Method of producing acid-additive salts of amidine compounds

专利摘要:
Novel amidine compounds represented by formula (I) (wherein R, and R2 each represents hydrogen, a straight or branched chain alkyl group containing 1 to 6 carbon atoms, R3 represents a straight or branched chain alkyl group containing 1 to 6 carbon atoms or R4-B-(VH2)n-, n represents -0- or NH-, R4 represents hydrogen, R5-CO- or -CH2-, R5 represents a straight or branched chain alkyl group containing 1 to 15 carbon atoms, and R, and Ra may optionally form a ring via 2 to 4 carbon atoms which may contain a double bond or a straight or branched alkyl substituent containing 1 to 4 carbon atoms) and medicinally acceptable acid addition salts thereof are useful as orally administrable anti-trypsin, anti-plasmin, anti-kallikrein, anti-thrombin, and anti-complement agents.
公开号:SU1456008A3
申请号:SU864027333
申请日:1986-03-24
公开日:1989-01-30
发明作者:Фудзии Сецуроу；Окутоме Тосиюки；Накаяма Тоео；Нуномура Сигеки；Судо Кимио；Ватанабе Синити；Куруми Масатеру；Аояма Такуо
申请人:Тории Энд Ко, Лтд (Фирма)；
IPC主号:

专利说明:

The invention relates to the synthesis of amidine derivatives, in particular, to a method for producing acid addition salts of amidine compounds having anti-trypsin, anti-plasminic, anti-cellreacrylate compounds.

five
protivotrombinovoy and protivokomplgmentmentnoy. activity.
New amidine compounds are characterized by the general structural formula I
where when a means
 Rlnx
Ra V. Well
Nzto R is hydrogen, C, -C-alkyl; R, j is hydrogen, methyl; R, j - C-C-alkyl, BUT (CH,) 2,
CHjCONlKCIlJz-, C., H j, COO (CH) j.
% when A means

s, .20- (cn) d-;
Ry
l4
iV- With
then R4 is hydrogen,
Rj is hydrogen, methyl,
Rfe is hydrogen, methyl, or A means
R is hydrogen;
OR
iPJy-sHH N
H
H
or
H
The aim of the invention is to develop a process for the preparation of new compounds with higher anti-complement activity and low toxicity.
The compound of formula (I) is obtained by the p action of an acid addition salt of a carboxylic acid derivative of formula II with an acid addition salt of 6-amidino-2-naphthol of formula III
N.-2.
R3
 COOH +
/.
(and)
soo
1YAN NH,
(I)
five
0
five
0
five
0
45
Q
five
(1) (ii)
1Ш2
where R, R and Rj are as defined above.
The method is carried out as follows.
The compounds of formula (I) are obtained by dissolving or suspending the carboxylic acid of formula (II) in an organic solvent, such as dimethylformamide, pyridine, and the like. followed by reacting the compound of formula II with a carboxylic acid activator, such as dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DFPA), commonly used in the dehydration-condensation reaction, and adding 6-amidino-2-naphthol (III) salt.
For example, if DCC is used in the dihydration-condensation reaction, the carboxylic acid derivative of formula (II) is added to a solvent such as pyridine, then 6-amidino-2-naphthol (III) is added and the mixture is stirred at -30 to 80 ° C, preferably at room temperature, 3-5 hours until the reaction is complete, but the reaction may continue for a day. Dicyclohexyl Urea (DSL-O precipitates or remains dissolved in a solvent. In the first case, the precipitate is collected by filtration, then suspended in an appropriate solvent, such as dimethylformamide, and the mixture is filtered to remove insoluble LH-1. After adding solvent to the filtrate such as ethyl ether, ethyl acetate, acetone, the precipitate is collected by filtration to obtain the compound of formula (I). Alternatively, the combined precipitate of DSL-1 and the compounds of formula (I) are collected by filtration, then added to the corresponding wuyun
to
with
n
: N
to 1.03 g of 4- (2-imidazolinyl) aminobenzoic acid methanesulfonate, 0.96 g of 6-amidino-2-naphthol methanesulfonate, 42 g of DMAF and 1.06 g of DCC, 5 ml of anhydrous pyridine are added. The mixture was stirred at room temperature for a day, after which 50 ml of acetone was added and the precipitate formed was collected by filtration. 40 ml of DCA are added to the obtained precipitate and, after stirring, the precipitate formed from -. filtered, 20 ml of water is added to it, the insoluble matter is filtered off. The filtrate was distilled off under reduced pressure, 200 ml of acetone was added to the residue, and after filtering the precipitate formed
,
Ш12
0.8 g of 4- (2-imidazolinyl) aminobenzoic acid 6-amidino-2-naphthyl ester are obtained.
Alternatively, 4 g of 4- (2-imidazolinyl) aminobenzoic acid hydrochloride, 4.67 g of 6-amidino-2-naphthol methanesulfonate and 0.2 g of D1-1AF are dissolved in 60 ml of anhydrous pyridine, to the resulting solution is added 5, 13 g of DCC, after which the reaction mixture is treated, as indicated in the column, via the carbonate salt to obtain 2.35 g of 4- (2-imidazolinyl) aminobenzoic acid 6-amidino-2-naphthyl ester dichlorohydrate.
Compounds 3-18 are prepared analogously to examples 1 and 2, and their characteristics are listed in Table. one.
100 ml of thionyl chloride are added to 3 g of 4- (2,2-dimethyl) guanidinobenzoic acid and the resulting mixture is heated under reflux for 1 hour.
ntexan is added to the mixture to give 4- (2,2-dimethyl) -guanidinobenzoyl chloride hydrochloride. To 3.1 g of 6-amino-2-naphthol methanesulfonate was added 40 ml of anhydrous pyridine. 4- (2,2-dimethyl) guanidinobenzoyl chloride hydrochloride is added to the cooled and stirred mixture and the resulting mixture is stirred overnight at room temperature. The mixture is added to 300 ml of ether to give an oil which is separated. The oil is admixed with 100 ml of water and a saturated sodium bicarbonate aqueous solution is added to the mixture, which gives a light yellow solid after separation. The solid is collected by filtration, washed with water and acetone, then suspended in 40 ml of dimethylformamide. 3.4 g of methanesulphonic acid is added to the suspension. 300 ml of ether are further added to the mixture. The resulting mixture is stirred. After removal of the ester, 300 ml of acetone is added and the mixture is stirred to obtain a white solid, 6-amidiio-2-naphthyl-4- (2,2-dimethyl) guanidinobenzoate dimethanesulfonate.
Testing and clinical significance of the protease inhibitors obtained from the point of view of inhibition of the above proteases, their role in a living organism, and connection with diseases.
Trypsin. Trypsin is a protease, originally existing in the form of zymogen-trypsinogen in the pancreas, secreted into the small intestine, where it is converted into trypsin by enterokinase present in the intestine. Trypsin plays a role
soo
NH
ira.
one of the enzymes that promote digestion. If for some reason trypsinogen is activated in the pancreas to form trypsin, the pancreatic tissue is damaged with the appearance of the clinical symptoms of pancreatitis. Experiments in rats have shown that when trypsin is injected into the pancreas, symptoms of acute pancreatitis appear, and the disease is cured by administering a trypsin inhibitor. Therefore, the compounds of formula I have a strong inhibitory activity against trypsin and can be used as an anti-trypsin agent, clinically effective in the treatment of pancreatitis. I
Plasmin. Plasmin refers to blood enzymes, usually existing in the form of zymogen - plasminogen, which is converted to plasmin upon activation of the tissue by plasminogen activator, such as urokinase. This enzyme is opposite to thrombin in its action, i.e. its action is manifested in the dissolution of fibrin. Plasmin plays an important role in ensuring the flow of blood through the capillaries. However, if for any reason this enzyme becomes abnormally activated, this leads to the occurrence of diseases associated with bleeding. The same enzyme is involved in inflammatory processes, increasing vascular permeability and causing the appearance of edema. As a consequence, the inhibitor of this enzyme is applicable as a medicine for the treatment of bleeding disorders and inflammatory processes.
Kallikrein. Kallikrein is an enzyme that is widely distributed.
in blood, other organs and glands, usually in the form of its precursor prekallikrein, which is activated by Hagemann factor or other proteases. This enzyme is involved in the blood pressure lowering system - kallikrein - kinin, which counteracts the rein - antitensin system, which plays a blood pressure, and plays an important role in regulating blood pressure. The enzyme is also involved in the exogenous blood coagulation system. In addition, kallikrein produced by organs or glands plays an important role in improving local circulation. However, the abnormal activation, in particular, abnormal local activation, of this enzyme is caused by a lack of local blood circulation due to the disruption of the blood coagulation system, causing inflammation, the appearance of ulcers. Thus, a kallikrein inhibitor is useful for regulating blood pressure and as a medicine for treating inflammations and ulcers.
Thrombin Thrombin is known as an enzyme with blood clotting activity. In the normal state, thrombin is formed upon the activation of prothrombin in the blood in the event of damage to the vascular walls. The action of thrombin is to decompose
35
Complement is one of the components of blood serum and consists of 9 components from C1 to C9. C1 is divided into three subcomponents: Clq, C1g, and CIs. Cir and CIs mean activated forms of C1g and CIs, respectively. Initially, the complement was considered to be part of the process of protection against infections in a living organism, because it has the ability to bacteriolize, but later its close connection with immunity became apparent. It was shown that 40
blood fibrinogen to fibrin. The resulting fibrin is deposited on the lesion activated by the immune complex.
increasing from C1 to C9 with the onset of cytolysis or hemolysis at the final stage (activation of C9). It was also shown that fragments (for example, SZa, C5a) formed during activation of the complement system increase vascular permeability and promote neutrophil chemotaxis or immune adhesion. The results of the study of the relationship between the abnormal part of the vessel wall, preventing the outflow of plasma components, while promoting tissue repair. However, if there is an abnormal activation for any reason, a coagulation system throughout the body produces tiny blood clots in the capillaries. Thus, the compounds of the formula I are applicable for the treatment of such diseases.
Antidrypsin, antiplasmin, antikallikreinovuyu and protivotrombinovuyu activity is revealed according to the well-known method Muramat-SU. The results are shown in Table. 2. Summarized in table. 2, the results are expressed as the molar concentration (HP) of the test compound, in which it inhibits by 50% the ability of each enzyme to hydrolyze tosylarginin methyl ester (META). Connection number
45
Noah activation of complement and various diseases, in particular, showed a close relationship of autoimmune diseases with complement. For example, autoimmune diseases associated with abnormal activation of a complement include autoimmune hemolytic anemia, autoimmune thrombopenia, leukopenia, renal glomerular damage, systematic lupus erythematosus, serum disorders, periarteritis of the nodes.
0
five
Q
25
thirty
35
corresponds to its number given in the examples. The number in parentheses indicates the percentage inhibition at a concentration of 1x10 M.
The compounds of formula I have a strong inhibitory activity against C1 esterase (C1g, C1g), the ability to inhibit hemolysis transmitted through complement, and therapeutic activity against Forsmean shock, in which activation of the complement system caused by the immune complex plays an important role. This indicates that the compounds of the formula I are applicable as a complementing drug, effective in the treatment of allergic diseases, such as complement-associated nephritis.

A. Anti-complement activity (Clf, C1s).
Complement is one of the components of blood serum and consists of 9 components from C1 to C9. C1 is divided into three subcomponents: Clq, C1g, and CIs. Cir and CIs mean activated forms of C1g and CIs, respectively. Initially, the complement was thought to be part of the process of protecting against infections in a living organism, because it has the ability to bacteriolize, but later its close connection with immunity became apparent. Complement has been shown to be activated by the immune complex.
40
45
Noah activation of complement and various diseases, in particular, showed a close relationship of autoimmune diseases with complement. For example, autoimmune diseases associated with abnormal activation of a complement include autoimmune hemolytic anemia, autoimmune thrombopenia, leukopenia, renal glomerular damage, systematic lupus erythematosus, serum disorders, periarteritis of the nodes.
914
The inhibitory effect of the compounds of formula 1 on the C1 esterase, kpoMe, of the effect of the compounds of the invention on the complement system is studied. The purpose was carried out (Vnnyh research was to determine the applicability of the compounds of formula I as drugs for treating autoimmune diseases,
B. Hemolysis, transmitted through complement. Hemolysis, transmitted through complement, is widely used as a means to determine the titer of complement. The principle of the method is that hemolysis is caused by the activation of complement when the latter is added to the complex of erythrocytes and their antibodies (immune complex). The degree of hemolysis varies in proportion to the amount of complement added. Therefore, when using a known amount of complement in admixture with a C1-esterase inhibitor, hemolysis should be suppressed in proportion to the inhibitory activity.
The inhibitory activity of the compounds of the invention with respect to the C1 esterase is shown in Table. 3
C. Shock Forssman.
In contrast to other animals, guinea pigs have a special antigen on the surface of their organs, called the Forssman antigen, which interacts in a special way with red blood cell antibodies, Bvc. Shock Forssman is a shock caused by the introduction of sheep erythrocyte antibodies to guinea pigs. Shock Forssman is a model in which the principal role is played by complement, it is associated with the -classical scheme, in which the complement system is activated on an incremental basis, starting from C1. Since the involvement of complement in autoimmune diseases has been established, Forssman’s shock is a useful tool for testing drugs for treating autoimmune diseases.
The effectiveness of compounds of the formula I in relation to shock Forssman when administered orally is shown in
tab. four.
Anti-complement activity
 . / gch gcho 4


A. Anti-CI Activity (Clr.CIs) and Inhibition of Transmitting Hemolysis Through Complement.
The activity against C1 esterase (Clf, CIs) is determined according to the OkaTig method.

g about 5
ten
Data on activity are given in tab. 3
B. Inhibition of transmitting through complement hemolysis is determined according to the method of Baker et al.
Given in Table. The 3 figures have the following meanings: C1 is the molar concentration of the test compound, at which it inhibits by 50% the ability of C1g to hydrolyze acetylargenin methyl ester (MEAA); CIs is the molar concentration of the test compound at which it inhibits by 50% the ability of CIs to hydrolyze acetyl tyrosine ethyl ester (EEAT); the numbers in parentheses indicate the percentage of inhibition at a concentration of 1x10 M.
0
S. Shock Forssman.
Experiments are given according to the method of I.G.Offerness and others.
Male Hartley guinea pig farms weighing approximately 350 g are used as experimental animals. Each guinea pig from the control group was injected with intravenous injection of hemolysin (the minimum dose causing shock, an activity of 5000 units, determined according to the Ogata method), after which the time until death occurred. Each guinea pig from the experimental group after oral administration of the compound (100 mg / kg) was intravenously administered hemolysin, after which the time until death occurred.
Mode of administration.
The compounds of formula I are most conveniently administered orally, although administration is possible in the form of suppositories or injections. The compounds are used as a drug, either alone or in combination with other drugs. They are usually used in the form of medical compositions, although they can be used in the form of pure compounds without any additives. The compounds of formula I can be used in the form of the following dosage forms: tablets, powders, capsules, syrups and solutions. Compositions for oral administration may contain conventional additives, such as binders, diluents, lubricants, disintegrators and excipients. Liquid dosage forms for oral administration can be in the form of aqueous and oily suspensions, solutions, emulsions, syrups or elixirs, a dry syrup can be used.
0
45
0
NNL / Zgchu) -1 | g U -Sooo) -l lnga HaN I - MoVf
 d.
i;) ii-g -COO- oK, - - OW
NH mlz
H NzS-lJ

(o) -co-5

(known) (compound 2)
/.:NH
CN (compound 3) (compound 4)
On irritation of the rectal mucous membrane, irritation of the digestive organs is judged, which determines the POSSIBILITY of taking the medication by mouth.
Compounds 2-4, 16, dissolved in distilled water, are administered through the rectum via a gastric probe to male rats kept in a cage for about 20 hours.
After insertion, the anus of the rat is closed with adhesive material.
The rats are sacrificed and autopsied 3 hours after the end of the entry. The condition of the rectum is observed with the naked eye. In each group, 3 rats were used, with dosages of 3, 10, 30 and 100 mg / kg being used.
Data on toxicity are given in table. 6
As can be seen from the table. 6, the well-known compound strongly irritates the rectal mucosa and cannot be administered by mouth for therapeutic purposes, while the proposed compounds do not cause irritation, which allows them to be taken as a medicine by mouth. ; LDyo are given in table. 7
Thus, the proposed method allows to obtain new compounds with low toxicity and high active component activity as compared with the known structural analogue.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining the acid-additive salts of 45 amidine compounds of general formula I
Oh geooCHO
lira
1Ш
where when a
EI Nz
Riin
MX
then R
- w
- C-C-alkyl, hydrogen; IX2 is hydrogen, methyl; .R. - C-C-alkyl, BUT (CH), CH 2 SO 4 H (CH 2) g-, e, COO (CH), C HsCH 2 O- (CH) 7-,
KV when A
RS
25
then R4 R is hydrogen;
Rj, RC is hydrogen, methyl;
or a 0
Lknn
five
n
H
H
or
Ss
n
characterized in that the acid addition salt of the carboxylic acid derivative of general formula II
45
40
50
soon
where A has the indicated meanings, is reacted with the acid addition salt of 6-amidino-2-naphthol of formula III
.
if necessary, the compound of formula I is converted from one salt to another. .
15
NzS-Nl
NZS-HN N
(- “)
H
H
about
N /
SNS N
ZS -S)
H N
to.
WITH
HC1 MSA 2 MSA 2HC1 2 MSA
2 MSA
2 MSA
2 MSA
H
N,
OS
2HC1
-irw /
NCS-1SH HN.,
2HC1
-TffA
YZS-N
2 MSA
1456008
16 T a b i c a 1
269-271 271-274
274-277 (decomp.) 242-244 (decomp.)
240-242
198-204
240-242
188 (different)
288-290 (decomp.)
255-259 (decomp.)
241-243 (decomp.)
17
1456008
HN, HsCj-HN
NzS-Kl
|
HsCa-HN / HgCa- V
H5C2-HN /
1SHL
nzs- (cis) з- ™
NZS--. NzS- (CH2) s-NC
HN
15
sixteen
17
18
but - (sn2)
V. G
2HC1
HN
H3CC01 H- (CH2) 2HC1
HN
205-208 (decomp.)
1725
Ci5H3iCOO- (CH2)
HN
@ -СН2-0- (СНг) 2-НН
2CiyH ,, COOH 105-109 (dec)
V- 2HC1
136-140 (dec
, 18 Continuation of table 1
2 MSA
38-242
HC1 MSA
1730
HC1 MSA
1730
2 MSA
240-243
2HC1
1720
2HC1
205-208 (decomp.)
1725
V- 2HC1
136-140 (decomp.)
Control i Group, exposed group, with compound i
Survival Survival
12911,108
390Survival
5041255
613Surfacing
404980
868855
Table3
Connection Inhibition of shock by Forssman,% survivors, at a dose, mg / kg
 --T ---,
0.1 0.3 I 1.0
2100
7О 31 33
1533
1633 66 100 100 18100
KnownOb 33
Ta.litzib Compound D Toxicity at dose, mg / kg
I 3 1 10 I 30 I 100 Known + + + ++
. "
about",.".-
4 16- - - Note. + - hyperemia in the mucous
rectal membrane; - - no change in the rectum.
Table
T
Connection lj, mg / kg (mouse)
Intravenous (Through the mouth
219300
X
358More .3000 5 58 Over 3000
1358More than 3000
169More than 3000

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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JP59155045A|JPH0461868B2|1984-07-25|1984-07-25|

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