United States Patent
`
`[19]
`
`Fujita et al.
`
`5,604,229
`.Patent Number:
`[11]
`[45] Date of Patent: Feb. 18, 1997
`
`
`
`llllllllllllllllllllllllllllllll|||||||l|||||l||||||lllllllllllllllllllllll
`US005604229A
`
`[54]
`
`2-AMJNO-1,3-PROPANEDIOL COMPOUND
`AND IMMUNOSUPPRESSANT
`
`[75]
`
`Inventors: Tetsuro Fujita, Muko; Shigeo Sasaki;
`Masahiko Yoneta, both of Kobe;
`Tadashi Mishina, Imma; Kunitomo
`Adachi, Iruma; Kenji Chiba, Imma, all
`of Japan
`
`[73] Assignees: Yoshitomi Pharmaceutical Industries,
`Ltd., Osaka; Taito Co., Ltd., Tokyo,
`both of Japan
`
`[21] Appl. No.:
`
`244,942
`
`[22] PCT Filed:
`
`Oct. 18, 1993
`
`[86] PCT No.:
`
`PCT/JP93/01515
`
`§ 371 Date:
`
`Jun. 17, 1994
`
`§ 102(e) Date:
`
`Jun. 17, 1994
`
`[87] PCT Pub. No.: WO94/08943
`
`PCT Pub. Date: Apr. 28, 1994
`
`[30]
`
`Foreign Application Priority Data
`
`Oct. 21, 1992
`Jul. 20, 1993
`
`[JP]
`[JP]
`
`Japan .................................. .. 4—283281
`Japan .................................. .. 5—179427
`
`[51]
`
`Int. Cl.6 .................... .. C07C 211/00; C07D 333/20;
`A01N 43/40; A01N 33/02
`........................ .. 514/255; 514/357; 514/372;
`[52] US. Cl.
`514/403; 514/427; 514/438; 514/459; 514/471;
`544/401; 546/246; 546/247; 546/334; 548/214;
`548/373.1; 548/516; 549/75; 549/426; 549/495;
`549/472; 564/336; 564/340; 564/342; 564/346;
`564/374; 564/383; 564/454; 564/ 123
`[58] Field of Search ..................................... 546/210, 246,
`546/247, 334; 560/172; 562/11; 558/169;
`514/114, 119, 357, 255, 372, 403, 427,
`438, 459, 471; 564/336, 340, 342, 346,
`374, 383, 454, 123; 549/75, 426, 495; 548/214,
`373.1, 516; 544/401
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`
`
`1/1988
`63—2904
`2/1988
`63—43140
`1/1992
`9309
`3/1992
`69320
`6/1992
`173723
`8/1992
`224548
`3/1993
`78294
`92/16236A2 10/ 1982
`
`Japan .
`Japan .
`Japan .
`Japan .
`Japan .
`Japan .
`Japan .
`WIPO .
`
`OTHER PUBLICATIONS
`
`Merck Index, No. 460 (2—Amino—2—methyl—1,3—propane
`diol) p. 73 1989.
`Bair et al., J. Med.Chem., “1—Pyrenylmethyl)amino alco-
`hols, a New Class Antitumor DNA Intercalators. Discovery
`and Initial Amine Side Chain Structure—Activity Studies”,
`1990, 33, pp. 2385—2393.
`Shetty et al., J. Org. Chem. Nov. 1960, pp. 2057—2059.
`Rembarz et al., J. Prakt. Chem., 68; vol. 37 (1—2); pp. 59—63.
`1968.
`Chemical Abstracts, vol. 85, No. 23, Dec. 6, 1976, Colum—
`bus,
`Ohio,
`US.
`abstract
`No.
`1774982,
`2,4—Di—1—aziridinyl—6—amino—s—triazines & Otkrytiya, Izo-
`bret., Prom. Obraztsy, Tovarnye znaki,vol. 53, No. 26, 1976,
`pp. 78—79, Malyugina, L. L. et al., & Chemical Abstracts 9th
`coll.
`Index
`page
`8505cs,
`1,4—Butanediol,
`2—an1ino—2—(hydroxymethyl)—.
`Derwent Abstract of Japan Patent Unexamined Pub. No.
`416/1987 published Jan. 1986.
`Derwent abstract of Japan Patent Unexamined Pub. No.
`192962/1984 published Nov. 1984.
`Merck Index, 11th Edition, No. 9684 (Tromethamine), pp.
`1536—1537 (1989).
`Derwent abstract of Japan Patent Unexamined Pub. 104087/
`1989 published Apr., 1989.
`Merck Index, No. 451 (2—Amino—2—ethyl—1,3—propanediol)
`1989.
`
`Primary Examinerwc. Warren Ivy
`Assistant Examiner—Raymond Covington
`Attorney, Agent, or Finn—Wenderoth, Lind & Ponack
`
`[57]
`
`ABSTRACT
`
`2-Amin0-1,3-propanediol compounds of the formula (I)
`
`('3H20R4
`RZR3N-(|I—CH10R5
`R
`
`(I)
`
`wherein R is an optionally substituted straight— or branched
`carbon chain, an optionally substituted aryl, an optionally
`substituted cycloalkyl or the like, and R2, R3, R4 and R5 are
`the same or different and each is a hydrogen, an alkyl, an
`aralkyl, an acyl or an alkoxycarbonyl, pharmaceutically
`acceptable salts thereof and immunosuppressants compris~
`ing these compounds as active ingredients.
`
`The 2-amino-1,3-propanediol compounds of the present
`invention show immunosuppressive action and are useful for
`suppressing rejection in organ or bone marrow tranplanta—
`tion, prevention and treatment of autoimmune diseases or as
`reagents for use in medicinal and pharmaceutical fields.
`
`52 Claims, N0 Drawings
`
`Apotex v. Novartis
`lPR2017-00854
`
`NOVARTIS 2007
`
`....................... .. 260/347.7
`11/1962 Shetty et al.
`3,062,839
`1/1967 Krum .. . .. .......
`. ..... 252/401
`3,324,043
`2/1969 Hostettler et al.
`.. 260/340.2
`3,426,042
`3/1969 Zenitz .. .. .......
`.. .... 424/325
`3,432,603
`5/1972 Cobb .............
`.. 260/584
`3,660,488
`11/1975 Kluepfel et al.
`. 424/122
`3,928,572
`2/1985 Saitoh et al.
`. 524/109
`4,499,221
`3/1990 Bair ...............
`.. 514/443
`4,910,218
`11/1991 Fujita et al.
`.......................... .. 514/440
`5,068,247
`FOREIGN PATENT DOCUMENTS
`
`
`
`.
`
`1/ 1982 European Pat. 0E. .
`0044203A2
`1/1991
`European Pat. OE.
`.
`0410176
`0450527A2 10/1991
`European Pat. OE. .
`51-54565
`5/1976
`Japan .
`57-21366
`211982
`Japan .
`57—156459
`9/1982
`Japan .
`58—101108
`6/1983
`Japan .
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2007
`
`

`

`5,604,229
`
`1
`
`2-AMINO-1,3-PROPANEDIOL COMPOUND
`AND IIVIMUNOSUPPRESSANT
`
`This application is a 371 of PCT/JP93/01515 filed Oct.
`18, 1993 and published as WO94/08943 Apr. 28, 1994.
`
`5
`
`TECHNICAL FIELD
`
`2
`DISCLOSURE OF THE INVENTION
`
`7
`The present invention relates to
`(1) a 2—amino—1,3-propanediol compound of the formula
`
`(IJH20R4
`R2R3N—(ll—CI-120R5
`R
`
`(I)
`
`The present invention relates to 2—amino-l,3-propanediol
`compounds useful as pharmaceuticals, particularly as an
`immunosuppressant.
`
`BACKGROUND ART
`
`wherein
`
`10
`
`R is an optionally substituted straight- or branched carbon
`chain which may have, in the chain, a bond, a hetero
`atom or a group selected from the group consisting of
`a double bond, a triple bond, oxygen, sulfur, sulfinyl,
`sulfonyl, —N(R6)— where R6 is hydrogen, alkyl,
`aralkyl, acyl or alkoxycarbonyl, carbonyl, optionally
`substituted arylene, optionally substituted cycloalky-
`lene, optionally substituted heteroarylene and an ali—
`cycle thereof, and which may be substituted, at the
`chain end thereof, by a double bond, a triple bond,
`optionally
`substituted aryl, optionally substituted
`cycloalkyl, optionally substituted heteroaryl or an ali-
`cycle thereof; an optionally substituted aryl, an option—
`ally substituted cycloalkyl, an optionally substituted
`heteroaryl or an alicycle thereof; and
`R2, R3, R4 and R5 are the same or diiferent and each is a
`hydrogen, an alkyl, an aralkyl, an acyl or an alkoxy—
`
`In recent years, cyclosporin is in use for suppressing
`rejection developed in transplanting organs. Inclusive of the
`compounds currently under development,
`the so-called
`immunosuppressants are expected to be useful as therapeutic
`agents for articular rheumatism and so on. Said cyclosporin,
`however, also poses problems of side effects such as renal
`disorders.
`
`Meanwhile, Japanese Patent Unexamined Publication No.
`104087/1989 discloses that an immunosuppressive sub-
`stance is obtained from a liquid culture of Isaria sinclairii
`and said substance has been confirmed to be (28,3R,4R)-
`(E)-2—amino-3,4-dihydroxy-2—hydroxymethyl-l4-oxoicosa-
`6-enoic acid of the formula
`
`15
`
`20
`
`25
`
`fi’
`’
`‘1’“
`THZ
`HOH2C—C—Cl-I — CH—CHZ —Cl-I =CH-— (CH2)5 —C —(CI-I2)5—CI-I3
`
`COzl-I
`
`OI-I
`
`disclosed in U.S. Pat. No. 3928572. In addition, Japanese
`Patent Unexamined Publication No. 128347/ 1991 states that
`a series of said compound has an immunosuppressive action.
`Refening to Merck Index, 11th edition, it is described that
`2—anu'no-2—methyl-l,3-propanediol
`(Index No.
`460),
`2—anIino-2-ethyl-1,3-propanediol
`(Index No. 451)
`and
`2—amino—2-hydroxymethyl-l,3-propanediol
`(also
`called
`tromethamine, Index No. 9684) can be used as surfactants,
`intermediates for pharmaceuticals, emulsifiers or gas adsor-
`bents and that
`tromethamine is medically usable as an
`alkalization agent. In Japanese Patent Unexamined Publica—
`tion No. 416/1987, a hair dye containing 2—amino—2-(Cl—C5
`alkyl)-1,3-propanediol is disclosed. U.S. Pat. No. 4,910,218
`and J. Med. Chem., vol. 33, 2385—2393 (1990)
`teach
`2-amino~2—(methyl or ethyl)-l,3-propanediol as an intenne—
`diate for an antitumor agent. Also, Japanese Patent Unex-
`amined Publication No. 192962/ 1984 teaches that the afore-
`mentioned 2—amino-2—(Cl—C5
`alkyl)—l,3-propanediol or
`2-amino—l,3-propanediol can be used as a stabilizer for an
`antigen or antibody-sensitized latex reagent. Moreover, U.S.
`Pat. No. 3,062,839 teaches 2—methyl- or ethyl-amino-Z-
`(furylmethyl, phenylmethyl or phenylmethyl substituted by
`lower alkyl, lower alkoxy, chloro, hydroxy or unsubstituted
`amine)—1,3—propanediol having a tranquilizer action and J.
`Org. Chem., vol. 25, 2057—2059 (1960) teaches 2—methy-
`larnino-2—(phenylmethyl or phenylmethyl substituted by
`2-methyl, 3-methyl, 4-methyl, 4—methoxy or 4-hydroxy)-l,
`3—propanediol. It is not known, however, that these com-
`pounds have immunosuppressive actions such as suppres-
`sion of
`rejection developed in organ transplantation,
`prevention and treatment of autoimmune diseases and the
`like.
`
`An object of the present invention is to provide novel
`2—amino—l,3-propanediol
`compounds
`having
`superior
`immunosuppressive action with less side efiects.
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`carbonyl, or R4 and R5 may be bonded to form an
`alkylene chain which may be substituted by alkyl, aryl
`or aralkyl;
`wherein the optionally substituted straight- or branched
`carbon chain may have a substituent selected from the group
`consisting of alkoxy, alkenyloxy, alkynyloxy, aralkyloxy,
`alkylenedioxy,
`acyl,
`alkylarnino,
`alkylthio,
`acylamino,
`alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkych—
`bamoyl, haloalkyl, haloalkoxy, nitro, halogen, amino,
`hydroxyimino, hydroxy, carboxy, optionally substituted
`aryl, optionally substituted aryloxy, optionally substituted
`cycloalkyl, optionally substituted heteroaryl and an alicycle
`' thereof; the aforementioned optionally substituted arylene,
`optionally substituted cycloalkylene, optionally substituted
`heteroarylene and an alicycle thereof may have a substituent
`selected firm the group consisting of alkoxy, alkenyloxy,
`alkynyloxy, aralkyloxy, alkylenedioxy, acyl, alkylamino,
`alkylthio,
`acylamino,
`alkoxycarbonyl,
`alkoxycarbony-
`lamino, acyloxy, alkylcarbamoyl, haloalkyl, haloalkoxy,
`nitro, halogen, amino, hydroxy and carboxy; and the option-
`ally substituted aryl, optionally substituted aryloxy, option-
`ally substituted cycloalkyl, optionally substituted heteroaryl
`and an alicycle thereof may have a substituent selected from
`the group consisting of alkyl, alkoxy, alkenyloxy, alkyny-
`loxy, aralkyloxy, alkylenedioxy, acyl, alkylarnino, alkylthio,
`acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy,
`alkylcarbamoyl, haloalkyl, haloalkoxy, nitro, halogen,
`amino, hydroxy and carboxy;
`provided that when R is C1—C5 alkyl, the alkyl should be
`substituted and when R is furylmethyl, phenylmethyl or
`phenylmethyl substituted by lower alkyl,
`lower alkoxy,
`chloro, hydroxy or amino, one of R2 and R3 is not methyl or
`ethyl, and a pharrnaceutically acceptable salt thereof;
`(2) a 2-amino-l,3-propanediol compound according to the
`above-mentioned (1), having the formula
`
`
`
`
`
`

`

`5,604,229
`
`
`
`(EH10R4
`R2R3N—(IC ——CH20R5
`CH1R1
`
`wherein
`
`(1-1)
`
`R1 is an optionally substituted straight- or branched
`carbon chain which may have, in the chain, a bond, a
`hereto atom or a group selected from the group con-
`sisting of a double bond, a triple bond, oxygen, sulfur,
`sulfinyl, sulfonyl, —N(R6)— where R6 is hydrogen,
`alkyl,
`aralkyl,
`acyl or alkoxycarbonyl,
`carbonyl,
`optionally substituted arylene, optionally substituted
`cycloalkylene, optionally substituted heteroarylene and
`an alicycle thereof; and which may be substituted, at
`the chain end (to-position) thereof, by a double bond, a
`triple bond, optionally substituted aryl, optionally sub—
`stituted cycloalkyl, optionally substituted heteroaryl or
`an alicycle thereof; an optionally substituted aryl, an
`optionally substituted cycloalkyl, an optionally substi-
`tuted heteroaryl or an alicycle thereof; and
`R2, R3, R4 and R5 are the same or different and each is a
`hydrogen, an alkyl, an aralkyl, an acyl or an alkoxy-
`carbonyl, or R4 and R5 may be bonded to form an
`alkylene chain which may be substituted by alkyl, aryl
`or aralkyl;
`wherein the optionally substituted straight- or branched
`carbon chain may have a substituent selected from the group
`consisting of alkoxy, alkenyloxy, alkynyloxy, aralkyloxy,
`alkylenedioxy,
`acyl,
`alkylamino,
`alkylthio,
`acylamino,
`alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcar-
`bamoyl, haloalkyl, haloalkoxy, nitro, halogen, amino,
`hydroxyimino, hydroxy, carboxy, optionally substituted
`aryl, optionally substituted aryloxy, optionally substituted
`cycloalkyl, optionally substituted heteroaryl and an alicycle
`thereof;
`and the aforementioned optionally substituted
`arylene, optionally substituted cycloalkylene, optionally
`substituted heteroarylene, an alicycle thereof, optionally
`substituted aryl, optionally substituted aryloxy, optionally
`substituted cycloalkyl, optionally substituted heteroaryl and
`an alicycle thereof may have a substituent selected from the
`group consisting of alkoxy, alkenyloxy, alkynyloxy, aralky-
`loxy, alkylenedioxy, acyl, alkylamino, alkylthio, acylamino,
`alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcar-
`bamoyl, haloalkyl, haloalkoxy, nitro, halogen, amino,
`hydroxy and carboxy;
`provided that when R1 is C l—C4 alkyl, the alkyl should be
`substituted and when R1 is furyl, phenyl or phenyl substi»
`tuted by lower alkyl,
`lower alkoxy, chloro, hydroxy or
`amino, one of R2 and R3 is not methyl or ethyl, and a
`pharmaceutically acceptable salt thereof;
`(3) a 2-amino-l,3-propanediol compound according to the
`above-mentioned (l) or (2), having the formula
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`(IX-[201148
`RlaR3aN —C — CH20R5a
`
`CHlea
`
`wherein
`
`(1’2)
`
`55
`
`Rla is an optionally substituted straight- or branched
`carbon chain which may have, in the chain, a bond, a
`hetero atom or a group selected from the group con-
`sisting of a double bond, a triple bond, oxygen, sulfur,
`sulfinyl, sulfonyl, —N(R6)—— where R6 is hydrogen,
`alkyl, aralkyl,
`acyl or alkoxycarbonyl,
`carbonyl,
`optionally substituted phenylene and optionally substi-
`tuted cycloalkylene; an optionally substituted phenyl or
`an optionally substituted cycloalkyl; and
`
`60
`
`65
`
`4
`Rza, R3a, R4a and Rsa are the same or different and each
`is a hydrogen, an alkyl, an acyl or an alkoxycarbonyl;
`wherein the optionally substituted phenyl and optionally
`substituted cycloalkyl may have a substituent selected from
`the group consisting of optionally substituted straight— or
`branched carbon chain which may have, in the chain, a bond,
`a hetero atom or a group selected from the group consisting
`of a double bond, a triple bond, oxygen, sulfur, sulfinyl,
`sulfonyl, ——(R6)-—— where R6 is hydrogen, alkyl, aralkyl, acyl
`or alkoxycarbonyl, carbonyl, optionally substituted phe-
`nylene and optionally substituted cycloalkylene, alkoxy,
`alkenyloxy, alkynyloxy, aralkyloxy, alkylenedioxy, acyl,
`alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxy-
`carbonylamino, acyloxy, alkylcarbamoyl, haloalkyl, nitro,
`halogen, amino, hydroxy, carboxy, optionally substituted
`phenyl, optionally substituted phenoxy and optionally sub-
`stituted cycloalkyl; the optionally substituted carbon chain
`may have a substituent selected from the group consisting of
`alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylenedioxy,
`acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl,
`alkoxycarbonylamino, acyloxy, alkylcarbamoyl, haloalkyl,
`nitro, halogen, amino, hydroxy, carboxy, optionally substi-
`tuted phenyl, optionally substituted phenoxy and optionally
`substituted cycloalkyl; and the aforementioned optionally
`substituted phenylene, optionally substituted cycloalkylene,
`optionally substituted phenyl, optionally substituted phe-
`noxy and optionally substituted cycloalkyl may have a
`substituent selected from the group consisting of alkoxy,
`alkenyloxy, alkynyloxy, aralkyloxy, alkylenedioxy, acyl,
`alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxy-
`carbonylamino, acyloxy, alkylcarbamoyl, haloalkyl, nitro,
`halogen, amino, hydroxy and carboxy; provided that when
`Rla is Cl—C4 alkyl, the alkyl should be substituted and
`when Rla is furyl, phenyl or phenyl substituted by lower
`alkyl, lower alkoxy, chloro, hydroxy or amino, one of R2a
`and R3a is not methyl or ethyl, and a pharmaceutically
`acceptable salt thereof;
`(4) a 2—amino-l,3~propanediol compound according to the
`above-mentioned (3), having the formula
`
`(1-3)
`
`substituted and when Rlb is furyl, phenyl or phenyl substi—
`
`(IZH20R4b
`RZbR3bN—(II —CH20R5b
`CHgR‘b
`
`wherein
`
`Rlb is an optionally substituted alkyl, an optionally sub-
`stituted alkenyl, an optionally substituted alkynyl, an
`optionally substituted phenyl or an optionally substi—
`tuted cycloalkyl, and
`sz, R3b, R4b and R5b are the same or different and each
`is a hydrogen, an alkyl or an acyl;
`wherein the optionally substituted alkyl, optionally substi-
`tuted alkenyl and optionally substituted alkynyl may have a
`substituent selected from the group consisting of alkoxy,
`alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alky-
`lthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino,
`acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy,
`carboxy, optionally substituted phenyl and optionally sub-
`stituted cycloalkyl; and the aforementioned optionally sub-
`stituted phenyl and optionally substituted cycloalkyl may
`have 1 to 3 substituents selected from the group consisting
`of alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy,
`aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxy-
`carbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl,
`haloalkyl, nitro, halogen, amino, hydroxy and carboxy;
`provided that when Rlb is C l—C4 alkyl, the alkyl should be
`
`

`

`5
`
`5,604,229
`
`lower alkoxy, chloro, hydroxy or
`tuted by lower alkyl,
`amino, one of R2b and R3b is not methyl or ethyl, and a
`pharmaceutically acceptable salt thereof;
`'
`(5) a 2—amino-l,3-propanediol compound according to the
`above-mentioned (l), (2), (3) 0r (4), having the formula
`
`ICH20R4b
`RZbR3bN—IC—CH20R5b
`Ra
`
`wherein
`
`(1-4)
`
`Ra is a straight— or branched chain alkyl having 12 to 22
`carbon atoms, which may have, in the chain, a bond or
`a hetero atom selected from the group consisting of a
`double bond, a triple bond, oxygen, sulfur, sulfinyl,
`sulfonyl, —(R6)— where R6 is hydrogen, alkyl,
`aralkyl, acyl 0r alkoxycarbonyl, and carbonyl, and
`which may have, as a substituent, alkoxy, alkenyloxy,
`alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio,
`acylamino,
`alkoxycarbonyl,
`alkoxycarbonylarnino,
`acyloxy,
`alkylcarbamoyl,
`nitro,
`halogen,
`amino,
`hydroxyimino, hydroxy or carboxy, and
`sz, R3b, R4b and R5b are the same or different and each
`is a hydrogen, an alkyl or an acyl, and a pharmaceuti-
`cally acceptable salt thereof;
`(6) a 2-amino-l,3-propanediol compound according to the
`above-mentioned (5), having the formula
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`(1-5)
`
`lCHZOI-I
`HZN —- C-— CHZOH
`
`Rd
`
`wherein
`
`(1-7)
`
`a
`a substituted phenylalkyl,
`Rd is a phenylalkyl,
`cycloalkylalkyl, a substituted cycloalkylalkyl, a het—
`eroarylalkyl, a substituted heteroaryl alkyl, a heterocy—
`clic alkyl or a substituted heterocyclic alkyl,
`wherein the alkyl moiety may have, in the carbon chain, a
`bond or a hetero atom selected from the group consisting of
`a double bond, a triple bond, oxygen, sulfur, sulfinyl, sul-
`fonyl, ——(R6)— where R6 is hydrogen, alkyl, aralkyl, acyl or
`alkoxycarbonyl, and carbonyl, and may have, as a substitu-
`ent, alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alky-
`lamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbo-
`nylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino,
`hydroxy or carboxy; and the substituted phenylalkyl, sub-
`stituted cycloalkylalkyl, substituted heteroarylalkyl and sub—
`stituted heterocyclic alkyl may have a substituent selected
`from the group consisting of alkyl, alkoxy, alkenyloxy,
`alkynyloxy, aralkyloxy, haloaralkyloxy, aralkyloxyalkyl,
`phenoxyalkyl, phenoxyalkoxy, alkylenedioxy, acyl, alky-
`larnino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbo—
`nylamino, acyloxy, alkylcarbamoyl, haloalkyl, haloalkoxy,
`nitro, halogen, amino, hydroxy and carboxy, and a pharma-
`ceutically acceptable salt thereof;
`(10) a 2-amino~l,3—propanediol compound according to the
`above-mentioned (9), having the formula
`
`(IX-Ion
`chR3cN.—IC—CHZOH
`Rb
`
`wherein
`
`Rb is a straight— or branched chain alkyl having 13 to 20
`carbon atoms, which may have, in the chain, an oxygen
`atom and which may have, as a substituent, nitro,
`halogen, amino, hydroxy or carboxy, and
`ch and R3c are the same or different and each is a
`hydrogen or an alkyl, and a pharmaceutically accept-
`able salt thereof;
`(7) a 2-amino-l,3—propanediol compound according to the
`above-mentioned (5) or (6), having the formula
`
`[Cl-IZOH
`HZN— IC—Cl-IZOH
`Rc
`
`wherein
`
`(1-6)
`
`Rc is a straight- or branched chain alkyl having 13 to 20
`carbon atoms or a straight- or branched chain alkyl
`having 13 to 20 carbon atoms which is substituted by
`halogen,
`and a pharmaceutically acceptable
`salt
`thereof;
`(8) a 2-arnino—l,3-propanediol compound according to the
`above-mentioned (5), (6) or (7), which is selected from
`- 2-arnino-2-tridecyl- l ,3-propanediol, 2—amino-2—tetradecyl-
`1,3—propanediol,
`2-amino-2-pentadecyl—1,3-propanediol,
`Z-arnino—Z—hexadecyl-l,3-propanediol, 2-amino-2—heptade-
`cyl—1,3-propanediol, 2-amino-2-octadecyl- l ,3-propanediol,
`2—amino-2-nonadecyl- 1 ,3 -propanediol, 2-amino-2-icosyl- l ,
`3—propanediol,
`2~amino—2—(lZ-fluorododecyl)-1,3—pro—
`panediol
`and
`2-amino-2—( l4-fluorotetradecyl)- l ,3—pro-
`panediol, and a pharmaceutically acceptable salt thereof;
`(9) a 2-amino—l,3—propanediol compound according to the
`above-mentioned (l), (2), (3) or (4), having the formula
`
`(IIHZOH
`HZN ~— C -- CHzOI-I
`
`Re
`
`35
`
`wherein
`
`(1-8)
`
`Re is a phenylalkyl wherein the alkyl moiety is a straight-
`or branched chain having 6 to 20 carbon atoms; a
`phenylalkyl which may be substituted by a straight- or
`branched chain C6—C20 alkyl optionally substituted by
`halogen, a straight- or branched chain C6—C20 alkoxy
`optionally substituted by halogen,
`a straight— or
`branched chain C6-C20 alkenyloxy, phenylalkoxy,
`halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy
`or phenoxyalkyl; a cycloalkylalkyl wherein the alkyl
`moiety is a straight- or branched chain having 6 to 20
`carbon atoms; a cycloalkylalkyl Substituted by a
`straight— or branched chain alkyl having 6 to 20 carbon
`atoms; a heteroarylalkyl wherein the alkyl moiety is a
`straight— or branched chain having 6 to 20 carbon
`atoms; a heteroarylalkyl substituted by a straight- or
`branched chain alkyl having 6 to 20 carbon atoms; a
`heterocyclic alkyl wherein the alkyl moiety is a
`straight— or branched chain having 6 to 20 carbon
`atoms, or a heterocyclic alkyl substituted by a straight~
`or branched chain alkyl having 6 to 20 carbon atoms;
`wherein the alkyl moiety may have, in the carbon chain, a
`bond or a hetero atom selected from the group consisting of
`a double bond, a triple bond, oxygen, sulfur, sulfinyl, sul-
`fonyl, —(Rfi)— where R6 is hydrogen, alkyl, aralkyl, acyl or
`alkoxycarbonyl, and carbonyl, and may have, as a substitu-
`ent, alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alky-
`lamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbo-
`nylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino,
`hydroxy or carboxy, and a pharmaceutically acceptable salt
`thereof;
`(11) a 2-amino-l,3-propanediol compound according to the
`above-mentioned (9) or (10), having the formula
`
`4o
`
`45
`
`50
`
`55
`
`60
`
`65
`
`
`
`
`
`

`

`5,604,229
`
`(1»9)
`
`CHZOH
`|
`HzN—C—CHZOH
`Rh
`
`wherein
`
`(H 1)
`
`
`
`(IZHZOH
`HzN—(li—CHZOH
`Rf
`
`wherein
`
`Rf is a phenylalkyl wherein the alkyl moiety is a straight-
`or branched chain having 6 to 20 carbon atoms which
`may have, in the carbon chain, one or two oxygen
`atoms; a phenylalkyl which may be substituted by a
`straight- or branched chain C6—C20 alkyl optionally
`substituted by halogen, a straight— or branched chain
`C6—C20 alkoxy optionally substituted by halogen, a
`straight— or branched chain C6—C20 alkenyloxy, phe—
`nylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phe-
`noxyalkoxy
`or
`phenoxyalkyl;
`a
`cycloalkylalkyl
`wherein the alkyl moiety is a straight- or branched
`chain having 6 to 20 carbon atoms which may have, in
`the carbon chain, one or
`two oxygen atoms;
`a
`cycloalkylalkyl substituted by a straight- or branched
`chain alkyl having 6 to 20 carbon atoms; a heteroary-
`lalkyl wherein the alkyl moiety is a straight— or
`branched chain having 6 to 20 carbon atoms which may
`have, in the carbon chain, one or two oxygen atoms; a
`heteroarylalkyl substituted by a straight- or branched
`chain alkyl having 6 to 20 carbon atoms; a heterocyclic
`alkyl wherein the alkyl moiety is a straight— or branched
`chain having 6 to 20 carbon atoms which may have, in
`the carbon chain, one or two oxygen atoms, or a
`heterocyclic alkyl substituted by a straight~ or branched
`chain alkyl having 6 to 20 carbon atoms;
`wherein the alkyl moiety may have, in the carbon chain, a
`substituent selected from the group consisting of alkoxy,
`alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alky—
`lthio, acylamino, alkoxycarbonyl, alkoxyCarbonylamino,
`acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy
`and carboxy, and a pharmaceutically acceptable salt thereof;
`(12) a 2-amino-l,3-propanediol compound according to the
`above~mentioned (9), (10) or (11), having the formula
`
`(In-12014
`HzN — (II—CHZOH
`Rg
`
`wherein
`
`(I—IO)
`
`Rg is a phenylalkyl wherein the alkyl moiety is a straight—
`or branched chain having 6 to 20 carbon atoms which
`may have, in the carbon chain, one or two oxygen
`atoms, a phenylalkyl which may be substituted by a
`straight- or branched chain C6—Cl4 alkyl optionally
`substituted by halogen, a straight— or branched chain
`C6—C14 alkoxy optionally substituted by halogen, a
`straight— or branched chain C6—Cl4 alkenyloxy, phe—
`nylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phe-
`noxyalkoxy
`or
`phenoxyalkyl;
`a
`cycloalkylalkyl
`wherein the alkyl moiety has 6 to 20 carbon atoms; a
`cycloalkylalkyl substituted by a straight— or branched
`chain alkyl having 6 to 14 carbon atoms; a heteroary-
`lalkyl wherein the alkyl moiety has 6 to 20 carbon
`atoms; a heteroarylalkyl substituted by a straight— or
`branched chain alkyl having 6 to 14 carbon atoms; a
`heterocyclic alkyl wherein the alkyl moiety has 6 to 20
`carbon atoms, or a heterocyclic alkyl substituted by a
`straight; or branched chain alkyl having 6 to 14 carbon
`atoms, and a pharmaceutically acceptable salt thereof;
`(13) a 2—amino-1,3-propanediol compound according to the
`above-mentioned (12), having the formula
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`substituted by halogen or a straight— or branched chain
`
`Rh is a phenylalkyl wherein the alkyl moiety has 6 to 20
`carbon atoms, a phenylalkoxyalkyl wherein the alkyl
`moiety and alkoxy moiety have 6 to 20 carbon atoms in
`total, a phenoxyalkyl wherein the alkyl moiety has 6 to
`20 carbon atoms or a phenoxyalkoxyalkyl wherein the
`alkyl moiety and alkoxy moiety have 6 to 20 carbon
`atoms in total, and a pharmaceutically acceptable salt
`thereof;
`(14) a 2-amino-1,3-propanediol compound according to the
`above-mentioned (13), which is selected from the group
`consisting of 2-amino-2-(8-phenyloctyl)-1,3-propanediol,
`2-amino-2—(9—phenylnonyl)-1,3-propanediol,
`2-amino-2-
`(lO-phenyldecyl)- l ,3-propanediol,
`2~amino-2-(l l-pheny-
`lundecyl)-l ,3—propanediol, 2-amino-2-(l 2-phenyldodecyl)-
`1,3-propanediol,
`2-amino-2—(l 3-phenyltridecyl)-l ,3-
`propanediol,
`2—amino-2-( l 4-phenyltetradecyl)-l ,3-
`propanediol,
`2-amino-2-( l 5-phenylpentadecyl)— l ,3-
`propanediol,
`2—amino-2-(16—phenylhexadecyl)-1,3-
`propanediol,
`2—amino-2-[6—(8-phenyloctyloxy)hexyl]— l ,3—
`propanediol,
`2-amino-2-(8-phenylmethyloxyoctyl)-1,3-
`propanediol, 2-amino-2-(9-phenoxynonyl)—1,3-propanediol,
`2—amino-2-( l 2-phenoxydodecy1)-l ,3-propanediol
`and
`2—amino—2-[6-(2-phenoxyethyloxy)hexyl]-1,3-propanediol,
`and a pharmaceutically acceptable salt thereof;
`(15) a 2-amino-l ,3-propanediol compound according to the
`above«mentioned (13) which is selected from the group
`consisting of 2-amino-2-(l0-phenyldecyl)-l,3-propanediol,
`2—amino-2~(l 3-pheny1tridecyl)— l ,3-propanediol, 2~amino-2~
`[6-(8-phenyloctyloxy)hexyl]—l,3-propanediol,
`2-amino-2-
`(8-phenylmethyloxyoctyl)- l ,3-propanediol,
`2-amino—2-(9-
`phenoxynonyl)-l ,3—propanediol,
`2-amino-2-(12—
`and
`phenoxydodecyl)-l,3-propanediol
`2-amino-2—[6-(2-
`phenoxyethyloxy)hexy1]—l ,3-propanediol,
`and
`a
`pharmaceutically acceptable salt thereof;
`(16) a 2—amino-1,3-propanediol compound according to the
`above-mentioned (12), having the formula
`
`CHon
`l
`HzN—C—Cl-leH
`Ri
`
`wherein
`
`(I— 1 2)
`
`Ri is a phenylalkyl substituted by a straight- or branched
`chain C6—C14 alkyl optionally substituted by halogen,
`a straight- or branched chain C6—Cl4 alkoxy optionally
`substituted by halogen or a straight» or branched chain
`C6—Cl4 alkenyloxy;
`wherein the alkyl moiety of phenylalkyl may be substituted
`by hydroxy, and a pharmaceutically acceptable salt thereof;
`(17) a 2-amino-1,3-propanediol compound according to the
`above-mentioned (16), having the formula
`
`(IIHZOH
`HzN—- ([I—CHZOH
`RJ'
`
`wherein
`
`(I-13)
`
`Rj is a phenylalkyl substituted by a straight- or branched
`chain C6—Cl4 alkyl optionally substituted by halogen,
`a straight» or branched chain C6—Cl4 alkoxy optionally
`
`

`

`5,604,229
`
`9
`C6—C14 alkenyloxy, wherein the alkyl moiety is a
`C2—C6 alkyl optionally substituted by hydroxy, and a
`pharmaceutically acceptable salt thereof;
`(18) a 2-amino-1,3-propanediol compound according to the
`above-mentioned (16) or (17), which is selected from the
`group consisting of 2—amino-2-[2-(4—heptylphenyl)ethyl]—1,
`3—propanediol, 2-amino-2~[2-(4-octylphcnyl)ethyl]-1,3-pr0-
`panediol,
`2—amin0—2—[2—(4~nony1phenyl)ethyl]—1 ,3 -pro-
`panediol,
`2—amino-2-[2—(4-decylphenyl)ethyl]—1,3-
`propanediol,
`2-amin0-2-[2—(4-undecylphenyl)ethyl]-1,3—
`propanediol,
`2—amino—2-[2~(4-dodecylphenyl)ethyl]- 1 ,3-
`propanediol,
`2—amino—2—[2—(4-tridecylphenyl)ethyl]— 1 ,3-
`propanediol,
`2-amino-2—[2—(4-tetradecylphenyl)ethyl]—1,3-
`propanediol,
`2-amin0-2-[2-(4-hexyloxyphenyl)ethyl]-1,3-
`propanediol, 2-amino-2—[2-(4-heptyloxyphenyl)ethyl]-1,3-
`propanediol,
`2—amino—2—[2—(4—octyloxypheny1)ethyl]-1,3-
`propanediol,
`2—amino—2—[2-(4—nonyloxypheny1)ethyl]— 1 ,3—
`propanediol,
`2—amino-2~[2—(4-decyloxypheny1)ethyl]- 1 ,3-
`propanediol,
`2—amin0-2—[2—(4—undecyloxyphenyl)ethyl]~1 ,
`3-propanediol,
`2-amino-2-[2-(4-dodecy10xyphenyl)ethyl]-
`1,3-propanediol, 2-arnino-2—[2-(4-t1idecyloxyphenyl)ethyl]-
`1,3—propanediol,
`2-amino-2— [2-(4-(8-
`fluorooctyl)pheny1)ethyl]— 1 ,3-pr0panedi01,
`2-amin0-2—[2»
`(4-(12-fluorododecyl)phenyl)ethyl]-1,3-propanediol,
`2-amino-2-[2-(4-(7-fluoroheptyloxy)phenyl)ethyl]-1,3—pro-
`panediol,
`2-amino-2-[2-(4-(11~fluoroundecyloxy)phenyl)
`ethy1]-1,3-propanedi01 and 2-amino—2‘[2—(4—(7—0ctenylox—
`y)phenyl)ethy1]—1,3—pr0panedi01, and a pharmaceutically
`acceptable salt thereof;
`(19) a 2-amino-1,3—pr0panediol compound according to the
`above-mentioned (16) or (17), which is selected from the
`group consisting of 2-amino—2~[2-(4—hepty1pheny1)ethyl]—1,
`3-propanediol, 2-amin0-2-[2—(4-octylphenyl)ethyl]-1,3-pr0—
`panediol,
`2-arnino-2—[2-(4-n0nylphenyl)ethyl]-1,3-pr0-
`panediol,
`2—amino-2
`-[2—(4-decylphenyl)ethy1]-1,3-
`propanediol,
`2-amin0-2-[2-(4-undecylphenyl)ethyl]—1,3-
`propanediol,
`2-amino-2-[2-(4-dodecylpheny1)ethy1]—1,3-
`propanediol,
`2— amino-2-[2-(4-hepty1oxypheny1)ethyl]— 1 ,3~
`propanediol,
`2-amino-2—[2-(4-octyloxypheny1)ethy1]-1,3-
`propanediol,
`2-amino-2- [2-(4-nonyloxypheny1)ethy1]-1,3-
`propanediol,
`2-amino-2-[2-(4—undecyl0xyphenyl)ethyl]—l,
`2-arnino—2-[2-(4~(7—
`3-propanediol
`and
`and
`a
`octenyloxy)pheny1)ethy1]-1,3-propanediol,
`pharmaceutically acceptable salt thereof;
`(20) a 2-amino-1,3—pr0panediol compound according to the
`above-mentioned (12), having the formula
`
`(III-120H
`HzN— C -— CHZOH
`Rk
`
`wherein
`
`(1.14)
`
`Rk is a phenylalkyl substituted by phenylalkoxy, halophe-
`nylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phe-
`noxyalkyl, and a pharmaceutically acceptable salt
`thereof;
`(21) a 2-amino-1,3-propanediol compound according to the
`above-mentioned (20), having the formula
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4o
`
`45
`
`50
`
`55
`
`(1-15)
`
`60
`
`ICHzOH
`H1N~“ IC"'CPIon
`R1
`
`wherein
`
`
`
`10
`
`atoms, phenylalkoxyalkyl wherein the alkoxy moiety
`and alkyl moiety have 2 to 8 carbon atoms in total,
`phenoxyalkoxy wherein the alkoxy moiety has 2 to 8
`carbon atoms or phenoxyalkyl wherein the alkyl moiety
`has 2 to 8 carbon atoms, where the alkyl moiety has 2
`t0 6 carbon atoms, and a pharmaceutically acceptable
`salt thereof;
`(22) a 2-amino~1,3-pr0panediol compound according to the
`above-mentioned (20) or (21), which is selected from the
`group consisting of 2-amino-2-[2-(4-phenylmethyloxyphe-
`nyl)ethy1]-1,3—propanediol, 2-amino—2—[2-(4—(2-phenylethy—
`loxy)phenyl)ethyl]—1,3—propanediol,
`2-amino-2-[2—(4-(3-
`phenylpropyloxy)phenyl)ethyl]-1,3-propanediol, 2-amino-
`2-[2—(4—(4-phenylbutyloxy)phenyl)ethyl]—1,3-propanediol,
`2-amino—2- [2-(4-(5-phenylpentyloxy)phenyl)ethy1]—1 ,3—
`propanediol,
`2—amino-2-[2-(4-(6-phenylhe