DE2758809A1 - DI-TAPE CLAMP ON 2-AMINOCYCLOPENT-1-EN-1-THIOCARBONYL TAPE CLAMP ON -DISULFIDES, SUCH CONTAINING MEDICINAL PRODUCTS AND METHODS FOR THE PRODUCTION THEREOF - Google Patents

Description

DR. STEPHAN G. BESZtDES PATENT ADVOCATE

8060 DACHAU AT I

PO8T COMPARTMENT 1

AM HEIDEWEG 2 TELEPHONE: DACHAU 43T1 Potttcheckkonto Munich (BU 700100 (O)

Account no. 1368 71

Bank account no. 906 JTO at the Kral »- and BfA- • parfcuu OKhMiliidaridorf (BU 700ItS40) (VIA Bayaiftotw Lndbank QIn

p 1 074

description

for patent application

JUDGE GEDEON VEGYESZETI GYAR RT.

Budapest, Hungary

concerning

Dl ~ {2-aminocyclopent-1-en-1-thiocarbonyl} -disulfide, drugs containing them and Method of making the same

The invention relates to new di- {2-aminocyclopent-1-en-1-thiocarbonyl} disulfides including their salts, such Medicinal products containing, in particular those with dopamine-β-hydroxylase-inhibiting action, and a process for the preparation the same.

According to current knowledge, the substances that influence nerve functions are almost exclusively effective by influencing the transmission of stimuli.

809827/0990 ORIGINAL INSPECTED

These processes are fairly well known; Based on this knowledge, there is the possibility of providing solohon connections with which these processes can be influenced more or less controlled. By intervening in the elementary nerve functions, however, will not only affects the nervous system, but also the processes controlled by the nervous system are influenced. to Efforts in this regard over the past few years include those inhibiting dopamine-ß-hydroxylase and this enzyme Means Concerning Research.

Dopanine-ß-hydroxylase is the last enzymatic stage of the biosynthesis of 1- (3 ', ^' - dihydroayphenyl) - ^ - -aminoethan-1-ol [noradrenalinJ, the ^{conversion of 4- (2>} -aminoethyl) - catechol [dopamineJ catalyzed in norepinephrine. Since 1- (3 ', V-dihydroxyphenyl) -2-aminoethan-1-ol [noradrenaline] is an important transmitter of stimuli in the sympathetic nervous system, its concentration plays a fundamentally important role in normal nerve functions and in the processes controlled by nerves. The dopamine-ß-hydroxylaso inhibiting substances offer an opportunity to intervene in the noradrenergic functions. This possibility is of great importance both from the point of view of research and therapy; for research because the decrease in the 1- (3 ', 4'-dihydroxyphenyl) -2-aminoethan-1-ol level [norepinephrine level] caused by dopamine-ß-hydroxylase inhibition makes investigating the consequences of the partial or complete elimination of the 1- (3 ' Λ ' -dihydroxyphonyl) -2-aminoethane-1-ole functions [noradrenaline functions], while in therapy the overfunction of the noradrenergic system can be compensated by the use of the dopamine-ß-hydroxyJn.se inhibiting agents. On the basis of current knowledge, the ^ opemin-ß-b ^ Bd ^ oatySLase ^ hemeenden means for

809827/0990

Treatment of high blood pressure and used in the therapy of Parkinson's disease.

It is known that benzyloxyamine and benzylhydrazine inhibit dopamine-β-hydroxylase (compare van der Schoot and coworkers: Advances in Drug Research, Volume 2. Page 47, Harper and Simmons; Nikodijevic and coworkers: J. Pharm. Exp. Therap. 140 [19633, 224), but cannot be used in therapy because of their short duration of action. Also the tetraethylthiuram disulfide (disulfiram) and its reducing substance we ohs egg product (reduction metabolite), the sodium diethyl dithiocarbamate (Goldstein and coworkers: Life page 5 L ¹ 964 ·] »763) as well as numerous Ν, Ν-disubstituted dithiocarbamates (Maj and coworkers: Eur. J. Pharmacol. 9 j / 1970, 183; Lippmann and coworkers: Arch. Int. Pharmacodyn. Ther. 189 Π9711, 348) show strong dopamine-β-hydroxylase-inhibiting effects. In vitro, 2,2-dipyridyl also shows a good inhibitory effect (Green, Biochim. Biophye. Acta 81 0i964j, 394). Bis- (1-methyl-4-homopiperazinylthiocarbonyl) disulfide is one of the most effective in vivo dopamine-β-hydroxylase-inhibiting agents (Florvall et al.: Acta Pharmaoeut. Sulcica, 2 D97O], 7). Numerous aromatic and aliphatisohe thioureas have long-lasting dopamine-ß-hydroxylaöe inhibitory effects (Johneon and co-workers: J. Pharm Ther Exptl 1 £ 1 C ¹⁹⁷⁰ i 80...).

Among the substances that can be produced by microbiological means, fusaric acid (5-butylpicolinic acid) in particular and their derivatives (compare, for example, Hidaka and co-workers: Moleo. Pharmacol. ^ [1973], 172) and that Oosponol (Umezawa and co-workers: J. Antibiotics, 2J? [1972 \ 239) and dopastine (Iinuma and coworkers: J. Agr. Biol. Ohem. 2§ [19743, 2 107) which inhibits dopamine β-hydroxylase Effects.

809827 / 0.9 90

Even with some of the well-known and already in the traffic brought drugs, for example 1-hydrazinophthalazine (Hydralazine), 1-methyl-2-mercaptoimidazo 1 (llethimazole) and 1-Phenyl-2-aminopropane (amphetamine) was subsequently determined to inhibit dopamine-β-hydroxylase.

Most of the above-mentioned compounds, however, have the common disadvantage that, although they do the dopamine-ß- -hydroxylase effectively inhibit, but (especially with longer Duration of treatment) are quite toxic and therefore cannot be used in therapy or can only be used to a very limited extent.

The invention is based on the object of providing new compounds with superior pharmacological effects, in particular the dopamine-β-hydroxylaee inhibiting effect to create lower toxicity, medicinal products containing them and a process for their manufacture.

There were now surprisingly new di- {2-aminocyclopent-i-en-i-thiocarbonyl ^ -disulfides with superior the dopamine-ß-hydroxylase inhibitory effect, which is essential are found to be less toxic than the known compounds.

The subject of the invention are therefore di- {2-aminocyclopent-1-en-1-thiooarbonyl} disulfides of the general formula

- 5 809827/0990

R stands for hydrogen, one, optionally by 1 or more alkoxy radical (s) [alkyl radical (s)]] with 1 to 4 carbon atoms, Hydroxy, carboxyl and / or amino group (s) substituted, alkyl radical with 1 to 6 carbon atoms, an alkenyl radical with 2 to 4 carbon atoms, a cycloalkyl radical with 3 to 8 carbon atoms or a phenyl radical,

and their salts.

The alkyl radical, for which R can stand, is preferably one having 1 to 4, in particular 2 to 4, carbon atoms . ··

It is also preferred that the alkoxy radical, with respect to two alkoxy radicals, by which the alkyl group, for which R can stand, can be substituted, is or are those having 1 or 2, in particular 1, carbon atoms .

As an alkenyl radical, for which R can stand, is

809827/0990

AlIyIrest preferred

Furthermore, it is preferred that the cycloalkyl radical, for which R can stand is one with 5 or 6 carbon atoms, in particular the cyclohexyl radical.

Particularly preferred compounds according to the invention are di- {2-aminocyclopent-1-en-1-thiocarbonylJ-disulfide, di- {2- [N- (n-butyl) -amino] -cyclopent-1-en-1-thiocarbonyl \ - -disulfide, the zinc salt of di- / 2- [N- (η-butyl) -amino) -cyclopent-i-en-i-thiocarbonyl ^ j-disulfide, di- {2- £ N- - (2 ¹ -methO3cyäthyl) -aminq] -cyclopent-1-en-1-thiocarbonyl \ --äieulfid, Di- [2- £ N- (cyclohexyl) -amino) -cyclopent-i-en-1- -thlocarbonylj -disulfid, Di - {2 - [[N- (ethyl) -amineq] -cyclopent- -1-en-1-thiocarbonylJ [-disulfide and di- (2- £ N- (allyl) -amino] -cyolopent-1-ene -i-thiocarbonyl} disulfide.

Furthermore, pharmaceuticals according to the invention, which 1 or more of the compounds according to the invention as active ingredient or active ingredients, advantageously together with customary pharmaceutical packaging means, included, provided.

As already mentioned, the compounds according to the invention have a strong dopamine-β-hydroxylase inhibiting effect Effect, whereby they are significantly less toxic than the known compounds with the same direction of action.

The dopamine-β-hydroxylase-inhibiting activity of the compounds according to the invention was determined by the following Experiments proven:

Male Wistar rats with body weights of 150 to 200 g were used. The dopamine-ß-hydroxylase inhibitory activity of the compounds investigated was

- 7 -809827/0990

due to the changes in the 1- (3 '>4'-dihydroxyphenyl) -2-aminoethan-i-ol concentration [noradrenaline concentration], the 4- (2'-aminoethyl) pyrocatechol concentration [j dopainine concentration] and the 1- (3', 4 ^l -Dihydroxyphenyl) -2-meth, ylaminoethan-1-ol concentration [adrenaline concentration] Determined in the brain, in the heart, in the spleen and in the adrenal gland. The concentration of 5-oxy-3-indolethylamine (serotonin) and of 5-hydroxyindolylacetic acid in the brain was also determined. The determinations were carried out in the following way:

The compounds to be investigated were administered intraperitoneally to the animals after 4 and 8 hours, respectively the animals were decapitated and their brain, heart, spleen and adrenal gland were quickly removed and covered with dry ice chilled metal plates placed and allowed to freeze. The frozen organs were stored at -20 ° 0 overnight at most .

To determine the 1- (3 '»4'-Dihydro3cyphenyl) -2-methj'lpmi no ätbab-1-ol concentration £ adrenaline concentration] in the adrenal gland, the adrenal glands were cleaned of fat and cut in 3» 0 cm * a 0.4 η Superchloric acid homogenized. The homogenized mixtures were ^{centrifuged at 0 0} O at 3,200 revolutions / minute for 10 minutes. In the supernatant liquid, the 1- (3 ', 4'-Dihydroxyι ι "', U ^ -methylaminoäthan-i-olkonzentrat JAdrenalin concentrate i fi> immediately after the method of Laverty and coworkers (Anal. Bioohem. 22 Ql968j, 269) certainly.

To determine the ί- (3 '^' Ethan-1-ol content of noradrenaline in the heart and in

- 8 809827/0990

of the spleen, both organs were weighed in the frozen state and then homogenized in a 0.05% of the disodium salt of ethylenediaminetetraeaige acid and 0.16 sodium pyrosulfite (N containing 0.4 η superchloric acid. The homogenized mixtures were centrifuged in the manner described above and the supernatant liquid was separated off by decanting and treated with a 0.1 m 2-amino-2-hydroxymethyl-1,3-propanediol buffer (Tris buffer) containing 20 g / l sodium hydroxide and 25 g of the disodium salt of ethylenediaminetetraacetic acid a pH of 8.0 -. The samples were then adjusted 0.1 with 100 mg of prepared aluminum oxide (cf. Anton and collaborations J. Phann Therap 138 19623 £ »360th.) was added and 20 minutes on a mechanical shaker The. Aluminum oxide was washed twice with 10% distilled water each time and then the 1- (3S4 ^l -dih3rdroxyphenyl) -2-aminoethen- -1-ol CNoradrenalin] was eluted with 1.0 cm * of 0.05 η superchloric acid 1- (3 ', 4 ^l Dihydroxyphenyl) -2-aminoethan-1-ol (noradrenaline) was determined in 0.5 cm * of the eluate. The determination was carried out according to the method of Shellenberger et al. (Anal. Biochem. J52 [197Ό »356) with the following modifications. 0.5 cm * of a 0.1 m sodium / potassium phosphate buffer with a content of 9 g / l of the disodium salt of ethylenediaminetetrnesic acid was added to 0.5 oar of the sluate - (3 ', 4'-Dihydroxyphenyl) -2-aminoethan-1-ol [noradrenaline] present; in the similar determination described below, 4- (2 * -aminoethyl) pyrocatechol (DopamiiO) is also included in the brain } were oxidized with 0.1 oar of a 0.1 η iodine solution (in 5% potassium iodide solution). After exactly 2 minutes, the oxidation was carried out by adding 0.25 oar of a 2.5% sodium sulfite solution (in a 4, 4

809827/0990 " ⁹ "

held in a drying cabinet ^{heated to 10O 0} G and then cooled in ice water. The fluorescence of 1- (3 ', 4 ^l -dihydroxyphenyl) -2-aminoethan-1-ol [noradrenaline]] was measured with an OPTON type spectrophotofluorometer at an excitation wavelength of 390 mu and an emission wavelength of 490 mn.

For the determination of 1- (3 ', 4'-dihydro3cyphenyl) -2-ejninoethan-1-ol [noradrenaline], 4- (2-aminoethyl) catechol CDopamine}, 5-oxy-3-indolethylamine [serotonin] and 5- Hydroxyindolylacetic acid in the brain, the brains were homogenized in 10 parts by volume of 0.4 η superchloric acid. The homogenized mixtures were stored at -20 ⁰ O overnight, then thawed, and centrifuged in the manner described above. Amounts of the homogenized mixtures containing 0.5 g of brain were removed and brought to a pH of 8.0 with the 0.1 m 2-amino-2-hydroxymethyl-1,3-propanediol buffer (Tris buffer) described above . 0.1 set. The samples were then treated in a manner similar to that described above for the determination of 1- (3 ', 4'-dihydroxyphenyl) -2-aminoethan-1-ol [noradrenaline] in the heart and in the spleen, with the difference that the elution was carried out with 1.5 cnr of 0.05 η superchloric acid. The 1- (3 ', 4'-dihydroxyphenyl) -2-aminoethane -I-0I- and 4- (2 * -aminoethyl) -pyrocatechin content [noradrenaline and dopamine contentQ were also in 0.5 cm * of the eluate after the Determined fluorometric ancestors described above, but with the difference that to read the fluorescence of 1- (3 ', 4'-dihydroxyphenyl) -2-eminoethane -I-0I ßioradrenalin3 samples with volumes of 0.5 cm * were used. The residue was kept at 100 ° 0 for 50 minutes and then cooled in ice water. The fluorescence of 4- (2'-aminoethyl) pyrocatechol ß) opaminll was read at an excitation wavelength of 325 * ψ and an emission wavelength of 360 mu.

- 10 -

8 09827/0990

In further experiments, apart from the 1- (3 '| 4 ^f -dihydroxyphenyl) -2-aminoethan-1-ol f noradrenaline and 4- (2 <-aminoethyl) pyrocatechol [dopamine] in the same samples, the amounts of 5-oxy -3-indolethylamine [serotonin] and 5-hydroxyindolyl acetic acid are determined. The brains were homogenized in 10 cnr 75% ethanol; and the homogenized mixtures were mixed with 0.2 cnr ei nor 10% of the disodium salt of ethylenediaminetetraacetic acid and aqueous solution containing 5% ascorbic acid; Then, the homogenized mixtures were kept overnight at -20 ⁰ C and centrifuged in the manner described above. 0.5 cm * of the supernatant liquid was diluted with the same volume of distilled water and poured onto columns (0.5 cm × 1.5 cm) containing a buffered ion exchange resin of the type Amberlite CG? () [200 to 400 mesH). After this solution had flowed through, the sulphons were washed with 5 our distilled water and then with 1.0 cnr of 0.2 η hydrochloric acid. (The liquid flowing through and the wax liquid contained with the distilled water were collected and used to determine the 5-hydroxyindoly] acetic acid). The 1- (3 *, V-dihydroxyphenyl) -2- -aminoethan-1-ol [noradrenalinJι 4- (2 * -AminoäthyI) -catechol 0) opamin3 and 5-oxy-3-indolethylamine [serotonin | were then eluted with a further 1.2 car of 0.2 η hydrochloric acid. The determinations were carried out with 0.3 oar dee eluates each.

1- (3 ', 4'-dihydroxyphenyl) -2-aminoethan-1-ol [jforadrenalin!] and 4- (2-arainoethyl) catechol CDopaminU were determined by the method of Shellenberger and Employees (see above) determined; the determination of the 5-oxy-3-indolethylamine (jBerotoninesJ was carried out according to the method of Curzon and co-workers (compare Brit. J. Pharmacol. ^ D97O3i 653) with the following modifications carried out '0.5 oar of 5-oxy-3-indolethylamine [serotonin

809827/0990

Samples containing 0.6 cnr of a freshly prepared 0.01% o-phthalaldehyde solution (obtained by 50-fold dilution of a 0.5% solution of o-phthalaldehyde in absolute ethanol with a 10 η hydrochloric acid) added, then the samples were kept on a boiling water bath for 10 minutes and then immediately cooled in tap water. The fluorescence values were read at an excitation wavelength of 360 mu and an emission wave I unc; * ¹ of 490 mn.

To determine 5-hydroxyindolylacetic acid, 10 cnr distilled water and 0.2 cm ^ concentrated hydrochloric acid were added to the flowing liquids collected in the manner described above and combined with the Wnooh water, and the samples thus obtained were coated with a resin of the Sephadex type G-10 filled columns with dimensions of 0.8 cm χ 4.0 cm cast. After flowing through the columns were each with 15 cm * of a 0.1 η hydrochloric acid and then with; 1.8 to 2.0 cnr of an aqueous 0.02 η ammonium hydroxide channel; washed, whereupon the 5-hydroxyindolylacetic acid was eluted with a further 2.0 cm * of the ammonium hydroxide solution. The determination of the 5-hydroxyindolylacetic acid was carried out on each 0.5 cm of the eluates according to the method of Korf et al. (Biochem. Pharmacol. 20 £ 976 » ⁶ 59).

The results of these tests are compiled in Table 1 below. As comparison substances were 2,2'-Dipyridyl, BisCi-methyl - ^ - homopiperazinylthiocarbonyl) - -disulfide and N-phenyl-N '- (2-thiazolyl) -thiourea are used. The values given in Table 1 are based on the amine values found in the parallel blank tests Percentages ι

- 12 809827/0990

- 12 table

Binding Administration
marriage type dose
in
■ g / kB dea ver
look for β number
the
Oar 1-04'-DU Brain
ca techin
[Dopanine] Geha]
n
5-OJ3T-3-
-indole- Lt from Or
at ganen
Hers Mils nijusaw Dl- {2-amino-
ajelopent-
-ttiio-
aarbonyl} -
^ BauUrid intra- 100
200
200 % SUBCBQ 6th
6th
6th 121.2
124.5
109.0 alga yours 87.2
60.2 intra-
intra- 100 Rhombus 6th 131.5 114.6
110.7 152.5
125.3 86.5
82.5
83.2 77.5 ncQ-cgclo-
pent-1-βη-Ι-
-thiooarbonyl- 200
200 4 hours 6th
6th 69.5
56.7
56.5 134.6
120.6 113.3 108.3 91.8 96.3
97.0 -dJ sulfide intra- 500 8 Sbxden 5 41.9 111.0 112.8
106.0 150.9
161.4 91.7
75.7 92.6
91.2 88.1 intra-
intra- 39.6
28.5 90.9 105.9 74.0 81.4 perorally 51.2 69.9
61.9 101.0

OO O CO

- 13 - Continuation of the table

link Administration
marriage type dose
in
mg / kg Zettdauar
ds \ hr-
such number
the
Bare 1-0 4'-DL- Gehix
4- (2 ^l -Anlno-
catechin
[Dopamine] Gebal
■ n
-Indole- t of Ore
at
aigaic acid ; anen
Her χ UJ ^ - -0 ', 4'-DL- Dt- f 2-JR - (<3fclo-
jeryl) - aminoj-
-cyclopent-i-
-βη-1-ttilo-
carbonyl} -
-dtsulfid intra- 200
200 4 bundles
8 chairs 6th
6th nyl> -2-emi-
" 1
L J 124.2
116.2 104.5
105.3 142.8
177.5 qji) -2-ami- 1111
-G ¹ , 4'-Di-
noätban-1-ol noatban-O-d. Dl- [2- [H- intra-
peritoneal 100 4 stuodm 5 64.6
76.9 99.0 106.7 - 94.7
89.5 83.2
68.7 - -fLtibLyD-ami-
noj-cyelo-
pent-1-
-βη-1-thio-
earbonyl} -
-dieulfide intra- 200
200
500 4 Sbxam.
8 aaxäm
4 aundm 6th
6th
5 41.8 134.9
121.7
106.7 112.5
103.9
117.5 155.0
195.4 92.9 64.1 - intra-
■ * ■ - ^
TfWTTlMBTH I 34.4
34.2
83.9 97.8
81.3
82.4 85.0
86.5 97.3
79.0 intra- perorally

OO OO O CD

- 14 - Continuation of Table 1

link

-aninoj-qydo- • pent-1-βη-1-thioarbonyl- -disulfide

equal substance]

Mode of administration

intra-

intrs-

intra

Dose in

200

200

37.5 75

the custom

4- probes

4 hours 4 hours

number the

Content of Organs Brain Ears

at

50.5

64.5

79.5 41.2

ca techin [Dopamln]

123.6

104.7

-indole-

112.7

108.0

100

acetic acid

117.1

125.7

100.0

91.8

104 58

Mils Mmrfn

^ TV ¹¹ IlT ¹ I KVI wlff '"

noä & an-i-Ql

66.1

88.5

100

ncjättan-4-4

95.3

69.8

80 63

cn oo oo ο

CD GD Κ>

- 15 - Table 1 continued

link

4 — boncgipe—

careoayldisulfide [Tfergleißhssubstansj

substance]

Mode of administration

Dose in

intra-

_ £ T "" H "A1

intra-

50

200

Duration

4 hours

number

the

animals

Formation of organs Brain heart

at

spleen

fiebemta »

24.6

31.6

4- <2-Απίηο-

catechin [bopamine]

-indoläöylanln

124

137

acetic acid

175

mettan-1-ol

96

106

nyO-2-amixethane-Vol

111

Ρ3Φ-2-

noätfaen— 1-d.

43

72

As can be seen from the data in Table 1 above, the compounds according to the invention lead to a strong, namely 20 to 7036-degree reduction in the 1- (3 ', «· -dihydroxypheny 1) -2-aminoethan-i-ol content in the brain (jforadrenal in ^ ohai tea], whereby at the same time almost always a Εγ1 ·· "'· ϊ ·"μ; des 4- (2 ^ aminoethyl) catechin content8' (dopamine h-Ό i <> r. 1 ,, \\ <* is sometimes considerable, namely up to 35T ¹ SrIg, observer w "r« l · · »was able to. For the 5-oxy-3-indolethylamine content QSero toning · - haltj this also applies to a somewhat lesser extent; the increase in The amount of 5-hydroxyindolyl hydrochloric acid has in some cases reached 50% and more.

The 1-O ^1, 4 '> Dlhydroxyphenyl) -2-aminoäthan-1-olgehnlt QforadrenalingehaltQ in the heart and in the spleen as well as the 1- (3 * A'-I> ihydroaqjrphenyl) -2-aethylaainoäthan- ^/ l-oil content CAdrenalingehalO in the adrenal gland were just fall by the compounds of this invention lowered, the lowering was dee but in most cases, and even in swar don in the brain a strong reduction of 1- (3 ', _4'-f dihydroxyphenyl) --2-aminoäthan-i- Oil-inducing compounds are less significant. The probable explanation for this fact is that the catechol amine is slow in this or ^ nnon, and the adrenal gland has relatively large stores of brenzoatechin amines [1 ~ (3 ', 4 ^l -dihydroxyphenyl) -2-aminoethan-1-ol ["noradrenaline \ and 1- (3 *, ^ ^l -dihydroxyphenyl) -2-methylajiinoethan-1-ol [adrenalin3 \ are present and the missing 1- (3'Λ'-dihydroxyphenyl) -2-aminoethan-1-ol content (noradrenaline content of The spleen and heart are quickly replaced by the circulatory system. Even when investigating the effects of known compounds which inhibit dopamine-β-hydroxylase, no clear reduction in the cataquinamine content in these organs was found, although the compounds according to the invention are more favorable in this regard than the comparative bonds as shown in Table 1 above

809827/0990 "- iy -

emerges .

The toxicities of compounds according to the invention and comparative compounds are summarized in Table 2 below.

809827/0 9 90

- 18 -Table

β »ο co

σ co α »

link Animal species Appointment type intraperitoneally LDcQ value
in
mg / kg Di- {2-aninocyclopent-1-en-1-tliiocarb.onyl} -
-disulfide mouse intraperitoneally ^ J800 Di- fe- pJ- (2-methoacyathyl) -aminq} -cyclopent-
-1-en-i-th.iocarbonylJ -disulfide mouse ■
intraperitoneally > 1,500 Di- j2- [N- (cyclohexyl) -amino] -cyclopent-1-en-
-1-thiocarbonyl] disulfide mouse intraperitoneally > 1,000 Di- {2- (N- (ethyl) -amine-O-cyclopent-1-en-1-
thiocarbonyl disulfide I.
Mouse \ intraperitoneally 1,000 to 1,500 Di- ^ 2- (N- (allyl) -amino3 -eye lopent-1-en-1-
-thiocarbonyl]; -disulf id I.
mouse > 1,000
I. I.

O CD CO Ni

- 19 -

Porting the table

link Animal species Agreement sart LDcQ value
in
mg / kg 2,2'-dipyridyl House
rat intraperitoneally
intraperitoneally 280
150 Bis- (1-methyl-Λ- h.omopip «razinyl) -thio-
carbonyl disulfide mouse intraperitoneally ^ 150 N-rienyl-N '- (2-thiazolyl) thiourea mouse
mouse intraperitoneally
perorally «680
> 1,000

tn ca co

From the data in Table 2 above, it can be seen that the toxicity values of the compounds according to the invention are extremely cheap, so that they can be used for a long time without harmful side effects can be administered *

Furthermore, from the above Tables 1 and. 2, finis the compounds according to the invention compare vei-bindutii.-ii all in all, taking into account both the dopamine-ß- -hydroxylaee howling effect and also the toxicity are superior.

The invention also provides a method for Production of the compounds according to the invention, which is characterized in that in a manner known per se a 2-Aminooyclopent-i-en-i-ditb.iocarboxylic acid of the general Formula '

N-H

Il,

wherein R is as defined above, is oxidized, whereupon the obtained di- {2-aminocyolopent-1-cn- -1-thiocarbonylJ-disulfide of the general formula I in an is converted into a sale in a known manner.

809827/0990

The aforementioned oxidation can contribute to the formation of disulfides suitable known oxidizing agents, for example hydrogen peroxide or potassium permanganate, can be carried out.

According to an advantageous embodiment of the inventive B-according Process is used as the starting material; " 2-aminocyclopent-1-en-1-dithiocarboxylic acid of the general Formula I in a suitable solvent, expediently water, dissolved or suspended, then the solution or respectively The suspension is first made alkaline, for example with sodium hydroxide solution, and shaken for a few minutes and then oxidized by adding an acid, advantageously sulfuric acid, and hydrogen peroxide.

Some of the 2-aminocyclopent-i-en-i-dithiocarboxylic acids of the general formula II used as starting materials for the process according to the invention are known (see J. Org. Chem. *> 7 £ 19723, 1727); the unknown other starting materials can be obtained by reacting the 2-aminocyclopent-1-en-1-dithiocarboxylic acid, which is unsubstituted on its nitrogen atom, with the corresponding amines of the general formula R ¹ - NH ₂ , where R 'has the above meanings of R with the exception of hydrogen may have been made.

The invention is explained in more detail by means of the following examples.

- ?? - 809827/0990

- mfc. -

example 1

Di-i2-rN- (allyl) -aminoJ-cyclopent-1-en-1- -thiocarbonyl ^ -disulfide

(Formula I with R ■ allyl residue)

2.98 g (0.015 mol) of 2- [N- (allyl) -amino3-cyoLopent-1-en-1-dithiocarboxylic acid were suspended in 30 cm * water, then 6.0 g (0.015 mol) of sodium hydroxide were in the form a 10% sodium hydroxide solution was added and the mixture was shaken for 10 minutes. A mixture of 3 cm * water, 0.9 g (0.0075 mol) of concentrated sulfuric acid and 0.9 g (0.0075 mol + 10%) of 30% hydrogen peroxide was then added at room temperature, and the mixture was then added for 3 hours shaken. The precipitated product was filtered off, washed with water and dried under a lamp. The product di- {2- [Li (allyl) -aminoJ-cyclopent-1-en-1} thiocarbonyl disulfide obtained in a yield of 84.4% of theory had a melting point of 140-141 ⁰ C.

Analysis:

calculated: S «32.3%, N x 7.08%; found: S · 31 * 84%, N «6.80%.

Example 2

Di-I2- (N- (ethyl) -amino3-cyclopent-1-en-1- thiocarbonyl disulfide

(Formula I with R »ethyl radical)

5.6 g (0.03 mol) of 2- (N- (ethyl) -amino]] -eye lopent-1-en-1-dithiocarboxylic acid were obtained suspended in 60 cnr water

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and 12.0 g (0.03 mol) of sodium hydroxide in the form of a 10% sodium hydroxide solution were added. The mixture was shaken for a few minutes and then a mixture of 8 cnr water, 1.65 g (0.016 mol) concentrated sulfuric acid and 1.86 g 30% hydrogen peroxide was added. The mixture was pounded for 3 hours, after which the precipitated product was filtered off, washed with water / water and dried under a lamp. The resulting crude product was then dissolved in a mixture of chloroform and benzene Volumverhältni r> 1: 3 dissolved and the solution was clarified with activated charcoal, filtered and allowed to stand overnight in a refrigerator. The deposited product was then filtered off, washed with benzene and air-dried. Had [2- £ N- (ethyl) -amino3-cyclopent-1-en-1-thiocarbonylj -disulfide a melting point of 150 ⁰ C. - the Di obtained as a product in a yield of 30% of theory

Analysis: S = 34 A%, N = 7 , 53%; calculated: S - 34 , 1%, N = 7 , 45%. found: example 3

Di-i2- £ N- (2'-methoxyethyl) amineq] cyclopent-1-ene-1-thiocarbonyl disulfide

(Formula I with R »2- [N- (methoxyethyl radical) 3

There was added 2.7 g (0.0125 mol) of 2- [N- (2'-methoxyethyl) - -amincfj-cyclopent-i-s - - dithiocarboxylic acid in 27 cnr V / Annor and the suspension was stirred at 20 ⁰ C with 5> 0 g (0.0125 mol) Nutriundiydrox.yd added in small portions in the form of a 10% sodium hydroxide solution. Daa mixture was shaken for a few minutes and then with a mixture of

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3 cm 'of water, 0.66 g (0.0067 mol) of concentrated sulfuric acid and 0.77 g (0.0067 mol) of 30% strength hydrogen peroxide were added, the mixture was shaken for 3 hours and left to stand overnight. The next day the deposited product was filtered off, washed with water and dried under a lamp. The di-i2-pi- (2'-metho3cyäthyl) -amino3-cyclopent-1 obtained in a yield of 48.2% of theory as product -en-i-thiocarbonylJ-disulfide had a melting point of 132 to 139 ⁰ O (with decomposition).

Analysis:

calculated: S - 29.65%, N - 6.48%; found: S-29.18%, N-6.39%.

Example 4

Di- ^ 2-rN- (cyclohexyl) -aminoJ-cyclopent-1- -βη-1-thiooarbonyl} disulfide

3.6 g (0.015 mol) of 2- {N- (cyclohexyl) -amino3- -cyclopent-i-en-i-dithiocarboxylic acid were suspended in 40 cm * water and with 6.0 g (0.015 mol) of sodium hydroxide in the form a 10% sodium hydroxide solution added. The mixture was shaken for 10 minutes and then added cm at 20 ⁰ C with a mixture of 5 * water, 0.8 g of concentrated sulfuric acid and 0.9 g of 30% hydrogen peroxide. The mixture was shaken for 4 hours, after which the precipitated product was filtered off, washed with water and dried under a lamp. The di-f2- £ n- (cyclohexyl) -aminoJ- cyclopent-i-ene-i-thiocarbonyl disulfide obtained as product in a yield of 64.6% had a melting point of 148 to 152 ⁰ O.

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-2g "

Analysis:

calculated: S = 26.55%, N = 5.83%; found: S - 23.67%, N ο 5.3%.

Claims 809827/0990

Claims (1)

Claims 1.) Di-f2-aminocyclopent-1-en-1-thiocarbony l} -disulfide the general formula wherein R represents hydrogen, an alkyl radical with 1 to 6 carbon atoms, optionally substituted by 1 or more alkoxy radical (s) with 1 to 4 carbon atoms, hydroxyl, carboxyl and / or amino group, an alkenyl radical with 2 to 4- Carbon atoms, a cycloalkyl radical with 3 to 8 carbon atoms or a phenyl radical, and their salts. 2.) Di- {2-arainooyclopent-1-en-1-thiocarbonylI-disulfide according to claim 1, characterized in that the alkyl radical for which R can stand is one with 609827/0990 ORIGINAL INSPECTED 1 to 4, especially 2 to 4, carbon atoms. J.) Di-te-aminocyclopent-i-en-i-thiocarbonylj-disulfide according to Claim 1 or 2, characterized in that the alkoxy radical or the alkoxy radicals by the or which the alkyl radical for which R can stand, can be substituted, such or is or are those with 1 or 2, in particular 1, carbon atoms. 4.) Di - ^ - aminocyclopent-i-en-i-thiocarbonyl} -disulfide According to claim 1, characterized in that the alkenyl radical for which R can stand is the allyl radical. 5 ·) Di - ^ - aminocyclopent-i-en-i-thiocarbonylj-disulfide according to claim 1, characterized in that the cycloalkyl radical, for which R can stand, one with 5 or 6 carbon atoms, in particular the cyclohexyl radical, is. 6.) Di - ^ - aminocyclopent-i-en-i-thiocarbonyljj -disulfid. 7.) Di- {2- |} i- (n-butyl) -amino3-cyclopent-1-en-1-thiocarbonylf -disulf id. 8.) Zinc salt of di-f2- [N- (n-butyl) -amino - cyclopent-1-en- -1-thiocarbonyl} disulfide. 9 ·) Di- {2- {N- (2 '-methoxyethyl) -amino] -cyclopent-'1-en-1- -thiocarbonylj -disulf id. 10.) Di- {2- | N- (cyclohexyl) -amino3-cyclopent-1-ene-1-thiocarbonylj -disulf id. H.) Di- [2- £ N- (ethyl) -aminoJ-cyclopent-1-en-1-thiocarbonyi \ -diaulfide. - 28 809827/0990 12.) Di- £ 2- £ N- (allyl) -amino3-cyclopent-1-en-1-thiocarbonylj- -disulfide. 13 ·) Medicinal products, characterized in that they contain 1 or more of the compounds according to Claims 1 to 12 as an active ingredient or active ingredients, expediently together with conventional pharmaceuticals Packaging means. 14.) Process for the preparation of the compounds according to claim 1 to 12, characterized in that in per se known manner a 2-aminocyclopent-i-en-i- -dithiocarboxylic acid of the general formula -R II C-SH wherein R is as defined in claims 1 to 12, oxidized, whereupon the obtained di - ^ - aminocyclppent-i-en-i-thiooarbonyfJ -disulf id of the general formula I converted into a salt in a manner known per se.