WO1993011134A1

WO1993011134A1 - [3H,7H]THIAZOLE[3,4-a]PYRIDINES HAVING ANTIASTHMATIC AND ANTIINFLAMMATORY ACTIVITIES ON THE RESPIRATORY TRACT

Info

Publication number: WO1993011134A1
Application number: PCT/EP1992/002784
Authority: WO
Inventors: Carmelo A. Gandolfi; Giorgio Long; Giampiero De Cillis; Licia Gallico
Original assignee: Boehringer Mannheim Italia S.P.A.
Priority date: 1991-12-06
Filing date: 1992-12-02
Publication date: 1993-06-10
Also published as: IT1252626B; AU3084292A; ITMI913269A1; TW212801B; ITMI913269A0

Abstract

Compounds of formula (I) having antiasthmatic and antiinflammatory activities on the respiratory tract and pharmaceutical compositions containing them.

Description

[3H,7H]THIAZOLE[3,4-a]PYRIDINES HAVING ANTIASTHMATIC

AND ANTIINFLAMMATORY ACTIVITIES ON THE RESPIRA-

TORY TRACT

The present invention relates to [3H,7H]thiazole[3,4-a]pyridines, a process for the preparation thereof and pharmaceutical compositions containing them.

More particularly, the invention relates to compounds of formula (I):

wherein:

R is (C₁-C₄) alkyl;

is free or salified carboxy group, an alkoxycarbonyl or cyano group or a group of formula -CONH(CH₂)_q-NRaRb, wherein q is an integer from 2 to 4; Ra is hydrogen, C₁-C₆ alkyl, benzyl; Rb is hydrogen or C₁-C₆ alkyl, or Ra and Rb, together with the nitrogen atom, form a pyrrolidino, piperidino, morpholino, 4- thiomorpholino, (C₁-C₄) alkylpiperazino group;

R₂ is a (C₃-C₇)cycloalkyl group, α, β or α-pyridyl, optionally substituted phenyl or a bicyclic ring in which a benzene ring is fused to a 5- or 6-membered heterocycle containing one or more heteroatoms selected from O, S and N, said bicyclic ring being linked through the benzene ring;

R₃ is a free or salified carboxy group or an alkoxycar- bonyl group;

D is a 5- or 6-membered heterocycle with 1-3 nitrogen atoms, optionally substituted with 1 or 2 amino, 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 groups.

By "optionally substituted phenyl" as herein used, we mean a phenyl ring, containing from 1 to 3 substituents selected from C₁-C₆ alkyl groups, such as methyl, ethyl, propyl, isopropyl, tert-butyl; (C₁- C₄)alkoxy such as methoxy, ethoxy or propoxy; (C₁- C₄)alkylthio such as methylthio, ethylthio; phenoxy; 4- hydroxyphenoxy; phenylthio; 4-hydroxyphenylthio; halogen atoms (chlorine, bromine or fluorine); cyano, azido, nitro, amino groups; (C₁-C₆)acylamino; trihaloacetylamino such as trifluoroacetylamino; methane- or trifluoromethanesulfonamido; benzene- or para-tolylsulfonamido; trihalomethyl such as trichloro- or trifluoromethyl; dihalomethoxy such as difluoromethoxy; trifluoromethoxy; free or salified carboxy; (C₁-C₄) alkoxycarbonyl.

Particularly preferred mono or poly-substituted phenyl groups are those bearing the following substituents: 2-chloro-, 3-chloro-, 4-chloro-, 2,3-dichloro-, 2-fluoro-, 2-fluoro-3-chloro-, 2-nitro-, 3-nitro-, 3- nitro-4-phenoxy-, 4-nitro-, 4-nitro-3-phenoxy-, 2- trif luoromethyl-, 3-trif luoromethyl-, 3-cyano-, 3- methoxy-, 2-amino-, 3-amino-, 4-amino-, 2- methanesulfonamido-, 3-methanesul fonamido-, 4-me- thanesulfonamido-, 3-methanesulfonamido-4-phenoxy-, 4- methanesulfonamido-3-phenoxy-, 4-fluoro-2,3-dichloro-, 3-carboxy-4-hydroxy-, 3-hydroxy-4-carboxy- and combinations thereof.

When R₂ is a (C₃-C₇)cycloalkyl group, this is preferably cyclopropyl, cyclopentyl or cyclohexyl.

When R₁ or R₃ are an alkoxycarbonyl group, this is preferably a (C₁-C₄) alkyl, allyl, propargyl, benzyl, p- methoxybenzyl, benzhydryl, trityl or trichloroethyl ester.

When R₂ is a bicyclic ring in which a benzene ring is fused with a 5- or 6-membered heterocyclic ring, this is preferably benzo-1,3-dioxolane-4-yl, 1,4- benzodioxolane-6-yl, 1,4-benzodioxolane-5-yl, benzo- furan-4-yl, benzofurazan-4-yl.

Preferred examples of D are: pyridin-2-yl, pyrimidin-4-yl, pyrimidin-2-yl or 1,3,5-triazin-2-yl, optionally substituted with 1 or 2 amino, monoalkylamino (methylamino, ethylamino), 2-pro- penylamino, 2-propynylamino, propylamino, isopro- pylamino or dialkylamino groups such as dime thy lamino, diethylamino, ethyl, 2-propenylamino and the like.

Particularly preferred meanings for D are: pyri- din-2-yl, [2,6-bis(diethylamino)pyrimidin-4-yl], [2,6- bis (2-propenylamino)pyrimidin-4-yl], [2,6-bis(ami- no)pyrimidin-4-yl], [2,6-bis(pyrrolidin-1-yl)pyrimidin- 4-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].

Particularly preferred compounds (I) are those in which R₁ and R₃ are alkoxycarbonyl groups, particularly methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, 2-propenyloxycarbonyl and tert-butoxycarbonyl groups, or those in which R₁ is a -CONH(CH₂)_q-NRaRb group, with q, Ra and Rb as defined above, and R₃ is an alkoxycarbonyl group as defined above; R₂ is an optionally substituted phenyl group or a

(C₃-C₇)cycloalkyl group, as defined above; R is methyl.

When in compounds of formula (I) an acid or basic group is present, this can be salified respectively with pharmaceutically acceptable bases or acids. The resulting non toxic salts are included in the invention, as well as the single enantiomers, the racemates and the diastereomers, or the mixtures thereof. Particularly, the compounds of formula (I) contain 2 chiral carbon atoms at the 3 and 7 positions and therefore sin and anti geometries can be defined, corresponding to formulae (la) and (lb):

(Ia)-sin (Ib)-anti

The compounds of formula (la) will be named hereinafter sin-[3H,7H] thiazole[3,4-a]pyridines or simply [3H,7H]thiazole[3,4-a]pyridines. Compounds of formula (lb) will be named anti-[3H,7H]thiazole[3,4- a_.pyridines, whereas the diastereomeric mixtures will be indicated as (s,a)-[3H,7H]thiazole[3,4-a]pyridines.

Both compounds of formula (la) and those of formula (lb), which are obtained from racemic dihydropyridines, are the racemic mixtures. The optically active compounds (la) will be defined (R)- or (S)-sin-[3H,7H]thiazole[3,4-a]pyridines or simply (R)- or (S)-[3H,7H]thiazole[3,4-a]pyridines; compounds (lb) will be named (R)- or ( S)-anti-[3H,7H]thiazole[3,4- a.pyridines.

The compounds of the invention of formula (I) are prepared by a process which consists in reacting a Michael acceptor of formula (Ila) or (llb):

wherein Hal is a halogen atom (chlorine, bromine or iodine) and R₄ is a (C₁-C₄) alkyl group, with a 1,4- dihydropyridine of formula (III):

wherein R e R₂ are as defined above; R₁ ' and R₃' have the same meanings as R₁ and R₃ except for the free or salified carboxy group; R₅ is hydrogen or a group of formula C(=NH)-NH₂ or C(=NH)-NH₂.H⁺P- wherein P- is the counter-ion of an inorganic or organic acid, such as hydrochloric, hydrobromic, acetic, camphorsulfonic, mandelic, tartaric, O,O'-dibenzoyltartaric acids.

The reaction of compound (II) with compound (III) is usually carried out in an inert solvent and in the presence of a suitable base, to give compounds of formula (Ic):

wherein R, R₁', R₂, R₃ ' and R₄ are as defined above, in form of a sin/anti diastereomeric mixture, the sin diastereomer prevailing. The resulting compounds of formula (Ic) can then be subjected to separation of the single diastereomers or they can be transformed into compounds of formula (I), by means of conventional reactions, such as:

a) hydrolysis of a carboxyester group to the corresponding carboxy group, which in its turn can be transformed into the succinimido ester, the acid chloride, the mixed anhydride or other known reactive carboxy derivatives; conventional hydrolysis procedures comprise, for example, hydrolysis of an allyloxycarbonyl group with ammonium formate, Pd/C and triphenylphosphine; alkali hydrolysis of a methoxy- or ethoxycarbonyl group; hydrolysis of a tert- butoxycarbonyl group with trimethylsilyl iodide, and the like;

b) reaction of the acids or of the reactive derivatives thereof obtained according to a) with amines of formula

H₂N-(CH₂)_q-NRaRb;

c) reduction of the free or salified carboxy group or of a corresponding mixed anhydride thereof or of a carboxyester group to primary alcohol (CH₂OH); suitable reducing agents comprise diborane or an alkali or alkaline-earth metal borohydride;

d) alcohols obtained according to c) can be converted into the compounds of the invention of formula (I) by reaction with thiocarbonyldiimidazole and subsequently with an amine of formula (IV):

(IV)

e) reduction of the aromatic nitro groups possibly present in compounds of formula (Ic) to give amino groups;

f) acylation of the amino groups obtained according to e) to give the corresponding amides and sulfonamides by reaction with carboxylic, alkylsulfonic or arylsulfonic acid halides or anhydrides;

g) salification and/or separation of optical, geometric or diastereomeric isomers according to conventional methods.

The reaction of compounds of formula (II) and (III) involves the formation of the intermediates of formula (Va) or (Vb):

which can then be cyclized to compounds of formula (Ic) without intermediate isolation.

Michael acceptors of formula (II) are known or they can be prepared with conventional methods; some of them are also commercially available. Particularly, among the compounds of formula (II) the following ones are mentioned: a) propargyl acid esters; b) α- haloacrylesters (obtained from acryl esters by haloge addition and subsequent dehydrohalogenation).

1,4-Dihydropyridines of formula (III) are know from WO87/00836 (12.02.1987) or they can be prepare according to the methods described in sai international application. Said compounds of formula (III) can be used both in form of racemates and of pure enantiomers. An useful method for the preparation of pure enantiomers of compounds of formula (III) can comprise the optical resolution of the isothiouronium salts with optically active acids, according to the procedure described in EP 90102951.2 (15.02.1990).

Piperazines of formula (IV) are described in WO87/01706 (26.03.1987).

The compounds of the invention turned out to be effective in preventing and/or decreasing the hyper- reactivity of the respiratory tract and in curing the phlogistic conditions which are related to acute and sub-chronical inflammation of bronchial mucosa.

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/1) 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 hyperreactivity. Such pharmacological effects are dose-related.

The compounds of the invention are also tested according to another experimental model, namely the Late Phase Reaction on sensitized guinea pigs (P.A. Hutson et al., Am. Rev. Respir. Dis. 137; (1988); 548-577. The Late Phase Reaction is characterized by an increase in bronchoalveolar lavage (BAL) of the number of eosi- nophils in guinea pigs sensitized to ovalbumin aerosol. The compounds of the invention are effective in reducing the number of eosinophils in BAL, which was made 72 hours after the ovalbumin challenge.

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. For the intended therapeutic uses, the compounds of the invention will be administered in the form of pharmaceutical compositions which can be prepared with conventional excipients and 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 routes.

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 1 to 50 mg of a compound of formula (I) for a patient weighing 70 kg, one or more times a day.

PREPARATION 1

To a suspension of S-[(6-methyl-5-methoxycarbonyl- 3-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 2-yl)methyl]isothiouronium chloride (20 g) in MeOH (200 ml), methyl propiolate (4.2 ml) and aqueous NaOH (35 %, 10.8 ml) are added in this order under inert gas atmosphere at room temperature and under stirring. After complete dissolution of the reagents, a crystalline precipitate forms which is redissolved by addition of DMF (40 ml). Stirring is continued for 12 more hours, during which a second precipitate forms which is filtered to obtain 14.6 g of methyl 2-(3-(5-methyl-6-metho- xycarbonyl-7-(3-nitrophenyl)-8-ethoxycarbonyl)[3H,7H]- thiazole[3,4-a]pyridinyl)acetate, m.p. 158-160°C.

PREPARATION 2 1 Litre of a sodium bicarbonate saturated aqueous solution is dropped into a suspension of 50 g of (7R)- S-[(6-methyl-5-methoxycarbonyl-3-ethoxycarbonyl-4-(3- nitrophenyl)-1,4-dihydropyridin-2-yl)methyl]isothiouro- nium-D(-)-mandelate in 1 1 of AcOEt, under strong stirring. At the end of the addition, the aqueous phase is removed, whereas the organic phase is dried over sodium sulfate and solvent is evaporated off under reduced pressure, keeping temperature below 40°C.

The residual (7R)-S-[(6-methyl-5-methoxycarbonyl- 3-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridin- 2-yl)methyl]isothioureide (37 g) is dissolved in 150 ml of methanol and quickly added with 9 ml of methyl propiolate, under mechanical stirring and inert gas atmosphere, and immediately after that with 35% aqueous NaOH (11.3 ml). Precipitation of the product takes place nearly immediately. After 15 minutes the reaction mixture is added with 37% hydrochloric acid to acid pH, then the crystalline solid is filtered and dried, to obtain 40.2 g of methyl (7R)-3-[(6-methyl-5-methoxycar- bonyl-3-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropy- ridin-2-yl)methylthio]acrylate.

To a solution of 40.2 g of methyl (7R)-3-[(6- methyl-5-methoxycarbonyl-3-ethoxycarbonyl-4-(3-nitro- phenyl)-1,4-dihydropyridin-2-yl)methylthio]acrylate in 110 ml of anhydrous DMF, 12.8 ml of 1,8-diazabicy- clo[5.4.0]undec-7-ene (DBU) are added, under stirring and inert gas atmosphere. Stirring is continued for 18 more hours, then the reaction mixture is cooled with water/ice and added with 37% hydrochloric acid to acid pH. The crystalline precipitate is separated by filtra tion, to obtain 35.7 g of methyl (7R)-2-(3-(5-methyl-6- methoxycarbonyl-7-(3-nitrophenyl)-8-ethoxycarbonyl)- [ 3H,7H]thiazole[3,4-a]pyridinyl)acetate, m.p. 126- 128°C.

PREPARATION 3

6.4 g of methyl (7R)-2-(3-(5-methyl-6-methoxycar- bonyl-7-(3-nitrophenyl)-8-ethoxycarbonyl)[3H,7H]thia- zole[3,4-a]pyridinyl) acetate are added under stirring to a suspension of LiBr (3.8 g) and sodium borohydride (1.75 g) in diglyme (10 ml), which has been proviously kept at room temperature for 30 minutes. The reaction mixture is heated to 50°C for one hour, then it is poured into water and acidified with IN hydrochloric acid. After extraction with AcOEt (3x15 ml), the combined or- ganic extracts are washed repeatedly with water (5x20 ml), dried over sodium sulfate and solvent is evaporated off under reduced pressure, to give 4.8 g of (7R)- 2-(3-(5-methyl-6-methoxycarbonyl-7-(3-nitrophenyl)-8- ethoxycarbonyl)[3H,7H]thiazole[3,4-a]pyridinyl)-etha- nol, m.p. 58-62°C, [α]_D= -51.9° (c=0.21 in EtOH).

PREPARATION 4

Following the procedure described in preparations 2 and 3, the following 2-([3H,7H]thiazole[3,4- a]pyridin-3-yl)ethanols are prepared:

5-methyl-6-methoxycarbonyl-7-(3-chlorophenyl)-8-ethoxy- carbonyl,

5-methyl-6-methoxycarbonyl-7-cyclohexyl-8-ethoxycar- bonyl,

5-methyl-6-allyloxycarbonyl-7-(3-nitrophenyl)-8-ethoxy- carbonyl,

5-methyl-6-allyloxycarbonyl-7-(3-chlorophenyl)-8-e- thoxycarbonyl,

5-methyl-6-allyloxycarbonyl-7-cyclohexyl-8-ethoxycar- bonyl.

EXAMPLE 1

A solution of 3.5 g of (7R)-2-(3-(5-methyl-6- methoxycarbonyl-7-(3-nitrophenyl)-8-ethoxycarbonyl)- [3H,7H]thiazole[3,4-a]pyridinyl)ethanol in 20 ml of anhydrous THF is added with 1.74 g of thiocarbonyldiimidazole, under stirring and inert gas atmosphere. After 5 hours, a solution of N-[3, 6-bis (diethylamino)pyridin-2-yl]piperazine (2.65 g) in 15 ml of THF is dropped into the reaction mixture, which is left for one more hour under stirring at room temperature, then the reaction mixture is added with 70 ml of water and repeatedly extracted with AcOEt (3x20 ml). The combined organic extracts are washed with water (3x10 ml), dried over sodium sulfate and solvent is evaporated off under reduced pressure. The residue (6.7 g) is purified by silica gel chromatography (200 g of silica; eluent methylene chloride/methanol 98/2) to give 4.3 g of (7R)-N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-(2-(3-(5- methyl-6-methoxycarbonyl-7-(3-nitrophenyl)-8-ethoxycar- bonyl)[3H,7H]thiazole[3,4-a]pyridinyl)ethoxythiocarbo- nyl)piperazine, m.p. sulfate 169-171°C, [α]_D=+4.4° (c-0.2 in EtOH).

EXAMPLE 2

Following the procedure described in example 1, the following (([3H,7H]thiazole[3,4-a]pyridinyl)etho- xythiocarbonyl)piperazines are prepared:

(7R)-N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N--(2- (3-(5-methyl-6-methoxycarbonyl-7-(3-nitrophenyl)-8- ethoxycarbonyl), m.p. sulfate 162-165°C,

N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(2- (3-(5-methyl-6-methoxycarbonyl-7-(3-nitrophenyl)-8- ethoxycarbonyl), ¹H NMR (200 MHz) δ 1.26 (t,3H), 1.95 (m,8H), 2.34 (m,2H), 2.59 (s,3H), 3.55 (m,14H), 3.67 (s,3H), 3.85 (m,2H), 4.14 (m,4H), 4.2 (d,1H), 4.65 (d,1H), 5.18 (s,1H), 5.5 (m,1H), 7.41 (t,1H), 7.6 (d,1H), 8.05 (m,2H),

N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(2-(3-(5- methyl-6-methoxycarbonyl-7-(3-chlorophenyl)-8-ethoxy- carbonyl), ¹H NMR (200 MHz) δ 1.25 (t,3H), 1.93 (m,8H), 2.35 (m,2H), 2.6 (s,3H), 3.55 (m,14H), 3.67 (s,3H), 3.85 (m,2H), 4.15 (m,4H), 4.2 (d,1H), 4.65 (d,1H), 4.87 (s,1H), 5.19 (s,1H), 5.51 (m,1H), 7.21 (m,4H),

N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-(2-(3-(5-me- thyl-6-methoxycarbonyl-7-(3-chlorophenyl)-8-ethoxycar- bonyl), ¹H NMR (200 MHz) δ 0.97 (t,6H), 1.1 (t,6H), 1.25 (t,3H), 2.35 (m,2H), 2.6 (s,3H), 2.98 (q,4H), 3.53 (m,10H), 3.68 (s,3H), 3.84 (m,2H), 4.14 (m,4H), 4.22 (d,1H), 4.66 (d,1H), 5.17 (s,1H), 5.51 (m,1H), 6.07 (d,1H), 7.1 (d,1H), 7.22 (m,4H),

N-(4,6-bis(pyrrolidin-l-yl)-l,3,5-triazin-2-yl)-N'-(2- (3-(5-methyl-6-methoxycarbonyl-7-(3-chlorophenyl)-8- ethoxycarbonyl), ¹H NMR (200 MHz) δ 1.25 (t,3H), 1.93 (m,8H), 2.36 (m,2H), 2.59 (s,3H), 3.53 (m,14H), 3.65

(s,3H), 3.85 (m,2H), 4.13 (m,4H), 4.22 (d,1H), 4.67 (d,1H), 5.17 (s,1H), 5.52 (m,1H), 7.21 (m,4H),

N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(2-(3-(5- methyl-6-methoxycarbonyl-7-cyclohexyl-8-ethoxycarbo- nyl), ¹H NMR (200 MHz) δ 0.98 (m,6H), 1.25 (t,3H), 1.49

(m,5H), 1.94 (m,8H), 2.35 (m,2H), 2.6 (s,3H), 3.54 (m, 14H) , 3 . 68 ( s,1H), 3 .85 (m, 2H) , 3 .91 ( d,1H), 4 . 13 (m, 4H) , 4 . 19 ( d,1H), 4 . 64 ( d,1H), 5.87 ( s,1H), 5.51 (m,1H),

N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-(2-(3-(5-me- thyl-6-methoxycarbonyl-7-cyclohexyl-8-ethoxycarbonyl),

¹H NMR (200 MHz) δ 0.98 (m,12H), 1.05 (t,6H), 1.25 (t,3H), 1.51 (m,5H), 2.35 (m,2H), 2.61 (s,3H), 2.98 (q,4H), 3.53 (m,10H), 3.66 (s,3H), 3.84 (m,2H), 3.91 (d,1H), 4.14 (m,4H), 4.22 (d,1H), 4.66 (d,1H), 5.51 (m,1H), 6.06 (d,1H), 7.1 (d,1H),

N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(2- ( 3-(5-methyl-6-methoxycarbonyl-7-cyclohexyl-8-ethoxy- carbonyl), ¹H NMR (200 MHz) δ 1.01 (m,6H), 1.25 (t,3H), 1.49 (m,5H), 1.94 (m,8H), 2.35 (m,2H), 2.6 (s,3H), 3.53 (m,14H), 3.65 (s,3H), 3.84 (m,2H), 3.91 (d,1H), 4.13 (m,4H), 4.19 (d,1H), 4.64 (d,1H), 5.52 (m,1H),

N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(2-(3-(5- methyl-6-allyloxycarbonyl-7-(3-nitrophenyl)-8-ethoxy- carbonyl), ¹H NMR (200 MHz) δ 1.25 (t,3H), 1.93 (m,8H), 2.31 (m,2H), 2.59 (s,3H), 3.55 (m,14H), 3.85 (m,2H), 4.13 (m,4H), 4.2 (d,1H), 4.61 (m,2H), 4.65 (d,1H), 4.84 (s,1H), 5.22 (m,3H), 5.49 (m,1H), 5.9 (m,1H), 7.41 (t,1H), 7.61 (d,1H), 8.05 (m,2H),

N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-(2-(3-(5-methyl-6-allyloxycarbonyl-7-(3-nitrophenyl)-8-ethoxycar- bonyl), ¹H NMR (200 MHz) δ 0.97 (t,6H), 1.04 (t,6H), 1.25 (t,3H), 2.33 (m,2H), 2.61 (s,3H), 2.98 (q,4H), 3.52 (m,10H), 3.84 (m,2H), 4.13 (m,4H), 4.21 (d,1H), 4.61 (m,2H), 4.66 (d,1H), 5.22 (m,3H), 5.49 (m,1H), 5.9 (m,1H), 6.06 (d,1H), 7.1 (d,1H), 7.42 (t,1H), 7.6 (d,1H), 8.05 (m,2H), N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(2- (3-(5-methyl-6-allyloxycarbonyl-7-(3-nitrophenyl)-8- ethoxycarbonyl), ¹H NMR (200 MHz) δ 1.25 (t,3H), 1.94 (m,8H), 2.33 (m,2H), 2.59 (s,3H), 3.53 (m,14H), 3.84 (m,2H), 4.14 (m,4H), 4.19 (d,1H), 4.62 (m,2H), 4.64 (d,1H), 5.22 (m,3H), 5.49 (m,1H), 5.91 (m,1H), 7.42 (t,1H), 7.61 (d,1H), 8.05 (m,2H),

N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(2-(3-(5- methyl-6-allyloxycarbonyl-7-(3-chlorophenyl)-8-ethoxy- carbonyl), ¹H NMR (200 MHz) δ 1.25 (t,3H), 1.93 (m,8H), 2.33 (m,2H), 2.6 (s,3H), 3.54 (m,14H), 3.83 (m,2H), 4.13 (m,4H), 4.2 (d,1H), 4.6 (m,2H), 4.65 (d,1H), 4.86 (s,1H), 5.21 (m,3H), 5.48 (m,1H), 5.89 (m,1H), 7.21 (m,4H),

N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-(2-(3-(5-me- thyl-6-allyloxycarbonyl-7-(3-chlorophenyl)-8-ethoxycar- bonyl), ¹H NMR (200 MHz) δ 0.96 (t,6H), 1.03 (t,6H), 1.25 (t,3H), 2.33 (m,2H), 2.58 (s,3H), 2.98 (q,4H), 3.51 (m,10H), 3.83 (m,2H), 4.13 (m,4H), 4.19 (d,1H), 4.62 (m,2H), 4.64 (d,1H), 5.22 (m,3H), 5.48 (m,1H), 5.89 (m,1H), 6.06 (d,1H), 7.11 (d,1H), 7.23 (m,4H), N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(2- (3-(5-methyl-6-allyloxycarbonyl-7-(3-chlorophenyl)-8- ethoxycarbonyl), ¹H NMR (200 MHz) δ 1.26 (t,3H), 1.93 (m,8H), 2.33 (m,2H), 2.57 (s,3H), 3.53 (m,14H), 3.84 (m,2H), 4.14 (m,4H), 4.21 (d,1H), 4.62 (m,2H), 4.66 (d,1H), 5.23 (m,3H), 5.48 (m,1H), 5.88 (m,1H), 7.22 (m,4H),

N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(2-(3-(5- methyl-6-allyloxycarbonyl-7-cyclohexyl-8-ethoxycarbonyl), 1H NMR (200 MHz) δ 0.98 (m,6H), 1.26 (t,3H), 1.51 (m,5H), 1.94 (m,8H), 2.33 (m,2H), 2.59 (s,1H), 3.53 (m,14H), 3.83 (m,2H), 3.91 (d,1H), 4.13 (m,4H), 4.19 (d,1H), 4.61 (m,2H), 4.64 (d,1H), 4.86 (s,1H), 5.22 (m,2H), 5.48 (m,1H), 5.88 (m,1H),

N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-(2-(3-(5-me- thyl-6-allyloxycarbonyl-7-cyclohexyl-8-ethoxycarbonyl), 1H NMR (200 MHz) δ 1.01 (m,12H), 1.05 (t,6H), 1.26 (t,3H), 1.49 (m,5H), 2.33 (m,2H), 2.59 (s,3H), 2.97 (q,4H), 3.52 (m,10H), 3.83 (m,2H), 3.9 (d,1H), 4.12 (m,4H), 4.2 (d,1H), 4.6 (m,2H), 4.65 (d,1H), 5.21

(m,2H), 5.48 (m,1H), 5.9 (m,1H), 6.06 (d,1H), 7.11 (d,1H),

N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(2- (3-(5-methyl-6-allyloxycarbonyl-7-cyclohexyl-8-ethoxy- carbonyl), ¹H NMR (200 MHz) δ 0.98 (m,6H), 1.25 (t,3H),

1.49 (m,5H), 1.93 (m,8H), 2.33 (m,2H), 2.59 (s,3H), 3.55 (m,14H), 3.83 (m,2H), 3.89 (d,1H), 4.13 (m,4H), 4.19 (d,1H), 4.59 (m,2H), 4.64 (d,lH), 5.21 (m,2H), 5.48 (m,1H), 5.87 (m,1H).

EXAMPLE 3

a) A solution of 1 g of N-[2,6-bis(pyrrolidin-1- yl)pyrimidin-4-yl]-N'-[2-(3-(5-methyl-6-allyloxycarbo- nyl-7-(3-nitrophenyl)-8-ethoxycarbonyl)[3H,7H]thiazo- le[3,4-a]pyridinyl)ethoxythiocarbonyl]piperazine in 8 ml of dioxane is added with 0.25 g of 10% Pd/C, 0.37 g of ammonium formate and 15 mg of triphenylphosphine, under stirring and inert gas atmosphere, then the reaction mixture is refluxed for 6 hours. After that, the reaction mixture is filtered through celite, diluted with AcOEt (10 ml) and washed repeatedly with water

(3x5 ml). The resulting organic phase is dried over so dium sulfate and solvent is evaporated off under reduced pressure, to obtain a residue (0.9 g) which is purified by silica gel chromatography (30 g silica; eluent Hexane/AcOEt 6/4). 0.8 g of N-[2,6-bis(pyr- rolidin-1-yl)pyrimidin-4-yl]-N'-[2-(3-(5-methyl-6-car- boxy-7-(3-nitrophenyl)-8-ethoxycarbonyl)[3H,7H]thiazo- le[3,4-a]pyridinyl)ethoxythiocarbonyl]piperazine are obtained,

b) A solution of 0.8 g of N-[2,6-bis(pyrrolidin-1- yl)pyrimidin-4-yl]-N'-[2-(3-(5-methyl-6-carboxy-7-(3- nitrophenyl)-8-ethoxycarbonyl)[3H,7H]thiazole[3,4-a]py- ridinyl)ethoxythiocarbonyl]piperazine in 5 ml of THF is added with 0.185 g of carbonyldiimidazole, under stirring and inert gas atmosphere. After 3 hours, the reaction mixture is added with 0.65 ml of 2-(N-pyrrolidin)ethylamine and stirring is continued for 5 more hours, then the mixture is diluted with 15 ml of water and extracted with AcOEt (3x5 ml). The combined organic extracts are washed with water, dried over sodium sul- fate and solvent is evaporated off under reduced pressure. The residue (1 g) is purified by silica gel chromatography (30 g silica; eluent Hexane/AcOEt 8/2) to give 0.82 g of N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4- yl]-N'-[2-(3-(5-methyl-6-(2-(N-pyrrolidin)ethylamino- carbonyl)-7-(3-nitrophenyl)-8-ethoxycarbonyl)[3H,7H]- thiazole[3,4-a]pyridinyl)ethoxythiocarbonyl]piperazine, ¹H NMR (200 MHz) δ 1.25 (t,3H), 1.84 (m,4H), 1.95 (m,8H), 2.33 (m,2H), 2.59 (s,3H), 2.8 (m,6H), 3.51 (m,16H), 3.84 (m,2H), 4.13 (m,4H), 4.19 (d,1H), 4.64 (d,1H), 4.84 (S,1H), 5.21 (s,1H), 5.48 (m,1H), 7.2 (b,1H), 7.41 (t,1H), 7.6 (d,1H), 8.03 (m,2H). EXAMPLE 4

Following the procedure described in example 1, starting from the (6-allyloxycarbonyl)[3H,7H]thiazole- [3,4-a]pyridines described in example 2, the following (6-(2-(N-pyrrolidin)ethylaminocarbonyl)[3H,7H]thiazole- [3,4-a]pyridinyl)ethoxythiocarbonyl)piperazines are obtained:

N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-(2-(3-(5-methyl-7-(3-nitrophenyl)-8-ethoxycarbonyl), ¹H NMR (200 MHz) δ 0.98 (t,6H), 1.03 (t,6H), 1.26 (t,3H), 1.85 (m,4H), 2.33 (m,2H), 2.59 (s,3H), 2.85 (m,10H), 3.51 (m,12H), 3.83 (m,2H), 4.13 (m,4H), 4.19 (d,1H), 4.64 (d,1H), 5.19 (s_.lH)_. 5.5 (m,1H), 6.07 (d,1H), 7.11 (d,1H), 7.18 (b,1H), 7.41 (t,1H), 7.6 (d,1H), 8.03 (m,2H),

N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(2- (3-(5-methyl-7-(3-nitrophenyl)-8-ethoxycarbonyl), ¹H NMR (200 MHz) δ 1.26 (t,3H), 1.84 (m,4H), 1.96 (m,8H), 2.33 (m,2H), 2.58 (s,3H), 2.81 (m,6H), 3.52 (m,16H), 3.83 (m,2H), 4.11 (m,4H), 4.18 (d,1H), 4.63 (d,1H), 5.19 (s,1H), 5.5 (m,1H), 7.15 (b,1H), 7.42 (t,1H), 7.59 (d,1H), 8.05 (m,2H),

N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(2-(3-(5- methyl-7-(3-chlorophenyl)-8-ethoxycarbonyl), ¹H NMR (200 MHz) δ 1.26 (t,3H), 1.84 (m,4H), 1.95 (m,8H), 2.35 (m,2H), 2.59 (s,3H), 2.82 (m,6H), 3.52 (m,16H), 3.83 (m,2H), 4.13 (m,4H), 4.19 (d,1H), 4.64 (d,1H), 4.86 (s,1H), 5.18 (s,1H), 5.48 (m,1H), 7.23 (m,5H),

N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-(2-(3-(5-me- thyl-7-(3-chlorophenyl)-8-ethoxycarbonyl), ¹H NMR (200 MHz) δ 0.96 (t,6H), 1.04 (t,6H), 1.26 (t,3H), 1.83 (m,4H), 2.33 (m,2H), 2.59 (s,3H), 2.79 (m,6H), 2.99 (q,4H), 3.51 (m,12H), 3.83 (m,2H), 4.13 (m,4H), 4.21 (d,1H), 4.66 (d,1H), 5.21 (s,1H), 5.48 (m,1H), 6.06 (d,1H), 7.11 (d,1H), 7.23 (m,5H),

N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(2-

(3-(5-methy1-7-(3-chlorophenyl)-8-ethoxycarbonyl), ¹H NMR (200 MHz) δ 1.25 (t,3H), 1.84 (m,4H), 1.95 (m,8H), 2.33 (m,2H), 2.59 (s,3H), 2.8 (m,6H), 3.5 (m,16H), 3.83 (m,2H), 4.15 (m,4H), 4.2 (d,1H), 4.65 (d,1H), 5.21 (s,1H), 5.5 (m,1H), 7.23 (m,5H),

N-(2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)-N'-(2-(3-(5- methyl-7-cyclohexyl-8-ethoxycarbonyl), ¹H NMR (200 MHz) £θ.99 (m,6H), 1.26 (t,3H), 1.51 (m,5H), 1.84 (m,4H), 1.95 (m,8H), 2.33 (m,2H), 2.6 (s,3H) , 2.81 (m,6H), 3.51 (m,16H), 3.83 (m,2H), 3.91 (d,1H), 4.13 (m,4H), 4.19

(d,1H), 4.64 (d,1H), 4.86 (s,1H), 5.5 (m,1H), 7.2 (b,1H),

N-(3,6-bis(diethylamino)pyridin-2-yl)-N'-(2-(3-(5-me- thyl-7-cyclohexyl-8-ethoxycarbonyl), ¹H NMR (200 MHz) δ 1 (m,12H), 1.05 (t,6H), 1.25 (t,3H), 1.5 (m,5H), 1.83 (m,4H), 2.33 (m,2H), 2.59 (s,3H), 2.8 (m,6H), 2.98 (q,4H), 3.51 (m,12H), 3.83 (m,2H), 3.91 (d,1H), 4.13 (m,4H), 4.2 (d,1H), 4.65 (d,1H), 5.48 (m,1H), 6.06 (d,1H), 7.1 (d,1H), 7.16 (b,1H),

N-(4,6-bis(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N'-(2-

(3-(5-methyl-7-cyclohexyl-8-ethoxycarbonyl), ¹H NMR (200 MHz) δ 0.98 (m,6H), 1.25 (t,3H), 1.51 (m,5H), 1.83 (m,4H), 1.94 (m,8H), 2.34 (m,2H), 2.59 (s,3H), 2.8 (m,6H), 3.51 (m,16H), 3.83 (m,2H), 3.9 (d,1H), 4.13 (m,4H), 4.19 (d,1H), 4.64 (d,1H), 5.5 (m,1H), 7.2 (b,1H).

Claims

Compounds of formula (I):

wherein:

R is (C₁-C₄) alkyl;

is free or salified carboxy group, an alkoxycarbonyl or cyano group or a group of formula -CONH(CH₂)_q-NRaRb, wherein q is an integer from 2 to 4; Ra is hydrogen, C₁-C₆ alkyl, benzyl; Rb is hydrogen or C₁-C₆ alkyl, or Ra and Rb, together with the nitrogen atom, form a pyrrolidino, piperidino, morpholino, 4- thiomorpholino, (C₁-C₄)alkylpiperazino group;

R₂ is a (C₃-C₇)cycloalkyl group, α , β or α-pyridyl, optionally substituted phenyl or a bicyclic ring in which a benzene ring is fused to a 5- or 6-membered heterocycle containing one or more heteroatoms selected from O, S and N, said bicyclic ring being linked through the benzene ring;

R₃ is a free or salified carboxy group or an alkoxycarbonyl group;

D is a 5- or 6-membered heterocycle with 1-3 nitrogen atoms, optionally substituted with 1 or 2 amino, 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 groups;

and the pharmaceutically acceptable salts, single enantiomers, racemates, diastereomers and mixtures thereof.

2. Compounds according to claim 1, wherein R₂ is selected from phenyl groups bearing the following substituents: 2-chloro-, 3-chloro-, 4-chloro-, 2 , 3-dichloro-, 2-fluoro-, 2-fluoro-3-chloro-, 2-nitro-, 3-nitro-, 3- nitro-4-phenoxy-, 4-nitro-, 4-nitro-3-phenoxy-, 2-tri- fluoromethyl-, 3-trifluoromethyl-, 3-cyano-, 3-methoxy- , 2-amino-, 3-amino-, 4-amino-, 2-methanesulfonamido-, 3-methanesulfonamido-, 4-methanesulfonamido-, 3-metha- nesulfonamido-4-phenoxy-, 4-methanesulfonamido-3-phe- noxy-, 4-fluoro-2,3-dichloro-, 3-carboxy-4-hydroxy-, 3- hydroxy-4-carboxy- and the combinations thereof or from benzo-1,3-dioxolane-4-yl, 1,4-benzodioxolane-6-yl, 1,4- benzodioxolane-5-yl, benzofuran-4-yl, benzofurazan-4-yl groups.

3. Compounds according to any one of the preceding claims wherein D is selected from the group consisting of pyridin-2-yl, [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)pyrimidin4-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(die- thylamino)pyridin-2-yl], [3,6-bis(pyrrolidin-1-yl)pyridin-2-yl], [3,6-bis(2-propenylamino)pyridin-2-yl].

4. Compounds according to any one of the preceding claims wherein R₁ and R₃ are both alkoxycarbonyl, or R₁ is a CONH(CH₂)_q-NRaRb group, with q, Ra and Rb as defined above, R₂ is as defined above, R is methyl.

5. Pharmaceutical compositions containing one or more compounds of formula (I) in a mixture with suitable excipients.

6. The use of compounds of formula (I) for the preparation of a medicament having antiasthmatic and antiinflammatory activities.