WO1993000342A1 - 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 Download PDF

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Publication number
WO1993000342A1
WO1993000342A1 PCT/EP1992/001377 EP9201377W WO9300342A1 WO 1993000342 A1 WO1993000342 A1 WO 1993000342A1 EP 9201377 W EP9201377 W EP 9201377W WO 9300342 A1 WO9300342 A1 WO 9300342A1
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bis
thiazol
piperazine
pyrrolidin
aminocarbonyl
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PCT/EP1992/001377
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French (fr)
Inventor
Gian Piero De Cillis
Giorgio Long
Simonetta D'alo'
Antonella Rozzi
Licia Gallico
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Boehringer Mannheim Italia S.P.A.
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Priority claimed from ITMI911714A external-priority patent/IT1248526B/en
Priority claimed from ITMI920786A external-priority patent/IT1255077B/en
Application filed by Boehringer Mannheim Italia S.P.A. filed Critical Boehringer Mannheim Italia S.P.A.
Priority to JP5501313A priority Critical patent/JPH07502014A/en
Priority to EP92912406A priority patent/EP0589985A1/en
Publication of WO1993000342A1 publication Critical patent/WO1993000342A1/en

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    • 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

2-Amino-4-aryl-thiazole derivatives have interesting pharmacological properties, particularly antiasthmatic and anti-inflammatory activities on the respiratory tract and they can be used to prepare pharmaceutical compositions useful for the treatment of bronchial hyper-reactivity.

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)
Figure imgf000003_0001
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)
Figure imgf000006_0001
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):
Figure imgf000007_0001
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),
Figure imgf000007_0002
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)
Figure imgf000036_0001
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):
Figure imgf000038_0001
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):
Figure imgf000038_0002
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.
PCT/EP1992/001377 1991-06-21 1992-06-17 2-amino-4-aryl-thiazoles with antiasthmatic and anti-inflammatory activities on the respiratory tract WO1993000342A1 (en)

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JP5501313A JPH07502014A (en) 1991-06-21 1992-06-17 2-Amino-4-aryl-thiazoles with anti-asthmatic, anti-inflammatory activity on the respiratory tract
EP92912406A EP0589985A1 (en) 1991-06-21 1992-06-17 2-amino-4-aryl-thiazoles with antiasthmatic and anti-inflammatory activities on the respiratory tract

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ITMI911714A IT1248526B (en) 1991-06-21 1991-06-21 2-amino-4-arylthiazoles with anti-asthmatic and anti inflammatory activity on the respiratory passages
ITMI91A001714 1991-06-21
ITMI92A000786 1992-04-01
ITMI920786A IT1255077B (en) 1992-04-01 1992-04-01 2-amino-4-aryl-thiazoles having antiasthmatic and anti- inflammatory activity on the airways

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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)

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WO2007077394A1 (en) * 2006-01-06 2007-07-12 Sanofi-Aventis 2-carbamide-4-phenylthiazole derivatives, preparation thereof and therapeutic use thereof
US7504511B2 (en) 2003-04-25 2009-03-17 Sanofi-Aventis 2-acylamino-4-phenylthiazole derivatives, preparation thereof and therapeutic application thereof
US7598392B2 (en) 2004-10-19 2009-10-06 Sanofi-Aventis 2-amido-4-phenylthiazole derivatives, the preparation and the therapeutic use thereof
US7598249B2 (en) 2004-12-30 2009-10-06 Janssen Pharmaceutica N.V. Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
US7767681B2 (en) 2004-07-09 2010-08-03 Sanofi-Aventis 2-Carbamide-4-phenylthiazole derivatives, preparation thereof and therapeutic use thereof
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WO2003057693A1 (en) * 2001-12-28 2003-07-17 Sumitomo Pharmaceuticals Co., Ltd. 5-membered cyclic compounds
US7504511B2 (en) 2003-04-25 2009-03-17 Sanofi-Aventis 2-acylamino-4-phenylthiazole derivatives, preparation thereof and therapeutic application thereof
US7777041B2 (en) 2003-04-25 2010-08-17 Sanofi-Aventis 2-acylamino-4-phenylthiazole derivatives, preparation thereof and therapeutic application thereof
US7767681B2 (en) 2004-07-09 2010-08-03 Sanofi-Aventis 2-Carbamide-4-phenylthiazole derivatives, preparation thereof and therapeutic use thereof
US7598392B2 (en) 2004-10-19 2009-10-06 Sanofi-Aventis 2-amido-4-phenylthiazole derivatives, the preparation and the therapeutic use thereof
US8530476B2 (en) 2004-12-30 2013-09-10 Janssen Pharmaceutica Nv Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
US7598249B2 (en) 2004-12-30 2009-10-06 Janssen Pharmaceutica N.V. Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
US9169224B2 (en) 2004-12-30 2015-10-27 Janssen Pharmaceutica Nv Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
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US20140004155A1 (en) * 2011-03-02 2014-01-02 Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd. 2-aminothiazole derivatives and methods of preparing and using the same
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US9771340B2 (en) 2011-03-02 2017-09-26 Wuhan Innamune Pharmaceutical Co., Ltd. 2-aminothiazole derivatives and methods of preparing and using the same
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AU2000092A (en) 1993-01-25
IE921972A1 (en) 1992-12-30
MX9202978A (en) 1993-02-01
EP0519449A1 (en) 1992-12-23
JPH07502014A (en) 1995-03-02
TW206968B (en) 1993-06-01
NZ243206A (en) 1994-07-26
EP0589985A1 (en) 1994-04-06

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