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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 . . . .

- - - - - - - - - - - - - - - - - - - - - - - - -- - - - - -

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.


6/41

3. The organogermanium compound as recited in

wherein Z represents a hydroxy group.


wherein Z represents an amino group.


wherein A represents a phenyl group, B represent

hydrogen atom or a lower alkyl group and Z repre

hydroxyl or amino group.


wherein B represents a hydrogen atom.


wherein B represents a lower alkyl group.

Descr ip t ion

BACKGROUND OF THE INVENTION

1. Field of the Invention


7/41

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


8/41

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


9/41

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


10/41

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


11/41

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): ##


12/41

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


13/41

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


14/41

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


15/41

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


16/41

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


17/41

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


18/41

______________________________________

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).


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


19/41

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.


______________________________________

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.


20/41

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


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


21/41

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).



22/41

______________________________________

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)


23/41

____________________________________________________

______________

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##


24/41

##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)


25/41

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


26/41

____________________________________________________

______________

TABLE (2)

____________________________________________________

______________poundCom-

##STR34## pointMelting

IR(KBr, cm.sup.-1)

(solvent)

NMR (.delta.)

(%)Yield____________________________________________________

______________

(8)

##STR35##

##STR36##

##STR37####STR38##

##STR39##

225.about.226 (dec)


27/41

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##


28/41

##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)


29/41

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


30/41

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


31/41

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


32/41

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)


33/41

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)

+ -- + --

____________________________________________________


34/41

______________

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) -- --

______________________________________


35/41

##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


36/41

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


37/41

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


38/41

(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


39/41

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


40/41

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.

* * * * *Tags:medical literaturePrev:Process for making a ORGANIC GERMANIUM (Dr.K. Asai History). By - ATP GlobalFoundtion. Series # 028Next:Medical / Technical Aspect of ORGANIC GERMANIUM (US PATENT #03). By -ATP GlobalFoundation. Series -#030editdelete

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