DD237662A5 - PROCESS FOR THE PREPARATION OF THIENO AND FURO (2,3-C) -PYRROLENES - Google Patents

Abstract

The invention relates to a process for the preparation of thieno and furo (2,3-c) -pyrroles, which are processed for use in human medicine and veterinary medicine for therapeutic purposes to preparations. By the process of the present invention, thieno and furo (2,3-c) pyrroles of the general formula wherein X1 and X2 represent an oxygen or sulfur atom, R1 is a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, an alkynyl group, a Alkoxyalkyl radical having 3 to 8 carbon atoms or an aromatic radical, R2 represents a hydrogen atom or a straight-chain or branched-chain alkyl radical, m is 2 or 3, wherein when m is 2, X1 and X2 denote a sulfur atom, U is a 3,4-diaminocyclobutene And U can also be one of the nitrogen-containing groups in which V is a nitrogen atom or the radical CH, W is NO 2 or CN, R is a hydrogen atom, a straight-chain or branched-chain alkyl radical having 1 to 8 carbon atoms or an alkynyl radical and R represents an alkyl group having 1 to 3 carbon atoms.

Description

NHR.

wherein V is nitrogen or CH, W is NO ₂ or CN, R 3 is hydrogen, straight or branched chain alkyl having 1 to 8 carbon atoms or alkynyl, and R _{4 is} alkyl of 1 to 3 Carbon atoms, characterized in that an amine of the general formula

^CH 2 ^X 2-! ^CH 2 ⁾ »- ^NH 2

wherein R ₁ , R ₂ , X ₁ , X ₂ and m have the above significance, each with a compound of the formula

CH S 3

V-W

OC "Ή 2 5

CH ₃ O

and then reacting the compound thus obtained with an amine R ₃ NH ₂ or a hydrazine R ₄ NH-NH ₂ , wherein R ₃ and R _{4 have} the above meaning.

For this 7-page formulas

Field of application of the invention

The thieno and furo [2,3-c] pyrroles prepared by the process of the present invention can be processed into secretory and anti-ulcer preparations for use in human and veterinary medicine.

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Characteristic of the known technical solutions

Histamine, which is present in numerous animal tissues, is involved in several physiological mechanisms, such as gastric acid secretion. The histamine acts to bind to the tissue receptors that are blocked in Hi-type receptors blocked by the classic antihistamine drugs, such as promethazine, and in H ₂ -type receptors that are resistant to this type of drug are insensitive and in particular responsible for the acid secretion of the stomach, divided.

Various compounds have been proposed as antagonists of H ₂ receptors for histamine and gastric acid and administered as drugs of drug compositions useful in the treatment of.

Gastric ulcers and other diseases caused by gastric acid or aggravated be used, especially cimetidine and ranitidine.

Numerous journals and monographs have already devoted themselves to the class of compounds of this type, which continues to be the subject of much work aimed at finding new, more effective and better adaptable compounds for the treatment of ulcer disease.

Chemically, comparison of the described compounds shows that they generally consist of an aromatic benzene ring or heterocyclic ring attached to a radical which is one of the nitrogen-containing radicals via an aliphatic chain most commonly bearing a heteroatom, primarily sulfur or oxygen Groups of organic chemistry is selected.

A relatively small number of fused bicyclic compounds possessing antagonistic properties of H ₂ receptors to histamine histamine appear to have been the subject of investigations.

Benzofuran derivatives are known from US Pat. No. 4,238,487 and imidazopyridines are disclosed by Belgian Pat. No. 779,775. PCT patent application WO 84/00544 describes compounds which are endowed with cell protecting and H ₂ antihistaminic properties and which are broadly defined as being derived from a bicyclic system consisting of a benzene nucleus or heterocyclic nucleus consists of five or six chain members and is connected to an aromatic or polyhydrogenated nitrogen-containing ring, and thus contain furo- and thienopyridine derivatives and isoquinoline derivatives.

The reaction equations and synthetic methods presented in the specification refer only to isoquinoline derivatives and furo- or thienopyridines, and the only compounds described are isoquinoline derivatives.

Neither of the proposed reaction schemes, nor any of the synthetic methods, makes it possible to prepare thieno and furo [2,3-c] pyrroles nor do they concern such systems.

French Patent 2384765 has as its object amino-substituted furan derivatives and French Patent 2391209 discloses aminoalkylthiophenes.

The compounds described in these two patents have a monocyclic dialkylaminoalkylfuran- or -thiophene structure.

These compounds used as drugs have a common mechanism of action of the type of "cimetidine".

Further, British Patent 2,098,988 entitled "1,2-Diaminocyclobutene-3,4-dione Derivatives" is particularly directed to compounds whose structure combines a thiophene or furan ring with an aminocyclobutylenedione end group.

These compounds, whose antihistaminic mechanism of action is comparable to that of "cimetidine", exhibit at most equivalent activity.

Object of the invention

The aim of the invention is the preparation of new better compounds with secretion-inhibiting and anti-ulcer properties.

Explanation of the essence of the invention

The object of the invention is a method for producing compounds with particularly strong antisecretory and anti-ulcer activity, which have a significantly better effect than compounds which are commonly used in therapy, such as cimetidine or ranitidine, or even against tetrahydroisoquinoline derivatives, which are preferred products in PCT patent application WO 84/00544 mentioned above.

These compounds of the invention are certain derivatives of bicyclic fused 5,6-dihydro-4H-thieno [2,3-clpyrrole and 5,6-dihydro-4H-furo [2,3-c] pyrrole systems represented by the following formulas I a and I b are reproduced.

(la) => ™ _v Il H (Ib)

These compounds according to the invention have the general formula

-3- 236

CH-X - (CH) - U 2 2 2 m

in which X ₁ and X ₂ each represent an oxygen atom or sulfur atom, Ri is a straight-chain or branched-chain alkyl radical having 1 to 8 carbon atoms, an alkynyl radical, preferably propargyl radical, an alkoxyalkyl radical having 3 to 8 carbon atoms or an aromatic radical, such as a phenyl or phenylalkyl radical , preferably a benzyl radical, R _{2 represents} a hydrogen atom or a straight-chain or branched-chain alkyl radical, m is 2 or 3, wherein X ₁ and X _{2 represent} a sulfur atom when m is 2, and U represents a SADiaminocyclobuten-i ^ -dione radical or Aminosulfonylformamidinrest and U is also one of the nitrogen-containing groups

fs

fs

U = -NH ^ Jj__J

~ ^NH *

(III) (IV) (V)

can mean.

In the formula (III), V may be a nitrogen atom or a CH fragment, W represents a preferably unsaturated group such as the cyano or nitro group, and R _{3 represents} a hydrogen atom, a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms or a Alkynyl, preferably the Propargylrest, in the formula (IV) R ₄ can be an alkyl group having 1 to 3 carbon atoms, but is preferably a methyl group, in the formula (V) R _{3 has} the same meaning as defined above.

R ₂ may preferably be methyl if X _{1 is} sulfur.

It should be noted that in the formulas (III) to (V) above, although the double bonds are indicated in specific positions, various other tautomeric forms are possible and the invention is equally concerned with tautomeric forms, both as the compounds of the invention as well as new intermediates of the synthesis.

Apart from the fact that the compounds according to the invention are superior to the known active in particular with respect to the antisecretory and anti-ulcer activity, it has been found that the H ₂ receptor antagonist effect on histamine of the compounds of the invention according to a mechanism for this activity is peculiar and of a weakly reversible type, giving these compounds markedly lasting antisecretory properties.

As specific compounds according to the invention may be mentioned the following:

N-cyano-N '- [2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N "-methylguanidine N- [2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] 2-pyrrolyl) methylthio] ethyl] -1-methylthio-2-nitroethenamine N- [2 - [( 5-Ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N'-methyl-2-nitroethene-1,1-diamine N-cyano- N '- [2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N "-isopropylguanidine N-cyano- N '- [2 - [(5,6-dihydro-5-methyl-4H-thieno [2,3-c] -2-pyrrollyl) -methylthio] -ethyl] -N "-methylguanidine N-cyano-N' - [2 - [(5,6-dihydro-5-isopropyl-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N "-methylguanidine N- [2 - [(5 -Benzyl-5,6-dihydro-4H-thieno [-2,3-c] -2-pyrrolyl) methylthio] ethyl] -N'-cyano-N "-methylguanidine 3 - [(5-ethyl-5 , 6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] -N-sulfamoylpropanamidine in N-cyano-N'-ethyl-N "- [2 - [(5-ethyl-5, 6-dihydro-4H-thieno [2,3-c] pyrrolyl) methylthio] ethyl] guanidine N- [2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3- c] -2-pyrrolyl (methylthio] ethyl] -1 -methyl-1H-1,2,4-triazole-3,5-diamine N-cyano-N '- [2 [(5,6-dihydro-5-phenyl-4H-thieno [2,3-c] - 2-pyrrolyl) methylthio] ethyl] -N "-methylguanidine N- [2 - [(5-ethyl-5,6, dihydro-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] -ethyl] -1-oxide thiadiazolo [1,2,5] -3,4-diamine N- [2 - [(5,6-dihydro-5-methyl-4H-thieno [2,3-c] -2 -pyrrolyl) -methylthio] -ethyl] -N'-methyl-2-nitroethene-1,1-diamine N - ^ - KB-ethyl-B ^ -dihydroH-furo ^ S-c 1-8 -pyrroly-D-methylthiol ethyl-N'-methyl -nitroethen-U-diamine N-cyano-N '- [2-t (5-ethyl-5,6-dihydro-4H-furo [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N "-methylguanidine NU-KS-ethyl-B ^ -dihydro-H-furo-S-c 1-8 -pyrroly-D-methylthiol-ethyl-1-methylthio-nitroethenamine N-cyano-N ' [2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N "-propargylguanidine N- [2 - [(5, 6-Dihydro-5-n-pentyl-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] ethyl] -N'-methyl-2-nitroethene-1,1-diamine N- [2 - [(5-ethyl-5,6-dihydro-3-methyl-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] ethyl] -N'-methyl-2-nitroethene-1, 1-diamine

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N- [2 - [(5,6-dihydro-5-n-propyl-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] ethyl] -1-oxidthiadiazol [1,2,5 ] -3,4-diamine N- [2 - [(5-ethyl-5,6-dihydro-3-methyl-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] - 1-methylthio-2-nitroethenamine N- [2 - [(5,6-Dihydro-5-n-pentyl-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -1- methylthio-2-nitroethenamine N-Cyano-N '- [2 - [(5,6-dihydro-5-phenyl-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -S -methylisothiourea N-cyano-N '- [2 - [(5-ethyl-5 _/ 6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -S-methylisothiourea N - [2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) methoxy] ethyl] -1-oxidthiadiazoI [1,2,5] -3 , 4-diamine

N- [2 - [[5,6-Dihydro-5- (2-methoxyethyl) -4H-thieno [2,3-c] -2-pyrrolyl] methylthio] ethyl] -1-oxidthiadiazol [1,2- , 5] -3,4-diamine 3-amino-4- [2 - [(5,6-dihydro-5-n-propyl-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] -ethylamino] -cyclobuten-1,2-dione N- [2 - [(5,6-dihydro-5-n-propyl-4H-furo [2,3-c] -2-pyrrolyl) -methylthio] -ethyl ] -1-oxide thiadiazolo [1,2,5] -3,4-diamine The compounds of the invention readily form acid addition salts with a mineral acid or organic acid. As mineral acid salts which are therapeutically acceptable, it is possible to cite, for example, the chlorohydrates, bromohydrates, sulfates, phosphates, sulfonates. Examples of particularly useful organic salts are the acetates, tartrates, citrates, camphosulfonates, maleates, fumarates and methanesulfonates. All of these addition salts are also within the spirit of the invention.

Because of their ability to inhibit gastric acid secretion in the organism, the compounds have anti-ulcer activity. This particularly strong and sustained action makes their use in the treatment of peptic ulcers and other similar pathological phenomena extremely interesting. It should be noted that the duration and intensity of the anti-secretory effect and anti-ulcer effect of the compounds according to the invention of the formula I on the nature of the heteroatoms Xi and X _2, but to a large extent also depend on the nature of the substituent R _1, and in this respect are compounds of the formula I which are particularly preferred, those in which Xi and X _{2 represent} a sulfur atom and Ri is a group as defined above and has an aliphatic radical of at least 2 carbon atoms, which is connected to the nitrogen atom of the pyrolysis.

A method commonly used to study the activity against gastric acid secretion is that of rats with ligated pylorus, as described by Shay, H., et al, Gastroenterology, 1945, 5, 43. Female rats of about 200 g, fasting for 72 h, receive the pylorus under light ether anesthesia tied. 4 hours later the animals are sacrificed and the stomach contents are removed for acidity measurement. The compounds are injected intraperitoneally shortly after pylorus detachment. The dose that reduces gastric acid by 50% (ED _S0 ) is calculated for each compound compared to an untreated group. Each compound is tested at three geometrically spaced dosages.

Each group comprises 10 rats.

The blockage of H ₂ histamine receptors in gastric acid secretion was studied in vitro on isolated guinea pig atrium and in vivo on the gastric hyperacidity method with histamine in the anesthetized rat.

Isolated guinea pig heart atrial: Albino guinea pigs weighing between 300 and 400g are killed and bled. After opening the thorax, the right atrium is rapidly removed and placed in a tray for isolated organs containing 100 ml of Krebs solution (composition in g / l: NaCl 6.9 -KCl 0.35-CaCl ₂ 0.28-MgSO ₄ O, 14 NaHCO ₃ 2.09 KH ₂ PO ₄ 0.16-glucose 2), maintained at 32 ° C, and vigorously oxygenated (95% O ₂ , 5% CO ₂ ).

The atrium is again connected to a measuring body of isometric pressure under a tension of 1 g. The spontaneous beats are recorded on a galvanometric recorder.

After a 1 h stabilization period, histamine doses accumulated in the survival medium are added every 5 min, causing acceleration of the beats by stimulating the histamine receptors that are in the heart tissue of H ₂ nature. The histamine is added until the rhythm of the atrium is no longer increased (maximum effect). One can then record the curve representing the change in rhythm as a function of the histamine concentration in the bath.

After rinsing and a 30 minute rest, the same experiment is repeated 30 minutes after the addition of an H ₂ antagonist to the bath (compound of the invention or control product).

Each compound is thus tested at three geometrically increasing concentrations, which, in the case of blockage of the H ₂ receptors, causes a shift in the histamine concentration / chronotropic action curves to the right. For each active compound, a pA _{2 is} determined, ie the cologarithm of the concentration of the test compound in which the histamine concentration must be doubled in order to recover a particular chronotropic effect. The calculation is carried out according to the method of O. Arunlakshana and HO ShNd, Br. J. Pharmac, 1959, 14, page 48.

A minimum of three atria are used for each compound tested.

This preparation thus allows to account for the nature, reversible or not, of the inhibition. In the first case, it will always be possible to displace the receptor antagonist when performing repeated rinses or when using a higher concentration of histamine, which is expressed by the curves of histamine concentration / chronotropic action, but in parallel but superimposable.

In contrast, in the second case (severe reversible inhibition), H ₂ -antagonism can not be completely abolished, either by flushing or by increased histamine concentrations, as indicated by the dose-response curves that are not superimposable (the maximum chronotropic effect decreasing as the concentration of the H ₂ antagonist increases).

Gastric hyperacidity with histamine in the anesthetized rat (Black et al, Nature, 1972, 236, page 385): Ethyl anesthetized rats receive continuous histamine perfusion (25 μg / kg / min) in a laryngeal vein. The stomach is continuously perfused with physiological saline of 37 ⁰ C at a constant rate of 3 ml / min.

A pyloric cannula collects the perfusate, whose acidity is continuously measured. Each compound to be tested is administered by intravenous route (a single dose per rat). The inhibition of the acid is measured with a delay corresponding to the maximum of action (variable delay from one compound to another). A minimum of three rats is used for each dose tested. For each active compound of the invention, the dose which reduces histamine-induced hyperacidity by 50% (ED ₆₀ ) is determined. In addition, for the most active compounds, the duration of action resulting from an intravenous injection of a single dose corresponding to the rounded up ED ₅₀ value is also measured.

The compounds of the invention are generally very low in toxicity. For example, the compound of Example 22 shows no toxic effect whatsoever when administered iv to mice or rats at a dose equal to 100 times the ED ₅₀ value in the gastric hyperacidity test with histamine in the anesthetized rat.

The following Tables 1 to 4 show for the methods described above, the activities of the compounds according to the invention and those of comparative products. It should be noted that the compound denoted by A in the following tables is N-methyl-N '- [3- (2-methyl-1,2,3,4-tetrahydro-5-isoquinolinoxy) -propyl] -2 nitro-1,2-diamine described and claimed in PCT Patent Application WO 84/00544 as a preferred compound.

Table 1

Rats with Shay resigned pylorus Table 2 ED ₅₀ and 95% pA2 relative strength Ranitidine = 1 connection border and 95 -% - Limits 0.75 of example no. (Mg / kg / i.p.) 6,98 (6,70-7,27) Cimetidine = 1 1.75 19 (9-40) 7.11 (6.85 to 7.38) 2.2 1 8 (4,4-14) 6.21 (5.97-6.46) 5.25 0.8 3 > 50 6.89 (6.66 to 7.13) 1.75 6 18 (7,5- ^ 13) 6.85 (6.64-7.06) 2.3 9.3 8th 8 (4-16) 7.68 (7.46-7.90) 5.2 0.9 11 1.5 (0.9-2.4) * 7.05 (6.82-7.29) 28 13 15 (8,3-27) 5.90 (5.67 to 6.14) 2.8 0.7 18 > 50 7.37 (7.17 to 7.58) 0.4 19 20 (9,5-42) 7.10 (6.87 to 7.34) 2.1 28 20 32 (18-58) * 7.77 (7.53-8.02) 1.3 14 21 0.5 (0.3-0.8) * 7.37 (7.08-7.67) 84 ' 15.5 22 1 (0.3-3) * 7.55 (7.29-7.81) , 4Z 28 28 0.9 (0.3-2.5) * 7.19 (6.95-7.44) 46.7 3.9 29 0.5 (0.2-1.2) * 7.51 (7.26-7.77) 84 20 30 3.6 (1.9 to 6.8) * 7.31 (7.01-7.62) 11.7 1.3 31 0.7 (0.3-1.6) 7,20 (6,94-7,47) 60 1 33 11 (6-21) 3.8 0.3 34 14 (6-32,2) 3 ranitidine 42 (24,7-71,4) 1 cimetidine > 50 Connection A isolated auricle of guinea pig connection relative strength Ranitidine = 1 of example no. 0.35 Cimetidine = 1 0.47 1 1.10 0.06 3 1.48 0.28 6 0.19 0.26 8th 0.89 1.74 11 0.81 0.41 13 5.50 0.03 18 1.29 0.85 19 0.09 0.46 20 2.69 2.14 21 1.45 0.85 22 6.76 1.29 28 2.69 0.56 29 4.07 1.17 30 1.78 0.74 31 3.72 0.58 33 2.34 34 1.82

Ranitidine cimetidine Compound A

7.44 (7,12-7,76) 6,94 (6,77-7,11) 5,88 (5,66-6,1)

3.16

0.087

0.32 0.028

Table 3

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Gastric hyperacidity with histamine in the anesthetized rat Compound of Example No.

ED ₅₀ and 95%

border

(Mg / kg / i.v.)

relative strength

Cimetidine = 1

Ranitidine = 1

1 3 6 8 11 13 18 19 20 21 22 28 29 30 31 33 34

0.6 (0.25-1.5)

0.3 (0.1-0.9)

> 5

0.5 (0,18-1,4)

0.4 (0.15-1)

0.03 (0.02-0.05)

0.5 (0,17-1,5)

> 5

0.1 (0.03-0.3)

0.6 (0.3-1.2)

0.05 (0.02 to 0.11)

0.2 (0.08-0.5)

0.1 (0.04-0.25)

0.2 (0.07-0.6)

0.15 (0.07-0.3)

0.2 (0.08-0.5)

0.25 (0.12-0.5)

2.7

0.15 0.3

0.18 0.22 3 0.18

0.9

0.15

1.8

0.45

0.9

0.45

0.6

0.45

0.36

Ranitidine cimetidine Compound A 0.09 (0.05-0.17) 4.4 0.4 (0.18-0.9) 1> 5 duration relative strength 1 0.22 Table 4 n * (minutes ± deviation) Cimetidine 1 Gastric hyperacidity with histamine in the anesthetized rat Compound of Example No. Ranitidine 1

1 3 8 11 13 18 20 21 22 28 29 30 31 33 34

3 112 ± 27 1.6 1.4 4 90 ± 20 1.3 1.2 3 128 ± 22 1.8 1.7 3 88 ± 24 1.2 1.1 CJI 120 ± 18 1.7 1.6 3 > 8h > 6.2 > 6.7 3 102 ± 22 1.4 1.3 3 76 ± 20 1.1 1 8th > 8h > 6.2 > 6.7 4 > 8h > 6.2 > 6.7 4 > 8h > 6.2 > 6.7 3 > 8h > 6.2 > 6.7 3 > 8h > 6.2 > 6.7 3 > 8h > 6.2 > 6.7 3 85 ± 21 1.2 1.1

Ranitidine cimetidine

71 ± 13 77 + 10

* η = number of trials

The present invention relates to pharmaceutical compositions which are formed by the products of general formula II, optionally in salt form, in the pure state or in the form of combinations with any other product which is pharmaceutically acceptable and may be inert or physiologically active. These drugs can be administered in a wide variety of different dosage forms, such as tablets, troches, capsules, powders, granules, etc. In these compositions, the active ingredient is mixed with one or more inert diluents, such as lactose or starch; substances other than diluents, such as lubricants, such as talc or magnesium stearate. When aqueous suspensions, elixirs or syrups for oral administration are desired, the essential active may be combined with various sweetening and / or flavoring agents, optionally with emulsifying and / or suspending agents, simultaneously with diluents such as water, ethanol, propylene glycol and various similar combinations. A pharmaceutical composition which is orally administrable and is in a unit dosage form containing from 5 to 500 mg of the active ingredient is considered to be of interest.

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example 10 mg active substance 100 mg lactose 30 mg as starch 6 mg talc 3 mg Povidone-binder 1 mg magnesium stearate

To prepare the compounds of general formula II in which X ₁ and X ₂ both denote a sulfur atom and U is a 3,4-diaminocyclobutene-1,2-dione radical, is allowed to successively under the S. Cohen and SG Cohen in J. Amer. Chem. Soc., 1966, 88, pages 1533 to 1536, a 3,4-dialkoxycyclobutene-1,2-dione, the preparation of which is also described in this publication, with an amine of the general formula VI

(VI)

in which Ri and R _{2 have} the same meaning as above, react, after which reacting the thus obtained intermediate with ammonia.

The compounds of general formula II, in which Χ _Ί and X _{2 denote} a sulfur atom and U is an N-Aminosulfonylamidinrest, can be prepared by reacting sulfamide with an imino ether of general formula VII

JZH SCH CH _ ^

² 2-2 \ (VII)

OCH

wherein Ri and R ₂ are as defined above. The reaction is carried out in a polar solvent, preferably an alcohol, such as methanol, under an inert atmosphere and at a temperature near ambient temperature.

The compounds of general formula II in which m has the value 2 and U is a nitrogen-containing radical corresponding to formula III can be prepared by reacting a compound of general formula VIII

'V / ^c

^x 2 2

2 2

' Nc

(VII)

wherein Xi, X ₂ , Ri, R ₂ , V and W have the above meaning, with an amine compound of the general formula RsNH ₂ , wherein R _{3 has} the above meaning, are prepared. The reaction may be carried out in any solvent or diluent compatible with the compounds present, but is preferably in a sufficiently polar solvent such as ethanol, methanol or acetonitrile and at a temperature between ambient and the reflux temperature of the solvent used can lie, carried out.

A second process for the preparation of the compounds of formula II wherein m is 2, U is a nitrogen-containing radical of formula III and Χι is a sulfur atom, is a halogenated compound of formula IX

wherein X is a halogen atom, preferably chlorine and Ri and R _{2 have} the above meaning, or one of their salts, preferably the hydrochloride, with a thiol of the general formula X.

NHR.

wherein R _{3 has} the above meaning, lets react. The reaction is carried out in a hydroxyl-containing solvent such as an alcohol at ambient temperature and in the presence of a basic agent which may be an alkali hydride, alcoholate, carbonate or bicarbonate, but is preferably sodium alcoholate prepared in situ when the selected solvent is one

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The thiols of the formula X can be prepared from a compound of the formula XI

= V-W (XI)

CH ₃ S

CH ₃ S

in which V and W have the above meanings and which are reacted with an amine of the formula R ₃ NH 2, in which R _{3 has} the above meaning, under the conditions described by JS Davidson, Chem. Ind. (London), 1965, 48, pages 1964 to 1965, and / or in the case where the link = VW = NCN group, by the method of FHS Curd et al, J.Chem.Soc, 1948, pages 1630 to 1636, starting from sodium cyanamide and an isothiocyanate of the formula R ₃ NCS. The compound thus obtained is treated with cysteamine hydrochloride in aqueous-alcoholic medium in the presence of a basic agent such as soda.

The compounds of general formula XI in which = V-W is a group = N-CN or = CH-NO 2 are known and their preparation is described by R.J. Timmons and L.S.Wittenbrookin J. Org. Chem., 1967, 32, pages 1566 to 1572, and by R. Gompper and H. Schaefer, Chem. Ber., 1967, 100, pages 591 to 604.

In order to prepare the compounds of general formula II in which m is 2 and U is an aminotriazole radical of general formula IV, a compound of general formula VIII in which = VW is a group = NCN is allowed to react with an alkylhydrazine of formula R ₄ NHNH ₂ , wherein R _{4 has} the above meaning, react. The reaction may be carried out in any solvent inert to the compounds present, such as in an aromatic hydrocarbon such as toluene, xylene, trimethylbenzene, etc., and may be carried out at a temperature between the ambient temperature and the reflux temperature of the solvent used ,

The compounds of the formula II in which U is an aminothiadiazole radical of the formula V can be obtained by reacting an amine of the general formula XII

(XII)

successively with a 3,4-dialkoxythiadiazolo [1,2,5] -S-oxide and an amine of the formula R ₃ NH ₂ , wherein R _{3 has} the above meaning, under the conditions of S. Karady et al. Heterocycles, 1981, 16, page 1561.

Another process for the preparation of compounds of general formula II in which U is a Thiadiazolrest of formula V and Xi and X _{2 are} both sulfur atoms, is an alcohol of formula XIII

(XIII)

wherein R ₁ and R _{2 have} the above meaning, with a thiol of formula XIV

0 t

(XIV)

HS- (CH) -NH ^'X NHR

2 m .3

wherein R ₃ and m have the above meanings and which can be prepared under the conditions of the above-mentioned publication by S. Karady et al., reacting successively with a 3,4-dialkoxythiadiazolo [1,2,5] -S -oxid dieCysteamin and an amine of the formula R ₃ NH _{2 is} reacted. The reaction of compound XIII with compound XIV is carried out in the presence of a dehydrating agent, preferably in the presence of concentrated hydrochloric acid, and at a temperature near 0 ° C.

The 3,4-dialkoxythiadiazolo [1,2,5] -S-oxides used are known compounds described by S. Karady et al. Heterocycles, 1981, 16, page 1561.

The above-defined intermediate amines of the general formula VI are novel compounds which can be prepared as the following reaction scheme 1 shows, according to which an ester of the general formula XV, wherein R is an alkyl group, preferably methyl or ethyl, in the alcohol accordingly XIII with the aid of reducing agents for the ester function, such as diborane or lithium and aluminum hydride, in a suitable solvent, such as ether or tetrahydrofuran, reduced.

-9- 236 662

COOR

-N.

I i

CH OH 2

(XV)

I) SHCH CH NH / HCl 2 2 2

2) base

CH CH CH NH 2 2 2 2

(XIII)

halogenation ·

SHCH CH NH Cl 2 2 3

base

(VI) (IX)

By reacting the alcohols XIII thus obtained with the cysteamine in the presence of a dehydrating agent under the conditions already indicated (condensation of an alcohol XIII with a thiol XIV), the desired compounds are obtained

Amines Vl in an acceptable yield.

A second method consists in converting an alcohol XIII into the corresponding halide IX, which is then treated with the cysteamine in basic medium under the conditions already mentioned (alkylation of the thiols of formula X). The halogenation of the alcohol XIII may be carried out with the aid of customary reactants, such as with thionyl chloride in an inert solvent such as chloroform or methylene chloride and at a temperature between 0 ⁰ C and the reflux temperature, but preferably at a temperature close to the ambient temperature.

The imino ethers of the general formula VII are obtained by the action of methanol on a nitrile of the general formula XVII

CH CH CH CN

(XVII)

wherein R ₁ and R _{2 have} the above meaning, under the usual conditions of the production of imino ethers, as can be found, for example, in Houben-Weyl, Methods of Organic Chemistry, 1952.8, page 697 described. The compounds of general formula XVII are novel and can be prepared according to the following Reaction Scheme 2 by alkylation of a halide IX with thiourea and subsequent hydrolysis of the intermediate isothiouronium salt under customary conditions, as described in particular in Houben-Weyl, Methoden der Organischen Chemie, 1955, 9 , Page 14, to obtain the corresponding thiol of formula XVI, which can be subsequently alkylated with an ω-halogenated propanenitrile, preferably with 3-chloropropanenitrile.

Scheme 2

(IX)

(XVI)

1) NH ₂ CSNH ₂

2) NaOH-H 0

3) H ⁺

XCH CH CN 2 2

base

This alkylation is carried out in a polar solvent such as methanol in the presence of a basic agent such as sodium methylate and at a temperature between 0 ° C and ambient temperature.

The compounds of general formula VIII are prepared by reacting an amine of general formula XII in which m is 2 with a compound of formula XI in any solvent or diluent compatible with the reactants present, preferably in a sufficiently polar solvent such as acetonitrile and at a temperature

iart

-ί- 236 662

The amines of general formula XII, wherein Χι is sulfur, X _{2 is} oxygen and m is 2, can be prepared by condensing a halide of formula IX with ethanolamine, the reaction preferably being carried out in an excess of ethanolamine.

The amines of general formula XII, in which Χ _Ί and X _{2 are} both sulfur atoms and m is 3, can be prepared by alkylating a thiol of formula XVI with an ω-halopropylamine, preferably 3-bromopropylamine, in basic medium or by reduction of a nitrile of general formula XVII with a known reducing agent of the nitrile function, such as lithium and aluminum hydride, in a suitable solvent, such as ether or tetrahydrofuran synthesized.

The amines of the general formula XII in which X-, an oxygen atom, X _{2 is} a sulfur atom and m 2, can be prepared by reducing an ester of the general formula XIX with the aid of a reducing agent for the ester function in a suitable solvent and subsequent condensation of the so obtained alcohol XVIII with cysteamine, as illustrated by the following reaction scheme 3.

Scheme 3

COOR

(XVI II)

I) HSCH CH NH - '/ HCl 2 2' 2 -

2) base

The alkylthienopyrrolecarboxylates of general formula XV are already partially described. These compounds can be prepared by the following known reaction sequence starting from an ester XXI which is subjected to a chloromethylation reaction. This gives the dihalide XX which is then converted to the desired ester XV by reaction with an amine RiNH ₂ according to the method of J. Feijen and H. Wynberg, Rec. Trav. Chim. PaysBas, 1970, 89, p. 639, is cyclized.

CY,

COOR

HCHO, HCl, ZnCl ₇

(XXI)

(XX)

(XV)

As the chloromethylating agent, it is possible to use the mixture of polyoxymethylene and hydrochloric acid as described by ChoSone, Nippon Kagaku Zasshi, 1965, 86, page 1331 -CA., 65, 13637c, preferably for the chloromethyl methyl ether held toxic.

The esters of general formula XIX, which are new products, can be prepared from 5-methyl-2-furanmethylcarbox'ylate as illustrated by the following Reaction Scheme-4.

-11- 236 662

Scheme 4

clck,

I i

HCHO, HCl, CHCl.

COOCH

CH ~ ^u CO CH 3 2 3

R NH

(XIX)

BrCH

AX

CO CH 2 3

In this reaction scheme, products known to be S-chloromethyl-methyl-δ-furan-methylcarboxylate and 2-bromomethyl-3-chloromethyl-5-furan-methylcarboxylate are those of AL Mndshoyan et al. In Doklady Akad. Nauk. Armyan, 1957,25, page 277 - CA. 52.12835 b and M.Valenta et al in Collection Czech. Chem. Commun., 1964, 29, page 1577 - CA., 61.6976g. The cyclization reaction with an amine of the formula RiNH ₂ is preferably carried out in a polar aprotic solvent, such as acetonitrile, under an inert atmosphere and at a temperature close to ambient temperature. The through the formula

OX

(XII)

represented amines, wherein R ₁ , R ₂ , Xi, X ₂ and m have the above meaning, wherein, when Χ _{Ί is} an oxygen atom, R _{2 is} a hydrogen atom, X _{2 is} a sulfur atom and m 2, the intermediates in the preparation of Compounds according to the formula II are part of the invention

 The compounds of formula XXII

(XXII)

I i

wherein Ri and R _{2 have} the above meanings and Y is one of the groups:

OH, halogen, SH, -S (CH ₂ ) ₂ CN, -S (CH ₂ )

OCH.

are intermediates in the preparation of the compounds of formula II when Χι is a sulfur atom, and are part of the invention.

The compounds of the formula XXIII

(XXIII)

wherein Ri is as defined above and Z is one of the groups -COOCH ₃ or -CH ₂ OH are intermediates in the preparation of the compounds of formula II when Χι represents an oxygen atom, and form part of the invention.

-12- 236 662 embodiments

In the following examples, the melting points are given in degrees Celsius and the boiling points in millibar.

Example 1 N-Cyano-N '- [2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N "-methylguanidine (formula I) to a solution of sodium methoxide in methanol, prepared by dissolving 0.9 g (0.039 gram atoms) of sodium in 50 cm ³ of methanol, are employed at a TemperaturzwischenO and 5 ° C a solution of 5.6 g (0.035 mol) of N-cyano-N '- (2-mercaptoethyl) -N "-methylguanidine in 40cm ^{3 of} methanol. The mixture is stirred at 0 ° C. for 2 h, then 4.2 g (0.0176 mol) of 2-chloromethyl-5-ethyl-5,6-dihydro-4H-thieno [2,3-c] are added at this temperature. -pyrroIchlorhydratzu. The stirring is continued for 42 h at ambient temperature, after which the mixture is evaporated, the residue is dissolved in a sufficient amount of chloroform, the resulting solution is washed with sodium carbonate solution and then with water, the organic phase is dried over sodium sulfate, filtered, the solvent is evaporated, the Residue dispersed in diisopropyl ether, filtered off with suction and dried. Weight = 3.3 g, yield = 58%, mp = 129-132 ° C, mp = 142-143 ° C (isopropanol).

NMR (DMSOd ₆ ): 1.3 (t) 3H (CH ₃ CH ₂ ), 2.6-3.3 (m) 7H (CH ₃ CH ₂ N, CH ₃ N, SCH ₂ ), 3.8- 4.3 (m) 8H (CH ₂ S, N-CH ₂ ), 6.8-7.3 (m) 3H (NH, aromatic H).

Analysis: C ₁₄ H ₂ IN ₅ S ₂ - MW = 323.48

% C% H% N% S

calculated: 51.98 6.54 21.65 19.83

found: 52.02 6.55 21.81 19.53

Example 2 IM- [2 - [(5-Ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -1-methylthio-2-nitroethenamine (Formula 2) A mixture of 7.8 g (0.032 mol) of 2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methyl thio] is heated at reflux conditions for 12 h. ethylamine and 5.3 g (0,032MoI) of 2,2'-bismethylthio-2-nitroethene in 100 cm ³ of acetonitrile. Then the reaction mixture is filtered, the filtrate is evaporated to dryness, the residue thus obtained is dispersed in the smallest amount of ethyl acetate required, filtered off with suction, the solid is washed with diisopropyl ether and then dried. Weight = 7g, yield = 61%, mp = 85-87 ° C, mp = 93-94 ⁰ C (diisopropyl ether / isopropanol, 1/1).

NMR (CDCl ₃ ): 1.2 (t) 3H (CH ₃ -CH ₂ ), 1.8 (s) 1H (NH), 2.4 (s) 3H (CH ₃ S), 2.6- 3.1 (m) 4H (SCH ₂ , CH ₃ CH ₂ N), 3.33-4.1 (m) 8H (CH ₂ N, CH ₂ S), 6.6 (s) and 6.75 ( s) 2H (= CH, aromatic H)

Analysis: C ₁₄ H ₂₁ N ₃ O ₂ S ₃ - GM = 359.53

% C% H% N% S.

calculated: 46.77 5.89 11.69 26.75

found: 46.52 5.90 11.85 26.45

Example 3 N- [2 - [(5-Ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N'-methyl-2-nitroethene 1,1-Diamine (Formula 3) A solution of 5.3 (0.0147 mol) of the compound of Example 2 in 15 cm ^{3 of} a 33% solution of methylamine in ethanol is heated at reflux conditions for 11 h, then the mixture is evaporated a, the resulting residue is dispersed in the sufficient amount of ethyl acetate, filtered off with suction and dried. Weight = 4.6 g, yield = 92%, mp = 96-101 ° C, mp = 99-101 ° C (ethyl acetate / isopropanol, 2/1).

NMR (CDCl ₃ ): 1.2 (t) 3H (CH ₃ -CH ₂ ), 2.6-4.08 (m) 15H (CH ₂ ), 6.6-7.3 (m) 3H (= CH, NH), 10.1 (s broadened) 1 H (NH).

Analysis: C ₁₄ H ₂₂ N ₄ O ₂ S ₂ -MG = 342.48

% C% H% N% S

calculated: 49.09 6.48 16.36 18.73

found: 49.09 6.39 16.19 18.90

Example 4 N-Cyano-N '- [2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N "-isopropylguanidine (Formula 4) To a methanolic solution of sodium methylate, prepared by dissolving 1 g (0.0434 gram atoms) of sodium in 50 cm ^{3 of} methanol and cooling to 0-5 ° C, is placed 7.2 g (0.0386 mol) of N -Cyano-N'-isopropyl-N "- (2-mercapto-ethyl) -guanidine in solution in 85cm ^{3 of} methanol. The mixture is stirred for 2 h between 0 and 5 ⁰ C, then placed 4.6 g (0.0193 mol) of 2-chloromethyl-5,6-dihydro-5-ethyl-4H-thieno [2,3-c] -pyrrolchlorhydrat in solution in 50cm ^{3 of} methanol. Stirring of the mixture is continued for 24 h at ambient temperature, then evaporated, the resulting residue is diluted in the sufficient amount of chloroform, the resulting solution is washed with sodium carbonate solution and then with water, the organic phase is dried over sodium sulfate, filtered, evaporated the solvent and the residue is dispersed in ethyl acetate, filtered off with suction and dried. Weight = 6.8g, Yield = 47%, mp = 92-95 ° C, mp = 97-99X (diisopropyl ether / isopropanol, 5/1). Analysis: C ₁₆ H ₂₅ N ₆ S ₂ - MW = 351.53

% C% H

calculated: 54.66 7.17

found: 54.40 7.24

The compounds of Examples 5, 6 and 7 below are prepared according to the procedure described in Example 1 using the appropriate 2-chloromethylthieno [2,3-c] pyrrole.

% N % S 19.93 18.24 20.16 18.31

236

Example 5 N-Cyano-N '- [2 - [(5,6-dihydro-5-methyl-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] ethyl] -N "-methylguanidine (Formula 5)

Mp = 145-147 ° C (isopropanol) Analysis: C ₁₃ H ₁₉ N ₆ S ₂ - MW = 309.45

% C% H% N% S

calculated: 50.46 6.19 22.63 20.72

Found: 50.34 6.21 22.45 20.57

Example 6: N-Cyano-N '- [2 - [(5,6-dihydro-5-isopropyl-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N "- Methylguanidine (Formula 6)

Mp = 120-121 ⁰ C (diisopropyl ether / isopropanol, 2/1). Analysis: Ci ₅ N ₃₃ N ₅ S ₂ -MG = 337.50

% C% H% N% S

calculated: 53.38 6.87 20.75 19.00

found: 53.49 6.97 20.99 19.17

Example 7 IM-t2 - [(5-Benzyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N'-cyano-N "-methylguanidine ( Formula 7)

F. = 122-123 ° C (diisopropyl ether / isopropanol, 1/3) Analysis: Ci ₉ H ₂₃ N ₅ S ₂ -MG = 385.54

% C% H% N% S

calculated: 59.19 6.01 18.17 16.63

found: 59,02 6,10 17,90 16,58

Example 8 S-KS-ethyl-Se-dihydro-H-thienoK.S-cis -pyrrolyl-1-methylthiol-N-sulfamoylpropanamidine (Formula 8) A mixture of 11.3 g was stirred in a reactor under a nitrogen atmosphere for 48 hours (0,0397MoI) S-IFS-ethyl-ö ^ -dihydro ^ H-thieno ^^ - ^ cl -pyrrolyD-methylthiol-methylpropanimidat and 7.6 g (0,08MoI) sulfamide in 100 cm ³ of methanol, evaporated, taken up the Residue in chloroform, filtered, the filtrate is evaporated and the residue is recrystallized from isopropanol. Weight = 3.8 g, yield = 28%, mp = 124-13O ⁰ C.

Dissolve this solid in chloroform by adding a little methanol, and chromatograph this solution on a silica gel column using a 5% solution of methanol in chloroform as the eluent. Weight 1 = 1,1g,

Mp = 137-139 ° C (isopropanol / ethanol, 4/1).

NMR (DMSO-d ₆ ): 1 (t) 3H (CH ₃ ), 2.25-3 (m) 6H (CH ₂ -C, SCH ₂ , CH ₂ N), 3-4.2 (m) 6H (CH ₂ S, NCH ₂ ), 6.4 (s) 2H (NH ₂ ), 6.75 (s) 1H (thiophene-H), 7-8.2 (m) 2H (NH ₂ ).

Analysis: C ₁₂ H ₂₀ N ₄ S ₃ -MG = 348.51

% C% H% N% S

Calculated: 41.35 5.79 16.08 27.60

found: 41.58 5.71 16.03 27.40

Example 9 N-Cyano-IM '- [2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N "-ethylguanidine (Formula 9) A solution of 5 g (0.0147 mol) of N-cyano-N '- [2 - [(5-ethyl-5,6-dihydro-1H-thieno) is heated at reflux conditions for 5 hours and 30 minutes -Cl 1 -pyrroly-dimethylthiol-ethyl-S-methylisothiourea and 19.9 g (0.441 mol) of ethylamine in 30 cm ^{3 of} ethanol, then the solution is evaporated and the resulting residue is crystallized from the sufficient amount of ethyl acetate, filtered off with suction and dried. weight = 3.4 g, yield = 68%, mp = 91-93 ⁰ C. Recrystallize the solids to a mixture of 20 cm ³ of diisopropyl ether and 10 cm ³ of isopropanol and then from a mixture of 15 cm ³ of diisopropyl ether and 20 cm ³ of ethyl acetate. Weight = 2.4g F. = 95-96 ° C Analysis: Ci ₅ H ₂₃ N ₅ S ₂ -MG = 337.50

% C% H% N% S

calculated: 53.38 6.87 20.75 19.00

found: 53,55 6,60 20,95 18,92

Example 10 N-Cyano-N'-t 2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -IM "-propargylguanidine ( Formula 10) A mixture of 3 g (0.0088 mol) N-cyano-N '- [2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c]) is heated at reflux conditions for 8 h. 2-pyrrollyl) -methylthio] -ethyl] -S-methylisothiourea and 7.3 g (0.132 mol) of propargylamine in 30 cm ^{3 of} methanol, then the solution is evaporated, the residue is then chromatographed in a chloroform solution on a silica gel column Eluents are successively used chloroform, ethyl acetate and 5% chloroform in methanol The fractions eluted with ethyl acetate and with chloroform / methanol are combined and evaporated to dryness to give a solid: weight = 1.7 g, yield = 56%, F = 107-110 ° C, F = 112-114 ° C (isopropyl ether / ethyl acetate, 1/3).

NMR (CDCl ₃ ): 2.4 (m) 1H (CH), 2.6-3.3 (m) 4H (S-CH ₂ , CH ₂ -H =), 3.3-3.6 ( m) 2H (CH ₂ N), 3.6-4.2 (m) 8H (NCH ₂ , CH ₂ ), 5.8-6.6 (m) 2H (NH), 6.7 (s) 1 H (thiophene-H)

Analysis: C ₁₆ H ₂₁ N ₅ S ₂ - MW = 347.50

% C% H% N% S

calculated: 55.3 6.09 20.16 18.45

Found: 55.35 6.15 20.12 18.17

-14- 236 662

Example 11

N- [2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -1-methyl-1H-triazole [1, 2,4] -3,5-diamine (Formula 11) A solution of 4.25 g (0.0925 mol) of methyl hydrazine and 6.75 g (0.0925 mol) of dry Ν is heated at reflux conditions under a nitrogen atmosphere for 2 h, Ν-dimethylformamide in 60cm ^{3 of} toluene. The solution is then cooled to 30 ° C. and 6.3 g (0.0185 mol) of N-cyano-N '- [2-t (5-ethyl-5,6-dihydro-4H-thieno [2,3- c] -2-pyrrolyl) methylthio] ethyl] -S-methylisothiourea. The mixture is heated to reflux for 7 h, then the solvent is evaporated, the residue is washed with water, extracted with chloroform, the chloroform phase is dried over sodium sulfate, concentrated and chromatographed on a column of silica, using chloroform, ethyl acetate and a solution of 5 successively % Chloroform in methanol as eluent. The fraction eluted with the latter mixture yields, after evaporation and crystallization of the residue from diisopropyl ether with a few drops of added acetone, a solid which is recrystallized from ethyl acetate. Weight = 1.8g, Yield = 28%, mp = 109-112 ° C (diisopropyl ether / ethyl acetate).

NMR (CDCl ₃ ): 1.08 (t) 3H (CH ₃ -CH ₂ ), 2.4-3.1 (m) 4H, 3.1-4.6 (m) 14H, 6.7 (s ) 1H (thiophene-H). Analysis: C ₁₄ H ₂₂ NeS ₂ -MG = 338.5

% C% H% N% S

calculated: 49.67 6.55 24.83 18.95

Found: 49.62 6.52 24.50 18.81

Example 12 N-Cyano-N '- [2 - [(5,6-dihydro-5-phenyl-4H-thieno [2,3-cis-2-pyrrolyl) -methylthio] -ethyl] -N'-methylguanidine ( Formula 12) At reflux conditions, a mixture of 2.5 g (0.0064 mol) of N-cyano-N '- [2 - [(5,6-dihydro-5-phenyl-4H-thieno [2,3-c ] -2-pyrrolyl) -methylthio] -ethyl] -S-methylisothiourea, 30 cm ^{3 of} a 33% solution of methylamine in ethanol and 30 cm ^{3 of} DMF and bubbled through an ethylamine stream for 5 hours, then the solvents are evaporated off the residue in isopropanol and crystallized from the sufficient amount of a mixture of water and DMF (2/3) to.

Weight = 1.4g, mp = 164-168 ° C, Yield = 58%.

NMR (DMSO D ₆ ): 2.85-3 (m) 5H (CH ₂ S, CH ₃ N), 3-3.6 (m) 2H (CH ₂ NH), 3.8-4.2 (s ) 2H (CH ₂ S), 4.2 ^ 4.8 (m) (CH ₂ N), 6.4-7.4 (m) 8H (aromatic H, NH).

Analysis: C ₁₈ H ₂₁ N ₅ S ₂ = 371.52 -MG

% C% H% N% S

calculated: 58.19 5.70 18.85 17.26

found: 58.19 5.73 19.01 17.18

Example 13 N-K-KS-ethyl-B-dihydro-H-thieno-S-cis-pyrroly-D-methylthiol-ethyl-1-oxide thiadiazolo [1,2,5] -3,4-diamine (Formula 13)

To a solution of 1.7 g (0.0089 mol) of 3,4-diethoxythiadiazolo [1,2,3] -1-oxide in 20 cm ^{3 of} methanol is added between 5 and 10 ⁰ C, a solution of 2.15 g (0, 0089 mol) of 2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine in 20 cm ^{3 of} methanol. The mixture is stirred for 5 dog 30 min at ambient temperature, then allowed to bubble through a stream of ammonia for 10 min at 0 C ^c. Stirring is continued for 4 hours at ambient temperature, then the resulting solid is filtered off with suction. Weight = 1.4g, mp = 174 ° C (decomposition), Yield = 60%, mp = 175 ° C (decomposition) (MeOH / DMF, 3/1). Analysis: C ₁₃ H ₁₉ N ₅ OS ₃ - MW = 357.52

% C% H% N% S

calculated: 43.67 5.36 19.59 26.91

found: 43.60 5.35 19.62 26.73

Example 14 IM- [2 - [(5,6-Dihydro-5-methyl-4H-thieno [2,3-c] -2-pyrrolyl) methylthio [-ethyl] -N'-methyl-2-nitroethene-1 1-Diamine (Formula 14) A solution of 2.4 g (0.0105 mol) of 2,2'-bis-methylthionitroethene and 1.75 g (0.0076 mol) of 2 - [(5.6 Dihydro-5-methyl-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine in 30 cm ³ acetonitrile, then cooled to -5 ° C, the resulting solid is filtered off (weight = 2, 4g, mp = 112-114 ⁰ C) and suspended in 15 cm ³ of a 33% solution of methylamine in ethanol. This mixture is heated to reflux for 6 h 30 min, then the solvents are evaporated. To isolate such a solid: weight = 1.9 g, yield = 72%, F. = 108-112 ° C (ethyl acetate / isopropanol ^ / I). Analysis: C ₁₃ H ₁₉ N ₃ O ₂ S ₃ -GM = 345.5

% C% H% N% S

calculated: 47.54 6.14 17.06 19.52

found: 47.65 5.98 16.88 19.78

Example 15 '-

IM [2 - [(5-ethyl-5,6-dihydro-4H-furo [2,3-c] -2-pyrrolyl) methylthio] ethyl] -N'-methyl-2-nitroethene-1, 1-diamine (formula 15)

A solution of 3.3 g (0.0136 mol) of 2 - [(5-ethyl-5,6-dihydro-4H-furo [2,3-c] -2-pyrrolyl) -methylthio is heated at reflux conditions for 9 h 30 min ] -ethylamine and 2.25 g (0.0136 mol) of 2,2'-bismethylthionitroethene in 35m ^{3 of} acetonitrile. It is evaporated to dryness, then the residue is taken up in 35 cm ^{3 of} a 33% methylamine solution in ethanol. This solution is heated frequently reflux conditions, then evaporated and chromatographed the residue thus obtained in solution in methanol on a column of 40 g of silica gel using methanol as eluent. The residue obtained is dispersed after evaporation of the methanol in ethyl acetate and filtered off with suction. Weight = 1.5g, yield = 33%, mp = 103-110 ° C, mp = 110-112 ° C (diisopropyl ether / isopropanol, 5/4)

Analysis: C ₁₄ H ₂₂ N ₄ O ₃ S -MG = 326.42

% C% H% N% S

calculated: 51.51 6.79 17.17 9.82

-15- 236 662

Example 16 N-Cyano-N '- [2 - [(5-ethyl-5,6-dihydro-4H-furo [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -N'-methylguanidine (Formula 16) A solution of 2.3 g (0.0095 mol) of 2 - [(5-ethyl-5,6-dihydro-4H-furo [2,3-c] -2) is heated at reflux conditions for 6 h. Then the solvent is evaporated and the residue is dispersed in ether, the solid thus obtained is taken up in 30 cm ^{3 of} ethyl acetate, heated to reflux, and then allowed to crystallize The solid is filtered off with suction and the residue is chromatographed in solution in a mixture of ethyl acetate and methanol on a column of 15 g of silica gel using ethyl acetate and then methanol as eluent, after evaporation to give a solid = 53-58 ° C. A solution of this solid in 20 cm ^{3 of} a 33% strength methylamine solution in ethanol is thenobtained at reflux conditions Then it is evaporated to dryness, the residue is dispersed in ether, filtered off with suction and dried. Weight = 1.3g, Yield = 44%. Mp = 125-128 ⁰ C, mp = 129-131 ⁰ C (ethyl acetate / isopropanol, 3/1).

NMR (CDCl ₃ ): 1.2 (t) (CH ₃ -CH ₂ ), 2.6-3.1 (m) (S-CH ₂ , CH ₃ -N, CH ₃ -CH ₂ ), 3, 5 (q) 2H (CH ₂ -NH), 3.8 (s) 6H (CH ₂ S, CH ₂ N), 5.7 (t) 1H (NH), 6.1 (m) 1 H ( NH), 6.2 (s) 1H (furan-H)

Analysis: C ₁₄ H ₂ iN ₅ OS - MW = 307.42

% C% H% N% S

calculated: 54.69 6.89 22.78 10.43

found: 54,55 6,74 22,60 10,57

Example 17 N- [2 - [(5-Ethyl-5,6-dihydro-4H-furo [2,3-c] -2-pyrrolyl) -methylthio] -ethyl-1-methylthio-2-nitroethenamine (Formula 17)

A solution of 2.3 g (0.0095 mol) of 2 - [(5-ethyl-5,6-dihydro-4H-furo [2,3-c] -2-pyrrolyl) is heated at reflux conditions for 6 hours. methylthio] ethylamine and 1.6 g (0.0095 mol) of 2,2'-bismethylthionitroethene in 25 cm ^{3 of} acetonitrile. The solution is then evaporated, and the residue is recrystallized from 25 cm ^{3 of} ethyl acetate in the presence of norite, and the solid is filtered off with suction and dried. Weight = 1.4 g, yield = 43%, mp = 77-79 ° C, mp = 80-82 ° C (chromatography on 10 g silica gel, eluent CH ₂ Cl ₂ , then methanol).

NMR (CDCl ₃ ): 1.1 (t) 3H (CH ₃ -CH ₂ ), 2.4 (s) 3H (CH ₃ S), 2.8 (m) 4H (SCH ₂ , CH ₂ N), 3.3-3.9 (m) 8H (CH ₂ N, CH ₂ S), 6.1 (s) 1 H (= CH-NO _2), 6.5 (s) 1 H (furan-H) , 10.5 (s) 1H (NH)

Analysis: C ₁₄ H ₂₁ N ₃ O ₃ S ₂ - MW = 343.46

% C% H% N% S

calculated: 48.95 6.16 12.23 18.67

found: 49,20 5,94 12,04 18,45

Example 18 N-> KS ^ -dihydro-B-n-pentyl ^ H-thieno ^ S-cl ^ -pyrroly-O-methylthiol-ethyll-N'-methyl ^ -nitroethene-i, 1-diamine (Formula 18)

Under the conditions of Example 3, this compound was prepared from N- [2 - [(5,6-dihydro-5-n-pentyl-4H-thieno [2,3-c] -2-pyrrolyl) -methoxy] - ethyl] -1-methylthio-2-nitroethenamine and methylamine. Weight = 3.6 g, yield = 86%, mp = 90-93 ° C, mp = 93-95 ° C (diisopropyl ether / isopropanol, 1/2)

Analysis: C ₁₇ H ₂₈ N ₄ O ₂ S ₂ - MW = 384.55

% C% H% N% S

calculated: 53.09 7.34 14.57 16.68

Found: 53.24 7.26 14.44 16.75

Example 19

N- [2 - [(5-ethyl-5,6-dihydro-3-methyl-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] ethyl] -N'-methyl-2- nitroethene-1,1-diamine (formula 19)

Under the conditions of Example 3, the compound was prepared from N- [2 - [(5-ethyl-5,6-dihydro-3-methyl-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] - ethyl] -1-methylthio-2-nitroethenamine and methylamine. F. = 112-113 ° C <diisopropyl ether / isopropanol).

Analysis: C ₁₅ H ₂₄ N ₄ O ₂ S ₂ - MW = 356.5

% C% H% N% S

calculated: 50.53 6.78 15.72 17.99

Found: 50.48 6.72 15.84 18.22

Example 20

N- [2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] ethyl] -N'-methyl-1-oxidthiadiazol [1, 2,5] -3,4-diamine (formula 20)

Under the conditions of Example 13, the compound was prepared using methylamine instead of ammonia. F. = 144-146X (isopropyl ether / isopropanol, 1/4).

NMR (CDCl ₃ ): 1.16 (t) 3H (CH ₃ -CH ₂ ), 2.35-3.1 (m) 7H (SCH ₂ , CH ₂ N, CH ₃ N), 3.1-4 (m) 8H (CH ₂ -S, NCH ₂ ), 6.7 (s) 1H (thiophene-H), 7.6-8.4 (s broadened) 2H (NH).

Analysis: C ₁₄ H ₂₁ N ₅ OS ₃ - MW = 371.55

% C% H% N% S

Calculated: 45.25 5.70 18.85 25.89

Found: 45.27 5.39 18.74 25.65

236

Example 21

(Formula 21)

A mixture of 1.7 g (Q, 0089 mol) of 3,4-diethoxythiadiazolo [1,2,5] -1-oxide and 0.5 g (0.0089 mol) of propargylamine in a solution in 20 cm ^{3 of} methanol is stirred at ambient temperature for 6 h , It is evaporated to dryness, then added between 5 and 1O ⁰ C 2.15 g (0,0089MoI) 2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2- pyrrolyl) -methylthio] -ethylamine in a solution in 20cm ^{3 of} methanol. This solution is stirred at ambient temperature for 17 h, then the precipitate formed is filtered off with suction. Weight = 1.8 g, yield = 51%, mp = 164-166 ⁰ C (decomposition, mp = 165-166 ° C (methanol / DMF, 1.8 / 1).

Example 22 N- [2 - [(5,6-Dihydro-5-n-propyl-4H-thieno [2,3-c] -2-pyrrolyl) methylthio [-ethyl] -1-oxide thiadiazole [1,2 , 5] -3Adiamine (formula 22) To a solution of 2,4g (0,0126MoI) 3,4-Diethoxythiadiazol [1,2,5] -1-oxide in 25cm ^{3 of} methanol is between 5 and 10 ⁰ C a Solution of 3.25 g (0.0126 mol) of 2 - [(5,6-dihydro-5-n-propyl-4H-thieno [2,3-c] -2-pyrrolylmethylthio] -ethylamine in 25 cm ^{3 of} methanol this mixture is stirred for 20 h at ambient temperature, then allowed to during min at 0 to 5 ⁰ C was bubbled a stream of ammonia tenth the stirring for 4 h at ambient temperature continued, then cooled to 0 ⁰ C and filtered off with suction and the precipitate formed Weight = 2.4g, Yield = 51%, mp = 178 ° C (decomposition), mp = 179 ° C (methanol / DMF, 1/1).

Analysis: C ₁₄ H ₂ IN ₅ OS ₃ - MW = 371.55

% C% H% N% S

Calculated: 45.25 5.70 18.85 25.89

found: 45,41 5,75 18,70 25,64

The compounds of the following Examples 23 and 24 were prepared according to the procedure described in Example 2 from the appropriate 2 - [(5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamines :

Example 23 N- [2 - [(5-Ethyl-5,6-dihydro-3-methyl-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] ethyl] -1-methylthio-2 -nitroethenamine (Formula 23) Ci ₅ H ₂₃ N ₃ O ₂ S ₃ -MG = 373.55, mp = 74-77 ° C (diisopropyl ether / isopropanol)

NMR (CDCl ₃ ): 2.46 (s) 3H (CH ₃ S).

Example24 · "..; ''

N - ^ - KB ^ -dihydro-S-n-pentyl-H-thieno-S-C 1-8 -pyrroly-D-methylthiol-ethyl-1-methylthio-nitroethenamine (Formula 24)

C ₁₇ H ₂₇ N ₃ O ₂ S ₅ - MW = 401.61, mp = 72-74X (isopropanol)

NMR (CDCl ₃ ): 2.46 (s) 3H (CH ₃ S).

Example 25 N-Cyano-N '- ^ - ClS ^ -dihydro-S-phenyl-H-thieno-S-cis -pyrroly-D-methylthiol-ethyl-S-methylisothiourea (Formula 25) C ₁₈ H ₂₀ N ₄ S ₃ - MG = 388.57

A mixture of 2.6 g (0.0094 mol) of 2 - [(5,6-dihydro-5-phenyl-4H-thieno [2,3-c] -2-pyrrolyl) -methylthiol-ethylamine is heated at reflux conditions and 1 , 4g (0.0094 mol) Cyanoimidodimethyldithiocarbonatin 50cm ³ acetonitrile. It sucks in the cold, the resulting solid, washed with diisopropyl ether and dried. Weight = 3g, Yield = 82%, mp = 189-193 ° C, F. = 195-197 ° C (H ₂ O / DMF, 4/15).

IR (KBr): vCN 2180cm " ¹ .

Example 26 N-Cyano-N'-O-EIS-ethyl-Se-dihydro-H-thieno-S-C 1-8 -pyrroly-D-methylthiol-ethyl-S-methylisothiourea (Formula 26) C ₁₄ H ₂₀ N ₄ S ₃ - MG = 340.53

This compound was prepared according to the procedure of Example 25 from 2 - [(5r-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine. F. = 112-114 ° C

IR (KBr): vCN = 2170crrT ¹ .

Example 27 N- [2 - [(5-Ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) methoxy] ethyl] -1-oxide thiadiazole [1,2,5] - 3,4-diamine (formula 27)

To a solution of 2.3 g (0.0168 mol) of 3,4-diethoxythiadiazole [1,2,5] -1-oxide in 30 cm ^{3 of} methanol is added between 5 and 10 ° C, a solution of 3.8 g (0.0168 mol ) 2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) methoxy] -ethylamine in 20cm ^{3 of} methanol. The mixture is stirred for 9 h at ambient temperature, then allowed to bubble between 0 and 5 ⁰ C for 10 min, a stream of ammonia. Continue stirring at ambient temperature for 5h then evaporate to dryness. The residue is taken up in water and chloroform, the organic phase is dried over sodium sulfate, the chloroform is evaporated, the residue is dispersed in the sufficient amount of isopropanol, filtered off with suction, washed with diisopropyl ether and dried. Weight = 1.5g, Yield = 26%, mp = 144-146X (decomp.), Mp = 149-150 ° C (methanol). Analysis: C ₁₃ H ₁₉ N ₅ O ₂ S ₂ - MW = 341.45

% C% H% N% S

calculated: 45.73 5.61 20.51 18.78

found: 46.01 5.49 20.25 18.68

236

Example 28 N- [2 - [(5-n-butyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrroly) methylthio] ethyl] -1-oxide thiadiazole [1,2,5 ] -3,4-diamine (formula 28)

To a solution of 4.1 g (0.0214 mol) of 3,4-diethoxythiadiazolo [1,2,5] -1-oxide in 40 cm ^{3 of} methanol is added between 0 and 10 ⁰ C, a solution of 5.8 g (0, 0214 MoI) 2 - [(5-n-butyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] ethylamine in 40 cm ^{3 of} methanol. The mixture is stirred for 17 h at ambient temperature, then allowed to bubble between 0 and 5 ° C an ammonia stream for 10min. The mixture is then stirred for 4 hours at ambient temperature, and the solid formed is filtered off with suction and dried. Weight = 5.1 g, yield = 62%, mp = 183-184 ° C (C ₂ H ₆ OHZDMF, 2/1). Analysis: C ₁₅ H ₂₃ N ₆ OS ₃ - MW = 285.57

% C% H% N% S

calculated: 46.72 6.01 18.17 24.95

found: 46.88 5.67 18.08 24.49

The compounds of the following Examples 29 to 33 were prepared according to the procedure of Example 28 from the appropriate 2 - [(5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] alkylamines and 3 , 4-Diethoxythiadiazol [1,2,5] -1-oxide.

Example 29 N- [2 - [(5-isobutyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethyl] -1-oxide thiadiazole [1,2,5] - 3,4-diamine (Formula 29)

Yield = 57%, mp = 178-179 ⁰ C (ethanol / DMF, 7/4). Analysis: C ₁₉ H ₂₃ N ₅ OS ₃ - MW = 385.57

% C% H% N% S

calculated: 46.72 6.01 18.17 24.95

found: 46.91 6.06 17.93 24.67

Example 30 N- [2 - [(5-n-Hexyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] ethyl] -1-oxide thiadiazole [1,2 , 5,3,4-diamine (Formula 30)

Mp = 180-181 ⁰ C (ethanol / DMF, 7/4), yield = 73%. Analysis: C ₁₇ H ₂₇ N ₅ OS ₃ - MW = 413.63

% C% H% N% S

calculated: 49.36 6.58 16.93 23.26

found: 49,41 6,59 16,63 22,95

Example 31

N424 (5,6-dihydro-5-n-ethyl-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] ethyl] -1-oxide thiadiazole [1,2,5] -3,4 diamine (formula 31)

Mp = 172-173 ⁰ C (ethanol), yield = 60%

Analysis: C ₁₆ H ₂₅ N ₅ OS ₃ - MW = 399.60

% C% H% N% S

calculated: 48.09 6.31 17.53 24.07

Found: 48.15 6.33 17.32 23.80

Example 32 N-tS-KB-ethyl-B-dihydro-H-thienoK.S-cis -pyrrolylmethylthiol-propyU-i-oxide thiadiazolo [1,2,5] -3,4-diamine (Formula 32)

Mp = 157-158 ⁰ C (isopropanol), yield = 27%. Analysis: C ₁₄ H ₂₁ N ₅ OS ₃ - MW = 371.55

% C% H

calculated: 45.25 5.70

found: 44.94 5.60

Example 33

N-t2 - [[5,6-Dihydro-5- (2-methoxyethyl) -4H-thieno [2,3-c] -2-pyrrolyl] methylthio] ethyl] -1-oxidthiadiazol [1,2, 5] -3,4-diamine (formula 33)

Mp = 174-176 ° C (ethanol), yield = 64%

Analysis: C ₁₄ H ₂₁ N ₅ O ₂ S ₃ - MW = 387.55

% C% H% N% S

calculated: 43.39 5.46 18.07 24.82

found: 43.19 5.38 18.18 24.84

Example 34 S-Amino ^ - ^ - KB.e-dihydro-B-n-propyl-H-thieno ^ -S-Cl ^ -pyrrolyD-methylthiol-ethylaminol-cyclobutene-1-dione (Formula 34)

To a solution of 2.6 g (0.01 mol) of N ^ -Ko ^ -Dihydro-Sn-propyl ^ H-thieno ^^ - cl ^ -pyrrolyll-methylthiol-ethylamine in 20cm ^{3 of} methanol is placed between 5 and 10 ° C, a solution of 1.4 g (0.01 mol) of 3,4-dimethoxycyclobutene-1,2-dione in 20 cm ^{3 of} methanol. The mixture is stirred at ambient temperature for 48 h, then allowed to bubble between 5 and 10 ⁰ C for 15 min an ammonia stream, after which stirring is continued for 4 h at ambient temperature. The resulting solid is filtered off, washed with ether and dried, then it is recrystallized from a mixture of 20 ml of ethanol and 20 ml of DMF. Weight = 0.9g, Yield = 25%, mp <320 ° C. Analysis: C ₁₆ H ₂₁ N ₃ O ₂ S ₂ - MW = 351.48% C% H

calculated: 54.67 6.02

Found: 54.59 5.92

% N % S 18.85 25.89 18,98 25,60

% N % S 11.96 18.25 11.94 18.52

-18- 236 662

Example 35 N- [2 - [(5,6-Dihydro-5-n-propyl-4H-furo [2,3-c] -2-pyrrolyl) methylthio] ethyl] -1-oxide thiadiazole [1,2 , 5] -3,4-diamine (formula 35) C ₁₄ H ₂₁ N ₆ O ₂ S ₂ -MW = 355.48

To a solution of 5.3 g (0.028 mol) of 3,4-diethoxythiadiazole [1,2,5] -1-oxide in 50 cm ^{3 of} methanol is placed between 5 and 10 ⁰ C, a solution of 6,7g (0,028MoI) 2 - [(5,6-dihydro-5-n-propyl-4H-furo [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine in 50cm ^{3 of} methanol. The mixture is then stirred for 20 h at ambient temperature, then allowed to bubble between 5 and 10 ° C an ammonia stream. Stirring is continued for 4 hours at ambient temperature, then evaporated to dryness, the residue thus obtained is dispersed in ether, filtered off with suction and dried. Weight = 7g, yield = 70%, mp = 46-148 ° C, mp = 154-156 ^C C (after three chromatographies on a silica gel column with a mixture of chloroform and ethanol, 95/5, then 90/10, as eluent)

Analysis: C ₁₄ H ₂₁ N ₅ O ₂ S ₂ + V2H ₂ O

% C% H% N% S

calculated: 46.16 6.09 19.22 17.59

found: 46.46 5.87 19.38 17.91

Example 36

The mixture is stirred for 4 h under a nitrogen atmosphere, a mixture of 44.8 g (0.167 mol) of 5-bromoethyl-4-chloromethyl-2-furanmethylcarboxylat and 22.6 g (0.502 mol) of ethylamine in a solution in 51 acetonitrile. Then the solvent and the excess of unreacted ethylamine are evaporated, the residue is taken up in 5 N hydrochloric acid, insoluble matter is removed by filtration, the filtrate is washed with ether and then neutralized by addition of sodium bicarbonate. It is extracted with ether, this ether phase is washed with water, then dried over sodium sulfate. After evaporation of the ether, the residue is taken up successively with hexane, heated in the presence of norite under reflux, hydrogenated, an oil is decanted off, the oil is partially evaporated off, the hexane is filtered off and evaporated to dryness. Weight = 13g, yield = 40%, F. = 52-54 ° C (diisopropyl ether).

NMR: 1.1 (t) 3H CH ₃ -CH ₂ , 2.8 (q) 2H CH ₂ N, 3 (s) 3H CH ₃ O, 3-3.9 (m) (4H NCH ₂ , 7, 1 (s) 1H, aromatic H. Analysis: C ₁₀ H ₁₃ NO ₃ - MW = 195.21

% C% H% N

calculated: 61.52 6.71 7.18

Found: 61.41 6.65 7.23

Example 37 5-Ethyl-5,6-dihydro-4H-furo [2,3-c] -2-pyrrolemethanol (Formula 37)

To a solution of 3g (0,079MoI) and lithium aluminum hydride, in solution in 150 cm ³ of ether are employed at ambient temperature 11.7 g (0,06MoI) 5-Ethyl-5,6-dihydro-4H-furo [2,3-c ] -2-pyrrolmethylcarboxylate in solution in 70cm ^{3 of} ether. It is heated for 2 h and 30 min at reflux conditions, then added to a cooled mixture of water and dilute sodium carbonate solution. The ether phase is decanted and the precipitate is extracted with ether. The various ether fractions are combined and dried over sodium sulfate, then evaporated to dryness to give a solid which is dispersed in diisopropyl ether. Weight = 5.1 g, mp = 67-69 ° C, Yield = 51%.

NMR (CDCl ₃ ): 1.2 (t) 3H CH ₃ -, 2.8 (q) 2H CH ₂ --CH ₃ , 3.8 (s) 4H CH ₂ - N, 3.9 (m) 1H OH; 4.6 (s) 2H CH ₂ O, 6.2 (s) 1 H, aromatic H. Analysis: C ₁₉ H ₁₃ NO ₂ - MW = 167.20

% C% H% N

calculated: 64.65 7.83 8.37

Found: 64.43 7.89 8.42

Example 38 2 - [(5-Ethyl-5,6-dihydro-4H-furo [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine (Formula 38) C ₁₁ H ₈ N ₂ OS'-MG = 242.34

To a solution of 2.5 g (0,022MoI) cysteamine hydrochloride in 8.8 cm ³ of concentrated hydrochloric acid are employed in small portions with cooling to 0 to 4 ° C 3.7 g (0,022MoI) 5-Ethyl-5,6-dihydro- 4H-furo [2,3-c] -2-pyrrolemethanol. The mixture is then stirred for ² h between 4 and 5 ° C, then it is kept for 48 h to -5 ⁰ C, followed by making alkaline by addition of sodium bicarbonate and extracted with ether. After the ether phase has been dried over sodium sulphate and then evaporated, an oil is obtained which is used in the following stage as it is obtained. Weight = 3.3 g, yield = 62%.

Example 39 5,6-Dihydro-5-n-propylfuro [2,3-c] -2-pyrrole methylcarboxylate (Formula 39)

C ₁₁ H ₁₅ NO ₃ -MG = 209.24

A mixture of 69 g (0.258 mol) of 5-bromomethyl-4-chloromethyl-2-furanemethylcarboxylate and 46 g (0.775 mol) of n-propylamine in 7.671 acetonitrile is stirred for 7 days at ambient temperature. The mixture is filtered, then the filtrate is evaporated to dryness, the resulting residue is taken up with 5N hydrochloric acid, insolubles are removed by suction, the filtrate is made alkaline by addition of sodium bicarbonate, extracted with ether, dried over sodium sulphate and evaporated to dryness. You get an oil that you use as you get it in the synthesis sequence. Weight = 31.4g, Yield = 58%.

-19- 236

Example 40 5,6-Dihydro-5-n-propylfuro [2,3-c] -2-pyrrolemethanol (Formula 40) C ₁₀ Hi ₅ NO ₂ - MW = 181.23 To a solution of 7g (0.1845 mol) Lithium and aluminum hydride in 350 cm ^{3 of} ether are added at reflux conditions 31.4 g (0.15 mol) of 5,6-dihydro-5-n-propylfuro [2,3-c] -2-pyrrolmethylcarboxylat in solution in 176cm ³ ether. Thereafter, the mixture is heated for 4 hours at reflux conditions, then treated as in Example 37. One isolates such a solid.

Weight = 11 g, yield = 40%, mp = 60-62 ⁰ C.

NMR (CDCl ₃ ): 0.9 (t) 3H (CH ₃ ), 1.5 (sext.) 2H (CH ₂ CH ₃ ), 2.7 (t) 2H (NCH ₂ CH ₂ -), 3, 7 (s) 4H (CH ₂ N), 3.9 (s) 1H (OH), 4.5 (s) 2H (CH ₂ OH), 6.1 (s) 1H aromatic.

Example 41

2 - [(5,6-Dihydro-5-n-propyl-4H-furo [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine (Formula 41) C ₁₂ H ₂₀ N ₂ OS-MG = 240.37 The preparation is carried out under the conditions of Example 38 from cysteamine chlorohydrate and 5,6-dihydro-5-n-propylfuro [2,3-c] -2-pyrrolemethanol. Treat the reaction mixture in the following manner: make alkaline with 1N soda solution, extract with ether, re-extract the aqueous phase with a mixture of ether and methanol after saturation with soda pads. The two organic phases are combined, dried over sodium sulfate, evaporated and distilled.

Kp. ₂ = 148-150 ⁰ C, Weight = 6.7 g, yield = 46%.

NMR (CDCl ₃ ): 1.2-1.8 (m) 2H (CH ₃ CH ₂ ), 1.5 (s) 1H (NH ₂ ), 2.5-3 (m) 6H (CH ₂ ) , 3.7 (q + s) 6H (CH ₂ S and CH ₂ N), 6.1 (s) 1 H (aromatic).

Example 42 S-ethyl-S 1 -dihydro-H-thieno-3-cis -pyrroloethylcarboxylate (Formula 42) C ₁₁ H ₁₅ NO ₂ S - MW = 225.3 In a reaction vessel under a nitrogen atmosphere, 126.6 g (0 5 mmol) 4,5-bischloromethyl-2-thiophenethylcarboxylate in acetonitrile, then 67.6 g (1.5 mol) of ethylamine are added. The mixture is stirred for days at ambient temperature, then filtered, the filtrate is evaporated to dryness, the resulting residue is dissolved in the sufficient amount of 1.5 N hydrochloric acid, the solution is filtered, washed with ether and allowed to pass through Addition of potassium carbonate alkaline. It is extracted with ether. After drying the ether phase over sodium sulfate and subsequent evaporation gives an oil which is distilled under reduced pressure. _{Bp 1iS} = 122-125 ° C, weight = 65.4g, yield = 58%, CPV SE 30 5-1m, T = 230 ° C: a single peak.

Following the procedure of Example 42, the following esters are prepared from the appropriate amine of 4,5-chloromethyl-2-thiophenethylcarboxylate:

Example 43 Be-Dihydro-B-methyl-H-thieno-cis-C 1-5 -pyrroloethylcarboxylate (formula 43) C ₁₀ H ₁₃ NO ₂ S-MG = 211.27 crude further processed in the next step.

Example 44 S-Benzyl-S 1 -dilydro ^ H-thienote A-c 1-8 pyrrole ethylcarboxylate (Formula 44) C ₁₆ H ₁₇ NO ₂ S - GM = 287.28 F. = 223-224 ° C

Example 45 5,6-Dihydro-5-isopropyl-4H-thieno [2,3-c] -2-pyrrolethylcarboxylate (Formula 45) C ₁₂ H ₁₇ NO ₂ S - MW = 239.33 further processed crude in the next step.

Example 46 ö ^ -dihydro-S-phenyl ^ H-thieno ^ S-Cl ^ -pyrrolethylcarboxylat (Formula 46) C ₁₅ H ₁₅ NO ₂ S - MW = 273.34 mp = 147-150 ⁰ C.

Example 47

C ₁₄ H ₂₁ N ₂ O ₂ S - MW = 267.38 Kp ₁₁ = 136-145 ° C

Example 48 S ^ -dihydro-Bn-propyl ^ H-thienoK ^ -Cl ^ -pyrrolethylcarboxylat (Formula 48) C ₁₂ H ₁₇ NO ₂ S - raw processed further in the next stage, MW = 239.44.

Example 49 δ-n-Butyl-δ-dihydro-H-thieno-S-cis-pyrrole methylcarboxylate (Formula 49) C ₁₂ H ₁₇ NO ₂ S - MW = 239.32 Kd, = 138-145 ° C.

-23- 236

Example 50 o-isobutyl-S ^ -dihydro ^ H-l ^ thienofoS--pyrrolmethylcarboxylat (Formula 50) C ₁₂ H ₁₇ NO ₂ S - MW = 239.23 _1F5 Kp = 120-125 ⁰ C..

Example 51 Sn-Hexyl-o-dihydro-H-thienol ^ S-cis-pyrrole methylcarboxylate (Formula 51) C ₁₄ H ₂₁ NO ₂ S - MW = 267.33 amorphous solid.

Example 52 5,6-Dihydro-5- (2-methoxyethyl) -4H-thieno [2,3-c] -2-pyrrolmethylcarboxylat (Formula 52) C ₁₁ H ₁₅ NO ₃ S MW = 241.30 raw used.

Example 53 5-Ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolemethanol (Formula 53) To a solution of 20 g (0.527 mol) of lithium and aluminum hydride in 11% ether is added under a Nitrogen atmosphere and heated to reflux, a solution of 65.1 g (0.289 mol) of 5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolethylcarboxylat in 400cm ^{3 of} ether. The heating is continued at reflux conditions for 4 h, then the mixture is cooled and introduced drop by drop 120 cm ^{3 of} water, then 100 cm ^{3 of} 30% sodium hydroxide solution. The organic phase is decanted, the ether is combined with it from the extraction of the precipitate formed, the whole is dried over sodium sulfate, evaporated to dryness and the resulting solid residue is dispersed in hexane, filtered off with suction and dried:

Weight = 50g, yield = 88%, mp = 85-87 ° C (hexane / isopropanol, 15/1).

NMR (CDCl ₃ ): 1.13 (t) 3H (CH ₃ ), 2.8 (q) 2H (CH ₂ -CH ₃ ), 3.85 (m) 4H (CH ₂ -N), 4.65 (s) 2H (CH ₂ O), 5 (s) 1H (OH), 6.55 (s) 1H (thiophene)

Analysis: C ₉ H ₁₃ NOS - MW = 183.16

% C% H% N -% S

calculated: 58.98 7.15 7.64 17.50

found: 58.92, 7.19, 7.61, 17.35

Following the procedure of Example 53, the following alcohols are prepared from the appropriate ester:

Example 54 5,6-Dihydro-5-methyl-4H-thieno [2,3-c] -2-pyrrolemethanol (Formula 54) C ₈ H ₁₁ NOS-MG = 169.24

F. = 105-107 ° C (diisopropyl ether / isopropanol).

Example 55 5,6-Dihydro-5-isopropyl-4H-thieno [2,3-c] -2-pyrrolemethanol (Formula 55) C ₁₀ H ₁₅ NOS - MW = 197.29

Mp = 118-120 ⁰ C (chromatography on alumina, eluant CHCl _3).

Example 56 5-Benzyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolmethanol (Formula 56) C ₁₄ H ₁₅ NOS - MW = 245.33 mp = 132-133 ⁰ C.

Example 57 5,6-Dihydro-5-phenyl-4H-thieno [2,3-c] -2-pyrrolemethanol (Formula 57)

Mp = 197-198 ⁰ C (THF).

Analysis: C ₁₃ H ₁₃ NOS - MW = 231.30

% C% H% N% S

calculated: 67.57 5.66 6.06 13.86

found: 67.44 5.65 6.13 13.77

Example 58 5,6-Dihydro-5-n-propyl-4H-thieno [2,3-c] -2-pyrrolemethanol (Formula 58) C ₁₀ H ₁₅ NOS-MG = 197.29 further crude.

Example 59 5,6-Dihydro-5-n-pentyl-4H-thieno [2,3-c] -2-pyrrolmethanol (Formula 59) C ₁₂ H ₁₉ NOS - MW = 295.34 used further crude.

Example 60 5-Ethyl-5,6-dihydro-3-methyl-4H-thieno [2,3-c] -2-pyrrolmethanol (Formula 60) C ₁₀ H ₁₅ NOS - GM = 197.29 used further crude.

-21- 236

Example 61 5-butyl-5,5-dihydro-4H-thieno [2,3-c] -2-pyrrolmethanol (Formula 61) C ₁₁ H ₁₇ NOS - MW = 211.32 mp = 78-80 ⁰ C.

Example 62 5-isobutyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolmethanol (Formula 62) C ₁₁ H ₁₇ NOS MW = 211.32 mp = 73-75 ⁰ C.

Example 63 5-n-Hexyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolemethanol (Formula 63) C ₁₃ H ₂₁ NOS-MG = 239.37 F. = 70-72 ° C.

Example 64 5,6-Dihydro-5- (2-methoxymethyl) -4 H -thieno [2,3-c] -2-pyrrolemethanol (Formula 64) C ₁₀ H ₁₅ NO ₂ S - MW = 213.29 m.p. 76-78 ° C.

Example 65 2-Chloromethyl-5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrole hydrochloride (Formula 65) C ₉ H ₁₃ Cl ₂ NS - MW = 238.17 To a solution of 45g (0,245MoI) 5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolmethanol in 500m ³ of chloroform are employed 35g (0,29MoI) at ambient temperature (using a cold mixture) Thionyl chloride too. The solution is then stirred for 2 hours at ambient temperature, then the solvent and the unreacted excess thionyl chloride are evaporated off. Thus obtained residue was dispergiertden at 200m ³ of isopropanol, filtered off and dried. Weight = 43.3g, yield = 74%, mp = 151-153X (decomposition).

Under the conditions of Example 65, the appropriate halides of the following Examples 66 to 68 are prepared from the appropriate alcohols.

Example 66 -

2-Chloromethyl-5,6-dihydro-5-methyl-4H-thieno [2,3-c] pyrrole chlorohydrate (Formula 66) C ₈ H ₁₁ Cl ₂ NS - MW = 224.15

Mp = 173-176 ° C (decomposition) (isopropanol / methanol).

Example 67 5-Benzyl-2-chloromethyl-5,6-dihydro-4H-thieno [2,3-c] pyrrole chlorohydrate (Formula 67) C ₁₄ H ₁₆ Cl ₂ NS - MW = 300.24 F. = 146- 148 ⁰ C.

Example 68 2-chloromethyl-5,6-dihydro-5-isopropyl-4H-thieno [2,3-c] -pyrolchlorhydrat (Formula 68) C ₁₀ H ₁₆ Cl ₂ NS-MG = 252.12 mp = 148- 15O ⁰ C.

Example 69 2 - [(5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) methylthio] ethylamine (Formula 69) C ₁₁ Hi ₈ N ₂ S ₂ - MG = 242.40 to a solution of 22,8g (0,2MoI) Cysteaminchlorhydrat in 400cm ³ of concentrated hydrochloric acid is slowly added between ⁰ and 5 C 36,1g (0,197MoI) 5-ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolmethanolzu. The mixture is then stirred for 3 h and 30 min at ambient temperature, then neutralized with sodium carbonate, extracted with ether, the ether phase is dried over sodium sulfate and evaporated. This gives an oil which is distilled under reduced pressure. Bp. ₀ , ₇ = 149-155 ° C, weight = 30.9 g, yield = 65%.

NMR (CDCl ₃ ): 1-1.14 (m) 5H (CH ₃ , NH ₂ ), 2.2-3.1 (m) 6H (S-CH ₂ , CH ₂ N), 3.86 (s ) 6H (NCH ₂ , CH ₂ S), 6.7 (s) 1 H (thiophene)

Example 70 2 - [(5,6-Dihydro-5-methyl-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine (Formula 70) C ₁₀ H ₁₆ N ₂ S ₂ -MG = 228.38 To a methanolic solution of sodium methylate prepared by dissolving 2.6 g of sodium in 50 cm ^{3 of} methanol is added a solution of 5.9 g (0.052 mol) of cysteamine chlorohydrate in 50 cm ^{3 of} methanol. The mixture is stirred for 2 h between 0 and 5 ° C, then a solution of 5.8 g (0.0258 mol) of 2-chloromethyl-5,6-dihydro-5-methyl-4H-thieno [2,3-c ] -pyrrolchlorhydrat in 60cm ^{3 of} methanol too. Continue stirring for 24 h at ambient temperature, then filter the mixture, evaporate the filtrate and take up the residue in chloroform. The chloroform phase is then washed with water, dried over sodium sulfate and then distilled under reduced pressure to give an oil after evaporation of the chloroform. Bp. ₀ , ₇ = 127-145 ⁰ C, weight = 2.4 g, yield = 41%.

Example 71 2 - [(5-Benzyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine (Formula 71) C ₁₆ H ₂₉ N ₂ S ₂ -MG = 304.47 The preparation is carried out according to Example 70 from o-benzyl ^ chloromethyl-S ^ -dihydro ^ H-thienol ^ a-cl-pyrrolchlorhydrat.

Kp.o, 7 = 155-210 ⁰ C.

According to the procedure of Example 69 from the suitable alcohols, the amines of the following Examples 72 bis

Example 72 2 - [(5,6-Dihydrophenyl-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine (Formula 72) C ₁₅ H ₁₈ NS ₂ -MG = 276.43

Mp = 128-133X (H ₂ OVDMF, 1/3).

Example 73 2 - [(5,6-Dihydro-5-n-pentyl-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine (Formula 73) C ₁₄ H ₂₄ N ₂ S ₂ - MG = 284.48 cf. ₂ = 188-199 ° C.

Example 74 2 - [(5-Ethyl-5,6-dihydro-3-methyl-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine (Formula 74) C ₁₂ H ₂₀ N ₂ S ₂ -MG = 256.43

Example 75 2 - [(5,6-Dihydro-5-propyl-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine (Formula 75) C ₁₂ H ₂₀ N ₂ S ₂ -MG = 256.43 Kp.os-1 = 158-161 ⁰ C.

Example 76 2 - [(5-Butyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine (Formula 76) C ₁₃ H ₂₂ N ₂ S ₂ -MG = 270.46 cp. _O , 6_o, 8 = 147-152 ⁰ C.

Example 77 2 - [(5-isobutyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine (Formula 77) C ₁₃ H ₂₂ N ₂ S ₂ -MG = 270.46 cp.0.7-0.9 = 150-154 ° C.

Example 78 2 - [(5-n-Hexyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine (Formula 78) C ₁₅ H ₂₆ N ₂ S ₂ - MG = 298.51

Example 79 2 - [{5 ₁ 6-Dihydro-5- (2-methoxyethyl) -4 H -thieno [2,3-c] -2-pyrrolyl) -methylthio] -ethylamine (Formula 79) C ₁₂ H ₂₀ N ₂ OS ₂ - MW = 272.43 KP.0.9-T = 170-172 ° C.

Example 80 2 - [(5-Ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) methoxy] ethylamine (Formula 80) C ₁₁ H ₁₈ N ₂ OS - MW = 226.34 A mixture of 12.5 g (0.0525 mol) of 2-chloromethyl-5-ethyl-5,6-dihydro-4H-thieno [2,3-c] pyrrole chlorohydrate and 150 cm ^{3 is} heated to 100 ° C for 6 hours 2-aminoethanol. The mixture is then evaporated to dryness, the residue is taken up in water, rendered alkaline by addition of potassium carbonate, extracted with ether, the ether phase is dried over sodium sulfate, evaporated to dryness and isolated an oil which is distilled under reduced pressure ,

Kp.! = 155-162 ° C, weight = 4g, yield = 33.6%.

NMR (CDCl ₃ ): 1.15 (t) 3H (CH ₃ -CH ₂ ), 2.3 (s) 2H (NH ₂ ), 2.6-3.1 (m) 4H (CH ₂ N), 3.5-4.1 (m) 8H (N-CH ₂ , CH ₂ O), 6.66 (s) 1H (thiophene)

Example 81 3 - [(5-Ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) methylthio-propylamine (Formula 81) C ₁₂ H ₂₀ N ₂ S ₂ -MG = 256.43 to a solution of sodium methoxide, prepared by dissolving 3 g of sodium in 50 cm ³ of methanol, are employed between 0 and 10 ⁰ C, a solution of 12.4 g (5-ethyl-5,6-dihydro-4H-thieno [2 , 3-c] -2-pyrrolyl) -methanethiol in 30cm ^{3 of} methanol. The mixture is stirred for 2 h at ambient temperature, then is added between 0 and 5 ⁰ C, a solution of 13.6 g of 3-Brompropylaminchlorhydrat in 50cm ^{3 of} methanol. The mixture is stirred at ambient temperature for 18 h, then evaporated to dryness, the residue is taken up in ether, the ether phase is washed with water, dried over sodium sulfate, the ether is evaporated, an oil is isolated and distilled under reduced pressure Print. Kp. ₀ , ₅ Miiiibar = 154-157 ° C, weight = 7.6 g, yield = 48%.

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-23- 236

Example 82 (5-Ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methanethiol (Formula 82) C ₉ H ₁₃ NS ₂ - MW = 199.33 Heated to reflux for 4 h, a mixture of 55.4 g (0.23 mol) of 2-chloromethyl-5-ethyl-5,6-dihydro-4H-thieno [2,3-c] pyrrole chlorohydrate and 17.7 g (0.23 mol) of thiourea in 650cm ³ ethanol. The mixture is allowed to cool, sucks the precipitate formed, washed with diisopropyl ether and dried (weight = 62.3 g). Then it is dissolved in a solution of 28.5 g Sodaplätzchen in 250cm ^{3 of} water. This solution is heated on a boiling water bath for 4 h, filtered in the cold, acetic acid is added to the filtrate to a pH of 6 and extracted with chloroform. The chloroform phase is dried over sodium sulfate and then distilled. Bp. ₀ , 6-i = 99-115 ° C, weight = 25g, yield = 63%.

Hydrochloride C ₉ H ₁₄ CINS _2: mp = 147-149 ⁰ C (diisopropyl ether / isopropanol, 1/4) NMR (CDCI _3): 1.4 (t) 3H (CHH, 2 (t) 1H (SH) , 3-5 (m) 8H (CH ₂ N, CH ₂ S), 6.6 (s) 1H (thiophene-H), 13 (m) 1 H (H ^+).

Analysis:

% C% H% N% CI% S

calculated: 45.84 5.98 5.94 15.04 27.2

found: 45.71 6.02 5.92 14.96 26.9

Example 83 3 - [(5-Ethyl-5,6-dihydro-4H-thieno [2,3-c] -2-pyrrolyl) -methylthio] -propanenitrile (Formula 83) C ₁₂ H ₁₆ N ₂ S ₂ -MG = 252.40 To a methanol solution of sodium methylate, prepared by dissolving 2.8 g of sodium in 50 cm ^{3 of} methanol, a solution of 22.9 g (5-ethyl-5,6-dihydro-4H) is added at 0 to 10 ° C. thieno [2,3-c] -2-pyrrolyl) -methanthiol in 100cm ³ of methanol. The mixture is stirred for 2 hours between 0 and 1O ⁰ C, then sets one 10.8 g 3-Chlorpropannitril to 100cm ³ in a solution in methanol. The stirring is continued for 42 h, then the mixture is filtered, the filtrate is evaporated to dryness, the residue is taken up with ether, the ether phase is washed with water, then it is dried with sodium sulphate, and then an evaporation of the ether is followed by isolation of an oil. which one distills. Bp ₁₁ = 175-176 ° C, weight = 19.1 g, yield = 66%.

NMR (CDCl ₃ ): 1.1 (t) 3H (CH ₃ ), 2.15-3 (m) 6H (CH ₂ N, SCH ₂ , CH ₂ CN), 3.6-4.1 (m) 6H (NCH ₂ , CH ₂ S), 6.6 (s) 1H (thiophene-H).

Example 84 S-tfS-ethyl-S ^ -dihydro-H-thieno-S-cis -pyrroly-O-methylthiol-propane-methylimidate (Formula 84) C ₁₃ H ₂₀ N ₂ OS ₂ -MG = 284.44 The mixture is allowed to stand for 4 h -5 ⁰ C to 5 ° C at the same time a hydrogen chloride gas stream and a nitrogen st rom into a solution of 10g (0,0396Mol) S-K-ethyl-S ^ -dihydro ^ H-thieno ^^ - cj ^ -pyrrolyD-methylthiol- propanenitrile in 40 cm ^{3 of} methanol and 80 cm ^{3 of} chloroform. Then the solvents are evaporated off and the residue is poured into 32 g of potassium carbonate in solution in 21 of ice-water. It is extracted directly with ether, the ether phase is dried over sodium sulfate and evaporated to dryness. There is thus obtained an oil which has been used as received in the following synthesis. Weight = 11.3g, quantitative yield

Example 85

(Formula 85) In a suspension of 2 g (0.0056 mol) of N - ^ - Kpyyy oxidthiadiazol [1,2,5] -3,4-diamine in 25cm ^{3 of} methanol, which is cooled to 0 to 5 ° C, allowed bubbling a stream of HCI to dissolution. The mixture is then stirred for 2 h between 0 and 10 ⁰ C, it comes to a precipitate, which is filtered off, washed with diisopropyl ether and dried. Weight = 2g, Yield = 83%, mp = 168-170 ⁰ C. Analysis: C ₁₃ H ₂₁ Cl ₂ N ₆ OS ₃ MG = 430.45

% C% H% CI% N% S

calculated: 36.27 4.92 '16.27 16.47 22.34

found: 36,33 4,87 16,23 16,40 22,14

Example 86

(Formula 86) This compound is prepared under the conditions of Example 85 from N- [2 - [(5,6-dihydro-5-n-propyl-4H-thieno [2,3-c] -2-pyrrolyl) methylthio ] -ethyl] -1-oxide thiadiazolo [1,2,5] -3,4-diamine. Analysis: C ₁₄ H ₂₃ Cl ₂ N ₅ OS ₃ -MG = 444.47

% C% H% CI% N% S

calculated: 37.83 5.22 15.95 15.76 21.64

found: 37.66 5.21 15.64 16.02 21.48

Example 87 S-Amino ^ -K-ftB ^ -dihydro-Sn-propyl ^ H-thieno ^ S-cl ^ -pyrrolyD-methylthiol-ethylaminol-cyclobutene-i ^ -dione (Formula 87) C ₁₆ H ₂₂ CIN ₃ O ₂ S ₂ - MW = 387.94 the preparation is carried out under the conditions of example 85 from 3-amino-4- [2 - [(5,6-dihydro-5-n-propyl-4H-thieno [2,3- c] -2-pyrrolyO-methylthiol-ethylamino-cyclobutene-i ^ -dione. mp = 145-147 ⁰ C (ethanol).

Analysis: C ₁₆ H ₂₂ CIN ₃ O ₂ S ₂ + 1 H ₂ O

% C% H% CI% N% S

calculated: 47.34 5.96 8.73 10.35 15.80

CH ₃ CH ₂ -N _n

S _n ^ CH ₂ SCH ₂ CH ₂

MH

CH ₃ CH ₂ -QfJf ⁰ "

CHNO-

SCH ₂ CH ₂ HH - < ²

HCH ₃

CH ₂ -N

γη γη CH ₃ CH ₂ _

CH ₃ CH ₇ -N1 IIf

, NCN

CH ₇ SCH ₉ CH ₇ NH - <^ ^NCN

^{LLL X} NHCH.

CH ₃

CH ₇ SCH ₉ CH ₉ NH- / ^{2 2 2} ^ N

₇ C ₉ C ₉ ^{2 2 2}

NCN

wOüJL,

Hi

CH ₃

HCH

12

CH ₃ -CH ₂ -N

NH ₂

I ₂ -S-CH ₂ -CH ₂ -NH "Y ^ _n

N- ^ 13

CH ₃ -N

NHCH 3

CH ₃ -W ₂ -

^{z L L X}

H-H02

HHCH ₃

16

HCN MHCH ₃

CH _T CH _? -N Il Il 3 2 Vx ^ flx ^ cHj-S-CHj-CHj-

17

CH ₃

^ CH ₂ -S-CH ₂ CH ₂ -18

HHCH ₃

CH ₃ -CH ₂ -NΜCH ₃ - (CH ₂ ) /

CH ₁ -CH ₉ - ^{3 2}

HHCH ₃

₂ -S-CH ₂ -CH ₂ -NH 20

CH ₃ -CH ₂ -N

21

NH-CH ₂ -C =CH N 0

22

CH ₂ -CH ₂ -N

, 23 ClHNO ₂ SCH ₃ CH-NO ₂

S-CHf

25

_γ S-CH ₉ -CH ₉ -NH

26

S-CH ₉ -CH ₉ -NH- ^

CH ₃ ^ _

CH-CH ₂ -N

CH ₃

Hö- S-CH ₉ -CH ₇ -NH- ^ ^{2 7 2} N-

CH ₉ SCH ₉ CH ₇

^{2 2 2}

SCH ₂ CH ₂ -NH _n ^ NH ₂

31

CH ₃ CH ₂ -N

32

CH OCH CH-N

J LL

CH ₂ SCH ₂ CH ₂ NH 33

CH ₃ CH ₂ CH ₂ -I

I

1CH ₇ NH / ^?

I '11

\ NH₇

35

CH ₃ -CH ₂ -N

38

CH ₂ -S-CH ₂ -CH ₂ -flH ₂

--- ir

CH ₃ CH ₂ CH ₂ 4

CH ₃ CH ₂ CH ₂ --N

CH ₃ - (CH ₂ I ₄ -M;

47

Fl

49

CH ₃ - (CH ₂ I ₅ -N _n JT] 51

SCH ₉ 53 ^L

CH ₃

CH-N

CH ₃ CH ₂ CH ₂ -H

H _v Jm1

₀₀₀₁ ; _H

COOEt

COOEt

46 CH ₃ -CH ₂ -CH ₂ -N

48

S "^ COOEt

CH

ChF

CH-CH ₂ -N]!

50

COOHe

CH ₃ -O-CH ₂ -CH ₂ -N _n 52

CHj-M

54

CH ₂ OH

56

Jf-U II

CH ₃ - (CH ₂ J ₄ -N

CH ₇ OH 57

OüL

59 ^{b L} CH ₃ -CH ₂ -CH ₂ -H

CH ₃ -CH ₂ -N

58

CH ₃ CH 2 OH

OHCH ₂ OH

61

CH ₃ - (CH ₂ I ₅ -NCH-CH ₂ - * L

<V ^

65

CHfCl, HCl ² CH ₃ -N '

66

I o Cl, HCl

-CH--!

CH _3, CH ₃ HCl

68

CH ₃ -CH ₂ -N _n Jm

69

S- ^ CH ₂ -S-CH ₂ -CH ₂ -NH ₂

CH ₃ -NI

XH ₂ -S-CH ₂ -CH ₂ -HH ₂ 70

CH ₂ -S-CH ₂ -CH 72

CH ₃ - (CH ₂ I ₄ -N Π Π

73

CH ₂ -S-CHfCH ₂ -NH ₂

ή ~ S "" CH ₂ CH ₂

CH ₃ -CH ₂ -CH ₂ -H JJ Π

^^^ S ^ CHo-S-CH ₉ -CHo-NHo

75 LLLL

SCH ₂ CH ₂ NH ₂

CH ₃

CH-CH ₂ -N

77

CH ₂ SCH ₂ CH ₂ HH ₂

CH ₃ -O-CH ₂ -CH ₂ -N 79S-CH ₇ CH ₇ -NH ₇

^{L L L}

C ₇ Hr-N Il I

NH ₂

80

Η «SCH * CH ₇ CH ₇ NH ₇

81

83CH ₂ SH

82

85

NH ₂

, / 2HCl

CHi-CH ₇ -CH ₇ -N

«3 ί L

86

CH ₃ -CH ₂ -CH ₂ -N '

87

, HD

NH ₂

Claims (2)

-1- 236 Invention claim: Process for the preparation of thieno and furo [2,3-c] pyrroles of the general formula ) -U 2 m wherein X ₁ and X ₂ denote an oxygen or sulfur atom, Ri represents a straight-chain or branched chain alkyl radical having 1 to 8 carbon atoms, an alkynyl radical, an alkoxyalkyl radical having 3 to 8 carbon atoms or an aromatic radical, R _{2 represents} a hydrogen atom or a straight-chain or branched-chain alkyl radical , m is 2 or 3, where, when m is 2, Χι and X _{2 is} a sulfur atom, U is a SADiaminocyclobuten-i ^ -dione or Aminosulfonylformamidinrest and U is also one of the nitrogen-containing groups 2 P NHR NH 0 T