U.S. patent number RE34,878 [Application Number 08/157,564] was granted by the patent office on 1995-03-14 for hypoglycemic agent.
This patent grant is currently assigned to Ajinomoto Co., Inc.. Invention is credited to Izumi Kamashiro, Yoshiko Seto, Hisashi Shinkai, Koji Toi, Shigeshi Toyoshima.
United States Patent |
RE34,878 |
Toyoshima , et al. |
March 14, 1995 |
**Please see images for:
( Certificate of Correction ) ** |
Hypoglycemic agent
Abstract
A compound of D-phenylalanine derivative for hypoglycemic use,
represented by the general formula ##STR1## R.sup.1 is selected
from hydrogen, alkyl of 1 to 5 carbon atoms, aryl of 6 to 12 carbon
atoms, aralkyl of 6 to 12 carbon atoms, ##STR2## --CH.sub.2
CO.sub.2 R.sup.3, --CH(CH.sub.3)--OCO--R.sup.3, and --CH.sub.2
--OCO--C(CH.sub.3).sub.3 ; R.sup.2 is selected from groups
comprising aryl of 6 to 12 carbon atoms, a hetero six-membered
ring, a hetero five-membered ring, cycloalkyl, or cycloalkenyl, any
of which groups may have one or more substituents; and R.sup.3 is
selected from hydrogen and alkyl of 1 to 5 carbon atoms; the salts
thereof, and precursors which can be converted thereto in the human
or animal body. Some of the compounds are novel per se.
Inventors: |
Toyoshima; Shigeshi (Funabashi,
JP), Seto; Yoshiko (Funabashi, JP),
Shinkai; Hisashi (Kawasaka, JP), Toi; Koji
(Kanagawa, JP), Kamashiro; Izumi (Yokohama,
JP) |
Assignee: |
Ajinomoto Co., Inc. (Tokyo,
JP)
|
Family
ID: |
13195452 |
Appl.
No.: |
08/157,564 |
Filed: |
November 23, 1993 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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844970 |
Mar 27, 1989 |
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Reissue of: |
146719 |
Jan 21, 1988 |
04816484 |
Mar 28, 1989 |
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Foreign Application Priority Data
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Mar 27, 1985 [JP] |
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60-62276 |
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Current U.S.
Class: |
514/563; 549/304;
560/40; 562/450; 514/529; 514/530; 549/467; 546/169; 546/323;
560/41; 562/445 |
Current CPC
Class: |
C07C
233/87 (20130101); C07D 213/82 (20130101); A61P
3/08 (20180101); C07C 235/52 (20130101); C07D
307/85 (20130101); C07C 233/63 (20130101); A61P
3/10 (20180101); C07C 2602/42 (20170501); C07C
2601/16 (20170501); C07C 2601/14 (20170501); C07C
2601/08 (20170501); C07C 2602/08 (20170501) |
Current International
Class: |
A61K
31/215 (20060101); A61K 31/21 (20060101); A61K
031/215 (); C07C 101/72 () |
Field of
Search: |
;562/445 ;560/40
;514/563,613 |
References Cited
[Referenced By]
U.S. Patent Documents
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4650785 |
March 1987 |
Toyoshima et al. |
4670584 |
June 1987 |
Toyoshima et al. |
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Foreign Patent Documents
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|
93551 |
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Sep 1983 |
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EP |
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2102412 |
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Feb 1983 |
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GB |
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Other References
Toyoshima et al., "Preparation of D-Phenylalanine Derivatives and
Their Use as Hypoglycemic Agents", CA 106 85057d (1987). .
European Search Report/Application No. 86 30
2217/26-11-1987..
|
Primary Examiner: Ivy; C. Warren
Assistant Examiner: Owens; A. A.
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier
& Neustadt
Parent Case Text
This application .Iadd.is a Reissue of Ser. No. 07/146,719, filed
Feb. 21, 1988, U.S. Pat. No. 4,816,182, which is a
.Iaddend.divisional of Ser. No. 844,970, filed Mar. 27, 1986, now
abandoned.
Claims
We claim:
1. A D-phenylalanine derivative of the formula
or a salt thereof or a precursor which can be converted into said
D-phenylalanine derivative in vivo, wherein:
R.sup.1 is hydrogen or C.sub.1-5 alkyl,
R.sup. is hydrogen or C.sub.1-5 alkyl; and
R.sup.4 is cyclohexane substituted at the 4- or 5-position by
methyl, ethyl, ispropyl, tert-butyl, ethene, or isopropene or
cyclohexene substituted at the 4- or 5-position by methyl, ethyl,
isopropyl, tert-butyl, ethene, or isopropene.
2. The D-phenylalanine derivative of claim 1, wherein R.sup.4 is
said substituted cyclohexane.
3. The D-phenylalanine derivative of claim 1, wherein R.sup.4 is
said substituted cyclohexane.
4. The D-phenylalanine derivative of claim 1, wherein the said
derivative is
N-(4-isopropylcyclohexylcarbonyl)-D-phenylalanine.
5. The D-phenylalanine derivative of claim 1, wherein the said
derivative is N-(4-isopropylcyclohexylcarbonyl)-D-phenylalanine:
N-[(S)-perilloyl]-D-phenylalanine;
N-(4-methylcyclohexylcarbonyl)-D-phenylalanine;
N-(4-ethylcyclohexylcarbonyl)-D-phenylalanine; or
N-(4-t-butylcyclohexylcarbonyl)-D-phenylalanine.
6. The D-phenylalanine derivative of claim 1, wherein the said
derivative is N-[(s)-perilloyl]-D-phenylalanine;
N-(trans-4-methylcyclohexylcarbonyl)-D-phenylalanine;
N-(trans-4-ethylcyclohexylcarbonyl)-D-phenylalanine;
N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine; or
N-(trans-4-t-butylcyclohexylcarbonyl)-D-phenylalanine.
7. The D-phenylalanine derivative of claim 1, wherein R.sup.1 is
hydrogen and R.sup.3 is hydrogen.
8. The D-phenylalanine derivative of claim 1, wherein R.sup.4 is
perilloyl.
9. The D-phenylalanine derivative of claim 1, wherein said
substituted cyclohexane is substituted at the 4-position.
10. The D-phenylalanine derivative of claim 1, wherein said
substituted cyclohexane is substituted at the 5-position.
11. The D-phenylalanine derivative of claim 1, wherein said
substituted cyclohexene is substituted at the 4-position.
12. The D-phenylalanine derivative of claim 1, wherein said
substituted cyclohexene is substituted at the 5-position.
13. The D-phenylalanine derivative of claim 1, wherein said
substituted cyclohexane or said substituted cyclohexene is
substituted with methyl, ethyl, isopropyl or tert-butyl.
14. The D-phenylalanine derivative of claim 1, wherein said
substituted cyclohexane or said substituted cyclohexene is
substituted by ethene, or isopropene.
15. A pharmaceutical composition, comprising a D-phenylalanine
derivative of claim 1 and a pharmaceutical excipient. .Iadd.16. The
compound N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine.
.Iaddend.
Description
FIELD OF THE INVENTION
The present invention relates to hypoglycemic agents useful as
antidiabetic drugs.
BACKGROUND TO THE INVENTION
Hitherto, as antidiabetic drugs for oral use, there have been
widely employed sulfonyl urea which shows hypoglycemic action
particularly through a promotion of the secretion of insulin, and a
biguanide which shows a hypoglycemic action particularly through
the metabolism of sugar. However, they are somewhat unsatisfactory
as to their side effects (see Textbook of Endocrinology 4th ed.,
1968, p. 719 (Saunders); Diabetes, 19, 785, 1970; Ann. Rev.
Pharmacol., 15, 351, 1975).
No report has ben found that a D-phenylalanine derivative possesses
hypoglycemic action.
SUMMARY OF THE INVENTION AND DESCRIPTION OF PREFERRED
EMBODIMENTS
According to one aspect of the invention there is provided for
pharmaceutical, particularly hypoglycemic, use, a D-phenylalanine
derivative represented by the general formula: ##STR3## or a salt
thereof, or a precursor which can be converted thereto in the human
or animal body. Such compounds can lower the value of blood sugar
and thus can be used as an antidiabetic drug for an oral use as
well as by injection.
Among the foregoing phenylalanine derivatives, those in the D-form
represented by the general formula: ##STR4## and the salts thereof
are novel.
In the above general formulae: R.sup.1 is hydrogen, alkyl of 1 to 5
carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
and sec-butyl, aryl of 6 to 12 carbon atoms such as phenyl, tolyl,
naphthyl, and ##STR5## aralkyl of 6 to 12 atoms such as benzyl,
##STR6## --CH.sub.2 CO.sub.2 R.sup.3, --CH(CH.sub.3)--OCO--R.sup.3,
or --CH.sub.2 --OCO--C(CH.sub.3).sub.3, R.sup.2 is a group
comprising aryl of 6 to 12 carbon atoms such as phenyl, naphthyl,
and indanyl, a hetero six-membered ring such as quinolynyl,
pyridyl, a hetero five-membered ring such as 2-benzofuranyl,
cycloalkyl such as cyclohexyl and cyclopentyl, bicycloalkyl such as
bicycloheptye, and cycloalkenyl such as 1-cyclohexenyl,
2-cyclohexeneyl, 3-cyclohexenyl, 1-cyclopentenyl and
2-cyclopentenyl, any of which groups optionally having one or more
substituents; R.sup.3 is hydrogen or lower alkyl such as methyl,
ethyl, isopropyl and pentyl; and R.sup.4 stands for those R.sup.2
groups which provide novel compounds hereof, notably phenyl which
has one or more alkyl substituents of 2 to 5 carbon atoms,
cyclohexyl which has one or more substituents cyclopentyl,
bicycloalkyl, cycloalkenyl, indanyl or 2-benzofuranyl, any of which
may have one or more substituents.
When an organic group in the above general formulae has a
substituent, examples of such substituents include a halogen atom
such as fluorine or chlorine, a hydroxyl group, a C.sub.1-5 alkyl
group such as methyl, ethyl, trichloromethyl, trifluoromethyl,
propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl, a C.sub.1-5
alkenyl group such as ethenyl, propenyl, and butenyl, an alkylidene
group such as ##STR7## a C.sub.1-5 alkyloxy such as methoxy and
ethoxy, a C.sub.1-5 alkyl group which has been substituted by such
C.sub.1-5 alkyloxy group such as methoxymethyl and 1-ethoxyethyl, a
C.sub.1-5 alkylene group which has been substituted by such
C.sub.1-5 alkyloxy group in the same manner as above such as
1-methoxyethylene. In the case of a substituted bicycloalkyl group
as stated above, it can include a bicycloheptyl or a derivative
thereof such as bicyclo (2,2,1)heptyl.
In the case of the compound represented by the general formula (I)
wherein R.sup.1 stands for a hydrogen atom, it can be formed by
conventional methods via the salts thereof with various cations
such as an alkali metal, for example sodium and potassium, an
alkali earth metal, for example, calcium, an inorganic base, for
example, ammonia, an organic base, for example, cyclohexylamine,
N-methyl-D-glucosamine, or a basic amino acid (lysine, arginine and
the like).
The D-phenylalanine derivative as shown by the formula (I)
mentioned above, can be prepared by using conventional N-acylating
reactions as in the Examples given below.
Most of the phenylalanine derivatives supplied by this invention
are novel compounds which have not been described yet in the
literature.
The D-phenylalanine derivatives used in the present invention are
useful as a hypoglycemic agent for treating diabetic mammals
including humans. The derivatives can be used for lowering blood
sugar by formulating them into a preparation such as tablets,
capsules, and elixirs for oral administration and into an aseptic
liquid preparation or an aseptic suspension preparation for
parenteral administration such as subcutaneous, intramuscular,
intavenous injection, and suppositories. The D-phenylalamine
derivatives in the present invention can be administered to a
subject necessitating such treatment (animals and humans) in a
dosage range of 0.1 to 1,000 mg per subject generally several times
a day, that is, in a total daily dosage of 0.2 to 2,000 mg. The
dosages varies according to the seriousness of disease, the body
weight of subjects, and other factors acknowledged by those skilled
in the art.
To produce the preparations using the D-phenylalanine derivatives
as described above for the present invention, they may be converted
to dosage forms such as tablets, granules, powders, capsules,
injections and suppositories by conventional methods.
For the production of oral preparations, there may be added the to
the D-phenylalanine derivative as the principal agent, adjuvants
such as fillers, binders, disintegrators, lubricants, colors, and
correctives, as necessary, and then formed by conventional methods
into tablets, coated tablets, granules, powders, capsules and the
like.
Examples of specific materials which can be incorporated into
tablets, capsules, and so forth are as follows: fillers such as
cornstarch, lactose, white sugar, glucose, sorbitol, and
crystalline cellulose; binders such as polyvinyl alcohol, polyvinyl
ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth
gelatine, shellac, hydroxypropyl cellulose, hydroxypropyl starch,
polyvinyl pyrrolidone; disintegrators such as starch, agar,
gelatine powder, crystalline cellulose, calcium carbonate, sodium
bicarbonate, calcium citrate, dextrin and pectin; lubricants such
as magnesium stearate, talc, polyethylene glycol, silica, hardened
plant oil; colors such as one which is allowed as an additive for
the medicines; correctives such as cocoa powder, mentha herb,
aromatic acid, mentha oil, borneol, cinnamon bark powder. These
tables and granules may be coated with sugar, gelatine, or the
like, as desired.
For the production of the injectable formulations, there may be
added to the phenylalanine derivative as the principal agent, a pH
adjusting agent, a buffer agent, a stabilizing agent, preservatives
or the like, as necessary to produce a material for subcutaneous,
intramuscular or intravenous injection by conventional methods.
EXAMPLES
The present invention will be further explained in the following
examples.
EXAMPLE 1
N-(4-Ethylbenzoyl)-D-phenylalanine
D-Phenylalaine 2 g (12 mmole) was dissolved in 10% aqueous sodium
hydroxide solution (10 ml), and acetone (10 ml) was added. An
acetone (5 ml) solution of 4-ethyl benzoyl chloride (2.5 g, 15
mmole) and a 10% aqueous sodium hydroxide solution were added
dropwise to the mixture obtained above while stirring and cooling
with ice over 20 minutes, the reaction solution being maintained at
pH 10. The reaction solution was returned to the room temperature,
stirred for 3 hours, and made an acidic with a dilute hydrochloric
acid solution to precipitate crystals. The crystals were filtered,
washed with water and recrystallized from ethyl acetate to obtain
N-(4-ethylbenzoyl)-D-phenylalanine (3.0 g, yield 83%).
m.p. 165.5.degree.-166.degree. C. Specific Rotation
[.alpha.].sub.D.sup.23 +4.4.degree. (C=1, methanol).
EXAMPLES 2 TO 11
For Examples 2 to 8, in the same manner as in Example 1, using the
following starting materials, each compound of 50 mmole, the
following product compounds were produced. The compounds in
Examples 9 to 11 were already known, and therefore were produced in
accordance with the following literature references:
Example 9: J. Amer. Chem. Soc., 73, 1644, 1951,
Example 10: Pol. J. Chem., 53, 2239, 1979, and
Example 11: J. Chromatogr., 264, 63, 1983.
__________________________________________________________________________
Example Starting Yield M.P. Specific No. Material Product (%)
(.degree.C.) Rotation
__________________________________________________________________________
2 D-phenylalanine N-(4-toldryl)- 83 152-155 [.alpha.].sub.D .sup.28
+46.2.degree. D-phenylalanine (C = 0.5, methanol) 3 D-phenylalanine
N-(2-fluoro- 74 91.5-93.5 [.alpha.].sub.D .sup.19 -8.8.degree.
benzoyl)-D- (C = 1, methanol) phenylalanine 4 D-phenylalanine
N-(3-fluoro- 81 112.5-116 [.alpha.].sub.D .sup.22 +48.6.degree.
benzoyl)-D- (C = 1, methanol) phenylalanine 5 D-phenylalanine
N-(4-fluoro- 80 142-145 [.alpha.].sub.D .sup.28 +40.4.degree.
benzoyl)-D- (C = 0.5, methanol) phenylalanine 6 D-phenylalanine
N-(3-trifluoro- 77 118-119 [.alpha.].sub.D .sup.28 +40.4.degree.
methylbenzoyl)- (C + 1, methanol) D-phenylalanine 7 D-phenylalanine
N-(4-trifluoro- 70 136-137.5 [.alpha.].sub.D .sup.28 +36.3.degree.
methylbenzoyl)- (C = 1, methanol) D-phenylalanine 8 D-phenylalanine
N-4-anisoyl)-D- 65 85-90 [.alpha.].sub.D .sup.20 +60.2.degree.
phenylalanine (C = 0.5, methanol) 9 D-phenylalanine N-benzoyl-D- 81
phenylalanine 10 D-phenylalanine N-nicotinoyl- 62 D-phenylalanine
11 D-phenylalanine N-(2-naphthoyl)- 83 D-phenylalanine
__________________________________________________________________________
EXAMPLE 12
N-Cyclopentylcarbonyl-D-phenylalanine
Cyclopentane carboxylic acid (1.5 g, 13 mmole) was dissolved in
chloroform (50 ml), and N-hydroxysuccinimide 1.7 g was added.
N,N'-Dicyclohexylcarbodiimide (3.0 g) was gradually added to the
mixture as obtained above while stirring and cooling with ice, and
the mixture was stirred for 1 hour at the same temperature. The
mixture was further stirred for 7 hours at room temperature.
Glacial acetic acid (2 ml) was added to the mixture, and stirred
for 1 hour. The insoluble matter was removed by filtration. The
filtrate was washed with saturated aqueous sodium bicarbonate
solution (30 ml), 1N aqueous hydrochloric acid solution (30 ml),
and water (30 ml), and dried over magnesium sulfate. The magnesium
sulfate was removed by filtration, and the solution thus obtained
was concentrated under reduced pressure to dryness. The matter was
recrystallized from ethyl acetate to afford cyclopentane carboxylic
acid N-hydroxysuccinimide ester (2.5 g, yield 91%).
The ester derivative thus obtained above (2.5 g), was dissolved in
chloroform (20 ml). This solution was added to a chloroform
solution (40 ml) of D-phenylalanine methyl ester hydrochloride (3.0
g, 14 mmole) and triethylamine (1.4 g), and the mixture thus
obtained was stirred for 18 hours at room temperature. The reaction
solution was washed with 1N aqueous hydrochloric acid solution (40
ml), saturated aqueous sodium bicarbonate solution (40 ml) and
water (40 ml), and dried over magnesium sulfate. The magnesium
sulfate was removed by filtration and the filtrate was concentrated
under reduced pressure to dryness. The matter was recrystallized
from ethyl acetate-n-hexane to afford
N-cyclopentylcarbonyl-D-phenylalanine methyl ester (3.0 g, yield
84%).
The methyl ester derivative (3.0 g) thus obtained above, was
dissolved in methanol (10 ml), and 1N aqueous sodium hydroxide
solution (20 ml) was added. The mixture was stirred for 30 minutes
at room temperature and then made acidic with an addition of a
dilute hydrochloric acid to precipitate crystals. The crystals were
filtered, washed with water, and recrystallized from methanol-water
to give the desired product (2.7 g, yield 80%).
m.p. 108.degree.-110.degree. C. Specific Rotation
[.alpha.].sub.D.sup.22 -35.2.degree. (C=0.5, methanol).
EXAMPLES 13 TO 18
For Examples 13 to 16, in the same manner as in Example 12, using
as the starting material the following compounds, each of 15 mmole,
the following products were obtained. The compounds of Examples 17
and 18 stated in the above table were known, and therefore were
produced in accordance with the following literature
references:
Example 17: BEXXA BELG. NO. 893553, 48, 1981, and
Example 18: Bull. Chem. Soc. Jpn., 57, 2171, 1984.
__________________________________________________________________________
Example Starting Yield M.P. Specific Rotation No. Material Product
(%) (.degree.C.) [.alpha.].sub.D .sup.22 (C = 0.5,
__________________________________________________________________________
methanol 13 2-benzofurane N-(2-benzofuran- 59 114-116 +89.6.degree.
carboxylic yl-carbonyl)- acid D-phenylalanine 14 5-indane
N-(5-indanyl- 64 160-161 +52.0.degree. carboxylic carbonyl)- acid
D-phenylalanine 15 3-cyclohexene N-(3-cyclo- 62 100-101
-12.6.degree. carboxylic hexenylcarbonyl-) acid D-phenylalanine 16
bicyclo- N-(bicyclo- 50 179-181 +33.4.degree. [2,2,1]heptan-
[2,2,1]heptan-2- 2-ylcarboxylic ylcarbonyl)-D- acid phenylalanine
17 cyclohexene N-cyclohexyl- 65 carboxylic carbonyl-D- acid
phenylalanine 18 benzoic acid N-benzoyl-D- 65 phenylalanine methyl
ester
__________________________________________________________________________
EXAMPLE 19
N-(4-Isopropylcyclohexylcarbonyl)-D-phenylalanine
Platinum oxide (200 mg) as a catalyst was suspended in acetic acid
(20 ml), and then (s)-(-)perillic acid (2 g, 12 mmole) was added.
The mixture thus obtained was stirred for 8 hours at room
temperature under a current of hydrogen gas. The catalyst was
removed by filtration, and the filtrate was concentrated under
reduced pressure to a dryness. The matter was recrystallized from
methanol-water to obtain 4-isopropyl cyclohexane carboxylic acid
(1.9 g, yield 93%).
After that, in the same manner as the reaction in Example 1,
N-(4-isopropylcyclohexylcarbonyl)-D-phenylalanine was produced. It
was crystallized from methanol-water to give the desired product
(2.5 g, yield 61%).
m.p. 230.degree.-232.degree. C. Specific Rotation
[.alpha.].sub.D.sup.22 -28.2.degree. (C=0.5, methanol).
EXAMPLE 20
ICR-CDI mice (Male, five weeks old, Body weight: 20 g) which had
been bred for one week, were abstained from food for 18 hours, and
then used as test subjects.
The phenylalanine derivative of the present invention was suspended
in 0.5% CMC-0.05M tris-hydrochloride buffer (pH 7.4). The sample
solution thus obtained was administered orally in fixed amounts to
the test subjects. A predetermined time later, the percentage
decrease in blood glucose with the comparison to the control group
was determined. The results are shown in the following table.
______________________________________ Decrease in Blood Glucose
(%) Example No. Amounts used (mg/kg) 60 Minutes
______________________________________ 1 25 34 2 100 32 3 100 24 4
100 24 5 100 43 6 250 37 7 100 33 8 100 38 9 100 34 10 250 19 11
250 17 12 50 22 13 100 31 14 250 28 15 100 28 16 250 16 17 100 27
18 250 37 19 25 50 ______________________________________
EXAMPLE 21
N-Cumoyl-D-Phenylalanine
Cumic acid (15.0 g, 91 mmole) was dissolved in chloroform (150 ml),
and N-hydroxysuccinimide (11.4 g, 99 mmole) was added thereto.
N,N'-Dicyclohexylcarbodiimide (20.4 g, 99 mmole) was added
gradually to the mixture obtained above while cooling with ice and
stirring, and then the mixture thus obtained was returned to room
temperature. The mixture was further stirred for 15 hours at room
temperature. Glacial acetic acid (5 ml) was added thereto, and the
mixture thus obtained was stirred and the insoluble matter was
removed by filtration. The filtrate was washed with saturated
aqueous sodium bicarbonate (300 ml) and water (300 ml), and dried
over magnesium sulfate. The magnesium sulfate was removed by
filtration, and the filtrate thus obtained was concentrated under
reduced pressure to dryness. The resultant substance was
recrystallized from ethyl acetate to obtain cumic acid
N-hydroxysuccinimide ester (18.8 g, yield 72 mmole).
The ester thus obtained above (18.8 g) was added to the chloroform
solution (150 ml) of D-phenylalanine methyl ester hydrochloride
(23.0 l g, 110 mmole) and triethylamine (10.8 g, 110 mmole), and
the mixture thus obtained was stirred for 15 hours at room
temperature. The reaction solution was washed with 1N aqueous
hydrochloric acid solution (300 ml), saturated aqueous sodium
bicarbonate (300 ml) and water (300ml) and dried over magnesium
sulfate. The magnesium sulfate thus used was removed by filtration,
and the filtrate thus obtained was concentrated under reduced
pressure to dryness.
The residue thus obtained was recrystallized from ethyl
acetate-n-hexane to obtain N-cumoyl-D-phenylalanine methyl ester
(20.5 g, yield 69%).
The methyl ester thus obtained above (20.5 g) was dissolved in
methanol (100 ml), and then 1N aqueous sodium hydroxide (100 ml)
was added thereto. The mixture thus obtained was stirred for 10
minutes at room temperature, and was made acidic with an addition
of diluted aqueous hydrochloric acid solution to precipitate
crystals. The crystals were filtered, washed with water and
recrystallized from methanol-water to give the desired product
(18.1 g, yield 64%).
m.p. 177.degree.-178.degree. C. Specific Rotation
[.alpha.].sub.D.sup.20 +25.5.degree. (C=1, methanol).
EXAMPLES 22 to 30
In the same manner as in Example 21, using as the starting material
the following compounds, each at 50 mmole, the following product
compounds were produced.
__________________________________________________________________________
Example Starting Yield M.P. Specific No. Material Product (%)
(.degree.C.) Rotation
__________________________________________________________________________
[.alpha.].sub.D .sup.20 (C = 1, methanol) 22 (s)-perillic N-[(s)-
44 109-110 -37.2.degree. acid perilloyl]-D- phenylalinine 23
trans-4-n- N-(trans-4-n- 48 104-105 -8.8.degree. propylcyclo-
propylcyclo- hexane hexylcarbonyl)- carboxylic D-phenylalanine acid
24 trans-4-n- N-(trans-4-n- 50 144-145 -7.5.degree. butylcyclo-
butylcyclohexyl- hexane carbonyl)-D- carboxylic phenylalanine acid
25 4-tert-butyl- N-(4-t-butyl- 55 177-178 +51.5.degree. benzoic
acid benzoyl)-D- phenylalanine 26 cuminic acid N-cumoyl-L- 63
121-123 [.alpha.].sub.D .sup.23 -29.3.degree. (C = 1, methanol)
phenylalanine 27 cyclopentane N-cyclopentyl- 40 115-117
[.alpha.].sub.D .sup.23 -30.1.degree. (C = 1, methanol) carboxylic
carbonyl-L- acid phenylalanine 28 trans-4- N-(trans-4- 43 124-125
[.alpha.].sub.D .sup.23 -11.5.degree. (C = 1, methanol)
methyl-cyclo- methylcyclohexyl- hexane carbo- carbonyl)-D-phenyl-
xylic acid alanine 29 trans-4-ethyl- N-(trans-4-ethyl- 53 96-97
[.alpha.].sub.D .sup.23 -11.1.degree. (C = 1, methanol) cyclohexane
cyclohexyl-carbo- carboxylic nyl)-D-phenylala- acid nine 30
trans-4-t- N-(trans-4-t- 49 160-161 [.alpha.].sub.D .sup.23
-9.0.degree. (C = 1, methanol) butyl-cyclo- butylcyclohexyl- hexane
carbo- carbonyl)-D-phenyl- xylic acid alanine
__________________________________________________________________________
EXAMPLE 31
N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine
Platinum oxide (500 mg) as a catalyst was suspended in acetic acid
(50 ml) and cumic acid (10 g, 61 mmole) was added thereto. The
mixture thus obtained was stirred vigorously for 2 hours at room
temperature under a pressure of hydrogen 5 kg/cm.sup.2. The
catalyst was removed by filtration, and the filtrate was
concentrated under reduced pressure to a solid state. The resultant
substance was distilled under reduced pressure of 1 mmHg
(1.3.times.10.sup.-3 kg/cm.sup.2), at 113.degree.-116.degree. C. to
obtain 4-isopropylcyclohexane carboxylic acid yielding 10 g (96%)
in a ratio of 3 parts of cis-form per 1 part of trans-form by
weight.
To methanol (70 ml) at less than -20.degree. C., thionyl chloride
(17 ml) was added dropwise, and the carboxylic acid (10 g) as
obtained above was added. The mixture thus obtained was stirred for
15 hours at room temperature, and then concentrated under reduced
pressure to a solid substance. The substance thus obtained was
distilled under reduced pressure of 0.7 mmHg (9.2.times.10.sup.-4
kg/cm.sup.2) at 66.degree. C. to obtain 4-isopropylcyclohexane
carboxylic acid methyl ester (9.5 g, yield 88%).
To the methyl ester (b 9.5 g) thus obtained, sodium hydride (120
mg) was added, and the mixture was heated at 150.degree. C. for 2
hours under a current of nitrogen gas. The reaction solution was
cooled and then subjected to a reduced pressure distillation of 0.7
mmHG (9.2.times.10.sup.-4 kg/cm.sup.2) at 66.degree. C. to obtain
4-isopropylcyclohexane carboxylic acid methyl ester in a ratio of 6
parts trans-form per 1 part cis-form.
The methyl ester (9.0 g) thus obtained was dissolved in methanol
(50 ml), and 1N aqueous sodium hydroxide solution (50 ml) was added
thereto. The mixture thus obtained was stirred for 10 minutes at
room temperature and made acidic with an addition of a dilute
aqueous hydrochloric acid solution to precipitate crystals. The
crystals were filtered, washed with water, and crystallized from
methanol-water to give trans-4-isopropylcyclohexane carboxylic acid
(6.8 g, yield 78%).
After that, in the same manner as in Example 21, using as a
starting material the carboxylic acid derivative (6.8 g, 40 mmole),
N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine was
produced, and recrystallized from methanol-water to give the
desired product (8.2 g, yield 65%).
m.p. 129.degree.-130.degree. C. Specific Rotation
[.alpha.].sub.D.sup.20 -9.4.degree. (C=1, methanol).
EXAMPLES 32 TO 35
In the same manner as in Example 26, using as the starting material
the following compounds, each of 40 mmole, the following product
compounds were produced.
__________________________________________________________________________
Example Starting Yield M.P. Specific Rotation No. Material Product
(%) (.degree.C.) [.alpha.].sub.D .sup.20 (C = 1,
__________________________________________________________________________
methanol) 32 trans-4- 4-(trans-4- 52 137-138 +8.8.degree.
isopropyl- isopropylcyclo- cyclohexane hexylcarbonyl)-D- carboxylic
phenylalanine acid methyl ester 33 trans-4- N-(trans-4- 56 130-131
+9.5.degree. isopropyl- isopropylcyclo- cyolohexane hexylcarbonyl)-
carboxylic L-phenylalanine acid 34 trans-4- N-(trans-4- 66 134--135
-- isopropyl- isopropylcyclo- cyclohexane hexylcarbonyl)-
carboxylic 2-phenylethylamine acid 35 trans-4- N-(trans-4- 58
129--130.5 +8.4.degree. isopropyl- isopropylcyclo- cyclohexane
hexylcarbonyl)- carboxylic D-phenylalanine acid benzylester
__________________________________________________________________________
EXAMPLE 26
N-(Cis-4-isopropylcyclohexylcarbonyl)-D-phenylalanine
4-Isopropylcyclohexane carboxylic acid methyl ester (9.5 g)
(Cis-form:trans-form=3:1) was obtained in the same manner as in
Example 26. Cis-4-isopropylcyclohexane carboxylic acid methyl ester
(7 g) was obtained from the product thus obtained by a high
performance liquid chromatography of YMC A-043 column using as the
solvent a mixture of n-hexane and 1,2-dichloro ethane in a ratio of
75:25.
After that, in the same manner as in Example 21, using as a
starting material the cis-form thus obtained (6.5 g, 38 mmole),
N-(Cis-4-isopropylcyclohexylcarbonyl)-D-phenylalanine was produced,
and recrystallized from methanol-water to give the desired product
(8 g, yield 66%).
m.p. 111.degree.-112.degree. C. Specific Rotation
[.alpha.].sub.D.sup.20 -13.2.degree. (C=1, methanol).
EXAMPLE 37
ICR-CDI mice (Male, five weeks old, Body weight: 20 g) were
abstained from food for 18 hours, and then used as test
subjects.
The phenylalanine derivative of the present invention was suspended
in 0.5% CMC-0.14M sodium chloride buffer solution (pH 7.4). The
solution thus obtained was administered orally in fixed volume
amounts to the test subjects. After a predetermined time, the
percentage decrease of the blood glucose against the control group
was determined. The results are shown in the following Table.
______________________________________ Example Amounts used in
sample Decrease in blood glucose No. mg/kg body weight after 60
minutes (%) ______________________________________ 21 25 26 22 100
43 23 100 35 24 100 30 25 100 32 26 100 0 27 100 0 28 6.25 24 29
6.25 31 30 6.25 30 31 1.5 30 32 6.25 37 33 100 23 34 100 14 35 25
24 36 100 27 ______________________________________
It is clear from the foregoing that the D-phenylalanine derivatives
as described above can be used as an antidiabetic drug for oral
administration as well as the more usual parenteral
administration.
* * * * *