EP0589985A1 - 2-amino-4-aryl-thiazoles with antiasthmatic and anti-inflammatory activities on the respiratory tract - Google Patents

2-amino-4-aryl-thiazoles with antiasthmatic and anti-inflammatory activities on the respiratory tract

Info

Publication number
EP0589985A1
EP0589985A1 EP92912406A EP92912406A EP0589985A1 EP 0589985 A1 EP0589985 A1 EP 0589985A1 EP 92912406 A EP92912406 A EP 92912406A EP 92912406 A EP92912406 A EP 92912406A EP 0589985 A1 EP0589985 A1 EP 0589985A1
Authority
EP
European Patent Office
Prior art keywords
bis
thiazol
piperazine
pyrrolidin
aminocarbonyl
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Withdrawn
Application number
EP92912406A
Other languages
German (de)
English (en)
French (fr)
Inventor
Gian Piero De Cillis
Giorgio Long
Simonetta D'alo'
Antonella Rozzi
Licia Gallico
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics SpA
Original Assignee
Boehringer Mannheim Italia SpA
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
Priority claimed from ITMI911714A external-priority patent/IT1248526B/it
Priority claimed from ITMI920786A external-priority patent/IT1255077B/it
Application filed by Boehringer Mannheim Italia SpA filed Critical Boehringer Mannheim Italia SpA
Publication of EP0589985A1 publication Critical patent/EP0589985A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines

Definitions

  • the present invention relates to 2-amino-4-arylthiazole derivatives, a process for the preparation thereof and pharmaceutical compositions containing them.
  • X is oxygen or sulfur
  • B is CH 2 , oxygen, sulfur or N-R;
  • R is C 1 -C 6 alkyl, phenyl optionally substituted with halogen in o-, m- or p-position; benzyl optionally substituted with halogen in the o-, m- or p- positions; bis (phenyl .methyl; bis(o-,m- or p-halophenyl)methyl; a
  • 5-6 membered heterocycle having 1 to 3 nitrogen atoms, optionally substituted with 1-2 amino groups, mono-C 1 - C 6 -alkylamino, mono-C 3 -C 7 -alkenyl- or mono-C 3 -C 7 - alkynylamino, di-C 1 -C 6 -alkylamino, C 1 -C 6 -alkyl-C 3 -C 7 - alkenylamino, piperidin-1-yl, morpholin-4-yl, pyrrolidin-1-yl.
  • Ar is phenyl optionally substituted with 1-3 substituents selected from halogen atoms; hydroxy; C 1 - C 6 alkoxy; C 1 -C 6 acyloxy; C 1 -C 6 alkyl; cyano; nitro; -SO 2 CH 3 ; -SO 2 NH 2 ; phenylsulfonyl optionally substituted with halogen in the o-, m- or p-positions; C 1 -C 6 alkylthio; phenyloxy or phenylthio optionally substituted with halogen in the o-, m- or p- positions; CF 3 ; NR'R", wherein R' and R", which may be the same or different, are hydrogen, C 1 -C 4 alkyl, acetyl or NR'R" is a pyrrolidino, piperidino, morpholino, 4- thiamorpholino group; -CH-NR'R" wherein R'
  • Ar is preferably phenyl or phenyl substituted with 1 or 2 hydroxy, C 1 -C 6 alkoxy, amino, halogen, (halosubstituted) phenylsulphonyl, cyano, nitro, phenylthio, alkoxycarbonyl and/or C 1 -C 6 alkyl groups, preferably tert-butyl groups, -NHSO 2 CH 3 .
  • Ar groups are phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 2,3-dihydroxyphenyl, 4-hydroxy-3,5-di-tert-butylphenyl, 2-, 3- or 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-bromophenyl, 3- or 4-trifluoromethylphenyl, 3- or 4-cyanophenyl, 4-nitrophenyl, 3-nitrophenyl, 3- or 4-phenylsulphonyl-phenyl, 3- or 4-(2'-chlorophenyl)sulphonylphenyl, 4-phenylthiophenyl, 4-((pyrrolidin-1-yl)methyl)phenyl, 2-, 3- or 4-aminophenyl, 3- or 4-methoxycarbonylphenyl, ⁇ -pyridyl, 3,4-dich
  • R is an heterocycle, it is preferably selected from pyridin-2-yl, pyrimidin-4-yl, pyrimidin-2-yl or 1,3,5-triazin-2-yl, which can optionally be substituted with 1 or 2 amino, mono-C 1 -C 6 -alkylamino, 2-propenylamino, 2-propynylamino, propylamino, isopropylamino, dimethylamino, diethylamino, ethyl-2-propenylamino, pyrrolidino groups.
  • R is selected from:
  • the present invention also relates to the salts of compounds of formula (I) with pharmaceutically acceptable acids.
  • the compounds of formula (I) have interesting pharmacological properties, particularly antiasthmatic and antiinflammatory activities on the respiratory tract.
  • the compounds of the invention show moreover marked antihistaminic effect.
  • 5-Phenyl-2-aminothiazole derivatives having antiinflammatory activity are disclosed in WO 8202383, 8202384 , 8202385, 8202386 and 8202553.
  • EP-A-0032058 discloses 5-aminoalkyl-2-aminothiazoles having antiallergic and antiasthmatic activities , whereas 2-amino-4-methyl-5-(4-phenyl)piperazino-alkylthiazoles having neuroleptic activity are disclosed in
  • Polish patent 106,675 (Cher ⁇ . Abstr. 95; 97851).
  • the compounds of formula I structurally differ from the prior-art thiazoles in the kind of substitution on the amine nitrogen. From the biological point of view, the distinguishing feature of the compounds of the invention resides in their particular ability in preventing and/or reducing bronchial hyperreactivity of the respiratory tract, thus resolving the phlogistic condition accompanying acute and subchronical inflammations of bronchial mucosa.
  • Ar' has the same meanings as Ar, or is a group which can be converted into Ar by removing any protective groups present, by reacting them first with carbonyldiimidazole or, when X is S, thiocarbonyldiimidazole, or similar difunctional carbonylating agents, then with amines of formula (III):
  • reaction of compound (II), with carbonyldiimidazole or its thioanalogue and amines (III) is generally carried out in anhydrous aprotic solvents, at temperatures ranging from room temperature to the reflux temperature of the reaction mixture.
  • Suitable solvents are ethyl ether, tetrahydrofuran, halogenated hydrocarbons, dimethylsufoxide, dimethylformamide.
  • carbonyldiimidazole can be replaced by similar reagents, such as phosgene or thiophosgene.
  • Ar 1 is as defined above and X is a chlorine, bromine or iodine atom, which compounds are known or can be prepared by widely known methods.
  • Bronchial hyper-reactivity is a clinical symptom of asthma and it is believed to be a direct consequence of an abnormal and latent contractility and sensitivity of the bronchial mucosa.
  • Bronchial hyper-reactivity can cause acute crisis of asthma after physical practice, and/or after exposure to external stimuli such as the inhalation of fog, pollutants, allergens and autacoids.
  • the bronchial hyper-reactivity conditions may be simulated by an experimental model consisting in the PAF infusion (600 ⁇ g/l) in male guinea-pigs weighing 400-450 g, kept under forced ventilation under urethane and pancuronium bromide anesthesia.
  • PAF which is one of the most important mediators involved in the inflammatory process of the airways, after infusion for 1 hour, causes an hyperreactivity reaction (bronchocostriction) to specific and different substances.
  • the activity of the compounds of the invention, in the considered pharmacological model, is shown by the prevention of the PAF-induced hyper-reactivity, measured as increase of the pulmonary insufflatory pressure (measured according to the modified procedure of Konzett and Rossler, Naun. Schmied. Arch. Exper. Pathol. Pharmacol. 191, 71, 1970).
  • the compounds of the invention which are administered 10 minutes before the PAF administration in dosages which vary between 2 and 50 ⁇ g/Kg, demonstrate a protective action which lasts at least 4-6 hours and results in a reduction of the PAF-induced hyperreacti vity. Such pharmacological effects are dose-related.
  • the compounds of the invention can be used in human therapy in the treatment of asthmatic and obstructive conditions of the respiratory tract, in the treatment of inflammatory phlogosis.
  • the compounds of the invention will be administered in the form of pharmaceutical compositions which can be prepared with excipients and conventional techniques such as, for example, those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA, 17th ed., 1985, adapted for administration by intramuscular, intravenous, oral, aerosol and rectal methods.
  • the daily dose will depend on several factors such as the gravity of the pathology and the condition of the patient: it will normally consist of from 1 to 50 mg of a compound of formula I for a patient weighing 70 kg, one or more times a day.
  • the 2-amino-4-arylthiazoles (II) are either commercially available or are prepared by reaction of the suitable cj f -bromoaryl-methylketones with thiourea, as disclosed in the following preparations 1-4.
  • Acetic anhydride (2.7 ml) is dropped into a solution of 2,3-dihydroxybenzoic acid (2 g) in 10 ml of pyridine, cooling to 0 ⁇ C. After 6 hours at room temperature, the reaction mixture is poured into 15 ml of 1N HCl and it is repeatedly extracted with AcOEt (3 ⁇ 50 ml). The combined organic extracts are washed with water, dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The resulting residue (3.5 g) is crystallized from diisopropyl ether to give 2.7 g of 2,3-diacetoxybenzoic acid, m.p. 151- 153°.
  • Carbonyldiimidazole (750 mg) is added to a solution of 2,3-diacetoxybenzoic acid (1 g) in 10 ml of anhydrous tetrahydrofuran, with stirring and under inert gas atmosphere. After one hour, the reaction mixture is added with 570 mg of dimethylaminopyridine and 670 mg of Meldrum acid. After 2 more hours, the reaction mixture is poured into 15 ml of 1N HCl and repeatedly extracted with AcOEt (3 ⁇ 30 ml). The combined organic extracts are washed with water, dried over sodium sulfate and solvent is evaporated off under reduce pressure.
  • the resulting residue (1.7 g) is purified by silica gel ⁇ hromatography (50 g, eluent 8/2 AcOEt/hexane), to obtain 1.4 g of 5-((2,3-diacetoxyphenyl) carbonyl)-2,2-dimethyl-4, 6-dioxo-1,3-dioxane.
  • Paratoluenesulfonic acid mono-hydrate (1.15 g) is added to a solution of 5-((2,3-diacetoxyphenyl)carbonyl)-2,2-dimethyl-4,6-dioxo-1,3-dioxane
  • Carbonyldiimidazole (920 mg) is added to a solution of 2-amino-4-(2, 3-diacetoxyphenyl) thiazole (1.5 g) in 10 ml of anhydrous tetrahydrofuran. After 1 hour, N-(3,6-bis-diethylamino-pyridin-2-yl)piperazine (1.7 g) is added to the reaction mixture. After 2 hours at room temperature, the reaction mixture is poured into a NaHCO 3 saturated solution (15 ml) and repeatedly extracted with AcOEt (3 ⁇ 30 ml). The combined organic extracts are washed with water, dried over sodium sulfate and the solvent is evaporated under reduced pressure.
  • the resulting residue (3 g) is purified by silica gel chromatography (90 g; eluent 95/5 AcOEt/MeOH), to obtain 2.5 g of N-(3,6-bis-diethylamino-pyridin-2-yl)-N'-(4-(2,3-diacetoxyphenyl)-thiazol- 2-yl)aminocarbonyl)piperazine.
  • hydrochloride 221-225oC N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4- ((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)aminocarbonyl)piperazine,
  • hydrochloride 200-203oC N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3,4-dichlorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(3,4-dichlorophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
  • N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(2-fluorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-bromophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine
  • N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (4-bromophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-bromophenyl)thiazol-2-yl)aminothiocarbonyl)
  • N-(4-fluorophenyl)-N'-((4-(3-bromophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4-cyanophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-cyanophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(4-cyanophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
EP92912406A 1991-06-21 1992-06-17 2-amino-4-aryl-thiazoles with antiasthmatic and anti-inflammatory activities on the respiratory tract Withdrawn EP0589985A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
ITMI911714A IT1248526B (it) 1991-06-21 1991-06-21 2-ammino-4-aril-tiazoli ad attivita' antiasmatica e antiinfiammatoria delle vie aeree
ITMI911714 1991-06-21
ITMI920786A IT1255077B (it) 1992-04-01 1992-04-01 2-ammino-4-aril-tiazoli ad attivita' antiasmatica e antiinfiammatoria delle vie aeree
ITMI920786 1992-04-01
PCT/EP1992/001377 WO1993000342A1 (en) 1991-06-21 1992-06-17 2-amino-4-aryl-thiazoles with antiasthmatic and anti-inflammatory activities on the respiratory tract

Publications (1)

Publication Number Publication Date
EP0589985A1 true EP0589985A1 (en) 1994-04-06

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ID=26330730

Family Applications (2)

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EP92912406A Withdrawn EP0589985A1 (en) 1991-06-21 1992-06-17 2-amino-4-aryl-thiazoles with antiasthmatic and anti-inflammatory activities on the respiratory tract
EP92110267A Pending EP0519449A1 (en) 1991-06-21 1992-06-17 2-Amino-4-aryl thiazoles with antiasthmatic and antiinflammatory activities on the respiratory tract

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP92110267A Pending EP0519449A1 (en) 1991-06-21 1992-06-17 2-Amino-4-aryl thiazoles with antiasthmatic and antiinflammatory activities on the respiratory tract

Country Status (8)

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EP (2) EP0589985A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
JP (1) JPH07502014A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
AU (1) AU2000092A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
IE (1) IE921972A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
MX (1) MX9202978A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
NZ (1) NZ243206A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
TW (1) TW206968B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
WO (1) WO1993000342A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)

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TW206968B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1993-06-01
IE921972A1 (en) 1992-12-30
NZ243206A (en) 1994-07-26
JPH07502014A (ja) 1995-03-02
WO1993000342A1 (en) 1993-01-07
EP0519449A1 (en) 1992-12-23
AU2000092A (en) 1993-01-25
MX9202978A (es) 1993-02-01

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