AU601659B2

AU601659B2 - Benzothiazinone derivatives, processes for their preparation medicaments containing them and their use

Info

Publication number: AU601659B2
Application number: AU71994/87A
Authority: AU
Inventors: Rainer Henning; Joachim Kaiser; Ulrich Lerch
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1986-04-28
Filing date: 1987-04-27
Publication date: 1990-09-13
Anticipated expiration: 2007-04-27
Also published as: DK213387A; IL82332A0; KR870010028A; NO871745L; PT84770A; NZ220100A; DE3614363A1; PT84770B; HU199814B; IL82332A; FI871813A0; EP0244723A3; NO871745D0; AU7199487A; ZA872972B; FI871813A7; JPS62258371A; DK213387D0; EP0244723A2; HUT45517A

Description

a Erlip 11147,1 Aktiong" ltdiaft J Pmkurist Authorized signetor' PAT 510 ppa. Reuter i.V. Otto :i 7 2 i -~iirw- COMMONWEALTH OF AUSTRAL 6 5 9 PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Application Number: Lodged: 71 ?JF 7 Class Int. Class C omplete Specification Lodged: Accepted: SPublished: P lriority Related Art: This do rmcniR contains the amendrLn-rts ride under bc-i:i cct for Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: HOECHST AKTIENGESELLSCHAFT 45 Bruningstrasse, D-6230 Frankfurt/Main Federal Republic of Germany ULRICH LERCH, RAINER HENNING and JOACHIM KAISER EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

iB Complete Specification for the invention entitled: BENZOTHIAZINONE DERIVATIVES, PROCESSES FOR THEIR PREPARATION MEDICAMENTS CONTAINING THEM AND THEIR USE The following statement is a full description of this invention, including the bqst method of performing it known to US 1.

I7 -1- HOECHST AKTIENGESELLSCHAFT HOE 86/F 088 Dr.v.F./mu Benzothiazinone derivatives, processes for their preparation, medicaments containing them and their use It is known that compounds which hinder the infLux of calcium ions into cells can be used as therapeutic agents for the treatment of various diseases, in particular of the cardiovascular system, in man and other warm-blooded animals.

Benzothiazinone derivatives having a calcium-antagonistic action are described in US Patent 4,584,300; the compounds listed therein are unsubstituted in the S 15 2-position of the heterocyclic ring.

S, Benzothie.inone derivatives having a calcium-antagonistic action are also to be found in US Patent 4,595,685. In the latter, compounds are described S 20 which carry a basic ether grouping on the 2-phenyl radical, the basic nitrogen being linked to the ether oxygen via a straight-chain or branched alkyl chain.

It has now been found, surprisingly, that compounds with a modified side chain on the 2-phenyl radical Sshow superior calcium-antagonistic properties.

The invention therefore relates to benzothiazinone St derivatives of the formula I, which have a calcium- 30 antagonistic action: R 3 R 4 R(4)' 0-A-B-T-D-E-F-G I N R(1) R I -2and to saLts thereof with pharmaceuticaLLy acceptable acids, and in this formula 1: Rl)' and are identicaL or different and independentLy of one another are hydrogen,

(C

1

-C

4 )-aLkyL, (C 1

-C

3 )-aLkoxy, F, CL, Br, CF 3 nitro, hydroxyL, acetamido or amino, R(2) is hydrogen, straight-chain or branched (C 1

-C

10 aLkyL, straight-chain or branched (C 3

-C

10 alkenyl, phenyL-(C 1

-C

4 )-aLkyL, the phenyL ring being unsubstituted or substituted by one, two or three substituents from the group comprising

(C

1

-C

4 )-aLkyL, (C 1

-C

3 )-aLkoxy, F, CL,

CF

3

(C

1

-C

2 )-akyLenedioxy or nitro, R(3) is ±E straight-chain or branched (C 1

-C

15 aLkyL, straight-chain or branched (C 3

-C

1 5 aLkemyL, (C4-C8)'cycoatkyL,

(C

4 -Cg)- I, cycLoaLkyL-(C 1

-C

4 )-aLkyL, phenyL or phenyL-

(C

1

-C

4 )-aLkyL, the phenyL radicaL being unsubstituted or substituted by one, two or three substituents from the group comprising (C 1

-C

4 aLkyL, (C 1 -C3)-alkoxy, F, CL, CF 3

(C

1 C2)-aLkyLenedioxy or nitro, R(4) and are identicaL or different and independentLy of one another are hydrogen, (C 1

-C

4 aLkyL, (C 1

-C

3 )-aLkoxy, F, CL, CF 3 nitro, hydroxyL, acetamido or amino, A is the group (CH2)m-X-(CH2)n, m being 1, 2, 3 or 4, but onLy 2, 3 or 4 if X is a heteroatom, 30 n being zero, 1, 2 or 3, but onLy 2 or 3 if X is a heteroatom, X is a CH 2 group, oxygen, suLfur, a carbonyl group, a CH(OH) group or a group -c- _4 i L-1 -3in which and are identical or different and are hydrogen or (Cl -C 4 )-alkyl, B is one of the following groups R(6)

R

R(

0 T and D together are -CH CH(OH)-, -CH 2 C-N-R(11) or -CH 2

-C-

0 Eis a (CH 2 radical, q being zero, 1, 2 or 3, or a 3 if D and/or F are a heteroatom, F is a single bond, an NR(12)-CO radical, a CO-NR(13) radical, a carbonyl group or an oxygen atom, G is phenyl, the phenyl ring being unsubstituted or substituted by one, two or' three substituents from 06 the group compromising (C 1 -C 4 )-alkyl, (C 1 -C 3 alkoxy, F, Cl, (C 1 -C 2 )-alkylene-dioxy or cyano, or 2-furyl, R(6) and R(7) and R(8) and R(9) are hydrogen, straightchain or branched (C -C 1 )-al kyl, (C -C )-alkanyol, 1 0 1 phenyl-(C 1 -alkyl, benzhydryl or benzhydryl- -C )-alkyl, phenyl-(C -C 4 alkanoyl or benzyl, the phenyl radicals being in each case unsubstituted or substituted by one, two or three radicals from the group comprising (C -C 4 )-alkyl, (C -C 4 alkoxy, (C 1 -C 2 )-alkylene-dioxy, F, Cl, Br, CF 3 or hydroxyl, and and R(11) and R(12) and R(13) are hydrogen or

(C

1

-C

5 )-al1kyl Ma 1 ~bb D i ak 6/1.6 0 M G

C,

i ~j -4-

I,

fi *1 i 0000 0 0000 0000 0 0 0 00 0 0000 0 00 00 0 000 00* 0 0 00 0 0 0 #00 00 00 0 000 o 00 00 0004 Those compounds of the formula I are preferred in which at Least one of the substituents and indices has the following meaning: R(1 and*R(1)' are identicaL or different and indlependlentLy of one another are hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chLorine, CE 3 nitro or acetamidlo, is hydrogen, R(Z) is hydrogen, straight-chain or branched (Cl--C 6 aLkyL, aLLyL, methaLLyL, benzyL, phenethyL, 4methoxybenzyL, 3,4-dimnethoxybenzyL, 3,4,5-tr imethoxybenzyL or 3,4-methyLenedioxybenzyL, R(3) is hydrogen, straight-chain or branched (Cl-C 2 aLkyL, aLLyL, methaLLyL, (C 5

-C

7 )-cycLoaLkyL, 15 (C 5

-C

1 ')-cyc LoaL kyL-( C '-C 4 LkyL benzyL, methyLbenzyL, fLuorobenzyL, methoxybenzyL, dimethoxybenzyL or phenyLethyL, R(4) is hydrogen, methyL, nme~hoxy, ethoxy, chlorine, nitro, hydroxyL, acetamidlo or amino, 20 is hydrogen, A is the group (CH2)m-X(CH2)n, m being 1, 2, 3 or 4, but onLy 2, 3 or 4 if X is a heteroatom, n is zero, 1, 2 or 3, but only 2 or 3 if X is a heteroatom, X is a CH 2 group, oxygen, sulfur, a carbonyL group, a CH(OH) group or a group R -C-R R(5) and being identical or different and being 30 hydrogen, methyl or ethyl, B is one of the following groups 00 4 000 04 0 0 0 0 00 R( 6) (8) R( 9L.

I

_N

=0M T and D together are -CH 2 -CH -C-N-R(1l) or 0 -CH -C- 2 1

O

E is a (CH 2 )q radical, q being zero, 1 or 2, or a -CH=CH radical, F is a single bond, an NR(12)-CO radical, a CO-NR(13) radical, a carbonyl group or an oxygen atom, G is phenyl or 2-furyl, the phenyl ring being unsubstituted or substituted by one or two substituents from the group comprising alkyl, F, Cl, (C 1

-C

2 )-alkylenedioxy or cyano or being substituted by one, two or three (C -C 2 alkoxy substituents, and R(10), R(ll), R(12) and R(13) are hydrogen or (C 1

-C

4 )-alkyl, as well as the salts of these compounds I with pharmaceutically acceptable acids.

Those compounds of the formula I are particularly preferred in which at least one of the substituents and indices has the following meaning: R(1) is hydrogen, methyl, methoxy, fluorine or chlorine, is hydrogen or methoxy, I, t is hydrogen, 25 R(2) is hydrogen, methyl, ethyl, propyl, isopropyl, r, butyl, sec. butyl, isobutyl, benzyl or phenethyl, R(3) is hydrogen, straight-chain or branched (C -C 1 )-alkyl, cyclopentyl, cylohexyl, cyclopent thylmethyl, cyclohexylmethyl, allyl, methallyl, benzyl, methylbenzyl, fluorobenzyl, methoxybenzyl, .0 dimethoxybenzyl or phenylethyl, R(4) is hydrogen, methoxy, methyl, chlorine, nitro or hydroxyl, is hydrogen elb Disk 6/1.60 MG

._I

oC -6- A is the group (CH 2 )m-X-(CH 2 m being 1, 2 or 3, but being only 2 or 3 if X is a heteroatom n being 0, 1 or 2, but only 2 if X is a heteroatom, X is a CH 2 group, oxygen, a carbonyl group a CH(OH) group or a group in which R(5) and are identical or different and are hydrogen or methyl, B is one of the following groups T R(7) S -N N- -N- \o -N N- 0 0 E is a (CH 2 )q radical, q being zero, 1 or 2, F is a single bond, an NR(12)-CO radical, a CO-NR(13) o 25 radical, a carbonyl group or an oxygen atom, G is phenyl, the phenyl ring being unsubstituted or substituted by 1 or 2 radicals from the group ,o.o comprising methyl, F, Cl, methylenedioxy or cyano, 0 or by 1, 2 or 3 methoxy radicals, or 2-furyl, and R(10), R(11), R(12) and R(13) are identical or different and are hydrogen or (C -C 3 )-alkyl, Melb Disk 6/1.60 MG "-o as well as the salts of these compounds I with pharmaceutically acceptable acids.

Such pharmaceutically acceptable acids can be inorganic acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, or nitric acid, or organic acids, such as tartaric acid, malic acid, Lactic acid, maLeic acid, fumaric acid, maLonic acid, oxalic acid, gluconic acid, camphorsulfonic acid, benzenesulfonic acid, acetic acid, propionic acid or p-toluenesulfonic acid.

The compounds of Formula I have asymmetric C-atoms and can therefore be in the form of enantiomers or diastereomers. The invention comprises both the pure isomers and their mixtures. These mixtures of diastereomers can be separated into the components by usual methods, for example by selective crystallization from suitable solvents or chromatography on silica gel or alumina. Racemates can be resolved into the individual enantiomers by usual methods, such as, for example, by forming a salt with optically active acids, such as camphorsulfonic acid or dibenzoyltartaric acid, and selective crystallization, or by forming derivatives with suitable optically active reagents, separation of the diastereomeric derivatives and redissociation.

The invention also relates to processes for the prei 30 paration of compounds of the formula I which comprise a) reacting a compound of the formula II

R

R 3 R 4) S R(4)' R(1) R(2 I R(2) -8in which R(4)' and A have the same meaning as in the formula I and in which Y is a Leaving group which can be displaced by a nucleophiLic reaction, in particular a chlorine, bromine or iodine atom, a sulfonic acid radical, preferably a metharnesulfon.' radical, a benzenesulfonyl radical, a toluenesulfonyl radical or a trifluoromethanesulfonyl radical, with a compound of the formula

III

H-B-T-D-E-F-G III, in which B, T, D, E, F and G have the same meaning as in formula I, under the conditions of a nucleophilic substitution, preferably in a polar organic solvent such as an alcohol, preferably methanol, ethanoL, propar .L or isopropanol or a lower ketone, preferably acetone or methyl ethyl ketone, or dimethylformamide, dimethyl S 'sulfoxide or sulfolan or a hydrocarbon, preferably toluene, in the presence or absence of an auxiliary base for intercepting the acid being formed, pre'erabLy in the presence of potassium carbonate, sodium carbonate, triethylamine, N-ethylmorpholine or pyridine, at a temperature between 0 and 1600C, preferably between and 1200C, or I b) reacting a compound of the formula IV I R(1) R(3) R(4) S(2) in which R(4) and R(4)' have the same meaning as in the formula I, with a compound of the formula V 'e

L

-9- Z-A-B-T-D-E-F-G

V,

in which Z is as defined for Y in the formula II and in which A, B, T, D, E, F and G have the same meaning as the formula I, either in a polar aprotic solvent such as dimethyLformamide, dimethyl sulfoxide, tetrahydrofuran, sulfolan or N-methylpyrrolidone, in the presence of a strong base such as sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, butyllithium or lithium hexamethyldisilazide, at a temperature between -40 and +600C, preferably between -10 and -30 0 C, or in a protic or aprotic polar organic solvent such as a lower alcohol, for example methanol, ethanol or isopropanol, or a lower ketone, preferably acetone or methyl ethyl ketone or in dimethylformamide, in the presence of a weak to moderately strong base such as an alkali metal or aLkaline earth metal hydroxide or carbonate or an amine such as, for example, triethylamine, N-ethylmorpholine, N-methyldiisopropylamine or pyridine, at a temperature between 0 and 1600C, preferably between 20 and 1200C, or c) reacting a compound of the formula V R(1) R(3) R(4) R 4 0-A-R(14) N O

S

R(1) R( R(2) 30

F

i in which R(4)' and A .ave the same meaning as in the formula I and in which R(14) is one of the following groups -Iil- -I *i I -XI* URlrl

I

/R(6)

-N

H

-N

0, -N NH v/R(7)

H

RB(

-N NH R(8) in which R(8) and R(9) have the same meaning as in the formula I, with a compound of the formula VI

W-C-E-F-G

II

0

VI,

in which E, F and G have the same meaning as in the formula I and W is a chlorine atom, a alkoxy group, a (C 1

-C

5 )-alkanoyLoxy group or an imidazole radical, under conventional amide formation conditions, compounds of the formula I being formed in which p is zero and D is a carbonyl group, or d) reacting a compound of the formula VII R(3)NR(4) n 0- CH 2 )m-CH-CH 2 0 0o

VII,

R(1) (2) in which R(4)' and m have the same meaning as in the formula I, with a compound of the formula VIII

L

,i -11- H-B-T-D-E-F-G VIII, in which B,T,D,E,F and G are defined as in the formula I, without a solvent or in the presence of a preferably poLar solvent such as methanol, isopropanol, acetone, THF or dimethylformamide, compounds of the formula I being formed in which A is the radical

-(CH

2 )m-CH-CH2-

OH

or e) reacting a compound of the formula V with a compound of the formula IX CH-CH-(CH2) -G

IX

0 in which F, G and q have the same meaning as in the formula I, under the reaction conditions described under compounds of the formula I being formed in which p is zero and D is a CH(OH) group.

Compounds of the formula II can be prepared from compounds of the formula IV by reaction with compounds of X SQ-A-Y X l. in which A has the same meaning as in the formula I, Y has the same meaning as the formula II and Q is as i defined for Y in the formula II, in the presence of bases such as, for example, sodium hydroxide, potassium carbonate, sodium methylate or potassium tertiary-butylate in a solvent such as, for example, tetrahydrofuran, methanol, dimethoxyethane, acetone, methyl ethyl ketone, dimethylformamide or dimethyl sulfoxide.

/3 -12- Compounds of the formuLa VI are obtained from compounds of the formula IV, for example with epichlorohydrin and a base (for m 1) by known methods, or by aLkyLation of compounds of the formula IV with compounds of the formuLa XI Y -(CH 2 )m-CH CH 2

XI

in which m has the same meaning as in the formula I and Y is as defined in the formuLa II, compounds of the formula XIII being formed

R

1 3) R(4)

XIII,

IR(1)

CH

2 CH CH N1m 2 R(1) R(2) in which R(1) R(4)' and m have the same meaning as in the formula I. Subsequent epoxidatiom of the compounds XIII by known I m methods, for example with m-chLoroperbenzoic acid in methyLene chloride, gives compounds of the formula VII.

1 Compounds of the formula V are obtained from compounds of the formula II by reactions with one of the compounds of the formulae XIIa, XIIb, XIIc, XIId or XIIe R(6) /R(7) HN HN N-P HN N P \p P XIIa-e HN R9 SN, HN N-P R(8) i -13in which R(8) and R(9) have the same meaning as in the formula I and in which P is a hydrogen atom, a

(C

1

-C

4 )-aLkoxycarbonyL group, a benzyLoxycarbonyL group, a trifluoroacetyl group or a trichLoromethyLcarbonyLoxy group, under the conditions described under process variant and by subsequent elimination of the group, if the latter is not hydrogen, by processes known from the literature.

il ar U" j Compounds of the formula IV are known from EP-A-146,893.

The compounds according to the invention, of the formula I, show hypotensive, in particular calcium-antagonistic actions and can therefore be used for the treatment of all pathological conditions which are caused by a disturbance in the calcium balance of a warm-blooded animal.

Their calcium-antagonistic activity can be demonstrated by the displacement of tritium-labeled nitrendipin as a biochemical test model.

For this purpose, membrane preparations which contain isolated calcium channels are charged with the labeled substance. After incubation with the test substance, the released radioactivity in the supernatent solution is determined. In this model, the compounds according to the invention, of the formula I, show IC 50 values of 10 6 molar to 10 10 molar. In further test models, by means of which a calcium-antagonistic action can be demonstrated, for example by the coronary blood flow in the isolated guinea pig heart or by the action potential of the isolated guinea pig papillary muscle, the compounds of the formula I likewise show a strong action.

The compounds according to the invention, of the formula I, and their pharmacologically acceptable salts reduce the influx of calci,,;; ions into cells and are therefore suitable for treating the cardiovascular system in the L7_ -14case of the relevant complaints, for example various forms of angina pectoris, tachycardia, heart arrhythmias and high blood pressure. They are active within a wide dose range. The level of the dose administered depends on the nature of the desired treatment, on the manner of administration and on the condition, type and size of the mammal treated. In oral dosage, satisfactory results are obtained with quantities of from 0.01 mg, preferably from 0.1 mg, and up to 100 mg, preferably up to 20 mg of a compound of the formula I per kg of body weight. In man, the daily dose varies between 10 and 800 mg, preferably 20 to 500 mg, and single dose of to 200 mg can be given, preferably once to three times daily.

o For intravenous and intramuscular administration, the O o daily dose is 1 to 300 mg, preferably to 5 to 150 mg.

o 0 a The pharmacologically usable compounds of the present S20 invention and their salts can be used for the prepa- 00 o. ration of pharmaceutical products which contain an active amount of the active substance together with excipients and which are suitable for enteral and 0 6 oo 2 parenteral administration. Preferably, tablets or So 25 gelatin capsules are used, which contain the active compound together with diluents, for example, lactose, o"e. dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine and lubricants such as siliceous earth, talc, oo stearic acid ot salts thereof, such as magnesium or 30 calcium stearate, and/or polyethylene glycol. Tablets *0 also contain binders such as magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone and, if necessary, dyes, flavourings and sweeteners.

Injectable solutions are preferably isotonic aqueous solutions or suspensions, which can have been sterilized and can contain auxiliaries such as preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or I- ibuffer substances. The pharmaceutical products according to the invention which, if desired, can contain further pharmacologically valuable substances, are prepared, for example, by means of conventional mixing, granulating and tableting processes and contain 0.1 up to about 75 preferably about 1 to about 50 of the active compound.

Unless explicitly stated otherwise, alkyl, alkenyl, alkoxy and alkylene always denote a straight or branched chain.

ar i f~: I The examples which now follow are intended to illustrate the invention without restricting it to these examples.

Example 1 3,4-Dihydro-2-isopropyL-4-methyL-2-C2-E4-E4-[2-(3,4,5trimethoxyphenyl)-acetyL]-piperazinyl]-butoxyl-phenyL3- 2H-1,4-benzothiazine-3-one hydrochloride 6.68 g (15 mmol) of 3,4-dihydro-2-isopropyl-4-methyl-2- [2-(bromobutoxy)-phenyl]-2H-1,4-benzothiazin-3-one were stirred for 5 hours under reflux in 30 ml DMF with 2.07 g of potassium carbonate and 6.63 g (22.5 mmol) of 3,4,5trimethoxyphenylacetic acid piperazide. After cooling, 250 ml of water were added, the water was decanted off from the oily residue and the latter was taken up in ethyl/acetate. After washing with water and drying, the mixture was concentrated. Chromatography on 250 g of silica gel with 9:1 methylene chloride methanol as the solvent gave 2.4 g of the title compound (free base) as an oiL.

1 H-NMR (CDCL 3 7.5 6.5 6.45 (s,2H); 4.2 3.9 3.8 3.6 3.4 (s,3H); 3.1 2.1 2.0 1.5 1.1 0.95 (2d,6H) ppm.

-16- The hydrochloride was obtained by adding ethanolic hydrochLoric acid, concentrating and triturating with petroleum ether, 1.7 g, melting point 125 OC.

CalcuLated C 3 7

H

4 5

N

3 0 6 S.HCl C 63.5 H 6.9 N 6.0 CL 5.1 Found C 62.6 H 7.1 N 5.8 CL The preparation of 3,4-dihydro-2-isopropyl-4-methyl-2- [2-(4-bromobutoxy)-phenyL]-2H-1,4-benzothiazin-3-one is described in EP-A-146,893.

3,4,5-TrimethoxyphenyLacetic acid piperazide is obtained as foLLows: 12.3 g of dicycLohexyLcarbodiimide and 8.8 g of NbenzyLpiperazine were added at room temperature to 11.3 g of 3 ,4,5-trimethoxyphenyLacetic acid and 23.3 ml of a soLution of 1-hydroxybenzotriazoLe. After 15 hours, the mixture was filtered with suction, and the filtrate was diluted with water. After extracting three times with ethyl acetate, the combined organic phases were washed once in each case with saturated NaHCO 3 so- Lution, 10 citric acid solution and saturated sodium chloride solution, dried and concentrated. The Nbenzyl-N'-trimethoxyphenylacetyl-piperazine was dissolved in 45 ml of methanol and hydrogenated with 1 g of palladium on animal charcoal for 8 hours at 80 0 C and Sunder 30 atmospheres H 2 pressure. After filtering off, the solution was concentrated, the residue was Ii dissolved in acetone and ethereal hydrochloric acid was added. The hydrochloride is filtered off with suction.

Yield 5.7 g, melting point 108 1100C.

,i MVlb Disk 611.60 MG -17- Example 2 3,4-D ihydro-2-isopropyL-4-methyL-2-E2-[4-E4-[2-(3,4,5trimethoxyphenyL)-propionyL]-piperazinyLj-butoxy>phenyL]-2H-1,4-benzoth iazin-3-one-hydrochLor ide 3.01 g (6.7 mmol) of 3,14-dlihydlro-4-methyL-2-[2-(4bromobutoxy)-phenyL ]-2H-1,4-benzothiaz in-3-one were heated to the boiL for 8 hours with 4.5 g of 3-(3.4,5trimethoxyphenyL)-propionic acid piperazidle and 1.4 g of potassium carbonate in 100 ml of isopropanoL. After cooling, the mixture was fiLtered, concentrated and chromatographed on siLica geL with 9:1 methylene chloride/methanoL. This g. ve 3.9 g of the free base as an o iL 1 H-NMR (CDCL 3 7.6 6.5 6.4 3.85 3.82 (2s,9H); 4.2 3.3 3.4 (s,3H); 2.0 (m,13H); 2.0 1.5 1.15 0.9 (2d,6H) ppm.

3 -(3,4,5-TrimethoxyphenyL )-propionic acid piperaz ide was obtained anaLogousLy to the instructions given for 3 ,4,5-trimethoxyphenyL)-propionic acid as the starting 3 4 -Dihydro- 2 -isopropyL-4-methyL-2-E2-(4-piperazinyL butoxyphenyLJ-2H-1,4-benzothiazin,3-one dlihydrochioridle g (10 mmoL) of 3,4-dihydro-isopropyL-4-methyL-2-

E

2 4 -bromobutoxy)-phenyL]-2H-1,4-benzothiazin3-one were heated to the boil for 16 hours in 50 ml ol isopropanol with 1.4 g of potassium carbonate and 2.58 g of anhydrous piperazine. After filtration, the mixture was concentrated, the residue was taken up in a mixture of ethyl acetate and toLuene, and the solution was -18washed three times with water, dried with sodium suLfate and concentrated. This gave 4.3 g of the title compound as an oiL (free base).

1 H-NMR (CDCL 3 7.6 6.4 3.9 3.38 3.0 2.4 (m,11H); 2.1 1.9 1.15 0.95 (2d,6H) ppm.

DihydrochLoride: colorless crystaLs, meLting point 110 0 C (decomposition) Example 4 3,4-Dihydro-2-isopropyL-4-methyL-2-[2-[4-[4-(2-furoyL)piperazinyLl-butoxyJ-phenyL]-2H-1,4-benzothiazin-3-one hydrochloride g of the compound from Example 3 and 1 g of triethylamine were dissolved in 50 mL of methyLene chloride.

At 0 0 4C to 5 0 C, 1.3 g of furan-2-carboxyLic acid chloride were added dropwise. After 4 hours, the mixture Was poured into ice water, and the organic phase was separated off, washed with saturated sodium bicarbonate solution and wa.er and dried with sodium sulfate.

This gave 4.3 g of the free base as an oil.

H-NMR (CDCL 3 7.6 6.3 (m,11H); 4.0 3.6 3.36 3.1 2.2 2.0 1.6 (m,4H); 1.1 0.9 (2d,6H) ppm.

3 The hydrochLorid was obtained from methanoic solution with ethereal hydrochloric acid, melting point 186 187 OC (decomposition) Calculated C 3 1

H

3 7

N

3 0 4 S.HCL C 63.75 H 6.55 N 7.2 CL 6.1 Found C 63.4 H 6.6 N 7.1 CL 6.2 -19- ExampLe 3,4-Dihydro-2-isopropyl-4-methyL-2-[2-E4-[4-( 3 4 trimethoxycinnamoyl)-piperazinyl]-butoxyJ-phenyL]- 2H-1,4-benzothiazin-3-one hydrochloride 4.6 g (10 mmol) of the compound from Example 3 were stirred for 18 hours at room temperature with 5 mL of a 30 solution of 1-hydroxybenzotriazoe in DMF, 4.6 g of dicyclohexylcarbodiimide and 2.5 g of 3,4,5-trimethoxycinnamic acid. After filtration with suction, the mixture was poured onto water, extracted with ethyL acetate, and the extract was washed with water, dried and concentrated. Chromatography on siLica geL gives 3.8 g of the free base as an oil.

e" 1H-NMR (CDCL 3 6= 7.6 6.4 (m,12H); 4.6 3.6 3.85 3.4 3.3 2.6 (m7H); 1.6 1.2 0.95 (2d,6H) ppm.

HydrochLoride: colorless crystals, melting point 193 1940C Calculated C 3 8

H

4 7

N

3 0 6 S.HCL C 64.3 H 6.8 N 5.9 CL Found C 63.2 H 6.8 N 5.8 CL Example 6 3,4-Dihydro-2-isopropyl-4-methyl-2-[2-E4-[4-(2hydroxy- 3-(2-cyano-phenoxy)-propyL]-piperzinyL]-butoxyJ-phenyL]- 2H-1,4-benzothiazin-3-one dihydrochLoride 4.6 g of the compound from Example 3 and 1.7 g of 2- (2,3-epoxypropoxy)-benzonitrile were stirred in 50 mL of methanol for 3 hours under reflux. After concentrating, the product was chromatographed on silica gel.

This gave 1.9 g of the free base as an oiL.

p 4

I

1 H-NMR (CDCL 3 S 7.6 6.5 (m,12H); 4.2 3.6 3,4 3.2 2.3 (m,13H); 2.0 1.6 (m,4H); 1.2 0.95 (2d,6H) ppm.

DihydrochLoridle: coLorLess crystaLs, meLting point 130 131 0 C (decomposition) CaLcuLated C 35

H

44

N

4 0 4 S.2HCL C 60.9 H 6.7 N 8.1 CL 10.3 Found C 59.8 H 6.7 N 7.5 CL 10.1 ExampLe 7 3,4-D ihydro-2- isopropy L-4-methyL-2-[2--E4-[4-E2-hydroxy-3- (2-c h 1o ro -ph e no xy p r op y L]-p ip e r a z i ny bu t o xy -p he n yL]- 2H-1,4-benzoth iaz in-3-one-dihydrochLoride 4.6 g of the compound from ExampLe 3 were reacted with 1.84 g of 1-(2-chLorophenoxy)-2,3-epoxypropane ana- LagousLy to the procedure described in ExampLe 6. This gave 2.7 g of the free base as an oiL.

1 H-NMR (CDCL 3 7.5 -6.8 (m,12H); 4.2 -3.6 3.4 3.1 -2.3 (m,13H); 2.0 -1.6 (m,4H); 1.15 0.95 C2d,6H) ppm.

DihydrochLoridle: coLorLess crystaLs, meLting point 195 oc CaLcuLated C 35

H

44

N

3 0 4 S.2HCL.H 2 0 C 57.7 H 6.6 N 5.8 CL 14.6 Found C 57.7 H 6.5 N 5.5 CL 14.2 ExampLe 8 3,4-Dihydro-2-isopropyL-4-methyL-2-[2-E4-E4-E2-hydroxy- 3-(2-methoxyphenoxy)-propyLJ-piperaz inyLJ-butoxy]phenyt J-2H-1,4-benzothiazin-3-one dlihydrochLoridle 4.6 g of the compound from Example 3 were reacted with 1.8 g of 1-(2-methoxy-phenoxy)-2,3-epoxy-propane It Ii -21analogously to the procedure described in ExampLe 6.

This gives 2.4 g of the free base as an oil.

H-NMR (CDCL 3 6 7.6 6.4 (m,12H); 4.2 3.6 3.8 3.4 3.1 2.3 (m,13H); 1.6 1.2 0.95 (2d,6H) ppm.

DihydrochLoride: colorLess crystaLs, meLting point 130 1320 (decomposition) CalcuLated C 36

H

47

N

3 0 5 S.2HCL.2H 2 0 C 58.2 H 7.2 N 5.7 CL 9.6 Found C 57.5 H 6.8 N 5.4 CL 9.1 ExampLe 9 3,4-Dihydro-2-isopropy-4-methyL-2-2-C4-E4-(2,6dimethyLaniLino-carbonyL)-methyL]-piperazinyL]-butoxylphenyl]-2H-1,4-benzothiazin-3-one-dihydrochLoride 4.5 g (10 mmoL) of the compound from ExampLe 3 were stirred for 10 hours at room temperature with 1.97 g mmoL) of chLoroacetic acid 2,6-dimethyaniLide in mL of methyLene chLoride. After concentrating, the product is chromatographed on 300 g of silica geL with 9:1 methylene chloride/methanol. This gives 2.0 g of the free base as an oil.

1 H-NMR (CDCL 3 7.5 6.4 (m,11H); 4.2 3.4 3.2 3.0 2.3 (m,11H); 2.2 (s,6H); 2.0 1.5 1.1 0.9 (2d,6H) ppm.

DihydrochLoride: colorless crystals, melting point 258 0

C

Calculated C 36

H

46

N

4 0 3 S.2HCL C 62.9 H 7.0 N 8.1 CL 10.3 Found C 63.1 H 6.8 N 8.0 CL 10.4 Chioroacetic acid 2,6-dimethylaniide is obtained from chloroacetyL chloride and 2,6-dimethyaniine by addition of pyridine in methylene chloride. CoLorless crystals, i -22melting point 148 149 0 C (from petroleum ether).

ExampLe 3,4-Dihydro-2-isopropyL-4-methyL-2-C2-E4-E4-(N-methyLcarbamoyl)-piperazinyL]-butoxyl-phenyL]-2H-1,4-benzothiazin-3-one g (10 mmol) of the compound from Example 3 were dissolved in 50 mL of methyLene chLoride. 0.57 g of methyL isocyanate were added dropwise. After 2 hours at room temperature, the mixture was concentrated and chromatographed on silica gel. This gave 4.0 g of the titLe compound as a colorless resin.

1H-NMR (CDCL 3 6= 2.5 6.3 5.1 (qH); 3.3 3.4 3.0 2.4 1.6 1.1 0.85 (2d,6H) ppm.

Example 11 3,4-Dihydro-2-isopropy-4-methyL-2-2-[4(4butyryL) piperazinyl)-butoxyl-pheny]-2H-1,4-benzothiazin-3-one 1.06 g of butyryL chloride were added dropwise to 4.5 g (10 mmoL) of the compound from Example 3 in 50 mL of methylene chloride. After 3 hours, the mixture is concentrated and chromatographed on silica gel. This gave 3.3 g of the title compound as a colorless resin.

1 H-NMR (CDCL 3 7.4 6.3 4.0 3.6 3.4 3.0 2.6 2.4 1.4 (m,9H); 1.2 0.8 (2d+t,9H) ppm.

L--

Example 12 3,4-Dihydro-2-isopr cinnamoyl)-piperazi thiazin-3-one hydro -23opyL-4-methyL-2-C2-[4-[4-(3-methoxynyL]-butoxy3-phenyL]-2H-1,4-benzochloride s 1 s i A mixture of 5 mL of a 30 solution of 1-hydroxybenzotriazole, 3 g of dicycLohexyLcarbodiimide, 4.6 g of the compound from Example 3 and 1.8 g of 3-methoxycinnamic acid was stirred for 4 hours at room temperature. After fiLtration with suction, the mixture was poured on the water and extracted with ethyL acetate. The organic phase was washed twice with water, dried with sodium sulfate and concentrated. The crude product was purified on 300 g of silica geL with 9:1 methyLene chloride/ methanol. This gave a 4.7 g of the free base as an oiL.

1 H-NMR (CDC1 3 6 8.0 6.5 (m,13H); 4.2 3.6 3.8 3.4 3.3 2.8 2.2 1.6 1.15 0.95 (2d,6H) ppm.

Hydrochloride: coLorLess crystals of melting point 800C (decomposition) Example 13 3,4-Dihydro-2-isopropyL-4-methyl-2-E2-E4-E4-(4-acetyl)piperazinyl]-butoxyl-phenyl]-2H-1,4-benzothiazin-3one hydrochloride 1.02 g of acetic anhydride were added dropwise to 4.5 g mmol) of the compound from Example 3 in 50 mL of methylene chloride. After 3 hours at room temperature, the mixture was concentrated and chromatographed on silica gel with 9:1 methyLene chloride/methanol as the solvent. This gives 2.7 g of the free base as a resin.

1 H-NMR (CDCL 3 7.5 6.4 4.0 3.4 3.4 3.0 2.2 2.0 2.0 A I I 5 It

A

-24- 1.6 1.1 0.8 (2d,6H) ppm.

HydrochLoridle: coLorLess crystaLs of meLting point 100 0 C (decomposition) Example 14 3, 4-D ih ydro-2-is op ropyL-4-me thyL-2-E 2-C4-C 4-C3-me thoxyp ani Iino-carbonyL )-methyL ]-piperazinyL]-butoxyj-phenyL]- 2H-1,4-benzoth iazin-3-one dlihydrochLoridle I g of the compound from ExampLe 3 were reacted with 2 g of chLoroacetyL-3-methoxyaniLide according to the procedure given in Example 9. This gave 4.9 g of the free base as a colorless oil.

1 H-NMR (CDCI 3 6=7.5 6.6 (m,12H); 3.7 (s,3H); 2: 3.4 4.0 -3.0 Cm,13H); 2.1 1.6 1.1- 200.7 (2d,6H) ppm.

colorless crystals, melting point 234 2360C (decomposition) Calculated C 35

H

44

N

4 0 4 S.2HCI.H 2 0 C 59.4 H 6.8 N 7.9 CL 10.0 Found C 59.4 H 6.8 N 7.9 CL 10.2 Example t 49 1 3,4-D ihydro-2-isopropyL-4-methyL-2-E2-[4-E4-(2,6dimethoxy-phenoxy)-acetyL]-piperazinyL]-butoxy--phenyLI -2H-1,4-tbenzoth iaz in-3-one hydrochloridle g (10 mmoL) of 3,4-dihydro-2-isopropyL-4-methyL-2- [2-(4-bromobutoxy)-phenyL J-2H-1 ,4-benzothi az in-3-one and 3.1 g of 1-(2,6-dimethoxyphenoxy)-acetyL-piperazine as weLl as 1.5 g of ground, dried potassium carbonate were stirred in 30 ml of DMF for 6 hours at 90 1000C.

The reaction mixture was partitioned between water and ethyl acetate, the phases were separated, and the ethyl acetate phase was washed with water and dried over magnesium suLfate. After concentrating, the product was purified on silica geL with ethyL acetate, This gave 4.3 g of the free base as a resin.

4 1H-NMR (iC 6 7.4 6.3 (m,11H); i 4.0 3.6 3.8 3.4 2.3 2.0 1.6 11 0.9 (2d,6H) ppm.

1180 1 10 Hydrochloride: colorLess crystaLs, meLting point 145- 1480C CalcuLated C 3 6

H

45

N

3 06S HCL C 63.2 H 6.8 N 6.1 CL 5.2 Found C 62.8 H 6.7 N 6.1 CL 1-(2,6-Dimethoxyphenoxy)-acetyLpiperazine was obtained as foLLows: 125 g (80 mmoL) of 2,6-dimethoxyphenoxyacetic acid were reacted with N-benzyLpiperazine (14.1 g) by the dicycLohexylcarbodiimide/hydroxybenzotriazoLe method (Example The 1-benzyL-4-(2,6-dimethoxyphenoxy)acetyLpiperazine (18 g) thus obtained was hydrogenated in 180 mL of methanol for 8 hours with 1.8 g of 10 palladium on carbon as the catalyst at 100 bar and 800C. After filtration and concentrating, this gave 6.6 g of 1-(2,6-dimethoxyphenoxy)-acetyl-piperazine, meLting point 174 175 0 C (from acetone/ethyl acetate).

Example 16 3,4-Dihydro-2-isopropyL-4-methy-2-C2-(oxiranyL-methoxy)phenyl]-2H-1,4-benzothiazin-3-one 4.7 g (15 mmoL) of 3,4-dihydro-2-isopropyL-4-methyL-2- (2-hydroxyphenyL)-2H-1,4-benzothiazin-3-one were stirred for 24 hours at 850C with 0.6 g of NaOH, 2 mL of H 2 0 and 50 mL of epichlorohydrin. After dilution with water, -26the mixture was extr-acted with methyLene chloridle, and the extract was dried with sodium sulfate and concentrated. This gave 5.3 g of the title compound as an I 1 H-NMR (CDCI 3 iS=76-6.4 4.2 3.8 3.4 3.4 -2.5 1.4 -0.7 (m,6H) p pm.- Example 17 3,4-Dihydro-2-isopropyL-4-methyL-2-[2-E2-hydroxy-3- [4-(3,4,5-trimethoxyphenyL)-acetyLJ-piperazinyL]propoxyJ-phenyL J-2H-1,4-benzoth iazin-3-one hydrochloride g of the compound from Example 16 were boiLed under refLux (10 hours) with 8 g of 1-(3,4,5-trimethoxyphenyL)-acetyL-piperazine in 50 ml of methanol. After concentrating, the product was chromatographed on 300 g of silica gel with 9:1 methyLene chloride/methanol.

This gave 4.7 g of the free base as a colorless resin.

1 H-NMR (CDCI 3 =7.5 6.4 6.3 (s,2H); 3.8 4.0 3.5 3.4 2.7 -2.3 1.3 0.8 (m,6H) ppm.

Hydrochloridle: colorless amorphous powder, melting point 85: C (decomposition) aa Calculated C 36

H

45

N

3 0 7 S.2HCI C 58.7 H 6.8 N 5.7 Found C 58.7 H 6.9 N 5.9 Example 18 3,4-D ihydro-2-isopropyL-4-methyL-2-E2-E2-hydroxy-3-E4- 3 3 butoxy]-phenyLI -2H-1 ,4-benzoth iaz in-3-one ji 5 1 -27 g of the compound from Example 16 were reacted with 8.4 g of 1-[3-C3,4,5-trimethoxyphenyL )-propionyLJ-piperazine according to the procedure given in ExampLe 17.

This gave 6.8 g of the titLe compound.

1 H-NMR (CDCL 3 =7.5 6.4 6.3 (s,2H); 3.8 Cs,9H); 4.0 3.5 3.4 2.7 2.3 (m,511); 2.0 1.8 1.3 0.6 (m,6H) ppm.

ExampLe 19 3,4-D ihydro-2-isopropyL-4-methyL-2-E2-[4-[4-E3-( 3 trimethoxyphenyL)-propionyL]-piperazinyL]-butoxy]-phenyL]- 2H-1,4--benzothiazin-3--one hydrochLoridle hit iv 15 6.68 g (15 mmoL) of 3,4-dihydro-2-isopropyL-4-methyL-2-- [2-(4-bromobutoxy)-phenyL ]-2H-1,4'-benzothiaz in-3-one were heated to 80 900 C for 3 hours in 30 mL of DMF with 2.07 g of ground, anhydrous potassium carbonate and 4.83 g of 4-E3-(3,4,5--trimethoxyphenyL )-propionyLaminoJ-piperidine. The mixture was poured onto 300 mL of ice water and extracted with ethyL acetate (twice), and the combined organic phases were washed twice with water, dried over sodium suLfate and concentrated. This gave 9.8 g of the free base, melting point 151 153 0

C.

1 H-NMR (CDCI 3 &7.4 6.4 6.3 (s,2H); 5.4 4.0 -3.6 Cm,3H); 3.7 3.4 (s,3H); -2.2 (m,11H); 2.0 1.5 Cm,4H); 1.1 0.9 (2d,6H) ppm.

HydrcuchLoride: coLorLess crystaLs, meLting point 138-140 0

C

(from ethanoL) CaLcuLated C 39

H

51

N

3 0 6 S.HCL.HZ0 C 62.9 Found C 63.4 H 7.3 H 7.5 N 5.6 N 5.8 4-E3-(3,4,5-TrimethoxyphenyL)-propionyLamino]-piperidine was obtained as follows: SdLt:S Tar regulating thle osmotic pressure and/or -28 24 g of 3-(3,4,5-trimethoxyphenyL)-propionic acid were reacted with 20.2 ml of 4-amino-l-benzyLpiperidine by the dicycLohexyLcarbodi imide/1-hydroxybenzotriazoLe procedure (Example The resuLting 1-benzyL-4--E3-C3,4,5-trimethoxyphenyL)-propionyLamino]--piperidine (36.1 g, melting point 93-950 C) was hydrogenated in 500 ml of metha- *noL for 12 hours with 10% Pd/c (5 g) at 100 bar H 2 pressure and 80 0 C. After fiLtration and concentrating, Ithis gave 26 g of melting point 110 0

C.

Example 3,4-D ihydro-2-isopropyL-4-methyL-2-[2-[2-E4-[4-(3,4,5trimethoxyphenyL)-acetyLaminoj-piperidinyLJ-butoxyJphenyL]-2H-1,4-benzothiazin-3-one hydrochloride g (10 mmoL) of 3,4-dihydro-2-isopropyL-4-methyL-2-E2- (4-bromobutoxy)-phenyL ]-2H-1,4--benzothi azin-3--one were reacted with 3.1 g of 4-(3,4,5-trimethoxyphenyL-acetyLamino)-piperidine by the procedure given in ExampLe 19.

j This gave 3.8 g of the free base as an oiL.

1 H-NMR (CDCL 3 =7.5 6.6 6.3 (s,2H); 5.65 4.0 -3.6 3.9 3.4 (s,3H); 3.5 1.5 (m,17H); 1.15 0.9 (2d,6H) ppm.

HydrochLoride: coLorless amorphous powder, meLting point 0 C (decomposition) 1 4 304-(3,4,5-TrimethoxyphenyLacetyLamino)-piperidine was obtained, as described in ExampLe 19, from 3,4,5-trimethoxyphenyLacetic acid.

ExampLe 21 3,4-Dihydro-2-isopropyL-4-methyL-2-E2-E4-E4-(4-fLuorobenzoyL)-piperazinyL]-butoxy)-phenyL]-2H-1,4-benzothiazin- 3-one (2d,6H) ppm.

9 I; 29 g (10 mmoL) of 3,4-dihydro-2-isopropyL-4-methyL-2-2- (4-bromobutoxy)-phenyL]-2H-1,4-benzothiazin-3-one were stirred in 100 mL of methanol for 2 hours at 40 0 C with 2.45 g of 4-(4-fLuorobenzoyL)-piperidine hydrochLoride and 1.2 g of NaOH, and the mixture was then heated to the boil for 3 hours. After concentrating, the product was partitioned between ethyl acetate and water. The organic phase was washed with water, dried with sodium sulfate and concentrated. Chromatography on silica gel with 9:1 methyLene chloride/methano as the solvent gave 2.1 g of a light brown resin.

1 H-NMR (CDCL 3 6 8.1 6.5 (m,12H); 3.9 (m,3H); 3.4 3.3 2.1 2.1 1.6 1.1 0.95 (2d,6H) ppm.

ExampLe 22 3,4-Dihydro-2-isopropyL-4-methyl-2-[2-[2-hydroxy-3-[4- (3-methoxyanilinocarbonyl )-methyl-piperazinylJ-propoxylphenyL]-2H-1,4-benzothiazin-3-one dihydrochloride 6.6 g (18 mmol) of the compound from ExampLe 16 were heated to the boil for 8 hours with 9.1 g (37 mmol) of 1-(3methoxyaniLinocarbonyl)-methyl-piperazine and 70 mL of methano. After concentrating, the product was chromatographed on 300 g of silica gel with 9:1 methylene chloride/methanol. This gave 2.7 g of the free base as a brownish, viscous oil.

1 H-NMR (CDCL 3 6 7.5 6.4 (m,12H); 4.2 3.3 (m,6H); 3.7 3.4 3.1 2.8 2.4 (m,8H); 1.4 1.0 0.7 (d,3H) ppm.

DihydrochLoride: colorless crystals, melting point 198- 200 0 C (decomposition) Calculated C 3 4

H

4 2

N

4 0 5 S.2HCL.H 2 0 C 57.5 H 6.5 N 7.9 Found C 56.8 H 6.0 N 7.1 Example 23 3,4-Dihydro-2-benzyL-4-methy trimethoxyphenyL)-propionyL] 2H-1,4-benzothiazin-3-one hy L-2-[2-E4-E-4--E3-(3,4,5- I-piperazinyLl-butoxyJ-phenyLl- 'drochLoridle @1 4 4414 I '41 14 It 1.

Ii.,.

11 I I g (10 mmoL) of 3,4-dihydro-2-benzyL-4-methyL-2-[2-(4bronobutoxy)-phenyL]-2H-1,4-benzothiazin-3-one, 1.4 g of potassium carbonate and 6 g of 1-[3-(3,4,5--trimethoxyphenyL)-propionyL]-piperazine were boiLed under refLux for 16 hours in 100 ml of DMF. After filtration, the mixture was diluted with ethyl acetate, washed with water (3 times), dried with sodium sulfate and concentrated.

Chromatography on silica gel gave 3.3 g of the free base.

1 H-NMR (CDCL 3 3 6.5 (m,13H); 6.4 (s,2H); 3.8 4.0-3.6 (mi,8H); 3.4 3.0 -2.2 (m,1OH); 1.6 (m,4H) ppm.

Hydrochloridle: colorless crystals, melting point 98-100 0

C

(decompos it ion) The preparation pf 3,4-di hydro-2-benzyL-4-methyL-2-E2-(4bromobutoxy-phenyL J-2H-1,4-benzoth iaz in-3-one is descr i- 25 bed in EP-A-146,893.

Example 24 3,4-Dihydro-2-benzyL-4-methyL-2-E2-[4-E4-C3,4,5-trimethoxyphenyL)-acetyLamino-.piperazinyL]-butoxy]-phenyLJ-2H-1,4benzoth iaz in-3-one hydrochloridle g of 3,4-di hydro-2-benzyL-4-methyL-2-E2-(4-bromobutoxy)phenyL]-2H-1,4-benzothiazin-3-one were reacted with 3.1 g of 4-(3,4,5-trimethoxyphenyL )-acetyLamino-piperidine analogously to the instructions given in Example 23. This gave 7.2 g of the free base as an oil.

I

of ethyl acetate and toLuene, and the solution was 31- I 1 H-NMR (CDCL 3 S=7.3 6.2 Cm,15H); 4.1 -3.3 (m,7H); 3.8 3.4 Cs,3H); 3.2 2.2 2.1 1.5 Cm,8H) ppm.

Hydrochloridle: coLorLess crystaLs, meLting point 115 0

C

(decomposition) ExampLe 3,4-D ihydro-2-benzyL-4-methyL-2-[2-E4-[4-E 3 3 3 ,1 4

,S-

trimethoxyphenyL)-propionyL]--piperazinyL]-butoxyJ-phenyL]- 2H-1,4--benzoth iazin-3-one hydrochLoridle This was prepared from 5 g of 3,4-dihydro-2-benzyL-4methyL-2-[2-(4-bromobutoxy)-phelyL -2H-1 ,4-benzoth iaz in- 3-one and 3.1 g of' 4-E3-(3,4,5-trimethoxyphenyL)-propioflyL amino]-piperidine in accordance with the instructions given in Example 23. Free base: coLorless resin, yield 3.2 g.

1 H-NMR (CDCL 3 =7.2 6.2 (m,15H); 4.1 3.3 Cm,7H); 3.8 3.4 3.2 2.2 2.1 ppm.

Hydrochloridle: colorless crystals, melting point 1140 C (decomposition) 4 4 4: K 32 la po-A\cO~ o.

COMPARATIVE EXAMPLE I (instant compounds vs 23767/84 (Santen)) 3H-Nitrendipine binding assay We determined the effect of the compounds of 3H-nitrendipine binding to rat brain cortical membranes according to the method described by R.J. Gould et al. (Proc. Natl. Acad.

Sci. USA 79, 3656 (1982)), with slight modifications.

Membrane preparations were washed several times and diluted l:1500(w/vol) with TRIS-HCl buffer, pH 7.4, of the following composition: 50 mM TRIS-HC1, 150 Mn NaCl, 1.0 mM CaC1 2 and 0.001 Genapol(R) (Hoechst AG). Incubation was performed in 5.5 ml-aliquots of the membrane suspension containing 3H-nitrendipine (0.1 nM; specific activity 81.3 Ci/mmol) and various concentrations of the test drug. After 60 min incubation at 25 0 C in a shaking water bath, the samples were cooled .in an ice-bath, and bound ligand was separated by vacuum filtration through Whatman GF/F glass fibre filters.

S. The filters were rinsed with ice-cold buffer, dried and vortexed with 3.5 ml of scintillation cocktail. We used 20 liquid scintillation counting for measurement of radioactivity remaining on the filters. Non-specific E binding was evaluated in the presence of 1 pm nifedipine.

values were determined using at least 4 5 different concentrations of the test compound in triplicate.

percentage displacement of specific 3H-nitrendipine binding was plotted on semi-logarithmic paper, and graphic interpolation yielded that molar drug. concentration which inhibited specific 3H-nitrendipine binding by Example of AU 71994/87 ICs 0 (nM) 4 6 i.7 7 2.4 1 4 4 0 7" E ~4EI IjtC.

L i e 2.2 110 1.2 16 110 1000 (of 23767/84 Santen Pharmaceutical Co. Ltd.) 4 4, I I~cllr COMPARATIVE EXAMPLE II 2 3 7 67/ 8 4 vs,37166/84) (Santen Pharmaceutical Co. Ltd. vs Hoechst AG) 3H-Nitrendipine binding assay We determined the effect of the compounds of 3H-nitrendipine binding to rat brain cortical membranes according to the method described by R.J. Gould et al. (Proc. Natl. Acad.

Sci. USA 79, 3656 (1982)), with slight modifications.

Membrane preparations were washed several times and diluted l:1500(w/vol) with TRIS-HC1 buffer, pH 7.4, of the following composition: 50 mM TRIS-HC1, 150 Mn NaCl, 1.0 mM CaCl 2 and 0.001 Genapol(R) (Hoechst AG). Incubation was performed in 5.5 ml-aliquots of the membrane suspension containing 3H-nitrendipine (0.1 nM; specific activity 81.3 Ci/mmol) and various concentrations of the test drug. After 60 min incubation at 25°C in a shaking water bath, the samples were cooled in an ice-bath, and bound ligand was separated by vacuum filtration through Whatman GF/F glass fibre filters.

The filters were rinsed with ice-cold buffer, dried and vortexed with 3.5 ml of scintillation cocktail. We used liquid scintillation counting for measurement of radioactivity remaining on the filters. Non-specific binding was evaluated in the presence of 1 pm nifedipine.

0a4 a25 percentage displacement of specific 3H-nitrendipine binding 4 was plotted on semi-logarithmic paper, and graphic a o interpolation yielded that molar drug concentration which inhibited specific 3H-nitrendipine binding by In all of the following compounds is, unless specified otherwise H in formula I nR(3)R R(3 R(2) 71# c T ii Furthermore is R(2)=CH 3 n~p= zero, X= oxygen and C3 \0 C= R(6) -N N-(CH 2 2 -C .COH C-C, C=c(/ C3 the position of Example No. m 4 4 the side chain is 2'.

R 3 R4 H H H 5' -OCH 3 I C 5 0 (nM) 1000 greater than 1000 '44 444* 4, 3716 6/8 4 compound eg.

No.

6 129 128 135 142 143 144 145 CH 3 CH 3 CH 3 CH 3 CH 3 C 2 H 5 C 2

H

5 (CH 3 2 CH (CH 2

CH

H

H (+)-form H (-)--form 5' -OCH H (-t)-form H (-)-form H (*-)-form H (-)-form 700 19 8 600 13 2 0.7 12 *This is a closely related compound of AU 23 767/84 (Santen Pharmaceutical Co. Ltd.) This is compound 78 of AU 23 767/84) (Santen Pharamaceutical Co. Ltd.) (see Comparative Example No. I).

Claims

1.A compound of the formuLa I and saLts thereof with IpharmaceuticaLLy acceptabLe acids R(1)~R3) R( R(2) I ;n whicii R(1, R(1) and are identicaL or different and independlently of one another are hydrogen, (Cl-C 4 )-aLkyL, (Cl-C 3 )-aLkoxy, F, CL, Br, CF 3 nitro, hydroxyL, acetamidlo or amino, R(2) is hydrogen, straight-chain or branched ('Cj-Cj 0 aLkyL, straight-chain or branched (C 3 -Cl 0 aLkenyL, phenyL-(Cl-C 4 )-aLkyL, the phenyL ring being unsubstituted or substituted by one, two or three substituents from the group comprising (CC-C 4 )-aLkyL, (Cl-C 3 )-aLkoxy, F, CL, CF 3 (Cl-C 2 )-aLkyLenedioxy or nitro, R(3) is tD straight-chain or branched (Cl-Cl 5 aLkyL, straight-chain or branched (C 3 -Cl 5 aLkemyL, C 4 -C 8 )-cycLoaLkyL, (C 4 -C 8 cycLoaLkyL-(Cl-C 4 )-aLkyL, phenyL or phenyL- (Cl-C 4 )-aLkyL, the phenyL radlicaL being un- substituted or substituted by one, two or three substituents from the group comprising (Cl C 4 aLkyL, (Cl-C 3 )-aLkoxy, F, CL, CF 3 (Cl- C 2 )-aLkyLenedioxy or nitro, R(4) and are identicaL or different and indle- pendlently of one another are hydrogen, (Cl-C 4 aLkyL, (Cl-C 3 )-aLkoxy, F, CL, CF 3 nitro, hydroxyt, acetamidlo or amino, A is the group (CH2)m-X-(CH2)n, m being 1, 2, 3 or 4, but only 2, 3 or 4 if X is a I

37- heteroatom, n being zero, 1, 2 or 3, but only 2 or 3 i x is~ a heteroatom,Ltis a CH 2 group, oxygen, sulfur, a carbonyl group, a CH(OH) group or a group I in which R(5) and are identical or different and are hydrogen or (C 1 -C 4 )-alkyl, B is one of the following groups 4454 4444 5554 44 44 4545 4 #4 45 4 454544 S 44 44 S ~.t R( 6) -N- R(8) R(9 R( 7 N -0D-r S~ L 4 -T and D together are -CH 2 CH(OH) -CH 2 C-g-R(11) or -H2g E is a (CH 2 )q radical, q being zero, 1, 2 or 3, or radical, but E is only (CH 2 )q with q 2 or 3 if D are a heteroatom, F is a single bond, an NR(12)-CO a CO-NR(13) radical, a carbonyl group or an oxygen is phenyl, the phenyl ring being unsubstituted or substituted by one, two or three substituents from comprising (C 1 -CO -alkyl, (C 1 -CO -alkoxy, F, Cl, (C 1 -C 2 )-alkylene, dioxy or cyano, or 2-furyl, a -CH=CH and/or F radical, atom, G the group R(6) and R(7 and R(8) and R(9) are hydrogen, straight- chain or branched (Cl-Cl 0 )-aLkyL, (Cl-C 6 aLkanoyL, phenyL-(CC-C 4 )-aLkyL, benzhydryL or benzhydryL-(C C-C 4 )-aL kyL, phenyL-( C -C 4 aLkanoyL or benzyL, the phenyL raoicaLs being in each case unsubstituted or substitued by one, two or three radicaLs from the group comprising (CC-C 4 )-aLkyL (C 1 -C 4 )-aLkoxy, (rC 1 -C 2 )-aLkyLene- dlioxy, F, CL, Br, CF 3 or hydroxyL, and and R(11) and R(12) and R(13) are hydrogen or (Cl-C 5 )-aLkyL 2. A compound Ilas cLaimed in cLaim 1, wherein at Least one of the substituents and indices has the foLLowing m ea n ing Il I I a 11 I I LI R(1 and R(1' are identicaL or different and indlepen- dlentLy of one another are hydrogen, methyl, ethyL, methoxy, ethoxy, fLuorine, chLorine, CF 3 nitro or acetamido, RC1)" is hydrogen, R(2) is hydrogen, straight-chain or branched (Cl-C 6 aLkyL, aLLyL, methaLLyL, benzyL, phenethyL, 4- methoxybenzyL, 3,4-dimethoxybenzyL, 3,4,5-tni- methoxybenzyL or 3,4-methyLenedioxybenzyL, R(3) is hydrogen, straight-chain or branched (Cl-Cl 2 aLkyL, aLLyL, methaLLyL, (C 5 -C 7 )-cycLoaLkyL, C 5 C 7 )-cyc LoaLkyL-(C C-C 4 )-aLkyL benzyL, methyLbenzyL, fLuorobenzyL, methoxybenzyL, dimethoxybenzyL or phenyLe-thyL, R(4) is hydrogen, methyL, methoxy, ethoxy, chLorine, nitro, hydroxyL, acetamidlo or amino, R(4)1 is hydrogen, A is the group (CH2)m-X-CCH2)n, m being 1, Z, 3 or 4, but only 2, 3 or 4 if X is a heteroatom, n is zero, 1, 2 or 3, but onLy 2 or 3 if X is a heteroatom, X is a CH 2 group, oxygen, suLfur, a carbonyL group, a CH(OH) group or a group R(5)-C-RC5) lk A, *0 (CAL L I t R(5) and being identical or different and being hydrogen, methyl or ethyl, B is one of the fellowing groups R(6) and D together are -CH -CH 2 -g-N-R(11) or -CH2-C- E ,is a (CH 2 )q radical, q being zero, 1 or 2, or a -CH=CH radical, but if D and/or F are a heteroatom, E is only (CH 2 )q with q 2 or 3, F is a single bond, an NR(12)-CO radical, a CO-NR(13) radical, a carbonyl group or an oxygen atom, G is phenyl or 2-furyl, the phenyl ring being unsubstituted or substituted by one or two substituents from the group comprising (Cl-C 2 )-alkyl, F, Cl, (C -C 2 )-alkylenedioxy or cyanc or being substituted by one, two or three (Cl-C 2 )-alkoxy substituents, and R(7), R(10), R(11), R(12) and-R(13) are hydrogen or (C -C )-alkyl. 3. A compound I as claimed in claim 1, wherein at least one of the substituents and indices has the following meaning: R(1) is hydrogen, methyl, methoxy, fluorine or chlorine, is hydrogen or methoxy, is hydrogen, R(2) is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, isobutyl, benzyl or phenethyl, ir- R(3) is hydrogen, straight-chain or branched (Cl-C 1 2 )-alkyl, cyclopentyl, cylohexyl, cyclopentyl-methyl, cyclohexylmethyl, allyl, methallyl, benzyl, methylbenzyl, fluorobenzyl, ethoxybenzyl, dimethoxybenzyl or phenylethyl, R(4) is hydrogen, methoxy, methyl, cholorine, nitro or hydroxyl, is hydrogen A is the group (CH 2 )m-X-(CH 2 )n, m being 1, 2 or 3, but being only 2 or 3 if X is a heteroatom, n being 0, 1 or 2, but only 2 if X is a heteroatom, X is a CH 2 group, oxygen, a carbonyl group, a CH(OH) group or a group in which R(5) and are identical or different and are hydrogen or methyl, B is one of the following groups I R(6) -N- -N 1 N- -N N- R(7) S N- -NbS and D together are -CH -CH 2 -g-N-R(11) or -CH 1'! f y -a E is a (CH2)q radicaL, q being zero, 1 or 2, F is a single bond, an NR(12)-CO radical, a CO-NR(13) radical, a carbonyl group or an oxygen atom, G is phenyl, the phenyl ring being unsubstituted or substituted by 1 or 2 radicaLs from the group comprising methyl, F, CL, methylenedioxy or cyano, or by 1, 2 or 3 methoxy radicals, or 2-furyL, and R(10), R(11), R(12) and R(13) are identical or different and are hydrogen or (C 1 -C 3 )-alkyl. 4. A process for preparing a compound I as claimed in claim 1, which comprises a) reacting a compound of the formula II, R( R(3) R(4) 1R(4)1 O-A-Y IR(1) (2) in which R(4)' and A have the same meaning as in the formula I and in which Y is a leaving group which can be displaced by a nucleophilic reaction, with a compound of the formula III H-B-T-D-E-F-G III, in which B, T, D, E, F and G have the same meaning as in the formula I, under the conditions of a nucleophilic sub- stitution, in the presence or absence of an auxiliary base for intercepting the acid being formed, at a temperature between 0 and 160 C, or b) reacting a compound of the formula IV R(1) R(3) R(4) (IV, l R(2 R( I R R( 2 1-.SEN' LS in which R(4) and R(4)' have the same meaning as in the formula I, with a com- pound of the formula V Z-A-B-T-D-E-F-G V, in which Z is defined in the same way as Y in the formula II and in which A, B, T, D, E, F and G have the same meaning as in the formula I, either in a polar aprotic solvent in the presence of a strong base at a temperature between -40 and +600C, or in a protic or aprotic poLar organic solvent in the presence of a weak to moderately strong base at a temperature between 0 and 1600C, or c) reacting a compound of the formula V R(3) R(4) 0O-A-R(14) N R(1) R(2) in which R(4)' e" and A have the same meaning as in the formula I and in which R(14) is one of the following groups H \H /H -N R(9 NH S. R(8) %1- WTI in which R(8) and R(9) have the same meaning as in the formula I, with a compound of the formula VI W-C-R-F-G VI, 0 in which E, F and G have the same meaning as in the formula I and W is a chlorine atom, a (C 1 -C 5 )-alkoxy group, a (Ci-C 5 )-aLkanoyLoxy group or an imidazole radical, under conventional amide formation conditions, compounds of the formula I being formed in which p is zero and D is a carbonyL group, or d) reacting a compound of the formula VII R 3) R 4 I-I R(4)' -(CH )m--cCH VII, No 0 R(1) (2) in which R(4)' and m have the same meaning as in the formuLa I, with a compound of the formula VIII 1 H-B-T-D-E-F-G VIII, J .in which B, T, D, E, F and G are as defined as in the formula I, without a soLvent or in the presence of a preferably polar solvent, compounds of the formula I being formed in which A is the radical -(CH 2 )m-CH-CH 2 OH or -r f7 tl :6 :Y e) reacting a compound of the formula V with a compound of the formula IX CH-CH-(CH 2 q-1-F-G 0 in which F, G and q have the same meaning as in the formula I, under the reaction conditions described under compounds of the formula I being formed in which p is 1 and D is a CH(OH)-group. A medicament which contains or is composed of a com- o e? pound I as claimed in claim 1. 6. The use of a compound I as claimed in claim 1 for the Streatment of disturbances in the calcium balance of a human or animal organism. DATED this 24th day of April 1987. P' HOECHST AKTIENGESELLSCHAFT EDWD. WATERS SONS PATENT ATTORNEYS QUEEN STREET MELBOURNE. VIC. 3000.