1,5-BENZOTHIAZEPINONE DERIVATIVES, THEIR PREPARATIONS AND PHARMACEUTICAL USE

Abstract: The invention relates to compounds of general formula (I) and pharmaceutically acceptable salts thereof, to processes for the preparation thereof and pharmaceutical compositions containing them. The new compounds, characterized by the presence on the basic nitrogen of at least a branched or cyclic alkyl group and/or by a substitution in the alkyl chain, are endowed with good calcium antagonistic properties and with a longer duration of action in comparison with diltiazem. Said compounds can be usefully utilized in several vascular pathologies such as hypertension and ischemic cardiopathy.

Description: 1,5-BENZOTHIAZEPINONB DERIVATIVES. THEIR PREPARATIONS AND PHARMACEUTICAL USE The present invention concerns diltiazem analogues, a process for their preparation and pharmaceutical compositions containing them. Diltiazem, disclosed in US 3562257, is a 1,5-ben- zothiazepinone derivative which, thanks to its calcium- antagonistic properties, is used in various cardio¬ vascular pathologies such as hypertension and ischemic cardiopathy. The pharmacolinetics of diltiazem in humans is however characterized by a short elimination half-life whereby the drug must be administered every 4-6 hours, with problems of patient's compliance and with very inconstant plasma concentrations. It has new been surprisingly found that 1,5-ben- zothiazepinone derivatives of general formula I, cha- racterized by the presence on the basic nitrogen of at least a branched or cyclic alkyl group and/or by a sub¬ stitution in the alkyl chain, are endowed with a longer duration of action in comparison with diltiazem, to¬ gether with similar or higher calcium antagonistic pro- perties. The compounds of the invention have the following formula: wherein R is hydrogen or an R-CO group wherein R~ is a C,-C 4 linear or branched alkyl or a phenyl group, op- tionally substituted by halogen atoms, methoxy or nitro groups; R.. and R_, which are the same or different, are a C.-C. linear or branched alkyl or a C,-C 7 cycloalkyl; R, is a C,-C. linear or branched alkyl; R. is hydrogen, chlorine, methoxy; n is 1 or 2; m is zero or 1 with the proviso that when is zero, at least one of R, and R- is a branched alkyl group or a cycloalkyl group. The invention concerns also the diastereoiso ers, the enantiomers or mixtures thereof of the compounds of formula I. The groups in positions 2 and 3 are in cis posi¬ tion and their configuration is 2S, 3S. Said US 3562257 discloses compounds of formula I wherein m is zero and R, and R_ are the same and repre¬ sent lower alkyl groups. All the examples refer to com- pounds wherein R., and R_ are methyl. Other analogues of diltiazem are disclosed in GB 2143532, EP 256888 and WO 8912633. The invention concern also the salts of the com¬ pounds I with pharmaceutically acceptable inorganic acids such as hydrochloric, hydrobromic, nitric, sulfu- nic, phosphoric acid and the like, as well as with pharmaceutically acceptable organic acids such as ace¬ tic, propionic, maleic, fumaric, malic, oxalic, tarta- ric, nitric, methansulfonic acid and the like. Particularly preferred compounds I are those whe- rein: - m is zero, n is 1, one of R. or R, is isopropyl, t- butyl, cyclopropyl, cyclohexyl and the other is methyl or isopropyl; - m is 1, n is 1, R-, is methyl and R, and R 2 are as above defined; - m is 1, n is 1, R- is hydrogen and R, and R 2 are as above defined. Particularly preferred compounds are those wherein R. is hydrogen and R is acetyl. Examples of C,-C 7 cycloalkyl residues are cyclo¬ propyl, cyclopentyl, cyclohexyl. The compounds of the inventions wherein R is hy¬ drogen or a R-CO group wherein R_is as above defined, are prepared by reacting a benzothiazepinone derivative of formula II with a compound of formula III wherein m, n, R., R 2 , R 3 , R. are as above defined and X is halogen. The so obtained compounds of formula I wherein R is H may be transformed in the compounds I wherein R is R-.CO by reaction with compounds of formula IV or their reactive derivatives R 5 COOH (IV) wherein R 5 has the above defined meanings. Alternatively, the compounds of formula I wherein R is a c -CO group wherein R.. is as above defined, may be prepared by reacting a compound of formula V wherein m, n, R_, R 2 , R., , R. are as above defined and Z is chlorine, bromine or a tosyloxy group. The intermediates of formula V may be prepared from the corresponding compounds of formula II by reac¬ tion with the compounds of formula VII wherein X is chlorine, bromine and m, n, Z and R, have the above defined meanings. The condensation of the compounds of formula II with a compound of formula III (optionally salified) is usually carried out in a solvent in the presence of an alkaline agent such as KOH, NaOH, K 2 CO,, NaH. Examples of salts of formula III are hydrochlo- ride, hydrobromide and the like. The solvents may be selected from aliphatic keto- nes (acetone, methylethylketone etc), ethylacetate, di- methylsulfoxide, dimethy1formamide, acetonitrile, te- trahydrofuran and dioxane. The reaction is carried out at a temperature from 0° to 100 C C, particularly from 20 to 70°C. The condensation of a compound of formula I wherein R is hydrogen with a compound of formula IV or with an active derivative thereof may be carried out in a solvent in the presence or in the absence of an acidity acceptor. An active derivative of compounds IV may be an anhydride (e.g. acetic, propionic) or a chloride (acetyl chloride, propionyl chloride and the like). Py- ridine, triethylamine, N-methylmorpholine and the like may be used as acidity acceptors whereas suitable sol¬ vents are acetic acid, chloroform, methylene chloride, dimethylformamide, tetrahydrofuran. The reaction tempe- rature ranges from 20 to 140 β C. The reaction for the preparation of compounds V may be carried out in an apolar or polar solvent such as methanol, ethanol, dioxane, acetonitrile, tetrahy¬ drofuran, N,N-dimethylformamide, methylene chloride, dimethylsulfoxide. The reaction temperature ranges form 0° to 150 C C according to the boiling temperature of the solvent. In order to neutralize the organic or inorganic acid HX released from the reaction, it is either possi¬ ble to use an excess of the base VI or an inorganic base such as potassium or sodium carbonate. Whenever the above reactions yield mixtures of diastereoisomers, these may be separated by usual methods (fractional crystallization, chromatography) . The compounds of formula I and their pharmaceuti- cally acceptable salts have advantageous calcium anta¬ gonistic properties. These properties were studied άji itro by displa¬ cement of 3H-diltiazem from its binding sites in the cardiac tissue (according to the method of H.Glossmann et al., FEBS 160, 226 (1983) or by the inhibition of the tonic contraction induced in the rabbit isolated atrium (according to the method of M.Spedding, Arch. Pharmacol. 3113, 234 (1982)). The p IC 50 and p A 2 values of several compounds of the invention are higher than 7. π j vivo the compounds of formula I turned out to have remarkable and long-la¬ sting anti-anginal properties as it was shown by the vasopressine-induced angina in the rat (according to the method of .Leitold, H.Laufen, Arzneim. Forsch. 33, 1117 (1983)). Several compounds have DE 50 's comparable to that of diltiazem but with a longer duration. In pharmacokinetic studies carried out in the conscious incannulated rat, several compounds show an elimination t 1/2 after oral administration higher than that of diltiazem. The compounds I are also endowed with a fa¬ vourable and long-lasting antihypertensive activity in the spontaneously hypertensive rat (SHR) test. As an example, the biological properties of the compounds cis(+)-3-acetyloxy-2,3-dihydro-3-[2-(N-iso- propyl-N-methylaminoethyl]-2-(4-methoxyphenyl)-1,5-ben- zothiazepin-4(5H)-one (Compound A) (Example 1) and of cis(+)-3-acetyloxy-2,3-dihydro-5-(2-methy1-3-dimethyla- minopropyl)-2(4-methoxyphenyl)-1,5-benzothiazepin- 4(5H)-one (Compound B) (diastereoisomer B, Example 3) in comparison with diltiazem. recepto- rabbit angina pharmaco- rial isolated vasopres- kinetics binding atrium sine test in the rat (pIC50) (pA2) rat (iv) (50 mg/kg/os) ED50 duration (mg/kg) (min) t 1/2 (min) The compounds I or their pharmaceutically accepta¬ ble salts may be used in form of pharmaceutical compo¬ sitions suitable for the oral or parenteral administra¬ tion. Usual excipients such as starch, lactose, glucose, arabic gum, stearic acid etc may be used. The pharma¬ ceutical compositions may be in solid form such as ta¬ blets, pills, capsules or suppositories or in liquid forms such as solutions, suspensions or emulsions. Moreover, if administered parenterally, the phar¬ maceutical preparations may be in form of sterile solu¬ tions. The compounds I will be usually administered in unit doses ranging form 1 to 100 mg to patients affec- ted by cardiovascular pathologies such as arrythmias, hypertension, ischemic cardiopathy. The following examples further illustrate the in¬ vention. The melting points are not correct, the identity of the compounds and their purity has been evaluated by elemental analysis (C,H,N) and IR, UV, NMR and mass spectrometry. EXAMPLE 1 Cis(+)-3-acetyloxy-2,3-dihydro-5-(2-N-isopropyl-N- methylaminoethyl)-2-(4-methoxyphenyl)-1,5-benzσthiaze- pin-4(5H)-one hydrobromide (a) A mixture of cis(+)-2,3-dihydro-3-hydroxy-2-(4- methoxyphenyl)-l,5-benzothiazepin-4(5H)-one (3.3 g), N- isopropyl-N-methylaminoethyl chloride hydrochloride (1.5 g) and K 2 C0 3 (1.5 g) was suspended in 30 ml methyl ethyl ketone and refluxed for 12 hours. The residue was treated with ethyl ether and diluted with HC1 (1:1). The organic phase was separated. The acid aqueous phase was alkalinized with 10% NaOH and extracted several times with ethyl ether. The organic phases were pooled and evaporated to dryness. The oily residue (3.1 g) was directly used for the subsequent reaction. (b) The product obtained in (a) was dissolved in 31 ml acetic anhydride and let to stand for 12 hours. The acetic anhydride was distilled off under vacuum. The residue was dissolved in 32 ml ethyl ether and treated with a 6N HBr solution in isopropyl alcohol to acid pH. The precipitate was separated by filtration and cry- stallised from acetone-ethyl ether. 2.4 g white solid were cbtained; m.p. 137-140"C. The following compounds were prepared according to the above procedure. cis(+)-3-acetyloxy-5-(2-N-ethyl-N-methylaminoethyl)- 2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin- 4(5H)-one oxalate monohydrate; m.p. 105-108°C (ethyl acetate) ; cis(+)-3-acetyloxy-5-(2-N-t-butyl-N-methylaminoe- thyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiaze- pin-4(5H)-one oxalate; m.p. 86-89°C (isopropyl alcohol- ethyl ether) ; cis(+)-3-acetyloxy-5-(2-N-cyclopropyl-N-methylamino- ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiaze- pin-4(5H)-one; cis(+)-3-acetyloxy-5-(2-N-cyclohexyl-N-methylamino- ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiaze- pin-4(5H)-one; cis(+)-3-acetyloxy-5-(2-N-diisopropyl-N-methylamino- ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiaze- pin-4(5H)-one oxalate; m.p. 86-89 β C (isopropyl alcohol- ethyl-ether). EXAMPLE 2 Cis(+)-3-acetyloxy-2,3-dihydro-5-(2-methyl-3-dimethyla- minopropyl)-2-(4-methoxyphenyl)-1,5-benzothiazepin- 4(5H)-one oxalate (diastereoisomer A) (a) cis(+)-3-acetyloxy-5-(3-chloro-2-methylpropyl)- 2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin- 4(5H)-one. 5 g cis(+)-3-acetyloxy-2,3-dihydro-2-(4-methoxy- phenyl)-l,5-benzothiazepin-4(5H)-one were dissolved in 30 ml dimethyIformamide, cooled at -7 β C. 1.4 g 88% KOH and, after 10 minutes, 3.8 g l-bromo-3-chloro-2- methyIpropane were slowly added. The temperature was then raised to 0°C and the mixture was stirred for 4 hours. The reaction mixture was then poured in 250 ml 0.6N NH.C1 solution and extracted with CH 2 Cl 2 . The collected organic phases were washed with H 2 0, dried on Na 2 S0 4 and evaporated under reduced pressure. 6 g a thick orange oil were obtained and were dissolved in hot isopropyl alcohol. A crystalline solid precipitated by cooling, m.p. 100-103 C C. The following compounds were prepared according the above procedure: cis(+)-3-acetyloxy-5-(3-chloro-2-ethylpropyl)-2,3-di- hydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one; - cis(+)-3-acetyloxy-5-(3-chloro-2-isopropyl)-2,3-dihy- dro-2-(4-methoxyphenyl)-l,5-benzothiazepin-4(5H)-one. (b) 5 g chloro derivative, obtained as in (a), were dissolved in 30 ml dimethy1formamide; 10 g dimethy- la ine and 0.05 g KI were added to the solution. The solution was then heated to 80 β C for 4 hours. The reaction mixture was then poured in 300 ml H 2 0 and the separated solid was extracted with ethyl ether. The organic phase was evaporated to dryness and the residue was reacted with 35 ml acetic anhydride at room temperature. After 48 hours the excess acetic anhydride was eliminated and the residue was treated with ethyl ether. The white solid was separated and salified with oxalic acid in isopropyl alcohol. 3.5 g product, which were purified by isopropyl alcohol crystallization, were obtained; m.p. 177-179 β C. W3 D 20 =148 (H 2 0). The following compounds were prepared according the above procedure: cis(+)-3-acetyloxy-2,3-dihydro-5-[2-methyl-3-(N-cy- clopropyl-N-methylamino)propyl3-2-(4-methoxyphenyl)- l,5-benzothiazepin-4(5H)-one; cis(+)-3-acetyloxy-2,3-dihydro-5-[2-methyl-3-(N-cy- clohexyl-N-methylamino)propyl]-2-(4-methoxyphenyl)-l,5- benzothiazepin-4(5H)-one; cis(+)-3-acetyloxy-2,3-dihydro-5-[2-methyl-3-(N-di- methylamino)propyl]-2-(4-methoxyphenyl)-1,5-benzothia- zepin-4(5H)-one. EXAMPLE 3 Cis(+)-3-acetyloxy-2,3-dihydro-5-(2-methyl-3-dimethyla- minopropyl) -2-(4-methoxyphenyl)-1,5-benzothiazepin- 4(5H)-one oxalate (diastereoisomer B) 5 g cis(+)-2,3-dihydro-3-hydroxy-2-(4-methoxyphe- nyl)-l,5-benzothiazepin-4(5H)-one, 2.9 g 2-methyl-3-di- methylaminopropylchloride hydrochloride, 5.7 g K-CO-,, 1.4 ml H 2 0 were reacted in 75 ml acetone, according to the procedure as in Example 1 (a), then reacted with 70 ml acetic anhydride, (see Example 1 (b)). The crude was treated with ethyl ether and the so obtained solid is filtered off and the solution was evaporated to dryness. This procedure was repeated. 4.3 g residue were dissolved in isopropyl alcohol and treated with 1.2 g oxalic acid. A solid, which was crystallized from acetone-ethyl ether, was obtained; m.p. 84-89°C; [o(3 D 20 =+119.3 (H 2 0). The following compounds was prepared according the above procedure: cis(+)-3-acetyloxy-7-chloro-2,3-dihydro-5-(2-methyl- 3-dimethylaminopropyl)-2-(4-methoxyphenyl)-1,5-ben- zothiazepin- (5H)-one (starting from cis(+)-2,3-dihy- dro-7-chloro-3-hydroxy-2-(4-methoxyphenyl)-1,5-ben- zothiazepin-4(5H)-one) . EXAMPLE 4 Cis( *)-2,3-dihydro-5-(2-N-isopropyl-N-methylamino- ethyl)-3-(2,2-dimethylpropanoyloxy)-2-(4-methoxyphe- nyl)-l,5-benzothiazepin-4(5H)-one and pharmaceutically acceptable salts thereof The raw material (obtained ad disclosed in Example 1 (a)), was dissolved in 15 ml anhydrous pyridine and treated with 0.23 g pivaloyl chloride. After 24 hours, the reaction mixture was poured in water and extracted with CH 2 C1 2 - The organic phases were collected and eva¬ porated to drynesε. 0.9 g residue were converted to the corresponding maleic acid salt; m.p. 128-130°C (acetone-isopropyl ether).

Claims: CLAIMS 1. Compounds of general formula I and their diastere- oisomers or enantiomers or mixtures thereof wherein R is hydrogen or an R^CO group wherein R-. is a C,-C. linear or branched alkyl or a phenyl group, op¬ tionally substituted by halogen atoms, methoxy or nitro groups; R., and R 2 , which are the same or different, are a C.-C. linear or branched alkyl or a C,-C-- cycloalkyl; R-, is a C,-C. linear or branched alkyl; R. is hydrogen, chlorine, methoxy; n is 1 or 2; m is zero or 1 with the proviso that when m is zero, at least one of R, and R 2 is a branched alkyl group or a cycloalkyl group. 2. A compound according to claim 1 which is cis(+)-3- acetyloxy-2,3-dihydro-5-(2-N-isopropyl-N-methylamino- ethyl)-2-(4-methoxyphenyl)-l,5-benzothiazepin-4-(5H)- one and their pharmaceutically acceptable salts. 3. A compound according to claim 1 which is cis(+)-3- acetyloxy-2,3-dihydro-5-(2-methyl-3-dimethylamino- propyl)-2-(4-methoxyphenyl)-l,5-benzothiazepin-4(5H)- one and their pharmaceutically acceptable salts. 4. Process for the preparation of compounds of gene¬ ral formula I consisting in the reaction of a benzothiazepinone derivative of formula II with a compound of formula III wherein m, n, R., R 2 , R 3 , R. are defined as in claim 1 and X is halogen. 5. A process for the preparation of compounds of general formula I consisting in the reaction of a compound of formula V with- an amine of formula VI ^ 2 HN (VI) ^" R l wherein m, n, R. ; R 2 , R,, R. are defined as in claim 1 and Z is chlorine, bromine or a tosyloxy group. 6. Pharmaceutical compositions comprising as an ac¬ tive principle an effective quantity of a compound ac¬ cording to claims 1-3 together with a suitable pharma- ceutical excipient. 7. Use of a compound according to claims 1-3 for the preparation of a medicament to be used in cardiovascular pathologies.

Inventors: CALIARI SATURNINO, FICI FRANCESCO, MANGHISI ELSO, SALIMBENI ALDO, CALIARI, SATURNINO, FICI, FRANCESCO, MANGHISI, ELSO, SALIMBENI, ALDO
Applicants: LUSO FARMACO INST, ISTITUTO LUSO FARMACO D'ITALIA S.P.A.
Application year: 1991
Main classification: C07D281
IPC codes: A61K31, A61P3, A61P9, C07D281