GB2068944A - Chemical compound - Google Patents
Chemical compound Download PDFInfo
- Publication number
- GB2068944A GB2068944A GB8101518A GB8101518A GB2068944A GB 2068944 A GB2068944 A GB 2068944A GB 8101518 A GB8101518 A GB 8101518A GB 8101518 A GB8101518 A GB 8101518A GB 2068944 A GB2068944 A GB 2068944A
- Authority
- GB
- United Kingdom
- Prior art keywords
- general formula
- compounds
- represent
- chemical compound
- ulcerstatic
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention concerns compounds of the general Formula I <IMAGE> where R1 and R2 represent an hydrogen atom, a lower alkyl group having at the most four carbon atoms or a nitro group and to their salts with pharmaceutically acceptable organic and inorganic acids. The compounds of Formula I are obtained by condensing compounds of general Formula II with compounds of general Formula III <IMAGE> In these formulae R1 and R2 represent that which they represented above and X represents a chlorine or bromine atom or a p-tosyloxy group. The compounds of Formula I are characterised by high ulcerstatic activity.
Description
SPECIFICATION
Chemical compound
The invention concerns and in particular relates to a process for the preparation of and application in the therapy of ulcers of compounds of the general Formula I
where R, and R2 represent an hydrogen atom, an inferior alkyl group with at the most four carbon atoms or a nitrogroup, starting from the compounds of formula II,
where R, and R2 represent that which they represented in formula I and from the compounds of the general formula III where X represents a chlorine atom or a bromine atom or a p-tosyloxy group.
It is known that the N (II) derivatives of 5,1 1-dihydro-6H-pyrido [2,3-b] [1,4]-benzodiazepin-6ones, possessing an hydrophile group in the second position of the acetyl group, are endowed with a considerable therapeutic activity in the treatment of ulcers (see for example S. R. Bahring-Kullmay,
Drugs of Today 13, 8 (1977), German Patent No. 1,795,183).
The most active compound brings the component N(4)-methyl-N (1 )-pyperazino-acetyl bound to the position N (11) of the main heterocyclic system. It has been stated (see W. Faberlein et al. Arzneim.
Forschung 27, 356 (1977)) that this compound possesses very high hydrophilic characteristics (log
P = + 0.10) and consequently a scarce capacity for penetrating in the lipoic corporeal areas. This characteristic ensures a high concentration in the gastric tract and a high ulcerstatic activity (see for example M. Leitold et al., Therapiewoche 27, 1517 (1977)).
Compounds of general Formula I have been found to possess even more advantageous chemicalphysical characteristics, especially a more favourable distribution between the lipophilic and hydrophilic means. Some of them show a very high ulcerstatic activity in standard experiments (see Table I).
It has now been found that compounds of the general Formula I possess a more suitable distribution between the lipophilic and the hydrophilic phases and inasmuchas they maintain all the significant components useful for pharmacological activity, they shown an advantageous therapeutic activity.
The following examples report the conditions and the techniques of the experimental work effected.
The present invention is illustrated but not limited in any way by the said examples.
EXAMPLE I 5,1 1 -dihydro- 11 -imidazol- 1 '-yl-acetyl-6H-pyrido [2,3-b] (1,4]-benzodia-zepin-6-one 5,1 1-dihydro-1 1-chloroacetyl-6H-pyrido-[2,3-b] [1,4]-benzodiazepin-6-one (2.87 g, 10 mmoles) and imidazole (3,40 g, 50 mmoles) in benzene (120 ml) are treated under reflux for 1-5 hours. After cooling and decantation of the solution, the resinous residue is washed with diisopropylether (3 x 30 ml) and then dissolved in methanol (25 ml). After short heating with charcoal the product is fiitered and water (100 ml) added to the filtrate.By cooling the raw product crystallises and by re-crystallisation with methanol-water, it delivers 2.1 7 g (64.5%) pure 5,11 -dihydro- 11 -imidazolacetyl-6H-pyrido-[2,3-b] [1,4]-benzodaizepin-6-one, melting point 248-2500C (with loss of water of crystallisation at 120-1500C). IR (K Br): 3530, 1690,1665,1595,1455, 1420,1350,1300,1280, 1275,1230, 1180, 1075, 960, 915, 810, 770, 750, 725, 660, 605 cm1.NMR (DMSO-d6)*in in ppm: 5,05 (dd, 2H), 6,9-7,0 (m, 1 H), 7,2-7,5 (m, 1 H), 7,4-8,1 (m, 7H), 8,3-8,6 (m, 1 H), 10,95 (s enlarged, 1 H); UV (MeOH): A max (); 206 (34400); 281(8000), c=10-5M.
Anal. for C17H13N5O2 x H20 (337,33) calc.: C 60,52; H4,48: N 20,76%
found: C 60,19; H4,50; N 20,54%
EXAMPLE II 5,11-dihydro-11-(2'-methylimidazol-1-yl-acetyl)-6H-pyrido-[2,3-b] [1,4]-benzodiazepin-6-one
5,1-dihydro-11-chloroacetyl-6H-pyrido-[2,3-b] [1,4]-benzodiazepin-6-one (0.86 g, 3.0 mmoles) and 2-methyl-imidazole (0.98 9, 12.0 mmoles) in an hydros benzene (40 ml) are heated under reflux for an hour. After cooling and decantation of the solution the resinous residue is washed with diisopropylether (4 x 20 ml) and dissolved in ethanol (25 ml). After short heating with charcoal it is filtered and the filtrate is evaporated up to above 10 ml.By addition of ether and by cooling the pure product crystallises, 0.475 9 (47.5%), m.p. 273-2760C, analytical sample, m.p. 278-2800C. IR (K
Br): 3200,1700,1665,1600, 1590,1450,1425,1360, 1310,1290, 1250,1230,1210,1185, 1150, 1130, 980, 960, 815, 750, 735, 670, 645, 605 cm-1, NMR (DMSO-d6): # in ppm: 2,22 (s, 3H), 4,93 (dd, 2H), 6,76 (s enlarged, 1H), 7,04 (s enlarged, 1H), 7,3-8,1 (m 6H), 8,3-8,6 (m, 1H), 11,05 (s enlarged, 1 H); UV (MeOH) A max (#); 205 (41200), 282 (8000); c = 10-5M.
Anal. for C18H15N5O2 (333,34)
calc.: C 64.85; H 4.54; N 21.01:
found: C 64.55; H 4.67; N 20.85%
EXAMPLE Ill 5,11-dihydro-11-(2'-methyl-4'-nitroimidazol-1'-yl-acetyl)-6H-pyrido-[2,3-b] [1,4]-benzodiazepin-6-one
Sodium hydride under Nitrogen at 0 C (2.0 millimoles, 0,087 g, as a 55% suspension in mineral oil) is added to 2-methyl-4(5)-nitroimidazole (0.254 9, 2.0 mmoles), dissolved in absolute methanol (20.0 ml).
After 30 minutes stirring, the 11-(2'-chloro-acetyl)-6H-pyrido-benzodiazepinic derivative (0.575 g, 2.0 mmoles), dissolved in DMF (dimethylformamide) (10 ml) is added to the yellow solution obtained.
After stirring for 18 hours at room temperature the precipitate is separated by filtration and the filtrate is evaporated up to about 2 ml. Water (20 ml) is added, the precipitate is separated by filtration and it s recrystallised by adding charcoal from ethanol-water. After a second crystallisation from acetonitrilediisopropylether, 0.542 9 (70%) of pure product are obtained, m.p. 175-1 770C. IR (K Br) 3230, 1685, 1655,1600,1590,1545, 1500,1445,1330,1295, 1260,1235,1180, 1135,965,910,835,755, 695,685 cm-1. NMR (DMSO-d6): 2,31(s, 3H), 4,8-5,6 (m, 2H), 7,3-8,1 (m, 6H), 8,3-8,6 (m, 2H), 10,6-11,2 (s enlarged, 1H), UV (MeOH) # max (3); 203 (58.000), 284 (15.00), c=10-5M.
Anal. for C18H14N6O4 (378,34)
calc.: C 57,14; H 3,73; N 22,21%
found: C 56,91; H 3,62; N 22,49% TABLE 1
Activity of some 6H-pyrido-[2,3-b] [1,4] benzodiazepin-6-one derivatives in the antiulcer test in rats
Stress Ulcer (a.) Serotonine ulcer (b.) Dose confidence Dose confidence R mg/kg N Ed50 mg/kg limits mg/kg N ED50 mg/kg limits # 5-15 20 7.8 6.2-9.5 10-40 30 25.6 21.0-32.0 # 5-50 20 19.5 12.5-25.0 10-90 30 65.8 12.5-80.0 # 10-120 20 61.8 55.5-72.0 10-120 30 no activity # 10-50 20 25.5 16.0-27.0 20-300 30 no activity Matiamide 50-60 20 95.5 78.6-101 25-100 30 105.7 95.6-108 Atropine sulphate 0.5-1.5 20 0.8 0.7-1.0 0.5-5.0 30 2.6 2.0-3.0 a. following W. Ludwig e M. Lipkin, Gastroenterology 56, 895 (1969) b. " M. Leitold et al. Therapierwoche, 27, 1532 (1977)
Claims (5)
1. A process for the preparation of compounds of the general formula I
where R1 and R2 represent an hydrogen atom, an inferior alkyl group, having four carbon atoms at most or a nitrogroup and their salts with pharmaceutically acceptable organic and inorganic acids, starting from compounds of the general Formula II
where R1 and R2 represent that which represented in general Formula I, and from compounds of the general Formula Ill where X represents a chlorine atom or a bron ine atom or a p-tosyloxy group.
2. A process according to claim 1, in which the alkylation with the compounds of the general
Formula Ill is effected in an inert solvent such as pyridine, toluene, tetrahydrofuran, dimethylformamide or dioxan.
3. A process according to claim 2, in which alkylation is effected at temperatures lying between room temperature and the reflux temperature of the solvents cited in claim 2.
4. A chemical compound of the general Formula I in which R1=R2=H, being a compound endowed with the highest ulcerstatic activity within the series of compounds herein claimed.
5. A chemical compound of the general Formula I of claim 1 for use as an ulcerstatic pharmaceutical composition.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT19423/80A IT1193371B (en) | 1980-01-24 | 1980-01-24 | 11- (2'-IMIDAZOL-1 '' - IL) -ACETYL-5,11-DIHYDRO-6H-PYRID 2,3-B 1,4 BENZODIAZEPIN-6-ONI, METHOD FOR THEIR PREPARATION AND APPLICATION IN THE THERAPY OF THE ULCER |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2068944A true GB2068944A (en) | 1981-08-19 |
Family
ID=11157749
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8101518A Withdrawn GB2068944A (en) | 1980-01-24 | 1981-01-19 | Chemical compound |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS56113783A (en) |
| BE (1) | BE887069A (en) |
| DE (1) | DE3102152A1 (en) |
| DK (1) | DK32481A (en) |
| ES (1) | ES8201157A1 (en) |
| FR (1) | FR2474501A1 (en) |
| GB (1) | GB2068944A (en) |
| GR (1) | GR72993B (en) |
| IT (1) | IT1193371B (en) |
| PT (1) | PT72392B (en) |
| SE (1) | SE8100333L (en) |
| YU (1) | YU16981A (en) |
| ZA (1) | ZA81510B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4210648A (en) * | 1977-05-31 | 1980-07-01 | Boehringer Ingelheim Gmbh | II-Aminoacyl-5,11-dihydro-6H-pyrido(2,3-B) (1,4)benzodiazepin-6-ones and salts thereof |
-
1979
- 1979-01-22 GR GR63939A patent/GR72993B/el unknown
-
1980
- 1980-01-24 IT IT19423/80A patent/IT1193371B/en active
-
1981
- 1981-01-14 BE BE0/203478A patent/BE887069A/en unknown
- 1981-01-19 GB GB8101518A patent/GB2068944A/en not_active Withdrawn
- 1981-01-21 SE SE8100333A patent/SE8100333L/en not_active Application Discontinuation
- 1981-01-22 YU YU00169/81A patent/YU16981A/en unknown
- 1981-01-23 FR FR8101328A patent/FR2474501A1/en active Pending
- 1981-01-23 DE DE19813102152 patent/DE3102152A1/en not_active Withdrawn
- 1981-01-23 DK DK32481A patent/DK32481A/en unknown
- 1981-01-23 JP JP889481A patent/JPS56113783A/en active Pending
- 1981-01-23 PT PT72392A patent/PT72392B/en unknown
- 1981-01-23 ZA ZA00810510A patent/ZA81510B/en unknown
- 1981-01-23 ES ES498768A patent/ES8201157A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| PT72392A (en) | 1981-02-01 |
| IT8019423A0 (en) | 1980-01-24 |
| IT1193371B (en) | 1988-06-15 |
| ES498768A0 (en) | 1981-12-01 |
| BE887069A (en) | 1981-05-04 |
| FR2474501A1 (en) | 1981-07-31 |
| SE8100333L (en) | 1981-07-25 |
| DK32481A (en) | 1981-07-25 |
| ES8201157A1 (en) | 1981-12-01 |
| GR72993B (en) | 1984-01-25 |
| PT72392B (en) | 1981-12-21 |
| DE3102152A1 (en) | 1981-12-10 |
| YU16981A (en) | 1983-10-31 |
| ZA81510B (en) | 1982-05-26 |
| JPS56113783A (en) | 1981-09-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE3006097C2 (en) | ||
| CA1257271A (en) | 6-vinyl-furo-(3,4-c)-pyridine derivatives | |
| IE47363B1 (en) | Imidazole derivatives | |
| Anderson et al. | Synthesis and antileukemic activity of 5-substituted 2, 3-dihydro-6, 7-bis (hydroxymethyl)-1H-pyrrolizine diesters | |
| EA005377B1 (en) | TETRAHYDROIMIDAZO[1,2-h][1,7]NAPHTHYRIDINE COMPOUNDS | |
| GB2104522A (en) | Tetrazine derivatives | |
| CA1108138A (en) | Triazine derivatives | |
| SU583758A3 (en) | Method of preparing 1,4-diazepine derivatives or salts thereof | |
| FI67697C (en) | PROCEDURE FOR THE PHARMACOLOGICAL PROPERTIES OF 5-STATIONARY SUBSTITUTES 5,10-DIHYDRO-11H-DIBENZO- (B, E) (1,4) DIAZEPIN-11-ONER | |
| GB2068944A (en) | Chemical compound | |
| Uchikawa et al. | Aminothiazole derivatives. I. A convenient synthesis of monocyclic and condensed 5‐aminothiazole derivatives | |
| WO2000047582A1 (en) | Triazolo-pyridazine derivatives as ligands for gaba receptors | |
| CA1154766A (en) | Antiallergic nitrogen bridgehead compounds and process for the preparation thereof | |
| US4968792A (en) | Psychotropic benzisothiazole derivatives | |
| EP0292051A2 (en) | Thienopyridine derivatives | |
| EP0491814B1 (en) | Tetracyclic imidazoquinazoline derivatives, preparation and pharmaceutical compositions | |
| US3759933A (en) | 3h-imidazo(4,5-c)pyridines | |
| CA1314885C (en) | Tricyclic derivatives which are agonists of cholinergic receptors, and drugs in which they are present | |
| CA1212945A (en) | S-triazolo¬1,5-a|-pyrimidine derivatives | |
| DE3225386A1 (en) | Substituted naphthylimidazo[4,5-b]pyridines, process for their preparation, and their use, and preparations containing these compounds | |
| WO1989006652A1 (en) | Antipsychotic gamma-carboline n-oxides | |
| CA1134363A (en) | Pyrano-heterocycles, process for preparing them and medicaments containing these compounds | |
| EP0320910A1 (en) | 2-Thiazolidinone derivatives, pharmaceutical compositions containing them, process for preparing same, and use | |
| KR920009884B1 (en) | 2,3-thiomorpholinedione-2-oxime derivatives and process for preparing same | |
| EP0003084B1 (en) | Spirobenzofuranone compounds, processes for their preparation and their use as medicines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |