NO871745L - BENZOTIAZINO DERIVATIVES, PROCEDURES FOR THEIR PREPARATION, PHARMACEUTICALS CONTAINING THEM AND THEIR USE. - Google Patents

Description

It is known that compounds which prevent the influx of calcium ions into the cells can be used as therapeutics for the treatment of various diseases, especially the cardiovascular system in humans and other warm-blooded animals.

Benzothiazinone derivatives with calcium antagonistic action are described in US patent 4,584,300, the compounds listed there are unsubstituted in the 2-position of the heterocycle.

Furthermore, benzothiazinone derivatives with calcium antagonistic action are mentioned in US patent 4 595 685. Here, compounds are mentioned which have a basic ether grouping at the 2-phenyl residue, the basic nitrogen being connected to the ether oxygen via a straight or branched alkyl chain.

It has now surprisingly been found that compounds with altered side chains at the 2-phenyl residue have superior calcium antagonist properties.

The invention therefore relates to benzothiazinone derivatives of formula I, which have a calcium antagonistic effect:

as well as their salts with pharmaceutically acceptable acids, wherein in formula I

R(l), R(l)' and R(l)" are the same or different and independently of each other mean hydrogen, (C1-C4)-alkyl, (C1-C3)-alkoxy, F, Cl, Br, CF3 , nitro, hydroxy, acetamido

or amino,

R(2) means hydrogen, (C^-C^q)-alkyl, straight or branched, (C3-C10 )-alkenyl, straight or

branched, phenyl-(C1-C4)-alkyl, wherein the phenyl ring is unsubstituted or substituted with one, two or three substituents from the group (C1-C4)-alkyl, (C1-C3)-alkoxy, F, Cl, CF3, ( C1-C2)-alkylenedioxy or

nitrous,

R(3) means hydrogen, (C^-C^5)-alkyl, straight or branched, (C3-C15)-alkenyl, straight or branched, (C4-C8)-cycloalkyl, (C4-C8)-cycloalkyl- (C-L-C4)alkyl, phenyl or phenyl-(C1-C4)-alkyl, the phenyl radical being unsubstituted or substituted with one, two or three substituents from the group (C1-C4)-alkyl, (C1-C3)-alkoxy, F, Cl, CF3, (C1-<C>2)-alkylenedioxy or nitro,

R(4) and R(4)' are the same or different and independently mean hydrogen, (C1-C4 )-alkyl, (C1-C3)-alkoxy, F, Cl, CF3, nitro, hydroxy, acetamido or

amino,

A means the group (CH2)m<->X-(CH2)n, wherein

m means 1, 2, 3 or 4,

whereas, however, m, when X is a heteroatom, means only 2, 3 or 4,

n means 0, 1, 2 or 3, if X means a heteroatom,

however, n means only 2 or 3,

X means a CH2 group, oxygen, sulfur, a carbonyl group, a CH(OH) group or a group

in which

R(5) and R(5)' are the same or different and mean hydrogen

or (C1-C4)-alkyl,

B means one of the following groups

T means a (CEtøJp residue, where p means 0, 1, 2 or 3,

however, p means only 1, 2 or 3, when D means the CHOH group, and when p means only 2 or 3, when D

means a heteroatom,

D means a CH(OH) group, a carbonyl group, a-NR(10)-CO group, a CO-NR(11) group or a

oxygen atom,

E means a (CHg^-residue, where q means 0, 1, 2 or 3,

or a -CH=CH residue, however, when D and/or F means a heteroatom, E means only (CH2)q with q = 2

or 3,

F means a single bond, a NR(12 )-C0 residue, a C0-NR(13) residue, a carbonyl group or an oxygen atom, G means phenyl, the phenyl ring being unsubstituted or substituted with one, two or three substituents from the group (C^-C^ )-alkyl, (C-L-C3 )-Alkoxy, F, Cl, (C^

C 8 )-alkylenedioxy or cyano or means 2-furyl,

R(6) and R(7) and R(8) and R(9) mean hydrogen, (C^C^)-alkyl, straight or branched, (C^-C^)-alkanoyl, phenyl-(C1- C4)-alkyl, benzhydryl or benzhydryl-(C^-C4)-alkyl, phenyl-(C1-C4)-alkanoyl or benzyl, the phenyl residues being respectively unsubstituted or substituted by one, two or three residues from the group ( C1-C4 )-alkyl, (C1-C4 )-alkoxy, (<C>1-C2)-alkylenedioxy, F, Cl, Br, CF3 or hydroxy,

R(10) and R(11) and R(12) and R(13) mean hydrogen or (C1-C5)-alkyl.

Preference is given to the compounds of formula I, in which at least one of the substituents and indices has the following meaning: R(l) and R(l)' are the same or different and independently mean hydrogen, methyl, ethyl, methoxy,

ethoxy, fluorine, chlorine, CF3, nitro or acetamido, R(1)" means hydrogen,

R(2) means hydrogen, (C^-C^ )-alkyl, straight or branched, allyl, methallyl, benzyl, phenethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4,5-trimethoxy-benzyl, 3 ,4-methylenedioxybenzyl,

R(3) means hydrogen, (C^-C^g)-alkyl, straight or branched, allyl, methallyl, (C5-C7)-cycloalkyl, (C5-c7 )-cycloalkyl-(C1-C4)-alkyl, benzyl, methylbenzyl, fluorobenzyl, methoxybenzyl, dimethoxybenzyl, phenylethyl,

R(4) means hydrogen, methyl, methoxy, ethoxy, chlorine, nitro,

hydroxy, acetamido or amino,

R(4)' means hydrogen,

A means the group (CH2)m-X-(CH2)n, wherein

m means 1, 2, 3 or 4,

however, m, when X means a heteroatom, means only 2, 3 or 4,

n means 0, 1, 2 or 3, if X means a heteroatom,

however only 2 or 3,

X means a CH2~ group, oxygen, sulphur, a carbonyl group, a CH(OH) group or a group R(5)-C-R(5' ), wherein R(5) and

R(5)' are the same or different and mean hydrogen, methyl or ethyl,

B means one of the following groups

T means a (CHgJp residue, where p means 0, 1 or 2, whereas when D means the CHOH group, p means only 1, 2 or 3, and when D means a heteroatom, p means

only 2 or 3,

D means a CH(OH) group, a carbonyl group, a-NR(10)-CO group, a C0-NR(11) group or a

oxygen atom,

E means a (CH2)q residue, where q means 0, 1 or 2,

or means a CH=CH residue,

F means a single bond, a NR(12)-C0 residue, a C0-NR(13) residue, a carbonyl group or an oxygen atom, G means phenyl or 2-furyl, the phenyl ring being unsubstituted or substituted with one or two substituents from the group (C 1 -C 8 )-alkyl, F, Cl, (C 1 -C 8 )-alkylenedioxy or cyano, or with one, two or

three (C 1 -C 8 )-alkoxy substituents,

R(6), R(7), R(8), R(9), R(10), R(ll) and R(12) and R(13)

means hydrogen or (C^-C^)-alkyl,

as well as the salts of these compounds of formula I with pharmaceutically acceptable acids.

Particular preference is given to compounds of formula I, in which at least one of the substituents and indices has the following meaning: R(l) means hydrogen, methyl, methoxy, fluorine or chlorine, R(l)' means hydrogen or methoxy,

R(l)" means hydrogen,

R(2) means hydrogen, methyl, ethyl, propyl, isopropyl,

butyl, sec. butyl, isobutyl, benzyl, phenethyl,

R(3) means hydrogen, (C^-C^2)-alkyl, straight or branched, cyclopentyl, cyclohexyl, cyclopentyl-methyl, cyclohexylmethyl, allyl, methallyl, benzyl, methylbenzyl, fluorobenzyl, methoxybenzyl, dimethoxybenzyl, phenylethyl,

R(4) means hydrogen, methoxy, methyl, chlorine, nitro or

hydroxy,

R(4)' means hydrogen,

A means the group (CHg)m-X-(CHg)n, wherein

m means 1,2 or 3,

however, when X is a heteroatom, m means only 2, 3 or 4,

n means 0, 1 or 2, however if X means a

heteroatom, n means only 2,

X means a CEtø group, oxygen, a carbonyl group, a CH(OH) group or a group

in which

R(5) and R(5)' are the same or different and mean hydrogen

or methyl,

B means one of the following groups

T means a (CHgip residue, p means 0, 1 or 2, however, when D means the CHOH group, p means only 1, 2 or 3, and p, when D means a heteroatom, means only

means 2 or 3,

D means a CH(OH) group, a carbonyl group, a-NR(10)-CO group, a CO-NR(11) group or a

oxygen atom,

E means a (CH2)p residue, where q means 0, 1 or 2,

F means a single bond, a NR(12 )-C0 residue, a C0-NR(13) residue, a carbonyl group or an oxygen atom,

G means phenyl, the phenyl ring being unsubstituted or substituted with one or two residues from the group methyl, F, Cl, methylenedioxy or cyano or with 1, 2 or

3 methoxy acid residues or means 2-furyl,

R(6), R(7), R(8), R(9), R(10), R(ll), R(12) and R(13) are the same or different and mean hydrogen or (C^ -C3)-alkyl,

as well as the salts of these compounds of formula I with pharmaceutically acceptable acids.

As such pharmaceutically acceptable acids, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic 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, camphor sulphonic acid are considered. , benzenesulfonic acid, acetic acid, propionic acid or p-toluenesulfonic acid.

The compounds of formula I have asymmetric C atoms and can therefore act as enantiomers or diastereomers. The invention covers the pure isomers as well as their mixtures. These mixtures of diastereomers can be separated by usual methods, for example selective crystallization from suitable solvents or chromatography on silica gel or aluminum oxide in the components. The racemates can be resolved by usual methods into the individual enantiomers, thus e.g. by salt formation with optically active acids such as camphorsulphonic acid or dibenzoyltartaric acid and selective crystallization or by derivatization with suitable optically active reagents, cleavage of the diastereomeric derivatives and back cleavage.

The method according to the invention for preparing the compounds of formula I is characterized by

a) a compound of formula II

wherein R(l), R(l)', R(l)", R(2), R(3), R(4), R(4)' and A have the same meaning as stated for formula I, and wherein Y means a leaving group which can be displaced nucleophilically, in particular a chlorine, bromine or iodine atom, a sulphonic acid residue, preferably a methanesulphonyl residue, a benzenesulphonyl residue, a toluenesulphonyl residue or a trifluoromethanesulphonyl residue, reacted with a compound of formula III

wherein B, T, D, E, F and G have the same meaning as stated for formula I, under conditions of a nucleophilic substitution, preferably in a polar organic solvent such as an alcohol, preferably methanol, ethanol, propanol or isopropanol or a lower ketone , preferably acetone or methyl ethyl ketone or dimethylformamide, dimethyl sulfoxide or sulfolane or a hydrocarbon, preferably toluene, with or without the presence of an auxiliary base to trap the acid that is formed, preferably in the presence of potassium carbonate, sodium carbonate, triethylamine, N-ethylmorpholine or pyridine , at a temperature between 0 and 160°C, preferably between 20 and 120°C, or that

b) a compound of formula IV

in which R(l), R(l)', R(l)", R(2), R(3), R(4) and R(4)<*> have the same meaning as stated for formula I, is converted with a compound of formula V,

wherein Z has the same meaning as Y in formula II and wherein A, B, T, D, E, F and G have the same meaning as given under formula I, either in a polar aprotic solvent such as dimethylformamide, dimethylsulfoxy, tetrahydrofuran, sulfolane or N- methylpyrrolidone, in the presence of a strong base such as sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, butyllithium or lithium hexamethyldisllazide, at a temperature between -40 and +60°C, preferably between 10 and -30°C, or in a protic or aprotic polar organic solvent such as a lower alcohol, for example methanol, ethanol, isopropanol or a lower ketone, preferably acetone or methyl ethyl ketone or in dimethylformamide, in the presence of a weak to medium strong base such as an alkali 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 160°C, preferably between 20 and 120°C, or that

c) a compound of formula V

wherein R(l), R(l)', R(2), R(3), R(4), R(4)' and A have the same meaning as in formula I, and wherein R(14) means a of the following groups in which R(6), R(7), R(8) and R(9) have the same meaning as stated for formula I, is reacted with a compound of formula VI

in which E, F and G have the same meanings as given for formula I, and W means a chlorine atom, a (C1-C5)-alkoxy group, a (C±-C§)-alkanoyloxy group or an imidazole residue, under normal amide formation conditions, as compounds of formula I are formed, in which p is 0 and D means a carbonyl group, or at

d) a compound of formula VII

in which R(l), R(l)', R(l)'\ R(2), R(3), R(4), R(4)' and m have the same meaning as stated for formula I, is converted with a compound of formula VIII in which B, T, D, E, F and G have the meaning given under formula I, without solvent or in the presence of a preferably polar solvent such as methanol, isopropanol, acetone, THF or dimethylformamide, forming compounds of formula I, in which A means the residue e) a compound of formula V is reacted with a compound of formula IX in which F, G and q have the meaning given under formula I, under the reaction conditions mentioned under alternative d), forming compounds of formula I, wherein p means 0 and D means a CH(OH) group. From compounds of formula IV it is possible by reaction with compounds of formula X

wherein A has the meaning given under formula I, Y has the meaning given under formula II, and Q has the same meaning as Y in formula II In the presence of bases such as e.g. sodium hydroxide, potassium carbonate, sodium methylate or potassium tertiary butylate in a solvent such as e.g. tetrahydrofuran, methanol, dimethoxyethane, acetone, methyl ethyl ketone, dimethylformamide or dimethylsulfoxide, compounds of formula II are prepared.

Compounds of formula VI are obtained from compounds of formula IV, e.g. with epichlorohydrin and base (form = 1) according to known methods or by alkylation of compounds of formula IV with compounds of formula XI

in which m has the same meaning as for formula I and Y has the same meaning as for formula II, forming compounds of formula XIII in which R(l), R(l)', R(l)'\ R(2), R (3), R(4), R(4)' and m have the same meaning as stated for formula I. Subsequent epoxidation of the compounds XIII according to known methods, e.g. with m-chloroperbenzoic acid in methylene chloride gives compounds of formula VII. Compounds of formula V are obtained from compounds of formula II by reaction with one of the compounds of formulas Xlla, Xllb, XIIc, Xlld or Xlle

in which R(6), R(7), R(8), R(9) have the same meaning as for formula I, and in which P means a hydrogen atom, a (C₁-C₁)-alkoxycarbonyl group, a benzyloxycarbonyl group, a trifluoroacetyl group or a trichloromethylcarbonyloxy group, relieves the conditions mentioned under process variant a) and

subsequent cleavage of the groups, if these do not mean hydrogen, according to methods known in the literature.

Compounds of formula IV are known from EP-A-146,893.

The compounds according to the invention with formula I have blood pressure-lowering, especially calcium-antagonistic effects and can therefore be used for the treatment of all disease states, which are due to a disturbance in the calcium balance in a warm-blooded animal.

Their calcium antagonistic action can be shown in the biochemical test model of displacement of tritiated nitrendipine.

In this way, membrane preparations containing the isolated calcium channels are charged with the labeled substance. After incubation with the test substance, the released radioactivity in the supernatant solution is determined. In this model, the compounds according to the invention of formula I have ICsg values of 10"<6>molar to 10-!-0 molar. In further test models in which calcium antagonistic action can be demonstrated, e.g. on the coronary perfusion on isolated guinea pig hearts or on the action potential of the isolated guinea pig papillary muscle, the compounds of formula I are likewise strongly active.

The compounds according to the invention with formula I and their pharmacologically tolerable salts reduce the inflow of calcium ions into the cells and are therefore suitable for treatment of the heart-circulatory system when correspondingly untreated, e.g. in various forms of Angina pectoris, Tachycardia, heart rhythm disturbances and high blood pressure. They are effective within a wide dose range. The height of the administered dose depends on the type of the desired treatment, on the method of administration, on the condition, on the type and on the size of the treated patient. By oral dosing, satisfactory results are obtained with doses from 0.01 mg, preferably from 0.1 mg and up to 100 mg, preferably up to 20 mg of a compound of formula I per kg body weight. In humans, the daily dose varies between 10 g and 800 mg, preferably 20 to 500 mg, as single doses of 5 to 200 mg can be administered, preferably one to three times a day.

For intravenous and intramuscular use, the dose is 1 to 300 mg, preferably 5 to 150 mg.

The pharmacologically usable compounds according to the invention and their salts can be used for the production of pharmaceutical preparations, which contain an effective amount of the active substance together with carrier substances and which are suitable for enteral and parenteral administration. Tablets or gelatin capsules containing the active substance together with diluents, e.g. lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and/or glycine and lubricants such as silica, talc, stearic acid or their salts, such as magnesium- or calcium stearate and/or polyethylene glycol. Tablets also contain binders such as magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if necessary, colourants, flavorings and sweeteners. Injectable solutions are preferably isotonic aqueous solutions or suspensions which can be sterilized and can contain excipients such as preservatives, stabilisers, wetting agents and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure and/or buffer substances. The pharmaceutical preparations which, if desired, can contain further pharmacologically valuable substances are prepared, e.g. using conventional mixing-granulating and coating methods and containing 0.1$ to approx. 75%, preferably approx. 1$ to approx. 50$ of the active substance.

Alkyl, alkenyl, alkoxy, alkylene, unless otherwise expressly stated, always mean a straight or branched chain.

The invention will be explained in more detail with the help of some examples.

Example 1

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-(2-(3,4,5-trimeth-oxyphenyl)-acetyl]-piperazinyl]-butoxy] - phenyl]-2H-1,4-benzothiazin-3-one hydrochloride

6.68 g (15 mmol) of 3,4-dihydro-2-isopropyl-4-methyl-2-[2-(4-bromobutoxy)-phenyl]-2H-1,4-benzothiazin-3-one was stirred in 30 ml DMF with 2.07 g potassium carbonate and 6.63 g (22.5 mmol) 3,4,5-trimethoxyphenylacetic acid piperazide for 5 hours under reflux. After cooling, 250 ml of water was added, the water was decanted from the oily residue and this was taken up in vinegar. After washing with water and drying, it was evaporated. Chromatography on 250 g of silica gel with methylene chloride/methanol (9:1) as eluent gave 2.4 g of the title compound (free base) as an oil.

1-H-NMR (CDCl 3 ): S = 7.5 - 6.5 (m, 8H); 6.45 8s, 2H);

4.2 - 3.9 (m, 2H); 3.8 (s, 9H); 3.6 (s, 2H); 3,4 (s,3H);

3.1 - 2.1 (m.IIH); 2.0 - 1.5 (m, 4H); 1.1 + 0.95 (2d,6H) ppm

The hydrochloride was obtained by mixing with ethanolic hydrochloric acid, evaporation and extraction with petroleum ether, 1.7 g, melting point 125°C.

Calculated: C37H45N306S.HC1 C 63.5 H6.9 N6.0 Cl 5.1 Found: C 62.6 H7.l N5.8 Cl 5.5

The preparation of 3,4-dihydro-2-isopropyl-4-methyl-2-[2-(4-bromobutoxy]-phenyl]-2H-1,4-benzothiazin-3-one is discussed in EP-A-146 893 .

The 3,4,5-trimethoxyphenylacetic acid piperazide is obtained in the following way: 11.3 g of 3,4,5-trimethoxyphenylacetic acid and 23.3 ml of a 30% solution of 1-hydroxybenztriazole were mixed at room temperature with 12.3 g dicyclohexylcarbodiimide and 8.8 g of N-benzylpiperazine. After 15 hours it was suctioned off, and the filtrate diluted with water. After three times of extraction with ethyl acetate, the combined organic phases were each washed once with saturated NaHCO₂ solution, 10⁻g citric acid solution and saturated sodium chloride solution, dried and evaporated. The thus formed N-benzyl-N'-trimethoxyphenyl-acetyl)-piperazine was dissolved in 45 ml of methanol and hydrogenated with 1 g of palladium on animal charcoal (10%) for 8 hours at 80°C and 30 atm Hg pressure. After filtration, it was evaporated and the residue dissolved in acetone and mixed with ethereal hydrochloric acid. The hydrochloride is sucked off. Yield 5.7 g, melting point 108-110°C. Example 2 3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-(2-3,4,5-trimet-oxyphenyl)-propionyl]-piperazinyl]-butoxy] - phenyl] -2H-1,4-benzothiazin-3-one hydrochloride 3.01 g (6.7 mmol) 3,4-dihydro-4-methyl-2-[2-(4-bromobutoxy)-phenyl]- 2H,1,4-benzothiazin-3-one was heated to boiling with 4.5 g of 3-(3,4,5-trimethoxyphenyl)-propionic acid-piperazine and 1.4 g of potassium carbonate in 100 ml of isopropanol for 8 hours. After cooling, it was filtered, evaporated and chromatographed on silica gel with methylene chloride/methanol (9:1). 3.9 g of the free base appeared as an oil. 1-H-NMR (CDCl 3 ): S = 7.6 - 6.5 (m, 8H); 6.4 (s, 2H); 3.85 + 3.82 (2s, 9H); 4.2 - 3.3 (m, 4H); 3,4 (s,3H); 3.0 - 2.0 (m, 13 H); 2.0 - 1.5 (m, 4H); 1.15 - 0.9 (2d,6H) ppm 3 -(3 , 4 , 5 -1 r imethoxyphenyl)-propionic acid-piperazine appeared analogously to the regulation specified for 3 , 4 , 5-trimethoxyphenyl-acetic acid-piperazide using 3-(3,4,5-trimethoxy-phenyl)-propionic acid as starting material.

Example 3

3,4-dihydro-2-isopropyl-4-methyl-2-[2-(4-piperazinyl)-butoxy-phenyl]-2H-1,4-benzothiazin-3-one dihydrochloride

4.5 g (10 mmol) of 3,4-dihydro-isopropyl-4-methyl-2-[2-(4-bromobutoxy)-phenyl]-2H-1,4-benzothiazin-3-one was heated to boiling in 50 ml of isopropanol with 1.4 g of potassium carbonate and 2.58 g of anhydrous piperazine for 16 hours. After filtration, it was evaporated, taken up in a mixture of ethyl acetate and toluene, washed three times with water, dried with sodium sulfate and evaporated. 4.3 g of the title compound was obtained as an oil (free base).

1-H-NMR (CDCl 3 ): S = 7.6 - 6.4 (m, 8H); 3.9 (+ .2H);

3.38 8s, 3H); 3.0 + 2.4 (m.IIH); 2.1 8s,1H); 1.9 - 1.5

(m, 4H); 1.15 - 0.95 (2d,6H) ppm

Dihydrochloride: Colorless crystals, melting point 110°C (under decomposition).

Example 4

3, 4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-(2-furyol )-piperazinyl]-but oksy]-phenyl]-2H-1,4-benzothiazine- 3-one hydrochloride

4.5 g of the compound from example 3 and 1 g of triethylamine were dissolved in 50 ml of methylene chloride. At 0°C to 5<0>C, 1.3 g of furan-2-carboxylic acid chloride was added dropwise. After 4 hours it was poured into ice water, the organic phase separated, washed with saturated sodium bicarbonate solution and water and dried with sodium sulfate. 4.3 g of the free base were obtained as an oil.

<1->H-NMR (CDCl 3 ): S = 7.6 - 6.3 (m,HH); 4.0 - 3.6 (m, 6H); 3.36 8s, 3H); 3.1 - 2.2 (m, 7H); 2.0 - 1.6 (m, 4H); 1.1 + 0.9 (2d,6H) ppm.

The hydrochloride was obtained from a methanolic solution with ethereal hydrochloric acid, melting point 186 - 187°C (under decomposition).

Calculated: C3H37N304<S.>HC1 C 63.75 H 6.55 N 7.2 Cl 6.1 Found: C 63.4 H6.6 N7.1 Cl 6.2

Example 5

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-(3,4,5-trimethoxy-cinnamoyl)-piperazinyl]-butoxy]-phenyl]-2H-1, 4-benzothiazin-3-one hydrochloride

4.6 g (10 mmol) of the compound from Example 3 was stirred with 5 ml of a 30% solution of 1-hydroxybenztriazole in DMF, 4.6 g of dicyclohexylcarbodiimide and 2.5 g of 3,4,5-trimethoxy -cinnamic acid for 18 hours at room temperature. After extraction, it was poured onto water, extracted with vinegar, washed with water, dried and evaporated. Chromatography on silica gel gives 3.8 g of free base as an oil.

<1>H-NMR (CDCl 3 ): S = 7.6 - 6.4 (m, 12 H); 4.6-3.6 (m,6H); 3.85 (s.9H); 3,4 (s,3H); 3.3 - 2.6 (m, 7H); 2.0 - 1.6

(m, 4H); 1.2 + 0.95 (2d,6H) ppm.

Hydrochloride: Colorless crystals, melting point 193 - 194°C.

Calculated: C38<H>47<N>306S.HC1 C 64.3 H6.8 N5.9 Cl 5.0 Found: C 63.2 H6.8 N5.8 Cl 5.0

Example 6

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-(2-hydroxy-3-(2-cyano-phenoxy)-propyl]-piperazinyl]-butoxy]- 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-epoxy-propoxy)-benzonitrile were stirred in 50 ml of methanol for 3 hours under reflux. After evaporation, it was chromatographed on silica gel. 1.9 g of free base was obtained as an oil.

1-H-NMR (CDCl 3 ): S = 7.6 - 6.5 (m, 12 H); 4.2-3.6 (m, 5H);

3,4 (s,3H); 3.2 - 2.3 (m, 13 H); 2.0 - 1.6 (m, 4H); 1.2 - 0.95 (2d,6H) ppm

Dihydrochloride: Colorless crystals, melting point 130 - 131°C (under decomposition).

Calculated:<C>35<H>44<N>4O4S.2HC1 C 60.9 H6.7 N 8.1 Cl 10.3 Found: C 59.8 H 6.7 N 7.5 Cl 10.1

Example 7

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[2-hydroxy-3-(2-chloro-phenoxy)-propyl]-piperazinyl]-butoxy]-phenyl]- 2H-1,4-benzothiazin-3-one dihydrochloride

4.6 of the compound from example 3 was reacted with 1.84 g of 1-(2-chlorophenoxy)-2,3-epoxypropane analogously to the method described in example 6. 2.7 g of the free base appeared as an oil.

% NMR (CDCl 3 ): S = 7.5 - 6.8 (m, 12 H); 4.2 - 3.6 (m, 7H);

3,4 (s,3H); 3.1 - 2.3 (m, 13 H); 2.0-1.6 (m, 4H);

1.15 + 0.95 (2d,6H) ppm

Dihydrochloride: Colorless crystals, melting point 195°C.

Calculated: C35<H>44<N>304S.2HC1.H20 C 57.7 H 6.6 N 5.8 Cl 14.6 Found: C 57.7 H6.5 N 5.5 Cl 14.2

Example 8

3, 4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-piperazinyl]-butoxy]-phenyl] -2H-1,4-benzothiazin-3-one dihydrochloride

4.6 g of the compound from example 3 was reacted with 1.8 g of 1-(2-methoxy-phenoxy)-2,3-epoxy-propane analogously to the method described in example 6. 2.4 g of the free base appeared as an oil.

1-H-NMR (CDCl 3 ): S = 7.6 - 6.4 (m, 12 H); 4.2 - 3.6 (m, 7H); 3.8 (s, 3H); 3,4 (s,3H); 3.1 - 2.3 (m, 13 H); 2.0 - 1.6

(m, 4H); 1.2 - 0.95 (2d,6H) ppm

Dihydrochloride: Colorless crystals, melting point 130 - 132°C (under decomposition).

Calculated: C36H47<N>305S.2HC1.2H20 C 58.2 H7.2 N 5.7 Cl 9.6 Found: C 57.7 H6.8 N 5.4 Cl 9.1

Example 9

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-(2,6-dimethylani-1 i no-carbonyl)-methyl]-piperazinyl]-butoxy]-phenyl] -2H-1,4-benzothiazin-3-one dihydrochloride

4.5 g (10 mmol) of the compound from example 3 was stirred with 1.97 g (10 mmol) of chloroacetic acid-2,6-dimethylanilide in 50 ml of methylene chloride for 10 hours at room temperature. After evaporation, chromatograph on 300 g of silica gel with methylene chloride/methanol (9:1). 2.0 g of the free base is obtained as an oil.

<i>H-NMR (CDCl 3 ): S = 7.5 - 6.4 (m,HH); 4.2 ( + .2H);

3.4 (s, 3H); 3.2 (s,2H); 3.0 - 2.3 (rn.IIH); 2.2 (s,6H);

2.0 - 1.5 (m, 4H); 1.1 + 0.9 (2d,6H) ppm

Dihydrochloride: Colorless crystals, melting point 258°C.

Calculated: C36<H>46<N>403S.2HC1 C 62.9 H7.0 N8.1 Cl 10.3 Found: C 63.1 H 6.8 N 8.0 Cl 10.4

Chloroacetic acid-2,6-dimethylanilide was obtained from chloroacetyl chloride and 2,6-dimethylaniline with the addition of pyridine in methylene chloride. Colorless crystals, melting point 148 - 149° C (from petroleum ether).

Example 10

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-(N-methyl-carbamoyl)-piperazinyl]-butoxy]-phenyl]-2H-1,4- benzothiazin-3-one

4.5 g (10 mmol) of the compound from example 3 was dissolved in 50 ml of methylene chloride. 0.57 g of methyl isocyanate was added dropwise. After 2 hours at room temperature, it was evaporated and chromatographed on silica gel. 4.0 g of the title compound were obtained as a colorless resin.

<1->H-NMR (CDCl 3 ): δ = 2.5 - 6.3 (m, 8H); 5.1 (q,1H);

4.0 - 3.3 (m, 6H); 3,4 (s,3H); 3.0 - 2.4 (m+d, 10H),

2.0 - 1.6 (m, 4H); 1.1 - 0.85 (2d,6H) ppm

Example 11

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-(4-butyryl)-piperazinyl)-butoxy]-phenyl]-2H-1,4-benzothiazin-3-one

4.5 g (10 mmol) of the compound from example 3 were mixed dropwise with 1.06 g of butyryl chloride in 50 ml of methylene chloride. After 3 hours it was evaporated and chromatographed on silica gel. 3.3 g of the title compound was obtained as a colorless resin. 1-H-NMR (CDCl 3 ): S - 7.4 - 6.3 (m, 8H); 4.0 - 3.6 (m, 6H);

3.4 (s, 3H); 3.0 - 2.6 (m, 6H); 2.4 - 1.4 (m, 9H); 1.2 + 0.8 (2d+t,9H) ppm

Example 12

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-(3-methoxy-cinnamoyl]-piperazinyl]-butoxy]-phenyl]-2H-1,4- benzothiazin-3-one hydrochloride

A mixture of 5 ml of a 30% solution of 1-hydroxybenztriazole, 3 g of dicyclohexylcarbodiimide, 4.6 g of the compound from example 3 and 1.8 g of 3-methoxycinnamic acid was stirred for 3 hours at room temperature. After suction, it was poured onto water and extracted with vinegar. The organic phase was washed twice with water, dried with sodium sulfate and evaporated. The crude product was purified on 300 kg of silica gel with methylene chloride/methanol (9:1). 4.7 g of the free base appeared as an oil.

1-H-NMR (CDCl 3 ): S = 8.0 - 6.5 (m, 13 H); 4.2 - 3.6 (m, 6H); 3.8 (s, 3H); 3,4 (s,3H); 3.3 - 2.8 (m, 7H); 2.2 - 1.6

(m, 4H); 1.15 - 0.95 (2d,6H) ppm

Hydrochloride: Colorless crystals of melting point 80°C (under decomposition).

Example 13

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-(4-acetyl^piperazinyl]-butoxy]-phenyl]-2H-1,4-benzotriazin-3-one- hydrochloride

4.5 g (10 mmol) of the compound from example 3 were mixed dropwise with 1.02 g of acetic anhydride in 50 ml of methylene chloride. After 3 hours at room temperature, it was evaporated and chromatographed on silica gel with methylene chloride/methanol (9:1) as eluent. 2.7 g of the free base appeared as a resin.

<1->H-NMR (CDCl 3 ): S = 7.5 - 6.4 8m, 8H); 4.0 - 3.4 (m, 6H);

3,4 (s,3H); 3.0-2.2 (m,7H); 2.0 (s, 3H); 2.0 - 1.6

(m, 4H); 1.1 + 0.8 (2d,6H) ppm.

Hydrochloride: Colorless crystals of melting point 100°C (under decomposition).

Example 14

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-(3-methoxy-anilino-carbonyl)-methyl[-piperazinyl]-butoxy]-phenyl]-2H-1 ,4-benzothiazin-3-one dihydrochloride 45 g of the compound from example 3 was reacted with 2 g of chloroacetyl-3-methoxyanilide according to the method specified in example 9. 4.9 g of the free base appeared as a colorless oil.

1-H-NMR (CDCl 3 ): S = 7.5 - 6.6 (m, 12 H); 3.7 8s, 3H);

3,4 (s,3H); 4.0 - 3.0 8m,13H); 2.1 - 1.6 (m, 4H);

1.1 - 0.7 (2d,6H) ppm.

Dihydrochloride: Colorless crystals, melting point 234 - 236°C (under decomposition).

Calculated: C35<H>44<N>4O4S.2HCl.H2O C 59.4 H 6.8 N 7.9 Cl 10.0 Found: C 59.6 H6.6 N 7.9 Cl 10.2

Example 15

3,4-dihydro-2-Isopropyl-4-methyl-2-[2-[4-[4-(2,6-dimethoxy-phenoxy)-acetyl]-piperazinyl]-butoxy]-phenyl]-2H- 1,4-benzo-thiazin-3-one hydrochloride 45 g (10 mmol) 3,4-dihydro-2-isopropyl-4-methyl-2-[2-(4-bromobutoxy)-phenyl]-2H-1 ,4-benzothiazin-3-one and 3.1 g of 1-(2,6-dimethoxyphenoxy)-acetyl-piperazine as well as 1.5 g of ground, dry potassium carbonate were stirred in 30 ml of DMF for 6 hours at 90-100°C . The reaction mixture was partitioned between water and vinegar, the phases separated, the acetic ester phase washed with water and dried over magnesium sulphate. After evaporation, it was purified on silica gel with vinegar. 4.3 g of the free base were obtained as a resin.

1->H-NMR (CDCl 3 ): S = 7.4 - 6.3 (m.11H); 4.5 (s, 2H);

4.0 - 3.6 (m, 6H); 3.8 (s,6H); 3,4 8s,3H); 3.0 - 2.3

(m, 7H); 2.0-1.6 (m, 4H); 11 + 0.9 (2d,6H) ppm.

Hydrochloride: Colorless crystals, melting point 144-148°C.

Calculated: C36<H>45<N>306S.HC1 C 63.2 H 6.8 N 6.1 Cl 5.2 Found: C 62.8 H 6.7 N 6.1 Cl 5.5

1-(2,6-dimethoxyphenoxy)-acetylpiperazine was obtained in the following way:

125 g (80 mmol) of 2,6-dimethoxyphenoxyacetic acid was reacted with N-benzylpiperazine (14.1 g) according to the dicyclohexylcarbodiimide/hydroxybenztriazole method (Example 5). The thus formed benzyl-4-(2,6-dimethoxyphenoxy)-acetylpiperazine (18 g) was hydrogenated in 180 ml of methanol with 1.8 g of palladium on carbon (10$) as catalyst at 100 bar and 80° C. for 8 hours.

After filtration and evaporation, 6.6 g of 1-(2,6-dimethoxyphenoxy)-acetyl-piperazine was obtained, melting point 174 - 175°C (from acetone/acetic ester).

Example 16

3,4-dihydro-2-isopropyl-4-methyl-2-[2-(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 was stirred with 0.6 g NaOH, 2 ml H20 and 50 ml epichlorohydrin for 24 hours at 85°C. After dilution with water, it was extracted with methylene chloride, dried with sodium sulfate and evaporated. 5.3 g of the title compound was obtained as an oil.

1-H-NMR (CDCl 3 ): S = 7.6 - 6.4 (m, 8H); 4.2 - 3.8 (m, 3H);

3.4 (s, 3H); 3.4 -2.5 (m, 4H); 1.4 - 0.7 (m,6H) ppm

Example 17

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[2-hydroxy-3-[4-(3,4,5-trimethoxy-phenyl)-acetyl]-piperazinyl]-propoxy ] -phenyl] -2H-1,4-benzothiazin-3-one hydrochloride

5.5 g of the compound from Example 16 was boiled with 8 g of 1-(3,4,5-trimethoxyphenyl)-acetyl-piperazine in 50 ml of methanol under reflux (10 hours). After evaporation, it was chromatographed on 300 g of silica gel with methylene chloride/methanol (9:1). 4.7 g of the free base was obtained as a colorless resin. 1 H-NMR (CDCl 3 ): S = 7.5 - 6.4 (m, 8H); 6.3 (s, 2H);

3.8 (s, 9H); 4.0 - 3.5 (m, 9H); 3,4 (s,3H); 2.7 - 2.3

(m, 5H); 1.3 - 0.8 (m,6H) ppm

Hydrochloride: Colorless amorphous powder, melting point below 85°C

cleavage.

Example 18

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[2-hydroxy-3-[4-[3-(3,4,5-trimethoxyphenyl)propionyl]-piperazinyl]-butoxy]- phenyl]-2H-1,4-benzothiazin-3-one

5.5 g of the compound from example 16 was formed with 8.4 g of 1-[3-(3,4,5-trimethoxyphenyl)-propionyl]-piperazine according to the method indicated in example 17. 6.8 of the title compound emerged. 1-H-NMR (CDCl 3 ): S = 7.5 - 6.4 (m, 8H); 6.3 (s, 2H);

3.8 (s, 9H); 4.0 - 3.5 (m, 9H); 3,4 (s,3H); 2.7 - 2.3

(m, 5H); 2.0 - 1.8 (m, 2H); 1.3 - 0.6 (m,6H) ppm

Example 19

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-[3-(3,4,5-tri-methoxyphenyl)-propionyl]-piperazinyl]-butoxy]-phenyl ]-2H-1,4-benzothiazin-3-one hydrochloride

6.68 g (15 mmol) of 3,4-dihydro-2-isopropyl-4-methyl-2-[2-(4-bromobutoxy)-phenyl]-2H-1,4-benzothiazin-3-one was heated with 2.07 g of ground, anhydrous potassium carbonate and 4.83 g of 4-[3-(3,4,5-trimethoxyphenyl)-propionyl-amino]-piperidine for 3 hours in 30 ml of DMF at 80-90° C. It was poured into 300 ml of ice water, extracted with ethyl acetate (2 times), the combined organic phases washed with water (2 times), dried over sodium sulfate and evaporated. 9.8 g of the free base were obtained, melting point 151-153°C.

1->H-NMR (CDCl 3 ): S = 7.4 - 6.4 (m, 8H); 6.3 (s, 2H);

5.4 (d, 1H); 4.0 - 3.6 (m, 3H); 3.7 8s, 9H); 3,4 (s,3H);

3.0 - 2.2 (m,HH); 2.0 - 1.5 (m, 4H); 1.1 + 0.9 (2d,6H) ppm

Hydrochloride: Colorless crystals, melting point 138-140°C

(from ethanol)

Calculated: C3gH51N3<0>6S.HCl.H20 C 62.9 H7.3 N 5.6 Found: C 63.4 H7.5 N5.8

4-[3-(3,4,5-1-trimethoxyphenyl)-propionyl-amino]-piperidine was obtained as follows: 24 g of 3-(3,4,5-trimethoxyphenyl)-propionic acid was reacted with 20.2 ml 4-amino-1-benzylpiperidine by the dicyclohexylcarbodiimide/1-hydroxybenzotriazole method (Example 5).

The resulting 1-benzyl-4-[3-(3,4,5-trimethoxyphenyl)-propionyl-amino]-piperidine (36.1 g, mp 93-95°C) was hydrogenated in 500 ml of methanol with Pd/C (10$, 5g) at 100 bar H2 pressure and 80° C for 12 hours. After filtration and evaporation, 26 g of melting point 110°C were obtained.

Example 20

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[2-[4-[4-(3,4,5-trimethoxyphenyl)-acetyl-amino]-piperidinyl]-butoxy] -phenyl]-2H-1,4-benzothiazin-3-one hydrochloride

4.5 g (10 mmol) of 3,4-dihydro-2-isopropyl-4-methyl-2-[2-(4-bromobutoxy)-phenyl]-2H-lm4-benzothiazin-3-one was reacted with 3, 1 g of 4-(3,4,5-trimethoxyphenyl-acetyl-amino)-piperidine according to the method specified in example 19. 3.8 g of free base appeared as an oil. 1-H-NMR (CDCl 3 ): S - 7.5 - 6.6 (m, 8H); 6.3 (s, 2H);

5.65 8s,1H); 4.0 - 3.6 (m, 3H); 3.9 (s.9H); 3,4 (s,3H);

3.5 - 1.5 (m, 17H); 1.15 - 0.9 (2d,6H) ppm

Hydrochloride: Colorless amorphous powder, melting point 85°C

during cleavage

4-(3,4,5-trimethoxyphenylacetyl-amino)-piperidine was obtained as indicated in example 19 from 3,4,5-trimethoxyphenylacetic acid.

Example 21

3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-(4-fluorobenzoyl)-piperazinyl]-butoxy]-phenyl]-2H-1,4-benzothiazine-3- Wed

4.5 g (10 mmol) of 3,4-dihydro-2-isopropyl-4-methyl-2-[2-(4-bromobutoxy)-phenyl]-2H-1,4-benzothiazin-3-one was stirred with 2.45 g of 4-(4-fluorobenzoyl)-piperidine hydrochloride and 1.2 g of NaOH in 100 ml of methanol for 2 hours at 40°C, then heated to boiling for 3 hours. After evaporation, it was partitioned between vinegar and water. The organic phase was washed with water, dried with sodium sulfate and evaporated. Chromatography on silica gel with methylene chloride/methanol (9:1) as eluent gave 2.1 g of light brown resin.

<1>H-NMR (CDCl 3 ): S = 8.1 - 6.5 (m, 12 H); 3.9 (m, 3H); 3,4 (s,3H); 3.3 - 2.1 (m, 7H); 2.1 - 1.6 (m, 8H); 1.1 + 0.95 (2d,6H) ppm.

Example 22

3,4-Dihydro-2-isopropyl-4-methyl-2-[2-[2-hydroxy-3-[4-(3-methoxyanilylnocarbenyl)-methyl]-piperazinyl]-propoxy]-phenyl]-2H-1 ,4-benzothiazin-3-one dihydrochloride

6.6 g (18 mmol) of the compound from Example 16 was heated to boiling for 18 hours with 9.1 g (37 mmol) of 1-(3-methoxy-anilino-carbonyl)-methyl-piperazine and 70 ml of methanol. After evaporation, it was chromatographed on 300 g of silica gel with methylene chloride/methanol (9:1). 2.7 g of the free base appeared as a brownish, viscous oil.

1-H-NMR (CDCl 3 ): S = 7.5 - 6.4 (m, 12 H); 4.2 - 3.3 (m, 6H);

3.7 (m, 3H); 3.4 (p. 3H); 3.1 (s,2H); 2.8 - 2.4 (m, 8H);

1.4 - 1.0 (m, 5H); 0.7 (d,3H) ppm

Dihydrochloride: Colorless crystals, melting point 198-200°C

during cleavage

Calculated: C34<H>42<N>4O5S.2HCl.2H2O C 57.5 H6.5 N7.9 Found: C 56.8 H6.0 N7.l

Example 23

3,4-dihydro-2-benzyl-4-methyl-2-[2-[4-[4-[3-(3,4,5-trimethoxy-phenyl)-propionyl]-piperazinyl]-butoxy] - phenyl]-2H-1,4-benzothiazin-3-one hydrochloride

5 g (10 mmol) 3,4-dihydro-2-benzyl-4-methyl-2-[2-(4-bromobutoxy)-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 in 100 ml of DMF for 16 hours under reflux. After filtration, it was diluted with ethyl acetate, washed with water (3 times), dried with sodium sulfate and evaporated. Chromatography on silica gel gave 3.3 g of the free base.

<1>H-NMR (CDCl 3 ): S = 7.3 - 6.5 (m, 13 H); 6.4 (s, 2H);

3.8 (s, 9H); 4.0 - 3.6 (m, 8H); 3,4 (s,3H); 3.0 - 2.2 (m, 10H); 2.0 - 1.6 (m,4H) ppm.

Hydrochloride: Colorless crystals, melting point 98-100°C

during cleavage

The preparation of 3,4-dihydro-2-benzyl-4-methyl-2-[2-(4-bromobutoxy)-phenyl]-2H-1,4-benzothiazin-3-one is discussed in EP-A-146 893 .

Example 24 3,4-dihydro-2-benzyl-4-methyl-2-[2-[4-[4-(3,4,5-trimethoxy-phenyl)-acetylamino]-piperazinyl]-butoxy]-phenyl] -2H-1,4-benzothiazin-3-one hydrochloride 5 g 3,4-dihydro-2-benzyl-4-methyl-2-[2-(4-bromobutoxy)-phenyl]-2H-1,4- benzothiazin-3-one was reacted with 3.1 g of 4-(3,4,5-trimethoxyphenyl)-acetylamino-piperidine analogously to the regulation given in example 23. 7.2 g of the free base appeared as an oil.

1->H-NMR (CDCl 3 ): S = 7.3 - 6.2 (m, 15 H); 4.1 - 3.3 (m, 7H); 3.8 (s, 9H); 3,4 (s,3H); 3.2 - 2.2 (m, 6H); 2.1 - 1.5 (m,8H) ppm

Hydrochloride: Colorless crystals, melting point 115°C

during cleavage

Example 25

3,4-dihydro-2-benzyl-4-methyl-2-[2-[4-[4-[3-(3,4,5-trimethoxy-phenyl)-propionyl]-piperazinyl]-butoxy]- phenyl]-2H-1,4-benzothiazin-3-one hydrochloride

Prepared from 5 g of 3,4-dihydro-2-benzyl-4-methyl-2-[2-(4-bromobutoxy)-phenyl]-2H-1,4-benzothiazin-3-one and 3.1 g of 4 -[3-(3,4,5-trimethoxyphenyl)-proplonyl-amino]-piperidine according to the regulation stated in example 23. Free base: colorless resin, yield 3.2 g.

1->H-NMR (CDCl 3 ): S = 7.2 - 6.2 (m, 15H); 4.1 - 3.3 (m, 7H); 3.8 (s, 9H); 3,4 (s,3H); 3.2 - 2.2 (m, 6H); 2.1 - 1.5

(m,1OH) ppm

Hydrochloride: Colorless crystals, melting point 114°C

during cleavage

Claims (5)

1. Process for the preparation of a compound I as well as their salts with pharmaceutically acceptable acids, in which R(l), R(l)' and R(l)" are the same or different and independent of each other means hydrogen, (C1 -C4 )-alkyl, (C1 -C3 )-alkoxy, F, Cl, Br, CF3 , nitro, hydroxy, acetamido or amino, R(2) means hydrogen, (C^-C^q)-alkyl, straight or branched, (C3-C10)-alkenyl, straight or branched, phenyl-(C^-C4)-alkyl, the phenyl ring being unsubstituted or saturated with one, two or three substituents from the group (C 1 -C 4 )-alkyl, (^-O 3 )-alkoxy, F, Cl, CF 3 , (C 1 -C 2 )-alkylenedioxy or nitro, R(3) means hydrogen, (C^ -C^5 )-alkyl, straight or branched, (<C>3 -C15 )-alkenyl, straight or branched, (C4-C8 )-cycloalkyl, (C4-C3 ) -cycloalkyl-(C^-C4 )alkyl, phenyl or phenyl-(C-1-C4 )-alkyl, the phenyl residue being unsubstituted or substituted with one, two or three substituents from the group (C^-C4 )_alkyl, (C-1- C3 )-Alkoxy , F, Cl, CF3 , ( C1-C2 )-alkylenedioxy or nitro, R(4) and R(4)' are the same or different and independently mean hydrogen, (C 1 -C 4 )-alkyl , (C 1 -C 3 )-alkyl, F, Cl, CF 3 , nitro, hydroxy, acetamido or amino, A means the group (CH2 )m -X-(CH2 )n , wherein m means 1, 2, 3 or 4, However, when X is a heteroatom, m is only 2, 3 or 4, n means 0, 1, 2 or 3, if X means a heteroatom, however, n means only 2 or 3, X means a CH2 group, oxygen, sulfur, a carbonyl group, a CH(OH) group or a group R(5)' are the same or different and mean hydrogen or (C1 -C4 )-alkyl, B means one of the following groups T means a (CH 2 )p residue, where p means 0, 1 or 2, where however, when D means the CHOH group, p means only 1, 2 or 3, and when D means a heteroatom, p means only 2 or 3, D means a CH(OH) group, a carbonyl group, a NR (10) - the CO group, a C0-NR( 11 ) group or an oxygen atom, E means a (CH2 )q residue, where q means 0, 1, 2 or 3, or a -CH=CH -residue, however, when D and/or F means a heteroatom, E means only (CH2 )q with = 2 or 3, F means a single bond, an NR(12 )-CO residue, a C0- NR(13) residue, a carbonyl group or an oxygen atom, G means phenyl, the phenyl ring being unsubstituted or substituted with one, two or three substituents from the group (C^C^ )-alkyl, (C1-C3 )-alkoxy, F, Cl, (C-^-Cg)-alkylenedioxy or cyano, or means 2-furyl, R (6) and R(7) and R(8) and R(9) mean hydrogen, (C^C^)-alkyl, straight or branched, (C^-C^ )-alkanoyl, phenyl-(C1-C4 )-alkyl, benzhydryl or benzhydryl-(C^ -C4 )-alkyl, phenyl-(C1 -C4 )-alkanoyl, or benzyl, the phenyl residues being respectively unsubstituted or substituted with one, two or three residues from the group ( C1-C4 )-alkyl, (C 1 -C 4 )-alkoxy , (C 1 -C 8 )-alkylenedioxy, F, Cl, Br, CF 3 or hydroxy, R(10) and R(11) and R(12) and R(13) mean hydrogen or (C^ (C 5 )-alkyl, characterized by ata) a compound of formula II wherein R(l), R(l)', R(l)", R(2), R(3), R(4), R(4)' and A have the same meaning as stated above for formula I, and wherein Y represents a leaving group which can be nucleophilically displaced, reacted with a compound of formula III wherein B, T, D, E, F and G have the same meanings as given for formula I, under conditions of a nucleophilic substitution, with or without the presence of an auxiliary base to trap the acid that is formed, at a temperature between 0 and 160 °C, or that b) a compound of formula IV in which R(l), R(l)', R(1)", R(2), R(3), R(4) and R(4)' have the same meaning as stated for formula I, reacted with a compound of formula V wherein Z has the same meaning as Y in formula II, and wherein A, B, T, D, E, F and G have the same meaning as given under formula I, either in a polar aprotic solvent in the presence of a strong base at a temperature between -40 and +60°C, or in a protic or aprotic polar organic solvent in the presence of a weak to medium strong base at a temperature between 0 and 160°C, orc) a compound of formula V wherein R(l), R(1)',R(1)", R(2), R(3), R(4), R(4)' and A have the same meaning as stated for formula I, and wherein R(14) means one of the following groups wherein R(6), R(7), R(8) and R(9) have the same meaning as stated for formula I, is reacted with a compound of formula VI in which E, F and G have the same meanings as given for formula I, and W means a chlorine atom, a (C1 -C5 )-alkoxy group, a (C1 -C5 )-alkanoyloxy group or an imidazole residue, under normal amide formation conditions, as compounds of formula I are formed, in which p means 0 and D means a carbonyl group, or atd) a compound of formula VII in which R(l), R(l)', R(D", R(2), R(3), R(4), R(4)' and m have the same meaning as stated for formula I, is reacted with a compound of formula VIII wherein B, T, D, E, F, G have the same meanings as given for formula I, without solvent or in the presence of a preferably polar solvent, resulting in compounds of formula I, wherein A represents the residue or ate) a compound of formula V is reacted with a compound of formula IX in which F, G and q have the same meaning as stated for formula I, under the reaction conditions mentioned under d), as compounds of formula I are formed, in which p is equal to 1 and D means a CH(OH) group. 2. Method according to claim 1, characterized in that at least one of the substituents and indices has the following meaning: R(l) and R(l)' are the same or different and independently mean hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, CF3 , nitro or acetamido, R(l)" means hydrogen, R(2) means hydrogen, (C^-C^ )-alkyl, straight or branched, allyl, methallyl, benzyl, phenethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4,5-trimethoxy-benzyl, 3 ,4-methylenedioxybenzyl, R(3) means hydrogen, (C^ -C^ g )-alkyl, straight or branched, allyl, methallyl, (C 5 -C 7 )-cycloalkyl, (C 5 -C 7 )-cycloalkyl-( C^-C^ )- alkyl, benzyl, methylbenzyl, fluorobenzyl, methoxybenzyl, dimethoxybenzyl, phenylethyl, R(4) means hydrogen, methyl, methoxy, ethoxy, chlorine, nitro, hydroxy, acetamido or amino, R(4)' means hydrogen, A means the group (CHg)m-X-(CHg)n, wherein m means 1, 2, 3 or 4, when X is a heteroatom, means m only 2, 3 or 4, n means 0, 1, 2 or 3, if X means a heteroatom, however, n means only 2 or 3, X means a CHg group, oxygen, sulfur, a carbonyl group, a CH(OH) group or a group R(5)-C-R(5)', in which R(5) and R(5)' are the same or different and mean hydrogen, methyl or ethyl, B means one of the following groups T means a (CHgJp residue, where p means 0, 1 or 2, where however, when D means the CHOH group, p means only 1, 2 or 3, and when D means a heteroatom, p means only 2 or 3, D means a CH(OH) group, a carbonyl group, a -NR(10) - CO group, a C0-NR(11) group or et oxygen atom, E means a (CHgiq residue, where q means 0, 1 or 2, or a -CH=CH-residue, in that when D and/or F means a heteroatom, E only means (CB^q with = 2 or 3, F means a single bond, a NR(12)-CO residue, a CO-NR( 13) residue, a carbonyl group or an oxygen atom, G means phenyl or 2-furyl, where the phenyl ring is unsubstituted or substituted with one or two substituents from the group (C^-Cg )-alkyl, F, Cl, (C±-Cg )-alkylenedioxy or cyano or with one, two or three (C^-Cg )-alkyl substituents , R(6), R(7), R(8), R(9), R(10), R(ll) and R(12) and R(13) mean hydrogen or (C 1 -C 4 )-alkyl . 3. Procedure According to claim 1, characterized in that at least one of the substituents and indices has the following meaning: R(l) means hydrogen, methyl, methoxy, fluorine or chlorine, R(l)' means hydrogen or methoxy, R(l)" means hydrogen, R(2) means hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, isobutyl, benzyl, phenethyl, R(3) means hydrogen, (C^ -C^ g )-alkyl, straight or branched, cyclopentyl, cyclohexyl, cyclopentyl-methyl, cyclohexylmethyl, allyl, methallyl, benzyl, methylbenzyl, fluorobenzyl, methoxybenzyl, dimethoxybenzyl, phenylethyl, R(4) means hydrogen, methoxy, methyl, chlorine, nitro or hydroxy, R(4)' means hydrogen, A means the group (CHg)m -X-(CHg)n , wherein m means 1, 2 or 3, however when X means a heteroatom, m means only 2, 3 or 4, n means 0, 1 or 2, if X means a heteroatom, means n however only 2, X means a CHg group, oxygen, a carbonyl group, a CH(OH) group or a group R(5)' are the same or different and mean hydrogen or methyl, B means one of the following groups T means a (CHgip residue, where p means 0, 1 or 2, however, if D means the CHOH group, p means only 1, 2 or 3, and in that if D means a heteroatom, means p only 2 or 3, D means a CH(OH) group, a carbonyl group, a -NR(10)-C0 group, a C0-NR(11) group or an oxygen atom, E means a (CHg^-residue, where q means 0, 1 or 2, F means a single bond, a NR(12)-C0 residue, a C0-NR(13) residue, a carbonyl group or an oxygen atom, G means phenyl, the phenyl ring being unsubstituted or substituted with one or two residues from the group methyl, F, Cl, methylenedioxy or cyano or with 1, 2 or 3 methoxy acid residues, or means 2-furyl, R(6) R(7), R(8), R(9), R(10), R(ll), R(12) and R(13) are the same or different and mean hydrogen or (C^ - C 3 )-alkyl. 4. Process for the preparation of a medicinal product, characterized in that a compound I obtained according to claim 1 is mixed with pharmaceutical common carrier substances. 5. Use of a compound I formed according to claim 1 for the production of a drug for the treatment of disturbances in calcium balance in a human or animal organism.