US3876799A - Pantetheine-s-sulfonic acid derivatives for promoting the growth of bi bifidum in infants - Google Patents
Pantetheine-s-sulfonic acid derivatives for promoting the growth of bi bifidum in infants Download PDFInfo
- Publication number
- US3876799A US3876799A US397752A US39775273A US3876799A US 3876799 A US3876799 A US 3876799A US 397752 A US397752 A US 397752A US 39775273 A US39775273 A US 39775273A US 3876799 A US3876799 A US 3876799A
- Authority
- US
- United States
- Prior art keywords
- solution
- pantetheine
- bifidum
- residue
- methanol
- 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.)
- Expired - Lifetime
Links
- 230000001737 promoting effect Effects 0.000 title claims abstract description 10
- 241000186016 Bifidobacterium bifidum Species 0.000 claims abstract description 14
- 210000000936 intestine Anatomy 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 13
- 230000037396 body weight Effects 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 abstract description 9
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 239000000243 solution Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 239000007864 aqueous solution Substances 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000000921 elemental analysis Methods 0.000 description 10
- 229960000903 pantethine Drugs 0.000 description 9
- 239000011581 pantethine Substances 0.000 description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 8
- DJWYOLJPSHDSAL-UHFFFAOYSA-N Pantethine Natural products OCC(C)(C)C(O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)C(O)C(C)(C)CO DJWYOLJPSHDSAL-UHFFFAOYSA-N 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 229910052791 calcium Inorganic materials 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- DJWYOLJPSHDSAL-ROUUACIJSA-N pantethine Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO DJWYOLJPSHDSAL-ROUUACIJSA-N 0.000 description 8
- 235000008975 pantethine Nutrition 0.000 description 8
- 229920001429 chelating resin Polymers 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- PQUCIEFHOVEZAU-UHFFFAOYSA-N Diammonium sulfite Chemical compound [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 description 6
- CILGDYPFLJJNKT-NAWJVIAPSA-L calcium;(2r)-2,4-dihydroxy-3,3-dimethyl-1-oxo-1-[[3-oxo-3-(2-sulfonatosulfanylethylamino)propyl]amino]butane Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSS([O-])(=O)=O.OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSS([O-])(=O)=O CILGDYPFLJJNKT-NAWJVIAPSA-L 0.000 description 6
- 229910000365 copper sulfate Inorganic materials 0.000 description 6
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- -1 phosphate radical Chemical class 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 5
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 5
- 159000000007 calcium salts Chemical class 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 229910052788 barium Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 229920005654 Sephadex Polymers 0.000 description 3
- 239000012507 Sephadex™ Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001340 alkali metals Chemical group 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000001342 alkaline earth metals Chemical group 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- ZNXZGRMVNNHPCA-UHFFFAOYSA-N Pantetheine Natural products OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS ZNXZGRMVNNHPCA-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 239000000401 methanolic extract Substances 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- ZNXZGRMVNNHPCA-VIFPVBQESA-N pantetheine Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS ZNXZGRMVNNHPCA-VIFPVBQESA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000006277 sulfonation reaction Methods 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000899771 Arenga undulatifolia Species 0.000 description 1
- 241000186000 Bifidobacterium Species 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 229940002008 bifidobacterium bifidum Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910021446 cobalt carbonate Inorganic materials 0.000 description 1
- MPMSMUBQXQALQI-UHFFFAOYSA-N cobalt phthalocyanine Chemical compound [Co+2].C12=CC=CC=C2C(N=C2[N-]C(C3=CC=CC=C32)=N2)=NC1=NC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 MPMSMUBQXQALQI-UHFFFAOYSA-N 0.000 description 1
- ZOTKGJBKKKVBJZ-UHFFFAOYSA-L cobalt(2+);carbonate Chemical compound [Co+2].[O-]C([O-])=O ZOTKGJBKKKVBJZ-UHFFFAOYSA-L 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 1
- 229940068140 lactobacillus bifidus Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 210000001995 reticulocyte Anatomy 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
Definitions
- phosphate radical refers to a radical hav- This application is a Contmuatton-In-Part of US. aping the formulaOPO (OM') wherein Mrepresents pllca l n, S 135,640, filed P 1971. now an alkali metal, an alkaline earth metal or an ammoabandoned. nium group. Examples of M and M are Calcium, So-
- This invention relates to chemical compounds having EMBODIMENTS the effect of promoting the growth of bifidobacterium
- the compounds (I) of the present invention have a bifidum (Lactobacillus bifidus) and, more particularly sulfonic acid radical in its molecule which would be to pantetheine-S-sulfonic acid, 4'-phosphostrongly acidic in the intestine when clinically adminispantetheine-S-sulfonic acid, their salts, and the methtered.
- Any sulfite or bisulfite salt can be used for this purgrowth factors of this microbe. pose so long as it can provide sulfite or bisulfite ions to It has been reported that pantetheine, pantethine, or the reaction solution. Suitable such salts include sothe like have a considerable effect in increasing the B. dium salts, potassium salts, ammonium salts or sulfur bifidum in in vitro tests. However, the results of clinical dioxide gas introduced in water. The sulfonation reactests using these compounds do not appear to be in action is generally conducted in an aqueous solution of cord with the effect accomplished in the in vitro tests. (II).
- Suitable metal ions include cupprous, cupis due mainly to the ingestion of these growth factors pric, ferrous, ferric, cobaltous, or cobaltic ions.
- the through the intestinal wall into the blood on the way to catalytic ion donor may be a salt which is composed of the position of the intestine where B. bifidum resides.
- the present compounds show considerable growth activity to B. bifdum, in in vitro tests.
- Clinical tests with the compounds (1) prove the increase of B. bifidum in the intestine of human infants. The tests were conducted according to the following procedure.
- Stool samples were aseptically collected from eight bottle-fed infants before weaning (2 to 4 months of age) during both control and administration periods.
- the infants were fed with bottled milk, while in the administration period they were fed with milk containing calcium pantetheine-S-sulfonate or calcium 4-phospho-pantetheine-S-sulfonate in the ratio of 8 mg/Kg body weight/day).
- the stool was collected and suspended in a physiological saline solution in a predetermined dilution.
- the number of B. bifidum in each stool were determined by culturing the B. bifidum in the suspended solution at 37C. for 48 to 78 hours in a Negishi medium for B. bidifum under anaerobic condition, and checking the colonies number.
- compound (1) caused a distinguishable increase in body weight, increase of the reticulocyte, increase of the soterocyte, and decrease in the blood level of chlorsterols and nitrogen value due to urea.
- the compounds (I) are a useful growth factor for B. bifidum in even clinical administration, and furthermore the method of preparation has a great advantage in providing a high yield.
- an effective amount of compound (1) is administered, preferably 0,8 mg/kg body weight/day to 80 mg/kg body weight/day.
- EXAMPLE 1 In 100 ml. of 0.2 M. Ammonia solution containing 0.2 M. of sodium sulfite, 555 mg. of pantetheine was dissolved. The solution was kept at room temperature for 22 hours and air was introduced. The reaction solution was concentrated to dryness in vacuo. The residue was extracted with methanol and methanol extracts were concentrated to dryness in vacuo. The residue dissolved in water was applied to the column filled with QAE-Sephadex (CO -Form, 1.5 X 19 cm.). The column was washed with water and eluted with 500 ml. of water and a solution of 500 ml. of 0.5 M. of NH HCO according to the linear gradient elution method.
- QAE-Sephadex CO -Form, 1.5 X 19 cm.
- the eluate was collected by 50 ml. offraction. The fractions of No. 5 and No. 6 were combined and concentrated to dryness in vacuo. The aqueous solution of the residue was passed through 40 ml. of the column filled with SE-Sephadex (CA-Form) and the column was eluted with water. The eluate was concentrated to dryness and the residue was dissolved in methanol.
- SE-Sephadex CA-Form
- EXAMPLE 2 In ml. of water, 8.05 g. of ammonium sulfite, 5.55 g. of pantethine and 500 mg. of copper sulfate were in order dissolved. 15 ml. of methanol was then added. The solution was allowed to stand in air overnight. The reaction solution was concentrated to dryness in vacuo and the residue was dissolved in methanol.
- the filtrate was concentrated to dryness.
- the aqueous solution of the residue was applied to the column of Amberlite (Ca-Form) and eluted with water. After the eluate was concentrated to dryness, the residue was dissolved in methanol and the insoluble substances were removed from the solution. Concentration of the aqueous solution of the residue yielded 7.2 g. of calcium pantetheine-S-sulfonate in powder form. The physical properties of this compound were found to be almost identical with those described in Example 1.
- the aqueous solution of the Calcium salt obtained by the method described above was passed through a column of Amberlite lR-l20 (H-Form) and eluted with water. Rapid concentration of the eluate to dryness at low temperature yielded a colorless powder of pantetheine- S-sulfonic acid.
- Example 3 The procedure of Example 2 was repeated using the barium form of the resin instead of lR-l20 (Ca-Form). The eluate was concentrated to dryness and the residue was extracted with methanol. Addition of acetone to the methanol solution yielded 8.1 g. of barium pantetheine-S-sulfonate.
- EXAMPLE 4 In 25 ml. of an aqueous solution containing 3 g. of sodium sulfite, a mixture of 1.1 of pantethine and 30 mg. of copper sulfate were dissolved. To the solution, 6 ml. of methanol was added and then air was introduced overnight. The reaction solution was concentrated to dryness in vacuo. The residue was extracted with methanol and the methanol solution was concentrated to dryness in vacuo.
- EXAMPLE 5 Sodium pantetheine-S-sulfonate obtained in the process of Example 4 was dissolved in water and the aqueous solution of the sodium salt was passed through the column of Amberlite lR-120 (Al-Form) and eluted with water. The eluate was concentrated to dryness in vacuo. The residue was dissolved in methanol and acetone was added to the solution. The resulting precipitate was dried in vacuo to give 1.3 g. of aluminum pantetheine-S-sulfonate in powder form.
- EXAMPLE 6 In a mixture of ml. of water and 5 ml. of methanol, 1.11 g. of pantethine, 1.25 g. of sodium hydrogen sulfite and 200 mg. of copper sulfate were dissolved. Air was introduced into the solution overnight. After neutralization with sodium hydroxide, the solution was concentrated to dryness in vacuo. The residue was extracted with methanol to give sodium pantetheine-S- sulfonate. The aqueous solution of the sodium salt was passed through a column of Amberlite 1R-120 (Ca- Form) and eluted with water. The eluate was concentrated to dryness in vacuo to give 1.3 g. of calcium pantetheine-S-sulfonate.
- EXAMPLE 7 In ml. of water, 1.11, g. of pantethine, 2.1 g. of ammonium sulfite and 100 mg. of ferric sulfate were dissolved. Air was introduced into the solution for 48 hours. Insoluble substances were filtered off and the filtrate was concentrated to dryness in vacuo. The residue was extracted with methanol and from the methanol solution, methanol was removed in vacuo. Treatment of the residue in a manner similar to that of Example 2 yielded 935 mg. of calcium pantetheine-S-sulfonate.
- EXAMPLE 8 ln 30 ml. ofwater, 1.11 g. of pantethine, 1.6 g. of ammonium sulfite and 100 mg. of cobalt carbonate were dissolved. Air was introduced into the solution for 48 hours. The reaction solution was concentrated to dryness in vacuo and the residue was extracted with methanol. After decolorizing the methanol solution with charcoal, methanol was removed from the filtrate. Treatment of the residue in a manner to that of Example 2 yielded 990 mg. of calcium pantetheine-S- sulfonate.
- EXAMPLE 9 In 20 ml. of water, 1.1 g. of pantethine and 2.1 g. of ammonium sulfite were dissolved and the solution was allowed to stand at room temperature overnight. The reaction solution was concentrated to dryness in vacuo and the residue was extracted with methanol. From the methanol extracts, methanol was distilled off. The aqueous solution of the residue was passed through a column of Amberlite lR-120 (Ba-Form) and eluted with water. The eluate was concentrated to dryness in vacuo. Addition of isopropanol to the residue dissolved in a small amount of methanol yielded 0.8 g. of barium pantetheine-S-sulfonate in powder form. The physical properties of this compound were found to be identical with those described in Example 3.
- the calcium salt thus obtained was subjected to the column of lR- (H-Form) and eluted with water. The eluate was concentrated under the reduced pressure to give 4'-phosphopanthetheine-S-sulfonic acid.
- EXAMPLE 1 1 In a manner similar to that of Example 10, by using barium hydroxide instead of calcium hydroxide, 2.3 g. of barium 4'-phosphopantetheine-S-sulfonate was obtained.
- EXAMPLE 12 About 431 mg. of calcium 4-phosphopantetheine was dissolved in 5 ml. of water. Into the solution, an aqueous solution containing 504 mg. of sodium sulfite and then an aqueous solution containing 20 mg. of copper sulfate were added. Air was introduced into the solution overnight. The precipitate was filtered off. The filtrate was concentrated to dryness in vacuo and the residue was extracted with methanol; then, the methanol was removed from the methanol solution. The aqueous solution of the residue was applied to a column of Amberlite lR-l20 (Na-Form) and eluted with water. Concentration of the eluate to dryness under the reduced pressure yielded 490 mg. of the sodium 4- phosphopantetheine-S-sulfonate in powder form.
- Amberlite lR-l20 Na-Form
- EXAMPLE 14 About 431 mg. of 4'-phosphopantethine calcium salt was dissolved in ml. of water. Into the solution, an aqueous solution containing 833 mg. of sodium hydrogen sulfite was added and followed with addition of an aqueous solution containing 20 ml. of copper sulfate. Air was introduced into the solution overnight. In a manner similar to that of Example 10, 445 mg. calcium 4'-phosphopantetheine-S-sulfonate was obtained.
- EXAMPLE 15 In 15 ml. of water, 431 mg. of 4'-phosphopantethine calcium salt, 670 mg. of ammonium sulfite and 50 mg. of ferrous sulfate were dissolved and air was introduced into the solution overnight. The reaction solution was treated in a manner similar to that of Example to give 450 mg. of calcium 4'-phosphopantetheine-S- sulfonate.
- EXAMPLE 16 In an aqueous solution containing 0.2 M. of ammonia and 0.2 M. of ammonium sulfite, 431 mg. of 4- elution method. The eluate was collected by 50 ml. of fraction. The fractions of No. 9 No. l l were concentrated to dryness in vacuo. The aqueous solution of the residue was subjected to the column of 40 ml. of SE- Sephadex (Ca-Form) and eluted with water. The eluate was concentrated to dryness in vacuo and the residue was dissolved in a small amount of water. Insoluble substances were filtered off.
- SE- Sephadex Ca-Form
- a method for promoting growth of B. bifidum in the intestine of a human infant which comprises administering to said infant an effective amount of a compound of the formula:
- Y represents a hydroxy group
- M represents a member selected from the group consisting of hydrogen, an alkali metal atom, an alkaline earth metal atom and an ammonium group.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Pantethelne-S-sulfonic acid, 4''-phospho-Pantetheine-S-sulfonic acid and their metal salts were synthesized and found to be clinically effective for promoting the growth of B. bifidum in the intestine of infants.
Description
United States Patent 1191 Tamara et al.
Apr. 8, 1975 PANTETIIEINE-S-SULFONIC ACID DERIVATIVES FOR PROMOTING THE GROWTH OF BI BIFIDUM IN INFANTS Inventors: Zenzo Tamura; Keizo Ohta; Osamu Nagase, all of Tokyo, Japan Assignee: Daiichi Seiyaku Company, Ltd.,
Related US. Application Data Continuation-in-part of Scr. No. 135,640, April 20, 197 l abandoned.
US. Cl. 424/303; 424/211 Int. Cl A61k 27/00 Field of Search 424/320, 336, 303;
Japan 45-33043 I References Cited UNITED STATES PATENTS 3.413330 11/1968 Westland 260/453 FOREIGN PATENTS OR APPLlCATIONS l.4l8.664 10/1965 France 260/453 R Primary E.\'aminer-St-anley J. Friedman Attorney, Agent, or Firm-Oblon, Fisher, Spivak, McClelland & Maier [57] ABSTRACT Pantethelne-S-sulfonic acid, 4-ph0spho-Pantetheine- S-suifonic acid and their metal salts were synthesized and found to be clinically effective for promoting the growth of B. bifidum in the intestine of infants.
2 Claims, No Drawings 3,876,799 1 2 PANTETI-IEINE-S-SULFONIC ACID DERIVATIVES wherein Y represents a hydroxy group, a phosphoryl FOR PROMOTING THE GROWTH OF BI BIFIDUM group or a phosphate radical and M represents hydro- IN INFANTS gen, an alkali metal atom, an alkaline earth metal atom, RELATI N HIP T R or an ammonium group.
O f APPLICATIONS 5 The term phosphate radical refers to a radical hav- This application is a Contmuatton-In-Part of US. aping the formulaOPO (OM') wherein Mrepresents pllca l n, S 135,640, filed P 1971. now an alkali metal, an alkaline earth metal or an ammoabandoned. nium group. Examples of M and M are Calcium, So-
BACKGROUND OF THE INVENTION l0 dium, Barium, Potassium, Aluminum, etc. 1' Field of The Invention DETAILED DESCRIPTION OF PREFERRED This invention relates to chemical compounds having EMBODIMENTS the effect of promoting the growth of bifidobacterium The compounds (I) of the present invention have a bifidum (Lactobacillus bifidus) and, more particularly sulfonic acid radical in its molecule which would be to pantetheine-S-sulfonic acid, 4'-phosphostrongly acidic in the intestine when clinically adminispantetheine-S-sulfonic acid, their salts, and the methtered. It is believed that this strong acidity in the intesods for preparing the same. tines hinders the intake of these compounds so that 2. Description Of Prior Art they are permitted to reach the microbe colony. Both the mortality and morbidity of breast-fed in- The compounds(l)of this invention can be produced fants are about one-half to one-third of those of bottleby the following method:'
CH OH Y CH C- CH -CONHCH -CH -CONHCH -CH -S- SO CH OH 3 I I 2 Y -CI-I C CH CONHCH -CH -CONHCH -CH -S-SO M.
fed infants, and it has been assumed that B. bifidum wherein Y and M are as defined above.
prevailing in the intestines of breast-fed infants may According to the above reaction scheme, sulfonation contribute to their relatively more healthy state. takes place on the sulfur atom of pantethine, 4-
Therefore, it seems desirable to increase the quantity phospho-pantethine or its salt (II) by the action of the of B. bifiudm in the intestines of infants and several insulfite salt or bisulfite salt.
vestigations have been directed toward establishing the 40 Any sulfite or bisulfite salt can be used for this purgrowth factors of this microbe. pose so long as it can provide sulfite or bisulfite ions to It has been reported that pantetheine, pantethine, or the reaction solution. Suitable such salts include sothe like have a considerable effect in increasing the B. dium salts, potassium salts, ammonium salts or sulfur bifidum in in vitro tests. However, the results of clinical dioxide gas introduced in water. The sulfonation reactests using these compounds do not appear to be in action is generally conducted in an aqueous solution of cord with the effect accomplished in the in vitro tests. (II). The reason for this disparity between the theoretical Catalytic metal ions can be used in the reaction soluand the actual effects has not yet been resolved. tion to complete the reaction smoothly with a high It was first hypothesized that the disparity of results yield of (1). Suitable metal ions include cupprous, cupis due mainly to the ingestion of these growth factors pric, ferrous, ferric, cobaltous, or cobaltic ions. The through the intestinal wall into the blood on the way to catalytic ion donor may be a salt which is composed of the position of the intestine where B. bifidum resides. at least one of these ions and a member selected from A need exists, therefore, for a compound which the group consisting of sulfuric acid, carbonic acid, hywould be applicable to clinical use for promoting the drochloric acid and sulfurous acid. In addition to these growth of bifidobacterium bifidum (hereinafter abbreions, air or oxygen may be introduced into the reaction viated to B. bifidum). solution in order to promote the reaction yield to a great extent. The reaction proceeds at temperatures of SUMMARY OF THE INVENTION between room temperature and 40C. for from several One object of this invention is thus to provide a novel hours to as much as 10 hours, although the exact time compound and a method for synthesizing said comis not critical and can be easily ascertained.
pound which would promote the growth of B. bifidum. The compounds (I) thus produced can be easily sepa- This and other objects have now herein been attained rated from the reaction mixture by conventional procein one aspect of the present invention by providing the dures and/or they may be converted to a desirable salt compound having the following general formula (I): such as a calcium, sodium, aluminum or barium salt by on OH Y cu c CH coxncu -cu -coNucn --CH -s-so M (1) 2 2 2 2 2 3 passing an aqueous solution of (1) through a column filled with an ion-exchange resin of desired metal form.
The present compounds show considerable growth activity to B. bifdum, in in vitro tests. Clinical tests with the compounds (1) prove the increase of B. bifidum in the intestine of human infants. The tests were conducted according to the following procedure.
Stool samples were aseptically collected from eight bottle-fed infants before weaning (2 to 4 months of age) during both control and administration periods. (In the control period, the infants were fed with bottled milk, while in the administration period they were fed with milk containing calcium pantetheine-S-sulfonate or calcium 4-phospho-pantetheine-S-sulfonate in the ratio of 8 mg/Kg body weight/day). The stool was collected and suspended in a physiological saline solution in a predetermined dilution. The number of B. bifidum in each stool were determined by culturing the B. bifidum in the suspended solution at 37C. for 48 to 78 hours in a Negishi medium for B. bidifum under anaerobic condition, and checking the colonies number.
Another desirable effect on the infants has been observed during the administration period; for example, it was found that compound (1) caused a distinguishable increase in body weight, increase of the reticulocyte, increase of the soterocyte, and decrease in the blood level of chlorsterols and nitrogen value due to urea.
As described above the compounds (I) are a useful growth factor for B. bifidum in even clinical administration, and furthermore the method of preparation has a great advantage in providing a high yield.
For promoting growth of B. bifidum in the intestine of a human infant an effective amount of compound (1) is administered, preferably 0,8 mg/kg body weight/day to 80 mg/kg body weight/day.
Having now generally described the invention, a more complete understanding can be obtained by reference to certain specific Examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.
EXAMPLE 1 In 100 ml. of 0.2 M. Ammonia solution containing 0.2 M. of sodium sulfite, 555 mg. of pantetheine was dissolved. The solution was kept at room temperature for 22 hours and air was introduced. The reaction solution was concentrated to dryness in vacuo. The residue was extracted with methanol and methanol extracts were concentrated to dryness in vacuo. The residue dissolved in water was applied to the column filled with QAE-Sephadex (CO -Form, 1.5 X 19 cm.). The column was washed with water and eluted with 500 ml. of water and a solution of 500 ml. of 0.5 M. of NH HCO according to the linear gradient elution method. The eluate was collected by 50 ml. offraction. The fractions of No. 5 and No. 6 were combined and concentrated to dryness in vacuo. The aqueous solution of the residue was passed through 40 ml. of the column filled with SE-Sephadex (CA-Form) and the column was eluted with water. The eluate was concentrated to dryness and the residue was dissolved in methanol.
Insoluble substances in the methanol solution were filtered off and the methanol was removed from the filtrate. The aqueous solution of the residue was concentrated to dryness.
The residue was dried in vacuo at 40C. to give 213 mg. of calcium pantetheine-S-sulfonate having a melting point of 174C. (decomp.)
[a],, 13.9 (1.95 H O) Elemental Analyses For C H O N S Ca:
Calcd; C, 35.00; H. 5.59; N 7.38;
Found; C, 34.85; H, 5.73; N,7.09.
EXAMPLE 2 In ml. of water, 8.05 g. of ammonium sulfite, 5.55 g. of pantethine and 500 mg. of copper sulfate were in order dissolved. 15 ml. of methanol was then added. The solution was allowed to stand in air overnight. The reaction solution was concentrated to dryness in vacuo and the residue was dissolved in methanol.
After filtering off the insoluble substance, the filtrate was concentrated to dryness. The aqueous solution of the residue was applied to the column of Amberlite (Ca-Form) and eluted with water. After the eluate was concentrated to dryness, the residue was dissolved in methanol and the insoluble substances were removed from the solution. Concentration of the aqueous solution of the residue yielded 7.2 g. of calcium pantetheine-S-sulfonate in powder form. The physical properties of this compound were found to be almost identical with those described in Example 1. The aqueous solution of the Calcium salt obtained by the method described above was passed through a column of Amberlite lR-l20 (H-Form) and eluted with water. Rapid concentration of the eluate to dryness at low temperature yielded a colorless powder of pantetheine- S-sulfonic acid.
Elemental Analyses For C m- 0 N 5 H O:
Calcd; C, 35.07; H, 6.43; N, 7.44;
Found; C, 35.00; H, 6.16; N, 7.70.
EXAMPLE 3 The procedure of Example 2 was repeated using the barium form of the resin instead of lR-l20 (Ca-Form). The eluate was concentrated to dryness and the residue was extracted with methanol. Addition of acetone to the methanol solution yielded 8.1 g. of barium pantetheine-S-sulfonate.
Elemental Analyses 3COCH3:
Calcd; C, 32.98; H, 5.32; N, 6.16
Found; C, 33.39; H, 5.55; N, 6.77.
EXAMPLE 4 In 25 ml. of an aqueous solution containing 3 g. of sodium sulfite, a mixture of 1.1 of pantethine and 30 mg. of copper sulfate were dissolved. To the solution, 6 ml. of methanol was added and then air was introduced overnight. The reaction solution was concentrated to dryness in vacuo. The residue was extracted with methanol and the methanol solution was concentrated to dryness in vacuo.
The residue was dissolved in ethanol and to the solution, ether was added. The resulting precipitate was collected by filtration and dissolved in water. The residue obtained by concentration of the aqueous solution in vacuo was dried in vacuo to give 1.4 g. of sodium pantetheine-S-sulfonate.
Elemental Analyses For C H ,O N S Na.%H O:
Calcd; C, 33.92; H, 5.69; N, 7.19; Na, 5.91;
Found; C, 33.98; H, 5.47; N, 6.93; Na, 6.06.
EXAMPLE 5 Sodium pantetheine-S-sulfonate obtained in the process of Example 4 was dissolved in water and the aqueous solution of the sodium salt was passed through the column of Amberlite lR-120 (Al-Form) and eluted with water. The eluate was concentrated to dryness in vacuo. The residue was dissolved in methanol and acetone was added to the solution. The resulting precipitate was dried in vacuo to give 1.3 g. of aluminum pantetheine-S-sulfonate in powder form.
Elemental Analyses For C H O N S ALCH- 3COCH3:
Calcd; C, 37.36; H, 6.01; N, 7.26; Found; C, 37.85; H, 6.26; N, 7.25.
EXAMPLE 6 In a mixture of ml. of water and 5 ml. of methanol, 1.11 g. of pantethine, 1.25 g. of sodium hydrogen sulfite and 200 mg. of copper sulfate were dissolved. Air was introduced into the solution overnight. After neutralization with sodium hydroxide, the solution was concentrated to dryness in vacuo. The residue was extracted with methanol to give sodium pantetheine-S- sulfonate. The aqueous solution of the sodium salt was passed through a column of Amberlite 1R-120 (Ca- Form) and eluted with water. The eluate was concentrated to dryness in vacuo to give 1.3 g. of calcium pantetheine-S-sulfonate.
EXAMPLE 7 In ml. of water, 1.11, g. of pantethine, 2.1 g. of ammonium sulfite and 100 mg. of ferric sulfate were dissolved. Air was introduced into the solution for 48 hours. Insoluble substances were filtered off and the filtrate was concentrated to dryness in vacuo. The residue was extracted with methanol and from the methanol solution, methanol was removed in vacuo. Treatment of the residue in a manner similar to that of Example 2 yielded 935 mg. of calcium pantetheine-S-sulfonate.
EXAMPLE 8 ln 30 ml. ofwater, 1.11 g. of pantethine, 1.6 g. of ammonium sulfite and 100 mg. of cobalt carbonate were dissolved. Air was introduced into the solution for 48 hours. The reaction solution was concentrated to dryness in vacuo and the residue was extracted with methanol. After decolorizing the methanol solution with charcoal, methanol was removed from the filtrate. Treatment of the residue in a manner to that of Example 2 yielded 990 mg. of calcium pantetheine-S- sulfonate.
EXAMPLE 9 In 20 ml. of water, 1.1 g. of pantethine and 2.1 g. of ammonium sulfite were dissolved and the solution was allowed to stand at room temperature overnight. The reaction solution was concentrated to dryness in vacuo and the residue was extracted with methanol. From the methanol extracts, methanol was distilled off. The aqueous solution of the residue was passed through a column of Amberlite lR-120 (Ba-Form) and eluted with water. The eluate was concentrated to dryness in vacuo. Addition of isopropanol to the residue dissolved in a small amount of methanol yielded 0.8 g. of barium pantetheine-S-sulfonate in powder form. The physical properties of this compound were found to be identical with those described in Example 3.
6 EXAMPLE 10 About 1.73 g. of 4-phosphopantethine calcium salt was dissolved in 20 ml. of water. Into the solution, 20 ml. of aqueous solution containing 50 mg. of copper sulfate were added. Air was introduced into the solution overnight. The resulting precipitate was filtered off and the filtrate was concentrated to dryness in vacuo. The residue was dissolved in water. The solution was applied to a column of Amberlite 1R-l20 (H-Form) and the column was eluted with water. The water eluate was neutralized with aqueous calcium hydroxide solution and concentrated in vacuo. The residue was dissolved in a small amount of water and the insoluble substance was filtered off. The filtrate was concentrated to dryness in vacuo. The residue was dried with phosphoric anhydride in vacuo to give 1.8 g. of calcium 4'-phosphopantetheine-S-sulfonate.
[a],, 7.2 (C 1.95, H O) Elemental Analyses For C H O N,P S Ca Calcd; C, 26.66; H, 4.08; N 5.65;
Found; C, 26.61; H, 4.08; N, 5.53.
The calcium salt thus obtained was subjected to the column of lR- (H-Form) and eluted with water. The eluate was concentrated under the reduced pressure to give 4'-phosphopanthetheine-S-sulfonic acid.
Elemental Analyses For C H O N PS :2 H O:
Calcd; C, 27.84; H, 5.74; N, 5.90;
Found; C, 28.28; H, 5.60; N, 6.20.
EXAMPLE 1 1 In a manner similar to that of Example 10, by using barium hydroxide instead of calcium hydroxide, 2.3 g. of barium 4'-phosphopantetheine-S-sulfonate was obtained.
Elemental Analyses For C H O N S Ba '2H O;
Calcd; C, 20.04; H, 3.36; N, 4.25;
Found; C, 20.11; H, 3.58; N, 3.98.
EXAMPLE 12 About 431 mg. of calcium 4-phosphopantetheine was dissolved in 5 ml. of water. Into the solution, an aqueous solution containing 504 mg. of sodium sulfite and then an aqueous solution containing 20 mg. of copper sulfate were added. Air was introduced into the solution overnight. The precipitate was filtered off. The filtrate was concentrated to dryness in vacuo and the residue was extracted with methanol; then, the methanol was removed from the methanol solution. The aqueous solution of the residue was applied to a column of Amberlite lR-l20 (Na-Form) and eluted with water. Concentration of the eluate to dryness under the reduced pressure yielded 490 mg. of the sodium 4- phosphopantetheine-S-sulfonate in powder form.
Elemental Analyses For C H O N PS Na 'ZH O:
Calcd; C, 24.45; H, 4.48; N, 5.18;
Found; C, 24.50; H, 4.60; N, 4.90.
EXAMPLE 13 In a manner similar to that of the foregoing Example 12, using the column of 1R-l20 (Al-Form) instead of lR-120 (Na-Form) yielded 420 mg. of aluminum 4- phosphopantetheine-S-sulfonate.
Elemental Analyses For C H O N PS AL3H O:
Calcd; C, 25.58; H, 5.08; N, 5.43;
Found; C, 25.56; H, 5.10; N, 5.30.
EXAMPLE 14 About 431 mg. of 4'-phosphopantethine calcium salt was dissolved in ml. of water. Into the solution, an aqueous solution containing 833 mg. of sodium hydrogen sulfite was added and followed with addition of an aqueous solution containing 20 ml. of copper sulfate. Air was introduced into the solution overnight. In a manner similar to that of Example 10, 445 mg. calcium 4'-phosphopantetheine-S-sulfonate was obtained.
EXAMPLE 15 In 15 ml. of water, 431 mg. of 4'-phosphopantethine calcium salt, 670 mg. of ammonium sulfite and 50 mg. of ferrous sulfate were dissolved and air was introduced into the solution overnight. The reaction solution was treated in a manner similar to that of Example to give 450 mg. of calcium 4'-phosphopantetheine-S- sulfonate.
EXAMPLE 16 In an aqueous solution containing 0.2 M. of ammonia and 0.2 M. of ammonium sulfite, 431 mg. of 4- elution method. The eluate was collected by 50 ml. of fraction. The fractions of No. 9 No. l l were concentrated to dryness in vacuo. The aqueous solution of the residue was subjected to the column of 40 ml. of SE- Sephadex (Ca-Form) and eluted with water. The eluate was concentrated to dryness in vacuo and the residue was dissolved in a small amount of water. Insoluble substances were filtered off.
Concentration of the filtrate to dryness in vacuo yielded 283 mg. of Calcium 4'-phosphopantetheine-S- sulfonate. [a],, 7.2 (1.94%: H O) MP higher than 300C.
Having now fully described the invention, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention.
What is claimed as new and intended to be covered by letters patent is:
l. A method for promoting growth of B. bifidum in the intestine of a human infant which comprises administering to said infant an effective amount of a compound of the formula:
wherein Y represents a hydroxy group, and M represents a member selected from the group consisting of hydrogen, an alkali metal atom, an alkaline earth metal atom and an ammonium group.
2. The method of claim 1, wherein said compound is administered in an amount of 0.8 mg/kg body weight/- day to mg/kg body weight/day.
Claims (2)
1. A METHOD FOR PROMOTING GROWTH OF B. BIFIDUM IN THE INTESTINE OF A HUMAN INFANT WHICH COMPRISES ADMINISTERING TO SAID INFANT AN EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA:
2. The method of claim 1, wherein said compound is administered in an amount of 0.8 mg/kg body weight/day to 80 mg/kg body weight/day.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US397752A US3876799A (en) | 1970-04-20 | 1973-09-17 | Pantetheine-s-sulfonic acid derivatives for promoting the growth of bi bifidum in infants |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP45033042A JPS49820B1 (en) | 1970-04-20 | 1970-04-20 | |
JP3304370A JPS4940212B1 (en) | 1970-04-20 | 1970-04-20 | |
US13564071A | 1971-04-20 | 1971-04-20 | |
US397752A US3876799A (en) | 1970-04-20 | 1973-09-17 | Pantetheine-s-sulfonic acid derivatives for promoting the growth of bi bifidum in infants |
Publications (1)
Publication Number | Publication Date |
---|---|
US3876799A true US3876799A (en) | 1975-04-08 |
Family
ID=27459733
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US397752A Expired - Lifetime US3876799A (en) | 1970-04-20 | 1973-09-17 | Pantetheine-s-sulfonic acid derivatives for promoting the growth of bi bifidum in infants |
Country Status (1)
Country | Link |
---|---|
US (1) | US3876799A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2517542A1 (en) * | 1981-12-04 | 1983-06-10 | Sogo Pharm | MEDICAMENT FOR IMPROVING LIPID METABOLISM |
US4749719A (en) * | 1983-09-21 | 1988-06-07 | Sogo Pharmaceutical Company Limited | Method of treating skin pigmentation abnormalities with pantetheine-S-sulfonic acid |
US6096536A (en) * | 1990-07-06 | 2000-08-01 | University Of New Mexico | In vitro cell culture in media containing beta-alanyl-taurine or carbobenzoxy beta-alanyl-taurine |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3413330A (en) * | 1966-10-14 | 1968-11-26 | Parke Davis & Co | Cycloalkylalkyloxy-alkylaminoethyl thiosulfates and salts thereof |
-
1973
- 1973-09-17 US US397752A patent/US3876799A/en not_active Expired - Lifetime
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3413330A (en) * | 1966-10-14 | 1968-11-26 | Parke Davis & Co | Cycloalkylalkyloxy-alkylaminoethyl thiosulfates and salts thereof |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2517542A1 (en) * | 1981-12-04 | 1983-06-10 | Sogo Pharm | MEDICAMENT FOR IMPROVING LIPID METABOLISM |
US4749719A (en) * | 1983-09-21 | 1988-06-07 | Sogo Pharmaceutical Company Limited | Method of treating skin pigmentation abnormalities with pantetheine-S-sulfonic acid |
US6096536A (en) * | 1990-07-06 | 2000-08-01 | University Of New Mexico | In vitro cell culture in media containing beta-alanyl-taurine or carbobenzoxy beta-alanyl-taurine |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US3821192A (en) | Process for preparing an iron-saccharide complex | |
US3506642A (en) | Stable orally active heparinoid complexes | |
Bojarski et al. | Stabilization of thymidylate kinase activity by thymidylate and by thymidine | |
US4420432A (en) | Crystalline salt of basic L-amino acid with L-malic acid and process for the preparation thereof | |
Riesenfeld et al. | Glucose homeostasis in the chicken | |
Durbin et al. | Specific Sequestering Agents for the Actinides: 4. Removal of 238Pu (IV) from Mice by Sulfonated Tetrameric Catechoyl Amides | |
US3876799A (en) | Pantetheine-s-sulfonic acid derivatives for promoting the growth of bi bifidum in infants | |
GB1487397A (en) | Heteropolyanions having antiviral properties | |
US3027303A (en) | Hematinic compositions | |
US3803119A (en) | Pantetheine-s-sulfonic acid derivatives and salts thereof | |
US4810695A (en) | Chitosan derivatives in the form of coordinated complexes with ferrous ions | |
US2427692A (en) | Therapeutic metal cevitamate compositions | |
Dinning et al. | Creatine metabolism in vitamin E deficiency. | |
CA1094289A (en) | Aluminum compound and medicament containing it | |
IE902656A1 (en) | Salts of n5,n10-methylene-5,6,7,8-tetrahydrofolic acid | |
Günther et al. | Pantethine analogs. The condensation of pantothenic acid with selenocystamine, with bis-(β-aminoethyl) sulfide and with 1, 2-dithia-5-azepane (a new ring system) 1, 2 | |
US3342683A (en) | Heparin from whale tissue and method of preparing same | |
US3576007A (en) | Water soluble salts of ellagic acid | |
US3657453A (en) | Intravenously injectable hemostatic compositions of water soluble salts of ellagic acid | |
US3340249A (en) | Adenosine triphosphate salts of l-ornithine and process for preparing the same | |
US2653897A (en) | Alkali metal salts of adenylic acid | |
GB2044265A (en) | Adenosine Triphosphate Metal Complexes, Processes for Their Preparation and Pharmaceutical Compositions Containing Them | |
US2192386A (en) | Insulin preparation and process | |
USRE37534E1 (en) | Pharmaceutical compositions | |
RU2166944C2 (en) | Plasma substitute solution with hemocorrecting and immunomodulating properties |