AU609681B2

AU609681B2 - 3-hydroxy-2-(4-methoxyphenyl)-5-(2-methylaminoethyl)-2, 3-dihydro-5h-1, 5-benzothiazepin-4-one derivatives, their preparation and their application in therapy

Info

Publication number: AU609681B2
Application number: AU26595/88A
Authority: AU
Inventors: Colombe Denys; Christian Hoornaert; Alistair Lochead; Jean-Claude Muller
Original assignee: Synthelabo SA
Current assignee: Synthelabo SA
Priority date: 1987-12-08
Filing date: 1988-12-07
Publication date: 1991-05-02
Anticipated expiration: 2008-12-07
Also published as: JPH01190632A; IL88608A0; HUT50797A; NO167802B; HU201538B; JPH01190674A; NZ227235A; EP0320361A1; DK681088A; FR2624117B1; FI885670A7; FI885670A0; AU2659588A; ZA889169B; NO885435L; DK681088D0; EP0320362A1; KR890009901A; FR2624117A1; PT89182A

Description

A!,IrTrN ACCEPTED AND AMENDMENTS ALLU D ,ad 77 U0 9t 6) COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COWLETh E S AlQ NAME ADDRESS OF APPLICANT: 'J'hiis corm'inlt contains thieamendments made under Section 49 and is correct for printing A t Synthelabo 58 rue de la Glaciere F-75013 Paris France NAME(S) OF INVENTOR(S): Alistair LOCHEAD Jean-Claude MULLER Christian HOORNAERT Colomnbe DENYS ADDRESS FOR SERVICER DAVIES COLTJSON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: 3-hydroxy-2-(4-methoxyphenyl)-5-(-2 methylaminoethyl)-2; 3-dihydro-511-l, 5-benzothiazepin-4-one derivatives, their preparation and their application in therapy The following statement is a full description of this invention, including the best method of performing it known to me/us:- 06- Ri

F-

Ii .14 75621 PAMIS CCO5Xx 1 R.C 8 Pan 72 140E145 Insert place and date of signature.

Signature of declarant(s) (no attestation required) Note: Initial all alterations.

4. The basic application.......... referred tc in paragraph 3 of this Declaration was the first application.......... made in a Convention country in respect of the invention the subject of the application.

Declared at Paris this 17th day of NovEnber 1988 DAVIES COLLISON, MELBOURNE and CANBERRA.

I:

la Ii I (I ft *9 9 9 o ee *0 9 9 9

((II

I

The present invention relates to 3 -hydroxy- 2 -(4-methoxyphenyl)-5-(2methylaminoethyl)2,3dihydro-5H-l,5-benzothiazepin-4-one derivatives, to their preparation and to compositions containing them.

The present invention provides a compound, in the form of a pure diastereoisomer or a mixture of diastereoisomers, which is a derivative of formula (I) 0CK 3 ap/c ca 2 wherein: Ri is a hydrogen atom or a c2-C4 alkanoyl group; and R2 is a phenyl group unsubstituted or substituted with from 1 to 3 substituents selected from halogen atoms and methylenedioxy, ethylenedioxy and C 1

-C

4 alkoxy groups, or a pharmacologically acceptable acid addition salt thereof.

Preferably Ri is a -COCH 3 group substituted with from 1 to 3 group and R2 is a phenyl substituents selected Ii

"I'

15 2 'from chlorine atoms and methoxy, methylenedioxy and athylenedioxy groups, for example a phenyl group substituted in the 3-position by a methoxy group, in the 3,4-positions by two methoxy groups, two chlorine atoms or a methylenedioxy group, in the 2,5- or 2,3-positions by two methoxy groups or in the 3,4,5-positions by three methoxy groups.

Since the carbon atoms at the 2- and 3-positions it r ,r are asymmetric, the compounds can exist in various t diastereoisomeric, racemic or optically pure forms. These various forms form part of the invention.

The compounds of the present invention may be prepared according to the scheme shown below.

The present invention provides a process for the 15 preparation of a compound as defined above wherein a benzothiazepinone of formula (VI)

OCH

3 OR1 H 0

(VI)

in which R1 is as defined above is reacted with a halogenated amine of formula (V) X1

(V)

H

3 C

C

2

-I

-3in which R2 is as defined above and Xl is a halogen atom and the compound of formula thus obtained is, if desired, converted to a pharmacologically acceptable acid addition salt thereof. X1 can, for example, be a chlorine or bromine atom.

The present invention also provides a process for the preparation of a compound as dGeined above wherein a benzothiazepine of formula (VIII):

OCH

3 in which R1 is as defined above is reacted with a tORi halogenated derivative of formula (II): X2-CH2-R2 in which R2 is as defined above and X2 is a halogen atom, and the compound of formula thus obtained is, if desired, converted to a pharmacologically acceptable acid addition salt thereof. X2 can, for example, be a chlorine or bromine atom.

~I i IR:: ,o 4 -4-

SCHEME

F

(II)

HO C2 10R2 I I *44 It. I I I 6

(III)

R2

OH

,N .oR2

H

3 C C 2

(VII)

H

N.,

6 R2

H

3 C CH 2

I

I I I 64 I 44 o 6 0 6 66 44 9 6 4 4 .9 ~4 464 6 4 4' 6 4

H

3 C C

,,R

(VI)

R2 (111) X2.% CH2 ,,eR 2 (viii) 5 These two reactions between an amine and a halogenated derivative are conventional, and hence proceed under conditions well known to those versed in the art. For example they may be carried out in an aprotic solvent such as acetone or 2-butanone, at the refluxing temperature, in the presence of a base capable of reacting with the acid 4 liberated, for example potassium carbonate, and optionally in the presence of a phase transfer catalyst such as Stetra-n-butylammonium iodide. It is self-evident that a compound of formula in which R1 is a hydrogen atom may f' be converted to a compound of formula in which R1 is a a C 2

-C

4 alkanoyl group by acylation, and that the reverse S" 'conversion is possible by hydrolysis.

s The benzothiazepinones of formula (VI) are 15 described, for example, in Chem. Pharm. Bull., 18, 2281 (1970), Chem. Pharm. Bull., 19, 595 (1971) and Helv. Chim.

4' Acta, 67, 916 (1984). The benzothiazepinones of formula (VIII) are described, for example, in Chem. Pharm. Bull., 26, 2889 (1978), J. Pharmacobio. Dyn., 7, 24 (1978) and J.

Cardiov. Pharmacol., 7, 152 (1984).

The halogenated amine of formula may be prepared, for example, from the corresponding alcohol of formula (IV) shown in the scheme wherein R2 is as defined above, by the action of a halogenating agent such as thionyl chloride. The amino alcohol of formula (IV) can itself be prepared according to any known method, for example by the 77 I 6 reaction of an amine of formula (VII) shown in the scheme wherein R2 is as defined above with 2-chloroethanol, or alternatively by the reaction of a halogenated derivative of formula (III) shown in the scheme wherein R2 is as defined above with 2-methylaminoethanol.

The compounds of formulae (III) and (VII) are described in the literature, and are for the most part commercially available. The non-commercialised compounds of formula (III) are readi,ly accessible from the alcohols of formula (II) shown in the scheme wherein R2 is as defined above.

The following Example illustrates in .detail the preparation of a compound according to the present invention.

The elemental microanalyses and the IR and NMR spectra confirm the structures of the products obtained t Example (+)-cis-3-Acetyloxy-2-(4-methoxyphenyl)-5-[2-{N-[2-(3,4methylenedioxyphenyl)methyl]methylamino}ethyl]-2,3-dihydro- 5H-1,5-benzothiazepin-4-one.

4 g (0.00915 mole) of (+)-cis-(2S,3S)-3-acetyloxy- 2-(4-methoxyphenyl)-5-(2-methylaminoethyl)-2,3-dihydro- 5H-1,5-benzothiazepin-4-one, 3 g (0.0366 mole) of potassium carbonate, 2.3 g (0.0137 mole) ofoC-chloro-3,4- (methylenedioxy)methylbenzene and 100 ml of 2-butanone are introduced into a 250 ml round-bottomed flask, and the 7 mixture is heated under reflux for 24 h. The mixture is filtered, the filtrate is evaporated and the residual oil is purified by chromatography on a silica column, eluting with a 97:3 dichloromethane/methanol mixture. The pure fraction is dissolved in 60 ml of ethanol and treated with 0.76 g of oxalic acid, and the salt which precipitates is filtered off and recrystallized in ethanol. 2.71 g of acetyloxy-2-(4-methoxyphenyl)-5-[2-{N-[2-(3,4methylenedioxyphenyl)-methyl]methylamino}ethyl]-2,3-dihydro- 5H-1,5-benzothiazepin-4-one oxalate is finally isolated.

Melting point: 71 0

C.

The table below illustrates the chemical structures

I

o and physical properties of a few compounds according to the invention.

t I t it I I i i

L

I

-8 TabLe

,OC~K

3 0 9* 0 9t1 rttf I L 4* 1 I if

I

994 4 90 9 *09* 09 9 9 9 0 9 *4 o 90 9 90 90 9 99 0* 9 9 9 9 0 *9 No. Rl R2 SaLt* 20 M.P. (OC) c.IqeOH X 1 COCH 3 c6 H 4-3-OCH 3OX. +86.5 164 3 64 3(0.5) 2 COCH C 6 Hj 3,4-(OCH )OX. +84.8 152 3 C63 2 3 COCH 3 c6 H -3,4-OCH2 0 OX. +87.5 71 3 6 2(0.5) 4 COCH 3 c 6Hf3 OCH3)2 ox-. +83.3 184 6

H

3 3 2(0.5) COCH 3 c 6 H i2,5-(OCH 3 2 OX. +89.3 108 (1) 6 COCH 3 c 6 H j2,3-(OCH 3 2 f um. +73.3 123 (1) 7 COCH 3 c 6 H 3 3,4-CL 2 OX. +82.4 178 8 COCH 3 c 6 H 3 3,40OCH 2

CH

2 0 OX. +75.9 114 (1) 9 COC 3 c 6 H 2 -3,4,5-(OCH 3 3 OX. +87.6 162 (0.3) 0x.

fumu.

oxaL.ate funarate 9 o I 00 Ir I 04 #0 0 00 0 d 90 0i 0 4 0o 0 00000 0 *011 The compounds of the invention were subjected to pharmacological tests which demonstrated their value as therapeutic substances.

A first test showed that they are calcium antagonists. The experimental protocol used is a variant of that used by Godfraind and Kaba (1969) (Blockade or reversal of the contraction induced by calcium and adrenaline in depolarized arterial smooth muscle, Br. J.

Pharmac., 36, 549-560).

The experiments were carried out on sections of rabbit thoracic aorta. The animals, "Fauves de Bourgogne" weighing 1.5 kg on average, are sacrificed by cervical dislocation and exsanguination. The thoracic aorta is rapidly removed and placed in an oxygenated 15 Krebs bicarbonate medium (95% 02 5% C02).

Sections of aorta approximately 1 cm long are prepared and installed in 20-ml organ cells containing oxygenated Krebs bicarbonate solution (pH 7.4) at 37 0

C.

Two U-shaped metal hooks having the same length as the sections are introduced into the bore of the latter.

One of the hooks is attached to the base of the cell.

The other, connected to an isometric strain gauge (Grass FT03), permits the recording, via a continuous preamplifier (Grass 7P1), of the contractile responses of the sections of aorta on a pen oscillograph (Grass 798). Compared with spiral or ring-shaped preparations, this method has the advantage of having greater regard IL i i 4~ 1 10 for the structural integrity of the vessels, and of recording only the radial component of the contractile responses, which represent the phenomenon of interest from the functional standpoint (regulation of arterial blood pressure). An initial tension of 4 g is applied to the preparations.

Phenoxybenzamine (1 uM) and propranolol (1 pM) are added to the different Krebs media in order to oo abolish the contractile responses linked to the activa- S' 10 tion of the vascular a- and B-adrenergic receptors.

o 00 0o 0 After one hour's stabilization in Krebs bicarbo- 0000 o nate medium, the tension applied to the aorta sections 0 04 is reduced to 2 g. After a delay period of 30 minutes, 0ao the preparations are incubated for about 10 minutes in a 15 Krebs bicarbonate solution without calcium in the pre- 00 sence of EDTA (200 1M) and propranolol (1 uM). This soluo -a "o tion is then replaced by a depolarizing Krebs medium 006* 00 0 0 (rich in potassium and depleted of sodium) without cal- 00 Ss* cium and containing propranolol (1 pM). After 5 minutes, a single calcium concentration of 1 mM is added to this solution, and a stabilization period of 30 minutes is observed, which enables the preparations to achieve stable contraction.

The test compounds are then added to the bath at cumulative doses, a Lapse of 30 minutes (the time generally necessary for obtaining a plateau) being observed between two concentrations, until there is complete 1 I r of 30 uM. At the end of the experiment, a supramaximal concentration of papaverine (300 uM) is added in order to determine the maximum possible reLaxation of each preparation.

The absolute values (in grams) for the initial contraction (after 1 mM CaCL2) and for the contraction after the different cumuative concentrations of vasodilatory compounds are obtained, for each preparatian, by difference with the minimal contraction observed minutes after the final addition of 300 M papaverine.

The percentage decrease in the contraction, relative to tr the contraction induced by 1 mM calcium, is calculated for each concentration of compound and each preparation, S and this individual percentage relaxation is averaged as X SEM. The mean values obtained (weighted by the reciprocal of the standard error of the mean) are analysed by means of a mathematical sigmoid curve model. The molar concentration inducing 50% relaxation of the response to calcium (EC 50 or alternatively its antilogarithm (pEC 50 is calculated.

For the compounds of the invention, the pEC 50 values are of the order of 5.0 to The compounds of the invention were also the subject of a test of inhibition of the specific binding of "PAF", platelet-activating factor.

i -L I 3 3 C CH 2 wherein: /2 12 The animals are rabbits weighing from 2.5 to 3 kg, anaesthetized with pentobarbital sodium (0.25 mg/kg intravenously) and maintained under artificial respiration by intubation. Blood is drawn from the carotid artery and collected in tubes containing a citrate-based anticoagulant. The tubes are subjected to a centrifugation at 100 g for 15 min, and the platelet-rich plasma is diluted with 2 volumes of 10 mM Tris/HCL buffer, pH 7.5, containing 150'mM sodium chloride and 2 mM EDTA (buffer After centrifugation at 1,000 g for 10 min at 4 0 C, the pellet is washed with 2 volumes of buffer A S: and a further centrifugation is performed.

The platelet-rich pellet is suspended in ice-cold buffer (10 mM Tris-HCl, pH 7.0, containing 5 mM magnesium t 15 chloride and 2 mM EDTA), homogenized and centrifuged at 30,000 g and at 4 0 C for 10 min. This operation is repeated, the resulting pellet is collected in the same buffer and homogenized and the membrane suspension is frozen in liquid nitrogen. For the binding inhibition test, the suspension is thawed and diluted with buffer to obtain a content of approximately 150 ig of protein per millilitre.

Aliquot amounts (30 ug of protein) of membranes are incubated in the presence of 10 mM Tris-HCL buffer, pH 7.0, containing 10 mM magnesium chloride and 0.25% (weight/volume) of bovine serum albumin, for 2 h at 0 C, with I nM tritiated PAF (C 3 H3-1-O-hexadecy-2- *s 13 'acetyl-sn-glyceryl-3-phosphorylcholine) in a final volume of 1 ml. The incubation is stopped by collecting the membranes and washing them rapidly with ice-cold buffer on Whatman filters, using a Skatron cell collector connected to a vacuum pump. The filters are dried and assayed by scintigraphic spectrometry. The specific binding is defined by the difference in radioactivity of the membranes observed in the absence and in the presence of 1 1M tritiated PAF.

The binding inhibition tests are performed under 0 the conditions described, in the presence of different concentrations of test compounds. The concentration

IC

50 (the concentration which inhibits the specific binding by 50%) is then determined for each compound by plotting the inhibition curve according to the method of Least squares.

The IC 50 values of the compounds of the invention, in this test, lie between 3 and 8 m.

Finally, the compounds of the invention were the subject of a test of inhibition of blood platelet aggregation induced by "PAF-acether" C1-0-(C 16

-C

18 alkyl)- 2 -acetyl-sn-glyceryl-3-osphosphorycholine.

The test is performed according to the method of Born CJ. Physiol., (1963), 168, 178-1953 on rabbit plate- Lets. The blood is drawn by cardiac puncture and collected over 3.8% strength trisodium citrate in the proportions Lr .r i i:l; ,of 1 volume of anticoagulant solution for 9 volumes of blood. A centrifugation is then performed at 250 g for min, the platelet-rich plasma is removed and the platelets are counted.

The pellet is subjected to a further centrifugation at 3,600 g for 15 min so as to obtain platelet-poor 0* st 1 200,000 to 300,000 plagelets per microlitre.

So 10 Aggregation is induced in vitro by means of PAFi nacether at the maximum concentration necessary for obtoa taining a maximal reversible response (normally between and 3.3 ng/ml). The changes in optical density are o: recorded by means of an aggregometer (300 il of platelet- 15 rich plasma per cell, 1,100 rpm at 37 0 C) until the point o 40 of maximal aggregation has been passed.

t For the tests, the compounds of the invention are dissolved in dimethyl sulphoxide and incubated for 2 a.

min at 37 0 C before the addition of PAF-acether.

The aggregation-inhibitory action of the compounds is expressed in terms of the IC 50 concentration, the concentration which inhibits by 50% the aggregation induced by PAF-acether.

The IC 50 values of the compounds of the invention, in this test, Lie between 1 and 10 pM.

The results of the pharmacological tests show that the compounds of the invention are calcium group substituted with from 1 to 3 substituents selected 5 .m

I

15 antagonists, and they can, on these grounds, be used for the treatment of various conditions for which this type of agent is indicated.

Thus, in particular, they may be used in cardiovascular medicine for the treatment of conditions requiring modulators of the trasmembranous and intracellular movements of calcium, most especially hypertension, angina, and cardiac arrhythmia.

They exhibit, in addition, antiatherogenic, platelet aggregation-inhibitory, cardiac anti-ischaemic, cerebral anti-ischaemic, antimigraine, antiepileptic, antiasthmatic and antiulcer effects. s- S' In the cardiovascular field, they may be used alone or in combination with other known active substances such as 1 diuretics, P-blockers, angiotensin-converting enzyme inhibitors and os-receptor antagonists.

In combination with agents designed to boost their effects or decrease their toxicity, they may also be indicated for the treatment of cancer or in transplantation.

Thus the present invention also provides a derivative of formula or a pharmacologically acceptable acid addition salt thereof for use in a method of treatment of the human or animal body by therapy especially treatment of hypertension, angina, cardiac arrhythmia, cardiac ischaemia, cerebral ischaemia, migraine, epilepsy, asthma, ulcers or cancer or a condition requiring an antiatherogenic

M

3N%, ,AR2 11 3 C C2 16 or platelet aggregation inhibitor. The present invention also provides the use of a derivative of formula or a pharmacologically acceptable acid addition salt thereof in the manufacture of a medicament for the treatment of hypertension, angina, cardiac arrhythmia, cardiac ischaemia, cerebral ischaemia, migraine, epilepsy, asthma, ulcers or cancer or a condition requiring an antiatherogenic or platelet aggregation inhibitor.

orThe compounds of the invention may be presented in any form suitable for oral or paren'eral administration, in combination with known excipients, for example in the form of tablets, hard gelatin capsules, dragees, capsules, and solutions or suspensions to be taken by mouth or injected.

The present ninvention therefore provides a pharmaceutical composition comprising a derivative of formula or a pharmacologically acceptable acid addition salt thereof and a pharmaceutically accpetable diluent.

The daily dosage can range, for example, from 30 to 300 mg orally and from 25 to 100 mg parenterally.

300 mg orally and from 25 to 100 mg parenterally.

i

Claims

2. A compound according to claim 1 wherein R1 is a
3. A compound according to claim 1 or 2 wherein R2 is a phenyl group substituted with from 1 to 3 substituents selected from chlorine atoms and methoxy, methylenedioxy and ethylenedioxy groups. S' I thereof. 2. A compound according to claim 1 wherein R1 is a 3. A compound according to claim 1 or 2 wherein R2 is a phenyl group substituted with from 1 to 3 substituents I formla (I J t.L±U L U I I tz CUIIIIU dCUUI L UI. LUL I LL. V '.tIt J V prepared according to any known method, for example by the -18 chlorine atoms or a methylenedioxy group, in the or 2,3-positions by two methoxy groups or in the 3,4,5 positions by three methoxy groups. A compound according to any one of the preceding claims in the form of an oxalate or fumarate salt.
6. A compound according to any one of the preceding claims specifically identified herein. e a defined in any one of the preceding claims wherein a benzothiazepinone of formula (VI): PCM 3 0 (VI) in which Rl is defined in claim 1 or 2 is reacted with a 1 halogenated ampine of formula (V) Dg I J ()c L^ introduced into a 250 ml round-bottomed flask, and the 19 in which R2 is as defined in any one of claims 1, 3 and 4 and Xl is a halogen atom, and the compound of formula (I) thus obtained is, if desired, converted to a pharmacologically acceptable acid addition salt therof.
8. A process for the preparation of a compound as defined in any one of claims 1 to 6 wherein a benzothiazepine of formula (VIII): OCH3 .0 R1 O 0 0 S N r (VIII) in which R1 is as defined in claim 1 or 2 is reacted with a 10 halogenated derivative of formula (III): t j X2-CH 2 -R2 in which R2 is as defined in any one of claims 1,3 and 4 and X2 is a halogen atom, and the compound of formula thus obtained is, if desired, converted to a pharmacologically acceptable acid addition salt thereof.
9. A process according to claim 8 substantially as defined in the tEimple. A compound as defined in any one of claims 1 to 6 whenever prepared by a process as defined in any one of claims 7 to 9. I- r., 20 .1l. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 6 or 10 and a pharmaceutically acceptable excipient.
12. A method of treatment of a subject suffering, or liable to suffer, from hypertension, angina, cardiac arrhythmia, cardiac ischaemia, cerebral ischaemia, migraine, epilepsy, asthma, ulcers or cancer or a condition requiring an antiatherogenic or platelet aggregation i inhibitor, which comprises administering to the subject an effective amount of a compound as defined in any one of claims 1 to 6 or 11. I I 13. The invention as herein described in- -e -w I'r nd-u-se-fu sects, en DATED this SEVENTH day of DECEMBER 1988 Synthelabo by DAVIES COLLISON Patent Attorneys for the applicant(s) 0otsf 5p libet ufr rm petnin nia ada arrhythmia,~~~ cada sheiceerlicam