DE1768655B2 - - Google Patents

Description

After gentle heating to complete and dispersant. They can be sterilized; the reaction is cooled and filtered. The product is precipitated by methanol from the filtrate, for example by filtration through a bacteria-proof fi l filtrate. The ter, incorporation of sterilizing agent into the precipitate, is filmed, washed and vacuum-dried in Va- compositions, irradiation or heating. A water-soluble 5 is obtained. You can also "in the form of a sterile solid compound powder, which is prepared in the usual organic solution, which is immediately insoluble. _Before use in sterile water or an analysis for C ₆ H ₈ N ₂ O ₅ Co (MW 247): other sterile injectable medium dissolved |

oTiTrf ¹ VlH) ^C C ² ^ ⁹ 8 ^{?: 10 The active ingredient} S ^{ehalt in the} addition according to the invention

= ^{e un} * '' ~ 'u- compositions can be varied, but it is |

necessary that it should represent such a proportion that

Example 5 a suitable dosage for the desired thera-:

peutic effect is obtained. Generally should

190 g 2-Ureidobutandisäure- (1.4) are dissolved in 1 1 water 15, the inventive preparations for oral administered ■

water is suspended and 1 g-atom of zinc is added in the form of the Carreichung in such a way that 0.5 to 5 g

bonats admitted. To complete the active ingredient per day and in the case of the parenteral

The sediment is heated, then cooled and filtered. Im administration 0.1 to 4 g of active ingredient per day.

The filtrate becomes the product by adding methanol to the effectiveness of the compounds according to the invention

precipitated, separated, washed and in vacuo 20 as a drug compared to known, similar

dried. The zinc salt obtained from the 2-ureido-active drugs. i butanedioic acid- (1,4) falls in the form of a white powder!

at. which is soluble in water and has the usual 1. anti-hyperammonemia and urogenetic properties

is insoluble in organic solvents. of the zinc salt of 2-ureidobutanedioic acid- (l, 4)

Analysis for C ₆ H ₈ N ₂ O ₅ Zn (MW 253.4): ² * ^The purpose of the investigation is to establish the

Calculated N 1105 7 is »" Effectiveness of the zinc salt of 2-ureidobutanedi-

found ".". ". NlIl 'Zn25 8 °° acid- (1,4), hereinafter referred to as CGZn, for

^s' -ο- reduction in hyperammonemia, observed in rats

The invention also relates to pharmaceutical compositions which are caused by acute ammonia poisoning and which contain one or more of the haematic levels of ammonia-new metal salts. These pharmaceutical non-ferrous nitrogen (N / NH ₃ ) and urea 15 and compositions can be oral or parenteral. Determined 60 minutes after administration of the toxic submixed with a solid or liquid pharmaceutical. These determinations allow chemical carriers to be administered. the effectiveness of the fixation and correction of Solid compositions for oral administration site 35 NH ₃ can deviation is over the urogenetischen detoxification pathway in the form of compressed tablets are.

Pills, dispersible powders and granules before- The results of the tests carried out are at. In these solid compositions, intraperitoneal administration is found in the table 1 after at least one of the new metal salts mixed, the results of at least one inert diluent such as 40 for oral administration in table 2. For comparison calcium carbonate, starch, alginic acid or lactose. In addition to the compound according to the invention, the compositions can also, as is customary with arginine and a mixture of zinc and 2-ureido, other substances besides the inert butanedioic acid administered in the same way. The thinners containing, for example, lubricants showed results leave the superior effectiveness as magnesium stearate. 45 recognize the compound according to the invention. The liquid compositions for oral administration - ammonia level is effectively reduced by these are pharmaceutically acceptable emulsions, depending on the dose administered, solutions, suspensions, syrups and elixirs, soft and in parallel with this, the content of urea increases the commonly used inert diluent nitrogen ( NZNH ₂ - CO - NH ₂ ). This indicates that agents such as water and liquid paraffin contain. In addition to the inert diluents, a considerable amount of ammonia is contained in urea. Better effectiveness can be seen in such compositions, including additives, such as intraperitoneal administration, but wetting and suspending agents, as well as sweeteners and additives, are clearly flavored when administered orally. recognizable. In a dosage of 1 mM / kg ip the compositions according to the invention for 55 inventive \ 'erbinde return the hematidy oral administration can see in capsules from absorbed ammonia values 60 minutes after the poisonable material, such as gelatin, which at least cation return to normal values. In the case of the control lines of the new metal salts with or without the addition of oils, the solid-diluent values are twice as high at the same time! or contain excipients. With the two comparison substances are to be submitted. 60 Am products according to the invention for parenteral monia values, which were significantly higher than the initial value, presented. The here with arginine in one adjustment comprise sterile aqueous or non-aqueous dosage of 1 mM / kg ip and with the mixture solutions, suspensions or emulsions. Examples of ammonia values achieved at 2 mM / kg po correspond for non-aqueous solvents or suspensions to those that use the connecting media according to the invention are propylene glycol, polyethylene glycol, plants in a dose of 0.25 mM / kg ip or oils such as olive oil and injectable organic 0.5 mM / kg po can be obtained, making an ester such as ethyl oleate. These compositions can also contain additives such as wetting agents, which are 4 times more effective than the compounds according to the invention. Emulsification results in comparison to the comparison substances.

Table 1

treatment

Ammoniumace did determination after 15 '

number of
Rats

N / NH ₃
- // ml ³

urea

Determination after 60 '

number of
Rats

N / NH,
- // ml ³

urea

Initial values

control

CGZi

CGZn

CGZn

mixture
Arginine

1.0

0.5

0.25

1.0

1.0

LD50 LD50 LD50 LD50 LD50 LD50 10
20th

1.6
25.3

7.8
14.1
18.6
12.3
20.3

215
293
384
399
342
396
321

10
20th

1.6
3.0
1.6

2.2
2.3
1.9
2.3

215 308 396 394 321 411 342

*) The products were administered 1 hour before the toxic substance.

Tabel

treatment

Determination after 15 ' N / NHj Urine- Determination according to N / NH _a AiTimonium- ■ /, 'ml' y / ml - // mP acetate number of 1.6 215 number of 1.6 Rats 25.3 293 Rats 3.0 10 15.7 365 10 1.8 LD50 20th 17.9 334 20th 1.9 LD 50 8th 25.6 330 8th 2.4 LD50 8th 14.5 360 8th 2.0 LD50 8th 17.9 386 8th 2.4 LD50 8th 8th LD50 8th 8th

urea

Initial values

control

CGZn 2

CGZn 1

CGZn 0.5

Mixture 2

Arginine

*) The products were administered 1 hour before the toxic substance.

215 308 437 339 369 380 416

2. Liver protection effect

of the cobalt salt of 2-ureidopentanedioic acid (1.5) in acute allyl alcohol intoxication

The liver damage caused by allyl alcohol can be seen both histologically and functionally clearly demonstrated by enzymatic determinations and the BSP test. The evoked Necrosis is found in the portal zone without changing the fat content of the liver cell.

The effectiveness of the compound of the invention was under these experimental conditions studied by giving it to rats in two servings: the first serving 1 hour before Administration of the toxic agent (allyl alcohol) and the second serving 6 hours afterwards. 24 hours later liver function was tested. The results obtained are shown in Table 3. They demonstrate clearly the pronounced protective effect of the compound CACo according to the invention. The ones in the bloodstream The amount of GNP retained was reduced, as were the values of serum GOT and GPT (bromosulfophthalein shows the altered dye-excreting capacity and the serum transaminase the hepatic one Necrosis, both of which are caused by the allyl alcohol).

CACo exerts its effectiveness even when the necrosis is particularly severe and therefore not without it further is reversible. In this case, too, CACo proved to be significantly more effective than the simple mixture its components. When CACo was administered peritoneally or orally to normal, non-poisoned animals, there were no noticeable changes in the parameters examined.

Tabel

treatment

dose
mM / kg

Mode of administration

Allyl alcohol intoxication number of
Rats

E.G.

mg%

G. O. T.

mU / ml

G. P. T.

tu U / ml

Initial value

CACo

Mixture ..

CACo

Mixture ..

1. p.

i. p. p. o. p. O.

4th
4th
4th
4th

18th

control

CACo 1

Mix 1

CACo 2

CACo 4

CACo 8

mixture

The rats were poisoned with 2 ml / kg orally of a 3% strength aqueous aluminum oxide solution.

i. p.

i. p. p. o. p. o. p. o. p. O.

5.1
5.0
5.0
5.3

5.2

23.3

10.8

12.0

9.1

7.9

7.2

12.0

164
101
108
158
173

1592
1259
1409
1193
1165
905
1020

593 368 459 431 331 315 406

3. Regenerating effect of the manganese salt of 2-ureidopentanedioic acid- (l, 5) (CAMn)

on the rat liver

The regenerative potency of CAMn was observed hours after partial hepatectomy in 120 males Rats with an average weight of 170 to 190 g (Sprague-Dawley strain), which were grouped were divided into 10 animals each. the

Compound according to the invention and, as a comparison, 2-ureidopentanedioic acid (1.5) (CADL) were administered subcutaneously 90 minutes before the operation at a dose of 1 g / kg. The results relating to the increase in liver weight, the percentage of hepatic regeneration, SGOT, SGPT, alkaline phosphatase and the percentage of H ₂ O are given in Table 4 below.

Tabel

Weight of
Rat in front of the
Surgery,
G Theoretical
Liver weight
ing Weight of
distant
Liver fragment
in g Product administered
and time of determination Rat weight
after
surgery
in g Liver weight
at autopsy
in g 185 ± 5.62
189.2 ± 4.03
189.2 ± 4.66 5.29 ± 0.24
5.43 ± 0.12
5.66 ± 0.21 3.71 ± 0.16
3.80 ± 0.08
3.96 ± 0.14 CAMn 18 hours
CADL 18 hours
Control 18 hours 182.3 ± 5.37
185.8 ± 3.76
185.5 ± 4.38 3.06 ± 0.15
2.92 ± 0.11
3.01 ± 0.11

increase
the liver weight

in g

% Liver regeneration

SGOT mU / m'i

SGPT

mU / ml

Alkaline
Phosphatase

1.47 ± 0.12
1.29 ± 0.08
1.31 ± 0.10

40.1 ± 3.98
33.5 ± 1.95

33.2 ± 3.22

913 ± 101.8 821 ± 49.2 728 ± 46.5

238 ± 31.4
209 ± 16.6
172.2 ± 15.1

172 ± 12.09
128.8 ± 5.94
184.8 ± 18.3

The values given relate to the average of a group of 10 animals each.

72.8 ± 0.44

72.5 ± 0.66

73.6 ± 0.28

Claims (3)

1 2 thing is due to the fact that N-carbamylasparagine claims: acid and N-carbamylglutamic acid represent physiological metabolites of nerve cells, while 1. Manganese, zinc or cobalt salts of the 2-ureido-certain metals are known to be present in endocellular metals butanedioic acid (1,4) and the 2-ureidopentäiidi- 5 respiratory enzyme processes of the neurons partial acid (1,4). to take. States of exhaustion seem to be closely related 2. Process for the production of the metal salts bond with a functional exhaustion of these according to claim 1, characterized in that respiratory processes stand. one 2-ureidobutanedioic acid- (1,4) or 2-ureido- The following examples illustrate the invention. Pentanedioic acid (l, 5) in aqueous solution in itself io in a known manner with a basic compound Example 1 of manganese, zinc or cobalt. 3. Pharmaceutical composition containing- About 176 g of d, l-2-ureidobutanedioic acid- (l, 4) tend at least one metal salt according to claim 1 in 11 water with stirring and then suspended in a mixture with a solid or liquid phar- 15 about 115 g of manganese carbonate added in portions, pharmaceutical carriers or diluents. To complete the resolution, see below Continue stirring slightly warmed. After filtering, the salt is removed from the aqueous solution precipitated by adding ethanol or acetone. 20 The precipitate is filtered off, with ethanol or Acetone washed and dried in vacuo. That The invention relates to the salts of manganese, zinc manganese salt of 2-ureidobutanedioic acid (l, 4) is called and cobalts of 2-l'reidobutanedioic acid (1.4) and the crystalline white powder obtained in water 2-ureidopentanedioic acid- (1,5). soluble and in common organic solvents The inventive 25 was found to be insoluble. The pH of a 1% aqueous New metal salts are particularly valuable when the solution is 7.5. Treatment of states of intoxication and fatigue or exhaustion. ^Anal y ^{se for} QH ₆ N ₂ O ₅ Mn (MW 229.06). The sodium salts of glutamine and asparagine- Calculated: Acids have been used extensively in human 30 C 26.23, H 2.64, N 12.24, O 34.93. Mn 24.00%: therapy as a detoxifying agent in the more symptomatic. found: Treatment of encephalopathies used which C 26.2, H 2.64, N 12.2, 0 34.9, Mn 24.0%.
are associated with liver damage because ...
these diseases on an increase in ammonia example λ
spiegeis in the blood can be attributed. The useful 35 176 g (1 mol) of 2-ureidopentanedioic acid (l, 5) can be suspended in 11 water for this purpose and with stirring with 119 g is probably due to the fact that both cobalt (II) - carbonate (1 g atom of Co) added. To verGlutamic acid as well as aspartic acid in a completion of the reaction is moderately heated, participate in complicated metabolic cycle, by means of filtered and the product from the filtrate with methanol whose ammonia is converted into urea, 40 precipitated, washed with methanol after separation and a non-toxic metabolite, the mainly dried in vacuum. This gives a crystalline one that is eliminated through the kidneys. Easily soluble in water and in common organic ones However, it has been shown that after administration of solvents, insoluble salt, of these two acids these into the corresponding. , ..., .. "... Carbamyl compounds are converted before they are 45 Analysis for C ₅ H ₁ N ₁ O ₄ Co (MW 233): ^ part of the above-mentioned detoxification mechanism- Calculated N 12.02, Co 25.3 ⁰ ^; can have. It is further possible that they found their N 11.9, Co 25.0%. biological effect associated with certain. . Amino acids like ornithine, arginine and citrulline example exercise, which also play an important role in the 50 A suspension of 88 g of 2-ureidopentanedioic acid Play detoxification mechanism. (1.5) in 500 ml of water, 0.5 g of The new metal salts according to the invention can atom zinc added in the form of zinc carbonate, by reacting N-carbamylglutamic acid basic ver 35 precipitates the product by adding ethanol. The low bond of one of the metals in question is filtered off, washed with methanol and placed. The salts formed in this way can be dried in vacuo. The zinc salt obtained can be isolated in a known manner, for example by means of a white powder which is soluble in water and insoluble in the vapors of the solution obtained in vacuo or in conventional organic solvents.
Precipitation by adding a water-miscible 6c, .. ^ -, -. R, ^
organic solvent e.g. B. Alcohols, Ketones ,! Analysis for C ₅ H ₆ N ₂ O ₅ Zn (MW 239.5): or glycol half esters. Examples of such organi- Calculated N 11.7, Zn 27.3%; see solvents are methanol, ethanol, Isopro- found N 11.8, Zn 27.2%. panol, acetone, methyl ethyl ketone and ethylene glycol ". . ,, monomethyl ether. 65 B e. s ρ ϊ e 1 4 It has been found that some of these new mé- 190 g of 2-ureidobutanedioic acid (1.4) are in 1 1 water tall salts have a pronounced effect against exhaustion, suspended and stirred with 119 g of coball (II) - have states, which probably adds to the carbonate (corresponding to 1 g atom of cobalt).