WO1995009162A1 - N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl) hydroxyacetamide-2-hydroxy-1,2,3-propenetricarboxylate bismuth (3+) complex and the method for preparation - Google Patents
N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl) hydroxyacetamide-2-hydroxy-1,2,3-propenetricarboxylate bismuth (3+) complex and the method for preparation Download PDFInfo
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- WO1995009162A1 WO1995009162A1 PCT/BG1994/000009 BG9400009W WO9509162A1 WO 1995009162 A1 WO1995009162 A1 WO 1995009162A1 BG 9400009 W BG9400009 W BG 9400009W WO 9509162 A1 WO9509162 A1 WO 9509162A1
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- Prior art keywords
- bismuth
- piperidinylmethyl
- phenoxy
- bismuth salt
- propyl
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- LUOYFQVUYMMTRC-UHFFFAOYSA-N bismuth(3+) Chemical compound [Bi+3].[Bi+3] LUOYFQVUYMMTRC-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 9
- 150000001621 bismuth Chemical class 0.000 claims abstract description 44
- BCCREUFCSIMJFS-UHFFFAOYSA-N 2-hydroxy-n-[3-[3-(piperidin-1-ylmethyl)phenoxy]propyl]acetamide Chemical compound OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 BCCREUFCSIMJFS-UHFFFAOYSA-N 0.000 claims abstract description 16
- KKMOSYLWYLMHAL-UHFFFAOYSA-N 2-bromo-6-nitroaniline Chemical compound NC1=C(Br)C=CC=C1[N+]([O-])=O KKMOSYLWYLMHAL-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002775 capsule Substances 0.000 claims abstract description 5
- 230000003993 interaction Effects 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000654 additive Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000012736 aqueous medium Substances 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- 241000590002 Helicobacter pylori Species 0.000 abstract description 8
- 229940037467 helicobacter pylori Drugs 0.000 abstract description 8
- 208000007107 Stomach Ulcer Diseases 0.000 abstract description 7
- 230000001120 cytoprotective effect Effects 0.000 abstract description 6
- 230000002496 gastric effect Effects 0.000 abstract description 6
- 208000000718 duodenal ulcer Diseases 0.000 abstract description 5
- 230000001262 anti-secretory effect Effects 0.000 abstract description 4
- 238000009835 boiling Methods 0.000 abstract 1
- 208000025865 Ulcer Diseases 0.000 description 15
- 231100000397 ulcer Toxicity 0.000 description 13
- 229960003320 roxatidine Drugs 0.000 description 11
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229960001340 histamine Drugs 0.000 description 5
- 239000008108 microcrystalline cellulose Substances 0.000 description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 229920003094 Methocel™ K4M Polymers 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229940044551 receptor antagonist Drugs 0.000 description 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 229940100445 wheat starch Drugs 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910052797 bismuth Inorganic materials 0.000 description 3
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 3
- 238000000265 homogenisation Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003699 antiulcer agent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000003891 oxalate salts Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- AUFIRGPROMANKW-UHFFFAOYSA-N CN1CC=CCC1 Chemical compound CN1CC=CCC1 AUFIRGPROMANKW-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 206010020601 Hyperchlorhydria Diseases 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products 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 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- REKWPXFKNZERAA-UHFFFAOYSA-K bismuth;2-carboxyphenolate Chemical compound [Bi+3].OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O REKWPXFKNZERAA-UHFFFAOYSA-K 0.000 description 1
- ZQUAVILLCXTKTF-UHFFFAOYSA-H bismuth;tripotassium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [K+].[K+].[K+].[Bi+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O ZQUAVILLCXTKTF-UHFFFAOYSA-H 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006161 blood agar Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000003926 complexometric titration Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000008196 pharmacological composition Substances 0.000 description 1
- -1 piperidine compound Chemical class 0.000 description 1
- 238000003918 potentiometric titration Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001974 tryptic soy broth Substances 0.000 description 1
- 108010050327 trypticase-soy broth Proteins 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/265—Citric acid
-
- 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
- C07F9/94—Bismuth compounds
Definitions
- the invention concerns the N-(3-(3-(1-piperidinylmethyl) phenoxy)propyl) hydroxyacetamide-2-hydroxy-l,2,3-propenetricar- boxylate bismuth (3 + ) complex (1:1:1), which possesses antisecretory cytoprotective and antibacterial activity when applied for the treatment of gastric and duodenal ulcer, and the method of preparation of the compound.
- N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl) hydroxyacetamide I in the form of oxalate salt, is known to possess a high histamine ⁇ -receptor antagonist activity with respect to various experimental ulcer models in animals [EP 024510/1.7.80; Bickel, N., A.Hering. Arznei-Forsch. (Drug Research), 36(11), 9, 1358, 1986.].
- bismuth salts e.g. bismuth citrate (in the form of tripotassium dicitrato bismuthate) and bismuth salicylate are used as antacids to suppress hyperacidity, as well as to treat gastric ulcers in humans [Wilson, T.R. Postgraduate Medical Journal, 51 (suppl.), 18, 1975; Wilson, T.R. Postgraduate Medical Journal, 51 (suppl.), 22, 1975; Wagner, S. Gut, 33, 179, 1992].
- bismuth citrate in the form of tripotassium dicitrato bismuthate
- bismuth salicylate are used as antacids to suppress hyperacidity, as well as to treat gastric ulcers in humans [Wilson, T.R. Postgraduate Medical Journal, 51 (suppl.), 18, 1975; Wilson, T.R. Postgraduate Medical Journal, 51 (suppl.), 22, 1975; Wagner, S. Gut, 33, 179, 1992].
- Bismuth citrate is found to possess an antibacterial effect against Helicobacter pylori, a microorganism which is an important pathogenetic agent for gastric and duodenal ulcers [Marshall, B. The American Journal of Gastroenterology, 86/1/, 16, 1991.].
- the aim of the invention is to synthesize a bismuth of salt I: N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl) hydroxyacetamide-2-hydroxy-1,2,3-propenetricarboxylate bismuth (3 + ) complex (1:1:1), with the following formula:
- the bismuth salt II was obtained by the interaction of N-(3-(3-(1-piperidinylmethyl)phenoxy) propyl) hydroxyacetamide free base with bismuth citrate, which is a complex of bismuth with citric acid, taken in equimolar quantities in the medium of a suitable solvent, e.g. water.
- the reaction between compound I and bismuth citrate proceede within the temperature range from 0 to 100 C, preferably between 80 and 100 C, for 3-4 hours.
- the reaction is considered to be completed when pH of the reaction mixture reaches 5.5-6.
- the bismuth salt obtained as a result of that reaction was isolated by filtering the reaction mixture, the aqueous filtrate was evaporated in vacuum to dry residue.
- the latter which is the raw bismuth salt, was purified with suitable organic solvents, such as alcohols (ethanol, isopropanol and butanol), ketones (acetone), preferably absolute ethanol, by suspending the salt in an organic solvent and by stirring the suspension for 10-20 min. The ethanol was decanted and the salt was treated with diethyl ether until a white crystalline product was obtained.
- the structure of the bismuth salt was proved by the data of the elementary analysis, data from the complexometric determination of the bismuth content, the potentiometric determination of the organic ligand content and by ⁇ H-MNR spectra. According to these data, the ratio of bismuth citrate to I is a 1:1.
- the initial piperidine compound I was obtained by the method described in [EP 024510]
- the bismuth salt of II was found to possess an antisecretory activity with respect to histamine-induced gastric secretion in rats.
- the antibacterial activity of the bismuth salt II was studied in in vitro experiments against Helicobacter pylori.
- the antibacterial effect of the bismuth salt was manifested at minimum inhibitory concentrations (MIC) within the 16-64 iq/ml range.
- the cytoprotective effect of the bismuth salt II was studied on an experimental model of ethanol-induced ulcers in rats, using a method described in [Konturek, S., T.Radecki, T.Brozowski. Eur. J. Pharmacol., 125, 185, 1986]. The comparisons were made with the histamine H 2 -receptor antagonist Roxatidine. The experimental results are shown in Table 1. Data show that in the control animals absolute ethanol induced ulcers with average total length of 83.5 7.4 mm and an average number of the ulcers 14.0 2.4.
- the bismuth salt II can be applied in the form of pharmaceutical compositions: as tablets or as capsules for oral administration.
- compositions were prepared using known methods of mixing the active substance with the respective additives.
- the bismuth salt II is incorporated between 30 and 70 % in a granulate with a matrix structure, containing 20-60 % lactic sugar, 20-50 % wheat starch, 15-60 % microcrystalline cellulose, 5-15 % highly dispersed colloidal silicon dioxide and hydroxypropylmethyl cellulose (methocel K4M) , as a binding agent constituting 3 to 15 % of the total weight of the tablet.
- the hydrophobic fillers added later to the granulated mass consist of 8-20 % cellulose, 1-6 % talcum and 0.1-3 % magnesium stearate of the total tablet weight.
- the pharmacological composition containing the bismuth salt II can also be obtained by simultaneous homogenization of the active substance and the additives mentioned above: lactic sugar, wheat starch, highly dispersed colloidal silicon dioxide, microcrystalline cellulose, talcum, magnesium stearate and hydroxypropylmethyl cellulose (methocel K4M) , which are moisten with ethanol until the mass becomes suitable for granulation, the mixture obtained was granulated, then dried, and after regranulation was capsulated in hard gelatin capsules.
- lactic sugar, wheat starch, highly dispersed colloidal silicon dioxide, microcrystalline cellulose, talcum, magnesium stearate and hydroxypropylmethyl cellulose (methocel K4M) which are moisten with ethanol until the mass becomes suitable for granulation, the mixture obtained was granulated, then dried, and after regranulation was capsulated in hard gelatin capsules.
- the bismuth salt II can be administered orally to human patients in doses of 100 to 600 mg/kg, preferably between 150 and 300 mg/kg.
- the single daily doses can be administered one to four times daily, preferably 1-2 times daily.
- the bismuth salt II possesses simultaneously antisecretory, cytoprotective and antibacterial effects, unlike the known histamine H -receptor antagonists, for which the latter two effects are very slight.
- the bismuth salt I is highly water-soluble, unlike the oxalate salt I and the bismuth citrate, which are practically water-insoluble. This property of the bismuth salt is a great advantage when it is administered orally for the treatment of the ulcer disease.
- the crystalline residue obtained was suspended in 52 ml absolute ethanol and the suspension was stirred for 20 minutes.
- the organic solvent was decanted and the bismuth salt II washed was suspended in 50 ml diethyl ether.
- the crystalline bismuth salt was filtered and additionally washed with fresh diethyl ether. Then it was dried in vacuo at 50-60 C.
- the content of bismuth citrate in the salt determined by complexometric titration, exceeded 98 %.
- the content of base I in the salt determined by potentiometric titration, exceeded 98 %.
- the animals were fasted for 38 hours but allowed free access to water.
- the ethanol-induced lesions resulted from the oral administration of absolute ethanol at a dose of 0.3 ml per 100 g body weight.
- the animals were sacrificed by intraperitoneal administration of an overdose of urethane.
- the stomachs were removed, incised along the greater curvature and placed in a 5 % formaldehyde solution for 20 min.
- the stomachs were tested macroscopically for destructive changes of the mucosa. The degree of the damage was evaluated by the average total length of the lesions and by the average total number of the ulcers.
- the studies of the antibacterial activity of the bismuth salt II were carried out using 32 Helicobacter pylori strains isolated from patients with gastritis and ulcer disease. The strains were isolated and identified using routine methods, and were incubated in trypticase-soy broth (Difco) with 15 % glycerine at a temperature of -25 C. Helicobacter pylori strain NCTC 11637 served as a control.
- the minimum inhibitory concentration (MIC) was determined through a series of dilutions of the agents tested on Muller- Hinton agar.
- the inoculi were obtained by washing 72-hour cultures of the strains with brain-heart broth (Gibco) on enriched charcoal-yeast blood agar, standardized to a density of 6x10 ⁇ microbial cells/ml (standard No 2 after McPherland) .
- the suspensions were inoculated on petri dishes containing Muller-Hinton agar with 7 % defibrinated ram blood and the antiulcer agents in the respective dilutions.
- Two petri dishes without the agents tested were included in the beginning and at the end of each series, and were cultivated under aerobic and micro-aerophilic conditions. They served as controls for the growth of the strains and for their possible contamination.
- the inoculated petri dishes were cultivated for 72 hours in a micro-aerophilic atmosphere (CampyPac Plus-BBL) at 37 C.
- the bismuth salt II manifested an anti-Helicobacter activity within the MIC range from 16 to 64 g/ml. Comparative tests with the agent De-Nol showed that the bismuth salt II possesses an anti-Helicobacter activity which is comparable to that of the agent De-Nol in the above MIC range.
- the histamine H 2 -antagonist Roxatidine did not manifest an anti-Helicobacter activity in the MIC range studied.
- the tablets were made using a rotation tablet machine with
- the components were moisten with 95 % ethanol until the mixture can be granulated.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl) hydroxyacetamide-2-hydroxy-1,2,3-propenetricarboxylate bismuth (3+) complex (1:1:1) with formula (II) is obtained as a result of the interaction between N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl) hydroxyacetamide and bismuth citrate in a boiling water. The bismuth salt (II) possesses a high antisecretory and cytoprotective activity, as well as an antibacterial effect against Helicobacter pylori, and is used in tablet form or as capsules for the treatment of gastric and duodenal ulcers.
Description
N-(3-(3-(1-PIPERIDINYLMETHYL)PHENOXY)PROPY ) HYDROXYACETAMIDE-2- HYDROXY-l,2,3-PROPENETRICARBOXYLATE BISMUTH (3+) COMPLEX AND THE
METHOD FOR PREPARATION
The invention concerns the N-(3-(3-(1-piperidinylmethyl) phenoxy)propyl) hydroxyacetamide-2-hydroxy-l,2,3-propenetricar- boxylate bismuth (3+) complex (1:1:1), which possesses antisecretory cytoprotective and antibacterial activity when applied for the treatment of gastric and duodenal ulcer, and the method of preparation of the compound.
N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl) hydroxyacetamide I, in the form of oxalate salt, is known to possess a high histamine ^-receptor antagonist activity with respect to various experimental ulcer models in animals [EP 024510/1.7.80; Bickel, N., A.Hering. Arznei-Forsch. (Drug Research), 36(11), 9, 1358, 1986.].
It is also known that some bismuth salts, e.g. bismuth citrate (in the form of tripotassium dicitrato bismuthate) and bismuth salicylate are used as antacids to suppress hyperacidity, as well as to treat gastric ulcers in humans [Wilson, T.R. Postgraduate Medical Journal, 51 (suppl.), 18, 1975; Wilson, T.R. Postgraduate Medical Journal, 51 (suppl.), 22, 1975; Wagner, S. Gut, 33, 179, 1992].
Bismuth citrate is found to possess an antibacterial effect against Helicobacter pylori, a microorganism which is an important pathogenetic agent for gastric and duodenal ulcers [Marshall, B. The American Journal of Gastroenterology, 86/1/, 16, 1991.].
The aim of the invention is to synthesize a bismuth of salt I: N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl) hydroxyacetamide-2-hydroxy-1,2,3-propenetricarboxylate bismuth (3+) complex (1:1:1), with the following formula:
which would have simultaneously histamine H2-antagonistic activity, cytoprotective and antibacterial activity against Helicobacter pylori, and which would be applied for the treatment of gastric and duodenal ulcers, as well as to develop a method for the preparation of this salt.
According to the invention, the bismuth salt II was obtained by the interaction of N-(3-(3-(1-piperidinylmethyl)phenoxy) propyl) hydroxyacetamide free base with bismuth citrate, which is a complex of bismuth with citric acid, taken in equimolar quantities in the medium of a suitable solvent, e.g. water.
The reaction between compound I and bismuth citrate proceede within the temperature range from 0 to 100 C, preferably between 80 and 100 C, for 3-4 hours. The reaction is considered to be completed when pH of the reaction mixture reaches 5.5-6. The bismuth salt obtained as a result of that reaction was isolated by filtering the reaction mixture, the aqueous filtrate was evaporated in vacuum to dry residue. The latter, which is the raw bismuth salt, was purified with suitable organic solvents, such as alcohols (ethanol, isopropanol and butanol), ketones (acetone), preferably absolute ethanol, by suspending the salt in an organic solvent and by stirring the suspension for 10-20 min. The ethanol was decanted and the salt was treated with diethyl ether until a white crystalline product was obtained.
The structure of the bismuth salt was proved by the data of the elementary analysis, data from the complexometric determination of the bismuth content, the potentiometric determination of the organic ligand content and by ^H-MNR spectra. According to these data, the ratio of bismuth citrate to I is a 1:1.
The initial piperidine compound I was obtained by the method described in [EP 024510]
The bismuth salt of II was found to possess an antisecretory activity with respect to histamine-induced gastric secretion in rats.
The antibacterial activity of the bismuth salt II was studied in in vitro experiments against Helicobacter pylori. The antibacterial effect of the bismuth salt was manifested at minimum inhibitory concentrations (MIC) within the 16-64 iq/ml range.
The cytoprotective effect of the bismuth salt II was studied on an experimental model of ethanol-induced ulcers in rats, using a method described in [Konturek, S., T.Radecki, T.Brozowski. Eur. J. Pharmacol., 125, 185, 1986]. The comparisons were made with the histamine H2-receptor antagonist Roxatidine. The experimental results are shown in Table 1. Data show that in the control animals absolute ethanol induced ulcers with average total length of 83.5 7.4 mm and an average number of the ulcers 14.0 2.4.
Treatment of the experimental animals with bismuth salt II at all doses led to a statistically significant reduction of the average total length of the lesions (p < 0.001). A significant decrease was also found of the other parameter studied, i.e. the average number of the ulcers. The highest degree of inhibition both of the length and of the number of the ulcers was reached at a dose of 87 mg/kg: 91 % and 74 %, respectively.
The results of the comparative studies of the bismuth salt II and the H^-receptor antagonist Roxatidine, applied in equimolar doses of 115 and 62 mg/kg, showed that bismuth salt II possesses a much stronger cytoprotective effect compared to Roxatidine, the difference in the effects being statistically significant (p < 0.01). Thus, at a dose of 115 mg/kg the bismuth salt inhibited the total length of the ulcers by 83 %, compared to a 54 % inhibition by Roxatidine, applied in an equimolar dose of 62 mg/kg. A similar inhibitory effect was also found with respect to the number of ulcers: 115 mg/kg of the bismuth salt II resulted in a 55 % reduction of the number of ulcers, compared to the 39 % reduction caused by Roxatidine at a dose of 62 mg/kg.
The bismuth salt II, according to the invention, can be applied in the form of pharmaceutical compositions: as tablets or as capsules for oral administration.
The pharmaceutical compositions were prepared using known methods of mixing the active substance with the respective additives.
Thus, the bismuth salt II is incorporated between 30 and 70 % in a granulate with a matrix structure, containing 20-60 % lactic sugar, 20-50 % wheat starch, 15-60 % microcrystalline cellulose, 5-15 % highly dispersed colloidal silicon dioxide and hydroxypropylmethyl cellulose (methocel K4M) , as a binding agent constituting 3 to 15 % of the total weight of the tablet. The hydrophobic fillers added later to the granulated mass consist of 8-20 % cellulose, 1-6 % talcum and 0.1-3 % magnesium stearate of the total tablet weight.
According to the invention, the pharmacological composition containing the bismuth salt II can also be obtained by simultaneous homogenization of the active substance and the additives mentioned above: lactic sugar, wheat starch, highly dispersed colloidal silicon dioxide, microcrystalline cellulose, talcum, magnesium stearate and hydroxypropylmethyl cellulose (methocel K4M) , which are moisten with ethanol until the mass becomes suitable for granulation, the mixture obtained was granulated, then dried, and after regranulation was capsulated in hard gelatin capsules.
The bismuth salt II can be administered orally to human patients in doses of 100 to 600 mg/kg, preferably between 150 and 300 mg/kg.
The single daily doses can be administered one to four times daily, preferably 1-2 times daily.
The advantages of the bismuth salt II in treatment of gastric and duodenal ulcers, compared to the known histamine H2- receptor antagonists, are as follows:
The bismuth salt II possesses simultaneously antisecretory, cytoprotective and antibacterial effects, unlike the known histamine H -receptor antagonists, for which the latter two effects are very slight.
- The bismuth salt I is highly water-soluble, unlike the oxalate salt I and the bismuth citrate, which are practically
water-insoluble. This property of the bismuth salt is a great advantage when it is administered orally for the treatment of the ulcer disease.
The examples given below illustrate the invention without being restrictive. Example 1
Preparation of N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl) hydroxyacetamide-2-hydroxy-1,2,3-propenetricarboxylate bismuth (3+) complex
3.84 g (12 mmol) of N-(3-(3-(1-piperidinylmethyl)phenoxy) propyl) hydroxyacetamide free base were suspended in 64 ml water. The mixture was heated to 90 C and then 5 g (12 mmol) of bismuth citrate were added. The reaction mixture was boiled with vigorous stirring for 4-5 hours. At the end of the reaction, pH of the mixture was 5.5-6. The mixture was cooled to room temperature and then the unreacted bismuth citrate was filtered. The aqueous filtrate was concentrated in vacuo until a solid residue was obtained. The residue was dissolved in 40 ml methanol, after which the solvent was evaporated in vacuo to dry substance. The crystalline residue obtained was suspended in 52 ml absolute ethanol and the suspension was stirred for 20 minutes. The organic solvent was decanted and the bismuth salt II washed was suspended in 50 ml diethyl ether. After stirring at room temperature for one hour, the crystalline bismuth salt was filtered and additionally washed with fresh diethyl ether. Then it was dried in vacuo at 50-60 C.
3.1 g (35 % of theoretical value) of the bismuth salt II were obtained in the form of white crystalline powder.
Anal. Calcd for C23H31N2OιoBi.H20: C 38.18, H 4.56, N 3.87, Bi 29.66. Found: C 37.78, H 4.76, N 4.20, Bi 28.40
Water content - 2.6 %.
The content of bismuth citrate in the salt, determined by complexometric titration, exceeded 98 %.
The content of base I in the salt, determined by potentiometric titration, exceeded 98 %.
XH-NMR (DMSO-d6): 8 = 1.54 (m, 6H, 3xCH2 of piperidine) , 1.82 (m, 2H, C-CH2-C), 2.44 (s, 4H, 2xCH2 of citrate), 2.68 (m, 4H, N(CH2)2 of piperidine), 3.24 (m, 2H, CH2NH), 3.72 (s, 2H,
Ar-CH2-N), 3.84 and 3.90 (two s, 4H, OCH2-C and COCH 0) , 6.68- 7.28 (m, 4H, 0-C5H4), 7.70 (brs, 1H, CONH) , 11.80 (brs, 1H) . Example 2.
Effect of the bismuth salt II on ethanol-induced gastric ulcers in rats.
Experiments were carried out on 114 male Wistar rats with average body mass of 236 20 g. The compounds tested were given one hour prior to the administration of ethanol. The experimental animals were treated orally with water solutions of the bismuth salt or of Roxatidine, taken for comparison, whereas the controls received only water under the same experimental conditions.
The animals were fasted for 38 hours but allowed free access to water. The ethanol-induced lesions resulted from the oral administration of absolute ethanol at a dose of 0.3 ml per 100 g body weight. One hour later, the animals were sacrificed by intraperitoneal administration of an overdose of urethane. Then the stomachs were removed, incised along the greater curvature and placed in a 5 % formaldehyde solution for 20 min. The stomachs were tested macroscopically for destructive changes of the mucosa. The degree of the damage was evaluated by the average total length of the lesions and by the average total number of the ulcers.
Statistical Analysis of the Results Obtained
The results obtained were statistically processed using variational analysis and the data are presented as mean values and mean standard errors.
Example 3.
Determination of the antibacterial effect of bismuth salt II against Helicobacter pylori.
The studies of the antibacterial activity of the bismuth salt II were carried out using 32 Helicobacter pylori strains isolated from patients with gastritis and ulcer disease. The strains were isolated and identified using routine methods, and were incubated in trypticase-soy broth (Difco) with 15 % glycerine at a temperature of -25 C. Helicobacter pylori strain NCTC 11637 served as a control.
For the purposes of comparison use was made of the antiulcer drug De-Nol and the histamine H -receptor antagonist Roxatidine.
The drugs tested were dissolved in sterile distilled water until concentration of 1280 J4g/ml was obtained. Then the solutions were further diluted until the desired concentrations were obtained.
The minimum inhibitory concentration (MIC) was determined through a series of dilutions of the agents tested on Muller- Hinton agar. The inoculi were obtained by washing 72-hour cultures of the strains with brain-heart broth (Gibco) on enriched charcoal-yeast blood agar, standardized to a density of 6x10^ microbial cells/ml (standard No 2 after McPherland) . Using a Steers replicator, the suspensions were inoculated on petri dishes containing Muller-Hinton agar with 7 % defibrinated ram blood and the antiulcer agents in the respective dilutions. Two petri dishes without the agents tested were included in the beginning and at the end of each series, and were cultivated under aerobic and micro-aerophilic conditions. They served as controls for the growth of the strains and for their possible contamination. The inoculated petri dishes were cultivated for 72 hours in a micro-aerophilic atmosphere (CampyPac Plus-BBL) at 37 C.
The lowest concentration of the agent tested, for which there was no visible growth or there were only isolated colonies, was determined as (MIC).
The experimental results are shown on Table 2.
It can be seen from the Table that the bismuth salt II manifested an anti-Helicobacter activity within the MIC range from 16 to 64 g/ml. Comparative tests with the agent De-Nol showed that the bismuth salt II possesses an anti-Helicobacter activity which is comparable to that of the agent De-Nol in the above MIC range.
The histamine H2-antagonist Roxatidine did not manifest an anti-Helicobacter activity in the MIC range studied.
Example 4.
Preparation of tablets Model composition:
Bismuth salt II 0.150 g
Lactose 0.030 g
Wheat starch 0.022 g
Microcrystalline cellulose 0.044 g
Highly dispersed colloidal silicon dioxide 0.010 g Methocel K4M 0.010 g
After sifting and homogenization, the components were granulated with 95 % ethanol, the mixture obtained was dried and after regranulation was powdered with the following additives: Microcrystalline cellulose 0.015 g
Talcum 0.006 g
Magnesium stearate 0.003 g
The tablets were made using a rotation tablet machine with
10 mm diameter of the punches and mechanical strength of the tablets ranging from 4.5 to 6 kg. Example 5. Preparation of capsules
Model composition: Bismuth salt II 0.150 g
Lactic sugar 0.040 g
Wheat starch 0.027 g
Microcrystalline cellulose 0.055 g
Highly dispersed colloidal silicon dioxide 0.010 g Talcum 0.005 g
Magnesium stearate 0.003 g
Methocel K4M 0.010 g
After sifting and homogenization, the components were moisten with 95 % ethanol until the mixture can be granulated.
After drying and regranulation, the mixture was capsulated in hard gelatine capsules No 1.
Table 1
Effects of the bismuth salt II and Roxatidine on ethanol-induced ulcers in rats
Compounds No of Average total % of No of % of and doses ani¬ length of the inhi¬ ulcers inhi¬
(mg/kg) mals ulcers (mm) bition bition p.o
Controls
(with water] 1 18 83.5 7.4 14.0 2.4
Bismuth salt II
29 13 39.4 10.1** -53 11.2 2.5** -20
58 12 48.5 18.3** -42 10.8 3.2* -23
87 14 7.9 3.7** -91 3.7 0.9** -74
115 14 14.1 7.9** -83 6.3 2.1** -55
Roxatidine
62 10 40.8 15.2** -54 8.6 2.3* -39
100 9 22.3 9.0** -73 6.1 1.7* -54
Presented are mean values the mean standard errors; * - statistical significance at p < 0.01 (compared
** to the controls); statistical significance at p < 0.001 (compared to the controls.
Table 2
Antibacterial effect of the bismuth salt II against 32 Helicobacter pylori strains
Compounds tested No of sensitive strains at concentrations (j*g/ml)
16 32 64 128 254
Bismuth salt II 1 15 14 2 —
De-Nol 3 17 12 - -
Roxatidine 0 0 0 0 0
Claims
1. N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl) hydroxyacet- amide-2-hydroxy-l,2,3-propenetricarboxylate bismuth (3+) complex (1:1:1) with formula II:
2. Method for preparation of the bismuth salt II according to Claim 1, characterized by the interaction of the N-(3-(3-(l- piperidinylmethyl)phenoxy)propyl) hydroxyacetamide with an equimolar amount of bismuth citrate, in aqueous medium, at a temperature of 80-100 C.
3. Method for preparation of the bismuth salt II according to Claim 2 , characterized by purification of the bismuth salt II by suspension in organic solvents, e.g. alcohols or ketones, preferably absolute ethanol, and subsequent treatment with diethyl ether.
4. Pharmaceutical composition according to Claim 1, containing the bismuth salt II with organic or inorganic additives, in the form of tablets or capsules.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BG98133A BG61302B1 (en) | 1993-09-30 | 1993-09-30 | N-/3-/3-/1-piperidineilmethyl/phenoxypropyl hydroxyacetamide 1,2,3-propenetricarboxilate bismuth /3+/ complex and method for its preparation |
| BG98133 | 1993-09-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995009162A1 true WO1995009162A1 (en) | 1995-04-06 |
Family
ID=3925439
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/BG1994/000009 WO1995009162A1 (en) | 1993-09-30 | 1994-07-28 | N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl) hydroxyacetamide-2-hydroxy-1,2,3-propenetricarboxylate bismuth (3+) complex and the method for preparation |
Country Status (2)
| Country | Link |
|---|---|
| BG (1) | BG61302B1 (en) |
| WO (1) | WO1995009162A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058958A (en) * | 2011-10-22 | 2013-04-24 | 杭州福斯特药业有限公司 | Synthetic method of roxatidine acetate hydrochloride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0024510A1 (en) * | 1979-07-03 | 1981-03-11 | Teikoku Hormone Mfg. Co., Ltd. | Phenoxypropyl amine derivatives, process for their preparation, and pharmaceutical compositions containing them |
| EP0282132A2 (en) * | 1987-03-09 | 1988-09-14 | The Procter & Gamble Company | Compositions and their use for treating gastrointestinal disorders |
| EP0367484A1 (en) * | 1988-10-26 | 1990-05-09 | Glaxo Group Limited | Carboxylic acid derivates |
| EP0454469A1 (en) * | 1990-04-26 | 1991-10-30 | Glaxo Group Limited | Carboxylic acid derivatives |
-
1993
- 1993-09-30 BG BG98133A patent/BG61302B1/en unknown
-
1994
- 1994-07-28 WO PCT/BG1994/000009 patent/WO1995009162A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0024510A1 (en) * | 1979-07-03 | 1981-03-11 | Teikoku Hormone Mfg. Co., Ltd. | Phenoxypropyl amine derivatives, process for their preparation, and pharmaceutical compositions containing them |
| EP0282132A2 (en) * | 1987-03-09 | 1988-09-14 | The Procter & Gamble Company | Compositions and their use for treating gastrointestinal disorders |
| EP0367484A1 (en) * | 1988-10-26 | 1990-05-09 | Glaxo Group Limited | Carboxylic acid derivates |
| EP0454469A1 (en) * | 1990-04-26 | 1991-10-30 | Glaxo Group Limited | Carboxylic acid derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058958A (en) * | 2011-10-22 | 2013-04-24 | 杭州福斯特药业有限公司 | Synthetic method of roxatidine acetate hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| BG61302B1 (en) | 1997-05-30 |
| BG98133A (en) | 1995-04-28 |
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