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Process for making Organic Germanium (USPATENT #02). By - ATP Global Foundation. Series# 029
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e d u c a t i o n a l d o c u m e n t st h a t w e h a v e a n d g i v e itt h e m t o y o u r d o c t o r.Y o u r d o c t o r m a y v e r yw e l l be g ra te fu l t ha t youd id . . . .
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Paten ts /P repa ra t ion o fO rganogermanium compoundUnited StatesPatent 4,681,960 Kakimoto , etal. July 21, 1987
Organogermanium
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compound
AbstractThe present invention provides (1) a
new organogermanium compound of
the following general formula:
##STR1## wherein A represents a
hydrogen atom, a lower alkyl group
such as a methyl or ethyl group or a
phenyl group, B represents a hydrogen
atom or a lower alkyl group as
mentioned above and Z represents a
hydroxyl or amino group and (2) an
opioid peptide-degrading enzymeinhibitor containing the compound (1)
as a principal ingredient.
.
Inventors: Kakimoto; Norihiro (Tokyo, JP);Katayama; Takashi (Tokyo, JP);Hazato; Tadahiko (Saitama, JP);Ohnishi; Tsutomu (Tokyo, JP)
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Assignee: Asai Germanium Research Ins(Tokyo, JP)
Appl. No.: 626787Filed: July 2, 1984
Foreign Application Priority DataJul 01, 1983[JP] 58-119856
Jul 11, 1983[JP] 58-125725
Current U.S. Class:Intern'l Class: Field of Search: 260/429 R
References Cited [Referenced By]U.S. Patent Documents
4271084 Jun., 1981Ishikawa et
al.
4508654 Apr., 1985 Chang et al.
Foreign Patent Documents55-105696 Aug., 1980 JP
57-203090 Dec., 1982 JP
Other References
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=/netahtml/search-adv.htm&r=0&f=S&l=50&d=CR87&Query=ref/4,681,960http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/4271084http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/4508654http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=/netahtml/search-adv.htm&r=0&f=S&l=50&d=CR87&Query=ref/4,681,960http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/4271084http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/4508654 -
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Chemical Abstracts 98, 215805a (1983).
Primary Examiner:Sneed; H. M. S.
Attorney, Agent or Firm:Burns, Doane, Swecker &
C l a i m sWhat is claimed is:
1. An organogermanium compound having the for
##STR66## wherein A represents a lower alkyl gr
phenyl group; when A represents a lower alkyl gro
represents a lower alkyl group connected to the s
carbon atom and Z represents a hydroxyl or aminwhen A represents a phenyl group, B represents a
hydrogen atom or a lower alkyl group and Z repre
hydroxyl or amino group; said alkyl group selecte
the group consisting of methyl, ethyl and propyl.
2. The organogermanium compound as recited in wherein A represents a lower alkyl group, B repre
lower alkyl group connected to the same carbon a
and Z represents a hydroxyl or amino group.
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3. The organogermanium compound as recited in
wherein Z represents a hydroxy group.
4. The organogermanium compound as recited in
wherein Z represents an amino group.
5. The organogermanium compound as recited in
wherein A represents a phenyl group, B represent
hydrogen atom or a lower alkyl group and Z repre
hydroxyl or amino group.
6. The organogermanium compound as recited in
wherein B represents a hydrogen atom.
7. The organogermanium compound as recited in
wherein B represents a lower alkyl group.
Descr ip t ion
BACKGROUND OF THE INVENTION
1. Field of the Invention
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The present invention relates to organogermanium
compounds having new structures and a strong o
peptide-degrading enzyme inhibitor containing the
as a principal ingredient.
2. Description of the Prior Art
Germanium (Ge), known as a homologue of carbo
semiconductive effect like silicon (Si) as a specia
property and, in addition, it has been studied in th
aspect for a long time. Recently, the studies of
organogermanium compounds have been advance
the results thereof have been reported and they h
attracted public attention in various technical fie
It is well known from reports of numerous scienti
meetings and literature that a carboxyethylgerma
sesquioxide (GeCH.sub.2 CH.sub.2 COOH).sub.2 O
as a macromolecular compound (a propionic acid
derivative of germanium) containing a 12-member
as a unit structure in which germanium atoms anoxygen atoms are arranged alternately, has quite
excellent physiological effects such as strong
hypotensive and antineoplastic effects, and it is f
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from toxicity or adverse reaction.
It has also been reported that when the above me
organogermanium compound is administered to a
who complains of pain such as a cancerous pain,
growth of the tumor is inhibited and the dose of a
narcotic analgesic such as morphine required for
relieving the pain can be reduced. For this fact, th
following hypothesis has been given.
Namely, when morphine or the like is administere
peptides generally called "opioid peptides" are lib
in vivo. This opioid peptide and morphine shre the
receptor to control the autoanalgesic activity in v
reason why the dose of morphine or the like can breduced by the administration of the organogerma
compound is that the organogermanium compoun
inhibits the action of opioid peptide-degrading en
which inactivate the opioid peptide by decompos
vivo to improve the efficiency of the opioid peptid
vivo.
However, the mechanism of the physiological act
the organogermanium compound has not fully bee
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known. As for the antineoplastic effects, some
researchers reported that the effect is realized ba
a germanium-oxygen bond in the structure. If an
organogermanium compound containing an analo
atom in place of the oxygen atom can be synthes
the use of the resulting compound for a purpose d
from that of the known organogermanium compou
be expected.
SUMMARY OF THE INVENTION
The present invention has been completed under
circumstances. It is an object of the present inve
provide organogermanium compounds having the
following general formula: ##STR2## wherein Arepresents a hydrogen atom, a lower alkyl group s
a methyl or ethyl group or a phenyl group, B repre
hydrogen atom or a lower alkyl group as mentione
above and Z represents a hydroxyl or amino group
Another object of the present invention is to provopioid peptide-degrading enzyme inhibitor which
comprises as a principal ingredient an organogerm
compound of the following general formula: ##ST
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wherein A represents a hydrogen atom, a lower a
group such as a methyl or ethyl group or phenyl g
represents a hydrogen atom or a lower alkyl grou
mentioned above and Z represents a hydroxyl or a
group.
DETAILED DESCRIPTION OF THE PREFERED
EMBODIMENTS
In the organogermanium compound of the presen
invention, a germanium atom is bonded with prop
acid derivative (when Z is OH) or its amide (when
NH.sub.2), in which a substituent A is placed in a
.alpha.-position and substituent(s) B is (are) place
.alpha.-position and/or .beta.-position to the germatom on this propionic acid skeleton to form a
germylpropionic acid as a base construction (in w
carbon atoms on the propionic acid skeleton not
with the substituent B are bonded with hydrogen
and germanium atoms of this base construction a
sulfur atoms are bonded in a ratio of 2/3 to formethylgermanium sesquisulfide.
The substituent A is a hydrogen atom, a lower alk
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group such as a methyl, ethyl or propyl group or a
substituted or unsubstituted phenyl group. The
substituent B is a hydrogen atom or an alkyl grou
mentioned in the substituent A. Therefore, the
organogermanium compounds of the present inve
include the following compounds: ##STR4##
The compounds in the present invention are repre
as above, since the ratio of the germylpropionic a
the sulfur atom is 2/3 in these compounds. The
compounds of the present invention may be repre
also as follows: ##STR5##
The compounds of the present invention having th
above mentioned structures may be prepared by vprocesses.
The compounds of the general formula (I) wherein
represents OH [i.e. compounds (I')] may be prepar
reacting a corresponding trichlorogermanium com
(II) with dry hydrogen sulfide gas (H.sub.2 S) in thpresence of a base such as pyridine in an organic
as shown by the following reaction scheme (I): ##
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The compounds of the general formula (I) wherein
NH.sub.2 [i.e. compounds (I")] may be prepared by
converting the same trichlorogermanium compou
as above into a corresponding acid chloride (III), t
reacting the same with ammonia (NH.sub.3) to fo
amide (IV) and reacting the product with dry halo
sulfide gas in the presence of a base in an organi
solvent in the same manner as above, as shown b
following reaction scheme (2): ##STR7##
In the above reaction scheme (1) and (2), a merca
compound of the formula: ##STR8## is formed by
reaction with hydrogen sulfide. This mercapto co
may be either isolated or not. When this compoun
isolated, intermolecular hydrogen sulfide elimoccurs to form a structure of the general formula
The trichlorogermanium compound (II) being used
above mentioned reaction may be prepared by a p
disclosed in the specification of Japanese Patent
Publication No. 2964/1971 as follows: ##STR9##Alternatively, the compound (II) may be prepared
directly reacting the same starting material as ab
with an acrylic acid derivative as follows: ##STR1
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The thus-obtained compounds of the present inve
including the above mentioned compounds (1) to
colorless, transparent crystals having a melting p
decomposition point) of generally around 200.deg
The results of elementary analyses coincide with
calculated from the respective molecular formula
differences between them being within the range
measuremental error. The results of infrared (IR)
absorption spectrum and nuclear magnetic reson
(NMR) absorption spectrum prove that the compo
the present invention are those shown by the abo
general formula (I).
The compounds of the present invention arecharacterized in that they are slightly soluble in w
and highly soluble in an organic solvent miscible
water, such as acetone or alcohol, namely they a
soluble, while the above mentioned
carboxyethylgermanium sesquioxide is slightly so
water and insoluble in an organic solvent at all.
The organogermanium compounds of the present
invention have the germanium-sulfur bonds very c
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the germanium-oxygen bonds in the known
carboxyethylgermanium sesquioxide. It is expect
therefore, when the compound of the present inve
administered to a living body, similar antineoplas
effect, etc., are obtained. In this connection, it is
noted that the effect of the organogermanium
compounds of the present invention resides in a s
inhibition of the opioid peptide-degrading actions
above mentioned opioid peptide-degrading enzym
Namely, as described above, the substances gene
called "opioid peptides" which are peptides found
living bodies are quite important compounds man
the autoanalgesic activity in vivo. The opioid pep
includes several compounds such as enkephalin ifrom swine or bovine brains by Hughes et al. in 19
having the following structure:
H.sub.2 N--Tyr--GlY--Gly--Phe--Met--OH
As the enzymes which degrade the opioid peptideas enkephalin, there have been found numerous e
such as dipeptidylaminopeptidase and aminopept
which can be separated from various living tissue
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purified. It has been found that when these enzym
reacted on the opioid peptides or their model com
in the presence of the compound of the present
invention, the compound of the invention strongly
the action of the enzymes.
The effects of the compounds of the present inve
are quite strong. For example, the compound (4) h
97.0% inhibition against the effect of aminopeptid
(derived from bovine longitudinal muscle) on enke
i.e. one of the opioid peptide. Thus, when an opio
peptide-degrading enzyme inhibitor in the form of
preparation such as tablets, powder, granules or
capsules or a liquid preparation such as an inject
containing the organogermanium compound of thpresent invention as the principal ingredient is
administered to a living body, the effects of the o
peptide-degrading enzyme is remarkably inhibited
the effective utilization of the opioid peptide is im
Consequently, the medical effects of a narcotic
substance such as morphine become remarkable dose of the narcotic substance to be used for obt
given medical effect can be reduced. Thus, side e
brought about by the continuous use of the narco
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substance such as habituation and addiction c
relieved.
Dipeptidylcarboxypeptidase which is one of the o
peptide-degrading enzymes acts also as an conve
enzyme for angiotensin I which is a precursor of
angiotensin II (an enzyme having a quite strong
hypertensive effect). Therefore, when this effect
enzyme is inhibited, the inhibitor also acts on a
renin/angiotensin/aldosterone system to exert pre
influences on the living body, particularly blood p
maintenance mechanism.
The following examples will further illustrat
invention.
EXAMPLE 1
Preparation of compound (I') of the present invent
Synthesis of compound (1):
25.2 g (0.1 mol) of .beta.-trichlorogermylpropionic
was dissolved in 200 ml of anhydrous benzene. 24
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mol) of anhydrous pyridine was added to the solut
the mixture was stirred. Then, dry hydrogen sulfid
was introduced therein for 60 min. Benzene was r
carefully from the resulting oily product and then
residue was dissolved in 100 ml of methanol. The
solution was added to 300 ml of purified water an
crystals thus formed were recrystallized from me
to obtain 16.2 g of compound (1) of the present in
in the form of colorless plate. Yield was 78%.
Compound (1):
melting point: 200.degree. C. (calculated from the
spectrum; the same shall apply hereinafter).
elementary analysis:
______________________________________
Ge C H S
______________________________________
found 37.44 18.61 2.62 24.83
calculated 37.41 18.58 2.62 24.88
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______________________________________
IR (KBr, cm.sup.-1): 3420, 1710, 425.
NMR (methanol d.sub.4 .sigma.): 1.97 (2H, t, Ge--
CH.sub.2), 2.67 (2H, t, CH.sub.2 --CO).
Synthesis of compound (4):
20.02 g (0.2 mol) of (E)-2-methyl-2-butenoic acid w
dissolved in 100 ml of dry ethyl ether. 36.0 g (0.2
trichlorogermane was added to the solution and s
for 2 hrs. Crystals thus formed were recrystallized
n-hexane to obtain 42.86 g (yield: 76.5%) of 2-met
(trichlorogermyl)butanoic acid in the form of colo
plate.
Then, 5.6 g (0.02 mol) of 2-methyl-3-
(trichlorogermyl)butanoic acid prepared as above
dissolved in 100 ml of anhydrous benzene. 5.2 g (0
mol) of anhydrous pyridine was added to the solut
the mixture was stirred and dry hydrogen sulfide
introduced therein for 60 min. A compound thus
precipitated was separated and then recrystallize
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anhydrous acetone or purified by isolating the sam
means of a molecular sieve such as Sephadex LH
(trade name) using methanol as a eluant to obtain
of compound (4) of the present invention. Yield w
72.1%.
Compound (4):
melting point: 235.degree. C.
elementary analysis:
______________________________________
Ge C H S
______________________________________
calculated: 32.73 27.07 4.09 21.68
found: 32.50 27.13 4.02 21.92
______________________________________
IR(KBr, cm.sup.-1): 3400, 2960, 1700, 1445, 1225,
680, 600, 425.
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NMR(CD.sub.3 OD, .sigma.)l: 1.33 (3H, dd, Ge--CH-
CH.sub.3), 1.40 (3H, dd, CO--CH--CH.sub.3), 2.18 (1
Ge--CH), 2.80 (1H, m, CO--CH).
Other compounds may also be prepared in the sam
manner as above. The physical properties of the
compounds (I') are shown in Tabel (1).
EXAMPLE 2
Preparation of compound (1") of the present inven
Synthesis of compound (11):
28.0 g (0.1 mol) of 2-methyl-3-(trichlorogermyl)butacid was treated with 100 ml of thionyl chloride a
distilled under reduced pressure to obtain 27.0 g
90.4%) of 2-methyl-3-(trichlorogermyl)-butanoyl ch
as a light yellow fraction having a boiling point of
99.degree. to 100.degree. C./6 mmHg.
5.8 g (0.02 mol) of this chloride was dissolved in 5
anhydrous benzene. Dry ammonia was introduced
under cooling with ice for 1 h. Then, dry hydrogen
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chloride gas was introduced therein for 1 h. 100 m
methyl acetate was added thereto and the mixtur
stirred and filtered. The filtrate was distilled and
residue was recrystallized from a liquid mixture o
acetone/benzene (1/2) to obtain 4.1 g (yield: 76.0%
methyl-3-(trichlorogermyl)butanamide.
10.8 g (0.04 mol) of the obtained 2-methyl-3-
(trichlorogermyl)butanamide was dissolved in 200
anhydrous benzene. 9.5 g (0.12 mol) of anhydrous
pyridine was added to the solution and the mixtur
stirred. Dry hydrogen sulfide gas was introduced t
for 60 min. A compound thus precipitated was sep
and then recrystallized from anhydrous acetone o
purified by isolating the same by means of a molesieve such as Sephadex LH-20 (trade name) using
methanol as a eluant to obtain 7.8 g of compound
the present invention. Yield was 88.3%.
Compound (11):
melting point: 205.degree. C. (decomposition).
elementary analysis:
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______________________________________
Ge C H N S
______________________________________
calculated:
32.87 27.20 4.56 6.34 21.87
found: 32.59 27.37 4.43 6.25 21.56
______________________________________
IR(KBr, cm.sup.-1): 3400, 3200, 2960, 1660, 1460,
780, 570, 420.
NMR(CD.sub.3 OD, .sigma.): 1.30 (3H, d, Ge--CH--
CH.sub.3), 1.38 (3H, d, CO--CH--CH.sub.3), 2.14 (1H
Ge--CH), 2.71 (1H, m, CO--CH).
Other compounds were prepared in the same man
above. The physical properties of the compounds
shown in Table (2).
TABLE (1)
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____________________________________________________
______________
Physical PropertiesCompound
##STR11## pointMelting
IR(KBr, cm.sup.-1)
(Solvent)
NMR (.delta.)
(%)Yield____________________________________________________
______________
(2)
##STR12##
##STR13##
##STR14####STR15##
185(dec)
3420, 1705, 425
CD.sub.3 OD
##STR16## 57.7
(3)##STR17##
##STR18##
##STR19##
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##STR20##
196(dec)
3410, 1705, 425CD.sub.3 OD
##STR21## 93
(5)
##STR22##
##STR23##
##STR24####STR25##
205(dec)
3450, 2960, 1700, 1460, 1380
1130,
680, 620, 425 CD.sub.3 OD
1.46(6H,s,(C .sub.3).sub.2), 2.60(2H
.sub.--H.sub.2)
80.3
(6)
##STR26##
##STR27####STR28##
##STR29##
265(dec)
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3450, 3040, 2850, 1710, 1600
1230,
700, 425 CD.sub.3 OD3.00(2H,d,C .sub.
CO), 3.55(1H,t,Ge
.sub.--H),
7.25(5H,m,C.sub
.6 .sub.--H.sub.5)
94.1(7)
##STR30##
##STR31##
##STR32##
##STR33##
215(dec)3450, 3030, 2980, 1705, 1455
820, 700,
680, 420 CD.sub.3 OD
1.43(3H,d,C .sub.-
), 3.27(2 .sub.--H,m
.sub.--H),7.17(5H,m,C.sub
.6 .sub.--H.sub.5)
86.0
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____________________________________________________
______________
TABLE (2)
____________________________________________________
______________poundCom-
##STR34## pointMelting
IR(KBr, cm.sup.-1)
(solvent)
NMR (.delta.)
(%)Yield____________________________________________________
______________
(8)
##STR35##
##STR36##
##STR37####STR38##
##STR39##
225.about.226 (dec)
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3340, 1665, 1620, 1240 1400
DMF-d.sub.7
1.98(2H,t,GeC .subH.sub.2
) 2.56(2H,t,COC .su
H.sub
.2) 60.2
(9)
##STR40####STR41##
##STR42##
##STR43##
##STR44##
248(dec)
3300, 3200, 1600, 1400 430CD.sub.3 OD
1.33(3H,d,GeCHC .s
H.sub
.3) 2.17.about.2.77
(3H,m,Ge .sub.--HC
H.sub.2) 84.1
(10)
##STR45##
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##STR46##
##STR47##
##STR48####STR49##
225(dec)
3300, 3200, 1660, 1460 1400
CD.sub.3 OD
1.23(3H,d,C .sub.--H
.67.about.2.25 (3H,
.sub.--HC .sub.--H.s
83.2
(12)
##STR50##
##STR51##
##STR52####STR53##
##STR54##
230(dec)
3400, 3200, 2960, 1660, 1460
CD.sub.3 OD
1.22(6H,s,C .sub.--H.sub.3CC
.sub.--H.sub.3) 2.60
.sub.--H.sub.2CO)
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76.5
(13)
##STR55####STR56##
##STR57##
##STR58##
##STR59##
210(dec)
3450, 3350, 3200, 1660, 1600765,
700, 420 CD.sub.3 OD
2.90(2H,m,C .sub.--
H.sub.2)
.55(1H,m,C .sub.--H
7.19(5H,s,C.sub.6 sub.5) 81.8
(14)
##STR60##
##STR61##
##STR62##
##STR63####STR64##
215(dec)
3450, 3350, 3200, 1660, 1455
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700,
CD.sub.3 OD
1.42(3H,m,C .sub.--H.sub.3)
.23(2H,m,CHC .sub
7.15(5H,S,C.sub.6
H.
sub.5) 82.3
__________________________________________________________________
EXAMPLE 3
Pharmacological effects of the compound of the p
invention
(1) As described above, the inhibitor of the presen
invention has a strong effect of inhibiting the acti
the opioid peptide-degrading enzyme. However, it
difficult to prove the effects of the products of the
present invention unlike other general medicines,
problems are posed because the number of cases
which narcotic drugs are used for the treatment o
diseases is not so large and the conditions of the
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patients in these cases are serious generally. On
other hand, however, some opioid peptides releas
vivo when such narcotic substances are given an
peptide-degrading enzymes have been known.
Accordingly, the effects of the products of the pre
invention were judged from inhibition rates realiz
the products were allowed to act on the opioid pe
degrading enzyme in the presence of the opioid p
in vitro.
In the tests, the product of the invention was add
opioid peptide such as enkephalin or its model
compound. After an incubation effected for a give
the inhibition rates of the product against the opi
peptide-degrading enzyme were examined. Variouopioid peptides were used. Generally, high inhibit
rates were exhibited as shown in Tables (3) and (
TABLE (3)
____________________________________________________
______________
Enzyme
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Orgin
Bovine longitudinal muscle
NameDipeptidylcarboxy-
Carboxy-
Dipeptidylamino-
Amino-
peptidase peptidase
peptidasepeptidase
Principal ingredient
Substrate
(1 .mu.g/1 ml)
Hip-His-Leu
Hip-L-PheAlaEnkephalin
Enkephalin
____________________________________________________
______________
Compound (1)
76.4% -- -- --Compound (2)
85.0% 6.2% -- --
Compound (3)
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80.0% -- 58% --
Compound (4)
60% -- -- --Compound (5)
78.8% -- + 88.0%
Compound (6)
74.2% 89.8% + 97.0%
Compound (7)
76.8% -- + --Compound (8)
78.3% -- -- --
Compound (9)
68.4% -- -- --
Compound (10)
73.4% -- -- --Compound (11)
+ -- + --
Compound (12)
+ -- + --
Compound (13)
+ -- + --Compound (14)
+ -- + --
____________________________________________________
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______________
TABLE (4)
______________________________________
Enzyme
OriginMonkey brain
Name
Dipeptidylaminopeptidase
Aminopeptidase
Substrate
Compound Enkephalin______________________________________
(1) 98.2% 87.8%
(2) 97.9% 87.6%
(3) 97.7% 85.6%
(8) -- --
(9) -- --(10) -- --
______________________________________
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##STR65##
Further, to confirm the inhibition effects of the
compounds of the present invention, 50% inhibitio
coefficients (IC.sub.50) were determined to obtai
results shown in Table (5). The effects of the com
of the present invention were thus clear.
TABLE (5)
____________________________________________________
______________
Principal ingredient
Enzyme origin Substrate
IC50
____________________________________________________
______________
Compound (2)
dipeptidyl-
bovine longitudinal
Hip-His-L-Lue
66 .mu.g/ml
carboxypeptidase
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muscle
" angiotensin
rat lung " 70 .mu.g/mconverting enzyme
" Angiotensin
monkey brain
" 78 .mu.g/ml
converting enzyme
Compound (5)amino- bovine longitudinal
Enkephalin
110 .mu.g/ml
peptidase muscle
Compound (6)
amino- bovine longitudinal" 19 .mu.g/ml
peptidase muscle
" carboxypeptidase
bovine longitudinal
Hip-L-PheAla
275 .mu.g/mlmuscle
" dipeptidyl-
bovine longitudinal
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Hip-His-Leu
100 .mu.g/ml
carboxypeptidasemuscle
____________________________________________________
______________
The inhibition rate (IC.sub.50) of the compound of
present invention containing the compound (6) as
principal ingredient on enkephalin (aminopeptidas
derived from bovine longitudinal muscle) was as h
19 .mu.g/ml. This fact suggests that the product c
used as an inhibitor against this enzyme.
The opioid peptide-degrading enzymes derived fro
bovine longitudinal muscle used in the above exa
were purified partially by a process of Goreustein
Snyder S. H., ["Life Sci." 25, 2065 (1979)]. The inh
effects of the compounds of the present invention
opioid peptide-degrading enzymes were determin
process of T. Hazato, M. Shimamura, T. Katayama
Yamamoto [B.B.R.C. 105, 470-475 (1982)] (for
dipeptidylaminopeptidase), a process of M. Shima
T. Hazato and T. Katayama [B.B.A., 756, 223-229
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(for aminopeptidase) and analogous processes.
(2) The effects of the compounds of the present in
on human bodies were examined.
A human cerebrospinal fluid was dialyzed by usin
of tris-HCl buffer having a pH of 7.0 for 5 hrs. Enke
degrading enzymes contained therein were analyz
according to a radioautography or the like. In the
cerebrospinal fluid, the aminopeptidase activity w
strongest. Further, dipeptidylaminopeptidase and
dipeptidylcarboxypeptidase activites which were
selective for bestatin were also recognized.
The compound (3) and (6) of the present inventionallowed to act on the respective enzymes. The co
(3) in a concentration of 2 mg/ml exhibited inhibit
effects on all the enzymes. The compound (6) in t
same concentration as that of the compound (3)
exhibited inhibition effects on aminopeptidase,
dipeptidylcarboxypeptidase and carboxypeptidas
On the other hand, the aminopeptidase alone was
according to cellulose column chromatography us
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NaCl solution as a eluant. IC.sub.50 values of the
two compounds on the aminopeptidase were dete
according to Porapak Q column process and high-
performance liquid chromatography using enkeph
the substrate. The results were compared with th
Arphamenin A and B the inhibitive actions of whic
the enkephalin-degrading enzyme have been know
shown in Table (6), the compounds of the present
invention in concentrations lower than those of
Arphamenin A and B exhibited the inhibition activ
TABLE (6)
______________________________________
Compound IC50 (.mu.g/m)
______________________________________
(3) 450
(6) 440
Arphamenine A 810
Arphamenine B 650
______________________________________
The external liquid used for the dialysis of the
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cerebrospinal fluid was examined minutely to rev
it contained an indogenous inhibitor against the
enkephalin-degrading enzymes.
Namely, it is considered that the human cerebro
fluid contains both the enkephalin-degrading enzy
and the indogenous inhibitors which inhibit these
enzymes and they are well-balanced under norma
conditions, a pain being caused when the balance
broken. This fact suggests the usefulness of t
compounds of the present invention in vivo.
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