CA2165386A1 - 2-amino-1,3-thiazepines and their use as inhibitors of nitric oxide synthase - Google Patents

Abstract

The present invention relates to 2-amino-1,3-thiazepines of the general formula I

Description

216~381~

2-AMINO-1,3-THIAZEPINES AND THEIR USE
AS INHIBITORS OF NITRIC OXIDE SYNTHASE
The present invention relates to thiazepines of the general formula I

X~
S
~Z-~ ~ H2 (I) which on account of their capacity to modulate endogenous nitric oxide production are useful medicaments for the prevention and control of conditions which are characterized by an impaired nitric oxide level. Commercial packages comprising pharmaceutically effective amounts of such compounds together with instructions for use in prevention or treatment of a disease caused by an increased nitric oxide level comprise another aspect of the invention.
Nitric oxide (NO) plays an important part in all sorts of physiological processes (see e.g. R. Henning, Nachr.
Chem. Tech. Lab. 41 (1993), 413; J. F. Kerwin, M. Heller, Med.
Res. Rev. 14 (1994), 23).
It has e.g. a relaxing effect on the smooth vessel musculature and in this way is substantially involved in the regulation of blood pressure, it controls blood clotting via inhibition of platelet aggregation, and it is involved, for example, in the brain as a neurotransmitter in the building up of the long-term memory. In NANC nerves of the peripheral nervous system, NO also functions as a messenger substance.

216~386 - la -The cytotoxic action of NO is used by macrophages for defence against infection.
Endogenous NO is formed from arginine with the aid of at least three different NO synthase isoenzymes.
All isoenzymes require NADPH, flavine adenine dinucleotide, flavine mononucleotide and tetrahydrobiopterin as cofactors. They differ with respect to their localization in the body, their controllability by Ca /calmodulin and their inducibility by endotoxins and cytokines. The constitutive, calcium-dependent NO

216~386 Ref. 3595 - 2 -Dr.ER/L10956 synthases are found, for example, in the endothelium and in the brain and are involved there in the -egulation of blood pressure and clotting or in conduction processes.
The cyto~ine-inducible, calcium-independe~t isoform occurs, for example, in macrophages, smooth muscle cells and hepatocytes. It i8 able to produce relati~ely large amounts of NO over a long period of time and is held responsible for inflammatory processes and the cytotoxic activity of the macrophages.
An impaired NO metabolism results in serious disorders and damage. The excessive formation of NO in septic or haemorrhagic shock thus leads to massive pathological blood pressure decreases. Excessively raised NO production is involved in the genesis of type 1 diabetes and atherosclerosis and also appears to be -esponsible for the glutamate-induced neurotoxicity after cerebral ischaemia. ~igh NO concent_ations can moreover lead to DNA damage by d~min~tion of cytosine.
The attempt to use a modulat on of NO production for the treatment of these syndromes was until now mainly realized with the aid of arginine analogues (GB-A-2 240 041; WO-A-93/13055; WO-A-93/24126; WO-A-94/02453; WO-A-94/07482). Further potential NO synthase inhibitors discussed in the literature are N-iminoethylornithine (McCall et al., Br.J.Pha-macol. 102 (1991), 234), ~m;no-guanidine (T.P.Mis~o et al., Eu-.J.Pharmacol. 233 (1993), 119; EP-A-547588), methylguanidine (~S-A-5 246 971), nitro- and cyanoaryls (WO-A-94/12163) and also pyri-midines, pyridines, pteridinones and indazoles (WO-A-94/14780). The inhibiting action of isothioureas on NO
synthase is disclosed in WO-A-94/12165. In add-tion to the open-chain isothioureas mainly in~estigated there, 2-amino-1,3-thiazole deri~ati~es are also mentioned.
Surpris-ngly it has now been found that thiaze-pine deri~ati~es of the general formula I are particu-larly highly suitable inhibitors o~-inducible NO synthase and inhibit NO formation substantially more strongly than the thiazole deri~atives mentioned i~ WO-A-94/12165. They . ~16538~
Ref. 3595 - 3 -Dr.ER/L10956 are thus suitable for the modulatiou of endogenous NO
production and can be used as active sub6tances i~
medicaments for the treatment of diseases which are characterized by an excessively high NO le~el. Only a few representatives of thiazepi~es of the general formula I
ha~e previously been described in the literature, but the ph~rm~cological properties or medicinal uses of compounds of the ge~eral formula I were pre~iously usk~own.
The present in~ention therefore relates to 2-amino-1,3thiazepi3es of the general formula I, X / N

Y`z-S ~ NH

n which W is CR R2 a~d R1 and R2 independently of one another a-e hydrosen, halogen, R3, R~, ORs, SR5, S(O)p-R6, where p is 1 or 2, ~R7R3, cyano, nitro, COOR9, CoNR7R~ or P(O)(O~) 2; or Rl and R2 together are (C1-C6)-alkylidene or (C3-C,)-cycloalkyl-idene, each of which can also ca-ry one or more Rl radicals, or R1 and R2 together are =0, =S, =N~, =NR3 or =NO~; or R1 and R2, together with the carbon atom to which they are bonded, form a radical of the general formula II

(CH2)~\ ~II) /\ / , ( C H 2 ~ n which can be completely or partly dehydrogenated, which can also be benzo-fused, which can be substituted by one or more identical or different R~ radicals a~d wherein m and n independently of one another are the numbers 0, 1, 2, 3, 4 or 5, but the sum of m + n has o~e of the ~alues 1, 2, 3, 4 or 5; or R1 or R2 is a f~ee ~alency which, with a similar free ~ale~cy on a~ atom which is bonded directly to the carbon atom carrying R1 and R2, forms a ~ Ref. 3595 _ 4 _ Dr.ER/L1095 double bond;
_ R i 8 (Cl-Clo)-alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-C,)- cycloalkyl, (Cg-Cl~)-be~zocycloalkyl or the radical of a 4- to 10-membered heterocycle ha~ing one to four ide~tical or different hete-oatoms from the series ~itrogen, oxygen and sulphur, which can be aromatic, pa-tly saturated or completely satu-ated, it being possible for the alkyl, alkenyl, alkynyl, cycloalkyl and the heterocyclic radical to be substituted by o~e or more identical or different Rl radicals;

R~ is phenyl or naphthyl, which can be substituted by one to three identical or diffe-ent radicals from the series (C~-C~)-alkyl, (C~-C,)-alkoxy, halogen, nitro, trifluorom-ethyl, cyano, hydroxyl, (C~-C~)-alkoxycarbonyl, carboxyl, carbamoyl, (Cl-C~)-alkyl-S(0)~, whe~e q is 0, 1 or 2, ~m;~o, (C~-C,)-alkylca-~o~yl~i~o, (C~-C4)-alkyl~m;no and di((Cl-C~)-alkyl)am no;

R5 and R5 i3depende~tly of one another are hyd-ogen, (Cl-C10)-alkyl in which the alkyl chain can also be i~terrupted by one to three oxygen atoms, (C2-C10)-alkenyl, (C3-C,) -cycloalkyl, R~, R~-(Cl-C6)-alkyl, the radical of a 5- to 7-membe-ed heterocycle ha~ing one to four ide~tical or diffe-e~t hete-oatoms from the series ~it-oge~, cxysen a-d sul?hu_, which can be aromatic, partly saturated or completely saturated, (Cl-C10)-alkanoyl, R'-C0, R'-(Cl-C6)-alkyl-C0, (Cl-C10)-alkoxycarbonyl, R~0-C0, R~-(Cl-Cc)-alkoxy-CO or a radical of the general formula III
NRll ~~ (III~

R6 is (C1-C~0)-alkyl, (C2-C~0)-alkenyl, R~ or R~-(Cl- C6 ) - alkyl;

- 2~6~386 - Ref. 3595 5 Dr.ER/~10956 R' and RJ independently of one another ha~e the me~n;ngs specified for Rs O~ are (Cl-C6)-alkylsulphonyl or R~-S(O) 2 or R' and R8, together with the nitrogen atom to which they are bonded, form a radical of the general formula rv /(CH2~r\
-N A (~v) ( CH2 ) s which can be substituted on the C~2 groups by one or more idestical or different Rl radicals and wherei~ r and s indepen-dently of one a~other are the numbers 1, 2, 3 or 4, but the sum of r + s is smaller than 6;

R' and R8 independently of R' and R8 ha~e the me~n;ngg speci ied for R' and R8;

R9 has one of the me~nings of R5, but is not the radical of the ge~eral formula II~;

RlD is (Cl-C5)-alkyl, (C3-C,)-cycloalkyl, the radical of a 5- to 7-m~mhered heterocycle ha~ing one to three ident-ical or differe~t heteroatoms from the series nitrogen,oxygen and sulphur, which can be aromatic, partly satu-rated or completely saturated, R4, halogen, oR5, SR5, S(O)p-R6, whe-e p is 1 or 2, NR7R3, the hydroY m;no group, the oxo s-ou?, cyano, ni~~o, COOR9, CONR' R8 or P(O) (~)2;

the radicals Rll, Rl2 and Rl3 independently of one anothe~
are hydrogen, (Cl-C6)-alkyl, ( C3 - C~ ) - CyC loalkyl, R~, (Cl-C6)-~lk~noyl, (Cl-C6)-alkyl-S(O) 2 or R~-S(O) 2;

Rl~ is (Cl-C~)-alkyl, benzyl, phenyl, (Cl-C6)-~lk~nQyl, (Cl-C6)-alkyl-S(O) 2 or R~-S(O) 2;

A is a methylene group which can b~-substituted by one or two identical or different Rl radicals, or is oxygen, sulphur or NRl~;

216~6 Ref. 3595 - 6 -Dr.ER/L10956 X i8 CR20R2l and R20 and R2l independently of the m~nings of the radicals RL-and R2 have the m~n;ngs specified for Rl and R2;

Y i8 CR22R23 and R;2 and R23 independently of the m~n i ng8 of the radicals Rl and R2 have the mea~ings specified for Rl and R2;

Z is CR2~R2s and R2~ and R25 independently of the me~n; ng8 of the radicals Rl and R2 have the me~n;ngs specified for R and R2;

where radicals of the g-oups W, X, Y and Z ca~ also be linked via a bond such that a bicyclic system o-tricyclic system is formed;

and their tautomeric f 0nm8 and al60 their pharmaco-losically tolerable salts as ph~rm~colosical active subst~ces.
Examples of compounds of the general fon~ula I in which a substituent i~ the groups W, X, Y and Z is a free valency which forms an endocyclic double bond with a f-ee valency on an atom bonded di~ectly to this group a-e, inter alia, the compounds of the formula Va to Vf ~ alogen is fluorine, chlorine, bromine or iodine, preferably fluor ne or chlo~ine.
Alkyl groups can be straight-chain or branched.
This also applies if they occur in other groups, for example in alkoxy, alkylmercapto, alkylidene, alkoxy-carbonyl or alkanoyl groups. Examples of alkyl groups which can occur in the compounds of the general formula I to be used according to the invention as such, i.e. as ( Cl - C~ ) -, ( Cl - C5 ) - or (C~-C10)-alkyl, or in other groups, are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl,~-3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl. Preferred alkyl groups are methyl, ethyl, n-216~38~
Ref. 3595 - 7 -Dr.ER/L10956 R I

2 ~~5 NN ~Z2 (Va) (Yb) ~Yc) 2 ~H2 XJ~

(Yd) (V~) (Vf) propyl, i-propyl, n-butyl, i-butyl a d tert-butyl.
Alke~yl and alky~yl radicals can also ~e 6t-aight-chain or branched. Exam?les of alke~yl radicals are ~inyl, l-propenyl, allyl, butenyl, 3-methyl-2-bute~yl, a~d examples of alkynyl radicals are ethy~yl, 1-propy~yl, proparsyl or 5-hexynyl.
The (C3-C,)-cycloalkyl radical is, for example, a cyclopropyl radical, a cyclobutyl radical, a cyclopentyl radical, a cyclohexyl radical or a cyclo-heptyl radical. Preferred cycloalkyl radicals are thecyclopentyl radical and the cyclohexyl radical.
The heterocyclic radical ha~ing 1, 2, 3 or 4 heteroatoms from the series nitrogen, oxygen and sulphur can be aromatic, partly saturated or completely saturated and can be fused. Preferred ring sizes of the heterocycle are 5-membered rinss, 6-m~hered rings and 7-membered rings. Examples of heterocycles from which the radical i5 deri~ed are azetidine, pyrrolidine, pyrrole, indole, pyrazole, imidazolidine, ;~;dazoline, ;~;dazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, tetrahydro-furan, furan, l,3-dioxolane, tetrahydrothiophene, thiophene, benzothiophene, l,3-dithiolane, 1,3-oxazoline, 216S~8~
Ref. 3595 - 8 -Dr.E~/110956 1,3-oxazole, 1,3,4-ox~ ole, furazan, 1,3-thiazolidine, 1,3-thiazole, piperidine, 1,2,5,6-tetrahydropyridine, 1,4-dihydropyridine, pyridine, ~uinoline, isoquinoline, pyridazine, pyrimidine, piperazine, 1,2,3-triazine, 1,3,5-triazine, perhydL~yLa~, 1,3-dioxane, 1,4-dioxane, 1,3-dithiane, dihydro-1,3-oxazine, morpholine, pe hydLo-1,4-thiazine, 5,6-dihydro-4~-1,3-thiazine, perhydro-azepine, pteridine and its deri~atives. The radicals can be bonded in any desired positions, pyridyl radicals e.g.
in the 2-position, the 3-position or the 4-position.
Nitrogen heterocycles can also be bonded via a nitrogen atom.
Examples of su~stituents which can be found on alkyl racicals and other radicals are phenyl, pyridyl, methoxy, hydroxyl, acetoxy, acetyl, 2-oxopropyl, ca-boxyl, methoxycarbonyl, ethoxycarbonyl, methyl-mercapto, methanesulphonyl, fluorine, ~;nocarbonyl, diethyl~mino and suanidino.
Exam?les of substituted alkyl sroups a-e benzyl, 2-?henylethyl, hydroxymethyl, methoxycarbonylmethyl, ~;noca-bonylmethyl and diethyl~minnmethyl.
In monosubstituted phenyl radicals the substituent can be located in the 2-position, the 3-position or the 4-position. If phenyl is disubstituted, 25 the substituents can be in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-position. Na?hthyl radicals can be present as l-napht~yl and 2-naphthyl radicals and can also be substituted in any desired positions. Examples of substi-tuted deri~atives of the phenyl radical preferred as aryl radical are 2-, 3- or 4-methylphenyl, 4-tert-butylphenyl, 2-, 3- or 4-methoxyphenyl, 3-ethoxyphenyl, 2,3-, 3,4- or 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3- ~m; no-phenyl, 3- or 4-dimethyl~nophenyl, 4-acetylaminophenyl, 2-, 3- or 4-fluorophenyl, 2,3- or 3,4-difluorophenyl, 2-, 35 3- or 4-chlorophenyl, 2,3-, 3,4-, 3,5- or 2,6-dichloro-phenyl, 4-bromophenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 2-, 3- or 4-nitrophenyl, 3- or 4-tri-fluoromethylphenyl, 2-, 3- or 4-cyanophenyl.

216~38G
- Ref. 3595 9 Dr.ER/L10956 - R5 radicals of alkyl ch~;nc~ which are inter-rupted by oxygen atoms, are, for exa~ple~ 2-methoxyethyl, 2-ethoxyethyl, 2-(2-methoxyethoxy)ethyl or 2-(2-(2-methoxyethoxy)ethoxy)ethyl.
Example6 of radicals of the general fo-mula rv are 1-azetidi~yl, pyrrolidino, 2,5-dimethylpyrrolidino, piperidino, 2,6-d~ethylpiperidino, 2,2-dimethyl-piperidi~o, morpholino, 1,4-thiazin-4-yl, 3,3-dimethyl-1,4-thiazin-4-yl, piperazino, 4-methylpiperazino, 4-acetylpiperazino, 4-methylsulphonylpipe-azi30, 4-phenylpiperazino or azepino.
The compounds of the general formula I can be present in various tautomeric for~s and in ~arious stereoisomeric forms, thus i3 the tautomeric form of the general formula VI.

X N H

~Z--S ~N H

The present invention includes not only the use of all tautomeric forms, but also that of all stereoiso-meric forms, that is e.g. that of pure enantiomers, enantiomer mixtures and race-mates, pure diastereomers and diastereomer mixtu-es or cis/tr~ns or E/Z isomers.
Suitable acids for the for~ation of pha-maco-losically acceptable acid addition salts of the compou~s of the general formula I are, for example: hydrochloric acid, hydrobromic acid, naphthalenedisulphonic acids, in particular naphthalene-1,5-disulphonic acid, phosphoric, nit-ic, sulphuric, oxalic, lactic, tarta-ic, acetic, salicylic, benzoic, formic, propionic, pivalic, diethyl-acetic, malonic, succinic, pimelic, fuma-ic, maleic, malic, sulph~;c, phenylpropionic, g'uconic, ascorbic, isonicotinic, methanesulphonic, p-toluenesulphonic, citric or adipic acid. The acid addition salts can be prepared as is customary by combination of the compo-nents, expediently in a suit2ble solvent or diluent.

216~8~
Ref. 3595 - 10 -Dr.ER/LlOg56 Compounds of the general formula I which contain an acidic group, ~or example a carboxylic acid group, ca~
form salts of this with inorganic or organic bases.
Suitable ph~rm~cologically acceptable 6alts are, for example, sodium salts, potassium salts, magnesium salts, calcium salts, ~mmon;um salts or salts with organic ~mines, for example ethanolamine or ~ino acids.
The thiazepine of the general formula I in which W, X, Y and Z simultaneously are the C~2 group is pre-ferred.
A few representatives of thiazepines of the general formula I are known as such, see J. Les6el, ph~-m-~ie 48 (19g3), 812; L.I. Rirkovskii, Metalloorg.
Rhim. 3 (1990), 1115; T. Rato et al., ~eterocycles 15 (1981), 399; J. B. Bream and J. Schmutz, ~elv. Chim. Acta 60 (1977), 2872; JP-B-46/021713; DE-A-1965309;
Y. Migalina et al., ~kr. Rhim. Zh. 35 (1969), 526 and E. W. Schubert and 0. Behner, Arch. Pha-m. 301 (1968), 750.
The present invention also relates to the previously undesc-ibed compou~ds of the general formula I as such, i.e. 2-7mino-1,3-th~azepines of the general formula I

I ll (I) r~Z_~NH

in which W is CRlRl and Rl and Rl independently of one another are hydrogen, halogen, R3, R~, oR5, SR5, S(O)p-R6, where p is 1 or 2, NR7R~, cyano, nitro, COOR9, CONR'R8 or P(O) (~)2; or Rl and R2 together are (Cl-C6)-alkylidene or (C3-C7)-cycloalkyl-idene, each of which can also carry one or more Rl radicals, or Rl and R7 together are~~=O, =S, =N~, =NR3 or =NO~; or Rl and R2, together with the carbon atom to which they are bonded, form a radical of the general formula II

Ref. 3595 - 11 -Dr.ER/~10956 tCH2)m C A (II) /\ /
(cH2)n which can be completely or pa-tly dehydrogenated, whlch can also be benzo-fused, which can be substltuted by one or more ideutical or different Rl radicals and whereiu m and n independently of one another are the numbers 0, 1, 2, 3, 4 or 5, but the sum of m + n has one of the ~alues 1, 2, 3, 4 or 5; or R~ or R2 is a f-ee ~alency which, with a similar f-ee ~alency o~ an atom which is bonded directly to the carbon atom ca-rying Rl and R', forms a double bond;

R3 is (C1-C10)-alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-C,)- cycloalkyl, (Cg-Cll)-benzocycloalkyl or the radical of a 4- to 10-m~be-ed hete-ocycle ha~iug one to four identical or different hete-oatoms f~om the series ~lt-ogen, oxygen and sulphur, which can be aromatic, partly saturated or completely satu-ated, it being possible for the alkyl, alkenyl, alkyuyl, cycloalkyl and the heterocyclic radical to be substituted by one or more identical or different Rl radicals;

R~ is phenyl or naphthyl, which can be substituted by one to three identical or different radicals from the ~e-ies (Cl-C~)-alkyl, (Cl-C~)-alkoxy, halogen, nitro, t-ifluoro-methyl, cyano, hydroxyl, (Cl-C~)-alkoxycarbonyl, ca-boxyl, carbamoyl, (Cl-C~)-alkyl-S(0)~, where q i8 0 ~ 1 or 2, a~; no, (C~-C~)-alkylcarbonylamino, (Cl-C~)-alkyl a~; ~0 and di((C~-C~)-alkyl)amino;

R5 and R5 independently of one another are hydrogen, (Cl-C10)-alkyl in which the alkyl chain can also be interrupted by cne to three o~yye~ atoms, (C2-C~0)-alkenyl, (C3-C7) -cycloalkyl, R~, R~-(C1-Cc)-alkyl, the radical of a 5- to 7-m~m~ered heterocycle ha~ing one 216~386 Ref. 3~95 - 12 -Dr.Eg/L10956 to four identical or different heteroatoms from the series nitroges, o~yy~ and sulphur, which can be aro-matic, partly saturated or completely saturated, (C -C10)-~1 k~noyl, R~-CO, R~- (Cl-C6) -alkyl-CO, (Cl-ClO)-alkoxy-carbonyl, R~O-CO, R~- (Cl-C6) -alkoxy-CO or a radical of the general formula III

~NRl 1 -C ~III) \~R12R13 R6 i8 (C~-C1O)-alkyl, (C2-C1O)-alkenyl, R~ or R~-(Cl-C6)-alkyl;

R7 and R~ independently of one another ha~e the me~ninss specified for Rs or are (Cl-C6)-alkylsulphonyl or R~-S(O), or R' and R3, together with the nitrogen atom to wkich they are bonded, fo~ a radical of the general for~ula IV
/~ C H 2 ) r -t~ A (~Y~
( CH2 ) S

which can be substituted on the C~2 groups by one or more identical or different Rl radicals and wherein r and 8 l; independently of one another a-e the numbe-s 1, 2, 3 or 4, but the sum of r + 8 i5 smaller than 6;

R7 and RB independently of R7 and Ra ha~e the me~n;ngs specified for R' and RB;

R9 has one of the m~nings of R~, but is not the radical of the general formula III;

Rl i8 (Cl-C6)-alkyl, (C3-C~)-cycloalkyl, the radical of a 5- to 7-membered heterocycle ha~ing one to three identical or different heteroatoms from the series nitrogen, oxygen and sulphur, which can be aromatic, 21653~3~
Ref. 3595 - 13 -Dr.ER/L10956 partly saturated or completely saturated, R~, haloge~, oR5, SR5, S(O)p-R6, where p is 1 or 2, NR'R', the hydroY;mino group, the oxo group, cyano, ~itro, CooR9, CONR7RJ or P(0)(0~)2;

th adicals Rll Rl2 and Rl3 indepeude~tly Or one a~other are hydrogen, (Cl-C6)-alkyl, (C3-C,)-cycloalkyl, R~, (Cl-C6)-~lk~noyl, (Cl-C6)-alkyl-S(0)2 or R~-S(0)2;

Rl~ is (C~-C~)-alkyl, be~zyl, phe~yl ~ (Cl-C6) -A1 k~noyl, (Cl-C6)-alkyl-S(0)2 or R~-S(0)2;

A is a methylene grou? which can be substituted by one or two identical or differe~t Rl radicals, o is oxygen, sulphur or NRl~;

X is CR20R2l a~d R20 a~d R2l i~depe~de~tly of the me~n;n5s of the radicals Rl a~d R2 ha~e the me~nlngs specified for Rl a~d R2;

22R23 ~d R22 a~d R23 indepe~de~tlY of _he e g of the radicals Rl a~d R2 ha~e the me~nings specified for R~ and R2;

Z is CR2~R25 and R2~ and R2s i~depe3de~tly of the me~n;ngs of the radicals Rl a~d R2 ha~e the me~nlnss specified for R~ and R2;

where radicals of the groups W, X, Y and Z can also be li~ked ~ia a bo~d such that a bicyclic system or tricyclic system is formed;

a~d their tautomeric forms a~d also their ph~r~co-logically tolerable salts, but where, ~~

a) if R20 and R2l are hydrogen, 216~386 Ref. 3595 - 14 -Dr.E~/L10956 al) R1 R2 R22 R23, R2~ and R25 c~not be hydrogen simultaneously;
a2) R22, R2~ and R25 cannot be hydrogen, R23 c~nnot be the carboxyl group and Rl and R2 together c~nnot be =O simul-taneously;a3) R22, R23 and R2~ cannot be hydrogen, R25 cannot be bromomethyl and Rl and R2 together cannot be =O simul-taneously;
a4) R1, R2, R2~ and R25 cannot be hydrogen and R22 and R23 together cannot be =O simultaneously;
a5) R1 c~nnot be hydrogen and R2 cannot be butyl and R22, R23, R2~ and R2s, together with the two carbon atoms to which they are bonded, cannot form a 2-oxo-1,2-dihydro-qu noli~e-3,g-diyl rad cal simultaneously;

b) if R20, R21, R22 and R23, together with the two carbon atoms to which they are bonded, form a 1,2-phenylene radical or a 4-chloro-1,2-phenylene radical, bl) Rl, R2 and R2~ cannot be hydrogen ~nd R2s c~nnot be phenyl 8 imultaneously;
b2) Rl, R2~ a~d R25 c~nnot be hydrogen and R2 c~nnot be phenyl simultaneously;
b3) R1 and R2 together cannot be =O and R2~ and R25 together c~nnot be =O simultaneously.

With respect to the substituents, such as haloge~
atoms, alkyl groups, etc. in the thiazepine derivatives as 8uch, what has been said above applies correspon-dingly.
The synthesis of the compounds of the general formula I can be car-ied out, for example, according to the following scheme:

Starting materials are ~=aminoalcohols of the general formula VII, in which W, X, Y and Z ha~e the me~n;n~s specified above. According to methods k~own per 216~386 ~ef. 3595 - 15 -Dr.ER/L10956 ~2 ~I~NH2 ~-N=C=S
X X
r\ \ \z~
Z-~H z _ (YII~ ~VIII) (IX) tSu-N=C=5 - t8u-NH2 ~_~ ~ H-tBu X S
~x) z~

~Z--S N H 2 ~ ~1N H - t 8 U

(I) ~XI) se, compounds of the general formula VIII are prepared from these in which E- is a group which can be replaced in a nucleophilic substitution reaction. E- is, for example, Cl-, 8r-, I-, C~SO20-, C6~sSO20-, substituted S benzenesulphonyloxy radicals, e.g. nitrobenzene-sulphonyloxy or toluenesulphonyloxy, or another acti~ated form of the hydroxyl group. ~he con~ersion of the hydroxyl group in VII can be carried out under customary conditions, for ex~ple, using thionyl chloride or - ~ Ref. 3595 - 16 -Dr.ER/L10956 bromide, using phosphorus halides, such as phosphorus pentachloride, phospho_u3 t~ichloride or phosphorus tribromide, using hydrogen bromide or hydrogen iodide or using aliphatic or aromatic sulphouyl chlorides. The compounds of the general formula VIII ca~ be cou~erted directly to the thioureas of the general formula X usi~g tert-butyl isothiocyanate or first converted, usins r e a g e n t 8 8 u c h a 8 th i op h o 8 g e u e o r N,N'-thiocarbo~yldiimidazole, to the isothiocya~ates of the general formula IX, which with tert-butyl~m;2e yield the thioureas of the general formula X, which cyclize to the 2-tert-butylamino-1,3-thiazepi~es of the general formula XI. The compouuds of the general formula I are obt~;n~hle from these by removal of the tert-butyl s_oup, for example by boiliug with dilute hydrochloric acid.
Sta_ting from the ~ no~lcohols of the general formula VII, using tert-butyl isothiocyanate, the thiourea3 of the general fo~mula XII
H H
H0~2~y~x~x ~ ~su ~XIi~

can also fi-st be prepared, which are then co~verted iuto the compou~ds of the ge~eral fo~mula X by couversion of the hydroxyl group to the g_oup E a3 specified above.
Sta-ti~g materials fo- anothe- synthetic route are the compou~ds of the geueral formula X~II

G Xl N

X ~ ~N H 2 Y `z~ ~N H

2-~
(I) ~XIII) Ref. 3595 - 17 -Dr.E~/L10~56 in which G is a group which reacts with a~;no g_oups in a substitution reaction or an addition reaction, for example the carboxyl, alkoxycarbonyl, aryloxycarbonyl, cyano or formyl group, the -CORl sroup or the -CRlR2-E' group, Rl and Rl being defined as specified abo~e, and in which E and also E' are identical or different s~oups which - like E in the general formula VIII - can be replaced in a nucleophilic substitution ~eaction, that is e.g. by chlorine, bromine, iodine or aliphatic or aro-matic 6ulphonyloxy radicals. The compounds of the generalformula XIII, w~ich ca~ be, for examrle, r-halocarbonyl compounds or, if G- in the gene-al formula XIII is -W-E', a,~-dibromides, ~,~-dichlorides or ~,~-disulphonates, yield the thiazepines of the general formula I with thlou-ea under customary conditions.
A further synthesis process is the reaction of thiourea with compounds of the gene-al formula XIV

Z X /

(I~) tXIV) in which the double bond between the group Z and the adjacent carbon atom is acti~ated by electron-withdrawing substituents, such that addition of the sulphu~ atom in the thiourea Z can take place, and i~ which G has the ~ean~ng specified for the formula XIII.
The details of the synthesis of compounds of the general formula I in J.B. Bream and J. Schmutz, ~el~.

216~:~86 ` Ref. 3595 - 18 -Dr.ER/L10956 Chim. Acta 60 (1977), 2872; J8-B-46/021713 and ~.W.
Schubert and O. Be^hner, Arch. Pharm. 301 (1968), 750 are completely part of the prese~t disclosure.
The inhibition of NO release according to the invention by the compounds of the general formula I can be determined by an acti~ity assay which is based 02 studies by ~redt and Snyder and also Sc~midt et al. (see D.S. Bredt and S.S. Snyder, Isolation of nitric oxide synthase, a c~lmo~ulin-requiriug enzyme, Proc. Natl.
Acad. Sci. ~SA 87 (1990), 682; E.~.~.W. Schmidt et al., Purification of a 601uble isoform of guanylyl cyclase-acti~ating factor 6y3thase, P-oc. Natl. Acad. Sci. USA 88 (1991), 365). I3 this as6ay, the coproduct L-cit-ulline for purified NO 6ynthase (NOS) obtained duri~g NO
formatio~ is deter_ined quantitatively. This is achieved by the use of 3~-radiolabelled L-argi~ine as a substrate of the e~zyme reactio~, which i8 reacted to gi~e 3~-L-citrulli~e and NO. Afte_ completion of ~e enzyme i~cubation, L-cit-ulline formed is removed from the reaction mixture f~om unused L-a~si~lne by mea~s o io~-excha~ge chromatography; the 3~-acti~ity determined by liquid scintillation measurement then co-responds to the amount of L-citrulline.
The inhibition of NO release by the compounds of the gene-al fo-mula I can also be determined i~
mac-ophages by NO measureme~t by means of oxyhaemoglobin:
Mice mac_ophages (M~) of the 6train RAW 264.7 a=e cultured i~ Petri dishes (10 cm diamete-). The nutrient medium employed is DMEM (Sigma No. D 5405), conditioned w~th 4 _M l-glut~;ne, 3.5 g of D-glucose/l, 50 ~/50 ~g/ml of pen/strep and 10% FCS, employed under 5~
CO2, 95% atmospheric humidity, 37C. The subconfluent cells a-e sc-aped off with the cell sc_ape-, taken up in medium, the cell count is determ- n~ (counting i~ Trypan 81ue solution 0.2%) and inoculated i~to 24-well plates (1 x 106 cells/ml, 1 ml /well). ~
About 18 hours after i~oculation, the well-adhered mouse macrophages are ~t_mulated with LPS (lipo-Ref. 3595 - 19 -Dr.3~/L10956 polysaccharide from E. coli serotype 0111:B4, Sigma No.
2630) and y-;nterferon (yIFN, mouse recombinant, Boehringer M~nnheim No. 1276905). To do this, the culture medium i8 aspirated f_om the cells a~d 1 ml/well (24-well plate) of i~cubation medium (~EM without Phenol Red (Biochrom F0385)), conditioned with 4 mM glutami~e, 3.5 g of glucose/l, 3.7 g of NaECO3/l, 110 mg of sodium ~yLuvGte/l, 50 ~/50 ~g/ml of peu/strep a~d 5% FCS, is added. 1 ~1 of LPS and 1 ~1 of yIFN are pipetted per ml of incubation medium.
The following concent-ations of the stimulators result from this:
140 ng of LPS/~l + 5 U of yIFN/ml During the stimulation for 4 hours, the de novo synthesis of the NO-producing enzyme NO sy~thase (iNOS) is induced. After this incubatio~ period, the incubation medium is aspirated and each well is rinsed twice with fresh incubation medium. Test medium (consisti~g of the incubation medium with the addltion of SOD (30 ~/ml), catalase (290 ~/ml), in~omethacin (3.5 ~g/ml), OxyEb (about 8 ~m) and test substance (0.05-250 ~M)) is added to the well (1 ml/well in the case of a 24-well plate).
As a control, the conditioned test medium is treated only with the sol~ent for the test substance. The plates charged with test medium a-e incubated in an incubator at 37C, 5% CO2 a~d 95% atmospheric humidity for 120 minutes. After the 120 minute incubation, the test medium is pipetted into plastic semimicro cuvettes and the extinction difference 576-592 nm is measured on a D~ 70.
Every 2 wells are charged with a test substance (~ = 2), one control on each plate is u3stimulated, and a stimulation control and a positive control (nitro-L-arglni~e, 500 ~M) are in~estigated comparatively to the test substa2ces. A6 a measurement of the test substances, the extinction difference 576-5g2 nm is compared to the s~im11l~tion control as a percentage. The extinction differeuce 576-592 n~ at time 0 of the test medium t_eated with the test substance is measured and the pE

216~81;
Ref. 3595 - 20 -Dr.3R/L10956 and the osmolality i8 determined.
After pipétting off the test medium, the cyto-toxicity of the test substance is tested (cell via-bility).
Diseases which result due to an increased N0 level, and which can thus be treated according to the in~ention with the compounds of the general formula I or which can be prevented with these, are in particular pathological blood pressure decreases, as occur in septic or haemorrhagic shock, in tumou- or cancer therapy with cytokines or in cirrhosis of the liver. In addition, infl~mm~tory disorders, such as rheumatoid arth_itis and in particular ulce-ative colitis, and also i3SUliD.-dependent diabetes mellitus and transplant rejection reactions.
~owever, the following disorders are also con-nected with an inc-eased production of nitric oxide and can be treated or prevented acco-ding to the invention.
In the ca-diovascular a-ea, these are arteriosclerosis, post-ischaemic tissue damage and infarct damage, reper-fusion d~ge, myoca-ditis based on a Coxsackie virus infection and cardiomyopathy; in the nervous system/
central ne-vous system area neuritis of differing aetio-genesis (forms of neuritis), encephalomyelitis, viral neurodegenerative disorders, Alzheimer's disease, hyperalgesia, epilepsy, migraine and opioid withdrawal symptoms; in the renal area acute kidney failure and nephritis of differing aetiogenesis, especially glomerulonephritis.
Additionally, application areas for the compounds of the general formula I are also treatments in the area of the stomach and of the uterus/the placenta and also an effect on sperm motility.
The compounds of the general formula I and their ph~rm~cologically acceptable salts can be employed as auxiliaries in biochemical and ph~rm~cological investiga-tions in research and in ~;~gnostic processes, and they can be ~min; stered to ~n;m:~l 8, preferably to m~ l 8, . Ref. 3595 - 21 - 216 ~
Dr.ER/L10956 and in particular tQ h?.m~nR, as me~;cines by themsel~es, in mixtu=es with one another or in the form of ph~rm~-ceutical preparations which enable enteral or parenteral ~;n;stration and which as acti~e constituent contain an effecti~e dose of at least one compound of the general formula I or of a salt thereof, in addition to customa~y ph~rmaceutically innocuous excipients and additives.
The medicines can be a~m;nistered orally, e.g. in the form of pills, tablets~ lacquered tablets, coated tablets, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures.
~m;n; stration, however, can also be ca-ried out rec-tally, e.g. in the form of suppositories, o-pa~enterally, e.g. in the form of injection solutio~s o_ inrusion solutio2s, or percutaneously, e.g. in the form of oin~ments o- tinctu_es.
In addition to the acti~e substances and exci-pients, the pharmaceutical p-epa_ations can additionally contain adcit ves, such as e.g. fillers, extenders, disintegrants, binders, glidants, wetting agents, stabi-lizers, emulsifying agents, preser~ati~es, sweetene-s, colourants, fla~ourings or a-omatizers, buffer sub-stances, and also sol~ents or solubilizers or agents for obt~;n;ng a depot effect, and also salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two o- more compounds of the gene-al formula I or thei- phanmacologically acceptable salts and additionally other therapeutically active substances.
Other therapeutically active substances of this type are, for example: ~-receptor blockers, such as e.g.
propranolol, pindolol, metoprolol; ~asodilators, such as e.g. carbocromen; t-anquillize-s, such as e.g. bar~ituric acid deri~ati~es, 1,4-benzodiazepines and meprobamate;
diuretics, such as e.g. chlorothiazide; cardiotonic agents, such as e.g. digitalis preparations; hypotensive agents, such as e.g. hydralazine, dihydralazine, ra~;pril, prazosin, clonidine, Rauwolfia alkaloids;
agents which dec~ease the fatty acid level in the blood, Ref. 3595 - 22 -Dr.Eg/LlOg56 such as e.g. bezafibrate, fenofibrate; agents for throm-bosis prophylaxis~ such as e.g. phe~procoumon; anti-i~flammatory substances, such as, for example, corti-costeroids, salicylates or propionic acid deri~ati~es, such as, for example, ibuprofen; antibiotics, such as e.g. penicilli~s or cephalosporins; N0 donors, such as e.g. organic nitrates or syd30ne imines or furoxanes.
The dose can ~ary within wide l;m;ts and i8 to be suited to the indi~idual conditions in each indi~idual case. In general, i3 the case of oral a~ministration a daily dose of about 0.5 to 100 mg, preferably 1 to 20 mg, per h~m~n indi~idual is appropriate. Also in the case of other administ-ation forms the daily dose is in similar ra~ges of amou3ts, i.e. in general also 0.5 to 100 mg/
person. The daily dose can be di~ided into two or more, e.g. 2 to 4, pa-t ~m n;strations.
To prepare the ph~rm~ceutical preparations, pk~ m~ceutically inert inorganic o- orsanic excipients can be used. To prepare pills, tablets, coated tablets and hard gelati~ capsules, e.g. lactose, maize starch or deri~ati~es thereof, talc, stearic acid or its salts etc.
can be used. Excipients for soft gelatin capsules and suppositories are e.g. fats, wzxes, semi-solid and liquid polyols, natural or hardened oils etc. Suitable exci-pients for the preparation of solutions and syrups aree.g. water, suc-ose, in~ert sugar, glucose, polyols etc.
Suitable ex^ipients for the preparation of injectio3 solutions are e.g. water, alcohols, glycerol, polyols or ~egetable oils.

ExamPle 1 2-Amino-4,5,6,7-tetrahydro-1,3-thiazepine hydrochloride a) 2-Amino-4,5,6,7-tetrahydro-1,3-thiazepine hydrochloride was prepared accordi~g to ~.W. Schubert and 0. Behner, Arch. Pharm. 301 (1968), 750. The physical 3~ data corresponded to the details there. l~-NMR (DMS0, 300 216~386 Ref. 359~ - 23 -Dr.E~/L10956 M~z): 1.67 ppm (quintet, 2~, ~-6); 1.94 (quintet, 2~
5); 3.09-3.18 (m,~2~, 8-7); 3.24 (q, 2~, ~-4); 9.20 (s, 1~, N~); 9.53 (8, 1~, N~); 10.34 (8, 1~, N~).

b) The ph~-m~cological activity was determined on macrophages by N0 measurement by means of oxyhaemoglobin as described abo~e. The IC50 ~alue was 1.3xlO-' M.

ExamPle 2 3-Amino-1,5-dih~drobenzo[e~[1,3]thiaze~ine hvd~ochloride a) 2-Am;n~m~thvlbenzyl alcohol hYdrochloride 20 g (0.13 mol) of 2-hydroxymethylbenzam;de in 450 ml of tet-ahydrofuran are added dropwise to a boiling suspension of lithium aluminium hydride in 500 ml of tet-ahydrofuran. The ~ixture is heated under reflnx for 5 h, stirred ove~night at room temperatu-e and treated dropwise with 91 ml of saturated potassium ca_bonate solution. The precipitate is filtered off with suction and washed with tetrahydrofuran. The combined filtrates are concentrated. The residue i8 taken up in 100 1 of isopropanol, treated with ethereal hydrochloric acid, and the precipitate formed is filtered off with suction and rec-ystallized from isopropanol.

Yield: 19.2 g. M.p. 225C

b) 3-Amino-1,5-dihYdrobenzo~e] ~1,3]thiazePine hydrochloride 7 g (40 mol) of 2-~m;n~methylbenzyl alcohol hydrochloride are suspended in 80 ~l of ethanol, a solution of potassium ethoxide in 10 ml of ethanol i8 added and the mixture is warmed to ~0C for 10 min. It is then cooled to 5C and the precipitated potassium chloride i8 filtered off with suction. 4.64 g (40 mol) of Ref. 3595 - 24 - 216~386 Dr.E~/L10956 tert-butyl isothiocyanate are added dropwise to the filtrate ~d the reaction mixture is heated under reflux for 4 h. After stirring over3ight, it i8 concentrated 03 a rotary e~aporator, the residue i8 taken up in 30 ml of aqueous hydrobromic acid (48% strength) and the mixture is heated unde~ reflux for 2 h. The reaction mixtu-e obt~;ne~ in this way is filtered, concentrated 03 a rotary e~aporator and chromatographed on silica gel using dichloromethane/methanol/water/acetic acid (85:15:2:2).
The main fraction is recrystallized f~om ethanol.

Yield: 0.88 g of white crystals. M.p. 246C (dec.) ~xam~le 3 2-Amino-5-~he~1-4,5,6,7-tetrah~d-o-1,3-thiazeDi~e hydrochloride a) 4-Amino-3-Dhe3Ylbutanol h~d-ochlo-ide 12.7 g (0.33 mol) of lithium aluminium hydride a_e initially introduced into 250 ml of diethyl ether, the mixture is cooled to 0C and 25 g (0.11 mol) of methyl 4-n tro-3-phenylbutyrate (M. J. Leonard et al., J.
Am. Chem. Soc. 73 (lg51), 857), dissol~ed in 100 ml of diethyl et~er, are added dropwise. The mixtu-e is heated under reflux for 2 h, hydrolysed with saturated potassium carbouate solution, treated with water and stir~ed at room temperature for 1 h. The precipitate is filtered off with suctio3 and boiled with dichloromethane. The com-bined organic phases are concentrated. The residue i8 taken up in 1 N hydrochloric acid and extracted with diethyl ether. The aqueous phase i8 rendered basic with sodium hydroxide solution and extracted with dichloro-methane. The residue which r~in~ after concen~ration is taken up in tetrahydrofuran and ~he hydrochloride i8 precipitated by addition of ethereal hydrochloric acid.
10.4 g of the hydrochloride are obtained, which are ~ ef. 3595 - 25 - 216S~
Dr.ER/L10956 ~loyed in the subsequent reaction without further purification. --b) 4-Chloro-2-phenylbutylamine hYdrochloride A solution of 10.4 g (52 mmol) of 4-a~ino-3-phenylbutanol hydrochloride in 50 ml of chloroform i8added dropwise at 0C to a suspension of 14.1 g (68 mmol) of phosphorus pentachloride and 5.2 g (52 mmol) of calcium carbonate in 100 ml of chloroform. The salt is the~ filtered off, the filt_ate is concent-ated and the residue which r~m~ n~ is employed in the subse~uent reaction without further purification.

c) 4-Chloro-2-~he~YlbutYl isothiocYanate 11.4 g (52 _mol) of 4-chloro-2-phenylbutyl~;ne hyd-ochloride a-e t-eated successi~ely with 50 1 of water, 50 ml of ethylene chloride and 10.4 g (104 mmol) of calcium carbonate. 6.9 g (60 mmol) of thiophosgene i~
10 ml of ethylene chloride are added dropwise at 10C
with cooling. The mixture is stirred at room temperature for 16 h and finally the salt is filtered of~ with suction. The phases of the filtrate are separated. After drying the organic phase and stripping off the solvent, it is distilled in a high vacuum.
Yield: 3.2 g of slightly yellow oil. B.p. (0.012 mbar) 130C.

d) 2-Amino-S-PhenYl-4,5,6,7-tetrahydro-1,3-thiazePine hYdrochloride 3.1 g (14 mmol) of 4-chloro-2-phenylbutyl isothiocyauate, dissol~ed in 5 ml of xylene, are added dropwise to a solution of 2.0 g (28 mmol) of tertbutyl7mine in 15 ml of xylene~ a~d the mixture is heated under reflux for 2 h. The precipitated salt is then filtered off and the filtrate is extracted three 211i538~
Ref. 3595 - 26 -Dr.E~/L10956 times with 10 ml of 2 N hydrochloric acid each time. The combi3ed aqueous -phases are heated under reflux until reaction is complete. For working up, the mixture is concentrated on a rotary e~aporator and, after chroma-tography on silica gel using butanol/acetic acid/water(8:2:2) (org. phase), the residue i8 c-ystallized from ethanol/ethyl acetate/hexane.

Yield: 0.5 g of white crystals. M.p. 234-235C.

ExamPle 4 2-Ami~o-6-~hen~1-4,5,6,7-tetrahYdro-1,3-thiaze~ine hYdrochloride a) E'hYl 4-nitro-2-~henYlbutvrate 147.7 g (0.34 mol) of Triton B (methanolic solution) are added dropwise to 179.8 g (2.95 mol) of ~it_omethane in 200 ml of tert-butanol a~d the mixture is sti~red at room temperature for 30 mi~. 86.5 g (0.49 mol) of ethyl 2-phenylacrYlate (Chem. Ber. 119 (1986), 3694), dissol~ed in 30 ml of tert-butanol, are added dropwise to this mixture and it is stir~ed at 70C for 4 h. For working up, it is concentrated on a rotary e~aporator, taken up in dichloromethane, washed with water and concentrated again. The residue is filtered through silica gel using hexane/ethyl acetate (2:1) and finally fractionally distilled in a high ~acuum. 26.7 g of colourless oil are obtained. B.p. (0.5 =) 148C.

b) 4-Amino-2-PhenYlbutanol hYdrochloride Correspon~ing to the preparation of 4-~ino-3-phenylbutanol hydrochloride (Example 3a), 42 g of product are obtained from 92.6 g (0.39 mol~ of ethyl 4-nitro-2-phenylbutyrate and 47.2 g (1.24 mol) of lithium aluminium hydride.

Ref. 3595 - 27 -Dr.ER/~10956 c) 4-Chloro-3-PhenYlbutYlamine hydro~hloride . _ Correspon~ing to the preparation of 4-chloro-2-phenybutyl~ine hydrochloride (Example 3b), 22.2 g of crude product are obtained from 19.3 g (96 mmol) of 4-~m;no-2-phenylbutanol hydrochloride, which are employed in the subsequent reaction without further purification.

d) 4-Chloro-3-PhenYlbut~l isothiocvanate Corresponding to the preparation of 4-chloro-2-phenylbutyl isothiocyanate (Example 3c), 3.~4 g of product are obtained ~rom 22.2 g (0.1 mol) of 4-chloro-3-phenylbutylamine hydrochloride. B.p. (0.04 mbar) 140C.

e) 2-Amino-6-Phenyl-4,5,6,7-tetrahydro-1,3-thiazepine h~drochloride 3.7 g (16 ~mol) of 4-chloro-3-phenylbutyl iso-thiocyanate are added d~opwise to a solution of 2.64 g(36 mmol) of tert-butylamine in 20 ml of xylene and the mixture is heated under reflux for 8 h. After stirring at room temperature for 16 h, the solid is filtered off with suction, the filt-ate is extracted three times with 2 N
hydrochloric acid and the combined extracts are heated under reflux for 2 h. The reaction mixture is concen-trated on a rotary e~aporator and chromatographed on silica gel using dichloromethane/methanol/acetic acid (50:10:1). The main fraction is concentrated, taken up in 2 N hydrochloric acid and freeze-dried. The oil which r~m~inR crystallizes on trituration with diethyl ether.

Yield: 0.33 g of beige crystals. M.p. 127C. (dec.) ExamPle 5 _, 2-Amino-4,7-dihYdro-1,3-thiaze~ine hYdrochloride 216S ~8G
~ef. 3595 - 28 -Dr.E~/L10956 a)- 4-Chlorobut-2-enYl isothiocYarate ._ Correspon~;ng to the preparation of 4-chloro-2-phe~ylbutyl isothiocyanate (Example 3c), 22.1 g of product are obtai~ed in the form of a colou-less oil from 30 g (0.21 mol) of 4-chlorobut-2-e~ylam;ne hydrochlo-ide (Synthesis (1988), 347), 27.9 g (0.24 mol) of thiophos-ge~e and 42.3 g (0.42 mol) of calcium carbonate. B.p.
(2 mm) 80C.

b) 2-Amino-4,7-dihYd-o-1,3-thiazePine hYd-ochloride Cor-espon~in~ to the preparation of 2-~m;no-5-phe~yl-4,5,6,7-tetrahydro-1,3-thiazepi3e hydrochloride (Example 3d) 3.3 g of product a-e obtained from 20.7 g (0.14 mol) of 4-c~lorobut-2-enyl isothiocyanate and 20.5 g (0.28 mol) of tert-butyl~m;~e after removal of the lS tert-butyl residue with half-concentrated hyd~ochlo~ic acid.

3eige crystals. M.p. 123-125C.

The following examples relate to ph~rm~ceutica preparation forms.

kxample A
Soft gelatin capsules cont~;n;ng 100 mg of active ~ub-stance per capsule:
per capsnle Active substance 100 mg 25 Triglyceride mixture fractionated from cocoa fat 400 mg Capsule contents 500 mg k~ample B
Injectio~ solution cont~; n i ng 2.0 mg of active substance30 per ml: ~

per ~1 216~386 Ref. 3595 - 29 -Dr.E~/L10956 Acti~e substance 2.0 mg Polyethylene glycol 400 5.0 mg Sodium chloride 2.7 mg Water for injection purposes to 1 ml R~a~l e C
3mulsion containing 60 mg of acti~e substance per 5 ml:
per 100 ml of ~lsion Active substance 1.2 g 10 Neut~al oil q.s.
Sodium carboxymethylcellulose 0.6 g Polyoxyethylene stearate q.s.
Glycerol, pure 0.2 to 2.0 g Fla~ouring q.s.
15 Water (demineralized o- distilled) to 100 ml ~xample D
Rectal pha~maceutical fo~m cont~ining 40 mg of active substa~ce per suppository:
per suppository 20 Acti~e substance 40 mg Suppository base to 2 g 13xamrle ~
Tablets contA i n i n5 40 mg of acti~e substance per tablet:
per tablet 25 Acti~e su~stance 40 mg Lactose 600 mg Maize sta-ch 300 mg Solu~le starch 20 mg Magnesium stearate 40 mg 1000 mg F~amrle F
Coated tablets containing 50 mg of acti~e co~o~d per coated tablet:
per coated . 216~38B
Ref. 35g5 30 Dr.ER/L10956 tablet Active substance ~ 50 mg Maize starch 100 mg Lactose 60 mg 5 sec calcium phosphate 30 mg Soluble sta-ch 5 mg Magnesium stearate 10 mg Colloidal 8ilicic acid 5 mg 260 mg ~ample G
The following recipes are suitable for the preparatio~ o~
the co3te~ts of hard gelatln capsules:
a) Acti~e sub6tauce 100 mg Maize starch 300 mg 400 mg b) Acti~e substa~ce 140 mg Mil~ sugar 180 mg Maize sta-ch 180 mg 500 mg ~ample ~
Drops ca~ be prepared according to the followiug recipe (100 mg of acti~e substance in 1 ml = 20 drops):
Acti~e substa3ce 10 g Methyl be~zoate 0.07 g Ethyl benzoate 0.03 g Ethanol, 96% st~ength 5 ml 30 Demineralized water to 100 ml

Claims (16)

1. A 2-amino-1,3-thiazepine of the general formula I

(I) in which W is CR1R2 and R1 and R2 independently of one another are hydrogen, halogen, R3, R4, OR5, SR5', S(O)p-R6, where p is 1 or 2, NR7R8, cyano, nitro, COOR9, CONR7'R8' or P(O) (OH)2; or R1 and R2 together are (C1-C6) - alkylidene or (C3-C7) -cycloalkyl-idene, each of which can also carry one or more R10 radicals, or R1 and R2 together are =O, =S, =NH, =NR3 or =NOH; or R1 and R2, together with the carbon atom to which they are bonded, form a radical of the general formula II

(II) which can be completely or partly dehydrogenated, which can also be benzo-fused, which can be substituted by one or more identical or different R10 radicals and wherein m and n independently of one another are the numbers 0, 1,

2, 3, 4 or 5, but the sum of m + n has one of the values 1, 2, 3, 4 or 5; or R1 or R2 is a free valency which, with a similar free valency or an atom which is bonded directly to the carbon atom carrying R1 and R2, forms a double bond;

R3 is (C1-C10) -alkyl, (C2-C10) -alkenyl, (C2-C10) -alkynyl, (C3-C7) - cycloalkyl, (C9-C11) -benzocycloalkyl or the radical of a 4- to 10-membered heterocycle having one to four identical or different heteroatoms from the series nitrogen, oxygen and sulphur, which can be aromatic, partly saturated or completely saturated, it being possible for the alkyl, alkenyl, alkynyl, cycloalkyl and the heterocyclic radical to be substituted by one or more identical or different R10 radicals;

R4 is phenyl or naphthyl, which can be substituted by one to three identical or different radicals from the series (C1-C4) -alkyl, (C1-C4) -alkoxy, halogen, nitro, trifluoro-methyl, cyano, hydroxyl, (C1-C4) -alkoxycarbonyl, carboxyl, carbamoyl, (C1-C4) -alkyl-S(O)q, where q is 0, 1 or 2, amino, (C1-C4) -alkylcarbonylamino, (C1-C4) -alkylamino and di((C1-C4)-alkyl)amino;

R5 and R5' independently of one another are hydrogen, (C1-C10)-alkyl in which the alkyl chain can also be interrupted by one to three oxygen atoms, (C2-C10)-alkenyl, (C3-C7) -cycloalkyl, R4, R4- (C1-C6)-alkyl, the radical of a 5- to 7-membered heterocycle having one to four identical or different heteroatoms from the series nitrogen, oxygen and sulphur, which can be aromatic, partly saturated or completely saturated, (C1-C10)-alkanoyl, R4-CO, R4-(C1-C6)-alkyl-CO, (C1-C10)-alkoxycar-bonyl, R4O-CO, R4-(C1-C6) -alkoxy-CO or a radical of the general formula III

(III) R6 is (C1-C10)-alkyl, (C2-C10)-alkenyl, R4 or R4-(C1-C6) -alkyl;

R7 and R8 independently of one another have the meanings specified for R5 or are (C1-C6) -alkylsulphonyl or R4-S(O)2 or R7 and R8, together with the nitrogen atom to which they are bonded, form a radical of the general formula IV

(IV) which can be substituted on the CH2 groups by one or more identical or different R10 radicals and wherein r and s independently of one another are the numbers 1, 2, 3 or 4, but the sum of r + s is smaller than 6;

R7' and R8' independently of R7 and R8 have the meanings specified for R7 and R8;

R9 has one of the meanings of R5, but is not the radical of the general formula III;

R10 is (C1-C6) -alkyl, (C3-C7) -cycloalkyl, the radical of a 5- to 7-membered heterocycle having one to three identical or different heteroatoms from the series nitrogen, oxygen and sulphur, which can be aromatic, partly saturated or completely saturated, R4, halogen, OR5, SR5, S(O)p-R6, where p is 1 or 2, NR7R8, the hydrox-imino group, the oxo group, cyano, nitro, COOR9, CONR7'R8' or P(O)(OH)2;

the radicals R11, R12 and R13 independently of one another are hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, R4, (C1-C6)-alkanoyl, (C1-C6)-alkyl-S(O)2 or R4-S (O)2;

A is a methylene group which can be substituted by one or two identical or different R10 radicals, or is oxygen, sulphur or NR14;

R14 is (C1-C4)-alkyl, benzyl, phenyl, (C1-C6)-alkanoyl, (C1-C6)-alkyl-S(O)2 or R4-S(O)2;

X is CR20R21 and R20 and R21 independently of the meanings of the radicals R1 and R2 have the meanings specified for R1 and R2;
Y is CR22R23 and R22 and R23 independently of the meanings of the radicals R1 and R2 have the meanings specified for R1 and R2;
Z is CR24R25 and R24 and R25 independently of the meanings of the radicals R1 and R2 have the meanings specified for R1 and R2;
where radicals of the groups W, X, Y and Z can also be linked via a bond such that a bicyclic system or tricyclic system is formed;
a tautomeric form thereof or a pharmaceutically acceptable salt thereof.

2. A 2-amino-1,3-thiazepine according to claim 1, in which W, X, Y and Z in the general formula I are the CH2 group.

3. Use of a 2-amino-1,3-thiazepine according to claim 1 or 2 for prevention or treatment of a disease caused by an increased nitric oxide level.

4. Use according to claim 3 for treatment or prevention of a pathological blood pressure decrease.

5. Use according to claim 4 wherein said pathological blood pressure decrease is a result of septic shock and cancer therapy using cytokines.

6. Use according to claim 3 for treatment or prevention of an inflammatory disorder.

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7. Use according to claim 6 wherein said inflammatory disorder is ulcerative colitis.

8. Use according to claim 3 for treatment or prevention of infarct damage or reperfusion damage.

9. Use according to claim 3 for treatment or prevention of a transplant rejection reaction.

10. Use according to claim 3 for treatment or prevention of a disorder of the nervous system from the series Alzheimer's disease, epilepsy and migraine.

11. A 2-amino-1,3-thiazepine of the general formula I

(I) in which W is CR1R2 and R1 and R2 independently of one another are hydrogen, halogen, R3, R4, OR5, SR5', S(O)p-R6, where p is 1 or 2, NR7R8, cyano, nitro, COOR9, CONR7'R8' or P(O) (OH)2; or R1 and R2 together are (C1-C6) -alkylidene or (C3-C7) -cycloalkyl-idene, each of which can also carry one or more R10 radicals, or R1 and R2 together are =O, =S, =NH, =NR3 or =NOH; or R1 and R2, together with the carbon atom to which they are bonded, form a radical of the general formula II

(II) which can be completely or partly dehydrogenated, which can also be benzo-fused, which can be substituted by one or more identical or different R10 radicals and wherein m and n independently of one another are the numbers 0, 1, 2, 3, 4 or 5, but the sum of m + n has one of the values 1, 2, 3, 4 or 5; or R1 or R2 is a free valency which, with a similar free valency or an atom which is bonded directly to the carbon atom carrying R1 and R2, forms a double bond;

R3 is (C1-C10)-alkyl, (C2-C10) -alkenyl, (C2-C10) -alkynyl, (C3-C7)- cycloalkyl, (C9-C11) -benzocycloalkyl or the radical of a 4- to 10-membered heterocycle having one to four identical or different heteroatoms from the series nitrogen, oxygen and sulphur, which can be aromatic, partly saturated or completely saturated, it being possible for the alkyl, alkenyl, alkynyl, cycloalkyl and the heterocyclic radical to be substituted by one or more identical or different R10 radicals;

R4 is phenyl or naphthyl, which can be substituted by one to three identical or different radicals from the series (C1-C4) -alkyl, (C1-C4) -alkoxy, halogen, nitro, trifluoro-methyl, cyano, hydroxyl, (C1-C4) -alkoxycarbonyl, carboxyl, carbamoyl, (C1-C4)-alkyl-S(O)q, where q is 0, 1 or 2, amino, (C1-C4) -alkylcarbonylamino, (C1-C4)-alkylamino and di((C1-C4) -alkyl)amino;

R5 and R5' independently of one another are hydrogen, (C1-C10)-alkyl in which the alkyl chain can also be interrupted by one to three oxygen atoms, (C2-C10)-alkenyl, (C3-C7) -cycloalkyl, R4, R4-(C1-C6)-alkyl, the radical of a 5- to 7-membered heterocycle having one to four identical or different heteroatoms from the series nitrogen, oxygen and sulphur, which can be aromatic, partly saturated or completely saturated, (C1-C10)-alkanoyl, R4-CO, R4-(C1-C6)-alkyl-CO, (C1-C10)-alkoxy-carbonyl, R4O-CO, R4-(C1-C6)-alkoxy-CO or a radical of the general formula III

(III) R6 is (C1-C10)-alkyl, (C2-C10)-alkenyl, R4 or R4-(C1-C6) -alkyl;

R7 and R8 independently of one another have the meanings specified for R5 or are (C1-C6)-alkylsulphonyl or R4-S(O)2 or R7 and R8, together with the nitrogen atom to which they are bonded, form a radical of the general formula IV

(IV) which can be substituted on the CH2 groups by one or more identical or different R10 radicals and wherein r and s independently of one another are the numbers 1, 2, 3 or 4, but the sum of r + s is smaller than 6;

R7' and R8' independently of R7 and R8 have the meanings specified for R7 and R8;

R9 has one of the meanings of R5, but is not the radical of the general formula III;

R10 is (C1-C6)-alkyl, (C3-C7)-cycloalkyl, the radical of a 5- to 7-membered heterocycle having one to three identical or different heteroatoms from the series nitrogen, oxygen and sulphur, which can be aromatic, partly saturated or completely saturated, R4, halogen, OR5, SR5', S(O)p-R6, where p is 1 or 2, NR7R8, the hydrox-imino group, the oxo group, cyano, nitro, COOR9, CONR7'R8' or P(O)(OH)2;

the radicals R11, R12 and R13 independently of one another are hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, R4, (C1-C6)- alkanoyl, (C1-C6)-alkyl-S(O)2 or R4-S(O)2;

R14 is (C1-C4) -alkyl, benzyl, phenyl, (C1- C6) -alkanoyl, (C1-C6) -alkyl-S(O)2 or R4-S(O)2;

A is a methylene group which can be substituted by one or two identical or different R10 radicals, or is oxygen, sulphur or NR14;

X is CR20R21 and R20 and R21 independently of the meanings of the radicals R1 and R2 have the meanings specified for R1 and R2;

Y is CR22R23 and R22 and R23 independently of the meanings of the radicals R1 and R2 have the meanings specified for R1 and R2;

Z is CR24R25 and R24 and R25 independently of the meanings of the radicals R1 and R2 have the meanings specified for R1 and R2;

where radicals of the groups W, X, Y and Z can also be linked via a bond such that a bicyclic system or tricyclic system is formed;

a tautomeric form thereof or a pharmaceutically acceptable salt thereof, but where, a) if R20 and R21 are hydrogen, a1) R1, R2, R22, R23, R24 and R25 cannot be hydrogen simulta-neously;
a2) R22, R24 and R25 cannot be hydrogen, R23 cannot be the carboxyl group and R1 and R2 together cannot be =O simul-taneously;
a3) R22, R23 and R24 cannot be hydrogen, R25 cannot be bromomethyl and R1 and R2 together cannot be =O simulta-neously;
a4) R1, R2, R24 and R25 cannot be hydrogen and R22 and R23 together cannot be =O simultaneously;
a5) R1 cannot be hydrogen and R2 cannot be butyl and R22, R23, R24 and R25, together with the two carbon atoms to which they are bonded, cannot form a 2-oxo-1,2-dihydroquinoline-3,4-diyl radical simultaneously;

b) if R20, R21, R22 and R23, together with the two carbon atoms to which they are bonded, form a 1,2-phenylene radical or a 4-chloro-1,2-phenylene radical, b1) R1, R2 and R24 cannot be hydrogen and R25 cannot be phenyl simultaneously;
b2) R1, R24 and R25 cannot be hydrogen and R2 cannot be phenyl simultaneously;
b3) R1 and R2 together cannot be =O and R24 and R25 together cannot be =O simultaneously.

12. A pharmaceutical composition comprising a pharma-ceutically effective amount of a compound according to claim 1 or 2 together with a pharmaceutically acceptable excipient or additive.

13. A pharmaceutical composition comprising a pharma-ceutically effective amount of a compound according to claim 11 together with a pharmaceutically acceptable excipient or additive.

14. Use of a compound according to claim 11 for prevention or treatment of a disease caused by an increased nitric oxide level.

15. A commercial package comprising a pharmaceutically effective amount of a compound according to claim 1 or 2 together with instructions for use thereof in prevention or treatment of a disease caused by an increased nitric oxide level.

16. A commercial package comprising a pharmaceutically effective amount of a compound according to claim 11 together with instructions for use thereof in prevention or treatment of a disease caused by an increased nitric oxide level.