GB2036555A - Anti-ulcer compositions - Google Patents
Anti-ulcer compositions Download PDFInfo
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- GB2036555A GB2036555A GB7936757A GB7936757A GB2036555A GB 2036555 A GB2036555 A GB 2036555A GB 7936757 A GB7936757 A GB 7936757A GB 7936757 A GB7936757 A GB 7936757A GB 2036555 A GB2036555 A GB 2036555A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Abstract
A pharmaceutical composition comprises as active principle one or more compounds of the general formula (I): <IMAGE> wherein R<1> is halogen, lower alkyl or lower alkoxy; n is an integer from 0 to 3; X is oxygen or sulphur; and R<2> is a linear, branched of cyclic alkyl or alkenyl of from 1 to 6 carbon atoms, atoms, together with a pharmaceutically suitable carrier, the composition being formulated for use in the treatment of gastric hyperacidity, acuted or chronic gastritis, a gastric or duodenal ulcer, duodenitis, a peptic ulcer of the oesophagus, neurogenic gastropathy, entiritus, colitis or other disorder and being in general formulated for therapeutic treatment of peptic ulcers.
Description
SPECIFICATION
Anti-ulcer compositions
The present invention relates to anti-ulcer compositions.
The present invention provides a pharmaceutical composition for the treatment of ulcers in which the active principle is a benzyiurea of benzylthiourea having the general formula (I):
wherein R' is halogen, alkyl or alkoxy (preferably lower alkyl, alkoxy); n is an integer from 0 to 3 and when n is 2 or 3 the substituents R' are preferably the same;
X is oxygen or sulphur; and
R2 is alkyl or alkenyl linear branched or cyclic, and preferably 1 to 6 carbon atoms.
With few exceptions, the compounds (I) have a clear anti-ulcer activity in various species of animals and against ulcers of diverse etiology.
The activity of some of, the compounds (I) is greater than that of cymetidine (Tagamet, Registered
Trade Mark) which is today one of the most successful anti-ulcer compounds.
The present compounds generally have a low toxicity and minor secondary effects, as well as a poor activity on the central nervous system.
Compounds having the urea of thiourea function have been use- for the treatment of ulcers have been used in recent years, following the discovery by
Smith Kline and French Laboratories Ltd of the H2 antagonists Burimamide and Metiamide (2), predecessors of Cymetidine.
Apart from Smith Kline and French Ltd, other laboratories, such as Beecham Group Ltd and John
Wyeth and Brother Ltd, have put forward compounds said to have an anti-ulcer activity and containing the urea of particularly the thiourea function.
The use of a heterocyclic ring, almost always aromatic, attached directly or thorough a short aliphatic chain, to the urea orthiourea function, is a characteristic of all these known compounds. In the cases of bu rimamide and metiamide, the imidazolyl ring ol histamine has been used, while in the other cases, a pyridine ring is normally used, sometimes joined to a piperidine ring.
From a structure-activity point of view, the novelty of the present compounds with anti-ulcer activity resides in the presence of a benzene ring joined to the urea orthiourea function through a methylene group.
Some of the compounds (I) have been described before in the literature, as indicated in the following
Tables I and II, and although in some cases diuretic orantiviral activities are cited, none of them referto the anti-ulcer properties.
The synthesis of the present benzylureas and ben zylthioureas is normally carried out by the reaction of equimolar amounts of a substituted amine with the appropriate isocyanate or isothiocyanate, optionally in the presence of a solvent such as diethyl ether, methanol, ethanol, isopropyl alcohol, benzene, toluene or a chlorinated solvent.
This reaction can be represented as follows:
wherein R', R2, n and X have meanings previously given.
The compounds (I) can also be prepared by reacting the appropriate amine with a substituted benzyl isocyanate or isothiocyanate, optionally in the pres ence of a solvent.
This reaction can be represented as follows:
wherein R', R2, n and X has meanings previously
given.
The reactions can be carried out over a wide temperature range, from 0 C to the boiling point of the solvent.
In the absence of a solvent, the addition should be effected carefully, since the reactions are rather exothermic; this addition should preferably be effected ata low temperature.
In the presence of a solvent, in order to accelerate the reaction, the temperature can be raised to the boiling point thereof.
Isolation ofthe product is generally rather simple, since all the products are crystalline and can be isolated by filtration, once the reaction mixture has been cooled.
In some cases it may be necessary to induce the crystallization, by seeding with crystals of the previously obtained compound, or by scraping with a glass rod.
The crystallized product of the reaction is highly pure, though recrystallization can be carried out with a suitable solvent if desired.
The following non-limiting Examples serve to illustrate the method of obtaining the urea and thioureas. Identification codes beginning "ITA" are given which are used further on in this specification.
Example I: N-benzyl-N'-ethylurea (I TA -234).
To a solution of 5.0 g (0.0467 mol) of benzylamine in 20 mi of anhydrous benzene, 3.7 ml (0.0467 mol) of ethyl isocyanate was slowly added. The reaction was exothermic. It was stirred for 2 hours at room temperature and allowed to stand overnight in a refrigerator. 7.6 g (92%) of a white crystalline solid mp 100.5-101 "C were obtained, by filtration.
Two recrystallizations with methanol raised the melting point to 105-106'C.
Infrared (KBr): strong bands at 3330 (NH), 1620 (C = 0),
1590 (C = 0) and 1250 cm-'.
NMR (CDC13): 87.01 ppm (s,5 aromatic) 86.04 ppm (5,1, NH) 85.70 ppm (5,1, NH) #4.11 ppm (d,2,CH-2-C6H5) 83.22-2.70 ppm (m, 2, CH-2-CH3) 80.92 ppm (t, 3, CH3).
Example II:N-(m-chlorobenzyl)-N'-ethylurea (ITA-312)
To a solution of 7.5 g (0.053 mol) of m-chlorobenzylamine in 25 ml of anhydrous benzene, 4.2 ml (0.053 mol) of ethyl isocyanate was added dropwise. A strong reaction took place. After cooling the white crystalline solid which separated was filtered and washed with benzene, giving 11.0 g (97%) of crystals, mp 120-121 C.
Infrared (KBr): strong bands at 3310 (NH),1620 (C O) 1580 (C = 0) and 1250 cm-'.
NMR (CDC13): 87.17 ppm (s, 4, aromatic) 86.23 ppm (5,1, NH)
85.72ppm(t,1,NH) 84.22 ppm (d, 2, CH-2-C8H5) 83.42-2.83 ppm (m, 2, CH-2-CH3)
8 1.03 ppm (t, 3, CH3)
Example III:N-(m-chlorobenzyl)-N'-(t-butyl)urea (ITA-401).
To a solution of 4.0 g (0.0287 mol) m-chlorobenzylamine in 20 ml of anhydrous ethyl ether, 3.33 ml (0.0287 mol) of tertbutyl isocyanate was added dropwise. The reaction was exothermic.
After cooling, the white crystalline solid which sepa
rated was filtered and washed with ether, giving 6.1 g (90%), mp 108-109"C.
Infrared (KBr): strong bands at 3330 (NH),1660 (C = O) 1565 (C = 0) and 1290 cm-'
NMR (CDC13):8 7.10 ppm (s, 4, aromatic) 85.90-5.55 ppm (m, 1, NH) 85.32-5.08 ppm (m, 1, NH)
84.12 ppm (d, 2, CH-2-NH2)
8 1.23 ppm (s, 9, CH-3)
Example IV: N-allyl-N'-benzylthiourea (ITA-412).
To a solution of 2.7 g (0.047 mol) of allylamine in 25 ml of anhydrous benzene, 7.0 g (0.047 mol) of benzyl isothiocyanate was slowly added. The reaction was exothermic. The mixture was stirred for3 hours at room temperature and after cooling to 0 C, crystallization was induced by scratching with a glass rod. The white crystalline solid which precipitated was collected by filtration and washed with benzene, giving 8.0 g (83%) of crystals, mp 91-93 C.
Infrared (KBr): strong bands at 3240 (NH),1550 (C = O) 1515(C=0) and 1220 cm-1
NMR (CDC13): 87.32 ppm (s,5, aromatic)
8 6.88-6.05 ppm (m, 2, NH) 85.81 ppm (m,1, olefinic) 85.15 ppm (d, 2, olefinic) 84.63 ppm (d, 2, CH-2-NH) 84.03 ppm (m, 2, CH-2-CH-CH2)
Example V:N-ethyl-N'-(o-fluorobenzyl)urea {ITA-3 10).
To a stirred solution of 7.1 g (0.057 mol) of o-fluorobenzylamine cooled at 0 C,4.5 ml (0.057 mol) of ethyl isocyanate was slowly added. The reaction was very exothermic and, after the addition, the crystalline mass thereby formed was washed with benzene and dried, giving 9.8 g (87%) of a white crystalline solid, mp 124.5-126 C.
Infrared (KBr): strong bands at 330 (NH),1620 (C = 0)
1570 (C = 0) and 1230 cm-1
NMR (CDC13); 87.08 ppm (m,4, aromatic) 86.54-5.27 ppm (m, 2, NH) 84.30 ppm (d, 2, CH-2-CH3) 83.14 ppm (m, 2, CH-2-CH3)
8 1.04 ppm (5,3, CH3)
Note: After exchanging the NMR sample with D20, the doublet at 84.30 was transformed into a singlet and the signal at 83.14 into a quadruplet. This trans- formation also happened with the rest of the compounds.
Using similar procedures, the other members of the series of ureas and of the series of thioureas specified in Tables I and II, respectively were synthesized. In the case of compounds not previously described in the literature the solvent used to recrystallize them is specified between parenthesis. Forthe other, known compounds the first bibliographic reference is given.
TABLE I: SERIES OF URREAS
Crystallization Rn R2 ITA Melting Point solvent or C Bibliographical Reference.
CH3 396 95-96 (1) 3-CI CH3 397 91 -93 (benzene) C2H5 234 105-106 (2) 2-CI C2H5 311 122-124 (EtOH) 3-Cl C2H5 312 120-121 (EtOH) 4-CI C2H5 239 147 (3) 4-CH3 C2H5 240 140 (3) 2-F C2H5 310 126-127 (benzene) 2-OCH3 C2H5 313 114-115 (benzene) 3-OCH3 C2H5 314 115.5-116 (benzene) 4-OCH3 C2H5 315 117-117.5 (benzene) 3,4-OCH3 C2H5 241 113 (3) n-C4H9 398 100-101 (4) 3-CI n-C4Hg 399 97-98 (EtOH) t-C4Hg 400 107-109 (5) 3-CI t-C4Hg 401 108-109 (benzene) cyclohexyl 402 161-163 (6) 3-CI cyclohexyl 403 171-171.5 (benzene) C5H5 404 169-171 4-CI C6H5 405 172.5-173.5 4-CIC6H4 406 211-213 4-CI 4-CIC6H4 407 228-230 1 -naphthyl 408 205-207 3-CI 1-naphthylo 409 189-191 TABLE IIL SERIES OF THIOUREAS
Crystallization R' R2 ITA Melting Point solvent or "C Bibliographical Reference.
CH3 410 76-78 (7) 3-CI CH3 411 62-64 (8) C2H5 316 102-103 (9) 3-CI C2H5 317 66-67 (10) 4-CI C2H5 318 100-101 (10) 4-CH3 C2H5 319 78 (3) 2-OCH3 C2H5 320 82-83 (benzene) 3-OCH3 C2H5 321 82-84 (benzene) 4-OCH3 C2H5 322 68-69 (benzene) allyl 412 91-93 (11) 4-CI allyl 413 80-81 (10) C6H5 414 142-144 4-C4 C6H5 415 142-143 Bibliography: (1) J. L. Boivin: Can. J. Chem.29 (1951)478-81 (2) A. E. Dixon: J. Chem. Soc. 67(1895)562 (3) P.Borgna: II Farmaco Ed. Sc. 32(1977)813 (4) Japan: 6,905,371 (5) G. Kh. Tyshchuk: Dokl. Akad. Nauk. Uzb. SSR24 (1967) 26-8 (6) Boyer J. H.: J. Heterocycl. Chem. 7(1970)59-70 (7) K. R. Bhaskar: Trans. Faraday Soc. 62 (1966) 29-38 (8) Ger. Offen 2,400, 111 (9) A. E. Dixon: J. Chem. Soc. 55(1889)300 (10) G. Vasilev: Dokl. Bolg. Akad. Nauk.28 (1975) 931-3 (11) T.A.Degurko: Dopov. Akad. Nauk. Ukr. RSR. Ser. B.35(1973) Anti-ulcer activity.
In order to study the anti-ulcer activity of the compounds, gastric ulcers were induced in rats by administration of indomethacin using the methods
Bonoma L.: Arzneimittel Forschung2l (1971) 1812-15 and Canestrini C.: Boll. Chim. Farm 114 (1975) 393-400. The protection afforded by the compounds (I) against gastric ulcers is shown in Table Ill and was evaluated by administering orally of a dose of 100 mg/kg of the compound to wistar rats.
More particularly, protection against the ulcerogenic effect of indomethacin was evaluated following the technique described by Bhargraveet al: Europ. J. Pharm.22 (1973)191 and by Canestrini etal (op cit), and killing the animals, 7 hours after oral administration of 20 mg/kg or the antiulcer compound. The anti-ulcer activity has been expressed in this in % of protection, using as a reference a product of proven activity, such as Zolimidine Martindale-The Extra Pharmacoposia, 27th Ed. (1977) (Pharmaceutical Press) page 1831.
TABLE III: Protection against gastric ulcer induced by
Indomethacin administered to wistar rats of either
sex at the dosage of20 mglkg (p.o.J
Anti-ulcer ITA activity 10 Animals Dosage expressed used per mg/kg in % of experiment (p.o.) protection 396 100 100 397 100 100 234 100 96 311 100 99 312 100 96 239 100 99 240 100 0 310 100 74 313 100 33 314 100 0 315 100 20 241 100 0 398 100 90 399 100 99 400 100 100 401 100 100 402 100 92 403 100 36 404 100 58 405 100 39 406 100 29 407 100 0 408 100 6 409 100 10 410 100 83 411 100 100 316 100 93 317 100 96 318 100 96 319 100 0 320 100 81 321 100 66 322 100 0 412 100 75 413 100 100 414 100 99 415 100 26 Cimetydine 99 The strong anti-ulcer activity of the following ureas and thioureas should be emphasized:
N-benzyl-N'-ethylurea (ITA-234), N (p-chlorobenzyl)-N'-ethyiurea (ITA-239), N (o-chlorobenzyl)-N'-ethylurea (ITA-311), N'-(mchlorobenzyl)-N'-ethylurea (ITA-312), Nbenzyl-N'-ethylthiourea (ITA-316), N (m-chlorobenzyl)-N'-ethylthiourea (ITA-319) and N-(p-ch lorobenzyl)-N'-ethylthiourea (lTA-31 8).
Selecting six of these compounds further new anti-ulcer activity tests were made, to determine the effective doses to 50% (ED50), when gastric ulcers were induced by indomethacin, by stress and cold (Takargi K.: Jap. J. Pharmacol. 19 (1964) 327) and by piloric ligature (Shay, H.: Kamarow, S. A.; Fells, S.
S.; Meranze, A.; Groenstein, M.; Siplet, H.; Gastroenterology5,43 (1945)) and when duodenal ulcers were induced by cysteamine (Selya, H.; Szabo, S.; Nature244,458 (1973).
Two species of animals, rats and mice, were tested, using, for all tests, cymetidine as the reference standard.
The results are shown in Table IV, and confirm the high anti-ulcer power of these compounds in different species of animals and in ulcers having different origins, exceeding the effect obtained with cymetidine.
ITA Ulcers induced by Indometacine Ulcers induced by Stress ED50 in ED50 in ED50 ED50 n mouse n rat n mouse n Rat 396 - - 10 10.0 10 15.0 - - 397 - - 10 11.0 - - - 234 - - 50 34.4 10 31.3 16 24.9 311 20 38.1 10 29.0 20 32.2 40 11.9 312 20 35.4 10 30.6 20 31.2 40 8.8 410 - - 10 2.0 10 4.4 - 411 - - 10 5.0 10 8.5 - 316 20 38.2 10 < 12.5 10 18.4 40 15.4 317 - - 10 < 12.5 - - - - 318 - - 10 4.4 - - - 412 - - 10 12.0 10 18.7 - 413 - - 10 10.0 10 1.4 - 414 - - 10 23.0 - - - imetidin 20 67.3 50 56.5 20 46.3 16 14 gastric ulcers induced by piloric Ligature.
ITA ED50 in rat 234 38 20 311 125 15 312 155 15 316 58 15 Cymetidine 320 15 duodenal ulcers induced by Cysteamine
ITA ED50 in rat n* 234 16.9 15 311 3.8 15 312 16.5 15 316 2.4 15 317 10.2 15 318 16.8 15 *n = number of animals.
Toxicity and secondary effects.
The toxicity of the drugs administered orally (p.o.) was evaluated in the wistar rat by the Litchfield and
Wilcoxon method J. Pharm. Exptl. Therap96 (1949); the LD50 being, in all the cases, greater than 4000
mg/kg.
Table V illustrates the indicative LD50 of the compound administered intraperitoneally (i.p.) to NMRI mouse and evaluated following the same procedure as in the prior case.
TABLE V: Indicative Toxicity of urreas and thioureas administered Ri.p.) to NMRI mice expressed in LD50 (mglkg).
ITA LD50 ind.
396 600 397 300 234 500 311 370 312 600 239 150 240 > 1330 310 600 313 600 314 600 315 370 241 950 398 600 399 750 400 600 401 350 402 1100 403 2500 404 > 3000 405 2500 406 > 3000 407 1750 408 > 3000 409 > 3000 410 600 411 420 316 950 317 190 318 190 319 600 320 190 321 370 322 300 412 420 413 120 414 200 415 230 Compounds of the series were subjected to a multi-dimensional screening using for this purpose the Irwin test Gordon Research Conference on Medicinal Chemistry (1959)99.
Table VI shows all the cases in which the reaction was positive.
TABLE Vl: Irwin's Test on MNRI mice.
Straub's Less in ITA Glue Convulsions Depression Reflexes 234 + 311 + + + + 312 + + 239 310 + + + + 240 313 + + 314 + 315 + 241 316 + + 317 + + 318 + + 319 + 320 + 321 + 322 +
Loss in Loss in sensivity Strength Lachrymation Mydriasis Pyloerection + + + + + + + + + + + + + + + + + + + + + To ascertain the effects of the selected compounds on the central nervous system, the following activities were determined in rats and mice: anticonvulsive activity (Barnes J.: J. Pharmacol. 13 (1961) 39, tranquillizing activity (Holten C.: Acta
Pharmacol. Toxicol. 12 (1956) 345, anti-parkinsonism activity (Morpurgo, C.; Arch. Inter. Pharmacodyn.
137 (1962) 84, anti-depressive activity Cotillo; J.
Pharm. Pharmacol.24 (1972)103, myorelaxing activity Kerlay, T. L.: J. Pharmacol. Exptl. Therap. 132 (1961) 360, anti-emetic activity (Turner: Screening
Methods in Pharmacology (Academic Press-1965 page 169), central adrenergic activity (Clark: Arch.
Intern. Pharmacodyn, 170 (1967) 350, central cholinergic activity (Turner: Screening Methods in
Pharmacology (Academic Press-1965) page 92), and activity on the spontaneous motility.
The results are given in Table VII.
TABLE VII: Effect on the Central Nervous System.
Anti- Anti- Anti- Central Dosage convulsive Tranquillizing parkinsonism depressing myorelaxing ITA (mglkg) activity activity activity activity activity 234 100 +++ + ++ 311 75 + + ++ 312 125 + + 316 50 . + + +
Anti- Central Central emetic adrenergic colinergic activity activity activity Spontaneous Mobility
Dosage ITA (mg/kg) Stimulant Depressor 234 100 311 75 312 125 * 316 50 ++ at the dosage of 200 mg/kg Number of animalsn = 10
The selected compounds prove to have a certain depressive effect only at a high dosage, and they prove to be valuable as tranquillizers, anticonvulsives and muscular relaxants.
The therapeutic index, a value obtained by the quotient of Lethal Dose/Effective Doses (LD50/ED50) in rats is shown, for the selected compounds, in
Table VIII.
TABLE Veil: Therapeutic index (LD50/ED50)
Therapeutic ITA index 234 > 116 311 > 138 312 > 131 316 > 320 317 > 320 Cymetidine 89 As can be seen, the compounds offer a wide safety range.
The usual dose range in human therapeutics is 50 mg to 2 grams daily, preferably at a dose of 1 to 50 mg/kg. Suitable unit dosage forms contain 5 to 750 mg, preferably 20 to 500 mg, and more preferably 25 to 150 mg, of compound (I).
TABLE VII: Dosage Recommended In Human
Therapy
Dose
ITA MG/Day
234 200-2000
311 40-800
312 30-700
316 40-800
The compounds (I) can be administered in various forms, particularly in capsules, tablets or injections, accompanied by the suitable vehicle, to be used in the case of gastric hyperacidity of any origin, acute and chronic gastritis, gastric and duodenal ulcers, duodenitis, peptic ulcers of the oesophagus, neurogenic gastropaty, enteritis, colitis, etc. The formulation of such compounds for such uses can be effected in a conventional manner. Suitable forms and vehicles are described for example in U.K.
Patent Specification No. 1444558 and No. 1461806; the reader is referred to these specifications for further details.
The following non-limiting Examples serve further to illustrate the invention.
Example 1
Tablets containing 50 mg of active ingredient
Active ingredient 50 mg
Anhydrous lactose U.S. Pharmacopeia
XIX (1975) 217 mg
Starch 30 mg
Magnesium stearate.
British Pharmacopeia 1973 3 mg
The starch employed was either corn or wheat starch (U.S. Pharmacopeia XIX (1975). The active ingredient, in granules smaller than 250 microns, and the other powdered ingredients were homogeneously mixed and compacted into tablets of 8.5 mm diameter. Forthe preferred tablets the active ingredient is lTA-234, 239,311,312,316,317, or318.
Example 2
Capsules containing 50 mg of active ingredient
Active ingredient 50 mg
Starch 170 mg
Magnesium stearate British
Pharmacopeia 1973 2 mg
The starch used was either corn or wheat starch (U.S. Pharmacopeia XIX (1975). The active ingredient, in granules smaller than 250 microns, was homogeneously mixed with the other powdered ingredients, and the mixture distributed in to hard gelatin no 3 capsules. The preferred active ingredient is one of those listed in Example 1.
Claims (8)
1. A pharmaceutical composition comprising as active principle one or more compounds of the genral formula (I):
wherein R1 is halogen, lower alkyl or lower alkoxy; n is an integer from 0 to 3; Xis oxygen or sulphur; and
R2 is a linear, branched of cyclic alkyl or alkenyl of from 1 to 6 carbon atoms, atoms, together with a pharmaceutically suitable carrier, the composition being formulated for use in the treatment of gastric hyperacidity, acuted or chronic gastritis, a gastric or duodenal ulcer, duodenitis, a peptic ulcer of the oesophagus, neurogenic gastropathy, entiritus, colitis or other disorder and being in general formulated for therapeutic treatment of peptic ulcers.
2. A pharmaceutical composition according to
Claim 1, which is formulated as a capsule, tablet, powder or other solid form.
3. A pharmaceutical composition according to
Claim 1, which is formulated as a liquid for injection.
4. A pharmaceutical composition according to
Claims 1, 2 or 3, wherein the active principle is
N-benzyl-N'-ethylurea (ITA-234).
5. A pharmaceutical composition according to
Claim 1,2 or 3 wherein the active principle is the ortho, meta, or paraisomer of Nchlorobenzyl-N'-ethylurea (ITA-311, ITA-312, or
ITA-239).
6. A pharmaceutical composition according to
Claim 1,2 or3, wherein the active principle is
N-benzyl-N'-ethylthiou rea (lTA-31 6).
7. A pharmaceutical composition according to
Claim 1,2 or 3, wherein the active principle is the meta or para isomer of Nchlorobenzyl-N'-ethylthiourea (ITA-317 or ITA-318).
8. The use of a compound of the general formula (I) as defined in Claim 1 in the therapeutic treatment of peptic ulcers.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES474449A ES474449A1 (en) | 1978-10-23 | 1978-10-23 | Anti-ulcer compositions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2036555A true GB2036555A (en) | 1980-07-02 |
| GB2036555B GB2036555B (en) | 1983-08-17 |
Family
ID=8476971
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7936757A Expired GB2036555B (en) | 1978-10-23 | 1979-10-23 | Anti-ulcer conpositions |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS5823866B2 (en) |
| BE (1) | BE879558A (en) |
| DE (1) | DE2942564A1 (en) |
| ES (1) | ES474449A1 (en) |
| FR (1) | FR2439772A1 (en) |
| GB (1) | GB2036555B (en) |
| IT (1) | IT1121487B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4460602A (en) * | 1981-06-30 | 1984-07-17 | The Procter & Gamble Company | Urea derivatives |
| US5441984A (en) * | 1994-01-06 | 1995-08-15 | Eli Lilly And Company | Urea, thiourea and guanidine derivatives |
| WO1997038682A1 (en) * | 1996-04-17 | 1997-10-23 | Bristol-Myers Squibb Company | Biphenylamido derivatives as melatonergic agents |
| EP1749523A1 (en) * | 2005-07-29 | 2007-02-07 | Neuropharma, S.A. | GSK-3 inhibitors |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3132690A1 (en) * | 1981-08-19 | 1983-03-17 | Bayer Ag, 5090 Leverkusen | (THIO) UREAS, A METHOD FOR THEIR PRODUCTION, THEIR USE AS A PLANT PROTECTION AGENT AND INTERMEDIATE PRODUCTS FOR THEIR PRODUCTION |
| US4879410A (en) * | 1986-11-03 | 1989-11-07 | American Cyanamid Company | Preparation of primary aralkyl urethanes and ureas and isocyanates derived therefrom |
| GR880100400A (en) * | 1988-06-21 | 1990-05-11 | Sandoz Ag | Thiourea derivatives |
| HU206082B (en) * | 1988-12-23 | 1992-08-28 | Sandoz Ag | Process for producing capsaicin derivatives and pharmaceutical compositions comprising such compounds |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3090810A (en) * | 1961-01-11 | 1963-05-21 | Baxter Laboratories Inc | Benzyl thioureas |
| US3164632A (en) * | 1963-02-04 | 1965-01-05 | Baxter Laboratories Inc | Benzyl ureas |
| JPS49171A (en) * | 1972-03-08 | 1974-01-05 | ||
| ES461209A1 (en) * | 1977-07-30 | 1978-05-01 | Invest Tecnica Aplicada | New procedure for the preparation of a bencilic derivative. (Machine-translation by Google Translate, not legally binding) |
-
1978
- 1978-10-23 ES ES474449A patent/ES474449A1/en not_active Expired
-
1979
- 1979-10-19 IT IT69040/79A patent/IT1121487B/en active
- 1979-10-22 JP JP54136933A patent/JPS5823866B2/en not_active Expired
- 1979-10-22 FR FR7926179A patent/FR2439772A1/en active Granted
- 1979-10-22 DE DE19792942564 patent/DE2942564A1/en not_active Withdrawn
- 1979-10-22 BE BE0/197758A patent/BE879558A/en not_active IP Right Cessation
- 1979-10-23 GB GB7936757A patent/GB2036555B/en not_active Expired
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4460602A (en) * | 1981-06-30 | 1984-07-17 | The Procter & Gamble Company | Urea derivatives |
| US5441984A (en) * | 1994-01-06 | 1995-08-15 | Eli Lilly And Company | Urea, thiourea and guanidine derivatives |
| WO1997038682A1 (en) * | 1996-04-17 | 1997-10-23 | Bristol-Myers Squibb Company | Biphenylamido derivatives as melatonergic agents |
| EP1749523A1 (en) * | 2005-07-29 | 2007-02-07 | Neuropharma, S.A. | GSK-3 inhibitors |
| WO2007017145A3 (en) * | 2005-07-29 | 2007-04-26 | Neuropharma Sa | Gsk-3 inhibitors |
| AU2006278829B2 (en) * | 2005-07-29 | 2012-03-29 | Asd Therapeutics Partners Llc | GSK-3 inhibitors |
| US8686042B2 (en) | 2005-07-29 | 2014-04-01 | Neuropharma, S.A. | GSK-3 inhibitors |
| KR101471999B1 (en) | 2005-07-29 | 2014-12-10 | 노스시라, 에스.에이. | -3 gsk-3 inhibitors |
| NO341454B1 (en) * | 2005-07-29 | 2017-11-13 | Noscira Sa | GSK-3 inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2942564A1 (en) | 1980-04-30 |
| IT1121487B (en) | 1986-04-02 |
| ES474449A1 (en) | 1979-05-01 |
| FR2439772A1 (en) | 1980-05-23 |
| FR2439772B1 (en) | 1984-03-23 |
| JPS5823866B2 (en) | 1983-05-18 |
| GB2036555B (en) | 1983-08-17 |
| IT7969040A0 (en) | 1979-10-19 |
| BE879558A (en) | 1980-02-15 |
| JPS5573652A (en) | 1980-06-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |