U.S. patent application number 10/342231 was filed with the patent office on 2003-10-23 for bisaryl compound and medicament for cancer treatment comprising the same.
This patent application is currently assigned to KYOWA HAKKO KOGYO CO., LTD.. Invention is credited to Asanuma, Naoki, Ikeda, Shun-ichi, Inaba, Tadashi, Kanda, Yuko, Kawamoto, Hiroshi, Kitaguchi, Hiroshi, Mizukami, Tamio, Satomura, Masato, Takahashi, Takeshi, Takashima, Masanobu, Takeuchi, Hiroshi, Tamaoki, Tatsuya, Tsukada, Yoshihisa, Yonetani, Yoshiyuki.
Application Number | 20030199560 10/342231 |
Document ID | / |
Family ID | 26466988 |
Filed Date | 2003-10-23 |
United States Patent
Application |
20030199560 |
Kind Code |
A1 |
Yonetani, Yoshiyuki ; et
al. |
October 23, 2003 |
Bisaryl compound and medicament for cancer treatment comprising the
same
Abstract
A medicament for treatment of cancer comprising a compound
represented by the following general formula (I) or a
physiologically acceptable salt thereof:
Ar.sup.1--S--R.sup.1--S--Ar.sup.2 wherein R.sup.1 represents a
nonmetal bridging group; Ar.sup.1 and Ar.sup.2 independently
represent a group selected from the group consisting of an aryl
group which has, on its ring, one to three hydroxyl groups
optionally substituted with a monovalent group and said aryl group
may have one to three substituents other than hydroxyl group on its
ring; and a heteroaryl group which has, on its ring, one to three
hydroxyl groups optionally substituted with a monovalent group, and
said heteroaryl group may have one to three substituents other than
hydroxyl group on its ring.
Inventors: |
Yonetani, Yoshiyuki; (Tokyo,
JP) ; Takahashi, Takeshi; (Numazu-shi, JP) ;
Kanda, Yuko; (Tokyo, JP) ; Mizukami, Tamio;
(Tokyo, JP) ; Tamaoki, Tatsuya; (Tokyo, JP)
; Ikeda, Shun-ichi; (Osaka, JP) ; Takashima,
Masanobu; (Minami-ashigara-shi, JP) ; Asanuma,
Naoki; (Minami-ashigara-shi, JP) ; Inaba,
Tadashi; (Minami-ashigara-shi, JP) ; Takeuchi,
Hiroshi; (Minami-ashigara-shi, JP) ; Kawamoto,
Hiroshi; (Minami-ashigara-shi, JP) ; Tsukada,
Yoshihisa; (Minami-ashigara-shi, JP) ; Satomura,
Masato; (Minami-ashigara-shi, JP) ; Kitaguchi,
Hiroshi; (Minami-ashigara-shi, JP) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 Pennsylvania Avenue, NW
Washington
DC
20037-3213
US
|
Assignee: |
KYOWA HAKKO KOGYO CO., LTD.
|
Family ID: |
26466988 |
Appl. No.: |
10/342231 |
Filed: |
January 15, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10342231 |
Jan 15, 2003 |
|
|
|
09424352 |
Feb 14, 2000 |
|
|
|
Current U.S.
Class: |
514/357 ;
514/408; 514/646 |
Current CPC
Class: |
C07D 251/38 20130101;
C07D 213/32 20130101; C07C 323/25 20130101; C07D 211/58 20130101;
C07D 317/22 20130101; C07D 215/06 20130101; C07D 233/64 20130101;
C07D 207/08 20130101; C07D 319/06 20130101; C07H 5/06 20130101;
C07D 277/56 20130101; C07D 239/58 20130101; C07D 211/60 20130101;
C07C 323/16 20130101; C07D 317/28 20130101; C07D 309/38 20130101;
C07C 323/40 20130101; A61P 35/00 20180101; C07D 239/42 20130101;
C07H 15/18 20130101 |
Class at
Publication: |
514/357 ;
514/646; 514/408 |
International
Class: |
A61K 031/44; A61K
031/135; A61K 031/40 |
Foreign Application Data
Date |
Code |
Application Number |
May 22, 1997 |
JP |
9-132398 |
Dec 17, 1997 |
JP |
9-347989 |
Claims
What is claimed is:
1. A medicament for treatment of cancer comprising a compound
represented by the following general formula (I) or a
physiologically acceptable salt thereof:
Ar.sup.1--S--R.sup.1--S--Ar.sup.2 wherein R.sup.1 represents a
nonmetal bridging group; Ar.sup.1 and Ar.sup.2 independently
represent a group selected from the group consisting of an aryl
group which has, on its ring, one to three hydroxyl groups
optionally substituted with a monovalent group and said aryl group
may have one to three substituents other than hydroxyl group on its
ring; and a heteroaryl group which has, on its ring, one to three
hydroxyl groups optionally substituted with a monovalent group and
said heteroaryl group may have one to three substituents other than
hydroxyl group on its ring.
2. The medicament for treatment of cancer according to claim 1
comprising a compound or a physiologically acceptable salt thereof,
wherein R.sup.1 is represented by the general formula (II):
--R.sup.2--N(R.sup.4)--R.sup.- 3-- (II) wherein R.sup.2 and R.sup.3
independently represent a divalent group; R.sup.4 represents a
monovalent group; and R.sup.4 may bind to R.sup.2 or R.sup.3 to
form a cyclic structure which may further bind to one or two
C.sub.1-4 alkylene groups to form a divalent group.
3. The medicament for treatment of cancer according to claim 1
comprising a compound or a physiologically acceptable salt thereof,
wherein R.sup.1 is represented by the general formula (III):
--R.sup.5--X.sup.1--R.sup.6-- - (III) wherein R.sup.5 and R.sup.6
independently represent a single bond or a divalent group not
containing a nitrogen atom; X.sup.1 represents an oxygen atom,
S(O).sub.k wherein k represents an integer of from 0 to 2, or
[(R.sup.9X.sup.2).sub.m(R.sup.10X.sup.3).sub.n(R.sup.11X.sup.4).sub.p]-
.sub.q wherein R.sup.9, R.sup.10 and R.sup.11 independently
represent a single bond or a divalent group not containing a
nitrogen atom, and any groups selected from R.sup.5, R.sup.6,
R.sup.9, R.sup.10 and R.sup.11 may bind together to form a cyclic
structure, X.sup.2, X.sup.3 and X.sup.4 independently represent an
oxygen atom, S(O).sub.r wherein r represents an integer of from 0
to 2, or a single bond, and m, n, p and q independently represent
an integer of from 1 to 3.
4. The medicament for treatment of cancer according to claim 1
comprising a compound or a physiologically acceptable salt thereof,
wherein R.sup.1 is 2,6-pyridinediyldimethyl group wherein the
pyridinediyldimethyl group may have one to three substituents other
than hydrogen atom on its ring.
5. The medicament for treatment of cancer according to claim 2
comprising a compound or a physiologically acceptable salt thereof,
wherein R.sup.2 and R.sup.3 are the same divalent groups; and
R.sup.4 is a C.sub.1-4 alkyl group which may have one to three
substituents other than hydrogen atom.
6. The medicament for treatment of cancer according to claim 2
comprising a compound or a physiologically acceptable salt thereof,
wherein R.sup.2 and R.sup.3 are the same divalent groups; R.sup.4
is represented by COR.sup.26 wherein R.sup.25 represents hydrogen
atom, a C.sub.1-4 alkyl group, an aryl group, a heteroaryl group, a
heterocyclic group, an aralkyl group, or NR.sup.26R.sup.27 wherein
R.sup.26 and R.sup.27 each represent hydrogen atom, a C.sub.1-4
alkyl group, an aryl group, a heteroaryl group, a heterocyclic
group, or an aralkyl group, and said alkyl group, aryl group,
heteroaryl group, heterocyclic group, and aralkyl group including
those for R.sup.26 and R.sup.27 may have one to three substituents
other than hydrogen atom.
7. The medicament for treatment of cancer according to claim 1
comprising a compound or a physiologically acceptable salt thereof,
wherein R.sup.1 is represented by
R.sup.1A--R.sup.1BCO--R.sup.1C--R.sup.1D--R.sup.1C--COR-
.sup.1B--R.sup.1A wherein R.sup.1A represents a C.sub.1-4 lower
alkylene group; R.sup.1B represents NH or methylene group; R.sup.1C
represents a single bond or methylene group; R.sup.1D represents a
divalent bridging cyclic hydrocarbon group, monocyclic hydrocarbon
group, or heterocyclic group, and said bridging cyclic hydrocarbon
group, monocyclic hydrocarbon group, or heterocyclic group may have
one to three substituents other than hydrogen atom.
8. The medicament for treatment of cancer according to any one of
claims 1 to 7 comprising a compound or a physiologically acceptable
salt thereof, wherein Ar.sup.1 and Ar.sup.2 independently represent
the aryl group.
9. The medicament for treatment of cancer according to claim 8
comprising a compound or a physiologically acceptable salt thereof,
wherein both of Ar.sup.1 and Ar.sup.2 are 4-hydroxyphenyl
groups.
10. The medicament for treatment of cancer according to claim 8 or
claim 9 comprising a compound or a physiologically acceptable salt
thereof, wherein R.sup.2 and R.sup.3 are the same groups, and the
minimum number of bridge-forming atoms of R.sup.2 and R.sup.3 are
from 1 to 10.
11. The medicament for treatment of cancer according to claim 10
comprising a compound or a physiologically acceptable salt thereof,
wherein R.sup.2 and R.sup.3 are the same groups, and the minimum
number of bridge-forming atoms of R.sup.2 and R.sup.3 are from 1 to
4.
12. The medicament for treatment of cancer according to claim 10 or
claim 11 comprising a compound or a physiologically acceptable salt
thereof, wherein R.sup.2 and R.sup.3 are the same linear or
branched divalent groups which may contain one to three oxygen
atoms.
13. The medicament for treatment of cancer according to any one of
claims 1 to 12 comprising a compound or a physiologically
acceptable salt thereof, wherein the total number of carbon atoms
is 35 or less.
14. The medicament for treatment of cancer according to any one of
claims 1 to 12, which is in the form of a pharmaceutical
composition comprising the compound according to any one of claims
1 to 13 or a physiologically acceptable salt thereof as an active
ingredient together with one or more pharmaceutical additives.
15. Use of the compound according to any one of claims 1 to 13 or a
salt thereof for the manufacture of the medicament for treatment of
cancer according to any one of claims 1 to 14.
16. A ribonucleotide reductase inhibitor which comprises the
compound according to any one of claims 1 to 13 or a salt
thereof.
17. The medicament for treatment of cancer according to any one of
claims 1 to 14, which is used for preventive and/or therapeutic
treatment of a disease caused by over-expression of ribonucleotide
reductase.
18. A selective cancer cell proliferation inhibitor which comprises
the compound according to any one of claims 1 to 13 or a salt
thereof.
19. A method for treatment of a cancer which comprises the step of
administering a therapeutically effective amount of the compound
according to any one of claims 1 to 13 or a salt thereof to a
patient.
20. A compound represented by the general formula (XII) or a salt
thereof:
Ar.sup.23--S--R.sup.22--N(R.sup.24)--R.sup.23--S--Ar.sup.24wherein
R.sup.22 and R.sup.23 independently represent a divalent group;
R.sup.24 represents a monovalent group or a monovalent atom;
R.sup.24 may bind to R.sup.22 and/or R.sup.23 to form a cyclic
structure, which may further bind to one or two C.sub.1-4 alkylene
groups to form a divalent group; Ar.sup.23 and Ar.sup.24
independently represent a group selected from the group consisting
of an aryl group which has, on its ring, one to three hydroxyl
groups optionally substituted with a monovalent group and said aryl
group may have one to three substituents other than hydroxyl group
on its ring, and a heteroaryl group which has, on its ring, one to
three hydroxyl groups optionally substituted with a monovalent
group and said heteroaryl group may have one to three substituents
other than hydroxyl group on its ring, provided that
R.sup.22--N(R.sup.24)--R.sup.23 except for the part of R.sup.24
does not contain an amide bond when R.sup.22 and R.sup.23 do not
form a ring, and provided that when Ar.sup.23 and Ar.sup.24 is
independently a phenyl group having one hydroxyl group on the ring,
not all of said phenyl groups have a tertiary alkyl group at a
position on the ring adjacent to the hydroxyl group.
21. The compound or the salt thereof according to claim 20, wherein
two or three groups selected from the group consisting of R.sup.22,
R.sup.23 and R.sup.24 form a ring.
22. The compound or the salt thereof, wherein R.sup.22 and R.sup.23
are the same divalent groups; and R.sup.2.sup.4 is a C.sub.1-4
alkyl group which may have one to three substituents other than
hydrogen atom.
23. The compound or the salt thereof, wherein R.sup.22 and R.sup.23
are the same divalent groups; R.sup.24 is represented by
COR.sup.125 wherein R.sup.126 represents hydrogen atom, a C.sub.1-4
alkyl group, an aryl group, a heteroaryl group, a heterocyclic
group, an aralkyl group, or NR.sup.126R.sup.127 wherein R.sup.126
and R.sup.127 each represent hydrogen atom, a C.sub.1-4 alkyl
group, an aryl group, a heteroaryl group, a heterocyclic group, or
an aralkyl group, and said alkyl group, aryl group, heteroaryl
group, heterocyclic group, and aralkyl group including those for
R.sup.126 and R.sup.127 may have one to three substituents other
than hydrogen atom.
24. The compound or the salt thereof, wherein
R.sup.22--N(R.sup.24)--R.sup- .23 is represented by
R.sup.101A--R.sup.101BCO--R.sup.101C--R.sup.101D--R.-
sup.101C--COR.sup.101B--R.sup.101A wherein R.sup.101A represents a
C.sup.1-4 lower alkylene group; R.sup.101B represents NH or
methylene group; R.sup.101C represents a single bond or methylene
group; R.sup.101D represents a divalent bridging cyclic hydrocarbon
group, monocyclic hydrocarbon group, or heterocyclic group, and
said bridging cyclic hydrocarbon group, monocyclic hydrocarbon
group, or heterocyclic group may have one to three substituents
other than hydrogen atom.
25. The compound or the salt thereof according to any one of claims
20 to 24, wherein Ar.sup.23 and Ar.sup.24 independently represent
an aryl group which has, on its ring, one to three hydroxyl groups
optionally substituted with a monovalent group and said aryl group
may have one to three substituents other than hydroxyl group on its
ring.
26. The compound or the salt thereof according to claim 25, wherein
both of Ar.sup.23 and Ar.sup.24 are 4-hydroxyphenyl groups.
27. The compound or the salt thereof according to any one of claims
20 to 26, wherein R.sup.22 and R.sup.23 are the same groups, and
the minimum number of bridge-forming atoms of R.sup.22 and R.sup.23
are from 1 to 10.
28. The compound or the salt thereof according to claim 27, wherein
R.sup.22 and R.sup.23 are the same groups, and the minimum number
of bridge-forming atoms of R.sup.22 and R.sup.23 are from 1 to
4.
29. The compound or the salt thereof according to any one of claims
20 to 28, wherein R22 and R.sup.23 independently represent
methylene group, ethylene group, propylene group or butylene
group.
30. The compound or the salt thereof according to any one of claims
20 to 28, wherein R.sup.22 and R.sup.23 are the same groups, and
represent methylene group, ethylene group, propylene group or
butylene group.
31. The compound or the salt thereof according to any one of claims
20 to 30, wherein the total number of carbon atoms is 35 or less.
Description
TECHNICAL FIELD
[0001] The present invention relates to a novel bisaryl compound
and a medicament for treatment of cancer which comprises said
compound or a known bisaryl compound as an active ingredient.
BACKGROUND ART
[0002] In the cell proliferation process, DNA replication process
is regulated by a family of enzymes relating to nucleic acid
synthesis. Among these enzymes, it has been reported that
ribonucleotide reductase (occasionally referred to as "RNR"
hereinafter in this specification) is a particularly important
enzyme involved in the biosynthesis of dNTPs, which are precursors
of DNA (Ann. Rev. Biochem, 57, pp.349-374).
[0003] In cancer cells, endless cell proliferation continues due to
over-expression of certain families of enzymes and the like, which
leads to death of the host. It has been reported that RNR is
over-expressed in cancer cells to maintain high ability of cell
proliferation of cancer cells (Cancer Research, 43, pp.3466-3492).
Moreover, there has also been reported a possibility that malignant
alteration of cancer is caused with accompanying expression of RNR
(Proc. Natl. Acad. Sci. USA, 93, pp.14036-14040). Therefore, an
agent selectively inhibiting RNR is expected to be able to exert
highly selective toxicity to cancer cells, and accordingly,
expected to be useful as a medicament for cancer treatment that
selectively inhibits the proliferation of cancer cells.
[0004] Hydroxyurea has been known as a compound exhibiting
antitumor activity by inhibiting RNR, and the compound is used
clinically as an anti-leukemia agent. However, the drug only has
weak inhibitory activity, and therefore a high blood concentration
need to be maintained for a long period of time to successfully
inhibit RNR. In addition, the drug causes strong side effects such
as bone marrow toxicity, and hence is not a satisfactory
therapeutic agent. For these reasons, it has been desired to
develop an RNR inhibitor which has potent RNR inhibitory activity
as well as reduced side effects including bone marrow toxicity, and
has a wide range of effective dosage.
[0005] As low molecular RNR inhibitors, there have so far been
reported polyhydroxybenzoic acid derivatives (Published Japanese
translation of PCT international publication (Kohyo) No.
60-501409/1985), alkoxyphenol compounds (Mol. Pharmacol., 45,
pp.792-796), thiosemicarbazone derivatives (Biochem. Pharmacol.,
48, pp.335-344), bipyridyl derivatives (Cancer Research, 53,
pp.19-26) and the like. However, RNR inhibitory activity and
anticancer activity of bisaryl derivatives have not been reported.
As for usefulness of bisaryl compounds composed of aryl groups
linked by means of plural sulfur atoms as anticancer agents,
derivatives comprising aromatic benzenesulfonamide groups as the
bisaryl moieties (Japanese Patent Publication (Kokoku) No.
42-10857/1967) have been reported, and the synthesis of an
anthramycin dimer has also been reported (Tetrahedron Lett., 129,
p.5105). It has also been known that certain bisaryl compounds have
antiviral activity (Japanese Patent Unexamined Publication (Kokai)
No. 5-501860/1993).
DISCLOSURE OF THE INVENTION
[0006] An object of the present invention is to provide a novel
bisphenol compound useful as an active ingredient of a
medicament.
[0007] Another object of the present invention is to provide an
medicament for treatment of cancer which comprises a bisphenol
compound having inhibitory activity against RNR as an active
ingredient.
[0008] A still further object of the present invention is to
provide a novel bisaryl compound useful as an active ingredient of
a medicament.
[0009] The inventors of the present invention found that the
compounds of the present invention represented by the following
formula have inhibitory activity against RNR and anticancer
activity, and thus they are useful as an active ingredient of a
medicament for treatment of cancer. The present invention was
achieved on the basis of these findings.
[0010] The present invention provides a medicament for treatment of
cancer which comprises a compound represented by the following
general formula (I):
Ar.sup.1--S--R.sup.1--S--Ar.sup.2
[0011] or a physiologically acceptable salt thereof,
[0012] wherein R.sup.1 represents a nonmetal bridging group,
Ar.sup.1 and Ar.sup.2 independently represent a group selected from
the group consisting of an aryl group which has, on its ring, one
or more hydroxyl groups optionally substituted with a monovalent
group (the aryl group may have one to three substituents other than
a hydroxyl group on its ring), and a heteroaryl group which has, on
its ring, one or more hydroxyl groups optionally substituted with a
monovalent group (the heteroaryl group may have one to three
substituents other than a hydroxyl group on its ring).
[0013] Preferred embodiments of the aforementioned invention
provided are as follows:
[0014] the above medicament for treatment of cancer which comprises
a compound represented by the aforementioned general formula (I) or
a physiologically acceptable salt thereof, wherein R.sup.1 is
represented by the general formula (II):
--R.sup.2--N(R.sup.4)--R.sup.3-- (II)
[0015] wherein R.sup.2 and R.sup.3 independently represent a
divalent group, R.sup.4 represents a monovalent group, and R.sup.4
may bind to R.sup.2 or R.sup.3 to form a cyclic structure;
[0016] the above medicament for treatment of cancer which comprises
the aforementioned compound or a physiologically acceptable salt
thereof, wherein R.sup.1 is represented by the general formula
(III):
--R.sup.5--X.sup.1--R.sup.6-- (III)
[0017] wherein R.sup.5 and R.sup.6 independently represent a single
bond or a divalent group not containing a nitrogen atom, X.sup.1
represents an oxygen atom, S(O).sub.k wherein k represents an
integer of from 0 to 2, or
[(R.sup.9X.sup.2).sub.m(R.sup.10X.sup.3).sub.n(R.sup.11X.sup.4).sub.p]-
.sub.q wherein R.sup.9, R.sup.10, and R.sup.11 independently
represent a single bond or a divalent group not containing a
nitrogen atom, and wherein any groups selected from R.sup.5,
R.sup.6, R.sup.9, R.sup.10 and R.sup.11 may bind together to form a
cyclic structure, X.sup.2, X.sup.3 and X.sup.4 independently
represent an oxygen atom, S(O).sub.r wherein r represents an
integer of from 0 to 2, or a single bond, and m, n, p and q
independently represent an integer of from 1 to 3;
[0018] the above medicament for treatment of cancer which comprises
the aforementioned compound or a physiologically acceptable salt
thereof, wherein R.sup.1 is 2,6-pyridinediyldimethyl group (the
pyridinediyldimethyl group may have one to three substituents other
than a hydrogen atom on its ring);
[0019] the above medicament for treatment of cancer which comprises
the aforementioned compound or a physiologically acceptable salt
thereof, wherein R.sup.2 and R.sup.3 are the same divalent groups,
and R.sup.4 is a C.sub.1-4 alkyl group which may have one to three
substituents other than a hydrogen atom;
[0020] the above medicament for treatment of cancer which comprises
the aforementioned compound or a physiologically acceptable salt
thereof, wherein R.sup.2 and R.sup.3 are the same divalent groups,
R.sup.4 is represented as COR.sup.25 wherein R.sup.25 represents a
hydrogen atom, a C.sub.1-4 alkyl group, an aryl group, a heteroaryl
group, a heterocyclic group, an aralkyl group, or NR.sup.26R.sup.27
wherein R.sup.26 and R.sup.27 each represent a hydrogen atom, a
C.sub.1-4 alkyl group, an aryl group, a heteroaryl group, a
heterocyclic group, or an aralkyl group, and said alkyl group, aryl
group, heteroaryl group, heterocyclic group, and aralkyl group
including those for R.sup.26 and R.sup.27 may have one to three
substituents other than a hydrogen atom; and
[0021] the above medicament for treatment of cancer which comprises
the aforementioned compound or a physiologically acceptable salt
thereof, wherein R.sup.1 is represented as
R.sup.1A--R.sup.1BCO--R.sup.1C--R.sup.1-
D--R.sup.1C--COR.sup.1B--R.sup.1A wherein R.sup.1A represents a
C.sub.1-4 lower alkylene group, R.sup.1B represents NH or a
methylene group, R.sup.1C represents a single bond or a methylene
group, R.sup.1D represent a divalent bridging cyclic hydrocarbon
group, a monocyclic hydrocarbon group, or a heterocyclic group, and
said bridging cyclic hydrocarbon group, monocyclic hydrocarbon
group, and heterocyclic group may have one to three substituents
other than a hydrogen atom.
[0022] According to further preferred embodiments of the
aforementioned each invention provided are the above medicament for
treatment of cancer which comprises the aforementioned compound or
a physiologically acceptable salt thereof, wherein Ar.sup.1 and
Ar.sup.2 independently represent the aforementioned aryl group; the
above medicament for treatment of cancer which comprises the
aforementioned compound or a physiologically acceptable salt
thereof, wherein both of Ar.sup.1 and Ar.sup.2 are 4-hydroxyphenyl
groups; the above medicament for treatment of cancer which
comprises the aforementioned compound or a physiologically
acceptable salt thereof, wherein R.sup.2 and R.sup.3 are the same
groups, and the minimum number of bridge-forming atoms thereof is
from 1 to 10, preferably 1 to 4; the above medicament for treatment
of cancer which comprises the aforementioned compound or a
physiologically acceptable salt thereof, wherein R2 and R3 are the
same divalent groups optionally having a branched chain (said
divalent groups may contain 1 to 3 oxygen atoms); the above
medicament for treatment of cancer which comprises the
aforementioned compound or a physiologically acceptable salt
thereof, wherein the total number of carbon atoms is 35 or less;
and the above medicament for treatment of cancer which comprises
the aforementioned compound or a physiologically acceptable salt
thereof, which is used as a medicament for preventive and/or
therapeutic treatment of a disease caused by over-expression of
ribonucleotide reductase.
[0023] As another aspect of the present invention, provided is a
ribonucleotide reductase inhibitor or a selective cancer cell
proliferation inhibitor which comprises a compound represented by
the aforementioned general formula (I) or (II).
[0024] As further aspects of the present invention, provided are
use of the aforementioned compound or a physiologically acceptable
salt thereof for the manufacture of the medicaments for treatment
of cancer which comprise a compound represented by the
aforementioned general formula (I) or (II), or a physiologically
acceptable salt thereof as an active ingredient, preferably the
medicaments for treatment of cancer in the form of a pharmaceutical
composition comprising the aforementioned compound or a
physiologically acceptable salt thereof together with an additive
for pharmaceutical preparations; and a method for treatment of
cancer which comprises the step of administering a therapeutically
effective amount of a substance selected form the aforementioned
compound and a physiologically acceptable salt thereof to a
patient.
[0025] The present invention further provides a compound
represented by the general formula (XII):
Ar.sup.23--S--R.sup.22--N(R.sup.24)--R.sup.23--S--Ar.sup.24
[0026] or a salt thereof,
[0027] wherein, R.sup.22 and R.sup.23 independently represent a
divalent group, R.sup.24 represents a monovalent group or a
monovalent atom, and R.sup.24 may bind to R.sup.22 and/or R.sup.23
to form a cyclic structure, and may further bind to one or two
C.sub.1-4 alkylene groups to form a divalent group, and Ar.sup.23
and Ar.sup.24 independently represent a group selected from the
group consisting of an aryl group which has, on its ring, one to
three hydroxyl groups optionally substituted with a monovalent
group (the aryl group may have one to three substituents other than
a hydroxyl group on its ring), and a heteroaryl group which has, on
its ring, one to three hydroxyl groups optionally substituted with
a monovalent group (the heteroaryl group may have one to three
substituents other than a hydroxyl group on its ring), provided
that R.sup.22--N(R.sup.24)--R.sup.23 except for the part of
R.sup.24 does not contain an amide bond when R.sup.22 and R.sup.23
do not form a ring, and provided that when each of Ar.sup.23 and
Ar.sup.24 is a phenyl group having one hydroxyl group on the ring,
not all of said phenyl groups have a tertiary alkyl group at a
position on the ring adjacent to the hydroxyl group.
[0028] As a preferred embodiment of the above invention, provided
is the aforementioned compound or a salt thereof, wherein two or
three groups selected from the group consisting of R.sup.22,
R.sup.23 and R.sup.24 form a ring or rings.
[0029] Further preferred embodiments provided are as follows:
[0030] the above compound or a salt thereof wherein R.sup.22 and
R.sup.23 are the same divalent groups, and R.sup.24 is a C.sub.1-4
alkyl group which may have one to three substituents other than a
hydrogen atom;
[0031] the above compound or a salt thereof wherein R.sup.22 and
R.sup.23 are the same divalent groups, R.sup.24 is represented by
COR.sup.125 wherein R.sup.125 represents a hydrogen atom, a
C.sub.1-4 alkyl group, an aryl group, a heteroaryl group, a
heterocyclic group, an aralkyl group, or NR.sup.126R.sup.127
wherein R.sup.126 and R.sup.127 each represent a hydrogen atom, a
C.sub.1-4 alkyl group, an aryl group, a heteroaryl group, a
heterocyclic group, or an aralkyl group, and said alkyl group, aryl
group, heteroaryl group, heterocyclic group, and aralkyl group
including those for R.sup.126 and R.sup.127 may have one to three
substituents other than a hydrogen atom; and
[0032] the above compound or a salt thereof wherein
R.sup.22--N(R.sup.24)--R.sup.23 is represented by
R.sup.101A--R.sup.101BC-
O--R.sup.101C--R.sup.101D--R.sup.101C--COR.sup.101B--R.sup.101A
wherein R.sup.101A represents a C.sub.1-4 lower alkylene group,
R.sup.101B represents NH or methylene group, R.sup.101C represents
a single bond or a methylene group, R.sup.101D represent a divalent
bridging cyclic hydrocarbon group, a monocyclic hydrocarbon group,
or a heterocyclic group, and said bridging cyclic hydrocarbon
group, monocyclic hydrocarbon group, and heterocyclic group may
have one to three substituents other than a hydrogen atom.
[0033] Further preferred embodiments provided are as follows:
[0034] the above compound or a salt thereof wherein Ar.sup.23 and
Ar.sup.24 independently represents an aryl group which has, on its
ring, one to three hydroxyl groups optionally substituted with a
monovalent group (the aryl group may have one to three substituents
other than a hydroxyl group on its ring);
[0035] the above compound or a salt thereof wherein both of
Ar.sup.23 and Ar.sup.24 independently represent a
hydroxy-substituted phenyl group;
[0036] the above compound or a salt thereof wherein Ar.sup.23 and
Ar.sup.24 independently represent a monohydroxy-substituted phenyl
group;
[0037] the above compound or a salt thereof wherein both of
Ar.sup.23 and Ar.sup.24 are 4-hydroxyphenyl groups;
[0038] the above compound or a salt thereof wherein the minimum
number of bridge-forming atoms of R.sup.22 and R.sup.23 are
independently from 1 to 10 [The term "minimum number of
bridge-forming atoms" used herein means a minimum number of atoms
that connect one atom and the other atom to be bridged. For
example, the minimum number of bridge-forming atoms is 3 for
1,3-propenylene group, 2 for 1,2-propenylene group, and 5 for
1,5-(4-butoxy-3-pentenylene) group. Also for example, the number is
3 for 1,3-phenylene group, 2 for 1,2-phenylene group, 3 for
2,4-quinolinediyl group, and 4 for 1,5-naphthylene, as well as 4
for ethylenedioxy group, 3 for malonyl group, and 4 for phthaloyl
group.];
[0039] the above compound or a salt thereof wherein R.sup.22 and
R.sup.23 are the same groups and each of the minimum numbers of
bridge-forming atoms thereof is 1 to 10, preferably 1 to 4;
[0040] the above compound or a salt thereof wherein R.sup.22 and
R.sup.23 independently represent methylene group, ethylene group,
propylene group or butylene group;
[0041] the above compound or a salt thereof wherein R.sup.22 and
R.sup.23 are the same groups, and represent methylene group,
ethylene group, propylene group or butylene group; and the above
compound or a salt thereof wherein the total number of carbon atoms
is 35 or less.
BEST MODE FOR CARRYING OUT THE INVENTION
[0042] The groups that constitute the general formulas (I) and (II)
will be explained specifically.
[0043] The aryl group represented by Ar.sup.1 and Ar.sup.2 in the
general formula (I) may be, for example, an aryl group having 6 to
12 carbon atoms, preferably phenyl group, naphthyl group or the
like. The term "aryl group" has the same meaning in the following
description unless otherwise indicated. The heteroaryl group may
be, for example, a heteroaryl group having 5 to 12
ring-constituting atoms, such as pyridyl group, pyrrolyl group,
imidazolyl group, quinolinyl group, thienyl group, and furyl group.
As the heteroaryl group, for example, a group comprising a 5- or
6-membered nitrogen-containing or oxygen-containing heteroaryl ring
having an enol type hydroxyl group and an active methine or active
methylene group, such as pyrazolone ring and pyridone ring, may
preferably used. The term "heteroaryl group" has the same meaning
in the following description unless otherwise indicated. It is
preferred that both of Ar.sup.1 and Ar.sup.2 are aryl groups, and
it is more preferred that both of Ar.sup.1 and Ar.sup.2 are phenyl
groups.
[0044] The number and the substituting position of the hydroxyl
group or the hydroxyl group substituted with a monovalent group on
the ring of the aryl group or the heteroaryl group are not
particularly limited, and they preferably have one hydroxyl group.
For example, when the aryl group is phenyl group, phenyl group
substituted with one hydroxyl group at the p-position (4-position)
may be exemplified. Examples of the monovalent group in the one to
three hydroxyl groups substituted with a monovalent group present
independently on the ring of the aryl group or the heteroaryl group
include, but not limited thereto, linear or branched C.sub.1-6
alkyl groups such as methyl group, ethyl group, n-propyl group,
isopropyl group, n-butyl group, sec-butyl group and tert-butyl
group; aryl groups such as phenyl group and naphthyl group;
C.sub.1-12 alkanoyl groups which may be substituted;
hydroxy(C.sub.2-6)alkyl groups such as hydroxyethyl group;
C.sub.7-15 aralkyl groups such as benzyl group and phenethyl group;
C.sub.6-12 aroyl groups; C.sub.1-6 alkylsulfonyl groups; C.sub.6-12
arylsulfonyl groups; C.sub.1-6 alkoxycarbonyl groups;
aryloxycarbonyl groups; hydroxyphenylthio(C.sub.1-6)alkyl groups;
aminocarbonyl groups substituted with 0 to two C.sub.1-6 alkyl
groups or C.sub.6-12 aryl groups; aminoalkylcarbonyl groups
substituted with 0 to two C.sub.1-6 alkyl groups or C.sub.6-12 aryl
groups; C.sub.1-6 alkoxy-substituted C.sub.1-6 alkanoyl groups,
C.sub.1-6 alkylamino-substituted C.sub.1-6 alkanoyl groups,
piperidinocarbonyl group, 4-piperidinopiperidinocarbonyl group,
N-t-butoxycarbonyl-N-methylg- lycyl group and the like.
[0045] On the ring of the aforementioned aryl group or the
heteroaryl group, one to three substituents other than a hydroxyl
group or a hydroxyl group substituted with a monovalent group may
be present. As such a substituent, examples which can be used are
as follows: a halogen atom selected from fluorine atom, chlorine
atom, bromine atom, and iodine atom; a C.sub.1-6 alkyl group such
as methyl group, ethyl group, n-propyl group, isopropyl group,
n-butyl group, sec-butyl group and tert-butyl group; a halogenated
C.sub.1-6 alkyl group such as trifluoromethyl group; a C.sub.1-6
alkoxyl group such as methoxy group, ethoxy group, n-propoxy group,
isopropoxy group, n-butoxy group, sec-butoxy group and tert-butoxy
group; a C.sub.1-6 alkylenedioxy group such as methylenedioxy group
and ethylenedioxy group; carboxyl group; a C.sub.1-6 alkoxycarbonyl
group; non-substituted amino group; a C.sub.1-6 alkyl-substituted
amino group such as methylamino group, dimethylamino group and
ethylamino group; cyano group or the like. Among them, halogen
atoms, C.sub.1-6 alkyl groups, C.sub.1-6 alkoxyl groups and the
like are preferred.
[0046] In the specification, the term "bridging group" means a
group or an atom that can form two independent covalent bonds. In
the specification, the term "divalent group" means the bridging
group which can form two independent covalent bonds, and contains
at least one carbon atom. The divalent group may have a chain-like
or a cyclic structure, or may have a combination of portions of a
chain-like structure and a cyclic structure.
[0047] R.sup.1 in the general formula (I) represents a divalent
group consisting of a nonmetal bridging group, which preferably
comprising atoms selected from the group consisting of carbon atom,
hydrogen atom, oxygen atom, nitrogen atom, sulfur atom, and
phosphorus atom, and has atoms excluding hydrogen the number of
which is 1 to 80. R.sup.1 may further contain one to three halogen
atoms.
[0048] These divalent groups may contain one to three unsaturated
bonds, such as a double bond consisting of a carbon-carbon bond,
carbon-oxygen bond, sulfur-oxygen bond, carbon-nitrogen bond, or
nitrogen-nitrogen bond, or triple bond consisting of a
carbon-carbon bond. Furthermore, they may contain one to three
covalent bonds including any hetero atoms such as carbamoyl bond,
sulfamoyl bond, ether bond, and disulfide bond as a partial
structure. For example, they may contain one to three cyclic
structures selected from monocyclic structures such as those
consisting of benzene ring, cyclohexane ring, tetrahydrofuran ring,
and pyranone ring, condensed rings such as naphthalene ring, indole
ring, and quinoline ring, and bicyclo structures such as
bicyclooctane ring. Furthermore, examples also include pyrrole
ring, piperidine ring, indole ring, pyridine ring, triazine ring,
pyrimidine ring, quinoline ring, oxazine ring, indazole ring,
thiazole ring and the like. When the divalent group is a cyclic
group or chain-like group, or when it contains a partial chain-like
structure, it may contain a branched chain.
[0049] The aforementioned ring that constitutes the divalent group,
and carbon atoms and/or hetero atoms constituting the backbone of
the divalent group may have one or more substituents thereon, for
example, those selected from the group consisting of a halogen atom
such as fluorine atom, chlorine atom, and bromine atom; a linear or
branched C.sub.1-6 alkyl group such as methyl group, ethyl group,
n-propyl group, isopropyl group, n-butyl group, sec-butyl group,
and tert-butyl group; a linear or branched C.sub.1-6 alkoxyl group
such as methoxy group, ethoxy group, n-propoxy group, isopropoxy
group, n-butoxy group, sec-butoxy group and tert-butoxy group
(those alkyl and alkoxyl groups may have a substituent such as
hydroxyl group, a C.sub.1-6 alkoxyl group, a C.sub.1-6
alkyl-substituted or non-substituted carbamoyl group,
non-substituted amino group, a C.sub.1-6 alkyl-substituted amino
group such as methylamino group, dimethylamino group, and
ethylamino group, a C.sub.1-6 cyclic amino group such as morpholino
group and piperidino group, and a C.sub.1-6 cyclic aminocarbonyl
group such as morpholino group and piperidino group); a C.sub.1-6
alkylenedioxy group such as methylenedioxy group and ethylenedioxy
group; carboxyl group; a C.sub.1-6 alkoxycarbonyl group;
non-substituted amino group or a C.sub.1-6 alkyl-substituted amino
group such as methylamino group, dimethylamino group and ethylamino
group; hydroxyl group; an aryl group such as phenyl group; a
C.sub.1-6 alkyl-substituted sulfonyl group; a C.sub.1-6 alkanoyl
group such as acetyl group and propionyl group; a halogenated
C.sub.1-6 alkanoyl group such as trifluoroacetyl group and
monochloroacetyl group; an alkoxy-substituted C.sub.1-6 alkanoyl
group such as methoxymethylcarbonyl group; cyano group; a C.sub.1-6
alkyl-substituted or non-substituted carbamoyl group; sulfamoyl
group; carboxyl group; sulfo group; a lactone ring or a lactam ring
consisting of 4 to 8 ring-constituting atoms; and a halogen
atom.
[0050] Preferred examples of the divalent group represented by
R.sup.1 include, for example, linear or branched C.sub.1-6 alkylene
groups such as methylene group, ethylene group, propylene group,
butylene group, and pentylene group; arylene groups such as
p-phenylene group, m-phenylene group, 1,4-naphthylene group, and
1,5-naphthylene group; heteroarylene groups such as
2,6-pyridinediyl group; vinylene group; ethynylene group;
propenylene group; propynylene group; C.sub.2-6 alkenylene groups
such as 1-butenylene group, and cis- and trans-2-butenylene group,
C.sub.2-6 alkynylene groups and the like. These divalent groups may
have one to three substituents selected from the aforementioned
substituents. Preferred examples of the alkylene group having one
or more substituents include, for example, oxo(C.sub.1-6)alkylene
groups such as 1-oxoethylene group, 1-oxo-2-methylethylene group,
and 1-oxopropylene group; and oxy(C.sub.1-6)alkylene groups such as
1-oxypropylene group, and 2-oxypropylene group and the like.
Divalent groups consisting of a suitable combination of groups
selected from alkylene groups, arylene groups and heteroarylene
groups are also preferred.
[0051] Those wherein R.sup.1 represents
R.sup.1A--R.sup.1BCO--R.sup.1C--R.-
sup.1D--R.sup.1C--COR.sup.1BR.sup.1A, wherein R.sup.1A represents a
C.sub.1-4 lower alkylene group, R.sup.1B represents NH or a
methylene group, R.sup.1C represents a single bond or a methylene
group, R.sup.1D represents a divalent bridging cyclic hydrocarbon
group, a monocyclic hydrocarbon group, or a heterocyclic group, and
said bridging cyclic hydrocarbon group, monocyclic hydrocarbon
group, and heterocyclic group may have one to three substituents
other than a hydrogen atom, are also preferred examples of the
divalent group. Examples of the divalent bridging cyclic
hydrocarbon group and monocyclic hydrocarbon group include, for
example, 1,1-cyclopentylene, 5,6-norbornenylene,
1,1-cyclopropylene, 1,1-cyclobutylene, 1,2-cyclobutylene,
1,2-cyclopentylene, 2,2-dimethyl-1,3-cyclopentylene,
1,1-cyclohexylene, 1,2-cyclohexylene, 1,3-cyclohexylene,
1,4-cyclohexylene, 1,3-adamantylene, 1,1-phenylene, 1,2-phenylene,
1,3-phenylene, 1,4-phenylene, 1,4-naphthylene, 2,3-naphthylene,
2,6-naphthylene, 1,8-naphthylene and the like. Examples of the
divalent heterocyclic group include, for example,
1,4-piperazinylene, 4-oxo-2,6-pyranylene, 2,3-pyrrolylene,
3,5-pyrazolylene, 2,3-indolylene, 2,6-pyridylene, 2,3-pyridylene,
2,4-pyridylene, 3,4-pyridylene, 2,5-pyridylene, 3,5-pyridylene,
2,3-pyrazinylene, 3,4-furylene, 4,5-imidazolylene,
1,2,3-triazol-4,5-ylene, 7-oxabicyclo[2.2.1]heptynyl-2,3-ylene,
tricyclo[4.2.1.0.sup.2.5]nona-3,7-dien-3,4-ylene,
2,2-dimethyldioxolan-4,- 5-ylene and the like. As preferred
substituents on the divalent bridging cyclic hydrocarbon group,
monocyclic hydrocarbon group, and heterocyclic group, those
exemplified for the substituents on the rings of the aforementioned
aryl group and heteroaryl group may be used.
[0052] The minimum number of bridging group-forming atoms of
R.sup.1 is preferably in the range of 1 to 20, more preferably 1 to
9, and most preferably 3 to 7. The total atom number of the whole
compound of the general formula (I) is preferably 50 or less.
[0053] The groups that constitute the compounds represented by the
general formula (II) will be specifically explained below.
[0054] The definition of the divalent group represented by R.sup.2
and R.sup.3 is the same as that of the divalent group represented
by RI in the general formula (I), provided that particularly
preferred minimum number of bridge-forming atoms of R.sup.2 and
R.sup.3 is in a range of from 1 to 3.
[0055] In the formula (II), R.sup.4 represents a monovalent group
or a monovalent atom. R.sup.4 may be, for example, a hydrogen atom,
hydroxyl group, amidino group, amino group, an alkyl group which
may be substituted, an aryl group which may be substituted, a
heteroaryl group which may be substituted, an aralkyl group which
may be substituted, an alkyl group substituted with a heteroaryl
group which may be substituted, or a group represented by any one
of the following formulas (XIII) to (XVI):
--CO--R.sup.25 (XIII)
[0056] wherein R.sup.25 represents a hydrogen atom, a C.sub.1-4
alkyl group which may be substituted, an aryl group which may be
substituted, a heteroaryl group which may be substituted, a
heterocyclic group which may be substituted, or an aralkyl group
which may be substituted;
--CO--NR.sup.26R.sup.27 (XIV)
[0057] wherein R.sup.26 and R.sup.27 independently represent a
hydrogen atom, a C.sub.1-4 alkyl group which may be substituted, an
aryl group which may be substituted, a heteroaryl group which may
be substituted, a heterocyclic group which may be substituted, or
an aralkyl group which may be substituted;
--SO.sub.2--R.sup.25 (XV)
[0058] wherein R.sup.25 has the same meaning as that defined above;
and
--SO.sub.2--NR.sup.26R.sup.27 (XVI)
[0059] wherein R.sup.26 and R.sup.27 have the same meanings as
those defined above.
[0060] Where R.sup.4 is an alkyl group which may be substituted,
the alkyl group may be linear or branched, and it may contain one
or more cyclic structures or one or more unsaturated bonds. The
number of carbon atoms thereof may preferably be 20 or less
including its substituent(s). Particularly preferred group may
contain 1 to 4 carbon atoms. Preferred examples of the substituent
include, but not limited thereto, halogen atoms such as fluorine
atom, chlorine atom, bromine atom, and iodine atom, hydroxyl group,
carboxyl group, vinyl group, ethynyl group, C.sub.3-8 cycloalkyl
groups, carbamoyl group which may have a substituent on the
nitrogen atom (one or two substituents selected from a C.sub.1-6
alkyl group, a halogenated C.sub.1-6 alkyl group, a
hydroxy-substituted C.sub.1-6 alkyl group, an aryl group, a
sulfonyl group, a C.sub.1-6 alkyl-substituted sulfonyl group, a
C.sub.1-6 alkanoyl group, a halogenated C.sub.1-6 alkanoyl group, a
hydroxy-substituted C.sub.1-6 alkanoyl group, an alkoxy-substituted
C.sub.1-6 alkanoyl group and the like), a sulfamoyl group which may
have a substituent on the nitrogen atom (one or two substituents
selected from those exemplified for the aforementioned carbamoyl
group), C.sub.1-20 alkanoyl groups, aroyl groups,
heteroarylcarbonyl groups, C.sub.1-20 alkanoylamino groups,
aroylamino groups, heteroarylcarbonylamino groups, C.sub.1-20
alkylsulfonyl groups, arylsulfonyl groups, heteroarysulfonyl
groups, C.sub.1-20 alkylsulfonylamino groups, arylsulfonylamino
groups, heteroarylsulfonylamino groups, an ureido group which may
have a substituent on the nitrogen atom (one or two substituents
selected from those exemplified for the aforementioned carbamoyl
group), a cyano group, an amino group which may have a substituent
on the nitrogen atom (one or two substituents selected from those
exemplified for the aforementioned carbamoyl group), C.sub.1-20
alkylthio groups, C.sub.1-20 alkoxyl groups, aryloxy groups,
heteroaryloxy groups, arylthio groups, arylthio groups substituted
with one to three hydroxyl groups, C.sub.1-20 alkoxycarbonyl
groups, aryloxycarbonyl groups, heteroaryloxycarbonyl groups, a
2-hydroxyethoxy group, polyether groups (2-methoxyethoxy group,
2-(2-methoxyethoxy)ethoxy group etc.), a succinimido group, a
guanidino group, aryl groups, aryl groups which are substituted
with one or two hydroxyl groups, aryl groups which are substituted
with 1 to 5 independently selected halogen atoms (a halogen atom
has the same meaning as that defined above), heteroaryl groups,
heterocyclic groups and the like.
[0061] The aryl group of the aforementioned aryl group, aroyl
group, aroylamino group, arylsulfonyl group, arylsulfonylamino
group, aryloxy group, and aryloxycarbonyl group, and the heteroaryl
group of the aforementioned heteroaryl group, heteroarylcarbonyl
group, heteroarylsulfonyl group, heteroarylsulfonylamino group,
heteroaryloxy group, and heteroaryloxycarbonyl group have the same
meanings as those defined above. Examples of the heterocyclic group
include, for example, dioxolanyl group, morpholino group, morpholyl
group, piperidyl group, dioxanyl group, imidazolyl group, thiazolyl
group, pyrimidinyl group, 2,2-dimethyl-1,3-dioxolanyl group and the
like.
[0062] Preferred examples of R.sup.4 include, but not limited
thereto, methyl group, ethyl group, propyl group, sec-butyl group,
cyclopropylmethyl group, allyl group, propargyl group,
2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-hydroxyethyl
group, 3-hydroxypropyl group, carbamoylmethyl group,
2-carbamoylethyl group, 2-(N,N-dimethylcarbamoyl)ethyl group,
2-(N-morpholinocarbonyl)ethyl group, 2-(N-piperidinocarbonyl)ethyl
group, sulfamoylmethyl group, acetylmethyl group,
2-(N-acetylamino)ethyl group, cyanomethyl group,
2-(N,N-diethylamino)ethyl group, 2-(N-morpholino)ethyl group,
2-(N-piperidino)ethyl group, 2-methylthioethyl group,
2-methoxyethyl group, hydroxyethoxyethyl group,
methoxycarbonylmethyl group and the like.
[0063] When R.sup.4 is an aryl group which may be substituted, the
number of carbon atom is preferably 20 or less including its
substituent(s). Preferred examples include, for example, phenyl
group which may be substituted and naphthyl group which may be
substituted. When these groups have a substituent, they may have
one to three substituents. Preferred examples of the substituent
are those exemplified as preferred substituents for R.sup.4 when it
represents the alkyl group. Among them, halogen atoms, hydroxyl
group, carbamoyl group and the like are particularly preferred.
When R.sup.4 is a heteroaryl group which may be substituted, the
number of carbon atoms is preferably 20 or less including its
substituent(s). Preferred examples include, for example, pyridyl
group, thienyl group, furyl group, imidazolyl group, quinolyl group
and the like. These groups may have one to three substituents
selected from those exemplified as preferred substituents for
R.sup.4 when it represents the alkyl group.
[0064] Where R.sup.4 is an aralkyl group which may be substituted
or an alkyl group substituted with a heteroaryl group which may be
substituted, the number of carbon atoms thereof is preferably 20 or
less including their substituent(s). Preferred examples include,
for example, benzyl group, 2-phenylethyl group, naphthylmethyl
group, 2-picolyl group, 3-picolyl group, (2-furyl)methyl group,
(2-thienyl)methyl group, (2-quinolyl)methyl group,
2-(2-pyridyl)ethyl group, 2-(N-imidazolyl)ethyl group and the like.
These groups may have one to three substituents selected from those
exemplified as preferred substituents for R.sup.4 when it
represents the alkyl group. Among them, halogen atoms, hydroxyl
group, carbamoyl group and the like are particularly preferred
substituents.
[0065] Where R.sup.4 is a group represented by the formula (XIII)
or the formula (XV), the group represented by R.sup.25 preferably
has 15 or less carbon atoms, and it may have one to three
substituents selected from those exemplified as preferred
substituents for R.sup.4 when it represents the alkyl group. The
aryl group, heteroaryl group, heterocyclic group and aralkyl group
for R.sup.25 have the same meanings as those defined above.
Preferred examples of R.sup.4 include, for example, acetyl group,
propionyl group, benzoyl group, 2-pyridylcarbonyl group,
3-pyridylcarbonyl group, 4-pyridylcarbonyl group, benzylcarbonyl
group, methanesulfonyl group, benzenesulfonyl group and the
like.
[0066] Where R.sup.4 is a group represented by the formula (XIV) or
the formula (XVI), those groups represented by R.sup.26 and
R.sup.27 preferably have 15 or less carbon atoms, and they may have
one to three substituents selected from those exemplified as
preferred substituents for R.sup.4 when it represents the alkyl
group. In addition, R.sup.26 and R.sup.27 may bind to each other to
form a ring structure. Preferred examples of R.sup.4 include, for
example, aminocarbonyl group, N-methylaminocarbonyl group,
N-phenylaminocarbonyl group, N-(2-pyridylamino)carbonyl group,
N,N-dimethylaminocarbonyl group, N,N-diethylaminocarbonyl group,
N-morpholinocarbonyl group, N-piperidinocarbonyl group,
aminosulfonyl group, N,N-dimethylaminosulfony- l group,
N,N-diethylaminosulfonyl group, N-morpholinosulfonyl group,
N-piperidinosulfonyl group and the like.
[0067] The ring structure which is formed by R.sup.4 together with
R.sup.2 or R.sup.3 includes saturated and unsaturated ring
structures. Examples of the ring include, for example, saturated or
unsaturated 3- to 18-membered monocyclic rings or condensed rings,
such as pyrrole ring, piperidine ring, indole ring, pyridine ring,
triazine ring, pyrimidine ring, quinoline ring, oxazine ring,
indazole ring, and thiazole ring. These rings may be partially or
fully reduced or oxidized. Furthermore, they may further bind to
one or two C.sub.1-4 alkylene groups to form a divalent group.
[0068] A compound in which one monovalent group such as an alkyl
group further bind to a nitrogen atom in the general formula (II)
to form a quaternary salt of the nitrogen atom may also be used as
an active ingredient of the medicament for treatment of cancer of
the present invention. As a counter ion of the quaternary salt, for
example, iodine ion, bromine ion, chlorine ion, perchlorate ion,
sulfate ion, phosphate ion, sulfamate ion, acetate ion, lactate
ion, citrate ion, tartrate ion, malonate ion, methanesulfonate ion,
ethanesulfonate ion, hydroxyethanesulfonate ion, benzenesulfonate
ion, p-toluenesulfonate ion, and cyclohexylsulfamate ion may be
used. Iodine ion, bromine ion, chlorine ion, and perchlorate ion
can be preferably used. As the monovalent group, C.sub.1-6 alkyl
groups such as methyl group are preferred.
[0069] Divalent groups preferred as R.sup.1, R.sup.2, and R.sup.3
in the general formula (I) and (II) will be exemplified blow.
However, the divalent group which can be used for the compound as
the active ingredient of the medicament for treatment of cancer-of
the present invention is not limited to these examples (in the
structures, Me represents methyl group). 1234567891011
[0070] The bisaryl compounds represented by the aforementioned
general formula (I) have inhibitory activity against ribonucleotide
reductase, and can selectively inhibit cancer cell proliferation.
Therefore, they can be used as an active ingredient of a medicament
for treatment of cancer, which can be administered to mammals
including human. Types of cancers to be treated by the medicament
of the present invention are not particularly limited, and the
medicament can be applied to solid cancers such as stomach cancer,
lung cancer, colon cancer, liver cancer, kidney cancer, breast
cancer, uterus cancer, skin cancer and brain tumor, as well as
non-solid cancers such as leukemia and lymphoma.
[0071] In addition, they are also useful as an active ingredient of
medicaments for preventive and/or therapeutic treatment of various
diseases in mammals including human accompanied by unusual
expression of ribonucleotide reductases deriving from host mammals
themselves, viruses, bacteria and the like, for example, herpes
syndrome caused by unusual proliferation of herpes simplex virus,
acquired immune deficiency syndrome caused by unusual proliferation
of AIDS virus and the like. Furthermore, the aforementioned
compounds, per se, can also be used as ribonucleotide reductase
inhibitors such as reagents in the fields of biochemistry,
pharmacology, genetic engineering and the like. As the active
ingredient of the medicament of the present invention, a substance
selected from the group consisting of the compounds of the
aforementioned general formula (I) and salts thereof, and hydrates
thereof and solvates thereof can be used, as well as any
combinations of two or more of substances selected from said
group.
[0072] Although the aforementioned substances, per se, may be used
as the medicament of the present invention, it is generally
preferred that the medicament is provided for administration as a
pharmaceutical composition that can be prepared by using one or
more pharmaceutically acceptable additives. Administration route of
the medicament of the present invention is not particularly
limited, and oral or parenteral administration may be selected.
Examples of the pharmaceutical compositions suitable for parenteral
administration include, for example, injections suitable for
intravenous, intraarterial, intraperitoneal or intrapleural
injection, drip infusions, preparations for intrarectal
administration (suppositories) and the like. Examples of the
pharmaceutical compositions suitable for oral administration
include, for example, tablets, capsules, granules, powders, syrups
and the like. However, applicable pharmaceutical compositions are
not limited to these examples, and those skilled in the art can
select a suitable form of composition from available pharmaceutical
compositions.
[0073] For example, for the manufacture of injections, the
aforementioned substances as an active ingredient may be dissolved
in a diluent available to those skilled in the art (for example,
physiological saline, glucose solution for injection, lactose
solution for injection, mannitol solution for injection and the
like), and then the solution may be subjected to an appropriate
sterilization treatment such as filtration sterilization, and
filled in hermetic containers such as ampoules. Preparation for
injection in a lyophilized form or powder for injection mixed with
sodium chloride may also be prepared according to the Japanese
Pharmacopoeia. As the pharmaceutical additives, for example,
carriers such as auxiliaries such as polyethylene glycol and HCO-60
(surfactant; Nikko Chemical Co. Ltd.), ethanol and/or liposome and
cyclodextrin may be incorporated. Pharmaceutical compositions
suitable for oral administration or intrarectal administration can
be prepared by mixing the aforementioned substances with
appropriate pharmaceutical additives such as excipients,
disintegrating agents, binders, lubricants, suspending agents,
isotonic agents, and emulsifiers in a conventional manner, and
formulating the mixture into an appropriate form.
[0074] Dosage and administration frequency of the medicament of the
present invention are not particularly limited. When the medicament
of the present invention is used for treatment of cancer, it can be
administered, for example, via intravenous route in an amount of
0.01 to 100 mg/kg (based on the weight of the active ingredient) at
intervals of every week to every 3 weeks. It is desirable to
suitably adjust the dosage and administration frequency depending
on various conditions, for example, route of administration, a kind
of an active ingredient, i.e., the compound of the aforementioned
formulas (I) to (III), the age and body weight of patients, the
condition, and frequency and severity of side effects such as bone
marrow suppression.
[0075] The bisaryl compounds represented by the aforementioned
general formula (I) may have one to three asymmetric carbons
depending on the kind of the substituents. Furthermore, a sulfur
atom may also serve as an asymmetric center. Any optical isomers in
an optically pure form based on one to three asymmetric carbons,
any mixtures of the aforementioned optical isomers, and racemates,
as well as diastereomers based on two or more asymmetric carbons,
any mixtures of such diastereomers and the like may be used as the
active ingredient of the medicament of the present invention. As
the active ingredient of the medicament of the present invention,
those in free form encompassed by the aforementioned formula as
well as physiologically acceptable salts thereof may be used.
[0076] Examples of such salts include, for example, hydrochlorides,
sulfates, phosphates, sulfamates, acetates, lactates, citrates,
tartrates, malonates, methanesulfonates, ethanesulfonates,
hydroxyethanesulfonates, benzenesulfonates, p-toluenesulfonates,
cyclohexylsulfamates and the like. These salts can be prepared by
dissolving the aforementioned compound as free base in water, an
aqueous organic solvent such as alcoholic solvent or a suitable
organic solvent containing a corresponding acid to form a uniform
solution, and isolating a salt after evaporation of water or the
organic solvent, or allowing the compound in free form to react
with an acid in an organic solvent. In the latter case, for
example, the resulting salt can be directly isolated, or recovered
by evaporation of the solvent. As the active ingredient of the
medicament of the present invention, the aforementioned compounds
in free form and salts thereof, and in addition, hydrates thereof
and solvates thereof can be used. Examples of the organic solvent
for forming the solvates include, for example, physiologically
acceptable solvents such as ethanol and ethylene glycol.
[0077] Specific examples of the compounds most suitably used for
the medicament of the present invention will be listed below.
However, the active ingredient of the medicament of the present
invention is not limited to the following compounds (in the tables,
the serial numbers in the first left column indicate the compound
numbers, Ph represents phenyl group, and p-HO-Ph represents
p-hydroxyphenyl group. In Table 3, "B" represents
p-hydroxyphenylthio group, Me represents methyl group, Et
represents ethyl group, and Ac represents acetyl group). 12
1TABLE 1 Com- pound No. Ar.sup.1 R.sup.1 Ar.sup.1 9 p-HO-Ph-
-C.sub.2H.sub.4-S-C.sub.2H.sub.4- p-HO-Ph- 10 p-HO-Ph-
-C.sub.2H.sub.4-S-C.sub.3H.sub.6- p-HO-Ph- 11 p-HO-Ph-
-C.sub.2H.sub.4-S-C.sub.4H.sub.4- p-HO-Ph- 12 p-HO-Ph-
-C.sub.2H.sub.4-S-C.sub.4H.sub.6- p-HO-Ph- 13 p-HO-Ph-
-C.sub.2H.sub.4-S-C.sub.4H.sub.8- p-HO-Ph- 14 p-HO-Ph-
-C.sub.3H.sub.6-S-C.sub.3H.sub.6- p-HO-Ph- 15 p-HO-Ph-
-C.sub.3H.sub.6-S-C.sub.4H.sub.6- p-HO-Ph- 16 p-HO-Ph-
-C.sub.3H.sub.6-S-C.sub.4H.sub.8- p-HO-Ph- 17 p-HO-Ph-
-C.sub.4H.sub.8-S-C.sub.4H.sub.8- p-HO-Ph- 18 p-HO-Ph-
-CH.sub.2CO-S-C.sub.2H.sub.4- p-HO-Ph- 19 p-HO-Ph-
-CH.sub.2CO-S-C.sub.3H.sub.6- p-HO-Ph- 20 p-HO-Ph-
-CH.sub.2CO-S-C.sub.4H.sub.8- p-HO-Ph- 21 p-HO-Ph-
-CH.sub.2CO-S-C.sub.4H.sub.6- p-HO-Ph- 22 p-HO-Ph-
-CH.sub.2CO-S-C.sub.4H.sub.4- p-HO-Ph- 23 p-HO-Ph-
-CH(CH.sub.3)CO-S-C.sub.2H.sub.4- p-HO-Ph- 24 p-HO-Ph-
-C.sub.2H.sub.4CO-S-CH.sub.2CH(OH)CH.sub.2- p-HO-Ph- 25 p-HO-Ph-
-CH.sub.2CO-S-C.sub.2H.sub.4NHCOCH.sub.2- p-HO-Ph- 26 p-HO-Ph-
-C.sub.2H.sub.4CO-S-C.sub.2H.sub.4NHCOC.sub.2H.sub.4- p-HO-Ph- 27
p-HO-Ph- -C.sub.2H.sub.4-O-C.sub.2H.sub.4- p-HO-Ph- 28 p-HO-Ph-
-C.sub.2H.sub.4-O-C.sub.3H.sub.6- p-HO-Ph- 29 p-HO-Ph-
-C.sub.2H.sub.4-O-C.sub.4H.sub.4- p-HO-Ph- 30 p-HO-Ph-
-C.sub.2H.sub.4-O-C.sub.4H.sub.6- p-HO-Ph- 31 p-HO-Ph-
-C.sub.2H.sub.4-O-C.sub.4H.sub.8- p-HO-Ph- 32 p-HO-Ph-
-C.sub.3H.sub.6-O-C.sub.3H.sub.6- p-HO-Ph- 33 p-HO-Ph-
-C.sub.3H.sub.6-O-C.sub.4H.sub.6- p-HO-Ph- 34 p-HO-Ph-
-C.sub.3H.sub.6-O-C.sub.4H.sub.8- p-HO-Ph- 35 p-HO-Ph-
-C.sub.4H.sub.8-O-C.sub.4H.sub.8- p-HO-Ph- 36 p-HO-Ph-
-CH.sub.2CO-O-C.sub.2H.sub.4- p-HO-Ph- 37 p-HO-Ph-
-CH.sub.2CO-O-C.sub.3H.sub.6- p-HO-Ph- 38 p-HO-Ph-
-CH.sub.2CO-O-C.sub.4H.sub.8- p-HO-Ph- 39 p-HO-Ph-
-CH.sub.2CO-O-C.sub.4H.sub.6- p-HO-Ph- 40 p-HO-Ph-
-CH.sub.2CO-O-C.sub.4H.sub.4- p-HO-Ph- 41 p-HO-Ph-
-CH(CH.sub.3)CO-O-C.sub.2H.sub.4- p-HO-Ph- 42 p-HO-Ph-
-C.sub.2H.sub.4CO-O-CH.sub.2CH.sub.2CH(OH)CH.sub.2- p-HO-Ph- 43
p-HO-Ph- -CH.sub.2CO-O-C.sub.2H.sub.4NHCOCH.sub.2- p-HO-Ph- 44
p-HO-Ph- -C.sub.2H.sub.4CO-O-C.sub.2H.sub.4NHCOC.sub.2H.sub.4-
p-HO-Ph-
[0078]
2TABLE 2 Compound No. Ar.sup.1 R.sup.2 R.sup.3 R.sup.4 Ar.sup.2 45
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -H p-HO-Ph- 46 p-HO-Ph-
-C.sub.3H.sub.6- -C.sub.3H.sub.6- -H p-HO-Ph- 47 p-HO-Ph-
-C.sub.4H.sub.8- -C.sub.4H.sub.8- -H p-HO-Ph- 48 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -OH p-HO-Ph- 49 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -C(=NH)NH.sub.2 p-HO-Ph- 50
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -COC.sub.3H.sub.7
p-HO-Ph- 51 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-COCH.sub.2CH.sub.2CO.su- b.2H p-HO-Ph- 52 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -COCH.sub.2CH.sub.2S-Ph-OH-p
p-HO-Ph- 53 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CHO
p-HO-Ph- 54 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -COCH.sub.3
p-HO-Ph- 55 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-SO.sub.2CH.sub.3 p-HO-Ph- 56 p-HO-Ph- -C.sub.3H.sub.6-
-C.sub.3H.sub.6- -CHO p-HO-Ph- 59 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CH.sub.2CH.sub.2NH.sub.2 p-HO-Ph- 60 p-HO-Ph-
-CH.sub.2CO- -C.sub.2H.sub.4- -H p-HO-Ph- 61 p-HO-Ph- -CH.sub.2CO-
-C.sub.3H.sub.6- -H p-HO-Ph- 62 p-HO-Ph- -CH.sub.2CO-
-C.sub.4H.sub.8- -H p-HO-Ph- 63 p-HO-Ph- -CH.sub.2CO-
-C.sub.4H.sub.6- -H p-HO-Ph- 64 p-HO-Ph- -CH.sub.2CO-
-C.sub.4H.sub.4- -H p-HO-Ph- 65 p-HO-Ph- -CH.sub.2CO-
-C.sub.4H.sub.4- -CHO p-HO-Ph- 66 p-HO-Ph- -CH(CH.sub.3)CO-
-C.sub.2H.sub.4- -H p-HO-Ph- 67 p-HO-Ph- -CH(CH.sub.3)CO-
-C.sub.2H.sub.4- -C.sub.2H.sub.4OH p-HO-Ph- 68 p-HO-Ph-
-C.sub.2H.sub.4CO- -CH.sub.2CH(OH)CH.sub.2 -C.sub.2H.sub.4OH
p-HO-Ph- 69 p-HO-Ph- -CH.sub.2CO- -C.sub.2H.sub.4NHCOCH.sub.2- -H
p-HO-Ph- 70 p-HO-Ph- -C.sub.2H.sub.4CO-
-CH.sub.2H.sub.4NHCOC.sub.2H.sub.4 -H p-HO-Ph- 71 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -C.sub.2H.sub.5 p-HO-Ph- 72
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -C.sub.3H.sub.7 p-HO-Ph-
73 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-C.ident.CH
p-HO-Ph- 74 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CH.sub.2-CH=CH.sub.2 p-HO-Ph- 75 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CH.sub.2-cyclopropyl p-HO-Ph- 76 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-SO.sub.2NH.sub.2
p-HO-Ph- 77 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-CN
p-HO-Ph- 78 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-CO-NH.sub.2 p-HO-Ph- 79 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -C.sub.2H.sub.4-CO-N(CH.sub.3).sub.2 p-HO-Ph- 80
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-CO-N(C.sub.2H.sub.5).su- b.2 p-HO-Ph- 81 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-CO-CH.sub.3 p-HO-Ph- 82
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-NH-CO-NH.sub.2 p-HO-Ph- 83 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -C.sub.2H.sub.4-NH-CO-CH.sub.3
p-HO-Ph- 84 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2F
p-HO-Ph- 85 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CF.sub.3
p-HO-Ph- 86 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-(N-succinimido) p-HO-Ph- 87 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -C.sub.2H.sub.4-S-CH.sub.3
p-HO-Ph- 88 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CH.sub.2-ethyleneacetal p-HO-Ph- 89 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CH.sub.2-(2-thienyl) p-HO-Ph- 90 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -furfuryl p-HO-Ph- 91 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-(4-pyridyl) p-HO-Ph- 92
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -o-hydroxybenzyl
p-HO-Ph- 93 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-m-hydroxybenzyl p-HO-Ph- 94 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -p-hydroxybenzyl p-HO-Ph- 95 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -(CH.sub.2).sub.3-OH p-HO-Ph- 96
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-NH-CO-CH.sub.3
p-HO-Ph- 97 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CH.sub.2-CO-NH.sub.2 p-HO-Ph- 98 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -benzyl p-HO-Ph- 99 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CH.sub.2-(3-pyridyl) p-HO-Ph- 100 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-(2-pyridyl) p-HO-Ph-
101 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CH.sub.2-(2-quinolinyl) p-HO-Ph- 102 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -C.sub.2H.sub.4-OH p-HO-Ph- 103 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -(CH.sub.2).sub.3-OCH.sub.3
p-HO-Ph- 104 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-(C.sub.2H.sub.4-OCH.sub.3 p-HO-Ph- 105 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -o-fluorobenzyl p-HO-Ph- 106 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -p-fluorobenzyl p-HO-Ph- 107
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-CO-(N-morpholi- no) p-HO-Ph- 108 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -C.sub.2H.sub.4-CO-(1-piperidyl)
p-HO-Ph- 109 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-N(C.sub.2H.sub.5).sub.2 p-HO-Ph- 110 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -C.sub.2H.sub.4-(N-morpholino)
p-HO-Ph- 111 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-(1-piperidyl) p-HO-Ph- 112 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-CH.sub.3 p-HO-Ph- 113
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-C.sub.2H.sub.5
p-HO-Ph- 114 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CO-C.sub.6H.sub.5 p-HO-Ph- 115 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CO-(2-pyridyl) p-HO-Ph- 116 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-(3-pyridyl) p-HO-Ph- 117
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-(4-pyridyl) p-HO-Ph-
118 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -SO.sub.2-CH.sub.3
p-HO-Ph- 119 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-SO.sub.2-C.sub.6H.sub.5 p-HO-Ph- 120 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CO-NH.sub.2 p-HO-Ph- 121 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-NH(CH.sub.3) p-HO-Ph- 122
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-N(CH.sub.3).sub.2
p-HO-Ph- 123 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CO-N(C.sub.2H.sub.5).sub.2 p-HO-Ph- 124 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CO-(N-morpholino) p-HO-Ph- 125 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-(1-piperidyl) p-HO-Ph- 126
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-NH-C.sub.6H.sub.5
p-HO-Ph- 127 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CO-NH-(2-pyridyl) p-HO-Ph- 128 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -SO.sub.2-NH.sub.2 p-HO-Ph- 129 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -SO.sub.2-N(C.sub.2H.sub.5).sub.2
p-HO-Ph- 130 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-SO.sub.2-(N-morpholino) p-HO-Ph-
[0079] 13
3 TABLE 3 131 B-B 132 B-CH.sub.2-B 133 B-C.sub.2H.sub.4-B 134
B-C.sub.3H.sub.6-B 135 B-C.sub.4H.sub.8-B 136 B-C.sub.5H.sub.10-B
137 B-C.sub.6H.sub.12-B 138 B-C.sub.7H.sub.14-B 139
B-C.sub.8H.sub.16-B 140 B-C.sub.9H.sub.18-B 141
B-C.sub.10H.sub.20-B 142 B-C.sub.11H.sub.22-B 143
B-C.sub.2H.sub.4-SO.sub.2-C.sub.2H.sub.4-SO.sub.2-C.sub.2H.sub.4-B
144 B-CH(CH.sub.3)-B 145 B-CH(C.sub.2H.sub.5)-B 146
B-CH(n-C.sub.3H.sub.7)-B 147 B-CH(C.sub.6H.sub.5)-B 148
B-CH(B)(p-HOC.sub.2H.sub.4O-C.sub.6H.sub.4-) 149
B-C(CH.sub.3).sub.2-B 150 B-CH(COOH)-B 151 B-CH(C.sub.2H.sub.4OH)-B
152 B-CH(CH.sub.3)-CH.sub.2-B 153 B-CH(C.sub.2H.sub.4OH)-CH.sub.2-B
154 B-CH(COOH)-CH.sub.2-B 155 B-CH(C.sub.2H.sub.5)-CH.sub.2-B 156
B-CH.sub.2-CH(OH)-CH.sub.2-B 157 B-CH.sub.2-C(CH.sub.2B).sub.2-CH-
.sub.2-B 158 B-CH.sub.2-S-CH.sub.2-B 159
B-CH.sub.2-CH=CH-CH.sub.2-B 160 B-CH.sub.2-C.ident.C-CH.sub.2-B 161
B-CH.sub.2-C.sub.6H.sub.4-CH.sub.2-B (-C.sub.6H.sub.4- is a
o-phenylene group) 162 B-C.sub.2H.sub.4-O-CH.sub.2-O-C.sub.2H.sub-
.4-B 163 B-C.sub.2H.sub.4-O-C.sub.2H.sub.4-O-C.sub.2H.sub.4-B 164
B-CH.sub.2-COO-C.sub.2H.sub.4-OCOCH.sub.2-B 165
B-CH.sub.2-COO-C.sub.3H.sub.6-OCOCH.sub.2-B 166
B-CH.sub.2CH(OH)CH.sub.2-O-C.sub.2H.sub.4-O-CH.sub.2CH(OH)CH.sub.2-B
167
B-(C.sub.2H.sub.4O).sub.2-CO-CH.sub.2-CO-(C.sub.2H.sub.4O).sub.2-B
168 B-(C.sub.2H.sub.4O).sub.2-CO-(trans)CH=CH-CO-(C.sub.2H.sub.4O-
).sub.2-B 169 B-CH.sub.2-COO-(C.sub.2H.sub.4O).sub.3-CO-CH.sub.2-B
170 B-CH.sub.2-COO-(C.sub.2H.sub.4O).sub.4-CO-CH.sub.2-B 171
B-(C.sub.2H.sub.4O).sub.3-C.sub.2H.sub.4-B 172
B-(C.sub.2H.sub.4O).sub.4-C.sub.2H.sub.4-B 173
B-(C.sub.2H.sub.4O).sub.5-C.sub.2H.sub.4-B 174
B-(C.sub.2H.sub.4O).sub.3-CO-(C.sub.2H.sub.4O).sub.3-B 175
B-(C.sub.2H.sub.4O).sub.2-CO-C.sub.2H.sub.4-CO-(C.sub.2H.sub.4O).sub.2-B
[0080] 141516171819202122
[0081] According to the present invention, there are provided novel
compounds represented by the general formula (XII):
Ar.sup.23--S--R.sup.22--N(R.sup.24)--R.sup.23--S--Ar.sup.24.
[0082] Ar.sup.23 and Ar.sup.24 in the general formula (XII) have
the same meanings as the aforementioned Ar.sup.1 and Ar.sup.2.
However, those wherein each of Ar.sup.23 and Ar.sup.24 is a phenyl
group having one hydroxyl group on the ring, and both of these
phenyl groups have a tertiary alkyl group at a position on the ring
adjacent to the hydroxyl group are excluded from the scope of the
invention concerning the novel compounds of the present invention.
R.sup.22, R.sup.23 and R.sup.24 in the general formula (XII) have
the same meanings as the aforementioned R.sup.2, R.sup.3, and
R.sup.4, provided that, when R.sup.22 and R.sup.23 do not form a
ring, R.sup.22--N(R.sup.24)--R.sup.23 except for the part of R24
does not contain an amide bond. Furthermore, in the above
definitions, R.sup.125, R.sup.126, R.sup.127, R.sup.101A,
R.sup.101B, R.sup.101C, and R.sup.101D have the same meanings as
R.sup.25, R.sup.26, R.sup.27, R.sup.1A, R.sup.1B, R.sup.1C and
R.sup.1D, respectively.
[0083] Examples of the divalent group suitable as R.sup.22,
R.sup.23, or R.sup.22--N(R.sup.24)--R.sup.23 will be exemplified
below. However, the divalent group which can be used for the
compound of the present invention is not limited to these examples.
2324252627282930313233
[0084] Particularly preferred compounds of the present invention
represented by the formula (XII) will be specifically exemplified
below. However, the compounds of the present invention are not
limited to the following exemplary compounds.
4TABLE 4 Compound No. Ar.sup.23 R.sup.22 R.sup.23 R.sup.24
Ar.sup.24 45 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -H p-HO-Ph-
46 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.3H.sub.6- -H p-HO-Ph- 47
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.4H.sub.8- -H p-HO-Ph- 48 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -OH p-HO-Ph- 49 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -C(=NH)NH.sub.2 p-HO-Ph- 50
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -COC.sub.3H.sub.7
p-HO-Ph- 51 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-COCH.sub.2CH.sub.2CO.s- ub.2H p-HO-Ph- 52 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -COCH.sub.2CH.sub.2S-Ph-OH-p
p-HO-Ph- 53 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CHO
p-HO-Ph- 54 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -COCH.sub.3
p-HO-Ph- 55 p-HO-Ph- -C.sub.2H.sub.6- -C.sub.3H.sub.6- -CHO
p-HO-Ph- 56 p-HO-Ph- -C.sub.2H.sub.6- -C.sub.3H.sub.6-
-COCH.sub.2Cl p-HO-Ph- 59 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CH.sub.2CH.sub.2NH.sub.2 p-HO-Ph- 71 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -C.sub.2H.sub.5 p-HO-Ph- 72
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -C.sub.3H.sub.7 p-HO-Ph-
73 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-C.ident.CH
p-HO-Ph- 74 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CH.sub.2-CH=CH.sub.2 p-HO-Ph- 75 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CH.sub.2-cyclopropyl p-HO-Ph- 76 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-SO.sub.2NH.sub.2
p-HO-Ph- 77 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-CN
p-HO-Ph- 78 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-CO-NH.sub.2 p-HO-Ph- 79 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -C.sub.2H.sub.4-CO-N(CH.sub.3).sub.2 p-HO-Ph- 80
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-CO-N(C.sub.2H.sub.5).su- b.2 p-HO-Ph- 81 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-CO-CH.sub.3 p-HO-Ph- 82
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-NH-CO-NH.sub.2 p-HO-Ph- 83 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -C.sub.2H.sub.4-NH-CO-CH.sub.3
p-HO-Ph- 84 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2F
p-HO-Ph- 85 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CF.sub.3
p-HO-Ph- 86 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-(N-succinimido) p-HO-Ph- 87 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -C.sub.2H.sub.4-S-CH.sub.3
p-HO-Ph- 88 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CH.sub.2-ethyleneaceta- l p-HO-Ph- 89 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CH.sub.2-(2-thienyl) p-HO-Ph- 90 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -furfuryl p-HO-Ph- 91 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-(4-pyridyl) p-HO-Ph- 92
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -o-hydroxybenzyl
p-HO-Ph- 93 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-m-hydroxybenzyl p-HO-Ph- 94 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -p-hydroxybenzyl p-HO-Ph- 95 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -(CH.sub.2).sub.3-OH p-HO-Ph- 96
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-NH-CO-CH.sub.3
p-HO-Ph- 97 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CH.sub.2-CO-NH.sub.2 p-HO-Ph- 98 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -benzyl p-HO-Ph- 99 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CH.sub.2-(3-pyridyl) p-HO-Ph- 100 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CH.sub.2-(2-pyridyl) p-HO-Ph-
101 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CH.sub.2-(2-quinolinyl) p-HO-Ph- 102 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -C.sub.2H.sub.4-OH p-HO-Ph- 103 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -(CH.sub.2).sub.3-OCH.sub.3
p-HO-Ph- 104 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-OCH.sub.3 p-HO-Ph- 105 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -o-fluorobenzyl p-HO-Ph- 106 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -p-fluorobenzyl p-HO-Ph- 107
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-CO-(N-morpholi- no) p-HO-Ph- 108 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -C.sub.2H.sub.4-CO-(1-piperidyl)
p-HO-Ph- 109 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-N(C.sub.2H.sub.5).sub.2 p-HO-Ph- 110 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -C.sub.2H.sub.4-(N-morpholino)
p-HO-Ph- 111 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-C.sub.2H.sub.4-(1-piperidyl) p-HO-Ph- 112 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-CH.sub.3 p-HO-Ph- 113
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-C.sub.2H.sub.5
p-HO-Ph- 114 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CO-C.sub.6H.sub.5 p-HO-Ph- 115 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CO-(2-pyridyl) p-HO-Ph- 116 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-(3-pyridyl) p-HO-Ph- 117
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-(4-pyridyl) p-HO-Ph-
118 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -SO.sub.2-CH.sub.3
p-HO-Ph- 119 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-SO.sub.2-C.sub.6H.sub.5 p-HO-Ph- 120 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CO-NH.sub.2 p-HO-Ph- 121 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-NH(CH.sub.3) p-HO-Ph- 122
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-N(CH.sub.3).sub.2
p-HO-Ph- 123 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CO-N(C.sub.2H.sub.5).sub.2 p-HO-Ph- 124 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -CO-(N-morpholino) p-HO-Ph- 125 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-(1-piperidyl) p-HO-Ph- 126
p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4- -CO-NH-C.sub.6H.sub.5
p-HO-Ph- 127 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-CO-NH-(2-pyridyl) p-HO-Ph- 128 p-HO-Ph- -C.sub.2H.sub.4-
-C.sub.2H.sub.4- -SO.sub.2-NH.sub.2 p-HO-Ph- 129 p-HO-Ph-
-C.sub.2H.sub.4- -C.sub.2H.sub.4- -SO.sub.2-N(C.sub.2H.sub.5).sub.2
p-HO-Ph- 130 p-HO-Ph- -C.sub.2H.sub.4- -C.sub.2H.sub.4-
-SO.sub.2-(N-morpholino) p-HO-Ph-
[0085] 3435363738
[0086] The compounds of the present invention may form an acid
addition salt, and may also form a base addition salt depending on
the types of substituents. Examples of the acid addition salt
include, but not limited thereto, mineral acid salts such as
hydrochlorides, sulfates and nitrates, and organic acid salts such
as p-toluenesulfonates, methanesulfonates, acetates,
chloroacetates, oxalates, trifluoromethanesulfonates, and
quinolinesulfonates. When they form a base addition salt, metal
salts such as sodium salts and potassium salts, ammonium salts such
as ammonium salts and triethylammonium salts and the like may be
used. The compounds of the present invention may also form
intramolecular zwitter ions based on a phenolic hydroxyl group and
a basic group, which also fall within the scope of the present
invention. Furthermore, the compounds of the aforementioned formula
(XI) and formula (XII) in free form or any salts thereof, and any
hydrates or any solvates of the compounds in free form or salts
thereof fall within the scope of the present invention. Solvents
that can form solvates are not particularly limited. For example,
the solvate may be formed with methanol, ethanol, acetone,
tetrahydrofuran, dichloromethane, chloroform, dimethylformamide or
the like.
[0087] The compounds of the present invention may have one or more
asymmetric carbons depending on the types of the substituents.
Furthermore, a sulfur atom may also serve as an asymmetric center.
Any optical isomers in optically pure form based on one or more
asymmetric carbons, mixtures of the optical isomers, racemates,
diastereomers based on two or more asymmetric carbons, mixtures of
the diastereomers and the like all fall within the scope of the
present invention.
[0088] Two or three groups selected from R.sup.22, R.sup.23, and
R.sup.24 may bind to each other, via a divalent group if required,
to form a saturated or unsaturated cyclic structure. In that case,
the nitrogen atom to which R.sup.24 binds may be an atom that
constitutes the ring. Examples of the ring include, for example,
pyrrole ring, piperidine ring, indole ring, pyridine ring, triazine
ring, pyrimidine ring, quinoline ring, oxazine ring, indazole ring,
thiazole ring and the like. These rings may have a partially or
completely reduced ring structure. Furthermore, those wherein one
more monovalent group such as an alkyl group further binds to the
nitrogen atom to which R.sup.24 binds to form a quaternary salt
also fall within the scope of the present invention. The counter
ion of the quaternary salt may be, for example, iodide ion, bromide
ion, chloride ion, perchlorate ion and the like. As the monovalent
group, C.sub.1-6 alkyl groups such as methyl group and the like are
preferred.
[0089] The methods for preparing the bisaryl compounds represented
by the aforementioned general formulas (I), (II) and (XII) are not
particularly limited, and they can be synthesized via various
synthetic routes. Methods for preparing typical compounds of the
present invention are specifically disclosed in Examples set out
below, and accordingly, those skilled in the art will readily
prepare bisaryl compounds falling within the scopes of the
aforementioned general formulas by referring to the method
described in Examples, adding suitable alterations and
modifications to the methods, if required, and suitably choosing
starting materials and reagents. For the preparation, one step, or
several combined steps selected from various condensation,
addition, oxidation, and reduction reactions and the like can be
used. These reactions are detailed in literature. For example,
various methods mentioned as unit operations and starting materials
disclosed in "Jikken Kagaku Koza" (Maruzen Co., Ltd., each separate
volume of the first to the 4th edition are available) can be
preferably used.
[0090] For example, it may be preferable to use a mercapto
compound, an amine compound and the like for a starting material
from viewpoints of a reaction operation and an yield. For example,
unit operations such as synthesis of thioether (sulfide) and
synthesis of ester; reactions of mercapto group with reactive
functional groups such as vinyl group, halogen atoms (including
haloalkyl groups), epoxy group, aziridine ring, acyl halide groups,
and isocyanate group; and amination reaction, amidation reaction,
alkylation reaction and the like are well known to those skilled in
the art. Therefore, it is possible to chose suitable methods from
the conventional methods considering an yield, easiness of reaction
and the like.
[0091] For example, in these production methods, when any of the
defined groups are changed under the condition of the reaction
steps, or unsuitable to proceed the reaction steps, desired steps
may be efficiently performed by using techniques commonly used in
the synthetic organic chemistry, for example, protection and
deprotection of functional groups, or treatments including
oxidation, reduction, and hydrolysis. Isolation and purification of
synthetic intermediates and target compounds in the aforementioned
steps can be performed by common techniques in the field of
synthetic organic chemistry, for example, filtration, extraction,
washing, drying, concentration, recrystallization, various
chromatography methods and the like. In addition, synthetic
intermediates may be used in subsequent steps without
isolation.
EXAMPLES
[0092] The present invention will be more specifically explained
with reference to the following examples. However, the scope of the
present invention is not limited to these examples. The compound
numbers used in the examples correspond to the compound numbers
shown in the aforementioned tables.
Example 1
[0093] Synthesis of Compound 45
[0094] Bis(2-chloroethyl)amine hydrochloride (17.8 g) and
thiohydroquinone (25.2 g) were added to a 1,000 ml flask provided
with a stirrer and a condenser, and methanol (300 ml) was added
thereto for dissolution. To this solution, a 28% solution (57.9 g)
of sodium methoxide in methanol was added dropwise at room
temperature. After the addition was completed, the reaction mixture
was stirred under reflux by heating for 3 hours, and then left
standing for one day. The reaction mixture was transferred to a 3
liter-beaker, 1,500 ml of water was added, and the deposited
product was separated. The crude product was recrystallized from
methanol to obtain 20 g of the target compound (m.p.
133-134.degree. C.).
[0095] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 2.61 (t, 4H), 2.83
(t, 4H), 3.38 (s, 1H), 6.72 (dd, 4H), 7.20 (dd, 4H), 9.55 (s,
2H)
Example 2
[0096] Synthesis of Compound 113
[0097] In a 100 ml three-neck flask, Compound 45 (3.2 g)
synthesized in Example 1 was dissolved in dimethylacetamide (15
ml), and propionic anhydride (1.4 ml) was dropwise added thereto
under ice cooling. The reaction mixture was stirred for 1 hour at
room temperature, poured into diluted hydrochloric acid, and
extracted with ethyl acetate. The organic layer was washed with
saturated brine, dried over magnesium sulfate, and concentrated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (ethyl acetate/hexane=7/3-1/1) to
obtain 3.58 g of the target compound.
[0098] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 0.37 (t, 3H), 2.04
(q, 2H), 2.90 (m, 4H), 3.30 (m, 4H), 6.76 (d, 4H), 7.20 (d, 4H),
9.57 (s, 1H), 9.60 (s, 1H)
Example 3
[0099] Synthesis of Compound 61
[0100] 3-Bromopropylamine hydrobromide (50.0 g) and methylene
chloride (300 ml) were put into a 1,000 ml flask provided with a
stirrer and a condenser, and triethylamine (46 g) was added thereto
at a temperature below 10.degree. C. Then, bromoacetyl chloride (36
g) was added dropwise to the mixture while keeping the temperature
of the reaction mixture at 20.degree. C. or below 20.degree. C.,
and then the mixture was stirred for 1 hour. The organic layer was
separated by filtration and concentrated, and the residue was
purified by silica gel column chromatography (developing solvent:
hexane/ethyl acetate=2:1) to obtain
(3-bromopropyl)-1-bromoacetamide (yield: 24%). Thiohydroquinone
(5.0 g) and (3-bromopropyl)-1-bromoacetamide (5.8 g) were added to
methanol (50 ml), and 28% sodium methoxide (7.6 g) was added
thereto with stirring and the mixture was stirred at 40.degree. C.
for 2 hours. Water (200 ml) was added to the reaction mixture, the
mixture was extracted with ethyl acetate, and the organic phase was
dried. The product obtained after evaporation of the solvent was
treated with acetonitrile to obtain crystals (m.p. 122-124.degree.
C.).
Example 4
[0101] Synthesis of Compound 1
[0102] 2,6-Dichloromethylpyridine (3.5 g), and thiohydroquinone
(5.0 g) were put into a 100 ml flask provided with a stirrer and a
condenser, and methanol (20 ml) and a 28% solution (7.7 g) of
sodium methoxide in methanol were added thereto at room
temperature. The mixture was warmed to 60.degree. C., and stirred
for 1 hour at the same temperature. After the methanol was
evaporated, the organic phase was extracted with ethyl acetate. The
organic phase was dried and concentrated to obtain crystals of the
target compound. The product was recrystallized from acetonitrile
to obtain the target compound (yield: 70%, m.p. 140-140.5.degree.
C.).
Example 5
[0103] Synthesis of Compound 27
[0104] Methanol (40 ml) was put into a flask provided with a
stirrer, thiohydroquinone (0.08 mol) and 48% aqueous NaOH (0.084
mol) were added thereto, and then bis-2-chloroethyl ether (0.04
mol) was dropwise added thereto with stirring at room temperature.
The mixture was maintained at 40.degree. C. for 4 hours, then added
to water (300 ml) and extracted with ethyl acetate. The organic
phase was washed with water and dried, and the solvent was
evaporated to obtain crude crystals of the target compound. The
crystals were recrystallized from benzene to obtain the target
compound (yield: 82%, m.p. 91-92.degree. C.).
Example 6
[0105] Synthesis of Compound 162
[0106] 62,.beta.'-Dichlorodiethylformal was synthesized according
to the method of Vinokurov D.M. The target compound was obtained in
the same manner as in Example 5 except that the above-obtained
compound was used as a halide starting material. The target
compound was obtained through recrystallization from a mixed
solvent of water and methanol (yield: 81%, m.p. 108-110.degree.
C.)
Example 7
[0107] Synthesis of Compound 124
[0108] Compound 45 (10.0 g) obtained in Example 1 was put into a
500 ml flask provided with a stirrer and a calcium chloride tube,
and dimethylacetamide (100 ml) was added thereto for dissolution.
To this solution was added triethylamine (7.78 ml) and
4-morpholinecarbonyl chloride (4.17 g), the mixture was stirred for
2 hours, then water was added thereto and the mixture was further
made neutral with hydrochloric acid. The organic layer was
extracted with ethyl acetate, washed with water (3 times) and with
saturated brine (2 times), then dried and concentrated to obtain
8.30 g of Compound 124 (semi-solid).
[0109] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 2.86 (t, 4H), 2.87
(t, 4H), 3.20 (t, 4H), 3.33 (t, 4H), 6.74(d, 4H), 7.23 (d, 4H),
9.61(s, 2H)
Example 8
[0110] Synthesis of Compound 97
[0111] Compound 45 (964 mg) obtained in Example 1 was put into a 20
ml flask provided with a calcium chloride tube, and
dimethylformamide (5 ml) was added thereto for dissolution. To this
solution was added sodium hydrogen carbonate (1 g), potassium
iodide (166 mg) and chloroacetamide (300 mg), and the mixture was
stirred at 80.degree. C. for 2 hours. The reaction mixture was
added to water, the mixture was extracted with ethyl acetate, and
the organic layer was washed with water (3 times) and saturated
brine (2 times), then dried and concentrated. The residue was
purified by silica gel chromatography (eluent: methylene
chloride/ethyl acetate=2/3), and the solvent was concentrated. The
residue was crystallized by adding hexane, filtered, washed and
dried to obtain 900 mg of Compound 97 (m.p. 105-106.degree.
C.).
[0112] .sup.1H-NMR (CD.sub.3OD) .delta. (ppm) 2.72 (t, 4H), 2.82
(t, 4H), 3.10 (s, 2H), 6.80 (d, 4H), 7.30 (d, 4H)
Example 9
[0113] Synthesis of Compound 190
[0114] 2-Fluorophenol (4.05 g), water (50 ml), copper sulfate
pentahydrate (18.0 g), and ammonium thiocyanate (11.0 g) were
successively put into a 300 ml flask provided with a stirrer, and
the mixture was stirred for 4 hours on a water bath (50.degree.
C.). The solid was removed by filtration, and the filtrate was
extracted with ethyl acetate, then dried and concentrated. The
residue was purified by silica gel chromatography (eluent:
hexane/ethyl acetate=10/1.5) to obtain 1.61 g of
3-fluoro-4-hydroxybenzothiocyanate.
[0115] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm) 5.79 (s, 1H), 7.07
(dd, 1H), 7.28 (dd, 1H), 7.36 (dd, 1H)
[0116] The resulting 3-fluoro-4-hydroxybenzothiocyanate (0.45 g)
was put into a nitrogen-purged 50 ml flask provided with a stirrer,
and dissolved in tetrahydrofuran (5.0 ml). The solution was cooled
to 0.degree. C., aluminium lithium hydride (0.10 g) was added
thereto, and then the mixture was stirred at room temperature for
20 minutes. To the mixture was then added ethyl acetate and
saturated aqueous ammonium chloride, and the mixture was
neutralized with diluted hydrochloric acid. The organic layer was
extracted with ethyl acetate, dried and concentrated. The residue
was purified by silica gel chromatography (eluent: hexane/ethyl
acetate=10/1.5) to obtain 0.13 g of
3-fluoro-4-hydroxythiophenol.
[0117] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm) 3.42 (s, 1H), 5.52
(s, 1H), 6.88 (dd, 1H), 7.00 (dd, 1H), 7.08 (dd, 1H)
[0118] The 3-fluoro-4-hydroxythiophenol (0.13 g) obtained above was
put into a 50 ml flask provided with a stirrer, and dissolved in
methanol (5.0 ml). The solution was bubbled with nitrogen gas for
about 15 minutes for deairing, sodium methoxide (28%, 0.20 ml) and
bis(2-chloroethyl) ether (0.52 ml) were added thereto, and then the
mixture was stirred for 2 hours (40.degree. C.). The mixture was
neutralized with diluted hydrochloric acid, and the organic layer
was extracted with ethyl acetate, dried and concentrated. The
residue was purified by silica gel chromatography (eluent:
hexane/ethyl acetate=5/1) to obtain 56 mg of Compound 190 (m.p.
87-88.degree. C.).
[0119] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm) 2.95 (t, 4H), 3.55
(t, 4H), 6.89 (dd, 1H), 7.03 (dd, 1H), 7.12 (dd, 1H)
Example 10
[0120] Synthesis of Compound 191
[0121] 5-Norbornene-2-dicarboxylic acid anhydride (1.30 g),
2-(4-hydroxyphenylthio)propylamine (3.66 g), and triethylamine
(2.02 g) were put into a 200 ml flask provided with a stirrer and a
condenser, dimethylformamide (50 ml) was added thereto for
dissolution, and then the solution was stirred at room temperature
for 17 hours. To the reaction mixture was added water, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1 N hydrochloric acid and then with saturated aqueous
sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (eluent: dichloromethane/ethyl
acetate=2/8) to obtain 1.76 g of Compound 191 as a semi-solid
substance.
[0122] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 1.20 (s, 2H), 1.51
(t, 4H), 2.72 (t, 4H), 2.90 (s, 2H), 2.98 (q, 4H), 3.03 (s, 2H),
6.07 (s, 2H), 6.72 (d, 4H), 7.34 (d, 2H), 9.56 (s, 2H)
Example 11
[0123] Synthesis of Compound 192
[0124] 1-Cyclopentane diacetic acid (0.93 g) was put into a 100 ml
flask provided with a stirrer and a condenser and tetrahydrofuran
(35 ml) was added thereto for dissolution. Then, to the solution
was added dicyclohexylcarbodiimide (2.06 g) and
2-(4-hydroxyphenylthio)propylamine (1.83 g), and the mixture was
stirred at 40.degree. C. for 6 hours. Insoluble materials were
removed from the reaction mixture by suction filtration, and the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel chromatography (eluent: hexane/ethyl
acetate=1/1) to obtain 1.09 g of Compound 192 as a semi-solid
substance.
[0125] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 1.18 (t, 2H), 1.58
(m, 4H), 2.13 (s, 2H), 2.76 (t, 2H), 3.14 (dd, 2H), 6.72 (d, 2H),
7.20 (d, 2H), 8.08 (t, 1H), 9.55 (s, 1H)
Example 12
[0126] Synthesis of Compound 100
[0127] Compound 45 (1.79 g) obtained in Example 1 was put into a 50
ml flask provided with a calcium chloride tube and
dimethylformamide (15 ml) was added thereto for dissolution. To
this solution was added sodium hydrogen carbonate (1.68 g) and
2-chloromethylpyridine hydrochloride (820 mg), and the mixture was
stirred at 70.degree. C. for 4 hours. The reaction mixture was
added to water and the mixture was extracted with ethyl acetate.
The extract was washed with water (3 times) and saturated brine (2
times), dried, and then concentrated. The residue was purified by
silica gel chromatography (eluent: methylene
chloride/methanol=20/1), the solvent was concentrated, and the
residue was crystallized by adding hexane, and then filtered to
obtain 1.57 g of Compound 100 (m.p. 80-81.degree. C.).
[0128] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 2.60 (t, 4H), 2.85
(t, 4H), 3.68 (s, 2H), 6.68 (d, 4H), 7.15 (d, 4H), 7.25 (t, 1H),
7.41 (d, 1H), 7.70 (t, 1H), 8.42 (d, 1H), 9.55 (s, 2H)
Example 13
[0129] Synthesis of Compound 193
[0130] Compound 97 (1.00 g) obtained in Example 8 was put into a
100 ml flask provided with a calcium chloride tube at room
temperature, and acetonitrile (10 ml) was added thereto for
dissolution. To this solution was added pyridine (2.1 ml) and
acetic anhydride (0.75 ml), and the mixture was stirred at room
temperature for 4.5 hours. The reaction mixture was concentrated
under reduced pressure. The residue was dissolved in ethyl acetate
(100 ml), and then washed with 1 N hydrochloric acid (50
ml.times.2). The organic layer was separated, and dried over
anhydrous sodium sulfate, and then the solvent was evaporated to
obtain 1.17 g of the target compound (yield: 89%, m.p.
139-142.degree. C.).
[0131] .sup.1H-NMR (CD.sub.3OD) .delta. (ppm) 2.30 (s, 6H),
3.15-3.50 (m, 8H), 4.12 (s, 2H), 7.12 (d, 4H), 7.50 (d, 4H)
Example 14
[0132] Synthesis of Compound 71
[0133] The reaction of Example 12 was repeated by using 940 mg of
ethyl iodide instead of 2-chloromethylpyridine hydrochloride, and
the product was purified by silica gel chromatography (eluent:
methylene chloride/methanol=20/1) to obtain Compound 71 (1.49 g) as
oil.
[0134] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 0.89 (t, 3H), 2.48
(q, 2H), 2.60 (t, 4H), 2.80 (t, 4H), 6.78 (d, 4H), 7.25 (d, 4H),
9.62 (6, 2H)
Example 15
[0135] Syntheses of Compounds 72 to 81, Compounds 84 to 88,
Compound 95, Compounds 102 to 103, Compounds 107 to 111, Compound
194, Compounds 197 to 201, Compounds 203 to 211 and Compound
213
[0136] The title compounds were synthesized in the same manner as
in Example 14 by allowing Compound 45 obtained in Example 1 to
react with corresponding alkylating agents.
Example 16
[0137] Syntheses of Compounds 89 to 91, Compounds 98 to 99,
Compound 101, Compounds 105 to 106 and Compound 196
[0138] The title compounds were synthesized in the same manner as
in Example 12 by allowing Compound 45 obtained in Example 1 to
react with corresponding arylmethyl halides or heteroarylmethyl
halides.
Example 17
[0139] Synthesis of Compound 92
[0140] Compound 92 was synthesized in accordance with the following
synthetic scheme. 39
[0141] Salicyl aldehyde (12.2 g), imidazole (7.2 g), and
dimethylformamide (70 ml) were put into a 200 ml three-neck flask
for dissolution, tert-butyldimethylsilyl chloride (16 g) was added
thereto at room temperature and the mixture was stirred at room
temperature for 1 hour. Then, the reaction mixture was poured into
water, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine, dried over magnesium
sulfate, and concentrated under reduced pressure to obtain Compound
92A (23.5 g) as oil. The resulting Compound 92A was used for the
subsequent reaction without further purification.
[0142] Compound 92A (18.9 g) was dissolved in 120 ml of methanol,
and sodium borohydride (760 mg) was added thereto. The reaction
mixture was stirred at room temperature for 1 hour, and then poured
into water and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine, dried over magnesium
sulfate, and concentrated under reduced pressure to obtain Compound
92B (18.8 g) as oil. The resulting Compound 92B was used for the
subsequent reaction without further purification.
[0143] Compound 92B (9.5 g), triethylamine (5.6 ml), and
N,N-dimethylaminopyridine (500 mg) were dissolved in acetonitrile
(50 ml), and methanesulfonyl chloride (4.6 g) was dropwise added
thereto. The reaction mixture was left standing at room temperature
overnight. The produced triethylamine hydrochloride was filtered,
and the filtrate was concentrated under reduced pressure. To the
residue was added hexane, and insoluble materials were removed by
filtration. Then, the filtrate was washed with aqueous citric acid,
water, and then saturated brine, then, dried over magnesium sulfate
and concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (eluent: hexane) to
obtain Compound C (7.0 g) as oil.
[0144] Compound 45 (4.8 g) synthesized in Example 1 and
dimethylacetamide (40 ml) were put into a 100 ml three-neck flask
for dissolution, and Compound 92B (4.1 g) was added thereto. The
reaction mixture was stirred at 80.degree. C. for 1 hour, and then
poured into water and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over
magnesium sulfate, and concentrated under reduced pressure. The
residue was dissolved in methylene chloride (70 ml), 10 ml of 1 M
solution of tetrabutylammonium fluoride in tetrahydrofuran was
added thereto, and then the mixture was allowed to react at room
temperature for 1 hour. The reaction mixture was poured into water,
and the mixture was extracted with methylene chloride. The organic
layer was washed with saturated brine, dried over magnesium
sulfate, and concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (eluent:
methylene chloride/methanol=100/3) to obtain Compound 92 (4.93 g)
as an amorphous.
Example 18
[0145] Syntheses of Compound 93 and Compound 94
[0146] The title compounds were synthesized in the same manner as
in Example 17 by allowing Compound 45 obtained in Example 1 to
react with benzyl chloride substituted with corresponding protected
hydroxyl group, and then deprotecting the product.
Example 19
[0147] Syntheses of Compound 50, Compound 51 and Compound 54
[0148] The title compounds were synthesized in the same manner as
in Example 2 by allowing Compound 45 obtained in Example 1 to react
with a corresponding acid anhydride.
Example 20
[0149] Synthesis of Compound 53
[0150] Compound 45 (2.0 g) obtained in Example 1, formic acid (290
mg), and dicyclohexylamide (1.4 g) were stirred in a mixed solvent
of chloroform (20 ml) and dimethyl sulfoxide (20 ml) at room
temperature for 4 hours. The reaction mixture was filtered, and the
residue was washed with ethyl acetate. Then, the filtrate and the
washing filtrate were combined, and washed with water, saturated
aqueous sodium hydrogen carbonate, and then saturated brine. The
organic layer was dried over sodium sulfate, and concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography to obtain 2.1 g of the target compound.
[0151] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 2.87 (m, 2H), 2.95
(m, 2H), 3.30 (m, 2H), 3.37 (m, 2H), 6.75 (d, 4H), 7.22 (d, 4H),
7.90 (s, 1H), 9.58 (broad, 2H)
Example 21
[0152] Synthesis of Compound 114
[0153] Compound 45 (9.64 mg) synthesized in Example 1, pyridine
(0.25 ml), and dimethylacetamide (5 ml) were added to a 30 ml
three-neck flask for dissolution. To the solution was added
dropwise benzoyl chloride (5.34 mg) under ice cooling, and the
mixture was stirred for 30 minutes under ice cooling, and then for
1 hour at room temperature. The reaction mixture was poured into
diluted hydrochloric acid, and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, dried
over magnesium sulfate, and then concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (eluent: methylene chloride/methanol=100/4), and
crystallized by adding hexane to obtain 510 mg of the target
compound.
Example 22
[0154] Syntheses of Compound 115, Compound 116 and Compound 117
[0155] The title compounds were synthesized in the same manner as
in Example 22 by allowing Compound 45 obtained in Example 1 to
react with a corresponding acid chloride, and purifying the product
with a silica gel column.
Example 23
[0156] Synthesis of Compound 125
[0157] The title compound was synthesized in the same manner as in
Example 7 by allowing Compound 45 obtained in Example 1 to react
with piperidinocarbonyl chloride.
Example 24
[0158] Synthesis of Compound 214
[0159] Compound 45 (1.29 g) obtained in Example 1 and D-mannose
(1.01 g) were stirred in ethanol (5 ml) at 100.degree. C. for 4
hours on an oil bath. To the reaction mixture was added ethyl
acetate (50 ml), the mixture was subjected to suction filtration,
and then the filtrate was concentrated. The resulting residue was
purified by silica gel column chromatography (methylene
chloride/methanol=9/1) to obtain 1.05 g of the target compound.
[0160] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 2.73 (m, 4H), 2.83
(m, 4H), 3.55-3.80 (m, 3H), 4.30-4.50 (m, 3H), 5.13 (s, 1H), 6.76
(d, 4H), 7.22 (d, 4H), 9.55 (s, 2H)
Example 25
[0161] Syntheses of Compounds 215 to 219
[0162] The title compounds were synthesized in the same manner as
in Example 24 by allowing Compound 45 obtained in Example 1 to
react with a corresponding saccharide.
Example 26
[0163] Synthesis of Compound 59
[0164] Compound 45 (500 mg) obtained in Example 1,
N-(2-(p-toluenesulfonyl- oxy)ethyl~phthalimide (537 mg), potassium
iodide (258 mg), and sodium hydrogen carbonate (131 mg) were
stirred in dimethylformamide (8 ml) at 150.degree. C. for 28 hours.
The reaction mixture was extracted with ethyl acetate, and the
organic layer was washed with saturated aqueous sodium hydrogen
carbonate, dried over magnesium sulfate, and concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography to obtain 260 mg of phthalimide compound.
[0165] The above phthalimide compound (260 mg) and hydrazine
monohydrate (31.58 mg) were stirred in ethanol (3 ml) with heating
for 3 hours. The reaction mixture was extracted with ethyl acetate,
and the organic layer was washed with saturated aqueous sodium
hydrogen carbonate, dried over magnesium sulfate, and concentrated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (chloroform/methanol=1/1) to
obtain 97 mg of the target compound.
[0166] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 2.10 (m, 2H),
2.50-3.00 (m, 10H), 6.87 (d, 4H), 7.27 (d, 4H)
Example 27
[0167] Syntheses of Compounds 82 to 83, Compound 195 and Compound
202
[0168] The title compounds were synthesized by allowing Compound 59
obtained in Example 26 to react with sodium isocyanate, acetic
anhydride, methanesulfonyl chloride and
3,5-dimethylpyrazole-1-carboxyamidine nitrate, respectively.
Example 28
[0169] Synthesis of Compound 48
[0170] 4-(2-Bromoethylthio)phenol (1.2 g) was dissolved in
dimethylformamide (10 ml) under nitrogen atmosphere, to this
solution was added imidazole (1.5 g) and tert-butyldimethylsilyl
chloride (2.45 g), and the mixture was stirred at room temperature
for one and a half hours. To the reaction mixture was added water,
the mixture was extracted with chloroform, and then the organic
layer was dried over sodium sulfate, and concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography to obtain 1.4 g of silyl compound.
[0171] The above silyl compound (1.4 g) and hydroxylamine
hydrochloride (150 mg) were mixed in ethanol (10 ml), sodium
carbonate (400 mg) was added thereto, and the mixture was refluxed
by heating for 8 hours. The reaction mixture was filtered, and the
residue obtained by concentrating the filtrate under reduced
pressure was purified by silica gel column chromatography (ethyl
acetate/hexane=1/4) to obtain 506 mg of hydroxylamine compound.
[0172] The above hydroxylamine compound (480 mg) was dissolved in
chloroform (10 ml), to the solution was added a solution of
tetrabutylammonium fluoride in tetrahydrofuran (1 equivalent) and
the mixture was stirred at room temperature for 20 minutes. The
reaction mixture was concentrated under reduced pressure, and the
resulting residue was purified by silica gel column chromatography,
and recrystallized from a chloroform-hexane mixed solvent to obtain
320 mg of the target compound.
[0173] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 2.85 (m, 6H), 3.00
(m, 2H), 6.77 (d, 4H), 7.22 (d, 4H), 8.98 (broad, 2H)
Example 29
[0174] Synthesis of Compound 49
[0175] Compounds 45 (200 mg) synthesized in Example 1 and
3,5-dimethylpyrazole-1-carboxyamidine nitrate (125 mg) were
dissolved in dimethyl sulfoxide (4 ml). To this solution was added
triethylamine (1.5 ml) and the mixture was stirred at 120.degree.
C. by heating for 4 hours. The reaction mixture was extracted with
ethyl acetate, and the organic layer was washed with saturated
aqueous sodium hydrogen carbonate, dried over magnesium sulfate,
and concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (ethyl
acetate/methanol=95/5) to obtain 30 mg of the target compound.
[0176] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 2.33 (s, 3H), 2.72
(m, 4H), 3.13 (m, 4H), 6.53 (d, 4H), 7.03 (d, 4H), 9.42 (s, 2H)
Example 30
[0177] Synthesis of Compound 52
[0178] In a 100 ml three-neck flask, thiohydroquinone (1.6 g) was
dissolved in methanol (15 ml) under nitrogen atmosphere. To this
solution was added an aqueous solution (0.7 ml) of sodium hydroxide
(0.51 g), N,N-bis(2-chloroethyl)-2-chloropropion-amide (1.0 g) was
further added, and the mixture was stirred at 50.degree. C. for 2
hours. To the reaction mixture was added ethyl acetate and diluted
hydrochloric acid for separation. The organic layer was washed with
saturated brine, dried over sodium sulfate, and concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (ethyl acetate/hexane=3/2). The resulting oil
was dissolved in methanol, water was added thereto, and then the
precipitates produced were collected by filtration, and dried under
reduced pressure to obtain 1.2 g of the target compound.
[0179] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 2.32 (t, 2H), 2.86
(m, 6H), 3.32 (m, 4H), 6.70 (d, 6H), 7.22 (m, 6H), 9.60 (s, 3H)
Example 31
[0180] Synthesis of Compound 212
[0181] Compound 71 (0.51 g) synthesized in Example 14 and
p-toluenesulfonic acid methyl ester (0.41 g) were stirred at
120.degree. C. for 5 hours on an oil bath. To the reaction mixture
was added ethyl acetate and acetone, the mixture was decanted, then
to the residue was added a solution of potassium iodide (0.35 g) in
acetone-methanol mixed solvent, and the mixture was subjected to
suction filtration. The residue obtained by concentrating the
filtrate under reduced pressure was purified by silica gel column
chromatography (methylene chloride/methanol=9/1-8/2), and the
resulting oil was crystallized by treatment with diethyl ether. The
crystals were collected by filtration, and dried under reduced
pressure to obtain 168 mg of the target compound.
[0182] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 1.00 (t, 3H), 2.97
(s, 3H), 3.0-3.5 (m, 10H), 6.80 (d, 4H), 7.32 (d, 4H), 9.80 (s,
2H)
Example 32
[0183] Syntheses of Compounds 220 to 223
[0184] The title compounds were synthesized by carrying out the
esterification in the same manner as in Example 13.
Example 33
[0185] Syntheses of Compound 224 and Compound 225
[0186] To a solution of Compound 97 (1.0 g) synthesized in Example
8 in acetone (10 ml) were added maleic acid (0.31 g), and further
ethyl acetate. The resulting precipitates were separated by
filtration, washed with ethyl acetate, and dried under reduced
pressure to obtain 1.25 g of the target compound.
[0187] .sup.1H-NMR (CD.sub.3OD) .delta. (ppm) 2.95 (m, 4H), 3.07
(m, 4H), 3.63 (s, 2H), 6.28 (s, 2H), 6.76 (d, 4H), 7.27 (d, 4H)
[0188] In a similar manner, Compound 225 was obtained by using
citric acid.
Example 34
[0189] Synthesis of Compound 226
[0190] Thiohydroquinone (5.05 g), 28% solution of sodium methoxide
(8.2 g) in methanol, and methanol (30 ml) were mixed under water
cooling. To the resulting solution was added a solution of
1,4-bis(5-bromopentanoyl)piper- azine (8.8 g) in methanol (10 ml),
and the mixture was stirred at 40.degree. C. for 2 hours. The
reaction mixture was cooled to room temperature, and concentrated
under reduced pressure. The resulting residue was dissolved in
ethyl acetate (200 ml), and washed with saturated brine (.times.2).
The precipitates produced were separated by filtration, and dried
under reduced pressure to obtain 9.00 g of the target compound.
[0191] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 1.30-1.60 (m, 12H),
2.27 (t, 4H), 2.74 (t, 4H), 3.25-3.46 (m, 8H), 6.72 (d, 4H), 7.18
(d, 4H), 9.53 (s, 2H)
Example 35
[0192] Synthesis of Compound 227
[0193] Thiohydroquinone (4.0 g) was dissolved in methanol (20 ml).
To this solution was added a 28% solution of sodium methoxide (6.7
g) in methanol, the mixture was stirred, a solution of
1,4-bis(2-chloropropiony- l)piperazine (3.8 g) in methanol (20 ml)
was further added thereto, and the mixture was refluxed by heating
for 4 hours. The reaction mixture was cooled to room temperature,
diluted hydrochloric acid was added thereto, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water, and the resulting precipitates were separated by filtration,
and washed with ethyl acetate. These crystals were dried under
reduced pressure to obtain 6.0 g of the target compound.
[0194] .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm) 2.60 (t, 4H), 2.96
(t, 4H), 3.28-3.56 (m, 8H), 6.76 (d, 4H), 7.23 (d, 4H), 9.62 (s,
2H)
Example 36
[0195] Synthesis of Compound 228
[0196] The title compound was synthesized in the same manner as in
Example 35.
[0197] The results of mass spectroscopy (Fast Atom Bombardment Mass
Spectroscopy, positive, p-Nitrobenzylalcohol) are described
below.
5 TABLE 5 Compound No. Parent peak 45 322 48 338 49 364 50 392 51
422 52 502 53 350 54 364 57 481 58 495 59 365 71 350 72 364 73 360
74 362 75 376 77 361 78 393 79 421 80 449 81 378 82 408 83 407 84
368 85 404 86 447 87 396 88 408 89 418 90 402 91 413 92 428 93 428
94 428 95 380 97 379 98 412 99 413 100 413 101 463 102 366 103 380
105 430 106 430 107 463 108 461 109 421 110 435 111 433 113 378 114
426 116 427 118 400 124 435 125 433 191 485 192 517 193 464 194 436
195 443 196 402 197 468 198 424 199 410 200 436 201 396 202 407 203
447 204 485 205 453 206 463 207 423 208 467 209 490 210 462 211 457
212 364 213 463 214 484 215 484 216 484 217 494 218 483 219 497 220
524 221 767 222 521 223 721 224 379 225 379
Test Example 1: Test of Measurement of RNR Inhibitory Activity
[0198] (a) Preparation of R1 and R2 Subunits of Human RNR
[0199] Starting from a plasmid p3I containing cDNA coding for R1
subunit of human RNR protein (disclosed in Nucleic Asids Research,
19, p.3741, 1991), a DNA was obtained, in which was introduced an
Nde I restriction site just before the translation initiation site
of R1 subunit and a Bam HI restriction site just after the
translation termination site in such a manner that the amino acid
sequence of R1 subunit was completely unchanged. The preparation of
DNA was carried out by methods of introducing mutations and DNA
amplification based on the PCR utilizing synthetic DNA fragments
according to the method described in the Molecular Cloning, 2nd
Edition. The Nde I/Bam HI restriction fragment containing a region
coding for the R1 subunit deriving from the DNA was inserted
between the NdeI and Bam HI sites of plasmid pET3a (Novagen) to
construct a plasmid pETR1. The plasmid was transformed in
Eschelichia coli BL21(.lambda. DE3)plysS strain (Novagen) to
construct a BL21(.lambda. DE3)plysSpETR1 strain also according to
the method described in the Molecular Cloning, 2nd Edition.
[0200] Similarly, a DNA fragment was obtained, from a human cell
strain HL60 cDNA library through the methods of introducing
mutations and DNA amplification based on the PCR utilizing
synthetic DNA fragments, which was introduced with an Nde I
restriction site just before the translation initiation site of R2
subunit and a Bam HI restriction site just after the translation
termination site in such a manner that the amino acid sequence of
R2 subunit were completely unchanged. The Nde I/Bam HI restriction
fragment containing the region coding for the R2 subunit deriving
from the DNA was inserted between the NdeI and Bam HI sites of
plasmid pET3a (Novagen) to construct a plasmid pETR2. This plasmid
was transformed into Eschelichia coli BL21(.lambda. DE3)plysS
strain (Novagen) also according to the method described in the
Molecular Cloning, 2nd Edition to construct a BL21(.lambda.
DE3)plysSpETR2 strain.
[0201] By using one loop, the BL21(.lambda. DE3) plysSpETR1 strain
was inoculated to 40 ml of Terrific Broth (containing 100 .mu.g/ml
of ampicillin and 20 .mu.g/ml of chloramphenicol and free from
glycerol, described in Molecular Cloning, 2nd Edition) contained in
a 300 ml Erlenmeyer flask, and cultured at 28.degree. C. overnight
with shaking. 30 ml of the culture broth was inoculated in 400 ml
of the same culture broth contained in a 2 liter Erlenmeyer flask,
and cultivation was carried out at 16.degree. C. with shaking. Two
hours after the start of the cultivation, IPTG was added to the
broth to a final concentration of 0.1 mM, and then the cultivation
was continued for 20 hours. Cells were collected from the culture
broth by centrifugation at 7,000.times.g for 10 minutes at
4.degree. C., and the cells collected were suspended in 20 ml of
Buffer A [50 mM HEPES-NaOH (pH 7.6), 1 mM MgCl.sub.2, 1 mM
dithiothreitol, 1 mM PMSF] cooled with ice. This suspension was
sonicated to disrupt the cells, and then centrifuged at
12,000.times.g for 20 minutes at 4.degree. C. The supernatant was
collected, streptomycin sulfate was added thereto to a final
concentration of 2% (W/V) and the mixture was maintained on ice for
20 minutes, and then centrifuged at 12,000.times.g for 20 minutes
at 4.degree. C. The supernatant was collected, an equal volume of
100% saturated aqueous ammonium sulfate was added thereto with
stirring, and then the mixture was maintained on ice overnight.
Precipitates were collected by centrifugation at 15,000.times.g for
20 minutes at 4.degree. C. and dissolved in 2 ml of Buffer A, and
then the solution was subjected to desalting and buffer
substitution with Buffer A by using PD-10 (Pharmacia Biotech) in a
conventional manner.
[0202] For all of the subsequent separation and purification steps,
FPLC System (Pharmacia Biotech) was used. The desalted fraction was
applied to Q-Sepharose FF (Pharmacia Biotech), and separation was
carried out under the following conditions: flow rate: 5.0
ml/minute, separation time: 50 minutes, eluent: 0 M to 0.5 M KCl
linear gradient in 10 mM potassium phosphate buffer (pH 7.0). The
fractions eluted from 10 minutes to 20 minutes were collected and
ammonium sulfate was added thereto to a final concentration of 0.5
M. The fractions were applied to Phenyl Sepharose HP (Pharmacia
Biotech) and eluted at a flow rate, of 3.0 ml/minute with 10 mM
potassium phosphate buffer (pH 7.0)/0.5 M ammonium sulfate for 15
minutes, with 10 mM potassium phosphate buffer (pH 7.0) for 15
minutes, and then with 10 mM potassium phosphate buffer (pH
7.0)/0.3% Tween 20 for 15 minutes. The fractions eluted in the last
15 minutes were collected and applied to Resource Q 1 ml (Pharmacia
Biotech), washed with 10 mM potassium phosphate buffer (pH 7.0),
and eluted at a flow rate of 1 ml/minute with 10 mM potassium
phosphate buffer (pH 7.0)/0.3 M KCl for 10 minutes. The fractions
eluted in the first 3 minutes were collected, and subjected to
desalting and buffer substitution with Buffer A by using PD-10 to
obtain a purified R1 preparation.
[0203] By using one loop, the BL21(.lambda. DE3) plysSpETR2 strain
was inoculated to 40 ml of Terrific Broth (containing 100 .mu.g/ml
of ampicillin and 20 .mu.g/ml of chloramphenicol and free from
glycerol, described in Molecular Cloning, 2nd Edition) in a 300 ml
Erlenmeyer flask, and cultured at 28.degree. C. overnight with
shaking. 30 ml of the culture broth was inoculated to 400 ml of the
same culture broth in a 2 liter Erlenmeyer flask, and then the
cultivation was carried out at 28.degree. C. with shaking. When
O.D. (600 nm) reached around 0.8, IPTG was added to the broth to a
final concentration of 1 mM, and the cultivation was continued for
6 hours. Cells were collected from the culture broth by
centrifugation at 7,000.times.g for 10 minutes at 4.degree. C., and
the cells obtained were suspended in 20 ml of Buffer A cooled with
ice. This suspension was sonicated to disrupt the cells, and then
centrifuged at 12,000.times.g for 20 minutes at 4.degree. C. The
supernatant was collected, streptomycin sulfate was added thereto
to a final concentration of 2% (W/V), and the mixture was
maintained on ice for 20 minutes, and then centrifuged at
12,000.times.g for 20 minutes at 4.degree. C. The supernatant was
collected, an equal volume of 100% saturated aqueous ammonium
sulfate was added thereto with stirring, and then the mixture was
maintained on ice overnight. Precipitates were collected by
centrifugation at 15,000.times. for 20 minutes at 4.degree. C. and
dissolved in 2 ml of Buffer A, and then the solution was subjected
to desalting and buffer substitution with Buffer A by using PD-10
(Pharmacia Biotech) in a conventional manner.
[0204] For all of the subsequent separation and purification steps,
FPLC System (Pharmacia Biotech) was used. The desalted fraction was
applied to Q-Sepharose FF (Pharmacia Biotech), and separation was
carried out under the following conditions: flow rate: 5.0
ml/minute, separation time: 50 minutes, eluent: 0 M to 0.5 M KCl
linear gradient in 10 mM potassium phosphate buffer (pH 7.0). The
fractions eluted from 10 minutes to 25 minutes were collected,
ammonium sulfate was added thereto to a final concentration of 0.5
M, and the mixture was applied to Resource ETH. The fractions were
eluted at a flow rate of 0.5 ml/minute with 10 mM potassium
phosphate buffer (pH 7.0)/0.5 M ammonium sulfate for 15 minutes,
with 10 mM potassium phosphate buffer (pH 7.0) for 15 minutes, and
then with 10 mM potassium phosphate buffer (pH 7.0)/0.3% Tween 20
for 15 minutes. The fractions eluted in the last 15 minutes were
collected and applied to Resource Q 1 ml (Pharmacia Biotech), and
then washed with 10 mM potassium phosphate buffer (pH 7.0)/0.5 M
ammonium sulfate at a flow rate of 1 ml/minute for 10 minutes. The
fractions were eluted with 10 mM potassium phosphate buffer for 10
minutes. The fractions eluted in the first 3 minutes were
collected, and subjected to desalting and buffer substitution with
Buffer A by using PD-10 to obtain a purified R2 preparation.
[0205] (b) In vitro Measurement of Human RNR Inhibitory
Activity
[0206] By using the above-obtained human RNR subunits, inhibitory
activity on the human RNR was tested in vitro. The composition of
the reaction mixture is as follows:
[0207] 50 mM HEPES-NaOH (pH 7.6)
[0208] 5 mM MgCl.sub.2
[0209] 10 mM Dithiothreitol
[0210] 100 .mu.M CDP
[0211] 1 mM ATP
[0212] 40 ng/ml Purified human RNR R1 subunit, and
[0213] 40 ng/ml Purified human RNR R2 subunit.
[0214] The above reaction mixture (25 .mu.l) containing a test
compound at an appropriate final concentration was prepared, and
the conversion from CDP to dCDP by RNR was carried out at
37.degree. C. for 30 minutes. The reaction mixture was subjected to
a heat treatment at 95.degree. C. for 5 minutes, and centrifuged at
10,000.times.g for 5 minutes at 4.degree. C. 20 .mu.l of the
supernatant was collected and 5 .mu.l of 25 mg/ml snake venom
(Sigma) was added thereto. Dephosphorylation reaction was carried
out at 37.degree. C. for 60 minutes to allow complete conversion of
CDP, ATP and dCDP as the reaction product present in the reaction
mixture into CR, AR and CdR, respectively. The reaction mixture was
subjected to a heat treatment at 95.degree. C. for 5 minutes, and
centrifuged at 10,000.times.g for 5 minutes at 4.degree. C. 180
.mu.l of acetonitrile was added to 20 .mu.l of the supernatant, and
the mixture was centrifuged again at 10,000.times.g for 5 minutes
at 4.degree. C., and the resulting supernatant was used as a sample
for analysis. The analysis was performed by high performance liquid
chromatography. Analytical conditions are as follows:
[0215] Column: Licrospher NH2 (Merck)
[0216] Flow rate: 1.5 ml/min
[0217] Detection: 270 nm, and
[0218] Eluent: acetonitrile/water (90:10, V/V).
[0219] CdR in the analyzed sample was identified and its
concentration was determined by comparison with elution time and
peak area with those of CdR at known concentration. A concentration
of a test compound which inhibited the RNR activity by 50% under
the aforementioned conditions was calculated by comparing a CdR
concentration in a sample, obtained from the reaction without drug
treatment, with a CdR concentration in a sample obtained from the
reaction wherein the test compound at a known concentration was
added, and the value obtained was determined as IC.sub.50.
Test Example 2: Test for Growth Inhibition of Hela S3 Cells
[0220] HeLa S3 cells prepared at 1.times.10.sup.4 cells/ml in MEM
culture medium containing 10% fetal bovine serum and 2 mM glutamine
were added to each well of a 96-well microtiter plate (0.1 ml for
each well). The cells were cultured at 37.degree. C. in a CO.sub.2
incubator for 24 hours, and then 0.05 ml of test compound
appropriately diluted with the above medium was added to each well,
and then the mixture was cultured at 37.degree. C. in a CO.sub.2
incubator for 72 hours. After the culture supernatant was removed,
each well was washed with 0.1 ml of PBS buffer twice, and 0.1 ml of
the aforementioned medium was added to each well again.
[0221] Cell Proliferation Kit II (Boehringer Mennheim) was used for
measurement of cell number in each well. After a coloring reaction
reagent was added, the plate was warmed to 37.degree. C. in a
CO.sub.2 incubator for 3 hours. Then, absorbances at 490 nm and 655
nm were measured by a microplate reader, and a value (difference of
absorbance) was calculated for each well by subtracting the
absorbance at 650 nm from the absorbance at 490 nm. By comparing
the differences of absorbance for cells without treatment and cells
treated with a test compound at a known concentration, a
concentration of test compound which inhibited the cell growth by
50% was calculated, and the value obtained was determined as
IC.sub.50. The values of RNR inhibitory activity obtained in
Example 8, and the values of cell growth inhibitory activity
obtained in Example 9 are shown in the following tables (the
compound numbers used in the tables correspond to the compound
numbers shown in the aforementioned tables).
6TABLE 6 RNR Inhibition Cell growth inhibition Compound No.
(IC.sub.50, .mu.M) (IC.sub.50, .mu.M) 1 4.26 5.15 7 4.82 >101 8
4.38 6.50 27 0.50 1.53 45 3.64 5.64 48 1.73 5.16 49 5.45 16.04 50
3.97 3.81 52 4.38 6.50 53 1.05 1.71 54 0.48 4.63 55 6.87 7.78 57
0.73 14.44 58 4.76 18.59 59 5.73 5.81 60 2.75 7.67 61 3.77 13.40 71
1.23 3.94 72 1.19 2.18 73 0.60 1.61 74 0.82 2.00 75 1.66 3.56 77
0.06 2.38 78 0.31 1.61 79 1.37 3.06 80 0.74 1.43 81 0.29 1.23 82
1.42 1.30 83 2.95 5.17 84 2.74 11.99 85 0.61 2.50 86 3.14 3.78 87
1.01 2.57 88 1.79 3.22 89 1.46 4.66 90 2.03 6.38 91 1.69 2.72 92
0.89 2.14 93 0.63 9.04 94 0.46 4.00 95 0.88 3.56 97 0.17 0.88 98
3.36 14.97 99 2.79 5.80 100 1.58 4.97 101 5.05 12.88 102 0.69 1.42
103 2.11 1.74 104 2.11 1.74 105 3.99 9.07 106 4.64 6.77 107 4.20
24.86 108 0.64 2.64 109 2.36 38.89 111 1.85 11.39 113 4.77 3.80 114
3.44 2.74 115 4.14 6.14 116 4.13 3.02 117 1.69 2.72 118 6.87 7.78
124 0.09 3.68 125 0.91 4.55 131 6.59 127.70 132 3.50 45.55 133 2.27
14.51 134 0.68 2.05 135 0.43 6.02 136 0.69 9.14 137 0.87 5.45 138
2.29 18.28 152 5.14 17.96 156 2.27 5.45 158 1.42 12.72 159 0.69
6.89 160 0.95 20.09 161 1.13 34.19 162 1.70 3.70 163 2.10 5.17 165
3.98 50.14 166 3.09 31.25 171 8.01 30.03 172 2.64 19.48 173 3.63
12.93 183 0.42 10.42 184 0.30 2.46 186 11.93 56.03 190 1.38 16.86
191 1.36 4.78 192 2.85 4.51 193 N.T. 0.36 194 0.84 11.71 195 0.55
3.16 196 1.52 7.08 197 3.24 4.06 198 4.86 4.85 199 3.99 5.14 200
4.20 4.13 201 2.49 4.29 202 1.87 42.64 203 3.18 3.45 204 1.50 3.38
205 1.19 7.32 206 1.13 3.31 207 0.87 1.71 208 3.46 5.93 209 2.67
3.09 210 5.91 2.82 211 3.24 3.04 213 2.06 179.95 214 2.69 7.73 215
3.68 12.72 216 3.63 11.54 218 4.97 23.18 219 3.51 25.20 220 5.20
0.29 222 0.43 0.36 224 0.42 0.40 225 0.63 0.55 N.T.: Not
tested.
Test Example 3: Antineoplastic Effect Against Human Ovary Cancer
A2780 Cells
[0222] 2 mm cubes (tumor fragments of 8 mm.sup.3) of human ovary
cancer A2780 cells were subcutaneously transplanted to nude mice
BALB/cAJcl-nu (CLEA JAPAN) in the abdomens. When the tumor volume
reached to from 50 to 300 mm.sup.3 after the transplantation, the
mice were arbitrarily divided into groups each consisting of 5
mice, and intraperitoneally administered with a drug solution once
a day for 5 days. After weighing compounds, the drug solution was
prepared before use by dissolving the drug in 99.5% ethanol (final
concentration: 5%, analytical grade, Kanto Kagaku) or
N,N-methylacetamide (final concentration: 5%, analytical grade,
Kanto Kagaku), adding CREMOPHOR EL (a derivative of caster oil and
ethylene oxide, final concentration: 10%, Sigma Chemical) to the
solution, and suspending the solution in physiological saline
(Otsuka Physiological Saline for Injection, Otsuka Pharmaceutical).
For evaluation of the effect, a tumor volume was calculated in
accordance with Equation 1, a ratio of tumor volume (V) after the
administration of drug solution to tumor volume (V.sub.0) before
the administration of drug solution was calculated (V/V.sub.0), and
the ratio was compared with that for the untreated group to
determine T/C (Equation 2). The results are shown in the table set
out below. In the table, administration dose, T/C and evaluation
day are shown.
Tumor volume (mm.sup.3)=Length (mm).times.Width (mm).times.Width
(mm).times.1/2 Equation 1:
T/C=(V/V.sub.0 for drug-administered group)/(V/V.sub.0 for
untreated group) Equation 2:
[0223]
7 TABLE 7 Compound Dose Antitumor Evaluation No. mg/kg/day activity
T/C day* 27 500 0.46 7 48 500 0.54 7 72 500 0.50 4 77 500 0.54 4 78
500 0.53 4 79 500 0.40 4 91 500 0.48 4 94 500 0.53 7 97 500 0.43 7
102 500 0.47 7 103 500 0.50 4 193 250 0.46 4 209 500 0.50 7 211 500
0.37 9 177 500 0.54 4 227 500 0.53 7 *Days after the first
administration of test compound
Test Example 4: Antineoplastic Effect Against Human Lung Cancer
Lu-65 Cells
[0224] 2 mm cubes (tumor fragments of 8 mm.sup.3) of human lung
cancer Lu-65 cells were subcutaneously transplanted to nude mice
BALB/cAJcl-nu (CLEA JAPAN) on their abdomens. When the tumor volume
reached to from 50 to 300 mm.sup.3 after the transplantation, the
mice were arbitrarily divided into groups each consisting of 5
mice, and intraperitoneally administered with a drug solution twice
a day for 5 days. After weighing compounds, the drug solution was
prepared before use by dissolving the drug in 99.5% ethanol (final
concentration: 5%, analytical grade, Kanto Kagaku), adding
CREMOPHOR EL (a derivative of caster oil and ethylene oxide, final
concentration: 10%, Sigma Chemical) to the solution, and suspending
the solution in physiological saline (Otsuka Physiological Saline
for Injection, Otsuka Pharmaceutical). For evaluation of the
effect, a tumor volume was calculated in accordance with Equation
1, a ratio of tumor volume (V) after the administration of drug
solution to tumor volume (V.sub.0) before the administration of
drug solution was calculated (V/V.sub.0), and the ratio was
compared with that for the untreated group to determine T/C
(Equation 2). The results are shown in the table set out below.
Tumor volume (mm.sup.3)=Length (mm).times.Width (mm).times.Width
(mm).times.1/2 Equation 1:
T/C=(V/V.sub.0 for drug-administered group)/(V/V.sub.0 for
untreated group) Equation 2:
[0225]
8 TABLE 8 Compound Dose Antitumor Evaluation No. mg/kg/day activity
T/C day* 27 1000 (500 .times. 2) 0.25 7 *Days after the first
administration of test compound
[0226] Industrial Availability
[0227] The compounds of the aforementioned formula (I) or (II),
which are the active ingredient of the medicament of the present
invention, can inhibit ribonucleotide reductase, and selectively
inhibit proliferation of cancer cells. Therefore, the medicament of
the present invention is useful, for example, as an agent for
cancer treatment. The novel compounds represented by the
aforementioned formula (XII) provided by the present invention are
useful as active ingredients of medicaments such as medicaments for
cancer treatment.
* * * * *