U.S. patent application number 10/851210 was filed with the patent office on 2004-10-28 for hydroxamic acid derivatives, the methods for preparation thereof and pharmaceutical compositions comprising thereof, as an active ingredient.
This patent application is currently assigned to ONO PHARMACEUTICAL CO., LTD.. Invention is credited to Kishimoto, Tadamitsu, Konishi, Mikio, Konno, Mitoshi, Naka, Masao, Sakaki, Katsuhito.
Application Number | 20040214896 10/851210 |
Document ID | / |
Family ID | 26549225 |
Filed Date | 2004-10-28 |
United States Patent
Application |
20040214896 |
Kind Code |
A1 |
Konno, Mitoshi ; et
al. |
October 28, 2004 |
Hydroxamic acid derivatives, the methods for preparation thereof
and pharmaceutical compositions comprising thereof, as an active
ingredient
Abstract
Hydroxamic acid derivatives of the formula (I) 1 (wherein all
the symbols have the same meaning as defined in the
specification.), non-toxic salts thereof or prodrugs thereof. The
compounds of the formula (I) inhibit producing IL-6, so it may be
used for the prevention and/or treatment of various inflammatory
diseases, sepsis, multiple myeloma, plasma cell leukemia,
osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma,
Kaposi's sarcoma, rheumatoid arthritis, hypergammaglobulinemia,
Castleman's disease, atrial myxoma, diabetes mellitus, autoimmne
diseases, hepatitis, colitis, graft versus host disease, infectious
diseases and endometriosis.
Inventors: |
Konno, Mitoshi;
(Mishima-gun, JP) ; Sakaki, Katsuhito;
(Mishima-gun, JP) ; Naka, Masao; (Mishima-gun,
JP) ; Konishi, Mikio; (Mishima-gun, JP) ;
Kishimoto, Tadamitsu; (Tondabayashi-shi, JP) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W.
SUITE 800
WASHINGTON
DC
20037
US
|
Assignee: |
ONO PHARMACEUTICAL CO.,
LTD.
|
Family ID: |
26549225 |
Appl. No.: |
10/851210 |
Filed: |
May 24, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10851210 |
May 24, 2004 |
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10088821 |
Mar 22, 2002 |
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6770644 |
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10088821 |
Mar 22, 2002 |
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PCT/JP00/06506 |
Sep 22, 2000 |
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Current U.S.
Class: |
514/575 |
Current CPC
Class: |
C07C 2601/08 20170501;
A61P 37/06 20180101; A61P 3/00 20180101; A61P 3/10 20180101; C07D
209/12 20130101; A61P 29/00 20180101; C07D 307/80 20130101; A61P
35/02 20180101; C07C 2601/02 20170501; C07C 2602/08 20170501; A61P
19/10 20180101; C07C 2603/26 20170501; C07D 213/30 20130101; C07C
259/06 20130101; C07D 273/00 20130101; C07D 211/22 20130101; C07D
277/24 20130101; C07C 323/62 20130101; A61P 1/04 20180101; C07C
2602/10 20170501; C07D 333/56 20130101; A61K 31/165 20130101; C07D
307/91 20130101; C07D 263/57 20130101; C07C 2601/14 20170501; A61P
43/00 20180101; C07D 333/16 20130101; C07C 2601/18 20170501; C07D
317/54 20130101; A61P 31/00 20180101; A61P 17/06 20180101; A61P
1/16 20180101; A61P 15/00 20180101; A61P 35/00 20180101; A61P 13/12
20180101; C07C 317/46 20130101; C07D 295/155 20130101; A61K 31/00
20130101 |
Class at
Publication: |
514/575 |
International
Class: |
A61K 031/19 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 24, 1999 |
JP |
P. HEI. 11-270459 |
Jul 7, 2000 |
JP |
P. 2000-206649 |
Claims
1. A method of inhibiting IL-6 production comprising administering
to a subject in need of treatment an effective amount of a
hydroxamic acid derivative of the formula (I): 263wherein, R.sup.1
is (a) C1-8 alkyl, (b) C2-8 alkenyl, (c) C2-8 alkynyl, (d) halogen,
(e) nitro, (f) nitrile, (g) trifluoromethyl, (h) trifluoromethoxy,
(i) --OR.sup.2, (j) --SR.sup.2, (k) --NR.sup.3R.sup.4, (l)
--COR.sup.5, (m) keto, (n) Cyc1, (o) C1-8 alkyl substituted by
--OR.sup.2, --SR.sup.2, --NR.sup.3R.sup.4, --COR.sup.5 or Cyc1, (p)
--SO.sub.2R.sup.10, (q) --O--(C1-8 alkylene)--OR.sup.11, (r) C1-8
alkyl substituted by nitrile, --SO.sub.2R.sup.10 or --O--(C1-8
alkylene)--OR.sup.11, (s) --O--(C1-8 alkylene)--NR.sup.12R.sup.13,
(t) --S--(C1-8 alkylene)--NR.sup.12R.sup.13- , (u) C1-8 alkyl
substituted by --O--(C1-8 alkylene)--NR.sup.12R.sup.13-- or
--S--(C1-8 alkylene)--NR.sup.12R.sup.13, (v) C2-8 alkenyl
substituted by --OR.sup.2, --SR.sup.2, --NR.sup.3R.sup.4,
--COR.sup.5, Cyc1, nitrile, --SO.sub.2R.sup.10, --O--(C1-8
alkylene)--OR.sup.11, --O--(C1-8 alkylene)--NR.sup.12R.sup.13 or
--S--(C1-8 alkylene)--NR.sup.12R.sup.13 or (w) C2-8 alkynyl
substituted by --OR.sup.2, --SR.sup.2, --NR.sup.3R.sup.4,
--COR.sup.5, Cyc1, nitrile, --SO.sub.2R.sup.10, --O--(C1-8
alkylene)--OR.sup.11, --O--(C1-8 alkylene)--NR.sup.12R.sup.13 or
--S--(C1-8 alkylene)--NR.sup.12R.sup.13; R.sup.2 is hydrogen,
C1-8alkyl, C2-9 acyl or Cyc1; R.sup.3 and R.sup.4 are each
independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1; R.sup.5 is
hydroxy, C1-8 alkyl, C1-8 alkoxy, --NR.sup.6R.sup.7 or Cyc1;
R.sup.6 and R.sup.7 are each independently hydrogen, C1-8 alkyl or
Cyc1; R.sup.10 is C1-8 alkyl or Cyc1; Cyc1 is C3-7 mono-carbocyclic
ring or 5-7 membered mono-cyclic hetero ring containing 1-4
nitrogen atom(s), one oxygen atom and/or one sulfur atom; R.sup.11
is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1; R.sup.12 and R.sup.13
are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1; m
is 0 or an integer of 1-5; ring A is C3-15 mono-, bi- or
tri-carbocyclic ring or 5-18 membered mono-, bi- or tri-cyclic
hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s)
and/or 1-2 sulfur atom(s); ring B is C5-15 mono-, bi- or
tri-carbocyclic aryl or 5-18 membered mono-, bi- or tri-cyclic
hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s)
and/or 1-2 sulfur atom(s); E is a bond, --CH.dbd.CH-- or
--C.ident.C--; R.sup.8 is (a) C1-8 alkyl, (b) C1-8 alkoxy, (c)
halogen, (d) nitro, (e) nitrile, (f) trifluoromethyl or (g)
trifluoromethoxy; with the proviso that when E is a bond, then,
optionally, R.sup.1 and R.sup.8, taken together, may be C1-4
alkylene; n is 0 or an integer of 1-5; R.sup.9 is hydrogen, C1-8
alkyl, C2-8 alkenyl or C2-8 alkynyl; a nontoxic salt thereof or a
prodrug thereof, as an active ingredient.
2. The method described in claim 1, wherein the prodrug of a
compound of the formula (I) as an active ingredient is represented
by a compound of the formula (IA): 264wherein, R.sup.14 is C1-8
alkyl substituted with C1-8 alkyl, C1-8 alkoxy, the other symbols
have the same meanings as defined in claim 1.
3. The method described in claim 1, wherein the prodrug of a
compound of the formula (I) as an active ingredient is represented
by comprising a compound of the formula (IB): 265wherein, the all
symbols have the same meanings as defined in claim 1.
4. A hydroxamic acid derivative of the formula (I): 266wherein,
R.sup.1 is (a) C1-8 alkyl, (b) C2-8 alkenyl, (c) C2-8 alkynyl, (d)
halogen, (e) nitro, (f) nitrile, (g) trifluoromethyl, (h)
trifluoromethoxy, (i) --OR.sup.2, (t) --SR.sup.2, (k)
--NR.sup.3R.sup.4, (l) --COR.sup.5, (m) keto, (n) Cyc1, (o) C1-8
alkyl substituted by --OR.sup.2, --SR.sup.2, --NR.sup.3R.sup.4,
--COR.sup.5 or Cyc1, (p) --SO.sub.2R.sup.10, (q) --O--(C1-8
alkylene)--OR.sup.11, (r) C1-8 alkyl substituted by nitrile,
--SO.sub.2R.sup.10 or --O--(C1-8 alkylene)--OR.sup.11, (s)
--O--(C1-8 alkylene)--NR.sup.12R.sup.13, (t) --S--(C1-8
alkylene)--NR.sup.12R.sup.13- , (u) C1-8 alkyl substituted by
--O--(C1-8 alkylene)--NR.sup.12R.sup.13-- or --S--(C1-8
alkylene)--NR.sup.12R.sup.13, (v) C2-8 alkenyl substituted by
--OR.sup.2, --SR.sup.2, --NR.sup.3R.sup.4, --COR.sup.5, Cyc1,
nitrile, --SO.sub.2R.sup.10, --O--(C1-8 alkylene)--OR.sup.11,
--O--(C1-8 alkylene)--NR.sup.12R.sup.13 or --S--(C1-8
alkylene)--NR.sup.12R.sup.13 or (w) C2-8 alkynyl substituted by
--OR.sup.2, --SR.sup.2, --NR.sup.3R.sup.4, --COR.sup.5, Cyc1,
nitrile, --SO.sub.2R.sup.10, --O--(C1-8 alkylene)--OR.sup.11,
--O--(C1-8 alkylene)--NR.sup.12R.sup.13 or --S--(C1-8
alkylene)--NR.sup.12R.sup.13, R.sup.2 is hydrogen, C1-8 alkyl, C2-9
acyl or Cyc1; R.sup.3 and R.sup.4 are each independently hydrogen,
C1-8 alkyl, C2-9 acyl or Cyc1; R.sup.5 is hydroxyl, C1-8 alkyl,
C1-8 alkoxy, --NR.sup.6R.sup.7 or Cyc1; R.sup.6 and R.sup.7 are
each independently hydrogen, C1-8 alkyl or Cyc1; R.sup.10 is C1-8
alkyl or Cyc1; Cyc1 is C3-7 mono-carbocyclic ring or 5-7 membered
mono-cyclic hetero ring containing 1-4 nitrogen atom(s), one oxygen
atom and/or one sulfur atom; R.sup.11 is hydrogen, C1-8 alkyl, C2-9
acyl or Cyc1; R.sup.12 and R.sup.13 are each independently
hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1; m is 0 or an integer of
1-5; ring A is C3-15 mono-, bi- or tri-carbocyclic ring or 5-18
membered mono-, bi- or tri-cyclic hetero ring containing 1-4
nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s);
ring B is C5-15 mono-, bi- or tri-carbocyclic aryl or 5-18 membered
mono-, bi- or tri-cyclic hetero aryl containing 1-4 nitrogen
atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s); E is a bond,
--CH.dbd.CH-- or --C.ident.C--; R.sup.8 is (a) C1-8 alkyl, (b) C1-8
alkoxy, (c) halogen, (d) nitro, (e) nitrile, (f) trifluoromethyl or
(g) trifluoromethoxy; with the proviso that when E is a bond then,
optionally, R.sup.1 and R.sup.8, taken together, is C1-4 alkylene
optionally; n is 0 or an integer of 1-5; R.sup.9 is hydrogen, C1-8
alkyl, C2-8 alkenyl or C2-8 alkynyl; with the proviso that when E
is --CH.dbd.CH-- or --C.ident.C--, ring A is C3-7 mono-carbocyclic
ring or 5-7 membered mono-cyclic hetero ring containing 1-4
nitrogen atom(s), one oxygen atom and/or one sulfur atom; with the
proviso that a compound wherein R.sup.1 is (a) C1-8 alkyl, (b) C2-8
alkenyl, (c) C2-8 alkynyl, (o) C1-8 alkyl substituted by
--OR.sup.2, --SR.sup.2, --NR.sup.3R.sup.4, --COR.sup.5 or Cyc1, (u)
C1-8 alkyl substituted by --O--(C1-8 alkylene)--NR.sup.12R.sup.13--
or --S--(C1-8 alkylene)--NR.sup.12R.sup.13- , (v) C2-8 alkenyl
substituted by --OR.sup.2, --SR.sup.2, --NR.sup.3R.sup.4,
--COR.sup.5, Cyc1, nitrile, --SO.sub.2R.sup.10, --O--(C1-8
alkylene)--OR.sup.11, --O--(C1-8 alkylene)--NR.sup.12R.sup.13 or
--S--(C1-8 alkylene)--NR.sup.12R.sup.13, or (w) C2-8 alkynyl
substituted by --OR.sup.2, --SR.sup.2, --NR.sup.3R.sup.4,
--COR.sup.5, Cyc1, nitrile, --SO.sub.2R.sup.10, --O--(C1-8
alkylene)--OR.sup.11, --O--(C1-8 alkylene)--NR.sup.12R.sup.13 or
--S--(C1-8 alkylene)--NR.sup.12R.sup.13; R.sup.2 is hydrogen, C1-8
alkyl, C2-9 acyl or Cyc1; R.sup.3 and R.sup.4 are each
independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1; R.sup.5 is
hydroxyl, C1-8 alkyl, C1-8 alkoxy, --NR.sup.6R.sup.7 or Cyc1;
R.sup.6 and R.sup.7 are each independently hydrogen, C1-8 alkyl or
Cyc1; R.sup.10 is C1-8 alkyl or Cyc1; Cyc1 is morpholine,
piperidine or piperazine; R.sup.11 is hydrogen, C1-8 alkyl, C2-9
acyl or Cyc1; R.sup.12 and R.sup.13 are each independently
hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1; m is an integer of 1-5;
ring A is a benzene ring; ring B is a benzene ring; E is a bond,
--CH.dbd.CH-- or --C.ident.C--; R.sup.8 is (a) C1-8 alkyl, (b) C1-8
alkoxy, (c) halogen, (d) nitro, (e) nitrile, (f) trifluoromethyl or
(g) trifluoromethoxy, with the proviso that when E is a bond then,
optionally, R.sup.1 and R.sup.8, taken together, is C1-4 alkylene;
n is 0 or an integer of 1-5; R.sup.9 is hydrogen, C1-8 alkyl, C2-8
alkenyl or C2-8 alkynyl, is excluded; a nontoxic salt thereof or a
prodrug thereof.
5. The prodrug of a compound of the formula (I) described in claim
4, which is represented by the formula (IA): 267wherein, R.sup.14
is C1-8 alkyl substituted with C1-8 alkyl, C1-8 alkoxy, the other
symbols have the same meaning as defined in claim 4.
6. The prodrug of a compound of the formula (I) described in claim
4, which is represented by the formula (IB): 268wherein, the all
symbols have the same meaning as defined in claim 4.
7. The compound described in claim 4, wherein E is a bond and ring
A is C3-15 mono-, bi- or tri-carbocyclic ring.
8. The compound described in claim 4, wherein E is a bond and ring
A is 5-18 membered mono-, bi-, or tri-cyclic hetero ring containing
1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or sulfur atom(s).
9. The compound described in claim 4, wherein E is --CH.dbd.CH-- or
--C.ident.C-- and ring A is C3-7 mono-carbocyclic ring.
10. The compound described in claim 4, wherein E is --CH.dbd.CH--
or --C.ident.C-- and A is 5-7 membered mono-cyclic hetero ring
containing 1-4 nitrogen atom(s), one nitrogen atom and/or one
sulfur atom.
11. The compound described in claim 4, which is (1)
N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide, (2)
N-hydroxy-6-(4-biphenyl)-6-hydroxyhexanamide, (3)
N-hydroxy-6-(4-cyclohex- ylphenyl)-6-hydroxyhexanamide, (4)
N-hydroxy-6-(4-(4-methylphenyl)phenyl)-- 6-hydroxyhexanamide, (5)
N-hydroxy-6-(4-(4-methoxyphenyl)phenyl)-6-hydroxy- hexanamide, (6)
N-hydroxy-6-(4-(trans-4-propylcyclohexyl)phenyl)-6-hydroxy-
hexanamide, (7)
(R)-N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexana- mide,
(8) (S)-N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide,
(9) N-hydroxy-6-(4-(benzofuran-2-yl)phenyl)-6-hydroxyhexanamide,
(10) N-hydroxy-6-(4-(pyridin-4-yl)phenyl)-6-hydroxyhexanamide, (11)
N-hydroxy-6-(4-(pyridin-3-yl)phenyl)-6-hydroxyhexanamide, (12)
N-hydroxy-6-(4-(2-chlorophenyl)phenyl)-6-hydroxyhexanamide, (13)
N-hydroxy-6-(4-(3-chlorophenyl)phenyl)-6-hydroxyhexanamide, (14)
N-hydroxy-6-(4-(4-bromophenyl)phenyl)-6-hydroxyhexanamide, (15)
N-hydroxy-6-(4-(thiophen-2-yl)phenyl)-6-hydroxyhexanamide, (16)
N-hydroxy-6-(4-(furan-2-yl)phenyl)-6-hydroxyhexanamide, (17)
N-hydroxy-6-(4-(1,3-dioxy-2,3-dihydroinden-5-yl)phenyl)-6-hydroxyhexanami-
de, (18)
N-hydroxy-6-(4-(4-methylthiophenyl)phenyl)-6-hydroxyhexanamide,
(19) N-hydroxy-6-(4-(naphthalen-1-yl)phenyl)-6-hydroxyhexanamide,
(20) N-hydroxy-6-(4-(naphthalen-2-yl)phenyl)-6-hydroxyhexanamide,
(21) N-hydroxy-6-(4-(4-acetylphenyl)phenyl)-6-hydroxyhexanamide,
(22) N-hydroxy-6-(4-(4-hydroxyphenyl)phenyl)-6-hydroxyhexanamide,
(23) N-hydroxy-6-(4-(dibenzofuran-4-yl)phenyl)-6-hydroxyhexanamide,
(24) N-hydroxy-6-(4-(2-methoxyphenyl)phenyl)-6-hydroxyhexanamide,
(25) N-hydroxy-6-(4-(3-methoxyphenyl)phenyl)-6-hydroxyhexanamide,
(26)
N-hydroxy-6-(4-(4-trifluoromethylphenyl)phenyl)-6-hydroxyhexanamide,
(27) N-hydroxy-6-(4-(4-t-butylphenyl)phenyl)-6-hydroxyhexanamide,
(28)
(R)-N-hydroxy-6-[4-(5-methylbenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,
(29)
(R)-N-hydroxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,
(30)
(R)-N-hydroxy-6-[4-(2-(4-methylthiophenyl)ethynyl)phenyl]-6-hydroxyh-
exanamide, (31)
(R)-N-hydroxy-6-[4-(4-methylthiophenyl)phenyl]-6-hydroxyhe-
xanamide, (32)
(R)-N-hydroxy-6-[4-(4-(dimethylaminomethyl)phenyl)phenyl]-6-
-hydroxyhexanamide, (33)
N-hydroxy-6-(4-(trans-4-butylcyclohexyl)phenyl)-6-
-hydroxyhexanamide, (34)
N-hydroxy-6-(4-(trans-4-hydroxycyclohexyl)phenyl)-
-6-hydroxyhexanamide, (35)
N-hydroxy-6-(4-cyclopentylphenyl)-6-hydroxyhexa- namide, (36)
N-hydroxy-6-[4-(morpholin-4-yl)phenyl]-6-hydroxyhexanamide, (37)
N-hydroxy-6-[3-(4-chlorophenyl)phenyl]-6-hydroxyhexanamide, (38)
N-hydroxy-6-[2-(4-chlorophenyl)phenyl]-6-hydroxyhexanamide, (39)
N-hydroxy-6-[4-((1E)-2-phenylvinyl)phenyl]-6-hydroxyhexanamide,
(40)
N-hydroxy-6-[4-((1E)-2-(pyridin-4-yl)vinyl)phenyl]-6-hydroxyhexanamide,
(41)
N-hydroxy-6-[4-((1E)-2-(pyridin-2-yl)vinyl)phenyl]-6-hydroxyhexanami-
de, (42)
N-hydroxy-6-[4-(4-chlorophenyl)phenyl]-6-hydroxyheptanamide, (43)
N-hydroxy-6-[4-(4-chlorophenyl)phenyl]-6-hydroxy-7-octenamide, (44)
N-hydroxy-6-(4-biphenyl)-6-hydroxyheptanamide, (45)
(+)-N-hydroxy-6-[4-(4-ethylphenyl)phenyl]-6-hydroxyheptanamide,
(46)
(-)-N-hydroxy-6-[4-(4-ethylphenyl)phenyl]-6-hydroxyheptanamide,
(47) (R)-N-hydroxy-6-(4-biphenyl)-6-hydroxyhexanamide, (48)
(R)-N-hydroxy-6-[4-(4-methylphenyl)phenyl]-6-hydroxyhexanamide,
(49)
(R)-N-hydroxy-6-[4-(3-methylphenyl)phenyl]-6-hydroxyhexanamide,
(50)
(R)-N-hydroxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,
(51)
(R)-N-hydroxy-6-[4-(2-phenylethynyl)phenyl]-6-hydroxyhexanamide,
(52)
(R)-N-hydroxy-6-[4-(benzothiophen-2-yl)phenyl]-6-hydroxyhexanamide,
(53)
(R)-N-hydroxy-6-[4-(4-(cyanomethyl)phenyl)phenyl]-6-hydroxyhexanamide,
(54) (R)-N-hydroxy-6-[4-(4-ethylphenyl)phenyl]-6-hydroxyhexanamide,
(55)
(R)-N-hydroxy-6-[4-(4-propylphenyl)phenyl]-6-hydroxyhexanamide,
(56) (R)-N-hydroxy-6-[4-(4-biphenyl)phenyl]-6-hydroxyhexanamide,
(57)
(R)-N-hydroxy-6-[4-(1-methylpiperidin-4-yl)phenyl]-6-hydroxyhexanamide,
(58) (R)-N-hydroxy-6-[4-(indol-2-yl)phenyl]-6-hydroxyhexanamide,
(59) (R)-N-hydroxy-6-[4-(4-cyanophenyl)phenyl]-6-hydroxyhexanamide,
(60) (R)-N-hydroxy-6-[4-phenyl-2-methylphenyl]-6-hydroxyhexanamide,
(61) (R)-N-hydroxy-6-(4-cycloheptylphenyl)-6-hydroxyhexanamide,
(62)
(R)-N-hydroxy-6-(9,10-dihydrophenanthren-2-yl)-6-hydroxyhexanamide,
(63)
(R)-N-hydroxy-6-[4-(1-ethoxycarbonylpiperidin-4-yl)phenyl]-6-hydroxyhexan-
amide, (64)
(R)-N-hydroxy-6-[4-(4-(N-methylcarbamoyl)phenyl)phenyl]-6-hydr-
oxyhexanamide, (65)
(R)-N-hydroxy-6-(4-cyclohexylphenyl)-6-hydroxyhexanami- de, (66)
(R)-N-hydroxy-6-[4-(5-hydroxybenzofuran-2-yl)phenyl]-6-hydroxyhex-
anamide, (67)
(R)-N-hydroxy-6-[4-(2-(4-methylphenyl)ethynyl)phenyl]-6-hydr-
oxyhexanamide, (68)
(R)-N-hydroxy-6-[4-((1E)-2-(4-methylphenyl)vinyl)pheny-
l]-6-hydroxyhexanamide, (69)
(R)-N-hydroxy-6-[4-(4-trifluoromethoxyphenyl)-
phenyl]-6-hydroxyhexanamide, (70)
(R)-N-hydroxy-6-[4-(4-ethylthiophenyl)ph-
enyl]-6-hydroxyhexanamide, (71)
(R)-N-hydroxy-6-[4-(4-methoxyphenyl)phenyl- ]-6-hydroxyhexanamide,
(72) (R)-N-hydroxy-6-[4-(4-(1-methylethyl)phenyl)ph-
enyl]-6-hydroxyhexanamide, (73)
(R)-N-hydroxy-6-[4-(4-(N,N-dimethylcarbamo-
ylmethyl)phenyl)phenyl]-6-hydroxyhexanamide, (74)
(R)-N-hydroxy-6-[4-(benz-
othiazol-2-yl)phenyl]-6-hydroxyhexanamide, (75)
(R)-N-hydroxy-6-[4-(4-(met-
hoxymethoxymethyl)phenyl)phenyl]-6-hydroxyhexanamide, (76)
(R)-N-hydroxy-6-[4-(6-methoxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,
(77)
(R)-N-hydroxy-6-[4-(6-methylbenzoxazol-2-yl)phenyl]-6-hydroxyhexanam-
ide, (78)
(R)-N-hydroxy-6-[4-(4-methoxymethylphenyl)phenyl]-6-hydroxyhexan-
amide, (79)
(R)-N-hydroxy-6-[4-(5-methoxybenzoxazol-2-yl)phenyl]-6-hydroxy-
hexanamide, (80)
(R)-N-hydroxy-6-[4-(4-methoxybenzoxazol-2-yl)phenyl]-6-hy-
droxyhexanamide, (81)
(R)-N-hydroxy-6-[4-(4-hydroxybenzoxazol-2-yl)phenyl]-
-6-hydroxyhexanamide, (82)
(R)-N-hydroxy-6-[4-(6-hydroxybenzoxazol-2-yl)ph-
enyl]-6-hydroxyhexanamide, (83)
(R)-N-hydroxy-6-[4-((1E)-2-(4-methylthioph-
enyl)vinyl)phenyl]-6-hydroxyhexanamide, (84)
(R)-N-hydroxy-6-[4-(5-methoxy-
benzofuran-2-yl)phenyl]-6-hydroxyhexanamide, (85)
(R)-N-hydroxy-6-[4-(5-me-
thylthiobenzofuran-2-yl)phenyl]-6-hydroxyhexanamide, (86)
(R)-N-hydroxy-6-[4-(4-(2-(dimethylamino)ethyl)phenyl)phenyl]-6-hydroxyhex-
anamide, (87)
(R)-N-hydroxy-6-[4-(4-(2-(dimethylamino)ethoxy)phenyl)phenyl-
]-6-hydroxyhexanamide, (88)
(R)-N-hydroxy-6-[4-(4-(2-(diethylamino)ethyl)p-
henyl)phenyl]-6-hydroxyhexanamide, (89)
(R)-N-hydroxy-6-[4-(4-(2-hydroxyet-
hyl)phenyl)phenyl]-6-hydroxyhexanamide, (90)
(S)-N-hydroxy-6-[4-(4-methylt-
hiophenyl)phenyl]-6-hydroxyhexanamide, (91)
(S)-N-hydroxy-6-[4-(2-(4-methy-
lthiophenyl)ethynyl)phenyl]-6-hydroxyhexanamide, (92)
(S)-N-hydroxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,
(93)
(S)-N-hydroxy-6-[4-(5-methylbenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,
(94)
(S)-N-hydroxy-6-[4-(4-(dimethylaminomethyl)phenyl)phenyl]-6-hydroxyh-
exanamide, (95)
(R)-N-hydroxy-6-[4-(4-(dipropylaminomethyl)phenyl)phenyl]--
6-hydroxyhexanamide, (96)
(R)-N-hydroxy-6-(5-phenylthiophen-2-yl)-6-hydrox- yhexanamide, (97)
(R)-N-hydroxy-6-(5-phenylbenzofuran-2-yl)-6-hydroxyhexan- amide,
(98)
(R)-N-hydroxy-6-[4-(4-(methoxycarbonyl)phenyl)phenyl]-6-hydrox-
yhexanamide, (99)
(R)-N-hydroxy-6-[4-(4-carboxyphenyl)phenyl]-6-hydroxyhex- anamide,
(100) (R)-N-hydroxy-6-[4-(4-methylsulfonylphenyl)phenyl]-6-hydrox-
yhexanamide, (101)
(R)-N-hydroxy-6-[4-(4-hydroxymethylphenyl)phenyl]-6-hyd-
roxyhexanamide, or a nontoxic salt thereof.
12. The compound described in claim 5, which is: (1)
N-(1-methoxy-1-methyl)ethoxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexana-
mide, (2)
N-(1-methoxy-1-methyl)ethoxy-6-(4-(benzofuran-2-yl)phenyl)-6-hyd-
roxyhexanamide, (3)
(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(5-methylbenzoxa-
zol-2-yl)phenyl]-6-hydroxyhexanamide, (4)
(R)-N-(1-methoxy-1-methyl)ethoxy-
-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide, (5)
(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(2-(4-methylthiophenyl)ethynyl)phen-
yl]-6-hydroxyhexanamide, (6)
(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-meth-
ylthiophenyl)phenyl]-6-hydroxyhexanamide, (7)
(R)-N-(1-methoxy-1-methyl)et-
hoxy-6-[4-(4-(dimethylaminomethyl)phenyl)phenyl]-6-hydroxyhexanamide,
(8)
(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(dipropylaminomethyl)phenyl)phen-
yl]-6-hydroxyhexanamide, (9)
N-methoxy-6-[4-(4-chlorophenyl)phenyl]-6-hydr- oxyhexanamide, or a
nontoxic salt thereof.
13. The compound described in claim 6, which is (1)
(R)-5-(5,5-dimethyl-1,4,2-dioxazolin-3-yl)-1-[4-(5-methylbenzoxazol-2-yl)-
phenyl]pentan-1-ol, (2)
(R)-5-(5,5-dimethyl-1,4,2-dioxazolin-3-yl)-1-[4-(4-
-methylthiophenyl)phenyl]pentan-1-ol, (3)
(R)-5-(5,5-dimethyl-1,4,2-dioxaz-
olin-3-yl)-1-[4-(4-(dimethylaminomethyl)phenyl)phenyl]pentan-1-ol,
or a nontoxic salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to hydroxamic acid
derivatives, the methods for preparation thereof and inhibitors of
interleukin-6 production comprising thereof, as an active
ingredient.
[0002] More particularly, it relates to (1) inhibitors of IL-6
production comprising hydroxamic acid derivatives of the formula
(I) 2
[0003] (wherein all the symbols have the same meaning as defined
hereinafter),
[0004] non-toxic salts thereof and prodrugs thereof, as an active
ingredient,
[0005] (2) novel hydroxamic acid derivatives of the above formula
(I), non-toxic salts thereof and prodrugs thereof and
[0006] (3) the methods for preparation of hydroxamic acid
derivatives of the above formula (I), non-toxic salts thereof and
prodrugs thereof.
BACKGROUND
[0007] Cytokine is a multifunctional factor which plays an
important role in the host defense system of living body and it
relates to various life phenomena. However, there are many diseases
which may be caused by overproduction thereof or overresponse
thereto.
[0008] IL-6 is a cytokine produced from various cells, e.g. T
cells, B cells, macrophages, kidney mesangial cells, fibroblasts,
and its various physiological effects are known e.g. induction of B
cells differentiation to antibody-producing cells, activation of T
cells, increase of platelets, and production of acute phase protein
from liver cells. But an abnormal production of IL-6 has been
observed in various inflammations, autoimmune diseases and
neoplastic diseases and it is suggested that IL-6 plays a certain
role in the causes of such pathophysiological situations. In the
experiment using an animal model in which IL-6 was forcibly
expressed, various types of diseases could be observed and such
results strongly suggest the existence of relationship between the
abnormal production of IL-6 and the cause of certain diseases
(Biochem. J., 265, 621 (1990), Immunol. Today, 11, 443 (1990), J.
Autoimmun., 5 Suppl A, 123 (1992), Clin. Immunol. Immunopathol.,
62, S60 (1992)).
[0009] Therefore inhibition of IL-6 production is expected to
improve various kinds of diseases such as inflammatory diseases as
a representative. The present invention is targeted for the
cytokine and provides novel medicines through inhibiting the
production thereof.
[0010] Clinical application of the compounds of the present
invention involves those diseases which may be caused and be
changed to worse by abnormal production of IL-6 or by overresponse
to them. Inhibitors of IL-6 production may be used for the
prevention and/or treatment of various inflammatory diseases,
sepsis, multiple myeloma, plasma cell leukemia, osteoporosis,
cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi's
sarcoma, rheumatoid arthritis, hypergammaglobulinemia, Castleman's
disease, atrial myxoma, diabetes mellitus, autoimmne diseases,
hepatitis, colitis, graft versus host disease, infectious diseases
and endometriosis (J. Immunol., 145, 4185 (1990), J. Exp. Med.,
172, 1505 (1990), J. Clin. Invest., 87, 739 (1991), J. Clin.
Invest., 89, 1681 (1992), EMBO J., 13, 1189 (1994), Hematol. Oncol.
Clin. North Am., 11, 159 (1997), Cytokines Cell Mol. Ther.,
4(3),161 (1998), Folia Med. (Plovdiv), 41(1), 78 (1999), JPEN J.
Parenter Enteral Nutr., 23(5), S20 (1999), J. Infect. Dis., 180(1),
10 (1999), Am. J. Obstet. Gynecol., 176(3), 593 (1997)).
[0011] For example, in the specification of Japanese Patent
Application Kokai S59-46244, it is described that hydroxamic acid
derivatives of the formula (X)
A.sup.x--B.sup.x--(CH.sub.2).sub.nX--CONHOH (X)
[0012] [wherein A.sup.x is R.sup.xX.sup.xm.sup.x (R.sup.x is
phenyl, pyrrolyl, thienyl imidazolyl or thiazolyl, X.sup.x is
halogen, lower alkyl, lower alkoxy or nitro, m.sup.x is 0 or an
integer of 1-2 and each X.sup.x is the same or different
optionally.), B.sup.x is --CHOH--, --CH--, --O--, or --CO--, or
--CO--, nX is an integer of 2-10.]
[0013] is useful as anti-parasite agent.
[0014] And in the U.S. Pat. No. 4,769,461, it is described that
hydroxamic acid derivatives of the formula (Y) 3
[0015] [wherein W.sup.Y is a bond, --O--, --S--, --NR.sup.2Y--,
--CH(OH)-- or --NR.sup.2Y--CO--, X.sup.Y is N or
[0016] CR.sup.2Y,
[0017] when nY=0, Y.sup.Y, is O, S, NR.sup.2Y or
C(R.sup.2Y).sub.2
[0018] when nY=1, Y.sup.Y is N or CR.sup.2Y,
[0019] Z.sup.Y is --CH.sub.2O--, --CH.sub.2--,
--CH.sub.2NR.sub.2Y--, --O--, --S--, --NR.sup.2Y--, --CO--,
--CONR.sup.2Y--, --CHR.sub.2YCHR.sup.2Y--,
--C(R.sup.2Y)=C(R.sup.2Y)-- or --C.ident.C--,
[0020] R.sup.1Y is hydrogen, lower alkyl, trifluoromethyl, nitro,
hydroxy, lower alkoxy, mercapto, lower alkylthio or halogen,
[0021] R.sup.2Y is hydrogen or lower alkyl,
[0022] nY is 0 or 1,
[0023] mY is 1-6.
[0024] With the proviso that when W.sup.Y is a bond, then mY is
0-5.] is useful as anti-inflammatory or anti-allergy agent by
inhibition of cyclooxygenase and lipoxygenase.
DISCLOSURE OF THE INVENTION
[0025] Energetic investigations have been carried out to discover a
compound possessing an inhibitory activity of IL-6 production. As a
results, the present inventors have found that the purpose has been
achieved by hydroxamic acid derivatives of the formula (I) or
non-toxic salts thereof.
[0026] Hydroxamic acid derivatives of the formula (I) of the
present invention have not been known as inhibitors of IL-6
production at all. Further, almost hydroxamic acid derivatives of
the formula (I), non-toxic salts thereof and prodrugs thereof are
novel compounds which are not known at all.
[0027] The present invention relates to
[0028] 1) an inhibitor of IL-6 production comprising hydroxamic
acid derivatives of the formula (I), 4
[0029] [wherein, R.sup.1 is
[0030] (a) C1-8 alkyl,
[0031] (b) C2-8 alkenyl,
[0032] (c) C2-8 alkynyl,
[0033] (d) halogen,
[0034] (e) nitro,
[0035] (f) nitrile,
[0036] (g) trifluoromethyl,
[0037] (h) trifluoromethoxy,
[0038] (i) --R.sup.2,
[0039] (j) --SR.sup.2,
[0040] (k) --NR.sup.3R.sup.4,
[0041] (l) --COR.sup.5,
[0042] (m) keto,
[0043] (n) Cyc1,
[0044] (o) C1-8 alkyl substituted by --OR.sup.2, --SR.sup.2,
--NR.sup.3R.sup.4, --CR.sup.5 or Cyc1,
[0045] (p) --SO.sub.2R.sup.10,
[0046] (q) O--(C1-8 alkylene)--OR.sup.11,
[0047] (r) C1-8 alkyl substituted by nitrile, --SO.sub.2R.sup.10 or
--O--(C1-8 alkylene)--OR.sup.11,
[0048] (s) --O--(C1-8 alkylene)--NR.sup.2R.sup.13,
[0049] (t) --S--(C1-8 alkylene)--NR.sup.12R.sup.13,
[0050] (u) C1-8 alkyl substituted by --O--(C1-8
alkylene)--NR.sup.12R.sup.- 13-- or --S--C1-8
alkylene)--NR.sup.12R.sup.13,
[0051] (v) C2-8 alkenyl substituted by --OR.sup.2, --SR.sup.2,
--NR.sup.3R.sup.4, COR.sup.5, Cyc.sub.1 nitrile,
--SO.sub.2R.sup.10, --O--(C1-8 alkylene)--OR.sup.11, --O--(C1-8
alkylene)--NR.sup.12R.sup.13 or --S--(C1-8
alkylene)--NR.sup.12R.sup.13 or
[0052] (w) C2-8 alkynyl substituted by --OR.sup.2, --SR.sup.2,
--NR.sup.3R.sup.4, --COR.sup.5, Cyc1, nitrile, --SO.sub.2R.sup.10,
--O--(C1-8 alkylene)--OR.sup.11, --O--(C1-8
alkylene)--NR.sup.12R.sup.13, or --S--(C1-8
alkylene)--NR.sup.12R.sup.13,
[0053] R.sup.2 is hydrogen, C1-8alkyl, C2-9 acyl or Cyc1,
[0054] R.sup.3 and R.sup.4 are each independently hydrogen, C1-8
alkyl, C2-9 acyl or Cyc1,
[0055] R.sup.5 is hydroxy, C1-8 alkyl, C1-8 alkoxy,
--NR.sup.6R.sup.7 or Cyc1,
[0056] R.sup.6 and R.sup.7 are each independently hydrogen, C1-8
alkyl or Cyc1,
[0057] R.sup.10 is C1-8 alkyl or Cyc1,
[0058] Cyc1 is C3-7 mono-carbocyclic ring or 5-7 membered
mono-cyclic hetero ring containing 14 nitrogen atom(s), one oxygen
atom and/or one sulfur atom,
[0059] R.sup.11 is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
[0060] R.sup.12 and R.sup.13 are each independently hydrogen, C1-8
alkyl, C2-9 acyl or Cyc.sub.1,
[0061] m is 0 or an integer of 1-5,
[0062] ring A is C3-15 mono-, bi- or tri-carbocyclic ring or 5-18
membered mono-, bi- or tri-cyclic hetero ring containing 14
nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),
[0063] ring B is C5-15 mono-, bi- or tri-carbocyclic aryl or 5-18
membered mono-, bi- or tri-cyclic hetero aryl containing 14
nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),
[0064] E is a bond, --CH.dbd.CH-- or --C.ident.C--,
[0065] R.sup.8 is
[0066] (a) C1-8 alkyl,
[0067] (b) C1-8 alkoxy,
[0068] (c) halogen,
[0069] (d) nitro,
[0070] (e) nitrile,
[0071] (f) trifluoromethyl or
[0072] (g) trifluoromethoxy.
[0073] With the proviso that when E is a bond, then R.sup.1 and
R.sup.8, taken together, may be optionally C1-4 alkylene.
[0074] n is 0 or an integer of 1-5,
[0075] R.sup.9 is hydrogen, C1-8 alkyl, C2-8 alkenyl or C2-8
alkynyl.], nontoxic salts thereof or prodrugs thereof, as an active
ingredient,
[0076] 2) Hydroxamic acid derivatives of the formula (I) 5
[0077] [wherein, R.sup.1 is
[0078] (a) C1-8 alkyl,
[0079] (b) C2-8 alkenyl,
[0080] (c) C2-8 alkynyl,
[0081] (d) halogen,
[0082] (e) nitro,
[0083] (f) nitrile,
[0084] (g) trifluoromethyl,
[0085] (h) trifluoromethoxy,
[0086] (i) --OR.sup.2,
[0087] (j) --SR.sup.2,
[0088] (k) --NR.sup.3R.sup.4,
[0089] (l) --COR.sup.5,
[0090] (m) keto,
[0091] (n) Cyc1,
[0092] (o) C1-8 alkyl substituted by --OR.sup.2, --SR.sup.2,
--NR.sup.3R.sup.4, --OR.sup.5 or Cyc1,
[0093] (p) --SO.sub.2R.sup.10,
[0094] (q) --O--(C1-8 alkylene)--OR.sup.11,
[0095] (r) --O--(C1-8 alkyl substituted by nitrile,
--SO.sub.2R.sup.10 or --O--(C1-8 alkylene)--OR.sup.11,
[0096] (s) --S--(C1-8 alkylene)--NR.sup.12R.sup.13,
[0097] (t) (C1-8 alkylene)--NR.sup.12R.sup.13,
[0098] (u) C1-8 alkyl substituted by --O--(C1-8
alkylene)--NR.sup.12R.sup.- 13-- or --S--(C1-8
alkylene)--NR.sup.12R.sup.13,
[0099] (v) C2-8 alkenyl substituted by --OR.sup.2, --SR.sup.2,
--NR.sup.3R.sup.4, --COR.sup.5, Cyc1, nitrile, --SO.sub.2R.sup.10,
--O--(C1-8 alkylene)--OR.sup.11, --(C1-8
alkylene)--NR.sup.12R.sup.13 or (C1-8 alkylene)--NR.sup.12R.sup.13
or
[0100] (w) C2-8 alkynyl substituted by --OR.sup.2, --SR.sup.2,
--NR.sup.3R.sup.4, --COR.sup.5, Cyc1, nitrile, --SO.sub.2R.sup.10,
--O--(C1-8 alkylene)--OR.sup.11, --O--(C1-8
alkylene)--NR.sup.12R.sup.13 or --S--(C1-8
alkylene)--NR.sup.12R.sup.13,
[0101] R.sup.2 is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
[0102] R.sup.3 and R.sup.4 are each independently hydrogen, C1-8
alkyl, C2-9 acyl or Cyc1,
[0103] R.sup.5 is hydroxyl, C1-8 alkyl, C1-8 alkoxy,
--NR.sup.6R.sup.7 or Cyc1,
[0104] R.sup.6 and R.sup.7 are each independently hydrogen, C1-8
alkyl or Cyc1,
[0105] R.sup.10 is C1-8 alkyl or Cyc1,
[0106] Cyc1 is C3-7 mono-carbocyclic ring or 5-7 membered
mono-cyclic hetero ring containing 14 nitrogen atom(s), one oxygen
atom and/or one sulfur atom,
[0107] R.sup.11 is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
[0108] R.sup.12 and R.sup.13 are each independently hydrogen, C1-8
alkyl, C2-9 acyl or Cyc1,
[0109] m is 0 or an integer of 1-5,
[0110] ring A is C3-15 mono-, bi- or tri-carbocyclic ring or 5-18
membered mono-, bi- or tri-cyclic hetero ring containing 14
nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),
[0111] ring B is C5-15 mono-, bi- or tri-carbocyclic aryl or 5-18
membered mono-, bi- or tri-cyclic hetero aryl containing 14
nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),
[0112] E is a bond, --CH.dbd.CH-- or --C.ident.C--,
[0113] R.sup.8 is
[0114] (a) C1-8 alkyl,
[0115] (b) C1-8 alkoxy,
[0116] (c) halogen,
[0117] (d) nitro,
[0118] (e) nitrile,
[0119] (f) trifluoromethyl or
[0120] (g) trifluoromethoxy.
[0121] With the proviso that when E is a bond then R.sup.1 and
R.sup.8, taken together, is C1-4 alkylene optionally.
[0122] n is 0 or an integer of 1-5,
[0123] R.sup.9 is hydrogen, C1-8 alkyl, C2-8 alkenyl or C2-8
alkynyl.
[0124] With the proviso that when E is --CH.dbd.CH-- or
--C.ident.C--, ring A is C3-7 mono-carbocyclic ring or 5-7 membered
mono-cyclic hetero ring containing 1-4 nitrogen atom(s), one oxygen
atom and/or one sulfur atom.], nontoxic salts thereof or prodrugs
thereof,
[0125] 3) the methods for preparation of hydroxamic acid
derivatives of the above formula (I), non-toxic salts thereof and
prodrugs thereof.
DETAILED EXPLANATION OF THE INVENTION
[0126] Unless otherwise specified, all isomers are included in the
present invention. For example, alkyl, alkoxy and alkylene groups
include straight or branched ones. In addition, isomers on double
bond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomers
generated from asymmetric carbon atom(s) (R-, S-, .alpha.,
.beta.-isomer, enantiomer, diastereomer), optically active isomer
(D-, L-, d-, I-, (+)-, (-)-isomer), polar compounds generated by
chromatographic separation (more polar compound, less polar
compound), equilibrium compounds, mixtures thereof at voluntary
ratios and racemic mixtures are also included in the present
invention.
[0127] In the present invention, C1-8 alkyl means methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, octyl and the isomers
thereof.
[0128] C2-8 alkenyl means vinyl, propenyl, butenyl, pentenyl,
hexenyl, heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl,
heptadienyl, octadienyl, hexatrienyl, heptatrienyl, octatrienyl and
the isomer thereof.
[0129] C2-8 alkynyl means ethynyl, propynyl, butynyl, pentynyl,
hexynyl, heptynyl, octynyl, butadiynyl, pentadiynyl, hexadiynyl,
heptadiynyl, octadiynyl, hexatriynyl, heptatriynyl, octatriynyl and
the isomer thereof.
[0130] Halogen means fluoride, chloride, bromide and iodide.
[0131] C1-4 alkylene means methylene, ethylene, trimethylene,
tetramethylene and the isomers thereof.
[0132] C1-8 alkylene means methylene, ethylene, trimethylene,
tetramethylene, pentamethylene, hexamethylene, heptamethylene,
octamethylene and isomers thereof.
[0133] C2-9 acyl means acetyl, propionyl, butyryl, valeryl,
hexanoyl, heptanoyl, octanoyl, nonanoyl and the isomers
thereof.
[0134] C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy,
pentyloxy, hexyloxy, heptyloxy, octyloxy and the isomers
thereof.
[0135] C3-7 mono-carbocyclic ring means C3-7 mono-aromatic
carbocyclic ring, partially saturated carbocyclic ring thereof and
fully saturated carbocyclic ring thereof. It includes, for example,
cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,
cyclopentene, cyclohexene, cycloheptene, cyclopentadiene,
cyclohexadiene, cycloheptadiene and benzene etc.
[0136] 5-7 membered mono-cyclic hetero ring containing 14 nitrogen
atom(s), one oxygen atom and/or one sulfur atom means 5-7membered
mono-cyclic hetero aryl containing 1-4 nitrogen atom(s), one oxygen
atom and/or one sulfur atom and partially or fully saturated one.
It includes, for example, pyrrole, imidazole, pyrazole, triazole,
tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine,
diazepine, furan, pyran, oxepine, oxazepine, thiophene, thiain
(thiopyran), thiepine, oxazole, isoxazole, thiazole, isothiazole,
oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine,
thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine,
pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline,
pyrazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,
dihydropyridine, dihydropyrimidine, dihydropyridazine, piperidine,
piperazine, tetrahydropyrimidine, tetrahydropyridazine,
dihydroazepine, dihydrodiazepine, tetrahydroazepine,
tetrahydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran,
tetrahydropyran, dihydrothiophene, tetrahydrothiophene,
dihydrothiain (dihydrothiopyran), tetrahydrothiain
(tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole,
dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole,
tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole,
tetrahydroxadiazole, tetrahydroxazine, tetrahydroxadiazine,
tetrahydroxazepine, tetrahydroxadiazepine, tetrahydrothiadiazole,
tetrahydrothiazine, tetrahydrothiadiazine, tetrahydrothiazepine,
tetrahydrothiadiazepine, morpholine and thiomorpholine etc.
[0137] C3-15 mono-, bi- or tri-carbocyclic ring means C3-15 mono-,
bi- and tri-aromatic carbocyclic ring, partially saturated
carbocyclic ring thereof and fully saturated carbocyclic ring
thereof. It includes, for example, cyclopropane, cyclobutane,
cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene,
cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene,
benzene, pentalene, indene, naphthalene, azulene, fluorene,
phenanthrene, anthracene, acenaphthylene, biphenylene,
perhydropentalene, perhydroindene, dihydronaphthalene,
tetrahydronaphthalene, perhydronaphthalene, perhydroazulene,
perhydrofluorene, perhydrophenanthrene, perhydroanthracene,
perhydroacenaphthylene and perhydrobiphenylene, etc.
[0138] 5-18 membered mono-, bi- or tricyclic hetero ring containing
14 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s)
means 5-18 membered mono-, bi- or tri-cyclic hetero aryl containing
14 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s)
and partially or fully saturated one. It includes, for example,
pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine,
pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran,
oxepine, oxazepine, thiophene, thiain (thiopyran), thiepine,
oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine,
oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine,
thiadiazine, thiazepine, thiadiazepine, indole, isoindole,
benzofuran, isobenzofuran, benzothiophene, isobenzothiophene,
indazole, quinoline, isoquinoline, phthalazine, naphthyridine,
quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole,
benzimidazole, carbazole, acridine, dibenzofuran, dibenzothiophene,
pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline,
pyrazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,
dihydropyridine, dihydropyrimidine, dihydropyridazine, piperidine,
piperazine, tetrahydropyrimidine, tetrahydropyridazine,
dihydroazepine, dihydrodiazepine, tetrahydroazepine,
tetrahydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran,
tetrahydropyran, dihydrothiophene, tetrahydrothiophene,
dihydrothiain (dihydrothiopyran), tetrahydrothiain
(tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole,
dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole,
tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole,
tetrahydrooxadiazole, tetrahydrooxazine, tetrahydrooxadiazine,
tetrahydrooxazepine, tetrahydrooxadiazepine, tetrahydrothiadiazole,
tetrahydrothiazine, tetrahydrothiadiazine, tetrahydrothiazepine,
tetrahydrothiadiazepine, morpholine, thiomorpholine, indoline,
isoindoline, dihydrobenzofuran, perhydrobenzofuran,
dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,
perhydrobenzothiophene, dihydroisobenzothiophene,
perhydroisobenzothiophene, dihydroindazole, dihydroquinoline,
tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,
tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,
tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine,
tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline,
tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,
tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,
tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole,
perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,
dihydrobenzimidazole, perhydrobenzimidazole, benzoxazepine,
benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzazepine,
benzodiazepine, indroxoazepine, indrotetrahydroxazepine,
indroxadiazepine, indrotetrahydroxadiazepine, indrothiazepine,
indrotetrahydrothiazepine, indrothiadiazepine,
indrotetrahydrothiadiazepi- ne, indroazepine,
indrotetrahydroazepine, indrodiazepine, indrotetrahydrodiazepine,
benzofurazan, benzothiadiazole, benzotriazole, imidazothiazole,
dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole,
dihydroacridine, tetrahydroacridine, perhydroacridine,
dihydrodibenzofuran, dihydrodibenzothiophene,
tetrahydrodibenzofuran, tetrahydrodibenzothiophene,
perhydrodibenzofuran, perhydrodibenzothiophen- e, 1,3-dioxaindan
and 1,4-dioxotetrahydronaphthalene.
[0139] C5-15 mono-, bi- or tri-carbocyclic aryl means
cyclopentadiene, cyclohexadiene, cycloheptadiene, cycloheptatriene,
benzene, indene, naphthalene, fluorene and anthracene etc.
[0140] 5-18 membered mono-, bi- or tri-cyclic hetero aryl
containing 14 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2
sulfur atom(s) means pyrrole, imidazole, triazole, tetrazole,
pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine,
diazepine, furan, pyran, oxepine, thiophene, thiain (thiopyran),
thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan,
oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine,
thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine,
indole, isoindole, benzofuran, isobenzofuran, benzothiophene,
isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine,
naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,
benzothiazole, benzimidazole, benzoxepine, benzoxazepine,
benzoxadiazepine, benzothiepine, benzothiazepine,
benzothiadiazepine, benzazepine, benzodiazepine, benzofurazan,
benzothiadiazole, benzotriazole, carbazole, acridine, dibenzofuran
and dibenzothiophene.
[0141] In the present invention, unless otherwise specified, as
will be apparent to those skilled in the art, a symbol
[0142] represents bonding to back of the paper (that is,
.alpha.-configuration),
[0143] represents bonding to front of the paper (that is,
.beta.-configuration),
[0144] represents .alpha.-, .beta.- or mixture thereof and
[0145] represents mixture of .alpha.-configuration and
.beta.-configuration.
[0146] [Salts]
[0147] Non-toxic salts of the present invention include all
non-toxic salts, for example, general salts, acid addition salts,
hydrate salts.
[0148] The compounds of the present invention may be converted into
the corresponding salts by conventional means. Water-soluble salts
are preferred. Suitable salts, for example, include:
[0149] salts of alkali metals (e.g. potassium, sodium), salts of
alkaline earth metals (e.g. calcium, magnesium), ammonium salts,
salts of pharmaceutically acceptable organic amines (e.g.
tetramethylammonium, triethylamine, methylamine, dimethylamine,
cyclopentylamine, benzylamine, phenethylamine, piperidine,
monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine,
arginine, N-methyl-D-glucamine).
[0150] The compounds of the present invention may be converted into
the corresponding acid addition salts by conventional means.
Water-soluble salts are preferred. Suitable salts, for example,
include:
[0151] salts of inorganic acids e.g. hydrochloride, hydrobromide,
sulfate, phosphate, nitrate; salts of organic acids e.g. acetate,
trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate,
citrate, benzoate, methanesulfonate, ethanesulfonate,
benzenesulfonate, toluenesulfonate, isethionate, glucuronate,
gluconate.
[0152] The compounds of the present invention and salts thereof may
be converted into the corresponding hydrates by conventional
means.
[0153] Furthermore, the prodrugs of the present invention means the
compounds that --CONHOH group of the formula (I) is converted to
6
[0154] (wherein, R.sup.14 is C1-8 alkyl substituted by C1-8 alkyl
or C1-8 alkoxy) or 7
[0155] Among the compounds of the present invention, preferred ring
A is C3-10 mono-, bi-carbocyclic ring or 5-10 membered mono-,
bi-cyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen
atom(s) and/or 1-2 sulfur atom(s). Especially, C5-7
mono-carbocyclic ring or 5-10 membered mono-, bi-cyclic hetero ring
containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2
sulfur atom(s) is preferable. Benzene, cyclohexane, benzoxazole,
benzothiazole, benzimidazole, benzothiophene or benzofuran is more
preferable.
[0156] Preferred R.sup.1 is (1) C1-8 alkyl, (2) --OR.sup.2, (3)
--SR.sup.2, (4) halogen, (5) Cyc1, (6) --NR.sup.3R.sup.4 or (7)
C1-8 alkyl substituted by --OR.sup.2, --SR.sup.2, halogen, Cyc1,
--NR.sup.3R.sup.4. Especially, (1) C1-8 alkyl, (2) C1-8 alkoxy, (3)
C1-8 alkylthio, (4) halogen, (5) 5-7 membered mono-cyclic hetero
ring containing 14 nitrogen atom(s), one oxygen atom and/or one
sulfur atom, (6) di(C1-8 alkyl)amino or (7) C1-8 alkyl substituted
by C1-8 alkoxy, C1-8 alkylthio, halogen, 5-7 membered mono-cyclic
hetero ring, di(C1-8 alkyl)amino is preferable. Methyl, methoxy,
methylthio, chloride, dimethylamino, dipropylamino, morpholine,
piperidine, piperazine, methoxymethyl, methylthiomethyl,
dimethylaminomethyl, dipropylaminomethyl, morpholine-1-ylmethyl,
piperidine-1-ylmethyl or piperazine-1-ylmethyl is more
preferable.
[0157] Preferred stereoisomer of hydroxy group is R configuration,
S configuration or mixture thereof. Especially, R or S
configuration is preferable. S configuration is more
preferable.
[0158] Preferred E is, preferably, a bond, --CH.dbd.CH-- or
--C.ident.C-- and a bond or --C.ident.C-- is preferable.
[0159] Preferred B ring is C1-5 mono- or bi-carbocyclic aryl or
5-15 membered mono- or bi-cyclic hetero aryl. Especially, benzene,
naphthalene, pyridine, thiophene, benzofuran or benzoxazole is
preferable.
[0160] Preferred R.sup.8 is C1-4 alkyl. Especially, methyl is
preferable.
[0161] Preferred R.sup.9 is hydrogen, C1-4 alkyl, C2-4 alkenyl or
C24 alkynyl. Especially, hydrogen, methyl or allyl is
preferable.
[0162] Preferred m is 0 or an integer of 1-5. Especially, 0 or 1 is
preferable.
[0163] Preferred n is 0 or an integer of 1-5. Especially, 0 or 1 is
preferable.
[0164] In the present invention, preferred compounds are compounds
prepared in example hereinafter, shown in the following table 1 to
7 and salts thereof etc.
1TABLE 1 (I-1) 8 No. 9 1 10 2 11 3 12 4 13 5 14 6 15 7 16 8 17 9 18
10 19 11 20 12 21 13 22 14 23 15 24 16 25 17 26 18 27
[0165]
2TABLE 2 (I-1) 28 No. 29 1 30 2 31 3 32 4 33 5 34 6 35 7 36 8 37 9
38 10 39 11 40 12 41 13 42 14 43 15 44 16 45 17 46 18 47 19 48 20
49
[0166]
3TABLE 3 (I-1) 50 No. 51 1 52 2 53 3 54 4 55 5 56 6 57 7 58 8 59 9
60 10 61 11 62 12 63
[0167]
4TABLE 4 (I-2) 64 No. 65 66 1 67 68 2 69 70 3 71 72 4 73 74 5 75 76
6 77 78 7 79 80 8 81 82
[0168]
5TABLE 5 (I-3) 83 No. R.sup.1 1 84 2 85 3 86 4 87 5 88 6 89 7 90 8
3-CH.sub.2--N(CH.sub.3).sub.2 9 2-CH.sub.2--N(CH.sub.3).sub.2 10
4-(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 11
3-(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 12
2-(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 13
3-CH.sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 14
2-CH.sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 15
4-O--(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 16
4-S--(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 17
4-O--(CH.sub.2).sub.2--N(CH.sub.3).sub.2 18
4-S--(CH.sub.2).sub.2--N(CH.sub.3).sub.2
[0169]
6TABLE 6 (I-4) 91 No. R.sup.1 1 92 2 93 3 94 4 95 5 96 6 97 7 98 8
99 9 100 10 4-CH.sub.2--N(CH.sub.3).sub.2 11
3-CH.sub.2--N(CH.sub.3).sub.2 12 2-CH.sub.2--N(CH.sub.3).sub.2 13
4-(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 14
3-(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 15
2-(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 16
4-CH.sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 17
3-CH.sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 18
2-CH.sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 19
4-O--(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 20
4-S--(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 21
4-O--(CH.sub.2).sub.2--N(CH.sub.3).sub.2 22
4-S--(CH.sub.2).sub.2--N(CH.sub.3).sub.2
[0170]
7TABLE 7 (I-5) 101 No. R.sup.1 1 102 2 103 3 104 4 105 5 106 6 107
7 108 8 109 9 110 10 4-CH.sub.2--N(CH.sub.3).sub.2 11
3-CH.sub.2--N(CH.sub.3).sub.2 12 2-CH.sub.2--N(CH.sub.3).sub.2 13
4-(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 14
3-(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 15
2-(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 16
4-CH.sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 17
3-CH.sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 18
2-CH.sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 19
4-O--(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 20
4-S--(CH.sub.2).sub.2--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 21
4-O--(CH.sub.2).sub.2--N(CH.sub.3).sub.2 22
4-S--(CH.sub.2).sub.2--N(CH.sub.3).sub.2
[0171] [Methods for Preparation of the Compounds of the Present
Invention]
[0172] Hydroxamic acid derivatives of the formula (I) in the
present invention, non-toxic salts thereof and prodrugs thereof may
be prepared by the following methods or the methods described in
examples.
[0173] [1] Among the compounds of the present invention, the
prodrugs of the formula (IA) may be prepared by the following
methods of (a)-(c).
[0174] (a) Among the prodrugs of the formula (IA), the compounds in
which R.sup.1 doesn't represent a group containing amino, thiol and
carboxy, that is, the compounds of the formula (IA-a) 111
[0175] (wherein, R.sup.1-a has the same meaning as R.sup.1. With
the proviso that R.sup.1-a doesn't represent a group containing of
amino, thiol and carboxy and the other symbols have the same
meaning as defined hereinbefore.) may be prepared by amidation of
the compounds of the formula (II) 112
[0176] (wherein, all the symbols have the same meaning as defined
hereinbefore.) and the compounds of the formula (III)
H.sub.2N--OR.sup.14 (III)
[0177] (wherein, R.sup.14 has the same meaning as defined
hereinbefore.).
[0178] The amidation is known. For example, it may be carried
out
[0179] (1) by the method with using acid halide,
[0180] (2) by the method with using mixed acid anhydride,
[0181] (3) by the method with using conducing agent etc.
[0182] Concrete description of these methods are as follows:
[0183] (1) The method with acid halide may be carried out, for
example; carboxylic acid is reacted with an acid halide (oxalyl
chloride or thionyl chloride etc.) in an organic solvent
(chloroform, methylene chloride, diethyl ether or tetrahydrofuran
etc.) or without solvents at from -20.degree. C. to a refluxing
temperature to give an acid halide. The obtained acid halide and an
amine are reacted in an organic solvent (chloroform, methylene
chloride, diethyl ether or tetrahydrofuran etc.) in the presence of
tertiary amine (pyridine, triethylamine, dimethylaniline or
dimethylaminopyridine etc.), at 0-40.degree. C. Also this reaction
may be carried out by the reaction with amine and acid halide in an
organic solvent, (dioxane or tetrahydrofuran etc.), with an aqueous
alkali solution (solution of bicarbonate or solution of sodium
hydroxide etc.) at 0-40.degree. C.
[0184] (2) The method with mixed acid anhydride may be carried out,
for example; carboxylic acid is reacted with an acid halide
(pivaloyl chloride etc.) or an acid derivative (ethyl chloroformate
or isobutyl chloroformate etc.) in an organic solvent (chloroform,
methylene chloride, diethyl ether or tetrahydrofuran etc.) or
without solvents, in the presence of tertiary amine (pyridine,
triethylamine, dimethylaniline or dimethylaminopylidine etc.), at
0-40.degree. C. The mixed acid anhydride is reacted with an amine
in an organic solvent (chloroform, methylene chloride, diethyl
ether or tetrahydrofuran etc.) at 0-40.degree. C.
[0185] (3) The method with condensing agent may be carried out, for
example; a carboxylic acid and an amine are reacted in an organic
solvent (chloroform, methylene chloride, dimethylformamide, diethyl
ether or tetrahydrofuran etc.) or without solvents in the presence
or absence of tertiary amine (pyridine, triethylamine,
dimethylaniline or dimethylaminopyridine etc.) using with
condensing agent (1,3-dicyclohexylcarbodiimido (DCC),
1-ethyl-3-[3-(dimethylamino)propyl]c- arbodiimido (EDC),
1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridi- nium
iodide or 1-propanephosphonic acid cyclic anhydride (PPA) etc.)
using or without 1-hydroxybenzotriazole (HOBt) at 0-40.degree.
C.
[0186] Preferably, the above reactions (1), (2) and (3) are carried
out under an atmosphere of an inert gas (argon, nitrogen etc.) on
anhydrous condition.
[0187] (b) Among the prodrugs of the formula (IA), the above
compounds of the formula (IA-a) may be prepared by coupling
reaction with the compounds of the formula (IV) 113
[0188] (wherein, X is halogen and the other symbols have the same
meaning as defined hereinbefore.) and the compounds of the formula
(V) 114
[0189] (wherein all the symbols have the same meaning as defined
hereinbefore.) or the compounds of the formula (VI) 115
[0190] (wherein all the symbols have the same meaning as defined
hereinbefore.).
[0191] The reaction is known. For example, it may be carried out in
an organic solvent (benzene, dimethylformamide, dioxane,
tetrahydrofuran, methanol, acetonitrile, dimethoxyethane or acetone
etc.) in the presence of a base (sodium ethylate, sodium hydroxide,
potassium hydroxide, triethylamine, sodium carbonate, sodium
hydrogen carbonate, potassium carbonate, cesium carbonate, thallium
carbonate, tripotassium phosphate, cesium fluoride, barium
hydroxide or tetrabutylammonium fluoride etc. ) and a catalyst
(tetrakis(triphenylphosphine)palladium (Pd(PPh.sub.3).sub.4),
dichlorobis(triphenylphosphine)palladium
(PdCl.sub.2(PPh.sub.3).sub.2), palladium acetate (Pd(OAc).sub.2),
palladium black, 1,1-bis(diphenylphosphinoferrocene)dichloro
palladium (PdCl.sub.2(dppf).sub.2), dichlorodiallylpalladium
(PdCl.sub.2(allyl).sub.2) or
iodephenylbis(triphenylphosphine)palladium (PhPdl(PPh.sub.3).sub.2)
etc.) at room temperature -120.degree. C.
[0192] (c) Among the prodrugs of the formula (IA), the compounds in
which R.sup.1 is a group containing at least one of amino, thiol or
carboxy, i.e., the compounds of the formula (IA-c) 116
[0193] (wherein, R.sup.1-c is a group containing at least one of
amino, thiol or carboxy and the other symbols have the same meaning
as defined hereinbefore.) may be prepared by the removal of a
protecting group in the compounds of the formula (IA-a) in which
amino, thiol or carboxy is protected by a protecting group, i.e.,
the compounds (IA-a1) 117
[0194] (wherein, R.sup.1-a1 is a group containing at least one of
protected amino, protected thiol or protected carboxy and the other
symbols have the same meaning as defined hereinbefore.).
[0195] A protecting group of amino includes, for example,
benzyloxycarbonyl, allyloxycarbonyl, t-butoxycarbonyl,
trifluoroacetyl or 9-fluorenylmethoxycarbonyl.
[0196] A protecting group of thiol includes, for example, benzyl,
methoxybenzyl, acetoamidemethyl, triphenylmethyl or acetyl.
[0197] A protecting group of carboxy includes, for example, methyl,
ethyl, t-butyl, benzyl or allyl.
[0198] The protecting group of amino, thiol or carboxy includes the
above one, in addition, the other protecting group which is
removable selectively and easily, for example, one described in T.
W. Greene et. al., Protective Groups in Organic Synthesis, Third
Edition, Wiley-Interscience, New York, 1999
[0199] The removal of a protecting group of amino, thiol or carboxy
is well known. For example, it is
[0200] (1) the removal of a protecting group in an alkaline
condition,
[0201] (2) the removal of a protecting group in an acidic
condition,
[0202] (3) the removal of a protecting group by hydrogenelysis,
or
[0203] (4) the removal of a protecting group using metal complex
etc.
[0204] Concrete description of these methods are as follows:
[0205] (1) The removal of protecting group in an alkaline condition
may be carried out, for example, in an organic solvent (methanol,
tetrahydrofuran or dioxane etc.) with hydroxide of alkaline metal
(sodium hydroxide, potassium hydroxide or lithium hydroxide etc.),
hydroxide of alkaline earth metal (barium hydroxide or calcium
hydroxide etc.), carbonate (sodium carbonate or potassium carbonate
etc.), or an aqueous solution thereof or a mixture thereof at
040.degree. C.
[0206] (2) The removal of protecting group in an acidic condition
may be carried out, for example, in an organic solvent
(dichloromethane, chloroform, dioxane, ethyl acetate or anisole
etc.), organic acid (acetic acid, trifluoroacetic acid or
methanesulfonic acid) or inorganic acid (hydrochloric acid or
sulfuric acid etc.), or a mixture thereof (hydrogen bromide/acetic
acid etc.) at 0-100.degree. C.
[0207] (3) The removal of a protecting group by hydrogenelysis may
be carried out, for example, in a solvent (ether (tetrahydrofuran,
dioxane, dimethoxyethane or diethylether etc.), alcohol(methanol or
ethanol etc.), benzene(benzene or toluene etc.), ketone (acetone or
methylethylketoneetc.), nitrile (acetonitrileetc.), amido
(dimethylformamide etc.), water, ethyl acetate, acetic acid or a
mixture thereof etc.) in the presence of a catalyst
(palladium-carbon, palladium black, palladium hydroxide, platinum
oxide, raney nickel etc.), at atmospheric or reduced pressure under
an atmosphere of hydrogen or ammonium formate at 0-200.degree.
C.
[0208] (4) The removal of a protecting group using metal complex
may be carried out, for example, in an organic solvent
(dichloromethane, dimethylformamide or tetrahydrofuran etc.) in the
presence of a trap reagent (tributyltin hydride or dimedone etc.)
and/or an organic acid (acetic acid etc.) with metal complex
(tetrakis(triphenylphosphine)pallad- ium(O) complex etc.) at
0-40.degree. C.
[0209] As well known to the person in the art, the aimed compounds
of present invention may be prepared easily by choice of these
reaction.
[0210] [2] Among the compounds of the present invention, hydroxamic
acid derivatives of the formula (I) may be prepared by the method
of (d) or (e).
[0211] (d) Among hydroxamic acid derivatives of the formula (I),
the compound wherein R.sup.1 doesn't represent a group containing
amino, thiol or carboxy, i.e., the compound of the formula (I-d)
118
[0212] (wherein, all the symbols have the same meaning as defined
hereinbefore.) may be prepared by the amidation with the compound
of the above formula (II) and hydroxyamine (H.sub.2N--OH).
[0213] The amidation may be carried out by the same procedure as
described hereinbefore.
[0214] (e) Hydroxamic acid derivatives of the formula (I) may be
prepared by the removal of a protecting group of the compounds of
the above formula (IA).
[0215] The removal of a protecting group of the hydroxamic acid is
known. For example, it is
[0216] (1) the removal of a protecting group in an alkaline
condition,
[0217] (2) the removal of a protecting group in an acidic
condition, or
[0218] (3) the removal of a protecting group by hydrogenelysis
etc.
[0219] The removal of a protecting group may be carried out by the
same procedure as described hereinbefore.
[0220] The reaction of the removal of a protecting group of
hydroxamic acid in the present invention means an ordinal one which
is well known to the person in the art, for example, the removal of
a protecting group in an alkaline condition, the removal of a
protecting group in an acidic condition or the removal of a
protecting group by hydrogenelysis. The aimed compounds of the
present invention may be prepared easily by choice of these
reaction.
[0221] As well known to the person in the art, a protecting group
of hydroxamic acid includes, for example, t-butyl,
--C(CH.sub.3).sub.2--OCH.- sub.3 and benzyl. In addition, such a
group includes the other protecting group which is removable
selectively and easily, for example, one described in T. W. Greene
et. al., Protective Groups in Organic Synthesis, Third Edition,
Wiley-Interscience, New York, 1999.
[0222] [3] Among the compounds of the present invention, the
prodrugs of the formula (IB) may be prepared by the removal of the
methanol in the compounds of the formula (IA) wherein R.sup.14 is
1-methoxy-1-methylethyl- , i.e., the compounds of the formula
(IA-3) 119
[0223] (wherein, all the symbols have the same meaning as defined
hereinbefore.).
[0224] The reaction of the removal of methanol is known. For
example, it may be carried out in an organic solvent (benzene,
toluene, dioxane or pyridine etc.) at 60-150.degree. C.
[0225] The compounds of the formula (II) and (IV) are known per se
or may be prepared according to the following Reaction Scheme 1 and
Reaction Scheme 2 or by known methods easily. 120 121
[0226] In reaction scheme,
[0227] R.sup.101 is C1-4 alkyl or
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.s- ub.3,
[0228] R.sup.1-a, R.sup.8, R.sup.9, R.sup.14, ring A, ring B, E, m,
n or X have the same meaning as defined hereinbefore.
[0229] In above reaction schemes, each reaction may be carried out
by each conventional technique. Further, in above reaction scheme,
the compounds of the formula (X), (XIV), (III), (V) and (VI) used
as starting materials have been known per se or may be prepared by
known methods easily.
[0230] In each reaction in the present specification, obtained
products may be purified by conventional techniques. For example,
purification may be carried out by distillation at atmospheric or
reduced pressure, by high performance liquid chromatography, by
thin layer chromatography or by column chromatography using silica
gel or magnesium silicate, by washing or by recrystallization.
Purification may be carried out after each reaction, or after a
series of reactions.
[0231] The other starting materials and each test compounds in the
present invention have been known per se or may be prepared by
known methods.
[0232] [Pharmacological Activities of the Compounds of the Present
Invention]
[0233] According to following experiments, it is confirmed that the
compound of the present invention has an inhibitory activity on
IL-6 production.
(1) The measurement of an Inhibitory Activity on IL-6 Production
from A549 Cells
[0234] [Method]
[0235] 1.5.times.10.sup.4 of A549 cells (human lung epithelial cell
line) were suspended in 100 .mu.L of Dulbecco's Modified Eagle
Medium (DMEM) containing 0.5% fetal bovine serum (abbreviated as
FBS) and incubated for a day and night in 96 well-microplate. 20
.mu.L of the test compound dissolved in dimethylsulfoxide (DMSO) at
various concentrations and 80 .mu.L of tumor necrosis
factor-.alpha. (TNF.alpha. (Genzyme Co., cat. No. TNF-H)) dissolved
in serum-free DMEM at the concentration of 12.5 ng/mL were added
thereto. After the incubation for 24 hours, the supernatant (100
.mu.L) was collected to measure the amount of IL-6 being produced
using enzyme linked immuno solvent assay (ELISA) (R&D Systems
Co., cat. No. D6050). Then the inhibitory activity of the test
compound was calculated and the 50% inhibitory concentration
(IC.sub.50) was determined. For example, the IC.sub.50 value of the
compound of example 3 was 0.052 .mu.M.
(2) The Measurement of an Inhibitory Activity on IL-6 Production
from Human Synovial Cells
[0236] [Method]
[0237] 3.0.times.10.sup.3 of synovial cells from rheumatoid
arthritis patients were suspended in 200 .mu.L of DMEM containing
10% FBS and incubated for a day and night in 96 well-microplate,
followed by the incubation for 5 hours in serum-free DMEM. 20 .mu.L
of the test compound dissolved in DMSO at various concentrations
and 80 .mu.L of interleukin-1.beta. (IL-1.beta. (Genzyme Co., cat.
No. 80-3688-01)). dissolved in DMEM containing 2.5% fetal bovine
serum at the concentration of 5 ng/mL were added thereto. After the
incubation for 24 hours, the supernatant (100 .mu.L) was collected
to measure the amount of IL-6 being produced using ELISA (R&D
Systems Co., cat. No. D6050). Then the inhibitory activity of the
test compound was calculated and the 50% inhibitory concentration
(IC.sub.50) was determined. For example, the IC.sub.50 value of the
compound of example 3 was 0.041 .mu.M.
(3) The Effect on Collagen-induced Arthritis Model in Rats
[0238] [Method]
[0239] Eight weeks old female DA rats were used. During the
experimental period, they were housed in animal room artificially
kept the room temperature of 24.+-.2.degree. C., humidity of
55.+-.5%, and 12 hours interval of light and dark cycle. They had
free access to a standard solid pellet chow (CE-2, Japan CLEA) and
drinking tap water, and were used for the experiment after a week
acclimation. The collagen-induced arthritis was performed by the
following method. After the mixing of bovine type II collagen (0.3%
collagen solution, KOKEN #K-41, lot.11214, abbreviated as CII),
incomplete Freund's adjuvant (DIFCO #0639-60) and saline with the
ratio of 1:2:1, the mixture was then ultra-sonicated to form
emulsion for 20 seconds.times.3 times at 1 minute interval. The
intradermal injection of 0.1 mL of the emulsion (0.75mg of CII/mL)
was performed on each four different portions of the back on day 0.
A week after the first immunization, arthritis was elicited by the
intradermal injection of 0.15 mL of the emulsion at the basal
portion of the tail. The test compound was suspended in 0.5%
carboxymethylcellulose solution, and was administered orally in the
morning and evening twice a day from day 0 to day 28. According to
the method of Osterman T et al. (Inflamm. Res., 44, 258-263, 1995),
the severity of arthritis was judged and scored. The hind paw
volume of each animal was also measured with the plethysmometer
(UNICOM, TK-101CMP). For example, 10 mg/kg/day (b.i.d.) of the
compound of the example 3 completely inhibited the development of
arthritis, and the example 3 even at the dose of 3 mg/kg/day showed
significant inhibition by approximately 60% on the arthritis score
and the hind paw edema.
[0240] [Toxicity]
[0241] The toxicity of the compounds of formula (I) of the present
invention, non-toxic salts thereof or prodrugs thereof is very low
and therefore the compounds may be considered safe for
pharmaceutical use.
[0242] [Application for Pharmaceuticals]
[0243] The compounds of the present invention possess an inhibitory
activity of IL-6 production in animal, especially human, so they
are useful for the prevention and/or treatment of, for example,
various inflammatory diseases, sepsis, multiple myeloma, plasma
cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal
cell carcinoma, Kaposi's sarcoma, rheumatoid arthritis,
hypergammaglobulinemia , Castleman's disease, atrial myxoma,
diabetes mellitus, autoimmne diseases, hepatitis, colitis, graft
versus host disease, infectious diseases and endometriosis.
[0244] For the purpose above described, the compounds of formula
(I), non-toxic salts thereof or prodrugs thereof may be normally
administered systemically or locally, usually by oral or parenteral
administration.
[0245] The doses to be administered are determined depending upon,
for example, age, body weight, symptom, the desired therapeutic
effect, the route of administration, and the duration of the
treatment. In the human adult, the doses per person are generally
from 1 mg to 1000 mg, by oral administration, up to several times
per day, and from 0.1 mg to 100 mg, by parenteral administration
(preferably intravenous administration), up to several times per
day, or continuous administration from 1 to 24 hours per day from
vein.
[0246] As mentioned above, the doses to be used depend upon various
conditions. Therefore, there are cases in which doses lower than or
greater than the ranges specified above may be used.
[0247] The compounds of the present invention may be administered
in the form of, for example, solid forms for oral administration,
liquid forms for oral administration, injections, liniments or
suppositories for parenteral administration.
[0248] Solid forms for oral administration include compressed
tablets, pills, capsules, dispersible powders, and granules.
Capsules include hard capsules and soft capsules.
[0249] In such solid forms, one or more of the active compound(s)
may be admixed with vehicles (such as lactose, mannitol, glucose,
microcrystalline cellulose, starch), binders (such as hydroxypropyl
cellulose, polyvinylpyrrolidone or magnesium metasilicate
aluminate), disintegrants (such as cellulose calcium glycolate),
lubricants (such as magnesium stearate), stabilizing agents, and
solution adjuvants (such as glutamic acid or aspartic acid) and
prepared according to methods well known in normal pharmaceutical
practice. The solid forms may, if desired, be coated with coating
agents (such as sugar, gelatin, hydroxypropyl cellulose or
hydroxypropylmethyl cellulose phthalate), or be coated with two or
more films. And further, coating may include containment within
capsules of absorbable materials such as gelatin.
[0250] Liquid forms for oral administration include
pharmaceutically acceptable solutions, suspensions and emulsions,
syrups and elixirs. In such forms, one or more of the active
compound(s) may be dissolved, suspended or emulized into diluent(s)
commonly used in the art (such as purified water, ethanol or a
mixture thereof). Furthermore, such liquid forms may also comprise
some additives, such as wetting agents, suspending agents,
emulsifying agents, sweetening agents, flavoring agents, aroma,
preservative or buffering agent.
[0251] Injections for parenteral administration include sterile
aqueous, suspensions, emulsions and solid forms which are dissolved
or suspended into solvent(s) for injection immediately before use.
In injections, one or more of the active compound(s) may be
dissolved, suspended or emulized into solvent(s). The solvents may
include distilled water for injection, physiological salt solution,
vegetable oil, propylene glycol, polyethylene glycol, alcohol, e.g.
ethanol, or a mixture thereof. Injections may comprise some
additives, such as stabilizing agents, solution adjuvants (such as
glutamic acid, aspartic acid or POLYSORBATE80 (registered trade
mark)), suspending agents, emulsifying agents, soothing agent,
buffering agents, preservative. They may be sterilized at a final
step, or may be prepared and compensated according to sterile
methods. They may also be manufactured in the form of sterile solid
forms such as freeze-dried products, which may be dissolved in
sterile water or some other sterile diluent(s) for injection
immediately before use.
[0252] Other forms for parenteral administration include liquids
for external use, ointments and endermic liniments, inhalations,
sprays, suppositories and pessaries for vaginal administration
which comprise one or more of the active compound(s) and may be
prepared by methods known per se.
[0253] Sprays may comprise additional substances other than
diluents, such as stabilizing agents (such as sodium sulfate),
isotonic buffers (such as sodium chloride, sodium citrate or citric
acid). For preparation of such sprays, for example, the method
described in the U.S. Pat. Nos. 2,868,691 or 3,095,355 may be
used.
The Best Mode for Carrying Out the Invention
[0254] The following reference examples and examples are intended
to illustrate the present invention, but do not limit them.
[0255] In chromatographic separations and TLC, the solvents in
parenthesis show the eluting and developing solvents and the ratios
of the solvents used are by volume.
[0256] The solvents in parenthesis in NMR show the solvents used
for measurement.
REFERENCE EXAMPLE 1
Ethyl 6-(4-(4-chlorophenyl)phenyl)-6-oxohexanoate
[0257] 122
[0258] To adipic acid mono ethyl ester (34.8 g) was added thionyl
chloride (72 mL). The reaction mixture was stirred at 100.degree.
C. for 1.5 hours. The reaction mixture was concentrated to give
adipinyl chloride mono ethyl ester. To a suspension of aluminium
chloride (53.3 g) in dichloromethane (500 mL) was added
4-chlorobiphenyl (37.7 g) at 5.degree. C. The reaction mixture was
stirred for 15 minutes and a solution of adipinyl chloride mono
ethyl ester in dichloromethane (200 mL) was added thereto at
5.degree. C. The reaction mixture was stirred at room temperature
for 2 hours. To the reaction mixture was added ice water and the
mixture was extracted with dichloromethane. The extract was washed
with water, a saturated aqueous solution of sodium hydrogen
carbonate and a saturated aqueous solution of sodium chloride,
dried over anhydrous magnesium sulfate, and concentrated. The
obtained residue was recrystallized from hexane/ethyl acetate and
dried to give the title compound (53.8 g) having the following
physical data.
[0259] TLC: Rf 0.60 (chloroform),
[0260] NMR (CDCl.sub.3): .delta. 8.04 (d, J=8.8 Hz, 2H), 7.64 (d,
J=8.8 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 4.14
(q, J=7.2 Hz, 2H), 3.03 (t, J=6.6 Hz, 2H), 2.38 (t, J=7.0 Hz, 2H),
1.95-1.60 (m, 4H), 1.26 (t, J=7.2 Hz, 3H).
REFERENCE EXAMPLE 2
Ethyl 6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanoate
[0261] 123
[0262] To a mixture solution of the compound prepared in reference
example 1 (10.02 g) in dichloromethane (300 mL) and methanol (100
mL) was added sodium borohydride (5.4 g) at 0.degree. C. The
reaction mixture was stirred at room temperature for 2 hours. The
reaction mixture was poured into a saturated aqueous solution of
ammonium chloride and extracted with dichloromethane. The extract
was washed with a saturated aqueous solution of sodium chloride,
dried over anhydrous sodium sulfate, and concentrated to give the
title compound (10.03 g) having the following physical data.
[0263] TLC: Rf 0.25 (chloroform),
[0264] NMR (CDCl.sub.3): .delta. 7.65-7.34 (m, 8H), 4.73 (t, J=6.2
Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 2.03 (t, J=7.0 Hz, 2H), 1.90-1.30
(m, 6H), 1.23 (t, J=7.0 Hz, 3H).
REFERENCE EXAMPLE 3
6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanoic acid
[0265] 124
[0266] To a solution of the compound prepared in reference example
2 (10.03 g) in ethanol (100 mL) was added 2N aqueous solution of
sodium hydroxide (50 mL). The reaction mixture was stirred at
60.degree. C. for 1 hour. To the reaction mixture was added 1N
aqueous solution of hydrochloric acid and the mixture was extracted
with ethyl acetate. The extract was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium sulfate,
and concentrated. The obtained residue was recrystallized from
isopropylalcohol and dried to give the title compound (9.12 g)
having the following physical data.
[0267] TLC: Rf 0.52 (chloroform:tetrahydrofuran:acetic
acid=10:4:1),
[0268] NMR(d.sub.6-DMSO): .delta. 11.80 (brs, 1H), 7.68 (d, J=8 Hz,
2H), 7.61 (d, J=8 Hz, 2H), 7.49 (d, J=8 Hz, 2H), 7.40 (d, J=8 Hz,
2H), 5.16 (brs, 1H), 4.65-4.40 (m, 1H), 2.18 (t, J=7 Hz, 2H),
1.80-1.05 (m, 6H).
EXAMPLE 1
N-(1-methoxy-1-methyl)ethoxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanam-
ide
[0269] 125
[0270] Under an atmosphere of argon, to a solution of the compound
prepared in reference example 3 (7.74 g) in dimethylformamide (150
mL) was added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (6.99
g), 1-hydroxybenzotriazol (5.58 g),
(1-methoxy-1-methylethyl)hydroxyamine (8.0 g) and triethylamine
(15.5 mL). The reaction mixture was stirred at room temperature
overnight. The reaction mixture was poured into ice water and
extracted with ethyl acetate. The extract was washed with a
saturated aqueous solution of sodium hydrogen carbonate and a
saturated aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate, and concentrated. The obtained residue was purified
by column chromatography on silica gel (ethyl
acetate:hexane:triethylamine=80:20:1) to give the compound of the
present invention (8.1 g) having the following physical data.
[0271] TLC: Rf 0.50 (ethyl acetate:methanol=20:1),
[0272] NMR(CDCl.sub.3): .delta. 7.73 (brs, 1H), 7.60-7.35 (m, 8H),
4.74 (t, J=6 Hz, 1H), 3.31 (s, 3H), 2.50-1.15 (m, 8H), 1.41 (s,
6H).
EXAMPLE 2
N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide
[0273] 126
[0274] To a solution of the compound prepared in example 1 (7.27 g)
in methanol (100 mL) was added concentrated hydrochloric acid (2.0
mL). The reaction mixture was stirred at room temperature for 30
minutes. The reaction mixture was concentrated and distilled off an
azetropic mixture with ethanol. To the obtained residue was added
ethyl acetate and the precipitated crystal was filtered and dried
to give the compound of the present invention (5.55 g) having the
following physical data.
[0275] TLC: Rf 0.21 (chloroform:methanol:acetic acid=10:1:1),
[0276] NMR(d.sub.6-DMSO): .delta. 10.31 (s, 1H), 8.64 (s, 1H), 7.68
(d, J=8.8 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H),
7.40 (d, J=8.4 Hz, 2H), 5.15 (d, J=4.4 Hz, 1H), 4.54 (m, 1H), 1.93
(t, J=7.3 Hz, 2H), 1.70-1.40 (m, 4H), 1.40-1.10 (m, 2H).
EXAMPLE 2(1)-2(5)
[0277] By the same procedure as a series of reactions of reference
example 1.fwdarw.reference example 2.fwdarw.reference example
3.fwdarw.example 1.fwdarw.example 2 using a corresponding benzene
derivative instead of 4-chlorobiphenyl, the following compounds of
the present invention were obtained.
EXAMPLE 2(1)
N-hydroxy-6-(4-biphenyl)-6-hydroxyhexanamide
[0278] 127
[0279] TLC: Rf 0.42 (ethyl acetate:methanol=39:1),
[0280] NMR(d.sub.6-DMSO): .delta. 10.29 (brs, 1H), 8.64 (brs, 1H),
7.66-7.58 (m, 4H), 7.47-7.30 (m, 5H), 5.18-5.09 (m, 1H), 4.57-4.55
(m, 1H), 1.91 (t, J=7.5 Hz, 2H), 1.64-1.44 (m, 4H), 1.40-1.20 (m,
2H).
EXAMPLE 2(2)
N-hydroxy-6-(4-cyclohexylphenyl)-6-hydroxyhexanamide
[0281] 128
[0282] TLC: Rf 0.32 (ethyl acetate),
[0283] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H), 7.19
(d, J=7.8 Hz, 2H), 7.12 (d, J=7.8 Hz, 2H), 4.98 (d, J=4.5 Hz, 1H),
4.40-4.38 (m, 1H), 2.48-2.40 (m, 1H), 1.89 (t, J=7.5 Hz, 2H),
1.81-1.12 (m, 16H).
EXAMPLE 2(3)
N-hydroxy-6-(4-(4-methylphenyl)phenyl)-6-hydroxyhexanamide
[0284] 129
[0285] TLC: Rf 0.43 (ethyl acetate),
[0286] NMR(d.sub.6-DMSO): .delta. 10.29 (brs, 1H), 8.62 (d, J=1.5
Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.36 (d,
J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 5.11 (d, J=4.5 Hz, 1H),
4.54-4.48 (m, 1H), 2.33 (s, 3H), 1.91 (t, J=7.5 Hz, 2H), 1.63-1.16
(m, 6H).
EXAMPLE 2(4)
N-hydroxy-6-(4-(4-methoxyphenyl)phenyl)-6-hydroxyhexanamide
[0287] 130
[0288] TLC: Rf 0.27 (chloroform:methanol:acetic acid=90:10:1),
[0289] NMR(d.sub.6-DMSO): .delta. 10.29 (brs, 1H), 8.63 (d, J=1.5
Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.34 (d,
J=8.1 Hz, 2H), 7.00 (d, J=8.1 Hz, 2H), 5.10 (d, J=4.5 Hz, 1H),
4.53-4.47 (m, 1H), 3.78 (s, 3H), 1.91 (t, J=7.2 Hz, 2H), 1.66-1.55
(m, 6H).
EXAMPLE 2(5)
N-hydroxy-6-(4-(trans-4-propylcycrohexyl)phenyl)-6-hydroxyhexanamide
[0290] 131
[0291] TLC: Rf 0.16 (ethyl acetate),
[0292] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H), 7.20
(d, J=8.5 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H), 4.98 (d, J=4.4 Hz, 1H),
4.43 (m, 1H), 2.41 (m, 1H), 2.00-0.90 (m, 21H), 0.88 (t, J=7.0 Hz,
3H).
REFERENCE EXAMPLE 4
Ethyl (R)-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanoate
[0293] 132
[0294] To a solution of the compound prepared in reference example
1 (17.2 g) in tetrahydrofuran (1500 mL) was added a solution of
1.0M (S)-2-methyl-oxazaborolidine in toluene (5 mL) at room
temperature. The reaction mixture was cooled to -15.degree. C. and
a solution of 2.0M borane-dimethylsulfide complex in
tetrahydrofuran (21.3 mL) was added thereto. The reaction mixture
was stirred at room temperature for 3 hours. To the reaction
mixture was added methanol and the mixture was stirred over night.
The reaction mixture was concentrated, diluted with ethyl acetate,
washed with water and a saturated aqueous solution of sodium
chloride, dried over magnesium sulfate, and concentrated. The
obtained residue was purified by column chromatography on silica
gel (hexane: ethyl acetate=1:1) to give the title compound (17 g,
94.2% e.e., HPLC) having the following physical data.
[0295] TLC: Rf 0.25 (chloroform),
[0296] HPLC: 13.7 min (retention time), Column: DAICEL CHIRAL CEL
AD-RH, 4.6.times.150 mm; Eluant: acetonitrile:water=75:25; UV: 260
nm; Flow rate: 1.0 mL/min.
REFERENCE EXAMPLE 5
Ethyl (S)-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanoate
[0297] 133
[0298] By the same procedure as a series of reactions of reference
example 4 using a solution of 1.0M (R)-2-methyl-oxazaborolidine in
toluene instead of a solution of 1.0M (S)-2-methyl-oxazaborolidine
in toluene , the title compound (91% e.e., HPLC) having the
following physical data was obtained.
[0299] TLC: Rf 0.25 (chloroform),
[0300] HPLC: 9.8 min (retention time), Column: DAICEL CHIRAL CEL
AD-RH, 4.6.times.150 mm; Eluant: acetonitrile:water=75:25; UV: 260
nm; Flow rate: 1.0 mL/min.
EXAMPLE 3
(R)-(+)-N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide
[0301] 134
[0302] By the same procedure as a series of reactions of reference
example 3.fwdarw.example 1.fwdarw.example 2 using the compound
prepared in reference example 4 instead of the compound prepared in
reference example 2, the compound of the present invention (98.7%
e.e., HPLC) having the following physical data was obtained.
[0303] TLC: Rf 0.21 (chloroform:methanol:acetic acid=10:1:1),
[0304] [.alpha.].sub.D: +9.27 (c 0.280, methanol),
[0305] HPLC: 16.8 min (retention time), Column: DAICEL CHIRAL
CELAD-RH, 4.6.times.150 mm; Eluant: acetonitrile:water=35:65; UV:
260 nm; Flow rate: 1.0 mL/min.
EXAMPLE 3(1)
(S)-(-)-N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide
[0306] 135
[0307] By the same procedure as a series of reactions of example 3
using the compound prepared in reference example 5 instead of the
compound prepared in reference example 4, the compound of the
present invention (>98% e.e., HPLC) having the following
physical data was obtained.
[0308] TLC: Rf 0.21 (chloroform:methanol:acetic acid=10:1:1),
[0309] [.alpha.].sub.D: -9.60 (c 0.265, methanol),
[0310] HPLC: 11.6 min (retention time), Column: DAICEL CHIRAL
CELAD-RH, 4.6.times.150 mm; Eluant: acetonitrile:water=35:65; UV:
260 nm; Flow rate: 1.0 mL/min.
REFERENCE EXAMPLE 6
N-(1-methoxy-1-methyl)ethoxy-6-(4-iodophenyl)-6-hydroxyhexanamide
[0311] 136
[0312] By the same procedure as a series of reactions of reference
example 1.fwdarw.reference example 2.fwdarw.reference example
3.fwdarw.example 1 using iodobenzene instead of 4-chlorobiphenyl,
the title compound having the following physical data was
obtained.
[0313] TLC: Rf 0.40 (ethyl acetate),
[0314] NMR(CDCl.sub.3): .delta. 7.69-7.63 (m, 3H), 7.08 (d, J=8.2
Hz, 2H), 4.64 (t, J=6.2 Hz, 1H), 3.31 (s, 3H), 2.42-1.21 (m, 8H),
1.41 (s, 6H).
EXAMPLE 4
N-(1-methoxy-1-methyl)ethoxy-6-(4-(benzofuran-2-yl)phenyl)-6-hydroxyhexana-
mide
[0315] 137
[0316] To a solution of the compound prepared in reference example
6 (440 mg) in dimethylformamide (10 mL) was added tri-potassium
phosphate (333 mg), tetrakis(triphenylphosphine)palladium (120 mg)
and benzofuran-2-boronic acid (400 mg). The reaction mixture was
stirred at 60.degree. C. for 2 hours. To the reaction mixture was
added water and the mixture was extracted with ethyl acetate. The
extract was washed with a saturated aqueous solution of sodium
chloride, dried over sodium sulfate and concentrated. The obtained
residue was purified by column chromatography on silica gel (ethyl
acetate:hexane=1:1.fwdarw.7:3.fwdarw.- 1:0) to give the compound of
the present invention (178 mg) having the following physical
data.
[0317] TLC: Rf 0.39 (ethyl acetate).
EXAMPLE 5
N-hydroxy-6-(4-(benzofuran-2-yl)phenyl)-6-hydroxyhexanamide
[0318] 138
[0319] By the same procedure as a series of reactions of example 2
using the compound prepared in example 4 instead of the compound
prepared in example 1, the compound of the present invention having
the following physical data was obtained.
[0320] TLC: Rf 0.29 (ethyl acetate),
[0321] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 7.85 (d, J=8.1 Hz,
2H), 7.65-7.59 (m, 2H), 7.42 (d, J=8.1 Hz, 2H), 7.37 (s, 1H),
7.32-7.21 (m, 2H), 4.58-4.51 (m, 1H), 1.90 (t, J=7.2 Hz, 2H),
1.62-1.14 (m, 6H).
EXAMPLE 5(1)-5(18)
[0322] By the same procedure as a series of reactions of example
4.fwdarw.example 5 using a corresponding boronic acid instead of
benzofuran-2-boronic acid, the following compounds of the present
invention were obtained.
EXAMPLE 5(1)
N-hydroxy-6-(4-(pyridin-4-yl)phenyl)-6-hydroxyhexanamide
[0323] 139
[0324] TLC: Rf 0.33 (chloroform:methanol:acetic acid=90:10:1),
[0325] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.63 (s, 1H), 8.61
(dd, J=4.8 Hz, 1.5 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.68 (dd, J=4.8
Hz, 1.5 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 5.21 (d, J=4.5 Hz, 1H),
4.58-4.52 (m, 1H), 1.91 (t, J=7.2 Hz, 2H), 1.64-1.14 (m, 6H).
EXAMPLE 5(2)
N-hydroxy-6-(4-(pyridin-3-yl)phenyl)-6-hydroxyhexanamide
[0326] 140
[0327] TLC: Rf 0.34 (chloroform:methanol:acetic acid=90:10:1),
[0328] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.86 (d, J=1.8 Hz,
1H), 8.62 (s, 1H), 8.54 (dd, J=4.8 Hz, 1.8 Hz, 1H), 8.06-8.02 (m,
1H), 7.65 (d, J=8.1 Hz, 2H), 7.48-7.43 (m, 1H), 7.42 (d, J=8.1 Hz,
2H), 5.17 (d, J=4.5 Hz, 1H), 4.56-4.50 (m, 1H), 1.90 (t, J=7.5 Hz,
2H), 1.63-1.18 (m, 6H).
EXAMPLE 5(3)
N-hydroxy-6-(4-(2-chlorophenyl)phenyl)-6-hydroxyhexanamide
[0329] 141
[0330] TLC: Rf 0.25 (ethyl acetate),
[0331] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H),
7.55-7.52 (m, 1H), 7.40-7.33 (m, 7H), 5.16 (d, J=4.5 Hz, 1H),
4.54-4.51 (m, 1H), 1.91 (t, J=6.9 Hz, 2H), 1.65-1.20 (m, 6H).
EXAMPLE 5(4)
N-hydroxy-6-(4-(3-chlorophenyl)phenyl)-6-hydroxyhexanamide
[0332] 142
[0333] TLC: Rf 0.23 (ethyl acetate),
[0334] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H), 7.68
(t, J=1.8 Hz, 1H), 7.63-7.60 (m, 3H), 7.46 (t, J=8.1 Hz, 1H),
7.40-7.37 (m, 3H), 5.16 (d, J=4.2 Hz, 1H), 4.54-4.50 (m, 1H), 1.90
(t, J=7.2 Hz, 2H), 1.63-1.20 (m, 6H).
EXAMPLE 5(5)
N-hydroxy-6-(4-(4-bromophenyl)phenyl)-6-hydroxyhexanamide
[0335] 143
[0336] TLC: Rf 0.35 (ethyl acetate:methanol=9:1),
[0337] NMR(d.sub.6-DMSO): .delta. 10.31 (s, 1H), 8.64 (s, 1H),
7.70-7.50 (m, 6H), 7.40 (d, J=8.4 Hz, 2H), 5.15 (d, J=4.5 Hz, 1H),
4.54 (m, 1H), 1.93 (t, J=7.2 Hz, 2H), 1.70-120 (m, 6H).
EXAMPLE 5(6)
N-hydroxy-6-(4-(thiophen-2-yl)phenyl)-6-hydroxyhexanamide
[0338] 144
[0339] TLC: Rf 0.26 (ethyl acetate),
[0340] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 8.62 (brs, 1H),
7.57 (d, J=8.7 Hz, 2H), 7.49 (dd, J=5.1 Hz, 1.2 Hz, 1H), 7.45 (dd,
J=3.6 Hz, 1.2 Hz, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.10 (dd, J=5.1 Hz,
3.6 Hz, 1H), 5.13 (d, J=4.5 Hz, 1H), 4.51-4.45 (m, 1H), 1.89 (t,
J=6.9 Hz, 2H), 1.60-1.15 (m, 6H).
EXAMPLE 5(7)
N-hydroxy-6-(4-(furan-2-yl)phenyl)-6-hydroxyhexanamide
[0341] 145
[0342] TLC: Rf 0.27 (ethyl acetate),
[0343] NMR(d.sub.6-DMSO): .delta. 10.28 (brs, 1H), 8.65 (brs, 1H),
7.70 (d, J=2.1 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz,
2H), 6.87 (d, J=3.6 Hz, 1H), 6.56 (dd, J=3.6 Hz, 2.1 Hz, 1H), 5.13
(d, J=4.5 Hz, 1H), 4.50-4.45 (m, 1H), 1.89 (t, J=7.2 Hz, 2H),
1.60-1.12 (m, 6H).
EXAMPLE 5(8)
N-hydroxy-6-(4-(1,3-dioxy-2,3-dihydroinden-5-yl)phenyl)-6-hydroxyhexanamid-
e
[0344] 146
[0345] TLC: Rf 0.22 (ethyl acetate),
[0346] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 8.62 (brs, 1H),
7.51 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 7.21 (d, J=1.8 Hz,
1H), 7.10 (dd, J=8.1 Hz, 1.8 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.03
(s, 2H), 5.10 (d, J=4.5 Hz, 1H), 4.52-4.47 (m, 1H), 1.90 (t, J=7.2
Hz, 2H), 1.60-1.12 (m, 6H).
EXAMPLE 5(9)
N-hydroxy-6-(4-(4-methylthiophenyl)phenyl)-6-hydroxyhexanamide
[0347] 147
[0348] TLC: Rf 0.27 (ethyl acetate),
[0349] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 8.62 (brs, 1H),
7.59 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz,
2H), 7.32 (d, J=8.4 Hz, 2H), 5.12 (d, J=4.2 Hz, 1H), 4.53-4.48 (m,
1H), 3.30 (s, 3H), 1.90 (t, J=7.2 Hz, 2H), 1.62-1.16 (m, 6H),
EXAMPLE 5(10)
N-hydroxy-6-(4-(naphthalen-1-yl)phenyl)-6-hydroxyhexanamide
[0350] 148
[0351] TLC: Rf 0.30 (ethyl acetate),
[0352] NMR(d.sub.6-DMSO): .delta. 10.31 (s, 1H), 8.64 (s, 1H),
7.99-7.91 (m, 2H), 7.80 (d, J=8.1 Hz, 1H), 7.58-7.39 (m, 8H), 5.19
(d, J=4.5 Hz, 1H), 4.61-4.55 (m, 1H), 1.94 (t, J=7.5 Hz, 2H),
1.68-1.23 (m, 6H).
EXAMPLE 5(11)
N-hydroxy-6-(4-(naphthalen-2-yl)phenyl)-6-hydroxyhexanamide
[0353] 149
[0354] TLC: Rf 0.27 (ethyl acetate),
[0355] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.27 (s, 1H), 8.19
(s, 1H), 7.99-7.90 (m, 3H), 7.83 (dd, J=8.1 Hz, 1.5 Hz, 1H), 7.75
(d, J=8.1 Hz, 2H), 7.55-7.47 (m, 2H), 7.43 (d, J=8.1 Hz, 2H), 5.16
(d, J=4.2 Hz, 1H), 4.60-4.51 (m, 1H), 1.91 (t, J=7.2 Hz, 2H),
1.66-1.20 (m, 6H).
EXAMPLE 5(12)
N-hydroxy-6-(4-(4-acetylphenyl)phenyl)-6-hydroxyhexanamide
[0356] 150
[0357] TLC: Rf 0.19 (chloroform:methanol:triethylamine=8:1:1),
[0358] NMR(d.sub.6-DMSO): .delta. 10.31 (s, 1H), 8.64 (s, 1H), 8.03
(d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H),
7.44 (d, J=8.4 HZ, 2H), 5.18 (d, J=4.5 Hz, 1H), 4.56 (m, 1H), 2.61
(s, 3H), 1.92 (t, J=7.8 Hz, 2H), 1.70-1.42 (m, 4H), 1.42-1.18 (m,
2H).
EXAMPLE 5(13)
N-hydroxy-6-(4-(4-hydroxyphenyl)phenyl)-6-hydroxyhexanamide
[0359] 151
[0360] TLC: Rf 0.23 (ethyl acetate),
[0361] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 9.47 (s, 1H), 8.62
(s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.31 (d,
J=8.4 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 5.07 (d, J=4.2 Hz, 1H),
4.51-4.45 (m, 1H), 1.90 (t, J=7.2 Hz, 2H), 1.62-1.17 (m, 6H).
EXAMPLE 5(14)
N-hydroxy-6-(4-(dibenzofuran4-yl)phenyl)-6-hydroxyhexanamide
[0362] 152
[0363] TLC: Rf 0.29 (ethyl acetate),
[0364] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.63 (s, 1H), 8.18
(d, J=7.2 Hz, 1H), 8.13 (dd, J=7.5 Hz, 1.2 Hz, 1H), 7.84 (d, J=8.1
Hz, 2H), 7.73 (d, J=7.2 Hz, 1H), 7.67 (dd, J=7.5 Hz, 1.2 Hz, 1H),
7.56-7.39 (m, 5H), 5.19 (d, J=4.2 Hz, 1H), 4.60-4.55 (m, 1H), 1.93
(t, J=7.2 Hz, 2H), 1.66-1.21 (m, 6H).
EXAMPLE 5(15)
N-hydroxy-6-(4-(2-methoxyphenyl)phenyl)-6-hydroxyhexanamide
[0365] 153
[0366] TLC: Rf 0.20 (chloroform:methanol:triethylamine=8:1:1),
[0367] NMR(d.sub.6-DMSO): .delta. 10.31 (s, 1H), 8.65 (s, 1H), 7.40
(d, J=8.4 Hz, 2H), 7.36-7.23 (m, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.10
(d, J=8.4 Hz, 1H), 7.02 (t, J=7.5 Hz, 1H), 5.11 (d, J=4.5 Hz, 1H),
4.51 (m, 1H), 3.76 (s, 3H), 1.93 (t, J=7.2 Hz, 2H), 1.68-1.15 (m,
6H).
EXAMPLE 5(16)
N-hydroxy-6-(4-(3-methoxyphenyl)phenyl)-6-hydroxyhexanamide
[0368] 154
[0369] TLC: Rf 0.20 (chloroform:methanol:triethylamine=8:1:1),
[0370] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.64 (s, 1H), 7.60
(d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 7.36 (t, J=8.1 Hz, 1H),
7.23-7.13 (m, 2H), 6.95-6.87 (m, 1H), 5.14 (d, J=4.2 Hz, 1H), 4.53
(m, 1H), 3.80 (s, 3H), 1.92 (t, J=7.2 Hz, 2H), 1.70-1.15 (m,
6H).
EXAMPLE 5(17)
N-hydroxy-6-(4-(4-trifluoromethylphenyl)phenyl)-6-hydroxyhexanamide
[0371] 155
[0372] TLC: Rf 0.20 (chloroform:methanol:triethylamine=8:1:1),
[0373] NMR(d.sub.6-DMSO): .delta. 10.31 (s, 1H), 8.65 (s, 1H), 7.89
(d, J=8.7 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H),
7.44 (d, J=8.7 Hz, 2H), 5.20 (d, J=4.2 Hz, 1H), 4.56 (m, 1H), 1.93
(t, J=7.5 Hz, 2H), 1.70-1.15 (m, 6H).
EXAMPLE 5(18)
N-hydroxy-6-(4-(4-t-butylphenyl)phenyl)-6-hydroxyhexanamide
[0374] 156
[0375] TLC: Rf 0.20 (chloroform:methanol:triethylamine=8:1:1),
[0376] NMR(d.sub.6-DMSO): .delta. 10.31 (s, 1H), 8.64 (s, 1H), 7.57
(d, J=8.4 Hz, 4H), 7.46 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H),
5.13 (d, J=4.2 Hz, 1H), 4.52 (m, 1H), 1.92 (t, J=7.2 Hz, 2H),
1.65-1.20 (m, 6H), 1.31 (s, 9H).
REFERENCE EXAMPLE 7
2-(2-methoxyethoxy)ethyl 6-(4-bromophenyl)-6-oxohexanoate
[0377] 157
[0378] To a solution of 6-(4-bromophenyl)-6-oxohexanoic acid (52 g)
in dichloromethane (200 mL) was added oxalyl chloride (32 mL). The
reaction mixture was stirred at 40.degree. C. for 3 hours. The
reaction mixture was concentrated. A solution of the obtained
residue in toluene (500 mL) was dropped to di(ethylene
glycol)methyl ether (65 mL) at 0.degree. C. The reaction mixture
was stirred at room temperature overnight and triethylamine (25 mL)
was dropped thereto at room temperature. The reaction mixture was
stirred at room temperature for 1 hour. The reaction mixture was
poured into water and extracted with ethyl acetate. The extract was
washed with water and a saturated aqueous solution of sodium
chloride, dried over anhydrous magnesium sulfate and concentrated.
To the obtained residue was added methanol and the precipitate was
filtrated. The filtrate was concentrated to give the title compound
(88 g) having the following physical data.
[0379] TLC: Rf 0.43 (hexane:ethyl acetate=2:3),
[0380] NMR(CDCl.sub.3): .delta. 7.81 (d, J=8.7 Hz, 2H), 7.60 (d,
J=8.7 Hz, 2H), 4.24 (t, J=4.8 Hz, 2H), 3.69 (t, J=4.8 Hz, 2H),
3.66-3.62 (m, 2H), 3.56-3.53 (m, 2H), 3.38 (s, 3H), 2.95 (t, J=7.2
Hz, 2H), 2.40 (t, J=7.2 Hz, 2H), 1.83-1.67 (m, 4H).
REFERENCE EXAMPLE 8
2-(2-methoxyethoxy)ethyl
6-[4-(N-(2-hydroxy-5-methylphenyl)carbamoyl)pheny-
l]-6-oxohexanoate
[0381] 158
[0382] Under an atmosphere of argon, to a solution of compound
prepared in reference example 7 (75 g) in dimethylacetamide (300
mL) was added 4-methyl-2-aminophenol (17.9 g),
dichlorobis(triphenylphosphine)palladium- (II) (2.78 g),
triphenylphosphine (2.07 g), 1,8-diazabicyclo[5.4.0]undec-7- -ene
(23.7 mL). The atmosphere of argon was replaced with carbon
monoxide. The reaction mixture was stirred at 150.degree. C. for
2.5 hours. The reaction mixture was poured into water and extracted
with ethyl acetate. The extract was washed with 1N hydrochloric
acid water and a saturated aqueous solution of sodium chloride,
dried over anhydrous magnesium sulfate and concentrated. The
obtained residue was washed with diethyl ether to give the title
compound (51.3 g) having the following physical data.
[0383] TLC: Rf 0.27 (hexane:ethyl acetate=1:2),
[0384] NMR(CDCl.sub.3): .delta. 8.29 (brs, 1H), 8.04 (d, J=8.7 Hz,
2H), 8.00-7.98 (m, 1H), 7.97 (d, J=8.7 Hz, 2H), 7.19 (s, 1H),
6.98-6.93 (m, 2H), 4.24 (t, J=5.0 Hz, 2H), 3.70 (t, J=5.0 Hz, 2H),
3.66-3.63 (m, 2H), 3.56-3.53 (m, 2H), 3.37 (s, 3H), 3.02 (t, J=6.9
Hz, 2H), 2.40 (t, J=6.9 Hz, 2H), 2.29 (s, 3H), 1.86-1.68 (m,
4H).
REFERENCE EXAMPLE 9
2-(2-methoxyethoxy)ethyl
6-[4-(5-methylbenzoxazol-2-yl)phenyl]-6-oxohexano- ate
[0385] 159
[0386] To a suspension of the compound prepared in reference
example 8 (49 g) in toluene (500 mL) was added camphor sulfonic
acid (24.9 g). The reaction mixture was stirred at. 150.degree. C.
for 3.5 hours with dehydrating with Dean-Stark. The reaction
mixture was poured into ice water and extracted with ethyl acetate.
The extract was washed with a saturated aqueous solution of sodium
hydrogen carbonate, water and a saturated aqueous solution of
sodium chloride, dried over anhydrous magnesium sulfate and
concentrated. The obtained residue was purified by column
chromatography on silica gel (dichloromethane:ethyl
acetate=10:1.about.1:1) to give the title compound (33.1 g) having
the following physical data.
[0387] TLC: Rf 0.42 (hexane:ethyl acetate=1:2),
[0388] NMR(CDCl.sub.3): .delta. 8.33 (d, J=8.7 Hz, 2H), 8.08 (d,
J=8.7 Hz, 2H), 7.58 (d, J=1.5 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.20
(dd, J=8.1, 1.5 Hz, 1H), 4.25 (t, J=4.8 Hz, 2H), 3.70 (t, J=4.8 Hz,
2H), 3.66-3.62 (m, 2H), 3.57-3.53 (m, 2H), 3.38 (s, 3H), 3.05 (t,
J=7.0 Hz, 2H), 2.50 (s, 3H), 2.42 (t, J=7.0 Hz, 2H), 1.87-1.70 (m,
4H).
REFERENCE EXAMPLE 9(1)
2-(2-methoxyethoxy)ethyl
6-[4-(benzoxazol-2-yl)phenyl]-6-oxohexanoate
[0389] 160
[0390] By the same procedure as a series of reactions of reference
example 8.fwdarw.reference example 9 using 2-aminophenol instead of
4-methyl-2-aminophenol, the title compound having the following
physical data were obtained.
[0391] TLC: Rf 0.45 (hexane:ethyl acetate=2:3),
[0392] NMR(CDCl.sub.3): .delta. 8.35 (d, J=8.8 Hz, 2H), 8.09 (d,
J=8.8 Hz, 2H), 7.85-7.77 (m, 1H), 7.67-7.58 (m, 1H), 7.45-7.37 (m,
2H), 4.24 (t, J=4.8 Hz, 2H), 3.72 (t, J=4.8 Hz, 2H), 3.67-3.62 (m,
2H), 3.58-3.53 (m, 2H), 3.38 (s, 3H), 3.05 (t, J=7.0 Hz, 2H), 2.42
(t, J=7.0 Hz, 2H), 1.90-1.70 (m, 4H).
REFERENCE EXAMPLE 10
2-(2-methoxyethoxy)ethyl
6-[4-(2-(4-methylthiophenyl)ethynyl)phenyl]-6-oxo- hexanoate
[0393] 161
[0394] Under an atmosphere of argon, to a mixture solution of the
compound prepared in reference example 7 (80 g) in
dimethylformamide (310 mL) and triethylamine (155 mL) was added
1-ethynyl-4-methylthiobenzene (27.5 g) and
dichlorobis(triphenylphosphine)palladium(II) (10.9 g). The reaction
mixture was stirred at 50.degree. C. for 3 hours. The reaction
mixture was poured into an aqueous solution of 2N hydrochloric acid
cooled with ice and extracted with ethyl acetate. The extract was
washed with 2N hydrochloric acid, a saturated aqueous solution of
sodium hydrogen carbonate and a saturated aqueous solution of
sodium chloride, dried over anhydrous magnesium sulfate and
concentrated. The obtained residue was purified by column
chromatography on silica gel (hexane:ethyl acetate=2:1.fwdarw.2:3
chloroform:methanol=20:1) to give the title compound (41.1 g)
having the following physical data.
[0395] TLC: Rf 0.21 (hexane:ethyl acetate 2:1),
[0396] NMR(CDCl.sub.3): .delta. 7.93 (d, J=8.6 Hz, 2H), 7.59 (d,
J=8.6 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H),
4.28-4.20 (m, 2H), 3.75-3.60 (m, 4H), 3.60-3.50 (m, 2H), 3.38 (s,
3H), 2.99 (t, J=7.0 Hz, 2H), 2.51 (s, 3H), 2.41 (t, J=7.0 Hz, 2H),
1.85-1.65 (m, 4H).
REFERENCE EXAMPLE 11
2-(2-methoxyethoxy)ethyl
6-[4-(4-methylthiophenyl)phenyl]-6-oxohexanoate
[0397] 162
[0398] By the same procedure as a series of reactions of example 4
using the compound prepared in reference example 7 and
4-methylthiophenylboroni- c acid, the title compound having the
following physical data was obtained.
[0399] TLC: Rf 0.24 (hexane:ethyl acetate=1:1),
[0400] NMR(CDCl.sub.3): .delta. 8.01 (d, J=8.7 Hz, 2H), 7.65 (d,
J=8.7 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.25
(t, J=4.8 Hz, 2H), 3.70 (t, J=4.8 Hz, 2H), 3.66-3.63 (m, 2H),
3.56-3.53 (m, 2H), 3.38 (s, 3H), 3.01 (t, J=6.9 Hz, 2H), 2.53 (s,
3H), 2.41 (t, J=6.9 Hz, 2H), 1.86-1.70 (m, 4H).
REFERENCE EXAMPLE 12
Methyl 6-[4-(4-methylthiophenyl)phenyl]-6-oxohexanoate
[0401] 163
[0402] By the same procedure as a series of reactions of reference
example 1 using monomethyl adipate and
4-(N,N-dimethylamino)methylbiphenyl, the title compound having the
following physical data was obtained.
[0403] TLC: Rf 0.51 (dichloromethane:methanol=4:1),
[0404] NMR(CDCl.sub.3): .delta. 8.01 (d, J=8.7 Hz, 2H), 7.68 (d,
J=8.7 Hz, 2H), 7.59 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 3.67
(s, 3H), 3.50 (s, 2H), 3.02 (t, J=7.0 Hz, 2H), 2.39 (t, J=7.0 Hz,
2H), 2.29 (s, 6H), 1.86-1.70 (m, 4H).
EXAMPLE 6
(R)-(+)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(5-methylbenzoxazol-2-yl)phenyl]-
-6-hydroxyhexanamide
[0405] 164
[0406] By the same procedure as a series of reactions of reference
example 4.fwdarw.reference example 3.fwdarw.example 1 using the
compound prepared in reference example 9, the compound of the
present invention having the following physical data was
obtained.
[0407] [.alpha.].sub.D: +22.46 (c 0.615, dimethylformamide),
[0408] TLC: Rf 0.34 (ethyl acetate),
[0409] NMR(CDCl.sub.3): .delta. 8.19 (d, J=8.1 Hz, 2H), 7.84 (brs,
1H), 7.54-7.53 (m, 1H), 7.47 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz,
1H), 7.16-7.13 (m, 1H), 4.80-4.75 (m, 1H), 3.30 (s, 3H), 2.48 (s,
3H), 2.42-2.08 (m, 2H), 1.94-1.32 (m, 6H), 1.41 (s, 6H).
EXAMPLE 6(1)-6(4)
[0410] By the same procedure as a series of reactions of example 6
using the compound prepared in reference example 9(1), 10, 11 or 12
instead of the compound prepared in reference example 9, the
compounds of the present invention having the following physical
data were obtained.
EXAMPLE 6(1)
(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhe-
xanamide
[0411] 165
[0412] TLC: Rf 0.50 (chloroform:methanol:acetic acid=90:10:1),
[0413] NMR(CDCl.sub.3): .delta. 8.22 (d, J=8.2 Hz, 2H), 7.83 (br,
1H), 7.75 (m, 1H), 7.59 (m, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.35 (m,
2H), 4.76 (t, J=6.5 Hz, 1H), 3.30 (s, 3H), 2.45-2.12 (m, 2H),
1.85-1.62 (m, 4H), 1.53-1.38 (m, 2H), 1.41 (s, 6H).
EXAMPLE 6(2)
(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(2-(4-methylthiophenyl)ethynyl)pheny-
l]-6-hydroxyhexanamide
[0414] 166
[0415] TLC: Rf 0.41 (chloroform:methanol:acetic acid=90:10:1),
[0416] NMR(CDCl.sub.3): .delta. 7.86 (br, 1H), 7.48 (d, J=8.4 Hz,
2H), 7.42 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4
Hz, 2H), 4.68 (t-like, J=6.0 Hz, 1H), 3.31 (s, 3H), 2.49 (s, 3H),
2.40-2.10 (m, 2H), 1.82-1.65 (m, 4H), 1.50-1.35 (m, 2H), 1.41 (s,
6H).
EXAMPLE 6(3)
(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-methylthiophenyl)phenyl]-6-hydrox-
yhexanamide
[0417] 167
[0418] TLC: Rf 0.44 (ethyl acetate),
[0419] NMR(CDCl.sub.3): .delta. 7.79 (br, 1H), 7.53 (d, J=8.5 Hz,
2H), 7.51 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.5
Hz, 2H), 4.71 (t, J=6.0 Hz, 1H), 3.30 (s, 3H), 2.52 (s, 3H),
2.43-2.08 (m, 2H), 1.90-1.65 (m, 5H), 1.57-1.36 (m, 1H), 1.41 (s,
6H).
EXAMPLE 6(4)
(R)-(+)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(dimethylaminomethyl)phenyl)p-
henyl]-6-hydroxyhexanamide
[0420] 168
[0421] [.alpha.].sub.D: +22.6 (c 1.04, dimethylformamide),
[0422] TLC: Rf 0.17 (chloroform:methanol=9:1),
[0423] NMR(d.sub.6-DMSO): .delta. 7.58 (d, J=8.1 Hz, 2H), 7.57 (d,
J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 5.12
(d, J=4.5 Hz, 1H), 4.52 (m, 1H), 3.39 (s, 2H), 3.18 (s, 3H), 2.14
(s, 6H), 1.98 (t, J=7.2 Hz, 2H), 1.65-1.54 (m, 2H), 1.49 (m, 2H),
1.40-1.18 (m, 2H), 1.24 (s, 6H).
EXAMPLE 7
(R)-(+)-N-hydroxy-6-[4-(5-methylbenzoxazol-2-yl)phenyl]-6-hydroxyhexanamid-
e
[0424] 169
[0425] By the same procedure as a series of reactions of example 2
using the compound prepared in example 6, the compound of the
present invention having the following physical data was
obtained.
[0426] TLC: Rf 0.28 (chloroform:methanol=9:1),
[0427] m.p.: 178-179.degree. C.,
[0428] [.alpha.].sub.D: +31.0 (c 1.05, dimethylformamide),
[0429] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.63 (s, 1H), 8.12
(d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 1H), 7.57 (m, 1H), 7.53 (d,
J=8.4 Hz, 2H), 7.22 (m, 1H), 5.31 (d, J=4.2 Hz, 1H), 4.59 (m, 1H),
2.43 (s, 3H), 1.91 (t, J=7.2 Hz, 2H), 1.65-1.56 (m, 2H), 1.54-1.45
(m, 2H), 1.41-1.18 (m, 2H).
EXAMPLE 7(1).about.7(4)
[0430] By the same procedure as a series of reactions of example 7
using the compound prepared in example 6(1)-(4) instead of the
compound prepared in example 6, if desired, the conversion into the
acid addition salts by conventional means, the following compounds
of the present invention were obtained.
EXAMPLE 7(1)
(R)-(+)-N-hydroxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide
[0431] 170
[0432] TLC: Rf 0.20 (chloroform:methanol:acetic acid=90:10:1),
[0433] m.p.: 160-161.degree. C.,
[0434] [.alpha.].sub.D: +10.10 (c 0.81, methanol),
[0435] NMR(d.sub.6-DMSO): .delta. 10.31 (s, 1H), 8.64 (s, 1H), 8.14
(d, J=8.2 Hz, 2H), 7.82-7.72 (m, 2H), 7.54 (d, J=8.2 Hz, 2H),
7.47-7.34 (m, 2H), 5.32 (d, J=4.4 Hz, 1H), 4.64-4.57 (m, 1H), 1.92
(t, J=7.0 Hz, 2H), 1.70-1.10 (m, 6H).
EXAMPLE 7(2)
(R)-(+)-N-hydroxy-6-[4-(2-(4-methylthiophenyl)ethynyl)phenyl]-6-hydroxyhex-
anamide
[0436] 171
[0437] TLC: Rf 0.43 (chloroform:methanol:acetic acid=60:10:1),
[0438] m.p.: 173-176.degree. C.,
[0439] [.alpha.].sub.D: +31.5 (c 1.02, dimethylformamide),
[0440] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.62 (s, 1H), 7.48
(d, J=8.0 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H),
7.28 (d, J=8.4 Hz, 2H), 5.22 (d, J=4.4 Hz, 1H), 4.60-4.45 (m, 1H),
2.51 (s, 3H), 1.92 (t, J=7.2 Hz, 2H), 1.70-1.10 (m, 6H).
EXAMPLE 7(3)
(R)-(+)-N-hydroxy-6-[4-(4-methylthiophenyl)phenyl]-6-hydroxyhexanamide
[0441] 172
[0442] TLC: Rf 0.23 (chloroform:methanol=9:1),
[0443] m.p.: 194-197.degree. C.,
[0444] [.alpha.].sub.D: +6.86 (c 0.105, methanol),
[0445] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.62 (s, 1H),
7.61-7.55 (m, 4H), 7.38-7.29 (m, 4H), 5.12 (d, J=4.4 Hz, 1H),
4.58-4.42 (m, 1H), 2.49 (s, 3H), 1.90 (t, J=7.4 Hz, 2H), 1.66-1.02
(m, 6H).
EXAMPLE 7(4)
(R)-(+)-N-hydroxy-6-[4-(4-(dimethylaminomethyl)phenyl)phenyl]-6-hydroxyhex-
anamide.hydrochloride
[0446] 173
[0447] TLC: Rf 0.14 (chloroform:methanol=2:1),
[0448] m.p.: 214-217.degree. C.,
[0449] [.alpha.].sub.D: +26.54 (c 0.11, methanol),
[0450] NMR(d.sub.6-DMSO): .delta. 10.79 (s, 1H), 10.33 (s, 1H),
8.63 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.64-7.62 (m, 4H), 7.39 (d,
J=8.2 Hz, 2H), 5.17 (d, J=3.9 Hz, 1H), 4.58-4.49 (m, 1H), 4.27 (s,
2H), 2.68 (s, 6H), 1.91 (t, J=6.9 Hz, 2H), 1.64-1.18 (m, 2H).
EXAMPLE 8(1).about.8(4)
[0451] By the same procedure as a series of reactions of reference
example 1.fwdarw.reference example 2.fwdarw.reference example
3.fwdarw.example 1.fwdarw.example 2 using a corresponding compound
instead of 4-chlorobiphenyl, the following compounds of the present
invention were obtained.
EXAMPLE 8(1)
N-hydroxy-6-(4-(trans-4-butylcyclohexyl)phenyl)-6-hydroxyhexanamide
[0452] 174
[0453] TLC: Rf 018 (ethyl acetate),
[0454] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.63 (s, 1H), 7.20
(d, J=8.2 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 4.99 (d, J=3.9 Hz, 1H),
4.42 (m, 1H), 2.40 (m, 1H), 1.91 (t, J=7.2 Hz, 2H), 1.90-0.90 (m,
21H), 0.85 (t, J=6.9 Hz, 3H).
EXAMPLE 8(2)
N-hydroxy-6-(4-(trans-4-hydroxycyclohexyl)phenyl)-6-hydroxyhexanamide
[0455] 175
[0456] TLC: Rf 0.12 (chloroform:methanol:triethylamine=8:1:1),
[0457] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.64 (s, 1H), 7.19
(d, J=8.1 Hz, 2H), 7.13 (d, J=8.1 Hz, 2H), 4.99 (d, J=4.5 Hz, 1H),
4.54 (d, J=4.5 Hz, 1H), 4.42 (q, J=4.5 HZ, 1H), 3.52-3.36 (m, 1H),
2.60-2.30 (m, 1H), 1.95-1.83 (m, 4H), 1.80-1.65 (m, 2H), 1.63-1.10
(m, 10H).
EXAMPLE 8(3)
N-hydroxy-6-(4-cyclopentylphenyl)-6-hydroxyhexanamide
[0458] 176
[0459] TLC: Rf 0.18 (chloroform:methanol:triethylamine=8:1:1),
[0460] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.64 (s, 1H), 7.20
(d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 5.00 (d, J=3.9 Hz, 1H),
4.43 (q, J=3.9 Hz, 1H), 3.00-2.85 (m, 1H), 2.06-1.84 (m, 4H),
1.83-1.38 (m, 10H), 1.38-1.10 (m, 2H).
EXAMPLE 8(4)
N-hydroxy-6-[4-(morpholin-4-yl)phenyl]-6-hydroxyhexanamide
[0461] 177
[0462] TLC: Rf 0.20 (chloroform:methanol=9:1),
[0463] NMR(d.sub.6-DMSO): .delta. 10.27 (s, 1H), 8.61 (s, 1H), 7.14
(d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 4.80 (d, J=4.2 Hz, 1H),
4.40-4.35 (m, 1H), 3.72-3.69 (m, 4H), 3.05-3.02 (m, 4H), 1.88 (t,
J=7.5 Hz, 2H), 1.62-1.07 (m, 6H).
EXAMPLE 9
N-hydroxy-6-[3-(4-chlorophenyl)phenyl]-6-hydroxyhexanamide
[0464] 178
[0465] By the same procedure as a series of reactions of example
4.fwdarw.reference example 2.fwdarw.reference example
3.fwdarw.example 1.fwdarw.example 2 using methyl
6-(3-bromophenyl)-6-oxohexanoate instead of the compound prepared
in reference example 6, the compound of the present invention
having the following physical data was obtained.
[0466] TLC: Rf 0.27 (ethyl acetate),
[0467] NMR(d.sub.6-DMSO): .delta. 10.28 (brs, 1H), 8.62 (brs, 1H),
7.75-7.64 z(m, 3H), 7.57 (s, 1H), 7.52-7.47 (m, 2H), 7.39 (t, J=7.5
Hz, 1H) 7.31 (d, J=6.9 Hz, 1H), 5.16 (d, J=4.5 Hz, 1H), 4.58-4.52
(m, 1H), 1.90 (t, J=7. 2 Hz, 2H), 1.64-1.20 (m, 6H).
EXAMPLE 9(1)
N-hydroxy-6-[2-(4-chlorophenyl)phenyl]-6-hydroxyhexanamide
[0468] 179
[0469] By the same procedure as a series of reactions of example 9
using methyl 6-(2-bromophenyl)-6-oxohexanoate instead of methyl
6-(3-bromophenyl)-6-oxohexanoate, the compound of the present
invention having the following physical data was obtained.
[0470] TLC: Rf 0.26 (ethyl acetate),
[0471] NMR(d.sub.6-DMSO): .delta. 10.24 (s, 1H), 8.61 (s, 1H), 7.56
(d, J=7.5 Hz, 1H), 7.49-7.46 (m, 2H), 7.40-7.24 (m, 4H), 7.11-7.09
(m, 1H), 5.03 (d, J=4.2 Hz, 1H), 4.49-4.44 (m, 1H), 1.80 (t, J=7.5
Hz, 2H), 1.56-1.02 (m, 6H).
EXAMPLE 10
N-hydroxy-6-[4-((1E)-2-phenylvinyl)phenyl]-6-hydroxyhexanamide
[0472] 180
[0473] By the same procedure as a series of reactions of reference
example 10.fwdarw.example 2 using the compound prepared in
reference example 6 and styrene, the compound of the present
invention having the following physical data was obtained.
[0474] TLC: Rf 0.34 (ethyl acetate),
[0475] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 7.59-7.51 (m, 4H),
7.38-7.21 (m, 5H), 7.21 (s, 2H), 4.49-4.45 (m, 1H), 1.89 (t, J=7.5
Hz, 2H), 1.60-1.12 (m, 6H).
EXAMPLE 10(1) AND 10(2)
[0476] By the same procedure as a series of reactions of example 10
using a corresponding compound instead of styrene, the following
compounds of the present invention were obtained.
EXAMPLE 10(1)
N-hydroxy-6-[4-((1E)-2-(pyridin-4-yl)vinyl)phenyl]-6-hydroxyhexanamide
[0477] 181
[0478] TLC: Rf 0.22 (ethyl acetate:methanol=9:1),
[0479] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 8.62 (s, 1H), 8.51
(d, J=5.4 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 7.53 (d, J=5.4 Hz, 2H),
7.51 (d, J=16.2 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.19 (d, J=16.2
Hz, 1H), 5.14 (d, J=4.8 Hz, 1H), 4.52-4.46 (m, 1H), 1.89 (t, J=7.5
Hz, 2H), 1.60-1.10 (m, 6H).
EXAMPLE 10(2)
N-hydroxy-6-[4-((1E)-2-(pyridin-2-yl)vinyl)phenyl]4-hydroxyhexanamide
[0480] 182
[0481] TLC: Rf 0.22 (ethyl acetate:methanol=9:1),
[0482] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H),
8.56-8.54 (m, 1H), 7.77 (dt, J=7.5 Hz, 1.5 Hz, 1H), 7.64 (d, J=16.2
Hz, 1H), 7.59 (d, J=7.8 Hz, 2H), 7.52 (d, J=8.1 Hz, 1H), 7.32 (d,
J=7.8 Hz, 2H), 7.27 (d, J=16.2 Hz, 1H), 7.25-7.21 (m, 1H), 5.13 (d,
J=4.5 Hz, 1H), 4.52-4.80 (m, 1H), 1.90 (t, J=7.5 Hz, 2H), 1.63-1.18
(m, 6H).
REFERENCE EXAMPLE 13
6-[4-(4-chlorophenyl)phenyl]-6-oxohexanoic acid
[0483] 183
[0484] By the same procedure as a series of reactions of reference
example 3 using the compound prepared in reference example 1, the
title compound having the following physical data was obtained.
[0485] TLC: Rf 0.50 (ethyl acetate),
[0486] NMR(d.sub.6-DMSO): .delta. 12.00 (s, 1H), 8.05 (d, J=8.4 Hz,
2H), 7.82 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4
Hz, 2H), 3.07 (t, J=6.6 Hz, 2H), 2.27 (t, J=7.4 Hz, 2H), 1.80-1.50
(m, 4H).
REFERENCE EXAMPLE 14
6-[4-(4-chlorophenyl)phenyl]-6-hydroxy heptanoic acid
[0487] 184
[0488] Under an atmosphere of argon, to a solution of the compound
prepared in reference example 13 (560 mg) in tetrahydrofuran (20
mL) was added 0.82 mmol/mL solution of methylmagnesium iodide in
diethylether (10.8 mL) at 0.degree. C. The reaction mixture was
stirred at room temperature for 1 hour. To the reaction mixture was
added 1N hydrochloric acid and the mixture was extracted with ethyl
acetate. The extract was washed with water and a saturated aqueous
solution of sodium chloride, dried over anhydrous magnesium
sulfate, and concentrated. The obtained residue was purified by
column chromatography on silica gel (hexane:ethyl acetate=1:1) to
give the title compound (442 mg) having the following physical
data.
[0489] TLC: Rf 0.30 (hexane:ethyl acetate=1:2),
[0490] NMR(CDCl.sub.3): .delta. 7.54-7.46 (m, 6H), 7.39 (d, J=8.4
Hz, 2H), 2.30 (t, J=7.2 Hz, 2H), 1.84 (m, 2H), 1.66-1.56 (m, 2H),
1.58 (s, 3H), 1.45-1.32 (m, 1H), 1.30-1.18 (m, 1H).
EXAMPLE 11
N-hydroxy-6-[4-(4-chlorophenyl)phenyl]-6-hydroxyheptanamide
[0491] 185
[0492] By the same procedure as a series of reactions of example
1.fwdarw.example 2 using the compound prepared in reference example
14, the compound of present invention having the following physical
data was obtained.
[0493] TLC: Rf 0.27 (ethyl acetate),
[0494] NMR(d.sub.6-DMSO): .delta. 10.24 (s, 1H), 8.60 (s, 1H), 7.67
(d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H),
7.48 (d, J=8.4 Hz, 2H), 4.87 (s, 1H), 1.85 (t, J=7.2 Hz, 2H),
1.74-1.60 (m, 2H), 1.44-1.34 (m, 2H), 1.30-1.20 (m, 1H), 1.05-0.93
(m, 1H).
EXAMPLE 11(1)
N-hydroxy-6-[4-(4-chlorophenyl)phenyl]-6-hydroxy-7-octenamide
[0495] 186
[0496] By the same procedure as a series of reactions of reference
example 14.fwdarw.example 11 using vinylmagnesium bromide instead
of methylmagnesium iodide, the compound of present invention having
the following physical data was obtained.
[0497] TLC: Rf 0.28 (ethyl acetate),
[0498] NMR(d.sub.6-DMSO): .delta. 10.26 (s, 1H), 8.62 (s, 1H), 7.67
(d, J=8.5 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.5 Hz, 4H),
6.12 (dd, J=17.2, 10.6 Hz, 1H), 5.21 (dd, J=17.2, 2.0 Hz, 1H), 5.15
(s, 1H), 5.00 (dd, J=10.6, 2.0 Hz, 1H), 1.84 (m, 2H), 1.83-1.72 (m,
2H), 1.42 (m, 2H), 1.32-1.22 (m, 1H), 1.12-1.00 (m, 1H).
EXAMPLE 11(2)
N-hydroxy-6-(4-biphenyl)-6-hydroxyheptanamide
[0499] 187
[0500] By the same procedure as a series of reactions of reference
example 14.fwdarw.example 11 using 6-(4-biphenyl)-6-oxohexanoic
acid instead of the compound prepared in reference example 13, the
compound of present invention having the following physical data
was obtained.
[0501] TLC: Rf 0.26 (ethyl acetate),
[0502] NMR(d.sub.6-DMSO): .delta. 10.25 (s, 1H), 8.61 (s, 1H),
7.65-7.62 (m, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H),
7.43-7.41 (m, 2H), 7.35-7.29 (m, 1H, 4.86 (s, 1H), 1.85 (t, J=7.2
Hz, 2H), 1.75-1.60 (m, 2H), 1.40 (s, 3H), 1.42-1.18 (m, 3H),
1.04-0.91 (m. 1H).
REFERENCE EXAMPLE 15
6-[4-(4-ethylphenyl)phenyl]-6-hydroxyheptanoic acid
[0503] 188
[0504] By the same procedure as a series of reactions of reference
example 14 using 6-[4-(4-ethylphenyl)phenyl]-6-oxohexanoic acid
instead of the compound prepared in reference example 13,
enantiomer mixture of the title compound was obtained. By the
following method, (+) isomer and (-) isomer of the title compound,
respectively, were obtained from enantiomer mixture.
[0505] The enantiomer mixture (6.66 g),
(1R,2R)-(+)-1,2-diphenylethylenedi- amine (4.33 g), ethyl acetate
(80 mL) and hexane (20 mL) were mixed. The mixture was refluxed and
dissolved completely. The mixture was cooled to room temperature
and the crystal precipitated. The precipitated crystal was filtered
and washed with a solution of hexane and ethyl acetate
(hexane:ethyl acetate=1:1). The filtrate was concentrated. The
obtained residue was used in the preparation of (-) isomer. The
precipitated crystal was dissolved into ethyl acetate and washed
with 1N hydrochloric acid, water and a saturated aqueous solution
of sodium chloride and dried over anhydrous magnesium sulfate and
concentrated to give (+) isomer of the title compound (2.44 g,
92.4% e.e, HPLC) having the following physical data.
[0506] The residue concentrated the filtrate was dissolved into
ethyl acetate and washed with 1N hydrochloric acid, water and a
saturated aqueous solution of sodium chloride, dried over anhydrous
magnesium sulfate and concentrated. The obtained residue,
(1S,2S)-(-)-1,2-diphenyle- thylenediamine (2.32 g), ethyl acetate
(50 mL) and hexane (10 mL) were mixed. The mixture was refluxed and
dissolved completely. The mixture was cooled to room temperature
and crystal precipitated. The precipitated crystal was filtered and
washed with a solution of hexane and ethyl acetate (hexane:ethyl
acetate=1:1). The precipitated crystal was dissolved into ethyl
acetate and washed with 1N hydrochloric acid, water and a saturated
aqueous solution of sodium chloride, dried over anhydrous magnesium
sulfate and concentrated to give (-) isomer of the title compound
(2.88 g, 89.9% e.e, HPLC) having the following physical data.
[0507] (+) Isomer:
[0508] TLC: Rf 0.46 (chloroform:methanol=9:1), Retention time: 6.99
min. Column: DAICEL CHIRAL CELAD-RH, 4.6.times.150 mm; Eluant:
acetonitrile:water=65:35; UV: 256 nm; Flow rate: 1.0 mL/min.
[0509] (-) Isomer:
[0510] TLC: Rf 0.46 (chloroform:methanol=9:1), Retention time:
14.40 min. Column: DAICEL CHIRAL CELAD-RH, 4.6.times.150 mm;
Eluant: acetonitrile:water=65:35; UV: 256 nm; Flow rate: 1.0
mL/min.
EXAMPLE 12
(+)-N-hydroxy-6-[4-(4-ethylphenyl)phenyl]-6-hydroxyheptanamide
[0511] 189
[0512] By the same procedure as a series of reactions of example 1
example 2 using (+) isomer of the compound prepared in reference
example 15, the compound of the present invention having the
following physical data was obtained.
[0513] [.alpha.].sub.D: +14.74 (c 0.555, methanol),
[0514] TLC: Rf 0.35 (chloroform:methanol=9:1),
[0515] NMR(d.sub.6-DMSO): .delta. 10.26 (s, 1H), 8.62 (s, 1H), 7.55
(d, J=8.4 Hz, 4H), 7.45 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H),
4.85 (s, 1H), 2.62 (q, J=7.4 Hz, 2H), 1.86 (t, J=7.4 Hz, 2H),
1.78-1.56 (m, 2H), 1.55-1.21 (m, 6H), 1.20 (t, J=7.4 Hz, 3H),
1.12-0.85 (m, 1H).
EXAMPLE 12(1)
(-)-N-hydroxy-6-[4-(4-ethylphenyl)phenyl]-6-hydroxyheptanamide
[0516] 190
[0517] By the same procedure as a series of reactions of example 12
using (-) isomer of the compound prepared in reference example 15,
the compound of the present invention having the following physical
data was obtained.
[0518] [.alpha.].sub.D: -12.18 (c 0.74, methanol),
[0519] TLC: Rf 0.35 (chloroform:methanol=9:1),
[0520] NMR(d.sub.6-DMSO): .delta. 10.26 (s, 1H), 8.62 (s, 1H), 7.55
(d, J=8.4 Hz, 4H), 7.45 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H),
4.85 (s, 1H), 2.62 (q, J=7.4 Hz, 2H), 1.86 (t, J=7.4 Hz, 2H),
1.78-1.56 (m, 2H), 1.55-1.21 (m, 6H), 1.20 (t, J=7.4 Hz, 3H),
1.12-0.85 (m, 1H).
EXAMPLE 13(1).about.13(44)
[0521] By the same procedure as a series of reactions of reference
example 4.fwdarw.reference example 3.fwdarw.example
1.fwdarw.example 2 using a corresponding ketone derivative instead
of the compound prepared in reference example 1, if desired, the
conversion into the acid addition salts by conventional means, the
following compounds of the present invention were obtained.
EXAMPLE 13(1)
(R)-(+)-N-hydroxy-6-(4-biphenyl)-6-hydroxyhexanamide
[0522] 191
[0523] [.alpha.].sub.D: +15.1 (c 0.245, methanol),
[0524] TLC: Rf 0.25 (chloroform:methanol:acetic acid=90:10:1),
[0525] NMR(d.sub.6-DMSO): .delta. 10.29 (s. 1H), 8.63 (s, 1H),
7.65-7.57 (m, 4H), 7.46-7.30 (m, 5H), 5.13 (d, J=4.5 Hz, 1H),
4.54-4.49 (m, 1H), 1.91 (t, J=7.2 Hz, 2H), 1.64-1.44 (m, 4H),
1.40-1.22 (m, 2H).
EXAMPLE 13(2)
(R)-(+)-N-hydroxy-6-[4-(4-methylphenyl)phenyl]-6-hydroxyhexanamide
[0526] 192
[0527] [.alpha.].sub.D: +11.53 (c 0.215, methanol),
[0528] TLC: Rf 0.22 (chloroform:methanol:acetic acid=90:10:1),
[0529] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.62 (s, 1H),
7.56-7.51 (m, 4H), 7.34 (d, J=8.1 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H),
5.11 (d, J=4.5 Hz, 1H), 4.52-4.48 (m, 1H), 2.32 (s, 3H), 1.90 (t,
J=7.5 Hz, 2H), 1.62-1.15 (m, 6H).
EXAMPLE 13(3)
(R)-(+)-N-hydroxy-6-[4-(3-methylphenyl)phenyl]-6-hydroxyhexanamide
[0530] 193
[0531] [.alpha.].sub.D: +8.43 (c 0.37, methanol),
[0532] TLC: Rf 0.22 (chloroform:methanol:acetic acid=90:10:1),
[0533] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H), 7.56
(d, J=8.1 Hz, 2H), 7.44-7.29 (m, 5H), 7.14 (d, J=7.5 Hz, 1H), 5.12
(d, J=4.5 Hz, 1H), 4.59-4.48 (m, 1H), 2.35 (s, 3H), 1.90 (t, J=7.2
Hz, 2H), 1.63-1.12 (m, 6H).
EXAMPLE 13(4)
(R)-(+)-N-hydroxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide
[0534] 194
[0535] [.alpha.].sub.D: +14.5 (c 0.195, methanol),
[0536] TLC: Rf 0.25 (chloroform:methanol:acetic acid=90:10:1),
[0537] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 8.62 (s, 1H), 7.84
(d, J=8.4 Hz, 2H), 7.65-7.58 (m, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.37
(s, 1H), 7.33-7.19 (m, 2H), 5.19 (d, J=4.4 Hz, 1H), 4.59-4.45 (m,
1H), 1.89 (t, J=7.2 Hz, 2H), 1.62-1.05 (m, 6H).
EXAMPLE 13(5)
(R)-N-hydroxy-6-[4-(2-phenylethynyl)phenyl]-6-hydroxyhexanamide
[0538] 195
[0539] TLC: Rf 0.24 (chloroform:methanol=9:1),
[0540] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 8.62 (s, 1H),
7.55-7.32 (m, 9H), 5.20 (d, J=4.4 Hz, 1H), 4.56-4.44 (m, 1H), 1.89
(t, J=7.0 Hz, 2H), 1.60-1.08 (m, 6H).
EXAMPLE 13(6)
(R)-(+)-N-hydroxy-6-[4-(benzothiophen-2-yl)phenyl]-6-hydroxyhexanamide
[0541] 196
[0542] [.alpha.].sub.D: +13.88 (c 0.085, methanol),
[0543] TLC: Rf 0.25 (chloroform:methanol:acetic acid=90:10:1),
[0544] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 8.62 (s, 1H),
7.96-7.92 (m, 1H), 7.84-7.79 (m, 2H), 7.70 (d, J=9.0 Hz, 2H), 7.39
(d, J=9.0 Hz, 2H), 7.36-7.28 (m, 2H), 5.18 (d, J=4.4 Hz, 1H),
4.59-4.48 (m, 1H), 1.89 (t, J=6.8 Hz, 2H), 1.65-1.10 (m, 6H).
EXAMPLE 13(7)
(R)-N-hydroxy-6-[4-(4-(cyanomethyl)phenyl)phenyl]-6-hydroxyhexanamide
[0545] 197
[0546] TLC: Rf 0.28 (ethyl acetate:methanol=9:1),
[0547] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H), 7.67
(d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H),
7.38 (d, J=8.1 Hz, 2H), 5.14 (d, J=4.5 Hz, 1H), 4.52 (m, 1H), 4.06
(s, 2H), 1.91 (t, J=7.2 Hz, 2H), 1.64-1.54 (m, 2H), 1.54-1.44 (m,
2H), 1.39-1.16 (m, 2H).
EXAMPLE 13(8)
(R)-N-hydroxy-6-[4-(4-ethylphenyl)phenyl]-6-hydroxyhexanamide
[0548] 198
[0549] TLC: Rf 0.29 (chloroform:methanol=9:1),
[0550] NMR(d.sub.6-DMSO): .delta. 10.42-10.20 (br, 1H), 8.75-8.55
(br, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.36 (d,
J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 5.12 (d, J=4.4 Hz, 1H),
4.58-4.45 (m, 1H), 2.62 (q, J=7.6 Hz, 2H), 1.91 (t, J=7.4 Hz, 2H),
1.70-1.10 (m, 6H), 1.19 (t, J=7.6 Hz, 3H).
EXAMPLE 13(9)
(R)-N-hydroxy-4-[4-(4-propylphenyl)phenyl]-6-hydroxyhexanamide
[0551] 199
[0552] TLC: Rf 0.29 (chloroform:methanol=9:1),
[0553] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.64 (s, 1H), 7.57
(d, J=8.4 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H),
7.25 (d, J=8.4 Hz, 2H), 5.12 (d, J=4.4 Hz, 1H), 4.58-4.44 (m, 1H),
2.57 (t, J=7.4 Hz, 2H), 1.92 (t, J=7.4 Hz, 2H), 1.72-1.10 (m, 8H),
0.90 (t, J=7.8 Hz, 3H).
EXAMPLE 13(10)
(R)-N-hydroxy-6-[4-(4-biphenyl)phenyl]-6-hydroxyhexanamide
[0554] 200
[0555] TLC: Rf 0.26 (chloroform:methanol=9:1),
[0556] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.64 (s, 1H),
7.78-7.60 (m, 8H), 7.54-7.30 (m, 5H), 5.15 (d, J=4.4 Hz, 1H),
4.59-4.46 (m, 1H), 1.91 (t, J=6.8 Hz, 2H), 1.65-1.10 (m, 6H).
EXAMPLE 13(11)
(R)-N-hydroxy-6-[4-(1-methylpiperidin-4-yl)phenyl]-6-hydroxyhexanamide.hyd-
rochloride
[0557] 201
[0558] TLC: Rf 0.12 (methanol),
[0559] NMR(d.sub.6-DMSO): .delta. 10.53 (br, 1H), 10.31 (s, 1H),
8.64 (br, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 5.06
(br, 1H), 4.44 (t, J=6.0 Hz, 1H), 3.46-3.28 (m, 3H), 3.09-2.96 (m,
2H), 2.73 (d-like, J=4.2 Hz, 3H), 2.00-1.87 (m, 6H), 1.58-1.41 (m,
4H), 1.37-1.15 (m, 2H).
EXAMPLE 13(12)
(R)-N-hydroxy-6-[4-(indol-2-yl)phenyl]-6-hydroxyhexanamide
[0560] 202
[0561] TLC: Rf 0.33 (chloroform:methanol:acetic acid=60:10:1),
[0562] NMR(d.sub.6-DMSO): .delta. 11.42 (s, 1H), 10.25 (s, 1H),
8.62 (s, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.47 (d, J=7.5 Hz, 1H)
7.40-7.30 (m, 3H), 7.10-7.00 (m, 1H), 7.00-6.90 (m, 1H), 6.81 (d,
J=1.2 Hz, 1H), 5.12 (d, J=4.5 Hz, 1H), 4.55-4.42 (m, 1H), 1.88 (t,
J=7.4 Hz, 2H), 1.70-1.40 (m, 4H), 1.40-1.10 (m, 2H).
EXAMPLE 13(13)
(R)-(+)-N-hydroxy-6-[4-(4-cyanophenyl)phenyl]-6-hydroxyhexanamide
[0563] 203
[0564] [.alpha.].sub.D: +4.60 (c 0.265, methanol),
[0565] TLC: Rf 0.34 (ethyl acetate:methanol=19:1),
[0566] NMR(d.sub.6-DMSO): .delta. 10.28 (brs, 1H), 8.63 (s, 1H),
7.90 (d, J=9.0 Hz, 2H), 7.85 (d, J=9.0 Hz, 2H), 7.68 (d, J=8.1 Hz,
2H), 7.42 (d, J=8.1 Hz, 2H), 5.19 (d, J=4.8 Hz, 1H), 4.58-4.51 (m,
1H), 1.90 (t, J=7.2 Hz, 2H), 1.59-1.14 (m, 6H).
EXAMPLE 13(14)
(R)-(+)-N-hydroxy-6-[4-phenyl-2-methylphenyl]-6-hydroxyhexanamide
[0567] 204
[0568] [.alpha.].sub.D: +18.31 (c 0.225, methanol),
[0569] TLC: Rf 0.37 (ethyl acetate:methanol=19:1),
[0570] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.64 (s, 1H),
7.63-7.60 (m, 2H), 7.46-7.39 (m, 5H), 7.34-7.28 (m, 1H), 5.02 (d,
J=4.5 Hz, 1H), 4.72-4.68 (m, 1H), 2.32 (s, 3H), 1.92 (t, J=6.9 Hz,
2H), 1.60-1.22 (m, 6H).
EXAMPLE 13(15)
(R)-N-hydroxy-6-(4-cycloheptylphenyl)-6-hydroxyhexanamide
[0571] 205
[0572] TLC: Rf 0.43 (ethyl acetate:methanol=9:1),
[0573] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 8.63 (s, 1H), 7.17
(d, J=8.3 Hz, 2H), 7.10 (d, J=8.3 Hz, 2H), 4.98 (d, J=4.5 Hz, 1H),
4.41 (m, 1H), 2.61 (m, 1H), 1.89 (t, J=7.2 Hz, 2H), 1.81-1.41 (m,
16H), 1.37-1.10 (m, 2H).
EXAMPLE 13(16)
(R)-N-hydroxy-6-(9,10-dihydrophenanthren-2-yl)-6-hydroxyhexanamide
[0574] 206
[0575] TLC: Rf 0.37 (ethyl acetate:methanol=9:1),
[0576] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.63 (s, 1H), 7.77
(d, J=7.2 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.31-7.17 (m, 5H), 5.10
(d, J=4.5 Hz, 1H), 4.47 (m, 1H), 2.79 (s, 4H), 1.91 (t, J=7.2 Hz,
2H), 1.63-1.44 (m, 4H), 1.41-1.17 (m, 2H).
EXAMPLE 13(17)
(R)-N-hydroxy-6-[4-(1-ethoxycarbonylpiperidin-4-yl)phenyl]6-hydroxyhexanam-
ide
[0577] 207
[0578] TLC: Rf 0.42 (ethyl acetate:methanol 9:1),
[0579] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H), 7.21
(d, J=8.3 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), 5.01 (d, J=4.2 Hz, 1H),
4.42 (m, 1H), 4.11-4.01 (m, 2H), 4.01 (q, J=7.0 Hz, 2H), 2.83 (m,
2H), 2.65 (m, 1H), 1.89 (t, J=7.2 Hz, 2H), 1.75-1.71 (m, 2H),
1.55-1.42 (m, 6H), 1.37-1.25 (m, 2H), 1.18 (t, J=7.0 Hz, 3H).
EXAMPLE 13(18)
(R)-(+)-N-hydroxy-6-[4-(4-(N-methylcarbamoyl)phenyl)phenyl]-6-hydroxyhexan-
amide
[0580] 208
[0581] [.alpha.].sub.D: +12.37 (c 0.08, methanol),
[0582] TLC: Rf 0.33 (chloroform:methanol=9:1),
[0583] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (brs, 1H),
8.48-8.43 (m, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H),
7.65 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.18 (brs, 1H),
4.56-4.50 (m, 1H), 2.78 (d, J=4.8 Hz, 3H), 1.90 (t, J=7.5 Hz, 2H),
1.63-1.11 (m, 6H).
EXAMPLE 13(19)
(R)-(+)-N-hydroxy-6-(4-cyclohexylphenyl)-6-hydroxyhexanamide
[0584] 209
[0585] [.alpha.].sub.D: +12.65 (c 0.16, methanol),
[0586] TLC: Rf 0.31 (chloroform:methanol=19:1),
[0587] NMR(d.sub.6-DMSO): .delta. 10.27 (s, 1H), 8.62 (s, 1H), 7.18
(d, J=8.1 Hz, 2H), 7.12 (d, J=8.1 Hz, 2H), 4.98 (d, J=4.2 Hz, 1H),
4.42-4.36 (m, 1H), 2.45-2.39 (m, 1H), 1.89 (t, J=7.2 Hz, 2H),
1.80-1.09 (m, 17H).
EXAMPLE 13(20)
(R)-N-hydroxy-6-[4-(5-hydroxybenzofuran-2-yl)phenyl]-6-hydroxyhexanamide
[0588] 210
[0589] TLC: Rf 0.27 (chloroform:methanol:acetic acid=60:10:1),
[0590] NMR(d.sub.6-DMSO): .delta. 10.25 (s, 1H), 9.18 (s, 1H), 8.60
(s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.35 (d,
J=8.8 Hz, 1H), 7.19 (s, 1H), 6.89 (d, J=2.6 Hz, 1H), 6.69 (dd,
J=8.8, 2.6 Hz, 1H), 5.17 (d, J=4.4 Hz, 1H), 4.60-4.40 (m, 1H), 1.88
(t, J=7.1 Hz, 2H), 1.70-1.10 (m, 6H).
EXAMPLE 13(21)
(R)-N-hydroxy-4-[4-(2-(4-methylphenyl)ethynyl)phenyl]-6-hydroxyhexanamide
[0591] 211
[0592] TLC: Rf 0.41 (chloroform:methanol:acetic acid=60:1 0:1),
[0593] NMR(d.sub.6-DMSO): .delta. 10.27 (s, 1H), 8.65 (s, 1H),
7.50-7.35 (m, 4H), 7.31 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H),
5.18 (d, J=4.4 Hz, 1H), 4.60-4.40 (m, 1H), 2.30 (s, 3H), 1.87 (t,
J=7.1 Hz, 2H), 1.65-1.00 (m, 6H).
EXAMPLE 13(22)
(R)-N-hydroxy-6-[4-((1E)-2-(4-methylphenyl)vinyl)phenyl]-6-hydroxyhexanami-
de
[0594] 212
[0595] TLC: Rf 0.43 (chloroform:methanol:acetic acid=60:10:1),
[0596] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 7.53-7.38 (m, 4H),
7.26 (d, J=8.0 Hz, 2H), 7.20-7.05 (m, 4H), 4.45 (t, J=6.4 Hz, 1H),
2.25 (s, 3H), 1.87 (t, J=7.0 Hz, 2H), 1.70-1.00 (m, 6H).
EXAMPLE 13(23)
(R)-N-hydroxy-6-[4-(4-trifluoromethoxyphenyl)phenyl]-6-hydroxyhexanamide
[0597] 213
[0598] TLC: Rf 0.25 (chloroform:methanol 9:1),
[0599] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H), 7.76
(d, J=8.7 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.43-7.38 (m, 4H), 5.15
(d, J=4.5 HZ, 1H), 4.55-4.95 (m, 1H), 1.90 (t, J=7.5 Hz, 2H),
1.63-1.12 (m, 6H).
EXAMPLE 13(24)
(R)-N-hydroxy-6-[4-(4-ethylthiophenyl)phenyl]-6-hydroxyhexanamide
[0600] 214
[0601] TLC: Rf 0.40 (ethyl acetate:methanol=4:1),
[0602] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H), 7.59
(d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 4H),
5.13 (br, 1H), 4.51 (t, J=6.0 Hz, 1H), 3.00 (q, J=7.2 Hz, 2H), 1.91
(t, J=7.0 Hz, 2H), 1.58 (m, 2H), 1.48 (m, 2H), 1.39-1.16 (m, 2H),
1.24 (t, J=7.2 Hz, 3H).
EXAMPLE 13(25)
(R)-N-hydroxy-6-[4-(4-methoxyphenyl)phenyl]-6-hydroxyhexanamide
[0603] 215
[0604] TLC: Rf 0.23 (ethyl acetate:methanol=4:1),
[0605] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.64 (s, 1H), 7.57
(d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H),
6.99 (d, J=8.5 Hz, 2H), 5.11 (d, J=4.2 Hz, 1H), 4.50 (m, 1H), 3.77
(s, 3H), 1.91 (t, J=7.2 Hz, 2H), 1.57 (m, 2H), 1.48 (m, 2H),
1.39-1.16 (m, 2H).
EXAMPLE 13(26)
(R)-N-hydroxy-6-[4-(4-(1-methylethyl)phenyl)phenyl]-6-hydroxyhexanamide
[0606] 216
[0607] TLC: Rf 0.20 (chloroform:methanol=9:1),
[0608] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (brs, 1H),
7.55 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz,
2H), 7.30 (d, J=8.4 Hz, 2H), 5.11 (brs, 1H), 4.50 (t, J=6.0 Hz,
1H), 2.98-2.82 (m, 1H), 1.90 (t, J=7.2 Hz, 2H), 1.62-1.20 (m, 6H),
1.21 (d, J=6.9 Hz, 6H).
EXAMPLE 13(27)
(R)-N-hydroxy-6-[4-(4-(N,N-dimethylcarbamoylmethyl)phenyl)phenyl]-6-hydrox-
yhexanamide
[0609] 217
[0610] TLC: Rf 0.21 (chloroform:methanol=9:1),
[0611] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.64 (s, 1H), 7.57
(d, J=8.0 Hz, 4H), 7.37 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H),
5.13 (d, J=4.4 Hz, 1H), 4.59-4.46 (m, 1H), 3.71 (s, 2H), 3.01 (s,
3H), 2.83 (s, 3H), 1.91 (t, J=7.0 Hz, 2H), 1.65-1.10 (m, 6H).
EXAMPLE 13(28)
(R)-N-hydroxy-6-[4-(benzothiazol-2-yl)phenyl]-6-hydroxyhexanamide
[0612] 218
[0613] TLC: Rf 0.24 (chloroform:methanol=9:1),
[0614] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.64 (s, 1H),
8.18-8.12 (m, 1H), 8.09-7.98 (m, 3H), 7.60-7.40 (m, 4H), 5.38-5.22
(m, 1H), 4.65-4.55 (m, 1H), 1.92 (t, J=7.4 Hz, 2H), 1.70-1.15 (m,
6H).
EXAMPLE 13(29)
(R)-N-hydroxy-6-[4-(4-(methoxymethoxymethyl)phenyl)phenyl]-6-hydroxyhexana-
mide
[0615] 219
[0616] TLC: Rf 0.30 (chloroform:methanol=9:1),
[0617] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.64 (s, 1H), 7.63
(d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H),
7.38 (d, J=8.0 Hz, 2H), 5.14 (d, J=4.4 Hz, 1H, 4.66 (s, 2H),
4.60-4.45 (m, 3H), 3.31 (s, 3H), 1.92 (t, J=7.0 Hz, 2H), 1.70-1.12
(m, 6H).
EXAMPLE 13(30)
(R)-(+)-N-hydroxy-6-[4-(6-methoxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanami-
de
[0618] 220
[0619] [.alpha.].sub.D: +7.31 (c 0.19, methanol),
[0620] TLC: Rf 0.15 (chloroform:methanol=9:1),
[0621] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (brs, 1H),
8.07 (d, J=8.7 Hz, 2H), 7.66 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.7 Hz,
2H), 7.40 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.7 Hz, 2.4 Hz, 1H), 5.29
(brs, 1H), 4.60-4.56 (m, 1H), 3.83 (s, 3H), 1.90 (t, J=7.5 Hz, 2H),
1.63-1.20 (m, 6H).
EXAMPLE 13(31)
(R)-N-hydroxy-4-[4-(6-methylbenzoxazol-2-yl)phenyl]4-hydroxyhexanamide
[0622] 221
[0623] TLC: Rf 0.28 (chloroform:methanol=9:1),
[0624] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.90-8.30 (br,
1H), 8.11 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.2 Hz, 1H), 7.59 (d, J=1.0
Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.21 (dd, J=8.2, 1.0 Hz, 1H),
5.60-4.90 (br, 1H), 4.60 (t, J=6.2 Hz, 1H), 2.46 (s, 3H), 1.91 (t,
J=7.4 Hz, 2H), 1.68-1.12 (m, 6H).
EXAMPLE 13(32)
(R)-N-hydroxy-6-[4-(4-methoxymethylphenyl)phenyl]-6-hydroxyhexanamide
[0625] 222
[0626] TLC: Rf 0.39 (chloroform:methanol=9:1),
[0627] NMR(d.sub.6-DMSO): .delta. 10.31 (s, 1H), 9.10-8.10 (br,
1H), 7.62 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4
Hz, 4H), 5.50-4.70 (br, 1H), 4.52 (t, J=6.2 Hz, 1H), 4.43 (s, 2H),
3.30 (s, 3H), 1.91 (t, J=7.4 Hz, 2H), 1.70-1.10 (m, 6H).
EXAMPLE 13(33)
(R)-N-hydroxy-4-[4-(5-methoxybenzoxazol-2-yl)phenyl]4-hydroxyhexanamide
[0628] 223
[0629] TLC: Rf 0.13 (chloroform:methanol:acetic acid=90:10:1),
[0630] NMR(d.sub.6-DMSO): .delta. 10.25 (s, 1H), 8.62 (s, 1H), 8.08
(d, J=8.3 Hz, 2H), 7.63 (d, J=9.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H),
7.31 (d, J=2.4 Hz, 1H), 6.96 (dd, J=9.0, 2.4 Hz, 1H), 5.29 (d,
J=4.5 Hz, 1H), 4.62-4.52 (m, 1H), 3.79 (s, 3H), 1.88 (t, J=7.2 Hz,
2H), 1.65-1.10 (m, 6H).
EXAMPLE 13(34)
(R)-N-hydroxy-6-[4-(4-methoxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide
[0631] 224
[0632] TLC: Rf 0.28 (chloroform:methanol=9:1),
[0633] NMR(d.sub.6-DMSO): .delta. 10.32 (s, 1H), 8.64 (s, 1H), 8.12
(d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.40-7.28 (m, 2H),
7.02-4.90 (m, 1H), 5.31 (d, J=4.4 Hz, 1H), 4.66-4.54 (m, 1H), 3.99
(s, 3H), 1.92 (t, J=7.4 Hz, 2H), 1.70-1.10 (m, 6H).
EXAMPLE 13(35)
(R)-(+)-N-hydroxy-4-[4-(4-(piperidin-1-ylmethyl)phenyl)phenyl]-6-hydroxyhe-
xanamide.hydrochloride
[0634] 225
[0635] [.alpha.].sub.D: +6.17 (c 0.12, methanol),
[0636] TLC: Rf 0.21 (chloroform:methanol=4:1),
[0637] NMR(d.sub.6-DMSO): .delta. 10.41-10.31 (m, 2H), 7.73 (d,
J=8.1 Hz, 2H), 7.65-7.61 (m, 4H), 7.39 (d, J=8.1 Hz, 2H), 4.52 (t,
J=6.3 Hz, 1H), 4.26 (d, J=5.1 Hz, 2H), 3.32-3.27 (m, 2H), 2.91-2.78
(m, 2H), 1.90 (t, J=7.2 Hz, 2H).
EXAMPLE 13(36)
(R)-(+)-N-hydroxy-6-[4-(4-hydroxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanami-
de
[0638] 226
[0639] [.alpha.].sub.D: +6.33 (c 0.12, methanol),
[0640] TLC: Rf 0.42 (chloroform:methanol=17:3),
[0641] NMR(d.sub.6-DMSO): .delta. 10.35 (s, 1H), 10.30 (s, 1H),
8.63 (s, 1H), 8.10 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H),
7.21-7.14 (m, 2H), 6.78-4.75 (m, 1H), 5.30 (d, J=4.5 Hz, 1H),
4.62-4.54 (m, 1H), 1.91 (t, J=7.2 Hz, 2H), 1.62-1.16 (m, 6H).
EXAMPLE 13(37)
(R)-N-hydroxy-6-[4-(6-hydroxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide
[0642] 227
[0643] TLC: Rf 0.21 (chloroform:methanol:acetic acid=60:10:1),
[0644] NMR(d.sub.6-DMSO): .delta. 10.25 (s, 1H), 9.80 (s, 1H), 8.60
(s, 1H), 8.03 (d, J=8.2 Hz, 2H), 7.56-7.42 (m, 3H), 7.05 (d, J=2.2
Hz, 1H), 6.81 (dd, J=8.4, 2.2 Hz, 1H), 5.25 (d, J=4.4 Hz, 1H),
4.62-4.50 (m, 1H), 1.88 (t, J=7.4 Hz, 2H), 1.70-1.10 (m, 6H).
EXAMPLE 13(38)
(R)-N-hydroxy-6-[4-((1E)-2-(4-methylthiophenyl)vinyl)phenyl]-6-hydroxyhexa-
namide
[0645] 228
[0646] TLC: Rf 0.22 (chloroform:methanol:acetic acid=90:10:1),
[0647] NMR(d.sub.6-DMSO): .delta. 10.25 (s, 1H), 7.50 (d, J=8.4 Hz,
2H), 7.49 (d, J=9.0 Hz, 2H), 7.30-7.05 (m, 6H), 4.45 (t, J=6.1 Hz,
1H), 2.45 (s, 3H), 1.87 (t, J=7.2 Hz, 2H), 1.65-1.00 (m, 6H).
EXAMPLE 13(39)
(R)-N-hydroxy-4-[4-(5-methoxybenzofuran-2-yl)phenyl]-6-hydroxyhexanamide
[0648] 229
[0649] TLC: Rf 0.27 (chloroform:methanol=9:1),
[0650] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.64 (s, 1H), 7.83
(d, J=8.4 Hz, 2H), 7.50 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H),
7.30 (s, 1H), 7.14 (d, J=2.6 Hz, 1H), 6.88 (dd, J=8.8, 2.6 Hz, 1H),
5.21 (d, J=4.4 Hz, 1H), 4.60-4.48 (m, 1H), 3.79 (s, 3H), 1.91 (t,
J=7.0 Hz, 2H), 1.68-1.14 (m, 6H).
EXAMPLE 13(40)
(R)-N-hydroxy-6-[4-(5-methylthiobenzofuran-2-yl)phenyl]-6-hydroxyhexanamid-
e
[0651] 230
[0652] TLC: Rf 0.27 (chloroform:methanol=9:1),
[0653] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.82-8.42 (br,
1H), 7.84 (d, J=8.4 Hz, 2H), 7.60-7.52 (m, 2H), 7.43 (d, J=8.4 Hz,
2H), 7.31 (s, 1H), 7.23 (dd, J=8.8, 2.0 Hz, 1H), 5.42-4.96 (br,
1H), 4.54 (t, J=6.4 Hz, 1H), 2.51 (s, 3H), 1.92 (t, J=7.0 Hz, 2H),
1.70-1.12 (m, 6H).
EXAMPLE 13(41)
(R)-(+)-N-hydroxy-6-[4-(4-(2-(dimethylamino)ethyl)phenyl)phenyl]-6-hydroxy-
hexanamide.hydrochloride
[0654] 231
[0655] [.alpha.].sub.D: +22.11 (c 0.635, dimethylformamide),
[0656] TLC: Rf 0.12 (chloroform:methanol=7:3),
[0657] NMR(d.sub.6-DMSO): .delta. 10.60 (s, 1H), 10.32 (s, 1H),
8.62 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H),
7.38-7.33 (m, 4H), 5.14 (d, J=4.2 Hz, 1H), 4.54-4.48 (m, 1H),
3.30-3.25 (m, 2H), 3.06-3.00 (m, 2H), 2.78 (s, 6H), 1.91 (t, J=7.2
Hz, 2H), 1.62-1.15 (m, 6H).
EXAMPLE 13(42)
(R)-(+)-N-hydroxy-6-[4-(4-(2-(dimethylamino)ethoxy)phenyl)phenyl]-6-hydrox-
yhexanamide.hydrochloride
[0658] 232
[0659] [.alpha.].sub.D: +20.47 (c 1.005, dimethylformamide),
[0660] TLC: Rf 0.32 (chloroform:methanol=4:1),
[0661] NMR(d.sub.6-DMSO): .delta. 10.56 (br, 1H), 10.32 (s, 1H),
8.63 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.35
(d, J=8.5 Hz, 2H), 7.07 (d, J=8.5 Hz, 2H), 5.12 (d, J=4.2 Hz, 1H),
4.05 (m, 1H), 4.39 (t, J=5.0 Hz, 2H), 3.50 (t, J=5.0 Hz, 2H), 2.83
(s, 6H), 1.91 (t, J=7.2 Hz, 2H), 1.57 (m, 2H), 1.50 (m, 2H),
1.39-1.17 (m, 2H).
EXAMPLE 13(43)
(R)-(+)-N-hydroxy-6-[4-(4-(2-(diethylamino)ethyl)phenyl)phenyl]-6-hydroxyh-
exanamide.hydrochloride
[0662] 233
[0663] [.alpha.].sub.D: 18.58 (c 0.93, dimethylformamide),
[0664] TLC: Rf 0.25 (chloroform:methanol=9:1),
[0665] NMR(d.sub.6-DMSO): .delta. 10.47 (brs, 1H), 10.32 (s, 1H),
8.62 (brs, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H),
7.37 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 5.13 (brs, 1H),
4.53-4.49 (m, 1H), 3.31-3.01 (m, 8H), 1.90 (t, J=6.9 Hz, 2H),
1.62-1.15 (m, 6H), 1.23 (t, J=6.9 Hz, 6H).
EXAMPLE 13(44)
(R)-N-hydroxy-4-[4-(4-(2-hydroxyethyl)phenyl)phenyl]-6-hydroxyhexanamide
[0666] 234
[0667] TLC: Rf 0.28 (chloroform:methanol=9:1),
[0668] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H), 7.56
(d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H),
7.27 (d, J=8.1 Hz, 2H), 5.12 (d, J=4.5 Hz, 1H), 4.64 (t, J=5.3 Hz,
1H), 4.51 (m, 1H), 3.61 (m, 2H), 2.74 (t, J=7.0 Hz, 2H), 1.91 (t,
J=7.0 Hz, 2H), 1.63-1.43 (m, 4H), 1.40-1.15 (m, 2H).
EXAMPLE 14(1).about.14(5)
[0669] By the same procedure as a series of reactions of reference
example 5.fwdarw.reference example 3.fwdarw.example
1.fwdarw.example 2 using a corresponding ketone derivative instead
of the compound prepared in reference example 1, if desired, the
conversion into the acid addition salts by conventional means, the
following compounds of the present invention were obtained.
EXAMPLE 14(1)
(S)-(-)-N-hydroxy-6-[4-(4-methylthiophenyl)phenyl]-6-hydroxyhexanamide
[0670] 235
[0671] [.alpha.].sub.D: -26.3 (c 0.99, dimethylformamide),
[0672] TLC: Rf 0.21 (chloroform:methanol=9:1),
[0673] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H), 7.60
(d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H),
7.32 (d, J=8.4 Hz, 2H), 5.12 (d, J=3.9 Hz, 1H), 4.51 (m, 1H), 2.50
(s, 3H), 1.91 (t, J=7.5 Hz, 2H), 1.65-1.15 (m, 6H),
EXAMPLE 14(2)
(S)-(-)-N-hydroxy-6-[4-(2-(4-methylthiophenyl)ethynyl)phenyl]-6-hydroxyhex-
anamide
[0674] 236
[0675] [.alpha.].sub.D: -33.4 (c 0.99, dimethylformamide),
[0676] TLC: Rf 0.19 (chloroform:methanol=9:1),
[0677] NMR(d.sub.6-DMSO): .delta. 10.28 (s, 1H), 8.62 (s, 1H), 7.47
(d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H),
7.27 (d, J=8.4 Hz, 2H), 5.20 (d, J=4.8 Hz, 1H), 4.51 (m, 1H), 2.49
(s, 3H), 1.90 (t, J=7.2 Hz, 2H), 1.60-1.40 (m, 4H), 1.35-1.15 (m,
2H).
EXAMPLE 14(3)
(S)-(-)-N-hydroxy-4-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide
[0678] 237
[0679] [.alpha.].sub.D: -11.5 (c 0.81, methanol),
[0680] TLC: Rf 0.21 (chloroform:methanol=9:1),
[0681] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.64 (s, 1H), 8.15
(d, J=8.4 Hz, 2H), 7.82-7.75 (m, 2H), 7.55 (d, J=8.4 Hz, 2H),
7.45-7.30 (m, 2H), 5.32 (d, J=4.8 Hz 4.65-4.56 (m, 1H), 1.92 (t,
J=7.0 Hz, 2H), 1.70-1.20 (m, 6H).
EXAMPLE 14(4)
(S)-(-)-N-hydroxy-6-[4-(5-methylbenzoxazol-2-yl)phenyl]-6-hydroxyhexanamid-
e
[0682] 238
[0683] [.alpha.].sub.D: -33.4 (c 0.99, dimethylformamide),
[0684] TLC: Rf 0.23 (chloroform:methanol=9:1),
[0685] NMR(d.sub.6-DMSO): .delta. 10.29 (d, J=1.5 Hz, 1H), 8.63 (d,
J=1.5 Hz, 1H), 8.12 (d, J=8.1 Hz, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.58
(d, J=1.2 Hz, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.23 (dd, J=8.4, 1.2 Hz,
1H), 5.32 (d, J=4.2,1H), 4.60 (m, 1H), 2.43 (s, 3H), 1.91 (t, J=6.9
Hz, 2H), 1.70-1.20 (m, 6H).
EXAMPLE 14(5)
(S)-(-)-N-hydroxy-6-[4-(4-(dimethylaminomethyl)phenyl)phenyl]-6-hydroxyhex-
anamide.hydrochloride
[0686] 239
[0687] [.alpha.].sub.D: -5.39 (c 0.495, water),
[0688] TLC: Rf 0.25 (chloroform:methanol=2:1),
[0689] NMR(d.sub.6-DMSO): .delta. 10.31 (m, 2H), 8.64 (s, 1H), 7.76
(d, J=8.0 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H),
7.41 (d, J=8.0 Hz, 2H), 5.16 (m, 1H), 4.53 (m, 1H), 4.29 (s, 2H),
2.71 (s, 6H), 1.91 (t, J=7.0 Hz, 2H), 1.65-1.15 (m, 6H).
EXAMPLE 15
(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(morpholin-4-ylmethyl)phenyl)phen-
yl]-6-hydroxyhexanamide
[0690] 240
[0691] By the same procedure as a series of reactions of reference
example 4.fwdarw.reference example 3.fwdarw.example 1 using methyl
6-[4-(4-(morpholin-4-ylmethyl)phenyl)phenyl]-6-oxohexanoate instead
of the compound prepared in reference example 1, the compound of
the present invention having the following physical data was
obtained.
[0692] TLC: Rf 0.46 (chloroform:methanol=6:1),
[0693] NMR(CDCl.sub.3): .delta. 7.74 (brs, 1H), 7.54 (d, J=8.1 Hz,
2H), 7.53 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1
Hz, 2H), 4.74-4.70 (m, 1H), 3.73-3.70 (m, 4H), 3.30 (s, 3H),
2.48-2.45 (m, 4H), 2.19-2.08 (m, 2H), 1.91-1.34 (m, 6H), 1.41 (s,
6H).
EXAMPLE 15(1)
(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(dipropylaminomethyl)phenyl)pheny-
l]-6-hydroxyhexanamide
[0694] 241
[0695] By the same procedure as a series of reactions of example 15
using methyl
6-[4-(4-(dipropylaminomethyl)phenyl)phenyl]-6-oxohexanoate instead
of methyl
6-[4-(4-(morpholin-4-ylmethyl)phenyl)phenyl]-6-oxohexanoate, the
compound of the present invention having the following physical
data was obtained.
[0696] TLC: Rf 0.31 (chloroform:methanol=9:1),
[0697] NMR(CDCl.sub.3): .delta. 7.76 (br, 1H), 7.57 (d, J=8.4 Hz,
2H), 7.52 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 4H), 4.72 (dd,
J=7.0, 5.8 Hz, 1H), 3.59 (s, 2H), 3.30 (s, 3H), 2.40 (t-like, J=7.5
Hz, 4H), 2.34 (m, 2H), 1.84-1.67 (m, 4H), 1.56-1.36 (m, 2H), 1.50
(m, J=7.5 Hz, 4H), 1.41 (s, 6H), 0.87 (t, J=7.5 Hz, 6H).
EXAMPLE 16
(R)-(+)-N-hydroxy-6-[4-(4-(morpholin-4-ylmethyl)phenyl)phenyl]-6-hydroxyhe-
xanamide.hydrochloride
[0698] 242
[0699] By the same procedure as a series of reactions of example 2
using the compound prepared in example 15 instead of the compound
prepared in example 1 and the conversion into the acid addition
salts by conventional means the compound of the present invention
having the following physical data was obtained.
[0700] [.alpha.].sub.D: +6.17 (c 0.12, methanol),
[0701] TLC: Rf 0.21 (chloroform:methanol=9:1),
[0702] NMR(d.sub.6-DMSO): .delta. 11.30 (brs, 1H), 10.32 (brs, 1H),
7.73 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.7 Hz,
2H), 7.39 (d, J=8.7 Hz, 2H), 4.52 (t, J=6.3 Hz, 1H), 4.34 (d, J=5.1
Hz, 2H), 3.94-3.75 (m, 4H), 3.20-2.95 (m, 4H), 1.93 (t, J=7.2 Hz,
2H), 1.65-1.15 (m, 6H).
EXAMPLE 16(1)
(R)-(+)-N-hydroxy-6-[4-(4-(dipropylaminomethyl)phenyl)phenyl]-6-hydroxyhex-
anamide
[0703] 243
[0704] By the same procedure as a series of reactions of example 16
using the compound prepared in example 15(1), or the conversion
into the acid addition salts by conventional means, the compounds
of the present invention having the following physical data were
obtained.
[0705] Free Form:
[0706] [.alpha.].sub.D: +20.85 (c 1.01, dimethylformamide),
[0707] TLC: Rf 0.37 (chloroform methanol=6:1),
[0708] NMR(d.sub.6-DMSO): .delta. 10.26 (br, 1H), 8.65 (br, 1H),
7.58 (d, J=8.4 Hz, 4H), 7.36 (d, J=8.4 Hz, 2H), 7.35, (d, J=8.4 Hz,
2H), 5.12 (br, 1H), 4.51 (t, J=6.0 Hz, 1H), 3.52 (s, 2H), 2.33 (t,
J=7.2 Hz, 4H), 1.91 (t, J=7.2 Hz, 2H), 1.64-1.55 (m, 2H), 1.51-1.37
(m, 6H), 1.36-1.17 (m, 2H), 0.82 (t, J=7.2 Hz, 6H).
[0709] Hydrochloride:
[0710] TLC: Rf 0.37 (chloroform:methanol=6:1),
[0711] NMR(d.sub.6-DMSO): .delta. 10.58 (br, 1H), 10.32 (s, 1H),
8.62 (br, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.65
(d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 5.17 (br, 1H), 4.53 (t,
J=6.3 Hz, 1H), 4.32 (s, 2H), 2.93 (m, 4H), 1.91 (t, J=7.2 Hz, 2H),
1.82-1.66 (m, 4H), 1.65-1.55 (m, 2H), 1.48 (m, 2H), 1.40-1.20 (m,
2H), 0.86 (t, J=7.2 Hz, 6H).
EXAMPLE 17(1) AND 17(2)
[0712] By the same procedure as a series of reactions of reference
example 4.fwdarw.reference example 3.fwdarw.example
1.fwdarw.example 2 using methyl
6-(5-phenylthiophen-2-yl)-6-oxohexanoate or methyl
6-(5-phenylbenzofuran-2-yl)-6-oxohexanoate instead of the compound
prepared in reference example 1, the following compounds of the
present invention were obtained.
EXAMPLE 17(1)
(R)-N-hydroxy-6-(5-phenylthiophen-2-yl)-6-hydroxyhexanamide
[0713] 244
[0714] TLC: Rf 0.19 (chloroform:methanol=9:1),
[0715] NMR(d.sub.6-DMSO): .delta. 10.42-10.20 (br, 1H), 8.80-8.55
(br, 1H), 7.64-7.56 (m, 2H), 7.43-7.20 (m, 4H), 6.90 (d, J=3.2 Hz,
1H), 5.59 (d, J=4.0 Hz, 1H), 4.80-4.65 (m, 1H), 1.93 (t, J=7.4 Hz,
2H), 1.76-1.15 (m, 6H).
EXAMPLE 17(2)
(R)-N-hydroxy-6-(5-phenylbenzofuran-2-yl)-6-hydroxyhexanamide
[0716] 245
[0717] TLC: Rf 0.28 (chloroform:methanol=9:1),
[0718] NMR(d.sub.6-DMSO): .delta. 10.31 (s, 1H), 8.65 (s, 1H), 7.83
(m, 1H), 7.70-7.52 (m, 4H), 7.50-7.28 (m, 3H), 6.75 (s, 1H), 5.53
(d, J=5.4 Hz, 1H), 4.72-4.58 (m, 1H), 1.93 (t, J=7.4 Hz, 2H),
1.84-1.62 (m, 2H), 1.60-1.18 (m, 4H).
REFERENCE EXAMPLE 16
(R)-benzyl
6-[4-(4-(methoxycarbonyl)phenyl)phenyl]-6-hydroxyhexanoate
[0719] 246
[0720] By the same procedure as a series of reactions of reference
example 4 using benzyl
6-[4-(4-(methoxycarbonyl)phenyl)phenyl]-6-oxohexanoate instead of
the compound prepared in reference example 1, the title compound
having the following physical data was obtained.
[0721] TLC: Rf 0.19 (chloroform:ethyl acetate=19:1).
REFERENCE EXAMPLE 17
(R)-6-[4-(4-(methoxycarbonyl)phenyl)phenyl]-6-hydroxyhexanoic
acid
[0722] 247
[0723] To a solution of the compound prepared in reference example
16 (1.36 g) in methanol (20 mL) and tetrahydrofuran (10 mL) was
added 10% palladium carbon (136 mg). Under an atmosphere of
hydrogen, the reaction mixture was stirred at room temperature for
1.5 hours. The reaction mixture was filtered and concentrated. The
obtained residue was washed with ether and dried to give the title
compound (951 mg) having the following physical data.
[0724] TLC: Rf 0.32 (chloroform:methanol=9:1).
EXAMPLE 18
(R)-N-hydroxy-6-[4-(4-(methoxycarbonyl)phenyl)phenyl]-6-hydroxyhexanamide
[0725] 248
[0726] By the same procedure as a series of reactions of example
1.fwdarw.example 2 using the compound prepared in reference example
17, the compound of present invention having the following physical
data was obtained.
[0727] TLC: Rf 0.28 (chloroform:methanol=9:1),
[0728] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.64 (s, 1H), 8.02
(d, J=8.4 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H),
7.42 (d, J=8.4 Hz, 2H), 5.18 (d, J=4.4 Hz, 2H), 4.61-4.48 (m, 1H),
3.86 (s, 3H), 1.91 (t, J=7.4 Hz, 2H), 1.67-1.10 (m, 6H).
EXAMPLE 19
(R)-N-hydroxy-6-[4-(4-carboxyphenyl)phenyl]-6-hydroxyhexanamide
[0729] 249
[0730] By the same procedure as a series of reactions of example
1.fwdarw.reference example 3.fwdarw.example 2 using the compound
prepared in reference example 17, the compound of present invention
having the following physical data was obtained.
[0731] TLC: Rf 0.16 (chloroform:methanol:acetic acid=90:10:1),
[0732] NMR(d.sub.6-DMSO): .delta. 10.31 (s, 1H), 8.00 (d, J=8.4 Hz,
2H), 7.75 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4
Hz, 2H), 5.40-4.90 (br, 1H), 4.61-4.47 (m, 1H), 1.92 (t, J=7.0 Hz,
2H), 1.70-1.10 (m, 6H).
REFERENCE EXAMPLE 18
(R)-methyl 6-[4-(4-methylthiophenyl)phenyl]-6-hydroxyhexanoate
[0733] 250
[0734] By the same procedure as a series of reactions of reference
example 4 using methyl
6-[4-(4-methylthiophenyl)phenyl]-6-oxohexanoate instead of the
compound prepared in reference example 1, the title compound having
the following physical data was obtained.
[0735] TLC: Rf 0.25 (hexane:ethyl acetate=2:1),
[0736] NMR(CDCl.sub.3): .delta. 7.57-7.49 (m, 4H), 7.39 (d, J=8.4
Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 4.72 (t, J=6.2 Hz, 1H), 3.65 (s,
3H), 2.32 (t, J=7.4 Hz, 2H), 1.88-1.25 (m, 6H).
REFERENCE EXAMPLE 19
(R)-methyl
6-[4-(4-methylsulfonylphenyl)phenyl]4-hydroxyhexanoate
[0737] 251
[0738] To a solution of the compound prepared in reference example
18 (335 mg) in dichloromethane (10 mL) was added m-chloroperbenzoic
acid (504 mg) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 1 hour. To the reaction mixture was added an
aqueous solution of sodium thiosulfate and the mixture was
extracted with ethyl acetate. The extract was washed with water and
a saturated aqueous solution of sodium chloride, dried over
anhydrous sodium sulfate and concentrated to give the title
compound (349 mg) having the following physical data.
[0739] TLC: Rf 0.51 (hexane:ethyl acetate=1:4),
[0740] NMR(CDCl.sub.3): .delta. 8.00 (d, J=8.4 Hz, 2H), 7.76 (d,
J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H),
4.80-4.72 (m, 1H), 3.66 (s, 3H), 3.09 (s, 3H), 2.32 (t, J=7.5 Hz,
2H), 1.90-1.30 (m, 6H).
EXAMPLE 20
(R)-(+)-N-hydroxy-6-[4-(4-methylsulfonylphenyl)phenyl]-6-hydroxyhexanamide
[0741] 252
[0742] By the same procedure as a series of reactions of reference
example 3.fwdarw.example 1.fwdarw.example 2 using the compound
prepared in reference example 19 instead of the compound prepared
in reference example 2, the compound of the present invention
having the following physical data was obtained.
[0743] [.alpha.].sub.D: +9.84 (c 0.125, methanol),
[0744] TLC: Rf 0.12 (chloroform:methanol=9:1),
[0745] NMR(d.sub.6-DMSO): .delta. 10.29 (s, 1H), 8.63 (s, 1H), 7.97
(d, J=8.7 Hz, 2H), 7.91 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H),
7.43 (d, J=8.7 Hz, 2H), 5.19 (d, J=4.5 Hz, 1H), 4.59-4.51 (m, 1H),
3.23 (s, 1H), 1.90 (t, J=7.5 Hz, 2H), 1.62-1.18 (m, 6H).
REFERENCE EXAMPLE 20
(R)-methyl
6-[4-(4-hydroxymethylphenyl)phenyl]-6-hydroxyhexanoate
[0746] 253
[0747] By the same procedure as a series of reactions of reference
example 4 using methyl 6-[4-(4-formylphenyl)phenyl]-6-oxohexanoate
instead of the compound prepared in reference example 1, the title
compound having the following physical data was obtained.
[0748] TLC: Rf 0.27 (hexane:ethyl acetate=1:1),
[0749] NMR(CDCl.sub.3): .delta. 7.59 (d, J=8.4 Hz, 2H), 7.57 (d,
J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H),
4.78-4.66 (m, 3H), 3.66 (s, 3H), 2.32 (t, J=7.6 Hz, 2H), 2.02-1.20
(m, 6H).
EXAMPLE 21
(R)-N-hydroxy-6-[4-(4-hydroxymethylphenyl)phenyl]-6-hydroxyhexanamide
[0750] 254
[0751] By the same procedure as a series of reactions of reference
example 3.fwdarw.example 1.fwdarw.example 2 using the compound
prepared in reference example 20 instead of the compound prepared
in reference example 2, the compound of the present invention
having the following physical data was obtained.
[0752] TLC: Rf 0.13 (chloroform:methanol=9:1),
[0753] NMR(d.sub.6-DMSO): .delta. 10.30 (s, 1H), 8.80-8.50 (br.
1H), 7.60 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0
Hz, 4H), 5.40-5.00 (br, 2H), 4.60-4.40 (m, 3H), 1.91 (t, J=7.0 Hz,
2H), 1.70-1.10 (m, 6H).
EXAMPLE 22
N-methoxy-6-[4-(4-chlorophenyl)phenyl]-6-hydroxyhexanamide
[0754] 255
[0755] By the same procedure as a series of reactions of example 1
using methoxylamine instead of
(1-methoxy-1-methylethyl)hydroxyamine, the compound of the present
invention having the following physical data was obtained.
[0756] TLC: Rf 0.27 (ethyl acetate),
[0757] NMR(CDCl.sub.3): .delta. 8.21 (br, 1H), 7.52 (d, J=8.0 Hz,
2H), 7.49 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 4H), 4.74-4.70 (m,
1H), 3.72 (s, 3H), 2.44-2.04 (m, 3H), 1.90-1.62 (m, 4H), 1.58-1.34
(m, 2H).
EXAMPLE 23
(R)-(+)-5-(5,5-dimethyl-1,4,2-dioxazolin-3-yl)-1-[4-(5-methylbenzoxazol-2--
yl)phenyl]pentan-1-ol
[0758] 256
[0759] A solution of the compound prepared in example 6 (3 g) in
toluene (100 mL) was stirred at 100.degree. C. for 3 hours. The
reaction mixture was concentrated. The obtained residue was washed
with isopropyl ether and dried to give the compound (2.83 g) of the
present invention having the following physical data.
[0760] [.alpha.].sub.D: +24.59 (c 0.81, dimethylformamide),
[0761] TLC: Rf 0.21 (hexane:ethyl acetate=2:1),
[0762] NMR(CDCl.sub.3): .delta. 8.21 (d, J=8.4 Hz, 2H), 7.54 (brs,
1H), 7.49 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 1H), 7.17-7.14 (m,
1H), 4.79-4.75 (m, 1H), 2.48 (s, 3H), 2.30 (t, J=7.2 Hz, 2H),
1.91-1.33 (m, 6H), 1.53 (s, 6H).
EXAMPLE 23(1) AND 23(2)
[0763] Using the compound prepared in example 6(3) or (4) instead
of the compound prepared in example 6, if desired, the conversion
into the acid addition salts by conventional means, the following
compounds of the present invention were obtained.
EXAMPLE 23(1)
(R)-5-(5,5-dimethyl-1,4,2-dioxazolin-3-yl)-1-[4-(4-methylthiophenyl)phenyl-
]pentan-1-ol
[0764] 257
[0765] TLC: Rf 0.57 (hexane:ethyl acetate=1:1),
[0766] NMR(CDCl.sub.3): 67.54 (d, J=8.5 Hz, 2H), 7.51 (d, J=8.5 Hz,
2H), 7.39 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 4.71 (m, 1H),
2.52 (s, 3H), 2.30 (t, J=7.5 Hz, 2H), 1.94-1.72 (m, 2H), 1.66 (m,
2H), 1.57-1.35 (m, 2H), 1.53 (s, 3H), 1.52 (s, 3H).
EXAMPLE 23(2)
(R)-5-(5,5-dimethyl-1,4,2-dioxazolin-3-yl)-1-[4-(4-(dimethylaminomethyl)ph-
enyl)phenyl]pentan-1-ol.1.5 fumaric acid salt
[0767] 258
[0768] [.alpha.].sub.D: +15.9 (c 1.16, dimethylformamide),
[0769] TLC: Rf 0.30 (chloroform:methanol=9:1),
[0770] NMR(d.sub.6-DMSO): .delta. 7.63 (d, J=8.3 Hz, 2H), 7.60 (d,
J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 6.57
(s, 3H), 4.54 (t, J=6.0 Hz, 1H), 3.71 (s, 2H), 2.34 (s, 6H), 2.26
(t, J=7.2 Hz, 2H), 1.67-1.23 (m, 6H), 1.43 (s, 6H).
EXAMPLE 24
(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(2-(morpholin-4-yl)ethoxy)phenyl)-
phenyl]-6-hydroxyhexanamide
[0771] 259
[0772] By the same procedure as a series of reactions of reference
example 4.fwdarw.reference example 3.fwdarw.example 1 using methyl
6-[4-(4-(2-(morpholin-4-yl)ethoxy)phenyl)phenyl]-6-oxohexanoate
instead of the compound prepared in reference example 1, the
compound of the present invention having the following physical
data was obtained.
[0773] TLC: Rf 0.50 (chloroform:methanol=9:1),
[0774] NMR(CD.sub.3OD): .delta. 7.52 (d, J=8.7 Hz, 2H), 7.51 (d,
J=8.7 Hz, 2H), 7.36 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 4.62
(t, J=6.6 Hz, 1H), 4.17 (t, J=5.4 Hz, 2H), 3.72 (t, J=4.7 Hz, 4H),
3.28 (s, 3H), 2.82 (t, J=5.4 Hz, 2H), 2.61 (t, J=4.7 Hz, 4H), 2.13
(t, J=7.2 Hz, 2H), 1.86-1.70 (m, 2H), 1.64 (m, 2H), 1.50-1.23 (m,
2H), 1.33 (s, 6H).
EXAMPLE 24(1)
(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(2-(morpholin-4-yl)ethyl)phenyl)p-
henyl]-6-hydroxyhexanamide
[0775] 260
[0776] By the same procedure as a series of reactions of example 24
using methyl
6-[4-(4-(2-(morpholin-4-yl)ethyl)phenyl)phenyl]-6-oxohexanoate
instead of methyl
6-[4-(4-(2-(morpholin-4-yl)ethoxy)phenyl)phenyl]-6-oxoh- exanoate,
the compound of the present invention having the following physical
data was obtained.
[0777] TLC: Rf 0.46 (chloroform:methanol=9:1),
[0778] NMR(CDCl.sub.3): .delta. 7.70 (brs, 1H), 7.55 (d, J=8.1 Hz,
2H), 7.51 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1
Hz, 2H), 4.74-4.69 (m, 1H), 3.77-3.73 (m, 4H), 3.30 (s, 3H),
2.87-2.81 (m, 2H), 2.65-2.60 (m, 2H), 2.55-2.53 (m, 4H), 2.19-1.32
(m, 8H), 1.41 (s, 6H).
EXAMPLE 25
(R)-(+)-N-hydroxy-6-[4-(4-(2-(morpholin-4-yl)ethoxy)phenyl)phenyl]-6-hydro-
xyhexanamide.hydrochloride
[0779] 261
[0780] By the same procedure as a series of reactions of example 2
using the compound prepared in example 24 instead of the compound
prepared in example 1 and the conversion into the acid addition
salts by conventional means, the compound of the present invention
having the following physical data was obtained.
[0781] [.alpha.].sub.D: +13.52 (c 0.84, dimethylformamide),
[0782] TLC: Rf 0.31 (chloroform:methanol=9:1),
[0783] NMR(d.sub.6-DMSO): .delta. 10.92 (brs, 1H), 10.30 (s, 1H),
8.61 (brs, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H),
7.35 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 5.12 (brs, 1H),
4.53-4.41 (m, 3H), 4.01-3.93 (m, 2H), 3.84-3.74 (m, 2H), 3.60-3.12
(m, 6H), 1.90 (t, J=7.2 Hz, 2H), 1.62-1.12 (m, 6H).
EXAMPLE 25(1)
(R)-(+)-N-hydroxy-6-[4-(4-(2-(morpholin-4-yl)ethyl)phenyl)phenyl]-6-hydrox-
yhexanamide.hydrochloride
[0784] 262
[0785] By the same procedure as a series of reactions of example 25
using the compound prepared in example 24(1) or the conversion into
the acid addition salts by conventional means, the compound of the
present invention having the following physical data was
obtained.
[0786] [.alpha.].sub.D: +16.80 (c 0.815, dimethylformamide), TLC:
Rf 0.41 (chloroform:methanol=17:3),
[0787] NMR(d.sub.6-DMSO): .delta. 10.82 (brs, 1H), 10.30 (s, 1H),
8.62 (brs, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H),
7.37 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 5.13 (brs, 1H),
4.53-4.49 (m, 1H), 4.00-3.96 (m, 2H), 3.96-3.72 (m, 2H), 3.51-3.47
(m, 2H), 3.39-3.25 (m, 2H), 3.18-3.02 (m, 4H), 1.90 (t, J=7.2 Hz,
2H), 1.64-1.16 (m, 6H).
[0788] [Formulation Example]
FORMULATION EXAMPLE 1
[0789] The following components were admixed in a conventional
technique, punched out to give 100 tablets each containing 50 mg of
active ingredient.
8 (R)-(+)-N-hydroxy-6-(4-(4-chlorophenyl)phenyl)- 5.0 g
6-hydroxyhexanamide calcium carboxymethylcellulose (disintegrant)
0.2 g magnesium stearate (lubricant) 0.1 g microcrystalline
cellulose 4.7 g
FORMULATION EXAMPLE 2
[0790] The following components were admixed in a conventional
technique. The solution was sterilized in a conventional technique,
filled in ampoules 5 ml each and freeze-dried in a conventional
technique to give 100 ampoules each containing 20 mg of active
ingredient.
9 (R)-(+)-N-hydroxy-6-(4-(4-chlorophenyl)phenyl)- 2.0 g
6-hydroxyhexanamide mannitol 20 g distilled water 500 mL
* * * * *