USOO595231.6A United States Patent (19) 11 Patent Number: 5,952,316 Fujita et al. (45) Date of Patent: Sep. 14, 1999

54) 2-AMINO-1,3-PROPANEDIOL COMPOUND 4-6932O 3/1992 Japan . AND IMMUNOSUPPRESSANT 4-173723 6/1992 Japan . 4-224.548 8/1992 Japan . 75 Inventors: Tetsuro Fujita, Muko; Shigeo Sasaki; 5–78294 3/1993 Japan . Masahiko Yoneta, both of Kobe; 92/16236 A2 10/1982 WIPO. Tadashi Mishina, Iruma; Kunitomo OTHER PUBLICATIONS Adachi, Iruma; Kenji Chiba, Iruma, all of Japan Merck Index, No. 460 (2-Amino-2-methyl-1,3-propane diol) p. 73 (1989). 73 Assignees: Yoshitomi Pharmaceutical Industries, Bair et al., J. Med. Chem., “1-Pyrenylmethyl)amino alco Ltd., Osaka; Taito Co., Ltd., Tokyo, hols, a New Class Antitumor DNA Intercalators. Discovery both of Japan and Initial Amine Side Chain Structure-Activity Studies”, 1990, 33, pp. 2385-2393. 21 Appl. No.: 08/911,602 Shetty et al., J. Org. Chem, Nov. 1960, pp. 2057-2059. Derwent Abstract of Japan Patent Unexamined Pub. No. 22 Filed: Aug. 14, 1997 416/1987 published Jan. 1986. Derwent abstract of Japan Patent Unexamined Pub. No. Related U.S. Application Data 192962/1984 published Nov. 1984. Merck Index, 11th Edition, No. 9684 (Tromethamine), pp. 60 Continuation of application No. 08/478,834, Jun. 7, 1995, 1536–1537 (1989). abandoned, which is a division of application No. 08/244, Derwent abstract of Japan Patent Unexamined Pub. 104087/ 942, Jun. 17, 1994, Pat. No. 5,604,229. 1989 published Apr., 1989. 30 Foreign Application Priority Data Rembarz et al., J. Prakt. Chem, 68; Vol. 37 (1-2); pp. 59–63 Oct. 21, 1992 JP Japan ...... 4-283281 (1968). Jul. 20, 1993 JP Japan ...... 5-179427 Chemical Abstracts, vol. 85, No. 23, Dec. 6, 1976, Colum bus, Ohio, U.S. abstract No. 177498z, 51) Int. Cl...... A01N 57/00; AO1N 43/60; 2,4-Di-1-aziridinyl-6-amino-s-triazines & Otkrytiya, Izo C07P 401/00; CO7P 211/00 bret., Prom. Obraztsy, Tovarnye Znaki, vol. 53, Nov. 26, 52 U.S. Cl...... 514/114; 514/119, 514/255; 1976, pp. 78-79, Malyugina, L.L. et al., & Chemical 514/357; 514/372; 514/403; 514/477; 514/438: Abstracts 9th coll. Index p. 8505cs, 1,4-Butanediol, 514/459; 514/471; 544/421; 546/210; 546/246; 2-amino-2-(hydroxymethyl). 546/247; 546/334; 548/214; 548/373; 548/516; Merck Index, No. 451 (2-Amino-2-ethyl-1,3-propanediol) 549/75; 549/426; 549/498; 560/11; 560/172; (1989). 564/336; 564/340; 564/342; 564/346; 564/374; Primary Examiner John Kight 564/383; 564/454; 564/123 Assistant Examiner Raymond Covington 58 Field of Search ...... 546/210, 246, Attorney, Agent, or Firm Wenderoth, Lind & Ponack, 546/247, 334; 560/172, 11; 556/169; 514/114, LLP. 119,357, 258,372, 403, 427, 438,459, 471; 564/336, 340, 342, 341, 374,383, 57 ABSTRACT 454, 123; 549/75, 426, 498; 548/214, 373.1, 516; 544/421 2-Amino-1,3-propanediol compounds of the formula (I) 56) References Cited (I) U.S. PATENT DOCUMENTS CHOR 3,062,839 11/1962 Shetty et al...... 260/347.7 R2R3N-C-CHORS 3,324,043 6/1967 Krum ...... 252/.401 R 3,426,042 2/1969 Hostettler et al. ... 260/340.2 3,432,603 3/1969 Zenitz...... 424/325

3,660,488 5/1972 Cobb ...... 260/584 wherein R is an optionally Substituted Straight- or branched 3,928,572 12/1975 Kluepfel et al. . ... 424/122 carbon chain, an optionally Substituted aryl, an optionally 4,910,218 3/1990 Bair ...... 514/443 substituted cycloalkyl or the like, and R. R. R' and Rare 5,068,247 11/1991 Fujita et al...... 514/440 the same or different and each is a hydrogen, an alkyl, an FOREIGN PATENT DOCUMENTS aralkyl, an acyl or an alkoxycarbonyl, pharmaceutically acceptable Salts thereof and immunosuppressants compris 0044203 A2 1/1982 European Pat. Off.. ing these compounds as active ingredients. O 450 527 A2 10/1991 European Pat. Off.. A-0 410 176 1/1992 European Pat. Off.. The 2-amino-1,3-propanediol compounds of the present 51-54565 5/1976 Japan. 55-21366 2/1982 Japan. invention show immunosuppressive action and are useful for 57-156459 9/1982 Japan. Suppressing rejection in organ or bone marrow tranplanta 58-101108 6/1983 Japan. tion, prevention and treatment of autoimmune diseases or as 63-2904 1/1988 Japan. reagents for use in medicinal and pharmaceutical fields. 63-43140 2/1988 Japan. 4-9309 1/1992 Japan. 8 Claims, No Drawings 5,952,316 1 2 2-AMINO-1,3-PROPANEDIOL COMPOUND An object of the present invention is to provide novel AND IMMUNOSUPPRESSANT 2-amino-1,3-propanediol compounds having Superior immunosuppressive action with leSS Side effects. This application is a continuation of now abandoned application, Ser. No. 08/478,834, filed Jun. 7, 1995, now 5 DISCLOSURE OF THE INVENTION abandoned, which is a divisional of Ser. No. 08/244.942 The present invention relates to filed Jun. 17, 1994, now U.S. Pat. No. 5,604,229. (1) a 2-amino-1,3-propanediol compound of the formula TECHNICAL FIELD (I) The present invention relates to 2-amino-1,3-propanediol 1O CHOR compounds useful as pharmaceuticals, particularly as an 23 5 immunosuppressant. R-R-N-C-CHOR R BACKGROUND ART 15 In recent years, cycloSporin is in use for Suppressing wherein rejection developed in transplanting organs. Inclusive of the R is an optionally Substituted Straight- or branched carbon compounds currently under development, the So-called chain which may have, in the chain, a bond, a hetero immunosuppressants are expected to be useful as therapeutic atom or a group Selected from the group consisting of agents for articular rheumatism and So on. Said cycloSporin, 20 a double bond, a triple bond, Oxygen, Sulfur, Sulfinyl, however, also poses problems of Side effects Such as renal Sulfonyl, -N(R)- where R is hydrogen, alkyl, disorders. aralkyl, acyl or alkoxycarbonyl, carbonyl, optionally Meanwhile, Japanese Patent Unexamined Publication No. Substituted arylene, optionally Substituted 104087/1989 discloses that an immunosuppressive Sub- cycloalkylene, optionally Substituted heteroarylene and stance is obtained from a liquid culture of Isaria Sinclairii an alicycle thereof, and which may be Substituted, at and said substance has been confirmed to be (2S,3R,4R)- the chain end thereof, by a double bond, a triple bond, (E)-2-amino-3,4-dihydroxy-2-hydroxymethyl-14-oxoicosa- optionally Substituted aryl, optionally Substituted 6-enoic acid of the formula cycloalkyl, optionally Substituted heteroaryl or an ali

NH2 OH HOHC-C-CH-CH-CH-CH=CH-(CH2) - C-(CH2)5- CH, CO2H OH disclosed in U.S. Pat. No. 3,928,572. In addition, Japanese cycle thereof, an optionally Substituted aryl, an option Patent Unexamined Publication No. 128347/1991 States that ally Substituted cycloalkyl, an optionally Substituted a Series of Said compound has an immunosuppressive action. heteroaryl or an alicycle thereof, and Referring to Merck Index, 11th edition, it is described that 40 R. R. R' and Rare the same or different and each is a 2-amino-2-methyl-1,3-propanediol (Index No. 460), hydrogen, an alkyl, an aralkyl, an acyl or an 2-amino-2-ethyl-1,3-propanediol (Index No. 451) and alkoxycarbonyl, or R' and R may be bonded to form 2-amino-2-hydroxymethyl-1,3-propanediol (also called an alkylene chain which may be Substituted by alkyl, tromethamine, Index No. 9684) can be used as surfactants, aryl or aralkyl, intermediates for. pharmaceuticals, emulsifiers orgas adsor- 5 wherein the optionally substituted straight- or branched bents and that tromethamine is medically usable as an carbon chain may have a Substituent Selected from the group alkalization agent. In Japanese Patent Unexamined Publica- consisting of alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, tion No. 416/1987, a hair dye containing 2-amino-2-(C1-C5 alkylenedioxy, acyl, alkylamino, alkylthio, acylamino, alkyl)-1,3-propanediol is disclosed. U.S. Pat. No. 4,910.218 alkoxycarbonyl, alkoxycarbonylamino, acyloxy, and J. Med. Chem., Vol. 33, 2385-2393 (1990) teach 50 alkylcarbamoyl, haloalkyl, haloalkoxy, nitro, halogen, 2-amino-2-(methyl or ethyl)-1,3-propanediol as an interme- amino, hydroxyimino, hydroxy, carboxy, optionally Substi diate for an antitumor agent. Also, Japanese Patent Unex- tuted aryl, optionally Substituted aryloxy, optionally Substi amined Publication No. 192962/1984 teaches that the afore- tuted cycloalkyl, optionally Substituted heteroaryl and an mentioned 2-amino-2-(C1-C5 alkyl)-1,3-propanediol or alicycle thereof; the aforementioned optionally Substituted 2-amino-1,3-propanediol can be used as a stabilizer for an is arylene, optionally Substituted cycloalkylene, optionally antigen or antibody-Sensitized latex reagent. Moreover, U.S. Pat. No. 3,062,839 teaches 2-methyl- or ethyl-amino-2- Substituted heteroarylene and an alicycle thereof may have (furylmethyl, phenylmethyl or phenylmethyl substituted by a Substituent Selected from the group consisting of alkoxy, lower alkyl, lower alkoxy, chloro, hydroxy or unsubstituted alkenyloxy, alkynyloxy, aralkyloxy, alkylenedioxy, acyl, amine)-1,3-propanediol having a tranquilizer action and J. alkylamino, alkylthio, acylamino, alkoxycarbonyl, Org. Chem., vol. 25, 2057-2059 (1960) teaches 60 alkoxycarbonylamino, acyloxy, alkylcarbamoyl, haloalkyl, 2-methylamino-2-(phenylmethyl or phenylmethyl substi- haloalkoxy, nitro, halogen, amino, hydroxy and carboxy; tuted by 2-methyl, 3-methyl, 4-methyl, 4-methoxy or and the optionally Substituted aryl, optionally Substituted 4-hydroxy)-1,3-propanediol. It is not known, however, that aryloxy, optionally Substituted cycloalkyl, optionally Substi these compounds have immunosuppressive actions Such as tuted heteroaryl and an alicycle thereof may have a Sub suppression of rejection developed in organ transplantation, 65 stituent Selected from the group consisting of alkyl, alkoxy, prevention and treatment of autoimmune diseases and the alkenyloxy, alkynyloxy, aralkyloxy, alkylenedioxy, acyl, like. alkylamino, alkylthio, acylamino, alkoxycarbonyl, 5,952,316 3 alkoxycarbonylamino, acyloxy, alkylcarbamoyl, haloalkyl, haloalkoxy, nitro, halogen, amino, hydroxy and carboxy, (I-2) provided that when R is C1-C5 alkyl, the alkyl should be CHOR'a substituted and when R is furylmethyl, phenylmethyl or phenylmethyl substituted by lower alkyl, lower alkoxy, RaRaN-C-CHOR a chloro, hydroxy or amino, one of R and R is not methyl or CHR a ethyl, and a pharmaceutically acceptable Salt thereof; (2) a 2-amino-1,3-propanediol compound according to the above-mentioned (1), having the formula wherein 1O R'a is an optionally substituted Straight- or branched carbon chain which may have, in the chain, a bond, a (I-1) hetero atom or a group Selected from the group con CHOR Sisting of a double bond, a triple bond, oxygen, Sulfur, R2R3N- - CHORS sulfinyl, Sulfonyl, -N(R)- where R is hydrogen, 15 alkyl, aralkyl, acyl or alkoxycarbonyl, carbonyl, CHR optionally Substituted phenylene and optionally Substi tuted cycloalkylene, an optionally Substituted phenyl or an optionally Substituted cycloalkyl, and wherein Ra, Ra, R'a and Ra are the same or different and each is a hydrogen, an alkyl, an acyl or an alkoxycarbonyl, R" is an optionally substituted straight- or branched wherein the optionally Substituted phenyl and optionally carbon chain which may have, in the chain, a bond, a Substituted cycloalkyl may have a Substituent Selected from hetero atom or a group Selected from the group con the group consisting of optionally Substituted Straight- or Sisting of a double bond, a triple bond, oxygen, Sulfur, branched carbon chain which may have, in the chain, a bond, sulfinyl, Sulfonyl, -N(R)- where R is hydrogen, a hetero atom or a group Selected from the group consisting alkyl, aralkyl, acyl or alkoxycarbonyl, carbonyl, 25 of a double bond, a triple bond, oxygen, Sulfur, Sulfinyl, optionally Substituted arylene, optionally Substituted sulfonyl, -N(R)- where R is hydrogen, alkyl, aralkyl, cycloalkylene, optionally Substituted heteroarylene and acyl or alkoxycarbonyl, carbonyl, optionally Substituted an alicycle thereof, and which may be Substituted, at phenylene and optionally Substituted cycloalkylene; alkoxy, the chain end (co-position) thereof, by a double bond, a alkenyloxy, alkynyloxy, aralkyloxy, alkylenedioxy, acyl, triple bond, optionally Substituted aryl, optionally Sub alkylamino, alkylthio, acylamino, alkoxycarbonyl, Stituted cycloalkyl, optionally Substituted heteroaryl or alkoxycarbonylamino, acyloxy, alkylcarbamoyl, haloalkyl, an alicycle thereof, an optionally Substituted aryl, an nitro, halogen, amino, hydroxy, carboxy, optionally Substi optionally Substituted cycloalkyl, an optionally Substi tuted phenyl, optionally Substituted phenoxy and optionally tuted heteroaryl or an alicycle thereof; and Substituted cycloalkyl, the optionally Substituted carbon 35 chain may have a Substituent Selected from the group R. R. R' and Rare the same or different and each is a consisting of alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, hydrogen, an alkyl, an aralkyl, an acyl or an alkylenedioxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, or R' and R may be bonded to form alkoxycarbonyl, alkoxycarbonylamino, acyloxy, an alkylene chain which may be Substituted by alkyl, aryl or aralkyl, alkylcarbamoyl, haloalkyl, nitro, halogen, amino, hydroxy, 40 carboxy, optionally Substituted phenyl, optionally Substi wherein the optionally Substituted Straight- or branched tuted phenoxy and optionally Substituted cycloalkyl, and the carbon chain may have a Substituent Selected from the group aforementioned optionally Substituted phenylene, optionally consisting of alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, Substituted cycloalkylene, optionally Substituted phenyl, alkylenedioxy, acyl, alkylamino, alkylthio, acylamino, optionally Substituted phenoxy and optionally Substituted alkoxycarbonyl, alkoxycarbonylamino, acyloxy, 45 cycloalkyl may have a Substituent Selected from the group alkylcarbamoyl, haloalkyl, haloalkoxy, nitro, halogen, consisting of alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, amino, hydroxyimino, hydroxy, carboxy, optionally Substi alkylenedioxy, acyl, alkylamino, alkylthio, acylamino, tuted aryl, optionally Substituted aryloxy, optionally Substi alkoxycarbonyl, alkoxycarbonylamino, acyloxy, tuted cycloalkyl, optionally Substituted heteroaryl and an alkylcarbamoyl, haloalkyl, nitro, halogen, amino, hydroxy alicycle thereof; and the aforementioned optionally Substi 50 and carboxy; provided that when R'a is C1-C4 alkyl, the tuted arylene, optionally Substituted cycloalkylene, option alkyl should be substituted and when R'a is furyl, phenyl or ally Substituted heteroarylene, an alicycle thereof, optionally phenyl Substituted by lower alkyl, lower alkoxy, chloro, Substituted aryl, optionally Substituted aryloxy, optionally hydroxy or amino, one of Ra and Ra is not methyl or ethyl, Substituted cycloalkyl, optionally Substituted heteroaryland and a pharmaceutically acceptable Salt thereof; an alicycle thereof may have a Substituent Selected from the (4) a 2-amino-1,3-propanediol compound according to the group consisting of alkoxy, alkenyloxy, alkynyloxy, 55 aralkyloxy, alkylenedioxy, acyl, alkylamino, alkylthio, above-mentioned (3), having the formula acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, haloalkyl, haloalkoxy, nitro, halogen, (I-3) amino, hydroxy and carboxy, CHOR'b provided that when R is C1-C4 alkyl, the alkyl should be 60 R2bRibN- – CHORb substituted and when R' is furyl, phenyl or phenyl substi tuted by lower alkyl, lower alkoxy, chloro, hydroxy or CHRib amino, one of R and R is not methyl or ethyl, and a pharmaceutically acceptable Salt thereof; 65 wherein (3) a 2-amino-1,3-propanediol compound according to the Rb is an optionally substituted alkyl, an optionally sub above-mentioned (1) or (2), having the formula Stituted alkenyl, an optionally Substituted alkynyl, an 5,952,316 S 6 optionally Substituted phenyl or an optionally Substi (7) a 2-amino-1,3-propanediol compound according to the tuted cycloalkyl, and above-mentioned (5) or (6), having the formula Rb, Rb, R"b and R b are the same or different and each is a hydrogen, an alkyl or an acyl, (I-6) wherein the optionally Substituted alkyl, optionally Substi tuted alkenyl and optionally Substituted alkynyl may have a CH2OH Substituent Selected from the group consisting of alkoxy, HN-C-CH-OH alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, a cylam in O, alko Xy carbonyl, Rc alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, 1O halogen, amino, hydroxy, carboxy, optionally Substituted phenyl and optionally Substituted cycloalkyl, and the afore wherein mentioned optionally Substituted phenyl and optionally Sub Rc is a straight- or branched chain alkyl having 13 to 20 stituted cycloalkyl may have 1 to 3 substituents selected carbon atoms or a Straight- or branched chain alkyl from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, 15 having 13 to 20 carbon atoms which is substituted by alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, halogen, and a pharmaceutically acceptable Salt alkylthio, a cylam in O, alko Xy carbonyl, thereof; alkoxycarbonylamino, acyloxy, alkylcarbamoyl, haloalkyl, (8) a 2-amino-1,3-propanediol compound according to the nitro, halogen, amino, hydroxy and carboxy; provided that above-mentioned (5), (6) or (7), which is selected from when Rb is C1-C4 alkyl, the alkyl should be substituted and 2-amino-2-tridecyl-1,3-propanediol, 2-amino-2-tetradecyl when R'b is furyl, phenyl or phenyl substituted by lower 1,3-propanediol, 2-amino-2-pentadecyl-1,3-propanediol, alkyl, lower alkoxy, chloro, hydroxy or amino, one of Rib 2-amino-2-hexadecyl-1,3-propanediol, 2-amino-2- and Rib is not methyl or ethyl, and a pharmaceutically heptadecyl-1,3-propanediol, 2-amino-2-octadecyl-1,3- acceptable Salt thereof; propanediol, 2-amino-2-nonadecyl-1,3-propanediol, (5) a 2-amino-1,3-propanediol compound according to the 25 2-amino-2-icosyl-1,3-propanediol, 2-amino-2-(12 above-mentioned (1), (2), (3) or (4), having the formula fluorododecyl)-1,3-propanediol and 2-amino-2-(14 fluorotetradecyl)-1,3-propanediol, and a pharmaceutically (I-4) acceptable Salt thereof; CHOR'b (9) a 2-amino-1,3-propanediol compound according to the RbRibN-C-CHORb above-mentioned (1), (2), (3) or (4), having the formula Ra (I-7) CH2OH wherein 35 Ra is a Straight- or branched chain alkyl having 12 to 22 HN-C-CH-OH carbon atoms, which may have, in the chain, a bond or Rd a hetero atom Selected from the group consisting of a double bond, a triple bond, oxygen, Sulfur, Sulfinyl, Sulfonyl, -N(R)- where R is hydrogen, alkyl, 40 wherein aralkyl, acyl or alkoxycarbonyl, and carbonyl, and Rd is a phenylalkyl, a Substituted phenylalkyl, a which may have, as a Substituent, alkoxy, alkenyloxy, cycloalkylalkyl, a Substituted cycloalkylalkyl, a alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, heteroarylalkyl, a Substituted heteroarylalkyl, a hetero acylamino, alkoxycarbonyl, alkoxycarbonylamino, cyclic alkyl or a Substituted heterocyclic alkyl, wherein acyloxy, alkylcarbamoyl, nitro, halogen, amino, 45 hydroxyimino, hydroxy or carboxy, and the alkyl moiety may have, in the carbon chain, a bond or a hetero atom Selected from the group consisting of Rb, Rb, Rb and Rib are the same or different and each a double bond, a triple bond, Oxygen, Sulfur, Sulfinyl, is a hydrogen, an alkyl or an acyl, and a pharmaceuti Sulfonyl, -N(R)- where R is hydrogen, alkyl, cally acceptable Salt thereof; aralkyl, acyl or alkoxycarbonyl, and carbonyl, and may (6) a 2-amino-1,3-propanediol compound according to the 50 have, as a Substituent, alkoxy, alkenyloxy, alkynyloxy, above-mentioned (5), having the formula aralkyloxy, acyl, alkylamino, alkylthio, acylamino, (I-5) alkoxycarbonyl, alkoxycarbonylamino, acyloxy, CH2OH alkylcarbamoyl, nitro, halogen, amino, hydroxy or car 55 boxy; and the substituted phenylalkyl, Substituted ReRicN-C-CHOH cycloalkylalkyl, Substituted heteroarylalkyl and Substi tuted heterocyclic alkyl may have a Substituent Selected Rb from the group consisting of alkyl, alkoxy, alkenyloxy, alky nyloxy, a ralkyl oxy, haloar alkyl oxy, wherein 60 aralkyloxyalkyl, phenoxyalkyl, phenoxyalkoxy, Rb is a straight- or branched chain alkyl having 13 to 20 alkylenedioxy, acyl, alkylamino, alkylthio, acylamino, carbon atoms, which may have, in the chain, an oxygen alkoxycarbonyl, alkoxycarbonylamino, acyloxy, atom and which may have, as a Substituent, nitro, alkylcarbamoyl, haloalkyl, haloalkoxy, nitro, halogen, halogen, amino, hydroxy or carboxy, and amino, hydroxy and carboxy, and a pharmaceutically R°c and Ric are the same or different and each is a 65 acceptable Salt thereof; hydrogen or an alkyl, and a pharmaceutically accept (10) a 2-amino-1,3-propanediol compound according to able Salt thereof; the above-mentioned (9), having the formula 5,952,316 8 have, in the carbon chain, one or two oxygen atoms, a (I-8) heteroarylalkyl Substituted by a straight- or branched chain alkyl having 6 to 20 carbon atoms, a heterocyclic CH2OH alkyl wherein the alkyl moiety is a Straight- or branched HN-C-CHOH chain having 6 to 20-carbon atoms which may have, in the carbon chain, one or two oxygen atoms, or a Re heterocyclic alkyl Substituted by a Straight- or branched chain alkyl having 6 to 20 carbon atoms, wherein wherein the alkyl moiety may have, in the carbon chain, a Re is a phenylalkyl wherein the alkyl moiety is a Straight Substituent Selected from the group consisting of alkoxy, or branched chain having 6 to 20 carbon atoms, a alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, phenylalkyl which may be substituted by a straight- or alkylthio, a cylamino, alko Xy carbonyl, branched chain C6-C20 alkyl optionally substituted by alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, a Straight- or branched chain C6-C20 alkoxy halogen, amino, hydroxy and carboxy, and a pharmaceuti optionally Substituted by halogen, a Straight- or 15 cally acceptable Salt thereof; branched chain C6-C20 alkenyloxy, phenylalkoxy, (12) a 2-amino-1,3-propanediol compound according to halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy the above-mentioned (9), (10) or (11), having the formula or phenoxyalkyl, a cycloalkylalkyl wherein the alkyl moiety is a Straight- or branched chain having 6 to 20 (I-10) carbon atoms, a cycloalkylalkyl Substituted by a CH2OH Straight- or branched chain alkyl having 6 to 20 carbon atoms, a heteroarylalkyl wherein the alkyl moiety is a HN-C-CHOH Straight- or branched chain having 6 to 20 carbon Rg atoms, a heteroarylalkyl Substituted by a Straight- or branched chain alkyl having 6 to 20 carbon atoms, a 25 heterocyclic alkyl wherein the alkyl moiety is a wherein Straight- or branched chain having 6 to 20 carbon Rg is a phenylalkyl wherein the alkyl moiety is a Straight atoms, or a heterocyclic alkyl Substituted by a Straight or branched chain having 6 to 20 carbon atoms which or branched chain alkyl having 6 to 20 carbon atoms, may have, in the carbon chain, one or two oxygen wherein the alkyl moiety may have, in the carbon chain, a atoms, a phenylalkyl which may be Substituted by a bond or a hetero atom Selected from the group consisting of straight- or branched chain C6-C14 alkyl optionally a double bond, a triple bond, oxygen, Sulfur, Sulfinyl, Substituted by halogen, a Straight- or branched chain Sulfonyl, -N(R)- where R is hydrogen, alkyl, aralkyl, C6-C14 alkoxy optionally Substituted by halogen, a acyl or alkoxycarbonyl, and carbonyl, and may have, as a Straight- or branched chain C6-C14 alkenyloxy, Substituent, alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, 35 phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, phenoxyalkoxy or phenoxyalkyl, a cycloalkylalkyl alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, wherein the alkyl moiety has 6 to 20 carbon atoms; a halogen, amino, hydroxy or carboxy, and a pharmaceutically cycloalkylalkyl Substituted by a Straight- or branched acceptable Salt thereof; chain alkyl having 6 to 14 carbon atoms, a heteroary (11) a 2-amino-1,3-propanediol compound according to 40 lalkyl wherein the alkyl moiety has 6 to 20 carbon the above-mentioned (9) or (10), having the formula atoms, a heteroarylalkyl Substituted by a Straight- or branched chain alkyl having 6 to 14 carbon atoms, a (I-9) heterocyclic alkyl wherein the alkyl moiety has 6 to 20 CH2OH carbon atoms, or a heterocyclic alkyl Substituted by a 45 Straight- or branched chain alkyl having 6 to 14 carbon HN-C-CHOH atoms, and a pharmaceutically acceptable Salt thereof; (13) a 2-amino-1,3-propanediol compound according to Rf the above-mentioned (12), having the formula wherein 50 (I-11) Rf is a phenylalkyl wherein the alkyl moiety is a Straight CH2OH or branched chain having 6 to 20 carbon atoms which may have, in the carbon chain, one or two oxygen HN-C-CHOH atoms, a phenylalkyl which may be Substituted by a straight- or branched chain C6-C20 alkyl optionally 55 Substituted by halogen, a Straight- or branched chain C6-C20 alkoxy optionally substituted by halogen, a wherein straight- or branched chain C6-C20 alkenyloxy, Rh is a phenylalkyl wherein the alkyl moiety has 6 to 20 phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, carbon atoms, a phenylalkoxyalkyl wherein the alkyl phenoxyalkoxy or phenoxyalkyl, a cycloalkylalkyl 60 moiety and alkoxy moiety have 6 to 20 carbon atoms in wherein the alkyl moiety is a Straight- or branched total, a phenoxyalkyl wherein the alkyl moiety has 6 to chain having 6 to 20 carbon atoms which may have, in 20 carbon atoms or a phenoxyalkoxyalkyl wherein the the carbon chain, one or two oxygen atoms, a alkyl moiety and alkoxy moiety have 6 to 20 carbon cycloalkylalkyl Substituted by a Straight- or branched atoms in total, and a pharmaceutically acceptable Salt chain alkyl having 6 to 20 carbon atoms, a heteroary 65 thereof; lalkyl wherein the alkyl moiety is a Straight- or (14) a 2-amino-1,3-propanediol compound according to branched chain having 6 to 20 carbon atoms which may the above-mentioned (13), which is selected from the group 5,952,316 9 10 consisting of 2-amino-2-(8-phenyloctyl)-1,3-propanediol, propanediol, 2-amino-2-2-(4-undecylphenyl)ethyl-1,3- 2-amino-2-(9-phenylnonyl)-1,3-propanediol, 2-amino-2- propanediol, 2-amino-2-2-(4-dodecylphenyl)ethyl-1,3- (10-phenyldecyl)-1,3-propanediol, 2-amino-2-(11 propanediol, 2-amino-2-2-(4-tridecylphenyl)ethyl-1,3- phenylundecyl)-1,3-propanediol, 2-amino-2-(12 propanediol, 2-amino-2-2-(4-tetradecylphenyl)ethyl-1,3- phenyldodecyl)-1,3-propanediol, 2-amino-2-(13 propanediol, 2-amino-2-2-(4-hexyloxyphenyl)ethyl-1,3- phenyltride cyl)-1,3-propanediol, 2-amino-2-(14 propanediol, 2-amino-2-2-(4-heptyloxyphenyl)ethyl-1,3- phenyltetradecyl)-1,3-propanediol, 2-amino-2-(15 propanediol, 2-amino-2-2-(4-octyloxyphenyl)ethyl-1,3- phenylpentadecyl)-1,3-propanediol, 2-amino-2-(16 propanediol, 2-amino-2-2-(4-nonyloxyphenyl)ethyl-1,3- phenylhexadecyl)-1,3-propanediol, 2-amino-2-6-(8- propanediol, 2-amino-2-2-(4-decyloxyphenyl)ethyl-1,3- phenyloctyloxy) hexyl-1,3-propanediol, 2-amino-2-(8- propanediol, 2-amino-2-2-(4-undecyloxyphenyl)ethyl-1, phenylmethyloxyoctyl)-1,3-propanediol, 2-amino-2-(9- 3-propanediol, 2-amino-2-2-(4-dodecyloxyphenyl)ethyl phenoxynonyl)-1,3-propanediol, 2-amino-2-(12 1,3-propanediol, 2-amino-2-2-(4-tridecyloxyphenyl)ethyl phenoxydodecyl)-1,3-propanediol and 2-amino-2-6-(2- 1,3-propanediol, 2-amino-2-2-(4-(8-fluorooctyl)phenyl) phenoxyethyloxy) hexyl-1,3-propanediol, and a ethyl-1,3-propanediol, 2-amino-2-2-(4-(12-fluorododecyl) pharmaceutically acceptable Salt thereof; 15 phenyl)ethyl-1,3-propanediol, 2-amino-2-2-(4-(7- (15) a 2-amino-1,3-propanediol compound according to fluoroheptyloxy)phenyl)ethyl-1,3-propanediol, 2-amino-2- the above-mentioned (13) which is selected from the group 2-(4-(11-fluoroundecyloxy)phenyl)ethyl-1,3-propanediol consisting of 2-amino-2-(10-phenyldecyl)-1,3-propanediol, and 2-amino-2-2-(4-(7-octenyloxy)phenyl)ethyl-1,3- 2-amino-2-(13-phenyltridecyl)-1,3-propanediol, 2-amino-2- propanediol, and a pharmaceutically acceptable Salt thereof; 6-(8-phenyloctyloxy)hexyl-1,3-propanediol, 2-amino-2- (19) a 2-amino-1,3-propanediol compound according to (8-phenylmethyloxyoctyl)-1,3-propanediol, 2-amino-2-(9- the above-mentioned (16) or (17), which is selected from the phenoxynonyl)-1,3-propanediol, 2-amino-2-(12 group consisting of 2-amino-2-2-(4-heptylphenyl)ethyl-1, phenoxydodecyl)-1,3-propanediol and 2-amino-2-6-(2- 3-propanediol, 2-amino-2-2-(4-octylphenyl)ethyl-1,3- phenoxyethyloxy) hexyl-1,3-propanediol, and a propanediol, 2-amino-2-2-(4-nonylphenyl)ethyl-1,3- pharmaceutically acceptable Salt thereof; 25 propanediol, 2-amino-2-2-(4-decylphenyl)ethyl-1,3- (16) a 2-amino-1,3-propanediol compound according to propanediol, 2-amino-2-2-(4-undecylphenyl)ethyl-1,3- the above-mentioned (12), having the formula propanediol, 2-amino-2-2-(4-dodecylphenyl)ethyl-1,3- propanediol, 2-amino-2-2-(4-heptyloxyphenyl)ethyl-1,3- (I-12) propanediol, 2-amino-2-2-(4-octyloxyphenyl)ethyl-1,3- propanediol, 2-amino-2-2-(4-nonyloxyphenyl)ethyl-1,3- CH2OH propanediol, 2-amino-2-2-(4-undecyloxyphenyl)ethyl-1, HN-C-CH-OH 3-propanediol and 2-amino-2-2-(4-(7-octenyloxy)phenyl) R ethyl-1,3-propanediol, and a pharmaceutically acceptable Salt thereof; 35 (20) a 2-amino-1,3-propanediol compound according to wherein the above-mentioned (12), having the formula Ri is a phenylalkyl substituted by a straight- or branched chain C6-C14 alkyl optionally substituted by halogen, (I-14) a Straight- or branched chain C6-C14 alkoxy optionally CH2OH Substituted by halogen or a Straight- or branched chain 40 C6-C14 alkenyloxy; HN-C-CHOH wherein the alkyl moiety of phenylalkyl may be substituted by hydroxy, and a pharmaceutically acceptable Salt thereof; Rk (17) a 2-amino-1,3-propanediol compound according to the above-mentioned (16), having the formula 45 wherein Rk is a phenylalkyl substituted by phenylalkoxy, (I-13) halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy CH2OH or phenoxyalkyl, and a pharmaceutically acceptable Salt thereof; HN-C-CHOH 50 (21) a 2-amino-1,3-propanediol compound according to Ri the above-mentioned (20), having the formula (I-15) wherein CH2OH R is a phenylalkyl Substituted by a Straight- or branched 55 chain C6-C14 alkyl optionally substituted by halogen, HN-C-CHOH a Straight- or branched chain C6-C14 alkoxy optionally Substituted by halogen or a Straight- or branched chain R C6-C14 alkenyloxy, wherein the alkyl moiety is a C2-C6 alkyl optionally substituted by hydroxy, and a 60 wherein pharmaceutically acceptable Salt thereof; R1 is a phenylalkyl substituted by phenylalkoxy wherein (18) a 2-amino-1,3-propanediol compound according to the alkoxy moiety has 2 to 8 carbon atoms, halophe the above-mentioned (16) or (17), which is selected from the nylalkoxy wherein the alkoxy moiety has 2 to 8 carbon group consisting of 2-amino-2-2-(4-heptylphenyl)ethyl-1, atoms, phenylalkoxyalkyl wherein the alkoxy moiety 3-propanediol, 2-amino-2-2-(4-octylphenyl)ethyl-1,3- 65 and alkyl moiety have 2 to 8 carbon atoms in total, propanediol, 2-amino-2-2-(4-nonylphenyl)ethyl-1,3- phenoxyalkoxy wherein the alkoxy moiety has 2 to 8 propanediol, 2-amino-2-2-(4-decylphenyl)ethyl-1,3- carbon atoms or phenoxyalkyl wherein the alkyl moiety 5,952,316 11 12 has 2 to 8 carbon atoms, where the alkyl moiety has 2 to 6 carbon atoms, and a pharmaceutically acceptable (I-17) Salt thereof; CH2OH (22) a 2-amino-1,3-propanediol compound according to the above-mentioned (20) or (21), which is selected from the HN-C-CHOH group consisting of 2- a mino-2-2-(4- Rn phenylmethyloxyphenyl)ethyl-1,3-propanediol, 2-amino 2-2-(4-(2-phenylethyloxy)phenyl)ethyl-1,3-propanediol, wherein 2-amino-2-2-(4-(3-phenylpropyloxy)phenyl)ethyl-1,3- Rn is a 1-alkyl-substituted piperidin-4-ylalkyl wherein the propanediol, 2-amino-2-2-(4-(4-phenylbutyloxy)phenyl) alkyl moiety has 6 to 20 carbon atoms in total, and a ethyl-1,3-prop a ne diol, 2-amino-2-2-(4-(5- pharmaceutically acceptable Salt thereof; phenylpentyloxy)phenyl)ethyl-1,3-propanediol, 2-amino (27) a 2-amino-1,3-propanediol compound according to 2-2-(4-(6-phenylhexyloxy)phenyl)ethyl-1,3-propanediol, the above-mentioned (26), which is selected from the group 2-amino-2-2-(4-(7-phenylheptyloxy)phenyl)ethyl-1,3- 15 consisting of 2-amino-2-2-(1-octylpiperidin-4-yl)ethyl-1, propanediol, 2-amino-2-2-(4-(8-phenyloctyloxy)phenyl) 3-propanediol and 2-amino-2-2-(1-dodecylpiperidin-4-yl) ethyl-1,3-propanediol, 2-amino-2-4-(6-(4-fluorophenyl) ethyl-1,3-propanediol, and a pharmaceutically acceptable hexyloxy)phenyl)ethyl-1,3-propanediol, 2-amino-2-2-(4- Salt thereof; (5-phenylpentyloxymethyl)phenyl)ethyl-1,3-propanediol, (28) a 2-amino-1,3-propanediol compound according to 2-amino-2-2-(4-(4-phenoxybutyloxy)phenyl)ethyl-1,3- the above-mentioned (12), having the formula propanediol, 2-amino-2-2-(4-(5-phenoxypentyloxy) phenyl)ethyl-1,3-propanediol, 2-amino-2-2-(4-(6- (I-18) phenoxyhexyloxy)phenyl)ethyl-1,3-propanediol, 2-amino CH2OH 2-2-(4-(7-phenoxyheptyloxy)phenyl)ethyl-1,3- 25 HN-C-CH-OH propanediol, 2-amino-2-2-(4-(4-phenoxybutyl)phenyl) RO ethyl-1,3-propanediol, 2-amino-2-2-(4-(5-phenoxypentyl) phenyl)ethyl-1,3-propanediol, 2-amino-2-2-(4-(6- phenoxyhexyl)phenyl)ethyl-1,3-propanediol and 2-amino wherein 2-2-(4-(7-phenoxyheptyl)phenyl)ethyl-1,3-propanediol, Ro is a thienylalkyl wherein the alkyl moiety has 6 to 20 and a pharmaceutically acceptable Salt thereof; carbon atoms, an alkyl-Substituted thienylalkyl wherein the alkyl moiety has 6 to 20 carbon atoms in total, (23) a 2-amino-1,3-propanediol compound according to pyridylalkyl wherein the alkyl moiety has 6 to 20 the above-mentioned (20) or (21) which is selected from the carbon atoms or an alkyl-Substituted pyridylalkyl group consisting of 2-amino-2-2-(4-(6-phenylhexyloxy) 35 wherein the alkyl moiety has 6 to 20 carbon atoms in phenyl)ethyl-1,3-propanediol and 2-amino-2-2-(4-(5- total, and a pharmaceutically acceptable Salt thereof; phenylpentyloxymethyl)phenyl)ethyl-1,3-propanediol, and (29) a 2-amino-1,3-propanediol compound according to a pharmaceutically acceptable Salt thereof; the above-mentioned (28), which is selected from the group (24) a 2-amino-1,3-propanediol compound according to consisting of 2-amino-2-2-(5-octyl-2-thienyl)ethyl-1,3- 40 propanediol, 2-amino-2-2-(5-nonyl-2-thienyl)ethyl-1,3- the above-mentioned (12), having the formula propanediol, 2-amino-2-2-(5-decyl-2-thienyl)ethyl-1,3- propanediol, 2-amino-2-2-(5-dodecyl-2-thienyl)ethyl-1,3- (I-16) propanediol, 2-amino-2-13-(2-thienyl)tride cyl-1,3- CH2OH propanediol, 2-amino-2-2-(5-octyl-2-pyridyl)ethyl-1,3- 45 propanediol, 2-amino-2-2-(5-decyl-2-pyridyl)ethyl-1,3- HN-C-CH-OH propanediol, 2-amino-2-13-(2-pyridyl)tridecyl-1,3- Rm propanediol, 2-amino-2-2-(2-octyl-5-pyridyl)ethyl-1,3- propanediol, 2-amino-2-2-(2-decyl-5-pyridyl)ethyl-1,3- 50 propanediol and 2-amino-2-13-(3-pyridyl)tridecyl-1,3- wherein propanediol, and a pharmaceutically acceptable Salt thereof; (30) a 2-amino-1,3-propanediol compound according to Rm is an alkyl-substituted cycloalkylalkyl wherein the the above-mentioned (1) or (2), having the formula alkyl moiety has 6 to 20 carbon atoms in total, and a pharmaceutically acceptable Salt thereof; 55 (I-19) (25) a 2-amino-1,3-propanediol compound according to CH2OH the above-mentioned (24), which is selected from the group HN-C-CHOH consisting of 2-amino-2-3-(4-heptylcyclohexyl)propyl-1, 3-propanediol, 2-amino-2-4-(4-butylcyclohexyl)butyl-1,3- Rp propanediol, 2-amino-2-2-(4-octylcyclohexyl)ethyl-1,3- 60 propanediol, 2-amino-2-2-(4-nonylcyclohexyl)ethyl-1,3- wherein propanediol and 2-amino-2-2-(4-dodecylcyclohexyl)ethyl Rp is a phenyl substituted by C6-C18 alkyl, a cycloalkyl, 1,3-propanediol, and a pharmaceutically acceptable Salt a heteroaryl or a heterocycle, and a pharmaceutically thereof; 65 acceptable Salt thereof; (26) a 2-amino-1,3-propanediol compound according to (31) a 2-amino-1,3-propanediol compound according to the above-mentioned (12), having the formula the above-mentioned (30), having the formula 5,952,316 13 14 (34) a 2-amino-1,3-propanediol compound according to (I-20) the above-mentioned (33), having the formula CH2OH (I-22) HN-C-CHOH CH2OH HN-C-CHOH wherein CHOH)Rr Rq is a phenyl substituted by C6-C18 alkyl, and a 1O pharmaceutically acceptable Salt thereof; (32) a 2-amino-1,3-propanediol compound according to wherein the above-mentioned (30) or (31), which is selected from the group consisting of 2-amino-2-(4-decylphenyl)-1,3- propane diol, 2-amino-2-(4-do de cylphenyl)-1,3- Rr is an alkyl optionally substituted by hydroxy and/or propanediol, 2-amino-2-(4-tetradecylphenyl)-1,3- 15 hydroxyimino which may have, in the chain, a double propanediol and 2-amino-2-(4-hexadecylphenyl)-1,3- bond or carbonyl, and a pharmaceutically acceptable propanediol, and a pharmaceutically acceptable Salt thereof; Salt thereof; (33) a 2-amino-1,3-propanediol compound according to (35) a 2-amino-1,3-propanediol compound according to the above-mentioned (1) or (2), having the formula the above-mentioned (33) or (34), which is selected from the group consisting of 2-amino-2-(1,2,12-trihydroxy-4- (I-21) octadecenyl)-1,3-propanediol, 2-amino-2-(1,2-dihydroxy-4- CHOR'a octade cenyl)-1,3-propane diol, 2-amino-2-(1,2- RaRaN-C-CHOR a dihydroxyoctadecyl)-1,3-propanediol, 2-amino-2-(1,12 25 dihydroxy-4-octadecenyl)-1,3-propanediol, 2-amino-2-(1,2, 4-trihydroxybutyl)-1,3-propanediol, 2-amino-2-(1,2,12 trihydroxyoctadecyl)-1,3-propanediol and 2-amino-2-(1,12 wherein dihydroxyoctade cyl)-1,3-propane diol, and a R" is an optionally substituted straight- or branched pharmaceutically acceptable Salt thereof; carbon chain which may have, in the chain, a bond, a (36) a 2-amino-1,3-propanediol compound according to hetero atom or a group Selected from the group con the above-mentioned (33), having the formula Sisting of a double bond, a triple bond, oxygen, Sulfur, sulfinyl, Sulfonyl, -N(R)- where R is hydrogen, (I-23) alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, 35 optionally Substituted arylene, optionally Substituted CH2OH cycloalkylene, optionally Substituted heteroarylene and HN-C-CHOH an alicycle thereof, and which may be Substituted, at the chain end (co-position) thereof, by a double bond, a triple bond, optionally Substituted aryl, optionally Sub 40 Stituted cycloalkyl, optionally Substituted heteroaryl or an alicycle thereof, an optionally Substituted aryl, an wherein optionally Substituted cycloalkyl, an optionally Substi tuted heteroaryl or an alicycle thereof, and RS is a phenylalkyl Substituted by a Straight- or branched Ra, R3a, R'a and Ra are the same or different and each 45 chain C6-C14 alkyl optionally substituted by halogen, is a hydrogen, an alkyl, an acyl or an alkoxycarbonyl, a Straight- or branched chain C6-C14 alkoxy optionally wherein the optionally Substituted Straight- or branched Substituted by halogen or a Straight- or branched chain carbon chain may have a Substituent Selected from the group consisting of alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, C6-C14 alkenyloxy, and a pharmaceutically acceptable alkylenedioxy, acyl, alkylamino, alkylthio, acylamino, 50 Salt thereof; alkoxycarbonyl, alkoxycarbonylamino, acyloxy, (37) a 2-amino-1,3-propanediol compound according to alkylcarbamoyl, haloalkyl, haloalkoxy, nitro, halogen, the above-mentioned (36), which is selected from the group amino, hydroxyimino, hydroxy, carboxy, optionally Substi consisting of 2-amino-2-1-hydroxy-2-(4-octylphenyl) tuted aryl, optionally Substituted aryloxy, optionally Substi ethyl-1,3-propanediol, 2-amino-2-2-(4-dodecylphenyl)-1- tuted cycloalkyl, optionally Substituted heteroaryl and an 55 hydroxyethyl-1,3-propanediol, 2-amino-2-2-(4- alicycle thereof; and the aforementioned optionally Substi heptyloxyphenyl)-1-hydroxyethyl-1,3-propanediol, tuted arylene, optionally Substituted cycloalkylene, option 2-amino-2-1-hydroxy-2-(4-undecyloxyphenyl)ethyl-1,3- ally Substituted heteroarylene, an alicycle thereof, optionally propanediol, 2-amino-2-2-(4-(8-fluorooctyl)phenyl)-1- Substituted aryl, optionally Substituted aryloxy, optionally hydroxyethyl-1,3-propanediol, 2-amino-2-2-(4-(12 Substituted cycloalkyl, optionally Substituted heteroaryland 60 an alicycle thereof may have a Substituent Selected from the fluorododecyl)phenyl)-1-hydroxyethyl-1,3-propanediol, group consisting of alkoxy, alkenyloxy, alkynyloxy, 2-amino-2-2-(4-(7-fluoroheptyloxy)phenyl)-1- aralkyloxy, alkylenedioxy, acyl, alkylamino, alkylthio, hydroxyethyl-1,3-propanediol and 2-amino-2-1-hydroxy acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, 2-(4-(11-fluoroundecyloxy)phenyl)ethyl-1,3-propanediol, alkylcarbamoyl, haloalkyl, haloalkoxy, nitro, halogen, 65 and a pharmaceutically acceptable Salt thereof; amino, hydroxy and carboxy, and a pharmaceutically accept (38) a 2-amino-1,3-propanediol compound according to able Salt thereof; the above-mentioned (1) or (2), having the formula 5,952,316 15 16

(I-24) (I-26) CHOR'a CHOR'a RaRaN-C-CHOR a RaRaN-C-CHOR a CHF CHRt wherein wherein Rt is an optionally Substituted Straight- or branched car RV is an optionally Substituted aryl, an optionally Substi bon chain which may have, in the chain, a bond, a tuted cycloalkyl, an optionally Substituted heteroaryl or hetero atom or a group Selected from the group con an alicycle thereof; Sisting of a double bond, a triple bond, oxygen, Sulfur, Ra, Ra, R'a and Ra are the same or different and each sulfinyl, Sulfonyl, -N(R)- where R is hydrogen, is a hydrogen, an alkyl, an acyl or an alkoxycarbonyl, alkyl, aralkyl, acyl or alkoxycarbonyl, carbonyl, 15 X is an oxygen, a Sulfur, a Sulfinyl, a Sulfonyl, -N(R)- optionally Substituted arylene, optionally Substituted where R is hydrogen, alkyl, aralkyl, acyl or alkoxy cycloalkylene, optionally Substituted heteroarylene and carbonyl; and an alicycle thereof, an optionally Substituted aryl, an C. and B are 0 or an integer of 1-20 provided that optionally Substituted cycloalkyl, an optionally Substi C+f=5-20, wherein the optionally substituted aryl, tuted heteroaryl or an alicycle thereof, and optionally Substituted cycloalkyl, optionally Substituted Ra, Ra, R'a and Ra are the same or different and each heteroaryl and an alicycle thereof may have a Substitu is a hydrogen, an alkyl, an acyl or an alkoxycarbonyl, ent Selected from the group consisting of alkyl, alkoxy, wherein the optionally Substituted Straight- or branched alkenyloxy, alkynyloxy, aralkyloxy, alkylenedioxy, carbon chain may have a Substituent Selected from the group acyl, alkylamino, alkylthio, acylamino, consisting of alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, 25 alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylenedioxy, acyl, alkylamino, alkylthio, acylamino, alkylcarbamoyl, haloalkyl, haloalkoxy, nitro, halogen, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, amino, hydroxy and carboxy, and a pharmaceutically alkylcarbamoyl, haloalkyl, haloalkoxy, nitro, halogen, acceptable Salt thereof; amino, hydroxy, carboxy, optionally Substituted aryl, option (42) a 2-amino-1,3-propanediol compound according to ally Substituted aryloxy, optionally Substituted cycloalkyl, the above-mentioned (41), having the formula optionally Substituted heteroaryl and an alicycle thereof, and the aforementioned optionally Substituted arylene, option (I-27) ally Substituted cycloalkylene, optionally Substituted CH2OH heteroarylene, an alicycle thereof, optionally Substituted 35 aryl, optionally Substituted aryloxy, optionally Substituted HN-C-CHOH cycloalkyl, optionally Substituted heteroaryl and an alicycle thereof may have a Substituent Selected from the group CHORw consisting of alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylenedioxy, acyl, alkylamino, alkylthio, acylamino, 40 wherein alkoxycarbonyl, alkoxycarbonylamino, acyloxy, Rw is a phenyl substituted by C4-C16 alkyl, and a alkylcarbamoyl, haloalkyl, haloalkoxy, nitro, halogen, pharmaceutically acceptable Salt thereof; amino, hydroxy and carboxy, and a pharmaceutically accept (43) a 2-amino-1,3-propanediol compound according to able Salt thereof; the above-mentioned (41) or (42), which is selected from the (39) a 2-amino-1,3-propanediol compound according to 45 group consisting of 2-amino-2-(4-octylphenoxymethyl)-1,3- the above-mentioned (38), having the formula propanediol, 2-amino-2-(4-decylphenoxymethyl)-1,3- propanediol, 2-amino-2-(4-dodecylphenoxymethyl)-1,3- (I-25) propanediol and 2-amino-2-(4-tetradecylphenoxymethyl)-1, CH2OH 3-propanediol, and a pharmaceutically acceptable Salt 50 thereof; HN-C-CH-OH (44) a pharmaceutical composition comprising either one CHF CHR of the above-mentioned compounds (1) through (4); (45) an immunosuppressant comprising a 2-amino-1,3- propanediol compound of the formula wherein 55 Ru is a phenyl substituted by alkyl having 4 to 16 carbon (I-28) atoms, and a pharmaceutically acceptable Salt thereof; (40) a 2-amino-1,3-propanediol compound according to CHOR the above-mentioned (38) or (39), which is selected from the R2R3N-C-CHORS group consisting of 2-amino-2-2-(4-octylphenyl)ethenyl 60 1,3-propanediol, 2-amino-2-2-(4-decylphenyl)ethenyl-1, R 3-propanediol, 2-amino-2-2-(4-dodecylphenyl)ethenyl-1, 3-propanediol and 2-amino-2-2-(4-tetradecylphenyl) wherein e the nyl-1,3-propanediol, and a pharmaceutically R is an optionally Substituted Straight- or branched carbon acceptable Salt thereof; 65 chain which may have, in the chain, a bond, a hetero (41) a 2-amino-1,3-propanediol compound according to atom or a group Selected from the group consisting of the above-mentioned (1) or (2), having the formula a double bond, a triple bond, Oxygen, Sulfur, Sulfinyl, 5,952,316 17 18 sulfonyl, -N(R)- where R is hydrogen, alkyl, The arylene at R, R' or Rt is exemplified by phenylene aralkyl, acyl or alkoxycarbonyl, carbonyl, optionally and naphthylene, with preference given to phenylene. Substituted arylene, optionally Substituted The cycloalkylene at R, R', R'a or Rt is that having 3 to cycloalkylene, optionally Substituted heteroarylene and 10 carbon atoms and is exemplified by cyclopropylene, an alicycle thereof, and which may be Substituted, at cyclobutylene, cyclop entylene, cyclohexylene, the chain end thereof, by a double bond, a triple bond, cycloheptylene, cyclooctylene, cyclononylene and optionally Substituted aryl, optionally Substituted cyclodecylene, with preference given to cyclohexylene. cycloalkyl, optionally Substituted heteroaryl or an ali cycle thereof, an optionally Substituted aryl, an option The heteroarylene at R, R' or Rt is a 5- or 6-membered ally Substituted cycloalkyl, an optionally Substituted heteroarylene optionally having, in the ring, 1 or 2 hetero heteroaryl or an alicycle thereof, and atoms Selected from nitrogen atom, oxygen atom and Sulfur R. R. R' and Rare the same or different and each is a atom and is exemplified by thiophen-(2,4-, 2,5- or 3,4-) hydrogen, an alkyl, an aralkyl, an acyl or an ylene, furan-(2,4-, 2,5- or 3,4-)ylene, pyrrol-(1,3-, 2,4-, 2,5- alkoxycarbonyl, or R' and R may be bonded by an or 3,4-)ylene, imidazol-(1,4-, 2,4- or 2.5-)ylene, thiazol-(2, alkylene chain which may be substituted by alkyl, aryl 4- or 2.5-)ylene, isothiazol-(3,4- or 3.5-)ylene, oxazol-(2,4- or aralkyl, 15 or 2.5-)ylene, isoxazol-(3,4- or 3.5-)ylene, pyridin-(2,4-, wherein the optionally Substituted Straight- or branched 2,5-, 2,6- or 3.5-)ylene, pyrimidin-(2,4- or 2.5-)ylene, carbon chain may have a Substituent Selected from the group pyrazin-2,5-ylene, pyridazin-(3.5- or 3,6-)ylene and pyran consisting of alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, (2,4-, 2,5- or 2,6-)ylene, with preference given to thiophen alkylenedioxy, acyl, alkylamino, alkylthio, acylamino, 2.5-ylene and pyridin-2,5-ylene. alkoxycarbonyl, alkoxycarbonylamino, acyloxy, The alicycle of the aforementioned heteroarylene at R, R' alkylcarbamoyl, haloalkyl, haloalkoxy, nitro, halogen, or Rt is the aforementioned heteroarylene when Saturated amino, hydroxyimino, hydroxy, carboxy, optionally Substi and is exemplified by pyrrolidine-(1,3-, 2,4-, 2,5- or 3,4-) tuted aryl, optionally Substituted aryloxy, optionally Substi ylene, piperidine-(1,4-, 2,4-, 2,5-, 2,6- or 3.5-)ylene, tuted cycloalkyl, optionally Substituted heteroaryl and an piperazine-1,4-ylene, morpholine-2,4 or 3,4-ylene and alicycle thereof; the aforementioned optionally Substituted 25 thiomorpholine-2,4 or 3,4-ylene. arylene, optionally Substituted cycloalkylene, optionally The aryl at R, R', Rt or RV is exemplified by phenyl and Substituted heteroarylene and an alicycle thereof may have naphthyl, with preference given to phenyl. a Substituent Selected from the group consisting of alkoxy, The cycloalkyl at R, R', Ra, Rb, Rp, Rt or Rv is alkenyloxy, alkynyloxy, aralkyloxy, alkylenedioxy, acyl, cycloalkyl having 3 to 10 carbon atoms and includes, for alkylamino, alkylthio, acylamino, alkoxycarbonyl, example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, haloalkyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl, with haloalkoxy, nitro, halogen, amino, hydroxy and carboxy, preference given to cyclohexyl. and the optionally Substituted aryl, optionally Substituted The heteroaryl at R, R', Rp, Rt or RV is a 5- or aryloxy, optionally Substituted cycloalkyl, optionally Substi 6-membered heteroaryl optionally having, in the ring, 1 to 4 tuted heteroaryl and an alicycle thereof may have a Sub 35 hetero atoms Selected from nitrogen atom, oxygen atom and Stituent Selected from the group consisting of alkyl, alkoxy, Sulfur atom and includes, for example, monocyclic het alkenyloxy, alkynyloxy, aralkyloxy, alkylenedioxy, acyl, eroaryl such as thienyl(2-thienyl, 3-thienyl), furyl(2-furyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, 3-furyl), pyrrolyl(1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), alkoxycarbonylamino, acyloxy, alkylcarbamoyl, haloalkyl, imidazolyl(2-imidazolyl, 4-imidazolyl), pyrazolyl(3- haloalkoxy, nitro, halogen, amino, hydroxy and carboxy, and 40 pyrazolyl, 4-pyrazolyl), triazolyl, tetrazolyl, thiazolyl(2- a pharmaceutically acceptable Salt thereof; thiazolyl, 4-thiazolyl), isothiazolyl(3-isothiazolyl, (46) an immunosuppressant comprising a 2-amino-1,3- 4-isothiazolyl), oxazolyl(2-oxazolyl, 4-oxazolyl), propanediol compound or a pharmaceutically acceptable Salt isooxazolyl(3-isooxazolyl, 4-isooxazolyl), pyridyl(2- thereof according to either one of the aforementioned (1) pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl, pyrimidinyl(2- through (43); 45 pyrimidinyl, 4-pyrimidinyl), pyridazinyl(3-pyridazinyl, (47) a pharmaceutical agent according to the aforemen 4-pyridazinyl) or pyranyl(2-pyranyl, 3-pyranyl, 4-pyranyl), tioned (45) or (46), wherein the immunosuppressant is an and bicyclic heteroaryl such as indolyl(2-indolyl, 3-indolyl), agent for Suppressing rejection; quinolyl(2-quinolyl, 3-quinolyl), isoquinolyl(1-isoquinolyl, (48) a pharmaceutical agent according to the aforemen 3-iso quinolyl), benzofuranyl (2-benzofuranyl, tioned (45) or (46), wherein the immunosuppressant is an 50 3-benzofuranyl), benzothienyl (2-benzothienyl, agent for the prevention and treatment of autoimmune 3-benzothienyl), 1H-benzimidazol-2-yl or chromenyl(2- diseases, and chromenyl, 3-chromenyl, 4-chromenyl). (49) a pharmaceutical agent according to the aforemen The alicycle of the aforementioned heteroaryl at R, R', Rt tioned (48), wherein the agent for the prevention and treat or RV is the above-mentioned monocyclic heteroaryl when ment of autoimmune diseases is an agent for the prevention 55 Saturated and includes, for example, pyrrollidinyl(1- and treatment of rheumatism. pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidyl(2- The groups represented by respective Symbols in the piperidyl, 3-piperidyl, 4-piperidyl), piperidino, piperazinyl, present specification are explained in the following. morpholinyl and thiomorpholinyl. The carbon chain at R, R', Ra or Rt is a straight- or The heterocycle at Rp means an alicycle of heteroaryl. branched carbon chain having 1 to 30 carbon atoms and is 60 The alkyl at Rb or Rr is a straight- or branched chain exemplified by methyl, ethyl, propyl, isopropyl, butyl, alkyl having 1 to 30 carbon atoms and is exemplified by isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, pentyl, isopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, nonadecyl, icosyl, henicosyl, docOSyl, tricosyl, tetracosyl, 65 hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl and he nicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, triacontyl. hexacosyl, heptacosyl, octacosyl, nonacosyl and triacontyl. 5,952,316 19 20 The straight- or branched chain alkyl having 12 to 22 phenoxyethyloxy) hexyl, 7-(2-phenoxyethyloxy) heptyl, carbon atoms at Ra and the Straight- or branched chain alkyl 8-(2-phenoxyethyloxy)octyl, 5-(3-phenoxypropyloxy) having 13 to 20 carbon atoms at Rb or Rc are the above p enty 1, 6-(3-phenoxypropyloxy) he Xyl, 7-(3- mentioned alkyl having the Specified numbers of carbon phenoxypropyloxy)heptyl, 8-(3-phenoxypropyloxy)octyl, atOmS. 5-(4-phenoxybutyloxy)penty 1, 6-(4-phenoxybutyloxy) The alkenylat R'b is a straight- or branched chain alkenyl hexyl, 7-(4-phenoxybutyloxy) he pty 1, 8-(4- having 2 to 30 carbon atoms and includes, for example, phenoxybutyloxy)octyl, 5-(6-phenoxyhexyloxy)pentyl, ethenyl, propenyl, isopropenyl, bute nyl, isobute nyl, 6-(6-phenoxyhexyloxy)hexyl, 7-(6-phenoxyhexyloxy) pentenyl, isopentenyl, hexenyl, heptenyl, octenyl, nonenyl, heptyl and 8-(6-phenoxyhexyloxy)octyl. decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, The cycloalkylalkyl at Rd, Re, Rf or Rg is that where the pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, alkyl moiety is a Straight- or branched chain alkyl having 1 nonadecenyl, icoSenyl, henicoSenyl, docoSenyl, tricoSenyl, to 30 carbon atoms and the cycloalkyl moiety is a cycloalkyl tetracoSenyl, pentacoSenyl, hexacoSenyl, heptacoSenyl, having 3 to 10 carbon atoms, and is exemplified by octacoSenyl, nonacoSenyl and triacontenyl. cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, The alkynyl at R'b is a straight- or branched chain alkynyl 15 1 - cyclohe Xylpropyl, 2-cyclohe Xyl propyl, having 2 to 30 carbon atoms and includes, for example, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 5-cyclohexylpentyl, ethynyl, propynyl, isopropynyl, butynyl, pentynyl, heXynyl, 6-cyclohexylhexyl, 7-cyclohexylheptyl, 8-cyclohexyloctyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, 9-cyclohexyl no nyl, 10-cyclohexyl de cyl, tride cynyl, tetradecynyl, pentadecynyl, hexadecynyl, 11-cyclohexylunde cyl, 12-cyclohexyldo de cyl, heptadecy nyl, octadecy nyl, nonade cynyl, icosy nyl, 13-cyclohexyltride cyl, 14-cyclohexyltetrade cyl, he nico Synyl, docosy nyl, trico Synyl, tetracosy nyl, 15-cyclohexylpentadecyl, 16-cyclohexylhexadecyl, pentacosynyl, hexacoSynyl, heptacoSynyl, octacoSynyl, 17-cyclohexylheptadecyl, 18-cyclohexyloctadecyl, nonacosynyl and triacontynyl. 19-cyclohe Xylnonade cyl, 20-cyclohexylico Syl, The phenylalkyl at Rd, Re, Rf, Rg, Ri, Rk or Rs is that 21-cyclohe Xylhe nico Syl, 22-cyclohe Xyldocosyl, where the alkyl moiety is a Straight- or branched chain alkyl 25 23-cyclohexyltrico Syl, 24-cyclohexyltetraco Syl, having 1 to 30 carbon atoms and includes, for example, 25-cyclohexylpentacosyl, 26-cyclohexylhexacosyl, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 27-cyclohexylheptacosyl, 28-cyclohe Xyloctacosyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 29-cyclohexylnonacosyl and 30-cyclohexyltriacontyl. 5-phenylpenty 1, 6-phenylhexyl, 7-phenylheptyl, The cycloalkylalkyl at Re, Rf or Rg where the alkyl 8-phenyloctyl, 9-phenylnonyl, 10-phenylde cyl, moiety has 6 to 20 carbon atoms is the above-mentioned 11-phenylundecyl, 12-phenyldodecyl, 13-phenyltridecyl, cycloalkylalkyl having the Specified numbers of carbon 14-phenylte trade cyl, 15-phenylpent a de cyl, atOmS. 16-phenylhexadecyl, 17-phenylhepta de cyl, The alkyl-substituted cycloalkylalkyl at Rm where the 18-phenyloctadecyl, 19-phenylnonadecyl, 20-phenylicosyl, alkyl moiety has 6 to 20 carbon atoms is exemplified by 21-phenylhenicosyl, 22-phenyldocosyl, 23-phenyltricosyl, 35 3-(4-heptylcyclohexyl)propyl, 4-(4-butylcyclohexyl)butyl, 24-phenylte traco Syl, 25-phenylp ent a co Syl, 2-(4-octylcyclohexyl)ethyl, 2-(4-nonylcyclohexyl)ethyl and 2 6-phenyl he X a co Syl, 27-phenylheptaco Syl, 2-(4-dodecylcyclohexyl)ethyl. 28-phenyloctac OSyl, 29-phenylnonaco Syl and The heteroarylalkyl at Rd, Re, Rf or Rg is that where the 30-phenyltriacontyl. alkyl moiety is a Straight- or branched chain alkyl having 1 The phenylalkyl at Re, Rf, Rg or Rh where the alkyl 40 to 30 carbon atoms and is exemplified by thienylalkyl and moiety has 6 to 20 carbon atoms and that at Rjor R1 where pyridylalkyl Such as (thienyl or pyridyl)methyl, 1-(thienyl or the alkyl moiety has 2 to 6 carbon atoms are the above pyridyl)ethyl, 2-(thienyl or pyridyl)ethyl, 1-(thienyl or mentioned phenylalkyl having the Specified numbers of pyridyl)propyl, 2-(thienyl or pyridyl)propyl, 3-(thienyl or carbon atoms. pyridyl)propyl, 4-(thienyl or pyridyl)butyl, 5-(thienyl or The phenylalkoxyalkyl at Rh where the alkyl moiety and 45 pyridyl)pentyl, 6-(thienyl or pyridyl)hexyl, 7-(thienyl or alkoxy moiety have 6 to 20 carbon atoms in total is exem pyridyl)heptyl, 8-(thienyl or pyridyl)octyl, 9-(thienyl or plified by 5-phenyl methyl oxy p enty 1, pyridyl)nonyl, 10-(thienyl or pyridyl)decyl, 11-(thienyl or 6-phenylmethyloxyhexyl, 7-phenylmethyloxyheptyl, pyridyl)undecyl, 12-(thienyl or pyridyl)dodecyl, 13-(thienyl 8-phenylmethyloxyoctyl, 9-phenylmethyloxynonyl, or pyridyl)tridecyl, 14-(thienyl or pyridyl)tetradecyl, 15 10-phenylmethyloxy decyl, 12-phenylmethyloxydodecyl, 50 (thienyl or pyridyl)pentadecyl, 16-(thienyl or pyridyl) 14- phenyl methyl oxyte trade cyl, hexadecyl, 17-(thienyl or pyridyl)heptadecyl, 18-(thienyl or 16-phenyl methyl oxy he X a de cyl, pyridyl)octadecyl, 19-(thienyl or pyridyl)nonadecyl, 20 18-phenylmethyloxyoctadecyl, 2-(8-phenyloctyloxy)ethyl, (thienyl or pyridyl)icosyl, 21-(thienyl or pyridyl)henicosyl, 3-(8-phenyloctyloxy)propyl, 4-(8-phenyloctyloxy)butyl, 22-(thienyl or pyridyl)docosyl, 23-(thienyl or pyridyl) 5-(8-phenyloctyloxy)pentyl, 6-(8-phenyloctyloxy)hexyl and 55 tricosyl, 24-(thienyl or pyridyl)tetracosyl, 25-(thienyl or 7-(8-phenyloctyloxy)heptyl. pyridyl)pentacosyl, 26-(thienyl or pyridyl)hexacosyl, 27 The phenoxyalkyl at Rh where the alkyl moiety has 6 to (thienyl or pyridyl)heptacosyl, 28-(thienyl or pyridyl) 20 carbon atoms is exemplified by 6-phenoxyhexyl, octacosyl, 29-(thienyl or pyridyl)nonacosyl and 30-(thienyl 7-phenoxyheptyl, 8-phenoxyoctyl, 9-phenoxynonyl, or pyridyl)triacontyl. 10-phenoxydecyl, 11-phenoxyundecyl, 12-phenoxydodecyl, 60 The heteroarylalkyl at Re, Rf or Rg where the alkyl 13-phe no Xy tride cyl, 14-p he no Xyte trade cyl, moiety has 6 to 20 carbon atoms is the above-mentioned 15-phenoxypentade cyl, 16-phenoxy he Xade cyl, heteroarylalkyl having the Specified numbers of carbon 17-phenoxyhepta de cyl, 18-phenoxyoctade cyl, atOmS. 19-phenoxynonadecyl and 20-phenoxylicosyl. The alkyl-substituted thienylalkyl at Ro where the alkyl The phenoxyalkoxyalkyl at Rh where the alkyl moiety 65 moiety has 6 to 20 carbon atoms in total is exemplified by and alkoxy moiety have 6 to 20 carbon atoms in total is 2-(5-octyl-2-thienyl)ethyl, 2-(5-nonyl-2-thienyl)ethyl, 2-(5- exemplified by 5-(2-phenoxyethyloxy)pentyl, 6-(2- decyl-2-thienyl)ethyl and 2-(5-dodecyl-2-thienyl)ethyl. 5,952,316 21 22 The thienylalkyl at Ro where the alkyl moiety has 6 to 20 Straight- or branched chain alkenyl having 2 to 20 carbon carbon atoms is thienylalkyl from among the above atoms and is exemplified by Vinyloxy, propenyloxy, mentioned heteroarylalkyls. Preferred is 13-(2-thienyl) isopropenyloxy, butenyloxy, isobutenyloxy, pentenyloxy, tridecyl. isopentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, The alkyl-substituted pyridylalkyl at Ro where the alkyl nonenyloxy, decenyloxy, undecenyloxy, dodecenyloxy, moiety has 6 to 20 carbon atoms in total is exemplified by tride ce nyloxy, tetrade cenyloxy, pentade ce nyloxy, 2-(5-octyl-2-pyridyl)ethyl, 2-(5-decyl-2-pyridyl)ethyl, 2-(2- hexadecenyloxy, heptadecenyloxy, octadecenyloxy, nonade octyl-5-pyridyl)ethyl and 2-(2-decyl-5-pyridyl)ethyl. cenyloxy and icoSenyloxy. The pyridylalkyl at Ro where the alkyl moiety has 6 to 20 The straight- or branched chain alkenyloxy having 6 to 20 carbon atoms is pyridylalkyl from among the above carbon atoms as a Substituent at Re or Rf and the Straight mentioned heteroarylalkyls. Preferred are 13-(2-pyridyl) or branched chain alkenyloxy having 6 to 14 carbon atoms tridecyl and 13-(3-pyridyl)tridecyl. as a Substituent at Rg, Ri, Rjor RS are the above-mentioned The heterocyclic alkyl at Rd, Re, Rf or Rg where the alkyl alkenyloxys having the Specified numbers of carbon atoms. moiety is a Straight- or branched chain alkyl having 1 to 30 The alkynyloxy as a substituent at R, R', Ra, Rb, Ra, carbon atoms and heterocyclic means an alicycle of Rd, Re, Rf, Rt or RV is that where the alkynyl moiety is a heteroaryl, is exemplified by 4-piperidylmethyl, 1-(4- 15 Straight- or branched chain alkynyl having 2 to 20 carbon piperidyl)ethyl, 2-(4-piperidyl)ethyl, 1-(4-piperidyl)propyl, atoms and is exemplified by ethynyloxy, propynyloxy, 2-(4-piperidyl)propyl, 3-(4-piperidyl)propyl, 4-(4-piperidyl) butynyloxy, penty nyloxy, heXynyloxy, hepty nyloxy, butyl, 5-(4-piperidyl)pentyl, 6-(4-piperidyl)hexyl, 7-(4- octynyloxy, nonynyloxy, decy nyloxy, undecynyloxy, piperidyl)heptyl, 8-(4-piperidyl)octyl, 9-(4-piperidyl)nonyl, dodecy nyloxy, tride cynyloxy, tetrade cynyloxy, 10-(4-piperidyl)decyl, 11-(4-piperidyl)undecyl, 12-(4- pentadecy nyloxy, hexadecy nyloxy, heptadecy nyloxy, piperidyl)dodecyl, 13-(4-piperidyl)tridecyl, 14-(4-piperidyl) octadecynyloxy, nonadecynyloxy and icoSynyloxy. tetradecyl, 15-(4-piperidyl)pentadecyl, 16-(4-piperidyl) The aralkyloxy as a substituent at R, R', R'a, Rb, Ra, Rd, hexadecyl, 17-(4-piperidyl)heptadecyl, 18-(4-piperidyl) Re, Rf, Rt or RV is that wherein the aralkyl is that where the octadecyl, 19-(4-piperidyl)nonadecyl, 20-(4-piperidyl) alkyl moiety is a Straight- or branched chain alkyl having 1 icosyl, 21-(4-piperidyl)henicosyl, 22-(4-piperidyl)docosyl, 25 to 20 carbon atoms and the aralkyloxy is exemplified by 23-(4-piperidyl)tricosyl, 24-(4-piperidyl)tetracosyl, 25-(4- phenylalkoxy Such as benzyloxy, 2-phenethyloxy, piperidyl)pentacosyl, 26-(4-piperidyl) hexacosyl, 27-(4- 1-phenylethyloxy, 1-phenylpropyloxy, 2-phenylpropyloxy, piperidyl)heptacosyl, 28-(4-piperidyl)octacosyl, 29-(4- 3-phenylpropyloxy, 4-phenylbutyloxy, 5-phenylpentyloxy, piperidyl) nonacosyl and 30-(4-piperidyl)triacontyl. 6-phenylhexyloxy, 7-phenylheptyloxy, 8-phenyloctyloxy, The heterocyclic alkyl at Re, Rf or Rg where the alkyl 9-phenyl no nyloxy, 10-phenylde cylo Xy, moiety has 6 to 20 carbon atoms is the above-mentioned 11-phenyl undecyl oxy, 12-phenyl dodecyl oxy, heterocyclic alkyl having the Specified numbers of carbon 13-phenyltridecyloxy or 14-phenyltetradecyloxy, and naph atOmS. thylalkoxy Such as naphthylmethyl or 2-naphthylethyl, with The 1-alkyl-substituted piperidin-4-ylalkyl at Rn where preference given to phenylalkoxy. the alkyl moiety has 6 to 20 carbon atoms in total is, for 35 The phenylalkoxy as a substituent at Re, Rf, Rg or Rk is example, 2-(1-octylpipe ridin-4-yl)ethyl and 2-(1- phenylalkoxy of the aforementioned aralkyloxy. dodecylpiperidin-4-yl)ethyl. The phenylalkoxy as a substituent at R1 where the alkoxy The alkyl as a substitutent at R, Rb, Rd, Rim, Rn, Ro or moiety has 2 to 8 carbon atoms is phenylalkoxy of the RV is a straight- or branched chain alkyl having 1 to 20 aforementioned aralkyloxy, having the Specified numbers of carbon atoms and is exemplified by methyl, ethyl, propyl, 40 carbon atoms. butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, The alkylenedioxy as a substituent at R, R', R'a, Rd, Rt dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, or RV is alkylenedioxy where the alkylene moiety is a heptadecyl, octadecyl, nonadecyl and icosyl. Straight- or branched chain alkylene having 1 to 20 carbon The straight- or branched chain alkyl having 6 to 20 atoms and is exemplified by methylenedioxy, ethylenedioxy, carbon atoms as a Substituent at Re or Rf, the Straight- or 45 propylenedioxy, trimethylenedioxy, butylenedioxy, 1,2- branched chain alkyl having 6 to 14 carbon atoms as a dimethylethylene dioxy, pent a methylene dioxy, substituent at Rg, Ri, R or Rs, the alkyl having 6 to 18 he Xa methylene dioxy, he pt a methylene dioxy, carbon atoms as a Substituent at Rp or Rd and the alkyl octa methylene dioxy, no name thylene dioxy, having 4 to 16 carbon atoms as a Substituent at Ru or RW are de came thylene dioxy, unde came thylene dioxy, the above-mentioned alkyls having the Specified numbers of 50 dode came thylene dioxy, tride came thylene dioxy, carbon atoms. tetrade camethylenedioxy, pentadecamethylenedioxy, The alkoxy as a substituent at R, R, Ra, Rb, Ra, Rd, Re, hexadecamethylenedioxy, heptadecamethylenedioxy, Rf, Rt or RV is a straight- or branched chain alkoxy having octadecamethylenedioxy, nonadecamethylenedioxy and 1 to 20 carbon atoms and is exemplified by methoxy, ethoxy, icosamethylenedioxy, with preference given to methylene propoxy, isopropoxy, butoxy, isobutoxy, Sec-butoxy, tert 55 dioxy and ethylenedioxy. butoxy, pentyloxy, isopentyloxy, tert-pentyloxy, hexyloxy, The acyl as a substituent at R, R', Ra, Rb, Ra, Rd, Re, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, Rf, Rt or RV is optionally substituted alkanoyl or aroyl, in dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, which alkanoyl is a Straight- or branched chain alkanoyl hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy having 1 to 20 carbon atoms, and is exemplified by formyl, and icosyloxy. 60 acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, The straight- or branched chain alkoxy having 6 to 20 heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, carbon atoms as a Substituent at Re or Rf and the Straight dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, or branched chain alkoxy having 6 to 14 carbon atoms as a hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl substituent at Rg, Ri, R or Rs are the above-mentioned and icosanoyl, where alkanoyl may be Substituted by phenyl. alkoxys having the Specified numbers of carbon atoms. 65 Examples of the alkanoyl optionally Substituted by phenyl The alkenyloxy as a substituent at R, R', Ra, Rb, Ra, include phenylacetyl and phenylpropionyl. Examples of Rd, Re, Rf, Rt or RV is that where the alkenyl moiety is a aroyl include benzoyl. 5,952,316 23 24 The alkylamino as a substituent at R, R', R'a, Rb, Ra, which may be substituted by phenyl. Examples thereof Rd, Re, Rf, Rt or RV is that where the alkyl moiety is a include benzyloxycarbonylamino. Straight- or branched chain alkyl having 1 to 20 carbon The acyloxy as a substituent at R, R', R'a, Rb, Ra, Rd, atoms, and is exemplified by methylamino, ethylamino, Re, Rf, Rt or RV is that where the acyl moiety is a straight propylamino, isopropylamino, butylamino, isobutylamino, or branched chain alkanoyl having 2 to 20 carbon atoms, and Sec -butylamino, tert-butylamino, penty lamino, is exemplified by acetoxy, propionyloxy, butyryloxy, is openty lamino, tert-penty lamino, he Xylamino, isobutyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptylamino, octylamino, nonylamino, decylamino, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, unde cylamino, do de cylamino, tride cylamino, unde canoyloxy, dodecanoyloxy, tride canoyloxy, tetradecylamino, pentadecylamino, hexadecylamino, tetradecanoyloxy, pentadecanoyloxy, hexadecanoyloxy, heptadecylamino, octadecylamino, nonadecylamino and heptadecanoyloxy, octadecanoyloxy, nonadecanoyloxy and icosylamino. icosanoyloxy. The alkylthio as a substituent at R, R', R'a, Rb, Ra, Rd, The alkylcarbamoyl as a substituent at R, R', R'a, Rb, Re, Rf, Rt or RV is that where the alkyl moiety is a straight Ra, Rd, Re, Rf, Rt or RV is that where the alkyl moiety is a or branched chain alkyl having 1 to 20 carbon atoms, and is 15 Straight- or branched chain alkyl having 1 to 20 carbon exemplified by methylthio, ethylthio, propylthio, atoms, and is exemplified by methylcarbamoyl, isopropylthio, butylthio, isobutylthio, Sec-butylthio, tert ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, butylthio, pentylthio, isopentylthio, tert-pentylthio, pentylcarbamoyl, hexylcarbamoyl, heptylcarbamoyl, hexylthio, heptylthio, octylthio, nonylthio, decylthio, octylcarbamoyl, nonylcarbamoyl, decylcarbamoyl, undecylthio, dodecylthio, tridecylthio, tetradecylthio, undecylcarbamoyl, dodecylcarbamoyl, tridecylcarbamoyl, pentade cylthio, hexadecylthio, heptadecylthio, te trade cylcarbamoyl, pent a de cylcarbamoyl, octadecylthio, nonadecylthio and icosylthio. he X a de cylcarbamoyl, he pta de cylcarbamoyl, The acylamino as a substituent at R, R', Ra, Rb, Ra, Rd, octadecylcarbamoyl, nonadecylcarbamoyl and icosylcar Re, Rf, Rt or RV is that where the acyl moiety is a straight bamoyl. or branched chain alkanoyl having 1 to 20 carbon atoms, and 25 The haloalkyl as a substituent at R, R', Ra, Rb, Rd, Rt is exemplified by for my lamino, acetylamino, or RV is that where the alkyl moiety is a straight- or branched propionylamino, butyrylamino, isobutyrylamino, chain alkyl having 1 to 20 carbon atoms, and is exemplified pentanoylamino, pivaloylamino, he Xanoylamino, by fluoromethyl, trifluoromethyl, chloromethyl, 2,2,2- heptanoylamino, octanoylamino, nonanoylamino, trifluoroethyl, perfluoroethyl, 3-chloropropyl, decanoylamino, undecanoylamino, dodecanoylamino, 3-fluoropropyl, 4-chlorobutyl, 4-fluorobutyl, tride cano y la mino, te trade cano y la mino, 5-chlorop enty 1, 6-chlorohexyl, 6-fluorohexyl, pent a de cano y la mino, he X a de cano y la mino, 7-chloroheptyl, 7-fluoroheptyl, 8-fluorooctyl, 9-fluorononyl, heptadecanoylamino, octadecanoylamino, nonadecanoy 10-fluorodecyl, 11-fluoroundecyl, 12-fluorododecyl, lamino and icosanoylamino. 13-fluorotridecyl, 14-fluorotetradecyl, 15-fluoropentadecyl, The alkoxycarbonyl as a substituent at R, R', Ra, Rb, 35 16 - fluorohexadecy 1, 17-fluorohept a de cyl, Ra, Rd, Re, Rf, Rt or RV is that where the alkoxy moiety is 18-fluoro octade cyl, 19-fluoro non a de cyl and an optionally Substituted Straight- or branched chain alkoxy 20-fluoroicosyl. having 1 to 20 carbon atoms, and is exemplified by The haloalkoxy as a substituent at R, R', Rd, Rt or RV has methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1 to 20 carbon atoms, and is exemplified by chloromethoxy, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, 40 bromomethoxy, fluoromethoxy, dichloromethoxy, tert-bu to Xy carbonyl, p enty lo Xy carbonyl, dibromomethoxy, difluoromethoxy, 2-chloroethoxy, is open tyloxycarbonyl, tert-penty loxycarbonyl, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 3-chloropropoxy, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, 3-fluoroprop o Xy, 2,2,3,3-tetrafluoro prop o Xy, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, 4-chlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, do de cylo Xy carbonyl, tride cylo Xy carbonyl, 45 5-fluoropentyloxy, 6-chlorohexyloxy, 6-fluorohexyloxy, tetradecyloxycarbonyl, pentade cyloxycarbonyl, 7-chloroheptyloxy, 7-fluoroheptyloxy, 8-fluorooctyloxy, hexadecyloxycarbonyl, heptade cyloxycarbonyl, 9-fluorononyloxy, 10-fluorodecyloxy, 11-fluoroundecyloxy, octadecyloxycarbonyl, nonadecyloxycarbonyl and 12-fluoro do de cyloxy, 13-fluorot ride cyl oxy, icosyloxycarbonyl, which may be substituted by phenyl. 14-fluorote tradecyloxy, 15-fluorope intadecyloxy, Examples thereof include benzyloxycarbonyl. 50 16-fluorohexadecyloxy, 17-fluoroheptadecyloxy, The alkoxycarbonylamino as a substituent at R, R', R'a, 18-fluorooctadecyloxy, 19-fluorononadecyloxy and Rb, Ra, Rd, Re, Rf, Rt or RV is that where the alkoxy 20-fluoroicosyloxy. moiety is an optionally Substituted Straight- or branched The halogen as a substituent at R, R', R'a, Rb, Ra, Rb, chain alkoxy having 1 to 20 carbon atoms, and is exempli Rc, Rd, Re, Rf, Rg, Ri, Rj, RS, Rt or RV is exemplified by fied by methoxycarbonylamino, ethoxycarbonylamino, 55 fluorine, chlorine, bromine and iodine. propoxycarbonylamino, isopropoxycarbonylamino, The aryl as a substituent at R, R or Rt is exemplified by butoxycarbonylamino, isobutoxycarbonylamino, tert phenyl and naphthyl, with preference given to phenyl. butoxycarbonylamino, pentyloxycarbonylamino, The aryloxy as a substituent at R, R'or Rt is exemplified isopentyloxycarbonylamino, tert-pentyloxycarbonylamino, by phenoxy and naphthyloxy, with preference given to he Xyloxycarbonylamino, heptyloxycarbonylamino, 60 phenoxy. octyloxycarbonylamino, no nyloxycarbonylamino, The cycloalkyl as a substituent at R, R, Ra, Rb or Rt decyloxycarbonylamino, undecyloxycarbonylamino, is that having 3 to 10 carbon atoms and is exemplified by dodecyloxycarbonylamino, tridecyloxycarbonylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetradecyloxycarbonylamino, pentadecyloxycarbonylamino, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl, with he X a decyl oxy carbonyl a mino, 65 preference given to cyclohexyl. heptadecyloxycarbonylamino, octadecyloxycarbonylamino, The heteroaryl as a substituent at R, R or Rt is a 5- or nonadecyloxycarbonylamino and icosyloxycarbonylamino, 6-membered heteroaryl optionally having, in the ring, 1 to 4 5,952,316 25 26 hetero atoms Selected from nitrogen atom, oxygen atom and Straight- or branched chain alkyls having 1 to 20 carbon Sulfur atom and includes, for example, monocyclic het atoms and have 2 to 20 carbon atoms in total, and is eroaryl such as thienyl(2-thienyl, 3-thienyl), furyl(2-furyl, eX emplified by phenylalkoxyalkyl Such as 3-furyl), pyrrolyl(1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), phenylmethyloxymethyl, 2-phenylethyloxymethyl, imidazolyl(2-imidazolyl, 4-imidazolyl etc.), pyrazolyl(3- 3-phenylpropyloxymethyl, 4-phenylbutyloxymethyl, pyrazolyl, 4-pyrazolyl etc.), triazolyl, tetrazolyl, thiazolyl 5-phenylpentyloxymethyl, 6-phenylhexyloxymethyl, (2-thiazolyl, 4-thiazolyl), isothiazolyl(3-isothiazolyl, 4-isothiazolyl), oxazolyl(2-oxazolyl, 4-oxazolyl), isoxazolyl 7-phenylheptyloxymethyl, 8-phenyloctyloxymethyl, (3-isooxazolyl, 4-isooxazolyl), pyridyl(2-pyridyl, 3-pyridyl, 9-phenylnonyloxymethyl, 10-phenyldecyloxymethyl, 4-pyridyl), pyrazinyl, pyrimidinyl (2-pyrimidinyl, 12-phenyl do de cyl oxy methyl, 4-pyrimidinyl), pyridazinyl(3-pyridazinyl, 4-pyridazinyl) 14- phenylte trade cyl oxy methyl, and pyranyl(2-pyranyl, 3-pyranyl, 4-pyranyl), and bicyclic 16-phenylhexadecyl oxy methyl O heteroaryl Such as indolyl(2-indolyl, 3-indolyl), quinolyl(2- 18-phenyloctadecyloxymethyl, and naphthylalkoxyalkyl quinoly 1, 3-quinolyl), isoquinolyl(1-isoquinolyl, such as 4-(2-naphthyl)butyloxymethyl, 5-(2-naphthyl) 3-iso quinolyl), benzofuranyl (2-benzofuranyl, pentyloxymethyl or 6-(2-naphthyl)hexyloxymethyl, with 3-benzofuranyl), benzothienyl (2-benzothienyl, 15 preference given to phenylalkoxyalkyl. 3-benzothienyl), 1H-benzimidazol-2-yl or chromenyl(2- The phenylalkoxyalkyl as a substituent at Re, Rf, Rg or chromenyl, 3-chromenyl, 4-chromenyl). Rk is that of the aforementioned aralkyloxyalkyl. The alicycle of the aforementioned heteroaryl as a Sub The phenylalkoxyalkyl as a substituent at Rl, where the stituent at R, R or Rt is the above-mentioned monocyclic alkoxy moiety and the alkyl moiety have 2 to 8 carbon atoms hetero aryl when Saturated Such as pyrrollidinyl(1- in total, is phenylalkoxyalkyl of the aforementioned pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidyl(2- aralkyloxyalkyl, having the Specified numbers of carbon piperidyl, 3-piperidyl, 4-piperidyl), piperidino, piperazinyl, atoms, in which the carbon number of the alkoxy moiety and morpholinyl or thiomorpholinyl. the alkyl moiety is respectively 1 to 7, with total being 2 to The carbon chain as a substituent at R'a is a straight- or 8. branched carbon chain having 1 to 30 carbon atoms Such as 25 The phenoxylalkyl as a substituent at Rd, Re, Rf, Rg or Rk methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, is that where the alkyl moiety is a Straight- or branched chain pentyl, isopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, alkyl having 1 to 20 carbon atoms and is exemplified by decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, phenoxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, 1-phenoxypropyl, 2-phenoxypropyl, 3-phenoxypropyl, he nicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, 4-phenoxybutyl, 5-phenoxypenty 1, 6-phenoxyhexyl, hexacosyl, heptacosyl, octacosyl, nonacosyl or triacontyl. 7-phenoxyheptyl, 8-phenoxyoctyl, 9-phenoxynonyl, The alkenyl as a substituent at R'b is a straight- or 10-phenoxydecyl, 11-phenoxyundecyl, 12-phenoxydodecyl, branched chain alkenyl having 2 to 20 carbon atoms Such as 13-phen oxytride cyl, 14-phen oxytetra de cyl, ethenyl, propenyl, isopropenyl, bute nyl, isobute nyl, 15-phenoxypenta de cyl, 16-phenoxy he Xade cyl, pentenyl, isopentenyl, hexenyl, heptenyl, octenyl, nonenyl, 35 17-phenoxyhepta de cyl, 18-phenoxyoctade cyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, 19-phenoxynonadecyl and 20-phenoxylicosyl. pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, The phenoxyalkyl as a substituent at R1, where the alkyl nonadecenyl or icoSenyl. moiety has 2 to 8 carbon atoms, is the aforementioned The alkynyl as a substituent at R'b is a straight- or phenoxyalkyl having the Specified numbers of carbon atoms. branched chain alkynyl having 2 to 20 carbon atoms Such as 40 The phenoxyalkoxy as a substituent at Rd, Re, Rf, Rg or ethynyl, propynyl, isopropynyl, butynyl, pentynyl, heXynyl, Rk is that where the alkoxy moiety is a Straight- or branched heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, chain alkoxy having 1 to 20 carbon atoms and is exemplified tride cynyl, tetradecynyl, pentadecynyl, hexadecynyl, by phe no Xy methoxy, 1-p he no Xy ethyl oxy, heptadecynyl, octadecynyl, nonadecynyl or icosynyl. 2-phen oxyethyl oxy, 1-p he no Xy propyl oxy, The haloaralkyloxy as a Substituent at Rd is that including 45 2-phe no Xy propyl oxy, 3-phe no Xy propyl oxy, aralkyl where the alkyl moiety is a Straight- or branched 4-phenoxybutyl oxy, 5-phe no Xy p enty lo Xy, chain alkyl having 1 to 20 carbon atoms, and is exemplified 6-phe no Xy he Xylo Xy, 7-p he no Xy he pty lo Xy, by halophenylalkoxy Such as 4-fluorobenzyloxy, 2-(4- 8-phe no Xy octyl oxy, 9-phe no Xy no nyloxy, fluorophenyl)ethyloxy, 1-(4-fluorophenyl)ethyloxy, 1-(4- 10-phenoxy de cyloxy, 11-phe no Xy unde cyloxy, fluorophenyl)propyloxy, 2-(4-fluorophenyl)propyloxy, 3-(4- 50 12-phenoxy dodecyloxy, 13-phenoxytride cyloxy, fluorophenyl)propyloxy, 4-(4-fluorophenyl)butyloxy, 5-(4- 14-phenoxytetradecyloxy, 15-phenoxypentadecyloxy, fluorophenyl)pentyloxy, 6-(4-fluorophenyl)hexyloxy, 7-(4- 16-phenoxyhexadecyloxy, 17-phenoxyheptadecyloxy, fluorophenyl)heptyloxy, 8-(4-fluorophenyl)octyloxy, 9-(4- 18-phenoxyoctadecyloxy, 19-phenoxynonadecyloxy and fluorophenyl)nonyloxy, 10-(4-fluorophenyl)decyloxy, 11 20-phenoxylicosyloxy. (4-fluorophenyl)undecyloxy, 12-(4-fluorophenyl) 55 The phenoxyalkoxy as a substituent at Rl, where the dodecyloxy, 13-(4-fluorophenyl)tridecyloxy or 14-(4- alkoxy moiety has 2 to 8 carbon atoms, is the aforemen fluorophenyl)tetradecyloxy, and halonaphthylalkoxy Such as tioned phenoxyalkoxy having the Specified numbers of (7-fluoro-2-naphthyl)methyloxy or 2-(7-fluoro-2-naphthyl) carbon atoms. ethyloxy, with preference given to halophenylalkoxy. The alkylat R, Ra, Rb, Ric, R, Ra, Rb, Ric, R, Ra, The halophenylalkoxy as a substituent at Re, Rf, Rg or Rk 60 R"b, R, Ra, Rb or R is that having 1 to 20 carbon atoms is that of the aforementioned haloaralkyloxy. and is exemplified by methyl, ethyl, propyl, isopropyl, butyl, The halophenylalkoxy as a substituent at R1, where the isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, alkoxy moiety has 2 to 8 carbon atoms, is halophenylalkoxy heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, of the aforementioned haloaralkyloxy, having the Specified tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, numbers of carbon atoms. 65 nonadecyl and icosyl. The aralkyloxyalkyl as a substituent at Rd is that where The aralkyl at R,R,R,R or R is that where the alkyl the alkyl moiety and the alkyl moiety of the aralkyl are moiety is a Straight- or branched chain alkyl having 1 to 20 5,952,316 27 28 carbon atoms and is exemplified by benzyl, 1-phenylethyl, undecyl oxy carbonyl, do de cylo Xy carbonyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, tride cyloxycarbonyl, tetrade cyloxycarbonyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, pentade cyloxycarbonyl, hexadecyloxycarbonyl, 6-phenylhexyl, 7-phenylheptyl, 8-phenyloctyl, heptadecyloxycarbonyl, octadecyloxycarbonyl, nonadecy 9-phenylnonyl, 10-phenyldecyl, 11-phenylundecyl, loxycarbonyl and icosyloxycarbonyl, which may be Substi 12-phenyldodecyl, 13-phenyltridecyl, 14-phenyltetradecyl, tuted by phenyl. Examples thereof include benzyloxycarbo 15-phenylp ent a de cyl, 16-phenyl he X a de cyl, nyl. 17- phenylhepta de cyl, 18-phenyl octa de cyl, The alkylene chain formed by R' and R is a straight- or 19-phenylnonadecyl and 20-phenylicosyl. branched chain alkylene having 1 to 5 carbon atoms and is The acyl at R, Ra, Rb, R, Ra, Rb, R, Ra, Rb, R, exemplified by methylene, ethylene, trimethylene, Ra, Rb or R is optionally substituted alkanoyl or aroyl propylene, butylene, 1,2-dimethylethylene and pentameth where the alkanoyl is a Straight- or branched chain alkanoyl ylene. having 1 to 20 carbon atoms, and alkoanoyl is exemplified The alkyl as a substituent at R' or R is a straight- or by formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, branched chain alkyl having 1 to 5 carbon atoms and is heXanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, 15 exemplified by methyl, ethyl, propyl, isopropyl, butyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, isobutyl, Sec-butyl, tert-butyl and pentyl. pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl, which may be Substituted by The aryl as a substituent at R' or R is, for example, phenyl. Examples thereof include phenylacetyl and phenyl phenyl or naphthyl. propionyl. Examples of aroyl include benzoyl. The aralkyl as a substituent at R' or R is that where the The alkoxycarbonyl at R, Ra, R, Ra, R", Ra, R, Ra alkyl moiety is a Straight- or branched chain alkyl having 1 or R is that where the alkoxy moiety is an optionally to 5 carbon atoms and is exemplified by benzyl, 2-phenethyl, Substituted Straight- or branched chain alkoxy having 1 to 20 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, carbon atoms and is exemplified by methoxycarbonyl, 3-phenylpropyl, 4-phenylbutyl and 5-phenylpentyl. ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, 25 The alkylene chain formed by R' and R, which is butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, Substituted by alkyl, aryl or aralkyl, is preferably ethylidene, penty loxycarbonyl, is open tyloxycarbonyl, tert isopropylidene, benzylidene or 2-phenylethylidene. pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, The preferable compounds of the present invention are octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, shown in the following tables.

CHOR R2RN-C-CHORS CHR

R1 R2 R3 R4 Rs

H H H H H H H H H H H H H H H H H H H H H H H H H H H H COCH, H COCH, COCH, H H H H H H H H COCH, H COCH, COCH, H H H H H H H H COCH, H COCH, COCH, H H H H H H H H COCH, H COCH, COCH, CHCHCCH)(CH), CHCHCCH). H H H H CHCHCCH)(CH), CHCHCCH). COCH, H COCH, COCH, H H H H COCH, H COCH, COCH, H H H H CH CH H H (CH2)CH(CH)CH H H H H H H H H COCH, H COCH, COCH, H H H H H H H H H H H H CHs H H H H H COCH, COCH, COCH H COCH, COCH, COCH H H H C5H11 H H H

5,952,316 57 58 -continued CHOR R2R3N-C-CHORS CHR

R R 2 R3 R 4 Rs

COCH, COCH, COCH, H H

5,952,316 63 64 -continued CHOR R2R3N- - CHORS CHR

R R 2 R3 R 4 Rs

H

5,952,316 75 76 -continued CHOR R2R3N-C-CHORS CHR

R R3 Rs COCH, COCH, H H COCH, COCH,

5,952,316 99 100 -continued CHOR R2R3N-C-CHORS R

R R3

CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO (CH)-2-CHN-4 CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO

CH-4-CHN CH-4-CHN CO CO CO (CH-)-4-CHN (CH2)-4-CHN CHCO CHCO CHCO (CH-)-4-C5HN (CH-)-4-CHN CHCO CHCO CHCO (CH2)4-CHN (CH2)4-CHN CHCO CHCO CHCO (CH)2-4-CHN H H

5,952,316 103 104 -continued CHOR R2R3N-C-CHORS R

R R3

CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO

CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO

CO CO CO

CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO H H 5,952,316 105 106 -continued CHOR R2R3N-C-CHORS R

R R3 R4 Rs CHCO CHCO CHCO H H CHCO CHCO CHCO H H CHCO CHCO CHCO H H CHCO CHCO CHCO H H CHCO CHCO CHCO H H CHCO CHCO CHCO H H CHCO CHCO CHCO H H CHCO CHCO CHCO H H H H H H H H H H H H H H H H H H H H H H C HCO CHCO CHCO H H CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO CHCO

5,952,316 109 110 -continued CHOR R2R3N-C-CHORS R

R3 R4

H. H.

H. H. -ON- CHCH H. H. (CH2)9 -ON-CH H. H. (CH2)10 -ONH H. H. (CH2) 11 -ONH H. H. CH -O- H. H. (CH)- O)- H. H. (CH2)- O)- H. H.

H. H.

H. H. (CH)-

H. H. (CH) -

H. H. O)- CHCH

5,952,316 149 150 -continued -continued tor tor R2R3N- – CHOR 5 R2R3N- – CHOR R R

R R2 R3 R4 RS R R2 R3 R4 Rs N \ (CH2)12CH3 H H H H H. H. H. H. (CH2)2 -Q (CH2)2 (CH2)11CH3 O NRN

N \ H. H. H. H. / \ (CH2)6CH3 H. H. H. H. (CH2)2 - y (CH2)7CH3 15 (CH2)-( s O NEN

\ H. H. H. H. (CH2)10CH3 H. H. H. H. (CH2)2 -K (CH2)11CH3 20 (CH2)2-k O NEN N \ H. H. H. H. (CH2)2 ( )—citat Examples of the pharmaceutically acceptable salts of the NF compounds of the formula (I) hereinafter referred to as H. H. H. H. Compound (I) include Salts with inorganic acids, Such as N \ hydrochloride, hydrobromide and Sulfate, Salts with organic (CH-( (CH2)11CH3 acids, Such as acetate, fumarate, maleate, benzoate, citrate, NF 30 malate, methaneSulfonate and benzeneSulfonate, and when carboxyl group is included, Salts with metals. Such as Sodium N (CH2)6CH3 H. H. H. H. Salt, potassium Salt, calcium Salt and aluminum Salt, Salts (CH2)2 -( y with amines, Such as triethylamine and salts with dibasic o amino acids, Such as lysine. The compounds of the present N invention encompass hydrates and Solvates. N (CH2)10CH3 H. H. H. H. When the compounds of the present invention include W \ geometric isomers, the present invention encompasses cis (CH2)2 compounds, trans- compounds and mixtures thereof. When NF 40 the compounds of the present invention have one or more asymmetric centers in the molecule, various optical isomers (CH2) N (CH2)6CH are obtained. The present invention also encompasses opti 22 26R-13 cal isomers, racemates, diastereomers and mixtures thereof. % The compounds of the present invention can be produced 45 by the following methods. N H. H. H. H. Method A (CH2)2 N -(CH2)6CH, ( ) A compound of the formula (II) 2 N 50

N RCH-G (II) (CH2)2 n 2 2 (CH2)7CH3 55 wherein R'CH is the same as the aforementioned R'CH, N RaCH, RbCH, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj. Rk, R1, Rim, Rn or Ro which are encompassed in R, and G (CH2)2 N is a leaving group in wide use in the field of organic Synthetic chemistry, Such as halogen (fluorine, chlorine, 2 (CH2)11CH3 60 bro mine, iodine), me thane Sulfonyl oxy, N p-toluenesulfonyloxy or trifluoromethaneSulfonyloxy hereinafter referred to as Compound (II)), or when R' has ( ) H. H. H. H. a functional group (e.g. amino, hydroxyl group, mercapto, (CH2)2 (CH2)7CH3 ketone, carboxyl), a compound with protection of the func NEN 65 tional group as necessary hereinafter referred to as Com pound B-(II) is condensed, in the presence of a base, with a compound of the formula (III) 5,952,316 151 152 alcohol, tetrahydrofuran, diethyl ether and ethylene glycol COOY (III) dimethyl ether. The temperature for the reduction of carboxyl is generally OHN-C-COOY from -20° C. to 80 C. and a temperature lower or higher than this temperature range may be Selected on demand. H The reduction of carboxyl is generally carried out for 30 minutes to 10 hours and the reaction period longer or shorter wherein Y is lower alkyl (e.g. methyl, ethyl, propyl, than the indicated period may be used as necessary. isopropyl, butyl, tert-butyl) or aralkyl (e.g. benzyl, After the reduction is carried out under the above nitrobenzyl, methoxybenzyl, methylbenzyl), and Q is an mentioned conditions or after removing the protecting group amino-protecting group widely used in the field of organic 1O on demand, the objective compound can be purified by a Synthetic chemistry, Such as acetyl, benzoyl, tert method known in the field of organic Synthetic chemistry, butoxycarbonyl or benzyloxycarbonyl, where the two Ys in Such as Solvent extraction, recrystallization, chromatogra the molecule in the formula may together form a ring Such phy and a method using an ion eXchange resin. as dioxane and Q and Y in the molecule may together form (Method B) a ring Such as oxazolidine or oxazine hereinafter referred to 15 A Compound (II) or a Compound B-(II) is condensed, in as Compound (III) to give a compound of the formula (IV) the presence of a base, with a compound of the formula (V)

COOY (IV) CHOZ (V) OHN-C-COOY OHN-C-COOY CHR H wherein R', Q and Y are as defined above hereinafter wherein Y and Q are as defined above, and Z is a hydroxy referred to as Compound (IV)), which is subjected to reduc 25 protecting group widely used in the field of organic Synthetic tion of carboxyl with a Suitable reducing agent and depro chemistry, Such as acetyl, benzoyl, benzyl, trimethylsilyl, tection as necessary to give a compound of the formula tert-butyldimethylsilyl, methoxymethyl, methoxyethoxym (I-29) ethyl or tetrahydropyranyl hereinafter referred to as Com pound (V) to give a Compound of the formula (VI) CH2OH (I-29) CHOZ (VI) HN-C-CHOH OHN-C-COOY CHR CHR 35 wherein R is as defined above hereinafter referred to as Compound (I-29) or an N- and/or O-protected compound wherein R', Q, Y and Z are as defined above hereinafter thereof. referred to as Compound (VI)). The obtained compound is Examples of the base to be used in the condensation then subjected to reduction of carboxyl with a suitable include Sodium hydroxide, Sodium methoxide, Sodium reducing agent and deprotection as necessary to give a ethoxide, Sodium hydride, potassium hydride, lithium 40 compound (I-29) or an N- and/or O-protected compound diisop ropylamide, butyl lithium, lithium thereof. hexamethyldisilaZane, triethylamine, diisopropylethylamine Examples of the base to be used in the condensation and 1,8-diazabicyclo5.4.0]undeca-7-ene. include Sodium hydroxide, Sodium methoxide, Sodium Examples of the organic Solvent to be used in the con ethoxide, Sodium hydride, potassium hydride, lithium densation include methanol, ethanol, tert-butyl alcohol, 45 diisop ropylamide, butyl lithium, lithium tetrahydrofuran, diethyl ether, ethylene glycol dimethyl hexamethyldisilaZane, triethylamine, diisopropylethylamine ether, dimethylformamide, dimethyl Sulfoxide, benzene, and 1,8-diazabicyclo5.4.0]undeca-7-ene. toluene, Xylene, dioxane, methylene chloride, chloroform, Examples of the organic Solvent to be used in the con dichloroethane and acetonitrile. densation include methanol, ethanol, tert-butyl alcohol, The condensation generally proceeds at a temperature of 50 tetrahydrofuran, diethyl ether, ethylene glycol dimethyl from -20° C. to 150° C. and a temperature lower or higher ether, dimethylformamide, dimethyl Sulfoxide, benzene, than this temperature range may be Selected on demand. toluene, Xylene, dioxane, methylene chloride, chloroform, The condensation is generally carried out for 30 minutes dichloroethane and acetonitrile. to 2 days and the reaction period longer or shorter than the The condensation generally proceeds at a temperature of indicated period may be used as necessary. 55 from -20° C. to 150° C. and a temperature lower or higher After the condensation is carried out under the above than this temperature range may be Selected on demand. mentioned conditions or after removing the protecting group The condensation is generally carried out for 30 minutes on demand, the Compound (IV) can be purified by a method to 2 days and the reaction period longer or shorter than the known in the field of organic Synthetic chemistry, Such as indicated period may be used as necessary. Solvent extraction, recrystallization, chromatography and a 60 After the condensation is carried out under the above method using an ion eXchange resin. mentioned conditions or after removing the protecting group Examples of the reducing agent to be used in the reduction on demand, the Compound (VI) can be purified by a method of carboxyl include metallic reducing reagent Such as known in the field of organic Synthetic chemistry, Such as Sodium borohydride, lithium borohydride or lithium alumi Solvent extraction, recrystallization, chromatography and a num hydride, and diborane. 65 method using an ion eXchange resin. Examples of the organic Solvent to be used in the reduc Examples of the reducing agent to be used for the reduc tion of carboxyl include methanol, ethanol, tert-butyl tion of carboxyl include metallic reducing reagent Such as 5,952,316 153 154 Sodium borohydride, lithium borohydride or lithium alumi Sodium borohydride, lithium borohydride or lithium alumi num hydride, and diborane. num hydride, and diborane. Examples of the organic Solvent to be used for the Examples of the organic Solvent to be used for the reduction of carboxyl include methanol, ethanol, tert-butyl reduction of carboxyl include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether and ethylene glycol alcohol, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether. dimethyl ether. The temperature of the reduction of carboxyl is generally The temperature of the reduction of carboxyl is generally from -20° C. to 80 C. and a temperature lower or higher from -20° C. to 80 C. and a temperature lower or higher than this temperature range may be Selected on demand. than this temperature range may be Selected on demand. The reduction of carboxyl is generally carried out for 30 The reduction is generally carried out for 30 minutes to 10 minutes to 10 hours and the reaction period longer or shorter hours and the reaction period longer or shorter than the than the indicated period may be used as necessary. indicated period may be used as necessary. After the reduction is carried out under the above Examples of the reducing agent to be used for the reduc mentioned conditions or after removing the protecting group tion of azide include metallic reducing reagent Such as on demand, the objective compound can be purified by a Sodium borohydride, lithium borohydride or lithium alumi method known in the field of organic Synthetic chemistry, 15 num hydride, and transition metal Such as palladium-carbon, Such as Solvent extraction, recrystallization, chromatogra platinum oxide, Raney nickel, rhodium or ruthenium for phy and a method using an ion eXchange resin. catalytic reduction. (Method C) Examples of the organic Solvent to be used for the A Compound (II) or a Compound B-(II) is condensed, in reduction of azide include methanol, ethanol, tert-butyl the presence of a base, with a compound of the formula (VII) alcohol, tetrahydrofuran, diethyl ether, dioxane, acetone, ethyl acetate, acetic acid, benzene, toluene, Xylene, dimeth ylformamide and dimethyl sulfoxide. COOY (VII) The temperature of the reduction of azide is generally N-C-COOY from -20° C. to 80 C. and a temperature lower or higher 25 than this temperature range may be Selected on demand. H After the reduction is carried out under the above mentioned conditions or after removing the protecting group wherein Y is as defined above hereinafter referred to as on demand, the objective compound can be purified by a Compound (VII) to give a compound of the formula (VIII) method known in the field of organic Synthetic chemistry, Such as Solvent extraction, recrystallization, chromatogra COOY (VIII) phy and a method using an ion eXchange resin. (Method D) N-C-COOY A Compound (II) or a Compound B-(II) is condensed, in CHR the presence of a base, with a compound of the formula (IX) 35 CHOZ (DX) wherein R' and Y are as defined above hereinafter referred to as Compound (VIII)). The obtained compound is then ON-C-CHOZ2 Subjected to reduction of carboxyl and azide with a Suitable H reducing agent and deprotection as necessary to give a 40 Compound (I-29) or an O-protected compound thereof. Examples of the base to be used for the condensation wherein Z' and Z are the same or different and each is include Sodium hydroxide, Sodium methoxide, Sodium hydroxyl-protecting group widely used in the field of ethoxide, Sodium hydride, potassium hydride, lithium organic Synthetic chemistry, Such as acetyl, benzoyl, benzyl, diisop ropylamide, butyl lithium, lithium 45 trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, hexamethyldisilaZane, triethylamine, diisopropylethylamine methoxyethoxymethyl or tetrahydropyranyl and Z' and Z and 1,8-diazabicyclo5.4.0]undeca-7-ene. may together form a ring Such as dioxane hereinafter Examples of the organic Solvent to be used for the referred to as Compound (IX) to give a compound of the condensation include methanol, ethanol, tert-butyl alcohol, formula (X) tetrahydrofuran, diethyl ether, ethylene glycol dimethyl 50 ether, dimethylformamide, dimethyl Sulfoxide, benzene, CHOZ (X) toluene, Xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile. ON-C-CHOZ2 The condensation generally proceeds at a temperature of CHR from -20° C. to 150° C. and a temperature lower or higher 55 than this temperature range may be Selected on demand. The condensation is generally carried out for 30 minutes wherein R', Z' and Z are as defined above hereinafter to 2 days and the reaction period longer or shorter than the referred to as Compound (X)). The obtained compound is indicated period may be used as necessary. then Subjected to reduction of nitro with a Suitable reducing After the condensation is carried out under the above 60 agent and deprotection as necessary to give a Compound mentioned conditions or after removing the protecting group (I-29) or an O-protected compound thereof. on demand, the Compound (VIII) can be purified by a Examples of the base to be used for the condensation method known in the field of organic Synthetic chemistry, include Sodium hydroxide, Sodium methoxide, Sodium Such as Solvent extraction, recrystallization, chromatogra ethoxide, Sodium hydride, potassium hydride, lithium phy and a method using an ion eXchange resin. 65 diisop ropylamide, butyl lithium, lithium Examples of the reducing agent to be used for the reduc hexamethyldisilaZane, triethylamine, diisopropylethylamine tion of carboxyl include metallic reducing reagent Such as and 1,8-diazabicyclo5.4.0]undeca-7-ene. 5,952,316 15S 156 Examples of the organic Solvent to be used for the Such as acetyl, benzoyl, tert-butoxycarbonyl or benzyloxy condensation include methanol, ethanol, tert-butyl alcohol, carbonylhereinafter referred to as Compound (XII) to give tetrahydrofuran, diethyl ether, ethylene glycol dimethyl a compound of the formula (IV-a) ether, dimethylformamide, dimethyl Sulfoxide, benzene, toluene, Xylene, dioxane, methylene chloride, chloroform, COOY (IV-a) dichloroethane and acetonitrile. The condensation generally proceeds at a temperature of O'HN-C-COOY from -20° C. to 150° C. and a temperature lower or higher R11 than this temperature range may be Selected on demand. The condensation is generally carried out for 30 minutes to 2 days and the reaction period longer or shorter than the wherein R', Q' and Y are as defined above hereinafter indicated period may be used as necessary. referred to as Compound (IV-a). The obtained compound is After the condensation is carried out under the above then subjected to reduction of carboxyl with a suitable mentioned conditions or after removing the protecting group reducing agent and deprotection as necessary to give a on demand, the Compound (X) can be purified by a method 15 compound of the formula (I-30) known in the field of organic Synthetic chemistry, Such as Solvent extraction, recrystallization, chromatography and a CH2OH (I-30) method using an ion eXchange resin. Examples of the reducing agent to be used for the reduc HN-C-CH-OH tion of nitro include metallic reducing reagent Such as R11 Sodium borohydride, lithium borohydride or lithium alumi num hydride, transition metal Such as palladium-carbon, platinum oxide, Raney nickel, rhodium or ruthenium for wherein R' is as defined above hereinafter referred to as catalytic reduction, and metal Such as iron, Zinc or tin. Compound (I-30) or an N- and/or O-protected compound Examples of the solvent to be used for the reduction of 25 thereof. nitro include water, methanol, ethanol, tert-butyl alcohol, Examples of the organic Solvent to be used for the tetrahydrofuran, diethyl ether, dioxane, acetone, ethyl addition include tetrahydrofuran, diethyl ether, ethylene acetate, acetic acid, benzene, toluene, Xylene, dimethylfor glycol dimethyl ether, dimethylformamide, dimethyl mamide and dimethyl sulfoxide. Sulfoxide, benzene, toluene, Xylene, dioxane, methylene The reduction of nitrogenerally proceeds at a temperature chloride, chloroform, dichloroethane and acetonitrile. of from -20° C. to 80 C. and a temperature lower or higher The addition generally proceeds at a temperature of from than this temperature range may be Selected on demand. -100° C. to 80 C. and a temperature lower or higher than After the reduction is carried out under the above this temperature range may be Selected on demand. mentioned conditions or after removing the protecting group The addition is generally carried out for 30 minutes to 2 on demand, the objective compound can be purified by a 35 days and the reaction period longer or shorter than the method known in the field of organic Synthetic chemistry, indicated period may be used as necessary. Such as Solvent extraction, recrystallization, chromatogra After the addition is carried out under the above phy and a method using an ion eXchange resin. mentioned conditions or after removing the protecting group The above-mentioned methods A through D can be used on demand, the Compound (IV-a) can be purified by a for the synthesis of the compounds of the formulas (I-1) to 40 method known in the field of organic Synthetic chemistry, (I-18). Such as Solvent extraction, recrystallization, chromatogra (Method E) phy and a method using an ion eXchange resin. A compound of the formula (XI) Examples of the reducing agent to be used for the reduc tion of carboxyl include metallic reducing reagent Such as 45 Sodium borohydride, lithium borohydride or lithium alumi wherein R' is the same as the aforementioned CHR', num hydride, and diborane. CHR'a, CHR'b, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj. Examples of the organic Solvent to be used for the reduction of carboxyl include methanol, ethanol, tert-butyl Rk, R1, Rim, Rn, Ro, Rp, Rd, CH=CHRt, CH=CHRu, alcohol, tetrahydrofuran, diethyl ether and ethylene glycol (CH2)C-X-(CH2)(BRV (when C.21) or CHORw which 50 are encompassed in R, M is a metal in wide use in the field dimethyl ether. of organic Synthetic chemistry, Such as lithium, magnesium The reduction of carboxyl generally proceeds at a tem chloride, magnesium bromide, magnesium iodide, copper, perature of from -20° C. to 80° C. and a temperature lower lithium copper or nickel, and n is an integer of 1 to 3 or higher than this temperature range may be Selected on hereinafter referred to as Compound (XI), or when R' has demand. a functional group (e.g. amino, hydroxyl group, mercapto, 55 The reduction of carboxyl is generally carried out for 30 ketone, carboxyl), a compound with protection of the func minutes to 10 hours and the reaction period longer or shorter tional group as necessary hereinafter referred to as Com than the indicated period may be used as necessary. pound B-(XI) is subjected to nucleophilic addition to a After the reduction is carried out under the above compound of the formula (XII) 60 mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a COOY (XII) method known in the field of organic Synthetic chemistry, Such as Solvent extraction, recrystallization, chromatogra O'N=C-COOY phy and a method using an ion eXchange resin. 65 The instant method can be used for the synthesis of the wherein Y is as defined above and Q' is an imino-protecting compounds of the formulas (I-1) to (I-20), (I-24), (I-25), group in wide use in the field of organic Synthetic chemistry, (I-26) when C.21 and (I-27). 5,952,316 157 158 (Method F) The condensation is generally carried out for 30 minutes A compound of the formula (XIII) to 2 days and the reaction period longer or shorter than the indicated period may be used as necessary. -- -- - After the condensation is carried out under the above RtCH2PPhHal O RuCH2PPHal mentioned conditions or after removing the protecting group (XIII-1) (XIII-2) on demand, the Compound (XV-1) or (XV-2) can be purified by a method known in the field of organic Synthetic chemistry, Such as Solvent extraction, recrystallization, chro wherein Hal is halogen Such as chlorine, bromine or iodine matography or a method using an ion eXchange resin. and Rt and Ru are as defined above hereinafter referred to The instant method can be used for the synthesis of the as Compound (XIII-1) or Compound (XIII-2)), or when Rt compounds of the formulas (I-24) and (I-25). By reducing and Ru have a functional group (e.g. amino, hydroxyl, the double bond of the compounds of the formulas (I-24) and mercapto, ketone, carboxyl), a compound with protection of (I-25), or an N- and/or O-protected compound thereof, the the functional group as necessary hereinafter referred to as compounds of the formulas (I-1) through (I-18) and (I-26) Compound B-(XIII-1) or Compound B-(XIII-2) is 15 when C.22 can be obtained. condensed, in the presence of a base, with a compound of the Examples of the reducing agent to be used for the reduc formula (XIV) tion of the double bond include metal reducing reagent Such as sodium borohydride, lithium borohydride or lithium (XIV) aluminum hydride, and transition metal Such as palladium carbon, platinum oxide, Raney nickel, rhodium or ruthenium CHOZ for catalytic reduction. QQ2N-C-CHOZ2 Examples of the organic Solvent to be used for the reduction of the double bond include methanol, ethanol, CHO tert-butyl alcohol, tetrahydrofuran, diethyl ether, dioxane, 25 acetone, ethyl acetate, acetic acid, benzene, toluene, Xylene, wherein Q' and Q are amino-protecting groups widely used dimethylformamide and dimethyl sulfoxide. in the field of organic Synthetic chemistry, Such as acetyl, The reduction of the double bond generally proceeds at a benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl or benzyl temperature of from -20° C. to 80° C. and a temperature lower or higher than this temperature range may be Selected and one of them may be hydrogen, and Z' and Z are as on demand. defined above hereinafter referred to as Compound (XIV) After the reduction is carried out under the above to give a compound of the formula (XV) mentioned conditions or after removing the protecting group on demand, the objective compounds of the formulas (I-1) (XV-1) through (I-18) and (I-26) when C.22 can be purified by a 35 method known in the field of organic Synthetic chemistry, CHOZ Such as Solvent extraction, recrystallization, chromatogra Olo2N- – CHOZ? phy or a method using an ion exchange resin. (Method G) h CHRt or A compound of the formula (XVI) (XV-2) 40 CHOZ R111CHG (XVI-1) QON-C-CHOZ2 RpCH.G (XVI-2) 45 O CHF CHR wherein Rt, Ru, Q, Q , Z' and Z are as defined above RqCHG (XVI-3) hereinafter referred to as Compound (XV-1) or Compound (XV-2)). The obtained compound is then subjected to depro 50 wherein R''' is the aforementioned CHR, CHR'a, tection as necessary to give a compound (I-24) or (I-25). CHR'b, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, R1, Rim, Examples of the base to be used in the condensation Rn or Ro which are encompassed in R, and Rp, Rd and G include Sodium hydroxide, Sodium methoxide, Sodium are as defined above hereinafter referred to as Compound ethoxide, potassium tert-butoxide, Sodium hydride, potas (XVI-1), Compound (XVI-2) or Compound (XVI-3)), or sium hydride, lithium diisopropylamide, butyl lithium, 55 when R', Rp and Rd have a functional group (e.g. amino, lithium he X a methyl disila Zane, trie thylamine, hydroxyl, mercapto, ketone, carboxyl), a compound with diisopropylethylamine, pyridine and 1,8-diazabicyclo5.4.0) protection thereof as necessary hereinafter referred to as undeca-7-ene. Compound B-(XVI-1), Compound B-(XVI-2) or Compound Examples of the solvent to be used for the condensation B-(XVI-3) is reacted with a compound of the formula include water, methanol, ethanol, tert-butyl alcohol, 60 (XVII) tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl Sulfoxide, benzene, M*(NO), (XVII) toluene, Xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile. wherein M is a metal Such as Sodium, potassium, The condensation generally proceeds at a temperature of 65 magenesium, Silver, calcium or lithium and n is an integer of from -20° C. to 150° C. and a temperature lower or higher 1 or 2 hereinafter referred to as Compound (XVII) to give than this temperature range may be Selected on demand. a compound of the formula (XVIII) 5,952,316 160 Examples of the solvent to be used for the condensation of the Compound (XVIII-1), (XVIII-2) or (XVIII-3) and R111CHNO, (XVIII-1) formalin include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dim RpCHNO, (XVIII-2) ethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, Xylene, dioxane, methylene chloride, O chloroform, dichloroethane and acetonitrile. Examples of the base to be used for the condensation include Sodium hydroxide, Sodium methoxide, Sodium 1O ethoxide, Sodium hydride, potassium hydride, triethylamine, RqCHNO, (XVIII-3) diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca wherein R', Rp and Rd are as defined above hereinafter 7-ene. referred to as Compound (XVIII-1), Compound (XVIII-2) The condensation generally proceeds at a temperature of or Compound (XVIII-3). The obtained compound is con from -20° C. to 150° C. and a temperature lower or higher densed with formalin in the presence of a base, and then 15 than this temperature range may be Selected on demand. Subjected to protection of hydroxyl as necessary to give a The condensation is generally carried out for 30 minutes to 2 days and the reaction period longer or shorter than the compound of the formula (XIX) indicated period may be used as necessary. After the condensation is carried out under the above (XIX-1) mentioned conditions or after removing the protecting group on demand, the Compound (XIX-1), (XIX-2) or (XIX-3) can CHOZ be purified by a method known in the field of organic ON- l - CHOZ2 Synthetic chemistry, Such as Solvent extraction, recrystallization, chromatography or a method using an ion k . 25 eXchange resin. Examples of the reducing agent to be used for the reduc (XIX-2) tion of nitro include metallic reducing reagent Such as Sodium borohydride, lithium borohydride or lithium alumi CHOZ num hydride, transition metal Such as palladium-carbon, ON- l - CHOZ2 platinum oxide, Raney nickel, rhodium or ruthenium for catalytic reduction, and metal Such as iron, Zinc or tin. r O Examples of the solvent to be used for the reduction of nitro include water, methanol, ethanol, tert-butyl alcohol, (XIX-3) tetrahydrofuran, diethyl ether, dioxane, acetone, ethyl CHOZ 35 acetate, acetic acid, benzene, toluene, Xylene, dimethylfor mamide and dimethyl sulfoxide. ON-C-CHOZ2 The reduction of nitrogenerally proceeds at a temperature of from -20° C. to 80° C. and a temperature lower or higher than this temperature range may be Selected on demand. 40 After the reduction is carried out under the above wherein R', Rp, Rd, Z and Z are as defined above mentioned conditions or after removing the protecting group hereinafter referred to as Compound (XIX-1), Compound on demand, the objective compound can be purified by a (XIX-2) or Compound (XIX-3). The obtained compound is method known in the field of organic Synthetic chemistry, then Subjected to reduction of nitro with a Suitable reducing Such as Solvent extraction, recrystallization, chromatogra agent and deprotection as necessary to give a desired com 45 phy or a method using an ion exchange resin. pound inclusive of the compounds (I-19) and (I-20). The instant method is suitable for the synthesis of the Examples of the solvent to be used for the condensation compounds (I-19) and (I-20), as well as for the synthesis of of nitrite (XVII) and the Compound (XVI-1), (XVI-2) or the compounds of the formulas (I-1) through (I-18). (XVI-3) include water, methanol, ethanol, tert-butyl alcohol, (Method H) tetrahydrofuran, diethyl ether, ethylene glycol dimethyl 50 A compound of the formula (XX) ether, dimethylformamide, dimethyl Sulfoxide, benzene, toluene, Xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile. RCHO (XX-1) The condensation generally proceeds at a temperature of from -20° C. to 150° C. and a temperature lower or higher 55 RrCHO (XX-2) than this temperature range may be Selected on demand. O The condensation is generally carried out for 30 minutes to 2 days and the reaction period longer or shorter than the indicated period may be used as necessary. 60 RSCHO (XX-3) After the condensation is carried out under the above mentioned conditions or after removing the protecting group wherein R', Rr and Rs are as defined above hereinafter on demand, the Compound (XVIII-1), (XVIII-2) or (XVIII referred to as Compound (XX-1), Compound (XX-2) or 3) can be purified by a method known in the field of organic Compound (XX-3) is condensed, in the presence of a base, Synthetic chemistry, Such as Solvent extraction, 65 with a Compound (IX) and subjected to protection of recrystallization, chromatography or a method using an ion hydroxyl as necessary to give a compound of the formula eXchange resin. (XXI) 5,952,316 162 Examples of the solvent to be used for the condensation (XXI-1) include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl Sulfoxide, benzene, toluene, Xylene, dioxane, methylene chloride, chloroform, toz dichloroethane and acetonitrile. ON- – CHOZ? The condensation generally proceeds at a temperature of CH(OZa)R , from -20° C. to 150° C. and a temperature lower or higher than this temperature range may be Selected on demand. The condensation is generally carried out for 30 minutes (XXI-2) to 2 days and the reaction period longer or shorter than the indicated period may be used as necessary. After the condensation is carried out under the above toz mentioned conditions or after removing the protecting group ON- i- CHOZ? 15 on demand, the Compound (XXI-1), (XXI-2) or (XXI-3) can CH(OZa)Rr O be purified by a method known in the field of organic Synthetic chemistry, Such as Solvent extraction, recrystallization, chromatography or a method using an ion (XXI-3) eXchange resin. Examples of the reducing agent to be used for the reduc CHOZ tion of nitro include metal reducing reagent Such as Sodium borohydride, lithium borohydride or lithium aluminum ON-C-CHOZ2 hydride, transition metal Such as palladium-carbon, plati num oxide, Raney nickel, rhodium or ruthenium for catalytic 25 reduction, and metal Such as iron, Zinc or tin. Examples of the solvent to be used for the reduction of wherein R', Rr, Rs, Z' and Z are as defined above and Za nitro include water, methanol, ethanol, tert-butyl alcohol, is hydrogen or a hydroxyl-protecting group in wide use in tetrahydrofuran, diethyl ether, dioxane, acetone, ethyl the field of organic Synthetic chemistry, Such as acetyl, acetate, acetic acid, benzene, toluene, Xylene, dimethylfor benzoyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, mamide and dimethyl sulfoxide. methoxymethyl, methoxyethoxymethyl or tetrahydropyra The reduction of nitrogenerally proceeds at a temperature nyl hereinafter referred to as Compound (XXI-1), Com of from -20° C. to 80° C. and a temperature lower or higher pound (XXI-2) or Compound (XXI-3). The obtained com than this temperature range may be Selected on demand. pound is then Subjected to reduction of nitro with a Suitable After the reduction is carried out under the above reducing agent and deprotection as necessary to give a 35 mentioned conditions or after removing the protecting group compound of the formula (XXII) on demand, the Compound (XXII-1), (I-22) or (I-23) can be purified by a method known in the field of organic Synthetic (XXII-1) chemistry, Such as Solvent extraction, recrystallization, chro matography or a method using an ion eXchange resin. CH2OH 40 Accordingly, the instant method can be used for the HN-C-CHOH synthesis of the compounds of the formulas (I-21) through (I-23). (Method I) Compound (XVIII-1) can be also produced by the fol (I-22) 45 lowing method. CH2OH A compound of the formula (XX) HN-C-CHOH R^CHO (XX) CH(OH)Rr or 50 wherein R is a straight- or branched carbon chain option (I-23) ally having a Substituent having a carbon number leSS 1 from that of the substituent at R' (hereinafter referred to as CH2OH Compound (XX) is condensed with nitromethane in the presence of a base to give a compound of the formula HN-C-CHOH 55 (XXIII)

RCH=CHNO, (XXIII) wherein R', Rr and Rs are as defined above hereinafter referred to as Compound (XXII-1), Compound (I-22) or 60 wherein R is as defined above hereinafter referred to as Compound (I-23)). Compound (XXIII)). The obtained compound is then Sub Examples of the base to be used for the condensation with jected to reduction of the double bond with a suitable aldehyde include Sodium hydroxide, Sodium methoxide, reducing agent to give a compound (XVIII-1). Sodium ethoxide, Sodium hydride, potassium hydride, Examples of the solvent to be used for the condensation lithium diisopropylamide, butyl lithium, lithium 65 include water, methanol, ethanol, tert-butyl alcohol, hexamethyldisilaZane, triethylamine, diisopropylethylamine tetrahydrofuran, diethyl ether, ethylene glycol dimethyl and 1,8-diazabicyclo-5.4.0]undeca-7-ene. ether, dimethylformamide, dimethyl Sulfoxide, benzene, 5,952,316 163 164 toluene, Xylene, dioxane, methylene chloride, chloroform, Examples of the base to be used for the condensation dichloroethane and acetonitrile. include Sodium hydroxide, Sodium methoxide, Sodium Examples of the base to be used for the condensation ethoxide, Sodium hydride, potassium hydride, triethylamine, include Sodium hydroxide, Sodium methoxide, Sodium diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca ethoxide, Sodium hydride, potassium hydride, triethylamine, 7-ene. diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca 7-ene. The condensation generally proceeds at a temperature of The condensation generally proceeds at a temperature of from -20° C. to 150° C. and a temperature lower or higher from -20° C. to 150° C. and a temperature lower or higher than this temperature range may be Selected on demand. than this temperature range may be Selected on demand. The condensation is generally carried out for 30 minutes The condensation is generally carried out for 30 minutes to 2 days and the reaction period longer or shorter than the to 2 days and the reaction period longer or shorter than the indicated period may be used as necessary. indicated period may be used as necessary. After the condensation is carried out under the above After the condensation is carried out under the above mentioned conditions or after removing the protecting group mentioned conditions or after removing the protecting group 15 on demand, the Compound (XXIV-1), (XXIV-2) or (XXIV on demand, the Compound (XXIII) can be purified by a 3) can be purified by a method known in the field of organic method known in the field of organic Synthetic chemistry, Synthetic chemistry, Such as Solvent extraction, Such as Solvent extraction, recrystallization, chromatogra recrystallization, chromatography or a method using an ion phy or a method using an ion exchange resin. Examples of the reducing agent to be used for the reduc eXchange resin. tion of the double bond include metallic reducing reagent Examples of the solvent to be used for the condensation such as lithium borohydride or lithium aluminum hydride, with formalin include water, methanol, ethanol, tert-butyl and transition metal Such as palladium-carbon, platinum alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dim oxide, Raney nickel, rhodium or ruthenium for catalytic ethyl ether, dimethylformamide, dimethyl sulfoxide, reduction. 25 benzene, toluene, Xylene, dioxane, methylene chloride, Examples of the organic Solvent to be used for the chloroform, dichloroethane and acetonitrile. reduction of the double bond include methanol, ethanol, Examples of the base to be used for the condensation tert-butyl alcohol, tetrahydrofuran, diethyl ether, dioxane, include Sodium hydroxide, Sodium methoxide, Sodium acetone, ethyl acetate, acetic acid, benzene, toluene, Xylene, ethoxide, Sodium hydride, potassium hydride, triethylamine, dimethylformamide and dimethyl sulfoxide. diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca The reduction of the double bond generally proceeds at a 7-ene. temperature of from -20° C. to 80° C. and a temperature The condensation generally proceeds at a temperature of lower or higher than this temperature range may be selected from -20° C. to 150° C. and a temperature lower or higher on demand. than this temperature range may be Selected on demand. After the reduction is carried out under the above 35 The condensation is generally carried out for 30 minutes mentioned conditions or after removing the protecting group to 2 days and the reaction period longer or shorter than the on demand, the Compound (XVIII-1) can be purified by a indicated period may be used as necessary. method known in the field of organic Synthetic chemistry, After the condensation is carried out under the above Such as Solvent extraction, recrystallization, chromatogra mentioned conditions or after removing the protecting group phy or a method using an ion exchange resin. 40 on demand, the Compound (XXI-1), (XXI-2) or (XXI-3) can (Method J) be purified by a method known in the field of organic Compound (XXI-1), Compound (XXI-2) and Compound Synthetic chemistry, Such as Solvent extraction, (XXI-3) can be also produced by the following method. recrystallization, chromatography or a method using an ion A Compound (XX-1), (XX-2) or (XX-3) is condensed eXchange resin. with nitromethane in the presence of a base and Subjected to 45 protection of hydroxyl as necessary to give a compound of (Method K) the formula (XXIV) Compound (XXI-1), Compound (XXI-2) and Compound (XXI-3) can be also produced by the following method. A compound (XXV) RCH(OZa)CHNO, (XXIV-1) 50 RrCH(OZa)CHNO, (XXIV-2) O ZOCHCHNO, (XXV) wherein Z is as defined above hereinafter referred to as RsCH(OZa)CHNO, (XXIV-3) 55 Compound (XXV) is condensed with a Compound (XX-1), wherein R', Rr, Rs and Za are as defined above hereinafter (XX-2) or (XX-3) in the presence of a base and subjected to referred to as Compound (XXIV-1), Compound (XXIV-2) or protection of hydroxyl as necessary, to give a compound of Compound (XXIV-3). The obtained compound is con densed with formalin in the presence of a base and then the formula (XXVI) Subjected to protection of hydroxyl as necessary to give a 60 Compound (XXI-1), (XXI-2) or (XXI-3). (XXVI-1) Examples of the solvent to be used for the condensation CHOZ include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ON-C-H ether, dimethylformamide, dimethyl Sulfoxide, benzene, 65 toluene, Xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile. 5,952,316 165 166 -continued be purified by a method known in the field of organic Synthetic chemistry, Such as Solvent extraction, (XXVI-2) recrystallization, chromatography or a method using an ion eXchange resin. CHOZ (Method L) ON-C-H A compound of the formula (XXVII) CH(OZa)Rr or WCHCOOY (XXVII) (XXVI-3) wherein W is azide, nitro or amino protected by a suitable CHOZ protecting group and Y is as defined above hereinafter referred to as Compound (XXVII) is condensed, in the ON-C-H presence of a base, with a compound of the formula 15 CH(OZa)Rs (XXVIII) wherein R', Rr, Rs, Z and Za are as defined above RCOHal (XXVIII-1) hereinafter referred to as Compound (XXVI-1), Compound (XXVI-2) or Compound (XXVI-3). The obtained com RCOHal (XXVIII-2) pound is condensed with formalin in the presence of a base and then Subjected to protection of hydroxyl as necessary to O give a Compound (XXI-1), (XXI-2) or (XXI-3). Examples of the solvent to be used for the condensation include water, methanol, ethanol, tert-butyl alcohol, 25 tetrahydrofuran, diethyl ether, ethylene glycol dimethyl RSCOHal (XXVIII-3) ether, dimethylformamide, dimethyl Sulfoxide, benzene, wherein R', Rr, Rs and Hal are as defined above hereinafter toluene, Xylene, dioxane, methylene chloride, chloroform, referred to as Compound (XXVIII-1), Compound (XXVIII dichloroethane and acetonitrile. 2) or Compound (XXVIII-3) to give a compound of the Examples of the base to be used for the condensation include Sodium hydroxide, Sodium methoxide, Sodium formula (XXIX) ethoxide, Sodium hydride, potassium hydride, triethylamine, diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca (XXIX-1) 7-ene. The condensation generally proceeds at a temperature of 35 W- – COOY from -20° C. to 150° C. and a temperature lower or higher C-R1 than this temperature range may be Selected on demand. 2 The condensation is generally carried out for 30 minutes O s to 2 days and the reaction period longer or shorter than the (XXIX-2) indicated period may be used as necessary. 40 After the condensation is carried out under the above mentioned conditions or after removing the protecting group W- – COOY on demand, the Compound (XXVI-1), (XXVI-2) or (XXVI C-Rr 2 3) can be purified by a method known in the field of organic O O Synthetic chemistry, Such as Solvent extraction, 45 recrystallization, chromatography or a method using an ion (XXIX-3) eXchange resin. H Examples of the solvent to be used for the condensation W-C-COOY with formalin include water, methanol, ethanol, tert-butyl C-Rs alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dim 50 Z ethyl ether, dimethylformamide, dimethyl sulfoxide, / benzene, toluene, Xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile. wherein R', Rr, Rs, W and Y are as defined above Examples of the base to be used for the condensation hereinafter referred to as Compound (XXIX-1), Compound include Sodium hydroxide, Sodium methoxide, Sodium 55 (XXIX-2) or Compound (XXIX-3). The obtained com ethoxide, Sodium hydride, potassium hydride, triethylamine, pound is condensed with formalin in the presence of a base diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca and Subjected to protection of hydroxyl as necessary to give 7-ene. The condensation generally proceeds at a temperature of a compound of the formula (XXX) from -20° C. to 150° C. and a temperature lower or higher 60 than this temperature range may be Selected on demand. (XXX-1) The condensation is generally carried out for 30 minutes CHOZ to 2 days and the reaction period longer or shorter than the indicated period may be used as necessary. After the condensation is carried out under the above 65 mentioned conditions or after removing the protecting group on demand, the Compound (XXI-1), (XXI-2) or (XXI-3) can 5,952,316 167 168 -continued on demand, the Compound (XXIX-1), (XXIX-2) or (XXIX (XXX-2) 3) can be purified by a method known in the field of organic Synthetic chemistry, Such as Solvent extraction, loz recrystallization, chromatography or a method using an ion W- - COOY eXchange resin. Examples of the solvent to be used for the condensation 2C-R with formalin include water, methanol, ethanol, tert-butyl O O alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dim (XXIX-3) ethyl ether, dimethylformamide, dimethyl sulfoxide, CHOZ benzene, toluene, Xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile. W-C-COOY Examples of the base to be used for the condensation include Sodium hydroxide, Sodium methoxide, Sodium 2C-Rs ethoxide, Sodium hydride, potassium hydride, triethylamine, O diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca 15 7-ene. wherein R', Rr, Rs, W, Y and Z are as defined above The condensation generally proceeds at a temperature of hereinafter referred to as Compound (XXX-1), Compound from -20° C. to 150° C. and a temperature lower or higher (XXX-2) or Compound (XXX-3). The obtained compound than this temperature range may be Selected on demand. is Subjected to reduction of carboxyl with a Suitable reducing The condensation is generally carried out for 30 minutes agent and protection of hydroxyl as necessary to give a to 2 days and the reaction period longer or shorter than the compound of the formula (XXXI) indicated period may be used as necessary. After the condensation is carried out under the above (XXXI-1) mentioned conditions or after removing the protecting group on demand, the Compound (XXX-1), (XXX-2) or (XXX-3) Hoz 25 can be purified by a method known in the field of organic W- - CHOZ2 Synthetic chemistry, Such as Solvent extraction, C-R1 recrystallization, chromatography or a method using an ion 2 eXchange resin. O s Examples of the reducing agent to be used for the reduc (XXXI-2) tion of carboxyl include metallic reducing reagent Such as Sodium borohydride, lithium borohydride or lithium alumi Hoz num hydride, and diborane. W-C-CHOZ2 Examples of the organic Solvent to be used for the 2C-Rr reduction of carboxyl include methanol, ethanol, tert-butyl O O 35 alcohol, tetrahydrofuran, diethyl ether and ethylene glycol (XXXI-3) dimethyl ether. The reduction of carboxyl generally proceeds at a tem CHOZ perature of from -20° C. to 80° C. and a temperature lower W-C-CHOZ2 or higher than this temperature range may be Selected on 40 demand. C-Rs M The reduction of carboxyl is generally carried out for 30 % minutes to 10 hours and the reaction period longer or shorter than the indicated period may be used as necessary. wherein R', Rr, Rs, W, Z' and Z are as defined above After the reduction is carried out under the above hereinafter referred to as Compound (XXXI-1), Compound 45 mentioned conditions or after removing the protecting group (XXXI-2) or Compound (XXXI-3) and the obtained com on demand, the Compound (XXXI-1), (XXXI-2) or (XXXI pound is Subjected to reduction of carbonyl with a Suitable 3) can be purified by a method known in the field of organic reducing agent, and reduction and deprotection as necessary, Synthetic chemistry, Such as Solvent extraction, to give a Compound (XXII-1), (I-22) or (I-23). recrystallization, chromatography or a method using an ion Examples of the solvent to be used for the condensation 50 eXchange resin. include water, methanol, ethanol, tert-butyl alcohol, Examples of the reducing agent to be used for the reduc tetrahydrofuran, diethyl ether, ethylene glycol dimethyl tion of carbonyl include metallic reducing reagent Such as ether, dimethylformamide, dimethyl Sulfoxide, benzene, Sodium borohydride, lithium borohydride or lithium alumi toluene, Xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile. num hydride, and diborane. Examples of the base to be used for the condensation 55 Examples of the organic Solvent to be used for the include Sodium hydroxide, Sodium methoxide, Sodium reduction of carbonyl include methanol, ethanol, tert-butyl ethoxide, Sodium hydride, potassium hydride, triethylamine, alcohol, tetrahydrofuran, diethyl ether and ethylene glycol diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca dimethyl ether. 7-ene. The reduction of carbonyl generally proceeds at a tem The condensation generally proceeds at a temperature of 60 perature of from -20° C. to 80° C. and a temperature lower from -20° C. to 150° C. and a temperature lower or higher or higher than this temperature range may be Selected on than this temperature range may be Selected on demand. demand. The condensation is generally carried out for 30 minutes The reduction of carbonyl is generally carried out for 30 to 2 days and the reaction period longer or shorter than the minutes to 10 hours and the reaction period longer or shorter indicated period may be used as necessary. 65 than the indicated period may be used as necessary. After the condensation is carried out under the above When (i) W=azide, examples of the reducing agent to be mentioned conditions or after removing the protecting group used for the reduction of azide include metallic reducing 5,952,316 169 170 agent Such as Sodium borohydride, lithium borohydride or The condensation is generally carried out for 30 minutes lithium aluminum hydride, and transition metal Such as to 2 days and the reaction period longer or shorter than the palladium-carbon, platinum oxide, Raney nickel, rhodium or indicated period may be used as necessary. ruthenium for catalytic reduction. After the condensation is carried out under the above Examples of the organic Solvent to be used for the mentioned conditions or after removing the protecting group reduction of azide include methanol, ethanol, tert-butyl on demand, the Compound (XXX-1), (XXX-2) or (XXX-3) alcohol, tetrahydrofuran, diethyl ether, dioxane, acetone, can be purified by a method known in the field of organic ethyl acetate, acetic acid, benzene, toluene, Xylene, dimeth Synthetic chemistry, Such as Solvent extraction, ylformamide and dimethyl sulfoxide. recrystallization, chromatography or a method using an ion The reduction of azide generally proceeds at a tempera eXchange resin. ture of from -20° C. to 80° C. and a temperature lower or (Method N) higher than this temperature range may be Selected on When W=nitro, Compound (XXXI-1), (XXXI-2) and demand. (XXXI-3) can be also produced by the following method. When (ii) W=nitro, examples of the reducing agent to be A compound (XXVIII-1), (XXVIII-2) or (XXVIII-3) and used for the reduction of nitro include metallic reducing a compound (XXXIII) reagent Such as Sodium borohydride, lithium borohydride or 15 lithium aluminum hydride, transition metal Such as palladium-carbon, platinum oxide, Raney nickel, rhodium or CHNO, (XXXIII) ruthenium for catalytic reduction, and metal Such as iron, hereinafter referred to as Compound (XXXIII) are con Zinc or tin. densed in the presence of a base to give a compound of the Examples of the solvent to be used for the reduction of nitro include water, methanol, ethanol, tert-butyl alcohol, formula (XXXIV) tetrahydrofuran, diethyl ether, dioxane, acetone, ethyl acetate, acetic acid, benzene, toluene, Xylene, dimethylfor (XXXIV-1) mamide and dimethyl sulfoxide. H The reduction of nitrogenerally proceeds at a temperature 25 of from -20° C. to 80 C. and a temperature lower or higher ON- – H C-R1 than this temperature range may be Selected on demand. 2 After the reduction is carried out under the above O s mentioned conditions or after removing the protecting group on demand, the Compound (XXII-1), (I-22) or (I-23) can be (XXXIV-2) purified by a method known in the field of organic Synthetic H chemistry, Such as Solvent extraction, recrystallization, chro ON- – H matography or a method using an ion eXchange resin. C-Rr Accordingly, the instant method is applicable to the 2 synthesis of the compounds of the formulas (I-21) through O O (I-23). 35 (XXXIV-3) (Method M) Compound (XXX-1), Compound (XXX-2) and Com pound (XXX-3) can be also produced by the following ON-C-H method. C-Rs A compound (XXVIII) and a compound of the formula 40 Z (XXXII) O (XXXII) wherein R', Rr and Rs are as defined above hereinafter referred to as Compound (XXXIV-1), Compound (XXXIV CHOZ 45 2) or Compound (XXXIV-3) and the obtained compound is W-C-COOY condensed with formalin in the presence of a base and Subjected to protection of hydroxyl as necessary to give a H Compound (XXXI-1), (XXXI-2) or (XXXI-3). Examples of the solvent to be used for the condensation wherein W, Y and Z are as defined above hereinafter 50 include water, methanol, ethanol, tert-butyl alcohol, referred to as Compound (XXXII) are condensed in the tetrahydrofuran, diethyl ether, ethylene glycol dimethyl presence of a base to give a Compound (XXX-1), (XXX-2) ether, dimethylformamide, dimethyl Sulfoxide, benzene, or (XXX-3). toluene, Xylene, dioxane, methylene chloride, chloroform, Examples of the solvent to be used for the condensation dichloroethane and acetonitrile. include water, methanol, ethanol, tert-butyl alcohol, 55 Examples of the base to be used for the condensation tetrahydrofuran, diethyl ether, ethylene glycol dimethyl include Sodium hydroxide, Sodium methoxide, Sodium ether, dimethylformamide, dimethyl Sulfoxide, benzene, ethoxide, Sodium hydride, potassium hydride, triethylamine, toluene, Xylene, dioxane, methylene chloride, chloroform, diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca dichloroethane and acetonitrile. 7-ene. Examples of the base to be used for the condensation 60 The condensation generally proceeds at a temperature of include Sodium hydroxide, Sodium methoxide, Sodium from -20° C. to 150° C. and a temperature lower or higher ethoxide, Sodium hydride, potassium hydride, triethylamine, than this temperature range may be Selected on demand. diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca The condensation is generally carried out for 30 minutes 7-ene. to 2 days and the reaction period longer or shorter than the The condensation generally proceeds at a temperature of 65 indicated period may be used as necessary. from -20° C. to 150° C. and a temperature lower or higher After the condensation is carried out under the above than this temperature range may be Selected on demand. mentioned conditions or after removing the protecting group 5,952,316 171 172 on demand, the Compound (XXXIV-1), (XXXIV-2) or Examples of the base to be used for the condensation (XXXIV-3) can be purified by a method known in the field include Sodium hydroxide, Sodium methoxide, Sodium of organic Synthetic chemistry, Such as Solvent extraction, ethoxide, Sodium hydride, potassium hydride, triethylamine, recrystallization, chromatography or a method using an ion diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca eXchange resin. 7-ene. Examples of the solvent to be used for the condensation The condensation generally proceeds at a temperature of with formalin include water, methanol, ethanol, tert-butyl from -20° C. to 150° C. and a temperature lower or higher alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dim than this temperature range may be Selected on demand. ethyl ether, dimethylformamide, dimethyl sulfoxide, The condensation is generally carried out for 30 minutes benzene, toluene, Xylene, dioxane, methylene chloride, to 2 days and the reaction period longer or shorter than the chloroform, dichloroethane and acetonitrile. indicated period may be used as necessary. Examples of the base to be used for the condensation After the condensation is carried out under the above include Sodium hydroxide, Sodium methoxide, Sodium mentioned conditions or after removing the protecting group ethoxide, Sodium hydride, potassium hydride, triethylamine, on demand, the Compound (XXXIV-1), (XXXIV-2) or diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca (XXXIV-3) can be purified by a method known in the field 15 of organic Synthetic chemistry, Such as Solvent extraction, 7-ene. recrystallization, chromatography or a method using an ion The condensation generally proceeds at a temperature of eXchange resin. from -20° C. to 150° C. and a temperature lower or higher (Method P) than this temperature range may be Selected on demand. When W=nitro, Compound (XXXI-1), Compound The condensation is generally carried out for 30 minutes (XXXI-2) and Compound (XXXI-3) can be also produced to 2 days and the reaction period longer or shorter than the by the following method. indicated period may be used as necessary. A Compound (XXV) and a Compound (XXVIII-1), After the condensation is carried out under the above (XXVIII-2) or (XXVIII-3) are condensed in the presence of mentioned conditions or after removing the protecting group a base to give a compound of the formula (XXXVI) on demand, the Compound (XXXI-1), (XXXI-2) or (XXXI 3) can be purified by a method known in the field of organic 25 Synthetic chemistry, Such as Solvent extraction, (XXXVI-1) recrystallization, chromatography or a method using an ion loz eXchange resin. ON- -H (Method O) C-R1 Compound (XXXIV-1), Compound (XXXIV-2) and Z Compound (XXXIV-3) can be also produced by the fol O s lowing method. (XXXVI-2) A Compound (XVII) and a compound of the formula (XXXV) floz 35 ON-C-H C-Rr O (XXXV-1) 2 H O (XXXVI-3) a-- H CHOZ C-R1 40 a ON- -H % s (XXXV-2) 2 C-Rs H O 45 a-- H wherein R', Rr, Rs and Z are as defined above hereinafter C-Rr M referred to as Compound (XXXVI-1), Compound (XXXVI % O 2) or Compound (XXXVI-3). The obtained compound is (XXXV-3) condensed with formalin in the presence of a base and H 50 Subjected to protection of hydroxyl as necessary to give a Compound (XXXI-1), (XXXI-2) or (XXXI-3). a-- H Examples of the solvent to be used for the condensation C-Rs include water, methanol, ethanol, tert-butyl alcohol, / tetrahydrofuran, diethyl ether, ethylene glycol dimethyl % ether, dimethylformamide, dimethyl Sulfoxide, benzene, 55 toluene, Xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile. wherein R', Rr, Rs and G are as defined above hereinafter Examples of the base to be used for the condensation referred to as Compound (XXXV-1), Compound (XXXV-2) include Sodium hydroxide, Sodium methoxide, Sodium or Compound (XXXV-3) are condensed in the presence of ethoxide, Sodium hydride, potassium hydride, triethylamine, a base to give a Compound (XXXIV-1), (XXXIV-2) or 60 diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca (XXXIV-3). 7-ene. Examples of the solvent to be used for the condensation The condensation generally proceeds at a temperature of include water, methanol, ethanol, tert-butyl alcohol, from -20° C. to 150° C. and a temperature lower or higher tetrahydrofuran, diethyl ether, ethylene glycol dimethyl than this temperature range may be Selected on demand. ether, dimethylformamide, dimethyl Sulfoxide, benzene, 65 The condensation is generally carried out for 30 minutes toluene, Xylene, dioxane, methylene chloride, chloroform, to 2 days and the reaction period longer or shorter than the dichloroethane and acetonitrile. indicated period may be used as necessary. 5,952,316 173 174 After the condensation is carried out under the above Examples of the base to be used for the condensation mentioned conditions or after removing the protecting group include Sodium hydroxide, Sodium methoxide, Sodium on demand, the Compound (XXXVI-1), (XXXVI-2) or ethoxide, Sodium hydride, potassium hydride, triethylamine, (XXXVI-3) can be purified by a method known in the field of organic Synthetic chemistry, Such as Solvent extraction, diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca recrystallization, chromatography or a method using an ion 7-ene. eXchange resin. The condensation generally proceeds at a temperature of Examples of the solvent to be used for the condensation from -20° C. to 150° C. and a temperature lower or higher with formalin include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dim than this temperature range may be Selected on demand. ethyl ether, dimethylformamide, dimethyl sulfoxide, The condensation is generally carried out for 30 minutes benzene, toluene, Xylene, dioxane, methylene chloride, to 2 days and the reaction period longer or shorter than the chloroform, dichloroethane and acetonitrile. indicated period may be used as necessary. Examples of the base to be used for the condensation After the condensation is carried out under the above include Sodium hydroxide, Sodium methoxide, Sodium mentioned conditions or after removing the protecting group ethoxide, Sodium hydride, potassium hydride, triethylamine, 15 diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca on demand, the Compound (XXXVII) can be purified by a 7-ene. method known in the field of organic Synthetic chemistry, The condensation generally proceeds at a temperature of Such as Solvent extraction, recrystallization, chromatogra from -20° C. to 150° C. and a temperature lower or higher phy or a method using an ion exchange resin. than this temperature range may be Selected on demand. Examples of the solvent to be used for the condensation The condensation is generally carried out for 30 minutes with formalin include water, methanol, ethanol, tert-butyl to 2 days and the reaction period longer or shorter than the alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dim indicated period may be used as necessary. ethyl ether, dimethylformamide, dimethyl sulfoxide, After the condensation is carried out under the above benzene, toluene, Xylene, dioxane, methylene chloride, mentioned conditions or after removing the protecting group 25 on demand, the Compound (XXXI-1), (XXXI-2) or (XXXI chloroform, dichloroethane and acetonitrile. 3) can be purified by a method known in the field of organic Examples of the base to be used for the condensation Synthetic chemistry, Such as Solvent extraction, include Sodium hydroxide, Sodium methoxide, Sodium recrystallization, chromatography or a method using an ion ethoxide, Sodium hydride, potassium hydride, triethylamine, eXchange resin. diisopropylethylamine and 1,8-diazabicyclo5.4.0]undeca (Method Q) Compound (X) can be also produced by the following 7-ene. method. The condensation generally proceeds at a temperature of A Compound (II) and a Compound (XXVII) (W=nitro) from -20° C. to 150° C. and a temperature lower or higher are condensed in the presence of a base to give a compound than this temperature range may be Selected on demand. of the formula (XXXVII) 35 The condensation is generally carried out for 30 minutes to 2 days and the reaction period longer or shorter than the (XXXVII) indicated period may be used as necessary. H After the condensation is carried out under the above ON-C-COOY 40 mentioned conditions or after removing the protecting group on demand, the Compound (XXXVIII) can be purified by a CHR method known in the field of organic Synthetic chemistry, Such as Solvent extraction, recrystallization, chromatogra wherein R' and Y are as defined above hereinafter referred phy or a method using an ion exchange resin. to as Compound (XXXVII)). The obtained compound is 45 Examples of the reducing agent to be used for the reduc condensed with formalin in the presence of a base and tion of carboxyl include metallic reducing reagent Such as Subjected to protection of hydroxyl as necessary to give a Sodium borohydride, lithium borohydride or lithium alumi compound of the formula (XXXVIII) num hydride, and diborane. Examples of the organic Solvent to be used for the (XXXVIII) 50 reduction of carboxyl include methanol, ethanol, tert-butyl CHOZ alcohol, tetrahydrofuran, diethyl ether and ethylene glycol ON-C-COOY dimethyl ether. CHR' The reduction of carboxyl generally proceeds at a tem 55 perature of from -20° C. to 80° C. and a temperature lower or higher than this temperature range may be Selected on wherein R', Y and Z are as defined above hereinafter demand. referred to as Compound (XXXVIII) and the obtained The reduction of carboxyl is generally carried out for 30 compound is Subjected to reduction of carboxyl with a minutes to 10 hours and the reaction period longer or shorter Suitable reducing agent and protection of hydroxyl as nec 60 essary to give a Compound (X). than the indicated period may be used as necessary. Examples of the solvent to be used for the condensation After the reduction is carried out under the above include water, methanol, ethanol, tert-butyl alcohol, mentioned conditions or after removing the protecting group tetrahydrofuran, diethyl ether, ethylene glycol dimethyl on demand, the Compound (X) can be purified by a method ether, dimethylformamide, dimethyl Sulfoxide, benzene, 65 known in the field of organic Synthetic chemistry, Such as toluene, Xylene, dioxane, methylene chloride, chloroform, Solvent extraction, recrystallization, chromatography or a dichloroethane and acetonitrile. method using an ion eXchange resin. 5,952,316 175 176 (Method R) After the condensation is carried out under the above A compound of the formula (XXXIX) mentioned conditions or after removing the protecting group on demand, the Compound (XXXXI-1) or (XXXXI-2) can (XXXIX-1) be purified by a method known in the field of organic Synthetic chemistry, Such as Solvent extraction, recrystallization, chromatography or a method using an ion toz eXchange resin. o'os--cloza In the instant method, a compound wherein X is Sulfinyl (CH2)CG or Sulfonyl can be obtained by oxidation of a compound (XXXIX-2) wherein X is Sulfur. CHOZ Accordingly, the instant method can be used for the synthesis of the compounds of the formulas (I-26) and QQ2N-C-CHOZ2 (I-27). It is also applicable to the Synthesis of the compounds CHG (I-1), (I-2), (I-4), (I-5) and (I-7) through (I-11). 15 (Method S) Compound (XXXXI-1) and Compound (XXXXI-2) can wherein Q', Q, Z, Z, G and C. are as defined above be also produced by the following method. hereinafter referred to as Compound (XXXIX-1) or Com A compound of the formula (XXXXII) pound (XXXIX-2) and a compound of the formula (XXXX) (XXXXII-1) Hoz QQ2N-C-CHOZ2 O (CH2)C1-XH or 25 Rw-OH (XXXX-2) (XXXXII-2) CHOZ wherein RV, Rw, X and B are as defined above hereinafter referred to as Compound (XXXX-1) or Compound (XXXX 2) are condensed in the presence of a base to give a compound of the formula (XXXXI) (XXXXI-1) wherein Q, Q , Z, Z, X and a are as defined above hereinafter referred to as Compound (XXXXII-1) or Com loz 35 pound (XXXXII-2) and a compound of the formula QQ2N-C-CHOZ2 (XXXXIII) (CH2)C-X-(CH2)(BRv or (XXXXI-2) Rv(CH)f-G (XXXXIII-1) O loz 40 Olo2N- - CHOZ2 Rw-G (XXXXIII-2) wherein RV, Rw, G and B are as defined above hereinafter referred to as Compound (XXXXIII-1) or Compound wherein RV, RW, X, Q', Q, Z, Z, C. and B are as defined 45 (XXXXIII-2) are condensed in the presence of a base and above hereinafter referred to as Compound (XXXXI-1) or the obtained compound is Subjected to deprotection on Compound (XXXXI-2) and the obtained compound is demand to give a Compound (XXXXI-1) or (XXXXI-2). Subjected to deprotection as necessary to give a compound Examples of the base to be used for the condensation (I-26) or (I-27). include Sodium hydroxide, Sodium methoxide, Sodium Examples of the base to be used for the condensation 50 ethoxide, Sodium hydride, potassium hydride, lithium include Sodium hydroxide, Sodium methoxide, Sodium diisop ropylamide, butyl lithium, lithium ethoxide, Sodium hydride, potassium hydride, lithium hexamethyldisilaZane, triethylamine, diisopropylethylamine diisop ropylamide, butyl lithium, lithium and 1,8-diazabicyclo5.4.0]undeca-7-ene. hexamethyldisilaZane, triethylamine, diisopropylethylamine Examples of the solvent to be used for the condensation and 1,8-diazabicyclo5.4.0]undeca-7-ene. 55 include water, methanol, ethanol, tert-butyl alcohol, Examples of the solvent to be used for the condensation tetrahydrofuran, diethyl ether, ethylene glycol dimethyl include water, methanol, ethanol, tert-butyl alcohol, ether, dimethylformamide, dimethyl Sulfoxide, benzene, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl toluene, Xylene, dioxane, methylene chloride, chloroform, ether, dimethylformamide, dimethyl Sulfoxide, benzene, dichloroethane and acetonitrile. toluene, Xylene, dioxane, methylene chloride, chloroform, 60 The condensation generally proceeds at a temperature of dichloroethane and acetonitrile. from -20° C. to 150° C. and a temperature lower or higher The condensation generally proceeds at a temperature of than this temperature range may be Selected on demand. from -20° C. to 150° C. and a temperature lower or higher The condensation is generally carried out for 30 minutes than this temperature range may be Selected on demand. to 2 days and the reaction period longer or shorter than the The condensation is generally carried out for 30 minutes 65 indicated period may be used as necessary. to 2 days and the reaction period longer or shorter than the After the condensation is carried out under the above indicated period may be used as necessary. mentioned conditions or after removing the protecting group 5,952,316 177 178 on demand, the Compound (XXXXI-1) or (XXXXI-2) can Sodium borohydride, lithium borohydride or lithium alumi be purified by a method known in the field of organic num hydride, and diborane. Synthetic chemistry, Such as Solvent extraction, Examples of the organic Solvent to be used for the recrystallization, chromatography or a method using an ion reduction of carboxyl include methanol, ethanol, tert-butyl eXchange resin. alcohol, tetrahydrofuran, diethyl ether and ethylene glycol (Method T) dimethyl ether. Compound (XXXXI-1) and Compound (XXXXI-2) can The reduction of carboxyl generally proceeds at a tem be also produced by the following method. perature of from -20° C. to 80° C. and a temperature lower A compound of the formula (XXXXIV) or higher than this temperature range may be Selected on demand. The reduction of carboxyl is generally carried out for 30 minutes to 10 hours and the reaction period longer or shorter O than the indicated period may be used as necessary. After the reduction is carried out under the above 15 mentioned conditions or after removing the protecting group Rw-OCHG (XXXXIV-2) on demand, the Compound (XXXXI-1) or (XXXXI-2) can wherein RV, Rw, G., X, C. and B are as defined above be purified by a method known in the field of organic hereinafter referred to as Compound (XXXXIV-1) or Com Synthetic chemistry, Such as Solvent extraction, pound (XXXXIV-2) and a Compound (III) are condensed in recrystallization, chromatography or a method using an ion the presence of a base to give a compound of the formula eXchange resin. (XXXXV) (Method U) A Compound (XIV) is added with a compound of the (XXXXV-1) fooy formula (XXXXVI) 25 OHN- - COOY (R')nM (XXXXVI-1) (CH2)C-X-(CH2)|BRv or (Rr)nM (XXXXVI-2) (XXXXV-2) COOY O OHN-C-COOY (Rs)nM (XXXXVI-3) wherein R', Rr, Rs, M and n are as defined above wherein RV, Rw, X, Q, Y, C. and B are as defined above 35 hereinafter referred to as Compound (XXXXVI-1), Com hereinafter referred to as Compound (XXXXV-1) or Com pound (XXXXVI-2) or Compound (XXXXVI-3) and the pound (XXXXV-2)). The obtained compound is subjected to mixture is Subjected to protection of hydroxyl as necessary reduction with a Suitable reducing agent and protection of to give a compound of the formula (XXXXVII) hydroxyl and amino as necessary to give a compound (XXXXI-1) or (XXXXI-2). 40 (XXXXVII-1) Examples of the base to be used for the condensation CHOZ include Sodium hydroxide, Sodium methoxide, Sodium ethoxide, Sodium hydride, potassium hydride, lithium QON-C-CHOZ’, diisop ropylamide, butyl lithium, lithium CH(OZa)R hexamethyldisilaZane, triethylamine, diisopropylethylamine 45 and 1,8-diazabicyclo5.4.0]undeca-7-ene. (XXXXVII-2) Examples of the solvent to be used for the condensation CHOZ include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl QON-C-CHOZ2 or ether, dimethylformamide, dimethyl Sulfoxide, benzene, 50 CH(OZa)Rr toluene, Xylene, dioxane, methylene chloride, chloroform, (XXXXVII-3) dichloroethane and acetonitrile. CHOZ The condensation generally proceeds at a temperature of from -20° C. to 150° C. and a temperature lower or higher Olo2N- i- CHOZ? than this temperature range may be Selected on demand. 55 The condensation is generally carried out for 30 minutes to 2 days and the reaction period longer or shorter than the indicated period may be used as necessary. wherein R', Rr, Rs, Q', Q, Z', Z and Za are as defined After the condensation is carried out under the above above hereinafter referred to as Compound (XXXXVII-1), mentioned conditions or after removing the protecting group 60 Compound (XXXXVII-2) or Compound (XXXXVII-3)). on demand, the Compound (XXXXV-1) or (XXXXV-2) can The obtained compound is Subjected to deprotection on be purified by a method known in the field of organic demand to give a Compound (XXII-1), (I-22) or (I-23). Synthetic chemistry, Such as Solvent extraction, Examples of the solvent to be used for the addition recrystallization, chromatography or a method using an ion include tetrahydrofuran, diethyl ether, ethylene glycol dim eXchange resin. 65 ethyl ether, dimethylformamide, dimethyl sulfoxide, Examples of the reducing agent to be used for the reduc benzene, toluene, Xylene, dioxane, methylene chloride, tion of carboxyl include metallic reducing reagent Such as chloroform, dichloroethane and acetonitrile. 5,952,316 179 18O The addition generally proceeds at a temperature of from tetrahydrofuran, diethyl ether, ethylene glycol dimethyl -100° C. to 80° C. and a temperature lower or higher than ether, dimethylformamide, dimethyl Sulfoxide, benzene, this temperature range may be Selected on demand. toluene, Xylene, dioxane, methylene chloride, chloroform, The addition is generally carried out for 30 minutes to 2 dichloroethane and acetonitrile. days and the reaction period longer or shorter than the The condensation generally proceeds at a temperature of indicated period may be used as necessary. from -20° C. to 150° C. and a temperature lower or higher After the addition is carried out under the above than this temperature range may be Selected on demand. mentioned conditions or after removing the protecting group The condensation is generally carried out for 30 minutes on demand, the Compound (XXXXVII-1), (XXXXVII-2) or to 2 days and the reaction period longer or shorter than the (XXXXVII-3) can be purified by a method known in the indicated period may be used as necessary. field of organic Synthetic chemistry, Such as Solvent After the condensation is carried out under the above extraction, recrystallization, chromatography or a method mentioned conditions or after removing the protecting group using an ion eXchange resin. on demand, the Compound (XXXXIX) can be purified by a Accordingly, the instant method can be used for the method known in the field of organic Synthetic chemistry, synthesis of the compounds of the formulas (I-21) through 15 (I-23). Such as Solvent extraction, recrystallization, chromatogra (Method V) phy or a method using an ion exchange resin. A compound of the formula (XXXXVIII) Examples of the base to be used for the amination include Sodium hydroxide, Sodium methoxide, Sodium ethoxide, Sodium hydride, potassium hydride, lithium (XXXXVIII) diisop ropylamide, butyl lithium, lithium COOY hexamethyldisilaZane, triethylamine, diisopropylethylamine H-C-COOY and 1,8-diazabicyclo5.4.0]undeca-7-ene. Examples of the solvent to be used for the amination H include water, methanol, ethanol, tert-butyl alcohol, 25 tetrahydrofuran, diethyl ether, ethylene glycol dimethyl wherein Y is as defined above hereinafter referred to as ether, dimethylformamide, dimethyl Sulfoxide, benzene, Compound (XXXXVIII) and a Compound (II) are con toluene, Xylene, dioxane, methylene chloride, chloroform, densed in the presence of a base to give a compound of the dichloroethane and acetonitrile. formula (XXXXIX) The amination generally proceeds at a temperature of from -20° C. to 150° C. and a temperature lower or higher (XXXXIX) than this temperature range may be Selected on demand. COOY The amination is generally carried out for 30 minutes to H-C-COOY 2 days and the reaction period longer or shorter than the 35 indicated period may be used as necessary. CHR After the amination is carried out under the above mentioned conditions or after removing the protecting group wherein R and Y are as defined above hereinafter referred on demand, the Compound (XXXXXI) can be purified by a to as Compound (XXXXIX) and the obtained compound is method known in the field of organic Synthetic chemistry, 40 Such as Solvent extraction, recrystallization, chromatogra reacted with an amination agent of the formula (XXXXX) phy or a method using an ion exchange resin. Examples of the reducing agent to be used for the reduc HN-Le (XXXXX) tion of carboxyl include metallic reducing reagent Such as where in Le means a leaving group Such as 2,4- Sodium borohydride, lithium borohydride or lithium alumi dinitrophenoxy, in the presence of a base to give a com 45 num hydride, and diborane. pound of the formula (XXXXXI) Examples of the organic Solvent to be used for the reduction of carboxyl include methanol, ethanol, tert-butyl (XXXXXI) alcohol, tetrahydrofuran, diethyl ether and ethylene glycol COOY dimethyl ether. 50 The reduction of carboxyl generally proceeds at a tem HN-C-COOY perature of from -20° C. to 80° C. and a temperature lower CHR or higher than this temperature range may be Selected on demand. wherein R' and Y are as defined above hereinafter referred 55 The reduction of carboxyl is generally carried out for 30 to as Compound (XXXXXI). The obtained compound is minutes to 10 hours and the reaction period longer or shorter Subjected to reduction of carboxyl with a Suitable reducing than the indicated period may be used as necessary. agent and deprotection as necessary to give a Compound After the reduction is carried out under the above (I-29). mentioned conditions or after removing the protecting group Examples of the base to be used for the condensation 60 on demand, the Compound (I-29) can be purified by a include Sodium hydroxide, Sodium methoxide, Sodium method known in the field of organic Synthetic chemistry, ethoxide, Sodium hydride, potassium hydride, lithium Such as Solvent extraction, recrystallization, chromatogra diisop ropylamide, butyl lithium, lithium phy or a method using an ion exchange resin. hexamethyldisilaZane, triethylamine, diisopropylethylamine The instant method can be used for the synthesis of the and 1,8-diazabicyclo5.4.0]undeca-7-ene. 65 compounds of the formulas (I-1) through (I-18), preferably Examples of the solvent to be used for the condensation for the synthesis of the compounds of the formulas (I-12) include water, methanol, ethanol, tert-butyl alcohol, and (I-13). 5,952,316 181 182 (Method W) heptadecyl, is produced, for example, by fermentation or by Of the compounds of the formula (I) of the present using a compound (XXXXXIII) produced by the fermenta invention, a compound wherein R is -CH(OH)Rr when it tion and having the formula is a compound of the formula (XXXXXIII) (XXXXXII) CH2OH CH2OH HN-C-COH HN-C-COH

as a starting meterial. Examples of the microorganism wherein Rr is as defined above hereinafter referred to as capable of producing the compound (XXXXXIII) include Compound (XXXXXII) or a derivative at carboxyl group those belonging to Ascomycetes or Fungi imperfecti, par thereof or a compound (XXXXXII) wherein the C-position ticularly the genera Isaria and Mycelia belonging to the of alkyl at Rr, which may have a double bond or carbonyl in 15 Fungi imperfecti and the genus Myriococcum (the genus the chain, is Substituted by hydroxyl, can be produced by Thielavia) belonging to Ascomycetes, which are respec reduction, hydrogenation, OZonolysis or oxidation known tively deposited at American Type Culture Collection as per se, which may be used Solely or in combination, of a Isaria Sinclairii ATCC No. 24400, Myriococcum albomyces corresponding lactone compound or a compound wherein ATCC No. 16425 and Mycelia Sterilia ATCC No. 20349. amino or hydroxy of a Compound (XXXXXII) or lactone Also, Myriococcum albomyces ATCC No. 16425 has been compound is protected by a protecting group. deposited at the Institute of Fermentation, Osaka as Examples of the derivative at the carboxyl group of the IFO32292. Compound (XXXXXII) include ester (e.g. methyl ester, Compound (XXXXXIII) can be produced, for example, ethyl ester, benzyl ester, p-nitrobenzyl ester, trimethylsilyl by a mutant Strain obtained by mutating the above ester, tert-butyldimethylsilyl ester), acid halide (e.g. acid 25 mentioned Strain by a conventional artificial mutating chloride), acid anhydride and mixed acid anhydride. method using ultraViolet rays, high frequency radiation, drug A Compound (I) wherein Rr is an a-position hydroxyl or the like. Substituted alkyl is preferably produced by using the afore The Compound (XXXXXIII)-producing cell may be cul mentioned lactone compound as a Starting material. tured in various culture media containing conventional nutri Reduction proceeds in a Solvent inert to the reaction and tion Sources for mold. For example, a medium may contain in the presence of a metal hydride complex at a temperature glucose, Starch, glycerin, Sugar Syrup, dextrin, molasses, from under cooling to under refluxing. Examples of the maltose, Xylose or the like as a carbon Source and an metal hydride complex include aluminum hydride, lithium inorganic or organic nitrogen compound Such as corn Steep aluminum hydride, lithium aluminum hydride-aluminum liquor, peptone, yeast extract, potato brew, meat broth, chloride, lithium trimethoxy aluminum hydride, Sodium 35 Soybean powder, wheat germ, potassium nitrate, Sodium bis(2-methoxyethoxy)aluminum hydride, diisobutyl alumi nitrate, ammonium Sulfate, casein, gluten meal, cottonseed num hydride, sodium borohydride, sodium hydride, lithium powder or feather powder as a nitrogen Source. Besides borohydride and borohydride, and examples of the solvent these, there may be contained additives conventionally used include alcohol Solvents Such as methanol, ethanol, isopro for culture Such as conventional inorganic Salt, organic or panol and diethylene glycol, hydrocarbon Solvents Such as 40 inorganic Substance which promotes the growth of cell and benzene, toluene and Xylene, halohydrocarbon Solvents Such enhances production of the Compound (XXXXXIII), and as methylene chloride, dichloroethane and chloroform, ether antifoaming agent. Solvents Such as diethyl ether, dipropyl ether, tetrahydrofu While the culture method is subject to no particular ran and dioxane, dimethylformamide, and dimethyl limitation, aerobic Submerged culture is desirable. The tem Sulfoxide, which may be used Solely or in combination. 45 perature appropriate for the culture is 20-35 C., preferably The reduction may be catalytic reduction using zinc 25–30 C. for the microorganisms belonging to the genus hydrochloric acid Saturated acetic anhydride, copper Isaria and 30–50° C., preferably 35–45° C. for the micro chromite catalyst, palladium-carbon, Raney nickel or rhe organisms belonging to the genus Myriococcum or Mycelia. nium oxide, or electroreduction. These reactions proceed in The Compound (XXXXXIII) produced in the culture a manner Similar to the reaction known per se. 50 medium is isolated therefrom by conventional StepS. Such as The hydrogenation generally proceeds according to a extraction and adsorption which may be used in combination method known per Se using a conventional catalyst Such as as necessary. For example, in the case of a microorganism a palladium, nickel or platinum catalyst. In the reaction, a belonging to the genus Isaria Such as Isaria Sinclairii, the Solvent inert to the reaction may be used and examples Compound (XXXXXIII) is taken out from the culture by thereof are as mentioned above. 55 filtering off the insoluble matters such as cells from the In the present invention, the compound obtained by the culture, isolation by centrifugation, passing the culture fil above-mentioned reactions can be used as a starting mate trate through Amberlite XAD-2 (trade mark) and adsorbing rial. Compound (XXXXXIII). The Compound (XXXXXIII) thus Of the Compounds (XXXXXII), a compound wherein Rr obtained is eluted with, for example, methanol and the eluate is an O-position hydroxyl-Substituted alkyl which may have 60 is fractionated by reversed phase chromatography, whereby a double bond or carbonyl in the chain and lactone com a highly purified product of Compound (XXXXXIII) can be pound thereof are known compounds reported in Japanese obtained. In the case of a microorganism belonging to the Patent Unexamined Publication Nos. 104087/1989 and genus Myriococcum or the genus Mycelia, Such as Myrio 128347/1991 mentioned above and are produced according coccum albomyces, Mycelia Sterilia or the like, cells are to the method described therein. Of the Compounds 65 Separated from the culture by filtration, centrifugation and (XXXXXII), a compound wherein Rr is an alkyl which may the like and the culture filtrate is treated in the same manner have a double bond or carbonyl in the chain, Such as as in the case of the microorganisms belonging to the genus 5,952,316 183 184 Isaria. The Compound (XXXXXIII) is extracted from the water bath, followed by stirring. After stirring the mixture at Separated cells by the use of methanol and the extract is room temperature for 30 minutes, 3.0 ml of water was added treated with Amberlite XAD-2 in the same manner as with thereto to Stop the reaction. The reaction mixture was the filtrate above and purified by chromatography and concentrated under reduced pressure and 100 ml of acetic recrystallization. anhydride and 80 ml of pyridine were added to the concen The 2-amino-1,3-propanediol compounds, isomers trate. The mixture was Stirred at room temperature over thereof and salts thereof of the present invention show night. The reaction mixture was poured into ice water to Superior immunosuppressive effect and are useful as a make the total amount 1600 ml and extracted three times SuppreSSant of rejection in organ or bone marrow transplan with 500 ml of ethyl acetate. The ethyl acetate layers were tation in mammals inclusive of human, cow, horse, dog, combined and washed with a 1 Naqueous hydrochloric acid mouse, rat etc., an agent for the prevention and treatment of Solution, a Saturated aqueous Sodium hydrogencarbonate autoimmune diseases Such as rheumatoid arthritis, atopic Solution and a Saturated aqueous Sodium chloride Solution in eczema (atopic dermatitis), Behcet’s disease, uvea diseases, order. The mixture was dehydrated over anhydrous magne systemic lupus erythematosus, Sjögren's syndrome, sium Sulfate and concentrated. The concentrate was purified poly Sclerosis, myasthenia gravis, diabetes type I, endocrine 15 by Silica gel column chromatography to give 1.35 g of eye disorders, primary biliary cirrhosis, Crohn's disease, 2-acetamido-1,3-diacetoxy-2-tetradecylpropane. glomerulonephritis, Sarcoidosis, psoriasis, pemphigus, melting point=84.0-85.5 C. aplastic anemia, idiopathic thrombocytopenic purpura, IR(KBr): 3310, 2950, 2920, 2840, 1750, 1655, 1550, allergy, polyarteritis nodosa, progressive Systemic Sclerosis, 1470, 1375, 1255, 1230, 1035, 900 cm mixed connective-tissue disease, aortitis Syndrome, polymyositis, dermatomyositis, Wegener's granulomatosis, EXAMPLE 2 ulcerative colitis, active chronic hepatitis, autoimmune hemolytic anemia, Evans Syndrome, bronchial asthma, pol 2-Acetamido-1,3-diacetoxy-2-tetradecylpropane (1.25 g) linosis and So on, and a reagent for use in medicine and was dissolved in 100 ml of methanol and 19.4 ml of a 1 N pharmacy. Also, the compounds protected with a protecting 25 aqueous Sodium hydroxide Solution was added thereto. The group are useful as intermediates for the Synthesis of the mixture was refluxed under heating for 6 hours. The mixture compounds having Superior pharmacological actions as was neutralized with a 1 N aqueous hydrochloric acid recited above. Solution and concentrated under reduced pressure. The con When these compounds are used as pharmaceuticals, an centrate was washed with water and ethyl acetate:hexane= effective amount thereof is generally admixed with carrier, 1:1 in order to give 791 mg of 2-amino-2-tetradecyl-1,3- excipient, diluent and So on and formulated into powder, propanediol hydrochloride. capsule, tablet, injection or the like for the administration to melting point=96.5-98.5° C. patients. A lyophilized preparation may be produced by a Rf: 0.55 (chloroform:methanol: water=65:35:5) method known per Se. IR(KBr): 3520, 3450, 3300, 3050, 2920, 2850, 1630, While the dose of these compounds varies depending on 35 1530, 1470, 1290, 1070, 1050 cm disease, Symptom, body weight, Sex, age and So on, they are administered, for example, to an adult daily by 0.01-10 mg EXAMPLE 3 (potency) in a single to several times divided doses when Suppressing rejection in kidney transplantation. (1) Diethyl 2-acetamidomalonate (3.0 g) was dissolved in Moreover, the compounds of the present invention can be 40 50 ml of dry ethanol and 1.13 g of sodium ethoxide was used in combination with other immunosuppreSSant Such as added thereto. A solution of 5.5 g of hexadecyl bromide in cyclosporin, azathioprine, Steroids or FK-506 (disclosed in 20 ml of ethanol was added thereto at room temprature with EP-A184.162, also known as tacrolimus). Stirring. The inside of the reaction vessel was displaced with The present invention is hereinafter explained in detail by nitrogen and the mixture was refluxed for about 15 hours. 45 The mixture was neutralized with a 1 Naqueous hydrochlo illustrating examples, to which the present invention is not ric acid Solution and concentrated. The concentrate was limited. purified by Silica gel column chromatography to give 4.37g EXAMPLE 1. of diethyl 2-acetamido-2-hexadecylmalonate. melting point=65.0-67.0° C. (1) Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 IR(KBr): 3300, 2920, 2850, 1745, 1650, 1515, 1210, 50 ml of dry ethanol and 1.13 g of sodium ethoxide was 1020 cm added thereto. A solution of 4.7 g of tetradecyl bromide in 20 ml of ethanol was added to the mixed solution while (2) Diethyl 2-acetamido-2-hexadecylmalonate (4.30 g) Stirring at room temperature. The inside of the reaction was dissolved in 200 ml of dry tetrahydrofuran and the vessel was displaced with nitrogen and the mixture was reaction vessel was equipped with a calcium chloride tube. refluxed for about 15 hours. Then, the mixture was neutral 55 Thereto was added 1.90 g of lithium aluminum hydride in an ized with a 1 N acqueous hydrochloric acid Solution and ice water bath and the mixture was Stirred. After Stirring the concentrated. The concentrate was purified by Silica gel mixture at room temperature for 30 minutes, 3.6 ml of water column chromatography to give 3.5 g of diethyl was added thereto to Stop the reaction. The reaction mixture 2-acetamido-2-tetradecylmalonate. was concentrated under reduced pressure and 100 ml of 60 acetic anhydride and 80 ml of pyridine were added to the melting point=58.5–60.5° C. residue. The mixture was stirred at room temperature over IR(KBr): 3280, 2970, 2930, 2860, 1750, 1655, 1525, night. The reaction mixture was poured into ice water to 1480, 1220, 1030 cm make the total amount 1600 ml and extracted three times (2) Diethyl 2-acetamido-2-tetradecylmalonate (3.40 g) with 500 ml of ethyl acetate. The ethyl acetate layers were was dissolved in 200 ml of dry tetrahydrofuran. The reaction 65 combined and washed with a 1 Naqueous hydrochloric acid vessel was equipped with a calcium chloride tube and 1.58 Solution, a Saturated aqueous Sodium hydrogencarbonate g of lithium aluminum hydride was added thereto in an ice Solution and a Saturated aqueous Sodium chloride Solution in 5,952,316 18S 186 order. The resultant mixture was dehydrated over anhydrous IR: 3280, 2920, 2850, 1750, 1735, 1645, 1565, 1385, magnesium Sulfate and concentrated. The concentrate was 1270, 1240, 1045 cm purified by Silica gel column chromatography to give 1.83 g of 2-acetamido-1,3-diacetoxy-2-hexadecylpropane. EXAMPLE 6 melting point=84-86 C. 2-Acetamido-1,3-diacetoxy-2-octadecylpropane (1.00 g) IR(KBr): 3300, 2920, 2850, 1740, 1655, 1560, 1390, was dissolved in 26 ml of methanol and 6.4 ml of a 1 N 1270, 1240, 1055 cm aqueous Sodium hydroxide Solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture EXAMPLE 4 was neutralized with a 1 N aqueous hydrochloric acid 2-Acetamido-1,3-diacetoxy-2-hexadecylpropane (1.75 g) Solution and concentrated under reduced pressure. The con was dissolved in 100 ml of methanol and 23.8 ml of a 1 N centrate was washed with water and ethyl acetate:hexane= aqueous Sodium hydroxide Solution was added thereto. The 1:1 in order to give 639 mg of 2-amino-2-octadecyl-1,3- mixture was refluxed under heating for 6 hours. The mixture propanediol hydrochloride. was neutralized with a 1 N acqueous hydrochloric acid 15 melting point 108.5–109.5° C. Solution and concentrated under reduced pressure. The con H-NMR (200MHz, CD, OD) 8: 3.64 (2H, d, J=11.48Hz, centrate was washed with water and ethyl acetate:hexane= -CHa-O-), 3.57 (2H, d, J-11.47HZ, -CHb-O-), 1:1 in order to give 892 mg of 2-amino-2-hexadecyl-1,3- 1.28 (34H, bris, CHx17), 0.90 (3H, t, J=6.35Hz, —CH) propanediol hydrochloride. IR: 3275, 2900, 2840, 1630, 1600, 1530, 1465, 1290, melting point=100.5–104.0° C. 1050 cm Rf: 0.55 (chloroform:methanol: water=65:35:5) IR(KBr): 3350, 2920, 2850, 1590, 1470, 1050 cm EXAMPLE 7 2-Amino-2-octadecyl-1,3-propanediol hydrochloride EXAMPLE 5 25 (100 mg) as obtained in Example 5 was dissolved in 200 ml (1) Diethyl 2-acetamidomalonate (5.0 g) was dissolved in of methanol and the mixture was dropwise added to 50 ml 64 ml of dry ethanol and 1.71 g of sodium ethoxide was of Diaion WA-10 (trade mark, anion exchange resin). The added thereto. A solution of 8.4 g of octadecyl bromide in 20 Solvent of the eluate was distilled away to give 64 mg of ml of dry ethanol was added thereto while stirring at room 2-amino-2-octadecyl-1,3-propanediol. temperature. The inside of the reaction vessel was displaced melting point=76.0-800° C. with nitrogen and the mixture was refluxed for about 15 IR: 3290, 3175, 2910, 2850, 1590, 1580, 1480, 1065, hours. The mixture was neutralized with a 1 N aqueous 1050, 1000 cm hydrochloric acid Solution and concentrated. The concen trate was purified by Silica gel column chromatography to EXAMPLE 8 give 6.4 g of diethyl 2-acetamido-2-octadecylmalonate. 35 (1) Diethyl 2-acetamidomalonate (3.0 g) was dissolved in melting point=70-71 C. 50 ml of dry ethanol and 1.3 g of sodium ethoxide was added H-NMR (200MHz, CDC1) 8: 6.77 (1H, bris, -NH-), thereto. A solution of 6.5 g of docosyl bromide in 20 ml of 4.24 (4H, q, J=7.16HZ, -OCH-x2), 2.35-2.26 (2H, m, dry ethanol was added thereto while Stirring at room tem C-Ha, Hb), 2.03 (3H, s, CHCONH-), 1.25 (38H, m, perature. The inside of the reaction vessel was displaced O-CH-CHX2, CH-x16), 0.88 (3H, t, J=6.47HZ, CH) 40 with nitrogen and the mixture was refluxed for about 15 IR: 3260,2910, 2850, 1745, 1640, 1515, 1210, 1020 cm hours. The mixture was neutralized with a 1 N aqueous (2) Diethyl 2-acetamido-2-octadecylmalonate (3.0 g) was hydrochloric acid Solution and concentrated. The concen dissolved in dry tetrahydrofuran and the reaction vessel was trate was purified by Silica gel column chromatography to give 4.2 g of diethyl 2-acetamido-2-docosylmalonate. equipped with a calcium chloride tube. In an ice water bath, 45 1.2 g of lithium aluminum hydride was added thereto and the melting point=79–80° C. mixture was stirred. Then, the mixture was stirred at room IR(KBr): 3300,2925, 2860, 1750, 1655, 1520, 1220 cm temperature for 30 minutes and 2.31 g of water was added (2) Diethyl 2-acetamido-2-docosylmalonate (4.15 g) was thereto to Stop the reaction. The reaction mixture was dissolved in dry tetrahydrofuran and the reaction vessel was concentrated under reduced pressure and 130 ml of acetic 50 eqipped with a calcium chloride tube. In an ice water bath, anhydride and 120 ml of pyridine were added to the con 1.4 g of lithium aluminum hydride was added thereto and the centrate. The mixture was Stirred at room temperature over mixture was stirred. The mixture was Stirred at room tem night. The resultant mixture was poured into ice water to perature for 30 minutes and 2.31 g of water was added make the total amount 2200 ml and extracted three times thereto to Stop the reaction. The reaction mixture was with 700 ml of ethyl acetate. The ethyl acetate layers were 55 concentrated under reduced pressure and 130 ml of acetic combined and washed with a 1 Naqueous hydrochloric acid anhydride and 120 ml of pyridine were added thereto. The Solution, an aqueous Sodium hydrogencarbonate Solution mixture was stirred at room temperature overnight. The and an aqueous Sodium chloride Solution in order. The reaction mixture was poured into ice water to make the total mixture was dehydrated over anhydrous magnesium Sulfate amount 2200 ml and extracted three times with 700 ml of and concentrated. The concentrate was purified by Silica gel 60 ethyl acetate. The ethyl acetate layers were combined and column chromatography to give 1.7 g of 2-acetamido-1,3- washed with a 1 Naqueous hydrochloric acid Solution, a diacetoxy-2-octadecylpropane. Saturated aqueous Sodium hydrogencarbonate Solution and a melting point=90–91 C. Saturated aqueous Sodium chloride Solution in order. The H-NMR (200MHz, CDC1) 8: 5.64 (1H, bris, -NH-), mixture was dehydrated over anhydrous magnesium Sulfate 4.30 (4H, s, —CHO-x2), 2.09 (6H, s, OCOCHx2), 1.97 65 and concentrated. The concentrate was purified by Silica gel (3H, s, NHCOCH), 1.25 (34H, bris, CHx17), 0.88 (3H, t, column chromatography to give 1.8g of 2-acetamido-1,3- J=6.47HZ, CH) diacetoxy-2-docosylpropane. 5,952,316 187 188 melting point=94-95 C. acetate:hexane=1:1 in order to give 817 mg of 2-amino-2- IR(KBr): 3280, 2920, 2850, 1750, 1655, 1520, 1480, icosyl-1,3-propanediol hydrochloride. 1220 cm melting point=109.5-111.0° C. Rf: 0.55 (chloroform:methanol: water=65:35:5) EXAMPLE 9 IR(KBr): 3300, 2910, 2850, 1640, 1600, 1480, 1065, 2-Acetamido-1,3-diacetoxy-2-docosylpropane (1.5 g) 1050 cm was dissolved in 40 ml of methanol and 9.6 ml of a 1 N aqueous Sodium hydroxide Solution was added thereto. The EXAMPLE 12 mixture was refluxed under heating for 6 hours., The mixture 1O (1) Diethyl 2-acetamidomalonate (15g) was dissolved in was neutralized with a 1 N acqueous hydrochloric acid 200 ml of dry ethanol and 5.6 g of sodium ethoxide was Solution and concentrated under reduced pressure. The con added thereto. To the reaction mixture, 22 g of 9-octadecenyl centrate was washed with water and ethyl acetate:hexane= chloride was added while Stirring at room temperature. The 1:1 in order to give 846 mg of 2-amino-2-docosyl-1,3- inside of the reaction vessel was displaced with nitrogen and propanediol hydrochloride. 15 the mixture was refluxed for about 15 hours. The mixture melting point=109.0-110.5° C. was neutralized with ethanol-concentrated hydrochloric acid Rf: 0.55 (chloroform:methanol: water=65:35:5) (11:1) and concentrated. The concentrate was purified by IR(KBr): 3500, 3450, 3290, 2920, 2850, 1640, 1530, Silica gel column chromatography to give 1.3 g of diethyl 1470, 1060 cm 2-acetamido-2-(9-octadecenyl)malonate as a colorless, oily and Viscous Substance. EXAMPLE 10 H-NMR (200MHz, CDC1) 8: 6.765 (1H, bris, -NH-), 5.340-5.310 (2H, m, CH=CH), 4.240 (4H, q, J=7.4Hz, (1) Diethyl 2-acetamidomalonate (3.0 g) was dissolved in –OCHx2), 2.032 (3H, s, CH CON), 1.990 (4H, m, C 50 ml of dry ethanol and 1.3 g of sodium ethoxide was added HCH=x2), 1.252 (26H, m, CHx13), 1.252 (6H, t, thereto. A solution of 6.0 g of icosyl bromide in 20 ml of dry 25 ethanol was added thereto while Stirring at room tempera J=7.2Hz, OCH-CHx2), 0.880 (3H, t, J=6.5Hz, CH) ture. The inside of the reaction vessel was displaced with (2) Diethyl 2-acetamido-2-(9-octadecenyl)malonate (1.3 nitrogen and the mixture was refluxed for about 15 hours. g) was dissolved in 30 ml of dry tetrahydrofuran and 450 mg The mixture was neutralized with a 1 Naqueous hydrochlo of lithium aluminum hydride was added thereto under ric acid Solution and concentrated. The concentrate was ice-cooling. The inside of the reaction vessel was displaced purified by Silica gel column chromatography to give 4 g of with dry nitrogen and the mixture was stirred. Then, the diethyl 2-acetamido-2-icosylmalonate. mixture was stirred at room temperature for 2 hours and 1 ml of water was added thereto to Stop the reaction. The reaction melting point=76.5-77.5° C. mixture was concentrated under reduced pressure and 10 ml IR(KBr): 2920, 2850, 1750, 1655, 1520, 1480, 1220 cm of acetic anhydride and 5 ml of pyridine were added thereto. (2) Diethyl 2-acetamido-2-icosylmalonate (3.7 g) was 35 The mixture was stirred at room temperature overnight. dissolved in dry tetrahydrofuran. The reaction vessel was Water was added to the reaction mixture under ice-cooling eqipped with a calcium chloride tube and the mixture was to make the total amount about 100 ml and the mixture was cooled to 0°C. Lithium aluminum hydride (1.4 g) was added extracted twice with 50 ml of ethyl acetate. The ethyl acetate thereto and the mixture was stirred. The mixture was stirred layers were combined and washed with a 1 N aqueous at room temperature for 30 minutes and 2.31 g of water was 40 hydrochloric acid Solution, a Saturated aqueous Sodium added thereto to Stop the reaction. The reaction mixture was hydrogencarbonate Solution and a Saturated aqueous Sodium concentrated under reduced pressure and 130 ml of acetic chloride solution in order. The mixture was dehydrated over anhydride and 120 ml of pyridine were added thereto. The anhydrous magnesium Sulfate and concentrated to give 430 mixture was stirred at room temperature overnight. The mg of 2-acetamido-1,3-diacetoxy-2-(9-octadecenyl)propane reaction mixture was poured into ice water to make the total 45 as a coloreless, oily and Viscous Substance. amount 2200 ml and extracted three times with 700 ml of IR(CHCl): 3460, 3420, 3010, 2940, 2860, 1750, 1690, ethyl acetate. The ethyl acetate layers were combined and washed with a 1 Naqueous hydrochloric acid Solution, a 1520, 1475, 1390, 1380, 1240(br), 1045,990 cm Saturated acqueous Sodium hydrogencarbonate Solution and a EXAMPLE 13 Saturated aqueous Sodium chloride Solution in order. The 50 mixture was dehydrated over anhydrous magnesium Sulfate 2-Acetamido-1,3-diacetoxy-2-(9-octadecenyl)propane and concentrated. The concentrate was purified by Silica gel (332 mg) was dissolved in 30 ml of methanol and 7.8 ml of column chromatography to give 1.7 g of 2-acetamido-1,3- a 1N aqueous Sodium hydroxide Solution was added thereto. diacetoxy-2-icosylpropane. The mixture was refluxed under heating overnight. The 55 mixture was neutralized with methanol-concentrated hydro melting point=93–94 C. chloric acid (11:1) and concentrated under reduced pressure. IR(KBr): 3280, 2920, 2855, 1775, 1755, 1650, 1565, The concentrate was dissolved in methanol-water (1:1) and 1480, 1385, 1270, 1245, 1045 cm Subjected to reversed phase column chromatography packing: Sep-Pak(Cs). After washing, the mixture was EXAMPLE 11 60 eluted with methanol. The eluate was concentrated to give 2-Acetamido-1,3-diacetoxy-2-icosylpropane (1.5 g) was 209 mg of 2-amino-2-(9-octadecenyl)-1,3-propanediol dissolved in 40 ml of methanol and 9.6 ml of a 1 Naqueous hydrochloride as a colorless, oily and Viscous Substance. Sodium hydroxide solution was added thereto. The mixture H-NMR (200MHz, CD, OD) 8: 5.385-5.315 (2H, m, was refluxed under heating for 6 hours. The mixture was CH=CH), 3.616 (2H, d, J=11.4Hz, OCHx2), 3.548 (2H, d, neutralized with a 1 N aqueous hydrochloric acid Solution 65 J=11.4Hz, OCHx2), 2.071-1957 (4H, m, CH-CH=x2), and the reaction mixture was concentrated under reduced 1.665–1.580 (2H, m, CCH), 1.39–1.28 (24H, m, CHx12), preSSure. The concentrate was washed with water and ethyl 0.896 (3H, t, J=6HZ, CH) 5,952,316 189 190 IR: 3300(br), 2920, 2850, 1600, 1500, 1465, 1050, 965 EXAMPLE 16 -1 C (1) A solution of 5.42 g of cinnamyl bromide, 5.43 g of EXAMPLE 1.4 diethyl 2-acetamidomalonate and 1.87 g of Sodium ethoxide in 70 ml of ethanol was refluxed under heating for 2 hours (1) Sodium (0.23 g) was added to 15 ml of absolute under a nitrogen atmosphere. The mixture was poured into ethanol and the mixture was stirred at room temperature for 200 ml of ice water and extracted with ethyl acetate. The 30 minutes in a nitrogen flow to give a 10 mmol solution of extract was dried over anhydrous Sodium Sulfate and the Sodium ethoxide in ethanol. To this solution, 1.98 g of solvent was distilled away. The residue was purified by silica diethyl 2-acetamidomalonate was added and the mixture gel chromatography (ethyl acetate:hexane=1:10-1:3) to give was heated at 50 C. for 30 minutes in a stream of nitrogen. 2.68 g of diethyl 2-acetamido-2-(3-phenyl-2-propenyl) 3-Phenylpropyl bromide was added thereto at room tem malonate as white crystals. perature and the mixture was refluxed under heating for 24 melting point=70-75° C. hours. The mixture was neutralized with dilute hydrochloric Rf. 0.38 (ethyl acetate:hexane=1:5) acid and ethanol was distilled away. The resultant residue was extracted with ethyl acetate. The ethyl acetate layer was 15 H-NMR (CDC1/TMS) 8: 1.31 (6H, t, J-7.5Hz), 1.56 washed with water and dried over anhydrous magnesium (2H, s), 2.09 (3H, s), 4.28 (4H, q, J=7.5Hz), 6.30–6.80 (2H, sulfate. The solvent was distilled away and the residue was m), 7.27 (5H, s) purified by Silica gel column chromatography (ethyl IR(KBr): 3280, 2990, 1740, 1640 cm acetate:hexane=1:4-1:1) and recrystallized from diisopropyl (2) A solution (80 ml) of 2.50 g of the above-mentioned ether-hexane to give 800 mg of diethyl 2-acetamido-2-(3- compound and 1.63 g of lithium borohydride in tetrahydro phenylpropyl)malonate as white crystals. furan was refluxed under heating for 2 hours under a melting point 76–77 C. nitrogen atmosphere. After the reaction, the Solvent was distilled away and the residue was evaporated to dryneSS. Rf: 0.58 (ethyl acetate:hexane=1:1) Acetic anhydride (14 ml) and 50 ml of pyridine were added H-NMR (90MHz, CDC1) 8: 1.22 (3H, t, J-7Hz), 25 to the residue and the mixture was stirred at room tempera 1.10–1.56 (4H, m), 2.02 (3H, s), 2.28–2.75 (2H, m), 4.21 ture overnight. The mixture was poured into ice water and (4H, q, J=7Hz), 6.75 (1H, brs), 7.02–7.42 (5H, m) extracted with ethyl acetate. The extract was washed with 2 IRV: 3259, 2980, 2863, 1738, 1648 cm N hydrochloric acid, a Saturated acqueous Sodium bicarbon MS(EI): 335(Mt) ate Solution and Saturated brine in order and dried. The (2) A solution (50 ml) of 1.0 g of the above-mentioned solvent was distilled away and the residue was purified by compound and 136 mg of lithium borohydride in tetrahy Silica gel column chromatography (ethyl acetate:hexane= drofuran was refluxed under heating for 1 hour in a nitrogen 3:1) to give 200 mg of 2-acetamido-1,3-diacetoxy-2-(3- flow. The reaction mixture was poured into 100 ml of ice phenyl-2-propenyl)propane as white crystals. water and extracted with ethyl acetate. The extract was melting point=88-90 C. washed and dried, and the solvent was distilled away. The 35 Rf: 0.70 (ethyl acetate) residue was purified by Silica gel column chromatography H-NMR (CDC1/TMS) 8: 1.96 (3H, s), 2.07 (6H, s), 2.82 (methanol: chloroform=1:20) to give 720 mg of (2H, d, J=7.5Hz), 4.36 (4H, s) 2-acetamido-2-(3-phenylpropyl)-1,3-propanediol as a IR(KBr): 3311, 3084, 1750, 1655, 1560 cm colorless, oily Substance. 40 MS(EI): 333(M) Rf: 0.30 (ethyl acetate) elemental analysis: calculated C 64.85, H 6.95, N 4.20 H-NMR (90MHz, CDC1,) 8: 1.47–1.89 (4H, m), 2.00 found C 64.85, H 6.88, N 4.15 (3H, s), 2.44–2.84 (2H, m), 3.73 (4H, dd, J=7Hz, 15Hz), 3.37–417 (2H, m), 5.51–5.97 (1H, m), 7.00-7:45 (5H, m) EXAMPLE 1.7 IRV: 3294, 2938, 1652 cm 45 2-Acetamido-1,3-diacetoxy-2-(3-phenyl-2-propenyl) propane (170 mg) was dissolved in 6 ml of methanol and 6 MS(EI): 251(M) ml of a 1 Naqueous Sodium hydroxide Solution was added EXAMPLE 1.5 thereto. The mixture was refluxed under heating for 3 hours. 2-Acetamido-2-(3-phenylpropyl)-1,3-propanediol (600 After the reaction, the Solvent was distilled away and the 50 residue was purified by Silica gel column chromatography mg) was dissolved in 25 ml of methanol and 11.9 ml of a 1 (methanol: chloroform=1:30-1:6) to give 70 mg of 2-amino Naqueous Sodium hydroxide Solution was added thereto. 2-(3-phenyl-2-propenyl)-1,3-propanediol as pale brown The mixture was refluxed under heating for 6 hours. The crystals. mixture was poured into 30 ml of ice water and neutralized with dilute hydrochloric acid. The solvent was distilled Rf: 0.14 (methanol: chloroform=1:10) away. Chloroform was added to the residue for extraction 55 IR(KBr): 3367,2935, 1556 cm and the chloroform layer was washed and dried. The solvent EXAMPLE 1.8 was distilled away and the residue was purified by column chromatography (chloroform:methanol=9:1-4:1) to give (1) 1-Phenyl-1-propyn-3-ol (5 g), 5.1 g of tosyl chloride 250 mg of 2-amino-2-(3-phenylpropyl)-1,3-propanediol as a and 20 ml of pyridine were stirred at room temperature for pale yellow, oily Substance. 60 1 hour. The reaction mixture was poured into 100 ml of ice water and extracted with ethyl acetate. The oil layer was Rf. 0.22 (methanol:chloroform=1:4) washed with 1 N hydrochloric acid and Saturated brine and H-NMR (90MHz, CDC1) 8: 1.11–1.98 (4H, m), dried over anhydrous sodium sulfate. The solvent was 2.43–2.75 (2H, m), 3.15–4.03 (4H, m), 3.62 (4H, bris), 7.19 distilled away. The residue was purified by Silica gel column (5H, s) 65 chromatography (ethyl acetate:hexane 1:5) to give 2.54 g of IRV: 3347, 3023, 2937, 1583 cm 3-phenyl-2-propynyl chloride as a pale yellow, oily Sub MS(EI): 209(M+1) Stance. 5,952,316 191 192 Rf. 0.81 (ethyl acetate:hexane=1:2) extracted with chloroform. The extract was dried over anhydrous Sodium Sulfate and the Solvent was distilled away. H-NMR (CDC1/TMS) 8: 4.37 (2H, s), 723–7.60 (5H, The residue was purified by Silica gel column chromatog ) raphy (ethyl acetate:hexane=1:6) to give 1.2814 g of 4-(4- IR(neat): 2222, 758,690 cm butylphenyl)butyl p-toluenesulfonate as a colorless, oily MS(70 eV): 150(M) Substance. (2) A Solution of 2.5g of the above-mentioned compound, H-NMR (CDC1/TMS) 8: 0.96 (3H, t, J=7Hz), 1.50-2.00 3.79 g of dimethyl 2-acetamidomalonate and 1.43 g of (8H, m), 2.48 (3H, s), 2.40-2.75 (4H, m), 4.08 (2H, t, Sodium ethoxide in 50 ml of ethanol was refluxed under J=6Hz), 7.07 (4H, m), 7.36 (2H, d, J=8Hz), 7.83 (2H, d, heating for 3 hours under a nitrogen atmosphere. Water (20 J=8Hz) ml) was added thereto to stop the reaction and the mixture IR: 2956, 2929, 2858, 1361 cm was extracted with ethyl acetate. The extract was dried over MS: 360(M) anhydrous Sodium Sulfate and the Solvent was distilled away. (2) The above-mentioned compound (1.2138 g) and 0.606 The residue was purified by Silica gel column chromatog g of sodium iodide were dissolved in 34 ml of 2-butanone raphy (ethyl acetate: hexane=1:7-1:2) to give 2.5 g of 15 and the mixture was refluxed under heating for 4 hours. The diethyl 2-acetamido-2-(3-phenyl-2-propynyl)malonate as mixture was poured into 100 ml of ice water and extracted white crystals. with ethyl acetate. The extract was dried over anhydrous melting point=94-96.5 C. Sodium sulfate and the solvent was distilled away. The residue was purified by Silica gel column chromatography Rf. 0.38 (ethyl acetate:hexane=1:2) (ethyl acetate:hexane=1:9) to give 0.953 g of 4-(4- H-NMR (CDC1/TMS) 8: 128 (6H, t, J=7.5Hz), 2.08 butylphenyl)-1-iodobutane as a red, oily Substance. (3H, s), 3.49 (2H, s), 4.30 (4H, q, J=7.5Hz), 6.98 (1H, bris), Rf: 0.75 (ethyl acetate:hexane=1:5) 7.16–749 (5H, m) H-NMR (CDC1/TMS) 8: 0.92 (3H, t, J=7Hz), 1.1.0-2.05 IR(KBr): 3260, 1747, 1643, 1197 cm (8H, m), 2.59 (4H, t, J-7.5Hz), 3.20 (2H, t, J-7Hz), 7.07 MS(70 eV): 331(M) 25 (5H, s) (3) A solution (50 ml) of 1.8g of the above-mentioned (3) A solution of 953.4 mg of the above-mentioned compound and 0.47 g of lithium borohydride in tetrahydro compound, 687.7 mg of diethyl 2-acetamidomalonate and furan was refluxed under heating for 1.5 hours under a 260 mg of sodium ethoxide in 10 ml of ethanol was refluxed nitrogen atmosphere. After cooling, the mixture was neu under heating for 3 hours under a nitrogen atmosphere. The tralized with 8 ml of a 1 N aqueous hydrochloric acid mixture was poured into 100 ml of ice water and extracted Solution and evaporated to dryness. Acetic anhydride (4 ml) with ethyl acetate. The extract was dried over anhydrous and 30 ml of pyridine were added to the residue and the Sodium sulfate and the solvent was distilled away. The mixture was stirred at room temperature for 2.5 hours. The residue was purified by Silica gel column chromatography reaction mixture was poured into ice water and extracted (ethyl acetate:hexane=1:3-1:2) to give 480 mg of diethyl with chloroform. The extract was washed with 1 N hydro 35 2-acetamido-2-4-(4-butylphenyl)butylmalonate as white chloric acid and Saturated brine in order and dried. The crystals. solvent was distilled away and the residue was purified by melting point=60–61 C. Silica gel column chromatography (ethyl acetate: hexane= Rf. 0.38 (ethyl acetate:hexane=1:2) 2:1) to give 430 mg of 2-acetamido-1,3-diacetoxy-2-(3- H-NMR (CDC1/TMS) 8: 0.93 (3H, t, J=6Hz), 1.24 (3H, phenyl-2-propynyl)propane as a colorless, oily Substance. 40 t, J=7Hz), 1.09–1.85 (8H, m), 2.02 (3H, s), 2.35 (2H, m), Rf. 0.64 (ethyl acetate) 2.58 (4H, t, J=7.5Hz), 4.25 (2H, q, J=6Hz), 6.75 (1H, brs), H-NMR (CDC/TMS) 8: 1.98 (3H, s), 2.07 (6H, s), 3.09 7.07 (4H, s) (2H, s), 4.47 (4H, s), 5.95 (1H, bris), 7.18–7.48 (5H, m) IR: 3270, 2930, 2850, 1740, 1640 cm IR(neat): 3293, 2135, 1745, 1662 cm 45 MS: 405(M), 290 MS(70 eV): 331(M) elemental analysis: calculated C 68.12, H 8.70, N 3.45 found C 68.25, H 8.69, N 3.55 EXAMPLE 1.9 (4) A solution (15 ml) of 450 mg of the above-mentioned 2-Acetamido-1,3-diacetoxy-2-(3-phenyl-2-propynyl) compound and 100 mg of lithium borohydride in tetrahy propane (430 mg) was dissolved in 8 ml of methanol and 8 50 drofuran was refluxed under heating for 2 hours under a ml of a 1 Naqueous Sodium hydroxide Solution was added nitrogen atmosphere. The mixture was neutralized with 2.5 thereto. The mixture was refluxed under heating for 2 hours. ml of a 2 Naqueous hydrochloric acid solution and dried to The solvent was distilled away and the residue was purified Solidness. Acetic anhydride (2 ml) and 4 ml of pyridine were by Silica gel column chromatography added to the residue and the mixture was stirred at room 55 temperature overnight. The reaction mixture was poured (methanol: chloroform=1:50-1:7) to give 230 mg of into ice water and extracted with ethyl acetate. The extract 2-amino-2-(3-phenyl-2-propynyl)-1,3-propanediol as a pale was washed with 2 N hydrochloric acid, a saturated sodium yellow, amorphous-like Solid. bicarbonate Solution and Saturated brine in order and dried. Rf: 0.20 (methanol: chloroform=1:5) The solvent was distilled away and the residue was purified IR(KBr): 3281, 2932, 1558, 1049 cm by Silica gel column chromatography (ethyl acetate:hexane= 60 3:1) to give 72.4 mg of 2-acetamido-1,3-diacetoxy-2-4-(4- EXAMPLE 2.0 butylphenyl)butylpropane as white crystals. (1) A solution of 1.1 g of 4-(4-butylphenyl)butanol, 1.05 melting point=68-71 C. g of tosyl chloride, 0.48 ml of pyridine and a catalytic Rf. 0.63 (ethyl acetate) amount of dimethylaminopyridine in dichloromethane was 65 H-NMR (CDC1/TMS) 8: 0.91 (3H, t, J=7Hz), 1.10–240 allowed to Stand at room temperature overnight. The reac (1OH, m), 1.93 (3H, s), 2.06 (6H, s), 2.58 (4H, t, J=7.5Hz), tion mixture was poured into 50 ml of ice water and 4.28 (4H, s), 5.62 (1H, bris), 7.07 (4H, s) 5,952,316 193 194 IR: 3298,3090, 2931, 2859, 1739, 1652, 1557 cm melting point=57-58 C. MS: 405(M) Rf. 0.42 (ethyl acetate:hexane=1:2) elemental analysis: calculated C 68.12, H 8.70, N 3.45 H-NMR (CDC1/TMS) 8: 0.91 (3H, t, J=6Hz), 1.24 (6H, found C 67.95, H 8.52, N 3.44 t, J=7Hz), 1.08-1.90 (12H, m), 2.02 (3H, s), 2.35 (2H, m), 2.58 (4H, t, J=7Hz), 4.23 (4H, q, J=7Hz), 6.74 (1H, brs), EXAMPLE 21 7.07 (4H, s) 2-Acetamido-1,3-diacetoxy-2-4-(4-butylphenyl)butyll IR: 3270, 2927, 2858, 1746, 1644, 1514 cm propane (66.2 mg) was dissolved in 2 ml of methanol and 2 MS: 433(M), 360, 318 ml of a 1 Naqueous Sodium hydroxide Solution was added elemental analysis : calculated C 69.25, H 9.07, N 3.23 thereto. The mixture was refluxed under heating for 4 hours. found C 69.44, H 8.97, N 3.26 The solvent was distilled away and the residue was purified (4) A solution (20 ml) of 840 mg of the above-mentioned by Silica gel thin layer chromatography compound and 211 mg of lithium borohydride in tetrahy (methanol:chloroform=1:4) to give 24.9 mg of 2-amino-2- drofuran was refluxed under heating for 4 hours under a 4-(4-butylphenyl)butyl-1,3-propanediol as white crystals. 15 nitrogen atmosphere. The mixture was neutralized with 2 N melting point=92-94 C. hydrochloric acid and the Solvent was evaporated to dryneSS. Rf. 0.15 (methanol:chloroform=1:4) Acetic anhydride (5.5 ml) and 16 ml of pyridine were added IR: 3276, 2928, 2858, 1560 cm to the residue and the mixture was stirred at room tempera ture overnight. The reaction mixture was treated conven EXAMPLE 22 tionally and the residue obtained was purified by Silica gel column chromatography (ethyl acetate:hexane=3:1) to give (1) 4-(4-Hexylphenyl)butanol (5.0 g) was dissolved in 20 244.5 mg of 2-acetamido-1,3-diacetoxy-2-4-(4- ml of pyridine and 4.88 g of tosyl chloride was added hexylphenyl)butylpropane as white crystals. thereto. The reaction mixture was left Standing at room melting point=61-64 C. temperature overnight. The reaction mixture was poured 25 into ice water and extracted with ethyl acetate. The extract Rf: 0.71 (ethyl acetate) was washed with 2 N hydrochloric acid, a Saturated aqueous H-NMR (CDC1/TMS) 8: Sodium bicarbonate Solution and Saturated brine in order and 0.88 (3H, t, J=6Hz), 1.10–1.90 (14H, m), 1.92 (3H, s), concentrated. The residue was purified by Silica gel column 2.04 (6H, s), 2.58 (4H, t, J=7Hz), 4.28 (4H, s), 5.58 (1H, chromatography (ethyl acetate:hexane=1:7) to give 2.21 g of brs), 7.06 (4H, s) 4-(4-hexylphenyl)butyl p-toluenesulfonate as a colorless, IR: 3313, 2928, 2856, 1750, 1656 cm oily Substance. MS: 433(M), 389, 373 Rf: 0.35 (ethyl acetate:hexane=1:5) elemental analysis: calculated C 69.25, H 9.07, N 3.23 H-NMR (CDC1/TMS) 8: 0.90 (3H, t, J=6Hz), 1.09–1.85 found C 69.26, H 9.01, N 3.22 (12H, m), 2.46 (3H, s), 2.53 (4H, m), 4.06 (2H, t, J=6Hz), 35 7.06 (4H, s), 7.34 (2H, d, J=8Hz), 7.81 (2H, d, J=8Hz) EXAMPLE 23 IR: 2927, 2856, 1599 cm 2-Acetamido-1,3-diacetoxy-2-4-(4-hexylphenyl)butyll MS: 388(M), 216 propane (200.2 mg) was dissolved in 7 ml of methanol and elemental analysis : calculated C 71.10, H 8.30 found C 40 1 N sodium hydroxide was added thereto. The mixture was 71.35, H 8.34 refluxed under heating for 5 hours. The solvent was distilled (2) The above-mentioned compound (2.21 g) and 1.02 g away and the residue obtained was purified by Silica gel thin of Sodium iodide were dissolved in 57 ml of 2-butanone and layer chromatography (methanol: chloroform=1:3) to give the mixture was refluxed under heating for 2 hours. The 79.7 mg of 2-amino-2-4-(4-hexylphenyl)butyl-1,3- reaction mixture was poured into ice water and extracted 45 propanediol as white crystals. with ethyl acetate. The extract was washed with Saturated melting point=99-102° C. brine, and dried and concentrated. The residue was purified Rf: 0.14 (methanol: chloroform=1:4) by Silica gel column chromatography (ethyl acetate:hexane= 1:9) to give 1.765g of 4-(4-hexylphenyl)-1-iodobutane as a IR: 3286, 2927, 2858, 1562, 1514 cm colorless, oily Substance: 50 EXAMPLE 24 Rf. 0.43 (ethyl acetate:hexane=1:5) (1) Concentrated Sulfuric acid (18.3 g) was gradually H-NMR (CDC1/TMS) 8: 0.90 (3H, t, J=6Hz), 1.05–2.05 added dropwise to 13.94 g of concentrated nitric acid and the (12H, m), 2.60 (4H, m), 3.21 (2H, t, J=7Hz), 7.10 (4H, s) mixture was vigorously Shaken for 10 minutes. To the mixed MS: 344(M+), 273, 175 55 Solution, 10 g of propyl bromide was gradually added elemental analysis : calculated C 55.82, H 7.32 found C dropwise at -20° C. and the mixture was stirred at -20° C. 55.81, H 7.32 for 1 hour. The reaction mixture was poured into 500 ml of (3) A solution of 1.6806 g of the above-mentioned ice water and extracted with ether. The extract was washed compound, 1.1133 g of diethyl 2-acetamidomalonate and and dried, and the solvent was distilled away. The residue 523 mg of sodium ethoxide in 20 ml of ethanol was refluxed 60 was purified by Silica gel column chromatography (ethyl under heating for 4.5 hours under a nitrogen atmosphere. acetate:hexane=1:9) to give 4.5g of 3-(4-nitrophenyl)propyl The reaction mixture was poured into ice water and bromide as a colorless, oily Substance. extracted with ethyl acetate. The extract was dried and Rf. 0.33 (ethyl acetate:hexane=1:15) concentrated. The residue was purified by Silica gel column (2) Sodium (0.68 g) was added to 40 ml of absolute chromatography (ethyl acetate:hexane=1:3) to give 870 mg 65 ethanol under ice-cooling. The mixture was stirred at room of diethyl 2-acetamido-2-4-(4-hexylphenyl)butylmalonate temperature for 30 minutes in a stream of nitrogen to give a as white crystals. Sodium ethoxide solution. To this solution, 1.98 g of diethyl 5,952,316 195 196 2-acetamidomalonate was added and 4.8g of the compound the above-mentioned compound in methylene chloride and of (1) above was dropwise added thereto. The mixture was the mixture was stirred at room temperature overnight. The refluxed under heating for 6 hours. The reaction mixture was reaction mixture was poured into ice water and extracted poured into 100 ml of ice water and extracted with ethyl with methylene chloride. The organic layer was washed and acetate. The extract was washed and dried, and the Solvent dried, and the solvent was distilled away. Petroleum ether was distilled away. The residue was purified by Silica gel was added to the residue and insoluble matters were filtered column chromatography (ethyl acetate:hexane=1:3-1: 1) to off. The petroleum ether layer was distilled away and the give 3.0 g of diethyl 2-acetamido-2-3-(4-nitrophenyl) residue was purified by Silica gel column chromatography propylmalonate as a yellow, oily Substance. (ethyl acetate:hexane 1:20) to give 4.6 g of 3-(3- Rf: 0.51 (ethyl acetate:hexane=1:1) undecyloxyphenyl)propyl bromide as a colorless, oily Sub (3) A solution (50 ml) of 1.0 g of the compound of (2) Stance. above and 228 mg of lithium borohydride in tetrahydrofuran H-NMR (90MHz, CDC1) 8: 0.83 (3H, t, J=7Hz), was refluxed under heating for 2 hours in a stream of 1.04–1.53 (16H, m), 1.55–1.86 (2H, m), 2.14 (2H, m, nitrogen. The reaction mixture was poured into 100 ml of ice J=7Hz), 2.70 (2H, t, J=7Hz), 3.34 (2H, t, J=7Hz), 3.90 (2H, water and extracted with ethyl acetate. The extract was 15 t, J=7Hz), 6.73–6.85 (3H, m), 7.14-7.42 (1H, m) washed and dried, and the solvent was distilled away. The IR: 2925, 2553, 1583, 1451, 1261 cm residue was purified by Silica gel column chromatography (3) Sodium (0.43 g) was added to absolute ethanol (40 ml) (methanol:chloroform=1:9) to give 400 mg of 2-acetamido under ice-cooling and the mixture was Stirred at room 2-3-(4-nitrophenyl)propyl-1,3-propanediol as a yellow, temperature for 30 minutes in a stream of nitrogen to give a oily Substance. 19 mmol Solution of Sodium ethoxide in ethanol. To this Rf. 0.22 (ethyl acetate) Solution, 4.0 g of diethyl 2-acetamidomalonate was added H-NMR (90MHz, CDC1) 8: 1.38–180 (4H, m), 2.00 and the mixture was stirred at 50 C. for 30 minutes in a (3H, s), 2.57-3.04 (2H, m), 3.39–4.28 (4H, m), 3.93 (2H, Stream of nitrogen. The compound (4.6 g) of (2) above was brs), 6.23–6.58 (1H, m), 7.17–7.63 (2H, m), 7.75-8.20 (2H, 25 added thereto at room temperature and the mixture was m) refluxed under heating for 6 hours. After cooling to room IRV: 3301, 2944, 1652, 1519 cm temperature, the mixture was neutralized with dilute hydro chloric acid and ethanol was distilled away. The residue was MS(EI): 296(M) extracted with ethyl acetate. The ethyl acetate layer was EXAMPLE 25 washed and dried, and the solvent was distilled away. The residue was purified by Silica gel column chromatography 2-Acetamido-2-3-(4-nitrophenyl)propyl-1,3- (ethyl acetate:hexane=1:5-1: 1) to give 4.2 g of diethyl propanediol (400 mg) was dissolved in 50 ml of methanol 2-acetamido-2-3-(3-undecyloxyphenyl)propylmalonate as and 6.7 ml of a 1 Naqueous Sodium hydroxide Solution was white crystals. added thereto. The mixture was refluxed under heating for 3 hours and neutralized with dilute hydrochloric acid. The 35 melting point=38-39 C. solvent was distilled away and chloroform was added to the H-NMR (90MHz, CDC1) 8: 0.88 (3H, t, J=7Hz), residue for extraction. The chloroform layer was washed and 1.12–1.90 (27H, m), 2.03 (3H, s), 2.27–2.73 (4H, m), 3.93 dried, and the solvent was distilled away. The residue was (3H, t, J=7Hz), 4.22 (4H, q, J=7Hz), 6.61–6.87 (3H, m), purified by Silica gel column chromatography 7.04–722 (1H, m) (methanol:chloroform=1:4) to give 100 mg of 2-amino-2- 40 IR: 3251, 2917, 1741, 1680 cm 3-(4-nitrophenyl)propyl-1,3-propanediol as a red, oily Sub MS(EI): 505(Mt) Stance. (4) A solution (20 ml) of 3.5g of the compound of (3) Rf. 0.13 (chloroform:methanol=4:1) above in anhydrous tetrahydrofuran was dropwise added to H-NMR (90 MHz, CDC1) 8: 1.1.0-2.05 (4H, m), a solution (50 ml) of 1.08 g of lithium aluminum hydride in 2.52-3.11 (2H, m), 3.19-3.86 (4H, m), 4.65 (4H, brs), 45 anhydrous tetrahydrofuran under ice-cooling and the mix 708–7.65 (3H, m), 7.70–8.18 (1H, m) ture was stirred under ice-cooling for 1 hour. The exceSS IRV: 3359, 2936, 2866, 1524 cm lithium aluminum hydride was decomposed and filtered off. The filtrate was extracted with ethyl acetate. The ethyl EXAMPLE 26 50 acetate layer was washed and dried. The Solvent was dis (1) A 15 Naqueous sodium hydroxide solution (2 ml) and tilled away and the residue was purified by Silica gel column a solution (10 ml) of 8.0 g of undecyl bromide in ethanol was chromatography (ethyl acetate, chloroform:methanol=9:1) added to a solution (30 ml) of 4.56 g of 3-(3-hydroxyphenyl) to give 1.6 g of 2-acetamido-2-3-(3-undecyloxyphenyl) propanol in ethanol and the mixture was stirred at 70° C. for propyl-1,3-propanediol as a colorless, oily Substance. 12 hours. The solvent was distilled away and the residue was 55 H-NMR (90MHz, CDC1) 8: 0.86 (3H, t, J=6Hz), extracted with ethyl acetate. The extract was washed with 1.05-1.45 (16H, m), 1.45–1.87 (6H, m), 1.99 (3H, s), Saturated Sodium hydrogencarbonate and brine, and dried 2.47-2.70 (2H, m), 3.64 (4H, dd, J=12Hz, 21 Hz), 3.82 (2H, over magnesium Sulfate. The Solvent was distilled away and t, J=6Hz), 3.79–4.10 (2H, m), 5.89 (1H, bris), 6.60–6.82 the residue was purified by Silica gel column chromatogra (3H, m), 7.03-7.31 (1H, m) phy (ethyl acetate:hexane=1:20-1:3) to give 7.37 g of 3-(3- 60 IR: 3307, 2926, 2857, 1652 cm undecyloxyphenyl)propanol as a colorless, oily Substance. MS(EI): 421 M+1) H-NMR (90MHz, CDC1) 8: 0.87 (3H, t, J=6Hz), 1.10-2.08 (20H, m), 1.60 (1H, bris), 2.69 (2H, t, J=6Hz), EXAMPLE 27 3.55-3.81 (2H, m), 3.94 (3H, t, J=6Hz), 6.62–6.87 (3H, m), 2-Acetamido-2-3-(3-undecyloxyphenyl)propyl-1,3- 7.06–7.23 (1H, m) 65 propanediol (1.4 g) was dissolved in 50 ml of methanol and (2) Carbon tetrabromide (5.68 g) and 4.49 g of triph 16.6 ml of a 1 Naqueous sodium hydroxide solution was enylphosphine were added to a solution (100 ml) of 5g of added thereto. The mixture was refluxed under heating for 3 5,952,316 197 198 hours. The mixture was poured into ice water and neutral romethane and the mixture was ice-cooled. MethaneSulfonyl ized with dilute hydrochloric acid. The solvent was distilled chloride (13.4 g) was dropwise added thereto and the away and chloroform was added to the residue for extrac mixture was stirred at room temperature for 1 hour. The tion. The chloroform layer was washed and dried. The reaction mixture was poured into ice water and extracted Solvent was distilled away and the residue was recrystallized with dichloromethane. The dichloromethane layer was from diisopropyl ether-hexane to give 0.9 g of 2-amino-2- washed with a Saturated potassium hydrogencarbonate 3-(3-undecyloxyphenyl)propyl-1,3-propanediol as white Solution, a 1% Saturated acqueous hydrochloric acid Solution crystals. and Saturated brine and dried over anhydrous magnesium melting point=71-72 C. sulfate. The solvent was distilled away and the residue was H-NMR (90MHz, CDC1) 8: 0.86 (3H, t, J=6Hz), purified by Silica gel column chromatography (eluent; ethyl 1.14–1.91 (22H, m), 2.20 (4H, bris), 2.60 (2H, t, J=6Hz), acetate:hexane=1:19) to give 31.6 g of the Subject compound 3.49 (4H, dd, J=10Hz, 13Hz), 3.94 (2H, t, J=6Hz), 6.62–6.86 as an oily substance (yield 95%). (3H, m), 7.05-7.21 (1H, m) H-NMR (CDC1) 8: 0.86 (3H, t, J=6Hz), 1.13–1.79 IR: 3344, 3289, 31.79, 2919, 1610 cm (12H, m), 2.58 (2H, t, J=6Hz), 2.82 (3H, s), 3.01 (2H, t, 15 J=6Hz), 4.39 (2H, t, J=6Hz), 7.12 (4H, s) MS(EI): 379(M) IRV Neat max: 2926, 1356, 1174 cm EXAMPLE 28 (5) 2-(4-Octylphenyl)ethyl Iodide Sodium iodide (18.13 g) was added to a solution (500 ml) 2-Amino-2-2-(4-octylphenyl)ethyl-1,3-propanediol of the above-mentioned compound (31.5 g) in 2-butanone (1) 2-(4-Octanoylphenyl)ethyl Acetate and the mixture was refluxed under heating for 4 hours. The Aluminum chloride (111.8 g) was added to dichloroet reaction mixture was concentrated and poured into ice water. hane (500 ml) in a stream of nitrogen and the mixture was The resultant mixture was extracted with ethyl acetate. The Stirred at room temperature. Then, phenethyl acetate (91.8 g) ethyl acetate layer was washed with Saturated brine and and decanoyl chloride (100 g) were dropwise added thereto 25 dried over anhydrous magnesium Sulfate. The Solvent was under ice-cooling and the mixture was Stirred at room distilled away and the residue obtained was purified by silica temperature overnight. The reaction mixture was poured gel column chromatography (eluent; ethyl acetate:hexane= into ice water and extracted with diethyl ether. The ether 1:20) to give 27.5 g of the Subject compound as an oily layer was washed with Saturated brine and dried over substance (yield 80%). anhydrous magnesium Sulfate. The Solvent was distilled H-NMR (CDC1) 8: 0.86 (3H, t, J=6Hz), 1.07–1.79 away and the residue was purified by Silica gel column (12H, m), 2.58 (2H, t, J=6Hz), 3.01-3.57 (4H, m), 7.11 (4H, chromatography (eluent; ethyl acetate:hexane=1:20) to give S) 61.3 g of the subject compound (yield 38%) as an oily IRV Neat max: 2925, 2853, 1168 cm Substance. (6) Diethyl 2-acetamido-2-(4-octylphenyl)ethyl Malonate IRV Neat max : 2929, 1740, 1685, 1236 cm 35 A solution (80 ml) of sodium ethoxide (8.2 g) in absolute (2) 2-(4-Octylphenyl)ethyl Acetate ethanol was dropwise added to diethyl acetamidomalonate Triethylsilane (28.8 ml) was added to a solution (86ml) of (26 g) in a stream of nitrogen and the mixture was stirred at the above-mentioned compound (24.9 g) in trifluoroacetic 65 C. for 30 minutes. Then, a solution of the above acid under ice-cooling and the mixture was stirred at room mentioned compound (13.8 g) in anhydrous tetrahydrofuran temperature for 2 hours. The solvent was distilled away and 40 was dropwise added thereto and the mixture was Stirred at thereto was added ice water and then a cool, Saturated 65 C. for 30 minutes. The reaction mixture was concen Sodium hydrogencarbonate Solution gradually. The mixture trated and poured into ice water. was extracted with ethyl acetate and the ethyl acetate layer The resultant mixture was extracted with ethyl acetate. was washed and dried over magnesium Sulfate. The Solvent The extract was washed with Saturated brine and dried over was distilled away and the residue obtained was purified by 45 anhydrous magnesium Sulfate. The Solvent was distilled Silica gel column chromatography (eluent; ethyl away and the residue was purified by Silica gel column acetate:hexane=1:20) to give 20.5g of the Subject compound chromatography (eluent; ethyl acetate:hexane=1:3) to give as an oily substance (yield 87%). 10.6 g of the subject compound (yield 61%). IRV Neat max : 2927, 2855, 1742, 1237 cm melting point 49-51. C. (3) 2-(4-Octylphenyl)ethyl Alcohol 50 H-NMR (CDC1) 8: 0.86 (3H, t, J=6Hz), 1.14 (6H, t, Sodium methoxide (11.9 g) was added to a solution of the J=6Hz), 1.20–1.73 (12H, m), 2.95 (3H, s), 2.30-2.83 (6H, above-mentioned compound (30.3 g) in methanol (300 ml) m), 4.21 (4H, q, J=6Hz), 6.74 (1H, s), 7.05 (4H, s) and the mixture was refluxed under heating for 3 hours. The IRV max : 3257, 2924, 1747, 1643 cm reaction mixture was concentrated and ice water was added 55 (7) 2-Amino-2-2-(4-octylphenyl)ethyl-1,3-propanediol thereto. The mixture was extracted with ethyl acetate and the (a) A solution (100 ml) of the above-mentioned compound ethyl acetate layer was washed with a 5% aqueous HCl (11.55g) in anhydrous tetrahydrofuran was dropwise added Solution and Saturated brine. The resultant mixture was dried to a solution (260 ml) of lithium aluminum hydride (3.03 g) over magnesium Sulfate. The Solvent was distilled away and in anhydrous tetrahydrofuran under ice-cooling in a stream the residue obtained was purified by Silica gel column 60 of nitrogen and the mixture was stirred at room temperature chromatography (eluent; ethyl acetate:hexane=1:15, ethyl for 2 hours. A Saturated aqueous Sodium Sulfate Solution was acetate) to give 25.0 g of the Subject compound as an oily added to the reaction mixture under ice-cooling. The result substance (yield 97%). ant aluminum hydroxide was filtered off and the resultant IRV Neat max : 3357, 2927, 2855, 1467 cm mixture was dried over anhydrous sodium sulfate. The (4) 2-(4-Octylphenyl)ethyl Methanesulfonate 65 solvent was distilled away and pyridine (40 ml) was added Triethylamine (16.4 ml) was added to a solution (500 ml) to the residue. Acetic anhydride (30 ml) was added thereto of the above-mentioned compound (25 g) in dichlo under ice-cooling and the mixture was left Standing at room