NZ209707A

NZ209707A - Sulphenamide derivatives and pharmaceutical compositions

Info

Publication number: NZ209707A
Application number: NZ209707A
Authority: NZ
Inventors: H Schickaneder; R Herter; S Postius; P Morsdorf; I Szelenyi; K H Ahrens
Original assignee: Heumann Ludwig & Co Gmbh
Priority date: 1983-10-06
Filing date: 1984-09-28
Publication date: 1986-11-12
Also published as: GR80476B; PT79288A; DK451784D0; ES536305A0; YU168384A; AU3268284A; DE3336410A1; IL72855A0; EP0141119A3; JPS60100562A; ES8505996A1; KR850002974A; EP0141119A2; DK451784A; ZA846898B; HUT35667A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £09707 * . ■ » 209707 Priority Date(s): ,.. / P.". Complete Specification Filed: ss: Ciass: | Publication Date: p * .Journal, No: NO DRA r N.2. PATENT OFFICE 2 8 SEP 1984 i.-:c5I\- !) Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "SULFENAMIDE DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND MEDICAMENTS CONTAINING THESE COMPOUNDS" -I-, WE LUDWIG HEUMANN & CO.GMBH of Heideloffstr. 18-28, D-8500 Nurnberg, Germany, a Germany company hereby declare the invention, for which I/we pray that a patent may be granted to-ae-/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- 209707 2 - ~ DESCRIPTION 1 This invention relates to new sulfenamide derivatives having a strong selective effect on histamine-F^-receptors, to processes for their production and to medicaments containing these compounds and, finally, to the use of 5 these compounds for therapeutic purposes. Cimetidine and ranitidine have already been used in the treatment of ulcers. Unfortunately, both cimetidine and ranitidine have relatively short half lives. Because of this, tablets containing doses of from 160 to 300 mg 10 in a therapeutically establised form have to be admininstered several times a day. Accordingly, there is a need for anti-ulcer agents which are more active and/or remain active for a longer period than cimetidine and ranitidine. By virtue of their specific I^-antagonistic activity, 15 the compounds obtainable in accordance with the invention inhibit the secretion of gastric acid when it is stimulated by histamine agonists [Ash and Schild, "Brit. J. Pharmacol. Chemother", 27, 427 (1966) and Black et al., "Nature", 236, 385 (1971)]. The pharmacological 20 activity of these compounds, which will be described in more detail hereinafter, may be demonstrated by a modified method according to DE-OS No. 27 34 070 in perfused rats' stomachs or by determining the pA2-values in vitro using the auricle of guinea pigs (cvf. Ariens, 25 Molecular Pharmacology, Vol. 1, Academic Press, New York, 1964). In addition, the H2 antagonistic effect can be demonstrated on female Heidenhain-Pouch dogs using the method of black et al., "Nature", 236, 385 (1971). In addition, the new compounds antagonize the effect of 30 histamine on the frequency of contraction of the isolated right atrium of guinea pigs, but have no effect on histamine-induced contractions on the isolated, smooth gastrointestinal muscle where they are produced by - -'J' 0 vr- m . 209707 3 " * " 1 H^-agonists. Since inhibitors for histamine-F^-receptors have an inhibiting effect both in regard to basal gastric acid secretion and also in regard to the secretion of gastric acid induced by gastrin, histamine, 5 rnethacholine or food, they may be used in the treatment of peptic ulcers caused by the excessive secretion of gastric acid and also in the treatment of hyperacidic gastritis. The object of the present invention is to provide 10 new inhibitors for histamine-F^-receptors having an improved and/or longer lasting effect. This object is achieved by the invention. Accordingly, the present invention relates to new sulfenamide derivatives corresponding to the following 15 general formula ch3 c J "\NCH„ J^^-^J-0-CH2CH2CH2NH-(\r r1 / ^ I t I f /' 20 \—/ - <*> S-R in which R* is a hydrogen atom and 2 25 R is a linear or branched-chain C^-Cg-alkyl or C^-C^-cycloalkyl radical or an unsubstituted or mono- to trisubstituted aryl or heteroaryl radical or 1 2 R and R together form an isothiazole ring or iso-30 thiazolinone ring, and to physiologically compatible salts thereof. 1 2 In general formula I, R is a hydrogen atom. R is a linear or branched-chain C^-C^-alkyl radical, such as the methyl, ethyl, propyl, isopropyl, butyl, 35 isobutyl, n-pentyl, isopentyl, n-hexyl or isohexyl vr\{« 9 ^ - 209707 1 radical, or a Cg-Cg-cycloalkyl radical, such as the cyclopentyl or cyclohexyl radical. 2 In addition, R may represent an unsubstituted or mono- to trisubstituted aryl or heteroaryl radical. 5 Examples of the aryl radical are phenyl, naphthyl, phenanthryl, etc., phenyl being preferred. The aryl radical may be unsubstituted or mono- to tri-substituted, more particularly by halogen, such as chlorine and bromine lower alkyl, particularly methyl and ethyl, lower alkoxy, 10 trifluoromethyl and nitro. In the context of the invention, "lower alkyl" and "lower alkoxy" etc. groups are understood to be groups containing from 1 to 6 carbon atoms in the alkyl portion. One preferred group of compounds according to the 15 invention is characterized in that R^" is a hydrogen 2 atom and R is a methyl, ethyl, isopropyl or cyclohexyl radical. Another preferred group of compounds according to the invention is characterized in that R* is a hydrogen 2 atom and R is a substituted or polysubstituted aryl 20 radical. For example, the phenyl ring may be substituted by a linear or branched lower alkyl group, preferably a C^-C^-alkyl group, more particularly by a methyl group. The alkyl group may be attached in the ortho-, meta- or 25 para-position, preferably in the para-position. Another preferred substituent is the trifluoromethyl group which may be attached in the ortho-,meta- or para-position of the phenyl rinq. Further substituents on the phenyl ring are nitro 30 groups and halogen atoms, particularly chlorine atoms, which substituents may be attached independently of one another, for example in the ortho-,mPta- or para-position. In the case of the disubstitution, the ortho-, para-(2,4-position on the phenyl ring) and the ortho-, ortho-35 (2,6-position on the phenyl ring) positions are preferred. o 20 £ - X - 209707 1 In the case of the trisubstitution, preference is attributed for example to the 2,4,6-position of the phenyl ring. 2 In addition, R may represent an unsubstituted 5 or mono- to trisubstituted heteroaryl group. Examples of heteroaryl groups are pyridyl, pyrimidinyl, piperazinyl, thiazolyl, benzothiazoly1, imidazolyl and pyrazolyl, pyridyl, pyrimidinyl and benzothiazolyl being preferred. The heteroaryl groups may be unsubstituted or mono-10 to trisubstituted by the same groups as described above for aryl. A single lower alkyl substitution, particularly a C.-C.-substitution, is particularly suitable. 12 Finally, the substituents R and R may together form an isothiazoline ring or an isothiazolinone ring. 15 The compounds according to the invention are produced by a process which is characterized in that an amine corresponding to the following formula CH3 ^ io yNCH2-kvC>-0-CH2CH2CH2NH-\\ (II) nh2 is subjected in known manner to a base-catalyzed reaction 25 a) with a sulfenyl halide corresponding to the following general formula R2-S-Hal (III) 2 30 in which Hal is a chlorine or bromine atom and R is as defined above, and the compound obtained is optionally converted into a physiologically compatible salt, or 35 b) with a sulfenylic acid chloride corresponding to the * 209707 £ - a' - following formula @c -ci CI (IV) and the compound obtained is optionally converted into a physiologically compatible salt, 10 The amines corresponding to the general formula II are known compounds and are described, for example, in EP-OS 0 057 564. The same applies to the sulfenyl i""""; chloride derivatives which are described, for example, E. Kuhle, The Chemistry of Sulfenic Acids; Georg Thieme 15 verlag, 1973. The reaction is carried out in an inert solvent, such as ether, tetrahydrofuran or dioxane, preferably tetrahydrofuran, at a temperature in the range from 0°C to 10°C and preferably at 5°C. Tertiary amines, 20 such as dimethylbenzylamine, preferably pyridine, may be used as the base. The reaction product is worked up in known manner, for example by concentration of the reaction mixture, crystallization and/or purification by column chromatography. 25 The invention also covers physiologically compatible salts of the above-mentioned compounds. 0 These salts may be formed, for example, with mineral acids, such as hydrochloric acid, hydrobromic acid and hydriodic acid, phosphoric acid, metaphosphoric acid, 30 nitric acid or sulfuric acid, or with organic acids, such as formic acid, acetic acid, propionic acid, phenyl iacetic acid, tartaric acid, citric acid, fumaric acid, methane sulfonic acid, etc. The compounds according to the invention may be 35 formulated in any way for administration. Accordingly, 209707 1 - wf - 1 the invention also relates to medicaments containing at least one compound according to the invention for use in human or veterinary medicine. The medicaments according to the invention may be conventionally produced 5 using one or more pharmaceutically compatible carriers or diluents. Accordingly, the compounds according to the invention may be formulated for oral, buccal, topical, parenteral or rectal administration, oral administration being 10 preferred. For oral administration, the medicament may be present, for example, in the form of tablets, capsules, powders, solutions, syrups or suspensions which ) have been conventionally produced using acceptable dilutents. For buccal administration, the medicament 15 may assume the form of tablets or capsules which have been conventionally formulated. The compounds according to the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may 20 be present in unit dose form as ampoules in multiple-dose containers with added preservative. The medicaments may assume such forms as suspensions, solutions or emulsions in oily or aqueous carriers and may contain formulation aids, such as suspending agents, 25 stabilizers and/or dispersants. Alternatively, the active principle may even be present in powder form for reconstitution before use with a suitable carrier, for example sterile, pyrogen-free water. 30 The compounds according to the invention may also be formulated for rectal preparations, for example suppositories or retention enemas containing, for example, conventional suppository bases, such as cocoa butter or other glycerides. 35 For topical application, the compounds according to 209707 3 n - 1 the invention may be conventionally formulated as ointments, creams, gels, "lotions, powders or sprays. For oral administration, a suitable daily dose of compounds according to the invention is from 1 to 4 5 doses containing a total of up to 5 mg to 1 g per day and preferably 5 to 250 mg per day, depending on the condition of the patient. In individual cases, it may be necessary to vary the dosage in dependence upon the reaction of the individual to the active principle or 10 its formulation and upon the time at which or intervals at which it is administered. For example, there are cases where it will be sufficient to administer less than the minimum dose specified above, whereas in other cases the dose administered will have to exceed the 15 upper limit indicated. The compounds according to the invention are distinguished from recognized medicaments acting in the same direction by an improvement in the pharmacological activity levels. This is apparent from the results 20 of the comparative pharmacological studies reported hereinafter. A recognized method for measuring -antagonistic activity is based on determination of the pA2_values in vitro on the isolated right auricle of guinea pigs. 25 pA2~values Cimetidine: 6.31 comparison Ranitidine: 6.81 comparison Example 1: R.80 30 Other compounds corresponding to general formula I show similar pharmacological activity. EXAMPLE 1 Production of I-methy1-5-{3-[3-(1-piperidinylmethyl)-phenoxy]-propylamino]-3-(4-methylbenzene-sulfenamido)-35 1H-1,2,4-triazole f* w 209707 \* - 1 a) Production of 2-[3-[3-(1-piperidinylmethyl)-phenoxy]-propyl]-lH-isoindole-l,3-(2H)-dione 28.7 g (0.15 mole) of 3-(1-piperidinyl)-phenol dissolved in 25 ml of warm absolute ethanol are added 5 dropwise to a solution of 3.45 g (0.15 mole) of sodium in 25 ml of absolute ethanol, followed by stirring for 1 hour at room temperature. 40.2 g (0.15 mole) of C*^, N- ( 3-bromopropyl) -phthalimide are then added in portions to the reaction solution which is subsequently heated 10 for 6 hours to reflux temperature and then concentrated in vacuo. The residue is taken up in ethylacetate, repeatedly extracted with 1 N NaOH solution, washed i /! with water until neutral and dried over sodium sulfate. The orange-yellow oil which accumulates after concentration 15 is further reacted without purification. Yield: 45 g (79.3% of the theoretical) b) Production of 3-[3-(1-piperidinylmethyl)-phenoxy]-propylamine 45 g (0.118 mole) of 2-[3-1 3-(1-piperidinylmethyl)- 20 phenoxy]-propyl]-1,H-isoindole~l'3-(2H)-dione are dissolved in 300 ml of ethanol, 16 ml (0.33 mole) of an 80% aqueous solution of hydrazine hydrate are added with stirring to the resulting solution,*followed by heating under reflux for 1 hour. The solid precipitated is 25 filtered off, the filtrate is concentrated in vacuo, the residue is taken up in ethylacetate, washed with water until neutral and dried over sodium sulfate. After concentration of the organic phase, the oily residue is distilled in a high vacuum. 30 B-P-0.01= 125 ~ 15°Cc Yield: 19.4 g (66.3% of the theoretical). c) Production of N-cyano-N*-13-(3-(1-piperidinylmethyl)-phenoxy]-propyl]-0-phenylisourea 7.89 g (33.1 mMole) of N-cyanodiphenylimido-35 carbonate are added with stirring at room temperature to t 1 5 10 15 20 25 30 35 .X. A'' ■■ 209707 10 - 8.22 g (33.1 mMoles) of 3-[3-(1-piperidinylmethyl)-phenoxy]-propylamine, in 7Qnl of isopropanol, followed by heating fcr 45 mirs to 50°C. The reaction solution is concentrated in vacuo, the residue is dissolved in ethylacetate and precipitated with ether. Colorless crystals melting at 123 to 124°C. Rf = 0.70 (CH2C12 / MeOH 70 : 30) Yield: 11.0 g (85% of the theoretical) d) Production of 1-methyl-N^-[3-[3-(1-piperidinylmethyl)-phenoxy]-propyl]-lH-l,2,4-triazole-3,5-diamine 3.92 g (10 mMoles) of N''-cyano-N'-[3-(1-piperidinylmethyl )-phenoxy]-propyl-0-phenylisourea and 0.57 g (13 mMoles) of methyl hydrazine are heated for 9 hours to reflux temperature in 200 ml of isopropanol. After the reaction solution has cooled, the solvent is removed in vacuo and the residue is precipitated from ether. Colorless crystals melting at 93 to 94°C. Rf = 0.5 (CH3OH / conc. NH3 80 : 1) Yield: 1.79 g (52% of the theoretical) e) Production of l-methyl-5-[3-[3-(1-piperidinylmethyl)-phenoxy]-propylamino]-3-(4-methylbenzene-sulfenamido)-1H—1,2,4-triazole fol N-CB2J\X-° CH3 —0-CHOCH~CHONH-(\ 2 2 2 NH-S-< >-CH 3 2.4 g (7.0 mMoles) of 1-methyl-N^-[3-[3-(1-piperidinylmethyl )-phenoxy]-propyl]-lH-l,2,4-triazole-3,5-diamine are dissolved in 30 ml of absolute tetrahydrofuran in the absence of moisture and 0.8 ml (10.5 mMoles) of absolute pyridine are added to the resulting solution which is then cooled to 0°C and reacted dropwise with a solution of 1.17 g (7.4 mMoles) of p-tolyl sulfonyl * 2 097 07 H K " 10 chloride in 5 ml of absolute tetrahydrofuran. After a reaction time of 1 hour at room temperature, the reaction solution is poured into 100 ml of a saturated aqueous NaHCO^-solution and extracted 3 times with 100 ml of ethylacetate. The organic phase is washed with water until neutrnl, dried over sodium sulfate and the solvent concentrated in vacuo. The residue is purified by column chromatography (A1203 neutral; eluent ethylacetate) Yellowish crystals melting at 63 to 65°C. Rf = 0.40 (Al203 neutral / ethylacetate) Yield: 0.3 g (10% of the theoretical) C25H34N60S (467) Calc.: C 64.24 H 7.28 N 17.99 S 6.85 Found: C 63.73 H 7.17 N 17.53 S 6.73 o 15 H-NMR-spectrum (CDC13, TMS as internal standard) 20 25 EXAMPLE 2 6 = 1.33 - 1.80 1.85 - 2.15 (m)(-(CH^)3) 6 H, (m)(-(CH2-) 2 H, 2.27 (s)(Ar-CH3) 3 H, 2.33 - '2.60 (N(CH2)2-) 3.43 4.03 4.60 (s)(-N-(CH3) ) 3 4 H, H, 3.4 4 - 3.68 (m)(-CH2~)(N-CH2) (t)(-OCH2) 2 H, 4 H, (t) ( -NH ) (replaceable by D20) 1 H, 6.67 - 7.40 (m) (arcmatic-H) (-N-H-S-) (replaceable by D20)9 H ppn 1-methyl-5-[3-[3-(1-piperd dinyImethy])-phenoxy]-propyl-amino]-3-(2-nitrobenzene-sulfenamido)-lH-l,2,4-triazole 30 35 \ NCH CH-I 3 -G-CH_CHTCH_NH-< N 2 2 2 l_!/ NO, V NH-S \ ■i-r- — «> n • i 209707 IZ V> 10 15 This compound is produced as in Example 1 from 2.4 g (7.0 mMoles) of 1-methyl-N^-[3-[3-{1-piperidinylmethy1)-phenoxy]-propyl]-lH-l,2,4-triazole-3,5-diamine and 1.40 g (7.4 mMoles) of 2-nitrobenzene sulfenyl chloride. Yellowish crystals melting at 71 to 73°C. Rf = 0.35 (Alneutral/ethylacetate) Yield: 0.6 g (17.6% of the theoretical) Calc.: C 57.95 H 6.28 S 6.44 Found: C 57.79 H 6.49 S 6.69 C24H31N7°3S 14981 H-NMR-spectrum: (dg-DMSO, TMS as internal standard) 20 6 = 1.23 - 1.63 (m)(-(CH2)3-) 6 H, 1.80 - 2.12 (m)(-CH~-) 2 H, 2.20 - 2.43 (m)(N(CH2)2) 4 H, 3.30 (s)(N-CH3) 3 H, 3.40 (s, broad)(N-CH2)(-CH2-) 4 H, 4.00 (t)(-0-CH2) 2 H, 6.40 (t)(replaceable by D20) (-NH) 1 H, 6.70 - 7.90 (m)(aromatic-H) 7 H 8.20 (s )(replaceable by D20)(NH-S) 1 H, 8.30 (d)(aromatic-H) 1 H ppm. 25 EXAMPLE 3 1-methyl-5-[3-[3-(1-piperidinylmethyl)-phenoxy]-propyl-amino]-3-(2,4-dinitrobenzene-sulfenamido)-1H-1,2,4-triazole 30 \ / NCH2- CH. -0-CH2CH2CH2NH "m: NH-S 35 This compound is produced as in Example 1 from 2.4 g (7.0 mMoles) of 1-methyl-N^-[3-[3-(1-piperidinyl-methyl)-phenoxy]-propyl]-1H-1,2,4-triazole-3,5-diamine and 1.73 g (7.4 mMoles) of 2,4-dinitrobenzene sulfenyl - \ ■ l- ,~ m n - 2 O97 o 7 chloride. Yellowish crystals melting at 149 to 150°C Rf = 0.25 (A120^ neutral/ethylacetate) Yield: 2.55 g (67% of the theoretical) C24H30N8°5S (543 Calc.: C 53.12 H 5.57 N 20.65 S 5.91 Found: C 52.80 H 5.52 N 20.26 S 5.79 H-NMR-spectrum: (dg-DMSO, TMS as 10 internal standard) o = 1.2 3 15 20 1, 2, 3, 3, 3. 4, 6, 6, 83 20 13 33 43 00 47 67 7.23 7.83 8.47 8.57 8.93 - 1.67 (m)( (-CH2-)3) 6 H, - 2.13 (m)(-CH2-) 2 H, - 2.43 (m)(-(CH2)2-) 4 H, -3.50 (m)(N-CH2) 2 H, (s) (N-CH3) 3 H, (s)(N-CH2) 2 H, (t)(0-CH2) 2 H, (t)( N-H) (replaceable by D20) 1 H, - 6.93 (m) (aromatic-H) 3 H, (t)(aromatic-H) 1 Hr (d)(aromatic-H) 1 H, (s) (NH) (replaceable by 02O) (dd)(aromatic-H) 1 H, (d)(aromatic-H) 1 H ppm. 25 EXAMPLE 4 1-methyl-5-[3— £ 3 — (1-piperidinylmethyl)-phenoxy]-propylamino]-3-(4-chlorobenzene-sulfenamido)-1H-1,2,4-triazole 30 35 nci! CH. I -N -o-ch2cii2ch2nh-' ^ N X I N This compound is produced as in Example 1 from 2.4 g (7.0 mMoles) of 1 -methyl-N"'-[ 3-[ 3-(1 -piperidinylmethyl) -phenoxy]-propyl)-1H-1,2,4-triazole-3,5-diamine and 209707 "t yr - 1.32 g (7.4 mMoles) of 4-chlorobenzene sulfenyl chloride Yellowish crystals melting at 47 to 48°C. Rf = 0.3 (Al20^ neutral/ethylacetate) 9 Yield: 0.6 (20% of the theoretical) C24H31N6OSC1 (487) 10 15 H-NMR-spectrum: (CDC13, TMS as internal standard) 6 = 1.33 - 1.70 (m)(-(CH2-)3) 1.83 - 2.10 (m)(-CH2-) 2 2.20 - 2.50 (m)("(CH2)2) 6 H, 4 H, H, H, 3.3 3 (s)(N-CH3) 3 H, 3.33 - 3.53 (m)(-CH2~) 2 3.4 3 (N-CH2) 2 H, 4.00 (t)(0-CH2) 2 H, 4.60 (t)( N-H)(replaceable by D20) 1 H, 6.53 - 7.43 (m) (aromatic-H) 8 H, 8.00 (s)(N-H) (replaceable by D20) 1 H £? EXAMPLE 5 l-methyl-5-[3-[3-(1-piperidinylmethyl)-phenoxy]-propylamino]-20 3-(3-trifluoromethylbenzene-sulfenamido)-1H-1,2,4-triazole 25 \ I j nch CH. I ' -o-ch2ch2ch2-nh- N n NH-S-f CF- 30 This compound is produced as in Example 1 from 2.4 g (7.0 mMoles) of 1-methyl-N -[3-[3-(1-piperidinyImethy1)-phenoxy]-propyl]-1H-1,2,4-triazole-3,5-diamine and 1.57 g (7.4 mMoles) of 3-trifluoromethylbenzene sulfenyl chloride. Amorphous solid; 35 Rf = 0.48 (Al2®^ neutral/ethylacetate) ■V"; *;l-v'T-,.vv'-f ,--uS v 209707 >6 Yield: 0.4 g (10% of the theoretical) Cal c. : C 57.68 II 6.00 N 16.14 S 6.16 Found: C 57.77 H 6.07 N 16.17 S 6.12 C25H31F3N6OS (521) 10 15 H-NMR-spectrum: (CDC13, TMS as internal standard) EXAMPLE 6 o = 1.20 " 1.67 (m)(-(CH2)3) 1.97 (m)(-CH2-) 2 H, 6 H, 2.23 - 2.50 (m)(-(CH2)2-) 4 H, 3.4 0 (s)(N-CH3 3.47 (s)(N-CH2 3.53 (t)(N-CH2) 3 H, 2 H, 2 H, 3.97 (t)(0-CH2) 2 H, 4.67 (t, broad) (N-H) (replaceable by D20) 1 H 6.57 - 7.63 (m)(aromatic-H) 8 H, 8.17 (s) (N-H) (replaceable by D20) 1 H ppm. N- [5-[3-[3-(1-piperidinylmethyl)-phenoxy]-propylamino]-l-methyl-lH-1,2,4-triazol-3-yl]-l,2-benzisothiazolin-3-one —/ This compound is produced as in Example 1 from 2.4 g (7.0 mMoles) of l-methyl-N5-[3-[3-(1-piperidinylmethyl)-phenoxy]-propylJ-1H-1,2,4-triazole-3,5-diamine and 30 1.52 g (7.4 mMoles) of 2-chlorocarbony1 benzene sulfenyl chloride. Colorless crystals melting at 132 to 133°C. Rf = 0.55 (Al203 neutral/ethylacetate/methanol 95:5) Yield: 0.39 g (15% of the theoretical) m K, V* ~ 9^ / Q 7 C24H30N6°2S (467) Calc.: C 61.78 H 6.48 N 18.01 S 6.87 Found: C 62.15 H 6.22 N 17.98 S 6.61 10 15 H-NMR-spectrum: (CDC13, TMS as internal standard) EXAMPLE 7 6 = 1.33 - 1.70 (m)(-(CH2-)3) 2.13 (m)(-CH2~) 2 H, 2.23 - 2.47 (m)(-(CH2)2-) 3.43 (s)(N-CH2~) 2 H, 3.60 (s)(N-CH3) 3 H, 3.67 (t)(N-CH2) 2 H, 4.13 (t)(0-CH2) 2 H, 6 H, 4 H, 5.07 (t)(N-H) (replaceable by D20) 1 H, 6.67 - 8.12 (m) (aromatic-H) 8 H ppm. 1-methyl-5-[3-[3-{1-piperidinylmethyl)-phenoxy]-propylamino]-3-(2-pyridine-sulfenamido)-1H-1,2,4-triazole 20 \ NCH. J© ch- -0-CH2CH2CH2NH-^ n N IL. NH-S 25 30 35 This compound is produced as in Example 1 from 2.4 g (7.0 mMoles) of l-methyl-N^-[3-[3-(1-piperidinylmethyl)-phenoxy ]-propyl ]-lH-l, 2 ,4-triazole-3 ,5-(iiamine and 1.07 g (7.4 mMoles) of 2-pyridine sulfenyl chloride. Colorless crystals melting at 141 to 142°C. Rf = 0.2 (Al203 neutral/ethylacetate) Yield: 0.67 g (21? of the theoretical) Calc.: C 60.90 H 6.85 N 21.62 Found: C 60.88 H 7.04 N 21.62 C23H31N7OS (454) H-NMR-spectrum: (CDCl3, TMS as internal standard) 6 = 1.33 - 1.73 (m)(-CH2)3-) 6 H, 1.97 (m)(-CH2- 2 H r 2.27 - 2.50 (m)(-CH2)2-) 4 H, m 209707 r. -it- 1 3.37 (s)(N-CH3) 3 II, 3.43 (s)(-CH2~) 2 H, 3.53 (t)(N-CH2) 2 H, 4.03 (t)(0-CH2) 2 H, 5 4.60 (t) (N-H) (replaceable by D^O) 1 H,. 6.67 - 7.63 (m) (aromatic-H) 7 H, C^ 7.67 ( s ) ( N-H ) (replaceable by D20) 1 Hr 8.4 3 (d)(aromatic-H) 1 H ppm. 10 example 8 3-(cyclohexane-sulfenamido)-1-methyl-5-[3—[3—(1-piperidinylmethyl )-phenoxy]-propylamino]-1H-1,2,4-triazole 15 -pch2ch2ch2nh nh-s- 20 This compound is produced as in Example 1 from 2.4 g (7.0 mMoles) of l-methyl-N^-[3-[3-(1-piperidinylmethyl )-phenoxy1-propylJ-1H-1,2,4-triazole-3,5-diamine and 1.11 g (7.4 mMoles) of cyclohexane sulfenyl chloride. 25 oil. Rf = 0.25 (A1203 neutral/ethylacetate) Yield: 0.29 g (9% of the theoretical) C-.H,oN£0S (459) Calc.: C 62.85 H 8.35 N 18.32 S t. 24 38 6 Found: C 62.98 H 8.34 N 17.74 S 1, 30 CJ ^H-NMR-spectrum: 1.17 - 2.17 (m) 18 H, (CDC13, TMS as 2.23 - 2.50 (m)(N(CH2)2) 4 H, internal standard) 2.97 (m)(-CH) 1 H, 3.4 3 (s)(N-CH2;N-CH3) 5 H, 35 m . ■ _ • 19 >1 - 209707 10 EXAMPLE 9 3.60 (t)(-CH2 2 H, 4.13 (t)(-0-CH2)2 H, 4.33 (t) (replaceable by D20)(-NH) 1 H, 5.33 (s) (replaceable by D20)(NH-S) 1 H, 6.67 - 7.30 (m) (aromatic-H) 4 H ppm 1-methyl-5-f 3-[3-(1-piperidinylmethyl)-phenoxy]-propylamine]-3-(methylsuIfenamido) -1H-1,2,4-triazole Cf3 ■OCH2CH2CH2NH r\ -<*s y-NH-S- N / CH. 15 G Q 20 25 30 This compound is produced as in Example 1 from 2.4 g (7.0 mMoles) of 1-methyl-N^-[3-f3-(1-piperidinylmethyl )-phenoxy]-propyl]-lH-l,2,4-triazole-3,5-diamine and 0.6 g (7.4 mMoles) of methyl sulfenyl chloride. Solidified oil. Rf = 0.27 (Al203 neutral/ ethylacetate) Yield: 0.3 g (11% of the theoretical) C19H30N6OS (391 ) H-NMR-spectrum: (CDC13 TMS as internal standard) 6 = 1.37 0 1.73 (m)(-CH2)3-) 6 H, 2.13 (m)(-CH2-) 2 Hr 2.40 (m)(N-(CH2)2 4 H, 2.43 (s)(SCH37 3 H, 3.45 (s, broad) (N-CH3, N-CH2) 5 H, 3.63 (t)(N-CH2) 2 H, 4.13 (t)(O-CH2) 2 H, 4.5 3 (t)(replaceable by D20)(N-H) 1 H, 5.93 (s )(replaceable by D20)(NH-S) 1 H, 6.67 - 7.33 (m)(aromatic-H) 4 H ppm. 35 • # A- 209707 - yi - 1 EXAMPLE 10 1-methyl-5-[3-[3-(1-piperidinylmethyl)-phenoxy]-propylamino] 3-(2-quinoline-suIfenamido)-lH-l ,2, 4-triazole 15 20 25 30 This compound is produced as in Example 1 from 2.4 g (7.0 mMoles) of 1-methyl-N5-[3-[3-(1-piperidinylmethyl )-phenoxy]-propyl]-lH-l,2,4-triazole-3,5-diamine and 1.44 g (7.4 mMoles) of 2-quinoline sulfenyl chloride. Amorphous solid melting at 50 to 60°C. Rf = 0.5 (A1203 neutral/ethylacetate/methanol 95:5) Yield: 0.28 g (8% of the theoretical) C27 H33N7OS (504) H-NMR-spectrum: (CDC13, TMS as internal standard) 6 = 1.30 - 1.70 (m)(-(CH2)3-) 6 H, 1.93 (m)(-CH2~) 2 H, 2.13 - 2.50 (m)(N-(CH2)2-) 4 H, 3.30 (s)(N-CH3) 3 H, 3.43 (s)(N-CH2) 2 H, 3.52 (t)(N-CH2) 2H, 3.93 (t)(0-CH2) 2 H, 4.7 3 (t)( replaceable by D20)(N-H) 1 H, 6.55 - 8.13 (m)(aromatic-H) 10 H, 8.24 (s) (replaceable by D2<D) (NH-S) 1 H ppm EXAMPLE 11 1-methyl-5-[3-{3-(1-piperidinylmethyl )-phenoxy]-propylamino] 3-(2-pyrimidine-su1fenamido)-lH-l ,2,4-triazole >3 - 2 09707 10 15 CH. \ NCH, o -0-CH2CH2CH2 -NH-^C N. N. \ N "•<2) This compound is produced as in Example 1 from 2.4 g (7.0 mMoles) of 1-methyl-N^-[3-[3-(1-piperidinyl-methyl)-phenoxy]-propylJ-1H-1,2,4-triazole-3,5-diamine and 0.98 g (7.4 mMoles) of 2-pyrimidine sulfenyl chloride. Colorless crystals melting at 119 to 121°C. Rf = 0.43 (silica gel; CH2Cl2/NEt3/CH3OH 90:10:1) Yield: 0.45 g (14% of the theoretical) C22H30N8OS- (455 Calc.: C 58.13 H 6.65 N 24.65 S 7.05 Found: C 58.03 H 6.67 N 24.60 S 6.94 H-NMR-spectrum: (dg-DMSO, TMS as 20 internal standard) 6 = 25 1. 27 -1.63 (m)(-(CH2)3~) 6 H, 1. 99 (m)(-CH2~) 2 Hr 2. 20 - 2.52~(m)(N-(CH2)2-) 4 H, 3. 30 (s)(N-CH3) 3 H,~ 3. 37 (m)(N-CH2) 2 H, 3. 45 (s)(N-CH2) 2 H, 4. 03 (t)(0-CH2) 2 H, 6. 37 (t) (replaceable by D20)(N-H) 1 H, 6. 73 - 7.3 7 (m) (aromatic-H) 5 H, 7. 97 ( s )(replaceable by D20)(NH-S) 1 H 8. 57 (d)(aromatic-H) 2 H ppm. 30 EXAMPLE 12 l-methyl-5-[3 — f 3—(1-piperidinylmethyl)-phenoxy]-propylaminoJ -3-(2-benzothiazole-suIfenamido)-lH-l,2,4-triazole </div>

Claims

<div class="application article clearfix printTableText" id="claims"> ,, 1,1 2097 07 NCH2-' o CH-I 3 N —N j-och2ch2ch2nh -4s. 3>-NH-< 10 15 This compound is produced as in Example 1 from 2.4 g (7.0 mMoles) of 1-methyl-N^-[3-[3-(1-piperidinylmethyl )-phenoxy]-propyl]-lH-l,2,4-triazole-3,5-diamine and 1.49 g (7.4 mMoles) of 2-benzothiazole sulfenyl chloride. Colorless amorphous solid melting at 67 to 71°C. Rf = 0.5 (A^O^ neutral; ethylacetate/methanol 95:5) Yield: 0.54 g (15% of the theoretical) C25H31N7OS2 (510) Calc.: c 58.91 H 6.13 N 19.24 Found: c 58.70 H 6.23 N 19.06 H-NMR-spectrum: (CDC13, TMS as 20 internal standard) 25 6 = 1.30 -1.80 (m)(-(CH2)3-) 6 H, 2.00 (m)(-CH2-) 2 U~ 2.27 - 2.53 (m)(N-(CH2)2) 4 H, 3.40 (s)(N-CH3) 3 H, 3.43 (s)(N-CH2) 2 H, 3.60 (t)(N-CH2) 2 H, 4.03 (t)(OCH2) 2 H, 4.67 (t)(replaceable by D20) (N-H) 1 H, 6.60 - 7.97 (m)(aromatic-H) 8 H, 8.60 (s )(replaceable by D20) (NH-S) 1 H ppm 208707 X> - z - WHAT -f/V/E CLAIM ISr-CLAIM&

1. Sulfenamide derivatives corresponding to the following general formula CH, I s : -0-CH_CH-CH-.NH-< N (I) \-L S N ^S-R2 in which .2 R1 is a hydrogen atom and R~ is a linear or branched-chain C^-Cg-alkyl or C^-C^-cycloalkylradical or an unsubstituted or mono- to tri-substituted aryl or heteroaryl radical, or R1 and R2 toqether" with the nitrogen and sulphur atans, to which they are attached form an isothiazoline ring or isothiazolinone ring, and physiologically compatible salts thereof.

2. Compounds as claimed in Claim 1, characterized 1 2 in that R is a hydrogen atom and R is a linear or branched-chain C^-C^-alkyl or C5~Cg-cycloalkyl radical.

3. C6mpounds as claimed in Claim 1, characterized 1 2 in that R is a hydrogen atom and R is an unsubstituted or mono- to trisubstituted aryl radical.

4. Compounds as claimed in Claim 1, characterized 1 2 in that R is a hydrogen atom and R is an unsubstituted or mono- to trisubstituted heteroaryl radical.

5. Compounds as claimed in Claim 1, characterized in that R^- and R^ together with the nitrogen and sulphur atans to which they are attached form an isothiazoline ring or isothiazolinone ring.

6. 1-methyl-5-(3-[3-{1-piperidinyImethyI)-phenoxy]-propylamino 1-3-(4-methyl benzene-suIfenamido)-1H-1,2,4-triazole and physiologically compatible salts thereof.

7. l-methyl-5-I3-[3-(1-piperidinylmethyl)-phenoxypA?> ?«*• <P, II* % % ^09707 - * - propylamino]-3-(4-chlorobenzene-su1fenamido)-1H-1,2,4-triazole and physiologically compatible salts thereof.

8. 1-methyl-5-[3-[3-{1-piperidinylmethyl)-phenoxy ]-propylamino]- 3-(3-trif 1 uoromethy1benzene-sulfenamido)-1H-1,2,4-triazole and physiologically compatible salts thereof.

9. 1-methyl-5-I 3-[3-(1-piperidinylmethyl)-phenoxy]-propylamino]-3-(2-pyridine-suIfenamido)-lH-l,2,4-triazole and physiologically compatible salts thereof.

10. A process for producing the sulfenamide derivatives claimed in any one of Claims 1 to 9, characterized in that an amine corresponding to the following formula NCH ch, l N -o-ch2ch2ch2nh -O (II) NH- is subjected to a base-catalyzed reaction in known manner a) with a sulfenyl halide corresponding to the following general formula R -S-Hal (III) in which Hal is a chlorine or bromine atom and 2 R is as defined in Claim 1, and the compound obtained is optionally converted into a physiologically compatible salt or b) with a sulfenylic acid chloride corresponding to the following formula 22&UG1986 209707 tr<f and the compound obtained is optionally converted into a physiologically compatible salt.

11. A medicament, characterized in that it contains a compound as claimed in any one of Claims 1 to 9 and at least one inert, pharmaceutically compatible carrier or an inert, pharmaceutically compatible diluent. BALDWIN, SON & CAREY $L. attorneys for the applicants </div>