CA1151183A - N-acylcarnosine aluminum salt, its preparation, and a digestive ulcer remedy containing such salt - Google Patents
N-acylcarnosine aluminum salt, its preparation, and a digestive ulcer remedy containing such saltInfo
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- CA1151183A CA1151183A CA000360183A CA360183A CA1151183A CA 1151183 A CA1151183 A CA 1151183A CA 000360183 A CA000360183 A CA 000360183A CA 360183 A CA360183 A CA 360183A CA 1151183 A CA1151183 A CA 1151183A
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- Prior art keywords
- aluminum
- acylcarnosine
- salt
- group
- process according
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Abstract
ABSTRACT OF THE DISCLOSURE
An N-acylcarnosine aluminum salt of the formula,
An N-acylcarnosine aluminum salt of the formula,
Description
~ ~5~
BA~KGROUND OF THE INVENTION
Field of the Invention __ This invention relates to novel N-acylcarnosine compounds, and more particularly, to an N-acylcarnosine aluminum salt, its preparation, and a digestive ulcer remedy containing such salt.
Description of the Prior Art In recent years, there has been a trend toward the increase of patients suffering from a digestive or peptic ulcer, and various attempts have been made to develop remedies for the ulcer.
The present inventors have synthesized a number of com-pounds and have investigated their pharmaceu-tical effects. As a result of thls investigation~, it has been found that N-acylcarnosine compounds of a specific type, which will appear hereinafter, exhibit a significantly excellent digestive ulcer-remedying or anti~ulcer effect and are low in toxicity and hence are satisfactory for actual use. Based upon this finding, the present invention has been accomplished.
SUMMARY OF THE INVENTION
Therefore, one object of the present invention is to provide a novel ~-acylcarnosine aluminum salt.
Another object of the invention is to provide a novel process for preparing an N-acylcarnosine aluminum salt.
A further object of the invention is to provide a novel digestive ulcer remedy which comprises an effective amount of an N-acylcarnosine aluminum salt .3 "
Briefly, these objects and other objects and advantages of this invention can be attained by an N-acylcarnosine aluminum salt of the formula (I), HCoo ~ AQ(OH) (I) ~ H ~ NHCOCH2CH2NHCOR J 3-n wherein R represents a lower alkyl group containing 1 to 6 carbon atoms, a phenyl group or a lower alkoxy group-substituted phenyl group, and n is an integer of 1 to 3.
DETAILED DESCRIPTION ~F THE INVENTION
The N-acylcarnosine aluminum salt of the formula (I) according to the present invention can be prepared, for example, by interacting an N-acylcarnosine of the formula (II), ~ 2 7 (II) HN ~ NHCOCH2CH2NHCOR
wherein R has the same meaning as defined above, with an aluminum alkoxide or an inorganic aluminum salt by any of the methods described below.
Method 1 An N-acylcarnosine is reacted wi-th an aluminum alkoxide to obtain an N-acylcarnosine aluminum salt of the formula (I).
The acylcarnosine useful as one of the starting materials is prepared, for example, by converting the corresponding car-boxylic acid to an acid halogenide in any usual manner and then reacting the halogenide with carnosine.
Typical examples of the aluminum alkoxide include aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum t-butoxide, aluminum cyclohexyloxide and the like~
, .~
~ - 2 -When the aluminum alkoxide contains any impurity such as aluminum hydroxide or a polymer thereof, it is preferable to remove the impurity by distillation, solvent extraction or th~
like. The reaction is favorably conducted in a suitable solvent at a temperature ranging from room temperature to 80C. Suita-ble solvents include water,an organic solvent such as methanol, ethanol, isopropanol or butanol, and a mixture thereof. After completion of the reaction, the solvent and secondarily pro-duced alcohols are removed from the reaction solution to obtain the desired N-acylcarnosine aluminum salt of ~he formula (I).
Method 2 An N-acylcarnosine is reacted with an inorganic aluminum salt, and the resulting aqueous reaction solution is passed through a column packed with an anion exchange resin to obtain the desired N-acylcarnosine aluminum salt of the formula (I).
Typical examples of the inorganic aluminum salt useful in method 2 include mineral acid salts of aluminum such as aluminum sulfate, aluminum nitrate and aluminum chloride.
The anion exchange resin useful in method 2 may be either a weakly basic resin or a strongly basic resin, and preferably, a weakly basic anion exchange resin such as Amberlite IR-45 is used.
The amount of the anion exchange resin depends on the amount of the ions of a mineral acid and on the type of the ions in an aqueous solution of the N-acylcarnosine and the mineral acid. Too small amounts of such resin adversely cause the mineral acid ions to introduce into an effluent, while excessive amounts induce the adsorption of ~he N-acylcarnosine *Trademark.
.
, 5~
to an objectionable degree. Accordingly, i-t is desirable that the anion exchange resin be used twice or three times equivalent of the N-acylcarnosine.
The concentration of the aqueous solution which is passed through the column is not critical but is preferably held at such a level that the concentration of the mineral acid ions is in the range of about 0.5 to 1 equivalent per liter of the solution. The space velocity is suitably in the range of about 0.5 to 2.
The aqueous solution which has come out of the column is concentrated under reduced pressure and evaporated to dryness to obtain the desired compound of the formula (I).
In either method 1 or method 2 above, when the molar ratio of an N-acylcarnosine to an aluminum alko~ide or an in-organic aluminum salt is varied, an N-acylcarnosine aluminum salt can be prepared which corresponds to such molar ratio.
The N-acylcarnosine aluminum salts typical of and practical for the present invention which were listed as samples A to I were tested to determine their digestive ulcer-curing effects and degrees of toxicity with the results tabulated in the following experimental examples.
Samples:
~ F==r- CH2iCHC ~~ (DL-form) B~ CH2lcHcoo ~ AQ(OH)2 (L-form) lHN~N NHCOCH2r~2NHCOCH3) 3 (L-form) C~2CHCOO
~ \"" NHCOCH2CH2MHCOCH ~ 2 Q H (L--form) E: ~ 1 r CH2CHCOO ~ AQ(O~) (L-form) H~ N NHCOCH2CH2NHCOCH2CH ~ 2 ~ ~ -r--CH2CHCOO
F: ~HN N NHCOCH2CH2NHCOCH2CH3 1,2 Q (L-form) ~N N NHCCH2CH2NHCC6H13 1 ( )2 (L-form) H: ~ CH2CHCOO ~ AQ(OH)2 (L-form) N j~ NHCOCH2CH2NHcO ~ J
~ -CH CHCOO CH30 I: 1- ¦ 2 ~== 1 AQ(OH)2 (L-form~
HN N NHCOCH2CH2NHCO ~ , ,J
It will be noted that as control compounds, use was made of L-carnosine, L-glutamine, N-acetyl-L-glutamine aluminum and aluminum sucrose sul~ate which are known to have an anti-ulcer effect for purposes of comparison. The anti-ulcer effects and degrees of toxicity of the N-acylcarnosine aluminum compounds according to the invention were determined using rats in which instances various gastric ulcer models of rats were utilized to estimate the anti-ulcer effects.
The experimental methods of ulcers and toxicity will beapparent from the following description.
Experiment 1 Shay's ulcer: Groups of ten male Donryu strain rats each weighing 210 to 230 g were deprived of food for 48 hours.
The pylorus of each rat was ligated according to the method of Shay et al [Gastroenterology, 5, 43-61 (1945)]. Each of th~ animals was allowed to stand abstained from food and water for fur~her 14 hours and then sacrificed to remove its stomach.
After collection of the gastric juice, the ulcerated area (mm2) in the forestomach of each rat was measured under a dissectlng microscope (10 x). The total area (mm2) of all the lesions of each rat was indicated as an ulcer index. Test medicine samples were given orally immediately after the pylorus liga-tion.
The experimental results are shown in Table 1.
Table 1 InhibitrY Effects on Shay's Ulcer on Rats Samples Dose Ulcer index ~ Inhibition Control _ 2.4 + 0.7 A 1,000 0.5 -~ 0.5 79.2 L-Carnosine 1,000 2.1 + 0.7 12.5 L-Glutamine 1,000 2.2 + 0.8 8.3 Aluminum sucrose sulfate 1,000 0.7 + 0.8 71.7 Control _ 2.5 + 0.7 B 1,000 0.6 + 0.4 76.0 L-Carnosine 1,000 2.2 + 0.8 12.0 L-Glutamine 1,000 2.3 + 0.7 8.0 N-Acetyl-L-glutamine aluminum 2,000 0.7 + 0.6 72.0 Alumlnum sucrose sulfate 1,000 0.8 + 0.9 68.0 Control _ 2.9 ~ 0.4 C 1,000 1.0 + 0.7 65.5 D 1,000 0.9 + 0.9 .69.0 N-Acetyl-L-glutamine aluminum 2,000 0.9 + 0.7 6~.0 Aluminum sucrose sulfate 1,000 0.8 + 0.6 72.4 Control _ 3.1 + 1.1 _ E 1,000 0.7 + 0.5 77.4 F 1,000 0.9 + 0.7 71.0 G 1,000 0O9 + 1.0 71.0 H 1,000 1.0 + 0.9 67.7 I 1,000 1.1 + 0.8 64.5 N-Acetyl-L
glutamine aluminum 2,000 1.0 + 0.6 67.7 Aluminum sucrose sulfate 1,000 0.9 + 0.5 71.0 Experiment 2 Stress ulcer: Groups of ten male Donryu strain rats each weighing 240 to 260 g were placed in a stress cage which served to immobilize the animals therein and then immersed in a water bath of 23C on a level with the xiphoid process according to the method of K. Takagi et al ~Jap. J. Pharmac., 18 (9), 9-19 (1968)], thereby imposing stress on each rat.
Seven hours after the immersion, each of the animals was with-drawn from the water bath and immediately sacrificed by a blow on the head, followed by removal of the stomach of each rat.
The stomach was slightly inflated by injecting a 1% formalin solution and then immediately immersed in a 1~ formalin solu-tion, followed by incising the stomach along its greater curva-ture to measure the length (mm) of each lesion in the glandular portion under a dissecting microscope (10 x). The total length (mm) of all the lesions of each rat was indicated as an ulcer index. Test medicine samples were given orally ten minutes before the immersion in water.
The results are shown in Table 2.
. , , ~, ~ 8 -.
, Table 2 Inhibitory Effects on Stress Ulcer in Rats Samples (mg/kg, P~o~! Ulcer index ~ Inhibition Control _15.2 + 3.2 A 3008.0 + 2.8 47.4 1,0004.4 _ 2.2 71.1 L-Carnosine30014.2 + 3.7 6.6 1,00010.7 _ 2.2 29.6 Aluminum sucrose sulfate 1,0006.5 ~ 6.0 56.7 _ Control _17.5 + 3.5 3009.2 + 3.0 47.4 B1,0004.8 + 2.6 72.6 L-Carnosine30016.0 + 4.0 8.6 1,00012.1 _ 2.5 30.9 N-Acetyl-L-glutamine aluminum2,0005.5 ~ 4.8 68~6 Aluminum sucrose sulfate 1,0007.3 + 6.8 58.3 .
A and B have the same meaning as defined above.
Experiment 3 Aspirin-induced ulcer: Groups of ten male Donryu strain rats each weiyhing 220 to 230 g were deprived of food for 24 hours. The pylorus of each rat was ligated under ether anethesia according to the method of S. Okabe et al ~Jap. J.
Pharmac. 24, 3S7-361 (1974)]. After the pylorus ligation, aspirin (100 mg/kg) was administered orally to each rat. Seven hours after the administration, each of the animals was sacri ficed under ether anesthesia to remove its stomach. After collection of the gastric juice and treatment with a 1~ formalin solution, the length (mm) of each lesion formed in ~he glandular portion was measured. The total length (mm) of all the lesions of each rat was indicated as an ulcer index. Test medicine samples w~re given orally immediately after the pylorus ligation.
The results are shown in Table 3.
Table 3 Inhibitory Effects on Aspirin-induced Ulcer in Rats Samples (mg/kg, P.O.~ Ulcer index % Inhibition Control _ 17.7 + 2.3 A 1~000 0.6 + 0.6 96.6 L-Glutamine 1,000 6.0 + 2.2 66.1 Aluminum sucrose sulfate 1,000 3.7 + 2.1 79.1 Control ]7.5 + 3.5 B 1,000 0.6 + 0.6 96.4 L-Glutamine 1,000 4.5 -~ 1.5 73.2 Aluminum sucrose sulfate 1,000 2.0 + 1.1 88.1 _ .
A and B have the same meaning as defined above.
Experiment 4 Indomethacin-induced ulcer: Groups of ten male Donryu strain rats each weighing 200 to 215 g were deprived of food for 24 hours. Then, the p~lorus was ligated under ether anethesia, after which indomethacin was administered subcutane-ously in an amount of 25 mg/kg to each rat. Seven hours after the administration, each of the animals was scarificed under ether anethesia to remove its stomach, followed by immersion in a 1% formalin solution for ten minutes. The stomach which had been semi-fixed was incised along its greater curvature, and the length (mm) of each lesion formed in the mucous membrane ~3l5~3 was measured under a dissecting microscope (10 x). The total length (mm) of all the lesions of each rat was indicated as an ulcer index. Test medicine samples were yiven orally ten minutes before the pylorus legation.
The results are shown in Table 4.
Table 4 Innibitory Effects on Indomethacin-induced Ulcer in Rats Samples (mg/kg, P.O.) Ulcer index ~ Inhibition _ Control _16.3 + 2.4 A 3006.5 + 2.2 60.1 L-Carnosine 33017.3 + 3.0 ~0 L-Glutamine 3009.5 + 4.1 41.8 Aluminum sucrose sulfate 3007.8 + 3.0 52.1 Control _16.8 + 2.1 B 3006.4 + 2.2 61.9 L-Carnosine 30017.1 + 3.1 ~0 L-Glutamine 3009.7 -~ 3.9 42.3 Aluminum sucrose sulfate 3007,4 ~ 2.8 56.0 ..
A and B have the same meaning as defined above.
Experiment 5 Histamine-induced ulcer: Groups of ten male Donryu strain rats each weighing 210 to 230 g were deprived of food for 48 hours and then administered intxaperitoneally with histamine phosphate (300 mg/kg). Four hours after the admini-stration, each of the animals was sacrificed under ether anesthesia, followed by removal of the stomach and immersion in a 1% formalin solution for ten minutes~ The stomach which had been semi-fixed was incised along the greater curvature, and the length (mm) of each lesion was measured under a dissect-ing microscope (10 x). The total length (mm) of all the lesions of each rat was indicated as an ulcer index. Test medicine samples were given orally before the histamine administration.
The results are shown ln Table 5.
Table 5 Inhibitory Effects on Histamine-induced Ulcer in Rats Samples ~mg/kg, P.O.) Ulcer index ~ Inhibition Control _24.1 + 4-7 A 3009.6 + 1.8 60.2 L-Carnosine 30017.3 + 3.2 28.2 Aluminum sucrose sulfate 30014.4 + 1.5 40.2 Control 23.0 + 3.0 _ ~
B 3009.1 + 1.9 60.4 L-Carnosine 30018.0 + 2.7 21.7 N-Acetyl-L-glutamine aluminum 2,0008.5 + 3.0 63.0 Aluminum sucrose sulfate 30010.7 + 2.1 53.5 A and B have the same meaning as defined above.
Experiment 6 Acute toxicity: Male and female Wister strain rats each weighing 150 to 200 g were divided into two groups, respective-ly, each group consisting of ten ra-ts, and were administered orally with some of the N-acylcarnosine aluminum compounds according to the invention. The thus treated rats were visually observed for seven days after the administration.
The results are shown in Table 6.
Table 6 Values of LD50 in Rats _ LD50 (mg/kg, P.O.) Samples _ _ Male Female A ~10,000 >10,000 B >10,000 >10,000 . ,, As is clearly seen from the experimental results of Tables 1 to 6, the N-acylcarnosine aluminum compounds or salts according to the invention exhibit an excellent inhibiting effeot on various ulcer models. That is, such salts, when administered orally in an amount of 300 or 1,000 mg/kg to rats in the tests of Shay's ulcer, stress ulcer, aspirin-induced ulcer, indomethanocin-induced ulcer and histamine-induced ulcer, are significantlv effective for inhibiting any of the ulcers and hence are more excellent than any existing anti-ulcer agents.
In the acute toxicity test, even when the N-acylcarnosine aluminum salts were amdinistered orally in an amount as large as 10 g/kg, no death of rats was recognized, and no or little change in general symptoms was observed.
Accordingly, the N-acylcarnosine al~minum slats of the preSent invention can be used as a digestive ulcer remedy which is higher in safety and more excellen-t in effectiveness than L-glutamine, N-acetyl-L-glutamine aluminum and aluminum sucrose sulfate which have now been widely used as anti-ulcer ~ . .
?~
agents. The N-acylcarnosine aluminum sal-ts may be administered either orally or parenterally and may be used in the form o~, for example, tablets, capsules, powders, granules and syrups for oral administration and also in the form oE injection for parenteral administration.
The amount of administration is generally in the range of 500 to 5,000 mg/day for adults, which may be varied depend-ing both on the age and on the symptom.
This invention will now be described in more detail with reference to certain specific Examples which are provided for purposes of illustration only and are not intended to be con-sidered as limiting.
Example 1 a) A solution of 5.36 g of N-acetyl-~l-carnosine* in 100 mQ of water was heated to about 40C. To the solution was added dropwise, with vigorous stirring, 90 mQ oE an isopropyl alcohol solution containing 4.08 g of aluminum isopropoxide.
After the addition, the reaction mixture was stirred at 40C
for ten minutes, and any insoluble materials were removed from the mi~ture by filtration. The solvent was removed under reduced pressure, and to the oily residue was added isopropyl alcohol for solidification. The resulting solid was crushed and powdered. The powder was washed sufficiently with iso-propyl alcohol and dried at 60C under reduced pressure to obtain 6.5 g (quantitative yeild) of colorless powder [mp:
210C (decomp.)]. 5 g of the t~us- obtained powder was dis-solved in 30 mQ oE water. 4.8 g of an N-acetyl-~L-carnosine aluminum salt was obtained from the solution by spray drying at 80C.
mp : 215C (decomp.) IR~ KBr cm 1 3400 (OH), 1630 (C=O), 1450, 1380 max NMR(D2O)~ : 1.88 (3H, s, -COCH3)
BA~KGROUND OF THE INVENTION
Field of the Invention __ This invention relates to novel N-acylcarnosine compounds, and more particularly, to an N-acylcarnosine aluminum salt, its preparation, and a digestive ulcer remedy containing such salt.
Description of the Prior Art In recent years, there has been a trend toward the increase of patients suffering from a digestive or peptic ulcer, and various attempts have been made to develop remedies for the ulcer.
The present inventors have synthesized a number of com-pounds and have investigated their pharmaceu-tical effects. As a result of thls investigation~, it has been found that N-acylcarnosine compounds of a specific type, which will appear hereinafter, exhibit a significantly excellent digestive ulcer-remedying or anti~ulcer effect and are low in toxicity and hence are satisfactory for actual use. Based upon this finding, the present invention has been accomplished.
SUMMARY OF THE INVENTION
Therefore, one object of the present invention is to provide a novel ~-acylcarnosine aluminum salt.
Another object of the invention is to provide a novel process for preparing an N-acylcarnosine aluminum salt.
A further object of the invention is to provide a novel digestive ulcer remedy which comprises an effective amount of an N-acylcarnosine aluminum salt .3 "
Briefly, these objects and other objects and advantages of this invention can be attained by an N-acylcarnosine aluminum salt of the formula (I), HCoo ~ AQ(OH) (I) ~ H ~ NHCOCH2CH2NHCOR J 3-n wherein R represents a lower alkyl group containing 1 to 6 carbon atoms, a phenyl group or a lower alkoxy group-substituted phenyl group, and n is an integer of 1 to 3.
DETAILED DESCRIPTION ~F THE INVENTION
The N-acylcarnosine aluminum salt of the formula (I) according to the present invention can be prepared, for example, by interacting an N-acylcarnosine of the formula (II), ~ 2 7 (II) HN ~ NHCOCH2CH2NHCOR
wherein R has the same meaning as defined above, with an aluminum alkoxide or an inorganic aluminum salt by any of the methods described below.
Method 1 An N-acylcarnosine is reacted wi-th an aluminum alkoxide to obtain an N-acylcarnosine aluminum salt of the formula (I).
The acylcarnosine useful as one of the starting materials is prepared, for example, by converting the corresponding car-boxylic acid to an acid halogenide in any usual manner and then reacting the halogenide with carnosine.
Typical examples of the aluminum alkoxide include aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum t-butoxide, aluminum cyclohexyloxide and the like~
, .~
~ - 2 -When the aluminum alkoxide contains any impurity such as aluminum hydroxide or a polymer thereof, it is preferable to remove the impurity by distillation, solvent extraction or th~
like. The reaction is favorably conducted in a suitable solvent at a temperature ranging from room temperature to 80C. Suita-ble solvents include water,an organic solvent such as methanol, ethanol, isopropanol or butanol, and a mixture thereof. After completion of the reaction, the solvent and secondarily pro-duced alcohols are removed from the reaction solution to obtain the desired N-acylcarnosine aluminum salt of ~he formula (I).
Method 2 An N-acylcarnosine is reacted with an inorganic aluminum salt, and the resulting aqueous reaction solution is passed through a column packed with an anion exchange resin to obtain the desired N-acylcarnosine aluminum salt of the formula (I).
Typical examples of the inorganic aluminum salt useful in method 2 include mineral acid salts of aluminum such as aluminum sulfate, aluminum nitrate and aluminum chloride.
The anion exchange resin useful in method 2 may be either a weakly basic resin or a strongly basic resin, and preferably, a weakly basic anion exchange resin such as Amberlite IR-45 is used.
The amount of the anion exchange resin depends on the amount of the ions of a mineral acid and on the type of the ions in an aqueous solution of the N-acylcarnosine and the mineral acid. Too small amounts of such resin adversely cause the mineral acid ions to introduce into an effluent, while excessive amounts induce the adsorption of ~he N-acylcarnosine *Trademark.
.
, 5~
to an objectionable degree. Accordingly, i-t is desirable that the anion exchange resin be used twice or three times equivalent of the N-acylcarnosine.
The concentration of the aqueous solution which is passed through the column is not critical but is preferably held at such a level that the concentration of the mineral acid ions is in the range of about 0.5 to 1 equivalent per liter of the solution. The space velocity is suitably in the range of about 0.5 to 2.
The aqueous solution which has come out of the column is concentrated under reduced pressure and evaporated to dryness to obtain the desired compound of the formula (I).
In either method 1 or method 2 above, when the molar ratio of an N-acylcarnosine to an aluminum alko~ide or an in-organic aluminum salt is varied, an N-acylcarnosine aluminum salt can be prepared which corresponds to such molar ratio.
The N-acylcarnosine aluminum salts typical of and practical for the present invention which were listed as samples A to I were tested to determine their digestive ulcer-curing effects and degrees of toxicity with the results tabulated in the following experimental examples.
Samples:
~ F==r- CH2iCHC ~~ (DL-form) B~ CH2lcHcoo ~ AQ(OH)2 (L-form) lHN~N NHCOCH2r~2NHCOCH3) 3 (L-form) C~2CHCOO
~ \"" NHCOCH2CH2MHCOCH ~ 2 Q H (L--form) E: ~ 1 r CH2CHCOO ~ AQ(O~) (L-form) H~ N NHCOCH2CH2NHCOCH2CH ~ 2 ~ ~ -r--CH2CHCOO
F: ~HN N NHCOCH2CH2NHCOCH2CH3 1,2 Q (L-form) ~N N NHCCH2CH2NHCC6H13 1 ( )2 (L-form) H: ~ CH2CHCOO ~ AQ(OH)2 (L-form) N j~ NHCOCH2CH2NHcO ~ J
~ -CH CHCOO CH30 I: 1- ¦ 2 ~== 1 AQ(OH)2 (L-form~
HN N NHCOCH2CH2NHCO ~ , ,J
It will be noted that as control compounds, use was made of L-carnosine, L-glutamine, N-acetyl-L-glutamine aluminum and aluminum sucrose sul~ate which are known to have an anti-ulcer effect for purposes of comparison. The anti-ulcer effects and degrees of toxicity of the N-acylcarnosine aluminum compounds according to the invention were determined using rats in which instances various gastric ulcer models of rats were utilized to estimate the anti-ulcer effects.
The experimental methods of ulcers and toxicity will beapparent from the following description.
Experiment 1 Shay's ulcer: Groups of ten male Donryu strain rats each weighing 210 to 230 g were deprived of food for 48 hours.
The pylorus of each rat was ligated according to the method of Shay et al [Gastroenterology, 5, 43-61 (1945)]. Each of th~ animals was allowed to stand abstained from food and water for fur~her 14 hours and then sacrificed to remove its stomach.
After collection of the gastric juice, the ulcerated area (mm2) in the forestomach of each rat was measured under a dissectlng microscope (10 x). The total area (mm2) of all the lesions of each rat was indicated as an ulcer index. Test medicine samples were given orally immediately after the pylorus liga-tion.
The experimental results are shown in Table 1.
Table 1 InhibitrY Effects on Shay's Ulcer on Rats Samples Dose Ulcer index ~ Inhibition Control _ 2.4 + 0.7 A 1,000 0.5 -~ 0.5 79.2 L-Carnosine 1,000 2.1 + 0.7 12.5 L-Glutamine 1,000 2.2 + 0.8 8.3 Aluminum sucrose sulfate 1,000 0.7 + 0.8 71.7 Control _ 2.5 + 0.7 B 1,000 0.6 + 0.4 76.0 L-Carnosine 1,000 2.2 + 0.8 12.0 L-Glutamine 1,000 2.3 + 0.7 8.0 N-Acetyl-L-glutamine aluminum 2,000 0.7 + 0.6 72.0 Alumlnum sucrose sulfate 1,000 0.8 + 0.9 68.0 Control _ 2.9 ~ 0.4 C 1,000 1.0 + 0.7 65.5 D 1,000 0.9 + 0.9 .69.0 N-Acetyl-L-glutamine aluminum 2,000 0.9 + 0.7 6~.0 Aluminum sucrose sulfate 1,000 0.8 + 0.6 72.4 Control _ 3.1 + 1.1 _ E 1,000 0.7 + 0.5 77.4 F 1,000 0.9 + 0.7 71.0 G 1,000 0O9 + 1.0 71.0 H 1,000 1.0 + 0.9 67.7 I 1,000 1.1 + 0.8 64.5 N-Acetyl-L
glutamine aluminum 2,000 1.0 + 0.6 67.7 Aluminum sucrose sulfate 1,000 0.9 + 0.5 71.0 Experiment 2 Stress ulcer: Groups of ten male Donryu strain rats each weighing 240 to 260 g were placed in a stress cage which served to immobilize the animals therein and then immersed in a water bath of 23C on a level with the xiphoid process according to the method of K. Takagi et al ~Jap. J. Pharmac., 18 (9), 9-19 (1968)], thereby imposing stress on each rat.
Seven hours after the immersion, each of the animals was with-drawn from the water bath and immediately sacrificed by a blow on the head, followed by removal of the stomach of each rat.
The stomach was slightly inflated by injecting a 1% formalin solution and then immediately immersed in a 1~ formalin solu-tion, followed by incising the stomach along its greater curva-ture to measure the length (mm) of each lesion in the glandular portion under a dissecting microscope (10 x). The total length (mm) of all the lesions of each rat was indicated as an ulcer index. Test medicine samples were given orally ten minutes before the immersion in water.
The results are shown in Table 2.
. , , ~, ~ 8 -.
, Table 2 Inhibitory Effects on Stress Ulcer in Rats Samples (mg/kg, P~o~! Ulcer index ~ Inhibition Control _15.2 + 3.2 A 3008.0 + 2.8 47.4 1,0004.4 _ 2.2 71.1 L-Carnosine30014.2 + 3.7 6.6 1,00010.7 _ 2.2 29.6 Aluminum sucrose sulfate 1,0006.5 ~ 6.0 56.7 _ Control _17.5 + 3.5 3009.2 + 3.0 47.4 B1,0004.8 + 2.6 72.6 L-Carnosine30016.0 + 4.0 8.6 1,00012.1 _ 2.5 30.9 N-Acetyl-L-glutamine aluminum2,0005.5 ~ 4.8 68~6 Aluminum sucrose sulfate 1,0007.3 + 6.8 58.3 .
A and B have the same meaning as defined above.
Experiment 3 Aspirin-induced ulcer: Groups of ten male Donryu strain rats each weiyhing 220 to 230 g were deprived of food for 24 hours. The pylorus of each rat was ligated under ether anethesia according to the method of S. Okabe et al ~Jap. J.
Pharmac. 24, 3S7-361 (1974)]. After the pylorus ligation, aspirin (100 mg/kg) was administered orally to each rat. Seven hours after the administration, each of the animals was sacri ficed under ether anesthesia to remove its stomach. After collection of the gastric juice and treatment with a 1~ formalin solution, the length (mm) of each lesion formed in ~he glandular portion was measured. The total length (mm) of all the lesions of each rat was indicated as an ulcer index. Test medicine samples w~re given orally immediately after the pylorus ligation.
The results are shown in Table 3.
Table 3 Inhibitory Effects on Aspirin-induced Ulcer in Rats Samples (mg/kg, P.O.~ Ulcer index % Inhibition Control _ 17.7 + 2.3 A 1~000 0.6 + 0.6 96.6 L-Glutamine 1,000 6.0 + 2.2 66.1 Aluminum sucrose sulfate 1,000 3.7 + 2.1 79.1 Control ]7.5 + 3.5 B 1,000 0.6 + 0.6 96.4 L-Glutamine 1,000 4.5 -~ 1.5 73.2 Aluminum sucrose sulfate 1,000 2.0 + 1.1 88.1 _ .
A and B have the same meaning as defined above.
Experiment 4 Indomethacin-induced ulcer: Groups of ten male Donryu strain rats each weighing 200 to 215 g were deprived of food for 24 hours. Then, the p~lorus was ligated under ether anethesia, after which indomethacin was administered subcutane-ously in an amount of 25 mg/kg to each rat. Seven hours after the administration, each of the animals was scarificed under ether anethesia to remove its stomach, followed by immersion in a 1% formalin solution for ten minutes. The stomach which had been semi-fixed was incised along its greater curvature, and the length (mm) of each lesion formed in the mucous membrane ~3l5~3 was measured under a dissecting microscope (10 x). The total length (mm) of all the lesions of each rat was indicated as an ulcer index. Test medicine samples were yiven orally ten minutes before the pylorus legation.
The results are shown in Table 4.
Table 4 Innibitory Effects on Indomethacin-induced Ulcer in Rats Samples (mg/kg, P.O.) Ulcer index ~ Inhibition _ Control _16.3 + 2.4 A 3006.5 + 2.2 60.1 L-Carnosine 33017.3 + 3.0 ~0 L-Glutamine 3009.5 + 4.1 41.8 Aluminum sucrose sulfate 3007.8 + 3.0 52.1 Control _16.8 + 2.1 B 3006.4 + 2.2 61.9 L-Carnosine 30017.1 + 3.1 ~0 L-Glutamine 3009.7 -~ 3.9 42.3 Aluminum sucrose sulfate 3007,4 ~ 2.8 56.0 ..
A and B have the same meaning as defined above.
Experiment 5 Histamine-induced ulcer: Groups of ten male Donryu strain rats each weighing 210 to 230 g were deprived of food for 48 hours and then administered intxaperitoneally with histamine phosphate (300 mg/kg). Four hours after the admini-stration, each of the animals was sacrificed under ether anesthesia, followed by removal of the stomach and immersion in a 1% formalin solution for ten minutes~ The stomach which had been semi-fixed was incised along the greater curvature, and the length (mm) of each lesion was measured under a dissect-ing microscope (10 x). The total length (mm) of all the lesions of each rat was indicated as an ulcer index. Test medicine samples were given orally before the histamine administration.
The results are shown ln Table 5.
Table 5 Inhibitory Effects on Histamine-induced Ulcer in Rats Samples ~mg/kg, P.O.) Ulcer index ~ Inhibition Control _24.1 + 4-7 A 3009.6 + 1.8 60.2 L-Carnosine 30017.3 + 3.2 28.2 Aluminum sucrose sulfate 30014.4 + 1.5 40.2 Control 23.0 + 3.0 _ ~
B 3009.1 + 1.9 60.4 L-Carnosine 30018.0 + 2.7 21.7 N-Acetyl-L-glutamine aluminum 2,0008.5 + 3.0 63.0 Aluminum sucrose sulfate 30010.7 + 2.1 53.5 A and B have the same meaning as defined above.
Experiment 6 Acute toxicity: Male and female Wister strain rats each weighing 150 to 200 g were divided into two groups, respective-ly, each group consisting of ten ra-ts, and were administered orally with some of the N-acylcarnosine aluminum compounds according to the invention. The thus treated rats were visually observed for seven days after the administration.
The results are shown in Table 6.
Table 6 Values of LD50 in Rats _ LD50 (mg/kg, P.O.) Samples _ _ Male Female A ~10,000 >10,000 B >10,000 >10,000 . ,, As is clearly seen from the experimental results of Tables 1 to 6, the N-acylcarnosine aluminum compounds or salts according to the invention exhibit an excellent inhibiting effeot on various ulcer models. That is, such salts, when administered orally in an amount of 300 or 1,000 mg/kg to rats in the tests of Shay's ulcer, stress ulcer, aspirin-induced ulcer, indomethanocin-induced ulcer and histamine-induced ulcer, are significantlv effective for inhibiting any of the ulcers and hence are more excellent than any existing anti-ulcer agents.
In the acute toxicity test, even when the N-acylcarnosine aluminum salts were amdinistered orally in an amount as large as 10 g/kg, no death of rats was recognized, and no or little change in general symptoms was observed.
Accordingly, the N-acylcarnosine al~minum slats of the preSent invention can be used as a digestive ulcer remedy which is higher in safety and more excellen-t in effectiveness than L-glutamine, N-acetyl-L-glutamine aluminum and aluminum sucrose sulfate which have now been widely used as anti-ulcer ~ . .
?~
agents. The N-acylcarnosine aluminum sal-ts may be administered either orally or parenterally and may be used in the form o~, for example, tablets, capsules, powders, granules and syrups for oral administration and also in the form oE injection for parenteral administration.
The amount of administration is generally in the range of 500 to 5,000 mg/day for adults, which may be varied depend-ing both on the age and on the symptom.
This invention will now be described in more detail with reference to certain specific Examples which are provided for purposes of illustration only and are not intended to be con-sidered as limiting.
Example 1 a) A solution of 5.36 g of N-acetyl-~l-carnosine* in 100 mQ of water was heated to about 40C. To the solution was added dropwise, with vigorous stirring, 90 mQ oE an isopropyl alcohol solution containing 4.08 g of aluminum isopropoxide.
After the addition, the reaction mixture was stirred at 40C
for ten minutes, and any insoluble materials were removed from the mi~ture by filtration. The solvent was removed under reduced pressure, and to the oily residue was added isopropyl alcohol for solidification. The resulting solid was crushed and powdered. The powder was washed sufficiently with iso-propyl alcohol and dried at 60C under reduced pressure to obtain 6.5 g (quantitative yeild) of colorless powder [mp:
210C (decomp.)]. 5 g of the t~us- obtained powder was dis-solved in 30 mQ oE water. 4.8 g of an N-acetyl-~L-carnosine aluminum salt was obtained from the solution by spray drying at 80C.
mp : 215C (decomp.) IR~ KBr cm 1 3400 (OH), 1630 (C=O), 1450, 1380 max NMR(D2O)~ : 1.88 (3H, s, -COCH3)
2.43 (2H, m, -CH2CH2NHCOCH3)
3.28 (4H, m, -COC~2CH2N- , -CH2C~COO)
4.09 (lH, m, -CH2CHCOO) 7.05, 8.10 (lHx2, sx2, imidazole ring protons) Elementary analysis as (CllH15N4O4)AQ(OH)2:
Calculated (~) : C 40.25, H 5.22, N 17.07, AQ 8.22 Found (~) : C 40.10, H 5.41, N 16.77, AQ 8.01 These analytical data confirm the following structure (A).
~ CH2CHCOO ~
A : ! ~ NHCOCH2CH2NHCOCH3 AQ(OE)2 (DL-form) * N-acetyl-DL-carnosine: A. Lukton and A. Sisti [J.O.C. 26, 617 (1961)]
b) A solution of 4.5 g of N-acetyl-DL-carnosine in 30 mQ of water was heated to about 60C. To the solution was added dropwise, with vigorous stirring, 25 mQ of an isopropyl alcohol solution containing 3.75 g of aluminum isopropoxide.
Ater the addition, the reaction mixture was stirred at 60C
for four hours, isopropyl alcohol was removed from the reaotion mixture under reduced pressure, and any insoluble materials were removed from the residual aqueous solution by filtration.
Calculated (~) : C 40.25, H 5.22, N 17.07, AQ 8.22 Found (~) : C 40.10, H 5.41, N 16.77, AQ 8.01 These analytical data confirm the following structure (A).
~ CH2CHCOO ~
A : ! ~ NHCOCH2CH2NHCOCH3 AQ(OE)2 (DL-form) * N-acetyl-DL-carnosine: A. Lukton and A. Sisti [J.O.C. 26, 617 (1961)]
b) A solution of 4.5 g of N-acetyl-DL-carnosine in 30 mQ of water was heated to about 60C. To the solution was added dropwise, with vigorous stirring, 25 mQ of an isopropyl alcohol solution containing 3.75 g of aluminum isopropoxide.
Ater the addition, the reaction mixture was stirred at 60C
for four hours, isopropyl alcohol was removed from the reaotion mixture under reduced pressure, and any insoluble materials were removed from the residual aqueous solution by filtration.
5.1 g (quantitative yield) of an N-acetyl-DL-carnosine alumlnum salt was obtained as colorless powder from the filtrate by spray drying at 80C.
The analytical data were in strict accord wi-th those obtained in item a) above.
.. ....
'~ ~
Example 2 a) A solution of ~00 g of N-acetyl-L-carnosine dis-solved in 5.2 Q of water was heated to about 60~C. To the solution was added dropwise, with vigorous stirring, 3.8 Q of an isopropyl alcohol solution containing 500 g of aluminum isopropoxide. After the addition, the mixture was stirred for three hours at 60C, and then isopropyl alcohol was removed from the reaction mixture under reduced pressure. Any inso-luble materials were removed from the reaction mixture by filtration. 690 g of an N-acetyl-L-carnosine aluminum salt was o~tained as colorless powder from the filtrate by spray drying at 80C.
mp : 235C (decomp.) [~]D : +15.9C (C = 5% in H2O) IRv max cm : 3400 (OH), 1360 (CO), 1450, 1380 NMR(D2o!~ : 1.98 (3H, s, COCH3) 2.53 (2H, m, -CH2CH2NHCOCH3) 3.40 (4H, m, -COCH2CH2N , -CH2CHCOO) 4.20 (lH, m, CH2CHCOO) 7.25, 8.53 (lHx2, sx2, imidazole ring protons) Elemental analysis as (C11H15N4O4) AQ (OH) 2:
Calculated (%) : C 40.25, H 5.22, N 17.07, AQ 8.22 Found (%) : C 40.13, H 5.19, N 17.01, AQ 8.27 These analytical data confirm the following structure (B).
B~ CH2CHCOO 1 AQ(OH)2 (L-form) HN N NHcocH2cH2NHcocH3 b) A solution of 120 g cf N-acetyl-L-carnosine dis-solved in 1 Q of water was heated to about 60C. To the solu-tion was added dropwise, with vigorous stirring, 800 mQ of an isopropyl alcohol solution containing 100 g of aluminum iso-propoxide. After the addition, the mixture was stirred for three hours at 60C, and then isopropyl alcohol was removed from the reaction mixture under reduced pressure. Any insolu-ble materials were removed from the residual aqueous solution by filtration,and the filtrate was concentrated to 300 mQ.
The resulting solution was freeze dried to obtain 151 g of an N-acetyl-L-carnosine aluminum salt as colorless powder.
The analytical data were in strict accord with those obtained in item a) above.
c) A solution of 3 g oE N-acetyl-L-carnosine dissolved in 25 mQ of water was heated to about 60C. To the solution was added dropwise, with vigorous stirring, 20 mQ of an iso-propyl alcohol solution containing 2.5 g of aluminum isopropo-xide. After the addition, the mixture was stirred for three hours at 60C. Any insoluble materials were removed from the residual aqueous solution by filtration, and the filtrate was concentrated to dryness, thereby yielding 3.5 g of an N-acetyl-L-carnosine aluminum salt as colorless powder.
The analytical data were in strict accord with those obtained in item a) above.
Example 3 To a solution of 0.70 g of aluminum isopropoxide dis-solved in 20 mQ of isopropyl alcohol was added 2.76 g of N-acetyl-L-carnosine at 60 C, and the mixture was stirred for one hour. 10 mQ of water was added to the reaction mixture which was stirred for 30 minutes until it became homogeneous.
After filtration of the reaction mixture, isopropyl alcohol of the filtrate was removed by evaporation under reduced pressure, and the residual aqueous solution was freeze dried to obtain 2.8 g (quantitative yielcl) of an N-acetyl-L-carnosine aluminum salt as colorless powder.
mp : 220C (decomp.) [a]D5 : +22.8C (C = 5% in H2O) IRv mas cm : 3400 (OH), 1630 (CO), 139Q, 1300 NMR (D2O)~ : 1.63 (3H, s, -COCH3) 2.21 (2H, t, -Cl-C_2CH2NH ) 2.95 (2H, m, -C_2~HCOO) 3.16 (-COCH2C_2NH-) 4.44 (lH, m, -CH2CHCOO) 7.41, 8.81 (lH~2, sx2, imidazole ring protons) Elemental analysis as (CllH14N4O4)3AQ:
Calculated (%) : C 47.82, H 5.48, N 20.28 Found (~) : C 47.58, H 5.24, N 20.08 These analytical data confirm the following structure (C).
CH~CHCOO
F: ~HN ~ NHCCH2CH2NHCCH3J 3 (L-form) ~ s~
Example 4 To a solution of 1.04 g of aluminum isopropoxide dis-solved in 20 mQ of isopropyl alcohol was added 2.73 g of N-acetyl-L-carnosine at 60C. 2.9 g (quantitative yield) of an N-acetyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 3.
mp : 218C (decomp.) [~]25 : +19.6C (C = 5% in H2O) IR~ max cm : 3400 (OH), 1630 (CO), 1390, 1300 NMR(D2O)~ : 1.91 ~3H, s, -COCH3) 2.42 (2H, t, -COC 2CH2N c ) 3.10 (2H, m, -CH2CHCOO) 3.32 (2H, t, -COCH2CH2NH-) 4.44 (lH, m, -CH2CHCOO) 7.09, 8.32 (lHx2, sx2,imidazole ring protons) E1ementalanalysis as (CllH15N404)2AQOH:
Calculated (%) : C 45.67, H 5.41, N 19.37 Found (%) : C 45.84, H 5.12, N 19.45 These analytical data confirm the followiny structure (D).
D: ~ HN N NHcocH2cH2NHcocH3 J2AQOH (L-form) Example 5 a) N-Propionyl-L-carnosine: To a solution of 2.42 of L-carnosine dissolved in 13 mQ of water was added 6.5 mQ of acetone. Thereafter, 4.14 g of propionyl chloride and 7.6 g of triethylamine were simultaneously added dropwise to the solution at such a rate that the reaction mixture did not exceed 20C in temperature and was maintained at a pH of 7.0 to 7.5. The dropwise addition took about one hour. After the addition, ac~tone was evaporated under reduced pressure, and the residue was adsorbed on a strong anion exchange resin (SA-lOA) in an amount of 130 mQ. The anion resin ~Jas washed with water and eluted with lN acetic acid, and the eluant was further adsorbed on a strong cation exchange resin (SK-lB) in an amount of 10 mQ. After the cation resin was washed with water and eluted with 2% aqueous ammonia, the eluant was eva-porated under reduced pressure to remove the greater part of ammonia. The residue was passed through 30 m~ of a weak cation exchange resin (IRC-50), and the portion o~ the residue which had not been adsorbed was distilled to dryness under reduced pressure to obtain a crude product. Recrystallization of the crude product from methanol-acetone (2:3) gave 1.46 g of N propionyl-L-carnosine as colorless crystal (yield: 48~).
mp : 206 ~ 209C (decomp.) [ ]25 : +20.4C (C = 3~ in H20) IRv max cm : 3300 (OH), 1630 (CO), 1540, 1390 NMR(D20~ : 1.06 (3H, t, J=8Hz, -H2CH3) 2.18 ~2H, q, J-8Hz, -CH2CH3) 2.44 (2H, t, J-7Hz, -NHCOCH2CH2NH-) 3.14 (2H, m, -C_2CHCOO) 3.36 (2H, t, J=7, -NHCOCH2CH2NH-) 4.44 (lH, m, -CH2CHCOO) 7.08, 8.48 (lHx2, sx2, imidazole ring protons) ~lemental analysis as C12H18N404:
Calculated (~) : C 51.04, H 6.44, N 19.85 Found (~) : C 50.95, H 6.43, N 19.77 b) To a solution of 0.8 g of aluminum isopropoxide dissolved in 11 mQ of isopropyl alcohol was added 1.11 g of N-propionyl-L-carnosine at 60C, 1.3 g (quantitative yield) of an N-propionyl-L-carnosine aluminum salt was obtained in the same way as in Example 3.
mp : 228C (deeomp.~
[~]25 : +11.4C tC = 3% in H2O) IRvmBaXcm~l : 3400 (OH), 1640 (C=O), 1540, 1400 NMR(D2O~ : 1.02 (3H, t, -COCH2CH3) 2.11 (2H, q, -COCH2CH3) 2.40 (2H, t, -COCH2CH2NH-) 3.08 (2H, m, -CH2CHCOO) 3.28 (2H, t, -COCH2C_2NH-) 4.44 (lH, m, -CH2CHCOO) 7.08, 8.26 (lHx2, sx2, imidazole ring protons) Elemental analysis as (C12H17N404)AQ(OH)2:
~ Calculated (%) : C 42.10, H 5.61, N 16.37 Found (%) : C 41.88, H 5.83, N 16.12 These anlytical data confirm the following structure (E`).
~ CH2CHCOO
E: l ~ NHcocH2cH2~Hcoc~2cH3J ( )2 Example 6 -To a solution of a 0.72 g of aluminum isopropoxide dis-solved in 15 mQ of isopropyl alcohol was added 1..97 g of N-propionyl~L-carnosine at 60C. Thereafter, 2.1 g (quantita-tive yield) on an N-propionyl-L-carnosine aluminum salt was obtained as colorless power in the same way as in Example 3.
mp : 220C (decomp.) [a]D5 : +14.5C (C = 1~ in H2) IRv mKaBx cm 1 3400 (OH), 1640 (C0), 1540 NMR(D20)~ : 1.02 (3H, t, -CH2CH3) 2.10 (2H, q, -CH2CH3) 2.42 (2H, t, -COCH2CH2NH-) 3.15 (2H, m, -CH2CHC00) 3.35 (2H, t, -COCH2CH2NH-) 4.44 (lH, m, -CH~CHC00) 7.80, 8.77 (lHx2, sx2, imidazole ring protons) Elemental analysis as (C12H17N404)2AQoH
Calculated (%) : C 47.51, H 5.83, N 18.48 Found (~) : C 47.37, H 5.78, N 18037 These analytical data confirm the following structure (F).
F: ~ ~ 2 2 HCCH2CX31 2 (L-form) -?~ - 22 --Example 7 a) N-Heptanoyl-L-carnosine: To a solution of 2.42 g of L-carnoslne dissolved in 13 mQ of water was adeed 6.5 m~ of acetone. 6.36 g of heptanoyl chloride was then added to the solution which was treated in the same procedure as described in item a) of Example 5 to obtain a crude product. Recrystalli-zation of the crude product from water-acetone (1:2) gave 1.66 g of N-heptanoyl-L-carnosine as colorless crystal (yield: 46 6 ) .
mp : 214~ 217~C (decomp.) [a]25 : +4.7~C (C = 2% in H2O) IRv max cm : 3290, 1635, 1530, 1400 NMR(D2O)~ : 0.72 (3H, ~, -CH3) 0.86 ~ 1.56 (8H, m, -CH2x4) 2.06 (2H, t, J=7Hz, -COCH2CH2-) 2.35 (2H, t, J=7Hz, -NHCOCH2CH2NH) 2.94 ~ 3.14 (2H, m, -CH2CHCOO) 3.26 (2H, t, J=7Hz, -NflCOCH2CH2NH) 4.26 ~ 4.44 (lH, m, -CH2CHCOO) 7.10r 8.42 (lHx2, sx2, imidazole ring protons) Elemental analysis as C16H26N4O4-Calculated (%) : C 56.77, H 7.76, N 16.56 Found (6) : C 56.81, H 7.85, N 16.38 . ~ .
, ~5~ 3 b) To a solution of 0.68 g of aluminum isopropoxide dissolved in 15 mQ of isopropyl alcohol was added l.13 g of N-heptanoyl-L-carnosine at 60~C. l.3 g (quantitative yield) of an N-heptanoyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 3.
mp : 280C < (decomp.) [a] D : +0. 4~C (C = 1~6 in H20) IRv m x c~ : 3400 (OH), 2930, 2860 ~Alkyl~, l640 (CO), 1540 NMR(D2O)~ : 0.80 (3H, t, -CH2CH3) l.20 (8H, m, -CH2-x4) 2.12 (2H, t, -CH2CH2CO-) 2.40 (2H, t, -CQCH2CH2NH-) 3.07 (2~, m, -CH2CHCOO) 3.31 (2H, t, -COCH2CH2NH-) 4.44 (lH, m, -CH2CHCOO) 7.06, 8.28 (lHx2, sx2, imidazole ring protons) Elemental analysis as (Cl6H25N4O4)AQ(OH~2:
Calc1llated (~) : C 48.23, H 6.84, N 14.06 Found (~) : C 48.03, H 6.87, N 13.77 These analytical data confirm the following structure (G).
~ , C~2C~COO ~
G: lHN N NHCCH2CH2NHCC6Hl3J ( )2 ,~, Example 8 a) N-Benzoyl-L-carnosine: To a solution of 2.42 g of L-carnosine dissolved in 13 mQ of water was added 6.5 mQ of acetone. Thereafter, 6.32 g of benzoyl chloride was added to the solution which was treated in the same procedure as des-cribed in item a) of Example 5 to obtain a crude product.
Recrystallization of the crude product from methanol-acetone (2:3) gave 1.69 g of N-benzoyl-~-carnosine as colorless crystal (yield: 48%).
mp : 217 ~219C (decomp.) [~]25 : +10.3C (C = 1~ in H2O) IRv mBar cm 1 3280, 1640, 1520, 1385 NMR(D20)~ : 2.48 (2H, t, J=7Hz, -COCH2CH2NH-) 3.02 (2H, m, -CH2CHCOO) 3.46 (2H, t, J=7Hz, -COCH2CH2NH-) 4.37 (lH, m, -CH2C_COO)
The analytical data were in strict accord wi-th those obtained in item a) above.
.. ....
'~ ~
Example 2 a) A solution of ~00 g of N-acetyl-L-carnosine dis-solved in 5.2 Q of water was heated to about 60~C. To the solution was added dropwise, with vigorous stirring, 3.8 Q of an isopropyl alcohol solution containing 500 g of aluminum isopropoxide. After the addition, the mixture was stirred for three hours at 60C, and then isopropyl alcohol was removed from the reaction mixture under reduced pressure. Any inso-luble materials were removed from the reaction mixture by filtration. 690 g of an N-acetyl-L-carnosine aluminum salt was o~tained as colorless powder from the filtrate by spray drying at 80C.
mp : 235C (decomp.) [~]D : +15.9C (C = 5% in H2O) IRv max cm : 3400 (OH), 1360 (CO), 1450, 1380 NMR(D2o!~ : 1.98 (3H, s, COCH3) 2.53 (2H, m, -CH2CH2NHCOCH3) 3.40 (4H, m, -COCH2CH2N , -CH2CHCOO) 4.20 (lH, m, CH2CHCOO) 7.25, 8.53 (lHx2, sx2, imidazole ring protons) Elemental analysis as (C11H15N4O4) AQ (OH) 2:
Calculated (%) : C 40.25, H 5.22, N 17.07, AQ 8.22 Found (%) : C 40.13, H 5.19, N 17.01, AQ 8.27 These analytical data confirm the following structure (B).
B~ CH2CHCOO 1 AQ(OH)2 (L-form) HN N NHcocH2cH2NHcocH3 b) A solution of 120 g cf N-acetyl-L-carnosine dis-solved in 1 Q of water was heated to about 60C. To the solu-tion was added dropwise, with vigorous stirring, 800 mQ of an isopropyl alcohol solution containing 100 g of aluminum iso-propoxide. After the addition, the mixture was stirred for three hours at 60C, and then isopropyl alcohol was removed from the reaction mixture under reduced pressure. Any insolu-ble materials were removed from the residual aqueous solution by filtration,and the filtrate was concentrated to 300 mQ.
The resulting solution was freeze dried to obtain 151 g of an N-acetyl-L-carnosine aluminum salt as colorless powder.
The analytical data were in strict accord with those obtained in item a) above.
c) A solution of 3 g oE N-acetyl-L-carnosine dissolved in 25 mQ of water was heated to about 60C. To the solution was added dropwise, with vigorous stirring, 20 mQ of an iso-propyl alcohol solution containing 2.5 g of aluminum isopropo-xide. After the addition, the mixture was stirred for three hours at 60C. Any insoluble materials were removed from the residual aqueous solution by filtration, and the filtrate was concentrated to dryness, thereby yielding 3.5 g of an N-acetyl-L-carnosine aluminum salt as colorless powder.
The analytical data were in strict accord with those obtained in item a) above.
Example 3 To a solution of 0.70 g of aluminum isopropoxide dis-solved in 20 mQ of isopropyl alcohol was added 2.76 g of N-acetyl-L-carnosine at 60 C, and the mixture was stirred for one hour. 10 mQ of water was added to the reaction mixture which was stirred for 30 minutes until it became homogeneous.
After filtration of the reaction mixture, isopropyl alcohol of the filtrate was removed by evaporation under reduced pressure, and the residual aqueous solution was freeze dried to obtain 2.8 g (quantitative yielcl) of an N-acetyl-L-carnosine aluminum salt as colorless powder.
mp : 220C (decomp.) [a]D5 : +22.8C (C = 5% in H2O) IRv mas cm : 3400 (OH), 1630 (CO), 139Q, 1300 NMR (D2O)~ : 1.63 (3H, s, -COCH3) 2.21 (2H, t, -Cl-C_2CH2NH ) 2.95 (2H, m, -C_2~HCOO) 3.16 (-COCH2C_2NH-) 4.44 (lH, m, -CH2CHCOO) 7.41, 8.81 (lH~2, sx2, imidazole ring protons) Elemental analysis as (CllH14N4O4)3AQ:
Calculated (%) : C 47.82, H 5.48, N 20.28 Found (~) : C 47.58, H 5.24, N 20.08 These analytical data confirm the following structure (C).
CH~CHCOO
F: ~HN ~ NHCCH2CH2NHCCH3J 3 (L-form) ~ s~
Example 4 To a solution of 1.04 g of aluminum isopropoxide dis-solved in 20 mQ of isopropyl alcohol was added 2.73 g of N-acetyl-L-carnosine at 60C. 2.9 g (quantitative yield) of an N-acetyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 3.
mp : 218C (decomp.) [~]25 : +19.6C (C = 5% in H2O) IR~ max cm : 3400 (OH), 1630 (CO), 1390, 1300 NMR(D2O)~ : 1.91 ~3H, s, -COCH3) 2.42 (2H, t, -COC 2CH2N c ) 3.10 (2H, m, -CH2CHCOO) 3.32 (2H, t, -COCH2CH2NH-) 4.44 (lH, m, -CH2CHCOO) 7.09, 8.32 (lHx2, sx2,imidazole ring protons) E1ementalanalysis as (CllH15N404)2AQOH:
Calculated (%) : C 45.67, H 5.41, N 19.37 Found (%) : C 45.84, H 5.12, N 19.45 These analytical data confirm the followiny structure (D).
D: ~ HN N NHcocH2cH2NHcocH3 J2AQOH (L-form) Example 5 a) N-Propionyl-L-carnosine: To a solution of 2.42 of L-carnosine dissolved in 13 mQ of water was added 6.5 mQ of acetone. Thereafter, 4.14 g of propionyl chloride and 7.6 g of triethylamine were simultaneously added dropwise to the solution at such a rate that the reaction mixture did not exceed 20C in temperature and was maintained at a pH of 7.0 to 7.5. The dropwise addition took about one hour. After the addition, ac~tone was evaporated under reduced pressure, and the residue was adsorbed on a strong anion exchange resin (SA-lOA) in an amount of 130 mQ. The anion resin ~Jas washed with water and eluted with lN acetic acid, and the eluant was further adsorbed on a strong cation exchange resin (SK-lB) in an amount of 10 mQ. After the cation resin was washed with water and eluted with 2% aqueous ammonia, the eluant was eva-porated under reduced pressure to remove the greater part of ammonia. The residue was passed through 30 m~ of a weak cation exchange resin (IRC-50), and the portion o~ the residue which had not been adsorbed was distilled to dryness under reduced pressure to obtain a crude product. Recrystallization of the crude product from methanol-acetone (2:3) gave 1.46 g of N propionyl-L-carnosine as colorless crystal (yield: 48~).
mp : 206 ~ 209C (decomp.) [ ]25 : +20.4C (C = 3~ in H20) IRv max cm : 3300 (OH), 1630 (CO), 1540, 1390 NMR(D20~ : 1.06 (3H, t, J=8Hz, -H2CH3) 2.18 ~2H, q, J-8Hz, -CH2CH3) 2.44 (2H, t, J-7Hz, -NHCOCH2CH2NH-) 3.14 (2H, m, -C_2CHCOO) 3.36 (2H, t, J=7, -NHCOCH2CH2NH-) 4.44 (lH, m, -CH2CHCOO) 7.08, 8.48 (lHx2, sx2, imidazole ring protons) ~lemental analysis as C12H18N404:
Calculated (~) : C 51.04, H 6.44, N 19.85 Found (~) : C 50.95, H 6.43, N 19.77 b) To a solution of 0.8 g of aluminum isopropoxide dissolved in 11 mQ of isopropyl alcohol was added 1.11 g of N-propionyl-L-carnosine at 60C, 1.3 g (quantitative yield) of an N-propionyl-L-carnosine aluminum salt was obtained in the same way as in Example 3.
mp : 228C (deeomp.~
[~]25 : +11.4C tC = 3% in H2O) IRvmBaXcm~l : 3400 (OH), 1640 (C=O), 1540, 1400 NMR(D2O~ : 1.02 (3H, t, -COCH2CH3) 2.11 (2H, q, -COCH2CH3) 2.40 (2H, t, -COCH2CH2NH-) 3.08 (2H, m, -CH2CHCOO) 3.28 (2H, t, -COCH2C_2NH-) 4.44 (lH, m, -CH2CHCOO) 7.08, 8.26 (lHx2, sx2, imidazole ring protons) Elemental analysis as (C12H17N404)AQ(OH)2:
~ Calculated (%) : C 42.10, H 5.61, N 16.37 Found (%) : C 41.88, H 5.83, N 16.12 These anlytical data confirm the following structure (E`).
~ CH2CHCOO
E: l ~ NHcocH2cH2~Hcoc~2cH3J ( )2 Example 6 -To a solution of a 0.72 g of aluminum isopropoxide dis-solved in 15 mQ of isopropyl alcohol was added 1..97 g of N-propionyl~L-carnosine at 60C. Thereafter, 2.1 g (quantita-tive yield) on an N-propionyl-L-carnosine aluminum salt was obtained as colorless power in the same way as in Example 3.
mp : 220C (decomp.) [a]D5 : +14.5C (C = 1~ in H2) IRv mKaBx cm 1 3400 (OH), 1640 (C0), 1540 NMR(D20)~ : 1.02 (3H, t, -CH2CH3) 2.10 (2H, q, -CH2CH3) 2.42 (2H, t, -COCH2CH2NH-) 3.15 (2H, m, -CH2CHC00) 3.35 (2H, t, -COCH2CH2NH-) 4.44 (lH, m, -CH~CHC00) 7.80, 8.77 (lHx2, sx2, imidazole ring protons) Elemental analysis as (C12H17N404)2AQoH
Calculated (%) : C 47.51, H 5.83, N 18.48 Found (~) : C 47.37, H 5.78, N 18037 These analytical data confirm the following structure (F).
F: ~ ~ 2 2 HCCH2CX31 2 (L-form) -?~ - 22 --Example 7 a) N-Heptanoyl-L-carnosine: To a solution of 2.42 g of L-carnoslne dissolved in 13 mQ of water was adeed 6.5 m~ of acetone. 6.36 g of heptanoyl chloride was then added to the solution which was treated in the same procedure as described in item a) of Example 5 to obtain a crude product. Recrystalli-zation of the crude product from water-acetone (1:2) gave 1.66 g of N-heptanoyl-L-carnosine as colorless crystal (yield: 46 6 ) .
mp : 214~ 217~C (decomp.) [a]25 : +4.7~C (C = 2% in H2O) IRv max cm : 3290, 1635, 1530, 1400 NMR(D2O)~ : 0.72 (3H, ~, -CH3) 0.86 ~ 1.56 (8H, m, -CH2x4) 2.06 (2H, t, J=7Hz, -COCH2CH2-) 2.35 (2H, t, J=7Hz, -NHCOCH2CH2NH) 2.94 ~ 3.14 (2H, m, -CH2CHCOO) 3.26 (2H, t, J=7Hz, -NflCOCH2CH2NH) 4.26 ~ 4.44 (lH, m, -CH2CHCOO) 7.10r 8.42 (lHx2, sx2, imidazole ring protons) Elemental analysis as C16H26N4O4-Calculated (%) : C 56.77, H 7.76, N 16.56 Found (6) : C 56.81, H 7.85, N 16.38 . ~ .
, ~5~ 3 b) To a solution of 0.68 g of aluminum isopropoxide dissolved in 15 mQ of isopropyl alcohol was added l.13 g of N-heptanoyl-L-carnosine at 60~C. l.3 g (quantitative yield) of an N-heptanoyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 3.
mp : 280C < (decomp.) [a] D : +0. 4~C (C = 1~6 in H20) IRv m x c~ : 3400 (OH), 2930, 2860 ~Alkyl~, l640 (CO), 1540 NMR(D2O)~ : 0.80 (3H, t, -CH2CH3) l.20 (8H, m, -CH2-x4) 2.12 (2H, t, -CH2CH2CO-) 2.40 (2H, t, -CQCH2CH2NH-) 3.07 (2~, m, -CH2CHCOO) 3.31 (2H, t, -COCH2CH2NH-) 4.44 (lH, m, -CH2CHCOO) 7.06, 8.28 (lHx2, sx2, imidazole ring protons) Elemental analysis as (Cl6H25N4O4)AQ(OH~2:
Calc1llated (~) : C 48.23, H 6.84, N 14.06 Found (~) : C 48.03, H 6.87, N 13.77 These analytical data confirm the following structure (G).
~ , C~2C~COO ~
G: lHN N NHCCH2CH2NHCC6Hl3J ( )2 ,~, Example 8 a) N-Benzoyl-L-carnosine: To a solution of 2.42 g of L-carnosine dissolved in 13 mQ of water was added 6.5 mQ of acetone. Thereafter, 6.32 g of benzoyl chloride was added to the solution which was treated in the same procedure as des-cribed in item a) of Example 5 to obtain a crude product.
Recrystallization of the crude product from methanol-acetone (2:3) gave 1.69 g of N-benzoyl-~-carnosine as colorless crystal (yield: 48%).
mp : 217 ~219C (decomp.) [~]25 : +10.3C (C = 1~ in H2O) IRv mBar cm 1 3280, 1640, 1520, 1385 NMR(D20)~ : 2.48 (2H, t, J=7Hz, -COCH2CH2NH-) 3.02 (2H, m, -CH2CHCOO) 3.46 (2H, t, J=7Hz, -COCH2CH2NH-) 4.37 (lH, m, -CH2C_COO)
6.99 ~lH, s, imidazole ring proton (5-position)]
7.1 ~7.6 (5H, m, benzene ring protons)
8.14 [lH, s, imidazole ring proton (2-position)]
Elemental analysis as C16H18N4O~:
Calculated (%) : C 58.16, H 5.50, N 16.96 Found (%) : C 58.21, H 5.65, N 16.93 , ~
b) To a solution of 0.8 g aluminum isopropoxide dis-solved in 15 mQ of isopropyl alcohol was added 1.27 g of N-benzoyl-L-carnosine at 60C. 1.5 g (quantitative yield) of an N-benzoyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 3.
mp : 280C< (decomp.) O
[a]D : +6.2 C (C = 1~ ln H2) IRv max cm : 3400 (OH~, 1630 (CO), 1540, 1400 NMR(D2O)~` : 2.55 (2H, t, -COCH2CH~NH-) 3.07 (2H, m, -CH2~HCOO) 3.55 (2H, t, -COCH2CH2NH-) 4.~4 (lH, m, -CH2C_COO) 6.99 [lH, s, imidazole ring proton (5-position)]
7.44 (5H, m~ benzene ring protons) 8.08 [lH, s, imldazole ring proton (2-position)]
Elemental analysis as (C16H17N4O4)AQ(OH)2:
Calculated (~) : C 49.23, H 4.92, N 14.36 Found (~) : C 49.18, H 4.86, N 14.18 These analytical data confirm the following structure (H).
~ CH~CHCOO
H- l ¦ I A AQ(OH) (L-form) HN~N NHCOCH2CH2NHCO ~ 2 Example 9 a~ N-(o-Methox~l)b~nzoyl-L-CarnoSine: To a solution Gf 2.42 g o~ L-carnosine dissolved in 13 mQ of water was added 6. 5 mQ of acetone. Thereafter, 7.67 g of o-methoxy benzoyl chloride was added to the solution which was treated in the same procedure as described in item a) of Example 5 to obtain a crude product. The crude product was very hygroscopic and then washed with ether to give 1.54 g of N-~o-methoxy)benzoyl-L-carnosine as colorless crystal (yield: 40%).
mp : 203C (decomp.) [ ] 25 : ~7.6C (C = 1~ in H20) IR~ max cm : 3380, 1630 NMR(CD30D) ~ : 2.56 (2H, t, J=7Hz, - COCH2CFI2NH-) 3.16 (2H, m, -CH2~HCOO) 3.60 (2H, t, J - 7Hz, -COCX2CH2NH-) 3.86 (3H, s, - OCH3) 4.55 (lH, m, CH2CHCOO) 6.85 ~ 7 ~ 85 (5H, m, benzene ring prontons and imidazole ring proton) 8.33 (lH, s, imidazole ring proton) Elemental analysis as C17H20N4O5:
Calculated (%) : C 56.65, H 5.60, N 15.55 Found (%) : C 56.61, H 5.58, N 15.61 b) To a solution of 0.68 g of aluminum isopropoxide dissolved in 15 mQ of isopropyl alcohol was added 1.20 g of N-(o-methoxy)benzoyl-L-carnosine at 60C. 1.~0 g (quantitative yield) of an N-(o-methoxy)benzoyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 3.
mp : 280C< (decomp.) [~]25 : ~2.7C (C = 1% in H23) IRv max cm : 3400 (OH), 1630 (CO), 1540, 1400, 1310 NMR(D2O)~ : 2.56 (2H, t, -COCH2CH2NH-) 3.29 (2H, m, -CH2CHCOO) 3.55 (2H, t, -COCH2CH2NH-) 3.83 (3H, s, -OCH3) 4.44 (lH, m, -CH2~HCOO) 6.95~ 7.65 (5H, m, benzene ring protons and imidazole ring proton) 7.96 (lH, s, imidazole ring proton) Elemental analysis as (C17H1gN4O5)AQ(OH)2:
Calculated (~) : C 48.57, H 5.05, N 13.33 Found (%) : C 48.42, H 4.92, N 13.18 These analytical data confirm the following structure (I).
~ CH2CHCOO CH ~
I ~ HN ~ NHCOCH2CH2NHC ~ AQ(OH)2 (L-form) Example 10 - Preparation: 1 g of a digestive ulcer remedy prepared in the form of granules contains the following ingredients.
IngredientsQuantity/g Compound B 200 mg Milk sugar 400 mg Corn starch400 mg Total: 1,000 mg Compound B is the same as defined above.
Elemental analysis as C16H18N4O~:
Calculated (%) : C 58.16, H 5.50, N 16.96 Found (%) : C 58.21, H 5.65, N 16.93 , ~
b) To a solution of 0.8 g aluminum isopropoxide dis-solved in 15 mQ of isopropyl alcohol was added 1.27 g of N-benzoyl-L-carnosine at 60C. 1.5 g (quantitative yield) of an N-benzoyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 3.
mp : 280C< (decomp.) O
[a]D : +6.2 C (C = 1~ ln H2) IRv max cm : 3400 (OH~, 1630 (CO), 1540, 1400 NMR(D2O)~` : 2.55 (2H, t, -COCH2CH~NH-) 3.07 (2H, m, -CH2~HCOO) 3.55 (2H, t, -COCH2CH2NH-) 4.~4 (lH, m, -CH2C_COO) 6.99 [lH, s, imidazole ring proton (5-position)]
7.44 (5H, m~ benzene ring protons) 8.08 [lH, s, imldazole ring proton (2-position)]
Elemental analysis as (C16H17N4O4)AQ(OH)2:
Calculated (~) : C 49.23, H 4.92, N 14.36 Found (~) : C 49.18, H 4.86, N 14.18 These analytical data confirm the following structure (H).
~ CH~CHCOO
H- l ¦ I A AQ(OH) (L-form) HN~N NHCOCH2CH2NHCO ~ 2 Example 9 a~ N-(o-Methox~l)b~nzoyl-L-CarnoSine: To a solution Gf 2.42 g o~ L-carnosine dissolved in 13 mQ of water was added 6. 5 mQ of acetone. Thereafter, 7.67 g of o-methoxy benzoyl chloride was added to the solution which was treated in the same procedure as described in item a) of Example 5 to obtain a crude product. The crude product was very hygroscopic and then washed with ether to give 1.54 g of N-~o-methoxy)benzoyl-L-carnosine as colorless crystal (yield: 40%).
mp : 203C (decomp.) [ ] 25 : ~7.6C (C = 1~ in H20) IR~ max cm : 3380, 1630 NMR(CD30D) ~ : 2.56 (2H, t, J=7Hz, - COCH2CFI2NH-) 3.16 (2H, m, -CH2~HCOO) 3.60 (2H, t, J - 7Hz, -COCX2CH2NH-) 3.86 (3H, s, - OCH3) 4.55 (lH, m, CH2CHCOO) 6.85 ~ 7 ~ 85 (5H, m, benzene ring prontons and imidazole ring proton) 8.33 (lH, s, imidazole ring proton) Elemental analysis as C17H20N4O5:
Calculated (%) : C 56.65, H 5.60, N 15.55 Found (%) : C 56.61, H 5.58, N 15.61 b) To a solution of 0.68 g of aluminum isopropoxide dissolved in 15 mQ of isopropyl alcohol was added 1.20 g of N-(o-methoxy)benzoyl-L-carnosine at 60C. 1.~0 g (quantitative yield) of an N-(o-methoxy)benzoyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 3.
mp : 280C< (decomp.) [~]25 : ~2.7C (C = 1% in H23) IRv max cm : 3400 (OH), 1630 (CO), 1540, 1400, 1310 NMR(D2O)~ : 2.56 (2H, t, -COCH2CH2NH-) 3.29 (2H, m, -CH2CHCOO) 3.55 (2H, t, -COCH2CH2NH-) 3.83 (3H, s, -OCH3) 4.44 (lH, m, -CH2~HCOO) 6.95~ 7.65 (5H, m, benzene ring protons and imidazole ring proton) 7.96 (lH, s, imidazole ring proton) Elemental analysis as (C17H1gN4O5)AQ(OH)2:
Calculated (~) : C 48.57, H 5.05, N 13.33 Found (%) : C 48.42, H 4.92, N 13.18 These analytical data confirm the following structure (I).
~ CH2CHCOO CH ~
I ~ HN ~ NHCOCH2CH2NHC ~ AQ(OH)2 (L-form) Example 10 - Preparation: 1 g of a digestive ulcer remedy prepared in the form of granules contains the following ingredients.
IngredientsQuantity/g Compound B 200 mg Milk sugar 400 mg Corn starch400 mg Total: 1,000 mg Compound B is the same as defined above.
Claims (24)
1. A process for preparing an N-acylcarnosine alumi-num salt of the formula (I), (I) wherein R represents a lower alkyl group having 1 to 6 carbon atoms, a phenyl group or a lower alkoxy group-substituted phenyl group, and n represents an integer of 1 to 3, which comprises:
(a) reacting an N-acylcarnosine of the formula II, (II) wherein R has the same meaning as defined above, with an aluminum alkoxide in the presence of a solvent, and removing said solvent and side produced alcohols from the reaction solution; or (b) reacting an N-acylcarnosine of the formula (II), (II) wherein R has the same meaning as defined above, with an inorganic aluminum salt, and subjecting the reaction mixture to separation by ion exchange.
(a) reacting an N-acylcarnosine of the formula II, (II) wherein R has the same meaning as defined above, with an aluminum alkoxide in the presence of a solvent, and removing said solvent and side produced alcohols from the reaction solution; or (b) reacting an N-acylcarnosine of the formula (II), (II) wherein R has the same meaning as defined above, with an inorganic aluminum salt, and subjecting the reaction mixture to separation by ion exchange.
2. The process according to Claim 1, wherein said aluminum alkoxide is selected from the group consisting of aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum t-butoxide and aluminum cyclohexyloxide.
3. The process according to Claim 1, wherein said solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol and a mixture thereof.
4. The process according to Claim 1, wherein the reaction is conducted at temperatures ranging from room tempera-ture to 80°C.
5. The process according to Claim 1, wherein said inorganic aluminum salt is selected from the group consisting of an aluminum sulfuric acid salt, an aluminum nitric acid salt and an aluminum chloric acid salt.
6. The process according to Claim 1, wherein said ion exchange separation is conducted with the use of a weakly basic anion exchange resin.
7. The process according to Claim 1, wherein said anion exchange resin is used twice or three times equivalent of the N-acylcarnosine.
8. A process for preparing an N-acylcarnosine aluminum salt of the formula (I), (I) wherein R represents a lower alkyl group having 1 to 6 carbon atoms, a phenyl group or a lower alkoxy group-substituted phenyl group, and n represents an integer of 1 to 3, which comprises reacting an N-acylcarnosine of the formula (II), (II) wherein R has the same meaning as defined above, with an aluminum alkoxide in the presence of a solvent, and removing said solvent and side produced alcohols from the reaction solution.
9. The process according to Claim 8, wherein said aluminum alkoxide is selected from the group consisting of aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum t-butoxide and aluminum cyclohexyloxide.
10. The process according to Claim 8, wherein said solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol and a mixture thereof.
11. The process according to Claim 8, wherein the reaction is conducted at temperatures ranging from room tem-perature to 80°C.
12. A process for preparing an N-acylcarnosine alumi-num salt of the formula (I), (I) wherein R represents a lower alkyl group having 1 to 6 carbon atoms, a phenyl group or a lower alkoxy group-substituted phenyl group, and n represents an integer of 1 to 3, which comprises reacting an N-acylcarnosine of the formula (II), (II) wherein R has the same meaning as defined above, with an inor-ganic aluminum salt, and subjecting the reaction mixture to separation by ion exchange.
13. The process according to Claim 12, wherein said inorganic aluminum salt is selected from the group consisting of an aluminum sulfuric acid salt, an aluminum nitric acid salt and an aluminum chloric acid salt.
14. The process according to Claim 12, wherein said ion exchange separation is conducted with the use of a weakly basic anion exchange resin.
15. The process according to Claim 12, wherein said anion exchange resin is used twice or three times equivalent of the N-acylcarnosine.
16. A process as in Claim 1, wherein N is equal to 1.
17. A process as in Claim 1, wherein N is equal to 2.
18. A process as in Claim 1, wherein N is equal to 3.
19. A process as in claim 1, wherein R is a lower alkyl group having 1 to 6 carbon atoms.
20. An N-acylcarnosine aluminum salt of the formula (I), (I) wherein R represents a lower alkyl group having 1 to 6 carbon atoms, a phenyl group or a lower alkoxy group-substituted phenyl group, and n represents an integer of 1 to 3, whenever prepared or produced by the process of Claim 1 or by any chemical equivalent thereof.
21. The N-acylcarnosine aluminum salt according to Claim 1, wherein n is equal to 1, whenever prepared or produced by the process of Claim 16 or by any chemical equivalent thereof.
22. The N-acylcarnosine aluminum salt according to Claim 1, wherein n is equal to 2, whenever prepared or produced by the process of Claim 17 or by any chemical equivalent thereof.
23. The N-acylcarnosine aluminum salt according to Claim 1, wherein n is equal to 3, whenever prepared or produced by the process of Claim 18 or by any chemical equivalent thereof.
24. The N-acylcarnosine aluminum salt according to Claim 1, wherein R is a lower alkyl group having 1 to 6 carbon atoms, whenever prepared or produced by the process of Claim 19 or by any chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP54-116717 | 1979-09-13 | ||
| JP11671779A JPS5640614A (en) | 1979-09-13 | 1979-09-13 | Novel type remedy for peptic ulcer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1151183A true CA1151183A (en) | 1983-08-02 |
Family
ID=14694059
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000360183A Expired CA1151183A (en) | 1979-09-13 | 1980-09-12 | N-acylcarnosine aluminum salt, its preparation, and a digestive ulcer remedy containing such salt |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US4342774A (en) |
| JP (1) | JPS5640614A (en) |
| CA (1) | CA1151183A (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5655378A (en) * | 1979-10-12 | 1981-05-15 | Nippon Chemiphar Co Ltd | N-(b-(n'-acylamino)propionyl)histidine aluminum salt and its preparation |
| US4762930A (en) * | 1981-12-11 | 1988-08-09 | Warner-Lambert Company | Process for the preparation of the aluminum salt of saccharin |
| US4772724A (en) * | 1986-12-02 | 1988-09-20 | Warner-Lambert Canada Inc. | Essentially pure acid hydroxyl ligand aluminum complexes and their preparation |
| CA1276022C (en) * | 1986-11-21 | 1990-11-06 | Arthur P. G. Wright | Essentially pure acidic amine ligand aluminum complexes and their preparation |
| US5286480A (en) * | 1992-06-29 | 1994-02-15 | The Procter & Gamble Company | Use of N-acetylated amino acid complexes in oral care compositions |
| US5352691A (en) * | 1993-02-16 | 1994-10-04 | Thomas Peter G | Effective treatment modality for adult respiratory distress syndrome using L-histidine |
| US5741807A (en) * | 1996-09-27 | 1998-04-21 | Cytos Pharmaceuticals, L.P. | Histidine compositions and methods for treating or preventing infectious and non-infectious diarrheas |
| US7001999B1 (en) * | 1998-04-15 | 2006-02-21 | Ludwig Institute For Cancer Research | Tumor associated nucleic acids and uses therefor |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA708696B (en) * | 1970-02-11 | 1971-11-24 | Erba Carlo Spa | Dibasic aluminium histidinate and process for its preparation |
| JPS52111572A (en) * | 1976-03-16 | 1977-09-19 | Santen Pharmaceutical Co Ltd | Nn*mercapto substituted acyl**hystidine |
| US4373868A (en) * | 1976-07-06 | 1983-02-15 | Varian Associates, Inc. | Diffusion pump for leak detector |
-
1979
- 1979-09-13 JP JP11671779A patent/JPS5640614A/en active Granted
-
1980
- 1980-09-10 US US06/185,774 patent/US4342774A/en not_active Expired - Lifetime
- 1980-09-12 CA CA000360183A patent/CA1151183A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5640614A (en) | 1981-04-16 |
| JPS6312844B2 (en) | 1988-03-23 |
| US4342774A (en) | 1982-08-03 |
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