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Withdrawn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)
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/en
Priority claimed from ITMI920786A external-priority patent/IT1255077B/en
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Withdrawn legal-status Critical Current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,

Abstract

Dérivés de 2-amino-4-aryl-thiazoles présentant des activités pharmacologiques intéressantes, notamment des activités antiasthmatique et anti-inflammatoire sur les voies respiratoires, et pouvant être utilisés pour préparer des compositions pharmaceutiques utilisées pour le traitement de l'hyperréactivité bronchique.2-Amino-4-aryl-thiazole derivatives having interesting pharmacological activities, in particular antiasthmatic and anti-inflammatory activities on the respiratory tract, and which can be used to prepare pharmaceutical compositions used for the treatment of bronchial hyperresponsiveness.

Description

2-amino-4-aryl-thiazoles with antiasthmatic and antl Inflammatory activities on the respiratory tract
The present invention relates to 2-amino-4-arylthiazole derivatives, a process for the preparation thereof and pharmaceutical compositions containing them.
More precisely the invention relates to compounds of formula (I)
wherein:
X is oxygen or sulfur;
B is CH2, oxygen, sulfur or N-R;
R is C1-C6 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-C1- C6-alkylamino, mono-C3-C7-alkenyl- or mono-C3-C7- alkynylamino, di-C1-C6-alkylamino, C1-C6-alkyl-C3-C7- alkenylamino, piperidin-1-yl, morpholin-4-yl, pyrrolidin-1-yl.
Ar is phenyl optionally substituted with 1-3 substituents selected from halogen atoms; hydroxy; C1- C6 alkoxy; C1-C6 acyloxy; C1-C6 alkyl; cyano; nitro; -SO2CH3; -SO2NH2; phenylsulfonyl optionally substituted with halogen in the o-, m- or p-positions; C1-C6 alkylthio; phenyloxy or phenylthio optionally substituted with halogen in the o-, m- or p- positions; CF3; NR'R", wherein R' and R", which may be the same or different, are hydrogen, C1-C4 alkyl, acetyl or NR'R" is a pyrrolidino, piperidino, morpholino, 4- thiamorpholino group; -CH-NR'R" wherein R' and R" are as defined above; -CO2R"' wherein R"' is hydrogen or C1-C4 alkyl; -NH-SO2-R"" wherein R"" is methyl, ethyl, trifluoromethyl or Ar is α, β or γ-pyridyl or N-oxides thereof.
Ar is preferably phenyl or phenyl substituted with 1 or 2 hydroxy, C1-C6 alkoxy, amino, halogen, (halosubstituted) phenylsulphonyl, cyano, nitro, phenylthio, alkoxycarbonyl and/or C1-C6 alkyl groups, preferably tert-butyl groups, -NHSO2CH3.
Particularly preferred 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, β-pyridyl, 3,4-dichlorophenyl, 4-methylsulfonylamino-3-phenoxy.
When 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-C1-C6-alkylamino, 2-propenylamino, 2-propynylamino, propylamino, isopropylamino, dimethylamino, diethylamino, ethyl-2-propenylamino, pyrrolidino groups.
Most preferably, R is selected from:
[2,6-bis(diethylamino)pyrimidin-4-yl],
[2,6-bis(2-propenylamino)pyrimidin-4-yl],
[ 2 ,6-bis(amino)pyrimidin-4-yl],
[ 2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl],
[4,6-bis(pyrrolidin-1-yl)pyrimidin-2-yl],
[4,6-bis(2-propenylamino)-1,3,5-triazin-2-yl],
[4,6-bis(diethylamino)-1,3,5-triazin-2-yl],
[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl],
[3,6-bis(diethylamino)pyridin-2-yl],
[3,6-bis(pyrrolidin-1-yl)pyridin-2-yl],
[3,6-bis(2-propenylamino)pyridin-2-yl],
methyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, phenyl, bis (phenyl)methyl, bis(p-fluorophenyl)methyl, bis(p-chlorophenylmethyl), bis(p-bromophenylmethyl).
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 (Cherα. Abstr. 95; 97851).
Finally, 4-phenyl-2-aminothiazole derivatives have been studied as local anaesthetic in J. Indian Chem. Soc. 1980, 57, pp 829-832 and 1982, 59, pp 773-5.
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.
The compounds of the invention of formula (I) are prepared from thiazoles of formula (II)
wherein 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):
wherein B is as defined above.
The 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. Of course carbonyldiimidazole can be replaced by similar reagents, such as phosgene or thiophosgene.
Compounds of formula (II) are known or they can be prepared by reacting thiourea with haloacetophenones of formula (IV),
wherein Ar1 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.
Compounds of formula (III) are widely known or have been described in WO 87/01706.
Compounds of formula (I), as mentioned above, have useful pharmacological properties, particularly for the treatment of bronchial hyper-reactivity.
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 μg/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 μg/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.
From what has been shown above it is clear that 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. in the intended therapeutic uses, 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 following Examples and Preparations further illustrate the invention.
The 2-amino-4-arylthiazoles (II) are either commercially available or are prepared by reaction of the suitable cjf-bromoaryl-methylketones with thiourea, as disclosed in the following preparations 1-4.
PREPARATION 1
Acetic anhydride (2.7 ml) is dropped into a solution of 2,3-dihydroxybenzoic acid (2 g) in 10 ml of pyridine, cooling to 0βC. 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°.
PREPARATION 2
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 σhromatography (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.
PREPARATION 3
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
(2 g) in 10 ml of acetonitrile. After 24 hours, the reaction mixture is poured into a NaHCO, saturated solution (20 ml) and repeatedly extracted with AcOEt (3x30 ml). The combined organic extracts are washed with water, dried over sodium sulfate and solvent is evaporated off under reduced pressure, to obtain 1.1 g of 2,3-diacetoxyacetophenone.
PREPARATION 4
Bromine (0.24 ml) is dropped into a solution of 2, 3-diacetoxyacetophenone (1 g) in 10 ml of dioxane, under stirring and keeping temperature at 0-5°C . When dropping is over, the reaction mixture is warmed to room temperature and stirring is continued for one hour, then it is poured into a NaHCO3 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 solvent is evaporated off under reduced pressure, to give 1.2 g of diacetoxyphenacyl bromide.
Thiourea (360 mg) is added to a solution of 2,3-diacetoxyphenacyl bromide (1 g) in 10 ml of ethanol. After 2 hours, 950 mg of 2-amino-4-(2,3-diacetoxyphenyl) thiazole are separated by filtration.
Following the same procedure of preparation 1 to 4, 2-amino-4-(4-acetoxyphenyl) thiazole, 2-amino-4-(4-acetoxy-3,5-di-tert-butylphenyl)thiazole and 2-amino-4-(3,4-diacetoxyphenyl)thiazole are prepared.
EXAMPLE 1
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 NaHCO3 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.
EXAMPLE 2
NaOH (0.37 ml, 35% aqueous solution) is added to a solution of N-(3,6-bis-diethylamino-pyridin-2-yl)-N'- (4-(2,3-diacetoxyphenyl)-thiazol-2-yl)aminocarbonyl)piperazine (2.5 g) in 10 ml of methanol. After one hour, the reaction mixture is poured into a 0.1N HCl solution (10 ml) 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 reduced pressure, to give 2 g of N-(3,6-bis-diethylaminopyridin-2-yl)-N'-(4-(2,3-dihydroxyphenyl)-thiazol-2-yl)aminocarbonyl)piperazine.
EXAMPLE 3
Following the procedures described in the above Examples, starting from thiazoles of Preparation 4 and the appropriate N-substituted piperazines, the following compounds of formula (I) are obtained:
N-(3,6-bis-diethylamino-pyridin-2-yl)-N'-(4-(4-hydroxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine;
N-(3,6-bis-diethylamino-pyridin-2-yl)-N'-(4-(4-hydroxy-3,5-di-tert-butylphenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. of hydrochloride 177-180ºC;
N-(3,6-bis-diethylamino-pyridin-2-yl)-N'-(4-(3,4-dihy droxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine;
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(4-(4-hy¬droxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine;
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(4-(4-hy¬droxy-3,5-di-tert-butylphenyl)thiazol-2-yl)aminocarbonyl)piperazine;
N-[4,6-bis(pyrrolidin-1-yl)pyrimidin-2-yl)-N'-(4-(4-hydroxy-3,5-di-tert-butylphenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 162-165ºC;
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(4-(3,4-dihydroxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine; N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(4-(2,3-dihydroxyphenyl)-thiazol-2-yl)aminocarbonyl)piperazine, m.p. 172-174°C;
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(4-(4-hydroxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine; N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(4-(4-hydroxy-3,5-di-tert-butylphenyl)thiazol-2-yl)aminocarbonyl)piperazine;
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(4-(3,4-dihydroxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine;
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(4-(2,3-dihydroxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine.
EXAMPLE 4
Following the procedures described in the above Examples, starting from acetophenone and the appropriate N-substituted piperazines, the following N,N'-disubstituted piperazines are obtained:
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(4- phenylthiazol-2-yl)-aminocarbonyl)piperazine, m.p. 155- 159°C;
N-(3,6-bis-diethylamino-pyridin-2-yl)-N'-(4-phenylthiazol-2-yl)aminocarbonyl)piperazine, m.p. of hydrochloride 159-162°C;
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(4-phenylthiazol-2-yl)aminocarbonyl)piperazine, m.p. 147- 148°C;
N-(4,6-bis(pyrrolidin-1-yl)pyrimidin-2-yl)-N'-((4-phenylthiazol-2-yl)aminocarbonyl)piperazine,
N-methyl-N'-((4-phenylthiazol-2-yl) aminocarbonyl)piperazine, m.p.151-152ºC,
N-(bis(4-fluorophenyl)methyl)-N'-((4-phenylthiazol-2-yl)aminocarbonyl)piperazine, m.p. of hydrochloride 166- 169°C,
N-(4-fluorophenyl) -N ' -((4-phenylthiazol-2-yl)aminocar¬bonyl)piperazine, m.p. of hydrochloride 232-234°C,
N-(bis(4-chlorophenyl)methyl)-N'-((4-phenylthiazol-2-yl)aminocarbonyl)piperazine,
N-(4-chlorophenyl)-N'-((4-phenylthiazol-2-yl)aminocar¬bonyl)piperazine,
N-(bis(phenyl)methyl)-N'-((4-phenylthiazol-2-yl)amino¬carbonyl)piperazine, m.p. of hydrochloride 187-189°C, N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4-methoxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. of hydrobromide 150-153°C,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-methoxyphenyl)thiazol-2-yl) aminocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(4-methoxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-methyl-N'-((4-(4-methoxyphenyl)thiazol-2-yl)amino carbonyl)piperazine, m.p. 140-143°C,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-methoxyphenyl)¬thiazol-2-yl)aminocarbonyl)piperazine,
N-(4-fluorophenyl)-N'-((4-(4-methoxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. of hydrobromide 210-214°C,
N-(bis(phenyl)methyl)-N'-((4-(4-methoxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 162-165°C,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3-methoxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(2-methoxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 171-173ºC,
N-methyl-N'-((4-(3-methoxyphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4-clorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. of hydrochloride 147-150ºC,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-clorophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)pyrimidin-2-yl)-N'-((4-(4-chlorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(4-chlorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-methyl-N'-((4-(4-clorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 137-139ºC,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-chlorophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4-fluorophenyl)-N'-((4-(4-chlorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 164-168ºC,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (3-chlorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(2- chlorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-methyl-N'-((4-(2-chlorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 146-150°C,
N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4-fluorophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4- fluorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 174-177°C,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (4-fluorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-methyl-N'-((4-(4-fluorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 150-153ºC,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-fluorophenyl)-thiazol-2-yl)aminocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(2-fluorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-bromophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-l,3,5-triazin-2-yl)-N'-((4- (4-bromophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-methyl-N'-((4-(4-bromophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. of hydrobromide 196-199°C, N-(4-fluorophenyl)-N'-((4-(4-bromophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. of hydrobromide 236-241°C,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(3-bromophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(4-fluorophenyl)-N'-((4-(3-bromophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4-cyanophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-cyanophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(4-cyanophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-methyl-N'-((4-(4-cyanophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(bis(4-chlorophenyl)methyl)-N'-((4-(4-cyanophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 183-185ºC, N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-cyanophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(3-cyanophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-nitrophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(4-nitrophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-methyl-N'-((4-(4-nitrophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 177-181ºC,
N-(4-fluorophenyl)-N'-((4-(4-nitrophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4-chlorophenyl)-N'-((4-(4-nitrophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3-nitrophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-methyl-N'-((4-(3-nitrophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4-phenylsulphonylphenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. of hydrobromide 161-164ºC, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4- phenylsulphonylphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)pyrimidin-2-yl)-N'-((4-(4- phenylsulphonylphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (4-phenylsulphonylphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-methyl-N'-((4-(4-phenylsulphonylphenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 169-171°C,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-phenylsulphonylphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (3-phenylsulphonylphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-methyl-N'-((4-(3-phenylsulphonylphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4- (2'-chlorophenylsulphonyl)phenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-(2'-chlorophenylsulphonyl)phenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 190-195ºC,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3-(2'-chlorophenylsulphonyl)phenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-((4-methylsulfonylamino-3-phenoxy)phenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. of hydrobromide 200-205ºC,
N-(bis(phenyl)methyl)-N'-((4-((4-methylsulfonylamino-3- phenoxy)phenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 162-165ºC,
N-methyl-N'-((4-((4-methylsulfonylamino-3-phenoxy)phenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4-phenyltiophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-phenyltiophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-methyl-N'-((4-(4-phenyltiophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 158-160ºC,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-aminophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(4-aminophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-methyl-N'-((4-(4-aminophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 163-165°C,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-aminophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3-aminophenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(2-aminophenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(3,6-bis(diethylamino)ρyridin-2-yl)-N'-((4-(4-((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. of 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,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (4-((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl) aminocarbonyl)piperazine, N-methyl-N'-((4-(4-((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. of hydrochloride 218-220ºC,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-((pyrrolidin- l'-yl)methyl)phenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4-fluorophenyl)-N'-((4-(4-((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. of hydrochloride 242-246ºC,
N-(4-chlorophenyl)-N'-((4-(4-((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)aminocarbonyl)piperazine, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3- ((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-methoxycarbonylphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (4-methoxycarbonylphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-methyl-N'-((4-(4-methoxycarbonylphenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 156-157°C,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (3-methoxycarbonylphenyl ) thiazol-2-yl ) aminocarbonyl ) piperazine ,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(pyridin-3-yl)thiazol-2-yl)aminocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(pyridin-3-yl)thiazol-2-yl)aminocarbonyl)piperazine, N-methyl-N'-((4-(pyridin-3-yl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. of 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-methyl-N'-((4-(3,4-dichlorophenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 148-151°C,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-trifluoromethylphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (4-trifluoromethylphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-methyl-N'-((4-(4-trifluoromethylphenyl)thiazol-2-yl)aminocarbonyl)piperazine, m.p. 173-174ºC,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3-trifluoromethylphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(3-trifluoromethylphenyl)thiazol-2-yl)aminocarbonyl)piperazine,
N-methyl-N'-((4-(3-trifluoromethylphenyl)thiazol-2-yl)aminocarbonyl)piperazine.
EXAMPLE 5
By substituting, in the procedure of Example 1, thiocarbonyl diimidazole to carbonyldiimidazole, the following thioureas are prepared starting from the suitable 2-amino-4-arylthiazoles and from the suitable N-substituted-piperazines:
N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-phenylthiazol-2-yl)aminothiocarbonyl)piperazine, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4- phenylthiazol-2-yl)aminothiocarbonyl)piperazine, m.p. 207-209°C,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- phenylthiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-phenylthiazol-2-yl)aminothiocarbonyl)piperazine,
N-(bis(4-fluorophenyl)methyl)-N'-((4-phenylthiazol-2- yl)aminothiocarbonyl)piperazine,
N-(4-fluorophenyl)-N'-((4-phenylthiazol-2-yl)aminothiocarbonyl)piperazine, m.p. 216-219°C,
N-(bis(4-chlorophenyl)methyl)-N'-((4-phenylthiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4-chlorophenyl)-N'-((4-phenylthiazol-2-yl)aminothiocarbonyl)piperazine,
N-(bis(phenyl)methyl)-N'-((4-phenylthiazol-2-yl)aminothiocarbonyl)piperazine,
N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4-methoxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-methoxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-l,3,5-triazin-2-yl)-N'-((4-(4-methoxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(4-methoxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-methoxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4-fluorophenyl)-N'-((4-(4-methoxyphenyl)thiazol-2- yl)aminothiocarbonyl)piperazine, m.p. of hydrobromide 240-242°C,
N-(bis(phenyl)methyl)-N'-((4-(4-methoxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3-methoxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(2-methoxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(3-methoxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4-chlorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. 170-174ºC,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-chlorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)pyrimidin-2-yl)-N'-((4-(4-chlorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(4-chlorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(4-chlorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-chlorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4-fluorophenyl)-N'-((4-(4-chlorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. 199-202°C,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(3-chlorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(2- chlorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-methyl-N'-((4-(2-chlorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4-fluorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4- fluorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (4-fluorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(4-fluorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. 188-192ºC,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-fluorophenyl)thiazol-2-yl)aminothiocarbonyl)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-methyl-N'-((4-(4-bromophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. of hydrobromide 233-239°C, N-(4-fluorophenyl)-N'-((4-(4-bromophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(3-bromophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
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,
N-methyl-N'-((4-(4-cyanophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(bis(4-chlorophenyl)methyl)-N'-((4-(4-cyanophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-cyanophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(3-cyanophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-nitrophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(4-nitrophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(4-nitrophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. 211-214ºC,
N-(4-fluorophenyl)-N'-((4-(4-nitrophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4-chlorophenyl)-N'-((4-(4-nitrophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3-nitrophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-methyl-N'-((4-(3-nitrophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4-phenylsulphonylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. of hydrobromide 202-205°C,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4- phenylsulphonylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)pyrimidin-2-yl)-N'-((4-(4-phenylsulphonylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (4-phenylsulphonylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(4-phenylsulphonylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. 193-197°C,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-phenylsulphonylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (3-phenylsulphonylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(3-phenylsulphonylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4- (2'-chlorophenylsulphonyl)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-(2'-chlorophenylsulphonyl)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3-(2'-chlorophenylsulphonyl)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-( 3 , 6-bis (diethylamino)pyridin-2-yl) -N ' - ( (4- ( (4- methylsulfonylamino-3-phenoxy)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(bis(phenyl)methyl)-N'-((4-((4-methylsuIfonyl)amino-3-phenoxy)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. of hydrobromide 227-230°C,
N-methyl-N'-((4-((4-methylsulfonylamino-3-phenoxy)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. of hydrobromide 216-221°C,
N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4-phenylthiophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-phenylthiophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(4-phenylthiophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. 206-208°C,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-aminophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(4-aminophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(4-aminophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-aminophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3-aminophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(2-aminophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-((4-(4- ((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)ami nothiocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4- ((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-l,3,5-triazin-2-yl)-N'-((4- (4-((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(4-((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. of hydrochloride 254-258ºC,
N-(bis(4-fluorophenyl)methyl)-N'-((4-(4-((pyrrolidin- 1'-yl)methyl)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4-fluorophenyl)-N'-((4-(4-((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(4-chlorophenyl)-N'-((4-(4-((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3- ((pyrrolidin-l'-yl)methyl)phenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-methoxycarbonylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4- (4-methoxycarbonylphenyl)thiazo1-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(4-methoxycarbonylphenyl)thiazol-2-yl)aminothiocarbonyl) piperazine, m.p. 188-189°C,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(3-methoxycarbonylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(pyridin-3-yl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(pyridin-3-yl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(pyridin-3-yl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. of hydrochloride 249-252ºC, N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3,4-dichlorophenyl)thiazol-2-yl)aminothiocarbonyl)¬piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(3,4-dichlorophenyl)'thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(3,4-dichlorophenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(4-trifluoromethylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(4-trifluoromethylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(4-trifluoromethylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. 217-222°C,
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-((4-(3-trifluoromethylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-((4-(3-trifluoromethylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine,
N-methyl-N'-((4-(3-trifluoromethylphenyl)thiazol-2- yl)aminothiocarbonyl)piperazine.
EXAMPLE 6
By substituting, in the procedure of Example 1, thiocarbonyl diimidazole to carbonyldiimidazole, the following thioureas are prepared starting from the suitable 2-amino-4-arylthiazoles and from the suitable
N-substituted-piperazines:
N-(3,6-bis-diethylamino-pyridin-2-yl)-N'-(4-(4-hydroxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine;
N-(3,6-bis-diethylamino-pyridin-2-yl)-N'-(4-(4-hydroxy- 3,5-diterbutylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. of hydrochloride 202-204ºC;
N-(3,6-bis-diethylamino-pyridin-2-yl)-N'-(4-(3,4-dihydroxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine; N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(4-(4-hydroxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine; N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(4-(4-hydroxy-3,5-ditertbutylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. 230-233°C;
N-(4,6-bis(pyrrolidin-1-yl)pyrimidin-2-yl)-N'-(4-(4-hydroxy-3,5-ditertbutylphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. 237-240°C;
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(4-(3,4-dihydroxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine;
N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(4-(2,3-dihydroxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine, m.p. 255-260°C;
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(4-(4-hydroxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine; N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(4- (4-hydroxy-3,5-ditertbutylphenyl)thiazol-2-yl)aminothiocarbonyl )piperazine;
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(4-(3,4-dihydroxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine;
N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(4- (2,3-dihydroxyphenyl)thiazol-2-yl)aminothiocarbonyl)piperazine.
EXAMPLE 7
Following the procedure of Example 1, the following ureas are prepared starting from 2-amino-4-arylthiazoles and from piperidine, morpholine, 4-thiamorpholine.
N-((4-phenylthiazol-2-yl)aminocarbonyl)piperidine, m.p.
144-147°C,
N-((4-phenylthiazol-2-yl)aminocarbonyl)morpholine,
N-((4-phenylthiazol-2-yl)aminocarbonyl)thiamorpholine, m.p. 163-165ºC,
N-((4-(4-methoxyphenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(4-methoxyphenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(4-methoxyphenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine, m.p. 170-172°C,
N-((4-(3-methoxyphenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(3-methoxyphenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(3-methoxyphenyl)thiazol-2-yl)aminocarbonyl)¬thiamorpholine, N-((4-(4-chlorophenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(4-chlorophenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(4-chlorophenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine, m.p. 160-161°C,
N-((4-(3-chlorophenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(3-chlorophenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(3-chlorophenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine,
N-((4-(2-chlorophenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(2-chlorophenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(2-chlorophenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine,
N-((4-(4-fluorophenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(4-fluorophenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(4-fluorophenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine, m.p. 177-180ºC,
N-((4-(3-bromophenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(3-bromophenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(3-bromophenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine,
N-((4-(4-nitrophenyl)thiazol-2-yl)aminocarbonyl) piperidine,
N-((4-(4-nitrophenyl)thiazol-2-yl)aminocarbonyl)morpholine, m.p. 192-194°C,
N-((4-(4-nitrophenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine, m.p. 197-200ºC,
N-((4-(3-nitrophenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(3-nitrophenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(3-nitrophenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine,
N-((4-(4-(phenylsulphonyl)phenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(4-(phenylsulphonyl)phenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(4-(phenylsulphonyl)phenyl)thiazol-2-yl)aminocarbonyl) thiamorpholine, m.p. 178-181ºC,
N-((4-(4-(2'-chlorophenylsulphonyl)phenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(4-(2'-chlorophenylsulphonyl)phenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(4-(2'-chlorophenylsulphonyl)phenyl)thiazol-2- yl)aminocarbonyl)thiamorpholine,
N-((4-(4-aminophenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(4-aminophenyl)thiazol-2-yl)aminocarbonyl)morpholine ,
N-((4-(4-aminophenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine, m.p. 200-204ºC,
N-((4-(3-aminophenyl)thiazol-2-yl)aminocarbonyl)piperidine, N-((4-(3-aminophenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(3-aminophenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine,
N-((4-(2-aminophenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(2-aminophenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(2-aminophenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine, m.p. 212-214ºC,
N-((4-(4-((pyrrolidin-1-yl)methyl)phenyl)thiazol-2-yl)aminocarbonyl)piperidine ,
N-( (4-(4-((pyrrolidin-1-yl)methyl)phenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(4-((pyrrolidin-1-yl)methyl)phenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine, m.p. of hydrochloride 220-222°C,
N-((4-(4-methoxycarbonylphenyl)thiazol-2-yl)aminocarbonyl)piperidine,
N-((4-(4-methoxycarbonylphenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(4-methoxycarbonylphenyl)thiazol-2-yl)aminocarbonyl) thiamorpholine,
N-((4-(4-trifluoromethylphenyl)thiazol-2-yl)amino¬carbonyl)piperidine,
N-((4-(4-trifluoromethylphenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(4-trifluoromethylphenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine,
N-((4-(3,4-dichlorophenyl)thiazol-2-yl)aminocarbonyl)piperidine, m.p. 155-158ºC, N-((4-(3,4-diσhlorophenyl)thiazol-2-yl)aminocarbonyl)morpholine,
N-((4-(3,4-dichlorophenyl)thiazol-2-yl)aminocarbonyl)thiamorpholine, m.p. 162-163°C.

Claims

1. Compounds of general formula (I)
wherein :
X is oxygen or sulfur;
B is CH2, oxygen, sulfur or N-R;
R is C1-C6 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 heteroσycle having 1 to 3 nitrogen atoms, optionally substituted with 1-2 amino groups, mono-C1- C6-alkylamino, mono-C3-C7-alkenyl- or mono-C3-C7-alkynylamino, di-C1-C8-alkylamino, C1-C6-alkyl-C3-C7-alkenylamino, piperidin-1-yl, morpholin-4-yl, pyrrolidin-1-yl,
and the pharmaceutically acceptable salts thereof.
2. Compounds according to claim 1 in which Ar is selected from phenyl, phenyl substituted with 1 or 2 hydroxy groups, alkoxy and/or C1-C6 alkyl, halogen, amino, phenylthio, phenylsulphonyl, cyano, nitro, alkoxycarbonyl.
3. Compounds according to claim 1 or 2 in which Ar is selected from 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 3,4-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, ß-pyridyl, 3,4-dichlorophenyl, 2,3-dihydroxyphenyl and R is 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-C1-C6-alkylamino, 2-propenylamino, 2-propynylamino, propylamino, isopropylamino, dimethylamino, diethylamino, ethyl-2-propenylamino, pyrrolidino groups.
4. Compounds according to claims 1-3, in which R is selected from [2,6-bis(diethylamino)pyrimidin-4-yl], [2,6-bis(2-propenylamino)pyrimidin-4-yl], [2,6-bis(amino)pyrimidin-4-yl], [2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl], [4,6-bis(pyrrolidin-1-yl)-pyrimidin-2-yl], [4,6-bis(2-propenylamino)-1,3,5-triazin-2-yl], [4,6-bis(diethylamino)-1,3,5-triazin-2-yl], [4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl], [3,6-bis(diethylamino)pyridin-2-yl], [3,6-bis(pyrrolidin-1-yl)pyridin-2-yl], [3,6-bis(2-propenylamino)pyridin-2-yl], methyl, phenyl, p-fluorophenyl, p-bromophenyl, p-chlorophenyl, bis(phenyl)methyl, bis(p-fluorophenyl)methyl, bis(p-chlorophenyl), bis(p-bromophenyl).
5. A process for the preparation of the compounds according to claims 1-4, which process comprises reacting a compound of formula (II):
wherein Ar' has the same meanings as Ar in claims 1-3 or it is a group which can be converted into Ar by removing any protective groups present, first with carbonyldiimidazole or simylar difunctional carbonylating reagents, then with piperazines of formula (III):
wherein B is as defined above.
6. Pharmaceutical compositions containing one compound of claims 1-4 as the active ingredient, in admixture with pharmaceutically acceptable carriers or excipients.
7. The use of the compounds of claims 1-4 as therapeutical agents.
8. The use of the compounds of claims 1-4 for the preparation of a medicament for the treatment of bronchial hyper-reactivity.
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 (en) 1991-06-21 1991-06-21 2-amino-4-arylthiazoles with anti-asthmatic and anti inflammatory activity on the respiratory passages
ITMI911714 1991-06-21
ITMI920786A IT1255077B (en) 1992-04-01 1992-04-01 2-amino-4-aryl-thiazoles having antiasthmatic and anti- inflammatory activity on the airways
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

Family

ID=26330730

Family Applications (2)

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
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

Family Applications Before (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)

Country Link
EP (2) EP0519449A1 (en)
JP (1) JPH07502014A (en)
AU (1) AU2000092A (en)
IE (1) IE921972A1 (en)
MX (1) MX9202978A (en)
NZ (1) NZ243206A (en)
TW (1) TW206968B (en)
WO (1) WO1993000342A1 (en)

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL115420A0 (en) 1994-09-26 1995-12-31 Zeneca Ltd Aminoheterocyclic derivatives
AU1608397A (en) 1996-02-02 1997-08-22 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
GB9602166D0 (en) 1996-02-02 1996-04-03 Zeneca Ltd Aminoheterocyclic derivatives
CN1228087A (en) * 1996-08-14 1999-09-08 曾尼卡有限公司 Substituted pyrimidine derivatives and their pharmaceutical use
UA56197C2 (en) 1996-11-08 2003-05-15 Зенека Лімітед Heterocyclic derivatives
ATE242774T1 (en) 1997-02-13 2003-06-15 Astrazeneca Ab HETEROCYCLIC COMPOUNDS THAT ARE USED AS OXIDOSQUALENE CYCLASE INHIBITORS
WO1998035956A1 (en) 1997-02-13 1998-08-20 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
GB9715895D0 (en) 1997-07-29 1997-10-01 Zeneca Ltd Heterocyclic compounds
GB9902989D0 (en) 1999-02-11 1999-03-31 Zeneca Ltd Heterocyclic derivatives
ATE449090T1 (en) * 2001-07-02 2009-12-15 High Point Pharmaceuticals Llc SUBSTITUTED PIPERAZINE AND DIAZEPANDE DERIVATIVES FOR USE AS HISTAMINE H3 RECEPTOR MODULATORS
WO2003057693A1 (en) * 2001-12-28 2003-07-17 Sumitomo Pharmaceuticals Co., Ltd. 5-membered cyclic compounds
AR042941A1 (en) * 2003-01-27 2005-07-06 Fujisawa Pharmaceutical Co DERIVATIVES OF TIAZOL, ITS PREPARATION, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR USE IN THE MANUFACTURE OF INHIBITING MEDICINES OF VASCULAR ADHESION PROTEIN-1 (VAP-1)
FR2854158B1 (en) 2003-04-25 2006-11-17 Sanofi Synthelabo 2-ACYLAMINO-4-PHENYLETHIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
GB0320197D0 (en) * 2003-08-28 2003-10-01 Novartis Ag Organic compounds
FR2872813B1 (en) * 2004-07-09 2007-01-19 Sanofi Synthelabo 2-CARBAMID-4-PHENYLTHIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2876692B1 (en) 2004-10-19 2007-02-23 Sanofi Aventis Sa 2-AMIDO-4-PHENYLTHIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
RU2423349C2 (en) 2004-12-24 2011-07-10 Астразенека Аб Heterocyclic compounds as ccr2b antagonists
GB0428327D0 (en) * 2004-12-24 2005-02-02 Astrazeneca Ab Method
UY29321A1 (en) 2004-12-30 2006-03-31 Janssen Pharmaceutica Nv PIPERAZINILUREAS AND PIPERIDINILUREAS AS AMID HYDROLASSES MODULATORS OF FATTY ACIDS
EP1863522A4 (en) 2005-03-18 2010-11-10 Univ California Compounds having activity in correcting mutant-cftr processing and uses thereof
JPWO2007020888A1 (en) 2005-08-12 2009-02-26 武田薬品工業株式会社 Brain / nerve cell protective agent and sleep disorder therapeutic agent
FR2895989B1 (en) * 2006-01-06 2010-04-30 Sanofi Aventis 2-CARBAMID-4-PHENYLTHIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
EP2102199B1 (en) * 2006-12-04 2011-04-27 AstraZeneca AB Antibacterial polycyclic urea compounds
UY31864A (en) 2008-06-04 2010-01-29 Astrazeneca Ab DERIVATIVES OF UREA HETERICÍCLICA AND METHODS OF USE OF THE SAME-332
TW201102065A (en) * 2009-05-29 2011-01-16 Astrazeneca Ab Heterocyclic urea derivatives and methods of use thereof
UA108233C2 (en) 2010-05-03 2015-04-10 Fatty acid amide hydrolysis activity modulators
CN102166214B (en) * 2011-03-02 2012-12-12 华中科技大学同济医学院附属同济医院 Medical application of aminothiazole type MyD88 specific inhibitor
CN102336720B (en) * 2011-03-02 2016-01-13 华中科技大学 Thiazolamine derivative and preparation method and application
CN102351854B (en) * 2011-07-29 2014-06-04 华中科技大学 Amino thiazole derivative and preparation method and medical purpose thereof
DE102011083283A1 (en) * 2011-09-23 2013-03-28 Beiersdorf Ag Heteroalkylamidothiazoles, their cosmetic or dermatological use and cosmetic or dermatological preparations containing such Heteroalkylamidothiazolen
WO2022232919A1 (en) * 2021-05-03 2022-11-10 UNIVERSITé LAVAL Viral rna polymerase inhibitors and uses thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2602792A (en) * 1950-11-24 1952-07-08 American Cyanamid Co 1-carbocycliccarbamyl-4-heterocyclic-piperazines
US4217355A (en) * 1978-04-24 1980-08-12 Pfizer Inc. Amide therapeutic agents
FR2429210A1 (en) * 1978-06-19 1980-01-18 Fabre Sa Pierre PHENYL-4 THIAZOLYL-2 OXAMATE DERIVATIVES USEFUL IN THE TREATMENT OF ASTHMA
JPS57136579A (en) * 1981-01-21 1982-08-23 Mitsui Toatsu Chem Inc Thiazolylurea derivative, its preparation, and pharmaceutical composition containing the same
US4501750A (en) * 1981-01-13 1985-02-26 Mitsui Toatsu Kaguku Kabushiki Kaisha Thiazole compounds, a process for preparing same and a pharmaceutical composition containing the thiazole compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9300342A1 *

Also Published As

Publication number Publication date
EP0519449A1 (en) 1992-12-23
JPH07502014A (en) 1995-03-02
AU2000092A (en) 1993-01-25
WO1993000342A1 (en) 1993-01-07
TW206968B (en) 1993-06-01
NZ243206A (en) 1994-07-26
MX9202978A (en) 1993-02-01
IE921972A1 (en) 1992-12-30

Similar Documents

Publication Publication Date Title
EP0589985A1 (en) 2-amino-4-aryl-thiazoles with antiasthmatic and anti-inflammatory activities on the respiratory tract
IE880721L (en) Thiazoles
GB2177395A (en) Thiazole derivatives
PT100352B (en) HETEROCYCLIC AMINES NOMINALLY DERIVED FROM PIPERAZINE, USEFUL ON ASTHMA THERAPY AND RESPIRATORY TRACT INFLAMMATION
US8236953B2 (en) Process for preparing piper azine derivatives
MXPA00009569A (en) Compounds with activity on muscarinic receptors.
JP2758077B2 (en) Heterocyclic derivatives, their preparation, and therapeutic uses
CA2655540A1 (en) Piperazinyl derivatives useful in the treatment of gpr38 receptor mediated diseases
HU210200B (en) Process for preparing biphenyl compounds and pharmaceutical compn. contg. them
US6380229B1 (en) 2-(N-cyanoimino)thiazolidin-4-one derivatives
CA1246071A (en) 4-substituted thiazole oxamic acids and salts and esters thereof
US20090215758A1 (en) Use of 2,5-Disubstituted Thiazol-4-One Derivatives in Drugs
US4560686A (en) Method for treating circulatory diseases by using (2-lower alkoxyphenyl)piperazine derivatives
US4054591A (en) 2-Cyano-3-or 4-(substituted amino)oxanilic acid derivatives
WO2004017966A1 (en) Five-membered heterocyclic compounds in the treatment of chronic and acute pain
KR101633950B1 (en) Sulfamoyl- phenyl-ureido benzamidine-derivatives as antimalarial agents
JPH0440348B2 (en)
HU190669B (en) Process for preparing 3,4-disubstituted 1,2,5-thiadiazole-1-oxides and -1,1-dioxides
US20110039848A1 (en) Five-membered ring compound
JPH05148234A (en) Alkanoic acid derivative
EP0536169B1 (en) [3H,7H]THIAZOLO [3,4-a]PYRIDINES WITH ANTIASTHMATIC AND ANTIINFLAMMATORY ACTIONS ON THE RESPIRATORY TRACT
CA1086729A (en) Tetrazole-5-carboxamide derivatives
US20110034466A1 (en) Novel five-membered ring compound
CA2105981A1 (en) Thiazole derivatives
US4087606A (en) 2-Cyano-3- or 4-(substituted amino)oxanilic acid derivatives

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19931210

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

RBV Designated contracting states (corrected)

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL PT SE

XX Miscellaneous

Free format text: VERBUNDEN MIT 92110267.9/0519449 (EUROPAEISCHE ANMELDENUMMER/VEROEFFENTLICHUNGSNUMMER) DURCH ENTSCHEIDUNG VOM 11.07.94.

17Q First examination report despatched

Effective date: 19950810

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19951221