U.S. patent application number 14/197381 was filed with the patent office on 2014-07-03 for novel compound and medical use thereof.
This patent application is currently assigned to ONO PHARMACEUTICALS CO., LTD.. The applicant listed for this patent is ONO PHARMACEUTICALS CO., LTD.. Invention is credited to Masaya KOKUBO, Koji YANO.
Application Number | 20140187630 14/197381 |
Document ID | / |
Family ID | 46171994 |
Filed Date | 2014-07-03 |
United States Patent
Application |
20140187630 |
Kind Code |
A1 |
KOKUBO; Masaya ; et
al. |
July 3, 2014 |
NOVEL COMPOUND AND MEDICAL USE THEREOF
Abstract
Provided is a levodopa prodrug that overcomes the problems
attributed to the blood kinetics of levodopa such as large number
of doses and the incidence of side effects due to frequent dosing.
(2S)-2-Amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, a salt thereof, or a solvate thereof is a levodopa
prodrug, and provides a flat blood concentration-time profile of
levodopa through oral administration, and therefore is useful as a
preventive and/or therapeutic agent for Parkinson's disease and/or
Parkinson's syndrome that overcomes the problems associated with
pharmaceutical preparations of levodopa.
Inventors: |
KOKUBO; Masaya; (Osaka,
JP) ; YANO; Koji; (Osaka, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ONO PHARMACEUTICALS CO., LTD. |
Osaka |
|
JP |
|
|
Assignee: |
ONO PHARMACEUTICALS CO.,
LTD.
Osaka
JP
|
Family ID: |
46171994 |
Appl. No.: |
14/197381 |
Filed: |
March 5, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13991025 |
May 31, 2013 |
|
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|
PCT/JP2011/077834 |
Dec 1, 2011 |
|
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14197381 |
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Current U.S.
Class: |
514/533 ;
560/108 |
Current CPC
Class: |
A61K 31/216 20130101;
A61K 31/277 20130101; A61K 31/122 20130101; A61K 31/24 20130101;
A61K 31/235 20130101; A61K 31/165 20130101; C07B 2200/13 20130101;
A61P 25/16 20180101; C07C 229/36 20130101; C07C 229/26 20130101;
A61K 31/198 20130101; A61K 45/06 20130101; A61K 31/4412 20130101;
A61P 43/00 20180101; A61K 31/12 20130101; A61K 31/165 20130101;
A61K 2300/00 20130101; A61K 31/198 20130101; A61K 2300/00 20130101;
A61K 31/216 20130101; A61K 2300/00 20130101; A61K 31/235 20130101;
A61K 2300/00 20130101; A61K 31/24 20130101; A61K 2300/00 20130101;
A61K 31/122 20130101; A61K 2300/00 20130101; A61K 31/277 20130101;
A61K 2300/00 20130101; A61K 31/12 20130101; A61K 2300/00 20130101;
A61K 31/4412 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/533 ;
560/108 |
International
Class: |
C07C 229/36 20060101
C07C229/36; C07C 229/26 20060101 C07C229/26 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 2, 2010 |
JP |
2010-269046 |
Claims
1. A method for preventing hyperkinetic child syndrome, toxemia of
pregnancy, malignant hypertension, or epilepsy, comprising
administering to a subject in need thereof an effective amount of
an amorphous solvate of an ornithine salt of
(2S)-2-Amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid.
2. A method for preventing orthostatic hypotension, subarachnoid
hemorrhage, cerebral infarction, bronchospasm accompanying
bronchial asthma or whooping cough, hypoglycemic symptoms due to
insulin injection, or iris adhesion in iridocyclitis, comprising
administering to a subject in need thereof an effective amount of
an amorphous solvate of an ornithine salt of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid.
3. A method according to claim 1, wherein hyperkinetic child
syndrome is prevented.
4. A method according to claim 1, wherein toxemia of pregnancy is
prevented.
5. A method according to claim 1, wherein malignant hypertension is
prevented.
6. A method according to claim 1, wherein epilepsy is
prevented.
7. A method according to claim 2, wherein subarachnoid hemorrhage
is prevented.
8. A method according to claim 2, wherein cerebral infarction is
prevented.
9. A method according to claim 2, wherein bronchospasm accompanying
bronchial asthma is prevented.
10. A method according to claim 2, wherein bronchospasm
accompanying whooping cough is prevented.
11. A method according to claim 2, wherein hypoglycemic symptoms
due to insulin injection is prevented.
12. A method according to claim 2, wherein iris adhesion in
iridocyclitis is prevented.
13. A method according to claim 2, wherein orthostatic hypotension
is prevented.
14. A medicament kit containing an effective amount of an amorphous
solvate of an ornithine salt of
(2S)-2-Amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid and instructions to administer it to a subject in need
of prevention of hyperkinetic child syndrome, toxemia of pregnancy,
malignant hypertension, epilepsy, orthostatic hypotension,
subarachnoid hemorrhage, cerebral infarction, bronchospasm
accompanying bronchial asthma or whooping cough, hypoglycemic
symptoms due to insulin injection, or iris adhesion in
iridocyclitis.
15-39. (canceled)
Description
TECHNICAL FIELD
[0001] The present invention relates to
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, a salt thereof, or a solvate thereof, and crystalline
forms thereof, which is useful for prevention and/or treatment of
Parkinson's disease and/or Parkinson's syndrome.
BACKGROUND ART
[0002] Parkinson's disease is one of the representative
neurodegenerative diseases in the elderly caused by degeneration or
loss of Dopamine neurons and is designated as a specified disease
(intractable disease). The prevalence of Parkinson's disease is
considered to be 100 to 300 people per 100,000 of the population,
and the clinical symptoms can be roughly divided into motor
symptoms and non-motor symptoms. As the motor symptoms,
extrapyramidal symptoms such as tremor, akinesia, rigidity, and
postural instability are observed, and among these, three symptoms:
tremor, akinesia, and rigidity are known as three main
characteristic features of Parkinson's disease.
[0003] On the other hand, as the non-motor symptoms, for example,
gastrointestinal symptoms such as constipation and drooling,
autonomic nervous symptoms such as orthostatic hypotension,
postprandial hypotension, hyperhidrosis, oily skin, urination
disorders, and erectile dysfunction, or psychiatric symptoms such
as apathy, anhedonia, depressive symptoms, anxiety, and visual
hallucination are developed. In addition, it is often the case that
patients with Parkinson's disease also develop a cognitive
impairment such as dementia.
[0004] Further, it is known that there are some cases where
symptoms similar to those of Parkinson's disease are caused by
diseases such as cerebrovascular disorders, brain tumors, and
encephalitides, or side effects of drugs, intoxication, etc. other
than Parkinson's disease. Those secondarily causing symptoms
similar to those of Parkinson's disease are collectively called
symptomatic parkinsonism, and symptomatic parkinsonism and primary
parkinsonism such as Parkinson's disease are collectively called
Parkinson's syndrome in some cases.
[0005] As a representative means for treating Parkinson's disease
and/or Parkinson's syndrome, dopamine replacement therapy has been
carried out. Levodopa (L-DOPA or L-3,4-dihydroxyphenylalanine),
which is one of the drugs to be used in the dopamine replacement
therapy, is a drug developed in the late 1960's, but has been still
used at present as a first-choice drug in the treatment of
Parkinson's disease.
[0006] However, levodopa has pharmacokinetic problems and also is
one of the drugs whose blood concentration is difficult to be
controlled at around an effective blood concentration. When
levodopa is orally administered, levodopa is rapidly absorbed by an
amino acid transporter present in the upper small intestine. The
blood concentration of levodopa reaches a maximum value at about 30
minutes to 2 hours after oral administration, and the half-life of
levodopa in the blood is about 1 hour, which is very short.
Further, the absorption of levodopa is susceptible to the gastric
residence time, the acidity of gastric acid, etc., and therefore is
not stable.
[0007] Then, 95% or more of the absorbed levodopa is metabolized by
an aromatic L-amino acid decarboxylase (AADC) in organs other than
the central nervous system (particularly in liver) and rapidly
converted into dopamine. Since dopamine cannot pass through the
blood-brain barrier, dopamine produced in organs other than the
central nervous system does not enter the brain. Therefore, it is
considered that the percentage of levodopa which is distributed in
the central nervous system and can exhibit its efficacy with
respect to the absorbed levodopa is less than 1%.
[0008] As described above, since levodopa has pharmacokinetic
problems that the absorption of levodopa is inconsistent, the blood
retention time of levodopa is short, and the percentage of levodopa
entered the central nervous system (brain uptake index) is low,
levodopa is required to be taken 3 times or more per day, and some
patients require to take levodopa as many as 12 times per day.
[0009] Moreover, levodopa also has a problem that the drug efficacy
is gradually lost when several years have passed from the start of
the treatment. This is because as the disease progresses, an
ability to store dopamine in the brain decreases so that the range
(therapeutic range) of blood concentration of levodopa, in which an
appropriate therapeutic effect is obtained, is reduced. Due to this
undesired property, even if a therapeutic effect is obtained by
taking levodopa three times per day in a patient at present, after
several years, the patient will have to take levodopa more than
three times per day.
[0010] Since the problem of levodopa that "large number of doses
are required" has been recognized from a long time ago, in order to
overcome the problem and obtain even a slightly higher therapeutic
effect on Parkinson's disease and/or Parkinson's syndrome, a method
for administering levodopa at a high dose, or a method for
inhibiting an aromatic L-amino acid decarboxylase in peripheral
tissues was contemplated in the past. As for the inhibition of an
aromatic L-amino acid decarboxylase in peripheral tissues, an
inhibitor of the enzyme (DCI: a dopa decarboxylase inhibitor) has
been developed, and a preparation obtained by adding a DCI to
levodopa (a levodopa/DCI combination preparation) is clinically
used at present. With respect to the levodopa/DCI combination
preparation, the brain uptake index of levodopa has been improved
as compared with the case where only levodopa is taken, and the
dose of levodopa is decreased to about one-fifth. However, the
half-life of levodopa in the blood does not change and is still
about 1 hour or so even if a DCI is added, and therefore, from the
viewpoint of maintaining the blood concentration of levodopa, there
is nothing developed.
[0011] On the other hand, as for the administration of levodopa at
a high dose, from the viewpoint of side effects, the implementation
is not practical. The effective range of blood concentration of
levodopa is narrow and also is close to the toxic range. In a case
where a treatment was attempted by actually administering levodopa
continuously at a dose close to the upper limit of the effective
blood concentration or slightly exceeding the limit, side effects
such as gastric symptoms, orthostatic hypotension, and palpitation
were caused in the initial stage of the treatment, and after 2 to 3
months from the start of the treatment, dyskinesia and serious
central nervous system side effects such as psychiatric symptoms
were developed. Among the patients who require levodopa, there are
not a few patients who cannot take levodopa at a sufficient dose
due to such side effects.
[0012] The problem that levodopa requires "large number of doses"
is not improved even by using levodopa and an inhibitor of levodopa
metabolism in combination or by changing the administration route
of levodopa itself. Further, side effects such as dyskinesia
developed by frequent exposure to levodopa at a concentration
exceeding the effective blood concentration are also problems which
have been desired to be solved for patients who require
levodopa.
[0013] In light of these circumstances, many prodrugs of levodopa
itself have been reported so far for solving the problems
attributed to the blood kinetics of levodopa such as "large number
of doses" and "the incidence of side effects due to frequent
dosing".
[0014] Examples of the prodrugs of levodopa include the following
compounds:
[0015] a conjugate of levodopa and GABA represented by the general
formula (A) described in WO 2009/101616:
##STR00001##
(wherein R.sup.1A to R.sup.3A each independently represent a
hydrogen atom, a 4-aminobutyryl, or butyryl group; and R.sup.4A
represents a hydrogen atom, an alkyl, butyryloxyalkyl, or
4-aminobutyryloxyalkyl group) (incidentally, the definitions of the
respective groups are excerpts) (see PTL 1);
[0016] 3,3-dimethyl-butyric acid
4-((S)-2-amino-2-methoxycarbonyl-ethyl)-2-(3,3-dimethyl-butyryloxy)phenyl
ester represented by the formula (B) described in WO
2009/022098:
##STR00002##
(see PTL 2);
[0017] a compound represented by the general formula (C) described
in WO 2008/079387:
##STR00003##
(wherein R.sup.1C represents C1-8 alkyl, substituted C1-8 alkyl,
C1-8 alkoxy, or the like; R.sup.2C and R.sup.1C each independently
represent C1-8 alkyl, substituted C1-8 alkyl, C1-8 alkoxy, or the
like; and R.sup.1C and R.sup.5C each independently represent a
hydrogen atom, C1-8 alkyl, substituted C1-8 alkyl, or the like)
(incidentally, the definitions of the respective groups are
excerpts) (see PTL 3);
[0018] a compound represented by the general formula (D) described
in WO 2007/104959:
##STR00004##
(wherein R.sup.1D and R.sup.2D each independently represent
--C(.dbd.O)R.sup.5D or --C(.dbd.O)OR.sup.5D, or at least one of
R.sup.1D and R.sup.2D represents a hydrogen atom and the other
represents --C(.dbd.O)R.sup.5D or --C(.dbd.O)OR.sup.5D; R.sup.3D
and R.sup.4D each independently represent a hydrogen atom, C1-C6
alkyl which may be substituted, C3-C6 cycloalkyl, or the like;
R.sup.5D represents a hydrogen atom, C1-6 alkyl which may be
substituted, or --CH.sub.2Q.sup.D; and Q.sup.D represents a 3- to
6-membered monocyclic carbocyclic ring or heterocyclic ring)
(incidentally, the definitions of the respective groups are
excerpts) (see PTL 4);
[0019] a compound represented by the general formula (E) described
in WO 2007/109882:
##STR00005##
(wherein X.sup.E represents NR.sup.7E (wherein R.sup.7E represents
a hydrogen atom, an acyl group, or the like); R.sup.1E represents a
hydrogen atom, NH.sub.2, C1-10 alkyl, or the like; R.sup.2E
represents a hydrogen atom, C1-10 alkyl, or the like; R'.sup.2E
represents a hydrogen atom, C1-10 alkyl, or the like; R.sup.3E
represents a hydrogen atom, .dbd.O, SR.sup.8E (wherein R.sup.8E
represents a hydrogen atom, C1-10 alkyl, or the like), or the like;
R.sup.4E and R.sup.5E each independently represent OH, NH.sub.2, or
SH; and R.sup.6E represents a hydrogen atom, F, Cl, Br, I, or the
like) (incidentally, the definitions of the respective groups are
excerpts) (see PTL 5);
[0020] a compound represented by the general formula (F) described
in WO 2006/119758:
##STR00006##
(wherein R.sup.1F and R.sup.2F each independently represent --H,
--CO--H, --CO--CH.sub.3, or the like; R.sup.3F represents
--CH.sub.2CH.sub.2--R.sup.5F, --H, --CH.sub.3, --C.sub.2H.sub.5, or
the like; R.sup.4F and R.sup.5F each independently represent
--CO--R.sup.6F, --CO--R.sup.7F, --H, or the like; and R.sup.6F and
R.sup.7F each independently represent a linear alkyl chain having 2
to 25 carbon atoms, a branched alkyl chain having 2 to 25 carbon
atoms, or the like) (incidentally, the definitions of the
respective groups are excerpts) (see PTL 6);
[0021] a compound represented by the general formula (G) described
in WO 2005/121070:
##STR00007##
(wherein R.sup.1G and R.sup.2G each independently represent a
hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, or
the like; R.sup.3G and R.sup.4G each independently represent a
hydrogen atom, --C(O)OR.sup.2G, --C(O)R.sup.7G, or the like;
R.sup.5G is selected from alkyl, substituted alkyl, aryl,
substituted aryl, and the like; R.sup.7G is selected from alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, and the
like; and nG represents an integer of 1 to 6) (incidentally, the
definitions of the respective groups are excerpts) (see PTL 7);
[0022] a compound represented by the general formula (H) described
in WO 2005/121069:
##STR00008##
(wherein Q.sup.H is selected from --X.sup.H--CO-- and
--CO--X.sup.H--; X.sup.H is selected from --O-- and --NR.sup.6H;
R.sup.6H is selected from a hydrogen atom, alkyl, substituted
alkyl, aryl, substituted aryl, and the like; nH represents an
integer of 2 to 4; R.sup.1H and R.sup.2H are each independently
selected from a hydrogen atom, alkyl, substituted alkyl, aryl,
substituted aryl, and the like; R.sup.3H and R.sup.4H are each
independently selected from a hydrogen atom, --C(O)OR.sup.7H,
--C(O)R.sup.7H, and the like; R.sup.5H is selected from a hydrogen
atom, alkyl, substituted alkyl, aryl, substituted aryl, and the
like; and R.sup.7H is selected from alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, and the like) (incidentally,
the definitions of the respective groups are excerpts) (see PTL
8);
[0023] a compound represented by the general formula (J) described
in European Patent Application Publication No. 728469:
##STR00009##
(wherein X.sup.1J represents a hydrogen atom, hydroxyl, methoxy,
ethoxy, acetyloxy, or the like; X.sup.2J represents hydroxy,
methoxy, ethoxy, acetyloxy, or the like; mJ+nJ is 5 or less;
R.sup.1J represents carbonyl, alkoxycarbonyl, benzyloxycarbonyl, or
the like; R.sup.2J represents a hydrogen atom, alkyl,
alkylcarbonyl, alkyloxycarbonyl, benzyloxycarbonyl, or the like;
and R.sup.3J represents a hydrogen atom, an alkyl group, or the
like) (incidentally, the definitions of the respective groups are
excerpts) (see PTL 9);
[0024] a compound represented by the general formula (K) described
in Japanese Patent Application Publication No. S49-061135:
##STR00010##
(wherein nK represents an integer of 0 to 2) (see PTL 10);
[0025] a compound represented by the general formula (L) described
in German Patent Application Publication No. 2153800:
##STR00011##
(wherein R.sup.1L represents C1-7 alkoxy, C3-8 alkenylalkoxy, or
phenyl C1-7 alkoxy; R.sup.2L represents a hydrogen atom; R.sup.3L
represents a hydrogen atom, a substituent containing 1 to 18 carbon
atoms, or the like; and R.sup.4L represents a substituent
containing 1 to 18 carbon atoms or the like) (incidentally, the
definitions of the respective groups are excerpts) (see PTL
11);
[0026] a compound represented by the general formula (M) described
in U.S. Pat. No. 4,065,566:
##STR00012##
(wherein R.sup.M represents a hydrogen atom, an acyl group, or
##STR00013##
R.sup.1M represents a hydroxyl group or a --OM.sup.M group; M.sup.M
represents an alkali metal or an ammonium ion; and R.sup.2M
represents
##STR00014##
(incidentally, the definitions of the respective groups are
excerpts) (see PTL 12);
[0027] a compound represented by the general formula (P) described
in Japanese Patent Application Publication No. S47-031949:
##STR00015##
(wherein R.sup.1P represents a hydrogen atom or an ester residue;
and R.sup.2PCO represents an organic acyl group) (incidentally, the
definitions of the respective groups are excerpts) (see PTL
13);
[0028] a compound represented by the general formula (Q) described
in Japanese Patent Application Publication No. S50-029527:
##STR00016##
(wherein nQ represents 0 to 2; and R.sup.Q represents CH.sub.3 or
C.sub.2H.sub.5) (see PTL 14);
[0029] a compound represented by the general formula (S) described
in Japanese Patent Application Publication No. S48-072150:
##STR00017##
(wherein R.sup.1S represents a hydrogen atom, a lower alkyl group
or a carboxyl-protecting group; and R.sup.2S represents an
amino-protecting group) (see PTL 15);
[0030] a compound represented by the general formula (T) described
in Japanese Patent Application Publication No. S47-031950:
##STR00018##
(wherein R.sup.1T represents a hydrogen atom or an ester residue;
and R.sup.2TCO represents an organic acyl group) (incidentally, the
definitions of the respective groups are excerpts) (see PTL
16);
[0031] a compound represented by the general formula (U) described
in U.S. Pat. No. 3,998,799:
##STR00019##
(wherein R.sup.U represents a hydrogen atom, an acyl group, or the
like; R.sup.1U represents a hydroxyl group or a --OM.sup.U group;
M.sup.U is se lected from the group consisting of an alkali metal
and an ammonium ion; R.sup.2U represents --COR.sup.3U; and R.sup.3U
represents an N,N--(C.sub.1-C.sub.2)-dialkylamino acid, a
C.sub.4-C.sub.6-cycloalkylamino acid, or the like) (incidentally,
the definitions of the respective groups are excerpts) (see PTL
17); and
[0032] a compound represented by the formula (V) described in
Neuropsychobiology, 1988, Vol. 19, No. 4, PP. 180-185:
##STR00020##
(see NPL 1).
[0033] However,
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, a salt thereof, or a solvate thereof, and the use
thereof disclosed in the present invention are not described in any
of these prior arts, and also are not derived from a combination of
any of these prior arts.
CITATION LIST
Patent Literature
[0034] PTL 1: WO 2009/101616 [0035] PTL 2: WO 2009/022098 [0036]
PTL 3: WO 2008/079387 [0037] PTL 4: WO 2007/104959 [0038] PTL 5: WO
2007/109882 [0039] PTL 6: WO 2006/119758 [0040] PTL 7: WO
2005/121070 [0041] PTL 8: WO 2005/121069 [0042] PTL 9: European
Patent Application Publication No. 728469 [0043] PTL 10: Japanese
Patent Application Publication No. S49-061135 [0044] PTL 11: German
Patent Application Publication No. 2153800 [0045] PTL 12: U.S. Pat.
No. 4,065,566 [0046] PTL 13: Japanese Patent Application
Publication No. S47-031949 [0047] PTL 14: Japanese Patent
Application Publication No. S50-029527 [0048] PTL 15: Japanese
Patent Application Publication No. S48-072150 [0049] PTL 16:
Japanese Patent Application Publication No. S47-031950 [0050] PTL
17: U.S. Pat. No. 3,998,799
NON PATENT LITERATURE
[0050] [0051] NPL 1: Neuropsychobiology, 1988, Vol. 19, No. 4, PP.
180-185
SUMMARY OF INVENTION
Technical Problem
[0052] An object of the present invention is to develop a levodopa
prodrug that overcomes the pharmacokinetic problems of levodopa in
patients with Parkinson's disease and/or Parkinson's syndrome and
can provide an effective blood concentration of levodopa in small
number of doses, more particularly, a levodopa prodrug that can
provide an effective blood concentration (an effective plasma
concentration: 0.4 to 1 .mu.g/mL) of levodopa in humans with a flat
blood concentration-time profile, and reduces the possibility of
developing side effects such as dyskinesia or wearing-off as much
as possible.
Solution to Problem
[0053] The inventors of the present invention made intensive
studies in order to solve the above object, and as a result, they
found that
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, which is a novel substance, solves the above object,
and thus completed the present invention.
[0054] That is, the present invention relates to:
[0055] [1]
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)p-
henyl)propanoic acid, a salt thereof, or a solvate thereof;
[0056] [2] the compound according to the above [1], which is
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid,
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate, or
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride;
[0057] [3] the compound according to the above [2], which is
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid;
[0058] [4] the compound according to the above [3], which has a
melting point of from about 177.0.degree. C. to about 181.9.degree.
C.;
[0059] [5] the compound according to the above [3] or [4], which
has at least peaks at 2.theta. of about 4.03, 7.21, 9.98, 10.72,
17.93, and 19.20 degrees in a powder X-ray diffraction
spectrum;
[0060] [6] the compound according to any one of the above [3] to
[5], which has peaks at 2.theta. of about 4.03, 7.21, 9.98, 10.72,
11.93, 12.90, 13.48, 14.65, 15.23, 15.99, 16.56, 17.23, 17.93,
19.20, 20.88, 21.66, 22.36, 22.50, and 24.58 degrees in a powder
X-ray diffraction spectrum;
[0061] [7] the compound according to any one of the above [3] to
[6], characterized by a powder X-ray diffraction spectrum chart
shown in FIG. 4;
[0062] [8] the compound according to any one of the above [3] to
[7], which has an exothermic peak at about 148.7.degree. C. and
also has endothermic peaks at about 184.7.degree. C., about
194.7.degree. C., and about 200.3.degree. C. in differential
scanning calorimetry;
[0063] [9] the compound according to any one of the above [3] to
[8], characterized by a differential scanning calorimetry chart
shown in FIG. 5;
[0064] [10] the compound according to any one of the above [3] to
[9], which shows absorption at 1771, 1720, 1632, 1602, 1543, 1506,
1469, 1451, 1387, 1359, 1316, 1287, 1203, 1165, 1093, 1069, 1026,
957, 937, 898, 863, 802, 742, 710, 687, 615, 557, 526, 490, 482,
452, 424, 416, and 408 cm.sup.-1 in an infrared absorption
spectrum;
[0065] [11] the compound according to any one of the above [3] to
[10], characterized by an infrared absorption spectrum chart shown
in FIG. 6;
[0066] [12] the compound according to the above [3], which has a
melting point of from about 174.7.degree. C. to about 179.0.degree.
C.;
[0067] [13] the compound according to the above [3] or [12], which
has at least a peak at 2.theta. of about 4.62 degrees in a powder
X-ray diffraction spectrum;
[0068] [14] the compound according to any one of the above [3],
[12], and [13], which has peaks at 2.theta. of about 4.62, 8.40,
9.54, 12.08, 15.38, and 18.16 degrees in a powder X-ray diffraction
spectrum;
[0069] [15] the compound according to any one of the above [3] and
[12] to [14], characterized by a powder X-ray diffraction spectrum
chart shown in FIG. 7;
[0070] [16] the compound according to any one of the above [3] and
[12] to [15], which has an exothermic peak at about 183.3.degree.
C. and also has endothermic peaks at about 192.2.degree. C. and
about 200.8.degree. C. in differential scanning calorimetry;
[0071] [17] the compound according to any one of the above [3] and
[12] to [16], characterized by a differential scanning calorimetry
chart shown in FIG. 8;
[0072] [18] the compound according to any one of the above [3] and
[12] to [17], which shows absorption at 1771, 1715, 1608, 1505,
1469, 1452, 1411, 1386, 1368, 1352, 1315, 1288, 1256, 1201, 1166,
1092, 1070, 1026, 955, 895, 865, 803, 744, 711, 675, 617, 605, 472,
444, 432, and 414 cm.sup.-1 in an infrared absorption spectrum;
[0073] [19] the compound according to any one of the above [3] and
[12] to [18], characterized by an infrared absorption spectrum
chart shown in FIG. 9;
[0074] [20] the compound according to the above [2], which is
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate;
[0075] [21] the compound according to the above [20], which has a
melting point of from about 132.0.degree. C. to about 136.0.degree.
C.;
[0076] [22] the compound according to the above [20] or [21], which
has at least peaks at 2.theta. of about 10.97, 11.58, 14.83, 16.36,
16.70, 19.42, 20.58, and 21.69 degrees in a powder X-ray
diffraction spectrum;
[0077] [23] the compound according to any one of the above [20] to
[22], which has peaks at 2.theta. of about 5.15, 6.97, 7.46, 10.97,
11.58, 13.74, 14.83, 15.20, 16.10, 16.36, 16.70, 17.35, 18.30,
18.83, 19.42, 19.95, 20.58, 21.69, 22.63, 22.84, and 24.00 degrees
in a powder X-ray diffraction spectrum;
[0078] [24] the compound according to any one of the above [20] to
[23], characterized by a powder X-ray diffraction spectrum chart
shown in FIG. 10;
[0079] [25] the compound according to any one of the above [20] to
[24], which has an endothermic peak at about 135.95.degree. C. in
differential scanning calorimetry;
[0080] [26] the compound according to any one of the above [20] to
[25], characterized by a differential scanning calorimetry chart
shown in FIG. 11;
[0081] [27] the compound according to any one of the above [20] to
[26], which shows absorption at 1780, 1712, 1599, 1508, 1452, 1388,
1316, 1289, 1217, 1166, 1120, 1090, 1071, 1036, 1026, 1010, 957,
900, 864, 817, 742, 713, 680, 622, 567, 550, 472, and 440 cm.sup.-1
in an infrared absorption spectrum;
[0082] [28] the compound according to any one of the above [20] to
[27], characterized by an infrared absorption spectrum chart shown
in FIG. 12;
[0083] [29] the compound according to the above [20], which has a
melting point of from about 132.3.degree. C. to about 135.3.degree.
C.;
[0084] [30] the compound according to the above [20] or [29], which
has at least peaks at 2.theta. of about 10.01, 11.88, 13.87, 15.01,
15.87, 16.07, 17.81, 18.65, 19.17, and 22.11 degrees in a powder
X-ray diffraction spectrum;
[0085] [31] the compound according to any one of the above [20],
[29], and [30], which has peaks at 2.theta. of about 4.04, 5.04,
5.54, 6.11, 6.60, 7.96, 8.62, 10.01, 10.32, 11.88, 12.88, 13.87,
15.01, 15.87, 16.07, 16.74, 17.17, 17.81, 18.65, 19.17, 19.72,
20.27, 20.93, 21.67, 22.11, 22.56, 23.11, 23.47, and 24.21 degrees
in a powder X-ray diffraction spectrum;
[0086] [32] the compound according to any one of the above [20] and
[29] to [31], characterized by a powder X-ray diffraction spectrum
chart shown in FIG. 13;
[0087] [33] the compound according to any one of the above [20] and
[29] to [32], which has an endothermic peak at about 134.54.degree.
C. in differential scanning calorimetry;
[0088] [34] the compound according to any one of the above [20] and
[29] to [33], characterized by a differential scanning calorimetry
chart shown in FIG. 14;
[0089] [35] the compound according to any one of the above [20] and
[29] to [34], which shows absorption at 1781, 1711, 1600, 1507,
1315, 1287, 1220, 1203, 1166, 1119, 1088, 1070, 1036, 1027, 1010,
944, 898, 863, 816, 713, 681, 617, 567, 531, 517, 507, 484, 470,
452, 437, 421, and 413 cm.sup.-1 in an infrared absorption
spectrum;
[0090] [36] the compound according to any one of the above [20] and
[29] to [35], characterized by an infrared absorption spectrum
chart shown in FIG. 15;
[0091] [37] the compound according to the above [2], which is
amorphous
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride;
[0092] [38] the compound according to the above [37], which has a
melting point of from about 112.0.degree. C. to about 117.0.degree.
C.;
[0093] [39] the compound according to the above [37] or [38],
characterized by a powder X-ray diffraction spectrum chart shown in
FIG. 16; [40] the compound according to any one of the above [37]
to [39], which has an endothermic peak at about 82.83.degree. C. in
differential scanning calorimetry;
[0094] [41] the compound according to any one of the above [37] to
[40], characterized by a differential scanning calorimetry chart
shown in FIG. 17;
[0095] [42] the compound according to any one of the above [37] to
[41], which shows absorption at 3409, 2992, 2944, 2865, 2629, 1970,
1774, 1718, 1655, 1601, 1585, 1508, 1470, 1452, 1428, 1388, 1369,
1317, 1290, 1258, 1204, 1168, 1125, 1093, 1070, 1026, 1003, 958,
866, 806, 741, 714, 687, 617, 530, 496, 467, 447, and 419 cm.sup.-1
in an infrared absorption spectrum;
[0096] [43] the compound according to any one of the above [37] to
[42], characterized by an infrared absorption spectrum chart shown
in FIG. 18;
[0097] [44] a pharmaceutical composition comprising
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, a salt thereof, or a solvate thereof;
[0098] [45] the pharmaceutical composition according to the above
[44], which is a preventive and/or therapeutic agent for
Parkinson's disease and/or Parkinson's syndrome;
[0099] [46] a medicament comprising a combination of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, a salt thereof, or a solvate thereof, and an aromatic
L-amino acid decarboxylase inhibitor, and/or a
catechol-O-methyltransferase inhibitor;
[0100] [47] the medicament according to the above [46], wherein the
aromatic L-amino acid decarboxylase inhibitor is carbidopa hydrate
or benserazide hydrochloride;
[0101] [48] the medicament according to the above [46], wherein the
catechol-O-methyltransferase inhibitor is entacapone, tolcapone,
nitecapone, BIA-3-202, or CGP-28014;
[0102] [49] the medicament according to any one of the above [46]
to [48], which is a combination preparation;
[0103] [50] a method for preventing and/or treating Parkinson's
disease and/or Parkinson's syndrome, characterized by comprising
administering to a mammal an effective amount of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, a salt thereof, or a solvate thereof;
[0104] [51] the method for prevention and/or treatment according to
the above [50], which further comprises administering an effective
amount of an aromatic L-amino acid decarboxylase inhibitor and/or a
catechol-O-methyltransferase inhibitor;
[0105] [52]
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, a salt thereof, or a solvate thereof for preventing
and/or treating Parkinson's disease and/or Parkinson's
syndrome;
[0106] [53]
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, a salt thereof, or a solvate thereof to be used in
combination with an aromatic L-amino acid decarboxylase inhibitor
and/or a catechol-O-methyltransferase inhibitor upon preventing
and/or treating Parkinson's disease and/or Parkinson's
syndrome;
[0107] [54] use of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, a salt thereof, or a solvate thereof for manufacture of
a preventive and/or therapeutic agent for Parkinson's disease
and/or Parkinson's syndrome;
[0108] [55] a preventive and/or therapeutic agent for Parkinson's
disease and/or Parkinson's syndrome, which comprises
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, a salt thereof, or a solvate thereof;
[0109] [56]
(S)-((4-(3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)-1,2-ph-
enylene)bis(oxy))bis(2-methyl-1-oxopropan-2,1-diyl) dibenzoate or a
salt thereof; and
[0110] [57]
(S)-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)-2-((tert-but-
oxycarbonyl)amino)propanoic acid or a salt thereof.
Advantageous Effects of Invention
[0111]
(2S)-2-Amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)pheny-
l)propanoic acid, a salt thereof, or a solvate thereof
(hereinafter, sometimes collectively abbreviated as "compound of
the present invention") is a levodopa prodrug that overcomes the
pharmacokinetic problems of levodopa and can provide an effective
blood concentration of levodopa in small number of doses. By taking
the compound of the present invention in place of levodopa, an
effective blood concentration of levodopa can be maintained for
about 16 hours in two doses per day (at most three doses per day)
in patients with Parkinson's disease and/or Parkinson's syndrome
who took levodopa in the past, preferably patients with Parkinson's
disease and/or Parkinson's syndrome who took levodopa in
combination with a DCI in the past. Since the same efficacy can be
obtained by dosing two times per day, also the drug compliance can
be improved in patients who had to take a levodopa preparation in 6
to 12 doses per day.
[0112] Further, the compound of the present invention is a prodrug
capable of providing an effective blood concentration (an effective
plasma concentration: 0.4 to 1 .mu.g/mL) of levodopa for a long
period of time in humans, and reduces the possibility of developing
side effects such as dyskinesia or wearing-off as much as possible
by providing a flat blood concentration-time profile of
levodopa.
[0113] In addition, the compound of the present invention is a drug
which raises no concern about mutagenicity. The examination made by
the inventors of the present invention revealed that among levodopa
prodrugs, particularly some compounds showing long blood retention,
there are not a few compounds confirmed to have mutagenicity in a
mutagenicity assay using mammalian cells. However, since the
compound of the present invention does not have mutagenicity, even
in the case where a drug has to be taken over a period as long as
several years or several decades such as Parkinson's disease and/or
Parkinson's syndrome, patients can continue to take the drug
without worrying.
BRIEF DESCRIPTION OF DRAWINGS
[0114] FIG. 1 shows a plasma concentration-time profile of levodopa
when levodopa or the compound of the present invention was
administered to dogs under the condition of using a DCI (carbidopa)
in combination.
[0115] FIG. 2 shows a simulation of a plasma concentration-time
profile of levodopa in humans obtained using the kinetic data of
levodopa or the compound of the present invention in dogs under the
condition of using a DCI (carbidopa) in combination.
[0116] FIG. 3 shows a change in rotational behavior when levodopa
or the compound of the present invention was administered under the
condition of using a DCI (benserazide) in combination to a rat
model injected with 6-hydroxydopamine into the medial forebrain
bundle.
[0117] FIG. 4 shows a powder X-ray diffraction spectrum chart of
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid (type A crystal) obtained in Example 9.
[0118] FIG. 5 shows a differential scanning calorimetry chart of
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid (type A crystal) obtained in Example 9.
[0119] FIG. 6 shows an infrared absorption spectrum chart of
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid (type A crystal) obtained in Example 9.
[0120] FIG. 7 shows a powder X-ray diffraction spectrum chart of
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid (type B crystal) obtained in Example 10.
[0121] FIG. 8 shows a differential scanning calorimetry chart of
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid (type B crystal) obtained in Example 10.
[0122] FIG. 9 shows an infrared absorption spectrum chart of
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid (type B crystal) obtained in Example 10.
[0123] FIG. 10 shows a powder X-ray diffraction spectrum chart of
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate (type A crystal) obtained in Example 6.
[0124] FIG. 11 shows a differential scanning calorimetry chart of
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate (type A crystal) obtained in Example 6.
[0125] FIG. 12 shows an infrared absorption spectrum chart of
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate (type A crystal) obtained in Example 6.
[0126] FIG. 13 shows a powder X-ray diffraction spectrum chart of
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate (type B crystal) obtained in Example 7.
[0127] FIG. 14 shows a differential scanning calorimetry chart of
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate (type B crystal) obtained in Example 7.
[0128] FIG. 15 shows an infrared absorption spectrum chart of
crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate (type B crystal) obtained in Example 7.
[0129] FIG. 16 shows a powder X-ray diffraction spectrum chart of
amorphous
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)p-
henyl)propanoic acid hydrochloride obtained in Example 5.
[0130] FIG. 17 shows a differential scanning calorimetry chart of
amorphous
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)p-
henyl)propanoic acid hydrochloride obtained in Example 5.
[0131] FIG. 18 shows an infrared absorption spectrum chart of
amorphous
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride obtained in Example 5.
DESCRIPTION OF EMBODIMENTS
[0132] In the present invention,
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is a compound represented by the following formula.
##STR00021##
[0133] As is appreciated by those skilled in the art, in the
present invention, unless otherwise specified, the symbol
indicates that the substituent attached thereto is behind the sheet
(i.e. .alpha.-configuration); the symbol indicates that the
substituent attached thereto is in front of the sheet (i.e.
.beta.-configuration); and the symbol / indicates that the
substituent attached thereto is in .alpha.-configuration,
.beta.-configuration, or a mixture thereof at an arbitrary
ratio.
[0134] In the present invention, unless otherwise specified, all
isomers are included. For example, isomers due to the presence of
asymmetric carbon or the like (R-isomer, S-isomer,
.alpha.-configuration, .beta.-configuration, enantiomers, and
diastereomers), optically active isomers having optical activity
(D-isomer, L-isomer, d-isomer, and l-isomer), polar compounds in
chromatographic separation (high-polar compounds and low-polar
compounds), equilibrium compounds (such as tautomers with an amide
bond), rotational isomers, mixtures thereof at an arbitrary ratio,
and racemic mixtures are all included in the present invention.
[0135] In the present invention,
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is converted into a corresponding salt by a known
method. As the salt, a water-soluble salt is preferred. Examples of
a suitable salt include acid addition salts (such as inorganic acid
salts such as hydrochlorides, hydrobromides, hydroiodides,
sulfates, phosphates, and nitrates; and organic acid salts such as
acetates, lactates, tartrates, benzoates, citrates,
methanesulfonates, ethanesulfonates, benzenesulfonates,
toluenesulfonates, p-toluenesulfonates (tosylates), isethionates,
glucuronates, and gluconates), salts of natural acidic amino acids
(such as aspartic acid and glutamic acid), salts of alkali metals
(such as potassium and sodium), salts of alkaline earth metals
(such as calcium and magnesium), ammonium salts, tetramethyl
ammonium salts, tetrabutyl ammonium salts, salts of
pharmaceutically acceptable organic amines (such as alkylamines
(such as methylamine, dimethylamine, trimethylamine, and
triethylamine), heterocyclic amines (such as pyridine, picoline,
and piperidine), alkanolamines (such as ethanolamine,
diethanolamine, and triethanolamine), dicyclohexylamine,
N,N'-dibenzylethylenediamine, cyclopentylamine, benzylamine,
dibenzylamine, phenethylamine, tris(hydroxymethyl)methylamine, and
N-methyl-D-glucamine), and salts of natural basic amino acids (such
as arginine, lysine, ornithine, and histidine).
[0136]
(2S)-2-Amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)pheny-
l)propanoic acid and a salt thereof can also be converted into a
solvate. The solvate is preferably low-toxic and water-soluble.
Examples of a suitable solvate include solvates with, for example,
water or an alcoholic solvent (such as ethanol).
[0137] In addition, each atom constituting
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, a salt thereof, or a solvate thereof may be substituted
with an isotope thereof (such as .sup.2H, .sup.3H, .sup.13C,
.sup.14C, .sup.35S, or .sup.125I), or the like as needed.
[0138] In the present invention,
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, a salt thereof, or a solvate thereof, that is, the
compound of the present invention is not limited to the crystal
form thereof, and may be crystalline or amorphous, or may be a
mixture of a crystalline compound and an amorphous compound at an
arbitrary ratio. It can be determined as to what crystal form the
compound of the present invention has by performing measurement
using known analytical methods to be used for crystallographic
analysis such as powder X-ray diffraction spectrometry,
differential scanning calorimetry, infrared absorption
spectrometry, and a melting point determination method alone or in
combination.
[0139] It has been confirmed that among the compounds of the
present invention, for example,
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid has at least two crystal forms (which are referred to as
type A crystal and type B crystal in a distinguishable manner in
the present description for the sake of convenience).
[0140] The type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is characterized in that, for example, in an analysis by
powder X-ray diffraction spectrometry, it has at least peaks at
2.theta. of about 4.03, 7.21, 9.98, 10.72, 17.93, and 19.20
degrees, preferably it has peaks at 2.theta. of about 4.03, 7.21,
9.98, 10.72, 11.93, 12.90, 13.48, 14.65, 15.23, 15.99, 16.56,
17.23, 17.93, 19.20, 20.88, 21.66, 22.36, 22.50, and 24.58 degrees,
more preferably it shows data shown in Table 3 in the
below-described Example 9, particularly preferably it shows
substantially the same data as a powder X-ray diffraction spectrum
chart shown in FIG. 4.
[0141] The type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is characterized in that, for example, in an analysis by
differential scanning calorimetry, it has an exothermic peak at
around 148.7.degree. C. and also has endothermic peaks at around
184.7.degree. C., 194.7.degree. C., and 200.3.degree. C.,
preferably it shows substantially the same data as a differential
scanning calorimetry chart shown in FIG. 5.
[0142] The type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is characterized in that, for example, in an analysis by
infrared absorption spectrometry, it shows absorption at 1771,
1720, 1632, 1602, 1543, 1506, 1469, 1451, 1387, 1359, 1316, 1287,
1203, 1165, 1093, 1069, 1026, 957, 937, 898, 863, 802, 742, 710,
687, 615, 557, 526, 490, 482, 452, 424, 416, and 408 cm.sup.-1,
preferably it shows substantially the same data as an infrared
absorption spectrum chart shown in FIG. 6.
[0143] The type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is characterized in that, for example, in an analysis by
a melting point determination method, it has a melting point of
from about 177.0.degree. C. to 181.9.degree. C.
[0144] The type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is characterized in that, for example, in an analysis by
powder X-ray diffraction spectrometry, it has at least a peak at
2.theta. of about 4.62 degrees, preferably it has peaks at 2.theta.
of about 4.62, 8.40, 9.54, 12.08, 15.38, and 18.16 degrees, more
preferably it shows data shown in Table 4 in the below-described
Example 10, particularly preferably it shows substantially the same
data as a powder X-ray diffraction spectrum chart shown in FIG.
7.
[0145] The type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is characterized in that, for example, in an analysis by
differential scanning calorimetry, it has an exothermic peak at
around 183.3.degree. C. and also has endothermic peaks at around
192.2.degree. C. and 200.8.degree. C., preferably it shows
substantially the same data as a differential scanning calorimetry
chart shown in FIG. 8.
[0146] The type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is characterized in that, for example, in an analysis by
infrared absorption spectrometry, it shows absorption at 1771,
1715, 1608, 1505, 1469, 1452, 1411, 1386, 1368, 1352, 1315, 1288,
1256, 1201, 1166, 1092, 1070, 1026, 955, 895, 865, 803, 744, 711,
675, 617, 605, 472, 444, 432, and 414 cm.sup.-1, preferably it
shows substantially the same data as an infrared absorption
spectrum chart shown in FIG. 9.
[0147] The type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is characterized in that, for example, in an analysis by
a melting point determination method, it has a melting point of
from about 174.7.degree. C. to 179.0.degree. C.
[0148] Further, it has been confirmed that among the compounds of
the present invention, for example,
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate has at least two crystal forms (which are
referred to as type A crystal and type B crystal in a
distinguishable manner in the present description for the sake of
convenience).
[0149] The type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is characterized in that, for example, in an
analysis by powder X-ray diffraction spectrometry, it has at least
peaks at 2.theta. of about 10.97, 11.58, 14.83, 16.36, 16.70,
19.42, 20.58, and 21.69 degrees, preferably it has peaks at
2.theta. of about 5.15, 6.97, 7.46, 10.97, 11.58, 13.74, 14.83,
15.20, 16.10, 16.36, 16.70, 17.35, 18.30, 18.83, 19.42, 19.95,
20.58, 21.69, 22.63, 22.84, and 24.00 degrees, more preferably it
shows data shown in Table 1 in the below-described Example 6,
particularly preferably it shows substantially the same data as a
powder X-ray diffraction spectrum chart shown in FIG. 10.
[0150] The type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is characterized in that, for example, in an
analysis by differential scanning calorimetry, it has an
endothermic peak at around 135.95.degree. C., preferably it shows
substantially the same data as a differential scanning calorimetry
chart shown in FIG. 11.
[0151] The type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is characterized in that, for example, in an
analysis by infrared absorption spectrometry, it shows absorption
at 1780, 1712, 1599, 1508, 1452, 1388, 1316, 1289, 1217, 1166,
1120, 1090, 1071, 1036, 1026, 1010, 957, 900, 864, 817, 742, 713,
680, 622, 567, 550, 472, and 440 cm.sup.-1, preferably it shows
substantially the same data as an infrared absorption spectrum
chart shown in FIG. 12.
[0152] The type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is characterized in that, for example, in an
analysis by a melting point determination method, it has a melting
point of from about 132.0.degree. C. to 136.0.degree. C.
[0153] The type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is characterized in that, for example, in an
analysis by powder X-ray diffraction spectrometry, it has at least
peaks at 2.theta. of about 10.01, 11.88, 13.87, 15.01, 15.87,
16.07, 17.81, 18.65, 19.17, and 22.11 degrees, preferably it has
peaks at 2.theta. of about 4.04, 5.04, 5.54, 6.11, 6.60, 7.96,
8.62, 10.01, 10.32, 11.88, 12.88, 13.87, 15.01, 15.87, 16.07,
16.74, 17.17, 17.81, 18.65, 19.17, 19.72, 20.27, 20.93, 21.67,
22.11, 22.56, 23.11, 23.47, and 24.21 degrees, more preferably it
shows data shown in Table 2 in the below-described Example 7,
particularly preferably it shows substantially the same data as a
powder X-ray diffraction spectrum chart shown in FIG. 13.
[0154] The type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is characterized in that, for example, in an
analysis by differential scanning calorimetry, it has an
endothermic peak at around 134.54.degree. C., preferably it shows
substantially the same data as a differential scanning calorimetry
chart shown in FIG. 14.
[0155] The type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is characterized in that, for example, in an
analysis by infrared absorption spectrometry, it shows absorption
at 1781, 1711, 1600, 1507, 1315, 1287, 1220, 1203, 1166, 1119,
1088, 1070, 1036, 1027, 1010, 944, 898, 863, 816, 713, 681, 617,
567, 531, 517, 507, 484, 470, 452, 437, 421, and 413 cm.sup.-1,
preferably it shows substantially the same data as an infrared
absorption spectrum chart shown in FIG. 15.
[0156] The type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is characterized in that, for example, in an
analysis by a melting point determination method, it has a melting
point of from about 132.3.degree. C. to 135.3.degree. C.
[0157] Further, it has been confirmed that among the compounds of
the present invention, for example,
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride has an amorphous crystal form.
[0158] The amorphous
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride is characterized in that, for example, in
an analysis by powder X-ray diffraction spectrometry, no
crystalline peaks are observed.
[0159] The amorphous
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride is characterized in that, for example, in
an analysis by differential scanning calorimetry, it has an
endothermic peak at around 82.83.degree. C., preferably it shows
substantially the same data as a differential scanning calorimetry
chart shown in FIG. 17.
[0160] The amorphous
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride is characterized in that, for example, in
an analysis by infrared absorption spectrometry, it shows
absorption at 3409, 2992, 2944, 2865, 2629, 1970, 1774, 1718, 1655,
1601, 1585, 1508, 1470, 1452, 1428, 1388, 1369, 1317, 1290, 1258,
1204, 1168, 1125, 1093, 1070, 1026, 1003, 958, 866, 806, 741, 714,
687, 617, 530, 496, 467, 447, and 419 cm.sup.-1, preferably it
shows substantially the same data as an infrared absorption
spectrum chart shown in FIG. 18.
[0161] The amorphous
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride is characterized in that, for example, in
an analysis by a melting point determination method, it has a
melting point of from about 112.0.degree. C. to 117.0.degree.
C.
[0162] The crystal form of the compound of the present invention is
specified by physicochemical properties disclosed in the present
description, however, the respective data can slightly vary due to
the nature thereof, and therefore, should not be strictly
interpreted.
[0163] For example, the data obtained by powder X-ray diffraction
spectrometry, for example, the relative intensity can slightly vary
depending on the direction of crystal growth, the grain size, the
measurement condition, etc. due to the nature thereof, and
therefore, a diffraction angle (2.theta.) or an overall pattern is
important for the determination of the identification of crystal
forms. Further, in the determination of the identification of
crystal forms, if necessary, a half-width is read from a powder
X-ray diffraction spectrum chart, and may be used in combination
with a diffraction angle (2.theta.), an overall pattern, or a
relative intensity.
[0164] Further, the data obtained by differential scanning
calorimetry or infrared absorption spectrometry can slightly vary
depending on the measurement condition, etc. due to the nature
thereof, and therefore, an overall pattern is important for the
determination of the identification of crystal forms.
[0165] Therefore, compounds showing an overall pattern of at least
one data obtained by powder X-ray diffraction spectrometry,
differential scanning calorimetry, and infrared absorption
spectrometry similar to that of the crystal form of the compound of
the present invention disclosed in the present description are all
included in the present invention.
[0166] Incidentally, although it can be easily understood by those
skilled in the art, in the below-described drawings in the present
description, in the powder X-ray diffraction spectrum chart, a
diffraction angle (2.theta.) (degrees) is indicated on the
horizontal axis (2-theta-scale), and a diffraction intensity is
indicated on the vertical axis (Lin (counts)); in the differential
scanning calorimetry chart, a time (min) or a temperature (.degree.
C.) is indicated on the horizontal axis, and a heat flux is
indicated on the vertical axis; and in the infrared absorption
spectrum chart, a wavelength is indicated on the horizontal axis
(wavenumber [cm.sup.-1]), and a transmittance is indicated on the
vertical axis (% T).
[0167] The compound of the present invention is a levodopa prodrug
and produces levodopa by being metabolized in vivo through, for
example, all or some of the following (1) to (7) intermediates:
[0168] (1)
(S)-2-amino-3-(3-((2-(benzoyloxy)-2-methylpropanoyl)oxy)-4-((2-hydroxy-2--
methylpropanoyl)oxy)phenyl)propanoic acid; [0169] (2)
(S)-2-amino-3-(4-((2-(benzoyloxy)-2-methylpropanoyl)oxy)-3-((2-hydroxy-2--
methylpropanoyl)oxy)phenyl)propanoic acid; [0170] (3)
(S)-2-amino-3-(3-((2-(benzoyloxy)-2-methylpropanoyl)oxy)-4-hydroxyphenyl)-
propanoic acid; [0171] (4)
(S)-2-amino-3-(3,4-bis((2-hydroxy-2-methylpropanoyl)oxy)phenyl)propanoic
acid; [0172] (5)
(S)-2-amino-3-(4-((2-(benzoyloxy)-2-methylpropanoyl)oxy)-3-hydroxyphenyl)-
propanoic acid; [0173] (6)
(S)-2-amino-3-(4-hydroxy-3-((2-hydroxy-2-methylpropanoyl)oxy)phenyl)propa-
noic acid; and [0174] (7)
(S)-2-amino-3-(3-hydroxy-4-((2-hydroxy-2-methylpropanoyl)oxy)phenyl)propa-
noic acid.
[0175] As described above, the compound of the present invention is
a prodrug capable of providing an effective blood concentration (an
effective plasma concentration: 0.4 to 1 .mu.g/mL) of levodopa for
a long period of time in humans, and reduces the possibility of
developing side effects such as dyskinesia or wearing-off as much
as possible by providing a flat blood concentration-time profile of
levodopa.
[0176] Although a description will be also given in the following
Examples, such properties of the compound of the present invention
are brought about by a combination of pharmacokinetic parameters of
the compound of the present invention, for example, (1) an "area
under the blood concentration-time curve (area under the curve
(AUC))" calculated from a blood concentration-time profile of
levodopa when the compound of the present invention is administered
and (2) a "ratio (Cmax/C6 hr) of a plasma concentration at 6 hours
after oral administration (C6 hr) and a maximum plasma
concentration (Cmax)" calculated from a blood concentration-time
profile of levodopa when the compound of the present invention is
administered.
[0177] Here, (1) the "area under the blood concentration-time curve
(area under the curve (AUC))" calculated from a blood
concentration-time profile of levodopa when the compound of the
present invention is administered can be used as an index of
exposure to levodopa, and (2) the "ratio (Cmax/C6 hr) of a plasma
concentration at 6 hours after oral administration (C6 hr) and a
maximum plasma concentration (Cmax)" calculated from a blood
concentration-time profile of levodopa when the compound of the
present invention is administered can be used as an index
indicating the "degree of flatness" of the blood concentration-time
profile of levodopa.
[0178] In dogs in which the organ distribution of carboxyesterase
is most similar to that of humans, in the case where the compound
of the present invention is orally administered at a dose of, for
example, 3 mg/kg expressed in terms of levodopa, the compound of
the present invention shows an AUC described in the above (1) of,
for example, 0.6 .mu.ghr/mL or more, preferably 0.7 .mu.ghr/mL or
more, more preferably 0.8 .mu.ghr/mL or more, particularly
preferably 0.85 .mu.ghr/mL or more. The values serving as the upper
limits of the respective ranges are the values of the AUC (as the
value in Examples, 0.96 .mu.ghr/mL is disclosed) of levodopa when
an equivalent amount of levodopa (here, 3 mg/kg) is orally
administered.
[0179] Further, under the same condition, the compound of the
present invention shows a Cmax/C6 hr described in the above (2) of,
for example 100 or less, preferably 75 or less, more preferably 50
or less, further more preferably 20 or less, particularly
preferably 10 or less.
[0180] The compound of the present invention can be a "prodrug
capable of providing an effective blood concentration of levodopa
for a long period of time" in humans by showing preferred values of
AUC described in the above (1) and Cmax/C6 hr described in the
above (2) in combination in a kinetic study in dogs, and can be "a
prodrug that reduces the possibility of developing side effects
such as dyskinesia or wearing-off as much as possible by providing
a flat blood concentration-time profile of levodopa".
[Method for Producing Compound of the Present Invention]
[0181] The compound of the present invention can be produced
according to a method shown in the below-described Examples. In
addition, the compound of the present invention can also be
produced according to a method shown below or a method similar
thereto, however, the production method is not limited thereto.
[0182] The compound of the present invention can be produced using
levodopa:
##STR00022##
as a starting material according to the following procedure: (A)
protection of the amino group.fwdarw.(B) protection of the carboxyl
group.fwdarw.(C) acylation of the hydroxyl group.fwdarw.(D)
deprotection of the protecting groups. Further, the order of the
steps (A) and (B) may be reversed as needed.
(A) Protection of Amino Group
[0183] A protection reaction for the amino group is well known, and
for example, (1) a method using an acid halide, (2) a method using
a mixed acid anhydride, (3) a method using a condensing agent, etc.
can be exemplified.
[0184] These methods will be specifically described below.
[0185] (1) The method using an acid halide is carried out, for
example, as follows. A carboxylic acid is reacted with an acid
halide agent (such as oxalyl chloride or thionyl chloride) in an
organic solvent (such as chloroform, dichloromethane, diethyl
ether, or tetrahydrofuran) or in the absence of any solvent at
-20.degree. C. to reflux temperature, and the obtained acid halide
is reacted with an amine in the presence of a base (such as
pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, or
diisopropylethylamine) in an organic solvent (such as chloroform,
dichloromethane, diethyl ether, or tetrahydrofuran) at 0 to
40.degree. C. Further, the method can also be carried out by
reacting the obtained acid halide with an amine using an alkaline
aqueous solution (such as an aqueous sodium bicarbonate solution or
a sodium hydroxide solution) in an organic solvent (such as dioxane
or tetrahydrofuran) at 0 to 40.degree. C.
[0186] (2) The method using a mixed acid anhydride is carried out,
for example, as follows. A carboxylic acid is reacted with an acid
halide (such as pivaloyl chloride, tosyl chloride, or mesyl
chloride), an acid derivative (such as ethyl chloroformate or
isobutyl chloroformate), or an acid anhydride derivative (such as
di-tert-butyl-dicarbonate) in an organic solvent (such as
chloroform, dichloromethane, diethyl ether, or tetrahydrofuran) or
in the absence of any solvent in the presence of a base (such as
pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, or
diisopropylethylamine) at 0 to 40.degree. C., and the obtained
mixed acid anhydride is reacted with an amine in an organic solvent
(such as chloroform, dichloromethane, diethyl ether, or
tetrahydrofuran) at 0 to 40.degree. C.
[0187] (3) The method using a condensing agent is carried out, for
example, as follows. A carboxylic acid is reacted with an amine in
an organic solvent (such as chloroform, dichloromethane, dimethyl
formamide, diethyl ether, or tetrahydrofuran) or in the absence of
any solvent in the presence or absence of a base (such as pyridine,
triethylamine, dimethylaniline, or dimethylaminopyridine) using a
condensing agent (such as 1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),
1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridiniumiodine,
or 1-propanephosphonic acid cyclic anhydride (T3P)) and using or
not using 1-hydroxybenztriazole (HOBt) at 0 to 40.degree. C.
[0188] The reactions in these methods (1), (2), and (3) are
preferably carried out in an inert gas (such as argon or nitrogen)
atmosphere under an anhydrous condition.
[0189] Examples of the protecting group for the amino group include
a benzyloxycarbonyl (Cbz) group, a tert-butoxycarbonyl (Boc) group,
an aryloxycarbonyl (Alloc) group, a
1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, a
trifluoroacetyl group, a 9-fluorenylmethoxycarbonyl (Fmoc) group, a
benzyl (Bn) group, a p-methoxybenzyl group, a benzyloxymethyl (BOM)
group, a 2-(trimethylsilyl)ethoxymethyl (SEM) group, and the
like.
(B) Protection of Carboxyl Group
[0190] A protection reaction for the carboxyl group is well known,
and for example, (1) a method using an acid halide, (2) a method
using a mixed acid anhydride, (3) a method using a condensing
agent, etc. can be exemplified.
[0191] These methods will be specifically described below.
[0192] (1) The method using an acid halide is carried out, for
example, as follows. A carboxylic acid is reacted with an acid
halide agent (such as oxalyl chloride or thionyl chloride) in an
organic solvent (such as chloroform, dichloromethane, diethyl
ether, or tetrahydrofuran) or in the absence of any solvent at
-20.degree. C. to reflux temperature, and the obtained acid halide
is reacted with an alcohol in the presence or absence of a base
(such as pyridine, triethylamine, dimethylaniline,
dimethylaminopyridine, or diisopropylethylamine) in an organic
solvent (such as chloroform, dichloromethane, diethyl ether, or
tetrahydrofuran) at 0.degree. C. to the reflux temperature of the
solvent used. Further, the method can also be carried out by
reacting the acid halide using an alkaline aqueous solution (such
as an aqueous sodium bicarbonate solution or a sodium hydroxide
solution) in an organic solvent (such as dioxane or
tetrahydrofuran) at 0 to 40.degree. C.
[0193] (2) The method using a mixed acid anhydride is carried out,
for example, as follows. A carboxylic acid is reacted with an acid
halide (such as pivaloyl chloride, tosyl chloride, or mesyl
chloride) or an acid derivative (such as ethyl chloroformate or
isobutyl chloroformate) in an organic solvent (such as chloroform,
dichloromethane, diethyl ether, or tetrahydrofuran) or in the
absence of any solvent in the presence of a base (such as pyridine,
triethylamine, dimethylaniline, dimethylaminopyridine, or
diisopropylethylamine) at 0 to 40.degree. C., and the obtained
mixed acid anhydride is reacted with an alcohol in an organic
solvent (such as chloroform, dichloromethane, diethyl ether, or
tetrahydrofuran) at 0 to 40.degree. C.
[0194] (3) The method using a condensing agent is carried out, for
example, as follows. A carboxylic acid is reacted with an alcohol
in an organic solvent (such as chloroform, dichloromethane,
dimethyl formamide, diethyl ether, or tetrahydrofuran) or in the
absence of any solvent in the presence or absence of a base (such
as pyridine, triethylamine, dimethylaniline, or
dimethylaminopyridine) using a condensing agent (such as
1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),
1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridiniumiodine,
or 1-propanephosphonic acid cyclic anhydride (T3P)) and using or
not using 1-hydroxybenztriazole (HOBt) at 0 to 40.degree. C.
[0195] The reactions in these methods (1), (2), and (3) are
preferably carried out in an inert gas (such as argon or nitrogen)
atmosphere under an anhydrous condition.
[0196] Examples of the protecting group for the carboxyl group
include methyl, ethyl, tert-butyl, trichloroethyl, benzyl (Bn),
phenacyl, p-methoxybenzyl, trityl, 2-chlorotrityl, and the
like.
(C) Acylation of Hydroxyl Group
[0197] The acylation of the hydroxyl group of a compound obtained
by protecting the amino group and the carboxyl group of levodopa,
that is, a compound represented by the formula:
##STR00023##
(wherein R.sup.101 represents a protecting group for the amino
group, and R.sup.102 represents a protecting group for the carboxyl
group) is carried out as follows. A carboxylic acid represented by
the formula:
##STR00024##
is reacted with an acid halide agent (such as oxalyl chloride or
thionyl chloride) in an organic solvent (such as chloroform,
dichloromethane, diethyl ether, or tetrahydrofuran) or in the
absence of any solvent at -20.degree. C. to reflux temperature, and
the obtained acid halide is reacted with an alcohol in the presence
of a base (such as pyridine, triethylamine, dimethylaniline,
dimethylaminopyridine, or diisopropylethylamine) in an organic
solvent (such as chloroform, dichloromethane, diethyl ether,
tetrahydrofuran, or acetonitrile) at 0 to 40.degree. C. Further,
the method can also be carried out by reacting the acid halide
using an alkaline aqueous solution (such as an aqueous sodium
bicarbonate solution or a sodium hydroxide solution) in an organic
solvent (such as dioxane or tetrahydrofuran) at 0 to 40.degree.
C.
(D) Deprotection of Protecting Groups
[0198] A deprotection reaction for the protecting groups
represented by R.sup.101 and R.sup.102 is known, and can be carried
out by the following method. Examples of the deprotection reaction
include:
[0199] (1) a deprotection reaction by an alkali hydrolysis,
[0200] (2) a deprotection reaction in an acidic condition,
[0201] (3) a deprotection reaction by hydrogenolysis,
[0202] (4) a deprotection reaction for a silyl group,
[0203] (5) a deprotection reaction using a metal, and
[0204] (6) a deprotection reaction using a metal complex.
[0205] These methods will be specifically described below.
[0206] (1) A deprotection reaction by alkali hydrolysis is carried
out, for example, in an organic solvent (such as methanol,
tetrahydrofuran, or dioxane) using an alkali metal hydroxide (such
as sodium hydroxide, potassium hydroxide, or lithium hydroxide), an
alkaline earth metal hydroxide (such as barium hydroxide or calcium
hydroxide), or a carbonate (such as sodium carbonate or potassium
carbonate), or a solution thereof or a mixture thereof at 0 to
40.degree. C.
[0207] (2) A deprotection reaction in an acidic condition is
carried out, for example, in an organic solvent (such as
dichloromethane, chloroform, dioxane, ethyl acetate, or anisole)
and in an organic acid (such as acetic acid, trifluoroacetic acid,
methanesulfonic acid, or p-toluenesulfonic acid) or an inorganic
acid (such as hydrochloric acid or sulfuric acid) or a mixture
thereof (such as a mixture of hydrogen bromide and acetic acid) at
0 to 100.degree. C.
[0208] (3) A deprotection reaction by hydrogenolysis is carried
out, for example, in a solvent (such as an ether-type solvent (such
as tetrahydrofuran, dioxane, dimethoxyethane, or diethyl ether), an
alcohol-type solvent (such as methanol or ethanol), a benzene-type
solvent (such as benzene or toluene), a ketone-type solvent (such
as acetone or methyl ethyl ketone), a nitrile-type solvent (such as
acetonitrile), an amide-type solvent (such as dimethylformamide),
water, ethyl acetate, acetic acid, or a mixed solvent of two or
more of these solvents) in the presence of a catalyst (such as
palladium-carbon, palladium black, palladium hydroxide, platinum
oxide, or Raney nickel) under normal or increased pressure in a
hydrogen atmosphere or in the presence of ammonium formate at 0 to
200.degree. C.
[0209] (4) A deprotection reaction for a silyl group is carried
out, for example, in an organic solvent miscible with water (such
as tetrahydrofuran or acetonitrile) using tetrabutyl ammonium
fluoride at 0 to 40.degree. C.
[0210] (5) A deprotection reaction using a metal is carried out,
for example, in an acidic solvent (such as acetic acid, a buffer
with a pH of from 4.2 to 7.2, or a mixed liquid of such a solution
and an organic solvent such as tetrahydrofuran) in the presence of
zinc powder at 0 to 40.degree. C., if necessary, by applying an
ultrasonic wave.
[0211] (6) A deprotection reaction using a metal complex is carried
out, for example, in an organic solvent (such as dichloromethane,
dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile,
dioxane, or ethanol), water, or a mixed solvent thereof in the
presence of a trap reagent (such as tributyltin hydride,
triethylsilane, dimedone, morpholine, diethylamine, or
pyrrolidine), an organic acid (such as acetic acid, formic acid, or
2-ethylhexanoic acid), and/or an organic acid salt (such as sodium
2-ethylhexanoate or potassium 2-ethylhexanoate) in the presence or
absence of a phosphine reagent (such as triphenylphosphine) using a
metal complex (such as tetrakistriphenylphosphine palladium(0),
bis(triphenylphosphine)palladium(II) dichloride, palladium(II)
acetate, or tris(triphenylphosphine)rhodium(I) chloride) at 0 to
40.degree. C.
[0212] Further, the deprotection reaction can be carried out by a
method other than the methods described above, for example, by a
method described in Protective Groups in Organic Synthesis (written
by T. W. Greene, John Wiley & Sons, Inc., 1999).
[0213] Although it can be easily understood by those skilled in the
art, the target compound of the present invention can be easily
produced by selecting a suitable deprotection reaction from the
above deprotection reactions.
[0214] Incidentally, as described above, the compound of the
present invention is not limited to the crystal form thereof. In
other words, the compound of the present invention may be
crystalline or amorphous, or may be a mixture of a crystalline
compound and an amorphous compound at an arbitrary ratio.
[0215] As for several crystal forms of the compound of the present
invention, detailed production methods therefor are disclosed in
the below-described Examples, and the production thereof can be
carried out according to the procedure. Further, such production
can be carried out according to a method described below or a
method similar thereto, however, the production method is not
limited thereto.
[0216] For example, crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate can be produced according to a method described
below, a method similar thereto, or a method described in
Examples.
[0217] More specifically, a type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate can be produced by the reaction of either of
the following Methods 1 and 2:
[0218] (Method 1) a method in which after
(2S)-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)-2-((tert-bu-
toxycarbonyl)amino)propanoic acid is subjected to a deprotection
reaction using p-toluenesulfonic acid, a solvate of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is produced without performing an isolation
operation, followed by drying by heating under reduced pressure,
whereby a type A crystal is produced; and
[0219] (Method 2) a method in which after
(2S)-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)-2-((tert-bu-
toxycarbonyl)amino)propanoic acid is subjected to a deprotection
reaction using p-toluenesulfonic acid, an amorphous compound is
taken out from the reaction mixture, and then recrystallized,
whereby a type A crystal is produced.
[0220] Hereinafter, the respective methods will be described in
detail.
(Method 1)
[0221] Method 1 is a method in which after
(2S)-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)-2-((tert-bu-
toxycarbonyl)amino)propanoic acid is subjected to a deprotection
reaction using p-toluenesulfonic acid, a solvate of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is produced without performing an isolation
operation, followed by drying by heating under reduced pressure,
whereby a type A crystal is produced.
[0222] A deprotection reaction for a tert-butoxycarbonyl group
using p-toluenesulfonic acid is known, and can be carried out, for
example, in an organic solvent (such as acetonitrile, ethanol,
ethyl acetate, tert-butylmethyl ether, n-heptane, isopropyl ether,
or a mixed solvent of two or more of these solvents) or in a mixed
solvent of such an organic solvent and water in the presence of 0.5
to 10 equivalents, preferably 0.5 to 3 equivalents, more preferably
0.5 to 1.5 equivalents of p-toluenesulfonic acid or a monohydrate
thereof at 0.degree. C. to the boiling point of the solvent used,
preferably at 0 to 90.degree. C.
[0223] Thereafter, a solvate obtained by subjecting the resulting
mixture to slurry stirring at 0.degree. C. to the boiling point of
the solvent used, preferably at 0 to 90.degree. C. without
performing an isolation operation is dried by heating under reduced
pressure at 30 to 100.degree. C., preferably at 30 to 70.degree.
C., whereby a type A crystal can be produced.
[0224] Incidentally, as the solvent to be used in Method 1, a mixed
solvent of acetonitrile and tert-butylmethyl ether, a mixed solvent
of ethyl acetate and tert-butylmethyl ether, or a mixed solvent of
acetonitrile and water is preferred.
(Method 2)
[0225] Method 2 is a method in which after
(2S)-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)-2-((tert-bu-
toxycarbonyl)amino)propanoic acid is subjected to a deprotection
reaction using p-toluenesulfonic acid, an amorphous compound is
taken out from the reaction mixture, and then recrystallized,
whereby a type A crystal is produced.
[0226] The amorphous compound to be subjected to recrystallization
can be prepared by concentrating the solvent used under reduced
pressure after the deprotection reaction described above (in Method
1).
[0227] The obtained amorphous compound is recrystallized in an
organic solvent (such as acetonitrile, ethanol, ethyl acetate,
tert-butylmethyl ether, n-heptane, isopropyl ether, or a mixed
solvent of two or more of these solvents) or in a mixed solvent of
such an organic solvent and water, or the obtained amorphous
compound is subjected to slurry stirring at 0.degree. C. to the
boiling point of the solvent used, preferably at 0 to 90.degree.
C., whereby a solvate is obtained. Then, the obtained solvate is
dried by heating under reduced pressure at 30 to 100.degree. C.,
preferably at 30 to 70.degree. C., whereby a type A crystal can be
produced.
[0228] Incidentally, as the solvent to be used for the deprotection
reaction in Method 2, acetonitrile, ethyl acetate, a mixed solvent
of acetonitrile and water, or a mixed solvent of ethyl acetate and
water is preferred, and particularly a mixed solvent of
acetonitrile and water is preferred. Further, the recrystallization
operation is preferably carried out in a mixed solvent of ethyl
acetate and tert-butylmethyl ether, a mixed solvent of acetonitrile
and tert-butylmethyl ether, a mixed solvent of ethyl acetate and
n-heptane, or a mixed solvent of ethanol and isopropyl ether, and
particularly preferably carried out in a mixed solvent of
acetonitrile and tert-butylmethyl ether.
[0229] On the other hand, a type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate can be produced by the reaction of either of
the following Methods 3 and 4:
[0230] (Method 3) a method in which after
(2S)-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)-2-((tert-bu-
toxycarbonyl)amino)propanoic acid is subjected to a deprotection
reaction using p-toluenesulfonic acid, a solvate of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is produced without performing an isolation
operation, followed by drying by heating under reduced pressure,
whereby a type B crystal is produced; and
[0231] (Method 4) a method in which after a type A crystal is
produced by the above-described Method 1 or 2, a solvate obtained
by performing recrystallization or slurry stirring in an organic
solvent (such as acetone) or in a mixed solvent of such an organic
solvent and water is dried by heating under reduced pressure,
whereby a type B crystal is produced.
[0232] Hereinafter, the respective methods will be described in
detail.
(Method 3)
[0233] Method 3 is a method in which after
(2S)-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)-2-((tert-bu-
toxycarbonyl)amino)propanoic acid is subjected to a deprotection
reaction using p-toluenesulfonic acid, a solvate of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is produced without performing an isolation
operation, followed by drying by heating under reduced pressure,
whereby a type B crystal is produced.
[0234] A deprotection reaction for
(2S)-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)-2-((tert-bu-
toxycarbonyl)amino)propanoic acid is carried out in acetone or a
mixed solvent of acetone and water in the presence of 0.5 to 10
equivalents, preferably 0.5 to 3 equivalents, more preferably 0.5
to 1.5 equivalents of p-toluenesulfonic acid or a monohydrate
thereof at 0 to 60.degree. C.
[0235] Thereafter, a solvate obtained by subjecting the resulting
mixture to slurry stirring at 0 to 60.degree. C. without performing
an isolation operation is dried by heating under reduced pressure
at 30 to 100.degree. C., preferably at 30 to 70.degree. C., whereby
a type B crystal can be produced.
[0236] Incidentally, as the solvent to be used in Method 3, acetone
is preferred.
(Method 4)
[0237] Method 4 is a method in which after a type A crystal is
produced by the above-described Method 1 or 2, a solvate obtained
by performing recrystallization or slurry stirring in an organic
solvent (such as acetone) or in a mixed solvent of such an organic
solvent and water is dried by heating under reduced pressure,
whereby a type B crystal is produced.
[0238] A solvate obtained by suspending a type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate produced by Method 1 or 2 in acetone or in a
mixed solvent of acetone and water, and then, subjecting the
resulting suspension to slurry stirring at 0 to 60.degree. C. is
dried by heating under reduced pressure at 25 to 100.degree. C.,
preferably at 25 to 70.degree. C., whereby a type B crystal can be
produced.
[0239] Incidentally, as the solvent to be used in Method 4, acetone
is preferred.
[0240] Further, crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid can be produced according to a method described below, a
method similar thereto, or a method described in Examples.
[0241] More specifically, the crude product can be produced by
subjecting
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride to the reaction of any of the following
Methods 5 to 7 using an inorganic base, an organic base, or an
organic epoxide compound:
[0242] (Method 5) a method in which
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride is desalted with an inorganic base;
[0243] (Method 6) a method in which
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride is desalted with an organic base; and
[0244] (Method 7) a method in which
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride is desalted with an organic epoxide
compound,
[0245] or subjecting
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate to the reaction of either of the following
Methods 8 and 9 using an inorganic base or an organic base:
[0246] (Method 8) a method in which
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is desalted with an inorganic base; and
[0247] (Method 9) a method in which
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is desalted with an organic base.
[0248] Hereinafter, the respective methods will be described in
detail.
(Method 5)
[0249] Method 5 is a method in which
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride is desalted with an inorganic base. A
desalting reaction for an amino acid hydrochloride with an
inorganic base is known, and the desalting is carried out by, for
example, performing the reaction in a solvent (such as
acetonitrile, ethyl acetate, tetrahydrofuran, dioxane, methanol,
ethanol, water, or a mixed solvent of two or more of these
solvents) using 0.5 to 10 equivalents, preferably 0.5 to 3
equivalents, more preferably 0.5 to 1.5 equivalents of an inorganic
base (such as sodium hydroxide, potassium hydroxide, or barium
hydroxide) or an aqueous solution thereof at 0.degree. C. to the
boiling point of the solvent used, preferably at 0 to 40.degree.
C.
(Method 6)
[0250] Method 6 is a method in which
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride is desalted with an organic base. A
desalting reaction for an amino acid hydrochloride with an organic
base is known, and the desalting is carried out by, for example,
performing the reaction in a solvent (such as acetonitrile, ethyl
acetate, tetrahydrofuran, dioxane, methanol, ethanol, water, or a
mixed solvent of two or more of these solvents) using 0.5 to 10
equivalents, preferably 0.5 to 3 equivalents, more preferably 0.5
to 1.5 equivalents of an organic base (such as triethylamine,
diisopropylethylamine, or N-methylpiperidine) at 0.degree. C. to
the boiling point of the solvent used, preferably at 0 to
40.degree. C.
(Method 7)
[0251] Method 7 is a method in which
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride is desalted with an organic epoxide
compound. A desalting reaction for an amino acid hydrochloride with
an organic epoxide compound is known, and the desalting is carried
out by, for example, performing the reaction in a solvent (such as
acetonitrile, ethyl acetate, tetrahydrofuran, dioxane, methanol,
ethanol, water, or a mixed solvent of two or more of these
solvents) using 0.5 to 10 equivalents of an organic epoxide
compound (such as epichlorohydrin, ethylene oxide, or styrene
oxide) at 0.degree. C. to the boiling point of the solvent used,
preferably at 0 to 60.degree. C.
(Method 8)
[0252] Method 8 is a method in which
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is desalted with an inorganic base. Here,
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate to be used as a starting material may be
crystalline or amorphous, or may be a mixture of a crystalline
compound and an amorphous compound at an arbitrary ratio. A
desalting reaction for an amino acid tosylate with an inorganic
base is known, and the desalting is carried out by, for example,
performing the reaction in a solvent (such as acetonitrile, ethyl
acetate, tetrahydrofuran, dioxane, methanol, ethanol, water, or a
mixed solvent of two or more of these solvents) using 0.5 to 10
equivalents, preferably 0.5 to 3 equivalents, more preferably 0.5
to 1.5 equivalents of an inorganic base (such as sodium hydroxide,
potassium hydroxide, or barium hydroxide) or an aqueous solution
thereof at 0.degree. C. to the boiling point of the solvent used,
preferably at 0 to 40.degree. C.
(Method 9)
[0253] Method 9 is a method in which
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate is desalted with an organic base. Here,
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate to be used as a starting material may be
crystalline or amorphous, or may be a mixture of a crystalline
compound and an amorphous compound at an arbitrary ratio. A
desalting reaction for an amino acid tosylate with an organic base
is known, and the desalting is carried out by, for example,
performing the reaction in a solvent (such as acetonitrile, ethyl
acetate, tetrahydrofuran, dioxane, methanol, ethanol, water, or a
mixed solvent of two or more of these solvents) using 0.5 to 10
equivalents, preferably 0.5 to 3 equivalents, more preferably 0.5
to 1.5 equivalents of an organic base (such as triethylamine,
diisopropylethylamine, or N-methylpiperidine) at 0.degree. C. to
the boiling point of the solvent used, preferably at 0 to
40.degree. C.
[0254] Then, crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid can be produced according to a method described below, a
method similar thereto, or a method described in Examples.
[0255] More specifically, a type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid can be produced by the reaction of either of the
following Methods 10 and 11:
[0256] (Method 10) a method in which after crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is produced by any of the above-described Methods 5 to
9, a type A crystal is produced without isolating the crude
product; and
[0257] (Method 11) a method in which after crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is produced by any of the above-described Methods 5 to
9, the crude product is isolated and converted into a type A
crystal.
[0258] Hereinafter, the respective methods will be described in
detail.
(Method 10)
[0259] Method 10 is a method in which after crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is produced by any of the above-described Methods 5 to
9, a type A crystal is produced without isolating the crude
product.
[0260] A crude product produced by any of the above-described
Methods 5 to 9, preferably Method 7 or 9 is subjected to slurry
stirring in a solvent used in the desalting reaction (such as
acetonitrile) at 0 to 80.degree. C., preferably 0 to 50.degree. C.,
more preferably 0 to 30.degree. C., followed by drying by heating
under reduced pressure at 25 to 100.degree. C., preferably 25 to
70.degree. C., whereby a type A crystal can be produced.
[0261] Incidentally, as the solvent to be used in Method 10,
acetonitrile is preferred.
(Method 11)
[0262] Method 11 is a method in which after crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is produced by any of the above-described Methods 5 to
9, the crude product is isolated and converted into a type A
crystal.
[0263] A crude product produced by any of the above-described
Methods 5 to 9 is isolated, and then suspended in an organic
solvent (such as acetonitrile). Subsequently, the resulting
suspension is subjected to slurry stirring at 0 to 80.degree. C.,
preferably 0 to 50.degree. C., more preferably 0 to 30.degree. C.,
followed by drying by heating under reduced pressure at 25 to
100.degree. C., preferably 25 to 70.degree. C., whereby a type A
crystal can be produced.
[0264] Incidentally, as the solvent to be used in Method 11,
acetonitrile is preferred.
[0265] On the other hand, a type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid can be produced by the reaction of either of the
following Methods 12 and 13:
[0266] (Method 12) a method in which after crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is produced by any of the above-described Methods 5 to
9, a type B crystal is produced without isolating the crude
product; and
[0267] (Method 13) a method in which after crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is produced by any of the above-described Methods 5 to
9, the crude product is isolated and converted into a type B
crystal.
[0268] Hereinafter, the respective methods will be described in
detail.
(Method 12)
[0269] Method 12 is a method in which after crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is produced by any of the above-described Methods 5 to
9, a type B crystal is produced without isolating the crude
product.
[0270] A crude product produced by any of the above-described
Methods 5 to 9 is subjected to stirring in a mixed solvent of a
solvent used in the desalting reaction (such as acetonitrile) and
water at a ratio of from 100:1 to 100:50, preferably from 100:1 to
100:10, more preferably from 100:5 to 100:10 at 0 to 80.degree. C.,
preferably 0 to 60.degree. C., followed by recrystallization by
adding an organic solvent (such as acetonitrile) thereto. The
resulting crystal is then dried by heating under reduced pressure
at 25 to 100.degree. C., preferably 25 to 70.degree. C., whereby a
type B crystal can be produced.
[0271] Incidentally, as the solvent to be used in Method 12,
acetonitrile is preferred.
(Method 13)
[0272] Method 13 is a method in which after crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid is produced by any of the above-described Methods 5 to
9, the crude product is isolated and converted into a type B
crystal.
[0273] A crude product produced by any of the above-described
Methods 5 to 9 is isolated, and then dissolved in a mixed solvent
of an organic solvent and water at a ratio of from 100:1 to 100:50,
preferably from 100:1 to 100:10, more preferably from 100:5 to
100:10, and the resulting solution is stirred at 0 to 80.degree.
C., preferably 0 to 60.degree. C., followed by recrystallization by
adding an organic solvent (such as acetonitrile) thereto. The
resulting crystal is then dried by heating under reduced pressure
at 25 to 100.degree. C., preferably 25 to 70.degree. C., whereby a
type B crystal can be produced.
[0274] Incidentally, as the solvent to be used in Method 13,
acetonitrile is preferred.
[0275] It is also possible to mutually convert the type A crystal
and the type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid to each other. That is, by subjecting the type A crystal
to the reaction of the above-described Method 12 or 13, the type B
crystal can be obtained. Meanwhile, by subjecting the type B
crystal to the reaction of the above-described Method 10 or 11, the
type A crystal can be obtained.
[0276] The compound of the present invention can be produced by a
known method other than the methods described above, for example,
by using a method described in Comprehensive Organic
Transformations: A Guide to Functional Group Preparations 2nd
Edition (Richard C. Larock, John Wiley & Sons. Inc, 1999) or
the like, or a partial modification of a known method, etc. in
combination.
[0277] In each reaction in the present description, the compound
used as the starting material is known per se, or can be easily
produced by a known method.
[0278] In each reaction in the present description, the reaction
with heating can be carried out, as is appreciated by those skilled
in the art, by using a water bath, an oil bath, a sand bath, or a
microwave.
[0279] In each reaction described in the present description, a
solid-phase supported reagent supported on a high-molecular polymer
(such as polystyrene, polyacrylamide, polypropylene, or
polyethylene glycol) may be used as needed.
[0280] In each reaction described in the present description, the
reaction product can be purified by a common purification method
such as distillation under normal or reduced pressure,
high-performance liquid chromatography using a silica gel or
magnesium silicate, thin-layer chromatography, an ion-exchange
resin, a scavenger resin or column chromatography, or washing or
recrystallization. Purification may be carried out after each
reaction or after a few reactions.
[Toxicity]
[0281] The compound of the present invention has low toxicity, and
therefore can be used safely as a pharmaceutical product. In
particular, since the compound of the present invention does not
have mutagenicity, even in the case where a drug has to be taken
over a period as long as several years or several decades such as
Parkinson's disease and/or Parkinson's syndrome, patients can
continue to take the drug without worrying.
[Application to Pharmaceutical Product]
[0282] The compound of the present invention is useful for
prevention and/or treatment of Parkinson's disease and/or
Parkinson's syndrome. Here, the prevention and/or treatment of
Parkinson's disease and/or Parkinson's syndrome literally refers to
prevention or treatment of Parkinson's disease or Parkinson's
syndrome, and also includes, for example, prevention of the
development of dyskinesia, reduction of the severity of dyskinesia,
inhibition of the progression of the symptoms of Parkinson's
disease or Parkinson's syndrome (protective effect on dopamine
newron), and prevention and/or treatment of non-motor symptoms of
Parkinson's disease or Parkinson's syndrome (such as sleep
disorders (such as sleep-onset insomnia, frequent nocturnal
awakening, REM sleep behavior disorder, sleep-disordered breathing,
sleep arousal disorder, delayed sleep phase syndrome, sleep terror,
nocturia, sleep paralysis, and sleep-related eating disorder),
psychiatric symptoms (such as depressive symptoms, anxiety, apathy,
anhedonia, visual hallucination, delusion, impulse control
disorder, and dopamine dysregulation), autonomic nervous symptoms
(such as gastrointestinal symptoms (such as nausea, constipation,
and drooling), orthostatic hypotension, postprandial hypotension,
hyperhidrosis, oily skin, urination disorders, and erectile
dysfunction), cognitive impairments, fatigue, sexual dysfunction,
numbness, and pain). Further, the compound of the present invention
is a levodopa prodrug, and therefore is also useful for prevention
and/or treatment of other diseases, for which levodopa is used as a
therapeutic agent, or against which levodopa is expected to have an
effect, such as Lewy body disease, depression, attention deficit
disorder, schizophrenia, manic-depressive illness, cognitive
impairments, RLS (restless legs syndrome), periodic limb movement
disorder, tardive dyskinesia, Huntington's disease, Tourette's
syndrome, hypertension, addiction disorder, congestive heart
failure, pain accompanying diabetic neuropathy, postherpetic
neuralgia, fibromyalgia, autism, drug dependence, disease such as
narcolepsy or excessive daytime sleepiness, dopa-responsive
dystonia, vegetative state, Perry syndrome, Segawa's disease,
malignant syndrome, ejaculation disorder, gastroparesis,
Lesch-Nyhan disease, amblyopia, pulmonary hypertension,
corticobasal degeneration, phenylketonuria, panic attack, decreased
libido, swallowing reflex disorder, and multiple system
atrophy.
[0283] The Lewy body disease may be any disease as long as it is a
disease in which Lewy bodies are pathologically observed, and for
example, Lewy body dementia, etc. are included.
[0284] Further, the compound of the present invention is also
useful for prevention and/or treatment of a disease which is
expected to be improved by dopamine stimulation and a disease which
is induced by a decrease in noradrenaline other than the diseases
described above.
[0285] Here, examples of the disease which is expected to be
improved by dopamine stimulation include hyperkinetic child
syndrome, toxemia of pregnancy, malignant hypertension, and
epilepsy.
[0286] Further, examples of the disease which is induced by a
decrease in noradrenaline include orthostatic hypotension,
subarachnoid hemorrhage, cerebral infarction, bronchospasm
accompanying bronchial asthma, whooping cough, or the like,
hypoglycemic symptoms due to insulin injection, and iris adhesion
in iridocyclitis.
[0287] The compound of the present invention may be used in
combination with, for example, a drug which is used for prevention
and/or treatment of Parkinson's disease and/or Parkinson's syndrome
for the purpose of, for example, (1) complementation and/or
enhancement of the preventive, therapeutic, and/or symptom
improving effect thereof, (2) improvement of the kinetics and
absorption thereof and reduction of the dose thereof, and/or (3)
reduction of side effects thereof. Examples of the drug to be used
in combination include levodopa or an analog thereof, an aromatic
L-amino acid decarboxylase inhibitor, a
catechol-O-methyltransferase inhibitor, a combination preparation
for dopamine replacement therapy containing such agents in
combination, a dopamine receptor agonist, a dopamine releaser, a
monoamine oxidase (MAO) inhibitor, a dopamine uptake inhibitor, an
anticholinergic agent, a nicotinic acetylcholine receptor agonist,
a noradrenaline receptor agonist, an .alpha.2 receptor antagonist,
a serotonin receptor agonist, a 5-HT1A selective agonist/D2
receptor antagonist, an adenosine receptor (A2A) antagonist, an
NMDA receptor antagonist, a cannabinoid receptor (CB1) agonist, an
AMPA receptor antagonist, a glutamate release inhibitor, an
antihistamine agent, an antiepileptic agent, an antidepressant, a
stimulant drug, a mixed lineage kinase inhibitor, an estrogen
analog, an antipsychotic drug, a neurotrophic factor, a
neuroprotective drug, an immunophilin ligand, a gene therapeutic
agent, a cell-based therapeutic agent, and a botulinum toxin.
[0288] Here, examples of levodopa or an analog thereof include
levodopa, melevodopa, etilevodopa, and the like.
[0289] Examples of the aromatic L-amino acid decarboxylase
inhibitor include benserazide, benserazide hydrochloride,
carbidopa, carbidopa hydrate, and the like.
[0290] Examples of the catechol-O-methyltransferase inhibitor
include entacapone, tolcapone, nitecapone, BIA-3-202, CGP-28014,
and the like.
[0291] Examples of the combination preparation for dopamine
replacement therapy containing such agents in combination include a
levodopa/benserazide combination preparation, a levodopa/carbidopa
combination preparation, a levodopa/carbidopa/entacapone
combination preparation, a melevodopa/carbidopa combination
preparation, and the like.
[0292] Examples of the dopamine receptor agonist include
cabergoline, pergolide, pergolide mesylate, bromocryptine,
bromocryptine mesylate, pramipexole, pramipexole hydrochloride
hydrate, ropinirole, ropinirole hydrochloride, talipexole,
.alpha.-dihydroergocryptine, apomorphine, apomorphine
hydrochloride, sumanirole, terguride, bifeprunox, piribedil,
lisuride, lisuride maleate, rotigotine, DAR-0100, SLV-308, and the
like.
[0293] Examples of the dopamine releaser include amantadine,
amantadine hydrochloride, budipine, and the like.
[0294] Examples of the monoamine oxidase (MAO) inhibitor include
selegiline, safinamide, safrazine, deprenil, mofegiline,
rasagiline, rasagiline mesylate, lazabemide, lazabemide
hydrochloride, and the like.
[0295] Examples of the dopamine uptake inhibitor include modafinil,
NS-2330, and the like.
[0296] Examples of the anticholinergic agent include
trihexyphenidyl, trihexyphenidyl hydrochloride, biperiden,
profenamine, metixene, metixene hydrochloride, piroheptine,
piroheptine hydrochloride, mazaticol, mazaticol hydrochloride, and
the like.
[0297] Examples of the nicotinic acetylcholine receptor agonist
include altinicline, altinicline maleate, and the like.
[0298] Examples of the noradrenaline receptor agonist include
droxidopa and the like.
[0299] Examples of the .alpha.2 receptor antagonist include
fipamezole and the like.
[0300] Examples of the serotonin receptor agonist include ACP-103
and the like.
[0301] Examples of the 5-HT1A selective agonist/D2 receptor
antagonist include sarizotan, sarizotan hydrochloride, and the
like.
[0302] Examples of the adenosine receptor (A2A) antagonist include
istradefylline, Sch-63390, VR-2006, and the like.
[0303] Examples of the NMDA receptor antagonist include remacemide,
remacemide hydrochloride, and the like.
[0304] Examples of the cannabinoid receptor (CB1) agonist include
AVE-1625 and the like.
[0305] Examples of the AMPA receptor antagonist include talampanel,
E-2007, and the like.
[0306] Examples of the glutamate release inhibitor include riluzole
and the like.
[0307] Examples of the antihistamine agent include promethazine and
the like.
[0308] Examples of the antiepileptic agent include zonisamide and
the like.
[0309] Examples of the antidepressant include nortriptyline,
imipramine, amitriptyline, clomipramine, desipramine, maprotiline,
mianserin, setiptiline, fluoxetine, fluvoxamine, sertraline,
paroxetine, mirtazapine, duloxetine, and the like.
[0310] Examples of the stimulant drug include methylphenidate and
the like.
[0311] Examples of the mixed lineage kinase inhibitor include
CEP-1347 and the like.
[0312] Examples of the estrogen analog include MITO-4509 and the
like.
[0313] Examples of the antipsychotic drug include clozapine,
quetiapine, quetiapine fumarate, olanzapine, risperidone, tiapride,
aripiprazole, and the like.
[0314] Examples of the neurotrophic factor include GDNF, PYM-50028,
SR-57667, leteprinim potassium, and the like.
[0315] Examples of the neuroprotective drug include TCH-346 and the
like.
[0316] Examples of the immunophilin ligand include GPI-1485 and the
like.
[0317] Examples of the gene therapeutic agent include CERE-120,
NLX-XI, P63, and the like.
[0318] Examples of the cell-based therapeutic agent include
spheramine and the like.
[0319] In particular, when the compound of the present invention is
administered, by administering the compound of the present
invention in combination with carbidopa, carbidopa hydrate,
benserazide, or benserazide hydrochloride, each of which is an
aromatic L-amino acid decarboxylase inhibitor, and/or entacapone,
tolcapone, nitecapone, BIA-3-202, or CGP-28014, each of which is a
catechol-O-methyltransferase inhibitor, the sustained blood
concentration-time profile of levodopa brought about by the
compound of the present invention is further prolonged. Therefore,
it becomes possible to maintain the blood concentration of levodopa
in a range of from 0.1 to 1.5 .mu.g/mL, preferably from 0.2 to 1.4
.mu.g/mL, more preferably from 0.3 to 1.2 .mu.g/mL, and
particularly preferably in a range of from 0.4 to 1 .mu.g/mL, which
is regarded as an effective blood concentration of levodopa, for
about 12 hours or more, preferably 14 hours or more, particularly
preferably 16 hours or more by dosing three times per day,
preferably two times per day.
[0320] The combined drug of the compound of the present invention
and any of these other drugs may be administered in the form of a
combination preparation containing both components in a single
formulation, or may be administered in the form of separate
formulations. The administration in the form of separate
formulations includes simultaneous administration and time lag
administration. In the case of time lag administration, the other
drug may be administered after the compound of the present
invention is administered, or the compound of the present invention
may be administered after the other drug is administered. The
respective administration routes may be the same or different.
[0321] The dose of the other drug can be appropriately selected on
the basis of a clinically used dose. Further, the mixing ratio of
the compound of the present invention and the other drug can be
appropriately selected according to the age and body weight of the
subject to be treated, administration route, dosing period, disease
to be treated, symptoms, combination, etc. For example, with
respect to one part by mass of the compound of the present
invention, 0.01 to 100 parts by mass of the other drug may be used.
As the other drug, two or more arbitrary drugs may be combined in
an appropriate ratio and administered. Further, the above-described
other drug includes not only drugs found to date but also drugs
found in future.
[0322] In order to use the compound of the present invention or the
combined drug of the compound of the present invention and other
drug for the above-described purpose, it is generally administered
systemically or locally in the form of an oral or parenteral
formulation.
[0323] The dose of the compound of the present invention varies
depending on the age, body weight, symptoms, therapeutic effect,
administration route, treatment time, etc., however, the compound
of the present invention is generally orally administered at a dose
of from 100 mg to 3 g per human adult one to several times per day,
or is parenterally administered at a dose of from 10 mg to 1 g per
human adult one to several times per day, or is continuously
administered intravenously during a period of from 1 hour to 24
hours in a day.
[0324] As described above, it is a matter of course that the dose
varies depending on various conditions, and therefore, a dose less
than the above-described dose may be sufficient in some cases,
whereas a dose exceeding the above range may be required in some
cases.
[0325] When the compound of the present invention or the combined
drug of the compound of the present invention and other drug is
administered, it is used by being formulated into a solid
preparation for internal use or a liquid preparation for internal
use for oral administration, a sustained-release preparation for
oral administration or an injectable preparation, a preparation for
external use, an inhalant, or a suppository for parenteral
administration, or the like.
[0326] Examples of the solid preparation for internal use for oral
administration include tablets, pills, capsules, powders, and
granules. Examples of the capsules include hard capsules and soft
capsules.
[0327] In such a solid preparation for internal use, one or more
active substance(s) is/are formulated into a preparation according
to a common procedure without being mixed with any additives or by
being mixed with an excipient (such as lactose, mannitol, glucose,
microcrystalline cellulose, or starch), a binder (such as
hydroxypropyl cellulose, polyvinylpyrrolidone, or magnesium
aluminometasilicate), a disintegrant (such as calcium glycolate
cellulose), a lubricant (such as magnesium stearate), a stabilizer,
a dissolution aid (such as glutamic acid or aspartic acid) or the
like. Further, if necessary, the preparation may be coated with a
coating agent (such as white soft sugar, gelatin, hydroxypropyl
cellulose, or hydroxypropylmethy cellulose phthalate), or may be
coated with two or more layers. Further, capsules made of an
absorbable substance such as gelatin are also included.
[0328] Examples of the liquid preparation for internal use for oral
administration include pharmaceutically acceptable liquid
preparations, suspensions, emulsions, syrups, and elixirs. In such
a liquid preparation, one or more active substance(s) is/are
dissolved, suspended, or emulsified in a generally used diluent
(such as purified water, ethanol, or a mixed liquid thereof).
Further, this liquid preparation may contain a wetting agent, a
suspending agent, an emulsifying agent, a sweetening agent, a
flavoring agent, an aromatizing agent, a preservative, or a
buffer.
[0329] Further, a sustained-release preparation for oral
administration is also effective. A gel forming substance to be
used in such a sustained-release preparation is a substance which
can swell by absorbing a solvent and form a jelly-like substance in
which the fluidity has been lost by connecting the resulting
colloidal particles to one another to form a three-dimensional net
like structure. The gel forming substance is used mainly as a
binder, a viscosity increasing agent, and a sustained-release base
in pharmaceutical use. For example, gum arabic, agar,
polyvinylpyrrolidone, sodium alginate, propylene glycol alginate
ester, a carboxyvinyl polymer, carboxymethyl cellulose, sodium
carboxymethyl cellulose, guar gum, gelatin, hydroxypropylmethyl
cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methyl
cellulose, or hydroxyethylmethyl cellulose can be used.
[0330] Examples of the injectable preparation for parenteral
administration include solutions, suspension, emulsions, and solid
injectable preparations which are dissolved or suspended in a
solvent before use. The injectable preparation is used by
dissolving, suspending, or emulsifying one or more active
substance(s) in a solvent. Examples of the solvent include
injectable distilled water, physiological saline, vegetable oils,
propylene glycol, polyethylene glycol, alcohols such as ethanol,
and a combination thereof. The injectable preparation may contain a
stabilizer, a dissolution aid (such as glutamic acid, aspartic
acid, or Polysorbate 80 (registered trademark)), a suspending
agent, an emulsifying agent, a soothing agent, a buffer, a
preservative, or the like. The injectable preparation is produced
by sterilization in a final step or by an aseptic procedure. It is
also possible to use the injectable preparation as an aseptic solid
preparation (for example, a lyophilized product is produced and
dissolved in sterilized or aseptic injectable distilled water or
another solvent before use).
[0331] Examples of the dosage form of the preparation for external
use for parenteral administration include propellants, inhalants,
sprays, aerosols, ointments, gels, creams, poultices, plasters,
liniments, and nasal agents. Such a preparation contains one or
more active substance(s) and is prepared according to a known
method or a commonly used formulation.
[0332] The propellant, inhalant, and spray may contain, other than
a generally used diluent, a stabilizer such as sodium hydrogen
sulfite and a buffer which provides isotonicity, for example, an
isotonic agent such as sodium chloride, sodium citrate, or citric
acid. A method for producing the spray is described in detail in,
for example, U.S. Pat. Nos. 2,868,691 and 3,095,355.
[0333] Examples of the inhalant for parenteral administration
include aerosols, powders for inhalation, and liquids for
inhalation. The liquid for inhalation may be in such a form that it
is used by being dissolved or suspended in water or another
appropriate vehicle before use.
[0334] Such an inhalant is prepared according to a known
method.
[0335] For example, a liquid for inhalation is prepared by
appropriately selecting a preservative (such as benzalkonium
chloride or paraben), a colorant, a buffer (such as sodium
phosphate or sodium acetate), an isotonic agent (such as sodium
chloride or concentrated glycerin), a viscosity increasing agent
(such as carboxyvinyl polymer), an absorption enhancer, or the like
according to need.
[0336] A powder for inhalation is prepared by appropriately
selecting a lubricant (such as stearic acid or a salt thereof), a
binder (such as starch or dextrin), an excipient (such as lactose
or cellulose), a colorant, a preservative (such as benzalkonium
chloride or paraben), an absorption enhancer, or the like according
to need.
[0337] When a liquid for inhalation is administered, a sprayer
(such as an atomizer or a nebulizer) is usually used, and when a
powder for inhalation is administered, an inhalator for a powder
preparation is usually used.
[0338] The ointment is produced according to a known or commonly
used formulation. For example, an ointment is prepared by mixing or
melting one or more active substance(s) in a base. The ointment
base is selected from known or commonly used bases. Examples of the
ointment base include higher fatty acids and higher fatty acid
esters (such as adipic acid, myristic acid, palmitic acid, stearic
acid, oleic acid, adipate, myristate, palmitate, stearate, and
oleate), waxes (such as beeswax, spermaceti wax, and ceresin),
surfactants (such as polyoxyethylene alkyl ether phosphate), higher
alcohols (such as cetanol, stearyl alcohol, and cetostearyl
alcohol), silicone oils (such as dimethylpolysiloxane),
hydrocarbons (such as hydrophilic petrolatum, white petrolatum,
purified lanolin, and liquid paraffin), glycols (such as ethylene
glycol, diethylene glycol, propylene glycol, polyethylene glycol,
and Macrogol), vegetable oils (such as castor oil, olive oil,
sesame oil, and terrapin oil), animal oils (such as mink oil, egg
yolk oil, squalane, and squalene), water, absorption enhancers, and
anti-rash agents. From these bases, one base is selected and used
alone or two or more bases are selected and used in admixture. The
ointment may further contain a moisturizer, a preservative, a
stabilizer, an antioxidant, an aromatizing agent, or the like.
[0339] The gel is produced according to a known or commonly used
formulation. For example, a gel may be prepared by melting one or
more active substance(s) in a base. The gel base is selected from
known or commonly used bases. Examples of the gel base include
lower alcohols (such as ethanol and isopropyl alcohol), gelling
agents (such as carboxymethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, and ethyl cellulose), neutralizing agents
(such as triethanolamine and diisopropanolamine), surfactants (such
as polyethylene glycol monostearate), gums, water, absorption
enhancers, and anti-rash agents. From these bases, one base is
selected and used alone or two or more bases are selected and used
in admixture. The gel may further contain a preservative, an
antioxidant, an aromatizing agent, or the like.
[0340] The cream is produced according to a known or commonly used
formulation. For example, a cream is produced by melting or
emulsifying one or more active substance(s) in a base. The cream
base is selected from known or commonly used bases. Examples of the
cream base include higher fatty acid esters, lower alcohols,
hydrocarbons, polyhydric alcohols (such as propylene glycol and
1,3-butylene glycol,), higher alcohols (such as 2-hexyldecanol and
cetanol), emulsifying agents (such as polyoxyethylene alkyl ethers
and fatty acid esters), water, absorption enhancers, and anti-rash
agents. From these bases, one base is selected and used alone or
two or more bases are selected and used in admixture. The cream may
further contain a preservative, an antioxidant, an aromatizing
agent, or the like.
[0341] The poultice is produced according to a known or commonly
used formulation. For example, a poultice is produced by melting
one or more active substance(s) in a base to form a kneaded
material, followed by applying and spreading the kneaded material
on a support. The poultice base is selected from known or commonly
used bases. Examples of the poultice base include viscosity
increasing agents (such as polyacrylic acid, polyvinylpyrrolidone,
gum arabic, starch, gelatin, and methyl cellulose), wetting agents
(such as urea, glycerin, and propylene glycol), fillers (such as
kaolin, zinc oxide, talc, calcium, and magnesium), water,
dissolution aids, tackifiers, and anti-rash agents. From these
bases, one base is selected and used alone or two or more bases are
selected and used in admixture. The poultice may further contain a
preservative, an antioxidant, an aromatizing agent, or the
like.
[0342] The plaster is produced according to a known or commonly
used formulation. For example, a plaster is produced by melting one
or more active substance(s) in a base and applying and spreading
the melt on a support. The plaster base is selected from known or
commonly used bases. Examples of the plaster base include polymeric
bases, oils and fats, higher fatty acids, tackifiers, and anti-rash
agents. From these bases, one base is selected and used alone or
two or more bases are selected and used in admixture. The plaster
may further contain a preservative, an antioxidant, an aromatizing
agent, or the like.
[0343] The liniment is produced according to a known or commonly
used formulation. For example, a liniment is prepared by
dissolving, suspending, or emulsifying one or more active
substance(s) in one or more material(s) selected from water, an
alcohol (such as ethanol or polyethylene glycol), a higher fatty
acid, glycerin, a soap, an emulsifying agent, and a suspending
agent. The liniment may further contain a preservative, an
antioxidant, an aromatizing agent, or the like.
[0344] As other compositions for parenteral administration,
suppositories for intrarectal administration, pessaries for
intravaginal administration, etc. each containing one or more
active substance(s) and formulated according to a common procedure
are included.
[0345] The entire contents of all Patent Literature and Non Patent
Literature or Reference Literature explicitly cited in this
description can be incorporated herein by reference as a part of
this description.
EXAMPLES
[0346] Hereinafter, the present invention will be described in
detail with reference to Examples and Biological Examples, however,
the present invention is not limited thereto. The compound of the
present invention and the compounds shown in Examples were named
using ACD/Name (Version 6.00, manufactured by Advanced Chemistry
Development, Inc.) or Chemdraw Ultra (Version 12.0, manufactured by
Cambridge Soft Corporation).
[0347] The solvents in the parentheses indicated in a part of
chromatographic separation and TLC denote the used elution solvents
or developing solvents, and the ratio is expressed on a volume
basis. The numerical values indicated in a part of NMR denote the
measurement values by .sup.1H-NMR when using the indicated
measuring solvents.
Example 1
2-(Benzoyloxy)-2-methylpropanoic acid
##STR00025##
[0349] 2-Hydroxyisobutyric acid (50 g) was dissolved in
acetonitrile (480 mL). To this solution, pyridine (78 mL) was
added, and then, benzoyl chloride (56 mL) was added thereto. The
resulting solution was stirred at room temperature for 40 minutes.
To the reaction mixture, 2 N hydrochloric acid (300 mL) was added
to acidify the solution, and then, extraction was performed with
ethyl acetate (400 mL.times.2). The organic layers were combined
and dried over magnesium sulfate. After magnesium sulfate was
removed by filtration, the solvent was concentrated under reduced
pressure. The resulting residue was recrystallized from
tert-butylmethyl ether/n-heptane, whereby the title compound (82 g,
82%) having the following physical properties was obtained.
[0350] TLC (Rf value): 0.37 (ethyl acetate)
[0351] NMR (300 MHz, CDCl.sub.3): .delta. 8.20-9.40 (br, 1H),
8.01-8.06 (m, 2H), 7.53-7.59 (m, 1H), 7.40-7.46 (m, 2H), 1.73 (s,
6H)
Example 2
(2S)-Benzyl
2-((tert-butoxycarbonyl)amino)-3-(3,4-dihydroxyphenyl)propanoate
##STR00026##
[0353] To (S)-3,4-dihydroxyphenylalanine (L-DOPA, 10.0 g), purified
water (30 mL) was added under an argon atmosphere to form a
suspension. To this solution, triethylamine (14.2 mL) was added,
and then, a solution of di-tert-butyl-dicarbonate (Boc.sub.2O, 13.3
g) in tetrahydrofuran (30 mL) was added thereto at room
temperature. The resulting solution was stirred at room temperature
for 14 hours. To the reaction mixture, 2 N hydrochloric acid (61
mL) was added under ice-cooling to acidify the solution, and then,
extraction was performed with ethyl acetate (200 mL.times.2). The
organic layers were combined and washed with a saturated aqueous
solution of sodium chloride (200 mL), and then dried over magnesium
sulfate. After magnesium sulfate was removed by filtration, the
solvent was concentrated under reduced pressure. The resulting
residue was used in the subsequent step without purification.
[0354] TLC (Rf value): 0.37 (dichloromethane:methanol:acetic
acid=17:3:1)
[0355] The crude product obtained in the previous step was
dissolved in N,N-dimethylformamide (51 mL). To this solution,
potassium hydrogen carbonate (7.6 g) was added under an argon
atmosphere, and then, benzyl bromide (7.3 mL) was added thereto.
The resulting solution was stirred at room temperature for 7 hours.
To the reaction mixture, 2 N hydrochloric acid (92 mL) was added
under ice-cooling to acidify the solution, and then, extraction was
performed with a mixed solution of n-heptane and ethyl acetate
(1:1) (150 mL.times.2). The organic layers were combined and washed
with water (75 mL.times.2) and a saturated aqueous solution of
sodium chloride (75 mL), and then dried over magnesium sulfate.
After magnesium sulfate was removed by filtration, the solvent was
concentrated under reduced pressure. The resulting residue was
recrystallized from ethyl acetate/n-heptane, whereby the title
compound (16.2 g, 2-step yield: 82%) having the following physical
properties was obtained.
[0356] TLC (Rf value): 0.64 (n-hexane:ethyl acetate:acetic
acid=50:50:1)
[0357] NMR (300 MHz, CDCl.sub.3): .delta. 7.31-7.40 (m, 5H), 6.98
(d, J=7.8 Hz, 1H), 6.44 (dd, J=7.8, 1.8 Hz, 1H), 6.40 (d, J=1.8 Hz,
1H), 5.26-5.64 (br, 2H), 5.05-5.23 (m, 2H), 5.00 (d, J=8.1 Hz, 1H),
4.50-4.58 (m, 1H), 2.94 (d, J=5.7 Hz, 2H), 1.41 (s, 9H)
Example 3
(2S)-((4-(3-Benzyloxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl-1,2-phen-
ylene)bis(oxy))bis(2-methyl-1-oxopropan-2,1-diyl) dibenzoate
##STR00027##
[0359] To the compound (90.7 g) produced in Example 1, toluene (227
mL) was added to form a suspension. To this solution,
N,N-dimethylformamide (0.8 mL) was added under an argon atmosphere,
and then, thionyl chloride (38.2 mL) was added thereto. The
reaction mixture was stirred at 70.degree. C. for 1 hour. The
reaction mixture was cooled to room temperature and then
concentrated under reduced pressure. To the residue, toluene (170
mL) was added, and the resulting solution was concentrated under
reduced pressure. This procedure was repeated twice, whereby an
acid chloride was obtained.
[0360] The compound (76.7 g) produced in Example 2 was dissolved in
acetonitrile (100 mL) under an argon atmosphere. To this solution,
triethylamine (83 mL) was added under ice-cooling, and
subsequently, the acid chloride produced by the previous reaction
was added thereto over 15 minutes. The resulting solution was
stirred for 1 hour under ice-cooling. To the reaction mixture, an
aqueous solution of 10% sodium hydrogen carbonate (800 mL) was
added, and then, extraction was performed with ethyl acetate (800
mL.times.2). The organic layers were combined, and washed with a
saturated aqueous solution of sodium chloride (800 mL), and then
dried over sodium sulfate. After sodium sulfate was removed by
filtration, the filtrate was concentrated under reduced pressure.
The resulting residue was purified by silica gel chromatography (a
medium-pressure preparative liquid chromatograph, Redisep
manufactured by Teledyne Isco, Inc. (column: main column 1.5 kg,
n-hexane:ethyl acetate=8:2-7:3 (gradient time: 15 minutes),
fractionation mode), whereby the title compound (118 g, 95%) having
the following physical properties was obtained.
[0361] TLC (Rf value): 0.44 (n-hexane:ethyl acetate=3:1)
[0362] NMR (300 MHz, CDCl.sub.3): .delta. 8.01-8.07 (m, 4H),
7.52-7.60 (m, 2H), 7.38-7.49 (m, 4H), 7.25-7.32 (m, 5H), 7.15 (d,
J=8.1 Hz, 1H), 7.05 (s, 1H), 6.91 (d, J=8.1 Hz, 1H), 5.12 (s, 2H),
5.02 (d, J=7.8 Hz, 1H), 4.55-4.63 (m, 1H), 3.09 (d, J=5.4 Hz, 2H),
1.81-1.85 (m, 12H), 1.39 (s, 9H)
Example 4
(2S)-3-(3,4-Bis((2-benzoyloxy)-2-methylpropanoyl)oxy)phenyl)-2-((tert-buto-
xycarbonyl)amino)propanoic acid
##STR00028##
[0364] The compound (134.4 g) produced in Example 3 was dissolved
in ethanol (400 mL). To this solution, 10% palladium-carbon (50%
hydrated, 14.6 g) was added under an argon atmosphere. This
solution was stirred at room temperature for 2 hours under a
hydrogen atmosphere. To the reaction mixture, ethyl acetate (400
mL) was added, and the resulting mixture was filtered through
Celite (trade name). Then, the filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (a medium-pressure preparative liquid chromatograph,
W-prep 2XY manufactured by Yamazen Corporation (column: main column
5L, inject column 3L, n-hexane:ethyl acetate=3:7-0:1 (gradient
time: 20 minutes), fractionation mode GR), whereby the title
compound (110 g, 86%) having the following physical properties was
obtained.
[0365] TLC (Rf value): 0.38 (n-hexane:ethyl acetate:acetic
acid=100:100:1)
[0366] NMR (300 MHz, CD.sub.3OD): .delta. 8.02-8.07 (m, 4H),
7.59-7.66 (m, 2H), 7.46-7.52 (m, 4H), 7.13-7.21 (m, 3H), 4.33 (dd,
J=9.0, 5.1 Hz, 1H), 3.18 (dd, J=13.5, 5.1 Hz, 1H), 2.93 (dd,
J=13.5, 9.0 Hz, 1H), 1.82 (s, 12H), 1.33 (s, 9H)
Example 5
(2S)-2-Amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)propa-
noic acid hydrochloride
##STR00029##
[0368] To the compound (110 g) produced in Example 4, a 4 N
hydrochloric acid-dioxane solution (500 mL) was added. The
resulting solution was stirred at room temperature for 1 hour.
Then, the reaction mixture was concentrated under reduced pressure,
whereby the title compound (93.2 g, 94%) having the following
physical properties was obtained. The obtained title compound was
amorphous and had a melting point of from about 112.0 to
117.0.degree. C. (measured by the capillary method described in the
Japanese Pharmacopoeia).
[0369] TLC (Rf value): 0.64 (ethyl acetate:acetic
acid:water=5:5:1)
[0370] NMR (300 MHz, CD.sub.3OD): .delta. 8.02-8.06 (m, 4H),
7.60-7.67 (m, 2H), 7.46-7.52 (m, 4H), 7.25-7.30 (m, 3H), 4.24 (dd,
J=8.4, 5.1 Hz, 1H), 3.37 (dd, J=15.0, 5.1 Hz, 1H), 3.13 (dd,
J=15.0, 8.4 Hz, 1H), 1.83 (s, 6H), 1.82 (s, 6H)
[0371] The powder X-ray diffraction spectrum chart, differential
scanning calorimetry chart, and infrared absorption spectrum chart
of the thus obtained amorphous
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid hydrochloride are shown in FIG. 16, FIG. 17, and FIG.
18, respectively.
(1) Powder X-Ray Diffraction Spectroscopy
[Measurement Conditions]
[0372] Apparatus: BRUKER DISCOVER with GADDS (C2)
[0373] Target: Cu
[0374] Filter: Not used
[0375] Voltage: 40 kV
[0376] Current: 40 mA
[0377] Exposure time: 180 sec
[Results]
[0378] In the powder X-ray diffraction spectroscopy using
Cu--K.alpha. radiation, no crystalline peaks were observed.
(2) Differential Scanning Calorimetry
[Measurement Conditions]
[0379] Apparatus: SEIKO INSTRUMENT DSC 6200
[0380] Amount of sample: 3.73 mg
[0381] Sample cell: Aluminum Standard 40 .mu.L (having a lid with a
pinhole)
[0382] Nitrogen flow rate: 40 mL/min
[0383] Temperature elevation rate: 10.degree. C./min
[0384] Temperature elevation starting temperature: 25.degree.
C.
[Results]
[0385] As a result, it was found that the compound has an
endothermic peak at around 82.83.degree. C.
(3) Infrared Absorption Spectroscopy
[Measurement Conditions]
[0386] Apparatus: FTIR-660 Plus/SENSIR DuraScope, JASCO
Corporation
[0387] Resolution: 4 cm.sup.-1
[0388] Number of scanning times: 32
[Results]
[0389] IR (Attenuated total reflectance method (hereinafter
abbreviated as "ATR method"): 3409, 2992, 2944, 2865, 2629, 1970,
1774, 1718, 1655, 1601, 1585, 1508, 1470, 1452, 1428, 1388, 1369,
1317, 1290, 1258, 1204, 1168, 1125, 1093, 1070, 1026, 1003, 958,
866, 806, 741, 714, 687, 617, 530, 496, 467, 447, and 419
cm.sup.-1
Reference Example 1
Benzyl 3-hydroxy-2,2-dimethylpropanoate
##STR00030##
[0391] 2,2-Dimethyl-3-hydroxypropanoic acid (10.0 g) was dissolved
in N,N-dimethylformamide (150 mL). To this solution, potassium
hydrogen carbonate (10.2 g) was added, and then, benzyl bromide
(10.7 mL) was added thereto. The resulting solution was stirred at
room temperature for 16 hours. To the reaction mixture, water (300
mL) was added, and extraction was performed with a mixed solution
of n-hexane and ethyl acetate (1:4) (200 mL.times.2). The organic
layers were combined and washed with a saturated aqueous solution
of sodium chloride (200 mL), and then dried over magnesium sulfate.
After magnesium sulfate was removed by filtration, the solvent was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (a medium-pressure
preparative liquid chromatograph, W-prep 2XY manufactured by
Yamazen Corporation (column: main column 4L, inject column 3L,
n-hexane:ethyl acetate=1:0-1:1 (gradient time: 15 minutes),
fractionation mode GR), whereby the title compound (17.6 g, 100%)
having the following physical properties was obtained.
[0392] TLC (Rf value): 0.39 (n-hexane:ethyl acetate=3:1)
[0393] NMR (CDCl.sub.3): .delta. 7.29-7.41 (m, 5H), 5.15 (s, 2H),
3.57 (d, J=6.3 Hz, 2H), 1.22 (s, 6H)
Reference Example 2
3-(Benzyloxy)-2,2-dimethyl-3-oxopropylthiophene-2-carboxylate
##STR00031##
[0395] The compound (2.0 g) produced in Reference Example 1 was
dissolved in dichloromethane (30 mL). To this solution,
triethylamine (2.7 mL) was added, and then, 2-thiophenecarboxylic
acid chloride (1.5 mL) was added thereto under ice-cooling. The
resulting solution was stirred for 2 hours under ice-cooling. To
the reaction mixture, a saturated aqueous solution of sodium
carbonate (30 mL) was added, and then, extraction was performed
with ethyl acetate (100 mL.times.2). The organic layers were
combined, and washed with a saturated aqueous solution of sodium
chloride (30 mL), and then dried over magnesium sulfate. After
magnesium sulfate was removed by filtration, the solvent was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (a medium-pressure
preparative liquid chromatograph, W-prep 2XY manufactured by
Yamazen Corporation (column: main column 2L, inject column L,
n-hexane:ethyl acetate=1:0-8:2 (gradient time: 15 minutes),
fractionation mode GR), whereby the title compound (3.0 g, 100%)
having the following physical properties was obtained.
[0396] TLC (Rf value): 0.65 (n-hexane:ethyl acetate=3:1)
[0397] NMR (CDCl.sub.3): .delta. 7.67-7.69 (m, 1H), 7.52-7.55 (m,
1H), 7.26-7.34 (m, 5H), 7.05-7.08 (m, 1H), 5.16 (s, 2H), 4.34 (s,
2H), 1.28 (s, 6H)
Reference Example 3
2,2-Dimethyl-3-((thiophene-2-carbonyl)oxy)propanoic acid
##STR00032##
[0399] The compound (3.0 g) produced in Reference Example 2 was
dissolved in ethanol (20 mL). To this solution, 10%
palladium-carbon (50% hydrated, 500 mg) was added under an argon
atmosphere. This solution was stirred at room temperature for 1
hour under a hydrogen atmosphere. To the reaction mixture, ethyl
acetate (20 mL) was added, and the resulting mixture was filtered
through Celite (trade name). Then, the filtrate was concentrated
under reduced pressure. The resulting residue was purified by
silica gel chromatography (a medium-pressure preparative liquid
chromatograph, W-prep 2XY manufactured by Yamazen Corporation
(column: main column 2L, inject column L, n-hexane:ethyl
acetate=8:2-0:1 (gradient time: 15 minutes), fractionation mode
GR), whereby the title compound (719 mg, 33%) having the following
physical properties was obtained.
[0400] TLC (Rf value): 0.60 (ethyl acetate)
[0401] NMR (CDCl.sub.3): .delta. 7.77-7.79 (m, 1H), 7.53-7.55 (m,
1H), 7.06-7.10 (m, 1H), 4.34 (s, 2H), 1.33 (s, 6H)
Reference Example 4
(2S)-((4-(3-(Benzyloxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)-1,2-ph-
enylene)bis(oxy))bis(2,2-dimethyl-3-oxopropan-3,1-diyl)
bis(thiophene-2-carboxylate)
##STR00033##
[0403] By performing the same procedure as in Example 3 using the
compound (735 mg) produced in Example 2 and the compound (1.3 g)
produced in Reference Example 3 in place of the compound produced
in Example 1, the title compound (1.5 g, 99%) having the following
physical properties was obtained.
[0404] TLC (Rf value): 0.60 (n-hexane:ethyl acetate=1:1)
[0405] NMR (CDCl.sub.3): .delta. 7.79-7.82 (m, 2H), 7.53-7.58 (m,
2H), 7.26-7.31 (m, 5H), 7.06-7.11 (m, 2H), 7.00 (d, J=8.4 Hz, 1H),
6.87-6.94 (m, 2H), 5.10 (s, 2H), 4.96-5.04 (m, 1H), 4.52-4.59 (m,
1H), 4.43 (s, 2H), 4.42 (s, 2H), 2.99-3.06 (m, 2H), 1.34-1.35 (m,
21H)
Reference Example 5
(2S)-3-(3,4-Bis((2,2-dimethyl-3-((thiophene-2-carbonyl)oxy)propanoyl)oxy)p-
henyl)-2-(tert-butoxycarbonyl)amino)propanoic acid
##STR00034##
[0407] By performing the same procedure as in Example 4 using the
compound (1.5 g) produced in Reference Example 4 in place of the
compound produced in Example 3, the title compound (588 mg, 44%)
having the following physical properties was obtained.
[0408] TLC (Rf value): 0.12 (ethyl acetate)
[0409] NMR (CDCl.sub.3): .delta. 7.74-7.85 (m, 2H), 7.03-7.18 (m,
4H), 6.99-7.12 (m, 3H), 4.43 (s, 2H), 4.42 (s, 2H), 4.05-4.22 (m,
1H), 3.06-3.14 (m, 1H), 2.83-2.91 (m, 1H), 1.36-1.48 (m, 21H)
Reference Example 6
(2S)-2-Amino-3-(3,4-bis((2,2-dimethyl-3-((thiophene-2-carbonyl)oxy)propano-
yl)oxy)phenyl)propanoic acid hydrochloride
##STR00035##
[0411] By performing the same procedure as in Example 5 using the
compound (580 mg) produced in Reference Example 5 in place of the
compound produced in Example 4, the title compound (528 mg, 100%)
having the following physical properties was obtained.
[0412] TLC (Rf value): 0.74 (ethyl acetate:acetic
acid:water=3:1:1)
[0413] NMR (CD.sub.3OD): .delta. 7.75-7.84 (m, 4H), 7.14-7.23 (m,
5H), 4.45 (s, 2H), 4.44 (s, 2H), 4.17-4.23 (m, 1H), 3.35-3.38 (m,
1H), 3.09 (dd, J=14.4, 8.4 Hz, 1H), 1.41-1.44 (m, 12H)
Reference Example 7
3-(Benzyloxy)-2,2-dimethyl-3-oxopropyl thiophene-3-carboxylate
##STR00036##
[0415] By performing the same procedure as in Reference Example 2
using the compound (2.0 g) produced in Reference Example 1 and
3-thiophenecarboxylic acid chloride (2.1 g) in place of
2-thiophenecarboxylic acid chloride, the title compound (3.1 g,
100%) having the following physical properties was obtained.
[0416] TLC (Rf value): 0.50 (n-hexane:ethyl acetate=5:1)
[0417] NMR (CDCl.sub.3): .delta. 7.89-7.91 (m, 1H), 7.39-7.42 (m,
1H), 7.24-7.38 (m, 6H), 5.16 (s, 2H), 4.31 (s, 2H), 1.32 (s,
6H)
Reference Example 8
2,2-Dimethyl-3-((thiophene-3-carbonyl)oxy)propanoic acid
##STR00037##
[0419] By performing the same procedure as in Reference Example 3
using the compound (3.1 g) produced in Reference Example 7 in place
of the compound produced in Reference Example 2, the title compound
(354 mg, 16%) having the following physical properties was
obtained.
[0420] TLC (Rf value): 0.12 (ethyl acetate)
[0421] NMR (CDCl.sub.3): .delta. 8.08-8.10 (m, 1H), 7.48-7.51 (m,
1H), 7.27-7.31 (m, 1H), 4.32 (s, 2H), 1.33 (s, 6H)
Reference Example 9
(2S)-((4-(3-(Benzyloxy)-2-(tert-butoxycarbonyl)amino)-3-oxopropyl)-1,2-phe-
nylene)bis(oxy))bis(2,2-dimethyl-3-oxopropan-3,1-diyl)
bis(thiophene-3-carboxylate)
##STR00038##
[0423] By performing the same procedure as in Example 3 using the
compound (533 mg) produced in Example 2 and the compound (785 mg)
produced in Reference Example 8 in place of the compound produced
in Example 1, the title compound (1.1 g, 100%) having the following
physical properties was obtained.
[0424] TLC (Rf value): 0.47 (n-hexane:ethyl acetate=2:1)
[0425] NMR (CDCl.sub.3): .delta. 8.10-8.12 (m, 2H), 7.49-7.52 (m,
2H), 7.23-7.33 (m, 7H), 6.85-6.97 (m, 3H), 5.10 (s, 2H), 4.98 (d,
J=8.7 Hz, 1H), 4.52-4.58 (m, 1H), 4.40 (s, 2H), 4.41 (s, 2H),
2.96-3.08 (m, 2H), 1.32-1.36 (m, 21H)
Reference Example 10
(2S)-3-(3,4-Bis((2,2-dimethyl-3-((thiophene-3-carbonyl)oxy)propanoyl)oxy)p-
henyl)-2-(tert-butoxycarbonyl)amino)propanoic acid
##STR00039##
[0427] By performing the same procedure as in Example 4 using the
compound (1.1 g) produced in Reference Example 9 in place of the
compound produced in Example 3, the title compound (324 mg, 33%)
having the following physical properties was obtained.
[0428] TLC (Rf value): 0.12 (ethyl acetate)
[0429] NMR (CDCl.sub.3): .delta. 8.20-8.24 (m, 2H), 7.45-7.52 (m,
4H), 6.99-7.12 (m, 3H), 4.41 (s, 2H), 4.40 (s, 2H), 4.19-4.26 (m,
1H), 3.06-3.14 (m, 1H), 2.84-2.90 (m, 1H), 1.24-1.34 (m, 21H)
Reference Example 11
(2S)-2-Amino-3-(3,4-bis((2,2-dimethyl-3-((thiophene-3-carbonyl)oxy)propano-
yl)oxy)phenyl)propanoic acid hydrochloride
##STR00040##
[0431] By performing the same procedure as in Example 5 using the
compound (323 mg) produced in Reference Example 10 in place of the
compound produced in Example 4, the title compound (294 mg, 100%)
having the following physical properties was obtained.
[0432] TLC (Rf value): 0.57 (ethyl acetate:acetic
acid:water=3:1:1)
[0433] NMR (CD.sub.3OD): .delta. 8.20-8.24 (m, 2H), 7.46-7.51 (m,
4H), 7.12-7.21 (m, 3H), 4.42 (s, 2H), 4.41 (s, 2H), 4.14-4.21 (m,
1H), 3.31-3.35 (m, 1H), 3.05-3.10 (m, 1H), 1.41-1.43 (m, 12H)
Reference Example 12
3-(Benzyloxy)-2,2-dimethyl-3-oxopropyl 2-methoxybenzoate
##STR00041##
[0435] By performing the same procedure as in Reference Example 2
using the compound (1.5 g) produced in Reference Example 1 and
2-methoxybenzoyl chloride (1.6 mL) in place of
2-thiophenecarboxylic acid chloride, the title compound (1.8 g,
72%) having the following physical properties was obtained.
[0436] TLC (Rf value): 0.66 (n-hexane:ethyl acetate=2:1)
[0437] NMR (CDCl.sub.3): .delta. 7.68 (dd, J=7.5, 2.1 Hz, 1H),
7.43-7.49 (m, 1H), 7.25-7.32 (m, 5H), 6.89-6.96 (m, 2H), 5.15 (s,
2H), 4.35 (s, 2H), 3.84 (s, 3H), 1.33 (s, 6H)
Reference Example 13
3-((2-Methoxybenzoyl)oxy)-2,2-dimethylpropanoic acid
##STR00042##
[0439] By performing the same procedure as in Reference Example 3
using the compound (1.8 g) produced in Reference Example 12 in
place of the compound produced in Reference Example 2, the title
compound (1.3 g, 91%) having the following physical properties was
obtained.
[0440] TLC (Rf value): 0.12 (n-hexane:ethyl acetate=3:1)
[0441] NMR (CDCl.sub.3): .delta. 7.78-7.82 (m, 1H), 7.43-7.47 (m,
1H), 6.93-6.99 (m, 2H), 4.34 (s, 2H), 3.86 (s, 3H), 1.34 (s,
6H)
Reference Example 14
(2S)-((4-(3-(Benzyloxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)-1,2-ph-
enylene)bis(oxy))bis(2,2-dimethyl-3-oxopropan-3,1-diyl)
bis(2-methoxybenzoate)
##STR00043##
[0443] By performing the same procedure as in Example 3 using the
compound (410 mg) produced in Example 2 and the compound (800 mg)
produced in Reference Example 13 in place of the compound produced
in Example 1, the title compound (592 mg, 65%) having the following
physical properties was obtained.
[0444] TLC (Rf value): 0.74 (n-hexane:ethyl acetate=1:1)
[0445] NMR (CDCl.sub.3): .delta. 7.76-7.81 (m, 2H), 7.41-7.50 (m,
2H), 7.25-7.31 (m, 5H), 6.82-6.99 (m, 7H), 5.07 (s, 2H), 4.94 (d,
J=7.8 Hz, 1H), 4.48-4.55 (m, 1H), 4.41 (s, 4H), 3.84 (s, 6H),
2.94-3.03 (m, 2H), 1.28-1.39 (m, 21H)
Reference Example 15
(2S)-3-(3,4-Bis((3-((2-methoxybenzoyl)oxy-2,2-dimethylpropanoyl)oxy)phenyl-
)-2-(tert-butoxycarbonyl)amino)propanoic acid
##STR00044##
[0447] By performing the same procedure as in Example 4 using the
compound (590 mg) produced in Reference Example 14 in place of the
compound produced in Example 3, the title compound (406 mg, 77%)
having the following physical properties was obtained.
[0448] TLC (Rf value): 0.12 (n-hexane:ethyl acetate=1:1)
[0449] NMR (CDCl.sub.3): .delta. 7.77-7.86 (m, 2H), 7.44-7.51 (m,
2H), 6.93-7.05 (m, 7H), 4.94-5.01 (m, 1H), 4.32-4.59 (m, 5H), 3.86
(s, 3H), 3.84 (s, 3H), 3.07 (d, J=5.4 Hz, 2H), 1.34-1.41 (m,
21H)
Reference Example 16
(2S)-2-Amino-3-(3,4-bis((3-((2-methoxybenzoyl)oxy-2,2-dimethylpropanoyl)ox-
y)phenyl)propanoic acid hydrochloride
##STR00045##
[0451] By performing the same procedure as in Example 5 using the
compound (400 mg) produced in Reference Example 15 in place of the
compound produced in Example 4, the title compound (360 mg, 98%)
having the following physical properties was obtained.
[0452] TLC (Rf value): 0.45 (ethyl acetate:acetic
acid:water=5:1:1)
[0453] NMR (CD.sub.3OD): .delta. 7.70-7.75 (m, 2H), 7.49-7.53 (m,
2H), 7.02-7.21 (m, 5H), 6.95-7.02 (m, 2H), 4.40 (s, 2H), 4.38 (s,
2H), 4.14 (dd, J=8.7, 5.1 Hz, 1H), 3.82-3.83 (m, 6H), 3.25-3.30 (m,
1H), 3.04 (dd, J=14.7, 8.7 Hz, 1H), 1.37-1.46 (m, 12H)
Reference Example 17
(2S)-2-Amino-3-(3,4-bis((2,2-diethylbutanoyl)oxy)phenyl)propanoic
acid hydrochloride
##STR00046##
[0455] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
2,2-diethylbutanoic acid in place of the compound produced in
Example 1, the title compound having the following physical
properties was obtained.
[0456] TLC (Rf value): 0.78 (ethyl acetate:acetic
acid:water=3:1:1)
[0457] NMR (CD.sub.3OD): .delta. 7.23 (dd, J=8.4, 1.8 Hz, 1H), 7.17
(d, J=8.4 Hz, 1H), 7.13 (d, J=1.8 Hz, 1H), 4.25 (dd, J=8.1, 5.4 Hz,
1H), 3.35 (dd, J=14.7, 5.4 Hz, 1H), 3.14 (dd, J=14.7, 8.1 Hz, 1H),
1.70-1.79 (m, 12H), 0.87-0.96 (m, 18H)
Reference Example 18
(2S)-2-Amino-3-(3,4-bis((2-ethyl-2-methylbutanoyl)oxy)phenyl)propanoic
acid hydrochloride
##STR00047##
[0459] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
2-ethyl-2-methylbutanoic acid in place of the compound produced in
Example 1, the title compound having the following physical
properties was obtained.
[0460] TLC (Rf value): 0.75 (ethyl acetate:acetic
acid:water=3:1:1)
[0461] NMR (CD.sub.3OD): .delta. 7.23 (dd, J=8.4, 2.1 Hz, 1H), 7.15
(d, J=8.4 Hz, 1H), 7.13 (d, J=2.1 Hz, 1H), 4.25 (dd, J=8.1, 5.1 Hz,
1H), 3.36 (dd, J=14.7, 5.1 Hz, 1H), 3.14 (dd, J=14.7, 8.1 Hz, 1H),
1.59-1.86 (m, 8H), 1.25 (s, 3H), 1.24 (s, 3H), 0.93-1.03 (m,
12H)
Reference Example 19
(2S)-2-Amino-3-(3,4-bis((4,4-dimethylpentanoyl)oxy)phenyl)propanoic
acid hydrochloride
##STR00048##
[0463] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
4,4-dimethylpentanoic acid in place of the compound produced in
Example 1, the title compound having the following physical
properties was obtained.
[0464] TLC (Rf value): 0.63 (ethyl acetate:acetic
acid:water=6:1:1)
[0465] NMR (CD.sub.3OD): .delta. 7.18-7.24 (m, 3H), 4.23 (dd,
J=8.4, 5.1 Hz, 1H), 3.38 (dd, J=14.7, 5.1 Hz, 1H), 3.12 (dd,
J=14.7, 8.4 Hz, 1H), 2.52-2.58 (m, 4H), 1.61-1.67 (m, 4H),
0.89-1.17 (m, 18H)
Reference Example 20
(2S)-2-Amino-3-(3,4-bis((3,3-dimethylpent-4-enoyl)oxy)phenyl)propanoic
acid hydrochloride
##STR00049##
[0467] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
3,3-dimethylpentenoic acid in place of the compound produced in
Example 1, the title compound having the following physical
properties was obtained.
[0468] TLC (Rf value): 0.45 (ethyl acetate:acetic
acid:water=6:1:1)
[0469] NMR (CD.sub.3OD): .delta. 7.13-7.25 (m, 3H), 5.99 (dd,
J=17.4, 10.5 Hz, 1H), 5.01-5.10 (m, 2H), 4.23 (dd, J=8.4, 5.1 Hz,
1H), 3.37 (dd, J=14.7, 5.1 Hz, 1H), 3.11 (dd, J=14.7, 8.4 Hz, 1H),
2.57 (s, 2H), 2.56 (s, 2H), 1.21-1.22 (m, 12H)
Reference Example 21
(2S)-2-Amino-3-(3,4-bis((3-ethyl-3-methylpentanoyl)oxy)phenyl)propanoic
acid hydrochloride
##STR00050##
[0471] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
3-ethyl-3-methylpentanoic acid in place of the compound produced in
Example 1, the title compound having the following physical
properties was obtained.
[0472] TLC (Rf value): 0.51 (ethyl acetate:acetic
acid:water=5:1:1)
[0473] NMR (CD.sub.3OD): .delta. 7.15-7.26 (m, 3H), 4.23 (dd,
J=8.4, 5.1 Hz, 1H), 3.38 (dd, J=14.7, 5.1 Hz, 1H), 3.17 (dd,
J=14.7, 8.4 Hz, 1H), 2.45 (s, 2H), 2.44 (s, 2H), 1.42-1.50 (m, 8H),
1.04 (s, 3H), 1.03 (s, 3H), 0.87-0.92 (m, 12H)
Reference Example 22
(2S)-2-Amino-3-(3,4-bis((3-isopropyl-4-methylpentanoyl)oxy)phenyl)propanoi-
c acid hydrochloride
##STR00051##
[0475] By performing the procedure of Example 3.fwdarw.Example 4
.fwdarw.Example 5 using the compound produced in Example 2 and
3-isopropyl-4-methylpentanoic acid in place of the compound
produced in Example 1, the title compound having the following
physical properties was obtained.
[0476] TLC (Rf value): 0.67 (ethyl acetate:acetic acid=3:1)
[0477] NMR (CD.sub.3OD): .delta. 7.15-7.26 (m, 3H), 4.13 (dd,
J=8.4, 5.1 Hz, 1H), 3.20-3.30 (m, 1H), 3.05-3.13 (m, 1H), 2.47 (d,
J=5.7 Hz, 2H), 2.46 (d, J=5.7 Hz, 2H), 1.79-1.90 (m, 4H), 1.65-1.72
(m, 2H), 0.89-0.99 (m, 24H)
Reference Example 23
(2S)-2-Amino-3-(3,4-bis((2-methylbenzoyl)oxy)phenyl)propanoic acid
hydrochloride
##STR00052##
[0479] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
2-methylbenzoic acid in place of the compound produced in Example
1, the title compound having the following physical properties was
obtained.
[0480] TLC (Rf value): 0.79 (ethyl acetate:acetic
acid:water=3:1:1)
[0481] NMR (CD.sub.3OD): .delta. 7.93-7.97 (m, 2H), 7.34-7.47 (m,
5H), 7.15-7.35 (m, 4H), 4.30-4.36 (m, 1H), 3.47 (dd, J=14.7, 5.1
Hz, 1H), 3.25 (dd, J=14.7, 8.4 Hz, 1H), 2.49 (s, 3H), 2.48 (s,
3H)
Reference Example 24
(2S)-2-Amino-3-(3,4-bis((4-hydroxybenzoyl)oxy)phenyl)propanoic acid
hydrochloride
##STR00053##
[0483] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
4-hydroxybenzoic acid in place of the compound produced in Example
1, the title compound having the following physical properties was
obtained.
[0484] TLC (Rf value): 0.62 (ethyl acetate:acetic
acid:water=3:1:1)
[0485] NMR (CD.sub.3OD): .delta. 7.82-7.88 (m, 4H), 7.30-7.40 (m,
3H), 6.73-6.78 (m, 4H), 4.23 (dd, J=8.7, 4.8 Hz, 1H), 3.44 (dd,
J=14.7, 4.8 Hz, 1H), 3.16 (dd, J=14.7, 8.7 Hz, 1H)
Reference Example 25
(2S)-2-Amino-3-(3,4-bis((2-(trifluoromethyl)benzoyl)oxy)phenyl)propanoic
acid
##STR00054##
[0487] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
2-trifluoromethylbenzoic acid in place of the compound produced in
Example 1, the title compound having the following physical
properties was obtained.
[0488] TLC (Rf value): 0.80 (ethyl acetate:acetic
acid:water=3:1:1)
[0489] NMR (CD.sub.3OD): .delta. 7.84-7.91 (m, 4H), 7.65-7.79 (m,
4H), 7.39-7.49 (m, 3H), 4.35 (dd, J=7.8, 5.1 Hz, 1H), 3.43 (dd,
J=14.4, 5.1 Hz, 1H), 3.20-3.27 (m, 1H)
Reference Example 26
(2S)-2-Amino-3-(3,4-bis((cyclopropanecarbonyl)oxy)phenyl)propanoic
acid hydrochloride
##STR00055##
[0491] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
cyclopropanecarboxylic acid in place of the compound produced in
Example 1, the title compound having the following physical
properties was obtained.
[0492] TLC (Rf value): 0.49 (ethyl acetate:acetic
acid:water=3:1:1)
[0493] NMR (CD.sub.3OD): .delta. 7.17-7.23 (m, 3H), 4.27 (dd,
J=8.7, 5.1 Hz, 1H), 3.37 (dd, J=14.7, 5.1 Hz, 1H), 3.12 (dd,
J=14.7, 8.7 Hz, 1H), 1.84-1.90 (m, 2H), 1.08-1.13 (m, 8H)
Reference Example 27
(2S)-2-Amino-3-(3,4-bis((1-methylcyclopropanecarbonyl)oxy)phenyl)propanoic
acid hydrochloride
##STR00056##
[0495] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
1-methylcyclopropanecarboxylic acid in place of the compound
produced in Example 1, the title compound having the following
physical properties was obtained.
[0496] TLC (Rf value): 0.23 (ethyl acetate:acetic
acid:water=6:1:1)
[0497] NMR (CD.sub.3OD): .delta. 7.15-7.25 (m, 3H), 4.26 (dd,
J=8.4, 4.8 Hz, 1H), 3.35 (dd, J=14.7, 4.8 Hz, 1H), 3.12 (dd,
J=14.7, 8.4 Hz, 1H), 1.33-1.46 (m, 10H), 0.93-0.97 (m, 4H)
Reference Example 28
(2S)-2-Amino-3-(3,4-bis(2-cyclopentylacetoxy)phenyl)propanoic acid
hydrochloride
##STR00057##
[0499] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
2-cyclopentylacetic acid in place of the compound produced in
Example 1, the title compound having the following physical
properties was obtained.
[0500] TLC (Rf value): 0.28 (ethyl acetate:acetic
acid:water=6:1:1)
[0501] NMR (CD.sub.3OD): .delta. 7.17-7.27 (m, 3H), 4.27 (dd,
J=8.4, 5.1 Hz, 1H), 3.28 (dd, J=14.7, 5.1 Hz, 1H), 3.13 (dd,
J=14.7, 8.4 Hz, 1H), 2.56-2.60 (m, 4H), 2.24-2.35 (m, 2H),
1.86-1.96 (m, 4H), 1.54-1.75 (m, 8H), 1.20-1.32 (m, 4H)
Reference Example 29
(2S)-2-Amino-3-(3,4-bis(2-cyclohexylacetoxy)phenyl)propanoic acid
hydrochloride
##STR00058##
[0503] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
2-cyclohexylacetic acid in place of the compound produced in
Example 1, the title compound having the following physical
properties was obtained.
[0504] TLC (Rf value): 0.30 (ethyl acetate:acetic
acid:water=6:1:1)
[0505] NMR (CD.sub.3OD): .delta. 7.16-7.56 (m, 3H), 4.23 (dd,
J=8.7, 5.1 Hz, 1H), 3.37 (dd, J=14.7, 5.1 Hz, 1H), 3.11 (dd,
J=14.7, 8.4 Hz, 1H), 2.44 (d, J=6.6 Hz, 2H), 2.43 (d, J=6.6 Hz,
2H), 1.61-1.88 (m, 12H), 1.01-1.40 (m, 10H)
Reference Example 30
(2S)-2-Amino-3-(3,4-bis(2-(1-methylcyclohexyl)acetoxy)phenyl)propanoic
acid hydrochloride
##STR00059##
[0507] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
2-(1-methyl)cyclohexylacetic acid in place of the compound produced
in Example 1, the title compound having the following physical
properties was obtained.
[0508] TLC (Rf value): 0.43 (ethyl acetate:acetic acid=3:1)
[0509] NMR (CD.sub.3OD): .delta. 7.21-7.31 (m, 3H), 4.28 (dd,
J=8.4, 4.8 Hz, 1H), 3.30-3.46 (m, 1H), 3.17 (dd, J=14.4, 8.4 Hz,
1H), 2.56 (s, 2H), 2.55 (s, 2H), 1.49-1.70 (m, 20H), 1.18 (s, 3H),
1.17 (s, 3H)
Reference Example 31
(2S)-2-Amino-3-(3,4-bis(2-(1-methylcyclopentyl)acetoxy)phenyl)propanoic
acid hydrochloride
##STR00060##
[0511] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
2-(1-methylcyclopentyl)acetic acid in place of the compound
produced in Example 1, the title compound having the following
physical properties was obtained.
[0512] TLC (Rf value): 0.29 (ethyl acetate:acetic acid=3:1)
[0513] NMR (CD.sub.3OD): .delta. 7.16-7.26 (m, 3H), 4.16 (dd,
J=8.7, 4.8 Hz, 1H), 3.22-3.40 (m, 1H), 3.05-3.13 (m, 1H), 2.56 (s,
2H), 2.57 (s, 2H), 1.50-1.73 (m, 16H), 1.16 (s, 3H), 1.15 (s,
3H)
Reference Example 32
(2S)-2-Amino-3-(3,4-bis((2-acetoxy-2-methylpropanoyl)oxy)phenyl)propanoic
acid hydrochloride
##STR00061##
[0515] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
2-(acetoxy)-2-methylpropionic acid in place of the compound
produced in Example 1, the title compound having the following
physical properties was obtained.
[0516] TLC (Rf value): 0.70 (ethyl acetate:acetic
acid:water=3:1:1)
[0517] NMR (CD.sub.3OD): .delta. 7.18-7.27 (m, 3H), 4.25 (dd,
J=8.4, 5.4 Hz, 1H), 3.37 (dd, J=14.7, 5.4 Hz, 1H), 3.13 (dd,
J=14.7, 8.4 Hz, 1H), 2.09 (s, 3H), 2.07 (s, 3H), 1.66-1.68 (m,
12H)
Reference Example 33
(2S)-2-Amino-3-(3,4-bis((2-(benzoyloxy)-2-ethylbutanoyl)oxy)phenyl)propano-
ic acid hydrochloride
##STR00062##
[0519] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
2-(benzoyloxy)-2-ethylbutanoic acid in place of the compound
produced in Example 1, the title compound having the following
physical properties was obtained.
[0520] TLC (Rf value): 0.51 (ethyl acetate:acetic
acid:water=5:1:1)
[0521] NMR (CD.sub.3OD): .delta. 8.01-8.06 (m, 4H), 7.61-7.64 (m,
2H), 7.49-7.52 (m, 4H), 7.25-7.47 (m, 3H), 4.22 (dd, J=8.4, 5.1 Hz,
1H), 3.32-3.35 (m, 1H), 3.05-3.16 (m, 1H), 2.20-2.37 (m, 8H),
0.97-1.03 (m, 12H)
Reference Example 34
(2S)-2-Amino-3-(3,4-bis(((S)-2-(benzoyloxy)propanoyl)oxy)phenyl)propanoic
acid hydrochloride
##STR00063##
[0523] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
(2S)-2-(benzoyloxy)propanoic acid in place of the compound produced
in Example 1, the title compound having the following physical
properties was obtained.
[0524] TLC (Rf value): 0.38 (ethyl acetate:acetic
acid:water=10:2:1)
[0525] NMR (CD.sub.3OD): .delta. 8.06-8.09 (m, 4H), 7.61-7.66 (m,
2H), 7.46-7.52 (m, 4H), 7.26-7.29 (m, 3H), 5.61-5.68 (m, 2H), 4.21
(dd, J=8.4, 5.4 Hz, 1H), 3.30-3.40 (m, 1H), 3.13 (dd, J=14.7, 8.1
Hz, 1H), 1.81 (d, J=7.2 Hz, 3H), 1.80 (d, J=7.2 Hz, 3H)
Reference Example 35
(2S)-2-Amino-3-(3,4-bis(((R)-2-(benzoyloxy)propanoyl)oxy)phenyl)propanoic
acid hydrochloride
##STR00064##
[0527] By performing the procedure of Example 3.fwdarw.Example
4.fwdarw.Example 5 using the compound produced in Example 2 and
(2R)-2-(benzoyloxy)propanoic acid in place of the compound produced
in Example 1, the title compound having the following physical
properties was obtained.
[0528] TLC (Rf value): 0.38 (ethyl acetate:acetic
acid:water=10:2:1)
[0529] NMR (CD.sub.3OD): .delta. 8.06-8.09 (m, 4H), 7.61-7.66 (m,
2H), 7.46-7.52 (m, 4H), 7.26-7.29 (m, 3H), 5.61-5.68 (m, 2H), 4.21
(dd, J=8.4, 5.4 Hz, 1H), 3.30-3.40 (m, 1H), 3.13 (dd, J=14.7, 8.1
Hz, 1H), 1.81 (d, J=7.2 Hz, 3H), 1.80 (d, J=7.2 Hz, 3H)
Reference Example 36
3-(Benzyloxy)-2,2-dimethyl-3-oxopropyl benzoate
##STR00065##
[0531] The compound (8 g) produced in Reference Example 1 was
dissolved in dichloromethane (40 mL). To this solution,
triethylamine (8 mL) was added, and then, benzoyl chloride (5.4 mL)
was added thereto under ice-cooling. The resulting solution was
stirred at room temperature for 4 hours. To the reaction mixture, a
saturated aqueous solution of sodium carbonate (30 mL) was added,
and then, extraction was performed with dichloromethane (100
mL.times.2). The organic layers were combined, and washed with a
saturated aqueous solution of sodium chloride (30 mL), and then
dried over sodium sulfate. After sodium sulfate was removed by
filtration, the solvent was concentrated under reduced pressure.
The resulting residue was purified by silica gel chromatography (a
medium-pressure preparative liquid chromatograph, W-prep 2XY
manufactured by Yamazen Corporation (column: main column 2L, inject
column L, n-hexane:ethyl acetate=1:0-9:1 (gradient time: 10
minutes), fractionation mode GR), whereby the title compound (12 g,
100%) having the following physical properties was obtained.
[0532] TLC (Rf value): 0.70 (n-hexane:ethyl acetate=2:1)
[0533] NMR (300 MHz, CDCl.sub.3): .delta. 7.89-7.93 (m, 2H),
7.50-7.57 (m, 1H), 7.36-7.42 (m, 2H), 7.23-7.33 (m, 5H), 5.16 (s,
2H), 4.37 (s, 2H), 1.34 (s, 6H)
Reference Example 37
3-(Benzoyloxy)-2,2-dimethylpropanoic acid
##STR00066##
[0535] By performing the same procedure as in Reference Example 3
using the compound (12 g) produced in Reference Example 36 in place
of the compound produced in Reference Example 2, the title compound
(5.7 g, 67%) having the following physical properties was
obtained.
[0536] TLC (Rf value): 0.22 (n-hexane:ethyl acetate=3:1)
[0537] NMR (CDCl.sub.3): .delta. 7.99-8.03 (m, 2H), 7.48-7.61 (m,
1H), 7.38-7.46 (m, 2H), 4.37 (s, 2H), 1.35 (s, 6H)
Reference Example 38
(S)-((4-(3-(Benzyloxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)-1,2-phe-
nylene)bis(oxy))bis(2,2-dimethyl-3-oxopropan-3,1-diyl)
dibenzoate
##STR00067##
[0539] By performing the same procedure as in Example 3 using the
compound (4.0 g) produced in Example 2 and the compound (5.7 g)
produced in Reference Example 37 in place of the compound produced
in Example 1, the title compound (7.4 g, 90%) having the following
physical properties was obtained.
[0540] TLC (Rf value): 0.51 (n-hexane:ethyl acetate=2:1)
[0541] NMR (CDCl.sub.3): .delta. 8.00-8.05 (m, 4H), 7.50-7.59 (m,
2H), 7.39-7.46 (m, 4H), 7.23-7.34 (m, 5H), 6.83-6.97 (m, 3H), 5.09
(s, 2H), 4.97 (d, J=8.4 Hz, 1H), 4.50-4.57 (m, 1H), 4.45 (s, 4H),
2.94-3.03 (m, 2H), 1.39-1.43 (m, 21H)
Reference Example 39
(S)-3-(3,4-Bis((3-(benzoyloxy)-2,2-dimethylpropanoyl)oxy)phenyl)-2-((tert--
butoxycarbonyl)amino)propanoic acid
##STR00068##
[0543] By performing the same procedure as in Example 4 using the
compound (7.4 g) produced in Reference Example 38 in place of the
compound produced in Example 3, the title compound (5.2 g, 79%)
having the following physical properties was obtained.
[0544] TLC (Rf value): 0.12 (n-hexane:ethyl acetate=2:1)
[0545] NMR (CDCl.sub.3): .delta. 8.00-8.04 (m, 4H), 7.54-7.61 (m,
2H), 7.41-7.48 (m, 4H), 6.97-7.05 (m, 2H), 6.91 (d, J=1.8 Hz, 1H),
4.99 (d, J=7.5 Hz, 1H), 4.42-4.50 (m, 5H), 2.98-3.11 (m, 2H),
1.40-1.42 (m, 21H)
Reference Example 40
(S)-2-Amino-3-(3,4-bis((3-(benzoyloxy)-2,2-dimethylpropanoyl)oxy)phenyl)pr-
opanoic acid hydrochloride
##STR00069##
[0547] By performing the same procedure as in Example 5 using the
compound (5.2 g) produced in Reference Example 39 in place of the
compound produced in Example 4, the title compound (4.3 g, 88%)
having the following physical properties was obtained.
[0548] TLC (Rf value): 0.34 (ethyl acetate:acetic
acid:water=6:1:1)
[0549] NMR (CD.sub.3OD): .delta. 7.97-8.02 (m, 4H), 7.57-7.63 (m,
2H), 7.43-7.51 (m, 4H), 7.12-7.18 (m, 3H), 4.54-4.66 (m, 4H), 4.09
(dd, J=8.7, 4.8 Hz, 1H), 3.06-3.25 (m, 1H), 2.99-3.07 (m, 1H),
1.43-1.44 (m, 12H)
Example 6
Crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate (type A crystal)
##STR00070##
[0551] To a suspension of p-toluenesulfonic acid monohydrate (2.82
g) in acetonitrile (4.2 mL) and water (1.13 mL), a solution of the
compound (8.32 g) produced in Example 4 in acetonitrile (37.8 mL)
was added. This solution was stirred at 70.degree. C. for 2 hours.
After the reaction mixture was cooled to room temperature,
tert-butylmethyl ether (254 mL) was added thereto. This solution
was stirred overnight at room temperature. After the solution was
further stirred under ice-cooling for 1 hour, a crystal was
obtained by filtration, followed by drying under reduced pressure
at 50.degree. C. for 16 hours, whereby a crystalline solvate of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate (7.43 g, 79%) was obtained. The total amount of
this crystal was suspended in ethyl acetate (74 mL) and the
resulting suspension was stirred at 60.degree. C. for 14 hours
while maintaining the suspended state. After the suspension was
left to cool to room temperature, the crystal was obtained by
filtration, followed by drying under reduced pressure at 65.degree.
C. for 1 hour and thereafter at 50.degree. C. for 16 hours, whereby
a type A crystal of the title compound (6.87 g, 92%) having the
following physical properties was obtained as a white crystal. The
crystal had a melting point of from about 132.0 to 136.0.degree. C.
(measured by the capillary method described in the Japanese
Pharmacopoeia).
[0552] TLC (Rf value): 0.56 (ethyl acetate:acetic
acid:water=10:1:1)
[0553] NMR (300 MHz, CD.sub.3OD): .delta. 8.06-8.03 (m, 4H),
7.71-7.62 (m, 4H), 7.52-7.48 (m, 4H), 7.31-7.20 (m, 5H), 4.27 (dd,
J=8.4, 5.1 Hz, 1H), 3.37 (dd, J=14.7, 5.1 Hz, 1H), 3.13 (dd,
J=14.7, 8.4 Hz, 1H), 2.36 (s, 3H), 1.83 (s, 12H)
[0554] The powder X-ray diffraction spectrum chart, differential
scanning calorimetry chart, and infrared absorption spectrum chart
of the thus obtained type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate are shown in FIG. 10, FIG. 11, and FIG. 12,
respectively.
(1) Powder X-Ray Diffraction Spectroscopy
[Measurement Conditions]
[0555] Apparatus: BRUKER DISCOVER with GADDS (C2)
[0556] Target: Cu
[0557] Filter: Not used
[0558] Voltage: 40 kV
[0559] Current: 40 mA
[0560] Exposure time: 180 sec
[Results]
[0561] The results of diffraction angle (2.theta.) (degrees) and
relative intensity (%) obtained by the powder X-ray diffraction
spectroscopy using Cu--K.alpha. radiation are shown in Table 1.
Incidentally, the relative intensity is obtained by calculating the
height (Lin (Counts)) of each peak when the height of the highest
peak is taken as 100%.
TABLE-US-00001 TABLE 1 Diffraction angle Relative intensity
(2.theta.) (degrees) (%) 5.15 100 6.97 95.0 7.46 11.3 10.97 17.9
11.58 50.9 13.74 8.5 14.83 30.4 15.20 17.0 16.10 21.8 16.36 26.5
16.70 15.3 17.35 15.7 18.30 18.2 18.83 13.8 19.42 28.2 19.95 20.4
20.58 28.6 21.69 24.1 22.63 13.0 22.84 12.4 24.00 17.4
(2) Differential Scanning calorimetry
[Measurement Conditions]
[0562] Apparatus: SEIKO INSTRUMENT DSC 6200
[0563] Amount of sample: 4.22 mg
[0564] Sample cell: Aluminum Standard 40 .mu.L (having a lid with a
pinhole)
[0565] Argon gas flow rate: 40 mL/min
[0566] Temperature elevation rate: 5.degree. C./min
[0567] Temperature elevation starting temperature: 25.degree.
C.
[Results]
[0568] As a result, it was found that the compound has an
endothermic peak at around 135.95.degree. C.
(3) Infrared Absorption Spectroscopy
[Measurement Conditions]
[0569] Apparatus: FTIR-660 Plus/SENSIR DuraScope, JASCO
Corporation
[0570] Resolution: 4 cm.sup.-1
[0571] Number of scanning times: 32
[Results]
[0572] IR (ATR method): 1780, 1712, 1599, 1508, 1452, 1388, 1316,
1289, 1217, 1166, 1120, 1090, 1071, 1036, 1026, 1010, 957, 900,
864, 817, 742, 713, 680, 622, 567, 550, 472, and 440 cm.sup.-1
Example 7
Crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate (type B crystal)
##STR00071##
[0574] The type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate (8.0 g) produced in Example 6 was suspended in
acetone (80 mL). This suspension was stirred at 50.degree. C. for
16 hours. After the reaction mixture was cooled to room
temperature, the mixture was stirred for 30 minutes, and then,
further stirred in an ice bath for 1 hour. A deposited crystal was
obtained by filtration, followed by drying under reduced pressure
at 60.degree. C. for 16 hours, whereby a type B crystal of the
title compound (7.1 g, 89%) was obtained as a white crystal. The
crystal had a melting point of from about 132.3 to 135.3.degree. C.
(measured by the capillary method described in the Japanese
Pharmacopoeia).
[0575] The powder X-ray diffraction spectrum chart, differential
scanning calorimetry chart, and infrared absorption spectrum chart
of the thus obtained type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate are shown in FIG. 13, FIG. 14, and FIG. 15,
respectively.
(1) Powder X-Ray Diffraction Spectroscopy
[Measurement Conditions]
[0576] Apparatus: BRUKER DISCOVER with GADDS (C2)
[0577] Target: Cu
[0578] Filter: Not used
[0579] Voltage: 40 kV
[0580] Current: 40 mA
[0581] Exposure time: 180 sec
[Results]
[0582] The results of diffraction angle (2.theta.) (degrees) and
relative intensity (%) obtained by the powder X-ray diffraction
spectroscopy using Cu--K.alpha. radiation are shown in Table 2.
Incidentally, the relative intensity is obtained by calculating the
height (Lin (Counts)) of each peak when the height of the highest
peak is taken as 100%.
TABLE-US-00002 TABLE 2 Diffraction angle Relative intensity
(2.theta.) (degrees) (%) 4.04 32.9 5.04 63.9 5.54 24.6 6.11 100
6.60 68.4 7.96 42.0 8.62 16.0 10.01 39.2 10.32 18.6 11.88 54.2
12.88 15.6 13.87 25.1 15.01 20.0 15.87 24.5 16.07 26.7 16.74 14.1
17.17 15.1 17.81 24.7 18.65 39.8 19.17 34.2 19.72 21.6 20.27 35.1
20.93 16.9 21.67 16.7 22.11 37.0 22.56 14.3 23.11 17.0 23.47 20.2
24.21 20.4
(2) Differential Scanning calorimetry
[Measurement Conditions]
[0583] Apparatus: SEIKO INSTRUMENT DSC 6200
[0584] Amount of sample: 3.08 mg
[0585] Sample cell: Aluminum Standard 40 .mu.L (having a lid with a
pinhole)
[0586] Argon gas flow rate: 40 mL/min
[0587] Temperature elevation rate: 5.degree. C./min
[0588] Temperature elevation starting temperature: 25.degree.
C.
[Results]
[0589] As a result, it was found that the compound has an
endothermic peak at around 134.54.degree. C.
(3) Infrared Absorption Spectroscopy
[Measurement Conditions]
[0590] Apparatus: FTIR-660 Plus/SENSIR DuraScope, JASCO
Corporation
[0591] Resolution: 4 cm.sup.-1
[0592] Number of scanning times: 32
[Results]
[0593] IR (ATR method): 1781, 1711, 1600, 1507, 1315, 1287, 1220,
1203, 1166, 1119, 1088, 1070, 1036, 1027, 1010, 944, 898, 863, 816,
713, 681, 617, 567, 531, 517, 507, 484, 470, 452, 437, 421, and 413
cm.sup.-1
Example 8
Crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl-
)propanoic acid
##STR00072##
[0595] To a solution of the type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate produced in Example 6 or the type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate produced in Example 7 (167 g) in acetonitrile
(2080 mL) and water (42 mL), a solution of triethylamine (21.4 g)
in acetonitrile (420 mL) was added dropwise. After the reaction
mixture was stirred for 16 hours, a deposited solid was obtained by
filtration and washed with acetonitrile (500 mL). Then, the solid
was dried at 50.degree. C. for 16 hours, whereby a crude product of
the title compound (106 g, 81%) was obtained as a white solid.
Example 9
Crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid (type A crystal)
##STR00073##
[0597] The crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid (31 g) produced in Example 8 was suspended in
acetonitrile (470 mL) in an argon atmosphere, and the resulting
suspension was stirred at room temperature (internal temperature:
from 23 to 24.degree. C.) for 24 hours. The resulting crystal was
obtained by filtration and washed with acetonitrile (94 mL). Then,
the crystal was dried under reduced pressure at 60.degree. C. for
24 hours, whereby a type A crystal of the title compound (31 g,
99%) was obtained as a white crystal. The crystal had a melting
point of from about 177.0 to 181.9.degree. C. (measured by the
capillary method described in the Japanese Pharmacopoeia).
[0598] The powder X-ray diffraction spectrum chart, differential
scanning calorimetry chart, and infrared absorption spectrum chart
of the thus obtained type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid are shown in FIG. 4, FIG. 5, and FIG. 6,
respectively.
(1) Powder X-Ray Diffraction Spectroscopy
[Measurement Conditions]
[0599] Apparatus: BRUKER DISCOVER with GADDS (C2)
[0600] Target: Cu
[0601] Filter: Not used
[0602] Voltage: 40 kV
[0603] Current: 40 mA
[0604] Exposure time: 180 sec
[Results]
[0605] The results of diffraction angle (2.theta.) (degrees) and
relative intensity (%) obtained by the powder X-ray diffraction
spectroscopy using Cu--K.alpha. radiation are shown in Table 3.
Incidentally, the relative intensity is obtained by calculating the
height (Lin (Counts)) of each peak when the height of the highest
peak is taken as 100%.
TABLE-US-00003 TABLE 3 Diffraction angle Relative intensity
(2.theta.) (degrees) (%) 4.03 100 7.21 15.3 9.98 10.7 10.72 10.6
11.93 12.5 12.90 10.5 13.48 11.9 14.65 12.3 15.23 12.7 15.99 15.2
16.56 13.6 17.23 14.6 17.93 19.3 19.20 18.8 20.88 12.4 21.66 12.2
22.36 11.7 22.50 10.8 24.58 8.7
(2) Differential Scanning calorimetry
[Measurement Conditions]
[0606] Apparatus: SEIKO INSTRUMENT DSC 6200
[0607] Amount of sample: 6.07 mg
[0608] Sample cell: Aluminum Standard 40 .mu.L (having a lid with a
pinhole)
[0609] Argon gas flow rate: 40 mL/min
[0610] Temperature elevation rate: 10.degree. C./min
[0611] Temperature elevation starting temperature: 25.degree.
C.
[Results]
[0612] As a result, it was found that the compound has an
exothermic peak at around 148.7.degree. C. and also has endothermic
peaks at around 184.7.degree. C., 194.7.degree. C., and
200.3.degree. C.
(3) Infrared Absorption Spectroscopy
[Measurement Conditions]
[0613] Apparatus: FTIR-660 Plus/SENSIR DuraScope, JASCO
Corporation
[0614] Resolution: 4 cm.sup.-1
[0615] Number of scanning times: 32
[Results]
[0616] IR (ATR method): 1771, 1720, 1632, 1602, 1543, 1506, 1469,
1451, 1387, 1359, 1316, 1287, 1203, 1165, 1093, 1069, 1026, 957,
937, 898, 863, 802, 742, 710, 687, 615, 557, 526, 490, 482, 452,
424, 416, and 408 cm.sup.-1
Example 10
Crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid (type B crystal)
##STR00074##
[0618] The crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid (104 g) produced in Example 8 was dissolved in
acetonitrile (520 mL) and water (104 mL) by heating under an argon
atmosphere. Then, acetonitrile (1560 mL) was added thereto, and
after the deposition of a crystal was confirmed, the reaction
mixture was stirred for 16 hours. The deposited crystal was
obtained by filtration and then washed with acetonitrile (312 mL).
Then, the crystal was dried under reduced pressure at 60.degree. C.
for 24 hours, whereby a type B crystal of the title compound (87 g,
84%) was obtained as a white crystal. The crystal had a melting
point of from about 174.7 to 179.0.degree. C. (measured by the
capillary method described in the Japanese Pharmacopoeia).
[0619] The powder X-ray diffraction spectrum chart, differential
scanning calorimetry chart, and infrared absorption spectrum chart
of the thus obtained type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid are shown in FIG. 7, FIG. 8, and FIG. 9,
respectively.
(1) Powder X-Ray Diffraction Spectroscopy
[Measurement Conditions]
[0620] Apparatus: BRUKER DISCOVER with GADDS (C2)
[0621] Target: Cu
[0622] Filter: Not used
[0623] Voltage: 40 kV
[0624] Current: 40 mA
[0625] Exposure time: 180 sec
[Results]
[0626] The results of diffraction angle (2.theta.) (degrees) and
relative intensity (%) obtained by the powder X-ray diffraction
spectroscopy using Cu--K.alpha. radiation are shown in Table 4.
Incidentally, the relative intensity is obtained by calculating the
height (Lin (Counts)) of each peak when the height of the highest
peak is taken as 100%.
TABLE-US-00004 TABLE 4 Diffraction angle Relative intensity
(2.theta.) (degrees) (%) 4.62 100 8.40 13.3 9.54 11.2 12.08 16.5
15.39 16.3 18.16 22.7
(2) Differential Scanning calorimetry
[Measurement Conditions]
[0627] Apparatus: SEIKO INSTRUMENT DSC 6200
[0628] Amount of sample: 5.68 mg
[0629] Sample cell: Aluminum Standard 40 .mu.L (having a lid with a
pinhole)
[0630] Argon gas flow rate: 40 mL/min
[0631] Temperature elevation rate: 10.degree. C./min
[0632] Temperature elevation starting temperature: 25.degree.
C.
[Results]
[0633] As a result, it was found that the compound has an
exothermic peak at around 183.3.degree. C. and also has endothermic
peaks at around 192.2.degree. C. and 200.8.degree. C.
(3) Infrared Absorption Spectroscopy
[Measurement Conditions]
[0634] Apparatus: FTIR-660 Plus/SENSIR DuraScope, JASCO
Corporation
[0635] Resolution: 4 cm.sup.-1
[0636] Number of scanning times: 32
[Results]
[0637] IR (ATR method): 1771, 1715, 1608, 1505, 1469, 1452, 1411,
1386, 1368, 1352, 1315, 1288, 1256, 1201, 1166, 1092, 1070, 1026,
955, 895, 865, 803, 744, 711, 675, 617, 605, 472, 444, 432, and 414
cm.sup.-1
Example 11
Crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid (type A crystal)
##STR00075##
[0639] By performing the same procedure as in Example 9 using the
type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid produced in Example 10 in place of the crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, the crystal was converted into a type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid.
Example 12
Crystalline
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid (type B crystal)
##STR00076##
[0641] By performing the same procedure as in Example 10 using the
type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid produced in Example 9 in place of the crude
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid, the crystal was converted into a type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid.
Biological Example 1
(1) Kinetic Study in Dogs
[0642] The relationship between the blood concentration of levodopa
and side effects in patients who take levodopa has been gradually
elucidated. For example, it is considered that dyskinesia is
developed by the frequent exposure to levodopa at a concentration
exceeding the effective blood concentration, and wearing-off is
developed by levodopa at a concentration lower than the effective
blood concentration. In order to reduce the number of doses of
levodopa and avoid side effects such as dyskinesia and wearing-off
in patients who take levodopa, it is necessary to maintain the
blood concentration of levodopa within a therapeutic range as long
as possible. The inventors of the present invention carried out a
kinetic study for each of the compound of the present invention
produced in Example 5, levodopa, and a group of compounds to be
used for comparison (compounds produced in Reference Examples 6,
11, 16, 18, 19, 21 to 23, 25 to 35, and 40, and
3,3-dimethyl-butyric acid
4-((S)-2-amino-2-methoxycarbonyl-ethyl)-2-(3,3-dimethyl-butyryloxy)phenyl
ester (hereinafter referred to as Compound X) described in WO
2009/022098) for the purpose of elucidating that the compound of
the present invention is a levodopa prodrug which provides such a
flat blood concentration-time profile of levodopa.
[0643] These levodopa prodrugs are prodrugs containing an ester
bond, and therefore, it is considered that among a number of
enzymes, carboxyesterase plays the most important role in the
process of producing levodopa by metabolizing the compound after
the compound is administered in vivo. Therefore, as an animal
species to be used for performing a kinetic study, dogs in which
the organ distribution of carboxyesterase is most similar to that
of humans were selected as subjects for evaluation.
[Preparation of Drug Solution for Administration]
[0644] A drug solution for oral administration was prepared by
weighing each of the compound of the present invention (Example 5),
levodopa, a group of compounds to be used for comparison (compounds
produced in Reference Examples 6, 11, 16, 18, 19, 21 to 23, 25 to
35, and 40, and Compound X) and dissolving it in a vehicle at 1
mg/mL expressed in terms of levodopa.
[Collection of Plasma Sample]
[0645] The thus obtained drug solution was administered by gavage
through a gastric tube into the stomach of dogs (male beagle dogs)
which were fasted from the day before the administration. At 15 and
30 minutes, and 1, 2, 4, 6, and 8 hours after administration of the
drug solution, 1 mL of blood was collected from a cephalic vein
with a heparinized syringe. Immediately after the collection, the
collected blood was centrifuged in a desktop centrifuge at 14500
rpm for 45 seconds. Then, acetonitrile containing 0.1125% formic
acid was added to the thus obtained plasma in an amount as twice as
large as the volume of the plasma, followed by stirring, and then,
the resulting sample was stored at -20.degree. C. until
measurement.
[Preparation of Analytical Sample and Analysis]
[0646] The sample was thawed on the measurement day, followed by
stirring and centrifugation at 13000 rpm for 3 minutes (at
4.degree. C.). The resulting supernatant was filtered and the
filtrate was analyzed by LC/MS/MS. The analysis was performed by
LC/MS/MS under the following conditions.
[LC/MS/MS Conditions]
[0647] Measurement Apparatus: API-5000 (manufactured by Applied
Biosystems, Inc.)
[0648] Analytical column: CAPCELL PAK CR (1:4) (4.6 mm,
I.D..times.250 mm, 5 .mu.m)
[0649] Analytical column temperature: 40.degree. C.
[0650] Flow rate: 1 mL/min
[0651] Mobile phase: A: 5 mM ammonium formate (pH 3.9), B:
acetonitrile (A/B=17/3)
[0652] Scan type: MRM
[0653] Polarity: negative
[0654] Detection (levodopa): m/z (precursor): 196.19, m/z
(product): 134.99
[0655] DP (Declustering Potential): -60
[0656] CE (Collision Energy): -25
[0657] CXP (Collision Cell Exit Potential): -17
[Results]
[0658] The results of the kinetic study in dogs are shown in Table
5.
TABLE-US-00005 TABLE 5 Dose expressed in terms of Dose: levodopa
AUC Compound (mg/kg) (mg/kg) (.mu.g .sup.+ hr/mL) Cmax/C6 hr
Levadopa 3 0.96 913.8 Example 3 9.3 3 0.89 8.0 Reference Example 6
10.0 3 0.66 14.7 Reference Example 11 10.0 3 0.52 23.9 Reference
Example 16 10.7 3 0.22 7.4 Reference Example 18 7.0 3 0.12 2.9
Reference Example 19 7.0 3 0.70 221.2 Reference Example 21 7.4 3
0.27 8.8 Reference Example 22 7.8 3 0.28 6.6 Reference Example 23
7.1 3 0.59 41.5 Reference Example 25 8.8 3 0.31 24.2 Reference
Example 26 5.6 3 0.45 18.0 Reference Example 27 6.1 3 0.84 58.7
Reference Example 28 6.9 3 0.68 304.4 Reference Example 29 7.3 3
0.59 98.5 Reference Example 30 7.8 3 0.36 12.8 Reference Example 31
7.3 3 0.42 18.7 Reference Example 32 7.5 3 0.53 40.7 Reference
Example 33 10.2 3 0.003 2.0 Reference Example 34 8.9 3 0.10 16.1
Reference Example 35 6.7 3 0.77 1039.6 Reference Example 40 9.8 3
0.81 4.3 Compound X 6.8 3 0.42 12.6
[0659] In the above Table 5, as the results of the kinetic study,
an "area under the blood concentration-time curve (area under the
curve (AUC))" serving as an index of exposure to levodopa, and a
"ratio (Cmax/C6 hr) of a plasma concentration at 6 hours after oral
administration (C6 hr) and a maximum plasma concentration (Cmax)"
serving as an index of a flat blood concentration-time profile of
levodopa are shown. Incidentally, the numerical value in the column
which indicates the dose expressed in terms of levodopa refers to a
dose equivalent to that of levodopa. Since the value of AUC when
levodopa was administered was 0.96, as the value of AUC is closer
to this value, the ratio of the test compound which permitted
exposure as levodopa is higher. Further, it is indicated that when
the value of Cmax/C6 hr is larger than 1 and also closer to 1, the
plasma concentration-time profile of levodopa is flatter.
[0660] The AUC and Cmax/C6 hr of the compound of the present
invention (Example 5) were both favorable as compared with those of
the compounds produced in Reference Examples 6, 11, 16, 18, 19, 21
to 23, and 25 to 35, and Compound X, and therefore it was confirmed
that the compound of the present invention is a compound which is
converted into levodopa to permit levodopa exposure at a high ratio
and also provides a flat plasma concentration-time profile of
levodopa.
[0661] In the case of the compounds used for comparison, for
example, the compounds produced in Reference Examples 6, 11, 19,
23, 27 to 29, 32, and 35, although the value of AUC was 0.5 or
larger, even the smallest value of Cmax/C6 hr was around 15, and
therefore, the compounds did not provide a flat plasma
concentration-time profile of levodopa.
[0662] On the other hand, in the case of the compound produced in
Reference Example 40, the AUC and Cmax/C6 hr were as favorable as
those of the compound of the present invention.
[0663] From the above results, it was revealed that among the group
of compounds of the same kind, only the compound of the present
invention and the compound produced in Reference Example 40 are
compounds which are converted into levodopa at a high ratio after
administration and also can provide a relatively high blood
concentration of levodopa over a long period of time.
(2) Kinetic Study in Dogs (Effect of Salt or Crystal Form on Blood
Kinetics)
[0664] In general, it is considered that when the salt or crystal
form is different, a difference in solubility thereof or the like
affects blood kinetics and sometimes causes a difference in potency
of efficacy. In the previous section (1), it was confirmed that the
compound of the present invention (hydrochloride, amorphous)
described in Example 5 can be absorbed through oral administration,
and therefore, it was confirmed as to whether or not other
compounds of the present invention are absorbed through oral
administration.
[Preparation of Drug Solution for Administration]
[0665] A drug solution for oral administration was prepared by
weighing each of the compound of the present invention produced in
Example 6 (a type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid tosylate), the compound of the present invention
produced in Example 9 (a type A crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid), and the compound of the present invention produced in
Example 10 (a type B crystal of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid) and suspending it in 0.5 w/v % methyl cellulose 400 at
6 mg/3 mL expressed in terms of levodopa.
[Collection of Plasma Sample]
[0666] The collection of a plasma sample was carried out according
to the previous section (1). However, the dose was set to 6 mg/3
mL/kg.
[Preparation of Analytical Sample and Analysis]
[0667] The preparation of an analytical sample and analysis were
carried out according to the previous section (1).
[Results]
[0668] The results of the kinetic study in dogs are shown in Table
6.
TABLE-US-00006 TABLE 6 (hr) Example 6 Example 9 Example 10
Concentration 0.25 0.046 0.014 0.014 of levodopa (.+-.0.030)
(.+-.0.010) (.+-.0.005) in dog plasma 0.5 0.168 0.099 0.119 (n = 4)
(.+-.0.048) (.+-.0.068) (.+-.0.046) 1 0.306 0.281 0.189 (.+-.0.126)
(.+-.0.148) (.+-.0.069) 2 0.323 0.311 0.230 (.+-.0.203) (.+-.0.216)
(.+-.0.092) 4 0.129 0.155 0.136 (.+-.0.109) (.+-.0.116) (.+-.0.116)
6 0.042 0.036 0.048 (.+-.0.043) (.+-.0.024) (.+-.0.050) 8 0.012
0.011 0.013 (.+-.0.012) (.+-.0.005) (.+-.0.012)
[0669] In the above Table 6, a change over time in the
concentration (.mu.g/mL) of levodopa observed in the plasma when
the compound of the present invention produced in Example 6, the
compound of the present invention produced in Example 9, or the
compound of the present invention produced in Example 10 was orally
administered to dogs is shown. The numeral expressed with .+-.in
the parenthesis represents a standard deviation.
[0670] Similarly to the case of the compound of the present
invention described in Example 5 (hydrochloride, amorphous) shown
in the previous section (1), all of the compound of the present
invention produced in Example 6, the compound of the present
invention produced in Example 9, and the compound of the present
invention produced in Example 10 can be absorbed through oral
administration, and also a significant difference exceeding the
range of variation was not observed in the concentration of
levodopa in the plasma seen after administration. From the above
results, it was revealed that all of the compounds of the present
invention can be orally administered regardless of the salt or
crystal form, have absorbability required for exhibiting their
efficacy, and can be used uniformly as pharmaceutical products.
[0671] Since the compound of the present invention is a levodopa
prodrug, if it can be confirmed that levodopa is produced after the
compound of the present invention is administered in vivo, it is
ensured that the compound of the present invention exhibits the
same efficacy as levodopa. That is, a kinetic study to confirm that
levodopa is produced by administering the compound of the present
invention can be considered to be equivalent to a pharmacological
study to evaluate efficacy.
[0672] From the above results, it was revealed that levodopa is
produced after administering the compound of the present invention
in vivo, and therefore, a desired efficacy can be obtained by
administering the compound of the present invention at a dose
increased or decreased as needed in a pharmacological study in
which levodopa exhibits its efficacy.
(3) Kinetic Study in Dogs (Combination Use with Dopa Decarboxylase
Inhibitor (DCI))
[0673] It was tested how the flat blood concentration-time profile
of levodopa provided by the administration of the compound of the
present invention demonstrated by the results shown in the above
section (1) is changed under the condition of using a widely and
clinically used DCI in combination. As the DCI, carbidopa was
used.
[Collection of Plasma Sample]
[0674] A drug solution for oral administration was prepared by
weighing each of the compound of the present invention produced in
Example 5 and levodopa and dissolving it in a vehicle at 1 mg/mL
expressed in terms of levodopa.
[0675] The thus obtained drug solution was administered by gavage
through a gastric tube into the stomach of dogs (male beagle dogs),
which were fasted from the day before the administration, and to
which an effective dose (60 mg/kg) of carbidopa (70566, AK
Scientific, Inc.) was administered. The dose of levodopa was 3
mg/kg, and the dose of the compound of the present invention
(Example 5) was 18.6 mg/kg (6 mg/kg expressed in terms of
levodopa). At 15 and 30 minutes, and 1, 2, 4, 6, and 8 hours after
administration of the drug solution, 1 mL of blood was collected
from a cephalic vein with a heparinized syringe. Immediately after
the collection, the collected blood was centrifuged in a desktop
centrifuge at 14500 rpm for 45 seconds. Then, acetonitrile
containing 0.1125% formic acid was added to the thus obtained
plasma in an amount as twice as large as the volume of the plasma,
followed by stirring, and then, the resulting sample was stored at
-20.degree. C. until measurement.
[Preparation of Analytical Sample and Analysis]
[0676] The preparation of an analytical sample and analysis were
carried out according to the method described in the same section
in the Biological Example 1(1).
[Results]
[0677] The plasma concentration-time profile of levodopa when the
compound of the present invention was administered to dogs is shown
in FIG. 1.
[0678] Under the condition of using carbidopa which is a widely and
clinically used DCI in combination, the blood concentration-time
profile of levodopa was compared between the case where levodopa
was administered and the case where the compound of the present
invention was administered. As a result, the plasma concentration
of levodopa in the case of administering levodopa reached a maximum
plasma concentration (Cmax) of 2.1 .mu.g/mL at 15 minutes after the
administration, and thereafter rapidly decreased, however, in the
case of administering the compound of the present invention in
place of levodopa, the plasma concentration of levodopa gradually
increased and reached Cmax of 1.0 .mu.g/mL at 4 hours after the
administration, and thereafter gradually decreased.
[0679] In humans, the effective plasma concentration of levodopa at
which the above-described side effects such as dyskinesia and
wearing-off are not developed is considered to be within a range of
from about 0.4 to 1 .mu.g/mL according to the publications
(Therapeutic Drug Monitoring, 2001, Vol. 23, pp. 621-629, Manuela
Contin et al.; and Clinical Pharmacology & Therapeutics, 2001,
Vol. 70, pp. 33-41, Dietz et al.).
[0680] From the results obtained in this Example, the time
(duration) for which the plasma concentration of levodopa was
within a range of from 0.4 to 1 .mu.g/mL was calculated, and found
to be 0.6 hours in the case of administering levodopa, and 4.3
hours in the case of administering the compound of the present
invention.
[0681] From the above result, it was found that the compound of the
present invention provides a sustained plasma concentration of
levodopa after oral administration also under the condition of
using widely and clinically used carbidopa in combination and
prolongs the duration of the effective blood concentration to about
7 times longer than in the case of administering levodopa. As
described above, since the organ distribution of carboxyesterase in
dogs is similar to that in humans, from the results of the kinetic
study using dogs, it was considered that the compound of the
present invention can provide a sustained plasma concentration of
levodopa also in humans.
(4) Simulation of Kinetics in Human Blood on Basis of Results of
Kinetic Study in Dogs
[0682] For the purpose of validating whether or not the effect of
releasing levodopa over a long period of time of the compound of
the present invention observed in the kinetic study in dogs is also
observed in humans, a simulation of kinetics in human blood was
carried out on the basis of the results of the kinetic study in
dogs described in the above section (3).
[Simulation of Kinetics in Human Blood]
[0683] By using the values obtained in the kinetic study in dog
blood in the above section (3), a prediction model that simulates
the kinetics in human blood was constructed.
[0684] Specifically, the blood concentration-time profile of
levodopa or the compound of the present invention obtained in the
kinetic study in dogs was input into Phoenix WinNonlin version 6.1
(Pharsight Corporation), which is kinetic analysis software, and
the fitting of the plasma concentration of levodopa was carried
out, whereby a prediction model that simulates the blood kinetics
of levodopa was constructed.
[0685] Into this prediction model, the values of blood kinetics
when a levodopa preparation was administered to humans described in
the literature (Br. J. Clin. Pharm., 1989, Vol. 28, pp. 61-69, D.
R. C. Robertson et al.) were input, and the kinetics of the
compound of the present invention in human blood was simulated.
[Results]
[0686] The results of the simulation of the kinetic of the compound
of the present invention in human blood and the values associated
with the blood kinetics of levodopa when a 100 mg tablet
(containing 100 mg of levodopa) of a commercially available
levodopa-carbidopa combination preparation (SINEMET (registered
trademark)) was taken described in the literature (Eur. J. Clin.
Pharmacol., 1993, Vol. 45, pp. 419-423, V. V. Myllyla et al.) are
shown in FIG. 2.
[0687] It is known that when the plasma concentration of levodopa
increases too much, dyskinesia is developed as a side effect, and
when the plasma concentration of levodopa decreases too much,
wearing-off is developed as a side effect. Therefore, if an
intermediate plasma concentration, at which such side effects are
not caused, can be continuously maintained, it can be used as an
excellent method for treating Parkinson's disease and/or
Parkinson's syndrome.
[0688] Similarly to the above-described analysis, the following
analysis was carried out by using the range of the plasma
concentration (0.4 to 1 .mu.g/mL) of levodopa, which was derived
from the publication, and in which side effects are not caused in
humans, as a therapeutic range.
[0689] In the case where a 100 mg tablet (containing 100 mg of
levodopa) of a commercially available levodopa-carbidopa
combination preparation (SINEMET (registered trademark)) was taken,
the plasma concentration of levodopa rapidly increased immediately
after taking the tablet and reached the maximum plasma
concentration (Cmax) which exceeds the upper limit of the
therapeutic range, and thereafter rapidly decreased. The time
period for which the plasma concentration of levodopa was within
the therapeutic range was calculated and found to be 2.3 hours in
the case where the levodopa preparation was administered.
[0690] On the other hand, the time period for which the plasma
concentration of levodopa was within the therapeutic range was
calculated and found to be 7.8 hours in the case where the compound
of the present invention was taken at a dose of 600 mg (200 mg
expressed in terms of levodopa).
[0691] Accordingly, it was found that the compound of the present
invention can provide a plasma concentration of levodopa in the
therapeutic range in humans for a long period of time, which is
about 3.4 times longer than the currently available levodopa
preparation, and particularly under the condition of using a DCI in
combination, the compound of the present invention can provide a
plasma concentration of levodopa in the therapeutic range over a
period of about 16 hours by dosing two times per day.
Biological Example 2
Mutagenicity Assay
[0692] In the treatment of Parkinson's disease and/or Parkinson's
syndrome, there is a possibility that a levodopa prodrug is
continued to be taken over a long period of time of several years
to several decades. Therefore, an evaluation was carried out as to
whether or not the compound of the present invention has
mutagenicity by a mutagenicity assay using mammalian cells.
[Method]
[0693] A mutagenicity assay using mammalian cells was carried out
as a commissioning test to be undertaken by Nissin Foods Holdings
Co., Ltd. The present method also called NESMAGET method is a
method in which the expression of p53R2 which is a DNA repair gene
is detected by luciferase activity, and the specific experimental
technique is described in JP-A-2005-000024 and Japanese Patent No.
4243716. In the determination as to whether or not the result of
this test was positive, the luciferase activity of p53R2 in the
case of a vehicle control (0.3% dimethylsulfoxide) was taken as
100%, and a concentration at which a relative luciferase activity
exceeded 200% was determined to be "concentration at which
mutagenicity was determined to be positive".
[Results]
[0694] The results of the mutagenicity assay for the compound of
the present invention (Example 5), the compound produced in
Reference Example 6, the compound produced in Reference Example 11,
the compound produced in Reference Example 16, and the compound
produced in Reference Example 40 are shown in Table 7.
TABLE-US-00007 TABLE 7 Mutagenicity assay (NESMAGET) Concentration
at which mutagenicity was determined to be positive Compound
(.mu.g/mL) Example 5 >200 Reference Example 6 2.4 Reference
Example 11 1.4 Reference Example 16 84 Reference Example 40 16
[0695] In the case of the compound produced in Reference Example 6,
the compound produced in Reference Example 11, the compound
produced in Reference Example 16, and the compound produced in
Reference Example 40, which showed a kinetic profile as favorable
as that of the compound of the present invention in the kinetic
study in dogs, the relative luciferase activity of p53R2 exceeded
200% when the concentrations thereof were 2.4, 1.4, 84, and 16
.mu.g/mL, respectively, and therefore, these compounds were
determined to be positive for mutagenicity. On the other hand, in
the case of the compound of the present invention, mutagenicity was
not observed even at a concentration of 200 .mu.g/mL.
[0696] From these results, it was revealed that among levodopa
prodrugs capable of providing a plasma concentration of levodopa
for a long period of time, there are not a few prodrugs shown to
have mutagenicity in the mutagenicity assay using mammalian cells.
On the other hand, the compound of the present invention did not
show mutagenicity even at a concentration of 200 .mu.g/mL, and
therefore, it was revealed that, even in the case where the
compound of the present invention is continued to be taken over a
long period of time of several years to several decades as in the
treatment of, for example, Parkinson's disease and/or Parkinson's
syndrome, the compound can be continued to be taken safely.
Biological Example 3
Model Injected with 6-Hydroxydopamine into Medial Forebrain
Bundle
[0697] For the purpose of confirming that the compound of the
present invention is metabolized into levodopa after oral
administration and exhibited an efficacy against Parkinson's
disease, the efficacy of the compound of the present invention in a
model injected with 6-hydroxydopamine into the medial forebrain
bundle which is an experimental Parkinson's disease model using an
animal was evaluated.
[Used Animal]
[0698] In the experiment, male Crl:CD(SD)IGS rats (Charles River
Japan, Inc.) supplied at 5 weeks of age were used. The rats were
housed in Econ cages (4 or less rats per cage) and were raised by
giving free access to solid feed CRF-1 (Oriental Yeast Co., Ltd.)
and tap water (in a water bottle) until they were subjected to the
experiment.
[Production of Model Injected with 6-OHDA into Medial Forebrain
Bundle]
[0699] When acclimation after shipping was completed, each of the
Crl:CD(SD)IGS rats at 6 weeks of age was anesthetized with
pentobarbital sodium (Somnopentyl (registered trademark) injectable
solution, 35 mg/kg, intraperitoneal injection). Subsequently, for
the purpose of preventing damage to norepinephrine neurons by
6-hydroxydopamine (6-OHDA), desipramine (25 mg/kg) was
intraperitoneally injected, and the rat was held and fixed by a
brain fixation device. A small bone window was opened with a hand
drill at a desired site, and 6-OHDA was injected into the medial
forebrain bundle according to the brain atlas of Paxinos and Watson
using a 30 G cannula (Brain Science Idea. Co. Ltd.) with a needle
tip cut at an angle of 45.degree. (site of injection: A=-4.5 mm,
L=+1.2 mm, and V=-7.8 mm with respect to the bregma, injection
amount: 8 .mu.g/4 .mu.L/8 min/site in each case). After injection,
in order to prevent backflow of the solution, the injection needle
was left in place for 2 minutes or more. Thereafter, the burr hole
was closed with an instant glue, and then sutured and disinfected
with iodine tincture.
[Confirmation of Induction of Pathology]
[0700] After two weeks from the injection of 6-OHDA, individuals in
which pathology was induced were selected. Specifically, the
below-described rotation test was employed, and when apomorphine
(0.05 mg/kg) which is a dopamine receptor agonist was
subcutaneously injected as a test substance, only rats which
behaved in such a manner that the number of rotations in 5 minutes
after 15 to 20 minutes from the administration was 20 or more were
selected as the rats in which pathology was induced.
[Rotation Test]
[0701] In a rotation test, a device configured such that a black
plastic circular cylinder having a diameter of 30 cm and a height
of 35 cm was placed upright in a black-painted bowl having an
opening diameter of 35 cm and a bottom diameter of 17 cm was used
(the height of the curve from the bottom of the bowl to the bottom
edge of the cylinder was set to 7 cm). The rat was placed in the
device (one rat per device) and acclimated to the device for 30
minutes. Thereafter, a test substance was administered to the rat,
and the rat was returned to the same device and videotaped. Then,
the taped video was analyzed, and the number of rotations every 5
minutes or 10 minutes was measured. As for the number of rotations,
a 360.degree. rotation in one direction was determined to be one
rotation. In the case where the direction (body's direction of
movement or movement direction) was changed during rotation, the
rotation was not included in the count.
[Examination of Effect of Compound of the Present Invention]
[0702] The rotational behavior in the case where the compound of
the present invention produced in Example 5 (100 mg/kg expressed in
terms of levodopa) was orally administered after a lapse of 1 week
or more from when the induction of pathology was confirmed was
evaluated until 6 hours after the administration (N=11). Further,
the rotational behavior in the case where levodopa (30 mg/kg) was
orally administered was also evaluated until 6 hours after the
administration in the same manner (N=11, crossover trial).
Incidentally, in each case, benserazide which is a dopa
decarboxylase inhibitor (8 mg/kg) was orally administered
concomitantly.
[Results]
[0703] The number of rotations (times) per 10 minutes made by the
rats until 6 hours (360 minutes) after the administration in the
administration group treated with levodopa (30 mg/kg) and in the
administration group treated with the compound of the present
invention produced in Example 5 (100 mg/kg expressed in terms of
levodopa) is shown in FIG. 3. In the drawing, the values of the
administration group treated with levodopa (30 mg/kg) are indicated
by L-dopa (30 mg/kg), and the values of the administration group
treated with the compound of the present invention produced in
Example 5 (100 mg/kg expressed in terms of levodopa) are indicated
by Compound of Ex. 5 (100 mg/kg). In addition, the respective
values are each a mean of the values obtained using 11 rats in each
group and its standard error.
[0704] In the case of the rats in the administration group treated
with levodopa, the number of rotations increased rapidly after the
administration and reached a maximum value (the number of
rotations: about 100 times) at 20 minutes after the administration.
On the other hand, in the case of the rats in the administration
group treated with the compound of the present invention produced
in Example 5, the number of rotations began to increase gradually
after a lapse of 60 minutes or more from the administration, and
reached a maximum value (the number of rotations: about 90 times or
more) at 140 minutes after the administration. In addition, even
when the compound of the present invention produced in Example 9
was used in place of the compound of the present invention produced
in Example 5, the same results were obtained.
[0705] From the above results, it was found that the compound of
the present invention exhibited the same activity as in the case of
administering levodopa after a lapse of a certain period of time
from oral administration. These results are consistent with the
characteristic of the compound of the present invention that the
compound of the present invention does not exhibit the
levodopa-like activity per se, but is metabolized into levodopa and
exhibits the efficacy.
Preparation Example 1
Tablet Containing 5 mg of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid
[0706] The respective components shown below were mixed according
to a common procedure, followed by tableting, whereby 10000 tablets
each containing 5 mg of the active ingredient were obtained.
[0707]
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)pheny-
l)propanoic acid: 50 g
[0708] carboxymethyl cellulose calcium (disintegrant): 20 g
[0709] magnesium stearate (lubricant): 10 g
[0710] microcrystalline cellulose: 920 g
Preparation Example 2
Injectable Preparation Containing 20 mg of
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)prop-
anoic acid
[0711] The respective components shown below were mixed according
to a common procedure, and the resulting solution was sterilized
according to a common procedure. Then, 5 mL aliquots of the
solution were charged into ampoules, and lyophilized according to a
common procedure, whereby 10000 ampoules each containing 20 mg of
the active ingredient were obtained.
[0712]
(2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)pheny-
l)propanoic acid: 200 g
[0713] mannitol: 20 g
[0714] distilled water: 50 L
INDUSTRIAL APPLICABILITY
[0715] The compound of the present invention is a levodopa prodrug,
and is useful as a preventive and/or therapeutic agent for
diseases, for which levodopa is used as a therapeutic agent, or
against which levodopa is expected to have an effect, such as
Parkinson's disease and/or Parkinson's syndrome, or diseases, which
are expected to be improved by dopamine stimulation, or diseases,
which are induced by a decrease in noradrenaline.
* * * * *