hydrocarbon solvent (e.g., dichloromethane, dichloroethane, chloroform) as well as ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetonitrile, or the like, if necessary, in the presence of a base (e.g., organic base such as triethylamine, pyridine, N,N-dimethylaminopyridine, N-methylmorpholine; inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, or the like) under cooling, at room temperature, or under heating, preferably at a temperature ranging from −20° C. to ice-cooling temperature, or from room temperature to a refluxing temperature of the reaction system, during several min to several hr, preferably for 0.5 hr to 24 hr, more preferably for 1 hr to 12 hr.

[0073] When R4 is alkyl, a free form may be used without converting the carboxy group (M-2) into the reactive derivatives and the reaction may be conducted in the presence of a condensing agent (e.g., dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-methylaminopropyl)carbodiimide, N,N′-carbonyldiimidazole, or the like) usually used in the condensation reaction of amine and carboxylic acid.

[0074] When the substituent of “optionally substituted aryl” or “optionally substituted heteroaryl” of the compound of the formula (M-2) is substituted with a hydroxy group, an amino group or the like, such a compound can be used after protection by acetyl group or the like in accordance with the well known method.

[0075] In the reaction of the other reactive derivatives or free acid (M-2) with the amine (M-1), the reaction conditions are determined according to the property of each reactive derivative or free acid, in accordance with a known method. The reaction product can be purified in accordance with a conventional purification, such as the extraction with a solvent, chromatography, recrystallization, and the like.

[0076] wherein Q is a protective group of an amino group; R2, X1 and R4 are as defined above.

[0077] The compounds represented by formula (M-1) can be prepared from the aldehyde derivative (Q is a protecting group such as benzyloxycarbonyl, t-butoxycarbonyl and the like) represented by a general formula (M-3a) or (M-3b) by one or more reaction(s) of a ylide compound under a Wittig reaction condition (Org. Reaction, 1965, 14, 270) in combination with other reactions.

[0078] For example, the aldehyde (M-3a) is reacted with phosphonium salt derived from 6-bromo-3-oxahexanoic acid described in WO97/40104 under a well known Wittig reaction condition to give a compound (M-4). The compound (M-4) is hydrogenated in the presence of palladium, platinum and the like to give a starting material (M-1a, X1═O), wherein R3 is —CH2CH2CH2CH2OCH2COOR4. Furthermore, after Wittig reaction using methoxymethyltriphenyl-phosphonium salt, followed by a hydrolysis with hydrochloric acid, formic acid, acetic acid and the like can furnish an aldehyde (M-3b). Under Wittig reaction condition using a stable ylide such as methyl (triphenylphophoranidene)acetate and the like or Honer-Emmons reaction condition using methyl dimethylphosphonoacetate, the above aldehyde can be converted into α,β-unsaturated carboxylic acid derivative represented by the formula (M-5). An alcohol derivative (M-6a, X1═O) which is obtained by reduction of compound (M-5) is reacted with halogenated acetic acid or its ester derivative in accordance with well known methods to give a starting compound (M-1b, X1═O) wherein R3 is —CH2CH═CHCH2OCH2COOR4. Further, after an alcohol derivative (M-6a, X1═O) is converted into a thiol derivative (X1═S) in accordance with well known methods, the obtained compound is reacted with halogenated acetic acid derivative as shown the above to give a starting compound (M-1b, X1═S) wherein R3 is —CH2CH═CHCH2SCH2COOR4. Also, after an alcohol derivative (M-6a, X1═O) is converted into a halogenated derivative in accordance with well known methods, the obtained compound is reacted with a glycolic acid or a thioglycollic acid in the presence of a base to give the above compound (M-1b, X1═S). The double bonds in the R3 can be reduced by hydrogenation in the presence of catalyst such as palladium, platinum, and the like at the suitable stage to give a corresponding saturated derivative (M-1a, X1═O or S) at ease.

[0079] The aldehyde (M-3b) is converted into a compound represented by the formula (M-7) by Wittig reaction using 2-(1,3-dioxolane-2-yl)ethyltriphenylphosphonium salt. A hydrogenation of the compound (M-7) and an acidic hydrolysis of acetal are carried out to give the aldehyde (M-3c) as shown in the above. Under Wittig reaction condition using a stable ylide such as methyl (triphenylphophoranidene)acetate and the like or Honer-Emmons reaction condition using methyl dimethylphosphonoacetate, the above aldehyde (M-3c) can be converted into a starting compound (M-1c) wherein R3 corresponds to —CH2CH2CH2CH2CH═CHCOOR4.

[0080] Amidation with a starting carboxylic acid (M-2) can be accomplished after a deprotection of an amino protecting group Q in a way of conversion to α-chain, if necessary.

[0081] In case of the introduction of a substituent(s) into the “optionally substituted aryl” or “optionally substituted heteroaryl”, the change of the functional group can be performed before or after reacting a carboxylic acid or its reactive derivative thereof (M-2) with the amine (M-1). For example, the compound having an aromatic heterocycle substituted with a nitro group can be prepared through the nitration of the compound with a nitrating acid. Moreover, the compound having an aromatic heterocycle substituted with an amino group can be prepared through the reduction of the above-obtained compound with tin in the presence of hydrochloride. Moreover, the compound having an aromatic heterocycle substituted with a hydroxy group can be prepared through the diazonization of the above-obtained compound and the hydrolysis with alkali. On the other hand, the compound having an aromatic heterocycle substituted with an alkoxy group can be prepared through the reaction of the diazonium derivative with alcohol. The compound having an aromatic heterocycle substituted with halogen can be prepared through Sandmeyer reaction, the reaction of the diazonium derivative with a copper salt (e.g., CuCl2, CuBr2). The compound having an aromatic heterocycle substituted with halogen can be also prepared through the direct reaction of the compound having an aromatic heterocycle with chlorine and the like. Using the above-mentioned methods appropriately, halogen can be introduced into a desired position(s). The group of alkyl, alkenyl or acyl group can be directly introduced into an aromatic heterocycle through Friedel Crafts reaction with alkylating agent, an alkenylating agent, or an acylating agent, respectively, in the presence of anhydrous aluminum chloride and the like.

[0082] When using the compound (I) of the present invention in treatment, it can be formulated into ordinary formulations for oral and parenteral administration. A pharmaceutical composition containing the compound (I) of the present invention can be in the form for oral and parenteral administration. Specifically, it can be formulated into formulations for oral administration such as tablets, capsules, granules, powders, syrup, and the like; or those for parenteral administration such as injectable solution or suspension for intravenous, intramuscular, or subcutaneous injection, inhalant, eye drops, nasal drops, suppositories, or percutaneous formulations such as ointment.

[0083] In preparing the formulations, carriers, excipients, solvents, and bases known to one having ordinary skill in the art may be used. In case of tablets, they are prepared by compressing or formulating an active ingredient together with auxiliary components. Examples of usable auxiliary components include pharmaceutically acceptable excipients such as binders (e.g., cornstarch), fillers (e.g., lactose, microcrystalline cellulose), disintegrants (e.g., starch sodium glycolate) or lubricants (e.g., magnesium stearate). Tablets may be coated appropriately. In case of liquid formulations such as syrups, solutions, or suspensions, they may contain suspending agents (e.g., methyl cellulose), emulsifiers (e.g., lecithin), preservatives, and the like. In case of injectable formulations, it may be in the form of solution, suspension, or oily or aqueous emulsion, which may contain suspension-stabilizing agents or dispersing agent, and the like. In case of an inhalant, it is formulated into a liquid formulation applicable to an inhaler. In case of eye drops, it is formulated into a solution or a suspension.

[0084] Especially, in case of a nasal drug for treating nasal blockage, it can be used as a solution or suspension prepared by a conventional formulating method, or administered as a powder formulated using a powdering agent (e.g., hydroxypropyl cellulose, carbopole) into the nasal cavity. Alternatively, it can be used as an aerosol filled into a special container together with a solvent of low boiling point.

[0085] In a case using as an eyewash drug for treating allergic conjunctivitis, it can be used as a solution or suspension of the compound or can be used by solving or suspending the compound before use. A stabilizing agent, solubilizing agent, suspending agent, emulsifier, buffer, preservatives and the like can be included. In a case using as an eyewash drug, aseptic treatment is preferable.

[0086] Although an appropriate dosage of the compound (I) varies depending on the administration route, age, body weight, sex, or conditions of the patient, and the kind of drug(s) used together, if any, and should be determined by the physician in the end, in the case of oral administration, the daily dosage can generally be between 0.01-100 mg, preferably 0.01-10 mg, more preferably 0.01-1 mg, per kg body weight. In case of parenteral administration, the daily dosage can generally be between 0.001-100 mg, preferably 0.001-1 mg, more preferably 0.001-0.1 mg, per kg body weight. The daily dosage can be administered in 1-4 divisions.

EXAMPLE

[0087] The following examples are provided to further illustrate the present invention and are not to be construed as limiting the scope.

Example 1

Preparation of (Ic-4)

[0088]

[0089] Process 1

[0090] To a solution of compound (1) (10.11 g, 39.9 mmol) in toluene (100 ml) was added triphenylphosphoranylidene acetic acid methyl ester (14.68 g, 43.9 mmol) and the resulting mixture was stirred for 17 h at room temperature. Hexane (100 ml) was added to the mixture and the insoluble residue was filtered off. The filtration was concentrated to give 16.56 g of residue. 16.12 g of the residue was dissolved in THF(160 ml), 2N lithium hydroxide aq. (40 ml) was added to the solution and the resulting mixture was stirred for 5 h at 60° C. After THF was concentrated in vacuo, the residue was diluted with water (100 ml). The water layer was washed with toluene twice and acidified with hydrochloric acid (pH=1) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried, and concentrated. To a solution of the residue in methanol was added 10% palladium-carbon (360 mg) and the resulting mixture was stirred for 3 h under hydrogen atmosphere. The reaction mixture was filtered and concentrated and the residues was dissolved in THF (120 ml). To the mixture were added triethylamine (6.2 ml, 44.5 mmol) and ethyl chloroformate (4.3 ml, 44.5 mmol ) at ice-cooling, and the resulting mixture was stirred for 30 min at ice-cooling. The insoluble salt was filtered off and sodium borohydride (3.06 g, 80.9 mmol) was added to the filtration. To the mixture was added methanol (40 ml) dropwise over 30 min and the mixture was stirred for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine respectively and dried. The residue was crystallized from hexane-ethyl acetate (90:10) to give compound (2) (8.77 g; yield 80%). mp. 90-92° C.

[0091] Process 2

[0092] To a solution of the compound (2) (1.68 g, 5.94 mmol) in toluene (17 ml) were added t-butyl bromoacetate (1.32 ml, 68.91 mmol), sodium hydrogensulfate (201 mg, 0.6 mmol) and 50% sodium hydroxide aq. (1.7 ml) and the resulting mixture was vigorously stirred for 22 h at room temperature. Toluene layer was separated, washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=7:1) to give compound (3) (1.60 g; yield 68%).

[0093] Process 3

[0094] To a solution of the compound (3) (10.42 g, 26.2 mmol) in methanol (50 ml) was added 4N dioxane solution of hydrogen chloride (65.5 ml, 262 mmol) and the resulting mixture was stirred for 5 h at room temperature. The reaction mixture was concentrated in vacuo to give crystalline residue. The residue was washed with hexane-ether to give compound (4) (6.88 g; yield 90%).

[0095] Process 4

[0096] To a solution of compound (4) (642 mg, 2.20 mmol) in THF (8 ml) were added thiophene-3-carboxylic acid (256 mg, 2.00 mmol), 1-hydroxybenzotriazole (27 mg, 0.20 mmol) and triethylamine (0.34 ml, 2.40 mmol) at ice-cooling. Further, 3-ethyl-3-(3-dimethylaminopropyl)carbodiimide (370 mg, 2.40 mmol) was added to the mixture at ice-cooling. The reaction mixture was stirred for 16 h at room temperature and diluted with ethyl acetate. The resulting mixture was washed with dilute hydrochloric acid and sodium hydrogencarbonate respectively, dried, concentrated, and chromatographed on silica gel (toluene-hexane=3:1) to give compound (5) (627 mg; yield 86%). m.p. 68-70° C.

[0097] Process 5

[0098] To a solution of compound (5) (620 mg, 1.70 mmol) in methanol (2 ml)-THF (1 ml) was added 4N sodium hydroxide aq.(1.0 ml, 4.0 mmol) and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was acidified with 2N hydrochloric acid. and extracted with ethyl acetate. The organic layer was washed with water and brine respectively, dried and concentrated. The residue was crystallized from methanol-water (5:7) to give compound (Ic-4) (461 mg; yield 77%). m.p. 104-105° C.

Example 2

Preparation of Compound (Ie-34)

[0099]

[0100] Process 1

[0101] To a solution of compound (2) (2.28 g, 8.05 mmol) in dichloromethane (20 ml) were added triphenylphosphine (2.32 g, 8.85 mmol) and N-bromosuccinimide (1.58 g, 8.85 mmol) at ice-cooling and the resulting mixture was stirred for 1 h at the same temperature. The reaction mixture was diluted with toluene, washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=9:1) to give compound (6) (2.70 g; yield 97%).

[0102] Process 2

[0103] To a solution of sodium methoxide (842 mg, 15.6 mmol) in methanol (20 ml) was added methyl thioglycolate (1.40 ml, 15.6 mmol) and the resulting mixture was stirred for 15 min at room temperature. To the mixture was added a THF (20 ml) solution of compound (6) (2.70 g, 7.80 mmol) and the resulting mixture was stirred for 15 h. The reaction was diluted with ethyl acetate, washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=78:22) to give compound (7) (2.84 g; yield 98%).

[0104] Process 3

[0105] 4N Ethyl acetate solution of hydrogen chloride (15 ml) was added to compound (7) (2.84 g, 7.64 mmol) and the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated in vacuo to give the residue. The residue was crystallized from hexane-ether to give compound (8) (2.16 g; yield 92%).

[0106] Process 4

[0107] To a solution of compound (8) (246 mg, 0.80 mmol) in THF (6 ml) were added benzothiophene-7-carboxylic acid (150 mg, 0.80 mmol), 1-hydroxybenzotriazole (11 mg, 0.08 mmol), triethylamine (0.12 ml, 0.96 mmol) at ice-cooling. Further, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (149 mg, 0.96 mmol) was added to the mixture at ice-cooling. The reaction mixture was stirred for 16 h at room temperature and diluted with ethyl acetate. The resulting mixture was washed with dilute hydrochloric acid and sodium hydrogencarbonate aq. respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=3:1) to give compound (9) (324 mg; yield 94%).

[0108] Process 5

[0109] To a solution of compound (9) (315 mg, 0.73 mmol) in THF (3.6 ml)-methanol (7.3 ml) was added 1N sodium hydroxide aq.(1.82 ml, 1.82 mmol) and the resulting mixture was stirred for 48 h at room temperature. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine respectively to give compound (Ie-34) (301 mg; yield 99%).

Example 3

Preparation of Compound (IIb-28)

[0110]

[0111] Process 1

[0112] A solution of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (3.0 ml, 14.3 mmol) and 18-crown-6 (5.64 g, 21.3 mmol) in THF (100 ml) was cooled at −55° C. and bis(trimethylsilyl)amide potassium (0.5M toluene solution, 28.5 ml, 14.3 mmol) was added dropwise to the mixture. The resulting mixture was stirred for 15 min. To the mixture was added a solution of compound (10) (2.0 g, 7.11 mmol) in THF (20 ml) was added dropwise over 15 min and the mixture was stirred for 1 h at the same temperature. The reaction mixture was allowed to warm to 0° C., diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=4:1) to give compound (11) (2.16 g; yield 90%).

[0113] Process 2

[0114] A solution of compound (11) (1.37 g, 4.05 mmol) in dichloromethane (10 ml)-hexane (10 ml) was cooled to −60° C. and diisopropylaluminum hydride (0.95M hexane solution, 10.7 ml, 10.2 mmol) was added dropwise to the solution. The mixture was stirred for 30 min at the same temperature and methanol (0.6 ml) was added. The resulting mixture was allowed to warm to room temperature and 2N hydrochloric acid was added. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium hydrogencarbonate aq. and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=2:1) to give compound (12) (1.14 g; yield 91%). m.p. 67-69° C.

[0115] Process 3

[0116] To a solution of compound (12) (1.03 g, 3.31 mmol) in toluene (10 ml) were added t-butyl bromoacetate (0.70 ml, 4.30 mmol), tetrabutylammonium hydrogensulfate (170 mg, 0.5 mmol), and 50% sodium hydroxide (1.5 ml) and the resulting mixture was vigorously stirred for 18 h at room temperature. The reaction mixture was extracted with toluene, washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=4:1) to give compound (13) (1.32 g; yield 94%).

[0117] Process 4

[0118] To a solution of compound (13) (1.3 g, 3.07 mmol) in toluene (3 ml) was added trifluoroacetic acid (3.5 ml, 46 mmol) and the resulting mixture was stirred for 3.5 h at 65° C. The reaction mixture was concentrated in vacuo and methanol (30 ml) and concentrated sulphuric acid (0.33 ml) were added to the mixture. The resulting mixture was stirred for 1 h at reflux. The reaction mixture was concentrated and the residue was dissolved in toluene. To the mixture was added triethylamine (4.3 ml, 30 mmol) and sodium hydrogencarbonate aq. respectively. The toluene layer was separated, washed with water and brine respectively, dried, and concentrated to give compound (14) (697 mg; yield 81%).

[0119] Process 5

[0120] To a solution of compound (14) (141 mg, 0.50 mmol) in THF (4 ml) were added 5-fluorobenzothiophene-3-carboxylic acid (98 mg, 0.50 mmol) and 1-hydroxybenzotriazole (7 mg, 0.05 mmol) at ice-cooling. Further, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (93 mg, 0.6 mmol) was added at the same temperature. The reaction mixture was stirred for 16 h at room temperature, diluted with ethyl acetate, washed with dilute hydrochloric acid and sodium hydrogencarbonate aq. respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=83:17) to give compound (15) (93 mg; yield 40%).

[0121] Process 6

[0122] To a solution of compound (15) (93 mg, 0.20 mmol) in THF (1 ml)-methanol (2 ml) was added 1N sodium hydroxide aq.(0.5 ml, 0.5 mmol) and the resulting mixture was stirred for 18 h at room temperature. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine respectively to give compound (IIb-28) (82 mg; yield 91%).

Example 4

Preparation of Compound (IIa-52)

[0123]

[0124] Process 1

[0125] A suspension of 2-(1,3-dioxorane-2-yl)ethyltriphenylphosphonium bromide (13.28 g, 30.0 mmol) in THF (60 ml) was cooled to −30° C. and potassium t-butoxide (6.73 g, 60.0 mmol) was added. The mixture was stirred for 1 h at 30° C. to 0° C. and allowed to cool to −25° C. To the mixture was added a solution of compound (10) (5.62 g, 20.0 mmol) in THF (40 ml) dropwise over 15 min. The reaction mixture was allowed to warm to 0° C., stirred for additional 1.5 h, diluted with water. The water layer was extracted with ethyl acetate and the extract is washed with water and brine, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=85:15) to give compound (16) (6.27 g; yield 86%).

[0126] Process 2

[0127] A solution of compound (16) (4.10 g, 11.2 mmol) in methanol (41 ml) was stirred for 2 h in the presence of 10% palladium-carbon (0.21 g) under hydrogen atmosphere. The reaction mixture was filtered and concentrated to give a residue (4.12 g; yield 100%). To a solution of the crude compound (3.68 g, 10.0 mmol) in acetone-water (4:1, 50 ml) was added pyridinium p-toluenesulfonate (503 mg, 2.0 mmol) and the mixture was heated for 6 h at reflux. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried, concentrated. A solution of the residue in toluene (35 ml) was added methyl (triphenylphosphoranylidene)acetate (2.93 g, 8.76 mmol) and the resulting mixture was stirred for 18 h at room temperature. The mixture was diluted with ethyl acetate, washed with water and brine, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=85:15) to give compound (17) (2.71 g; yield 71%).

[0128] Process 3

[0129] To a solution of compound (17) (2.35 g, 6.19 mmol) in dichloromethane (38 ml) was added trifluoroacetic acid (3.82 ml, 49.5 mmol) and the resulting mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in toluene (50 ml) and water (10 ml). The water layer was alkalinized with 2N sodium hydroxide (pH=10). Toluene layer was separated, washed with water and brine, dried, and concentrated to give compound (18) (1.70 g, yield 98%).

[0130] Process 4

[0131] To a solution of compound (18) (280 mg, 1.0 mmol) in THF (5 ml) were added 5-acetoxybenzofuran-3-carboxylic acid (220 mg, 1.0 mmol), 1-hydroxybenzotriazole (13 mg, 0.1 mmol). Further, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (200 mg, 1.3 mmol) was added at ice-cooling. After the reaction mixture was stirred for 16 h at room temperature, the mixture was diluted with toluene, washed with dilute hydrochloric acid and sodium hydrogencarbonate aq. respectively, dried, and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate=3:1) to give compound (19) (422 mg; yield 88%). m.p. 119-120° C.

[0132] Process 5

[0133] To a solution of compound (19) (422 mg, 0.88 mmol) in THF (5.6 ml) was added 1N lithium hydroxide aq. (3.0 ml, 3.0 mmol) and the resulting mixture was stirred for 20 h at room temperature. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine respectively, dried, and concentrated. The residue was crystallized from hexane-ethyl acetate to give compound (IIa-52) (327 mg; yield 87%). m.p. 159-160° C.

[0134] The structure and physical property of the compound prepared in accordance with the above examples are shown below. Each sign such as Ia, Ib, IIe, and IIf used in the following Tables means the partial structure represented below:

1TABLE 1

R1IaIbIcIdIeIf

Ia-1Ib-1Ic-1Id-1Ie-1If-1

Ia-2Ib-2Ic-2Id-2Ie-2If-2

Ia-3Ib-3Ic-3Id-3Ie-3If-3

Ia-4Ib-4Ic-4Id-4Ie-4If-4

Ia-5Ia-5Ic-5Id-5Ie-5If-5

Ia-6Ib-6Ic-6Id-6Ie-6If-6

Ia-7Ib-7Ic-7Id-7Ie-7If-7

Ia-8Ib-8Ic-8Id-8Ie-8If-8

Ia-9Ib-9Ic-9Id-9Ie-9If-9

Ia-10Ib-10Ic-10Id-10Ie-10If-10

[0135]

2

TABLE 2

R1
Ia
Ib
Ic
Id
Ie
If

Ia- 11
Ib-11
Ic-11
Id-11
Ie-11
If-11

Ia- 12
Ib-12
Ic-12
Id-12
Ie-12
If-12

Ia- 13
Ib-13
Ic-13
Id-13
Ie-13
If-13

Ia- 14
Ib-14
Ic-14
Id-14
Ie-14
If-14

Ia- 15
Ia-15
Ic-15
Id-15
Ie-15
If-15

Ia- 16
Ib-16
Ic-16
Id-16
Ie-16
If-16

Ia- 17
Ib-17
Ic-17
Id-17
Ie-17
If-17

Ia- 18
Ib-18
Ic-18
Id-18
Ie-18
If-18

Ia- 19
Ib-19
Ic-19
Id-19
Ie-19
If-19

Ia- 20
Ib-20
Ic-20
Id-20
Ie-20
Ief-20

[0136]

3

TABLE 3

R1
Ia
Ib
Ic
Id
Ie
If

Ia- 21
Ib-21
Ic-21
Id-21
Ie-21
If-21

Ia- 22
Ib-22
Ic-22
Id-22
Ie-22
If-22

Ia- 23
Ib-23
Ic-23
Id-23
Ie-23
If-23

Ia- 24
Ib-24
Ic-24
Id-24
Ie-24
If-24

Ia- 25
Ia-25
Ic-25
Id-25
Ie-25
If-25

Ia- 26
Ib-26
Ic-26
Id-26
Ie-26
If-26

Ia- 27
Ib-27
Ic-27
Id-27
Ie-27
If-27

Ia- 28
Ib-28
Ic-28
Id-28
Ie-28
If-28

Ia- 29
Ib-29
Ic-29
Id-29
Ie-29
If-29

Ia- 30
Ib-30
Ic-30
Id-30
Ie-30
If-30

[0137]

4

TABLE 4

R1
Ia
Ib
Ic
Id
Ie
If

Ia-31
Ib-31
Ic-31
Id-31
Ie-31
If-31

Ia-32
Ib-32
Ic-32
Id-32
Ie-32
If-32

Ia-33
Ib-33
Ic-33
Id-33
Ie-33
If-33

Ia-34
Ib-34
Ic-34
Id-34
Ie-34
If-34

Ia-35
Ia-35
Ic-35
Id-35
Ie-35
If-35

Ia-36
Ib-36
Ic-36
Id-36
Ie-36
If-36

Ia-37
Ib-37
Ic-37
Id-37
Ie-37
If-37

Ia-38
Ib-38
Ic-38
Id-38
Ie-38
If-38

Ia-39
Ib-39
Ic-39
Id-39
Ie-39
If-39

Ia-40
Ib-40
Ic-40
Id-40
Ie-40
If-40

[0138]

5

TABLE 5

R1
Ia
Ib
Ic
Id
Ie
If

Ia- 41
Ib-41
Ic-41
Id-41
Ie-41
If-41

Ia- 42
Ib-42
Ic-42
Id-42
Ie-42
If-42

Ia- 43
Ib-43
Ic-43
Id-43
Ie-43
If-43

Ia- 44
Ib-44
Ic-44
Id-44
Ie-44
If-44

Ia- 45
Ia-45
Ic-45
Id-45
Ie-45
If-45

Ia- 46
Ib-46
Ic-46
Id-46
Ie-46
If-46

Ia- 47
Ib-47
Ic-47
Id-47
Ie-47
If-47

Ia- 48
Ib-48
Ic-48
Id-48
Ie-48
If-48

Ia- 49
Ib-49
Ic-49
Id-49
Ie-49
If-49

Ia- 50
Ib-50
Ic-50
Id-50
Ie-50
If-50

[0139]

6

TABLE 6

R1
Ia
Ib
Ic
Id
Ie
If

Ia- 51
Ib-51
Ic-51
Id-51
Ie-51
If-51

Ia- 52
Ib-52
Ic-52
Id-52
Ie-52
If-52

Ia- 53
Ib-53
Ic-53
Id-53
Ie-53
If-53

Ia- 54
Ib-54
Ic-54
Id-54
Ie-54
If-54

Ia- 55
Ia-55
Ic-55
Id-55
Ie-55
If-55

Ia- 56
Ib-56
Ic-56
Id-56
Ie-56
If-56

Ia- 57
Ib-57
Ic-57
Id-57
Ie-57
If-57

Ia- 58
Ib-58
Ic-58
Id-58
Ie-58
If-58

Ia- 59
Ib-59
Ic-59
Id-59
Ie-59
If-59

Ia- 60
Ib-60
Ic-60
Id-60
Ie-60
If-60

[0140]

7

TABLE 7

R1
Ia
Ib
Ic
Id
Ie
If

Ia-61
Ib-61
Ic-61
Id-61
Ie-61
If-61

Ia-62
Ib-62
Ic-62
Id-62
Ie-62
If-62

Ia-63
Ib-63
Ic-63
Id-63
Ie-63
If-63

Ia-64
Ib-64
Ic-64
Id-64
Ie-64
If-64

Ia-65
Ia-65
Ic-65
Id-65
Ie-65
If-65

Ia-66
Ib-66
Ic-66
Id-66
Ie-66
If-66

Ia-67
Ib-67
Ic-67
Id-67
Ie-67
If-67

Ia-68
Ib-68
Ic-68
Id-68
Ie-68
If-68

Ia-69
Ib-69
Ic-69
Id-69
Ie-69
If-69

Ia-70
Ib-70
Ic-70
Id-70
Ie-70
If-70

[0141]

8

TABLE 8

R1
Ia
Ib
Ic
Id
Ie
If

Ia- 71
Ib-71
Ic-71
Id-71
Ie-71
If-71

100

Ia- 72
Ib-72
Ic-72
Id-72
Ie-72
If-72

101

Ia- 73
Ib-73
Ic-73
Id-73
Ie-73
If-73

102

Ia- 74
Ib-74
Ic-74
Id-74
Ie-74
If-74

103

Ia- 75
Ia-75
Ic-75
Id-75
Ie-75
If-75

104

Ia- 76
Ib-76
Ic-76
Id-76
Ie-76
If-76

105

Ia- 77
Ib-77
Ic-77
Id-77
Ie-77
If-77

106

Ia- 78
Ib-78
Ic-78
Id-78
Ie-78
If-78

107

Ia- 79
Ib-79
Ic-79
Id-79
Ie-79
If-79

108

Ia- 80
Ib-80
Ic-80
Id-80
Ie-80
If-80

[0142]

9

TABLE 9

109

R1
Ia
Ib
Ic
Id
Ie
If

110

Ia- 81
Ib- 81
Ic- 81
Id- 81
Ie- 81
If-81

111

Ia- 82
Ib- 82
Ic- 82
Id- 82
Ie- 82
If-82

112

Ia- 83
Ib- 83
Ic- 83
Id- 83
Ie- 83
If-83

113

Ia- 84
Ib- 84
Ic- 84
Id- 84
Ie- 84
If-84

114

Ia- 85
Ib- 85
Ic- 85
Id- 85
Ie- 85
If-85

115

Ia- 86
Ib- 86
Ic- 86
Id- 86
Ie- 86
If-86

116

Ia- 87
Ib- 87
Ic- 87
Id- 87
Ie- 87
If-87

117

Ia- 88
Ib- 88
Ic- 88
Id- 88
Ie- 88
If-88

118

Ia- 89
Ib- 89
Ic- 89
Id- 89
Ie- 89
If-89

119

Ia- 90
Ib- 90
Ic -90
Id- 90
Ie- 90
If-90

[0143]

10

TABLE 10

120

R1
Ia
Ib
Ic
Id
Ie
If

121

Ia-91
Ib-91
Ic-91
Id-91
Ie-91
If-91

122

Ia-92
Ib-92
Ic-92
Id-92
Ie-92
If-92

123

Ia-93
Ib-93
Ic-93
Id-93
Ie-93
If-93

124

Ia-94
Ib-94
Ic-94
Id-94
Ie-94
If-94

125

Ia-95
Ib-95
Ic-95
Id-95
Ie-95
If-95

126

Ia-96
Ib-96
Ic-96
Id-96
Ie-96
If-96

127

Ia-97
Ib-97
Ic-97
Id-97
Ie-97
If-97

128

Ia-98
Ib-98
Ic-98
Id-98
Ie-98
If-98

129

Ia-99
Ib-99
Ic-99
Id-99
Ie-99
If-99

130

Ia-100
Ib-100
Ic-100
Id-100
Ie-100
If-100

[0144]

11

TABLE 11

131

Ia
Ib
Ic
Id
Ie
If

132

Ia-101
Ib-101
Ic-101
Id-101
Ie-101
If-101

133

Ia-102
Ib-102
Ic-102
Id-102
Ie-102
If-102

134

Ia-103
Ib-103
Ic-103
Id-103
Ie-103
If-103

135

Ia-104
Ib-104
Ic-104
Id-104
Ie-104
If-104

136

Ia-105
Ib-105
Ic-105
Id-105
Ie-105
If-105

137

Ia-106
Ib-106
Ic-106
Id-106
Ie-106
If-106

138

Ia-107
Ib-107
Ic-107
Id-107
Ie-107
If-107

139

Ia-108
Ib-108
Ic-108
Id-108
Ie-108
If-108

140

Ia-109
Ib-109
Ic-109
Id-109
Ie-109
If-109

141

Ia-110
Ib-110
Ic-110
Id-110
Ie-110
If-110

[0145]

12

TABLE 12

142

Ia
Ib
Ic
Id
Ie
If

143

Ia-111
Ib-111
Ic-111
Id-111
Ie-111
If-111

144

Ia-112
Ib-112
Ic-112
Id-112
Ie-112
If-112

145

Ia-113
Ib-113
Ic-113
Id-113
Ie-113
If-113

146

Ia-114
Ib-114
Ic-114
Id-114
Ie-114
If-114

147

Ia-115
Ib-115
Ic-115
Id-115
Ie-115
If-115

148

Ia-116
Ib-116
Ic-116
Id-116
Ie-116
If-116

149

Ia-117
Ib-117
Ic-117
Id-117
Ie-117
If-117

150

Ia-118
Ib-118
Ic-118
Id-118
Ie-118
If-118

151

Ia-119
Ib-119
Ic-119
Id-119
Ie-119
If-119

152

Ia-120
Ib-120
Ic-120
Id-120
Ie-120
If-120

[0146]

13

TABLE 13

153

Ia
Ib
Ic
Id
Ie
If

154

Ia-121
Ib-121
Ic-121
Id-121
Ie-121
If-121

155

Ia-122
Ib-122
Ic-122
Id-122
Ie-122
If-122

156

Ia-123
Ib-123
Ic-123
Id-123
Ie-123
If-123

157

Ia-124
Ib-124
Ic-124
Id-124
Ie-124
If-124

158

Ia-125
Ib-125
Ic-125
Id-125
Ie-125
If-125

159

Ia-126
Ib-126
Ic-126
Id-126
Ie-126
If-126

160

Ia-127
Ib-127
Ic-127
Id-127
Ie-127
If-127

161

Ia-128
Ib-128
Ic-128
Id-128
Ie-128
If-128

162

Ia-129
Ib-129
Ic-129
Id-129
Ie-129
If-129

163

Ia-130
Ib-130
Ic-130
Id-130
Ie-130
If-130

[0147]

14

TABLE 14

164

Ia
Ib
Ic
Id
Ie
If

165

Ia-131
I-131b
Ic-131
Id-131
Ie-131
If-131

166

Ia-132
I-132b
Ic-132
Id-132
Ie-132
If-132

167

Ia-133
I-133b
Ic-133
Id-133
Ie-133
If-133

168

Ia-134
I-134b
Ic-134
Id-134
Ie-134
If-134

169

Ia-135
I-135b
Ic-135
Id-135
Ie-135
If-135

170

Ia-136
I-136b
Ic-136
Id-136
Ie-136
If-136

171

Ia-137
I-137b
Ic-137
Id-137
Ie-137
If-137

172

Ia-138
I-138b
Ic-138
Id-138
Ie-138
If-138

173

Ia-139
I-139b
Ic-139
Id-139
Ie-139
If-139

174

Ia-140
I-140b
Ic-140
Id-140
Ie-140
If-140

[0148]

15

TABLE 15

175

Ia
Ib
Ic
Id
Ie
If

176

Ia-141
Ib-141
Ic-141
Id-141
Ie-141
If-141

177

Ia-142
Ib-142
Ic-142
Id-142
Ie-142
If-142

178

Ia-143
Ib-143
Ic-143
Id-143
Ie-143
If-143

179

Ia-144
Ib-144
Ic-144
Id-144
Ie-144
If-144

180

Ia-145
Ib-145
Ic-145
Id-145
Ie-145
If-145

181

Ia-146
Ib-146
Ic-146
Id-146
Ie-146
If-146

182

Ia-147
Ib-147
Ic-147
Id-147
Ie-147
If-147

183

Ia-148
Ib-148
Ic-148
Id-148
Ie-148
If-148

184

Ia-149
Ib-149
Ic-149
Id-149
Ie-149
If-149

185

Ia-150
Ib-150
Ic-150
Id-150
Ie-150
If-150

[0149]

16

TABLE 16

186

Ia
Ib
Ic
Id
Ie
If

187

Ia-151
Ib-151
Ic-151
Id-151
Ie-151
If-151

188

Ia-152
Ib-152
Ic-152
Id-152
Ie-152
If-152

189

Ia-153
Ib-153
Ic-153
Id-153
Ie-153
If-153

190

Ia-154
Ib-154
Ic-154
Id-154
Ie-154
If-154

191

Ia-155
Ib-155
Ic-155
Id-155
Ie-155
If-155

192

Ia-156
Ib-156
Ic-156
Id-156
Ie-156
If-156

193

Ia-157
Ib-157
Ic-157
Id-157
Ie-157
If-157

194

Ia-158
Ib-158
Ic-158
Id-158
Ie-158
If-158

195

Ia-159
Ib-159
Ic-159
Id-159
Ie-159
If-159

196

Ia-160
Ib-160
Ic-160
Id-160
Ie-160
If-160

[0150]

17

TABLE 17

197

Ia
Ib
Ic
Id
Ic
If

198

Ia-161
Ib-161
Ic-161
Id-161
Ic-161
If-161

199

Ia-162
Ib-162
Ic-162
Id-162
Ic-162
If-162

200

Ia-163
Ib-163
Ic-163
Id-163
Ic-163
If-163

201

Ia-164
Ib-164
Ic-164
Id-164
Ic-164
If-164

202

Ia-165
Ib-165
Ic-165
Id-165
Ic-165
If-165

203

Ia-166
Ib-166
Ic-166
Id-166
Ic-166
If-166

[0151]

18

TABLE 18

204

IIa
IIb
IIc
IId
IIe
IIf

205

IIa-1
IIb-1
IIc-1
IId-1
IIe-1
IIf-1

206

IIa-2
IIb-2
IIc-2
IId-2
IIe-2
IIf-2

207

IIa-3
IIb-3
IIc-3
IId-3
IIe-3
IIf-3

208

IIa-4
IIb-4
IIc-4
IId-4
IIe-4
IIf-4

209

IIa-5
IIb-5
IIc-5
IId-5
IIe-5
IIf-5

210

IIa-6
IIb-6
IIc-6
IId-6
IIe-6
IIf-6

211

IIa-7
IIb-7
IIc-7
IId-7
IIe-7
IIf-7

212

IIa-8
IIb-8
IIc-8
IId-8
IIe-8
IIf-8

213

IIa-9
IIb-9
IIc-9
IId-9
IIe-9
IIf-9

214

IIa-
IIb-
IIc-
IId-
IIe-
IIf-

10
10
10
10
10
10

[0152]

19

TABLE 19

215

IIa
IIb
IIc
IId
IIe
IIf

216

IIa-11
IIb-11
IIc-11
IId-11
IIe-11
IIf-11

217

IIa-12
IIb-12
IIc-12
IId-12
IIe-12
IIf-12

218

IIa-13
IIb-13
IIc-13
IId-13
IIe-13
IIf-13

219

IIa-14
IIb-14
IIc-14
IId-14
IIe-14
IIf-14

220

IIa-15
IIb-15
IIc-15
IId-15
IIe-15
IIf-15

221

IIa-16
IIb-16
IIc-16
IId-16
IIe-16
IIf-16

222

IIa-17
IIb-17
IIc-17
IId-17
IIe-17
IIf-17

223

IIa-18
IIb-18
IIc-18
IId-18
IIe-18
IIf-18

224

IIa-19
IIb-19
IIc-19
IId-19
IIe-19
IIf-19

225

IIa-20
IIb-20
IIc-20
IId-20
IIe-20
IIf-20

[0153]

20

TABLE 20

226

IIa
IIb
IIc
IId
IIe
IIf

227

IIa-21
IIb-21
IIc-21
IId-21
IIe-21
IIf-21

228

IIa-22
IIb-22
IIc-22
IId-22
IIe-22
IIf-22

229

IIa-23
IIb-23
IIc-23
IId-23
IIe-23
IIf-23

230

IIa-24
IIb-24
IIc-24
IId-24
IIe-24
IIf-24

231

IIa-25
IIb-25
IIc-25
IId-25
IIe-25
IIf-25

232

IIa-26
IIb-26
IIc-26
IId-26
IIe-26
IIf-26

233

IIa-27
IIb-27
IIc-27
IId-27
IIe-27
IIf-27

234

IIa-28
IIb-28
IIc-28
IId-28
IIe-28
IIf-28

235

IIa-29
IIb-29
IIc-29
IId-29
IIe-29
IIf-29

236

IIa-30
IIb-30
IIc-30
IId-30
IIe-30
IIf-30

[0154]

21

TABLE 21

237

IIA
IIb
IIc
IId
IIe
IIf

238

IIa-31
IIb-31
IIc-31
IId-31
IIe-31
IIf-31

239

IIa-32
IIb-32
IIc-32
IId-32
IIe-32
IIf-32

240

IIa-33
IIb-33
IIc-33
IId-33
IIe-33
IIf-33

241

IIa-34
IIb-34
IIc-34
IId-34
IIe-34
IIf-34

242

IIa-35
IIb-35
IIc-35
IId-35
IIe-35
IIf-35

243

IIa-36
IIb-36
IIc-36
IId-36
IIe-36
IIf-36

244

IIa-37
IIb-37
IIc-37
IId-37
IIe-37
IIf-37

245

IIa-38
IIb-38
IIc-38
IId-38
IIe-38
IIf-38

246

IIa-39
IIb-39
IIc-39
IId-39
IIe-39
IIf-39

247

IIa-40
IIb-40
IIc-40
IId-40
IIe-40
IIf-40

[0155]

22

TABLE 22

248

IIa
IIb
IIc
IId
IIe
IIf

249

IIa-41
IIb-41
IIc-41
IId-41
IIe-41
IIf-41

250

IIa-42
IIb-42
IIc-42
IId-42
IIe-42
IIf-42

251

IIa-43
IIb-43
IIc-43
IId-43
IIe-43
IIf-43

252

IIa-44
IIb-44
IIc-44
IId-44
IIe-44
IIf-44

253

IIa-45
IIb-45
IIc-45
IId-45
IIe-45
IIf-45

254

IIa-46
IIb-46
IIc-46
IId-46
IIe-46
IIf-46

255

IIa-47
IIb-47
IIc-47
IId-47
IIe-47
IIf-47

256

IIa-48
IIb-48
IIc-48
IId-48
IIe-48
IIf-48

257

IIa-49
IIb-49
IIc-49
IId-49
IIe-49
IIf-49

258

IIa-50
IIb-50
IIc-50
IId-50
IIe-50
IIf-50

[0156]

23

TABLE 23

259

IIa
IIb
IIc
IId
IIe
IIf

260

IIa-51
IIb-51
IIc-51
IId-51
IIe-51
IIf-51

261

IIa-52
IIb-52
IIc-52
IId-52
IIe-52
IIf-52

262

IIa-53
IIb-53
IIc-53
IId-53
IIe-53
IIf-53

263

IIa-54
IIb-54
IIc-54
IId-54
IIe-54
IIf-54

264

IIa-55
IIb-55
IIc-55
IId-55
IIe-55
IIf-55

265

IIa-56
IIb-56
IIc-56
IId-56
IIe-56
IIf-56

266

IIa-57
IIb-57
IIc-57
IId-57
IIe-57
IIf-57

267

IIa-58
IIb-58
IIc-58
IId-58
IIe-58
IIf-58

268

IIa-59
IIb-59
IIc-59
IId-59
IIe-59
IIf-59

269

IIa-60
IIb-60
IIc-60
IIe-60
IIe-60
IIf-60

[0157]

24

TABLE 24

270

IIa
IIb
IIc
IId
IIe
IIf

271

IIa-61
IIb-61
IIc-61
IId-61
IIe-61
IIf-61

272

IIa-62
IIb-62
IIc-62
IId-62
IIe-62
IIf-62

273

IIa-63
IIb-63
IIc-63
IId-63
IIe-63
IIf-63

274

IIa-64
IIb-64
IIc-64
IId-64
IIe-64
IIf-64

275

IIa-65
IIb-65
IIc-65
IId-65
IIe-65
IIf-65

276

IIa-66
IIb-66
IIc-66
IId-66
IIe-66
IIf-66

277

IIa-67
IIb-67
IIc-67
IId-67
IIe-67
IIf-67

278

IIa-68
IIb-68
IIc-68
IId-68
IIe-68
IIf-68

279

IIa-69
IIb-69
IIc-69
IId-69
IIe-69
IIf-69

280

IIa-70
IIb-70
IIc-70
IId-70
IIe-70
IIf-70

[0158]

25

TABLE 25

281

IIa
IIb
IIc
IId
IIe
IIf

282

IIa-71
IIb-71
IIc-71
IId-71
IIe-71
IIf-71

283

IIa-72
IIb-72
IIc-72
IId-72
IIe-72
IIf-72

284

IIa-73
IIb-73
IIc-73
IId-73
IIe-73
IIf-73

285

IIa-74
IIb-74
IIc-74
IId-74
IIe-74
IIf-74

286

IIa-75
IIb-75
IIc-75
IId-75
IIe-75
IIf-75

287

IIa-76
IIb-76
IIc-76
IId-76
IIe-76
IIf-76

288

IIa-77
IIb-77
IIc-77
IId-77
IIe-77
IIf-77

289

IIa-78
IIb-78
IIc-78
IId-78
IIe-78
IIf-78

290

IIa-79
IIb-79
IIc-79
IId-79
IIe-79
IIf-79

291

IIa-80
IIb-80
IIc-80
IId-80
IIe-80
IIf-80

[0159]

26

TABLE 26

292

IIa
IIb
IIc
IId
IIe
IIf

293

IIa-81
IIb-81
IIc-81
IId-81
IIe-81
IIf-81

294

IIa-82
IIb-82
IIc-82
IId-82
IIe-82
IIf-82

295

IIa-83
IIb-83
IIc-83
IId-83
IIe-83
IIf-83

296

IIa-84
IIb-84
IIc-84
IId-84
IIe-84
IIf-84

297

IIa-85
IIb-85
IIc-85
IId-85
IIe-85
IIf-85

298

IIa-86
IIb-86
IIc-86
IId-86
IIe-86
IIf-86

299

IIa-87
IIb-87
IIc-87
IId-87
IIe-87
IIf-87

300

IIa-88
IIb-88
IIc-88
IId-88
IIe-88
IIf-88

301

IIa-89
IIb-89
IIc-89
IId-89
IIe-89
IIf-89

302

IIa-90
IIb-90
IIc-90
IId-90
IIe-90
IIf-90

[0160]

27

TABLE 27

303

IIa
IIb
IIc
IId
IIe
IIf

304

IIa-91
IIb-91
IIc-91
IId-91
IIe-91
IIf-91

305

IIa-92
IIb-92
IIc-92
IId-92
IIe-92
IIf-92

306

IIa-93
IIb-93
IIc-93
IId-93
IIe-93
IIf-93

307

IIa-94
IIb-94
IIc-94
IId-94
IIe-94
IIf-94

308

IIa-95
IIb-95
IIc-95
IId-95
IIe-95
IIf-95

309

IIa-96
IIb-96
IIc-96
IId-96
IIe-96
IIf-96

310

IIa-97
IIb-97
IIc-97
IId-97
IIe-97
IIf-97

311

IIa-98
IIb-98
IIc-98
IId-98
IIe-98
IIf-98

312

IIa-99
IIb-99
IIc-99
IId-99
IIe-99
IIf-99

313

IIa-100
IIb-100
IIc-100
IId-100
IIe-100
IIf-100

[0161]

28

TABLE 28

314

IIa
IIb
IIc
IId
IIe
IIf

315

IIa-101
IIb-101
IIc-101
IId-101
IIe-101
IIf-101

316

IIa-102
IIb-102
IIc-102
IId-102
IIe-102
IIf-102

317

IIa-103
IIb-103
IIc-103
IId-103
IIe-103
IIf-103

318

IIa-104
IIb-104
IIc-104
IId-104
IIe-104
IIf-104

319

IIa-105
IIb-105
IIc-105
IId-105
IIe-105
IIf-105

320

IIa-106
IIb-106
IIc-106
IId-106
IIe-106
IIf-106

321

IIa-107
IIb-107
IIc-107
IId-107
IIe-107
IIf-107

322

IIa-108
IIb-108
IIc-108
IId-108
IIe-108
IIf-108

323

IIa-109
IIb-109
IIc-109
IId-109
IIe-109
IIf-109

324

IIa-110
IIb-110
IIc-110
IId-110
IIe-110
IIf-110

[0162]

29

TABLE 29

325

IIa
IIb
IIc
IId
IIe
IIf

326

IIa-111
IIb-111
IIc-111
IId-111
IIe-111
IIf-111

327

IIa-112
IIb-112
IIc-112
IId-112
IIe-112
IIf-112

328

IIa-113
IIb-113
IIc-113
IId-113
IIe-113
IIf-113

329

IIa-114
IIb-114
IIc-114
IId-114
IIe-114
IIf-114

330

IIa-115
IIb-115
IIc-115
IId-115
IIe-115
IIf-115

331

IIa-116
IIb-116
IIc-116
IId-116
IIe-116
IIf-116

332

IIa-117
IIb-117
IIc-117
IId-117
IIe-117
IIf-117

333

IIa-118
IIb-118
IIc-118
IId-118
IIe-118
IIf-118

334

IIa-119
IIb-119
IIc-119
IId-119
IIe-119
IIf-119

335

IIa-120
IIb-120
IIc-120
IId-120
IIe-120
IIf-120

[0163]

30

TABLE 30

336

IIa
IIb
IIc
IId
IIe
IIf

337

IIa-121
IIb-121
IIc-121
IId-121
IIe-121
IIf-121

338

IIa-122
IIb-122
IIc-122
IId-122
IIe-122
IIf-122

339

IIa-123
IIb-123
IIc-123
IId-123
IIe-123
IIf-123

340

IIa-124
IIb-124
IIc-124
IId-124
IIe-124
IIf-124

341

IIa-125
IIb-125
IIc-125
IId-125
IIe-125
IIf-125

342

IIa-126
IIb-126
IIc-126
IId-126
IIe-126
IIf-126

343

IIa-127
IIb-127
IIc-127
IId-127
IIe-127
IIf-127

344

IIa-128
IIb-128
IIc-128
IId-128
IIe-128
IIf-128

345

IIa-129
IIb-129
IIc-129
IId-129
IIe-129
IIf-129

346

IIa-130
IIb-130
IIc-130
IId-130
IIe-130
IIf-130

[0164]

31

TABLE 31

347

R1
IIa
IIb
IIc
IId
IIe
IIf

348

IIa-131
IIb-131
IIc-131
IId-131
IIe-131
IIf-131

349

IIa-132
IIb-132
IIc-132
IId-132
IIe-132
IIf-132

350

IIa-133
IIb-133
IIc-133
IId-133
IIe-133
IIf-133

351

IIa-134
IIb-134
IIc-134
IId-134
IIe-134
IIf-134

352

IIa-135
IIb-135
IIc-135
IId-135
IIe-135
IIf-135

353

IIa-136
IIb-136
IIc-136
IId-136
IIe-136
IIf-136

354

IIa-137
IIb-137
IIc-137
IId-137
IIe-137
IIf-137

355

IIa-138
IIb-138
IIc-138
IId-138
IIe-138
IIf-138

356

IIa-139
IIb-139
IIc-139
IId-139
IIe-139
IIf-139

357

IIa-140
IIb-140
IIc-140
IId-140
IIe-140
IIf-140

[0165]

32

TABLE 32

358

R1
IIa
IIb
IIc
IId
IIe
IIf

359

IIa-141
IIb-141
IIc-141
IId-141
IIe-141
IIf-141

360

IIa-142
IIb-142
IIc-142
IId-142
IIe-142
IIf-142

361

IIa-143
IIb-143
IIc-143
IId-143
IIe-143
IIf-143

362

IIa-144
IIb-144
IIc-144
IId-144
IIe-144
IIf-144

363

IIa-145
IIb-145
IIc-145
IId-145
IIe-145
IIf-145

364

IIa-146
IIb-146
IIc-146
IId-146
IIe-146
IIf-146

365

IIa-147
IIb-147
IIc-147
IId-147
IIe-147
IIf-147

366

IIa-148
IIb-148
IIc-148
IId-148
IIe-148
IIf-148

367

IIa-149
IIb-149
IIc-149
IId-149
IIe-149
IIf-149

368

IIa-150
IIb-150
IIc-150
IId-150
IIe-150
IIf-150

[0166]

33

TABLE 33

369

R1
IIa
IIb
IIc
IId
IIe
IIf

370

IIa-151
IIb-151
IIc-151
IId-151
IIe-151
IIf-151

371

IIa-152
IIb-152
IIc-152
IId-152
IIe-152
IIf-152

372

IIa-153
IIb-153
IIc-153
IId-153
IIe-153
IIf-153

373

IIa-154
IIb-154
IIc-154
IId-154
IIe-154
IIf-154

374

IIa-155
IIb-155
IIc-155
IId-155
IIe-155
IIf-155

375

IIa-156
IIb-156
IIc-156
IId-156
IIe-156
IIf-156

376

IIa-157
IIb-157
IIc-157
IId-157
IIe-157
IIf-157

377

IIa-158
IIb-158
IIc-158
IId-158
IIe-158
IIf-158

378

IIa-159
IIb-159
IIc-159
IId-159
IIe-159
IIf-159

379

IIa-160
IIb-160
IIc-160
IId-160
IIe-160
IIf-160

[0167]

34

TABLE 34

380

R1
IIa
IIb
IIc
IId
IIe
IIf

381

IIa-161
IIb-161
IIc-161
IId-161
IIe-161
IIf-161

382

IIa-162
IIb-162
IIc-162
IId-162
IIe-162
IIf-162

383

IIa-163
IIb-163
IIc-163
IId-163
IIe-163
IIf-163

384

IIa-164
IIb-164
IIc-164
IId-164
IIe-164
IIf-164

385

IIa-165
IIb-165
IIc-165
IId-165
IIe-165
IIf-165

386

IIa-166
IIb-166
IIc-166
IId-166
IIe-166
IIf-166

[0168]

35

TABLE 35

Compound No.
Physical property

Ia-04
mp 175-178° C.; 1H-NMR (CDCl3—CD3OD) δ 1.04 (1H, m), 1.25-1.49

(10H, m), 1.57-1.66 (2H, m), 2.00 (1H, m), 2.15-2.22 (2H, m), 2.51

(1H, m), 3.82 (1H, m), 5.77 (1H, dt, J = 15.9, 1.5 Hz), 6.41 (1H, d,

J = 7.8 Hz), 6.95 (1H, dt, J = 15.9, 7.1 Hz), 7.34 (1H, dd, J = 3.0,

4.8 Hz), 7.41 (1H, dd, J = 1.5, 4.8 Hz), 7.90 (1H, dd, J = 1.5, 3.0

Hz); IR (Nujol) 3363, 3105, 2627, 1697, 1618, 1554, 1248 cm−1;

[α]D25 + 44.3 ± 0.8° (c = 1.011, MeOH); Anal. (C19H25NO3S) Calcd. (%):

C, 65.68; H, 7.25; N, 4.03; S, 9.23 Found (%): C, 65.58; H, 7.18; N,

4.03; S, 9.18

Ia-17
mp 155-157° C.; 1H-NMR (CDCl3—CD3OD) δ 1.04 (1H, m), 1.22-1.53

(10H, m), 1.60-1.71 (2H, m), 2.02 (1H, m), 2.17-2.23 (2H, m), 2.58

(1H, m), 3.92 (1H, m), 5.78 (1H, dt, J = 15.6, 1.5 Hz), 6.33 (1H, d,

J = 7.5 Hz), 6.97 (1H, dt, J = 15.6, 6.9 Hz), 7.38-7.49 (2H, m),

7.86-7.89 (3H, m), 8.30 (1H, dd, J = 0.9, 6.9 Hz); IR (Nujol) 3276,

2671, 1693, 1622, 1529, 1421, 1377, 1298, 1277, 1254 cm−1; [α]D25 +

38.5 ± 0.8° (c = 1.018, MeOH); Anal. (C23H27NO3S.0.2H2O) Calcd.

(%): C, 68.87; H, 6.88; N, 3.49; S, 7.99 Found (%): C, 68.93; H,

7.01; N, 3.55; S, 7.87

Ia-20
mp 129-131° C.; 1H-NMR (CDCl3) δ 1.01 (1H, m), 1.26-1.52 (10H,

m), 1.60-1.66 (2H, m), 2.02 (1H, m), 2.18-2.25 (2H, m), 2.49 (3H,

s), 2.58 (1H, m), 3.95 (1H, m), 5.80 (1H, d, J = 15.6 Hz), 6.06 (1H,

d, J = 7.8 Hz), 7.04 (1H, dt, J = 15.6, 7.1 Hz), 7.23 (1H, dd, J = 1.2,

8.4 Hz), 7.74 (1H, d, J = 8.4 Hz), 7.80 (1H, s), 8.14 (1H, s); IR

(Nujol) 3269, 3078, 2677, 1697, 1649, 1624, 1539, 1437, 1377,

1298, 1281 cm−1; [α]D25 + 32.0 ± 0.7° (c = 1.005, MeOH); Anal.

(C24H29NO3S) Calcd. (%): C, 70.04; H, 7.10; N, 3.40; S, 7.79 Found

(%): C, 69.83; H, 7.10; N, 3.43; S, 7.64

Ia-28
mp 138-140° C.; 1H-NMR (CDCl3) δ 1.02 (1H, m), 1.21-1.52 (10H,

m), 1.59-1.70 (2H, m), 2.01 (1H, m), 2.17-2.24 (2H, m), 2.56 (1H,

m), 3.92 (1H, m), 5.79 (1H, dt, J = 15.6, 1.5 Hz), 6.14 (1H, d, J =

8.1 Hz), 7.03 (1H, dt, J = 15.6, 7.1 Hz), 7.16 (1H, td, J = 8.6, 2.7

Hz), 7.77 (1H, dd, J = 4.8, 8.6 Hz), 7.91 (1H, s), 8.07 (1H, dd, J =

2.7, 10.2 Hz); IR (Nujol) 3276, 2671, 1695, 1624, 1533, 1442, 1433,

1296, 1277, 1246, 1200 cm−1; [α]D25 + 35.6 ± 0.8° (c = 1.014, MeOH);

Anal. (C23H26FNO3S.0.2H2O) Calcd. (%): C, 65.91; H, 6.35; F, 4.53;

N, 3.34; S, 7.65 Found (%): C, 65.99; H, 6.38; F, 4.42; N, 3.39; S,

7.57

Ia-34
mp 172-173° C.; 1H-NMR (CDCl3—CD3OD) δ 1.08 (1H, m), 1.29-1.55

(10H, m), 1.60-1.69 (2H, m), 2.03 (1H, m), 2.14-2.21 (2H, m), 2.60

(1H, m), 3.96 (1H, m), 5.76 (1H, dt, J = 15.6, 1.5 Hz), 6.57 (1H, d, J =

7.5 Hz), 6.97 (1H, dt, J = 15.6, 7.1 Hz), 7.38 (1H, d, J = 5.7 Hz),

7.42 (1H, t, J = 7.8 Hz), 7.59 (1H, d, J = 5.7 Hz), 7.65 (1H, d, J =

6.9 Hz), 7.95 (1H, d, J = 7.8 Hz); IR (Nujol) 3302, 2698, 1739,

1693, 1657, 1622, 1581, 1568, 1547, 1205 cm−1; [α]D25 + 35.0 ± 0.7°

(c = 1.013, MeOH); Anal. (C23H27NO3S.0.2H2O) Calcd. (%): C,

68.87; H, 6.88; N, 3.49; S, 7.99 Found (%): C, 68.92; H, 7.05; N,

3.44; S, 7.67

[0169]

36

TABLE 36

Compound No.
Physical property

Ia-49

1
H-NMR (CDCl3) δ 1.02 (1H, m), 1.29-1.74 (12H, m), 2.02 (1H, m),

2.17-2.24 (2H, m), 2.56 (1H, m), 3.44 (3H, s), 3.96 (1H, m), 4.79

(2H, s), 5.79 (1H, dt, J = 15.6, 1.2 Hz), 5.98 (1H, d, J = 7.8 Hz),

7.01 (1H, dt, J = 15.6, 7.2 Hz), 7.33-7.40 (2H, m), 7.77 (1H, dd, J =

7.2, 2.4 Hz), 8.14 (1H, s); IR (CHCl3) 3442, 2682, 1695, 1652,

1573, 1508, 1425, 1284, 1205, 1120 cm−1; [α]D25.0 + 31.0 ± 0.7°

(c = 1.009, MeOH); Anal. (C25H31NO5.0.5H2O) Calcd. (%): C, 69.10;

H, 7.42; N, 3.22 Found (%): C, 68.83; H, 7.48; N, 3.30

Ia-51

1
H-NMR (CDCl3—CD3OD) δ 1.03 (1H, m), 1.20-1.51 (9H, m), 1.59-

1.71 (3H, m), 2.01 (1H, d, J = 3.6 Hz), 2.15-2.22 (2H, m), 2.56 (1H,

s), 3.90 (1H, m), 5.77 (1H, d, J = 15.6 Hz), 6.90 (1H, dd, J = 2.1, 8.4

Hz), 6.96 (1H, dt, J = 15.6, 6.9 Hz), 6.99 (1H, d, J = 2.1 Hz), 7.58

(1H, d, J = 8.4 Hz), 8.01 (1H, s); IR (KBr) 3350, 3141, 1695, 1628,

1560, 1523, 1493, 1441, 1367, 1279, 1225, 1136, 1124 cm−1;

[α]D27 + 26.6 ± 0.7° (c = 1.008, MeOH); Anal. (C23H27NO5.0.3H2O)

Calcd. (%): C, 68.57; H, 6.91; N, 3.48 Found (%): C, 68.47; H, 6.91;

N, 3.66

Ia-52

1
H-NMR (CDCl3—CD3OD) δ 1.02 (1H, m), 1.22-1.48 (9H, m), 1.57-

1.60 (3H, m), 1.98 (1H, d, J = 3.3 Hz), 2.11-2.18 (2H, m), 2.53 (1H,

s), 3.89 (1H, m), 5.75 (1H, dd, J = 1.5, 15.3 Hz), 6.31 (1H, d, J = 7.8

Hz), 6.90 (1H, dd, J = 2.4, 8.7 Hz), 6.96 (1H, dt, J = 15.3, 6.9 Hz),

7.33 (1H, d, J = 8.7 Hz), 7.43 (1H, d, J = 2.4 Hz), 8.07 (1H, s); IR

(KBr) 3347, 1695, 1635, 1558, 1524, 1462, 1309, 1271, 1192, 1173,

1134 cm−1; [α]D25 + 20.1 ± 0.6° (c = 1.013, MeOH); Anal.

(C23H27NO5.0.4H2O) Calcd. (%): C, 68.27; H, 6.92; N, 3.46 Found

(%): C, 68.12; H, 7.00; N, 3.59

Ia-54

1
H-NMR (CDCl3) δ 1.05 (1H, m), 1.23-1.72 (10H, m), 2.02 (1H, m),

2.18-2.25 (2H, m), 2.55 (1H, m), 3.94 (1H, m), 5.79 (1H, dt, J =

15.6, 1.5 Hz), 5.91 (1H, d, J = 8.1 Hz), 7.03 (1H, dt, J = 15.6, 6.9

Hz), 7.09-7.16 (1H, m), 7.25 (1H, dd, J = 9.0, 1.8 Hz), 7.84 (1H, dd,

J = 9.0, 5.4 Hz), 8.06 (1H, s); IR (CHCl3) 3442, 2680, 1695, 1652,

1563, 1506, 1257, 1224, 1218, 1133, cm−1; [α]D25.0 + 25.4 ± 0.7°

(c = 1.005, MeOH); Anal. (C23H28FNO4.0.1H2O) Calcd. (%): C, 68.85;

H, 6.58; F, 4.73; N, 3.49 Found (%): C, 68.65; H, 6.43; F, 4.59; N,

3.60

Ia-56

1
H-NMR (CDCl3) δ 1.12 (1H, m), 1.29-1.53 (9H, m), 1.60-1.74 (3H,

m), 2.04 (1H, d, J = 3.6 Hz), 2.16-2.22 (2H, m), 2.57 (1H, s), 4.03

(1H, m), 5.77 (1H, d, J = 15.6 Hz), 6.89 (1H, d, J = 2.1 Hz), 7.02

(1H, dt, J = 15.3, 7.2 Hz), 7.36 (1H, t, J = 7.5 Hz), 7.57 (1H, d, J =

7.8 Hz), 7.74 (1H, dd, J = 1.2, 7.5 Hz), 7.74 (1H, d, J = 2.1 Hz), 8.11

(1H, dd, J = 1.2, 7.5 Hz); IR (CHCl3) 3435, 2679, 1695, 1653, 1595,

1547, 1533, 1475, 1458, 1421, 1306, 1286, 1167, 1120 cm−1;

[α]D25.5 + 47.7 ± 0.9° (c = 1.003, MeOH); Anal. (C23H27NO40.1H2O)

Calcd. (%): C, 72.08; H, 7.15; N, 3.65 Found (%): C, 72.01; H, 7.11;

N, 3.72

[0170]

37

TABLE 37

Compound No.
Physical property

Ia-65

1
H-NMR (CDCl3) δ 1.02 (1H, m), 1.27-1.71 (12H, m), 2.01 (1H, d, J =

3.9 Hz), 2.16-2.23 (2H, m), 2.48 (1H, br s), 3.92 (1H, m), 5.81

(1H, d, J = 15.6 Hz), 6.08 (1H, d, J = 8.4 Hz), 6.80 (1H, d, J = 1.5

Hz), 6.98 (1H, dt, J = 5.4 and 0.6 Hz), 7.03 (1H, dt, J = 15.6 and

6.9 Hz), 10.49 (1H, s); IR (CHCl3) 3446, 3215, 1726, 1693, 1643,

1541, 1504, 1477, 1462, 1402, 1373, 1303, 1248 cm−1; [α]D26 + 67.8 ±

1.1° (c = 1.002, MeOH) Anal. (C21H26N2O3S.0.25CH3COOEt)

Calcd. (%): C, 63.43; H, 6.77; N, 6.72; S, 7.69 Found (%): C, 63.66;

H, 6.60; N, 6.93; S, 7.60

Ia-66

1
H-NMR (CDCl3) δ 1.02 (1H, m), 1.27-1.70 (12H, m), 2.01 (1H, d, J =

3.6 Hz), 2.15-2.22 (2H, m), 2.51 (1H, br s), 3.92 (1H, m), 5.80

(1H, d, J = 15.6 Hz), 6.08 (1H, d, J = 7.8 Hz), 6.77 (1H, d, J = 2.1

Hz), 6.88 (1H, d, J = 5.4 Hz), 6.95 (1H, d, J = 5.4 Hz), 7.03 (1H,

dt, J = 15.6 and 6.9 Hz), 11.07 (1H, s); IR (CHCl3) 3444, 3191,

2677, 1693, 1639, 1543, 1518, 1475, 1458, 1421, 1396, 1378, 1296,

1279, 1255 cm−1; [α]D26 + 55.3 ± 1.0° (c = 1.001, MeOH) Anal.

(C21H26N2O3S.0.3H2O) Calcd. (%): C, 64.36; H, 6.84; N, 7.15; S,

8.18 Found (%): C, 64.22; H, 6.48; N, 7.13; S, 8.22

Ia-95
mp 113-114° C.; 1H-NMR (CDCl3—DMSO—d6) δ 1.12 (1H, m), 1.26

(3H, t, J = 6.9 Hz), 1.27-1.64 (12H, m), 2.01 (1H, m), 2.15-2.22 (2H,

m), 2.57 (1H, br s), 3.90 (1H, m), 4.14 (2H, q, J = 6.9 Hz), 4.48 (2H,

br s), 5.57 (1H, br s), 5.77 (1H, d, J = 15.6 Hz), 6.68 (1H, br s), 6.92

(1H, dd, J = 15.6, 7.2 Hz), 7.38 (1H, br d, J = 8.1 Hz), 7.81 (1H, d,

J = 8.1 Hz), 7.95 (1H, s), 8.33 (1H, br s); IR (CHCl3) 3446, 1703,

1653, 1514, 1435, 1300, 1223, 1134 cm−1; [α]D23 + 5.5 ± 0.5° (c = 1.008,

MeOH) Anal. (C27H34N2O5S.0.3H2O) Calcd. (%): C, 64.34; H,

6.92; N, 5.56; S, 6.36 Found (%): C, 64.27; H, 6.69; N, 5.54; S, 6.37

Ic-04
mp 105-107° C.; 1H-NMR (CDCl3) δ 1.02 (1H, m), 1.20-1.70 (12H,

m), 2.00 (1H, m), 2.49 (1H, br s), 3.47-3.58 (2H, m), 3.91 (1H, m),

4.04 (2H, s), 6.07 (1H, d, J = 7.2 Hz), 7.34 (1H, dd, J = 3.0, 5.1 Hz),

7.37 (1H, dd, J = 1.5, 5.1 Hz), 7.88 (1H, dd, J = 1.5, 3.0 Hz); IR

(Nujol) 3354, 3093, 2553, 1730, 1612, 1556, 1240, 1138 cm−1; [α]D25 +

46.6 ± 0.9° (c = 1.009, MeOH); Anal. (C18H25NO4S) Calcd. (%): C,

61.51; H, 7.17; N, 3.99; S, 9.12 Found (%): C, 61.45; H, 7.32; N,

4.06; S, 9.10

Ic-17
mp 149-151° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.21-1.72 (12H,

m), 2.02 (1H, m), 2.57 (1H, br s), 3.47-3.58 (2H, m), 3.98 (1H, m),

4.03 (2H, s), 6.14 (1H, d, J = 7.8 Hz), 7.40 (1H, d, J = 7.8 Hz), 7.44

(1H, dt, J = 1.2, 7.5 Hz), 7.46 (1H, dt, J = 1.2, 7.5 Hz), 7.87 (1H,

dd, J = 1.2, 7.5 Hz), 7.88 (1H, s), 8.29 (1H, dd, J = 1.2, 7.5 Hz); IR

(Nujol) 3296, 2528, 1726, 1604, 1558, 1240, 1228, 1140 cm−1; [α]D25 +

38.1 ± 0.8° (c = 1.013, MeOH); Anal. (C22H27NO4S) Calcd. (%): C,

65.18; H, 6.78; N, 3.49; S, 7.99 Found (%): C, 65.62; H, 7.06; N,

3.51; S, 7.78

[0171]

38

TABLE 38

Compound No.
Physical property

Ic-19
mp 145-147° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.21-1.33 (2H, m),

1.40-1.71 (10H, m), 2.01 (1H, m), 2.48 (3H, s), 2.6 (1H, br s),

3.47-3.58 (2H, m), 3.97 (1H, m), 4.03 (2H, s), 6.12 (1H, d, J = 7.8

Hz), 7.28 (1H, m), 7.65 (1H, m), 7.78 (1H, s), 8.15 (1H, d, J = 8.4

Hz); IR (Nujol) 3288, 2521, 1724, 1601, 1560, 1225, 1138 cm−1;

[α]D25 + 36.8 ± 0.8° (c = 1.008, MeOH) Anal. (C23H29NO4S) Calcd.

(%): C, 66.48; H, 7.03; N, 3.37; S, 7.72 Found (%): C, 66.33; H,

7.03; N, 3.30; S, 7.43

Ic-20
mp 135-136° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.21-1.72 (12H,

m), 2.02 (1H, m), 2.49 (3H, s), 2.57 (1H, br s), 3.48-3.59 (2H, m),

3.97 (1H, m), 4.03 (2H, s), 6.12 (1H, d, J = 7.5 Hz), 7.23 (1H, dd, J =

1.5, 8.4 Hz), 7.74 (1H, d, J = 8.4 Hz), 7.83 (1H, s), 8.12 (1H, d, J =

1.5 Hz); IR (Nujol) 3384, 3361, 2546, 1736, 1718, 1616, 1533, 1225,

1140 cm−1; [α]D25 + 32.4 ± 0.7° (c = 1.003, MeOH); Anal. (C23H29NO4S)

Calcd. (%): C, 66.48; H, 7.03; N, 3.37; S, 7.72 Found (%): C, 66.31;

H, 7.32; N, 3.34; S, 7.60

Ic-22
mp 76-79° C.; 1H-NMR (CDCl3—CD3OD) δ 1.07 (1H, m), 1.20-1.32

(2H, m), 1.34-1.70 (10H, m), 2.00 (1H, m), 2.57 (1H, br s), 3.44-

3.55 (2H, m), 3.88 (1H, m), 4.00 (2H, s), 6.43 (1H, d, J = 7.8 Hz),

6.97 (1H, dd, J = 2.4 and 8.7 Hz), 7.25 (1H, d, J = 2.4 Hz), 7.65

(1H, s), 8.06 (1H, d, J = 8.7 Hz); IR (CHCl3) 3599, 3437, 1780,

1649, 1603, 1516, 1124 cm−1; [α]D25 + 36.4 ± 0.8° (c = 1.013, MeOH)

Anal. (C22H27NO5S.0.6H2O) Calcd. (%): C, 61.69; H, 6.64; N, 3.27;

S, 7.49 Found (%): C, 61.58; H, 6.37; N, 3.54; S, 7.48

Ic-23
mp 149-151° C.; 1H-NMR (CDCl3) δ 1.08 (1H, m), 1.21-1.86 (12H,

m), 1.99 (1H, m), 2.22 (2H, br s), 2.56 (1H, m), 3.53 (2H, t, J = 6.0

Hz), 3.92 (1H, m), 4.03 (2H, s), 6.31 (1H, d, J = 7.2 Hz), 7.00 (1H,

dd, J = 2.1, 8.7 Hz), 7.67 (1H, d, J = 8.7 Hz), 7.72 (1H, d, J = 2.4

Hz), 7.83 (1H, s); IR (Nujol) 3313, 3104, 2636, 1743, 1626, 1599,

1552, 1439, 1248, 1190, 1153, 1124 cm−1; [α]D26 + 33.6 ± 0.7°

(c = 1.002%, MeOH); Anal. (C22H27NO5S) Calcd. (%): C, 63.29; H,

6.52; N, 3.35; S, 7.68 Found (%): C, 62.99; H, 6.66; N, 3.39; S, 7.57

Ic-28
mp 149-151° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.21-1.72 (12H,

m), 2.03 (1H, m), 2.56 (1H, br s), 3.48-3.60 (2H, m), 3.95 (1H, m),

4.04 (2H, s), 6.11 (1H, d, J = 8.1 Hz), 7.16 (1H, dt, J = 2.4, 8.7 Hz),

7.78 (1H, dd, J = 4.8, 8.7 Hz), 7.92 (1H, s), 8.05 (1H, dd, J = 2.4, 9.9

Hz); IR (Nujol) 3384, 3361, 2546, 1736, 1718, 1616, 1533, 1225,

1140 cm−1; [α]D25 + 35.6 ± 0.8° (c = 1.014, MeOH); Anal.

(C22H26FNO4S) Calcd. (%): C, 62.99; H, 6.25; F, 4.53; N, 3.34; S,

7.64 Found (%): C, 62.84; H, 6.51; F, 4.44; N, 3.41; S, 7.40

Ic-34
mp 154-157° C.; 1H-NMR (CDCl3) δ 1.09 (1H, m), 1.24-1.72 (12H,

m), 2.04 (1H, m), 2.59 (1H, br s), 3.47-3.58 (2H, m), 4.02 (1H, m),

4.02 (2H, s), 6.42 (1H, d, J = 7.5 Hz), 7.38 (1H, d, J = 5.4 Hz), 7.43

(1H, d, J = 7.5 Hz), 7.59 (1H, d, J = 5.4 Hz), 7.61 (1H, d, J = 7.5

Hz), 7.96 (1H, dd, J = 0.9, 7.5 Hz); IR (Nujol) 3288, 2540, 1726,

1614, 1577, 1554, 1319, 1244, 1225, 1138 cm−1; [α]D25 + 39.8 ± 0.8°

(c = 1.017, MeOH); Anal. (C22H27NO4S) Calcd. (%): C, 65.81; H,

6.78; N, 3.49; S, 7.99 Found % C, 65.53; H, 6.94; N, 3.52; S, 7.76

[0172]

39

TABLE 39

Compound No.
Physical property

Ic-39

1
H-NMR (CDCl3) δ 1.10 (1H, m), 1.25-1.71 (12H, m), 2.03 (1H, m),

2.58 (1H, br s), 3.49-3.56 (2H, m), 3.98 (3H, s), 4.02 (2H, s), 4.03

(1H, m), 6.40 (1H, d, J = 8.4 Hz), 6.42 (2H, s), 7.42 (1H, t, J = 7.5

Hz), 7.66 (1H, d, J = 7.5 Hz), 7.93 (1H, d, J = 7.5 Hz); IR (CHCl3)

3451, 1780, 1732, 1649, 1508, 1373, 1220, 1151 cm−1; [α]D24 +

37.0 ± 0.8° (c = 1.008, MeOH); Anal. (C23H29NO5S.0.3H2O) Calcd.

(%): C, 63.22; H, 6.83; N, 3.21; S, 7.34 Found (%): C, 63.26; H,

6.78; N, 3.23; S, 7.17

Ic-49

1
H-NMR (CDCl3) δ 1.06 (1H, m), 1.29-1.36 (2H, m), 1.36-1.74 (10H,

m), 2.03 (1H, m), 2.53 (1H, m), 3.45 (3H, s), 3.52 (2H, dt, J = 6.3,

1.5 Hz), 4.00 (1H, m), 4.02 (2H, s), 4.79 (2H, s), 6.07 (1H, d, J = 7.8

Hz), 7.33-7.40 (2H, m), 7.77 (1H, dd, J = 6.9, 2.1 Hz), 8.16 (1H, s);

IR (CHCl3) 3440, 2829, 1652, 1573, 1509, 1226, 1205, 1124 cm−1;

[α]D25.0 + 33.3 ± 0.7° (c = 1.016, MeOH); Anal. (C24H31NO6) Calcd. (%):

C, 67.11; H, 7.27; N, 3.26 Found (%): C, 66.82; H, 7.39; N, 3.32

Ic-51

1
H-NMR (CDCl3—CD3OD) δ 1.08 (1H, m), 1.25-1.28 (2H, m), 1.37-

1.62 (10H, m), 1.99 (1H, d, J = 3.3 Hz), 2.54 (1H, s), 3.45-3.49 (2H,

m), 3.87 (1H, m), 4.00 (2H, s), 6.44 (1H, d, J = 7.8 Hz), 6.88 (1H,

dd, J = 2.1, 8.7 Hz), 6.97 (1H, d, J = 2.1 Hz), 7.60 (1H, d, J = 8.7

Hz), 8.02 (1H, s); IR (KBr) 3365, 3140, 1734, 1628, 1560, 1527,

1493, 1440, 1363, 1279, 1220, 1136, 1124 cm−1; [α]D27 + 29.1 ± 0.7°

(c = 1.016, MeOH); Anal. (C22H27NO6.0.5H2O) Calcd. (%): C, 64.38;

H, 6.88; N, 3.41 Found (%): C, 64.39; H, 6.95; N, 3.66

Ic-52

1
H-NMR (CDCl3—CD3OD) δ 1.07 (1H, m), 1.24-1.30 (3H, m), 1.45-

1.49 (5H, m), 1.59-1.65 (4H, m), 2.00 (1H, d, J = 3.3 Hz), 2.59 (1H,

s), 3.52 (2H, t, J = 6.0 Hz), 3.89 (1H, m), 4.00 (1H, d, J = 16.5 Hz),

4.06 (1H, d, J = 16.5 Hz), 6.14 (1H, d, J = 8.1 Hz), 6.90 (1H, dd, J =

2.1, 9.0 Hz), 7.34 (1H, d, J = 2.1 Hz), 7.36 (1H, d, J = 9.0 Hz), 8.06

(1H, s); IR (CHCl3) 3438, 3267, 1730, 1647, 1620, 1558, 1514,

1468, 1169, 1134 cm−1; [α]D27 + 25.0 ± 0.7° (c = 1.003, MeOH); Anal.

(C22H27NO6.0.3H2O) Calcd. (%): C, 64.95; H, 6.84; N, 3.44 Found

(%): C, 64.84; H, 6.96; N, 3.62

Ic-54

1
H-NMR (CDCl3) δ 1.04 (1H, m), 1.25-1.32 (2H, m), 1.43-1.68 (10H,

m), 2.03 (1H, m), 2.53 (1H, m), 3.53 (2H, t, J = 6.6 Hz), 3.96 (1H,

m), 4.04 (2H, s), 6.04 (1H, d, J = 8.1 Hz), 7.09-7.16 (1H, m), 7.25

(1H, dd, J = 8.4, 2.4 Hz), 7.84 (1H, dd, J = 8.4, 5.7 Hz), 8.10 (1H,

s); IR (CHCl3) 3440, 2875, 1656, 1563, 1506, 1224, 1216, 1205

cm−1; [α]D26.0 + 27.6 ± 0.7° (c = 1.018, MeOH); Anal.

(C22H26FNO5.0.6H2O) Calcd. (%): C, 63.79; H, 6.62; F, 4.59; N, 3.38

Found (%): C, 63.48; H, 6.49; F, 4.47; N, 3.59

Ic-65
mp 148-149° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.27-1.30 (2H, m),

1.41-1.52 (6H, m), 1.59-1.71 (4H, m), 2.01 (1H, d, J = 3.3 Hz), 2.45

(1H, s), 3.53 (2H, dt, J = 1.5, 6.3 Hz), 3.94 (1H, m), 4.07 (2H, s),

6.13 (1H, d, J = 8.1 Hz), 6.78 (1H, d, J = 1.5 Hz), 6.98 (1H, d, J =

5.1 Hz), 7.23 (1H, d, J = 8.1 Hz), 10.27 (1H, s); IR (KBr) 3367,

3292, 3111, 2758, 2636, 2544, 1712, 1601, 1574, 1510, 1458, 1325,

1250, 1225, 1138 cm−1; [α]D25 + 66.6 ± 1.1° (c = 1.008, MeOH); Anal.

(C20H26N2O4S.0.1H2O) Calcd. (%): C, 61.23; H, 6.68; N, 7.14; S,

8.17 Found (%): C, 61.20; H, 6.79; N, 7.25; S, 8.25

[0173]

40

TABLE 40

Compound No.
Physical property

Ic-66
mp 143-144° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.24-1.30 (2H, m),

1.38-1.52 (6H, m), 1.59-1.67 (4H, m), 2.01 (1H, d, J = 3.0 Hz), 2.48

(1H, s), 3.52 (2H, t, J = 6.3 Hz), 3.94 (1H, m), 4.07 (2H, s), 6.12

(1H, d, J = 8.4 Hz), 6.73 (1H, d, J = 1.8 Hz), 6.88 (1H, d, J = 5.4

Hz), 6.93 (1H, d, J = 5.4 Hz), 10.80 (1H, s); IR (KBr) 3348, 3105,

2754, 2648, 2551, 1738, 1587, 1556, 1520, 1437, 1425, 1223, 1146

cm−1; [α]D25 + 50.5 ± 0.9° (c = 1.014, MeOH); Anal.

(C20H26N2O4S.0.1H2O) Calcd. (%): C, 61.23; H, 6.68; N, 7.14; S,

8.17 Found (%): C, 61.13; H, 6.79; N, 7.17; S, 8.07

Ic-81

1
H-NMR (CDCl3—CD3OD) δ 1.06 (1H, m), 1.20-1.28 (2H, m), 1.34-

1.49 (6H, m), 1.55-1.63 (4H, m), 1.95 (1H, d, J = 3.6 Hz), 2.42 (3H,

s), 2.56 (1H, brs), 3.48 (2H, t, J = 6.5 Hz), 3.84 (1H, br s), 4.01 (2H,

s), 6.37 (1H, d, J = 7.5 Hz), 6.71 (1H, d, J = 2.1 Hz), 7.16 (1H, d, J =

2.1 Hz), 8.10 (1H, s); IR (KBr) 3361, 3134, 1734, 1635, 1560,

1529, 1458, 1415, 1362, 1288, 1198, 1165, 1136 cm−1; [α]D24 +

28.1 ± 0.7° (c = 1.012, MeOH) Anal. (C23H29NO6.0.5H2O) Calcd.

(%): C, 65.08; H, 7.12; N, 3.30 Found (%): C, 65.14; H, 7.06; N, 3.43

Ic-84
mp 133-135° C.; 1H-NMR (CDCl3) δ 1.09 (1H, m), 1.22-1.70 (12H,

m), 2.01 (1H, d, J = 3.3 Hz), 2.55 (1H, br s), 3.50-3.68 (2H, m),

3.96-4.09 (3H, m), 4.21-4.35 (2H, m), 6.11 (1H, m), 7.64 (1H, dd, J =

1.8, 8.7 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.85 (1H, br s), 8.18 (1H, br

s); IR (Nujol) 3323, 2924, 1736, 1599, 1562, 1514, 1448, 1281,

1217, 1142 cm−1; [α]D24 + 21.7 ± 0.6° (c = 1.017%, MeOH); Anal.

(C25H32N2O6S) Calcd. (%): C, 61.45; H, 6.60; N, 5.73; S, 6.56 Found

(%): C, 61.26; H, 6.41; N, 5.70; S, 6.48

Ic-86

1
H-NMR (CDCl3) δ 1.16-1.69 (13H, m), 1.92 (1H, br s), 2.39 (1H, br

s), 3.41 (2H, t, J = 5.4 Hz), 3.68 (1H, m), 3.92 (2H, s), 5.83 (2H, s),

7.65 (1H, dd, J = 2.1, 8.7 Hz), 7.83 (1H, d, J = 8.7 Hz), 8.23 (1H, d,

J = 8.4 Hz), 8.25 (1H, s), 8.27 (1H, d, J = 2.1 Hz), 8.77 (1H, s),

12.53 (1H, br s); IR (Nujol) 3332, 2924, 1724, 1680, 1631, 1572,

1529, 1444, 1375, 1350, 1244, 1128 cm−1; [α]D24 + 23.6 ± 0.6°

(c = 1.014%, MeOH); Anal. (C23H29N3O5S.0.4H2O) Calcd. (%): C,

59.18; H, 6.43; N, 9.00; S, 6.87 Found (%): C, 59.33; H, 6.48; N,

8.87; S, 6.48

Ic-95
mp 118-120° C.; 1H-NMR (CDCl3—DMSO—d6) δ 1.16 (1H, m), 1.26

(3H, t, J = 7.2 Hz), 1.27-1.66 (12H, m), 2.01 (1H, m), 2.59 (1H, m),

3.52 (2H, m), 3.90 (1H, m), 4.00 (2H, s), 4.14 (2H, q, J = 7.2 Hz),

4.48 (2H, br s), 5.62 (1H, br s), 6.68 (1H, br s), 7.38 (1H, br d, J =

8.7 Hz), 7.81 (1H, d, J = 8.7 Hz), 7.96 (1H, s), 8.31 (1H, br s); IR

(CHCl3) 3442, 1724, 1655, 1516, 1477, 1435, 1225, 1217, 1132,

1059 cm−1; [α]D23 + 25.9 ± 0.7° (c = 1.012, MeOH) Anal.

(C26H34N2O6S.0.2H2O) Calcd. (%): C, 61.69; H, 6.85; N, 5.53; S,

6.33 Found (%): C, 61.71; H, 6.73; N, 5.48; S, 6.32

[0174]

41

TABLE 41

Compound No.
Physical property

Ic-99

1
H-NMR (d6—DMSO) δ 1.19-1.68 (13H, m), 1.93 (1H, br s), 2.43 (1H,

br s), 3.41 (2H, t, J = 6.6 Hz), 3.49 (2H, s), 3.71 (1H, m), 3.92 (2H,

s), 7.38 (1H, br s), 7.87 (1H, dd, J = 1.8, 8.7 Hz), 8.07 (1H, br s),

8.09 (1H, d, J = 8.4 Hz), 8.35 (1H, d, J = 6.6 Hz), 8.39 (1H, s), 8.85

(1H, d, J = 1.2 Hz); IR (Nujol) 3340, 3251, 2927, 1741, 1655, 1624,

1539, 1458, 1377, 1244, 1134 cm−1; [α]D25 + 24.2 ± 0.6° (c = 1.009%,

MeOH); Anal. (C23H28N2O5S.0.5H2O) Calcd. (%): C, 60.91; H, 6.44;

N, 6.18; S, 7.07 Found (%): C, 60.89; H, 6.57; N, 5.80; S, 6.91

Ic-115
mp 133-135° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.21-1.34 (2H, m),

1.40-1.72 (10H, m), 2.02 (1H, m), 2.47 (3H, s), 2.53 (3H, s), 2.57

(1H, br s), 3.48-3.59 (2H, m), 3.97 (1H, m), 4.03 (2H, s), 6.12 (1H,

d, J = 7.5 Hz), 7.05 (1H, s), 7.84 (1H, s), 7.94 (1H, s); IR (Nujol)

3344, 2540, 1730, 1614, 1539, 1219, 1142 cm−1; [α]D25 + 34.7 ± 0.7°

(c = 1.012, MeOH) Anal. (C23H29NO4S) Calcd. (%): C, 67.10; H,

7.27; N, 3.26; S, 7.64 Found (%): C, 66.81; H, 7.50; N, 3.18; S, 7.32

Ic-128

1
H-NMR (CDCl3) δ 1.05 (1H, m), 1.19-1.68 (12H, m), 1.99 (1H, br

s), 2.57 (1H, br s), 3.48 (2H, t, J = 6.3 Hz), 3.49 (2H, s), 3.95 (1H,

m), 3.99 (2H, s), 4.85 (2H, br s), 6.27 (1H, d, J = 8.1 Hz), 7.47 (1H,

d, J = 9.9 Hz), 7.76 (1H, s), 8.07 (1H, d, J = 8.4 Hz); IR (CHCl3)

3435, 3192, 2954, 1730, 1637, 1520, 1435, 1275 cm−1; [α]D26 +

29.9 ± 0.7° (c = 1.011%, MeOH); Anal. (C22H26NO5SF.0.4H2O) Calcd.

(%): C, 59.20; H, 6.14; N, 3.14; S, 7.18; F, 4.26 Found (%): C, 59.16;

H, 5.90; N, 3.05; S, 7.09; F, 4.14

Ic-129
mp 135-137° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.22-1.69 (12H,

m), 2.04 (1H, br s), 2.56 (1H, br s), 3.54 (2H, dt, J = 1.5, 6.6 Hz),

3.96 (1H, m), 3.98 (3H, s), 4.03 (2H, s), 6.12 (1H, d, J = 6.9 Hz),

7.52 (1H, d, J = 10.5 Hz), 7.77 (1H, s), 8.04 (1H, d, J = 8.4 Hz); IR

(Nujol) 3334, 2924, 1745, 1618, 1535, 1498, 1462, 1415, 1281, 1259

cm−1; [α]D24 + 23.6 ± 0.6° (c = 1.014%, MeOH); Anal. (C23H28NO5SF)

Calcd. (%): C, 61.45; H, 6.28; N, 3.12; S, 7.13; F, 4.23 Found (%):

C, 61.17; H, 6.33; N, 3.03; S, 7.04; F, 4.03

Ic-135

1
H-NMR (CDCl3—DMSO—d6) δ 1.17 (1H, m), 1.26-1.66 (12H, m), 2.00

(1H, m), 2.56 (1H, m), 3.53 (2H, t, J = 6.3 Hz), 3.86 (1H, m), 4.01

(2H, s), 6.62 (1H, br d, J = 8.1 Hz), 7.40 (2H, br s), 7.96 (1H, s),

8.17 (1H, s); IR (nujol) 1726, 1633, 1556, 1303, 1252, 1176, 1130

cm−1; [α]D24 + 19.5 ± 0.6° (c = 1.009, MeOH)

Ic-140
mp 96-98° C.; 1H-NMR (DMSO—d6) δ 1.18-1.31 (8H, m), 1.49-1.56

(5H, m), 1.94 (1H, m), 2.38 (1H, br s), 3.40 (2H, t, J = 6.5 Hz), 3.47

(2H, s), 3.68 (1H, m), 3.93 (2H, s), 6.88 (1H, br s), 7.26 (1H, dd, J =

1.5 and 8.7 Hz), 7.50 (1H, br s), 7.54 (1H, d, J = 8.7 Hz), 7.94 (1H,

d, J = 1.5 Hz), 8.12 (1H, d, J = 6.6 Hz), 8.59 (1H, s); IR (Nujol)

3386, 3276, 3195, 3064, 2549, 1747, 1697, 1666, 1624, 1560, 1128

cm−1; [α]D25 + 22.0 ± 0.6° (c = 1.006, MeOH) Anal.

(C24H30N2O6.0.8H2O) Calcd. (%): C, 63.09; H, 6.97; N, 6.13 Found

(%): C, 63.18; H, 6.98; N, 5.94

[0175]

42

TABLE 42

Compound No.
Physical property

Ic-142

1
H-NMR (CDCl3—CD3OD) δ 1.19 (1H, m), 1.26-1.31 (2H, m), 1.39-

1.64 (10H, m), 1.98 (1H, m), 2.55 (1H, br s), 3.50 (2H, t, J = 6.3

Hz), 3.86 (1H, m), 4.01 (2H, s), 6.44 (1H, br s), 6.88 (1H, d, J = 7.2

Hz), 7.29 (1H, br s), 7.50 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 1.8

and 8.4 Hz), 8.22 (1H, s), 8.45 (1H, d, J = 1.8 Hz); IR (CHCl3) 3026,

3014, 2875, 1728, 1662, 1587, 1562, 1510, 1126 cm−1; [α]D25 +

19.6 ± 0.6° (c = 1.008, MeOH) Anal. (C23H28N2O6.0.5H2O) Calcd.

(%): C, 63.14; H, 6.68; N, 6.40 Found (%): C, 63.02; H, 6.49; N, 6.35

Ie-34

1
H-NMR (CDCl3) δ 1.08 (1H, m), 1.23-1.71 (12H, m), 2.03 (1H, d, J =

3.3 Hz), 2.60 (1H, br s), 2.63 (2H, t, J = 6.9 Hz), 3.18 (2H, br s),

4.03 (1H, m), 6.45 (1H, d, J = 7.5 Hz), 7.38 (1H, d, J = 5.7 Hz), 7.42

(1H, t, J = 7.5 Hz), 7.58 (1H, d, J = 5.4 Hz), 7.63 (1H, d, J = 6.9

Hz), 7.96 (1H, d, J = 7.8 Hz); IR (CHCl3) 3452, 2954, 1711, 1649,

1520, 1495, 1458, 1300, 1284 cm−1; [α]D26 + 38.1 ± 1.6° (c = 0.502%,

MeOH); Anal. (C22H27NO3S2.0.3H2O) Calcd. (%): C, 62.47; H, 6.58;

N, 3.31; S, 15.16 Found (%): C, 62.53; H, 6.63; N, 3.38; S, 15.16

Ie-49

1
H-NMR (CDCl3) δ 1.07 (1H, m), 1.29-1.68 (12H, m), 2.01 (1H, m),

2.55 (1H, m), 2.64 (2H, t, J = 7.5 Hz), 3.18 (2H, s), 3.44 (3H, s),

3.99 (1H, m), 4.78 (2H, s), 6.12 (1H, d, J = 7.2 Hz), 7.33-7.40 (2H,

m), 7.79 (1H, dd, J = 6.9, 1.8 Hz), 8.17 (1H, s); IR (CHCl3) 3440,

2670, 1710, 1650, 1573, 1562, 1509, 1425, 1297, 1238, 1224 cm−1;

[α]D24.0 + 33.2 ± 0.7° (c = 1.019, MeOH); Anal. (C24H31NO5S.0.2H2O)

Calcd. (%): C, 64.18; H, 7.05; N, 3.12 Found (%): C, 64.11; H, 7.11;

N, 3.24

IIa-22

1
H-NMR (CDCl3) 60.94 (1H, d, J = 10.2 Hz), 1.11 (3H, s), 1.23 (3H,

s), 1.34-1.54 (6H, m), 1.65-1.89 (2H, m), 2.00 (1H, m), 2.13-2.39

(5H, m), 4.32 (1H, m), 5.75 (1H, dt, J = 15.9, 1.2 Hz), 6.22 (1H, d, J =

8.7 Hz), 6.98 (1H, dd, J = 2.1, 9.0 Hz), 6.99 (1H, td, J = 7.2, 15.9

Hz), 7.26 (1H, d, J = 2.1 Hz), 7.58 (1H, s), 8.08 (1H, d, J = 9.0 Hz);

IR (KBr) 3300, 1695, 1603, 1522, 1468, 1417, 1236 cm−1; [α]D26 +

31.3 ± 0.7° (c = 1.000, MeOH); Anal. (C25H31NO4S.0.4H2O) Calcd.

(%): C, 66.91; H, 7.14; N, 3.12; S, 7.14 Found (%): C, 66.81; H,

7.05; N, 3.13; S, 7.07

IIa-23
mp 189-192° C.; 1H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.2 Hz), 1.13

(3H, s), 1.25 (3H, s), 1.28-2.39 (14H, m), 4.31 (1H, m), 5.78 (1H, d,

J = 15.6 Hz), 6.19 (1H, d, J = 9.6 Hz), 6.99 (1H, m), 7.01 (1H, dd, J =

8.7, 2.7 Hz), 7.66 (1H, d, J = 8.7 Hz), 7.67 (1H, s), 7.89 (1H, d, J =

2.7 Hz); IR (Nujol) 3199, 2683, 1684, 1635, 1599, 1525, 1437,

1304, 1286, 1225 cm−1; [α]D26.0 + 26.8 ± 0.7° (c = 1.011, MeOH); Anal.

(C25H31NO4S.0.3H2O) Calcd. (%): C, 68.00; H, 7.08; N, 3.17; S, 7.26

Found (%): C, 68.09; H, 6.94; N, 3.16; S, 7.18

[0176]

43

TABLE 43

Compound No.
Physical property

IIa-24

1
H-NMR (CDCl3) δ 0.96 (1H, d, J = 9.9 Hz), 1.15 (3H, s), 1.27 (3H,

s), 1.32-1.60 (6H, m), 1.66-1.90 (2H, m), 2.04 (1H, m), 2.17-2.43

(5H, m), 4.29 (1H, m), 5.79 (1H, d, J = 15.6 Hz), 6.49 (1H, d, J = 9.0

Hz), 6.93 (1H, dd, J = 2.7, 5.7 Hz), 7.02 (1H, td, J = 6.9, 15.6 Hz),

7.31 (1H, d, J = 2.7 Hz), 7.32 (1H, t, J = 5.7 Hz), 7.65 (1H, s), 12.09

(1H, s); IR (CHCl3) 3521, 3454, 2686, 1695, 1651, 1624, 1585,

1562, 1522, 1456, 1271 cm−1; [α]D27 + 29.4 ± 0.7° (c = 1.004, MeOH);

Anal. (C25H31NO4S.0.4H2O) Calcd. (%): C, 66.91; H, 7.14; N, 3.12;

S, 7.14 Found (%): C, 66.97; H, 7.01; N, 3.23; S, 7.17

IIa-28
mp 172-174° C.; 1H-NMR (CDCl3) δ 0.96 (1H, d, J = 9.9 Hz), 1.13

(3H, s), 1.25 (3H, s), 1.30-2.42 (14H, m), 4.31 (1H, m), 5.79 (1H, dt,

J = 15.6, 1.5 Hz), 6.08 (1H, d, J = 9.3 Hz), 7.03 (1H, dt, J = 15.6, 7.2

Hz), 7.17 (1H, dt, J = 8.7, 2.7 Hz), 7.80 (1H, dd, J = 8.7, 5.1 Hz),

7.83 (1H, s), 8.07 (1H, dd, J = 10.2, 2.7 Hz); IR (Nujol) 3374, 2719,

1698, 1650, 1627, 1525, 1442, 1431 cm−1; [α]D24.0 + 28.2 ± 0.7°

(c = 1.012, MeOH); Anal. (C30H37NO4S.1.1H2O) Calcd. (%): Calcd.

(%): C, 67.57; H, 6.50; N, 3.15; S, 7.22 Found (%): C, 67.35; H,

6.76; N, 3.26; S, 7.12

IIa-34
mp 141-142° C.; 1H-NMR (CDCl3) δ 0.96 (1H, d, J = 9.9 Hz), 1.16

(3H, s), 1.24 (3H, s), 1.29-2.42 (14H, m), 4.39 (1H, m), 5.77 (1H, d,

J = 15.6 Hz), 6.43 (1H, d, J = 8.7 Hz), 7.01 (1H, dt, J = 15.6, 3.6

Hz), 7.38 (1H, d, J = 5.4 Hz), 7.43 (1H, t, J = 7.5 Hz), 7.54 (1H, d, J =

7.5 Hz), 7.59 (1H, d, J = 5.4 Hz), 7.96 (1H, d, J = 7.5 Hz); IR

(Nujol) 3380, 2686, 1699, 1619, 1581, 1461, 1234, 1200 cm−1;

[α]D25.0 + 48.8 ± 0.9° (c = 1.009, MeOH); Anal. (C25H31NO3S) Calcd.

(%): C, 70.55; H, 7.34; N, 3.29; S, 7.53 Found (%): C, 70.35; H,

7.33; N, 3.31; S, 7.44

IIa-51
mp 211-213° C.; 1H-NMR (CDCl3—CD3OD) δ 0.94 (1H, d, J = 9.9 Hz),

1.15 (3H, s), 1.24 (3H, s), 1.36-1.55 (6H, m), 1.70 (1H, m), 1.83

(1H, m), 2.02 (1H, m), 2.15-2.38 (5H, m), 4.29 (1H, m), 5.74 (1H, d,

J = 15.6 Hz), 6.90 (1H, dd, J = 2.1, 8.7 Hz), 6.90 (1H, dt, J = 15.6,

6.9 Hz), 7.00 (1H, d, J = 2.1 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.99 (1H,

s); IR (KBr) 3425, 3255, 2600, 1938, 1685, 1626, 1605, 1579, 1522,

1442, 1265, 1146, 1128, 1107 cm−1; [α]D27 + 23.9 ± 0.6° (c = 1.004,

MeOH); Anal. (C25H31NO5.0.1H2O) CaLcd. (%): C, 70.27; H, 7.36; N,

3.28 Found (%): C, 70.13; H, 7.34; N, 3.47

IIa-52
mp 159-160° C.; 1H-NMR (CDCl3) δ 0.92 (1H, d, J = 9.9 Hz), 1.11

(3H, s), 1.21 (3H, s), 1.36-1.50 (6H, m), 1.63 (1H, m), 1.79 (1H, m),

1.98 (1H, s), 2.10-2.20 (4H, m), 2.30 (1H, s), 4.30 (1H, s), 5.69 (1H,

d, J = 15.6 Hz), 6.20 (1H, d, J = 9.0 Hz), 6.91 (1H, dd, J = 2.4, 9.0

Hz), 6.94 (1H, dt, J = 15.6, 6.9 Hz), 7.33 (1H, d, J = 9.0 Hz), 7.56

(1H, d, J = 2.4 Hz), 7.98 (1H, s); IR (KBr) 3255, 2688, 1684, 1643,

1560, 1522, 1306, 1288, 1269, 1219, 1192, 1167, 1134 cm−1; [α]D25 +

21.8 ± 0.6° (c = 1.020, MeOH); Anal. (C25H31NO5) Calcd. (%): C,

70.57; H, 7.34; N, 3.29 Found (%): C, 70.41; H, 7.16; N, 3.34

[0177]

44

TABLE 44

Compound No.
Physical property

IIa-54

1
H-NMR (CDCl3) δ 0.95 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.24 (3H,

s), 1.32-1.57 (6H, m), 1.69-1.88 (2H, m), 2.02 (1H, m), 2.16-2.24

(4H, m), 2.35 (1H, m), 4.32 (1H, m), 5.78 (1H, dt, J = 15.3, 1.5 Hz),

6.02 (1H, d, J = 9.0 Hz), 7.02 (1H, dt, J = 15.3, 6.9 Hz), 7.09-7.15

(1H, m), 7.26 (1H, dd, J = 8.7, 2.1 Hz), 7.82 (1H, dd, J = 8.7, 5.4

Hz), 8.05 (1H, s); IR (CHCl3) 3446, 2680, 1695, 1652, 1257, 1220,

1214 cm−1; [α]D25.0 + 23.3 ± 0.6° (c = 1.008, MeOH); Anal.

(C25H30FNO4.0.4H2O) Calcd. (%): C, 69.07; H, 7.14; F, 4.37; N, 3.22

Found (%): C, 68.82; H, 6.89; F, 4.49; N, 3.34

IIa-66

1
H-NMR (CDCl3) δ 0.95 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.24 (3H,

s), 1.40-1.55 (6H, m), 1.70-1.85 (2H, m), 2.00 (1H, br s), 2.12-2.37

(5H, m), 4.30 (1H, m), 5.80 (1H, d, J = 15.6 Hz), 6.17 (1H, d, J = 9.0

Hz), 6.68 (1H, d, J = 2.1 Hz), 6.88 (1H, d, J = 5.4 Hz), 6.94 (1H, d,

J = 5.4 Hz), 7.03 (1H, dt, J = 15.6 and 6.9 Hz), 11.22 (1H, s); IR

(CHCl3) 3448, 3188, 1693, 1637, 1543, 1518, 1471, 1421, 1396,

1385, 1257, 1232 cm−1; [α]D26 + 18.2 ± 0.6° (c = 1.005, MeOH) Anal.

(C23H30N2O3S.0.2H2O) Calcd. (%): C, 66.06; H, 7.33; N, 6.70; S,

7.66 Found (%): C, 66.19; H, 7.06; N, 6.83; S, 7.35

IIa-81
mp 167-168° C.; 1H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.2 Hz), 1.13

(3H, s), 1.23 (3H, s), 1.33-1.54 (6H, m), 1.64 (1H, m), 1.80 (1H, m),

1.99 (1H, br s), 2.12-2.38 (5H, m), 2.44 (3H, s), 4.31 (1H, m), 5.71

(1H, d, J = 15.6 Hz), 6.08 (1H, d, J = 9.6 Hz), 6.72 (1H, d, J = 2.1

Hz), 6.97 (1H, dt, J = 15.6 and 6.9 Hz), 7.30 (1H, d, J = 2.1 Hz),

7.97 (1H, s); IR (KBr) 3276, 2686, 1693, 1643, 1610, 1562, 1518,

1460, 1417, 1385, 1367, 1284, 1200, 1136 cm−1; [α]D24 + 23.0 ± 0.6°

(c = 1.020, MeOH) Anal. (C26H33NO5.0.2HO) Calcd. (%): C, 70.47;

H, 7.60; N, 3.16 Found (%): C, 70.50; H, 7.47; N, 3.35

IIa-94

1
H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.25 (3H,

s), 1.42-1.56 (6H, m), 1.70-1.88 (2H, m), 2.00 (1H, m), 2.03 (3H, s),

2.18-2.38 (5H, m), 4.31 (1H, m), 4.55 (2H, m), 5.78 (1H, d, J = 15.6

Hz), 6.18-6.23 (2H, m), 6.98 (1H, dt, J = 15.6, 6.9 Hz), 7.34 (1H,

dd, J = 1.8, 8.4 Hz), 7.77 (1H, s), 7.79 (1H, d, J = 8.4 Hz), 8.31 (1H,

br s); IR (CHCl3) 3446, 1695, 1655, 1514, 1471, 1435, 1369, 1222,

1215 cm−1; [α]D24 + 23.4 ± 0.6° (c = 1.006, MeOH) Anal.

(C28H36N2O4S.0.4H2O) Calcd. (%): C, 66.74; H, 7.36; N, 5.56; S,

6.36 Found (%): C, 66.79; H, 7.23; N, 5.51; S, 6.39

IIa-99
mp 130-133° C.; 0.85 (1H, d, J = 9.6 Hz), 1.12 and 1.19 (3H, s),

1.25-2.38 (12H, m), 3.99 (1H, m), 5.72 (1H, d, J = 15.6 Hz), 6.79

(1H, dt, J = 6.6, 15.6 Hz), 7.38 (1H, s), 7.87 (1H, dd, J = 1.8, 8.7

Hz), 8.05-8.13 (3H, m), 8.31 (1H, s), 8.82 (1H, d, J = 1.2 Hz); IR

(Nujol) 3375, 3178, 2918, 1703, 1653, 1626, 1527, 1460, 1398, 1255

cm−1; [α]D25 + 27.9 ± 0.7° (c = 1.011%, MeOH); Anal.

(C26H32N2O4S.0.7AcOEt) Calcd. (%): C, 65.23; H, 7.15; N, 5.28; S,

6.05 Found (%): C, 64.99; H, 6.91; N, 5.52; S, 6.18

[0178]

45

TABLE 45

Compound No.
Physical property

IIb-28

1
H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.26 (3H,

s), 1.59 (1H, ddd, J = 2.7, 5.7, 13.5 Hz), 1.95-2.57 (7H, m), 4.06-

4.27 (4H, m), 4.33 (1H, m), 5.60-5.80 (2H, m), 6.18 (1H, d, J = 9.0

Hz), 7.17 (1H, dt, J = 3.0, 9.0 Hz), 7.79 (1H, dd, J = 4.8, 8.7 Hz),

7.89 (1H, s), 8.04 (1H, dd, J = 2.7, 9.9 Hz); IR (CHCl3) 3442, 3022,

1734, 1651, 1603, 1564, 1516, 1496, 1471, 1433, 1244, 1119 cm−1;

[α]D25 + 43.8 ± 1.4° (c = 1.003%, MeOH); Anal. (C24H28NO4SF.0.4H2O)

Calcd. (%): C, 63.67; H, 6.41; F, 4.20; N, 3.09; S, 7.08 Found (%): C,

63.73; H, 6.35; F, 4.11; N, 3.20; S, 7.07

IIc-04
mp 132-134° C.; 1H-NMR (CDCl3) δ 0.94 (1H, d, J = 9.9 Hz), 1.13

(3H, s), 1.23 (3H, s), 1.40-1.86 (8H, m), 2.00 (1H, m), 2.13 (1H, m),

2.18-2.37 (2H, m), 3.53 (2H, t, J = 6.0 Hz), 4.04 (2H, s), 4.28 (1H,

m), 6.14 (1H, d, J = 9.0 Hz), 7.31-7.36 (2H, m), 7.85 (1H, m); IR

(Nujol) 3373, 3105, 2528, 1736, 1601, 1556, 1215, 1138 cm−1; [α]D25 +

22.7 ± 0.6° (c = 1.004, MeOH); Anal. (C20H29NO4S) Calcd. (%): C,

63.30; H, 7.70; N, 3.69; S, 8.45 Found (%): C, 63.10; H, 7.73; N,

3.74; S, 8.34

IIc-17
mp 125-126° C.; 1H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.2 Hz), 1.13

(3H, s), 1.25 (3H, s), 1.40-1.93 (8H, m), 2.02 (1H, m), 2.17-2.41

(3H, m), 3.53 (2H, t, J = 6.3 Hz), 4.02 (2H, s), 4.36 (1H, m), 6.21

(1H, d, J = 9.0 Hz), 7.37-7.49 (2H, m), 7.84 (1H, s), 7.87 (1H, m),

8.30 (1H, m); IR (Nujol) 3282, 2540, 1724, 1604, 1554, 1246, 1228,

1130, 1109 cm−1; [α]D25 + 29.6 ± 0.7° (c = 1.013, MeOH); Anal.

(C24H31NO4S) Calcd. (%): C, 67.10; H, 7.27; N, 3.26; S, 7.46 Found

(%): C, 66.88; H, 7.10; N, 3.30; S, 7.25

IIc-19

1
H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.24 (3H,

s), 1.40-1.92 (8H, m), 2.01 (1H, m), 2.17-2.40 (3H, m), 2.48 (3H, s),

3.47-3.58 (2H, m), 3.97 (1H, m), 4.02 (2H, s), 4.34 (1H, m), 6.21

(1H, d, J = 9.3 Hz), 7.28 (1H, m), 7.65 (1H, m), 7.75 (1H, s), 8.16

(1H, d, J = 8.4 Hz); IR (CHCl3) 3442, 2567, 1780, 1732, 1649, 1514,

1242, 1134 cm−1; [α]D25 + 28.7 ± 0.8° (c = 1.003, MeOH) Anal.

(C25H33NO4S.0.4H2O) Calcd. (%): C, 66.61; H, 7.56; N, 3.11; S, 7.11

Found (%): C, 66.67; H, 7.37; N, 3.03; S, 6.88

IIc-20
mp 87-90° C.; 1H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.5 Hz), 1.14

(3H, s), 1.26 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.18-2.41

(3H, m), 2.49 (3H, s), 3.54 (2H, t, J = 6.0 Hz), 4.02 (2H, s), 4.35

(1H, m), 6.20 (1H, d, J = 8.4 Hz), 7.23 (1H, dd, J = 0.6, 8.4 Hz), 7.74

(1H, d, J = 8.4 Hz), 7.80 (1H, s), 8.11 (1H, d, J = 0.6 Hz); IR (Nujol)

3411, 3357, 1736, 1604, 1531, 1219, 1134 cm−1; [α]D25 + 27.4 ± 0.7°

(c = 1.013, MeOH); Anal. (C25H33NO4S.0.3H2O) Calcd. (%): C, 66.87;

H, 7.54; N, 3.12; S, 7.14 Found (%): C, 66.90; H, 7.50; N, 3.23; S,

7.05

[0179]

46

TABLE 46

Compound No.
Physical property

IIc-21
mp 183-185° C.; 1H-NMR (d6—DMSO) δ 0.84 (1H, d, J = 9.6 Hz), 1.11

(3H, s), 1.18 (3H, s), 1.22-1.60 (7H, m), 1.93 (1H, m), 2.10-2.34

(6H, m), 3.41 (2H, t, J = 6.3 Hz), 3.92 (2H, s), 3.97 (1H, m), 6.79

(1H, d, J = 7.8 Hz), 7.24 (1H, t, J = 7.8 Hz), 7.77 (1H, d, J = 7.8

Hz), 7.97 (1H, d, J = 6.9 Hz), 8.18 (1H, s), 10.39 (1H, br), 12.53

(1H, br); IR (Nujol) 3425, 3303, 3093, 2598, 1729, 1604, 1574,

1522, 1469, 1282, 1230, 1122 cm−1; [α]D27 + 32.1 ± 0.7° (c = 1.000,

MeOH); Anal. (C24H31NO5S.0.4H2O) Calcd. (%): C, 63.66; H, 7.08;

N, 3.09; S, 7.08 Found (%): C, 63.79; H, 7.14; N, 3.15; S, 7.06

IIc-22

1
H-NMR (CDCl3) δ 0.93 (1H, d, J = 10.2 Hz), 1.10 (3H, s), 1.23 (3H,

s), 1.38-1.92 (8H, m), 1.99 (1H, m), 2.16-2.38 (3H, m), 3.46 (2H, t,

J = 6.3 Hz), 3.95 (2H, s), 4.32 (1H, m), 6.32 (1H, d, J = 9.0 Hz),

6.96 (1H, dd, J = 2.1, 9.0 Hz), 7.24 (1H, t, J = 2.1 Hz), 7.51 (1H, s),

8.04 (1H, d, J = 9.0 Hz); IR (KBr) 3359, 1734, 1603, 1523, 1469,

1236, 1128 cm−1; [α]D26 + 26.8 ± 0.7° (c = 1.015, MeOH); Anal.

(C24H31NO5S.0.4H2O) Calcd. (%): C, 63.66; H, 7.08; N, 3.09; S, 7.08

Found (%): C, 63.64; H, 7.13; N, 3.07; S, 6.99

IIc-23

1
H-NMR (CDCl3) δ 0.98 (1H, d, J = 10.5 Hz), 1.12 (3H, s), 1.24 (3H,

s), 1.38-2.40 (12H, m), 3.47 (2H, t, J = 6.6 Hz), 3.97 (2H, s), 4.33

(1H, m), 5.36 (2H, br s), 6.28 (1H, d, J = 9.0 Hz), 7.00 (1H, dd, J =

2.1, 8.7 Hz), 7.65 (1H, d, J = 8.7 Hz), 7.71 (1H, s), 7.98 (1H, d, J =

2.1 Hz); IR (CHCl3) 3438, 3238, 1730, 1637, 1601, 1518, 1436,

1124 cm−1; [α]D24 + 23.7 ± 0.6° (c = 1.004, MeOH); Anal.

(C24H31NO5S.0.5H2O) Calcd. (%): C, 63.41; H, 7.10; N, 3.08; S, 7.05

Found (%): C, 63.40; H, 6.98; N, 3.25; S, 7.09

IIc-24

1
H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.5 Hz), 1.16 (3H, s), 1.20 (3H,

s), 1.40-1.92 (8H, m), 2.04 (1H, m), 2.18-2.42 (3H, m), 3.55 (2H, t,

J = 6.3 Hz), 4.04 (2H, s), 4.30 (1H, m), 6.55 (1H, d, J = 8.7 Hz),

6.93 (1H, dd, J = 2.4, 6.6 Hz), 7.32 (1H, d, J = 2.4 Hz), 7.33 (1H, d,

J = 6.6 Hz), 7.67 (1H, s), 12.10 (1H, s); IR (CHCl3) 3508, 3450,

2684, 1780, 1732, 1624, 1585, 1562, 1523, 1456, 1269 cm−1; [α]D27 +

28.4 ± 0.7° (c = 1.000, MeOH); Anal. (C24H31NO5S.0.5H2O) Calcd.

(%): C, 63.41; H, 7.10; N, 3.08; S, 7.05 Found (%): C, 63.48; H,

6.98; N, 3.16; S, 6.98

IIc-27

1
H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.25 (3H,

s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.17-2.41 (3H, m), 3.53 (2H, t,

J = 6.6 Hz), 4.03 (2H, s), 4.32 (1H, m), 6.18 (1H, d, J = 8.7 Hz),

7.21 (1H, dt, J = 2.4, 9.0 Hz), 7.53 (1H, dd, J = 2.4, 8.4 Hz), 8.33

(1H, dd, J = 5.1, 9.0 Hz); IR (CHCl3) 3508, 3442, 1780, 1732, 1651,

1603, 1516, 1468, 1244, 1122 cm−1; [α]D25 + 29.2 ± 0.7° (c = 1.006,

MeOH); Anal. (C24H30FNO4S.0.3H2O) Calcd. (%): C, 63.64; H, 6.81;

F, 4.19; N, 3.09; S, 7.08 Found (%): C, 63.65; H, 6.76; F, 4.10; N,

3.14; S, 7.16

[0180]

47

TABLE 47

Compound No.
Physical property

IIc-28
mp 144-146° C.; 1H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.5 Hz), 1.13

(3H, s), 1.25 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.17-2.41

(3H, m), 3.52-3.57 (2H, m), 4.03 (2H, s), 4.33 (1H, m), 6.16 (1H, d,

J = 8.4 Hz), 7.17 (1H, dt, J = 2.7, 8.7 Hz), 7.78 (1H, dd, J = 5.1, 8.7

Hz), 8.06 (1H, dd, J = 2.7, 9.9 Hz); IR (Nujol) 3286, 2538, 1722,

1608, 1552, 1244, 1136 cm−1; [α]D25 + 27.3 ± 0.7° (c = 1.009, MeOH);

Anal. (C24H30FNO4S) Calcd. (%): C, 64.41; H, 6.76; F, 4.24; N, 3.13;

S, 7.16 Found (%): C, 64.23; H, 6.84; F, 4.16; N, 3.19; S, 7.12

IIc-34
mp 95-96° C.; 1H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.5 Hz), 1.17

(3H, s), 1.24 (3H, s), 1.40-1.96 (8H, m), 2.02 (1H, m), 2.18-2.41

(3H, m), 3.47-3.58 (2H, m), 4.01 (2H, s), 4.40 (1H, m), 6.50 (1H, d,

J = 8.7 Hz), 7.38 (1H, d, J = 5.7 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.55

(1H, d, J = 7.8 Hz), 7.59 (1H, d, J = 5.7 Hz), 7.96 (1H, dd, J = 1.2,

7.8 Hz); IR (Nujol) 3265, 2544, 1728, 1608, 1577, 1550, 1319,

1240, 1225, 1128, 1111 cm−1; [α]D25 + 45.6 ± 0.9° (c = 1.006, MeOH);

Anal. (C24H31NO4S) Calcd. (%): C, 67.10; H, 7.27; N, 3.26; S, 7.46

Found (%): C, 66.88; H, 7.14; N, 3.34; S, 7.43

IIc-39

1
H-NMR (CDCl3) δ 0.99 (1H, d, J = 10.2 Hz), 1.17 (3H, s), 1.24 (3H,

s), 1.44-1.94 (8H, m), 2.02 (1H, m), 2.18-2.40 (3H, m), 3.53 (2H, t,

d = 6.3 Hz), 3.98 (3H, s), 4.01 (2H, s), 4.40 (1H, m), 6.43 (1H, s),

6.49 (1H, d, J = 8.7 Hz), 7.42 (1H, t, J = 7.5 Hz), 7.58 (1H, dd, J =

0.9, 7.5 Hz), 7.93 (1H, dd, J = 0.9, 7.5 Hz); IR (CHCl3) 3455, 1780,

1732, 1649, 1508, 1373, 1205, 1151 cm−1; [α]D24 + 41.7 ± 0.8°

(c = 1.007, MeOH); Anal. (C25H33NO5S.0.2H2O) Calcd. (%): C, 64.82;

H, 7.27; N, 3.02; S, 6.92 Found (%): C, 64.85; H, 7.30; N, 3.10; S,

6.64

IIc-41

1
H-NMR (CDCl3) δ 0.98 (1H, d, J = 9.9 Hz), 1.19 (3H, s), 1.25 (3H,

s), 1.46-1.96 (8H, m), 2.03 (1H, m), 2.22-2.41 (3H, m), 3.53 (2H, t,

J = 6.3 Hz), 4.00 (2H, s), 4.43 (1H, m), 6.53 (1H, d, J = 9.3 Hz),

7.44-7.56 (3H, m), 7.66 (1H, d, J = 6.3 Hz), 7.91 (1H, m), 8.18 (1H,

m), 8.30 (1H, d, J = 7.5 Hz); IR (CHCl3) 3454, 1780, 1731, 1649,

1512, 1444, 1217, 1122 cm−1; [α]D25 + 45.4 ± 0.8° (c = 1.013, MeOH);

Anal. (C28H33NO4S.0.3H2O) Calcd. (%): C, 69.34; H, 6.98; N, 2.89;

S, 6.61 Found (%): C, 69.21; H, 7.01; N, 3.04; S, 6.59

IIc-49

1
H-NMR (CDCl3) δ 0.97 (1H, d, J = 9.9 Hz), 1.17 (3H, s), 1.25 (3H,

s), 1.49-2.39 (12H, m), 3.45 (2H, s), 3.51 (2H, t, J = 6.3 Hz), 4.00

(3H, s), 4.37 (1H, m), 4.79 (2H, s), 6.20 (1H, d, J = 9.3 Hz), 7.32-

7.40 (2H, m), 7.74 (1H, dd, J = 7.2, 1.5 Hz), 8.16 (1H, s); IR

(CHCl3) 3444, 2829, 1733, 1650, 1573, 1508, 1471, 1425, 1384,

1367, 1214 cm−1; [α]D24.0 + 24.8 ± 0.6° (c = 1.020, MeOH); Anal.

(C26H35NO6.0.5H2O) Calcd. (%): C, 66.93; H, 7.78; N, 3.00 Found

(%): C, 66.85; H, 7.78; N, 3.10

[0181]

48

TABLE 48

Compound No.
Physical property

IIc-51

1
H-NMR (CDCl3) δ 0.93 (1H, d, J = 9.9 Hz), 1.14 (3H, s), 1.23 (3H,

s), 1.41-1.90 (8H, m), 2.00 (1H, m), 2.17-2.38 (3H, m), 3.49 (2H, t,

J = 6.3 Hz), 3.99 (2H, s), 4.29 (1H, m), 6.27 (1H, d, J = 9.0 Hz), 6.89

(1H, dd, J = 2.1, 8.7 Hz), 6.99 (1H, d, J = 2.1 Hz), 7.56 (1H, d, J =

8.7 Hz), 8.00 (1H, s); IR (KBr) 3475, 1734, 1626, 1560, 1518, 1493,

1471, 1441, 1385, 1367, 1265, 1221, 1122 cm−1; [α]D27 + 22.3 ± 0.6°

(c = 1.000, MeOH); Anal. (C24H31NO6.0.5H2O) Calcd. (%): C, 65.74;

H, 7.35; N, 3.19 Found (%): C, 65.79; H, 7.43; N, 3.36

IIc-52

1
H-NMR (CDCl3) δ 0.98 (1H, d, J = 10.5 Hz), 1.13 (3H, s), 1.24 (3H,

s), 1.48-1.90 (8H, m), 2.01 (1H, m), 2.18-2.40 (3H, m), 3.49 (2H, t,

J = 6.5 Hz), 3.95 (1H, d, J = 16.5 Hz), 4.02 (1H, d, J = 16.5 Hz),

4.32 (1H, m), 6.12 (1H, d, J = 9.0 Hz), 6.91 (1H, dd, J = 2.7, 9.0 Hz),

7.36 (1H, d, J = 9.0 Hz), 7.52 (1H, d, J = 9.0 Hz), 7.98 (1H, s); IR

(CHCl3) 3442, 3265, 1730, 1643, 1620, 1558, 1514, 1468, 1385,

1367, 1190, 1167, 1136 cm−1; [α]D27 + 21.6 ± 0.6° (c = 1.006, MeOH);

Anal. (C24H31NO60.5H2O) Calcd. (%): C, 65.74; H, 7.35; N, 3.19

Found (%): C, 65.80; H, 7.46; N, 3.34

IIc-56

1
H-NMR (CDCl3) δ 0.99 (1H, d, J = 10.2 Hz), 1.25 (6H, s), 1.47-1.79

(7H, m), 1.92-2.05 (2H, m), 2.19 (1H, m), 2.25-2.39 (2H, m), 3.51

(2H, t, J = 6.3 Hz), 3.96 (1H, d, J = 16.2 Hz), 4.00 (1H, d, J = 16.2

Hz), 4.46 (1H, m), 6.89 (1H, d, J = 2.1 Hz), 7.37 (1H, t, J = 7.8 Hz),

7.69 (1H, d, J = 2.1 Hz), 7.74 (1H, dd, J = 1.2, 7.8 Hz), 7.88 (1H, d,

J = 9.3 Hz), 8.13 (1H, dd, J = 1.2, 7.8 Hz); IR (CHCl3) 3435, 2665,

2573, 2474, 1780, 1732, 1651, 1606, 1595, 1547, 1535, 1473, 1421,

1367, 1352, 1325, 1296, 1167, 1120 cm−1; [α]D25.5 + 14.7 ± 0.5°

(c = 1.007, MeOH); Anal. (C24H31NO5.0.3H2O) Calcd. (%): C, 68.81;

H, 7.60; N, 3.34 Found (%): C, 68.71; H, 7.60; N, 3.44

IIc-65
mp 191-192° C.; 1H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.5 Hz), 1.15

(3H, s), 1.25 (3H, s), 1.46-1.88 (8H, m), 2.01 (1H, m), 2.11 (1H, m),

2.21-2.37 (2H, m), 3.51-3.58 (2H, m), 4.07 (2H, s), 4.30 (1H, m),

6.21 (1H, d, J = 9.3 Hz), 6.68 (1H, d, J = 1.2 Hz), 6.99 (1H, d, J =

5.4 Hz), 7.23 (1H, dd, J = 0.6, 5.4 Hz), 11.27 (1H, s) ; IR (KBr)

3433, 3276, 2663, 2534, 1736, 1591, 1541, 1508, 1473, 1458, 1244,

1228, 1211, 1151 cm−1; [α]D25 + 18.0 ± 06° (c = 1.008, MeOH); Anal.

(C22H30N2O4S.0.1H2O) Calcd. (%): C, 62.86; H, 7.24; N, 6.66; S,

7.63 Found (%): C, 62.81; H, 7.30; N, 6.80; S, 7.47

IIc-66

1
H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.24 (3H,

s), 1.46-1.88 (8H, m), 2.01 (1H, m), 2.14 (1H, m), 2.21-2.37 (2H,

m), 3.53 (2H, t, J = 6.6 Hz), 4.07 (2H, s), 4.29 (1H, m), 6.20 (1H, d,

J = 9.3 Hz), 6.64 (1H, d, J = 2.1 Hz), 6.86 (1H, d, J = 5.4 Hz), 6.92

(1H, d, J = 5.4 Hz), 11.06 (1H, s); IR (CHCl3) 3448, 3209, 1726,

1631, 1543, 1518, 1126 cm−1; [α]D25 + 14.4 ± 0.5° (c = 1.007, MeOH);

Anal. (C22H30N2O4S.0.4H2O) Calcd. (%): C, 62.06; H, 7.29; N, 6.58;

S, 7.53 Found (%): C, 62.02; H, 7.31; N, 6.67; S, 7.56

[0182]

49

TABLE 49

Compound No.
Physical property

IIc-81

1
H-NMR (CDCl3) δ 0.92 (1H, d, J = 10.2 Hz), 1.09 (3H, s), 1.20 (3H,

s), 1.41-1.73 (7H, m), 1.82 (1H, m), 1.96 (1H, br s), 2.14-2.35 (3H,

m), 2.41 (3H, s), 3.46 (2H, t, J = 6.3 Hz), 3.98 (2H, s), 4.27 (1H, m),

6.22 (1H, d, J = 9.0 Hz), 6.72 (1H, d, J = 2.1 Hz), 7.24 (1H, d, J =

2.1 Hz), 8.03 (1H, s); IR (CHCl3) 3599, 3442, 3265, 2565, 1730,

1645, 1608, 1570, 1514, 1460, 1417, 1385, 1367, 1329, 1286, 1240,

1137 cm−1; [α]D24 + 24.2 ± 0.6° (c = 1.014, MeOH) Anal.

(C25H33NO6.O.4H2O) Calcd. (%): C, 66.62; H, 7.55; N, 3.10 Found

(%): C, 66.66; H, 7.47; N, 3.29

IIc-84

1
H-NMR (CDCl3) δ 0.98 (1H, d, J = 10.2 Hz), 1.12 (3H, s), 1.25 (3H,

s), 1.34 (2H, t, J = 7.5 Hz), 1.44-2.41 (10H, m), 3.56 (2H, br t, J =

5.4 Hz), 4.04 (2H, br s), 4.22-4.40 (3H, m), 6.22 (1H, d, J = 9.0 Hz),

7.65 (1H, dd, J = 1.5, 8.7 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.78 (1H, br

s), 8.22 (1H, br s); IR (CHCl3) 3437, 2924, 1730, 1651, 1514, 1441,

1319 cm−1; [α]D24 + 20.9 ± 0.6° (c = 1.010%, MeOH); Anal.

(C27H36N2O6S.0.4H2O) Calcd. (%): C, 61.90; H, 7.08; N, 5.35; S,

6.12 Found (%): C, 61.82; H, 6.85; N, 5.30; S, 6.09

IIc-86

1
H-NMR (d6—DMSO) δ 0.85 (1H, d, J = 8.7 Hz), 1.11 (3H, s), 1.18

(3H, s), 1.27-2.38 (12H, m), 3.41 (2H, t, J = 6.3 Hz), 3.73 (2H, s),

3.97 (1H, m), 5.83 (2H, br s), 7.61 (1H, dd, J = 2.1, 8.7 Hz), 7.83

(1H, d, J = 8.7 Hz), 7.98 (1H, d, J = 6.6 Hz), 8.18 (1H, br s), 8.28

(1H, d, J = 2.1 Hz), 8.73 (1H, s), 12.54 (1H, br s); IR (Nujol) 3334

2923, 1676, 1633, 1571, 1523, 1442, 1377, 1244, 1126 cm−1; [α]D24 +

19.1 ± 0.6° (c = 1.018%, MeOH); Anal. (C25H33N3O5S.0.4H2O) Calcd.

(%): C, 60.68; H, 6.88; N, 8.49; S, 6.48 Found (%): C, 60.73; H,

6.86; N, 8.67; S, 6.41

IIc-94

1
H-NMR (CDCl3) δ 0.98 (1H, d, J = 10.2 Hz), 1.15 (3H, s), 1.26 (3H,

s), 1.48-1.91 (8H, m), 2.02 (1H, m), 2.06 (3H, s), 2.18-2.40 (3H, m),

3.51 (2H, t, J = 6.3 Hz), 3.90 and 3.97 (each 1H, ABq, J = 16.2 Hz),

4.36 (1H, m), 4.49 (1H, dd, J = 6.3, 15.0 Hz), 4.61 (1H, dd, J = 6.3,

15.0 Hz), 6.27 (1H, br d, J = 9.0 Hz), 6.41 (1H, br s), 7.33 (1H, br d,

J = 8.7 Hz), 7.76 (1H, s), 7.79 (1H, d, J = 8.7 Hz), 8.29 (1H, br s);

IR (CHCl3) 3444, 1733, 1653, 1516, 1471, 1435, 1367, 1240, 1130

cm−1; [α]D24 + 23.2 ± 0.6° (c = 1.015, MeOH) Anal.

(C27H36N2O5S.0.3H2O) Calcd. (%): C, 64.08; H, 7.29; N, 5.54; S,

6.34 Found (%): C, 63.99; H, 7.24; N, 5.46; S, 6.35

IIc-95
mp 133-134° C.; 1H-NMR (CDCl3—DMSO—d6) δ 0.96 (1H, d, J = 9.9

Hz), 1.13 (3H, s), 1.25 (3H, s), 1.26 (3H, t, J = 7.5 Hz), 1.42-2.03

(9H, m), 2.22-2.39 (3H, m), 3.52 (2H, t, J = 6.6 Hz), 3.99 (2H, s),

4.14 (2H, q, J = 7.5 Hz), 4.29 (1H, m), 4.49 (2H, br s), 5.50 (1H, br

s), 6.34 (1H, br d, J = 8.7 Hz), 7.38 (1H, d, J = 8.1 Hz), 7.82 (1H, d,

J = 8.1 Hz), 7.84 (1H, br s), 8.30 (1H, s); IR (CHCl3) 3446, 1722,

1653, 1514, 1471, 1435, 1385, 1238, 1132, 1061 cm−1; [α]D23 +

22.9 ± 0.6° (c = 1.013, MeOH) Anal. (C28H38N2O6S) Calcd. (%): C,

63.37; H, 7.22; N, 5.28; S, 6.04 Found (%): C, 63.18; H, 7.14; N,

5.23; S, 5.95

[0183]

50

TABLE 50

Compound No.
Physical property

IIc-96

1
H-NMR (CDCl3) δ 0.98 (1H, d, J = 10.5 Hz), 1.16 (3H, s), 1.26 (3H,

s), 1.47-1.72 (7H, m), 1.86 (1H, m), 2.02 (1H, m), 2.18-2.39 (3H,

m), 2.92 (3H, s), 3.51 (2H, m), 3.96 and 4.03 (each 1H, ABq, J =

16.5 Hz), 4.36 (1H, m), 4.44 (2H, br s), 5.75 (1H, br s), 6.24 (1H, br

d, J = 8.7 Hz), 7.41 (1H, br d, J = 8.1 Hz), 7.76 (1H, s), 7.83 (1H, d,

J = 8.1 Hz), 8.42 (1H, br s); IR (CHCl3) 3442, 1734, 1649, 1516,

1496, 1471, 1437, 1327, 1223, 1149, 1074 cm−1; [α]D26 + 19.2 ± 0.6°

(c = 1.010, MeOH) Anal. (C26H36N2O6S2.0.4H2O) Calcd. (%): C,

57.41; H, 6.82; N, 5.15; S, 11.79 Found (%): C, 57.36; H, 6.65; N,

5.02; S, 11.65

IIc-97

1
H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.24 (3H,

s), 1.48-1.72 (7H, m), 1.89 (1H, m), 2.00 (1H, m), 2.16-2.38 (3H,

m), 3.49 (2H, t, J = 6.6 Hz), 3.89 and 3.96 (each 1H, ABq, J = 16.5

Hz), 4.25 (1H, br d, J = 15.0 Hz), 4.32 (1H, m), 4.46 (1H, br d, J =

15.0 Hz), 6.37 (1H, d, J = 8.4 Hz), 7.21 (1H, dd, J = 1.2, 8.7 Hz),

7.71 (1H, d, J = 8.7 Hz), 7.74 (1H, s), 8.21 (1H, br s); IR (CHCl3)

3440, 1720, 1645, 1601, 1518, 1471, 1437, 1240, 1215, 1132 cm−1;

[α]D25 + 23.7 ± 0.6° (c = 1.009, MeOH) Anal. (C26H35N3O5S.0.5H2O)

Calcd. (%): C, 61.15; H, 7.11; N, 8.23; S, 6.28 Found (%): C, 61.02;

H, 6.81; N, 8.14; S, 6.30

IIc-99
mp 164-166° C.; 1H-NMR (d6—DMSO) δ 0.85 (1H, d, J = 9.6 Hz), 1.12

(3H, s), 1.19 (3H, s), 1.24-2.37 (12H, m), 3.41 (2H, t, J = 6.3 Hz),

3.92 (2H, s), 3.99 (1H, m), 7.38 (1H, br s), 7.87 (1H, dd, J = 2.1, 8.7

Hz), 8.05-8.13 (3H, m), 8.32 (1H, s), 8.82 (1H, d, J = 1.2 Hz); IR

(Nujol) 3448, 3356, 3211, 2925, 1718, 1691, 1639, 1520, 1462,

1402, 1254, 1144 cm−1; [α]D25 + 28.4 ± 0.7° (c = 1.008%, MeOH); Anal.

(C25H32N2O5S.0.2H2O) Calcd. (%): C, 63.05; H, 6.86; N, 5.88; S,

6.73 Found (%): C, 63.01; H, 6.78; N, 5.84; S, 6.70

IIc-115

1
H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.25 (3H,

s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.18-2.41 (3H, m), 2.46 (3H, s),

2.53 (3H, s), 3.47-3.58 (2H, m), 4.02 (2H, s), 4.35 (1H, m), 6.22

(1H, d, J = 8.4 Hz), 7.05 (1H, s), 7.83 (1H, s), 7.93 (1H, s); IR

(CHCl3) 3508, 3440, 1780, 1732, 1649, 1514, 1242, 1126 cm−1;

[α]D25 + 30.4 ± 0.7° (c = 1.017, MeOH) Anal. (C26H35NO4S.0.2H2O)

Calcd. (%): C, 67.71; H, 7.74; N, 3.01; S, 6.95 Found (%): C, 67.37;

H, 7.91; N, 2.95; S, 6.79

IIc-128

1
H-NMR (CDCl3) δ 0.99 (1H, d, J = 10.5 Hz), 1.12 (3H, s), 1.25

(each 3H, s), 1.41-2.41 (12H, m), 3.49 (2H, t, J = 7.5 Hz), 3.99 (2H,

s), 4.32 (2H, s), 5.05 (2H, br s), 6.29 (1H, d, J = 9.0 Hz), 7.48 (1H,

d, J = 10.2 Hz), 7.67 (1H, s), 8.09 (1H, d, J = 8.7 Hz); IR (CHCl3)

3579, 3438, 3192, 2924, 1730, 1635, 1518, 1433, 1277 cm−1; [α]D26 +

22.4 ± 0.6° (c = 1.014%, MeOH); Anal. (C24H30NO5SF.0.6H2O) Calcd.

(%): C, 60.77; H, 6.63; N, 2.95; S, 6.76; F, 4.00 Found (%): C, 60.72;

H, 6.35; N, 2.85; S, 6.58; F, 4.01

[0184]

51

TABLE 51

Compound No.
Physical property

IIc-129

1
H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.5 Hz), 1.15 (3H, s), 1.25 (3H,

s), 1.44-2.40 (12H, m), 3.55 (2H, t, J = 6.3 Hz), 3.98 (3H, s), 4.02

(2H, s), 4.32 (1H, m), 6.19 (1H, d, J = 6.6 Hz), 7.62 (1H, d, J = 10.5

Hz), 7.69 (1H, s), 8.07 (1H, d, J = 8.1 Hz); IR (CHCl3) 3444, 2924,

1780, 1732, 1649, 1512, 1466, 1415, 1263, 1225 cm−1; [α]D25 +

22.5 ± 0.6° (c = 1.006%, MeOH); Anal. (C25H32NO5SF.0.2H2O) Calcd.

(%): C, 62.40; H, 6.79; N, 2.91; S, 6.66; F, 3.95 Found (%): C, 62.32;

H, 6.74; N, 2.86; S, 6.72; F, 3.88

IIc-135

1
H-NMR (CDCl3—DMSO—d6) δ 0.93 (1H, d, J = 10.2 Hz), 1.16 (3H, s),

1.23 (3H, s), 1.42-1.74 (7H, m), 1.91-2.02 (2H, m), 2.20-2.36 (3H,

m), 3.52 (2H, t, J = 6.9 Hz), 4.00 (2H, s), 4.27 (1H, m), 6.34 (1H, br

d, J = 8.4 Hz), 7.35 (1H, dd, J = 2.1, 8.7 Hz), 7.42 (1H, d, J = 8.7

Hz), 7.96 (1H, d, J = 2.1 Hz), 8.11 (1H, s); IR (nujol) 3440, 1724,

1635, 1556, 1298, 1252, 1173, 1128 cm−1; [α]D24 + 17.1 ± 0.6°

(c = 1.004, MeOH)

IIe-04
mp 79-81° C.; 1H-NMR (CDCl3) δ 0.95 (1H, d, J = 9.9 Hz), 1.21 (3H,

s), 1.23 (3H, s), 1.36-1.88 (8H, m), 2.00 (1H, m), 2.10-2.38 (3H, m),

2.65 (2H, t, J = 6.9 Hz), 3.17 (1H, d, J = 14.7 Hz), 3.22 (1H, d, J =

14.7 Hz), 4.27 (1H, m), 6.18 (1H, d, J = 9.0 Hz), 7.32-7.36 (2H, m),

7.86 (1H, dd, J = 1.5, 2.4 Hz); IR (Nujol) 3396, 3361, 3109, 3076,

2617, 1720, 1631, 1593, 1543, 1508, 1234, 1221, 1124 cm−1; [α]D26 +

29.4 ± 0.7° (c = 1.005, MeOH); Anal. (C20H29NO3S2) Calcd. (%): C,

60.72; H, 7.39; N, 3.54; S, 16.21 Found (%): C, 60.73; H, 7.45; N,

3.61; S, 16.17

IIe-17
mp 176-178° C.; 1H-NMR (CDCl3) δ 0.98 (1H, d, J = 9.9 Hz), 1.13

(3H, s), 1.25 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.18-2.41

(3H, m), 2.66 (2H, t, J = 6.9 Hz), 3.15 (1H, d, J = 14.7 Hz), 3.21

(1H, d, J = 14.7 Hz), 4.36 (1H, m), 6.24 (1H, d, J = 8.7 Hz), 7.40

(1H, dt, J = 1.2, 7.5 Hz), 7.45 (1H, dt, J = 1.2, 7.5 Hz), 7.85 (1H, s),

7.87 (1H, dd, J = 1.2, 7.5 Hz), 8.30 (1H, dd, 1.2, 7.5 Hz); IR (Nujol)

3425, 3091, 3059, 2632, 1726, 1608, 1522, 1261, 1250, 1215, 1126

cm−1; [α]D26 + 34.0 ± 0.7° (c = 1.002, MeOH); Anal. (C24H31NO3S2)

Calcd. (%): C, 64.68; H, 7.01; N, 3.14; S, 14.39 Found (%): C, 64.48;

H, 7.01; N, 3.15; S, 14.25

IIe-20
mp 117-118° C.; 1H-NMR (CDCl3) δ 0.98 (1H, d, J = 10.5 Hz), 1.14

(3H, s), 1.26 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.18-2.42

(3H, m), 2.49 (3H, s), 2.66 (2H, t, J = 6.9 Hz), 3.16 (1H, d, J = 14.7

Hz), 3.21 (1H, d, J = 14.7 Hz), 4.35 (1H, m), 6.23 (1H, d, J = 8.7

Hz), 7.23 (1H, dd, J = 1.2, 8.4 Hz), 7.74 (1H, d, J = 8.4 Hz), 7.82

(1H, s), 8.11 (1H, d, J = 1.2 Hz; IR (Nujol) 3348, 1726, 1597, 1537,

1255, 1219 cm−1; [α]D26 + 31.9 ± 0.7° (c = 1.002, MeOH); Anal.

(C25H33NO3S2) Calcd. (%): C, 65.32; H, 7.24; N, 3.05; S, 13.95

Found (%): C, 65.15; H, 7.05; N, 3.10; S, 13.93

IIe-21
mp 170-172° C.; 1H-NMR (d6—DMSO) δ 0.84 (1H, d, J = 9.9 Hz), 1.11

(3H, s), 1.18 (3H, s), 1.28-1.60 (7H, m), 1.94 (1H, m), 2.12-2.34

(6H, m), 2.55 (2H, t, J = 7.2 Hz), 3.17 (2H, s), 3.97 (1H, m), 6.79

(1H, d, J = 7.8 Hz), 7.24 (1H, t, J = 7.8 Hz), 7.78 (1H, d, J = 7.8

Hz), 7.98 (1H, d, J = 6.6 Hz), 8.18 (1H, s), 10.39 (1H, br), 12.46

(1H, br); IR (Nujol) 3357, 3246, 32613, 1693, 1595, 1574, 1541,

1469, 1296, 1228 cm−1; [α]D27 + 38.7 ± 0.80 (c = 1.004, MeOH); Anal.

(C24H31NO4S2) Calcd. (%): C, 62.44; H, 6.77; N, 3.03; S, 13.89

Found (%): C, 62.25; H, 6.86; N, 3.08; S, 13.60

[0185]

52

TABLE 52

Compound No.
Physical property

IIe-22

1
H-NMR (CDCl3) δ 0.93 (1H, d, J = 10.2 Hz), 1.10 (3H, s), 1.23 (3H,

s), 1.36-1.92 (8H, m), 1.99 (1H, m), 2.16-2.39 (3H, m), 2.56 (2H, t,

J = 7.2 Hz), 3.13 (2H, s), 4.32 (1H, m), 6.35 (1H, d, J = 9.0 Hz),

6.95 (1H, dd, J = 2.1, 9.0 Hz), 7.24 (1H, t, J = 2.1 Hz), 7.51 (1H, s),

8.03 (1H, d, J = 9.0 Hz); IR (KBr) 3361, 2661, 1707, 1603, 1523,

1468, 1236 cm−1; [α]D26 + 23.2 ± 0.6° (c = 1.015, MeOH); Anal.

(C24H31NO4S2.0.4H2O) Calcd. (%): C, 61.48; H, 6.84; N, 2.99; S,

13.68 Found (%): C, 61.51; H, 6.74; N, 3.01; S, 13.67

IIe-24

1
H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.5 Hz), 1.15 (3H, s), 1.26 (3H,

s), 1.40-1.92 (8H, m), 2.03 (1H, m), 2.18-2.42 (3H, m), 2.64 (2H, t,

J = 7.2 Hz), 3.19 (2H, s), 4.29 (1H, m), 6.59 (1H, d, J = 8.4 Hz),

6.92 (1H, dd, J = 2.1, 6.6 Hz), 7.31 (1H, t, J = 2.1 Hz), 7.32 (1H, t,

J = 6.6 Hz), 7.69 (1H, s), 12.22 (1H, s); IR (CHCl3) 3508, 3452,

2683, 1711, 1624, 1585, 1562, 1523, 1456, 1271, 1227, 1217, 1205

cm−1; [α]D26 + 34.1 ± 0.7° (c = 1.005, MeOH); Anal. (C24H31NO4S)

Calcd. (%): C, 62.44; H, 6.77; N, 3.03; S, 13.89 Found (%): C, 62.48;

H, 6.86; N, 3.03; S, 13.63

IIe-28
mp 197-199° C.; 1H-NMR (CDCl3) δ 0.98 (1H, d, J = 10.5 Hz), 1.14

(3H, s), 1.25 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.18-2.41

(3H, m), 2.66 (2H, t, J = 6.9 Hz), 3.16 (1H, d, J = 15.0 Hz), 3.21

(1H, d, J = 15.0 Hz), 4.33 (1H, m), 6.19 (1H, d, J = 9.3 Hz), 7.16

(1H, td, J = 2.4, 8.7 Hz), 7.78 (1H, dd, J = 4.8, 8.7 Hz), 7.88 (1H, s),

8.07 (1H, dd, J = 2.4, 10.2 Hz); IR (Nujol) 3423, 3087, 2636, 1728,

1606, 1523, 1444, 1433, 1248, 1203, 1128 cm−1; [α]D26 + 31.0 ± 0.7°

(c = 1.013, MeOH); Anal. (C24H30FNO3S2.0.1AcOEt) Calcd. (%): C,

62.03; H, 6.57; F, 4.02; N, 2.96; S, 13.57 Found (%): C, 61.84; H,

6.48; F, 3.96; N, 2.98; S, 13.56

IIe-34
mp 143-144° C.; 1H-NMR (CDCl3) δ 0.98 (1H, d, J = 10.2 Hz), 1.17

(3H, s), 1.24 (3H, s), 1.40-1.96 (8H, m), 2.02 (1H, m), 2.19-2.41

(3H, m), 2.64 (2H, t, J = 7.2 Hz), 3.15 (1H, d, J = 15.0 Hz), 3.20

(1H, d, J = 15.0 Hz), 4.41 (1H, m), 6.53 (1H, d, J = 8.7 Hz), 7.38

(1H, d, J = 5.4 Hz), 7.43 (1H, t, J = 7.8, Hz), 7.43 (1H, t, J = 7.8

Hz), 7.55 (1H, dd, J = 1.2, 7.8 Hz), 7.59 (1H, d, 5.4 Hz), 7.96 (1H,

dd, J = 1.2, 7.8 Hz); IR (Nujol) 3421, 3402, 2625, 1712, 1618, 1579,

1529, 1250, 1215, 1120 cm−1; [α]D26 + 48.2 ± 0.9° (c = 1.016, MeOH);

Anal. (C24H31NO3S2) Calcd. (%): C, 64.68; H, 7.01; N, 3.14; S, 14.39

Found (%): C, 64.49; H, 6.85; N, 3.16; S, 14.12

IIe-54

1
H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.24 (3H,

s), 1.41-2.40 (12H, m), 2.64 (1H, t, J = 7.2 Hz), 3.19 (2H, s), 4.33

(1H, m), 6.14 (1H, d, J = 8.7 Hz), 7.12 (1H, dt, J = 6.0, 2.4 Hz), 7.25

(1H, dd, J = 8.4, 2.4 Hz), 7.81 (1H, dd, J = 8.4, 6.0 Hz), 8.09 (1H,

s); IR (CHCl3) 3446, 2674, 1710, 1654, 1563, 1506, 1490, 1257,

1220, 1205 cm−1; [α]D26.0 + 22.8 ± 1.2° (c = 0.510, MeOH); Anal.

(C24H30FNO4S.0.2H2O) Calcd. (%): C, 63.89; H, 6.79; F, 4.21; N,

3.10; S, 7.11 Found (%): C, 63.83; H, 6.93; F, 4.02; N, 3.18; S, 7.15

[0186]

53

TABLE 53

Compound No.
Physical property

IIf-28

1
H-NMR (CDCl3) δ 0.96 (1H, d, J = 9.9 Hz), 1.13 (3H, s), 1.25 (3H,

s), 1.42-1.86 (9H, m), 2.02 (1H, m), 2.20-2.39 (4H, m), 4.31 (1H,

m), 6.01 (1H, d, J = 8.7 Hz), 7.16 (1H, dt, J = 2.4, 9.0 Hz), 7.77 (1H,

dd, J = 4.5, 9.0 Hz), 7.84 (1H, s), 8.08 (1H, dd, J = 2.4, 10.2 Hz); IR

(CHCl3) 3516, 3444, 1709, 1653, 1603, 1564, 1514, 1471, 1433,

1250, 1142 cm−1; [α]D25 + 33.6 ± 0.7° (c = 1.007, MeOH) Anal.

(C23H28FNO3S.0.2H2O) Calcd. (%): C, 65.60; H, 6.80; N, 3.33; F,

4.51; S, 7.61 Found (%): C, 65.70; H, 6.70; N, 3.28; F, 4.32; S, 7.56

IIf-84

1
H-NMR (CDCl3) δ 0.95 (1H, d, J = 9.9 Hz), 1.10 (3H, s), 1.25 (3H,

s), 1.32 (3H, t, d = 7.2 Hz), 1.44-1.86 (9H, m), 2.00 (1H, m), 2.21-

2.39 (4H, m), 2.24 (2H, q, J = 7.2 Hz), 4.30 (1H, m), 6.15 (1H, m),

7.65 (1H, br d, J = 8.4 Hz), 7.76 (1H, d, J = 8.4 Hz), 7.78 (1H, s),

8.18 (1H, br s); IR (CHCl3) 3510, 3437, 1713, 1651, 1606, 1570,

1514, 1441, 1319, 1225, 1207, 1169, 1155, 1080, 1066 cm−1; [α]D24 +

26.3 ± 0.7° (c = 1.009, MeOH) Anal. (C26H34N2O5S.0.4H2O) Calcd.

(%): C, 63.24; H, 7.10; N, 5.67; S, 6.49 Found (%): C, 63.35; H,

6.88; N, 5.55; S, 6.34

[0187] The compounds prepared in Examples above were tested for determining the in vivo and in vitro activities according to the method as shown in Experimental examples below.

Experiment 1

Binding Activity to PGD2 Receptor

[0188] (1) Preparation of Human Platelet Membrane Fraction

[0189] Blood was collected using a plastic syringe containing 3.8% sodium citrate from the vein of healthy volunteers (adult male and female), then put into a plastic test tube and mixed by slow-reversion. The sample was then centrifuged at 1800 rpm, for 10 min at room temperature, and the supernatant containing PRP (platelet-rich plasma) was collected. The PRP was re-centrifuged at 2300 rpm, for 22 min at room temperature to obtain platelets. The platelets were homogenized using a homogenizer (Ultra-Turrax) followed by centrifugation 3 times at 20,000 rpm, 10 min at 4° C. to obtain a platelet membrane fraction. After protein determination, the membrane fraction was adjusted to 2 mg/ml and preserved in a refrigerator at −80° C. until using for the binding test.

[0190] (2) Binding to PGD2 Receptor

[0191] To a binding-reaction solution (50 mM Tris/HCl, pH 7.4, 5 mM MgCl2) (0.2 ml) were added the human platelet membrane fraction (0.1 mg) and 5 nM [3H]PGD2 (115 Ci/mmol), and the mixture was reacted at 4° C. for 90 min. After the reaction, the mixture was filtered through a glass fiber filter paper and washed several times with cooled physiological saline, then the radioactivity retained on the filter paper was measured. The specific-binding ratio was calculated by subtracting the non-specific binding ratio which is the radioactivity similarly measured in the presence of 10 μM PGD2 from the total binding. The inhibitory activity of each compound was expressed as the concentration required for 50% inhibition (IC50), which was determined by depicting a substitution curve by plotting the binding ratio (%) in the presence of each compound, where the binding ratio in the absence of a test compound is 100%.

Experiment 2

Evaluation of Antagonistic Activity Against PGD2 Receptor Using Human Platelet

[0192] Peripheral blood was collected from a healthy volunteer using a syringe in which 1/9 volume of a citric acid/dextrose solution was previously added. The sample was subjected to centrifugation at 1200 rpm for 10 min to obtain the supernatant (PRP: platelet rich plasma). The resultant PRP was washed 3 times with a washing buffer and the number of platelets was counted with a micro cell counter. A suspension adjusted to contain the platelets at a final concentration of 5×108/ml was warmed at 37° C., then subjected to the pre-treatment with 3-isobutyl-1-methylxanthine (0.5 mM) for 5 min. To the suspension was added a test compound diluted at various concentration, and 10 minutes later, 0.1 μM PGD2 was added to induce the reaction 2 minutes later, hydrochloric acid was added to terminate the reaction. The platelet was destroyed with an ultrasonic homogenizer. After centrifugation, the cAMP in the supernatant was determined by radioimmunoassay. PGD2 receptor antagonism of a drug was evaluated as follows: the inhibition rate regarding cAMP increased by the addition of PGD2 was determined at each concentration, and the concentration of the drug required for 50% inhibition (IC50) was calculated.

[0193] The results of Experiment 1 and 2 are shown below.

54TABLE 54Binding activity to PGD2Inhibitory activity for thereceptor in human plateletincrease of cAMP caused byCompoundmembrane fractionPGD2 in human plateletNo.IC50 (μM)IC50 (μM)Ia-170.011Ia-200.017Ia-650.018Ic-220.010Ic-230.01Ic-520.0740.01IIa-40.019IIa-170.015IIa-220.0037IIa-230.0330.0025IIa-280.016IIa-340.014IIa-520.0037IIa-540.015IIa-660.017IIc-40.018IIc-170.0054IIc-200.015IIc-220.0046IIc-230.00950.0049IIc-240.013IIc-280.013IIc-340.011IIc-520.00350.0082IIc-810.008IIc-860.008IIc-960.017IIc-970.011IIc-990.006IIc-1280.005IIc-1290.018IIc-1350.003IIe-220.0048IIe-240.0057IIe-280.017IIe-340.019IIf-840.020

Experiment 3

Change of Plasma Concentration of Drug in Rat

[0194] Compound (0.5 to 2 mg/kg) was administered intravenously to Jcl-SD male rats. The concentration of the unchanged compound was measured at 2, 5, 15, 30, 60, 120, and 240 min after the administration by the use of HPLC (determination limit; 0.05 μg/ml) and LC/MS/MS (determination limit; 0.001 μg/ml) and the half life of the disappearance was calculated.

387

55TABLE 55Half life of theCompound No.disappearance (min)Reference compound 18.0IIa-4 21.6IIc-4 44.3IIe-4 40.0Reference compound 217.0IIa-3434.6IIc-3466.7Reference compound 38.7IIa-5216.7IIc-5223.4

[0195] Industrial Applicability

[0196] The compound of the present invention represented by the formula (I) having an antagonistic activity against PGD2 receptor, is metabolically stable, and is useful in the improvement of conditions due to excessive production of PGD2.

Pgd2 receptor antagonistic pharmaceutical compositions

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