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WO1993016053A1 - Nouveaux derives bistetrazoles ayant une activite antiallergique et cytoprotective - Google Patents

Nouveaux derives bistetrazoles ayant une activite antiallergique et cytoprotective Download PDF

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Publication number
WO1993016053A1
WO1993016053A1 PCT/EP1993/000326 EP9300326W WO9316053A1 WO 1993016053 A1 WO1993016053 A1 WO 1993016053A1 EP 9300326 W EP9300326 W EP 9300326W WO 9316053 A1 WO9316053 A1 WO 9316053A1
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WO
WIPO (PCT)
Prior art keywords
group
benzamide
tetrazol
compounds
formula
Prior art date
Application number
PCT/EP1993/000326
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English (en)
Inventor
Francesco Makovec
Walter Peris
Lucio Claudio Rovati
Luigi Angelo Rovati
Original Assignee
Rotta Research Laboratorium S.P.A.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Rotta Research Laboratorium S.P.A. filed Critical Rotta Research Laboratorium S.P.A.
Publication of WO1993016053A1 publication Critical patent/WO1993016053A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • Novel bistetrazol derivatives having an anti-allergic and cytoprotective activity
  • the present invention relates to novel N-phenylbenzamide and N-pyridine-benzamide derivatives represented by the following general formula:
  • A is the benzene ring or the pyridine ring and R 1 and R 2 both represent the group (1H-tetrazol-5-yl)
  • R 1 and R 2 both represent the group (1H-tetrazol-5-yl
  • R 2 is in the ortho, meta or para position in ring A
  • R 2 can be in the ortho or meta position in ring A, and their pharmaceutically acceptable salts.
  • These compounds have proved to have remarkable pharmacological effects with respect to mammals, one of which is their powerful inhibiting activity on the release of chemical agents causing allergic or immunological reactions.
  • a further property consists in their equally powerful protective and healing activity with respect to the epithelial mucose membranes.
  • a further activity is their ant isecretion activity with respect to various secretion stimulants, such as histamine, carbachol and pentagastrine.
  • the aforementioned compounds can thus be used advantageously in the treatment of various human diseases, such as those which are due to hypersensitivity to allergens, such as bronchial asthma, for example, allergic rhinitis or conjunctivitis, or other pathological conditions of further organs or areas, or in the treatment of diseases of the digestive system, such as those deriving from gastric secretion disorders or mucosal lesions, i.e. peptic and gastro-duodenal ulcers, colitis, or in allergies and intolerance in the alimentary system.
  • the process for preparing N-phenyl and N-pyridinylbenzamido-bis-tetrazol derivatives according to the invention is characterized by a two-stage synthesis, illustrated in diagram 1.
  • Diagram 1 Process for synthesising the compounds claimed according to the invention.
  • aniline or aminopyridine optionally substituted in R 2 with the cyano group is made to react with the stoichiometric amount of benzoyl chloride optionally substituted in R 1 with the cyano group dissolved in a polar solvent, preferably tetrahydrofurane, in the presence of a tertiary base such as tr iethylamine, for example, which acts as a hydrochloric acid acceptor, at a temperature of between 0 and 20° C, preferably approximately 10° C, for an amount of time which can vary from approximately one hour to twenty-four hours; in general, the reaction is considered to be complete after 12 hours.
  • a polar solvent preferably tetrahydrofurane
  • a tertiary base such as tr iethylamine, for example, which acts as a hydrochloric acid acceptor
  • the solvent evaporates under vacuum, the residue is taken up with water, filtered, washed until it is neutral and dried.
  • the compound is then converted into the bis-tetrazol derivative as a result of being reacted in the hot state with sodium azide and ammonium chloride in a high-boiling point solvent, preferably dimethyl formamide, at a temperature of between 60° and 140° C (preferably 100 ° C).
  • a high-boiling point solvent preferably dimethyl formamide
  • the reaction time varies between 8 and 36 hours and on average 24 hours are sufficient for the reaction to be completed.
  • the reaction mixture is diluted with water and acidified.
  • the precipitate is filtered, washed to neutralize it and optionally crystallized.
  • the process consists of a modification of the Goose and Blair method (Immunology 16 (1969, 749-760).
  • Male rats weighing approximately 250g are treated intra-muscularly with 25 mg/kg of grade V ovalbumin dissolved in 0.5 .ml of a Bordetella Pertussis suspension. 14 days later, after sensibilization, the animals are sacrificed by being anaesthetized with ether, the blood being sampled and the serum maintained at -70° C after the titre has been tested for IgE specific to the ovalbumin present therein.
  • the products in question are administered intramuscularly 15 minutes before the antigen.
  • the animals are sacrificed 30 minutes after the antigen has been administered, the skin from the back is inverted and the maximum and minimum diameters of each spot are measured.
  • the response from each animal can be evaluated as a mean value of the four diameters.
  • the compounds are administered in different doses (generally 5 animals per dose per group) such that it is possible to calculate an active 50 dose (ID50), the dose which can inhibit 50% of the passive cutaneous anaphylactic (PCA) reactions in the animals treated in accordance with the tests.
  • ID50 active 50 dose
  • PCA passive cutaneous anaphylactic
  • Table 2 Effects on cutaneous anaphylaxis in rats passively sensitized (PCA) with antiserum IgE and the antigen ovalbumin
  • the protective activity with respect to mucose membranes is assessed in a test ulcer induced by administering alcohol orally to rats. It has recently been reported that the antiallergic medicament sodium chromoglycate (DSCG) appears to be effective in the prevention of ethanol-induced gastric mucosal necrosis (J. Goossens et al .Br.J.Pharmcol.91 (1987), 165-169).
  • DSCG sodium chromoglycate
  • necrotic lesions which are counted and classified according to the method described herebelow which is a variant of the method described in Med. Exp .4,284-292 (1961), consisting in allocating arbitrary points according to the number and severity of the lesions, according to the following criteria:
  • An index of the lesions is thus obtained which is the total number of lesions multiplied by their relative points.
  • the compounds are administered intravenously in various doses such that a protective ID50 dose can be calculated, that is the dose (given intravenously in mg/kg) which can inhibit 50% of gastric mucosal damage induced by the harmful agent.
  • a protective ID50 dose can be calculated, that is the dose (given intravenously in mg/kg) which can inhibit 50% of gastric mucosal damage induced by the harmful agent.
  • the ant isecret ion activity is determined in rats, using male animals weighing approximately 200 g and anaesthetised with urethane. Gastric secretion is stimulated using pentagastrine, histamine and carbachol. The slightly modified method of K.S. Lai (Gut 5 (1964), 327-341) is used.
  • the oesophagus and duodenum are incanulated.
  • Perfusion is performed using a tepid solution (37°) of physiological solution which has been passed through the stomach by means of a peristaltic pump at a constant rate of 1 ml/minute. After stabilising for 20 minutes, perfusion with the stimulant dissolved in physiological solution is performed for 120 minutes in the dose indicated in Table 4 at a rate of 0.95 ml/hour. After 60 minutes' perfusion (basal stimulation), the product in question is administered intravenously in a bolus and perfusion of the stimulant is continued for a further 60 minutes. The acid secret i on is continuously recorded as a function of the time.
  • the activity of the product is evaluated as a percentage of the reduction in the acidity secreted after the product has been administered compared with the basal acidity measured during the first 60 minutes' collection time in which only the stimulant was present.
  • the antagonistic compounds tested are administered in different doses such that it is possible to calculate an ID50 which is the dose (given intravenously in mg/kg) which can inhibit up to 50% of the effect of the various agents stimulating the secretion in question.
  • Table 4 shows the activities of the compounds expressed as ID50 in the three different situations discussed, that is under the stimulus of pentagastrine, histamine and carbachol in the doses indicated in the table.
  • Table 4 Antagonistic activity (ID50 mg/kg given intravenously) compared with gastric acid secretions induced by different agents in rats
  • Pentagastrine His ⁇ anine Carbadiol (30 mcg/kg/h) (2..8 mg/kg/h) (30 mcg/kg/h)
  • a ID50 is the intravenous dose in mg/kg of product required to inhibit by 50% the acid secretion induced by different agents in the dose indicated and administered by intravenous infusion.
  • NT not tested
  • the antisecretion activity displayed by the compounds claimed against various stimulants is al so highly potent .
  • the most active compound is compound 3 which exhibits an antisecretion ID50 of approximately 10 mg/kg in each of the test conditions studied, in which the gastric secretion of pentagastrine, histamine and carbachol is stimulated.
  • the compounds claimed the least advantageous appear to be those in which tetrazol R 1 is in the ortho position (for example compound 10).
  • DSCG is used as the comparison compound since the literature shows (A.K. Nicol et al., J. Pharm. Pharmcol. 1981,33, 554-556) that it inhibits the acid secretion stimulated by pentagastrine. Under the test conditions using a stimulant concentration 10 times greater than that used in the cited method, the effect of DSCG is relatively modest, reducing the stimulated secretion of pentagastrine by only 19%, in the very high intravenous dose of 100 mg/kg.
  • test data given above show the manner in which the compounds to which the invention relates have a remarkable antiallergic, antisecretion and cytoprotect ive activity.
  • Some of the compounds claimed, for example compounds 3 and 9, have an antianaphylactic activity in vivo in the PCA test which is approximately 40 times greater than the compound DSCG, which is a recognized reference standard in the scientific literature.
  • these compounds also have a strong cytoprotective effect which is approximately 50 times greater than DSCG in the case of the more active compounds which enables damage to the epithelial membranes in contact with harmful agents to be prevented.
  • the favourable use of the compounds to which the invention relates in the treatment of all pathological conditions supported by allergic components such as for example bronchial asthma or rhinitis or allergic conjunctivitis is recommended.
  • the compounds in question can act on the mastocytes in the form of a mechanism which is similar to a cytoprotective mechanism by stabilizing the cellular membranes, which would inhibit the release of chemical agents causing bronchospastic reactions in the lungs and inflammation of the mucosae.
  • the above test data also show that the compounds to which the invention relates can be considered as a remarkable therapeutic innovation in the treatment of some pathological conditions of the gastro-duodenal tract, such as for example gastric and duodenal ulcers, ulcerative colitis, etc.
  • these compounds display notable antagonistic activity with respect to gastric acid secretion induced by various stimulants such as pentagastrine, histamine and carbachol.
  • Their anti-ulcer activity thus appears to be explained by a dual protective mechanism which inhibits both an excess formation of gastric acid stimulated by various agents and protects the mucose membranes from harmful agents.
  • these compounds can also be used to prevent or cure lesions to any tissue exposed to harmful pathogens which damage the integrity thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Composés phénylméthanamide-N et pyridinyl-benzamide-N selon la formule (I) dans laquelle A représente le noyau benzénique ou pyridinique et R1 et R2 représentent tous les deux le groupe (1H tétrazol-5-yle), et dans laquelle, si R1 et dans la position ortho ou méta dans le groupe benzamidique, R2 est dans la position ortho, méta ou para dans le noyau A, alors que si R1 est dans la position para dans le groupe benzamidique, R2 peut être dans la position ortho ou méta dans le noyau A. L'invention décrit également leurs sels pharmaceutiquement acceptables.
PCT/EP1993/000326 1992-02-13 1993-02-11 Nouveaux derives bistetrazoles ayant une activite antiallergique et cytoprotective WO1993016053A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITTO920114A IT1256870B (it) 1992-02-13 1992-02-13 Derivati bis-tetrazolici ad attivita' antiallergica e citoprotettiva
ITTO92A000114 1992-02-13

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WO1993016053A1 true WO1993016053A1 (fr) 1993-08-19

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001064268A (ja) * 1999-06-25 2001-03-13 Nippon Nohyaku Co Ltd ベンズアミド誘導体及び農園芸用殺虫剤並びにその使用方法
EP1195375A4 (fr) * 1999-06-25 2002-11-27 Nihon Nohyaku Co Ltd Derives de benzamide, insecticides pour l'agriculture/l'horticulture, et utilisation
WO2003016304A1 (fr) * 2001-08-15 2003-02-27 E. I. Du Pont De Nemours And Company Amides aryle ortho-heterocycliques substitues permettant de lutter contre des ravageurs invertebres
WO2005040121A3 (fr) * 2003-10-16 2005-06-23 Abbott Lab Amides inhibant le recepteur de sous-type 1 des vanilloides 'vr1'
MY120647A (en) * 2000-12-20 2005-11-30 Nihon Nohyaku Co Ltd Benzamide derivatives and agricultural and horticultural insecticides and method for using thereof.
US7078423B2 (en) 2002-07-18 2006-07-18 Inotek Pharmaceuticals Corporation 5-Aryltetrazole compounds, compositions thereof, and uses therefor
US7087631B2 (en) 2002-07-18 2006-08-08 Inotek Pharmaceuticals Corporation Aryltetrazole compounds, and compositions thereof
JP2015506360A (ja) * 2012-01-06 2015-03-02 ユニバーシティ・オブ・サウス・フロリダ 組成物、使用方法および処置方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986005779A1 (fr) * 1985-04-03 1986-10-09 Yamanouchi Pharmaceutical Co., Ltd. Derives d'antipyrine
EP0286364A2 (fr) * 1987-04-06 1988-10-12 Riker Laboratories, Inc. Di-t-butylphénols substitués
WO1990009989A1 (fr) * 1989-02-22 1990-09-07 Rotta Research Laboratorium S.P.A. Derives de n-phenylbenzamide avec action anti-ulcereuse et anti-allergique et procede servant a leur preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986005779A1 (fr) * 1985-04-03 1986-10-09 Yamanouchi Pharmaceutical Co., Ltd. Derives d'antipyrine
EP0286364A2 (fr) * 1987-04-06 1988-10-12 Riker Laboratories, Inc. Di-t-butylphénols substitués
WO1990009989A1 (fr) * 1989-02-22 1990-09-07 Rotta Research Laboratorium S.P.A. Derives de n-phenylbenzamide avec action anti-ulcereuse et anti-allergique et procede servant a leur preparation

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1195375A4 (fr) * 1999-06-25 2002-11-27 Nihon Nohyaku Co Ltd Derives de benzamide, insecticides pour l'agriculture/l'horticulture, et utilisation
US6642379B1 (en) 1999-06-25 2003-11-04 Nihon Nohyaku Co., Ltd. Benzamide derivatives, insecticides for agricultural and horticultural use and usage thereof
JP2001064268A (ja) * 1999-06-25 2001-03-13 Nippon Nohyaku Co Ltd ベンズアミド誘導体及び農園芸用殺虫剤並びにその使用方法
MY120647A (en) * 2000-12-20 2005-11-30 Nihon Nohyaku Co Ltd Benzamide derivatives and agricultural and horticultural insecticides and method for using thereof.
US7375232B2 (en) 2001-08-15 2008-05-20 E.I. Du Pont De Nemours And Company Ortho-heterocyclic substituted aryl amides for controlling invertebrate pests
WO2003016304A1 (fr) * 2001-08-15 2003-02-27 E. I. Du Pont De Nemours And Company Amides aryle ortho-heterocycliques substitues permettant de lutter contre des ravageurs invertebres
US7629463B2 (en) 2001-08-15 2009-12-08 E. I. Du Pont De Nemours And Company Ortho-heterocyclic substituted aryl amides for controlling invertebrate pests
US7078423B2 (en) 2002-07-18 2006-07-18 Inotek Pharmaceuticals Corporation 5-Aryltetrazole compounds, compositions thereof, and uses therefor
US7087631B2 (en) 2002-07-18 2006-08-08 Inotek Pharmaceuticals Corporation Aryltetrazole compounds, and compositions thereof
US7135491B2 (en) 2002-07-18 2006-11-14 Inotek Pharmaceuticals Corp. 5-Aryltetrazole compounds and uses thereof
WO2005040121A3 (fr) * 2003-10-16 2005-06-23 Abbott Lab Amides inhibant le recepteur de sous-type 1 des vanilloides 'vr1'
JP2007508387A (ja) * 2003-10-16 2007-04-05 アボット・ラボラトリーズ バニロイド受容体サブタイプ１（ｖｒ１）受容体を阻害するアミド
US7595332B2 (en) 2003-10-16 2009-09-29 Abbott Laboratories Amides that inhibit vanilloid receptor subtype 1 (VR1)
US7037927B2 (en) 2003-10-16 2006-05-02 Abbott Laboratories Amides that inhibit vanilloid receptor subtype 1 (VR1) receptor
JP2015506360A (ja) * 2012-01-06 2015-03-02 ユニバーシティ・オブ・サウス・フロリダ 組成物、使用方法および処置方法
EP2800568A4 (fr) * 2012-01-06 2015-06-10 Univ South Florida Compositions, procédés d'utilisation et procédés de traitement
US9556131B2 (en) 2012-01-06 2017-01-31 University Of South Florida Compositions, methods of use, and methods of treatment
US10604493B2 (en) 2012-01-06 2020-03-31 University Of South Florida Compositions, methods of use, and methods of treatment

Also Published As

Publication number Publication date
ITTO920114A0 (it) 1992-02-13
ITTO920114A1 (it) 1993-08-13
IT1256870B (it) 1995-12-27

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