GB2177690A - Antitussive and mucus regulating 2-substituted thiazolidines - Google Patents

Antitussive and mucus regulating 2-substituted thiazolidines Download PDF

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Publication number
GB2177690A
GB2177690A GB08517553A GB8517553A GB2177690A GB 2177690 A GB2177690 A GB 2177690A GB 08517553 A GB08517553 A GB 08517553A GB 8517553 A GB8517553 A GB 8517553A GB 2177690 A GB2177690 A GB 2177690A
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Prior art keywords
methyl
group
thiazolidine
hydrogen
formula
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GB8517553D0 (en
Inventor
Carmelo A Gandolfi
Odoardo Tofanetti
Sergio Tognella
Silvano Spinelli
Raimondo Russo
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Boehringer Ingelheim Italia SpA
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Boehringer Biochemia Robin SpA
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Priority to GB08517553A priority Critical patent/GB2177690A/en
Priority to HU852765A priority patent/HU195492B/en
Priority to NZ212831A priority patent/NZ212831A/en
Priority to AU45242/85A priority patent/AU582770B2/en
Priority to IL75891A priority patent/IL75891A/en
Priority to CA000487403A priority patent/CA1270250A/en
Priority to GR851845A priority patent/GR851845B/el
Priority to ES545575A priority patent/ES8605249A1/en
Priority to IE187985A priority patent/IE58518B1/en
Priority to DK341985A priority patent/DK169474B1/en
Priority to JP60166620A priority patent/JPS6163669A/en
Priority to DE8585109445T priority patent/DE3574590D1/en
Priority to AT85109445T priority patent/ATE48421T1/en
Priority to EP85109445A priority patent/EP0169581B1/en
Publication of GB8517553D0 publication Critical patent/GB8517553D0/en
Publication of GB2177690A publication Critical patent/GB2177690A/en
Priority to US07/266,559 priority patent/US4857643A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms

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Abstract

2-Substituted thiazolidines compounds have the formula <IMAGE> wherein: X is a CH2, O, S; R is hydroxy, or an ester thereof of formula Rc-CO2-C1-C6-alkoxy, CH2=CH-CH2O-; HC IDENTICAL C-CH2-O-; methyl R, is hydrogen and <IMAGE> R2 is hydrogen or a free or esterified carboxy group; R3 is hydrogen, a C1-C2alkylsulphonyl group, a phenyl, p-Cl phenyl, p-methylsulphonyl group or an acyl group of formula RdCO; p is zero or 1 with the proviso that when X is sulphur p is zero; both Ra and Rb are hydrogen or methyl; Rc and Rd, which are the same or different are: hydrogen or are chosen from various defined organic groups, or are salts with non toxic bases or acids thereof, enantiomers, diastereoisomers or mixtures thereof. The compounds are useful as antitussive or mucus regulating agents.

Description

SPECIFICATION Antitussive and mucus regulating 2-substituted thiazolidines The present invention relates to antitussive and mucus regulating 2-substituted thiazolidines, to process for their preparation and to pharmaceutical and veterinary compositions containing them.
The compounds Df the invention are 2-substituted thiazolidines of the formula (I)
wherein XisaCH2,O,S; R is hydroxy, or an ester thereof offormula Rc0O2, lower C1-C6-alkoxy, CH2=CH-CH20-; HC -C-CH2-O;- methyl; R1 is hydrogen and
R2is hydrogen orafreeoresterified carboxy group; R3 is hydrogen, a C-C2 alkylsulphonyl group, a phenyl, p-Cl-phenyl, p-methylsulphonyl group or an acyl group offormula RdCO; p is zero or 1 with the proviso that when Xis sulfur p is zero; both Ra and Rb, are hydrogen or methyl;Rcand Rd, which are the same or different are: hydrogen,
wherein n isO oran integerfrom 1 to 7; R1, P2, are both hydrogen orone ofthem is hydrogen and the other one is lower C1C4 alkyl or phenyl and 0 is selected in the group consisting of: -NH2; a mono or di-substituted amino,t-butoxycarbonylamino orC-C2 acylamino group; an ether-O (CH2),-T orthioether S-Tchain, wherein T is an unsubstituted or mono-or polysubstituted phenyl ring ora group of formula (CH2)m-T, wherein T1 is selected in the group consisting of H, OH, OCH3, OC2H2-, free and esterified carboxy group, NH2, a C1-C2-acylamino or mono- or disubstituted amino group, our a group offormula
wherein Re is hydrogen, methyl or ethyl and m is an integer from 1 to 3, a phenyl, phenoxy or phenylthio ring unsubstituted or mono- or polysubstituted in them, o, and p-positiona; a group offormula -(CH2)n-SCO- (CH2)nP3wherein m and n have the above defined meanings and P3 is a lower01-07, linear or branched, alkyl chain, a C3-C6-cycloalkyl, a disubstituted aminogroup, a phenyl or phenoxy ring, optionally mono- or polysubstituted in the o, m and p-positions; and alkenyl chain offormula
wherein T has the above defined meanings.
The term "mono substituted amino group" comprises, within the meanings thereof, an amino group sub stituted by a C1-C6, linear or branched alkyl group or by groups having formula: -CH2-CH2-O-CHrCH3, -CH2- CH2-O-CH2-OH, -CH2-CH2-N H-CH2-CH3, -CH2-CH2-NH-CH2-CH2-OH or
The substituents of a disubstituted amino group according to the invention may be linear or branched Cs -C6 alkyl groups or, taken together, they represent an unsaturated or unsaturated nitrogen ring such as morpholin-a-yl, pyrrolidin-1 -y, piperidin-1 -yl, 4-methyl-piperazinl-yl, 4-ethyl-piperazin-1 -yl, 4-(2' hydroxyethyl)piperazin-1 -yl, 4-phenyl-piperazin-1 -yl, 4-(3'-chlorophenyl)piperazin-1 -y, 4-(4'fluorophenyl)piperazin-1 -yl; imidazol-1 -yl, 3-pyridil, 4-pyridyl.
Finally, the term "mono- or polysubstituted phenyl", according to the invention, means phenyl groups which are substituted by a fluorine atom in the para position, by chlorine atoms in the meta and para positions or by a CF3 in the meta positions or phenyl groups offormula
wherein Z1 is H orCOCH3and Z2 is H, CH3 or COCH3 and N is an amino, C-C2acylamino ormono-ordisubstitu- ted amino groups, as above defined.
The optical antipodes, i.e. enantiomers, racemic mixtures thereof, diastereoisomers mixtures of compounds offormula I, have also to be considered as an object of the invention as well as non-toxic salts, both for pharmaceutical and veterinary use.
More particularly, the present invention relates to pharmaceutically acceptable base addition salts when in formula I a free carboxy group is present, and to pharmaceutically acceptable acid addition salts when in formula I R3 is hydrogen or an acyl group in which is present a basic organic moiety.
Typical examples of pharmacologically acceptable non-toxic bases are organic bases e.g. organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, diisopropylamine, N-methyl-Nhexylamine, tromethamine, cyclohexylamine, N-methyl-N-cyclohexylamine, a-phenylethylamine, - phenylethylamine, N,N-dimethylethanolamine, N,N-diethylethanolamine, ethylendiamine, piperidine, morpholine, piperidine, piperazine, galactamine, N-methyl-glucamine, ephedrine, lysine, arginine; and inorganic bases such as alkali and alkali-earth metal hydroxydes as well as aluminium and zinc hydroxydes.
Typical examples of pharmacologically acceptable non-toxic acids are organic acids such as acetic, formic, propionic, fumaric, maleic, malic, malonic, benzoic, salicylic, 3,4,5-trimethoxybenzoic, methanesulphonic, benzenesulphonic, canfosulphonic, lactic, aspartic, glutamic, Land D-2-phenyl-thiazolidin-5-carboxylic acid, cystin and cystein; and inorganic acids such as nitric, phosphoric, sulphoric, hydrochloric, hydrobromic acids.
Preferred salts ofthe invention comprise compounds offormula I wherein R2 is a carboxy group salified with one ofthe above cited bases. Salts of piperazine and imidazole derivatives are even more preferred.
In formulae ofthis specification whe wavy line bond ( ) indicates that the substituents has not a definite stereochemical identity, i.e. that the substituent may be both of (R) and (S) configuration; the broken line ( ) indicates that a substituent is of (S) absolute stereochemistry; the heavy solid line ( ) indicates that a substituent is of (R) absolute configuration.
Particularly preferred compounds ofthe invention have the formula I wherein R1, R2, Ra and Rare hydrogen.
Specific examples of preferred compounds ofthe invention arethefollowing: 3-(3'-morpholinomethyl-4'-hydroxy-3'-methoxy-cinnamoyl)-2-(O-methoxyphenoxy)-methyl-thiazolidine; 3-(3'-pyrrolidylmethyl-4'-hydroxy-3'-methoxy-cinnamoyl)-2-(O-hydroxyphenoxy)-methyl-thiazol id ine; 3-[3-(2-hydroxyethylamino)ethylaminopropanoy1 ]-2-(O-methoxyphenoxy)methyl-thiazolidine and its maleate; 3-[3-(amidazol-1 -yl)propionyl]-2-(O-methoxyphenoxy)methyl-thiazolidine; 3-(3,6-dioxa-capriloyl )-2-(O-methoxyphenoxy) methyl-thiazolidine; 3-(acetylaminoacetyl-2-(O-methoxyphenoxy)methyl-thiazolidine.
The compounds ofthe invention are prepared by reaction of a stabilized ylide of the formula (11)
wherein R, Ra, Rb, R1, R2 and pare as above defined, with an aldehyde oftheformula (Ill) T-CHO (III) wherein T is also as above defined,to give, after optional removal of the protective groups, 3-thiazolidine acrylamidesoftheformula la
which, when T is H, C1-C4-lower alkyl and phenyl can be optionally reacted with nucleophiles such as amines (i.e. H2N-(CH2)m-Ta, monosubstituted and disubstituted amines) and thiols (i.e.:: HS-(CH2)m-T1,unsubstituted or mono or polysubstituted thiophenols) to obtain a Michael adduct of formula (Ib)
wherein R, R1, Ra, Rb, R2, p, x are as above defined and Q' is selected in the group consisting of HN-(CH2)n-Tr (m, n and T1 are as above defined) unsubstituted, mono or polysubstituted phenylthio group.
The thiazolidines of formula II are disclosed in the british patent application No.8419254(27.07.1984), in the Applicant's name.
The aldehydes of formula Ill are known compounds or may be prepared using for instance Moffat's oxyda tion conditions from the alcohols of formula Ila (T-CH20H) or by DIBAH reduction of the esters of theformula Illb (T-CO2Rf), said alcohols and/or esters being well-known compounds.
The reaction between the stabilized ylides of the formula II and the aldehydres offormula III is thewell- known Wittig reaction whose experimental procedure is also well-known; it is generally performed by mixing the reagents in equimolecular ratio in an inert solvent such as an halogenated solvent, an ethereal solvent (THF, dimethoxyethane, etc.), hydrocarbons (cyclohexane, benzene,toluene, hexane,) acetonitrile or using a mixture thereof, preferably at room temperature.
The Michael addition oftheabove defined nucleophilestotheacrylamides oftheformula Ia is also a well-known reaction. Preferred solvents are alcohols and the reaction is carried out by mixing the reagent and heating at the refluxtemperature.
Alternatively, the compounds offormula la wherein T is hydrogen, lowerC,-C4alkyl and phenyl may be optically prepared by reaction of a compound of formula (IV)
wherein R, R1, Ra, Rb, R2, p, are as above defined with an activated form, such as chloride or mixed anhydride, of an acrylic acid such as CH2= CH-CO2H and (C1-C4)AIk-CH=CH-CO2H orofcinnamicacid.
Likewise, the compounds offormula lb may be optionally obtained fromthethiazolidines offormula IV by reaction with activated forms of the acids ofthe formula (V)
wherein Q' and P1 are as above defined.
Thiazolidines ofthe formula Ic
wherein Rg is hydrogen, C1-C2 acyl and CO-O-(CH3)3 are prepared by reaction of a thiazolidine offormula IV with an activated form of an a-(C,-C2)-acyl-aminoacid and of a BOC-amino acid followed by optional cleavage ofthe protected amino group.
Finally, starting from the same thiazolidines offormula IV, by reaction with an activated form of an acid of formula VI T,-(CH2)n-O-(CH2)m-CO2H (Vl) 3-acyl-substituted thiazolidines offormula Id are prepared
wherein R, R1, Ra, Rb, R2, m, p,T, X are as above defined and m1 is 1 or 2. Reaction ofthiazolidines lVwith tertbutoxy carbonate gives compounds offormula I wherein R3 is -CO2C(CH3)3.
The thiazolidines IV are also disclosed in the above mentioned co-pending patent application, wherein it is also described the best procedure for carrying out these acylation reactions. Optionally, the acylation reaction can be carried out by reacting thiazolidine IV with the selected acid using a carbodiimide such asdicyclohexylcarboniimide as activating agent.
The thiazolidines offormula I wherein R is hydroxy and R3 is CO2C(CH3)3 may be optionally reacted with a lower C1-C6-alkyl halide, a propargyl halide and allyl halide in an aprotic solvent such as dimethylformamide, in the presence of potassium carbonate, to give a compound offormula I wherein R is a lower C1 -C6 alkoxy, CH2 = CH-CH2-O- and HC=CH-CH2-O-.
The subsequent optional cleavage of the protectivet-butoxy-carbonyl group with trifluoroacetic acid gives the corresponding thiazolidines offormula IV, with better results in comparison with the procedure disclosed in said patent application.
The compounds 3-[(3,6-dioxa-capriloyl )-2-(O-methoxyphenoxy)-methyl-thiazol idine, 3-(3-th is-6-oxa capriloyl)-2-(O-methoxyphenoxy)-methyl4hiazolidine, 3-(3-imidazolyl-propionyl)-2-(O-methoxyphenoxy)- methyl-thiazolidine, 3-(3'-imidazol-1 -yl)-propionyl-2-(O-propargyloxyphenoxymethyl)-thiazolidine, when tested to a dosage level 0.01-0.08 M, are mucus regulating agents at least as effective as 0.153 M of 5carboxymethylcysteine.
Moreover, the compounds 3-(acetylglicinyl)-2-(O-methoxyphenoxy)-methyl-thiazolidine, 3-BOC-2-(Omethoxyphenoxy)-methyl-thiazol idine, 3-glicinyl-2-(O-methoxyphenoxy)-methyl-thiazolidine and its 2-(O allyloxyphenoxy)-methyl analogue are also endowed with good antitussive properties with ED50 ranging from 3 to 30 mg/kg.
The compounds 3-[3-(2-(2-hydroxyethylamino)ethyl-amino)propionyl)]-2-(O-methoxyphenoxy)-methyl thiazolidine maleate and its 2-O-propargyloxy analogue are also particularly effective as antitussive agents with an ED50 ranging from 3 to 6 mg/kg and are both characterized by a very prolonged duration of action.
The compounds of the invention are also characterized by a pronounced ability to induce relaxation of the bronchial and tracheal smooth muscle.
For instance, 3-(3'-morpholinomethyl-4'-hydroxy-5'-methoxy-cinnamoyl)-2-(O-methoxyphenoxy)- methyl-thiazolidine. HCI is able to relaxe "in vitro" guinea pig trachea smooth muscle strips contracted by methacoline with ED50 of 1.9 x 10-4. The spasmolytic activity of the new substance favourably compares with thatofdihydroxypropyltheophylline (ED50 0.76x 10-4M). After intrajugularadministration, the compound appears 3-6 times more active than aminophylline in the resolution of bronchospasm induced by i.v. histamine in anestethized guinea-pigs (Konzett-Resslertest).
Therefore, compounds I are effective antitussive, bronchodilating and mucus regulating agents. They may be administered by oral, sublingual, intravenous, subcutaneous, intramuscular, rectal or inhalatory route.
The inhalatory route is particularly preferred when a mucus regulating action is requested.
The preferred doses of the compounds range from 0.05 to about 5 mg/kg/day, according to the patient's conditions, weight, age, and administration route.
The preferred doses by inhalatory route range from 0.05 to 1 mg/kg/day.
As previously stated, the compounds ofthe invention can be administered eitherto humans oranimals in a variety of dosage forms, e.g., orally in the form oftablets, capsules, or liquids; rectally, in the form os su p- positories; parenterally, subcutaneously of intramuscularly, with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; in the form of sterile implants for prolonged action. The pharmaceutical or veterinary compositions containing the compounds of the invention may be prepared in conventional ways and contain conventional carriers and/ordiluents.
For example, for intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For subcutaneous or intramuscular injection, sterile solutions or suspensions in aqueous or non-aqueous media may be used; for tissue implants, a sterile tablet or silicone rubber capsule containing or impregnated with the compound is used.
Conventional carriers or diluents are, for example, water, gelatine, lactose, dextrose, saccharose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium or magnesium stearate, glycol, starch, arabic gum,tragacenXh gum, alignic acid or alginates, lecithin, polysorbate, vegetable oils, etc.
For administration by nebulizer, a suspension or a solution ofthe compound ofthe invention, preferably in the form of a salt, such as the sodium salt in water (and/orthe nitrate salt) can be used. Alternatively, the pharmaceutical preparation can be in the form of a suspension or of a solution of the compound ofthe invention in one ofthe usual liquefied propellants, such as dichlorodifluoromethane or dichlorotetra fluoroethane, administered from a pressurized container such as an aerosol bomb. When the compound is not soluble in the propellant it may be necessary to add a co-solvent, such as ethanol, dipropylene glycol and/ora surfactantto the pharmaceutical formulation.
The following examples illustrate but do not limit the present invention.
Example 1 Tert-butylcarbonate (19.3 g) is added to a stirred solution of 2-[2'-(O-hydroxyphenyl)ethyl]-thiazolidine (18.5 g) in dimethylformamide (20 ml) at room temperature. After 1 hour, the mixture is diluted with water (200 ml) and the crystalline precipitate is filtered outto give 2-[2'-(O-hydroxyphenyl)ethyl]-3-BOC-thiazolidine (26.5g),m.p. 113-114"C.
lnsimilarwaythefollowing BOC-thiazolidine are prepared: 2-[2'-(O-hydroxyphenyl)ethyl]-3-BOC-4-carboethoxy-thiazolidine, oil, H-NMR (CHC13-THMS): 1.3 (3H, t, CH2-CW13); 1.5 (9H, s, -C(CH3)3); 3.3 (2H, d, s 4.3 (2H, q, CH2-CH3); 6.7-7.2 (4H, m ); 2-(2'-O-hydroxyphenoxy)methyl-3-BOC-thiazolidine, m.p. 11 0 C; 2-(2'-O-hydroxyphenoxy)methyl-3-BOC4-carbethoxy-thiazolidine, oil H-NMR (CHCl3-THMS): 1.5 (9H, s, -C(CH3)3).
Example2 A solution of 2-(2'-O-hydroxyphenoxy)methyl-3-BOC-thiazolidine (1 g) in anhydrous DMF (10 ml) is stirred with 0.3 ml of ally bromide and potasium carbonate (1 g)for5 hours. After dilution with water (100 ml), and extraction with ethyl ether (2 x 30 ml), the organic phases are washed with water, dried on Na2SO4and evaporated to dryness.
The residue 2-(2'-O-allyloxyphenoxy)methyl-3-BOC-thiazolidine (oil: H-N MR (CDCI3-THMS):1.4 1.4(9H, s, C(CH3)3; 4.55 (2H, d, -CH2-CH=); 5.6-5 (3H, m, CH2,
6.4-5.6(1 H, m, -Cl'=) is treated in dichloromethane (5 ml) with trifluoroacetic acid (4 ml) and stirred for a hour at room temperature. The mixture is evaporated to dryness in vacuum, the residue is partitioned between 5% aqueous KHCO3 and dichloromethane to give, afterthe usual work-up 2-(2'-Oallyloxyphenoxy)methyl-thiazolidine, m.p. 49-51"C. An analytical sample has m.p. 55-56"C.
Using in the same procedure the propargyl chloride, the following derivatives are prepared: 2-(2'-O-propargyloxyphenoxy)methyl-3-BOC-thiazolidine, m.p. 83-85"C; 2-(2'-O-propargyloxyphenoxy)methyl-tShiazol idine, m.p. 78-79"C (from ethanol).
Example3 Asolution of3-morpholinomethyl-4-hydroxy-5-methoxy-benzaldehyde (5.02 g) in ethylacetate (50 ml) is treated with 3-triphenylphosphilydene-methylcarbonyl-2-(O-methoxyphenoxy)-methyl-th iazol idine (11.8 g) at room temperature. After2 2 days, the mixture is extracted with 12% aqueous HCI (5 x 50 ml). The combined aqueous extracts are treated with 20% aqueous NaOH until pH Sand then with 5% aqueous NaHCO3 until pH 7.8-8, extracted with dichloromethane (2 x 25 ml) to give a crude material which is purified by SiO2column chromatography (hexane:ethylacetate 1:1).
The oil (5.3 g) is treated in ethylacetate with 6N HCI in isopropanol to give 3-(3'-morpholinomethyl-4'- hydroxy-3'-methoxy-cinnamoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine hydrochloride (4.9 g) m.p. 124- 126CC.
In similarwaythe following compounds are prepared 3-(3'-pyrrolidylmethyl-4'-hydroxy-5'-methoxycinnamoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine-hydrochloride, m.p. 134-136"C; 3-(3'-morpholinomethyl-4'-hydroxy-5'-methoxy-cinnamoyl)-2-(O-hydroxyphenoxy)methyl-thiazolidine maleate; 3-(3'-diethylaminomethyl-4'-hydroxy-5'-methoxycinnamoyl)-2-(O-propargyloxyphenoxy)methyl- thiazolidine-hydrochloride.
Example4 Using the procedure of the Example 3 the following aldehydes: 2-(4-methyl-piperazin-1 '-yl)ethanal 2-(morpholin-1 '-yl)ethanal 3-(morpholin-1 '-yl)propanal the following 3-substituted thiazolidines are prepared: 3-[4-(4-methylpiperazin-1-yl)-2-butenoyl]-2-(O-methoxyphenoxy)methyl-thiazolidine maleate; 3-[4-(morpholin-1 -yl)-2-butenoyl]-2-(O-methoxyphenoxy)-methyl-thiazolidine-hydrochloride; 3-[5-(morpholin-1-y)-2-pentenoyl]-2-(O-methoxyphenoxy)-methyl-thiazolidine-hydrochloride; 2-(2-pentenoyl )-2-(O-methoxyphenoxy) methyl-thiazolidine.
Example5 Asolution of acryloylchloride (12.2 ml) in CH2C12 is added to a stirred solution of 2-(O methoxyphenoxy)methyI-thiazolidine (30.5 g) and triethylamine (20.7 ml) in CH2C12(130 ml), cooled atO.S"C.
The mixture is kept for 3 hours at 0-5"C, the triethylamine hydrocloride is removed by filtration and the eluate is washed with water, 5% aqueous NaHCO3, water. After drying on Na2SO4, and evaporation ofthe solvent, the crude residue is crystallized from ethylacetate to give 3-acryloyl-2-(O-methoxyphenoxy)methylthiazolidine m.p. 56-58"C. Using in the procedure the 2-(O-hydroxyphenoxy)methyl-thiazolidine and cooling the reaction mixture at -15 - -10 C, the 3-acryloyl-2-(O-hydroxyphenoxy)methyl-thiazolidine is obtained. A solution ofthese acryloylthiazolidines (1.1 g) in ethanol (20 ml) are treated with (2hydroxyethylamino)ethylamine (0.42 ml).
The reaction mixture is kept for 28 hours at room temperature and evaporated to dryness. The residue is partitioned between water and ethylacetate. The organic phase is separated, washed with water, dried on Na2NO4 and evaporated to dryness.
Asolution ofthe residual oil (1 .6g) in dry acetone (20 ml) is treated with a solution ofmaleicacid (0.48g) in acetone (6 ml) to give a crystalline precipitate, to give: 3-(3-(2-hydroxyethylamino)ethyl)aminopropanoyl-2-((O-methoxyphenoxy)methyl-thiazolidine bis maleate m.p. 128-130"C.
3.(3-(2-hydroxyethylamino)ethyl)aminopropanoyl-2-(O-hydroxymethyl)thiazolidine bis maleate m.p. 134- 136"C; 3-(3-(2-hydroxyethylamino)ethyl)aminopropanoyl-2-(O-proparbyloxy-methyl)thiazolidine bis maleate.
Example 6 In inert gas atmosphere, cysteamine hydrochloride (0.38 g) is treated with 2-(O-methoxyphenoxymethyl)3-acryloyl-thiazolidine (0.8 g) in ethanol (25 ml) for 12 hours at room temperature and then for8 hours atreflux temperature.
The reaction mixture is cooled at room temperature and after two days the crystalline precipitate is filtered to give 0.62 g of3-(5-amino-4-thia-hexanoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine-hydrochloride m.p.
116-118"C.
Using the same procedure N-acetyl-cysteine, in the presence of catalytic amount of sodium methylate, 3-(5-carboxy-5-acetylamino-4-thia-hexanoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine m.p. 119-121"C, is prepared.
Example 7 By treatment of the above described acryloythiazolidine in ethanol with imidazole,the following compounds are prepared: 3-(3-im idazol-1 -yl )-propionyl-2-(O-propargyloxyphenoxy)-methyl-thiazolidine; 3-(3-imidazol-1-yl)-propionyl-2-(O-methoxyphenoxy)methyl-thiazolidine m.p. 115-117 C (as nitrate).
Example 8 A solution of 2-morpholine-ethylchloride hydrochloride (0.18 g) in water (5 ml) is added to a solution of 3-(2-mercaptoacetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine in aqueous N sodium hydroxyde (10 ml), in inert gas atmosphere and stirred overnight at room temperature.
The aqueous phase is extracted with ethylether, and the combined organic phase are collected, washed with NaOH, water, dried on Na2SO4 and evaporated to dryness to give 3-[5-(morpholin-1 -yl)-3-thia- pentanoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine (oil), hydrochloride m.p. 158-1 600C.
Example 9 Asolution of 1-iodo-pentane (0.21 ml) in methanol (2 ml) is added to a solution of 3-(2-metcaptoacetyl)-2 (O-methoxyphenoxy)methyl-thiazolidine (0.5 g) in a sodium methylate solution (from 42 mg of sodium in 10 ml of methanol). The mixture is stirred for 3 hours at room temperature, diluted with N aqueous sodium hydroxide (60 ml) and then extracted with ethylacetate to give after the usual work-up, 0.44 g of 3-(3-thia octanoyl)-2-(O-methoxyphenoxy)methyl-thiazolidineoil.UsinginthisproceduretheR-bromomethylacetate as alkylating agent, the 3-(4-carbomethoxy-34hia-succinoyl)-2-(O-methoxyphenoxy)methyl4hiazolidine, m.p. 77-79 C, is obtained.
Example 10 Asolution ofdicyclohexylcarbodiimide (1.75 g) in dimethylformamide (10 ml) is added to a stirred suspen- sion of phenylthioacetic acid (1.449) and 2-(O-hydroxyphenoxy)methyl-thiazolidine in dimethylformamide (15 ml).
After two hours, the idcyclohexylurea is filtered out and the solution is diluted with water (150 ml) and extracted with ethylether. The organic phases are collected and, afterthe usual work-up, the residual oil is purified by chromatography on SiO2 (hexane-AcOEt 1:1) to give 1.8 g 3-(phenylthioacetyl)-2- (hydroxyphenoxy)methyl-thiazolidine m.p. 94-96"C.
In similarway,thefollowing derivatives are prepared: 3-(phenylthioacetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, m.p. 97-99"C; 3-(3-thia-pentanoyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, m.p. 66-67"C.
Example 11 A solution of 1-acetylcysteine disodium salt (638 mg) in MeOH (3 ml) is treated with a solution of 3-(a- chloroacetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine (o.88 g) in dimethoxyethane (10 ml). After 2 hours at room temperature the mixture is evaporated to dryness and the residue is partitioned between ethyl acetate and aqueous 20% NaH2PO4 solution.
The organic phase, afterthe usual work-up, gives 0.76 g of3-(5-carboxy-5-acetylamino-3-thia-pentanoyl)-2- (O-methoxyphenoxy)methyl-thiazolidine, m.p. 69-78 C.
Example 12 a-Methoxy-acetylchloride (7.3 ml) is added to a stirred solution of 14.8 g 2-(O-methoxyphenoxy)methyl- thiazolidine andtriethylamine (11.2 ml) in sym-dichloroethane (100 ml), cooled at0.5C. After 1 hour, the mixture is washed with water. After the usual work-up and crystallization from isopropanol, 11.46 g of 3-(a methoxyacetyl)-2-(O-methoxyphenoxy)methyl4hiazolidine, m.p. 76-77"C are obtained.
Using the same procedure the 3,6-dioxa-capriloyl-chloride and the 3-this-6-oxacapriloyl chloride, the following compounds are obtained: 3-(3,6-dioxa-capriloyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, oil, H-NMR (CDCl3-THMS):1.3 (3H,t, CH2-CH3); 3.7 (6H, m, -O-CH2-CH2-O-CH2); 3.8 (3H, s, O-CH39; 6.5 (4H s 3-(3-thia-6-oxa-capriloyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, oil, H-NMR (CDC13-THMS): 1.3 (3H, t, CH2CH3); 3.82 (3H, s, OCH3).
Example 13 N,N'-Dicyclohexylcarbodiimide (22.7 g) is added to a stirred solution of 2-(O-methoxyphenoxy)methyl- thiazolidine (22.6 g), N-acetylglycine (12.9 g) and 4-dimethylaminopyridine (1.08 g) in sym-dichloroethane cooled at 0 C. After 12 hours, the dicyclohexylurea is removed by filtration, and the organic phase is washed with 5% aqueous NaHCO3, water and then it is dried on Na2SO4.After removal of solvents in vacuum, the residual oil is crystallized from isopropanol to give 3-(N-acetylaminoacetyl)-2-(O-methoxyphenoxy)methylthiazolidine, m.p. 1 19-120"C. Using in this procedure BOC-giycine and N-formylglycine, the corresponding 3-(N-formylaminoacetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, m.p. 104-1 060C, 3-(BOC-glycinyl)-2-(O- methoxyphenoxy)methyl-thiazolidine oil, are prepared.
By treatment of the BOC-derivate with trifluoroacetic acid and methylene chloride at room temperature, using the procedure of the Example 2, the 3-(glycinyl) compound is prepared.
By treatment of a solution ofthe N-formyl-glycinyl compound (15.07 g) in methanol (250 ml) with 8N HCI solution in isopropanol (9 ml) for8 hours at room temperature, followed by concentration of the mixture at volume of50 ml andfiltration,12 9 of 3-glycinyl2-2(0-methoxyphenoxy)methyl-thiazolidine.HCI m.p. 182-184"C, are obtained.
Example 14 A stirred solution of 3,5-dibromo-salicylaldehyde (8.37 g), 3-g lycinyl-2-(O-methoxyphenoxy) methyl- thiazolidine-hydrochloride (9.54 g) and triethylamine (4.14 ml) in methanol (250 ml) is heated at refluxtemperaturefor3 hours and then colled to room temperature. Stirring in continued for 8 hours to precipitate 15.12 g of3-(2-(3,5-dibromo-2-hydroxy-benzylidenamino-acetyl)-2-(O-methoxyphenoxy)methyl-thiazolidine, m.p.
126-1 30"C.
10% NaBH4 on alumina (1 1.8 g) is added to a stirred solution ofthis compound in ethylacetate (250 ml).After 6 hours, the organic phase is filtered, washed with water and dried on Na2SO4.
Aftertreatmentwith 8N HCI in isopropanol (4.8 ml), 3-(3',5'-dibromo-6' hydroxyphenyl)methylaminoacetyl-2-(O-methoxyphenoxy)methyl-thiazolidine-hydrochloride (12.9 g), m.p.
193-196"C, is obtained.

Claims (5)

1. Compoundshavingformula I
wherein: XisaCH2,O,S; R is hydroxy, or an esterthereof of formula RC-CO2- lower C1-C6-alkoxy, CH2=CH-CH2O-; HCaC-CH2-O-; methyl R1 is hydrogen and
R2 is hydrogen or a free or esterified carboxy group; R3 is hydrogen, a C1-C2 alkylsulphonyl group, a phenyl, p-Cl -phenyl, p-methyisulphonyl group or an acyl group of formula RdCO; p is zero or 1 with the proviso thatwhen X sulphur p is zero; both Ra and Rb are hydrogen or methyl; Rc and Rd, which are the same or different are: hydrogen, 0 C(CH3)3, -(CH2)n-Q and
from 1 to 7;P1, P2, are both hydrogen or one of them is hydrogen and the other one is lower C1-C4 alkyl or phenyl and Q is selected in the group consisting of: -NH2; a mono or di-substituted amino, t-butoxy carbonylamino or C1-C2 acylamino group; an ether-O (CH2)m-TorthioetherS-T chain, wherein T is an unsubstituted or mono- or polysubstituted phenyl ring or a group offormula (CH2)m-T1,wherein T1 is selected in the group consisting of H, OH, OCH3, Oc2H2-, free and esterified carboxy group, NH2, aC1-C2-acylamino or mono- or disubstituted amino group, or a group of formula
wherein Re is hydrogen, methyl or ethyl and m is an integer from 1 to 3; a phenyl, phenoxy or phenylthio ring unsubstituted or mono- or polysubstituted in them, o, and p-positions; a group of formula -( CH2),-SCO-(CH2),P3 wherein m and n have the above defined meanings and P3 is a lower C1-C7, linear or branched, alkyl chain, a C3-C6-cycloalkyl, a disubstituted aminogroup, a phenyl or phenoxy ring, optionally mono- or polysubstituted in the o, m and p-positions; an alkenyl chain offormula
wherein T has the above defined meanings; the term "mono substituted amino group" comprising, within the meanings thereof, an amino group substituted by a C1-C6, linear or branched alkyl group or by groups having formula: -CH2-CH2-O-CH2-CH3, -CH2- CH2-O-CH2-CH2-OH, -CH2-CH2-NH-CH2-CH3, -CH2-CH2-NH-CH2-CH2-OH or
the substituents our a disubstituted amino group according to the invention may be linear or branched C1-C6 alkyl groups or, taken together, they represent an unsaturated or usaturated nitrogen ring such as morpholin1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, 4-methyl-piperazin-1 -yI, 4-theyl-poperazin-1 -yl, 4-(2' hydroxyethyl)piperazin-1 -yl, 4-ethyl-piperazin-1 -yl, 4-(3'-chlorophenyl)piperazin-1 -yl, 4-(4' fluorophenyl)piperazin-1 -yl; imidazol-1 -yI, 3-pyridil, 4-pyridyl; the term "mono- or polysubstituted phenyl",according to the invention, meaning phenyl groups which are substituted by a fluorine atom in the para position, by chlorine atoms in the meta and para positions or by a CF3 in the meta positions or phenyl groups offormula
wherein Z1 is H or COCH3 and Z2 iS H, CH3 or COCH3 and N is an amino, C1-C2 acylamino or mono- ordisubstitu ted amino groups, as above defined;; salts with non toxic bases or acids thereof, enantiomers, diastereoisomers or mixtures thereof.
2. Acompoundselected in the group consisting of: 3-(3'-morpholinomethyl-4'-hydroxy-3'-methoxy cinnamoyl)-2-(O-methoxyphenoxy)-methyl-thiazolidine; 3-(3'-pyrrol idyl methyl-4'-hydroxy-3'-methoxy-cin namoyl)-2-(O-hydroxyphenoxy)-methyl-thiazol idine; 3-[3-(2-hydroxyethylamino)ethylaminopropanoyl]-2-(O-methoxyphenoxy)methyl-thiazolidine and its mal eate; 3-[3-(imidazol-1 -yl) propionyl]-2-(O-methoxyphenoxy)methyl-thiazolidine; 3-(3,6-dioxa-capriloyl)-2-(O-methoxyphenoxy)methyl-thiazolidine; 3-(acetylaminoacetyl-2-(O-methoxyphenoxy)methyl-thiazolidine.
3. Pharmaceutical compositions endowed with antitussive, mucus regulating and antibronchospastic ac tivitycontaining as the active principle at least a compound of claims 1-2 in admixturewith at least a carrieror excipient.
4. A process for the preparation of compounds offormula I characterized in that a compound offormula Il
wherein R, Ra, Rb, R1, R2, X and p have the above defined meanings, is reacted with an aldehyde of formula Ill T-CHO (III) wherein Thasthe above defined meanings and thattheso obtained compounds offormula la
wherein T is H, C1 -C4 alkyl or phenyl are optionally reacted with mono- or disubstituted amines, amines of formula H2N-(CH2)m-T, wherein m and T1 have the above defined meanings, unsubstituted or mono- or polysubstitutedthiophenols orthiols having formula HS-(CH2)n,-T" wherein m and T1 have the above defined meanings.
5. A processforthe preparation of compounds offormula I characterized in that a compound offormula IV
wherein R, R1, Ra, Rb, R2, p and X are as above defined, is reacted with an acid of formula RdCOOH, wherein R, is as above defined, in the presence of a condensation agent orwith an activated form thereof selected in the group of acyl halides and anhydrydes.
GB08517553A 1984-07-27 1985-07-11 Antitussive and mucus regulating 2-substituted thiazolidines Withdrawn GB2177690A (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
GB08517553A GB2177690A (en) 1985-07-11 1985-07-11 Antitussive and mucus regulating 2-substituted thiazolidines
HU852765A HU195492B (en) 1984-07-27 1985-07-18 Process for producing 2-substituted thiazolidine derivatives with antitussive and mucus regulating action and pharmaceuticals comprising these compounds as active ingredient
NZ212831A NZ212831A (en) 1984-07-27 1985-07-22 Thiazolidine derivatives and pharmaceutical compositions
AU45242/85A AU582770B2 (en) 1984-07-27 1985-07-22 Antitussive and mucus regulating 2-substituted thiazolidines
IL75891A IL75891A (en) 1984-07-27 1985-07-23 Antitussive and mucus regulating 2-substituted thiazolidines,their preparation and pharmaceutical compositions containing them
CA000487403A CA1270250A (en) 1984-07-27 1985-07-24 Antitussive and mucus regulating 2-substituted thiazolidines
GR851845A GR851845B (en) 1984-07-27 1985-07-25
ES545575A ES8605249A1 (en) 1984-07-27 1985-07-26 Antitussive and mucus regulating 2-substituted thiazolidines.
IE187985A IE58518B1 (en) 1984-07-27 1985-07-26 Antitussive and mucus regulating 2-substituted thiazolidines
DK341985A DK169474B1 (en) 1984-07-27 1985-07-26 Anti-cough and mucus regulating 2-substituted thiazolidines, processes for their preparation, and pharmaceutical agents containing such
JP60166620A JPS6163669A (en) 1984-07-27 1985-07-26 2-substituted thiazolidine, manufacture and antitussive and mucus regulator containing same
DE8585109445T DE3574590D1 (en) 1984-07-27 1985-07-26 Cough-relieving and mucus-regulating 2-substituted thiazoles.
AT85109445T ATE48421T1 (en) 1984-07-27 1985-07-26 COUGH SUPPRESSION AND MURPH REGULATOR 2-SUBSTITUTED THIAZOLE.
EP85109445A EP0169581B1 (en) 1984-07-27 1985-07-26 Antitussive and mucus regulating 2-substituted thiazolidines
US07/266,559 US4857643A (en) 1984-07-27 1988-11-03 Antitussive and mucus regulating 2-substituted thiazolidines

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0169581A2 (en) * 1984-07-27 1986-01-29 BOEHRINGER BIOCHEMIA ROBIN S.p.A. Antitussive and mucus regulating 2-substituted thiazolidines
GB2164333A (en) * 1984-07-27 1986-03-19 Boehringer Biochemia Srl Thiazolidines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0169581A2 (en) * 1984-07-27 1986-01-29 BOEHRINGER BIOCHEMIA ROBIN S.p.A. Antitussive and mucus regulating 2-substituted thiazolidines
GB2164333A (en) * 1984-07-27 1986-03-19 Boehringer Biochemia Srl Thiazolidines

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