WO2005082873A2 - 1,4-benzothiazepans and derivatives thereof - Google Patents

Abstract

The invention relates to novel compounds of 1,4-benzothiazepans and 1,4-benzothiazepins, especially of 5-one compounds, and to the use of the same as medicaments.

Description

New 1,4-benzothiazepanes and derivatives

The invention relates to new compounds of 1,4-benzothiazine-epanes / -epines, in particular 5-ones, and their use as medicaments.

Benzothiazepines are generally described as pharmaceuticals, especially for the treatment of heart diseases, especially cardiovascular diseases. Importantly, for example, Diltiazem ^® (cis (+) -5- (2-dimethylaminoethyl) - 2,3,4, 5-tetrahydro-2- (4-methoxyphenyl) -4-oxo-l, 5- benzothiazepine-3- ylacetate) for use after kidney transplants and hypertension.

Hofmann and Fischer also describe the synthesis of 1,4-benzothiazepin-5- (4H) -one and 4-methyl-l, 4-benzothiazepin-5- (4H) -one (Hofmann, Fischer, Chem Ber. 121, 2147 -2150). Other known compounds are 1, 4-benzothiazepin-5 (4H) -thione, 1, 4-benzothiazepin-5 (4H) -one - 2, 3, 4-trimethyl, 1,4-benzothiazepin-5 (4H) -one -3-ethyl-4-methyl, 1,4-benzothiazepine-5 (4H) -one -3, 4-dimethyl, 1, 4-benzothiazepine-5 (4H) -one-1, 1-dioxide (Chemical Abstracts) ,

The object of the invention is to provide new 1,4-benzothiazane-epanes / epines, in particular the 5-ones, of the general formula I.

with X = S, SO, S0 ₂ and Y = 0, S or NH, NR ₄₀ and Z is one or more substituents on the benzene radical;

Ri is H, OH, Cι-Ci4-alkyl, cycloalkyl, _Cι-C4 alkyl-cycloalkyl, Hetreocycloalkyl, _{Cι-C4-alkyl-heterocycloalkyl,} C ₂ -Cι ₄ - alkenyl, aryl, Cι-C ₄ alkyl Aryl, heteroaryl, C 1 -C ₄ alkyl heteroaryl, A C 1 -C ₄ alkyl, A cycloalkyl, A C 1 -C ₄ alkyl cycloalkyl, A heterocycloalkyl, A C 1 -C ₄ alkyl heterocycloalkyl , AC ₂ -C ₄ -alkenyl, A-aryl, A-C ₄ -C ₄ alkyl aryl, A-heteroaryl, A-C ₄ -C ₄ alkyl alkyl heteroaryl with A = 0, NH, S, SO, S0 ₂ , C (0), C (S), NH-C (O), NH-C (S), C (0) -0,

R ₂ H, OH, -CC ₄ alkyl, cycloalkyl, -C ₄ alkyl cycloalkyl, heterocycloalkyl, C ₄ -C ₄ alkyl heterocycloalkyl, C2-C ₁₄ - alkenyl, aryl, C 1 -C 4 alkyl Aryl, heteroaryl, C 1 -C ₄ -alkyl heteroaryl, A-C 1 -C ₄ -alkyl, A-cycloalkyl, A-C ₄ -C ₄ alkyl-cycloalkyl, A-heterocycloalkyl, A-C ₄ -C ₄ alkyl Heterocycloalkyl, AC ₂ -C ₄ alkenyl, A aryl, A C 1 -C ₄ alkyl aryl, A heteroaryl, A C 1 -C ₄ alkyl alkyl heteroaryl with A = 0, NH, S, SO, S0 ₂ , C (0), C (S), NH-C (O), NH-C (S), C (0) -0,

R21 H, CH ₃ , aryl

R ₃ H, OH, -CC ₄ -alkyl, cycloalkyl, -C ₄ -alkyl-cycloalkyl, heterocycloalkyl, -C-C4-alkyl heterocycloalkyl, C2-C ₁₄ - alkenyl, aryl, Cχ-C ₄ -alkyl- Aryl, heteroaryl, dC ₄ -alkyl heteroaryl, A-Cι-Cι- ₄ alkyl, A-cycloalkyl, A-Cι-C ₄ alkyl-cycloalkyl, A-heterocycloalkyl, A-Cι-C ₄ alkyl-heterocycloalkyl, AC ₂ -C ₄ -alkenyl, A-aryl, A-Cχ-C ₄ -alkyl aryl, A-heteroaryl, A--C-C ₄ alkyl alkyl heteroaryl with A = 0, NH, S, SO, S0 ₂ , C (0), C (S), NH-C (O), NH-C (S), C (0) -0,

R31 H, CH ₃ , aryl

or R ₂ and R _{3 can be} a bond, or R ₂ and R _{3 form} a 5-6-membered substituted or unsubstituted cycloalkyl, where at least one carbon atom can be replaced by a hetero atom and / or one or more double bonds can be present, R ₂ ι and R ₃ ι also forming a bond can,

R40 C 1 -C 4 alkyl, cycloalkyl, C 1 -C 4 alkyl cycloalkyl, heterocycloalkyl, C 1 -C ₄ alkyl heterocycloalkyl, C ₂ -C ₁₄ alkenyl, aryl, C 1 -C ₄ alkyl aryl, heteroaryl, C 1 -C _{4 4} -alkyl heteroaryl, A-Cι-Cι-alkyl, A-cycloalkyl, A-Cι-C ₄ alkyl-cycloalkyl, A-heterocycloalkyl, A-Cι-C-alkyl heterocycloalkyl, AC ₂ -Cι ₄ -alkenyl A-aryl, A-Cι-C ₄ alkyl aryl, A-heteroaryl, A-Cι-C alkyl alkyl heteroaryl with A = 0, C (0), C (S),

ZH, OH, CF _3, halo, Cι-Cι ₄ alkyl, cycloalkyl, C ₁ -C4- alkyl-cycloalkyl, Hetreocycloalkyl, Cι-C ₄ -alkyl heterocycloalkyl, C ₂ -Cι ₄ alkenyl, aryl, Cι- C ₄ -alkyl-aryl, heteroaryl, -C-C-alkyl-heteroaryl, A-Cι-Cι- ₄ alkyl, A- cycloalkyl, A-Cι-C-alkyl-cycloalkyl, A-heterocycloalkyl, A- -C-C ₄ -Alkyl-heterocycloalkyl, AC ₂ -Cι ₄ -alkenyl, A-aryl, A-Ci-C-alkyl-aryl, A-heteroaryl, A--C-C ₄ -alkyl alkyl heteroaryl with A = 0, NH, S SO, S0 ₂ , C (0), C (S), NH-C (0), NH-C (S), C (0) -0, (provision) and if X = S or S0 ₂ , Y = 0 or S, R ₂ and R ₃ = a bond, R _2i , R31, Z = H or R _2i , R31 = CH ₃ , C2H5, H and Z = H, Ri cannot be H or CH ₃ ,

or the general formula II

where Ri disappears,

with X = S, SO, S0 ₂ or 0 and = 0, S, SO, S0 ₂ , and Z is one or more substituents on the benzo radical;

R41 H, C 1 -C ₄ -alkyl, cycloalkyl, C 1 -C ₄ -alkyl-cycloalkyl,

Hetreocycloalkyl, -C-C ₄ alkyl heterocycloalkyl, C ₂ -Cχ-

Alkenyl, aryl, Cχ-C ₄ alkyl aryl, heteroaryl, C ₁ -C alkyl

Heteroaryl, and R ₂ , R21, R ₃ , R31 Z is as defined in formula I, and if X = S or S0 ₂ , W = 0, Rι cannot be CH ₃ ,

their stereoisomers, tautomers and their physiologically acceptable salts.

All of the above-mentioned substituents can be read independently of one another and can have the same or different structure.

Preferred embodiments are carried out as follows:

In formula I, Y is preferably 0.

1,4-Benzothiazepine derivatives of the formula I, ie those in which R ₂ and R _{3 form} a bond, are preferred.

If R ₂ and R _{3 form} a cycle, benzene is preferred, specifically according to formula I in the formation of formula III

, wherein R21 and R31 is a bond and R ₂ and R _{3 form} a ring closure to cycloalkene. The cycloalkene can be substituted, for example with substituents as defined in Z.

Also preferred are compounds of the 1,4-benzothiazepine derivatives of the formula I with Y = 0, preferably 1,4 benzothiazepine (4H) 5-one with RI = Cl-C4-aryl or RI = CC ₄ alkyl.

Benzothiazepin-5- (4iϊ) -one compounds of the general formula IV are preferred

with R21 and R ₃ ι independently of one another or identical to H, CH ₃ , phenyl K at least one or more, identical or different: H, F, Cl, OH, 0CH ₃ , NHCOCH ₃ , phenoxy, in particular 4-F, 2,4 Difluoro, 3, 4-dimethoxy, 4-phenoxy, 2-phenoxy, R ₅₀ = H, CH ₃ , C ₂ H ₅ , phenyl, Z at least one or more, identical or different: H, F, Cl, OH, OCH3, in particular 7, 8-dimethoxy, 7-OH, 8-OH, 7-F, 7-Cl, 7-NHCOCH ₃

According to the invention, particular preference is given to compounds such as: 4-isopropyl-1,4-benzothiazepin-5 {AH) -one 4- (4-fluorobenzyl) -1, 4-benzothiazepine-5 {AH) -one 4- (2-chlorobenzyl) -1, 4-benzothiazepin-5 {AH) -one 4-benzyl-l, 4-benzothiazepine 5 (AH) -one 4- (1-phenylethyl) -1, 4-benzothiazepin-5 (AH) -one

The following definitions apply to the individual substituents in the description and the claims:

The ter "alkyl" by itself or as part of another substituent means a linear or branched alkyl chain radical of the length given in each case. Preferred are alkyls with 1 to 6 carbon atoms, in particular with 1 to 4 carbon atoms. For example, C ₄ alkyl means, for example Methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl, C ₆ alkyl, for example C ₄ alkyl, pentyl, 1 Pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl or 3, 3-dimethyl-butyl. The alkyls can be substituted with up to 3 substituents, preferably up to 1 substituent, the substituents independently of one another being OH, N0 ₂ , CN, CF ₃ , OR, SH, SR ₅ , COOH, C00R ₅ , NH ₂ , NHR ₅ , NR5R6, halogen, aryl, heteroaryl, heterocycloalkyl may have, where the radicals R5 and Rβ independently of one another may mean C 1 -C 8 -alkyl, cycloalkyl, C 1 -C ₄ -alkyl-cycloalkyl. The alkyls are preferably unsubstituted hen formula -C ₄ alkyl CH ₃ , C ₂ H5, C ₃ H ₇ and C2-C4-alkyl are preferred.

The term "alkenyl" by itself or as part of another substituent means a linear or branched alkyl chain radical with one or more C = C double bonds of the length indicated in each case, wherein a plurality of double bonds are preferably conjugated. Alkylenes having 1 to 6 carbon atoms are preferred , in particular with 1 to 4 or 2 to 4 carbon atoms. For example, C ₂ _6-alkenyl means, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1, 3-butdienyl, 2,4- Butdienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentdienyl, 2, 4-pentdienyl, 1, 4-pentdienyl, 1-hexenyl, 2-hexenyl, 1, 3-hediexyl, 4-methyl l-pentenyl or 3, 3-dimethyl-butenyl. The alkenyls can be substituted with up to 3 substituents, preferably up to 1 substituent, the substituents independently of one another meaning OH, N0 ₂ , CN, CF ₃ , OR ₅ , SH, SR ₅ , COOH, COOR5, NH _{2 /} NHR ₅ , NR ₅ R ₆ , halogen, aryl, heteroaryl, heterocycloalkyl can have, where the radicals R5 and Re independently of one another can mean C 1 -C 8 -alkyl, cycloalkyl, C 1 -C 4 -alkyl-cycloalkyl. The alkenyls are preferably not substituted.

The term "halogen" stands for fluorine, chlorine, bromine, iodine, preferably bromine and chlorine.

The term "cycloalkyl" by itself or as part of another substituent includes unsaturated (single or multiple, preferably single) or saturated, cyclic hydrocarbon groups with 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohex-2, 4-dienyl, 4-methyl-cyclohexyl, 3-methyl-cyclohexyl, cycloheptyl or cyclooctyl. Saturated cycloalkyls are preferred. The cycloalkyls can be substituted be with up to 3 substituents, preferably up to 1 substituent, the substituents independently of one another meaning Ci-Cδ-alkyl, OH, N0 ₂ , CN, CF ₃ , OR5, SH, SR ₅ , Cι-C ₃ alkylhydroxy, C ₁ -C ₆ alkyl-OR ₅ , COOH, COOR5, NH ₂ , NHR ₅ , NR ₅ Re, halogen, aryl, C 1 -C ₄ -alkylaryl, heteroaryl, C1-C4- heteroalkylaryl, the radicals R5 and R δ independently of one another can mean C 1 -C 6 -alkyl, cycloalkyl, C 1 -C 4 -alkyl cycloalkyl, aryl.

The term "heterocycloalkyl" by itself or as part of another substituent includes cycloalkyl groups in which up to two CH ₂ groups are formed by oxygen, sulfur or Nitrogen atoms can be replaced and one or two further CH ₂ groups can be replaced by one or two carbonyl functions, carbothionyl functions or a carbonyl function and a carbothionyl function, for example pyrrolidine, piperidine, morpholine or

The heterocycloalkyls can be substituted like the cycloalkyls.

The term "aryl" by itself or as part of another substituent includes aromatic ring systems with up to 3 rings, in which at least 1 ring system is aromatic and which are substituted with up to 3 substituents, preferably up to 1 substituent, the substituents being independent of one another the meaning Ci-Cβ-alkyl, OH, N0 ₂ , CN, CF ₃ , OR ₅ , SH, SR ₅ , Ci-Ce alkylhydroxy, -C-C ₆ alkyl-OR ₅ , COOH, COOR5, NH ₂ , NHR5 , NR5R6, halogen can have, where the radicals R ₅ and R δ independently of one another can mean C 1 -C 8 -alkyl, cycloalkyl, C 1 -C ₄ -alkyl-cycloalkyl, aryl.

In addition to phenyl and 1-naphthyl and 2-naphthyl, preferred aryls are:

Furthermore, 2.4 substituents on the aryl are preferred.

The term "heteroaryl" by itself or as part of another substituent includes aromatic ring systems with up to 3 rings, and up to 3 identical or different heteroatoms N, S, 0, in which at least 1 ring system is aromatic and those with up to 3 substituents , preferably up to 1 substituents are substituted, the substituents independently of one another being Ci-Cδ-alkyl, OH, N0 ₂ , CN, CF ₃ , OR ₅ , SH, SR ₆ , Ci-Ce-alkylhydroxy, -C-C ₆ -Alkyl-OR ₅ , COOH, COOR5, NH ₂ , NHR5, NR5R6, halogen, where the radicals R5, Rβ can independently have the meanings given above.

Preferred heteroaryls are:

Surprisingly, it has now been found that the compounds according to the invention are suitable as painkillers with a central or peripheral point of attack and, moreover, have a suitable effect on the central nervous system, in particular the brain and spinal cord. This includes pallative and curative effects. In particular, the invention relates to a psychotropic drug with a central damping effect.

The invention therefore relates to an analgesic, neuroleptic, antidepressant, antiepileptic, anxiolytic, transquilizer or muscle relaxant (myotonolytics) containing at least one compound of the formulas I, II, III and / or IV according to the invention.

The invention therefore relates to an agent for the treatment and prophylaxis of diseases of the central nervous system, in particular psychopathological syndromes, such as in acute psychosis or schizophrenia, anxiety and tension, depression, cerebral and spinally triggered spasticity (e.g. baclofen, dantrolene), local muscle spasms, also for the treatment and prophylaxis of neurological diseases such as Parkinson's syndrome, and for the treatment and prophylaxis of cerebral convulsions, such as epilepsy.

Furthermore, the substances according to the invention have an action against inflammatory diseases. They are therefore suitable for the treatment and prophylaxis of allergies, rheumatoid arthritis, Crohn's disease, neoplastic tumors, inflammatory diseases, autoimmune diseases, degenerative joint diseases, diseases of the rheumatic type with cartilage degradation, chronic polyarthritis, joint trauma, immobilization-related cartilage dysfunction, septicorexia, septicorexia, septicorexia, and septicorexia, septicorexia, septicorexia, and septicorexia, septicostasis -Adhesion, diseases due to increased TNF-alpha Concentrations, cachexia, Crohn's disease, rejection after transplantation.

The invention further relates to medicaments containing at least one of the above compounds of formula I, II, III and IV or the known compounds 1, 4-benzothiazepin-5- (4H) - one and 4-methyl-l, 4-benzothiazepin-5- ( 4H) -one (Fischer, Hofmann (supra)), 1,4-benzothiazepine-5 (4H) -thione, 1,4-benzothiazepine-5 (4H) -one - 2,3,4-trimethyl, 1,4 - Benzothiazepin-5 (4H) -one -3-ethyl-4-methyl, 1,4-benzothiazepin-5 (4H) -one -3, 4-dimethyl, 1, 4-benzothiazepin-5 (4H) -one- 1, 1-dioxide in addition to the usual pharmaceutical carriers and auxiliaries and additives.

All mentioned indications are described in Pschyrembel ^® , de Gruyter, Berlin. The compounds of the formulas I, II, III and IV can be present as such or, if they have acidic or basic groups, in the form of their salts with physiologically compatible bases or acids. Examples of such acids are: hydrochloric acid, citric acid, trifluoroacetic acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, succinic acid, malic acid, sulfuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine. Examples of bases are alkali ions, preferably Na, K, alkaline earth ions, preferably Ca, Mg, ammonium ions.

The compounds of the invention can be administered orally in a conventional manner. The application can also be done i.V., i.m., with vapors or sprays through the nasopharynx.

The dosage depends on the age, condition and weight of the patient as well as the type of application. As a rule, the daily dose of active ingredient per person is between approximately 0.1 μg / kg, in particular 1 mg / kg and 1 g / kg when administered orally. This dose can be given in 2 to 4 single doses or once a day, especially as a slow-release form.

The compounds according to the invention can be used in solid or liquid form in the customary pharmaceutical application forms, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, solutions or sprays. These are manufactured in the usual way. The active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al .: Pharmaceuticals Technology, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way usually contain the active ingredient in an amount of 0.1 to 99% by weight. The invention therefore also relates to a corresponding pharmaceutical composition which also contains a compound according to the invention in the form of a medicament.

Examples:

The following examples serve to explain the

Invention without restricting the invention to these.

example 1

General scheme for the synthesis of 1,4 benzothiazepin-5 (4H) - on:

i: SOC12, ii: R-NH2, iii: NaBH4, EtOH, iV: bromoacetaldehyde diethylacetal, v: 4-toluenesulfonic acid, toluene

a.) Preparation of 2, 2 "-Bis (aminocarbonyl) diphenyl disulfides (III):

A solution of 5 mmol of the acid chloride (obtained from I by heating for 3 hours with a 10-fold excess)

Thionyl chloride and removal of the thionyl chloride in vacuo) in 10 ml abs. THF is dissolved in a solution of A ins (20 mmol)

30 ml abs. Dichloromethane, with ice cooling, registered. The

Reaction time is about 1 hour stirring.

The amides are filtered off with suction and washed once with 0.5 N HCl and twice with water. Then the precipitation with

Washed dichloromethane, petroleum ether and dichloromethane again and dried.

The yields are almost 100% each.

b.) Reduction and alkylation:

A solution of 10 mmol of NaBH ₄ in 3 ml of water is added dropwise to a suspension of 1 mmol of the disulfide obtained in 10 ml of ethanol stirred at about 70 ° C. with a drop of 6N-NaOH, added dropwise while gassing with nitrogen. The mixture is stirred for a few hours at about 70 ° C. under an N ₂ atmosphere until no disulfide can be detected by TLC, a little more NaBH _{4 is} added and the mixture is heated further. Then 6N-NaOH to pH ca.10 and 2.5 mmol of the acetal are added dropwise and the oil bath is set to about 80 ° C. The solution is heated under nitrogen gas for about 5 hours. After the reaction (TLC) the mixture is concentrated, the residue is taken up in 10 mL dichloromethane and saturated with 10 mL. NaHC03 solution extracted. The aqueous phase is shaken twice with 10 mL dichloromethane, the organic phases are combined, dried with MgSÜ4 and concentrated. V is obtained as an oily substance which crystallizes when scratched with a spatula. This is suctioned off and washed with petroleum ether. Yield of V: 71-78% -

c.) Cyclization to 1,4-benzothiazepin-5-ones (VI): 1 mmol acetal amide (V) is dissolved in 12.5 ml boiling toluene. After adding 0.05 mmol of p-toluenesulfonic acid, the mixture is heated under reflux for about 15 hours, a methanol / toluene mixture being distilled off via a Vigreux column. It is advisable to add a drop of water to the reaction mixture approximately every 2-3 hours. The reaction is complete when the batch has turned wine red and no methanol / toluene mixture can be distilled off when water is added. For working up, the mixture is saturated with approx. 10 mL. NaHC0 ₃ - stirred, the phases are separated and the aqueous is extracted twice with 10 L dichloromethane. The combined organic phases are dried with MgSÜ4 and concentrated. The crude oil, which is colored differently depending on the amine used, is purified by column chromatography. For about 500 mg of crude oil, about 20 ml of silica gel is slurried in the eluent mixture and filled into a column with a small diameter (0-1.5 cm). The elution is carried out with a mixture of dichloromethane / ethyl acetate / petroleum ether = 60/10/30. The desired product runs right at the front as a colored band and can therefore be easily caught. A DC (Rf value approx. 0.7) and the band at approx. 1635 cm ^-1 in the IR spectrum serve as a control. After concentration and drying, the benzothiazepinon is obtained as an analytically pure colored oil.

4-isopropyl-l, 4-benzothiazepine-5 (4H) -one, MW 219.3

IR: 1616 cm-1 (0 = 0)

^X H-NMR ([D6J-DMS0): δ (ppm):

6.05 (d, 6H, -CH3); 4.95 (sept., 1H, CH); 6.45 (d, 1H, S-CH);

6.71 (d, 1H, N-CH); 7.33-7.61 (m, 4H aromat.)

¹³ C-NMR ([D6] -DMS0): δ (pp):

19.9 (-CH3); 46.4 (CH); 116.4 (S-CH); 128.1, 130.3, 131.0,

131.8 (4C tert., Aromatic); 133.3 (N-CH}; 139.0, 140.0 (2C quart., Aromat.); 167.6 (C = 0)

4- (4-fluorobenzyl) -1, 4-benzothiazepin-5 (4H) -one, MW 285.3

IR: 1636 cm-1 (C = 0)

^ Η NMR ([D6] -DMSO): δ (ppm): 4.90 (s, 2H, -CH ₂ ~); 6.32 (d, 1H, S-CH); 6.76 (d 1H, N-CH); 7.17-7.64 (m, 8H, aromat.)

¹³ C-NMR ([D6] -DMSO): δ (ppm):

51.13 (-CH ₂ -); 115.2 (S-CH); 115.5, 115.7 (FC-CH);

128.8, 129.5, 129.6, 131.1, 132.0, (6C tert. Aromatics); 137, 7

(N-CH); 133.8, 139.3, 140.0 (3C quart. Aromat.); 163.0 (C-F);

169.0 (C = 0)

4- (2-chlorobenzyl) -1, 4-benzothiazepin-5 (4H) -one, MW 301.8

IR: 1645 cm-1 (C = 0)

^X H-NMR ([D6] -DMSO): δ (ppm):

4.99 (s, 2H, -CH ₂ -); 6.37 (d, 1H, S-CH); 6.79 (d, 1H, N-CH);

7.31-7.65 (m, 8H aromat.)

¹³ C-NMR ([D6] -DMSO): δ (ppm):

49.8 (-CH ₂ -); 114.8 (S-CH); 127.3, 127.4, 128.4, 128.8,

129.3, 130.8, 131.6, 131.7 (8C tert. Aromatics); 137.5 (N-CH);

131.8, 134.0, 138.7 (3C quart., Aromat.); 168.5 (C = 0)

4-benzyl-1,4-benzothiazepine-5 (4H) -one, MW 267.4

IR: 1635 cm-1 (C = 0) Hi-NMR ([D6] -DMSO): δ (ppm) 4.93 (s, 3H, -CH ₂ -); 6.31 (d, IH, S-CH); 6.75 (d, IH, N-CH);

7.25- 7.65 (m, 9H, aromat.)

¹³ C-NMR ([D6] -DMSO): δ (ppm):

51.4 (-CH2-); 114.5 (S-CH); 126.9, 127.1, 128.34, 128.38,

130.7, 131.4, 131.6 (7C tert., Aromat.); 137.3 (N-CH); 137.1,

138.9, 1.39.6 (3C quart., Aromat.); 168.5 (C = 0)

4- (1-phenylethyl) -1, 4-benzothiazepin-5 (4H) -one, MW 281.4

IR: 1634 cm-1 (C = 0)

1H NMR ([D6] -DMSO); δ (ppm):

2.90 (t, 2H, -CH ₂ -); 3.88 (t, 2H, _N-CH2); 6.22 (d, IH S-CH);

6.62 (d, IH, N-CH); 7.18-7.58 (m, 9H, aromat.)

13C-NMR ([D6] -DMSO): δ (ppm):

33.7 (-CH ₂ -); 19.8 _(N-CH2); 113.7 (S-CH); 126.2,

128.18, 128.22, 128.8, 130.5, 131.3, 131.5 (7C tert., Aromat.); 137.1 (N-CH); 138.4, 139.1, 139.7 (3C quart., Aromat.); 168.2 (C = 0)

Example 2:

Pharmacological testing of 4- (4-fluorobenzyl) -1, 4-benzothiazepin-5- (4H) -on a) Irwin test (S.Irwin, Psychopharmacologia 1968 (13), 222- 257)

The test substance was administered in doses of 4, 8, 16, 32 and 64 mg / kg ip mice and behavior changes after 15, 30, 60, Observed for 120 and 180 min and after 24 h. In the 8-64 mg / kg dose range, slight to moderate central excitation, increased stimulus to touch, increased anxiety and increased muscle tone were observed as biological effects. b) Formalin-paw test (H. Wheeler-Aceto, A. Cowan, Psychopharmacology 1991 (104), 35-44)

The test substance was administered in doses of 4, 16, 32 and 64 mg / kg i.p. Mice administered (10 mice each, 10 min before the formal injection; 8 mg / kg morphine for reference). A dose of 64 mg / kg showed a significant antinociceptive effect compared to the control group (shortening of the "licking time" by 61%).

Claims

claims

1. Compounds of formula I.

with X = S, SO, S0 ₂ and Y = 0, S or NH, NR ₄₀ and Z is one or more substituents on the benzene radical;

Ri H, OH, C 1 -C ₄ alkyl, cycloalkyl, dC ₄ alkyl cycloalkyl, heterocycloalkyl, C ₁ -C ₄ ~ alkyl heterocycloalkyl, C ₂ -C 4 alkenyl, aryl, C ₁ -C ₄ alkyl aryl, heteroaryl, C 1 -C ₄ -alkyl heteroaryl, A-C 1 -C ₄ -alkyl, A- cycloalkyl, A-C 1 -C ₄ -alkyl-cycloalkyl, A-heterocycloalkyl, A-C ₄ -C ₄ -alkyl heterocycloalkyl, AC ₂ - C ₄ alkenyl, A aryl, A C 1 -C ₄ alkyl aryl, A heteroaryl, A ₄ -C ₄ alkyl alkyl heteroaryl with A = 0, NH, S, SO, Ξ0 ₂ , C (0 ), C (S), NH-C (O), NH-C (S), C (0) -0,

R ₂ H, OH, C 1 -C ₄ alkyl, cycloalkyl, C 1 -C ₄ alkyl cycloalkyl, heterocycloalkyl, C ₁ -C ₄ alkyl heterocycloalkyl, C ₂ -Ci4 alkenyl, aryl, C ₁ -C ₄ alkyl Aryl, heteroaryl, C 1 -C ₄ -alkyl heteroaryl, A-C 1 -C ₄ -alkyl, A-cycloalkyl, A-C ₁ -C ₄ -alkyl-cycloalkyl, A-heterocycloalkyl, AC ₁ -C ₄ -alkyl-heterocycloalkyl, AC ₂ -C ₄ alkenyl, A aryl, A C 1 -C ₄ alkyl aryl, A heteroaryl, A ₄ -C ₄ alkyl alkyl heteroaryl with A = 0, NH, S, SO, S0 ₂ , C (0), C (S), NH-C (O), NH-C (S), C (0) -0,

R21 H, CH ₃ , aryl R ₃ H, OH, -CC ₄ alkyl, cycloalkyl, -C ₄ alkyl cycloalkyl, heterocycloalkyl, C C-C4-alkyl heterocycloalkyl, C- ₄ -alkenyl, aryl, C 1 -C ₄ -alkyl- Aryl, heteroaryl, C 1 -C ₄ -alkyl heteroaryl, A-C 1 -C ₄ -alkyl, A- cycloalkyl, A-C ₄ -C ₄ alkyl-cycloalkyl, A-heterocycloalkyl, A-C ₄ -C ₄ alkyl Heterocycloalkyl, AC ₂ -C ₄ alkenyl, A aryl, A C 1 -C ₄ alkyl aryl, A heteroaryl, A C 1 -C ₄ alkyl alkyl heteroaryl with A = 0, NH, S, SO, S0 ₂ , C (0), C (S), NH-C (O), NH-C (S), C (0) -0,

R ₃ ι H, CH ₃ , aryl

or R ₂ and R _{3 can be} a bond,

or R2 and R _{3 form} a 5-6 membered substituted or unsubstituted cycloalkyl, where at least one carbon atom can be replaced by a hetero atom and / or one or more double bonds can be present, where R2 ₁ and R31 can also form a bond,

R40 C ₁ -C ₄ alkyl, cycloalkyl, C ₁ -C ₄ alkyl cycloalkyl, heterocycloalkyl, C ₁ -C ₄ alkyl heterocycloalkyl, C ₂ -C ₁₄ alkenyl, aryl, C ₁ -C ₄ alkyl aryl, heteroaryl, Cι -C-alkyl- heteroaryl, AC ₁ -Cι ₄ alkyl, A-cycloalkyl, A-Cι-C ₄ alkyl-cycloalkyl, A-heterocycloalkyl, A-Cι-C ₄ alkyl-heterocycloalkyl, AC ₂ -Cι _4th -Alkenyl, A-aryl, A -CC-C ₄ -alkyl-aryl, A-heteroaryl, A -CC-C-alkyl-alkylheteroaryl with A = 0, C (0), C (S),

ZH, OH, CF _3, halo, Cι-Cι ₄ alkyl, cycloalkyl, C1-C4-alkyl-cycloalkyl, Hetreocycloalkyl, Cι-C ₄ -alkyl heterocycloalkyl, C ₂ -Cι ₄ alkenyl, aryl, Cι-C alkyl-aryl, heteroaryl, _Cι-C4 alkyl-heteroaryl, A-Cι-Cι ₄ alkyl, cycloalkyl A-, _A-Cι-C4 alkyl-cycloalkyl, A-Hetreocycloalkyl, A-Cι-C ₄ -Alkyl-heterocycloalkyl, Ä-C ₂ -C ₁ -alkenyl, A-aryl, _A-Cι-C4 alkyl-aryl, heteroaryl-A, AC ₁ -C ₄ alkyl alkylheteroaryl with A = 0, NH, S, SO, S0 _2, C (0), C (S) NH- C (O), NH-C (S), C (0) -0,

and if X = S or S0 ₂ , Y = 0 or S, R ₂ and R ₃ = a bond, R _2i , R ₃₁ , Z = H or R21, R31 = CH ₃ , C ₂ H ₅ , H and ZH, Ri cannot be H or CH ₃

or the general formula II

where Ri disappears,

with X = S, SO, S0 ₂ or 0 and W = 0, S, SO, S0 ₂ , and Z is one or more substituents on the benzene radical;

R ₄ H, C ₁ -C ₄ alkyl, cycloalkyl, C ₄ alkyl cycloalkyl, heterocycloalkyl, C ₄ alkyl heterocycloalkyl, C ₂ -C ₄ alkenyl, aryl, C 1 -C ₄ alkyl Aryl, heteroaryl, -CC alkyl heteroaryl,

and R ₂ , R21, R3, R31, Z is as defined in formula I and if X = S or S0 ₂ , W = 0, R41 cannot be CH ₃ ,

their stereoisomers, tautomers and their physiologically acceptable salts. Compounds according to claim 1, namely 1, 4-benzothiazepin-5- (AH) -one - compounds of the general formula IV

with R ₂ ι and R31 independently of one another or the same

H, CH ₃ , phenyl

K at least one or more, the same or different:

H, F, Cl, OH, OCH ₃ , NHCOCH3, phenoxy, in particular 4-F,

2,4-difluoro,

3, 4-dimethoxy, 4-phenoxy, 2-phenoxy,

R ₅₀ = H, CH ₃ , C2H5, phenyl,

Z at least one or more, the same or different:

H, F, Cl, OH, OCH3, especially 7, 8-dimethoxy, 7-OH, 8-

OH, 7-F, 7-C1, 7-NHCOCH3.

Compounds according to claim 1, namely

4-isopropyl-l, 4-benzothiazepine-5 (4E) -one, 4- (4-fluorobenzyl) -1, 4-benzothiazepine-5 (AH) -one, 4- (2-chlorobenzyl) -1, 4- Benzothiazepin-5 (4-fr) -one, 4-benzyl-l, 4-benzothiazepin-5 (AH) -one, 4- (1-phenylethyl) -1, 4-benzothiazepin-5 (AH) -one.

Medicament containing at least one compound according to claims 1 to 3 or 1, 4-benzothiazepin-5- (AH) -one, 4-methyl-l, 4-benzothiazepin-5- (AH) -one, 1, 4-benzothiazepine 5 (4H) -thione, 1,4-benzothiazepine-5 (4H) -one - 2,3,4-trimethyl, 1,4-benzothiazepine-5 (4H) -one -3-ethyl-4-methyl, 1 , 4-benzothiazepine-5 (4H) -one -3, 4-dimethyl, 1,4-benzothiazepine-5 (4H) -one-1, 1-dioxide.

5. analgesic, neuroleptic, antidepressant, antiepileptic, anxiolytic, transquilizer or muscle relaxant (myotonolytics) containing at least one compound according to claim 4.

6. Medicament according to claim 4 for the treatment and prophylaxis of diseases of the central nervous system, in particular psychopathological syndromes, such as in acute psychosis or schizophrenia, anxiety and tension, depression, cerebral and spinally triggered spasticity (e.g. baclofen, dantrolene), local muscle spasms, further for the treatment and prophylaxis of neurological diseases such as Parkinson's syndrome, and for the treatment and prophylaxis of cerebral convulsions, such as epilepsy, and for the treatment and prophylaxis of inflammatory diseases and allergies, rheumatoid arthritis, Crohn's disease, neoplastic tumors, inflammatory diseases, autoimmune diseases, degenerative joint diseases , Diseases of the rheumatic type with cartilage breakdown, chronic polyarthritis, joint trauma, immobilization-related cartilage loss, septic shock, diseases with disturbed leukocyte adhesion, diseases due to increased TNF-alpha concentrations, Cac hexie, Crohn's disease, rejection after transplantation.

7. Pharmaceutical composition containing at least one compound according to one of claims 1 to 3 or a medicament according to one of claims 4 to 6 and possibly in combination with at least one further suitable medicament and a pharmaceutical carrier, together with auxiliaries and additives.