Note: Descriptions are shown in the official language in which they were submitted.
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DESCRIPTION
ANTICACHECTIC COMPOSITION
TECHNICAL FIELD
The present invention relates to a medicinal com-
position for the prophylaxis and treatment of cachexia
which develops in chronic diseases such as malignant
tumor, tuberculosis, diabetes, blood dyscrasia,
endocrine disease, infectious disease, or acquired
immunodeficiency syndrome.
BACKGROiJND ART
Cachexia is a systemic syndrome with progressive
loss of body weight, anemia, edema, and anorexia as
cardinal symptoms which develops in chronic diseases
such as malignant tumor, tuberculosis, diabetes, blood
dyscrasia, endocrine disease, infectious disease, and
acquired immunodeficiency syndrome [e. g. Kern et al.,
Cancer Cachexia, J. Parenteral and Enteral Nutrition,
286-298 (1988) and American Journal of Medicine,
,$~, 289-291 (1988)].
In cachexia, therapeutic nutrition and endocrine
therapy are generally administered but a satisfactory
anticachectic modality remains to be established. Par-
ticularly where cachexia is caused by a malignant
tumor, the available anticancer chemotherapy cannot be
administered when cachexia is progressing, with the
result that the treatment encounters a serious setback.
Moreover, any therapeutic nutrition for relief of
cachectic symptoms may rather exacerbate the malignant
tumor and detract from the life expectancy of the
patient. While cachexia is frequently caused by the
malignant tumors, administration of an antitumor agent
in such settings may result in control of the tumors
but generally side effects of the drug develop in
superimposition, the net result being no improvement in
cachexia [Nelson et al., Journal of Clinical Oncology,
Z ~. ....
24205-1164
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2
~, 213-225 (1994)).
In the above state of the art, there is a standing
need for an anticachectic composition that should
ameliorate or inhibit progression of cachectic symptoms
such as loss of body weight.
DISCLOSURE OF INVFN'~ION
The present invention relates toga medicinal com
position for the prophylaxis and treatment of cachexia
which comprises a compound of the formula:
~_ ~y~~ ~~g2~n_ A E~ C---C-0 ( ~
A Cl~
Q~,.NH
wherein R represents a hydrocarbon group that may be
substituted or a heterocyclic group that may be substi-
tuted; Y represents a group of the formula -CO-,
-CH(OH)-, or -NR3- (R3 represents an alkyl group that
may be substituted); m is 0 or 1; n is 0, 1 or 2; X
represents CH o.r N; A represents a bond or a bivalent
aliphatic hydrocarbon group having 1 to 7 carbon atoms;
Q represents oxygen or sulfur; Ri represents hydrogen
or an alkyl group; ring E may have further 1 to 4
substituents, which may form a ring in combination with
R1; L and M each represent hydrogen or are
combined with each other to form a bond; provided that
when m and n are 0, X represents CH, A represents a
bond, Q represents sulfur, R1, L and M each
represent hydrogen, and ring E does not have further
substituents, R does not represent dihydrobenzopyranyl;
or a salt thereof (hereinafter referred to simply as
Compound (I)).
Referring to the hydrocarbon group that may be
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substituted for R, the hydrocarbon group includes
aliphatic, alicyclic, alicyclic-aliphatic, aromatic-
aliphatic, and aromatic hydrocarbon groups. The
preferred number of carbon atoms constituting such
hydrocarbon groups is 1 to 14.
The aliphatic hydrocarbon group is preferably a
Ci_8 aliphatic hydrocarbon group. The aliphatic
hydrocarbon group includes saturated C1_8 aliphatic
hydrocarbon groups (e. g. alkyl groups) such as methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
t-butyl, pentyl, isopentyl, neopentyl, t-pentyi, hexyl,
isohexyl, heptyl, and octyl; and unsaturated Cz_8
aliphatic hydrocarbon groups (e. g. alkenyl, alkadienyl,
alkynyl, and alkadiynyl groups) such as ethenyl, 1-
propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-
pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-
hexenyl, 2,4-hexadienyl, 5-hexenyl, i-heptenyl, 1-
octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-
butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,
4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-
hexynyl, 1-heptynyl, and 1-octynyl.
The alicyclic hydrocarbon group is preferably a
C3_~ alicyclic hydrocarbon group. The alicyclic
hydrocarbon group includes saturated C3_~ alicyclic
hydrocarbon groups (e.g. cycloalkyl groups) such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, etc. and unsaturated CS_~ alicyclic
hydrocarbon groups (e.g. cycloalkenyl and
cycloalkadienyl groups) such as 1-cyclopentenyl, 2-
cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-
cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-
cycloheptenyl, 3-cycloheptenyl, and 2,4-cyclo-
heptadienyl.
The alicyclic-aliphatic hydrocarbon group is a
group consisting of the above-described alicyclic
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hydrocarbon group and aliphatic hydrocarbon group (e. g.
cycloalkyl-alkyl and cycloalkenyl-alkyl groups) and is
preferably a C4_9 alicyclic-aliphatic hydrocarbon group.
Specifically, the alicyclic-aliphatic hydrocarbon group
includes cyclopropylmethyl, cyclopropylethyl,
cyclobutylmethyl, cyclopentylmethyl, 2-
cyclopentenylmethyl, 3-cyclopentenylmethyl,
cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclo-
hexenylmethyl, cyclohexylethyl, cyclohexylpropyl,
cycloheptylmethyl, cycloheptylethyl, etc.
The aromatic-aliphatic hydrocarbon group is
preferably a C~_13 aromatic-aliphatic hydrocarbon group
(e. g. aralkyl and arylalkenyl groups). The aromatic-
aliphatic hydrocarbon group includes C~-9 phenylalkyl
such as benzyl, phenethyl, 1-phenylethyl, 3-
phenylpropyl, 2-phenylpropyl and 1-phenylpropyl; C11-is
naphthylalkyl such as a-naphthylmethyl, a,-
naphthylethyl, j3-naphthylmethyl, and J3-naphthylethyl;
C8_lo phenylalkenyl such as styryl and 4-phenyl-1,3-
butadienyl; and Clz-13 naphthylalkenyl such as 2-(2-
naphthyl)vinyl.
The aromatic hydrocarbon group is preferably a C6_
14 aromatic hydrocarbon group (e.g. aryl groups ). The
aromatic hydrocarbon group includes phenyl and naphthyl
{a-naphthyl, ~3-naphthyl).
Referring to the formula (I), the heterocyclic
group in a heterocyclic group that may be substituted
for R is a 5- to 7-membered monocyclic heterocyclic
group containing 1 to 4 hetero-atoms selected from
oxygen, sulfur, and nitrogen in addition to carbon as
ring members or a condensed heterocyclic ring group.
The condensed heterocyclic ring may for example be one
consisting of such a 5- to 7-membered monocyclic
heterocyclic group and a S-membered ring containing 1
or 2 nitrogen atoms, a benzene ring, or a 5-membered
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ring containing one sulfur atom.
Specifically the heterocyclic group includes 2-
pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-
pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-
5 pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-
pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-
pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2-
thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-
oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl, 1,2,4-
triazol-3-yl, 1,2,3-triazol-4-yl, tetrazol-5-yl,
benzimidazol-2-yl, indol-3-yl, 1H-indazol-3-yl, 1H-
pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyridin-6-
yl, 1H-imidazo[4,5-b]pyridin-2-yl, IH-imidazo[4,5-
c]pyridin-2-yl, 1H-imidazo[4,5-b]pyrazin-2-yl, and
benzopyranyl. The preferred heterocyclic group is
pyridyl, oxazolyl, or thiazolyl.
Referring to the formula (I), the hydrocarbon
group and heterocyclic group for R may respectively
have 1 to 5, preferably 1 to 3 substituents at
substitutable positions. Such substituents include for
example aliphatic hydrocarbon groups, alicyclic
hydrocarbon groups, aryl groups, aromatic heterocyclic
groups, nonaromatic heterocyclic groups, halogen,
nitro, amino group that may be substituted, aryl groups
that may be substituted, hydroxy group that may be
substituted, thiol that may be substituted, and
carboxyl group that may be esterified.
The aliphatic hydrocarbon group includes straight
chain or branched aliphatic hydrocarbon groups having 1
to~l5 carbon atoms, such as alkyl, alkenyl, and alkynyl
groups.
The preferred alkyl group is a C1_lo alkyl group,
such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neo-
pentyl, t-pentyl, 1-ethylpropyl, hexyl, isohexyl, l,I-
dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-
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ethylbutyl, hexyl, pentyl, octyl, nonyl, and decyl.
The preferred alkenyl group is a CZ_lo alkenyl
group, such as vinyl, ally!, isopropenyl, 1-propenyl, '
2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-
pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,
1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-
hexenyl.
The preferred alkynyl group is a Cz_lo alkynyl
group, such as ethynyl, 1-propynyl, 2-propynyl, 1
butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,
3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-
hexynyl, 4-hexynyl, and 5-hexynyl.
The alicyclic hydrocarbon group includes saturated
and unsaturated alicyclic hydrocarbon groups having 3
to 12 carbon atoms, such as cycloalkyl, cycloalkenyl,
and cycloalkadienyl groups.
The preferred cycloalkyl group is a C3_lo
cycloalkyl group, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,
bicyclo[3.2.I]octyl, bicyclo[3.2.2]nonyl,
bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, and
bicyclo[4.3.I]decyl.
The preferred cycloalkenyl group is a C3_lo
cycloalkenyl group, such as 2-cyclopenten-1-yl, 3-
cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl.
The preferred cycloalkadienyl group is a C4_lo
cycloalkadienyl group, such as 2,4-cyclopentadien-1-yl,
2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl.
The term "aryl group" means a monocyclic or
condensed polycyclic aromatic hydrocarbon group. As
preferred examples, C6_14 aryl groups such as phenyl, a
naphthyl, anthryl, phenanthryl, acenaphthylenyl can be
mentioned. Particularly preferred are phenyl, 1-
naphthyl, and 2-naphthyl.
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The preferred aromatic heterocyclic group includes
5- to 7-membered monocyclic aromatic heterocyclic
groups containing 1 to 4 hetero-atoms selected from
oxygen, sulfur, and nitrogen in addition to carbon as
ring members, such as furyl, thienyl, pyrrolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-
oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-
thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; and
dicyclic or tricyclic condensed aromatic heterocyclic
groups containing 1 to 5 hetero-atoms selected from
oxygen, sulfur, and nitrogen in addition to carbon as
ring members, such as benzofuranyl, isobenzofuranyl,
benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl,
benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl,
benzothiazolyl, 1,2-benzisothiazolyl, 1H-
benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl,
quinazolinyl, quinoxalinyl, phthalazinyl,
naphthyridinyl, purinyl, pteridinyl, carbazolyl, oc-
carbolinyl, j3-carbolinyl, y-carbolinyl, acridinyl,
phenoxazinyl, phenothiazinyl, phenazinyl,
phenoxathiinyl, thianthrenyl, phenanthridinyl,
phenanthrolinyl, indolizinyl, pyrrolo[1,2-
b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-
a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-
b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-
triazolo[4,3-a]pyridyl, and 1,2,4-triazolo[4,3-
b]pyridazinyl.
The preferred nonaromatic heterocyclic group
includes oxiranyl, azetidinyl, oxetanyl, thietanyl,
. pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl,
tetrahydropyranyl, morpholinyl, thiomorpholinyl,
piperazinyl, pyrrolidino, piperidino, and morpholino.
The halogen includes fluorine, chlorine, bromide,
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and iodine, and is preferably fluorine or chlorine.
The amino group that may be substituted includes
amino (-NHz) that may be mono- or di-substituted by,
for example, C1_lo alkyl groups, C3_lo cycloalkyl groups,
Cz_io alkenyl groups, C3_lo cycloalkenyl groups, C1_13 acyl
groups (e.g. Cz_io alkanoyl groups, C~_13 arylcarbonyl
groups), or C6_iz aromatic groups. As examples of the
substituted amino group, there can be mentioned methyl-
amino, dimethylamino, ethylamino, diethylamino,
dibutylamino, diallylamino, cyclohexylamino,
acetylamino, propionylamino, benzoylamino, phenylamino,
and N-methyl-N-phenylamino.
The acyl group in the acyl groups that may be
substituted includes C1_13 acyl groups. For example,
formyl and groups formed between carbonyl and C1_io
alkyl, C3_lo cycloalkyl, Cz_lo alkenyl, C3_~o cycloalkenyl,
Cs-iz aryl, or aromatic heterocyclic groups {e. g.
thienyl, furyl, pyridyl). The preferred acyl group
includes acetyl, propionyl, butyryl, isobutyryl,
valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,
octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl,
cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-
cyclohexenecarbonyl, benzoyl, nicotinoyl. The substi-
tutent in the substituted acyl groups includes C1_3
alkyl, C1_3 alkoxy groups, halogen (e. g. chlorine,
fluorine, bromine, etc.), nitro, hydroxy, and amino.
Referring to the hydroxy group that may be
substituted, the substituted hydroxy includes alkoxy,
alkenyloxy, aralkyloxy, acyloxy, and aryloxy groups.
The preferred alkoxy group includes C1_lo alkoxy
groups, such as methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy,
isopentyloxy, neopentyloxy, hexyloxy, heptyloxy,
nonyloxy, cyclobutoxy, cyclopentyloxy, and
cyclohexyloxy.
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The preferred alkenyloxy group includes CZ_io
alkenyloxy groups, such as allyloxy, crotyloxy, 2-
pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, and
2-cyciohexenylmethoxy.
The preferred aralkyloxy group includes C7_lo
aralkyloxy groups, such as phenyl-C1_4 alkyloxy (e. g.
benzyloxy, phenethyloxy, etc.).
The preferred acyloxy group includes CZ_13 acyloxy
groups, more preferably Cz_4 alkanoyloxy (e. g.
acetyloxy, propionyloxy, butyryloxy, isobutyryloxy,
etc.).
The preferred aryloxy group includes C6_~4 aryloxy
groups, such as phenoxy, and naphthyloxy. This aryloxy
group may have 1 or 2 substituents such as halogen
(e.g. chlorine, fluorine, bromine, etc.). The
substituted aryloxy group includes 4-chlorophenoxy.
Referring to the thiol group that may be
substituted, the substituted thiol group includes
alkylthio, cycloalkylthio, aralkylthio, and acylthio
groups.
The preferred alkylthio group includes C1_io
alkylthio groups, such as methylthio, ethylthio,
propylthios, isopropylthio, butylthio, isobutylthio,
sec-butylthio, t-butylthio, pentylthio, isopentylthio,
neopentylthio, hexylthio, heptylthio, and nonylthio.
The preferred cycloalkylthio group includes C3_io
cycloalkylthio groups such as cyclobutylthio,
cyclopentylthio, and cyclohexylthio.
The preferred aralkylthio group includes C~_io
aralkylthio groups, such as phenyl-C1_4 alkylthio (e. g.
benzylthio, phenethylthio, etc.).
The acylthio group is preferably a Cz_13 acylthio
group, more preferably a Cz_4 alkanoylthio group (e. g.
acetylthio, propionylthio, butyrylthio, isobutyrylthio,
etc.).
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The carboxyl group that may be esterified includes
alkoxycarbonyl, aralkyloxycarbonyl, and aryloxycarbonyl
groups. '
The preferred alkoxycarbonyl group includes CZ_s
5 alkoxycarbonyl groups, such as methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl.
The preferred aralkyloxycarbonyl group includes
C8_lo aralkyloxycarbonyl groups, such as benzyloxy-
carbonyl.
10 The preferred aryloxycarbonyl group includes C~_ls
aryloxycarbonyl groups, such as phenoxycarbonyl, and p-
tolyloxycarbonyl.
The preferred substituent on the hydrocarbon or
heterocyclic group for R includes C1_lo alkyl groups,
aromatic heterocyclic groups, and C6_14 aryl groups.
Particularly preferred is C1_3 alkyl, furyl, thienyl,
phenyl, or naphthyl.
Referring to the formula (I), when the substituent
on the hydrocarbon or heterocyclic group for R is an
alicyclic hydrocarbon group, an aryl group, an aromatic
heterocyclic group, or a nonaromatic heterocyclic
group, this substituent may be further substituted by
one or more, preferably 1 to 3 suitable substituents.
As such substituents, there can be mentioned C1_6 alkyl
groups, C~_6 alkenyl groups, C~_6 alkynyl groups, C3_~
cycloalkyl groups, C6_14 aryl groups (e. g. phenyl,
naphthyl, etc.), aromatic heterocyclic groups (e. g.
thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.),
nonaromatic heterocyclic groups (e. g. tetrahydrofuryl,
morpholino, thiomorpholino, piperidino, pyrrolidino,
piperazino, etc.), C7_9 aralkyl groups, amino, N-mono(Ci_ -
4 ) alkylamino groups , N, N-di ( C1_4 ) alkylamino groups , C2_$
acylamino groups (e. g. acetylamino, propionylamino,
benzoylamino, etc . ) , amidino, CZ_8 acyl groups ( a . g . CZ_$
alkanoyl groups, etc.), carbamoyl, N-mono(C1_
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4)alkylcarbamoyl groups, N,N-di(C1_4)alkylcarbamoyl
groups, sulfamoyl, N-mono(C1_4)alkyisulfamoyl groups,
N, N-di ( C1_4 ) alkylsulfamoyl groups , carboxyl , C2_$
alkoxycarbonyl groups , hydroxy, Cl_4 alkoxy groups , C2_s
' 5 alkenyloxy groups, C3_~ cycloalkyloxy groups, C~_9
aralkyloxy groups, C6_i4 aryloxy groups (e. g. phenyloxy,
naphthyloxy, etc.), mercapto, C1_4 alkylthio groups, C~_9
aralkylthio groups, C6_14 arylthio groups (e. g. phenyl-
thio, naphthylthio, etc.), sulfo, cyano, azido, nitro,
nitroso, and halogen (e. g. fluorine, chlorine, bromine,
iodine).
In the formula (I), R is preferably a heterocyclic
group that may be substituted. More preferably, R is
pyridyl, oxazolyl, or thiazolyl group, which may have 1
Z5 to 3 substituents selected from C1_3 alkyl, furyl,
thienyl, phenyl, and naphthyl.
Referring to the formula (I), Y represents -CO-,
-CH(OH)-, or -NR3-. Y is preferably -CH(OH}- or -NR3-
and more preferably -CH(OH)-. Referring to an alkyl
group that may be substituted for R3, the alkyl group
includes C1_4 alkyl groups, such as methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-
butyl. The substituent includes halogen (e. g.
fluorine, chlorine, bromine, iodine}, C1_~ alkoxy groups
(e. g. methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-
butoxy, t-butoxy), hydroxy, nitro, and Ci_4 acyl groups
(e.g formyl, acetyl, propionyl, etc.).
The symbol n represents 0, 1 or 2 and is
preferably 0 or 1.
~ The symbol X represents CH or N and is preferably
CH.
Referring to the formula (I), A represents a bond
' or a bivalent aliphatic hydrocarbon group having 1 to 7
carbon atoms. This aliphatic hydrocarbon group may be
straight-chain or branched and may further be saturated
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or unsaturated. Thus, for example, -CHz-, -CH(CH~)-,
-(CHz)z-. -CH(CZHS)-, -{CHz)~-~ -(CH2)4w -{CHz)s-
- ( CHz ) s-. - ( CHz ) ~-, etc . can be mentioned for the
saturated bivalent aliphatic hydrocarbon group, while
-CH=CH-, -C { CH3 ) =CH-, -CH=CH-CHz-, -C ( C2H5 ) =CH-, -CHz- ,
CH= CH-CHz-, -CHz-CHz-CH=CH-CHz-, -CH=CH-CH=CH-CHz-,
-CH=CH-CH=CH-CH=CH-CHz-, etc. can be mentioned for the
unsaturated bivalent aliphatic hydrocarbon group. The
symbol A preferably represents a bond or a bivalent
aliphatic hydrocarbon group having 1 to 4 carbon atoms,
which is preferably a saturated group. More
preferably, A represents a bond, -CHz- or -{CHz)z-
Still more preferably, A represents a bond or -(CHz}z--
The alkyl group for R1 includes C1_4 alkyl groups
such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, and t-butyl. Preferably, R1
represents hydrogen.
Referring to the formula (I), the partial
structural formula:
/~ /
E~ is preferably
the formula:
wherein each symbols has the same meanings as defined
above.
Furthermore, ring E may optionally have I to 4
substituents at substitutable positions. Such
substituents include an alkyl group, a hydroxy group
that may be substituted, halogen, an acyl group that
may be substituted, nitro, and an amino group that may
be substituted. These substituents may be the same as
the substituents mentioned for the hydrocarbon or
heterocyclic group for R.
Ring E, the partial structural formula:
SUBSTITUTE SHEET (RULE 26)
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R2
E~ is preferably
the formulao
X
' S wherein R2 represents hydrogen, an alkyl group, a
hydroxy group that may be substituted, halogen, an acyl
group that may be substituted, nitro, or an amino group
that may be substituted.
The alkyl group, hydroxy group that may be
substituted, halogen, acyl group that may be
substituted, and amino group that may be substituted,
for RZ, may each be the same as that mentioned for the
hydrocarbon or heterocyclic group for R. Preferably,
RZ is hydrogen, hydroxy group that may be substituted,
or halogen. More preferably, RZ is hydrogen or hydroxy
group that may be substituted. Particularly preferred
is hydrogen or a C1_4 alkoxy group .
L and M respectively represent hydrogen or may be
combined with each other to form a bond, and preferably
they are hydrogen.
Referring to the formula (I}, the compound in
which L and M are combined with each other to form a
bond:
R' ~
R- (y)~- (CHZ)n- ~ H E~A-CHy=0
\X~ Q~NH C I - A 1 )
0
wherein each symbols has the same meanings as defined
above, may exist as (E)- and (Z)- isomers, owing to the
double bond at 5-position of the azolidinedione ring.
The compound in which L and M respectively repre-
sent hydrogen:
SUBSTITUTE SHEET (RULE 26)
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i4
R~
A-CY)~-CCH2)n- ~H E~'A'OHZyH-C=0
~X Q~iNH < I - A 2 )
a
0
wherein each symbols has the meanings as defined above,
may exist as optical isomers, i.e. (R}- and (S)-forms,
with respect to the asymmetric carbon at 5-position of
the azolidinedione ring. This compound includes those
optically active compounds, i.e. (R)- and (S)-forms, as
well as the racemic form.
Referring to the formula (I) of the present
invention, when m and n are 0; X represents CH; A
represents a bond; Q represents sulfur; R1, L, and M
respectively represent hydrogen; and ring E does not
have further substituents, R is not dihydrobenzo-
pyranyl.
The preferred compound of the formula (I) is the
compound in which R represents pyridyl, oxazolyl, or
thiazolyl group, optionally having 1 to 3 substituents
selected from the group consisting of C1_3 alkyl, furyl,
thienyl, phenyl, and naphthyl; Y represents -CH(OH)-; n
is 0 or 1; X represents CH; A represents a bond or -
(CHZ)Z-; RI represents hydrogen; ring E, namely the
partial structural formula:
/ ~2
is the /
formula: W
X
RZ is hydrogen or a C~_4 alkoxy group; and L and M .
respectively represent hydrogen.
As preferred species of the compound of the .
formula (I), the following compounds {1) to (7) are
mentioned.
(1) 5-[4-[2-(5-ethyl-2-pyridyl)ethoxyjbenzylj-2,4-
_ SUBSTITUTE SHEET (RULE 26j
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thiazolidinedione,
(2) 5-[4-[2-hydroxy-2-{5-methyl-2-phenyl-4-oxazolyl)-
ethoxy]benzyl]-2,4-thiazolidinedione,
(3) (R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolyl-
Y
5 methoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione,
(4) (S)-(-)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolyl-
methoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione,
(5) 5-[3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolyl-
methoxy)phenyl]propyl]-2,4-oxazolidinedione,
10 (6) 5-[5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolyl-
methoxy)phenyl]pentyl]-2,4-oxazolidinedione,
(7) 5-[3-[3,5-dimethoxy-4-[2-[(E)-styryl]-4-oxazolyl-
methoxy)phenyl]propyl]-2,4-oxazolidinedione (hereafter,
these compounds are sometimes simply referred to as
15 compound (1), compound (2), and the like).
Among the above compounds, compounds (1) to {3),
(5), and (6) are preferred, and compounds (1) to (3)
are particularly preferred.
The salt of compound (I) of the present invention
is preferably a pharmacologically acceptable salt,
which includes salts with inorganic bases, salts with
organic bases, salts with inorganic acids, salts with
organic acids, and salts with basic or acidic amino
acids.
The preferred salt with an inorganic base includes
alkali metal salts such as sodium salt, potassium salt,
etc.; alkaline earth metal salts such as calcium salt,
magnesium salt, etc.; aluminum salt, and ammonium
salts.
~ The preferred salt with an organic base includes
salts with trimethylamine, triethylamine, pyridine,
picoline, ethanolamine, diethanolamine,
triethanolamine, dicyclohexylamine, N,N'-
dibenzylethylenediamine, etc.
The preferred salt with an inorganic acid includes
salts with hydrochloric acid, hydrobromic acid, nitric
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acid, sulfuric acid, phosphoric acid, etc.
The preferred salt with an organic acid includes
salts with formic acid, acetic acid, trifluoroacetic
acid, fumaric acid, oxalic acid, tartaric acid, malefic
acid, citric acid, succinic acid, malic acid,
methanesulfonic acid, benzenesulfonic acid, p-
toluenesulfonic acid, etc.
The preferred salt with a basic amino acid
includes salts with arginine, lysine, ornithine, etc.
The preferred salt with an acidic amino acid includes
salts with aspartic acid, glutamic acid, etc.
The most preferred of all the above-mentioned
salts is sodium salt or potassium salt.
Compound (I} or a salt thereof of the present
invention can be produced in accordance with methods
described in JP-A 555(1980)-22636 (EP-A-8203), JP-A
560(1985)-208980 (EP-A-155845), JP-A S61(1986)-286376
(EP-A-208420), JP-A 561(1986)-085372 (EP-A-177353), JP-
A 561(1986)-267580 (EP-A-193256), JP-A H5(1993}-86057
(WO-A-9218501), JP-A H7(1995)-82269 (EP-A-605228), JP-A
H7(1995)-101945 (EP-A-612743), EP-A-643050, EP-A-710659
(JP Application H7(1995)-284106), etc, or methods
analogous thereto.
Compound (I) or a salt thereof of the present
invention (hereinafter referred to as compound of the
present invention) have anticachectic activity, that is
the activity to relieve the systemic syndrome featuring
progressive loss of body weight (inclusive of weight
loss due to lipolysis and weight loss due to myolysis),
anemia, edema, and anorexia in chronic diseases such as
malignant tumor, tuberculosis, diabetes, blood
dyscrasia, endocrine disease, infectious disease, and
acquired immunodeficiency syndrome. In addition, the ,
toxic potential of the compound of the present
invention is low.
The composition for prophylaxis and treatment of
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the present invention can be used as an agent for
prophylaxis and treatment of cachexia or an agent for
treatment of malnutrition in mammals (e.g man, mouse,
rat, rabbit, dog, cat, bovine, equine, swine, monkey,
' 5 etc.).
The cachexia is, for example, cancer cachexia,
tuberculosis cachexia, diabetic cachexia, hemodyscrasia-
related cachexia, endocrine disease-associated
cachexia, infectious disease-associated cachexia, or
acquired immunodeficiency syndrome-associated cachexia.
The composition for prophylaxis and treatment of
the present invention can be used preferably in
cachexia associated with malignant tumor, especially a
carcinoma.
The composition for prophylaxis and treatment of
the present invention includes the compound of the
invention as such. Usually, the composition is
provided in a pharmaceutical dosage form by formulating
the compound of the invention with per se known
pharmaceutically acceptable carriers.
As the pharmaceutically acceptable carrier a
variety of organic and inorganic carriers in common use
as raw materials for pharmaceutical preparations are
employed. Thus, the carrier includes the excipient,
lubricant, binder, and disintegrator for a solid dosage
form; and the solvent, solubilizer, suspending agent,
isotonizing agent, buffering agent and local analgesic
for a liquid dosage form. Where necessary,
pharmaceutical additives such as the preservative,
antioxidant, coloring agent, sweetener, etc. can also
be used.
The preferred excipient includes lactose, sucrose,
D-mannitol, starch, crystalline cellulose, light
silicic anhydride, etc.
The preferred lubricant includes magnesium
stearate, calcium stearate, talc, colloidal silica,
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etc.
The preferred binder includes crystalline
cellulose, sucrose, D-mannitol, trehalose, dextrin,
hydroxypropylcellulose, hydroxypropylmethylceilulose,
polyvinylpyrrolidone, etc.
The preferred disintegrator includes starch,
carboxymethylcellulose, carboxymethylcellulose calcium,
croscarmellose sodium, carboxymethylstarch sodium, etc.
The preferred solvent includes water for
injection, alcohol, propylene glycol, macrogol, sesame
oil, corn oil, tricaprylin, etc.
The preferred solubilizer includes polyethylene
glycol, propylene glycol, D-mannitol, trehalose, benzyl
benzoate, ethanol, trisaminomethane, cholesterol, tri-
ethanolamine, sodium carbonate, sodium citrate, etc.
The preferred suspending agent includes
surfactants such as stearyltriethanolamine, sodium
lauryl sulfate, laurylaminopropionic acid, lecithin,
benzalkonium chloride, benzethonium chloride, glyceryl
monostearate, etc. and hydrophilic polymers such as
polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl-
cellulose sodium, methylcellulose,
hydroxymethylcellulose, hydroxyethylcellulose, and
hydroxypropylcellulose.
The preferred isotonizing agent includes sodium
chloride, glycerin, D-mannitol, etc.
The preferred buffering agent includes buffer
solutions such as phosphate, acetate, carbonate,
citrate.
~ The preferred local anesthetic includes benzyl
alcohol.
The preferred antiseptic includes p-hydroxybenzoic
esters, chlorobutanol, benzyl alcohol, phenethyl ,
alcohol, dehydroacetic acid, sorbic acid, etc.
The preferred antioxidant includes salts of
sulfurous acid, ascorbic acid, etc.
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The above medicinal composition can be
manufactured by the established pharmaceutical
procedures, for example the procedures described in the
Japanese Pharmacopoeia.
The medicinal composition can be provided in a
variety of dosage forms, e.g. oral dosage forms such as
tablets, capsules (inclusive of soft capsules and
microcapsules), powders, granules, and syrups; and non-
oral dosage forms such as injections, suppositories,
pellets, and drip infusions. These dosage forms can be
safely administered either orally or non-orally.
The dosage of the composition for prophylaxis and
treatment of the present invention differs depending on
the subject, route of administration, clinical
condition, etc. For oral administration to an adult
patient with cachexia, for instance, the usual unit
dose is about 0.1 mg/kg to about 30 mg/kg, preferably
about 2 mg/kg to about 20 mg/kg, as the compound of the
invention which is an active ingredient, which dose is
preferably administered once to 3 times a day.
The composition for prophylaxis and treatment of
the present invention can be administered together with
other drugs such as chemotherapeutic agents and
immunotherapeutic agents to the same subject, either
concurrently or at staggered times. The dosage of
these drugs can be appropriately selected by referring
to the respective recommended clinical dose ranges.
The mixing ratio of the composition for prophylaxis and
treatment of the present invention and other drugs can
be~appropriately selected according to the subject, age
and body weight of the subject, current clinical
status, administration time, dosage form, method of
administration, and combination of drugs, among other
f actors .
The preferred chemotherapeutic agent includes
alkylating agents (e. g. cyclophosphamide, ifosfamide),
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antimetabolites (e. g. methotrexate, 5-fluorouracil),
antitumor antibiotics (e. g. mitomycin, adriamycin),
antitumor plant alkaloids (e. g. vincristine, vindesine,
Taxol), cisplastin, carboplatin, and etoposide.
5 Particularly preferred are Flutron and Neo-Flutron,
which are 5-fluorouracil derivatives.
The preferred immunotherapeutic agent includes
fungal or bacterial cell wall components (e. g. muramyl
dipeptide derivatives, picibanil), immunostimulant
10 polysaccharides (e. g. lentinan, schizophyllan,
Krestin), recombinant cytokines (e. g. interferons,
interleukins (IL)), and colony stimulating factors
(e. g. granulocyte colony stimulating. factor,
erythropoietin). Particularly preferred are IL-1, IL-
15 2, and IL-12.
Furthermore, drugs which are documented as being
anticachectic in an animal model or clinically, such as
cyclooxygenase inhibitors (e. g. indomethacin) [Cancer
Research, 49, 5935-5939, (1989)], progesterone
20 derivatives (e.g. megestrol acetate) [Journal of
Clinical Oncology, 1~,, 213-225, 1994], glucocorticoids
(e. g. dexamethasone), metoclopramides,
tetrahydrocannabinols {the same literature as above),
lipid metabolism improving agents (e. g. eicosapentanoic
acid) [British Journal of Cancer, ~$, 314-318, 1993],
growth hormone, IGF-1, and antibodies to the cachexia-
inducing factors TNF-oc, LIF, IL-6, and oncostatin M may
also be used together with the composition for
prophylaxis and treatment of the present invention.
The compound of the present invention can be used
in combination with diuretic. In this case, the
administration time of the compound of the present
invention and diuretic are not limited, and they can be
administered to the same subject, either concurrently
or at staggered times. The dosage of the diuretic can
be appropriately selected by referring to the
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recommended clinical dose ranges. The mixing ratio of
the compound of the present invention and diuretic can
be appropriately selected according to the subject, age
and body weight of the subject, current clinical
status, administration time, dosage form, method of
administration, and combination, among other factors.
For example, when the subject is man, diuretic is used
in a proportion of usually about 0.01 to about 100
weight parts, preferably about 0.1 to about 20 weight
parts, relative to one weight part of the compound of
the present invention.
The diuretic includes xanthine derivative
preparations (e. g. theobromine and sodium salicylate,
theobromine and calcium salicylate), thiazide
preparations (e. g. ethiazide, cyclopenthiazide,
trichlormethiazide, hydrochlorothiazide,
hydroflumethiazide, benzylhydrochlorothiazide,
penflutizide, polythiazide, methyclothiazide),
antialdosterone preparations (e. g. spironolactone,
triamterene), carbonate dehydratase inhibitors (e. g.
acetazolamide), chiorbenzenesulfonamide preparations
(e. g. chlorthalidone, mefruside, indapamide),
azosemide, isosorbide, ethacrynic acid, piretanide,
bumetanide, and furosemide.
Among the compound of the present invention,
especially a compound which has a bivalent aliphatic
hydrocarbon group having 1 to 7 carbon atoms for A in
the formula (I) or a salt thereof, has an activity to
prevent and treat atherosclerosis, and an activity to
regulate appetite and food intake in disorders
associated with under-eating, such as anorexia nervosa,
and disorders associated with over-eating, such as
obesity and anorexia bulimia. Therefore, such a
compound or a salt thereof can be used, as such or by
providing in a pharmaceutic dosage form in the same
manner as described above, as an agent for prophylaxis
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and treatment of atherosclerosis, or medicine for the
regulation of appetite and food intake.
The subject, dosage form, and dosage of the agent
for prophylaxis and treatment and the medicine are analogous
to those in the case of the above-described composition for
prophylaxis and treatment of the present invention.
Among the compound of the present invention, a
compound or a salt thereof which has a bivalent aliphatic
hydrocarbon group having 1 to 7 carbon atoms for A in the
formula (I), has an activity to treat impaired glucose
tolerance, namely an activity to reduce fasting insulin
levels, improve insulin sensitivity, and return glucose
tolerance to the normal range. Based on such an activity,
the compound or a salt thereof can treat impaired glucose
tolerance in order to prevent or delay the onset of
noninsulin-dependent diabetes melitus. Such a compound or a
salt thereof can be used, as such or by providing in a
pharmaceutical dosage form in the same manner as described
above, as a treating agent of impaired glucose tolerance.
The subject, dosage form, and dosage of the
treating agent are analogous to those in the case of the
above-described composition for prophylaxis and treatment of
the present invention.
As well known in the art, the medicinal
composition may be put in a container for practical use, and
the container may be placed in a commercial package for
marketing. Such a commercial package includes a written
matter describing an indication of the medicinal composition
as required by law.
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22a
BEST MODE FOR CARRYING OUT THE INVENTION
The following examples and test examples are
intended to describe the present invention in further detail
and should by no means be construed as defining the scope of
the invention.
Example 1 (Production of capsules)
1 ) Compound ( 2 ) 10 0 mg
2) Microcrystalline cellulose 30 mg
3) Lactose 37 mg
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4) Magnesium stearate 3 mg
Total: 170 mg
The above components 1), 2), 3) and 4) were mixed
and filled in a gelatin capsule.
S Example 2 (Production of soft capsules)
1) Compound (2) 50 mg
2} Corn oil 100 mg
Total: 150 mg
The components 1) and 2) were mixed and filled in
a soft capsule in a conventional manner.
Example 3 (Production of tablets)
1) Compound (2) 100 mg
2} Lactose 34 mg
3) Corn starch 10.6 mg
4) Corn starch (paste) 5 mg
5) Magnesium stearate 0.4 mg
6} Carboxymethylcellulose calcium 20 mg
Total: 170 mg
The above components 1) to 6) were mixed and
compressed with a tableting machine in a conventional
manner.
Test Example 1 (Antilipolytic activity)
In accordance with the method of Green et al.
[Endocrinology, 134, 2581-2588 (1994)], the
antilipolytic activity of the compound of the present
invention was evaluated by quantitating the glycerol
released from fat cells in rat epididymis adipose
tissue.
Thus, the rat epididymis adipose tissue was iso-
lated, cut into pieces with a pair of scissors, and
digested into fat cells by agitating in collagenase-
containing phosphate buffer for 1 hour. To a culture
solution containing fat cells was added 10 ng/ml of IL-
1(i (manufactured by Pharmingen, PM-19101V). Then, in
treatment groups, solutions of compound (2) in N,N-
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dimethylformamide at graded concentrations were
respectively added. After 24 hours, the supernatant
was recovered and the glycerol therein was quantitated
with an assay kit (manufactured by Sigma, 337-A). The
amount of released glycerol in each group treated with
compound (2) relative to that in the control group was
determined to find the inhibition rate and the 50~
inhibition concentration ICso of the compound was
calculated. The antilipolytic concentration IGSO value
of compound {2) was 4 nM.
Test Example 2 (Weight loss inhibitory activity in
tumor-bearing mice)
Using the mouse colon cancer cell line Colon 26
(Tanaka et al., Cancer Research, 50, 4528-4532 (1990)),
which is a system known to be high in the
reproducibility of cancer cachectic symptoms, the
inhibitory effect of the compound of the present
invention on lipolysis and body weight loss was
evaluated.
Thus, 1x106 Colon 26 cells were transplanted sub-
dermaly in 4-week-old CDF1 mice. On day 14 after
transplantation, the mice were divided into groups
according to tumor size. A 5g (w/v) gum arabic
suspension containing compound (2) was administered
orally in a dose of 1.0 mg/kg to one group of mice and,
as a control, a 5~ (w/v) gum arabic suspension was
similarly administered to another group, once daily for
7 days in each case. An additional group of mice was
not, transplanted with Colon 26 cells (normal group).
On days 14, 18 and 21 after transplantation, the mice
were weighed. On day 22 after transplantation, each
mouse was autopsied and the epididymis adipose tissue
was isolated and weighed. Changes in mouse body weight
and adipose tissue weight are shown in Table 1 and
Table 2, respectively.
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Table 1 Changes in body weight (g) of tumor-bearing
mice
5 14th Day after 18th Day after 21st Day after
transplantation transplantation transplantation
Normal group 28.3 29.4 29.4
Control group 25.4 23.3 21.3
10 Medicated group 26.3 26.3 25.6
15 Table 2 Adipose tissue weights (mg)
of tumor-bearing mice
2 2nd Day of ter
20 transplantation
Normal group 769
Control group 74
Medicated group 271
It will be apparent from Tables 1 and 2 that the
compound of the present invention suppresses lipolysis
and weight loss which are cancer cachectic symptoms due
to transplantation of mouse colon cancer cell line
Colon 26, indicating that it is useful as a treating
agent for cachexia.
Comparative Example
The antilipolytic activity of indomethacin was
evaluated by the same method as in Test Example 1. The
antilipolytic concentration ICso value of indomethacin
was not less than 30 mM.
Industrial Applicability
The composition for prophylaxis and treatment of
the present invention is of value as an agent for
prophylaxis and treatment of cachexia which develops in
chronic diseases such as malignant tumor, tuberculosis,
diabetes, blood dyscrasia, endocrine disease,
infectious disease, and acquired immunodeficiency
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syndrome. The composition for prophylaxis and
treatment of the present invention is conducive to
relief of the systemic syndrome, the cardinal signs of
which are progressive loss of body weight (inclusive of
weight loss due to lipolysis and weight loss due to '
myolysis), anemia, edema, and anorexia, in said chronic
diseases.
