GB2071083A - Novel N-acylcarnosine aluminum salts, for treatment of digestive ulcers - Google Patents
Novel N-acylcarnosine aluminum salts, for treatment of digestive ulcers Download PDFInfo
- Publication number
- GB2071083A GB2071083A GB8028945A GB8028945A GB2071083A GB 2071083 A GB2071083 A GB 2071083A GB 8028945 A GB8028945 A GB 8028945A GB 8028945 A GB8028945 A GB 8028945A GB 2071083 A GB2071083 A GB 2071083A
- Authority
- GB
- United Kingdom
- Prior art keywords
- aluminum
- acylcarnosine
- aluminum salt
- salt according
- carnosine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 208000025865 Ulcer Diseases 0.000 title claims abstract description 36
- 230000001079 digestive effect Effects 0.000 title claims abstract description 11
- 231100000397 ulcer Toxicity 0.000 title claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 102
- 229910001868 water Inorganic materials 0.000 claims description 42
- 229910052782 aluminium Inorganic materials 0.000 claims description 33
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 239000011541 reaction mixture Substances 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 14
- -1 aluminum alkoxide Chemical class 0.000 claims description 11
- 239000011347 resin Substances 0.000 claims description 10
- 229920005989 resin Polymers 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000002474 experimental method Methods 0.000 claims description 8
- 239000003957 anion exchange resin Substances 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 3
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 claims description 2
- DIZPMCHEQGEION-UHFFFAOYSA-H aluminium sulfate (anhydrous) Chemical group [Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O DIZPMCHEQGEION-UHFFFAOYSA-H 0.000 claims description 2
- JPUHCPXFQIXLMW-UHFFFAOYSA-N aluminium triethoxide Chemical compound CCO[Al](OCC)OCC JPUHCPXFQIXLMW-UHFFFAOYSA-N 0.000 claims description 2
- 239000006227 byproduct Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical group [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- MGQIWUQTCOJGJU-UHFFFAOYSA-N [AlH3].Cl Chemical compound [AlH3].Cl MGQIWUQTCOJGJU-UHFFFAOYSA-N 0.000 claims 1
- JLDSOYXADOWAKB-UHFFFAOYSA-N aluminium nitrate Chemical compound [Al+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O JLDSOYXADOWAKB-UHFFFAOYSA-N 0.000 claims 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 230000000767 anti-ulcer Effects 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 51
- 241000700159 Rattus Species 0.000 description 29
- 125000002883 imidazolyl group Chemical group 0.000 description 23
- 239000000843 powder Substances 0.000 description 22
- 238000000921 elemental analysis Methods 0.000 description 17
- 108010087806 Carnosine Proteins 0.000 description 16
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 description 16
- 230000002829 reductive effect Effects 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 229930006000 Sucrose Natural products 0.000 description 15
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 15
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 15
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 description 15
- 239000005720 sucrose Substances 0.000 description 15
- 229940044199 carnosine Drugs 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- 230000003902 lesion Effects 0.000 description 9
- 210000002784 stomach Anatomy 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000002198 insoluble material Substances 0.000 description 8
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 7
- 229930182816 L-glutamine Natural products 0.000 description 7
- KSMRODHGGIIXDV-YFKPBYRVSA-N N-acetyl-L-glutamine Chemical compound CC(=O)N[C@H](C(O)=O)CCC(N)=O KSMRODHGGIIXDV-YFKPBYRVSA-N 0.000 description 7
- 108700016464 N-acetylcarnosine Proteins 0.000 description 7
- BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 210000001187 pylorus Anatomy 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 description 5
- 239000011707 mineral Substances 0.000 description 5
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 229960001138 acetylsalicylic acid Drugs 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000007654 immersion Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010042220 Stress ulcer Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 208000000718 duodenal ulcer Diseases 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229960000905 indomethacin Drugs 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- QRYRORQUOLYVBU-VBKZILBWSA-N Carnosic acid Natural products CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000003699 antiulcer agent Substances 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 230000000762 glandular Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- BNGXYYYYKUGPPF-UHFFFAOYSA-M (3-methylphenyl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].CC1=CC=CC(C[P+](C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 BNGXYYYYKUGPPF-UHFFFAOYSA-M 0.000 description 1
- RZNHSEZOLFEFGB-UHFFFAOYSA-N 2-methoxybenzoyl chloride Chemical compound COC1=CC=CC=C1C(Cl)=O RZNHSEZOLFEFGB-UHFFFAOYSA-N 0.000 description 1
- 108010054404 Adenylyl-sulfate kinase Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010060891 General symptom Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 102100039024 Sphingosine kinase 1 Human genes 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- UCVODTZQZHMTPN-UHFFFAOYSA-N heptanoyl chloride Chemical compound CCCCCCC(Cl)=O UCVODTZQZHMTPN-UHFFFAOYSA-N 0.000 description 1
- 229960001660 histamine phosphate Drugs 0.000 description 1
- ZHIBQGJKHVBLJJ-UHFFFAOYSA-N histamine phosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.NCCC1=CNC=N1 ZHIBQGJKHVBLJJ-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000012608 weak cation exchange resin Substances 0.000 description 1
- 210000002417 xiphoid bone Anatomy 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Novel N-acylcarnosine aluminum salts of the formula, <IMAGE> wherein R represents alkyl group having 1 to 6 carbon atoms, a phenyl group or a lower alkoxy group-substituted phenyl group, l represents an integer of 1 to 5, m represents an integer 1 to 3, and n represents an integer of 0 to 8, possess a digestive ulcer-remedying or anti-ulcerous effect.
Description
SPECIFICATION
N-Acylcarnosine aluminum salts, methods of preparing such salts, and digestive ulcer remedies containing such salts
This invention relates to novel N-acylcarnosine aluminum salts, their preparation, and a digestive ulcer remedy containing such a salt.
In recent years, there has been a trend toward the increase of patients suffering from a digestive or peptic ulcer, and attempts have been made to develop remedies for the ulcer.
The present applicants have synthesized a number of compounds and have investigated their pharmaceutical effects. As a result of this investigation, it has been found that N-acylcarnosine compounds of a specific type, which will hereinafter be defined, exhibit a significantly excellent digestive ulcerremedying or anti-ulcerous effect and are low in toxicity and hence are satisfactory for actual use. The present invention is based upon this finding.
It is, therefore, an object of the present invention to provide novel N-acylcarnosine aluminum salts.
Another object of the invention is to provide novel processes for preparing N-acylcarnosine aluminum salts.
A further object of the invention is to provide a novel digestive ulcer remedy which comprises an effective amount of such a novel N-acylcarnosine aluminum salt.
According to the invention, there is provided an N-acylcarnosine aluminum salt of the formula (I),
wherein R represents a lower alkyl group containing 1 to 6 carbon atoms, a phenyi group or a lower alkoxy group substituted phenyl group, e is an integer of 1 to 5, m is an integer of 1 to 3, and n is an integer ofO to 8.
The N-acylcarnosine aluminum salts of the formula (I) according to the present invention can be prepared, for example, by reacting an N-acylcarnosine of the formula (II),
wherein R has the same meaning as defined above, with an aluminum alkoxide in the presence of a solvent, and removing the solvent and alcohols produced as side-products from the reaction mixture.
Alternatively, the N-acylcarnosine of the formula (II) may be reacted with an inorganic aluminum salt and the resulting reaction mixture separated using an exchange resin.
Preferred ways of carrying out the two methods are given below:
Method I
An N-acylcarnosine is reacted with an aluminum alkoxide to obtain an N-acylcarnosine aluminum salt of the formula (I).
The N-acylcarnosine used as one of the starting materials is prepared, for example, by converting the corresponding carboxylic acid to an acid halogenide in any usual manner and then reacting the halogenide with carnosine. The carnosine used as the starting material for the N-acylcarnosine is of the L-, D- or DLform.
Typical examples of aluminum alkoxides which can be used include aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum t-butoxide, and aluminum cyclohexyloxide. 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 the like. The reaction is conducted in a suitable solvent at a temperature ranging from room temperature to 800C. Suitable solvents include water, an organic solvent such as methanol, ethanol, isopropanol or butanol, and mixtures thereof. After completion of the reaction, the solvent and secondarily-produced alcohols are removed from the reaction solution to obtain the desired N-acylcarnosine aluminum salt of the 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 anionic 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 anionic exchange resin useful in method 2 may be either a weakly basic resin or a strongly basic resin; preferably, a weakly basic anionic exchange resin such as Amberlite IR-45 is used.
The amount of the anionic 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 a resin adversely cause the mineral acid ions to be introduced into the effluent, while excessive amounts induce the adsorption of the N-acylcarnosine to an objectionable degree. Accordingly, it is desirable that the anionic exchange resin be used in an amount twice or three times the 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 leaves 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 alkoxide or an inorganic aluminum salt is varied, an N-acylcarnosine aluminum salt can be prepared which corresponds to the molar ratio used.
The N-acylcarnosine aluminum salts typical as practical examples of the present invention which are listed below as examples A to 0, were tested to determine their digestive ulcer-curing effects and their degrees of toxicity with the results tabulated in the following experimental examples.
Samples:
It will be noted that as control compounds, use was made of L-carnosine, L-glutamine, N-acetyl-Lglutamine aluminum, and aluminum sucrose sulfate which are know to have an anti-ulcerous effect for purposes of comparison. The anti-ulcerous effects and degrees of toxicity of the N-acylcarnosine aluminum salts according to the invention were determined using rats in which various forms of gastric ulcer were induced and utilized to estimate the anti-ulcerous effects.
The experimental methods of measuring ulcers and toxicity will be apparent from the following description.
Experiment 1
Shay's ulcer: Groups often 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 the animals was allowed to remain without food and water for a further 14 hours and then killed and its stomach removed. After collection of the gastric juice, the ulcerated area (mm2) in the forestomach of each rat was measured under a dissecting microscope (10x). 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 ligation.
The experimental results are shown in Table 1.
TABLE 1
Inhibition effects on Shay's ulcer in rats
Dose
Samples (mg/kg, P.O.) Ulcer index % Inhibition Control 2.410.7 7 A 1,000 0.5 + 0.5 79.2
B 1,000 0.47 + 0.4 80.4
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 2.9 + C 1,000 0.7 1 0.8 75.9
D 1,000 0.81 0.6 72.4
N-Acetyl-L-glutamine
aluminum 2,000 0.9 1 0.7 69.0
Aluminum sucrose
sulfate 1,000 0.8 + 0.6 72.4
Control 2.510.7 E 1,000 0.6 + 0.4 76.0
L-Carnosine 1,000 2.2 + 0.7 8.0
N-Acetyl-L-glutamine
aluminum 2,000 0.7 + 0.6 72.0
Aluminum sucrose
sulfate 1,000 0.8 + 0.9 68.0 Control 2.9 + F 1,000 1.0 + 0.7 65.5
G 1,000 0.9 1 0.9 69.0
H 1,000 0.6 1 0.8 79.3
N-Acetyl-L-glutamine
aluminum 2,000 0.9 t 0.7 69.0
Aluminum sucrose
sulfate 1,000 0.8 + 0.6 72.4
TABLE 1 (cont'd)
Dose
Samples (mg/kg, P.O.) Ulcer index % Inhibition
Control 3.111.1 1,000 0.7 1 0.5 77.4
J 1,000 0.910.7 71.0
K 1,000 0.81 0.8 74.2
L 1,000 0.911.0 71.0
M 1,000 1.0 f 0.9 67.7
N 1,000 1.110.8 64.5
N-Acetyl-L-glutamine
aluminum 2,000 1.0 1 0.6 67.7
Aluminum sucrose
sulfate 1,000 0.910.5 71.0
Experiment 2
Stress ulcer:Groups of ten male Donryu strain rats each weighing 240 to 260 9 were placed in a stress cage which served to immobilize the animals therein and then immersed in a water bath of 23 C on a level with the xiphoid process according to the method of K. Takagi et al [Jap. J. Pharmac., 78(9). 9 - 19, 1968], thereby imposing stress on each rat. Seven hours after the immersion, each of the animals was withdrawn from the water bath and immediately killed by a blow on the head, followed by removal of the stomach of each rat. The stomach was slightly inflated by injecting 1% formalin solution and then immediately immersed in a 1% formalin solution, followed by incising the stomach along its greater curvature 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.
TABLE 2
Inhibitory effects on stress ulcer in rats
Dose
Samples (mg/kg, P.O.) Ulcer index % Inhibition Control 15.2 15.2 - A 300 8.0 1 2.8 47.4
1,000 4.412.2 71.1
B 300 8.1 1 2.9 46.7
1,000 4.5 f 2.4 70.4
L-Carnosine 300 14.2 3.7 6.6
1,000 10.7 + 2.2 29.6
Aluminum sucrose
sulfate 1,000 6.51 6.0 56.7
Control - 17.5 + 3.5
E 300 9.2 + 3.0 47.4
1,000 4.81 2.6 72.6
L-Carnosine 300 16.0 4.0 8.6
1,000 12.1 f 2.5 30.9
N-Acetyl-L-glutamine
aluminum 2,000 5.5 1 4.8 68.6
Aluminum sucrose
sulfate 1,000 7,3 6.8 58.3
A, B and E have the same meaning as defined above.
Experiment 3
Aspirin-induced ulcer: Groups of ten male Donryu strain rats each weighing 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, 357-361, 1974). After the pylorus ligation, aspirin (100 mg/kg) was administered orally to each rat. Seven hours afterthe administration, each of the animals was killed under ether anesthesia for the removal of its stomach. After collection of the gastric juice and treatment with a 1% formalin solution, the length of each lesion formed in the glandular portion was measured. The total length (mm) of all the lesions of each rat was indicated as an ulcer index. Test medicine samples were given orally immediately after the pylorus ligation.
The results are shown in Table 3.
TABLE 3
Inhibitory effects on aspirin-induced ulcer in rats
Dose
Samples (mg/kg, P.O.) Ulcer index % Inhibition
Control - 17.7 + 2.3
A 1,000 0.6 + 0.6 96.6
B 1,000 0.7 + 0.6 96.0
L-Glutamine 1,000 6.0 It 2.2 66.1
Aluminum sucrose
sulfate 1,000 3.7 i 2.1 79.1
Control - 17.5 + 3.5
E 1,000 0.6 + 0.6 96.4
L-Glutamine 1,000 4.5 i 1.5 73.2
Aluminum sucrose
sulfate 1,000 2.0 + 1.1 88.1
A, B and E 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 pylorus was ligated under ether anethesia, after which indomethacin
was administered subcutaneously in an amount of 25 mg/kg to each rat. Seven hours after the
administration, each of the animals was killed under ether anethesia for the removal of 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 portion 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 given orally ten minutes before the pylorus ligation.
The results are shown in Table 4.
TABLE 4
Inhibitory effects on indomethacin-induced ulcer in rats
Dose
Samples (mg/kg, P.O.) Ulcer index % Inhibition
Control - 16.3 + 2.4
A 300 6.5 i 2.2 60.1
B 300 6.0 + 2.4 63.2
L-Carnosine 300 17.3 + 3.0 ~0 L-Glutamine 300 9.5+4.1 4.1 41.8 Aluminum sucrose
sulfate 300 7.8 + 3.0 52.1
Control - 16.8 + 2.1 - C 300 6.7 + 3.0 60.1
D 300 6.5 + 2.5 61.3
E 300 6.4 + 2.2 61.9
L-Carnosine 300 17.1 + 3.1 ~0 L-Glutamine 300 9.7 + 3.9 42.3
Aluminum sucrose
sulfate 300 7.4 t 2.8 56.0
A, B, C, D and E 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 histamine phosphate (300 mg/kg) was administered intraperitoneally. Four hours after the administration, each of the animals was killed under ether anesthesia, followed by removal of its 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 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 before the histamine administration.
The results are shown in Table 5.
TABLE 5
Inhibitory effects on histamine4nduced ulcer in rats
Dose
Samples (mg/kg, P.O.) Ulcer index %Inhibition
Control - 24.1 + 4.7
A 300 9.6 i 1.8 60.2
B 300 9.4 l 2.0 61.0
L-Carnosine 300 17.3 i 3.2 28.2
Aluminum sucrose
sulfate 300 14.4+ 1.5 40.2
Control - 23.0 i 3.0
E 300 9.1 i 1.9 60.4
L-Carnosine 300 18.0 + 2.7 21.7
N-Acetyl-L-glutamine
aluminum 2,000 8.5 + 3.0 63.0
Aluminum sucrose
sulfate 300 10.7 + 2.1 53.5
A, B and E 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 respectively, each group consisting often rats, and the N-acylcarnosine aluminum salts according to the invention were administered orally. 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
C > 10,000 > 10,000
D > 10,000 > 10,000
E > 10,000 > 10,000 A, B, C, D and E have the same meaning as defined above.
As is clearly seen from the experimental results of Tables 1 to 6, the N-acylcarnosine aluminum salts according to the invention exhibit an excellent inhibiting effect on various ulcer models. That is to say, the
N-acylcarnosine aluminum salts, when administered orally in an amount of 300 or 1000 mg/kg to rats in the tests of Shay's ulcer, stress ulcer, aspirin-induced ulcer, indomethanocin-induced ulcer and histamineinduced ulcer, are significantly effective for inhibiting any of the ulcers and hence are much better than any existing anti-ulcer agents.
In the acute toxicity test, even when the N-acylcarnosine aluminum salts were administered orally in an amount as large as 10 g/kg, no deaths of rats were noted and no or little change in general symptoms was observed.
Accordingly, the N-acylcarnosine aluminum salts of the present invention can be used as a digestive ulcer remedy which is higher as regards safety and better in effectiveness than L-glutamine, N-acetyl-L-glutamine aluminum and aluminum sucrose sulfate which are now widely used as anti-ulcer agents. The
N-acylcarnosine aluminum salts may be administered either orally or parenterally and may be used in the form of, for example, tablets, capsules, powders, granules and syrups for oral administration and also in the form of injections for parenteral administration.
The administration amount is generally in the range of 500 to 5000 mg/day for adults, which may be varied depending both on the age of the patient and on the symptoms.
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 regarded as limiting.
Example 1
a) A solution of 5.36 g of N-acetyl-DL-carnosine* in 100 m( of water was heated to about 40"C. To the solution was added dropwise. with vigorous stirring, 90 m( of isopropyl alcohol solution containing 4.08 g of aluminum isopropoxide. After the addition, the reaction mixture was stirred at 400C for ten minutes, and any insoluble materials were removed from the mixture 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 isopropyl alcohol and dried at 600C under reduced pressure to obtain 6.5 g (quantitative yield) of colorless powder [mp: 210"C (decomp.)l.5 g of the thus obtained powder was dissolved in 30 mt of water. 4.8 g of an N-acetyl-DL-carnosine aluminum salt was obtained from the solution by spray drying at 80"C.
mp: 215"C (decomp.)
NMR (D2O)o: 1.88 (3H, s, -COCH3)
2.43 (2H, m, -CH2CH2NHCOCH3)
7.05,8.10 (1hex2, sx2, imidazole ring protons)
Elementary analysis as (C11 H15N404!A (OH)2: Calculated: C 40.25, H 5.22, N 17.07, At 8.22 (%)
Found: C40.10, H5.41, N 16.77, At 8.01 (%)
These analytical data confirm the following structure (A).
* 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 mt of water was heated to about 60"C. To the solution was added dropwise, with vigorous stirring, 25 mt of an isopropyl alcohol solution containing 3.75 g of aluminum isopropoxide. After the addition, the reaction mixture was stirred at 60"C for four hours, isopropyl alcohol was removed from the reaction mixture under reduced pressure, and any insoluble materials were removed by filtration from the residual aqueous solution. 5.1 g (quantitative yield) of
N-acetyl-DL-carnosine aluminum salt was obtained as colorless powder from the filtrate by spray drying at 80"C.
The analytical data were in strict accord with those obtained in item a) above.
Example 2
a) A solution of 600 g of N-acetyl-L-carnosine dissolved in 5.2 t of water was heated to about 60"C. To the solution was added dropwise, with vigorous stirring, 3.8 ç of an isopropyl alcohol solution containing 500 g of aluminum isopropoxide. After the addition, the mixture was stirred for three hours at 60"C, and then isopropyl alcohol was removed from the reaction mixture under reduced pressure. Any insoluble materials were removed by filtration from the reaction mixture. 690 g of an N-acetyl-L-carnosine aluminum salt was obtained as colorless powder from the filtrate by spray drying at 80 C.
mp: 235"C (decomp.) [a]: + 15.9 (C = 5% in H20)
NMR (D20)5: 1.98 (3H, s, -COCH3)
2.53 (2H, m, -CH2CH2NHCOCH3)
7.25, 8.53 (1 Hx2, sx2, imidazole ring protons) Elemental analysis as (CllH15N404)A(OH)2: Calculated: C 40.25, H 5.22, N 17.07, Al8.22 (%)
Found: C4O.13, H5.19, N 17.01, Af'8.27(%) These analytical data confirm the following structure (E).
b) A solution of 120 g of N-acetyl-L-carnosine dissolved in 1 e of water was heated to about 60"C. To the solution was added dropwise, with vigorous stirring, 800 mt of an isopropyl alcohol solution containing 100 g of aluminum isopropoxide. After the addition, the mixture was stirred for three hours at 6O0C, and then isopropyl alcohol was removed from the reaction mixture under reduced pressure. Any insoluble materials were removed by filtration from the residual aqueous solution, and the filtrate was concentrated to 300 mf.
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 of N-acetyl-L-carnosine dissolved in 25 mt of water was heated to about 60or. To the solution was added dropwise, with vigorous stirring, 20 m4 of an isopropyl alcohol solution containing 2.5 g of aluminum isopropoxide. After the addition, the mixture was stirred for three hours at 60"C. Any insoluble materials were removed by filtration from the residual aqueous solution, 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
0.816 g of aluminum isopropoxide in 6.6 mg of isopropanol was heated and then stirred at about 60"C for 30 minutes to which was added 0.536 g of N-acetyl-DL-carnosine. The resulting mixture was stirred at 60 C for three hours, and then isopropyl alcohol was removed from the reaction mixture under reduced pressure.
To the residue was added 10 mt of water, and the mixture was stirred at 600C for one hour. Any insoluble materials were removed by filtration, and the filtrate was condensed. To the residue was added isopropyl alcohol. The resulting solidified aluminum salt was collected by filtration. After sufficient washing of the solid with isopropyl alcohol, 0.81 g (quantitative yield) of N-acetylcarnosine aluminum salt was obtained as colorless powder.
mp: 280"C < (decomp.)
1660 ~ 1610 (C=O) 1590 ~ 1540 (COO)
NMR (D20) o: 2.00 (3H, S -COCH3) 2.54 (2H, m, -CH2CH2NH-)
7.36,8.66 (1 Hx2, sx2 imidazole ring protons)
Elemental analysis as (C1,H20N4Og)A 2(OH)5:
Calculated: C 32.52, H 4.96, N 13.79, At 13.28 (%)
Found: C 32.63, H 5.27, N 13.89, At 13.31 (%)
These analytical data confirm the following structure (B).
Example 4
a) A solution of 60 g of N-acetyl-DL-carnosine in 500 m: of water was heated to about 60"C. To the solution was added dropwise, with vigorous stirring, 250 mt of an isopropyl alcohol solution containing 27.5 g of aluminum isopropoxide.
After the addition, the reaction mixture was stirred at 60"C for three hours, and then any insoluble materials were removed by filtration from the mixture. The solvent was concentrated to a 1/10 volume under reduced pressure. To the viscous solution was added isopropyl alcohol for solidification. The resulting solid was crushed and powdered. The powder was washed sufficiently with isopropyl alcohol and dried at 60"C under reduced pressure to obtain 61.8 g (quantitatively yield) of N-acetyl-DL-carnosine aluminum salt.
b) 5 g of the thus obtained powder of N-acetyl-DL-carnosine aluminum salt was dissolved in 30 me of water. 4.8 g of an N-acetyl-DL-carnosine aluminum salt was obtained from the solution by spray drying at 80"C.
mp: 223"C (decomp.) NMR(D20)o: 1.91 (3H, s, COCH3)
2.43 (2H,t, -COCH2CH2NH-)
3.28 (2H,t, -COCH2CH2NH-)
7.07,8.25 (1 Hx2, sx2, imidazole ring protons)
These analytical data confirm the following structure (C).
c) 1.39 g of aluminum isopropoxide in 20 mt of isopropyl alcohol was heated to 60"C to which was added 3.04 g of N-acetyl-DL-carnosine at 60 C. The mixture was stirred for one hour. Thereafter, 10 me of water was added to the reaction mixture.
After stirring for 30 minutes, any insoluble materials were removed from the resulting homogeneous solution by filtration. Isopropyl alcohol of the filtrate was removed by evaporation under reduced pressure.
The residual aqueous solution was freeze dried to obtain 3.35 g (quantitative yield) of an N-acetyl-DLcarnosine aluminum salt as colorless powder.
The analytical data were in strict accord with those obtained in item b) above.
Example 5
To a solution of 1.33 g of aluminum isopropoxide dissolved in 20 me of isopropyl alcohol was added 2.91 g of N-acetyl-L-carnosine at 6O0C, and the mixture was stirred for one hour. 10 me of water was added to the reaction mixture which was stirred for 30 minutes until it became homogeneous. After filtration, isopropyl alcohol of the filtrate was removed by evaporation under reduced pressure, and the residual aqueous solution was freeze dried to obtain 3.2 g (quantitative yield) of an N-acetyl-L-carnosine aluminum salt as colorless powder.
mp: 218"C (decomp.) ta]25: +19.0 (C=5% in H20)
1600 (CO) NMR(D20): 1.91 (3H, s, -COCH3)
2.43 (2H,t, -COCH2CH2NH-)
3.28 (2H, t, COCH2CH2NH-)
7.07, 8.25 (1 Hx2, sx2, imidazole ring protons)
Elemental analysis as (C1,H15N404)5At3(OH)4: Calculated: C44.47, H 5.37, N 18.86 (%) Found:C 44.39, H 5.34, N 18.62 (%)
These analytical data confirm the following structure (D).
Example 6
To a solution of 0.70 g of aluminum isopropoxide dissolved in 20 me 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 m( of water was added to the reaction mixture which was stirred for 30 minutes until it became homogeneous. After filtration, 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 yield) of N-acetyl-L-carnosine aluminum salt as colorless powder.
mp: 220 C (decomp.) [a]D5: + 22.80 (C=5% in H20)
NMR (D20) 5:1.63 (3H, S, -COCH3)
3.16 (-COCH2CH2NH-)
7.41,8.81 Hx2, sx2, imidazole ring protons) Elemental analysis as (C11H15N404)3At: 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 (F).
Example 7
To a solution of 1.04 g of aluminum isopropoxide dissolved in 20 me of isopropyl alcohol was added 2.73 g of N-acetyl-L-carnosine at 60"C. 2.9 9 (quantitative yield) of N-acetyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 6.
mp: 218C (decomp.) Fal2J: +19.6 (C=5% in H2O)
NMR (D20) 5:1.91 (3H, s, -COCH3)
2.42 (2H, t, -COCH2CH2N =
3.32 (2H, t, -COCH2CH2NH-)
7.09, 8.32 (1 Hx2, sx2 imidazole ring protons)
Elemental analysis as (C11H15N404)2At OH:
Calculated: C 45.67, H 5.41, N 19.37 (%)
Found: C45.84, H 5.12, N 19.45 (%) These analytical data confirm the following structure (G).
Example 8
To a solution of 3.13 g of aluminum isopropoxide dissolved in 35 me of isopropyl alcohol was added 1.37 g of N-acetyl-L-carnosine at 60OC, and the mixture was stirred for one hour until it became homogeneous, 25 me of water was added to the reaction mixture which was stirred for 30 minutes.
Isopropyl alcohol of the mixture was evaporated under reduced pressure, and water was added to the residual solution. The clear solution was freeze dried to obtain 2.4 g (quantitative yield) of N-acetyl-Lcarnosine aluminum salt as colorless powder.
mp: 280 C < (decomp.) [al25: +8.5 (C=1% in H20)
NMR (D20)8: 1.79 (3H, s, -COCH3)
2.32 (2H,t, -COCH2CH2NH-)
3.69 (2H, t, -COCH2CH2NH-)
7.04,8.17 (1Hx2, sx2 imidazole ring protons)
Elemental analysis as (C11 H15N404)Ae3(OH)8: Calculated: C27.28, H4.80, N11.57(%) Found: C27.34, H4.62, N 11.65(%) These analytical data confirm the following structure (H).
Example 9
a) N-Propionyl-L-carnosine: To a solution of 2.42 of L-carnosine dissolved in 13 mb of water was added 6.5 mt 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 20 C in temperature and was maintained at a pH of 7.0 to 7.5. The dropwise addition took about one hour. After the addition, acetone was evaporated under reduced pressure, and the residue was adsorbed on a strongly anionic exchange resin (SA-1 OA) in an amount of 130 m. The anionic resin was washed with water and eluted with 1N acetic acid, and the eluant was further absorbed on a strongly cationic exchange resin (SK-1 B) in an amount of 1 Om.After the cationic resin was washed with water and eluted with 2% aqueous ammonia, the eluant was evaporated under reduced pressure to remove the greater part of ammonia. The residue was passed through 30 m6 of a weak cation exchange resin (IRC-50), and the portion of the residue which had not been absorbed 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 crystals (yield: 48%).
mp: 206 ~ 209 C (decomp.) [α]D25: + 20.4? (C=3% in H20)
NMR (D20) 5:1.06 (3H, t, J=8Hz, -CH2CH3)
2.18 (2H, q,J=8Hz, -CH2CH3) 2.44 (2H, t, J=7Hz, -NHCOCK2CH2NH-)
3.36 (2H, t, J=7, -NHCOCH2CH2NH-)
7.08, 8.48 (1 Hx2, sx2, imidazole ring protons)
Elemental 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 15 me of isopropyl alcohol was added 1.11 g of N-propionyl-L-carnosine at 600C, 1.3 g (quantitative yield) of an N-propionyl-L-carnosine aluminum salt was obtained in the same way as in Example 6.
mp: 228 C (decomp.) [α]D25: +11.4 (C=3% in H20)
NMR (D20) 5:1.02 (3H, t, -COCH2CH3)
2.11 (2H, q, -COCH2CH3) 2.40 (2H,t, -COCH2CH2NH-)
3.28 (2H,t, -COCH2CH2NH-)
7.07,8.26 (1 Hx2, sx2 imidazole ring protons)
Elemental analysis as (C12H17N404)Ae(OH)2:
Calculated: C42.10, H5.61, N 16.37(%) Found: C41.88, H5.83, N16.12(%) These analytical data confirm the following structure (I).
Example 10
To a solution of a 0.72 g of aluminum isopropoxide dissolved in 15 me of isopropyl alcohol was added 1.97 g of N-propionyl-L-carnosine at 60 C. Then, 2.1 g (quantitative yield) of an N-propionyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 6.
mp: 220 C (decomp.) [α]D25: +14.5 (C=1% in H20)
NMR (D20) 5:1.02 (3H,t, -CH2CH3)
2.10 (2H, q, -CH2CH3) 2.42 (2H,t, -COCH2CH2NH-)
3.35 (2H,t, -COCH2CH2NH-)
7.80, 8.27 (1 Hx2, sx2, imidazole ring protons)
Elemental analysis as (C12H17N404)2AtOH: Calculated: C47.51, H 5.83, N 18.48 (%) Found: C 47.37, H 5.78, N 18.37 (%)
These analytical data confirm the following structure (J).
Example 11 To a solution of 0.76 g aluminum isopropoxide dissolved in 15 me of isopropyl alcohol was added 1.75 g of
N-propionyl-L-carnosine at 60 C.1.9 g (quantitative yield) of an N-propionyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 6.
mp: 2200C (decomp.) [ai25: (C=1% in H20)
NMR (D2O)#: 1.02 (3H,t, -CH2CH3) 2.10 (2H, q, -CH2CH3)
2.42 (2H, t, -COCH2CH2NH-)
3.32 (2H, t, -COCH2CH2NH)
7.08,8.27 (1 Hx2, sx2 imidazole ring protons)
Elemental analysis as (C12H17N4O4)5Al3(OH)4:
Calculated: C46.32, H 5.78, N 18.01 (%)
Found: C46.25, H5.72, N17.94(%)
These analytical data confirm the following structure (K).
Example 12
a) N-Heptanoyl-L-carnosine:To a solution of 2.42 g of L-carnosine dissolved in 13 mt of water was added 6.5 mt of acetone. 6.36 g of heptanoyl chloride was then added to the solution, and reaction mixture was treated in the same procedure as described in item a) of Example 9 to obtain a crude product.
Recrystallization of the crude product from water-acetone (1 :2) gave 1.66 g of N-heptanoyl-L-carnosine as colorless crystals (yield: 46%).
mp: 214 - 217" (decomp.) [a]25: +4.7 (C=2% in H20)
NMR (D20) â: 0.72 (3H, m, -CH3) 0.86- 1.56 (8H, m, -C112x4) 2.06 (2H, t, J=7Hz, -COCH2CH2-)
2.35 (2H, t, J=7Hz, -NHCOCH2CH2NH)
3.26 (2H, t, J=7Hz, -NHCOCH2CH2NH)
7.10, 8.42 (1 Hx2, sx2, imidazole ring protons)
Elemental analysis as C16H26N404:
Calculated: C56.77, H 7.76, N 16.56 (%) Found:C 56.81, H 7.85, N 16.38 (%)
b) To a solution of 0.68 g of aluminum isopropoxide dissolved in 15 mt of isopropyl alcohol was added 1.13 g of N-heptanoyl-L-carnosine at 60"C. 1.3 g (quantitative yield) of an N-heptanoyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 6.
mp: 280 C < (decomp.) [a]D5: +0.4 (C=1% in H20)
NMR (D20) â: 0.80 (3H, t, -CH2CH3)
1.20 (8H, m, -CH2-x4)
2.12 (2H,t, -CH2CH2CO-) 2.40 (2H,5,-COCH2CH2NH-)
3.07 (2H, m, -CH2CHCOO)
3.31 (2H,t, -COCH2CH2NH-) 4.44(1 H, m, -CH2CHCOO) 7.06, 8.28 (1 Hx2, sx2, imidazole ring protons)
Elemental analysis as (C16H25N404)At(OH)2: Calculated: C 48.23, H 6.84, N 14.06 (%)
Found: C48.03, H 6.87, N 13.77 (%)
These analytical data confirm the following structure (L).
Example 13
a) N-Benzoyl-L-carnosine: To a solution of 2.42 g of L-carnosine dissolved in 13 me of water was added 6.5 me of acetone. Thereafter, 6.32 g of benzoyl chloride was added to the solution, and the reaction mixture was treated in the same procedure as described in item a) of Example 9 to obtain a crude product.
Recrystallization of the crude product from methanol-acetone gave 1.69 g of N-benzoyl-L-carnosine as colorless crystals (yield: 48%).
mp: 217 ~ 219 C (decomp.) [α]D25: +10.35 (C=1% in H20)
NMR (D20) â: 2.48 (2H, t, J--7Hz,-COCH2CH2NH-)
3.46 (2H, t, J=7Hz, -COCH2CH2NH-)
6.99 [1 H, s, imidazole ring proton (5-position)] 7.1 ~ 7.6 (5H, m, benzene ring protons)
8.14 [1H, s, imidazole ring proton (2-position)]
Elemental analysis as C16H18N404:
Calculated:C 58.16, H 5.50, N 16.96 (%)
Found: C58.21, H 5.65, N 16.93 (%) b) To a solution of 0.8 g aluminum isopropoxide dissolved in 15 m4 of isopropyl alcohol was added 1.27 g of N-benzoyl-L-carnosine at 600C. 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 6.
mp: 280 C < (decomp.) [a]D5: +620 (C=1% in H20)
NMR (D20) â: 2.55 (2H, t, -COCH2CH2NH-)
3.55 (2H,t, -COCH2CH2NH-)
6.99 [1 H, s, imidaziole ring proton (5-position)] 7.44 (5H, m, benzene ring protons)
8.08 [1 H, s, imidazole ring proton (2-position)]
Elemental analysis as (C16H17N404At(OH)2: Calculated: C49.23, H4.92, N 14.36(%) Found: C49.18, H 4.86, N 14.18 (%)
These analytical data confirm the following strycture (M).
Example 14
To a solution of 0.80 g of aluminum isopropoxide dissolved in 15 ml of isopropyl alcohol was added 0.65 9 of N-benzoyl-L-carnosine at 60 C. 0.9 g (quantitative yieid) of an N-benzoyl-L-carnosine aluminum salt was obtained as colorless powder in the same way as in Example 6.
mp: 235 (decomp.) [α]D25: +4,1 (C=1% in H20)
NMR (D20) â: 2.55 (2H, t, -COCH2CH2NH-)
3.56 (2H, t, -COCH2CH2NH-)
6.99 [1 H, s, imidazole ring proton (5-position)] 7.45 (5H, m, benzene ring protons)
8.08 [1 H, s, imidazole ring proton (2-position)l
Elemental analysis as (C16H17N4O4)Al2(OH)5:
Calculated: C41.03, H 4.74, N 11.96 (%) Found: C40.88, H 4.67, N 11.89 (%)
These analytical data confirm the following structure (0).
Example 15
a) N-(o-Methoxy)benzoyl-L-carnosine: To a solution of 2.42 g of L-carnosine dissolved in 13 me of water was added 6.5 mC of acetone. Thereafter, 7.67 g of o-methoxy benzoyl chloride was added to the solution, and the reaction mixture was treated in the same procedure as that described in item a) of Example 9 to obtain a crude product.The crude product was very hygroscopic and then washed with ether to give 1.54 9 of N-(o-methoxy)benzoyl-L-carnosine as colorless crystals (yield: 40%)
mp: 2030C (decomp.) [a]5: +7.6 (C=1% in H20)
NMR (CD30D) b: 2.56 (2H, t, J=7Hz, -COCH2CH2NH-)
3.60 (2H, t, J=7Hz, -COCH2CH2NH-) 3.86 (3H,s, -OCH3)
6.85 ~ 7.85 (5H, m, benzene ring protons and imidazole ring proton)
8.33 (1H, s, imidazole ring proton)
Elemental analysis as C17H20N405:
Calculated: C 56.65, H 5.60, N 15.55 (%)
Found:C56.61, H 5.58, N 15.61 (%)
b) To a solution of 0.68 g of aluminum isopropoxide dissolved in 15 ml of isopropyl alcohol was added 1.20 g of N-(o-methoxy)benzoyl-L-carnosine at 60 C.1.40 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 6.
mp: 280 C < (decomp.) [a]D5: +2.7 (C=1% in H20)
NMR (D20) ô: 2.56 (2H,t, -COCH2CH2NH-)
3.55 (2H, t, -COCH2CH2NH-) 3.83 (3H,s, -OCH3)
6.95 ~ 7.65 (5H, m, benzene ring protons and imidazole ring proton) 7.96 (1 H, s, imidazole ring proton)
Elemental analysis as (C17H19N405)At(OH)2: Calculated: C 48.57, H 5.05, N 13.33 (%)
Found: C48.42, H4.92, N 13.18(%) These analytical data confirm the following structure (N).
Example 16
Preparation: 1 g of a digestive ulcer remedy prepared in the form of granules contains the following
ingredients.
Ingredients Ouantitylg
Compound E* 200 mg
Milk sugar 400 mg
Corn starch 400 mg
Total 1000 mug * Compound E is the same as defined above.
Claims (21)
1. An N-acylcarnosine aluminum salt of the formula (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, e represents an integer of 1 to 5, m represents an integer 1 to 3, and n represents an integer of 0 to 8.
2. An N-acylcarnosine aluminum salt according to Claim 1, wherein e is 1, m is 1, and n is 2.
3. An N-acylcarnosine aluminum salt according to Claim 1, wherein e is 1, m is 2, and n is 5.
4. An N-acylcarnosine aluminum salt according to Claim 1, wherein e is 1, m is 3, and n is 8.
5. An N-acylcarnosine aluminum salt according to Claim 1, wherein e is 2, m island n is 1.
6. An N-acylcarnosine aluminum salt according to Claim 1, wherein e is 3, m is 1, and n is zero.
7. An N-acylcarnosine aluminum salt according to Claim 1, wherein e is 5, m is 3, and n is 4.
8. An N-acylcarnosine aluminum salt according to any one of the preceding Claims, wherein R is a lower alkyl group having 1 to 6 carbon atoms.
9. An N-acylcarnosine aluminum salt according to Claim 8, wherein R is a methyl group.
10. An N-acylcarnosine aluminum salt according to any of the preceding Claims, wherein the acylcarnosine is of an L-form.
11. An N-acylcarnosine aluminum salt according to Claim 1 substantially as described with reference to any of the foregoing experiments and examples.
12 A process for preparing an N-acylcarnosine aluminum salt according to Claim 1, which comprises reacting an N-acylcarnosine of the formula (II),
wherein R has the same meaning as in Claim 1, with an aluminum alkoxide in the presence of a solvent, and removing said solvent and alcohols produced as side products from the reaction solution.
13. A process according to Claim 12, wherein said aluminum alkoxide is aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum t-butoxide, or aluminum cyclohexyloxide.
14. A process according to Claim 11, 12 or Claim 13, wherein said solvent is water, methanol, ethanol, isopropanol, or butanol, or a mixture of two or more of these.
15. A process as claimed in any one of Claims 11 to 14, wherein the reaction is carried out at a temperature in the range of from room temperature to 8O0C.
16. A process for preparing an N-acylcarnosine aluminum salt according to Claim 1, which comprises reacting an N-acvlcarnosine of the formula (II),
wherein R has the same meaning as in Claim 1 with an inorganic aluminum salt, and separating the resulting reaction mixture using an exchange resin.
17. A process according to Claim 16, wherein said inorganic aluminum salt is an aluminum sulfuric acid salt, an aluminum nitric acid salt, or an aluminum hydrochloric acid salt.
18. A process according to Claim 16 or Claim 17, wherein said exchange resin is a weakly basic anionic exchange resin.
19. A process according to any one of Claims 16 to 18, wherein said exchange resin is used in an amount of twice or three times the equivalent of the amount of N-acylcarnosine.
20. A process for preparing an N-acylcarnosine according to Claim 1 substantially as described with reference to any of the foregoing examples.
21. A remedy for inhibiting a digestive ulcer, which comprises an effective amount of an N-acylcarnosine aluminum salt according to Claim 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11671779A JPS5640614A (en) | 1979-09-13 | 1979-09-13 | Novel type remedy for peptic ulcer |
| JP13996679A JPS5665876A (en) | 1979-10-31 | 1979-10-31 | N-(beta-(n'-acylamino)propionyl)histidineammonium salt and its preparation |
| JP16827479A JPS5692276A (en) | 1979-12-26 | 1979-12-26 | Dialuminum salt of n-(beta-(n'-acylamino)propionyl) histidine and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2071083A true GB2071083A (en) | 1981-09-16 |
| GB2071083B GB2071083B (en) | 1983-06-02 |
Family
ID=27313212
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8028945A Expired GB2071083B (en) | 1979-09-13 | 1980-09-08 | N-acylcarnosine aluminum salts for treatment of digestive ulcers |
Country Status (7)
| Country | Link |
|---|---|
| AR (1) | AR226569A1 (en) |
| BR (1) | BR8005895A (en) |
| DE (1) | DE3034248A1 (en) |
| ES (1) | ES495028A0 (en) |
| FR (1) | FR2464943A1 (en) |
| GB (1) | GB2071083B (en) |
| IT (1) | IT1166485B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1261850A (en) * | 1985-01-19 | 1989-09-26 | Masahiro Takaya | Homocarnosine or acylhomocarnosine salts |
Family Cites Families (1)
| 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 |
-
1980
- 1980-09-08 GB GB8028945A patent/GB2071083B/en not_active Expired
- 1980-09-09 AR AR282457A patent/AR226569A1/en active
- 1980-09-11 DE DE19803034248 patent/DE3034248A1/en active Granted
- 1980-09-12 FR FR8019789A patent/FR2464943A1/en active Granted
- 1980-09-12 BR BR8005895A patent/BR8005895A/en unknown
- 1980-09-12 IT IT68412/80A patent/IT1166485B/en active
- 1980-09-12 ES ES495028A patent/ES495028A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| FR2464943A1 (en) | 1981-03-20 |
| ES8200666A1 (en) | 1981-10-16 |
| DE3034248A1 (en) | 1981-04-02 |
| ES495028A0 (en) | 1981-10-16 |
| IT8068412A0 (en) | 1980-09-12 |
| IT1166485B (en) | 1987-05-06 |
| GB2071083B (en) | 1983-06-02 |
| FR2464943B1 (en) | 1985-03-29 |
| AR226569A1 (en) | 1982-07-30 |
| BR8005895A (en) | 1981-03-31 |
| DE3034248C2 (en) | 1989-09-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19940908 |