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United States Patent |
5,008,454
|
Inoue
,   et al.
|
April 16, 1991
|
Propanediol derivatives, their production and use
Abstract
Novel compounds having the formula:
R.sup.1 --OCH.sub.2 CH.sub.2 CH.sub.2 O--(CH.sub.2).sub.n --R.sup.2
wherein R.sup.1 stands for a higher alkyl group; R.sup.2 stands for a
primary to tertiary amino group or a quaternary ammonium group; and n
denotes an integer of 3 to 10; and salts thereof, have excellent
anti-tumor action and therefore are useful as anti-tumor agents.
Inventors:
|
Inoue; Keizo (Tokyo, JP);
Nomura; Hiroaki (Takatsuki, JP);
Tasaka; Akihiro (Suita, JP)
|
Assignee:
|
Takeda Chemical Industries, Ltd. (Osaka, JP)
|
Appl. No.:
|
492330 |
Filed:
|
March 12, 1990 |
Foreign Application Priority Data
| Aug 18, 1987[JP] | 62-204795 |
Intern'l Class: |
C07C 215/40 |
Field of Search: |
564/281,294,285
558/452
|
References Cited
U.S. Patent Documents
3449430 | Jun., 1969 | Dohr et al. | 564/505.
|
4080381 | Mar., 1978 | Burke et al. | 564/505.
|
4482713 | Nov., 1984 | Strickler | 564/294.
|
4650865 | Mar., 1987 | Lange et al. | 564/505.
|
Foreign Patent Documents |
0109255 | May., 1964 | EP | 564/294.
|
0094586 | Nov., 1983 | EP | 564/294.
|
0142333 | May., 1985 | EP | 564/294.
|
0146258 | Jun., 1985 | EP | 564/294.
|
01507 | Mar., 1986 | WO | 564/294.
|
Other References
Barry, B. W., et al., "C. M. C., Counterion Binding and Thermodynamics of
Ethoxylated Anionic and Cationic Surfactants", Colloid & Polymer Science,
vol. 256, (1978) pp. 251-260.
|
Primary Examiner: Reamer; James H.
Attorney, Agent or Firm: Wegner, Cantor, Mueller & Player
Parent Case Text
This application is a continuation of U.S. application Ser. No. 07/227,531,
filed Aug. 3, 1988, now abandoned.
Claims
What is claimed is:
1. A compound of the formula:
R.sup.1 --OCH.sub.2 CH.sub.2 CH.sub.2 O--(CH.sub.2).sub.n --R.sup.2(I)
wherein R.sup.1 stands for the alkyl group having 8 to 22 carbon atoms
which is unsubstituted or substituted by C.sub.3-8 cycloalkyl, phenyl,
halogen, cyano, ethynyl, oxo or C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
hydroxy, nitro or halogen;
R.sup.2 stands for a quaternary ammonium group represented by the formula:
##STR10##
wherein R.sup.3, R.sup.4, and R.sup.5 independently stand for C.sub.1-5
alkyl, n denotes an integer of 3 to 10;
wherein said compound represented by the formula (I) is in the form of a
pharmaceutically acceptable salt with an anion or an intramolecular salt
with an anion in the molecule of said compound.
2. A compound according to claim 1, wherein R.sup.1 stands for C.sub.8-22
alkyl.
3. A compound according to claim 1, wherein R.sup.1 stands for n-octadecyl.
4. A compound according to claim 1, wherein R.sup.2 stands for
trimethylammonium group.
5. A compound according to claim 1, wherein n denotes an integer of 3 to 8.
6. A compound according to claim 1, wherein n denotes an integer of 4 to 6.
7. A compound according to claim 1, which is an acid anion salt of
N-[4-[3-(octadecyloxy)propoxy]butyl-N,N,N-trimethylammonium.
8. A compound according to claim 1, which is an acid anion salt of
6-[3-(octadecyloxy)propoxy]hexyl-N,N,N-trimethylammionium.
Description
INDUSTRIAL FIELD OF THE UTILIZATION
This invention relates to propanediol derivatives useful as medicines. More
specifically, the present invention relates to compounds represented by
the formula:
R.sup.1 --OCH.sub.2 CH.sub.2 CH.sub.2 O--(CH.sub.2).sub.n --R.sup.2[I]
[wherein R.sup.1 stands for a higher alkyl group; R.sup.2 stands for a
primary to tertiary amino group or a quaternary ammonium group; and n
denotes an integer of 3 to 10] and salts thereof.
PRIOR ART
Recently, physiological activities of lipid derivatives have attracted
attention. For example, the platelet activating factor shown by the
formula [II] [hereinafter abbreviated as PAF] has attracted attention as
an important chemical mediator in living bodies, because it shows a
variety of strong physiological actions such as platelet-activating
action, vessel permeability-enhancing action and blood pressure-lowering
action [C. A. Demopoulos, R. N. Pinckard, and D. J. Hanahan, J. Biol.
Chem., 254, 9355 (1979); J. Benveniste et al., C. R. Acad. Sci(D), 289,
1037 (1979)].
In addition, the phospholipid shown by the formula [III], which is an
analog to the compounds of the formula [II], is known to have an
anti-tumor action. [W. E. Berdel et al., Anticancer Res. 1, 345 (1981);
the official gazette of Japanese Unexamined Patent Publication No.
134027/1977]. However, this compound has such side effects as platelet
aggregation and hypotensive action due to its structural similarity to
PAF. [D. J. Hanahan et al., Biochem. Biophys. Res. Commun., 99, 183
(1981)].
On the other hand, lipids having no phosphate group, represented by the
formula [IV] [wherein R.sup.3 =long chain alkyl; R.sup.4 =short chain or
long chain alkyl or acyl having 2 to 5 carbon atoms;
X.dbd.O(CH.sub.2).sub.m --R.sup.5 ; m=an integer of 1 to 12; and R.sup.5
=amino group, acylamino group or quaternary ammonium group] were disclosed
to exhibit antagonism to PAF, and to be possibly useful as a therapeutic
agent for disorders due to PAF. [the official gazette of Japanese
Unexamined Patent Publication No. 100544/1985; the official gazette of
Japanese Unexamined Patent Publication No. 198445/1983; T. Miyamoto et
al., Kyoto Conference of Prostaglandins, Nov. 26-28, 1984, Abst. p. 99].
However, no concrete disclosure has yet been made in respect of anti-tumor
actions.
##STR1##
PROBLEMS THAT THE INVENTION IS DESIGNED TO SOLVE
In recent years, it has been gradually elucidated that the characteristics
of tumor cells, such as abnormal proliferation of cells or disorders of
intracellular interaction, are derived from structural and functional
abnormalities of the carcinoma cell's membrane.
On the other hand, it has become apparent that amphipathic lipids have
affinity to cell membrane and possibly exert various influences on
cellular metabolism and functions.
The present inventors supposed that, among amphipathic lipids, there is a
possibility of existence of compounds having a high selectivity to tumor
cells and useful as anti-tumor agents, and they have diligently conducted
an intensive study.
There have already been found several reports that tumor cells are inferior
to normal cells in the alkyl-ether cleavage activity [Wykle, R. L. and
Snyder, F., The Enzymes of Biological Membranes, Martonosi, A., Ed., Vol.
2, Plenum Press, New York, 1976, 87; Lin, H. J., Ho, F. C. S., and Lee, C.
L. H., Cancer Res., 38, 946 (1978); Modolell, M., Andreesen, R., Pahlke,
W., Brugger, U., and Munder, P. G., Cancer Res., 39, 4681 (1976)], and
therefore it is expected that lipids having an alkyl ether group are
accumulated in tumor cells more than-in normal cells because of slow
metabolism in tumor cells, and then the lipids show selective
cytotoxicity.
Further, it is known that the membrane electric potential of tumor cells is
lower than that of normal cells due to increase of sialate on the surface
of the membrane, and it is expected that cationic lipids show higher
affinity with tumor cells. [T. J. Lampidis et al., Biomedicine &
Pharmacotherapy, 39, 220(1985)]. The present inventors have found that the
cationic lipids having an ether-linkage represented by the general formula
[I] exhibit a strong inhibitory effect on proliferation of tumor cells,
the mechanism of which is different from that of known carcinostatic
agents attacking DNA directly, with less undesirable side effects, thus
the present invention being completed.
MEANS OF SOLVING THE PROBLEMS
The present inventors have diligently conducted intensive studies aiming at
development of a drug having an excellent antitumor action but showing no
PAF-like action, and have found that the compounds of the general formula
[I] show a strong inhibitory effect on proliferation of tumor cells but
have neither platelet-aggregating nor blood pressure-lowering actions, the
side effects being thus diminished, and the present invention has been
completed.
More specifically, the present invention is to provide compounds
represented by the general formula:
R.sup.1 --OCH.sub.2 CH.sub.2 CH.sub.2 O--(CH.sub.2).sub.n --R.sup.2[I]
wherein R.sup.1 stands for a higher alkyl group; R.sup.2 stands for a
primary to tertiary amino group or a quaternary ammonium group; and n
denotes an integer of 3 to 10 and salts thereof.
In the above-mentioned general formula [I], the higher alkyl group
represented by R.sup.1 includes straight-chain alkyl groups having 8 to 22
carbon atoms, such as n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,
n-tetradecyl, n-hexadecyl, n-heptadecyl, n-octadecyl and n-eicosyl, and
branched chain alkyl groups having 8 to 22 carbon atoms, such as
18,18-dimethylnonadecyl, 19,19-dimethyleicosyl, 19-methyleicosyl,
3,7,11-trimethyldodecyl and 3,7,11,15-tetramethylhexadecyl. The said
higher alkyl groups may have a substituent such as cycloalkyl, aryl,
halogen (about 1 to 7), cyano, ethynyl, oxo or lower alkoxy. The said
lower alkoxy group includes alkoxy groups of 1 to 4 carbon atoms, such as
methoxy and ethoxy. The said cycloalkyl group includes 3- to 8-membered
cycloalkyl groups such as cyclopentyl and cyclohexyl. The said aryl group
includes phenyl, and the said phenyl group may be substituted with
lower(C.sub.1-4)alkyl, lower(C.sub.1-4)alkoxy, hydroxy, nitro or halogen.
Halogens as substituents of the above-mentioned higher alkyl group and the
phenyl group include fluorine, bromine and chlorine. When R.sup.1 is a
substituted higher alkyl group, the position at which the substitution
occurs may be any substitutive position of the higher alkyl group. When
the substituent is cycloalkyl, aryl, halogen, cyano or ethynyl, the
substitutive position is preferably the .omega.(omega)-position of the
higher alkyl group. The said substituted alkyl groups include, among
others, 13-cyclopentyltridecyl, 12-cyclohexyldodecyl, 10-cyclohexyldecyl,
12-phenyldodecyl, octadecan-17-ynyl, hexadecan-15-ynyl, 2-oxooctadecyl,
16-cyanohexadecyl, 2-methoxyeicosyl, 2-methoxyoctadecyl,
18-chlorooctadecyl, 18,18-dichlorooctadecyl, 18,18,18-trifluorooctadecyl,
18,18,18-trichlorooctadecyl, 14,14,15,15,16,16,16-heptafluorohexadecyl and
16,16,17,17,18,18,18-heptafluorooctadecyl.
The primary to tertiary amino group represented by R.sup.2 includes groups
represented by the formula:
##STR2##
wherein R.sup.3 and R.sup.4 independently stand for hydrogen or a lower
alkyl group, or R.sup.3 and R.sup.4, taken together with the adjacent
nitrogen atom, form a cyclic amino group.
The lower alkyl group represented by R.sup.3 or R.sup.4 includes alkyl
groups having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, butyl
and pentyl, among which a methyl group is preferable.
The cyclic amino group includes 5- or 6-membered cyclic amino groups, such
as pyrrolidino, piperidino, piperazino and morpholino, and these groups
may be substituted with a substituent such as a lower alkyl group having 1
to 4 carbon atoms (e.g. methyl, ethyl, propyl, butyl), a hydroxyl group, a
hydroxyethyl group, an aminoethyl group, a carboxy group, a
lower(C.sub.1-4)-alkoxycarbonyl group, a carbamoyl group or a ureido
group.
The quaternary ammonium group represented by R.sup.2 includes groups shown
by the formula:
##STR3##
wherein R.sup.3, R.sup.4 and R.sup.5 independently stand for hydrogen or a
lower alkyl group or
##STR4##
stands for a cyclic ammonium group.
The lower alkyl group represented by R.sup.3, R.sup.4 or R.sup.5 includes
alkyl groups having 1 to 5 carbon atoms (e.g. methyl, ethyl, propyl,
butyl, pentyl), among which a methyl group is preferable.
The cyclic ammonium group includes pyridinio, oxazolio, thiazolio,
pyridazinio, quinolinio, isoquinolinio,
1-[lower(C.sub.1-4)alkyl]pyrrolidinio,
1-[lower(C.sub.1-4)-alkyl]piperidinio,
N-[lower(C.sub.1-4)alkyl]morpholinio and
1-[lower(C.sub.1-4)alkyl]piperazinio, and these groups may be further
substituted with a substituent such as a lower alkyl group having 1 to 4
carbon atoms (e.g. methyl, ethyl, propyl, butyl), a hydroxyl group, a
hydroxyethyl group, an aminoethyl group, a carboxy group, a
lower(C.sub.1-4)alkoxycarbonyl group, a carbamoyl group or a ureido group.
n denotes an integer of 3 to 10, preferably an integer of 3 to 8 and more
preferably an integer of 4 to 6.
When R.sup.2 is a primary to tertiary amino group, the compound [I] may
form a pharmaceutically acceptable salt with an inorganic acid (e.g.
hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid) or an
organic acid (e.g. acetic acid, lactic acid, tartaric acid, citric acid,
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
toluenesulfonic acid).
When R.sup.2 is a quaternary ammonium group, the compound [I] forms a salt
with an anion (X.sup.-) such as a pharmaceutically acceptable anion of an
inorganic acid (e.g. hydrochloric acid, hydrobromic acid, hydriodic acid,
sulfuric acid) or an organic acid (e.g. acetic acid, lactic acid, tartaric
acid, citric acid, methanesulfonic acid, ethanesulfonic acid,
benzenesulfonic acid, toluenesulfonic acid) or forms an intramolecular
salt with an anion in the molecule. Desirable anions include a halogen ion
(e.g. chlorine ion, bromine ion, iodine ion), an anion of methanesulfonic
acid, and an anion of p-toluenesulfonic acid. The anion in the molecule
includes a carboxylato group (carboxy group) and an oxido group (hydroxy
group).
The compound [I] of the present invention can be produced by, for example,
the following methods.
##STR5##
[wherein Y stands for benzenesulfonyloxy,
lower(C.sub.1-4)-alkylbenzenesulfonyloxy,
lower(C.sub.1-4)alkanesulfonyloxy or halogen (e.g. bromine, chlorine), and
the other symbols are of the same meaning as defined above].
The compound [I] can be obtained by allowing the compound [IX] to react
with an amine
##STR6##
The said reaction is conducted, using an excess amount of the amine, in
said amine or a suitable solvent (e.g. water, ethanol, toluene,
tetrahydrofuran, etc. or a mixture thereof) at -20.degree. C. to
+150.degree. C., preferably at 0.degree. C. to +80.degree. C. Separation
and purification of the compound I] from the reaction mixture can be
performed by known procedures such as solvent distillation,
solvent-extraction and column chromatography (silica gel).
The starting compound [IX] can be produced by, for example, the procedure
shown below.
##STR7##
The compound [IX] can be obtained by allowing the compound [VIII] to react
with a sulfonyl halide in a suitable anhydrous solvent (e.g. benzene,
toluene, dichloromethane, chloroform, pyridine, etc., or a mixture
thereof) in the presence of a base (e.g. tertiary amines such as
triethylamine and pyridine) at -20.degree. C. to +100.degree. C.,
preferably at -10.degree. C. to +50.degree. C. [Y=benzenesulfonyloxy,
lower alkylbenzenesulfonyloxy or lower alkanesulfonyloxy]. The sulfonyl
halides to be employed include, for example, benzenesulfonyl halide (e.g.
benzenesulfonyl chloride), a lower(C.sub.1-4)-alkylbenzenesulfonyl halide
(e.g. toluenesulfonyl chloride) and a lower(C.sub.1-4)alkanesulfonyl
halide (e.g. methanesulfonyl chloride). The compound [IX] (Y=halogen) can
be obtained by allowing the compound [VIII] to react with an anhydrous
hydrogen halide (e.g. hydrogen chloride, hydrogen bromide), thionyl halide
(e.g. thionyl chloride, thionyl bromide), phosphorus halide (e.g.
phosphorus pentachloride, phosphorus trichloride, phosphorus pentabromide,
phosphorus tribromide) or phosphorus oxychloride in an inert solvent (e.g.
dichloromethane) at -20.degree. C. to +50.degree. C.
The compound [IX], wherein Y stands for halogen, can also be obtained by
allowing an alkali metal halide (e.g. sodium bromide, sodium iodide) to
react with the compound [IX] wherein Y stands for benzenesulfonyloxy,
lower alkylbenzenesulfonyloxy or lower alkanesulfonyloxy.
The compound [VIII] can be obtained by allowing the compound [VII] to react
with the compound represented by the formula:
HO(CH.sub.2).sub.n OH.
The reaction is conducted in a suitable solvent (e.g. benzene, toluene,
hexane, dioxane, tetrahydrofuran, etc.) in the presence of a strong base
(e.g. sodium hydroxide, potassium hydroxide, etc., or an aqueous solution
thereof), and, when the conditions are hydrous, preferably in the presence
of a phase-transfer catalyst (e.g. cetyltrimethylammonium chloride,
benzyltrimethylammonium chloride), at -20.degree. C. to +150.degree. C.,
preferably +20.degree. C. to +100.degree. C.
The reaction of [VI].fwdarw.[VII] can be conducted in the same manner as
that of [VIII].fwdarw.[IX], and the reaction of [V].fwdarw.[VI] can be
conducted in the same manner as that of [VII].fwdarw.[VIII].
The compound [VIII] can also be produced by the following method.
##STR8##
wherein R stands for a hydroxyl-protecting group such as a trityl group, a
benzyl group or a tetrahydropyranyl group, and the other symbols are of
the same meaning as defined above.
The reactions of [X].fwdarw.[XI] and [XI].fwdarw.[XII] can be conducted in
the same manner as that of the reaction of [VII].fwdarw.[VIIII]
The reaction of [XII].fwdarw.[VIII] is a reaction to remove the protecting
group. When R is a trityl group or a tetrahydropyranyl group, the compound
[XII] is subjected to a reaction in the presence of an acid (e.g.
hydrochloric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic
acid, etc.), in a suitable aqueous solvent (e.g. methanol, ethanol,
dioxane, etc. or a mixture thereof), at -10.degree. C. to +120.degree. C.,
preferably at 0.degree. C. to +80.degree. C.
When R is a benzyl group, the compound [VIII] can be obtained by subjecting
the compound [XII] to hydrogenolysis in a suitable solvent (e.g. alcohol,
aqueous acetic acid, etc.) in the presence of a suitable catalyst (e.g.
palladium-carbon).
The compound [XII] can also be obtained by allowing the compound [VI] to
react with the compound [X] in the same manner as the reaction of [VII]
.fwdarw.[VIII].
The compound [IX] wherein Y is halogen can also be produced by, for
example, the following process.
##STR9##
wherein Y stands for halogen.
This reaction can be conducted in the same manner as that of [VII] [VIII].
Compounds obtained by the respective processes mentioned above can, upon
necessity, be separated and purified by means of silica gel column
chromatography. Eluents include a hexane-ethyl acetate mixture, a
dichloromethane-ethyl acetate mixture, etc.
When R.sup.2 is a primary to tertiary amino group, the salt of the compound
[I] may, in some instances, be obtained by the above-mentioned production
methods, but, when necessary, it can be obtained by addition of an
inorganic or organic acid.
When R.sup.2 is a quaternary ammonium group, the anion(X.sup.-) can be
exchanged with another anion by using anion-exchange resin, if necessary.
Representative methods of production of the compound (I) are described
above, but the methods of production of the compound (I) should not be
limited only to these.
EFFECT
Antitumor activity of the compounds of the present invention is shown by
Test Examples given later.
The compounds [I] have a remarkable cell-killing action against tumor cells
and exhibit remarkable antitumor effects on administration to
cancer-bearing warm-blooded animals. Further, the compounds [I] have no
platelet activating action (PAF action), thus exhibiting no side-effect
caused by PAF action (e.g. platelet aggregation, blood pressure lowering
action, etc.).
Schedule, route and dosage of the administration can be selected according
to the subject and symptoms to be treated; the dose for a mammal is
usually about 0.1 to 150 mg/kg (body weight)/day, preferably 2 to 40 mg/kg
(body weight)/day, on the compound (I) basis. Frequency of administration
of the compound is about 1 to 3 times a day, or at the intervals of 2 to 7
days. The compound can also be administered by intravenous drip infusion
over a long period to maintain the level of the compound over a long
period. In parenteral administration of the compound, further improvement
in safety, for example, prevention of tissue (local) impairment without
affecting the efficacy, can be expected by combination with serum albumin
or various globulins.
The compounds [I] and the salts thereof are excellent both in hydrophilic
and in lipophilic properties, with low toxicities, and therefore can be
safely administered orally or parenterally to mammals as powders as they
are or as a pharmaceutical composition in a suitable dosage form.
Pharmaceutical compositions used for the administration contain an
effective amount of the compound [I] or a salt thereof and a
pharmaceutically acceptable carrier or excipient.
Injections for the parenteral administration by this invention include
sterilized aqueous or non-aqueous solutions, suspensions and emulsions.
Aqueous solutions and suspensions include distilled water for injection
and physiological saline. Non-aqueous solutions and suspensions include
Intralipids, propylene glycol, vegetable oils such as olive oil, alcohols
such as ethanol, and polysorbate 80, etc. Such compositions may contain
additionally adjuvants such as antiseptics, moistening agents, emulsifiers
and dispersants, and aqueous injections may contain adjuvants such as
glucose, serum albumin, serum (plasma) globulins, etc. These preparations
are sterilized by, for example, filtration through a bacteria-retention
filter, combination of a disinfectant or ultraviolet ray irradiation.
Sterilized solid preparations are also produced, which are dissolved in
sterilized water or sterilized solvent for injection prior to use. Tablets
and capsules can be prepared in accordance with conventional methods. To
prepare these solid compositions, the compound [I] or a salt thereof is
mixed with at least one inactive carrier or excipient such as lactose,
mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose or
starch. The compositions may contain an additive other than inactive
carriers or excipients, for example, a lubricant such as magnesium
stearate or a disintegrator such as calcium cellulose gluconate.
EXAMPLES
In the following, the present invention is illustrated in more detail by
Working Examples and Reference Examples, but this invention should not be
limited to these Examples.
Reference Example 1
Synthesis of 3-(octadecyloxy)propyl methanesulfonate:
In dichloromethane (50 ml) is dissolved 3-(octadecyloxy)propanol (8.0 g).
To the solution are added, under ice-cooling, methanesulfonyl chloride
(4.18 g) and triethylamine (5.1 ml). The mixture is stirred at room
temperature for one hour. The reaction mixture is washed with water and an
aqueous solution of sodium hydrogencarbonate, successively, and then
dried. The solvent is distilled off under reduced pressure to give the
above-titled compound (9.7 g).
IR(KBr)cm.sup.-1 : 2925, 2852, 1468, 1352, 1330, 1162, 1120, 970, 952, 948
NMR(90 MHz, CDCl.sub.3) .delta.: 0.87 (3H, t), 1.25 (32H, m), 1.95 (2H, m),
2.97 (3H, s), 3.3 to 3.85 (4H, m), 4.33 (2H, t)
Reference Example 2
Synthesis of 4-[3-(octadecyloxy)propoxy]butanol:
Sodium hydride (1.2 g) is heated at 70.degree. C. for 10 minutes in
dimethyl sulfoxide (50 ml), to which is added 1,4-butanediol (4.5 g). The
mixture is heated for one further hour. To this reaction mixture is added
dropwise a solution of 3-(octadecyloxy)propyl methanesulfonate obtained in
Reference Example 1 (4.06 g) in dimethyl sulfoxide (15 ml), and the
mixture is stirred at 70.degree. C. for one hour. The reaction mixture is
poured into cold water, and the mixture is subjected to extraction with a
mixture of hexane and ethyl acetate. The extract is washed with water and
then dried, and the solvents are then distilled off under reduced
pressure. The residue is subjected to purification by means of silica gel
column chromatography to obtain the above-titled compound (2.2 g).
IR(KBr)cm.sup.-1 : 3425, 3350, 2925, 2852, 1492, 1470, 1372, 1350, 1120,
960
NMR(90 MHz, CDCl.sub.3) .delta.: 0.87 (3H, t), 1.1 to 2.1 (38H, m), 3.1 to
3.6 (10H, m)
Reference Example 3
Synthesis of 4-[3-(octadecyloxy)propoxy]butyl methanesulfonate:
Using the alcohol compound obtained in Reference Example 2 (2.2 g),
mesylation is conducted in the same manner as that in Reference Example 1
to obtain the above-titled compound (2.6 g).
IR(KBr)cm.sup.-1 : 2925, 2850, 1468, 1350, 1330, 1160, 1120, 970, 950
NMR(90 MHz, CDCl.sub.3) .delta.: 0.87 (3H, t), 1.1 to 2.1 (38H, m), 2.97
(3H, s), 3.1 to 3.8 (3H, m), 4.3 (2H, t)
Working Example 1
Synthesis of N-[4-[3-(octadecyloxy)propoxy]butyl]-N,N,N-trimethylammonium
methanesulfonate:
A solution of the mesylate obtained in Reference Example 3 (1.3 g) in
toluene (10 ml) containing trimethylamine (2 g) is stirred for 3 days at
room temperature, and further stirred for 8 hours at 40.degree. C. The
reaction mixture is concentrated, and the residue is subjected to
purification by means of silica gel chromatography (eluent:
chloroform-methanol-water=65:25:4). Reprecipitation from
chloroform-acetone gives the above-titled compound as colorless powder
(1.0 g).
IR(KBr)cm.sup.-1 : 2925, 2855, 1470, 1210, 1190, 1115, 1060
NMR(90 MHz, CDCl.sub.3) 6: 0.87 (3H, t), 1.25 (32H, m), 1.4 to 2.0 (6H, m),
2.73 (3H, s), 3.31 (9H, s), 3.25 to 3.65 (10H, m)
Working Example 2
Synthesis of N-[4-[3-(octadecyloxy)propoxy]butyl]pyridinium
methanesulfonate:
A solution of the mesylate obtained in Reference Example 3 (1.3 g) in
pyridine (6 ml) is heated at 80.degree. C. for 16 hours. The reaction
mixture is concentrated, and the residue is subjected to reprecipitation
from chloroform-acetone to obtain the above-titled compound (1.36 g).
IR(KBr)cm.sup.-1 : 2915, 2850, 1630, 1488, 1465, 1370, 1205, 1190, 1110,
1050, 785
NMR(90 MHz, CDCl.sub.3) .delta.: 0.87 (3H, t), 1.25 (32H, m), 1.4 to 2.25
(6H, m), 2.75 (3H, s), 3.3 to 3.55 (8H, m), 4.90 (2H, t), 8.07 (2H), 8.45
(1H), 9.26 (2H)
Reference Example 4
Synthesis of 1-bromo-6-[3-(octadecyloxy)propoxy]hexane:
3-(Octadecyloxy)propanol (5.0 g), 1,6-dibromohexane (11.1 g) and
cetyltrimethylammonium chloride (0.97 g) are added to toluene (60 ml). To
the mixture is added a 50% aqueous solution of sodium hydroxide (12.2 g),
and the resulting mixture is stirred at 80.degree. C. for 7 hours. After
the reaction, the organic layer is separated, and the aqueous layer is
subjected to extraction with n-hexane. The organic layers are combined,
washed with dilute hydrochloric acid, dried and concentrated. The residue
is subjected to purification by means of silica gel chromatography to
obtain the above-titled compound as colorless solid (2.44 g).
IR(film)cm.sup.-1 : 2940, 2870, 1470, 1370, 1120, 720
NMR(90 MHz, CDCl.sub.3) .delta.: 0.86 (3H), 1.02 to 2.19 (42H), 3.12 to
3.62 (10H)
Reference Example 5
Synthesis of 1-bromo-3-[3-(octadecyloxy)propoxy]propane:
Employing 3-(octadecyloxy)propanol (5 g), 1,3-dibromopropane (9.2 g) and
cetyltrimethylammonium chloride (0.97 g), a reaction and aftertreatment
are conducted in the same manner as those in Reference Example 4 to obtain
the above-titled compound (0.53 g).
IR(film)cm.sup.-1 : 2940, 2870, 1470, 1370, 1120
NMR(90 MHz, CDCl.sub.3) .delta.: 0.88 (3H), 1.03 to 2.27 (36H), 3.23 to
3.67 (10H)
Working Example 3
Synthesis of 6-[3-(octadecyloxy)propoxy]hexyl-N,N,N-trimethylammonium
bromide:
The bromide obtained in Reference Example 4 (1.45 g) is stirred in toluene
(10 ml) containing trimethylamine (2 g) at 50.degree. C. for 63 hours. The
reaction mixture is concentrated under reduced pressure, and the residue
is subjected to reprecipitation from a mixture of chloroform-acetone-ether
to give the above-titled compound as colorless powder (1.43 g).
IR(CHCl.sub.3)cm.sup.-1 : 2920, 2850, 1460, 1360, 1220, 1100
NMR(90 MHz, CDCl.sub.3) .delta.: 0.87 (3H), 1.07 to 1.97 (42H), 3.27 to
3.76 (l0H), 3.45 (9H)
Working Example 4
Synthesis of 3-[3-(octadecyloxy)propoxy]propyl-N,N,N-trimethylammonium
bromide:
Employing the bromide obtained in Reference Example 5 (0.44 g), a reaction
is conducted in the same manner as that in Working Example 4 to give the
above-titled compound (0.35 g).
IR (CHCl3).sub.m.sup. -1 : 2920, 2850, 1460, 1370, 1220, 1100
NMR(90 MHz, CDCl.sub.3) .delta.: 0.85 (3H), 1.12 to 2.25 (36H), 3.22 to
3.82 (l0H), 3.48 (9H)
Reference Example 6
Synthesis of 1-bromo-8-[3-(octadecyloxy)propoxy]octane:
Using 3-(octadecyloxy)propanol (5 g), 1,8-dibromooctane (12.7 g),
cetyltrimethylammonium chloride (0.96 g) and a 50% aqueous solution of
sodium hydroxide (12 g), a reaction is conducted in the same manner as
that in Reference Example 4 to give the above-titled compound as colorless
solid (4.2 g).
IR(KBr)cm.sup.-1 : 2925, 2850, 1490, 1462, 1380, 1110
NMR(90 MHz, CDCl.sub.3) .delta.: 0.87 (3H, t), 1.10 to 2.0 (46H, m), 3.36
to 3.73 (10H, m)
Reference Example 7
Synthesis of 1-bromo-5-[3-(octadecyloxy)propoxy]pentane:
Employing 3-(octadecyloxy)propanol (5 g), 1,5-dibromopentane (10.8 g),
cetyltrimethylammonium chloride (0.96 g) and a 50% aqueous solution of
sodium hydroxide (12 g), a reaction and aftertreatment are conducted in
the same manner as those in Reference Example 4 to obtain the above-titled
compound as colorless wax (3.75 g).
IR(KBr)cm.sup.-1 : 2930, 2850, 1490, 1468, 1370, 1115
NMR(90 MHz, CDCl.sub.3) .delta.: 0.87 (3H, t), 1.0 to 2.0 (40H, m), 3.25 to
3.56 (10H, m)
Working Example 5
Synthesis of N-[8-[3-(octadecyloxy)propoxy]octyl]-N,N,N-trimethylammonium
chloride:
In dioxane (15 ml) is dissolved 1-bromo-8-[3-(octadecyloxy)propoxy]octane
obtained in Reference Example 6 (1.2 g). To the solution is added a 30%
aqueous solution of trimethylamine, and the reaction mixture is heated at
60.degree. C. for 20 hours. The reaction mixture is concentrated and the
residue is dissolved in dichloromethane. The solution is washed with an
aqueous solution saturated with sodium chloride, dried and concentrated.
The residue is subjected to reprecipitation from chloroform-acetone to
give the above-titled compound as colorless powder (1.06 g).
IR(KBr)cm.sup.-1 : 3430, 2925, 2852, 1492, 1485, 1380, 1112
NMR(90 MHz, CDCl.sub.3) .delta.: 0.87 (3H, t), 1.0 to 1.90 (54H, m), 3.45
(9H, s), 3.26 to 3.70 (10H, m)
Working Example 6
Synthesis of N-[8-[3-(octadecyloxy)propoxy]octyl]-thiazolium chloride:
1-Bromo-8-[3-(octadecyloxy)propoxy]octane obtained in Reference Example 6
(0.3 g) is heated in thiazole (0.5 ml) at 80.degree. C. for 13 hours. The
reaction mixture is concentrated and the residue is dissolved in
dichloromethane. The solution is washed with an aqueous solution saturated
with sodium chloride, dried and concentrated. The residue is subjected to
reprecipitation from chloroform-acetone to give the above-titled compound
as pale brown powder (0.23 g).
IR(KBr)cm.sup.-1 : 2925, 2852, 1645, 1550, 1495, 1468, 1380,
NMR(90 MHz, CDCl.sub.3) .delta.: 0.87 (3H, t), 1.1 to 2.1 (46H, m), 3.25 to
3.60 (8H, m), 4.84 (2H, t), 8.33 (2H, m), 11.56 (1H)
Working Example 7
Synthesis of N-[5-[3-(octadecyloxy)propoxy]pentyl]-N,N,N-trimethylammonium
chloride:
1-Bromo-5-[3-(octadecyloxy)propoxy]pentane obtained in Reference Example 7
(1.5 g) is dissolved in toluene (6 ml) containing trimethylamine (1.2 g).
The reaction mixture is stirred at 50.degree. C. for 24 hours and then
concentrated. The residue is dissolved in dichloromethane, and the
solution is washed with an aqueous solution saturated with sodium
chloride, dried and concentrated. The residue is subjected to
reprecipitation from chloroform-acetone to give the above-titled compound
as colorless solid (1.50 g).
IR(KBr)cm.sup.-1 : 3450, 2925, 2852, 1480, 1465, 1380, 1115
NMR(90 MHz, CDCl.sub.3) .delta.: 0.87 (3H, t), 1.0 to 2.0 (40H, m), 3.20 to
3.70 (l0H, m), 3.48 (9H, s)
Working Example 8
Synthesis of N-[5-[3-(octadecyloxy)propoxy]-pentyl]pyridinium chloride:
In pyridine (4 ml) is dissolved 1-bromo-5-[3-(octadecyloxy)propoxy]pentane
obtained in Reference Example 7 (1.5 g). The reaction mixture is stirred
at 90.degree. C. for 15 hours, and then concentrated. The residue is
dissolved in dichloromethane, and the solution is washed with an aqueous
solution saturated with sodium chloride, dried and concentrated. The
residue is subjected to reprecipitation from chloroform-acetone to give
the above-titled compound as colorless solid (0.90 g)
IR(KBr)cm.sup.-1 : 3425, 2925, 2852, 1632, 1490, 1464, 1380,
NMR(90 MHz, CDCl.sub.3) .delta.: 0.87 (3H, t), 1.10 to 2.4 (40H, m), 3.30
to 3.56 (8H, m), 5.21 (2H, t), 8.33 (2H), 8.50 (1H), 9.63 (2H, d)
Working Example 9
Synthesis of
1-N-[6-[3-(octadecyloxy)propoxy]-hexyl]pyridinio-3-carboxylate:
1-Bromo-6-[3-(octadecyloxy)propoxy]hexane obtained in Reference Example 4
(1.0 g) is heated with ethyl nicotinate (0.66 g) at 90.degree. C. for 19
hours. After the reaction mixture is cooled, ether is added to the
reaction mixture and the precipitate is collected by filtration to give
1-N-[6-[3-(octadecyloxy)propoxy]-hexyl]-3-ethoxycarbonylpyridinium bromide
(1.0 g). To this compound in methanol (25 ml) is added with stirring 2N
sodium hydroxide (4 ml), and the mixture is stirred at room temperature
for 20 minutes. The reaction mixture is neutralized with 1 N hydrochloric
acid, concentrated under reduced pressure, and extracted with
dichloromethane. The extract is washed with an aqueous solution saturated
with sodium chloride, dried and concentrated. The residue is subjected to
purification by means of silica gel chromatography
(chloroform-methanol-water= 65:25:4) and then to reprecipitation from
chloroform-acetone to give the above-titled compound as pale yellow powder
(0.63 g).
IR(KBr)cm.sup.-1 : 3440, 2950, 2852, 1485, 1466, 1380, 1116
NMR(90 MHz, CDCl.sub.3) .delta.: 0.87 (3H, t), 1.1 to 1.2 (42H, m), 3.20 to
3.57 (8H, m), 4.92 (2H, br-t), 7.94 (1H, t), 8.97 (2H, d), 9.88 (1H, s)
EFFECTS OF THE INVENTION
The effects of the compounds of the present invention are described in
detail by the following Test Examples.
Test Example 1
The effect of the compound of this invention in inhibiting multiplication
of myelogenous leukemia cells (HL-60) is shown in Table 1. The assay was
conducted as follows.
HL-60 cells (myelogenous leukemia cell lines) were suspended
(2.times.10.sup.5 cells/ml) in a GIT culture medium (Wako Pure Chemical
Industries, Ltd.). Each hole of a 96-hole Microwell plate was inoculated
with 0.2 ml of the suspension. The plate was incubated statically for 20
hours (37.degree. C. and 5% CO.sub.2), there was added 1 .mu.Ci of [.sup.3
H]thymidine(5 Ci/mmol.), and the incubation was continued for further 4
hours. For determination of the amount of thymidine incorporated into
cells, acid-insoluble fractions were collected with a glass-filter, and
the radioactivity was determined by means of a liquid scintillation
counter. The concentration of the drug required for reducing the
radioactivity incorporated into cells to 50% of the control group was
assumed to be IC.sub.50 value of the compound.
TABLE 1
______________________________________
Inhibition of Propagation of
Test Compound HL-60 cells (IC.sub.50 : .mu.g/ml)
______________________________________
Compound of Working
1.25
Example 1
Compound of Working
0.62
Example 2
Compound of Working
1.25
Example 3
Compound of Working
1.25
Example 4
Compound of Working
5
Example 5
Compound of Working
2.5
Example 7
Compound of Working
1.25
Example 8
______________________________________
Test Example 2
Antitumor action of the compound of Working Examples
ICR mice (a group consisting of 5 mice) were inoculated intraperitoneally
with 1.times.10.sup.5 Sarcoma 180 cells per mouse. Then, 0.33 mg/mouse of
a compound dissolved in physiological saline was intraperitoneally
administered three times, i.e. 1 hour, 1 day and 2 days after the
inoculation. Shown in Table 2 are the life-span prolongation ratio against
the control group without treatment and the number of surviving mice on
the 60th day after the initiation of the test.
TABLE 2
______________________________________
60th day
Life-span prolong-
number of survi-
gation ratio vors/number of
Test Compound (T/C, %)*.sup.1
mice tested
______________________________________
Compound of Working
295 2/5
Example 1
Compound of Working
342 2/5
Example 3
Control group 100 0/5
______________________________________
*.sup.1 Calculation was made only on died mice
Test Example 3
C3H/He mice (a group consisting of 5 mice) were inoculated
intraperitoneally with 1.times.10.sup.4 MM46 cells per mouse, and given
0.25 mg/mouse of a drug for 4 consecutive days starting from the second
day after the inoculation. Shown in Table 3 are the life-span prolongation
ratio against the control group without treatment (provided that
calculation was made on mice whose survival days were not longer than 60
days) and the number of surviving mice on the 60th day after the
inoculation of MM46 cells.
TABLE 3
______________________________________
Life-span prolong-
60th day
gation ratio No. of survivors/
Test Compound (T/C, %) No. of mice tested
______________________________________
Compound of Working
-- 5/5
Example 1
Control group 100 0/5
______________________________________
Test Example 4
Antitumor action of the compound of Working Example
ICR mice (a group consisting of 6 mice) were inoculated with
1.times.10.sup.5 Sarcoma 180 cells per mouse in the dorsal subcutis, and
then 0.3 mg/mouse of a test compound dissolved in physiological saline was
orally administered 9 times starting from the 8th day (8th to 10th, 13th
to 17th and 20th days). On the 21st day, a tumor was enucleated, and the
weight of the tumor was measured. The ratio of tumor weight of the treated
group against that of the control group without treatment by drug is shown
in Table 4.
TABLE 4
______________________________________
Weight of tumor
Test Compound (T/C, %)
______________________________________
Compound of Working
24
Example 3
Control group 100
______________________________________
As stated in the foregoing, the present invention provides drugs effective
as antitumor agents.
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