DE3324771A1 - HETEROCYCLIC COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

- 7 description

The invention relates to new heterocyclic derivatives having an effect on histamine receptors. The invention also relates to Process for the preparation of these heterocyclic derivatives, pharmaceuticals containing the named derivatives, and the use of these derivatives in therapy.

It has now been found that certain heterocyclic derivatives have potent activity as H ^ antagonists. These compounds, which are described in more detail below, show, for example, an inhibition of gastric acid secretion when this is stimulated via histamine receptors (Ash and Schild, Brit. J. Pharmacol. Chemother, 1966, 27 , 427). The ability of the compounds to inhibit can be demonstrated in the perfused rat stomach by the method according to GBPS 1,565,966. The method is modified by using sodium pentobarbitone (50 mg / kg) as an anesthetic instead of urethane. The ability of the compounds can also be demonstrated in conscious dogs equipped with Heidenhain pouches using the methods described by Black et al., Nature 1972, 236 , 385. The compounds further antagonize the effect of histamine on the frequency of contraction of the isolated right atrium of the guinea pig.

Compounds with a histamine H ~ blocking activity can Used in the treatment of conditions where it is beneficial to lower stomach acid, especially in gastric and peptic ulcers. You can continue to use prophylaxis during surgery and treatment of allergic and inflammatory conditions known to be caused by histamine be evoked. For example, they can be used either alone or in combination with other active ingredients in treatment used by allergic and inflammatory conditions of the skin.

The invention relates to compounds of the general formula (I):

NR ₃ R ₄

R ₁ R ₂ NAIkQO (CH ₂ ) _n CH (CH ₂ ) _m NH-US (O) (D.

^No.

in which R _{1 represents} hydrogen, C .... -alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl, heteroaralkyl or alkyl which is substituted by cycloalkyl, hydroxy, alkoxy, amino, alkylamino or dialkylamino, and R _{2 represents} Is hydrogen or a C ₁ , alkyl group or R 1 and R ₂ together with the nitrogen atom to which they are attached form a 5- to 10-membered ring which can be saturated or which can contain at least one double bond which is unsubstituted or which can be substituted by one or more C.-j-alkyl groups, for example methyl, or a hydroxyl group and / or which can contain a further heteroatom, namely oxygen or sulfur, Alk for a straight-chain or branched alkylene chain with 1 to 3 carbon atoms, Q stands for a benzene ring, which has been incorporated into the remainder of the molecule by bonds in 1- and 3- or 1- and 4-positions, Rj. Stands for hydrogen or acyl, η and m, which are the same or verse can be different, in each case mean 1 or 2, R- stands for hydrogen or alkyl, R. for hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, pyridyl, aralkyl, heteroaralkyl or alkyl, which is represented by hydroxy, C. ^ - Alkoxy, amino, C. _ ₃ -alkylamino or C _1-3 -dialkylamino is substituted, or R., and R. together with the nitrogen atom to which they are attached form a 5- to 7-membered ring, the may contain a further heteroatom, for example oxygen, and r is an integer, namely 1 or 2, as well as the physiologically acceptable salts, solvates and hydrates thereof.

The term "alkyl" as used herein for a group or part of a group means that said group is straight-chain or branched. Unless stated otherwise, it has 1 to 6 carbon atoms and in particular 1 to 4 carbon atoms, such as, for example, methyl or ethyl. The terms "alkenyl" and "alkynyl" mean that the groups contain 3 to 6 carbon atoms. The term "cycloalkyl" means that the group has 3 to 8 carbon atoms. The term "aryl" for part of a group, when used for the group R _1, preferably means phenyl or substituted phenyl, such as, for example, phenyl, which is substituted by one or more C ₁ -alkyl or -alkoxy groups or halogen atoms, for example fluorine is. The term "aryl" as part of a group, when applied to the group R, preferably means phenyl. The term "acyl" means an aroyl, for example benzoyl, aralkanoyl, such as phenylacetyl, or C, _g -alkanoyl group, for example an acetyl group. The term “heteroaryl” as part of a group, when applied to the group R _{1, means} a 5- or 6-membered monocyclic ring which contains 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. Examples of these are the groups thienyl, pyrrolyl, pyridyl, furyl or thiazolyl, which can optionally be substituted by C 1, - alkyl, C 1, - alkoxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or halogen. The term “heteroaryl” as part of a group, when applied to the group R, preferably means pyridyl, furyl or imidazolyl. The alkyl portion of a heteroaralkyl group is a straight or branched C, _ ₄ alkyl chain and the heteroaryl ring is linked to the alkyl portion 0 through a carbon atom.

Preferred compounds of the formula (I) are those in which R _{1 is} Cg-alkyl (for example methyl, propyl, butyl or heptyl), C, -alkyl which is substituted by a trifluoromethyl group (for example 2,2,2-trifluoroethyl ), C ₂ _ ₄ alkyl, which --alkylaminogruppe by a hydroxy group or a di-C ₁ is substituted (eg 3-hydroxypropyl or Dimethy1aminoethy1), Cc _-7

- IU ~

alkyl (eg cyclohexyl), C ₃ _ ₅ ~ alkenyl (such as allyl), alkyl (eg benzyl) or a heteroaryl c._ ₃ alkyl group, wherein the heteroaryl ring contains one heteroatom (for example, 2-furylmethyl), R ^ stands for hydrogen or methyl or R ₁ R "N stands for a 5- to 7-membered ring, which optionally has a double bond, an oxygen atom or an alkyl (eg methyl) substituent (eg piperidino, morpholino, 4-methylpiperidino , Pyrrolidino, hexamethyleneimino or tetrahydropyridino), Alk stands for methylene, Q stands for a benzene ring which has been incorporated into the rest of the molecule through bonds in the 1- and 3-positions, R-. is hydrogen, R ₄ is hydrogen, C, _g alkyl, alkenyl, alkynyl, phenyl, phen-C, alkyl., _pyridyl-3 c._ alkyl (furyl-C | _ ₃ -alkyl or imidazolyl-C . _ ₃ ~ alkyl) or C ^^ - alkyl which _{is substituted by hydroxy or C 1} , -alkoxy, Rj stands for hydrogen or alkanoyl and the sum of η and m is 2 or 3.

More preferably, R _- -RN stands for di-C ₁ _-- alkylamino (for example dimethylamino), furylmethylamino or a 5- to 7-membered ring, such as piperidino or hexamethyleneimino, R. stands for hydrogen, R. stands for is hydrogen, C ... alkyl (eg methyl or n-propyl), C ₃ _ _g alkynyl (for example, 2-propynyl), phenyl, pyridyl-C ₁ _ ₃ ~ alkyl (eg 3-pyridylmethyl), furyl-Cj ^ alkyl (for example, 2-furylmethyl), or C ₂ _ ₄ alkyl, which is substituted by hydroxy or C _1-3 alkoxy (for example, 2-hydroxyethyl or 2-methoxyethyl), and R ₅ is hydrogen or alkanoyl (eg Acetyl).

A particularly preferred group of compounds are compounds of the formula (IA):

in which R ₁ R “N stands for dimethylamino or a 5-, 6- or 7-membered ring (for example piperidino or hexamethyleneimines), the sum of η and m is 2 or 3, r has the value 1 or 2, R ₅ represents hydrogen or acetyl and R. hydrogen / C _1, alkyl (for example methyl or n-propyl), propynyl, pyridylmethyl (eg 3-Pyridy! methyl), hydroxy-C ₂ _ ₄ ~ alkyl (for example hydroxyethyl), or C ₁ ^ -AIkOXy-C-. -Alkyl (eg methoxyethyl) and the physiologically acceptable salts, solvates and hydrates thereof.

Particularly preferred compounds are:

1-JJ4-Amino-1,2,5-thiadiazol-3-yl) ~ amino3-3- [3- (1-piperidinylmethyl) -phenoxyJ-2-propanol-S, S-dioxide, 1- £. (4 -Amino-1,2,5-thiadiazol-3-yl) -aminoJ-3-n3- (1-piperidinylmethyl) -phenoxyJ-2-propanol-S-oxide, 1-^ - (methylamino) -1,2 , 5-thiadiazol-3-ylJ-aminoJ-3 -) _ 3- (1-piperidinylmethy 1) -phenoxyJ-2-propanol-S-oxide, ¹ ~ IL ⁴ ~ (methylamino) -1 ₇ 2,5-thiadiazole- 3-ylI-aminq] -3- [3- (1-piperidinylmethyl) -phenoxyj-2-propanol-S, S-dioxide, 1- £ 3- (1-piperidinylmethyl) -phenoxyj-3- [£ 4- (propylamino ) -1,2,5-thia-diazol-3-ylj-amino-2-propanol-S, S-dioxide, 1- £ (4-amino-1,2,5-thiadiazol-3-yl) -aminoj -4- | 23- (1-piperidinylmethy 1) -phenoxy ^] -2-butanol-S, S-dioxide, 1- [^ 3- (1-piperidinylmethy 1) -phenoxyj-3- £ [_4- [^ (3-pyridinylmethy 1) -aminoJ-1, 2,5-thiadiazol-3-yl3-amino-2-propanol-S, S-dioxide, 1-LL4 - [_ (2-methoxyethyl) -aminoj -1 # 2,5-thiadiazol-S-ylJ-aminoJ-S-Qs- (1-piper idinylmethy 1) -phenoxyj-2-propanol-S / S-dioxide, 1-) (4-amino-1,2, 5-thiadiazol-3-yl) aminoj -3- [3- (1-dimethylaminomethyl 1) -phenoxyj-2-propanol-S / S-dioxide / 1-j ^ (4-Amino-1,2,5-thiadiazol-3-yl) -aminqJ-3- [3 ~ (1-piperidinylmethy1) -phenoxy ^ -2-propanol-S, S. -dioxide, acetate (ester) and 1- {j4-amino-1, 2 / S-thiadiazol-3-yl) -aminoj-3- £ .3-Γ (hexahydro-1H-azepin-1-yl) -methyIj -phenoxyj -2-propanol-S, S-dioxide and the physiologically acceptable salts thereof.

The invention includes the compounds of formula (I) in the form of the physiologically acceptable salts with inorganic and organic acids. Particularly suitable salts are e.g. the hydrochlorides, hydrobromides, sulfates, methanesulfonates ...

Acetates, Maleates, Succinates, Citrates, Tartrates, and Fumarates Benzoates. The compounds of the formula (I) and their salts can also form hydrates. The hydrates of the compounds de] Formula (I) are considered part of the invention. The compounds of formula (I) can show tautomerism, and the Formulas are intended to include all tautomers. If optical isomers exist, then the formulas are intended to include all diastereoisomers and optical enantiomers and mixtures thereof. It will point out indicated that the invention also includes the bioprecursors of the compounds of formula (I). Under the name "Biovorläufer" compounds are to be understood which have a different formula, such as the compounds of the formula (I), which, however, after administration to the animal or man, is converted in the body to a compound of the formula (I) will.

The compounds of formula (I), preferably in the form of a salt / can be administered in any desired manner be mulated. The invention therefore also comprises medicaments which contain at least one compound according to claim 1 and which are adapted for use in human or veterinary medicine. Such drugs can conventionally under Use of pharmaceutically acceptable carriers or excipients. Such medicines can also, if necessary, other active ingredients, e.g. H .. antagonists, contain.

The compounds of formula (I) can therefore be used for oral, buccal, topical, parenteral or rectal administration be formulated. Oral administration is preferred.

For oral administration, the drug can be in the form of, for example, tablets, capsules, powders, solutions, syrups or have suspensions. These shapes can be made in a conventional manner with acceptable excipients. For buccal administration, the drug can be in the form of tablets or lozenges, which in conventional Wise formulated.

The compounds of formula (I) can be used for parenteral administration be formulated by bolus injection or continuous infusion. Formulations for injection can be found in Unit dose form can be presented in ampoules or multi-dose containers with the addition of a preservative. the Medicaments can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles. You can also use formulation auxiliaries such as suspension, Stabilizing or dispersing agents included. Alternatively the active ingredient can be in powder form for reconstitution with a soluble vehicle, e.g., sterile, pyrogen-free water, before use.

The compounds (I) according to the invention can also be used in rectal Forms such as suppositories or retention enemas containing, for example, conventional suppository bases such as cocoa butter or other glycerides can.

For topical application, the compounds of the formula (I) be formulated in the form of ointments, creams, gels, lotions, powders or sprays in a conventional manner.

For internal administration, a suitable daily dose regimen of the compounds according to the invention is 1 to 4 doses to a total amount of 5 mg to 1.5 g / day, preferably 5 to 500 mg / day, depending on the patient's condition depends.

In the methods given below for the preparation of the compounds of the formula (I), it may be necessary at certain reaction stages to protect various reactive substituents in the starting materials for a certain reaction and then to remove the protective group. Such protection and the subsequent removal of the protective group can be particularly relevant when R ₁ and / or R "in are used to prepare the compounds of the formula (I)

■ - · "" CV J 4 * -_

Intermediate products are hydrogen atoms. Standard protection and Spin-off methods can be used. For example, an amino group can be protected by the formation of a phthalimide, which is then treated with a hydrazine, e.g. hydrazine hydrate, or a primary amine such as methylamine can be.

In the description below of the processes used to prepare the compounds of formula (I) or intermediates suitable for their preparation, R. through R have ₅ , Alk, Q, n, m and r, if nothing otherwise stated, the definition given in connection with the formula (I).

Compounds of the formula (I) in which R ₁ . stands for hydrogen can be prepared by using a diamine of the formula (II):

? ^R 5
R ₁ R ₉ NAIkQO (CH ₉ ) CH (CH ₉ ) NH ₉ (II)

with a compound of the formula (III): R ⁶ ρ

(III) (0) _r

where R _{fi is} the group -NR_R. or is a group which can be converted into this group and P represents a group which can be split off, such as alkoxy, for example methoxy or ethoxy, or alkylthio, for example methylthio.
35

In one embodiment of this method, the diamine (II) with a compound of the formula (III) in which R, - the

Group -NR R. is to be implemented. The reaction may be an alkanol such as methanol in the absence or presence of a suitable solvent, for example, at a temperature of 0 to 100 ⁰ C, preferably at room temperature, are performed. 5

Alternatively, the diamine (II) can be treated with a compound of the formula (III) in which R _{g is} a group which can be converted into the group -NR ₃ R ₄ , for example a removable group such as alkoxy (e.g. methoxy or ethoxy), phenoxy or alkylthio (e.g. Methylthio), in particular methoxy, is, in the presence of a solvent, for example methanol or tetrahydrofuran, at a temperature in the range from -80 to +50 ⁰ C, preferably -5 to +30 ⁰ C, are implemented, whereupon the subsequent conversion of the cleavable group Rg joins the group -NR ₃ R ₄ . This may be by reaction with the appropriate amine R ₃ R ₄ NH in the absence or presence of a suitable solvent, for example an alkanol, such as methanol, are achieved at a temperature of 0 to 100 ⁰ C, preferably at room temperature.

Compounds of the formula (I) in which R _{5 represents} acyl can be prepared by adding a compound of the formula (IV):

R ⁶ OH> = - N

R ^ NAlkCOiCH ^ CHfCH ^ NH- ^ v ^ S (O) ₁ (IV)

where R, - is the group -NR R. or a group which can be converted into this group, treated with an acid corresponding to the acyl group R_ or an activated derivative thereof (e.g. an acid anhydride or acid chloride) and, if R, one in the group -NR_R- convertible group that converts group R _fi to group -NR ₃ R ₄ . The reaction with an acid can at a temperature of 50 ⁰ C to the reflux temperature of the acid is carried out. The reaction with the activated derivative of an acid can be carried out at a temperature of -10 to

+ 10O ⁰ C, optionally in the presence of a solvent (for example pyridine, tetrahydrofuran, acetone or dimethylformamide) and optionally in the presence of a base (for example pyridine, triethylamine or an alkali metal carbonate, such as potassium carbonate). If one of the groups or both groups R 1 and R is or are hydrogen or R contains a hydroxy or NH group, then it can be advantageous to carry out the above acylation reaction with a compound of the formula (IV) in which R _g a group convertible into the group NR ₃ R ₄ group, for example, a methoxy group, to carry out and that, the subsequent conversion of the group R in NR ^ R., as described above, to connect.

Compounds of the formula (I) in which Alk is CH ₂ and 15R ₁ - is hydrogen can be prepared by using an aldehyde of the formula (V):

NR ₃ R ₄

° ^R 5 j \

OHC-QO (CH ₉ KCH (CH ₉ ) NH-C S (O) (V)

with an amine R ₁ R ₉ NH in a solvent such as tetrahydrofuran or an alkanol, for example ethanol, and then a reduction, for example using a hydride reducing agent such as an alkali or alkaline earth metal borohydride / for example sodium borohydride or lithium aluminum hydride or hydrogen and a noble metal catalyst such as palladium or platinum. The reactions can be carried out at a temperature of 0 to 30 ⁰ C. With this method, the group NR_.R. in certain cases (especially when both groups R ₃ and R _{4 are} hydrogen) are converted to another meaning within the definition of NR ₃ R ₄ .

The intermediates of the formula (V) can be prepared from compounds

of formula (VI):

OR ₅

WQO (CH ₂ ) _n CH (CH ₂ J _n NH ₂ (VI)

in which W stands for a protected aldehyde group, e.g. a cyclic acetal group, e.g. an ethylene ace-.al group, after Methods can be prepared analogous to those used in connection with the preparation of compounds of the formula (I) from the amine of the formula (II) were described,

Diamines of the formula (II) and intermediates of the formula (VI) can according to the methods as described in the published European patent application with the publication no. 0071434 are described, or by analogous methods getting produced.

Intermediate products of the formula (III) are either known compounds or they can be prepared by methods analogous to the methods disclosed in US Pat European patent application with publication no. 0040696 are described.

If the product of one of the above processes is a free base or an acid addition salt, especially a physiological one acceptable salt, is required, then the salt can be formed in a conventional manner. For example, there is a generally applicable method of salt formation in it, appropriate amounts of the free base and acid in in a suitable solvent, for example an alcohol such as ethanol or an ester such as ethyl acetate. The transformation also includes the internal conversion of a salt of the compound of formula (I) to another salt.

The invention is illustrated in the examples.

In the following examples and preparation examples, the temperatures are given in ⁰ C and the following abbreviations are used:

Compound A: 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide, Compound B: 3,4-dimethoxy-i, 2,5-thiadiazole-i-oxide, Compound C: I-Amino-S-Jls- (1-piperidinylmethyl) -phenoxyJ-2-

propanol

Compound D: 1-Amino-3- [3- (1,3-dioxolan-2-yl) -phenoxy! -2-propanol.

X values are used in the NMR spectra.

In the absence of any information to the contrary, silica gel was used for the column chromatography Merck silica gel 60 (7734) under Ver Use one of the following solvent systems:

System A: methanol: 0.88 ammonia (200: 1)

System B: dichloromethane: ethanol: 0.88 ammonia (10: 8: 1

System C: dichloromethane: ethanol: 0.88 ammonia (25: 8: 1

System D: dichloromethane: ethanol: 0.88 ammonia (50: 8: 1

System E: dichloromethane: ethanol: 0.88 ammonia (100: 8: '

Preparative high-performance liquid chromatography (HPLC) was performed using a DuPont-Zorbax-Sil 21.22mmx25cm column carried out.

Production example 1

2- [3-D- (1,3-dioxolan-2-yl) -phenoxyJ-2-hydroxypropy3j-1H-isoindole-1,3 (2H) -dione

A mixture of 2- (oxiranylmethyl) -1H-isoindole-1,3 (2H) -dione (60.96 g) and 3- (1,3-dioxolan-2-yl) phenol (49.0 g) in xylene (300 ml) was heated to 140 ° under nitrogen for 24 h. Sodium hydride (0.5 g) was added and the mixture became heated to 140 ° for a further 2 h. The mixture was cooled and

■ .. ■ -.Τ Τ9.- ■ = ■ '- ■' -

evaporated and the residue was dissolved in chloroform, washed with 2N sodium hydroxide solution, dried and evaporated to give the title compound (61 g) as a white solid, m.p. 114-116 °.

Production example 2

1-Amino-3-L3- (1,3-dioxolan-2-yl) -phenoxyJ-2-propanol

2- [j3 - [_ 3- (1,3-Dioxolan-2-yl) -phenoxy] -2-hydroxypropyl] -1 H -isoindole-1,3 (2H) -dione (45 g) was dissolved in tetrahydrofuran (500 ml) and hydrazine hydrate (25 ml) at room temperature Stir for 72 hours. The resulting precipitate was removed by filtration and washed with diethyl ether. The FiI-kicks and the wash waters were combined and evaporated to give a white solid (22 g) which was continuous was extracted with hot diethyl ether. When the ether solution cooled, white crystals formed which were filtered off and dried to give the title compound (14 g) as a white solid, m.p. 58-63 ° became.

Preparation Example 3 3-Amino-4-methoxy-1,2,5-thiadiazole-i, 1-dioxide

Hexamethyldisilazane (0.41 g) was added dropwise to a stirred Solution of compound A (0.51 g) in dry dichloromethane (2.5 ml) given from room temperature. The reaction mixture was stirred and used for 24 hours chromatographed from 4% methanol / dichloromethane. In this way the title compound (0.19 g) was obtained as a white solid / M.p. 167-171 °.

Production example 4

4-methoxy-N, N-dimethyl-1,2,5-thiadiazol-3-amine-1,1- dioxide

A solution of dimethylamine (0.70 g) in dry methanol (25 ml) was added dropwise to a stirred suspension of Compound A (2/79 g) in dry room temperature methanol (25 ml) given, whereby a colorless solution was obtained. The reaction mixture was stirred for 2 hours and filtered, to give the title compound (2.10 g) as a white solid, Mp 133-136 °.

example 1
10

1- L (4-Amino-1,2,5-thiadiazol-3-yl) -amino -3-L3- (1-piperidinylmethyl) -phenoxyJ-2-propanol-S _/ S-dioxide hydrate

A solution of compound C (1.06 g) in methanol (25 ml) was added dropwise to a stirred suspension of the compound A (0.71 g) was added to methanol (20 ml) and the mixture was stirred at 0-5 ° for 2 h. Anhydrous ammonia was added to the Solution bubbled in for 10 min and the mixture was allowed to stir for 17 h Stirred at ambient temperature. The solution was evaporated to give a white foam which could be made using of System A was chromatographed to give a gum. This material was created using the System B chromatographed, whereby the title compound (0.38 g) as a light yellow foam, mp about 100 ° (softening) obtained became.

NMR (CDCl ₃ + d ⁴ MeOH) 2.73 to 3.33, m (4H), 5.80, m (1H), 5.95, m (2H), c6.30, m (4H), c7 , 30, m (4H), c8.40, m (6H).

Example2

a) 1-LC4- (methylamino) -1, 2, 5-thiadiazol-3-ylJ-ainineQ3-3-

L3- (1-piperidiny! Methyl) -phenoxyJ-2-propanol-S, S-dioxide

A solution of compound C (1.2 g) in methanol (25 ml) was added dropwise to a stirred suspension of the compound A (0.80 g) was placed in methanol (20 ml) and the mixture became

Stirred for 30 min at room temperature. Methylamine anhydrous was bubbled into the solution for 15 minutes and the mixture was stirred at ambient temperature for 1 hour. The solution was evaporated to give a yellow foam which was chromatographed using System C became. In this way the title compound (1/27 g) was obtained as a white foam, m.p. 85-95 ° (softening), 146 to 148 ° (flow).

NMR (C ₅ D ₅ N) 2.71, t (1H), 2.88 to 3.14, m (3H), 5.46, m (1H), 5.84, d (2H), 5, 94 to 6.20, ABX (2H), 6.48, s (2H), 7.08, s (3H), 7.64, m (4H), 8.50, m (4H), 8.65 , m (2H).

b) In a similar manner, this procedure turned Compound C (1.2 g), Compound A (0.8 g) and n-propylamine (0.36 g) with the exception that the crude product was chromatographed with system D, the compound 1 - [_ 3- (1 -Piperidiny! Methyl) -phenoxyJ-3-LL4- (propylamino) -1,2, 5-thiadiazol-3-yl] -amino3-2-propanol-S, S-dioxide (1.50 g) as a cream-colored solid, mp 206 ° to 209 °.

Found: C 54.6 H 7.1 N 15.6 S7.2

theoretical values for

C ₃₀ H ₃₁ N ₅ O ₄ SC 54.9 H 7.1 N 16.0 S 7.3%.

c) In a similar way, this procedure was used to convert 4-amino-1 - [] 3- (1-piperidiny! methyl) -phenoxy-2-butanol (0.62 g), Compound A (0.4 g) and ammonia with the exception that the crude product was obtained twice using System C was chromatographed, the compound 4 - {_ (4-Amino-1, 2,5-thiadiazol-3-yl) -aminoj -1-1_3 - (1-piperidinylmethyl) -phenox £] 2-butanol-S, S-dioxide (0.30 g) as a white foam, m.p. 88-94 °.

NMR (d ⁶ -DMSO) 2.70 to 3.20, m (4H), 6.00 to 6.15, m (3H), 6.40 to 6.65, m (4H), 7.60 to 7.75, m (4H), 8.00 to 8.30, m (2H), 8.40 to 8.70, m (6H).

II ..--- · .- \ j \ j ί. -t ι ι i - 22 -

d) In a similar manner, this procedure was used to convert 1-amine-4-1 * 3- (1-piperidinylmethyl) -phenoxyJ-2-butanol (1.25 g), compound A (0.8 g) and ammonia with the exception of that the crude product was chromatographed using System C and by HPLC using Ethanol + 0.5% 0.880 ammonia, the compound 1 - £ (4-Amino-1,2,5-thiadiazol-3-yl) -aminoJ-4-j ^ 3- (1 -piperidinyl methyl) phenoxy] -2-butanol-S, S-dioxide (0.46 g) as a white solid, melting point approx. 163 ° (softening). 10

NMR (C ₅ D ₅ N) 2.70, t (1H), 2.84 to 3.14, m (3H), 5.55, m (1H) c5.75, m (2H), 6.08 to 6.33, ABX (2H), 6.55, s (2H), 7.63, m (4H), c7.98, m (2H), 8.48, m (4H), 8.64, m (2H).

e) Similarly, following this procedure, Compound C (1.2 g), Compound A (0.8 g) and 3-aminomethylpyridine (0.54 g) except that the crude product using the system C was chromatographed and was recrystallized from isopropanol, the compound 1- £ 3- (1-piperidinyl methyl!) phenoxy] -3 - [[^ 4- [(3-pyridinylmethyl) -aminoj-1,2, 5-thiadiazol -3-ylJ -aminoJ-2-propanol-S, S-dioxide (1.24 g) as a white solid, mp 164.5 ° to 167.5 °, was obtained.

Found: C 56.5 H 6.3 N 17.1 S 6.6

theoretical values for

C ₂₃ H ₃₀ N ₆ O ₄ SC 56.8 H 6.2 N 17.3 S 6.6%.

f) In a similar manner, after this procedure from the compound C (1.2 g), the compound A (0.8 g) and 2-Methoxyethylamine (0.38 g) with the exception that the crude product was chromatographed using System C and was crystallized from ethanol, the compound 1- ^ 4-Q2-methoxyethyl) -aminoj-1 , 2,5-thiadiazol-3-yl7-amino,] -3-j3- (1-piperidinylmethyl) -phenoxyJ-2-propanol-S, S-dioxide (1.24 g) as a white solid, m.p. 146-150 °.

Found: C 52.9 H 6.9 N 15.2 S 6.8

theoretical values for
C ₂₀ H ₃₁ N ₅ O ₅ S: C 53.0 H 6.5 N 15.4 S 7.1%.

g) In a similar manner, after this procedure from the compound C (1.2 g), the compound A (0.8 g) and Ethanolamine (0.30 g) with the exception that the crude product is chromatographed using System D and from isopropanol was recrystallized, the compound 1- ££ 4- [j2-Hydroxy ethyl) -amino] -1, 2, 5-thiadiazol-3-yll-amino3-3 - [_ 3- (1-piperidiny! methyl) -phenoxyJ-2-propanol-S, S-dioxide (1.04 g) was obtained as a white solid, m.p. 177-180 °.

Found: C 51.6 H 6.7 N 15.7 S 7.2

theoretical values for

C ₁₉ H ₂₉ N ₅ O ₅ S: C 51.9 H 6.7 N 15.9 S 7.3%.

h) In a similar manner, this procedure turned Compound C (1.2 g), Compound A (0.8 g) and 2-propyl-1-amine (0.37 g) with the exception that the crude product was chromatographed and screened using System C HPLC using chloroform: ethanol (3: 2) further purified the compound 1 - [_ 3- (1-piperidinylmethyl) phenoxyj-3-H [ji- (2-propynylamino) .- 1,2,5-thiadiazole -3-yl] - aminoJ-2-propanol-S, S-dioxide (0.68 g) as a white solid, m.p. approx. 90 ° (softening), 100 to 105 ° (melting).

NMR (C ₅ D ₅ N) 2.74 _# t (1H), 2.90 to 3.18, m (3H), 5.48, m (1H), 5.65, d (2H), 5, 86, d (2H), 5.96 to 6.23, ABX (2H), 6.59, s (2H), 6.80, t (1H), c7.65, m (4H), c8.50 , m (4H), c8.70, m (2H).

i) Similarly, following this procedure from the compound C (1.2 g), the compound A (0.8 g) and aniline (0.63 g) with the exception that the mixture after the addition of the Aniline was stirred for 2 days and the product chromatographed using System D and under HPLC Use of ethanol: chloroform (2: 1) + 0.5% 0.880 ammo

niak was further purified, the compound 1- [_ [_ 4- (phenylamino) -1,2, S-thiadiazol-S-ylJ-aminoJ-S-j_3- (1-piperidinylmethyl) -phenoxyJ-2-propanol-S, S-dioxide (0.59 g) as a white solid, m.p. 207-209 °.

Found: C 58.3 H 6.3 N 14.7 S 6.4

theoretical values for

C ₃₃ H ₂₉ N ₅ O ₄ S: C 58.6 H 6.2 N 14.8 S 6.8%.

Example3

1- [I (4-amino-1,2,5-thiadiazol-3-yl) -amino] -3-L3- (1-piperidinylmethyl) -phenoxyj-2-propanol-S-oxide

A solution of the compound C (1.2 g) in methanol (25 ml) was added dropwise to a stirred suspension of the compound B (0.8 g) in methanol (20 ml) and the solution became 1.5 ^{at 8 ° C} stirred for h. Anhydrous ammonia was bubbled into the solution for 10 minutes and the mixture was stirred at ambient temperature for 18 hours. The solution was evaporated to give a white foam which was chromatographed using System C. The resulting foam was precipitated from chloroform, whereby the title compound (0.60 g) was obtained as a light cream colored powder, mp about 100 ° (softening).

NMR (C ₅ D ₅ N) 2.71, t (1H), 2.85, br.s (1H), 2.94, dm (1H), 3.05, dm (1H), 5.28, m (1H), 5.74, d (2H), 5.85 to 6.07, ABX (2H) ₇ 6.50, m (2H), 7.60, m (4H), 8.48 to 8 , 65, m (6H). 30th

Example 4

1- ΕΓ4- (Methylamino) -1,2,5-thiadiazol-3-yLj-aminol-S-Cs- (1-piperidinylethyl) -phenoxyJ-2-propanol-S-oxide 35

A solution of compound C (1.2 g) in methanol (25 ml) was added dropwise to a stirred suspension of the compound

B (0.72 g) was added to methanol (20 ml) and the solution was stirred at room temperature for 30 minutes. Anhydrous methylamine was bubbled into the solution for 15 minutes and the mixture was stirred at ambient temperature for 1.5 hours. The solution was evaporated to give a white foam which was chromatographed using System C to give the title compound (0.96 g) as a white solid, m.p. 140-143 ° (124 ° softening).
10

Found: C 54.6 H 7.0 N 17.7 S 8.3

theoretical values for

C ₁ "Η ^ Ν, -Ο .-, S: C 54.9 H 6.9 N 17.8 S 8.2%.

Example .. 5

1-E (4-Amino-1,2,5-thiadiazol-3-yl) -amino] -3- Ϊ3- (1-dimethylaminomethyl) -phenoxy ^ -2-propanol-S, S-dioxide

A solution of 1-amino-3-jj3- (1-dime thy laminomethyl) -phenoxyj 2-propanol (0.38 g) in dry methanol (20 ml) was added dropwise to a stirred suspension of 3-amino-4-methoxy-1,2,5-thiadiazole-1,1-dioxide (0.28 g) in dry methanol (20 ml) and the reaction mixture was at room temperature Stirred for 1 hour. The solution was evaporated to give a yellow foam which was identified by HPLC using of ethanol: hexane (3: 1) + 0.5% 0.880 ammonia to give the title compound (0.32 g) as white Solid, m.p. 110-113 °, was obtained.

NMR (C ₅ D ₅ N) 2.70 to 3.15, m (4H), 5.40, m (1H), 5.82, d (2H), 5.90 'to 6.10, ABX ( 2H), 6.64, s (2H), 7.83, s (6H).

Example 6 35

1-Ep4- (dimethylamino) -I, 2,5-thiadiazol-3-ylI? -Amino3-3-L3- (1-piperidiny! Methyl) -phenoxyj-2-propanol-S, S-dioxide

; -. ο Ji.t / / I

'- 26 -

A solution of compound C (1.2 g) in methanol (25 ml) was added dropwise to a stirred suspension of 4-methoxy-N, N-dimethyl-1,2,5-thiadiazol-3-amine-1,1-dioxide (0.86 g) in methanol (20 ml) at room temperature. After 15 minutes, Krista! A white solid precipitated out of the solution. The reaction mixture was stirred for an additional hour and then filtered, to remove the title compound (1.27 g). This was a white solid, mp 144 ° to 147 °.

NMR (C ₅ D ₅ N) 2.65 to 3.10, m (4H), 5.18, m (1H), 5.74, d (2H), 5.94, d (1H), 6, 14, d (1H), 6.56, s (2H), 6.83, s (6H) ₇ 7.66, m (4H), 8.40 to 8.70, m (6H).

Example 7 15

1 ~ L (4-Amino-1 _/ 2,5-thiadiazol-3-yl) -aminoJ-S-LS- (1-piperidinylmethyl) -phenoxyJ-2-propanol-S, S-dioxide, acetate (ester)

1- £ (4-Amino-1,2,5-thiadiazol-3-yl) -aminoI-3- [3- (1-piperidinylmethyl) -phenoxyI-2-propanol-S, S-dioxide (1.5 g) in glacial acetic acid (35 ml) was refluxed for 72 hours. The solvent was removed in vacuo and the resulting dark oil was chromatographed using System D twice whereby the title compound (0.17 g) was obtained as a yellow foam, m.p. ca. 90 ° (softening).

NMR (C ₅ D ₅ N) 2.74, t (1H), 2.90 to 3.20, m (3H), 4.30, m (1H), 5.73, m (2H), 5, 93, ABX (2H), 6.60, s (2H), 7.69, m (4H), 8.00, s (3H), 8.40 to 8.80, m (6H).
30th

Example 8

a) 1- [j4-Amino-1,2,5-thiadiazol-3-yl) -aminoJ-3-L3- £ (hexahydro-1H-azepin-1 -yl) -methylj -phenoxyIl-2-propanol- S, S-dioxide

A solution of compound D (1.0 g) in methanol (25 ml)

"- 27 -

was added dropwise to a stirred suspension of Compound A (0.74 g) in methanol (20 ml) and the mixture was stirred at room temperature for 30 minutes. Anhydrous ammonia was bubbled into the solution for 10 minutes and the mixture was stirred at ambient temperature for 1 hour. The solution was evaporated / leaving a yellow Foam was obtained which was dissolved in ethanol (20 ml) and treated with 2N hydrochloric acid (4 ml). After 30 minutes Hexamethyleneimine (1.98 g) was added to the reaction mixture and stirring was continued for 2 hours. Sodium borohydride (0.5 g) was added portionwise to the reaction mixture, which was then stirred and cooked at room temperature overnight Addition of water was quenched. The crude product was extracted into ethyl acetate and concentrated, whereby a dark foam was obtained which was determined by chromatography using System C and by HPLC using from ethanol: chloroform (2: 1) + 0.5% 0.880 ammonia to give the title compound (60 mg) as white Foam, m.p. 90 ° (softening) was obtained.

NMR (C ₅ D ₅ N) 5.40, m (1H), 5.82, d (2H), 5.92 to 6.20, ABX (2H), 6.42, s (2H), 7, 45, m (4H) ₇ 8.48, m (8H).

b) In a similar manner, using this procedure, compound D (1.0 g), compound A (0.74 g), Ammonia and furfurylamine (2.20 g) with the exception that the crude product is chromatographed using System E. was, the compound 1-IJ3-L j ^ -Furanylmethy ^ -aminoJ-methyljphenoxyll-S-lIj ^ -l ^ -furanylmethyl) -aminoJ-1,2,5-thiadiazol-3-ylJ-aminoJ-2-propanol-S, S-dioxide (0.65 g) as a white solid, m.p. 150-153 °.

NMR (C ₅ D ₅ N) 2.42, d (1H), 2.66, d (1H), 2.75, t (1H), 2.93, m

(2H), 3.16, dd (1H), 3.56 to 3.80, 2xd + 2xdd (4H), 5.38, s

(2H), 5.52, m (1H), 5.91, d (2H), 6.00 to 6.25, ABX (2H), c6.16, 2xs (4H).

W * - "Τ II

mg / tablet , 0 20th , 5 178 , 5 1

- 28 examples of medicinal products

Tablets

Active ingredient

Microcrystalline Cellulose USP

Magnesium stearate BP

Compression weight 200.0

The active ingredient is sifted through a suitable sieve / mixed with the extenders and using punches compressed with a diameter of 7 mm.

Tablets of other strengths can be made by changing the compression weight and using appropriate punches used.

The tablets can be film-coated with suitable film-forming materials, such as hydroxypropylmethyl cellulose, using standard techniques will. Alternatively, the tablets can also be coated with sugar.

Injectable preparations for intravenous administration 25

% Weight / vol.

Active ingredient 0.2

Sodium Chloride BP as required

Water for injection BP to 100.00

Sodium chloride can be added to adjust the tonicity of the solution, and the pH can be acid or alkali be adjusted in order to obtain the optimal stability and / or to facilitate the dissolution of the active substance. Alternatively suitable buffer salts can be used.

The solution is made, clarified and in ampoules more suitable

Size filled and melted there. The injectable preparation is made using heating in an autoclave sterilized within an acceptable cycle. Alternatively, the solution can be sterilized by filtration and transferred to sterile ampoules filled under aseptic conditions. The solution can be made under an inert atmosphere of nitrogen or other suitable gases.

Claims (9)

PATENT LAWYERS AND APPROVED REPRESENTATIVES BEFORE THE EUROPEAN PATENT OFFICE DR. WALTER KRAUS D I PLO M C H EM IKER · D R.-IN G. AN N EKÄTE WEIS ERT DIPL-ING. SPECIALIZATION CHEMISTRY IRMGARDSTRASSE 15 ■ D-8OOO MUNICH 71 · TELEPHONE 0 8 9 / 797077-797078 · TELEX O5-212156 kpald TELEGRAM CRAUS PATENT 38 53 WK / rm GLAXO GROUP LIMITED London / England Heterocyclic compounds, processes for their preparation and pharmaceuticals containing these compounds Claims ^r 1 A heterocyclic compounds of the general formula (I): NR ₃ R ₄ R ₁ R ₂ NAIkQO (CH ₂ ) _n CH (CH ₂ ) _m NH - (^ / S (O) ₃ , (I) in which R- stands for hydrogen, C, ... -alkyl, cycloalkyl, alkenyl, Alkynyl, aralkyl, trifluoroalkyl, hoteroaralkyl or Alkyl which is substituted by cycloalkyl, hydroxy, alkoxy, amino, alkylamino or dialkylamino, and R _{2 is} hydrogen or a C 1-4 alkyl group, or R ₁ and R "together with the nitrogen atom to which they are attached, one 5- to 10-membered ring which can be saturated or which can contain at least one double bond, which can be unsubstituted or substituted by one or more C,., - alkyl groups or a hydroxyl group and / or which can be another heteroatom, namely oxygen or sulfur, Alk stands for a straight-chain or branched alkylene chain with 1 to 3 carbon atoms, Q stands for a benzene ring whose incorporation into the rest of the molecule through bonds in 1- and 3- or 1- and A- positions is done, R _n . represents hydrogen or acyl, η and m, which can be identical or different, each have the value 1 or 2, R ^ represents hydrogen or alkyl, R. represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, pyridyl, Aralkyl, heteroaralkyl or alkyl which is substituted by hydroxy, Cj _- J-AlkOXy, amino, C - ^ - alkylamino or C. -.- dialkylamino, or R-. and R. together with the nitrogen atom to which they are attached can form a 5- to 7-membered ring which can contain a further heteroatom, and r is an integer, namely 1 or 2, and the physiologically acceptable salts , Solvates and hydrates thereof. 2. Compounds according to claim 1 , characterized in that R _{1 represents} C ₁ "-alkyl, C.. -Alkyl which is substituted by a trifluoromethyl group, C ₂ _.- alkyl which is substituted by hydroxy or a di- C,, -. alkylamino group is substituted, C ₅ alkyl group _ ₇ cycloalkyl C -._ _7, .- alkenyl, phenyl-C, -.- alkyl or a heteroaryl-C-.-., wherein the heteroaryl ring contains one heteroatom , R _{2 is} hydrogen or methyl or R ₁ R ^ N is a 5- to 7-membered ring which optionally contains a double bond, an oxygen atom or an alkyl substituent, Alk is methylene, Q is a benzene ring, whose Einar- processing in the rest of the molecule is done through bonds in 1- and 3-positions, R_ stands for hydrogen, R. for hydrogen, C., -alkyl, alkenyl, alkynyl, phenyl, phen-C -.- alkyl, pyridyl- C, - alkyl, Fury 1-C,., - alkyl or Imida-ZoIyI-C ₁ _., - alkyl or C "_. -Alkyl, which is substituted by hydroxy or C - alkoxy, R - represents hydrogen or alkanoyl and the sum of η and m is 2 or 3. 3. Compounds according to claim 1, characterized in that R ₁ R ₉ N represents a di-C _1- . -Alkylamino group or furylmethylamino group or a 5- to 7-membered ring, R _{3 represents} hydrogen, R _{4 represents} Hydrogen, C, ₄ -alkyl, C ₃ _ ₆ ~ alkynyl, phenyl, pyridyl-C, --alkyl, furyl-C] _ ₃ -alkyl or C ₂ _ ₄ ~ alkyl, which is replaced by hydroxy or C _1-3 - AIkO-xy is substituted, and R, - is hydrogen or alkanoyl. 4. Heterocyclic compounds of the general formula (IA): in which R..R "N stands for dimethylamine or a 5-, 6- or 7-membered ring, the sum of η and m is 2 or 3, r has the value 1 or 2, R _n . stands for hydrogen or acetyl and R. for hydrogen, _{C.. -alkyl, propynyl, pyridylmethyl, hydroxy-C 2.} -alkyl or C _1-3 -AlkOXy-C _3- . -alkyl, as well as the physiologically acceptable salts, Solvates and hydrates thereof. 5. Compounds according to claim 1, namely compounds from of the group 1- £ (4-amino-1,2,5-thiadiazol-3-yl) -aminqJ-3- [J3- (1-piperidiny! methyl) -phenoxy ^ -2-propanol-S, S-dioxide , 1 - £ (4-Amino-1,2,5-thiadiazol-3-yl) -aminoJ-3- ^ 3- (1-piperidinylmethyl) phenoxyJ-2-propanol-S-oxide, 1-LL4- (methylamine) -1,2,5-thia- diazol-3-ylJ -aminoJ-3-j_3- (1-piperidinylmethyl) -phenoxyJ-2-propanol-S-oxide and 1- [J_4- (methylamino) -1, 2, 5-thiadiazol-3-ylJ-aminoJ-3 - {] _ 3- (1-piperidinylmethyl) -phenoxyJ-2-propanol-S, S-dioxide, and the physiologically acceptable salts thereof. 6. Compounds according to claim 1, namely compounds from the group 1-Γ.3- (1-piperidinylmethyl) -phenoxyJ-3- £ [jl- (propylamino) -1,2,5-thiadiazol-3-ylJ -amino- 2-propanol-S, S-dioxide, 1- [j4-amino-1,2,5-thiadiazol-3-yl) -amino] -4- [j3- (1-piperidinylmethyl) -phenoxyJ-2-butanol- S, S-dioxide, 1 - [^ 3- (1-piperidinylmethyl) -phenoKy2-3- [J_4 - \ ^ (3-pYr ± ainY imethyl) -amino-J-1, 2 ₇ 5-thiadiazole-3- yl] -amino-2-propanol-S, S-dioxide, 1-LQ "H (2- methoxyethyl) -amino] -1,2,5-thiadiazol-3-yl ~ j -amino_3-3 - [_ 3- (1-piper idiny lmethyl) -phenoxyJ-2-propanol-S, S-dioxide, 1- | _ {4-amino-1, 2, 5-thiadiazol-3-yl) -3- -aminoj | _3- ( 1 -dimethylaminomethyl) -phenoxy3-2-propanol-S, S-dioxide and 1- £ (4-amino-1, 2 _/ 5-thiadiazol-3-yl) -aminoj -3-j_3- (1 -piperidinylmethyl) - phenoxyJ-2-propanol-S, S-dioxide, acetate (ester), and the physiologically acceptable salts thereof. 7. 1 - £ (4-Amino-1,2,5-thiadiazol-3-yl) -aminoI-3 - [^ 3- £ (hexahydro-1H-azepin-1-yl) -methyl] -phenoxyI-2 -propanol-S, S-dioxide and the physiologically acceptable salts thereof. 8. Process for the preparation of the heterocyclic compounds (I) according to claim 1 , characterized in that one a) for the preparation of compounds in which R ₁ - is hydrogen / a diamine of the formula (II): ? ^R 5
R ₁ R ₂ NAlkQO (CH ₂ ) _n CH (CH ₂ ) _in NH ₂ (II) with a compound of the formula (III): ι A NN
\ wherein R, for the group -NR-R. or one in this group convertible group and P means a leaving or separable group, converts, b) for the preparation of compounds in which R ₅ for Acyl, a compound of formula (IV): 15 OH = )> _{ CH ₂ ) _mN HV ₍ ^X KT ^r in which R _{g stands} for the group -NR ₃ R ₄ or a group which can be converted into this group, with an acid corresponding to the acyl group Rj. or an activated derivative thereof, and if R _fi a group which can be converted into the group -NR R. Group is, the group R _g into the group -NR-R. converts or c) for the preparation of compounds in which Alk is CH ₂ and R _{5 is} hydrogen, an aldehyde of the formula (V): OHC-QO (CH ₂ ) _n CH (CH ₂ ) _m NH - (^ .S (0) _r (V) ^H treated with an amine R..R "NH in a solvent, then carries out a reduction and, if necessary converting the compound of formula (I) thus formed into a physiologically acceptable salt. 9. Medicament, characterized in that it contains at least one compound of the formula (I) according to any one of claims 1 to 7 together with at least one pharmaceutically acceptable carrier or diluent and optionally one or more other active ingredients.