WO1994017068A1 - Composes de 1,2,4-triazolo tricyclique a activite anti-inflammatoire et d'immunomodulation - Google Patents

Composes de 1,2,4-triazolo tricyclique a activite anti-inflammatoire et d'immunomodulation Download PDF

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Publication number
WO1994017068A1
WO1994017068A1 PCT/IB1994/000010 IB9400010W WO9417068A1 WO 1994017068 A1 WO1994017068 A1 WO 1994017068A1 IB 9400010 W IB9400010 W IB 9400010W WO 9417068 A1 WO9417068 A1 WO 9417068A1
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Prior art keywords
group
carbon atoms
compound
substituted
alkyl group
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Ceased
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PCT/IB1994/000010
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English (en)
Inventor
Sten Albrechtsen
Jens Hansen
Eyvind Langvad
Edgar Eriksoo
Kaj Johansson
Karl-Erik Lundvall
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BTG International Ltd
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British Technology Group Ltd
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Priority to AU58912/94A priority Critical patent/AU5891294A/en
Publication of WO1994017068A1 publication Critical patent/WO1994017068A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to tricyclic condensed 1 ,2,4-triazolo derivatives. These compounds are useful in therapy.
  • Korshak et al (Izv. Akad. Nauk Gruz. SSR Ser. Khim 1976, 2 103-108) described the synthesis of this compound from phtalic anhydride and benzamidrazone. Korhsak et al (Macromolecules 1975, 582-593) discloses this compound as an intermediate in the production of polymeric materials. The thermal and hydrolytic stability of this compound was reported by Korshak et al (lzv. Akad. Nauk SSR, Ser. Khim 1977, 1381-1388) and thermal degradation experiments and cleavage by nucleophilic agents have been described by Korshak et al (12v. Akad. Nauk SSR, Ser.
  • the compound 2-phenyl-5H-1,2,4-triazolo[5,1-a]isoindol-5-one and substituted derivatives of this compound possess anti-inflammatory and immunomodulatory properties and thus are useful in therapy, especially in the treatment of autoimmune disorders such as chronic inflammatory diseases including psoriasis, rheumatoid arthritis and inflammatory bowel disease.
  • heterocyclic ring containing one or two of the heteroatoms N, O and S, optionally mono- or di-substituted by an alkyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon atoms, halogen, or OH
  • R 5 , R 6 and R 7 which may be the same or different are H, OH, an alkyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon atoms, CF 3 , a halogen or the group NR 2 R 3 wherein R 2 and R 3 are as defined above,
  • the compound optionally being in the form of a pharmaceutically acceptable pro-drug formed at one or more hydroxy groups in a substituted 1,2-phenylene group A and/or a substituted group R 1 for use in therapy.
  • the preferred compounds are those in which A is 1 ,2-phenylene, optionally mono- or di- substituted with substituents as defined above and R 1 is a phenyl group, a pyridyl, thienyl, pyrazinyl or furyl group, optionally mono- or di- substituted with substituents as defined above.
  • R 1 is a phenyl group, a pyridyl, thienyl, pyrazinyl or furyl group, optionally mono- or di- substituted with substituents as defined above.
  • the halogens are F or Cl.
  • the most preferred compound is 2-phenyl-5H-1,2,4-triazolo
  • the invention further provides a compound of the general formula (I) defined above but with the proviso that when A is 1 ,2-phenylene, R 1 is not phenyl.
  • the compound of the general formula (I) may be prepared by for example the following methods.
  • One method for the preparation of the compounds of the general formula (I) is the cyclization of the open-chain carboxylic of general formula (III) below
  • One such method is to treat a carboxylic acid of the general formula (III) with a dehydrating agent such as dicyclohexylcarbodiimide.
  • Another such method is to convert the carboxylic acid group of the compounds (III) into a reactive derivative such as an acid chloride or an anhydride which by ring closure forms the desired compound of the general formula (I).
  • reagents useful for the cyclization of compound, of the general formula (III) are 1,1-carbonyl-diimidazole and the open chain sulfonyl halides such as p-toluenesulfonylchloride and methanesulfonyl chloride.
  • the intermediate carboxlic acids (III) are known compounds and can be prepared by conventional methods (J.B. Polya. "1,2,4,-triazoles" in A.R. Katritzky, Ch. W. Rees (Editors) Comprehensive Heterocyclic Chemistry 5, 1984. Pergamon Press Oxford).
  • a compound of the invention may be administered to a subject (including a human) in the form of a pharmaceutical composition.
  • the invention further provides a pharmaceutical composition comprising a compound of formula (I) in association with a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutical composition may be formulated into various forms for administration purposes. These pharmaceutical compositions are desirably in unitary dosage form adapted for administration orally, rectal ly, percutaneously, or by parental injection.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin.
  • Said additives may facilitate the administration on the skin.
  • Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g. as a transdermal patch, as a spot-on or as an ointment. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used in the specification and as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, injectable suspensions and the like.
  • the compounds of formula (I) may also be prepared in the form of pro-drugs in which when A is an OH-substituted
  • 1,2-phenylene group and/or R 1 is an OH-substituted heterocyclic ring or an OH-substituted group of formula (II), the H atom is replaced by a group R4 wherein R4 is a pro-drug providing radical.
  • Pro-drugs of the compounds of the invention may take various forms known as useful in pharmaceutically active compounds.
  • esters may be esters, carbonate esters and phosphate esters.
  • examples of such pro-drug types can be found in P. Krogsgaard-Larson, H. Bundgaard "A textbook of Drug Design and Development” (1991) Harwood Academic Publishers.
  • the present invention is especially useful in the treatment of patients suffering from chronic inflammatory diseases.
  • the present invention also includes a method for treating chronic inflammatory disease in a subject in need of such treatment which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) as defined hereinbefore.
  • the invention also provides the use of a compound of formula (I) for the manufacture of a novel medicament for use in the treatment of chronic inflammatory diseases.
  • a suitable dosage of the compounds of formula (I) would depend on the severity of the disease being treated. In general it is contemplated that an effective amount would be from
  • reaction mixture was then poured into water and the precipitate formed was filtered off and dried.
  • Example 3 Manufacturing process for tablets a 20mg
  • Example 4 Preparation of a Suspension for Injection 20 mg/ml Active compound, mesh 100 20mg
  • the substances are mixed and filled in capsules.
  • a cream containing active compound is produced in the fol lowing way:
  • mice Male CF/1 mice weighing approximately 25g at the start of the experiment were used. On day 1 the abdomen of the mice was shaved. On day 1 and 2 the mice were sensitized by applying 25 ⁇ l of a 0.5% solution of the allergenic compound 2,4-dinitro-fluorobenzene (DNFB) in a 4:1 acetone: olive oil mixture on the shaved area. The challenge response was produced on day 7 applying 10 ⁇ l of the DNFB solution used above on the left ear.
  • DNFB 2,4-dinitro-fluorobenzene
  • the thickness of the ears was measured immediately before and 24 hours after the challenge.
  • the mice were anaesthetised in ether prior to taking the readings.
  • the test compounds were suspended in a methocel solution.
  • the methocel solution was prepared by dissolving 30g of methocel 4000-HG, 45g of sodium chloride and 25g of Kremofor EL in 5 litres of water and the obtained solution was sterilized.
  • the methocel solutions including the test compounds were administered by intraperitoneal injections 26 and 2 hours before and 22 hours after the challenge.
  • the control group was treated with the methocel solution.
  • the thickness of the ears is an expression of the inflammatory response.
  • the inhibitory effect of the test compounds is expressed in per cent after comparison with the control groups.
  • mice consisting of 10 male CF/1 mice weighing approximately 25g at the start of the experiment were used.
  • test compounds were administered suspended in a methocel solution (see Example 7).
  • the animals in the control group were treated with the methocel solution.
  • the thickness of the ears was measured immediately before and three hours after the application of the croton oil solution.
  • the thickness of the ears is an expression of the inflammatory response to croton oil.
  • the inhibitory effect of the test compounds is expressed in per cent after comparison with the control group.
  • mice older than 7 weeks at the start of the experiment were immunized using a chicken collagen-II (cc-II) solution (lmg cc-II/ml 0.1M acetic acid) emulsified in complete Freunds Adjuvant (CFA) in the ratio 1:1.
  • CFA complete Freunds Adjuvant
  • mice were boosted in a similar way using 100 ⁇ l of the emulsion (50 ⁇ cc-II).
  • the compound 2-phenyl-5H-1,2,4-triazolo[5,1-a]isoindol-5-one was suspended in a methocel solution (See Example 7).
  • the methocel solution including the test compound was administered daily by intraperitoneal injections.
  • Treatments were given on weekdays in the period from day 21 after immunization to day 54.
  • Example 10 Anti-inflammatory effects of compounds of formula (I): Croton oil induced chronic inflammation
  • the effects of the compounds of the general formula (I) were determined using the croton oil, induced chronic inflammation of the mouse ear.
  • the thickness of the ears together with the infiltration of neutrophilic granulocytes is an expression of the inflammatory response.
  • Groups consisting of 10 male CF/1 mice weighing approximately 25g at the start of the experiment were used.
  • test compounds were administered suspended in a methocel solution (see Example 7).
  • the animals in the control group were treated with the methocel solution.
  • test compounds were administered by intra peritoneal injections on day 2 through 5.
  • the response was measured as the thickness of the ears 24 hours after the latest croton oil and drug treatment. The thickness was measured immediately before the first croton oil application and on day 2 through 6.
  • a dose dependent reduction in the induced ear thickness was measured.
  • Example II Carrageenin induced rat paw oedema
  • the paw oedema was induced by the injection of 100 ⁇ l of 0.1% lambda carrageenin (Sigma type 4 (C3889)) dissolved in 0.9% saline in each paw.
  • the test compound, 2-phenyl-5H-1,2,4-triazolo[5,1-a]isoindol- 5-one was administered orally one hour before the induction of the paw oedema.
  • the compound was given in the dose 200 ⁇ mol/kg/body weight and a control drug, Piroxicam was used as a positive reference in the concentration 30 ⁇ moles per kg of body weight. There was also a control group who were not treated.

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

Abstract

Composé répondant à la formule générale (I), dans laquelle A représente 1,2-phénylène éventuellement mono- ou di-substitué par un groupe alkyle C1-4, un groupe alcoxy C1-4, CF3, halogène, OH ou NR2R3 où R2 et R3, identiques ou différents, représentant H ou un groupe alkyle C1-4; 4-cyclohexène-cis-1,2-ylène; 1-cyclohexène-1,2-ylène; ou cis-1,2-cyclohexylène; et R1 représente un hétérocycle penta- ou hexagonal renfermant un ou deux hétéroatomes sélectionnés parmi N, O et S, et étant éventuellement mono- ou di-substitué par un groupe alkyle C1-4, un groupe alcoxy C1-4, halogène ou OH; un groupe cyclohexyle; ou un groupe répondant à la formule (II), dans laquelle R5, R6 et R7, identiques ou différents, représentent H, OH, un groupe alkyle C1-4, un groupe alcoxy C1-4, CF3, halogène ou le groupe NR2R3 où R2 et R3 ont les notations précisées ci-dessus; le composé se présentant éventuellement sous la forme d'un précurseur de médicament pharmaceutiquement acceptable formé au niveau d'un ou plusieurs groupes hydroxy dans un groupe 1,2-phénylène substitué A et/ou un groupe R1 substitué à usage thérapeutique.
PCT/IB1994/000010 1993-01-19 1994-01-18 Composes de 1,2,4-triazolo tricyclique a activite anti-inflammatoire et d'immunomodulation Ceased WO1994017068A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58912/94A AU5891294A (en) 1993-01-19 1994-01-18 Tricyclic 1,2,4-triazolo compounds with anti-inflammatory and immunomodulatory properties

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9300127A SE9300127L (sv) 1993-01-19 1993-01-19 Tricyliska kondenserade 1,2,4-triazoloderivat användbara såsom antiinflammatoriska medel
SE9300127-9 1993-01-19

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WO1994017068A1 true WO1994017068A1 (fr) 1994-08-04

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AU (1) AU5891294A (fr)
GB (1) GB2278842A (fr)
SE (1) SE9300127L (fr)
WO (1) WO1994017068A1 (fr)
ZA (1) ZA94382B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055118A3 (fr) * 1997-06-05 1999-04-15 Irilab Ltd Utilisation de derives aromatiques heterocycliques d'azote dans le traitement topique de maladies des tissus epitheliaux

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3895113A (en) * 1973-05-25 1975-07-15 Lepetit Spa Antifertility methods employing triazoloisoquinoline derivatives
US4007276A (en) * 1973-05-25 1977-02-08 Gruppo Lepetit, S.P.A. Triazolo isoindole derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3895113A (en) * 1973-05-25 1975-07-15 Lepetit Spa Antifertility methods employing triazoloisoquinoline derivatives
US4007276A (en) * 1973-05-25 1977-02-08 Gruppo Lepetit, S.P.A. Triazolo isoindole derivatives

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 109, no. 21, 21 November 1988, Columbus, Ohio, US; abstract no. 190324y, MEHTA: "Reactions of cyclic anhydrides with thiosemicarbazide." page 705; column 2; *
CHEMICAL ABSTRACTS, vol. 86, no. 5, 31 January 1977, Columbus, Ohio, US; abstract no. 29720w, KORSHAK: "Synthesis and study of heterocyclic systems based on benzamidrazone." page 360; column 1; *
INDIAN J. CHEM., SECT. B,, vol. 26B, no. 12, 1987, pages 1130 - 1132 *
IZV. AKAD. NAUK GRUZ. SSR, SER. KHIM, vol. 2, no. 2, 1976, pages 103 - 108 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055118A3 (fr) * 1997-06-05 1999-04-15 Irilab Ltd Utilisation de derives aromatiques heterocycliques d'azote dans le traitement topique de maladies des tissus epitheliaux
US6323230B1 (en) 1997-06-05 2001-11-27 Geange Ltd. Use of nitrogen heterocyclic aromatic derivatives in the topical treatment of the epithelial tissues diseases

Also Published As

Publication number Publication date
SE9300127L (sv) 1994-07-20
AU5891294A (en) 1994-08-15
SE9300127D0 (sv) 1993-01-19
GB2278842A (en) 1994-12-14
GB9400900D0 (en) 1994-03-16
ZA94382B (en) 1995-07-19

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