AU593776B2 - Derivatives for thieno and furo - (2,3-C) pyrroles, process of preparation, and pharmaceutical compositions containing them - Google Patents

Description

n d AUSTRALiA PatentIs Act COMPLETE SPECIFICX TION

(ORIGINAL)

Class Int. Class Application Number .g Lodged: Complete Specification Lodged: Ar':epted: Published: Priority 593776 Laadf),jItS made 1iujnder Sectioii 4'9 and is correct for priitig.

Related Art, APPLICANT'S REF.: 2711/750/22 Name(s) of Applicant(s): LIPHA, LYONNAISE INDUSTRIELLE PHARMACEUT1QUE Ade~lress(es) of Applicant(s): Actual Inventor(s): 34, rue Saint Romain, 69008 Lyon France, DIDIER FESTAL, DENIS DESCOURS, JEAN-CLAUDE DEPIN YVETTE QUENTIN S Address for Service is: PHILLIPS, ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia, 3000 04 It i2omplete Specificationi for the invention entitled: "DERI.VATIVES FOR TI-IENO AND FURO [2,3 C] PYR POT 1

ES,

PROCESS-OF PREPARATION, AND PHARMACEUTICAL COMPOSITIOn,3 CONTAINING THEM" The, following statement is a full description of this inventioia, 'Ificluding the best method of perform~rg it known to applicant(s): Pi9/3/84 1 la- DERIVATIVES FOR THIENO AND FURO F2,3-c] PYRROLES, PROCESSES OF PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM Field of the Invention ,oo, This invention relates to derivatives of 5,6-dihydroe. o 4H-thieno [2,3-cl pyrrole and 5,6-dihydro-4H-furo r2,3-cl Spyrrole, processes for preparation of these compounds, and pharmaceutical compositions containinq them.

o a 0 Backqround of the Invention Histamine, present in numerous animal tissues, is involved in several physiological mechanisms, for example, secretion of stomach acid. Histamine acts by fixinq onto tissular receptors which are subdivided into H 1 type receptors, blocked by standard antihistamine drugs such as Promethazine, and

H

2 type receptors which are insensitive to this type of drugs and are responsible particularly for stomach acid secretion.

Various compounds have been proposed as antagonists to

H

2 histamine receptors and, beyond that, of gastric acidity and have been proposed as active ingredients of pharmaceutical compositions useful in treatment of gastric ulcers and other disorders caused or exacerbated by gastric acidity, in particular, and Ranitidine.

a r 2 Many journals and monographs have already been devoted to the class of compounds of this type which continues to be the subject of numerous works aimed at findinq new more active compounds better suited to treating ulcers.

Chemically, comparison of the compounds described shows that they generally consist of a heterocyclic or benzene aromatic ring, linked, by an aliphatic chain most often comprisinq a heteroatom, princ.pally sulfur or oxyqen, to a radical selected from organic nitrogen groups.

A relatively small number of condensed bicyclic compounds, havina antiulcerous properties derived from action antagonistic to H 2 histamine receptors, seem to have been the subject of studies.

Benzofuran derivatives are known from U.S. patent No 4,238,487 and imidazopyridines are known from Belqian patent 779,775.

0 International patent application WO 84/00544 and U.S.

4,520,025 describe compounds endowed with cytoprotective and H2 antihistamic properties broadly defined as able to be derived from a bicyclic system consisting of a benzene or heterocyclic ring with 5 or 6 groups joined to an aromatic or polyhydrogen nitrogen ring, thus including furo- and thieno-pyridine and isoquinolein derivatives.

reaction diagrams and synthesis processes presented in the descriptive part relate only to isoauinolein and furo- and S thieno-pyridine derivatives, and the only compounds described are isoquinolein derivatives.

None of the reaction diagrams oroposed and none of the synthesis processes disclose nor make it possible to prepare thieno and furo pyrrole systems.

U.S. patent 4,279,819 has as i.ts object S aminosubstituted derivatives of furan and French patent 2,391,209, aminoalkylthiophenes.

The compounds described in these two patents have a dialkylamino alkyl furan or thiophene monocyclic structure.

These compounds used as pharmaceutical compositions have a standard action mechanism of the "Cimetidine" type.

3- Further, U.S. patents 4,390,701 and 4,395,553, titled: "1,2-diamino-cyclobutene-3,4-dione derivatives" have as their object compounds whose structure associates a thiophene or furan ring with an aminocyclobutenedione termination.

These compounds, whose antihistamic action mechanism is comparable to that of "Cimetidine," exhibit an activity that is equivalent at most.

According to this invention, it has just been accidentally discovered that certain derivatives of fused bicyclic systems of 5,6-dihydro-4H-thieno r2,3-cl pyrrole and |,6-dihydro-4H-furo r2,3-c] pyrrole, represented respetively by formulas Ia and Ib below, 6 1 6 1 S 2 2 5 H I 3 4 '4 S(I a) (I b) ft have particularly strong antisecretory and antiulcerous properties and that in this reqard they show themselves to be considerably superior to the compounds currently used in therapy such as Cimetidine or Ranitidine or also the tetrahydroisoquinolein derivatives described as preferred products in U.S. patent 4,520,025 cited above, and to which they have been compared because of the structural relationship that is Sconsidered to exist between these various compounds. Further, it has been found that the action antagonistic to H 2 receptors I .V 'frought about by these compounds proceeds by a mechanism that is oriqinal for this activity, of a type that is slightly r-versible, thus giving them remarkable lonq-lastinq S antisecretory properties.

NL.

I~I~x~, iZ -4- Summary of Invention The compounds of the invention have the formula X CH X (CH

IR

2

(II)

wherein X 1 and X 2 designate, an oxygen or sulfur atom; R1 designates a linear or branched alkyl radical containing 1 to 8 carbon atoms, an alkynyl radical, preferably proparqyl, an alkoxyalkyl containing 3 to 8 carbon atoms or ciradical such as phenyl or phenylalkyl, preferably benzyl; R2 can designate a hydrogen atom or a linear or branched alkyl radical, preferably a methyl radical, in which case X 1 necessarily designates a atom7 m being equal to 2, U can represent an a- n y -crmi. radical or a 3,4-diamino cyclobutene-1,2- *o dione radical, in which cases X 1 and X 2 both designate a sulfur atom; with m 2, U can also represent a nitrogen structure answering to general formula III or also an aminotriazole o heterocyclic radical of general formula IV; U can also represent o an aminothiadiazole radical of formula V, provided that when X 1 designates an oxygen atom, m is equal to 2.

0 NH f A 2 1 j -NH: N N *.HR -NH -NH NHR 1/ NHR 3 4 4 (III) (IV) (V)

I

In formula (III), V can represent a nitrogen atom or a CH fragment, W a group, preferably unsaturated, such as cyano or nitro, and R 3 a hydrogen atom, a linear or branched alkyl group O U containing 1 to 8 carbon atoms, arn alkynyl radical, preferably propargyl; in formula (IV) R 4 can designate an alkyl group containing 1 to 3 carbon atoms, but preferably a methyl group; in formula R 3 has the meanings defined above.

It should also be noted that in formulas III to V above, although double bonds have been placed in particular positions, different other tautomeric forms are possible and that the invention also has these tautomeric forms as its object both in regard to the compounds of the invention and new synthesis intermediates.

As specific compounds of the invention there can be cited: *N-cyano N'-[ethyl--2-[(5-ethyl-5,6 dihydro-4H-2-pyrrolo thiophene) methylthioll N" methylguanidie; N-[ethyl-2-[(5-ethyl 5,6-dihydro-4H-2-pyrrolo (3,4-b) th.l"mhene) methyl thiol] N'-methyl 2-nitroethene 1,1-diamine; N-cyano N'-Ilethyl 2-I2-pyrrolo-(5,6-dihydro a, 4-b) thiophene) methyl thio]] N"-methylguanidine; d. .3-[2-pyrrolo-(5-ethyl 5,6-dihydro-4H(3,4-b) thiophene) a methyl thio] N-sulfamoyl propanamidine; 4 N-5-Ilethyl 2-[2-pyrrolo-(5-ethyl 5,6-dihydro-4H (3,4-b) thiophene) methyl thio]] methyl-l-lH triazole [1,2,4] L 3, *N-[ethyl 2-[2-pyrrolo-(5-ethyl 5,6-dihydro-4H (3,4-b) thiophene) methyl thio 1-oxide thiadiazole [1,2,5] 3, 4-diamine; *N-Iiethyl 2-[2-pyrrolo-(5,6 dihydro 5-n pentyl-4H (3,4-b) thiophene) methyl thioll N'-methyl nitrothene 1,1-diamine; .N-Ilethyl 2-]2-pyrrolo-(5-ethyl 5,6-dihydro 3-methyl-4H thiophene) methyl thio]] N'-methyl 2-nitroethene 1, 1-diamine; *N-[ethyl 2-2-pyrrolo-(5-ethyl 5,6-dihydro-4H (3,4-b) thiophene) methyl thio]] N'-methyl 1-oxide thiadiazole 3,4.-diamine; N-[ethyl 2-[2-pyrrolo-(5--ethyl 5,6-dihydro-4H (3,4-b) t hiophene) methyl thio]] N'-propargyl 1-oxide thiadiazole 3,4-diamine; r

-I

7 N-[ethyl 2-[2-Pyrrolo-(5,6 dihydro 5-n pentyl-4H-(3,4-b) thiophene) methyl thio]] 1--oxide thiadiazole [1,2,51 3 ,4-diamine; N-[ethyl-2-112-pyrrolo-(5-n butyl 5,6-dihydro-4H (3,4-b) thiophene) methyl thio]] 1-oxide thiadiazole [1,2,51 3, 4-diamine; N* ehl22-yrl 5-sb-y 5,6-dihydro-4H (3,4-b) thiophene) methyl thiol] 1-oxide thiadiazole [1,2,5] 3, 4-diamine; .N-[ethyl-2-12-pyrrolo-(5-n hexyl .5,6-dihydro-4H thiophene) methyl thiol] 1-oxide thiadiazole [1,2,5] 3, 4-diamine; N-Iiethyl-2-[2-liyrrolo-(5-n pentyl 5,6 dihydro-4H (3,4-b) thiophene)/ methyl thio]] 1-oxide thiadiazole [1,2,5] 3, 4-diamine; N-[ethyl-2-[2-pyrrolo-(5-(2-methoxyethyI dihydro-4H-(3,4-b) thiophene) methyl thio)] thiadiazole 3,4 diamine; *3--amino-[4-ethylamino-21(2-pyrrolo 5-n propyl 5,6 dihydro--4H-(3,4-b) thiophene) cyclobuthene-1,2 dione.

ft t, 5,6 1-oxide] -7propyill 1-oxide thiadiazole [1,2,51 3,4-diamine; N-[ethyl 2-[2-pyrrolyl-[5,6-dihydro 5-(2-me yethyl)-4H.thiero methylthioll 1-oxide t L azole [1,2,51 3,4diarnine; 3-amino-4-[ethylami -[(2-pyrrolyl-5,6-dihydro 4H-thieno .methylthioj cyclobutene-l,2--dione.

2-[2-pyrrolyl-[5,6-dihydro 5-n-propyl-4H-furo [2,3ri i 'n 1 1 n irp tbia 7n 1 3 4-di ami nP? The compounds of the invention easily form addition salts with inorganic or organic acids; as inorganic salts acceptable in therapy there can be cited, for example, hydrochlorides, hydrobromides, sulfates, phosphates, sulfonate; examples of organic salts that are particularly useful are acetates, tartrates, citrates, camphosulfonates, maleates, fumarates, methanesulfonates. All these addition sal.ts also come *,withi,.n the scope of the invention.

secrtionBecause of their cap.:acity to inhibit gastric acid secrtionin the organism, the Qoompounds are endowed with antiulcerou-- activity; this particularly, intense arid lasting action makes their use extremely interesting in the treatment of peptic ulcers and other similar pathological manifestations. It should be noted that the length and intensity of the antisecretory and antiulce-rous actions of the compounis of the invention of formula I are a function of the nature of the j heteroatom Xl and X 2 but also, in great part, of the nature of substituent RI and that, in this regard, the compounids of formula I particularly preferred are those for which XI and X 2 designate a sulfur atom and Rl represents a group as defined above and having an aliphatic fragment link~ed tco the nitrogen atom of the pyrrole ring by at least two carbon atoms.

A mcothod currently used for study of gastric Santisecretory agents consists of rats with tied pylorus according to H. Shay et alt, Gastroenterology', 1945, 5, 43: femnale tats of about 200 g, fasting for 72 hours, had their pylorus ligated under slight ether anesthesia. Four hours latoir, the animals 4;L.~J Z)t Ii -8were sacrificed and the content of their stomach removed to measure acidity. The compounds were injected intraperitoneally just after ligation of the pylorus. The dose lowering gastric acidity 50% (DE 50) was calculated for each compound, in relation to an untreated batch. Each compound ted in 3 geometrically spaced doses. Each batch comprised 10 rats.

Blockage of the H 2 histamine receptors involved in the secretion of stomach acid secretion was studied in vitro on the isolated guinea pig auricle and in vivo by the method of histamine gastric hyperacidity in the anesthetized rat.

Isolated guinea pig auricle: Albino quinea pigs weighing between 300 and 400 g were killed by a blow to the head and bled. After opening of the thorax, the right auricle was quickly removed and placed in an isolated organ tank containing 100 mg of Krebs (composition in g/l: NaCI 6.9 KCl 0.35 -CaC12 0.28 Mg S04 NaHC0 3 2.09 KH2PO4 0.16, glucose 2) kept at' oO°o 32 0 C and strongly oxygenated (95% 02, 5% CO 2 d The auricle was connected to an isometric stress gage, under tension of 1 g. The spontaneous beatings were recorded on O* a galvanometric recorder.

After a 1-hour stabilization period, accumulated doses ,I of histamine were added to the survival medium, every 5 minutes, which caused an acceleration of the beats by stimulation of the histamine receptors which in cardiac tissues is of an H 2 nature.

Histamine was added until the auricle beating rate no longer increased (maximum effect). It was then possible to plct the curve representing the variation of beating as a function of the :-ncentration of histamine in the bath. After rinsing and rest for 30 minutes, the same experiment was resumed for 30 minutes after having added an H 2 antagonist in the bath (compound of the invention or reference product).

This compound was thus tested in 3 geometrically Sincreasing concentrations which, in the case of blockinq of H 2 receptors, caused a right shift of the histamine/chronGtropic concentration curves. For each active compound, we determined a PA2, the cologarithm of the concentration of the test I i l~ ly~.

9 compound for which it was necessary to double the histamine concentration to find a given chronotropic effect. The Calculation was made by the method of 0. Arunlakshana and H.O.

Shild, Br. J. Pharmac., 1959, 14, 48.

This preparation also made it possible to take into account the nature, reversible or not, of the inhibition. In the first place, it will always be possible to remove the antagonist of the receptors by performing repeated rinsings or by using a stronger concentration of histamine, which will be refleuted by parallel but superposable histamine/chronotropic effect concentration curves.

On the other hand, in the second case (inhibitiorn that is hard to reverse), the H2 cannot be cor-letely taken away either by rinsings or by high histamine concentrations, which is reflected by dose/effect curves that are not superposable (the maximum chronotropic effect is increasingly weaker when the H 2 o.t, antagonist concentration increases).

o Histamine gastric hyperacidity in anesthetized rats: (Black et al, Nature, 1972, 236, 3R5): Rats anesthetized with *oo ethylurethane received a continuous histamine perfusion S ug/Kg/minute) in a jugular vein. The stomach was continuously perfused withphysiological serum at 37 0 C, under a constant flow of 3 ml/minute.

A pyloric (annular collected the perfusate, the acidity of which was measured continuously. Each compoutnd to be examined was administered intravenously (a single dose per rat).

Inhibition of acidity was measured at a period corresponding to the maximum of action (period variable from one compound to the Snext). A minimum of 3 rats was used for each dose tested. The dose reducing by 50% (DE.50) the hyperacidity induced by histamine was determined for each active compound of the S invention. Moreover, the period of action resulting from intravenous injection of a single dose corresponding to rounded SD 50 was measured for the mot active compounds.

The compounds of the invention are generally not very toxic, For example, the compound of example 22 has no toxic

I

effect when adm'nistere- I.V. to Mice or rats, in a dose representing 100 times its DR in the histamine hyperacidity test in anesthetized rats.

The following tables 1 to 4 give, for the methods described above, the activities of the compounds c- the invention and the reference products. It should be pointed out that the compound marki d A in the following tahles designates N-methyl N'rpropyl 3-(2-nethyl-l,2,3,4-tetrahydro-5-isoquinoleini oxy)2nitro-ethene--l,1-diamine described and claimed as the preferred compound in U.S. patent 4,520,025.

TABLE T Rats with tied Pylorlis DER5 0 and limits at 95% (mg/kg/I.P.) according to Shay RelativeEffectiveness C~ie ine =1 Ranitidine=1 Compound oE Example No: .1 3 18 19 21 22 t 28 29 31 33 34 Raiidn Cimet-idlne Compound1 A 1 0.

3 14 42 (9-40) (4 4-14) (7 .5-43) (4-16) (0.9-2.4 (8 .3-27) (9 .5-42.) (18-58) S (0.3-0.11) (0 3-3 .9 (0.3-2.5) .5 (0.2-1.2) .6 (1.9-6.8) (6-11 6-32.2j) t 2.2 5 .25 2.3 5.2 28 2.8 2.1I 1.3 84 42 46.*7 84 ,11.7 60 3.8 7 1 1 7 9./3 0.9 0.7 0.4 28 14 .15.5 2~8 3.9 1.3 1 0.3 r

-U,

11 TABLE 2 Isolated Guinea Pig Auricle Compound of Example No: 1 3 6 8 11 13 1 f 19 21 22 28 29 30 31 33 34 Ranitidine Cimetidine Compound A pA2 and limits at 95% (mg/kg/I.P.) 6.98 (6.70-7.27) 7.11 (6.85-7.38) 6.21 (5.97-6.45) 6.8,9 (6,,66-7.13) 6.85 f,6.64-7.06) 7.68 (7.46-7.90) *7.05 (6.82-7.29) 5,90 (5.67-6.14) 7.37 (7.17-7.58) 7.10 (6.87-7.34) *7.77 (7.53-8.02) *7.37 (7.08-7.67) *-7.55 (7.29-7.81) *7.19 (6.95-7.44) *7.51 (7.26-7.77) *7.31 (7.01-7.62) 7.20 (6.94-7.47) 7.44 (7.12-7.76) 6.94 (6.77-7.11) 5,88 (5,66-6.1 Relative Effectiveness Cimetidine 1 Ran tidine 1 1.10 0.35 1.48 0.47 0.19 0.06 0.89 0.28 0.81 0.26 5.50 1.74 1.29 0.41 0.09 0.03 2.69 0.85 1.45 0.46 6.76 2.14 2.69 0.85 4.07 1.29 1.78 0.56 3.72 1.17 2.34 (,.74 1.82 ,M 3.16 L 1 0.32 0.087 0.028

'I

It 4 t~

I'

4 t t,

I

1 I 4*

I

4 44 44*4 4 I 44 0~ 4#4 I 44 I, 4 4* Inhibition reversible with difficulty.

4 12 TABLE 3 Hystamine Gastric Hyperacidity in Anesthetized Rats Compound of Example No: 1 3 6 8 11.

13 18 19 21 22 28 29 30 31 33 34 Ranitidine Cimetidine Compound A DE50 and limits at 95% (mg/kg/I.P.) Relative Effectiveness Cimetidine 1 Ranitidine 1 0.6 0.3 >o 0.5 0.4 0.03 0.5 0.1 0.6 0.05 0.02 0.1 0.2 0.15 0.2 0.25 0. 4 0.4 (0.25-1.5) (0.1-0.9) (0 .18-1 .4) (0.15-1) (0.02-0.05) (0.17-1 .5) (0.03-0.3) (0.3-1.2) (0.02-0.11) (0.08-0.5) (0.04-0.25) (0.07-0.6) (0.07-0.3) (0.08-0.5) (0.12-0.5) (0.05-0.17) (0.18-0.9) 0.7 1.3 0.8 1 13.3 0.8 4 0.7 8 2 4 2 2.7 2 1.6 4.4 1 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 1 0.22 9 8, o g 0 O o9: 8 *Q O

Q

o 8i 0 8 0 I

I

I~(P

L08 ~~r W-l 4 '*1 .4 S* ~1~ Ald 26 5.3 g (0.032 mole) of bis-2,2'-methylthio 2-nitroethene in 100 cc ot acetonitrile is refluxed for 12 h -iir* Ihn h, k i L i i I I 13 TABLE 4 Histamine Gastric Hyperacidity in Anesthetized Rats Compound of Example No: 1 3 8 11 13 18 21 22 28 29 31 33 34 Ranitidine Cimetidine Period of Action n* (minute E.S.) Relative Effectiveness Cimetidine 1 Ranitidine 1 112 27 90 20 128 -1 22 88 24 120 18 hours 102 22 76 20 hours hours 8 hours 8 hours hours 8 hours 85 21 71 13 77 1.6 1.3 1.8 1.2 1.7 6.2 1.4 1.1 6.2 6.2 6.2 6.2 6.2 >6.2 1.2 1.4 1.2 1.7 1.1 1.6 6.7 1.3 1 6.7 6.7 6.7 6.7 6.7 6.7 1.1 t *c

I

*9 I *1

I

I t I t It I tt tfi n number of tests This invention relates to pharmaceutical compositions consisting of products of general formula II, optionally in the form of a salt, in the pure state or in the form of admixtures with any other product that is pharmaceutically acceptable which can be inert or physiologically active. These pharmaceutical compositions can be administered in a great variety of dosage forms such as tablets, capsules, powders, granules, etc. In 1 these compositions, the active ingredient is mixed with one or more inert diluents such as lactose or starch. Further, these compositions can comprise substances other than diluents, for S. i -oew 14 example, lubricants such as talc or magnesium stearate. When aqueous suspensions, elixirs or syrups are desired for oral administration, the essential active ingredient can be associated theie with various sweetening and/or flavoring agents, if necessary, emulsifiers and/or agents for pj-'ting into suspension at the same time as diluents such as water, ethanol, propylene glycc and various similar additives.

A pharmaceutical composition for oral dministration and offered in the form of unit dose containing 5 to 500 mg of active principle is preferred.

The following example, given in a nonlimiting way, .llustrates a composition of this type: Example: Active 10 mg 100 mg Wheat mg 6 mg Polyvidone mg oR ,ot. Magnesium 1 mg To prepare the compounds of general formula II in which

X

1 and X 2 both represent a sulfur atom and U a 3,4-diamino-l,2cyclobutenedione radical, there are made to react successively, under the conditions described by S. Cohen and S.G. Cohen, J.

Amer. Chem. Soc. 1966, 88, 1533-1536, a 3,4-dialkoxy-l,2cyclobutenedione, whose preparation is also described in this publication, with an amine of general formula VI 1 H SSCH2CH2NH2 2 2 22

R

2

(VI)

in which R 1 and R 2 have the same meanings as above, then reacting the intermediate compound thus obtained with ammonia.

The compounds of general formula II, in which X 1 and X 2 represent a sulfur atom and U an N-aminosulfonylamidine radical, can be prepared by the action of sulfamide on an imino ether of general formula VII.

i- i 1

I

hk i 15 CH SCH CH I R 1 -N 2 2 S1 OCH 3

R

2

(VII)

in which RI and R 2 have the same meaning as above. The reaction is performed in a polar solvent, preferably an alcohol such as methanol, under inert atmosphere and at a temperature close to ambient temperature.

The compounds of general formula II in which m has a value of 2 and U designates a nitrogen radical corresponding to formula III, can he prepared by the reaction of a compound of general formula VIII, 0 Id

S-V-W

S" x CH x -CH CH -NH 4, 2 2 2 2 R /I C H

R

t R2

(VIII)

in which X 1

X

2 RI, R 2 V and W have the same meanings as above, with an amino compound of the formula R 3 NH2, in which R3 has the meanings defined above; the reaction can performed in any solvent or diluent compatible with the compounds present, but preferably in a rather polar solvent such as ethanol, methanol or acetonitrile and at a temperature that can be between ambient temperature and reflux temperature of the solvent used.

A second process for preparing the compounds of formula II in which m has the value 2, U designates a nitrogen radical of formula III and X 1 represents a sulfur atom, consists in making a I 16 v R N 16 halogen compound of formula IX or one of its salts, prefera the hydrochloride S CH- H H NH 2 22 1

R

2 2 I X in which X designates a halogen, preferably chlorine, R1 and P 2 S having the same meaningss above, react with a thio of general Sformula X V- W 3 HS CH CH NH 2 2

NHR

3

(X)

temperature and in the presence of a basicagent which can e an CH -v-w CH t

(XI)

4 if 7 17 in which V and W have the same meanings as above, said compound being made to react with an amine of the formula R 3

NH

2 in which R3 has the above meanings, under the conditions described by J.S.

Davidson, Chem. Ind. (London), 1965, 48, 1964-5, and/or in case the linking V-W represents an -NCN group, according to the process of F.H.S. Curd et al., J. Chem. Soc., 1948, 1630-6, from sodium cyanamide and an isothiocyanate of the formula R 3 NCS; then the resulting compound is treated with cysteamine hydrochloride in a dilute alcohol solution in the presence of a basic agent such as soda.

The compounds of general formula XI, in which the group =V-W represent a group =N-CN or =CH-N0 2 are known and their preparation is described, respectively, by R.J. Timmons and L.S.

Wittenbrook, J. Org. Chem., 1967, 32, 1566-72 and by R. Gomppers and H. Schaefer, Chem. Rer., 1967, 100, 591-604.

To prepare the compounds of general formula II, in which m is equal to 2 and U represents an aminotriazole radical of general formula IV, the compound of general formula VIII, in which the group =V-W designates a linking =NCN, is made to react with an alkylhydrazine of the formula R4NHNH 2 in which R4 has the above meanings; the reaction can be performed in any solvent that is inert in regard to the compounds present, such as, for example, an aromatic hydrocarbon such as toluene, xylene, trimethylbenzene, etc. and at a temperature that can be between ambient temperature and the reflux temperature of the solvent used.

The compounds of formula II in which U represents an aminothiadiazole radical of formula V can be obtained by making an amine of general formula XII 41 iI I I 1

CH

2

X

2 -(CH)2 -NH 2 S-N II R

R

4 t4 t. C I S( 4a44 4 a 4

(XII)

-i si 18 react successively with a 3,4-dialkoxy thiadiazole S oxide and an amine of the formula R3NH 2 in which R 3 has the above meanings, according to the indications of S. Karady et al., Heterocycles, 1981,16, 1561.

Another process for the preparation of the compounds of general formula II in which U designates a thiadiazole radical of formula V and X1 and X2 both represent a sulfur atom consists in making an alcohol of formula XIII CH OH R -N

I

R2 R

(XIII)

in which R 1 and R 2 have the same meaning as above, react with a thiol of formula XIV in which R 3 and m have the meanings indicated above 0 HS-(CH -NH NHR 44., 2 m 3 (XIV) and which can be prepared under the conditions of the publication of S. Karady et al., cited above, by causing the reaction on a 3,4-dialkoxy thiadiazole [1,2,51 S oxide of the cysteamine and an amine of the formula R3NH2. The reaction of compound XIII with compound XIV is performed in the presence of a dehydration agent, preferably hydrochloric acid, and at a temperature close to 0°.

The 3,4-dialkoxy thiadiazole S oxides used are known compounds, which have been prepared according to the S indications of S. Karady et al., Heterocycles. 1981, 16, 1561.

i ii 1- ^f 19 19 The intermediate amines, of general formula VI defined above, are new compounds which can be prepared as the following reaction diagram 1: DIAGRAM 1 /11" COOR 2R (XV) l) SHCH CH NH /HC1 2) Base 3 6 CH OH R -N

R

2

(XIII)

Shalogination i i t I

I

k CH SCH CH NH 2 2 2 2 R

-N

1

N

R

2 R 8 1 SHCH CH NH Cl 0 2 2 3 Base ,CH X 2

R

(IX)

P,

t it if t I t (vI) according to which an ester of general formula XV is reduced, in which R designates an alkyl group, preferably methyl or ethyl, to the corresponding alcohol XIII with reducing agents of the ester function such as horane or lithium or aluminum hydride in suitable solvent such as ether or tetrahydrofuran. When the resulting alcohols XIII are made to react with cysteamine in the presence of a dehydrating agent under the conditions already indicated (cf. condensation ofl an alcohol XIII with a thiol XIV) an acceptable yield of the desired amines VT is obtained.

A second process consists in transforming an alcohol S XIII into a corresponding halide IX which is then treated with cysteamine in a basic medium under the conditions already 'mentioned (cf. alkylation of the thiols of formula X); halogenation of alcohols XIII can be performed by means of the usual reagents such as thionyl chloride in an inert solvent such 20 as chloroform or methylene chloride and at a temperature between 0 C and reflux temperature but preferably at a temperature close to ambient temperature.

Imino ethers of general formula VII are obtained by the action of methanol on a nitrile of general formula XVII.

CH SCH CH CN 2 22 ,R -Nc 2 (XVII) in which R 1 and R2 have the above meanings, under the usual conditions for preparation of imino ethers such as those described, for example, in Houben-Weyl, Methoden der Organischen Chemie, 1952, 8, 697.

The compounds of general formula XVII are new and can be prepared according to the reaction sequence of following diagram 2: St DIAGRAM 2 CH X SNHCH2SH 2 1) NH-CSNH 2) NaOH-H 0 R 2 R 2 2 3) H

(XVI)

IX) XCH CH CN 2 .2 (XVI) (XVII) Base by alkylation of a halide IX by thiourea then hydrolysis of the *I"1 intermediate isothiouronium salt under the usual conditions as described particularly in Houben-Weyl, Methoden der Organischen 21 Chemie, 1955, 9, 14, to obtain the corresponding thiol of Formula XVI which can then be alkylated by a /-&halogen propane nitrile, preferably 3-chloropropane nitrile. This alkylation is performed 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 making an amine of general formula XII, in which m is equal to 2, react with a compound of formula XI in any solvent or diluent compatible with the reagents present, but preferably in a rather polar solvent such as acetonitrile and at a temperature that is most often the reflux temperature of the solvent selected.

The amines of general formula XII, in which X 1 designates a sulfur atom, X 2 is an oxygen atom and m is equal to 2 can be prepared by condensation of a halide of formula IX with ethanolamine, the reaction being preferably performed in an excess of ethanolamine.

The amines of general formula XII, in which X 1 and X 2 both designate a sulfur atom and m is equal to 3 can he I* synthesized by alkylation of a thiol of formula XVI by a halogenopropylamine, preferably 3-bromopropylamine in a basic medium or else by reduction of a nitrile of general formula XVII by a known reducing agent having a nitrile function, for example, lithium or aluminum hydride in a suitable solvent, such as ether or tetrahydrofuran.

The amines of general formula XII in which X 1 designates an oxygen atom, X 2 a sulfur atom and m equal to 2 can be prepared by reduction of an ester of general formula XIX with a reducing agent of the ester fvnction in a suitable solvent by Scondensation of alcohol XVIII thus obtained with cysteamine as shown by following diagram 3:

S

A/II j C2 4 4$U -1 r ii -71 22 DIAGRAM 3

COOR

(XIX)

(XVIII)

1. £HSCH:CHNH /HC1 ,CH2SCH2CH2 NH2 R -I Some alkyl thienopyrrole carboxylates have already b~een described; these compounds can be prepared according to the following known reaction sequence: K COOR S COOR S OOR IHCHO IHC1 zncl- 0 1

R

1

,NH

2 C11 21 f (XXI) (XX)

(XV)

t~I 14t%4L 4 C 6 *66*46 6 0 9 23 by starting with an ester XXI which is subjected to a chloromethylati,on re~actioni dihalide XX is thus obtained which is then cyclized to the 6c9sired ester XV by reaction with an amine RlNH 2 according to the technique of J. Feijen and H. Wynberg Rec. Tray. Chim. Pays Ras, 1970, 89, 639.

The polyoxymethylene-hydrochloric acid mixture as described by Cho Sone, Nippon Kagaku 7asshi, 1965, 86, 1331 65f, 13637C, preferabLv chloromethyl methyl ether, said to be toxic, can he used as chloromethylation agent.

The efiters of general formula XIX, which are new products, can be prepared from methyl 5-methyl 2-furan carboxylate as 8hown in following diagram 4: DIAGRAM 4 HOHO, HC1 CH ClCH2-NN, CH- X 1COOCHCH1/ 3, 3 CH 0 O 2 0H3 itt Br R 1 iNH 2C1OH., lBrCH 2 CO OH (XIX)23 In this fiagram, methy. 3-chloromethyl 2-methyl p carboxyl.,te and methyl 2-bromomethyl 3-chlot-omethyl 2-methyl furan carboxylate are known products described, respectively, by 1 A.Th. Mndzhoyan et al., D~oklady Akad Nauk. Armyan 1957, 25# 277 -CA 52, 12835 b, and M. Valenta et al., Collection Czech. Chem.

Commun., 1964, 9,1577- CA, 61 6976 g; the cyclization reaction Swith RiNH 2 is preferably performed in an aprotic, polar solvent Ssuch as acetonitrile, under inert atmosphere and at a temperature close to ambient temperature.

fl; -u-i 24 The amines represented by the formula CH 2

X

2 -(CH 2 m-NH 2 (XI I) w~l~rein PI, R2, Xl, X2, and m have the meanings defined above provided that when X 1 represents an oxygen atom, R2 represents a hydrogen atom, X2 a sulfur atom and m is equal to 2, intermediates in the preparation of compounds according to formula TT are part of the invention.

Also, the compounds of formula XXII

IIH

2

(XXII)

tf 0

{L

in which Rl an(, R2 have the meanings defined above and Y designates the

F

groups: OH, halogen, SH r -S (CH 2 2CN, -S (CH 2 2

C.

OCH~

are irnermediates in the preparation of the compounds of formnula 11 when Xl is a, qu.Lfur atom, being part of the invention.

FUrther, the compounds of formula XXII R0 4 4 4 414 '4

(XXIII)

>4 L- -9q 25 in which Rl has the meanin(,L indicated above and 2 designates a g'roup: -COOCH 3 or -CH 2 OH, are intermediates in the preparation of the compounds of formula TI when XI represents an oxygen atom and, for this reason, are part of the invention.

Examples illustrating the invention in a nonlimiting manner are given below. Melting points are indicated in degrees centigrade and boiling points in millibars.

EXAMPLE 1: N-cyano N'-[ethyl-2-[2-pyrrolyl-(5-cthyl 5r.6-dihydro- 4H'-e- -12eahal )mtthiol I N"-mnet'nyl guanidine (Formulq 1) A solution of 5.n' g (0.035 mole) of N-cyano N'(2mercaptoethyl) N"-methyl guanidine in 40 cc of methanol is added to a solution of sodium methylate in methanol, prepared by dissolving 0.9 g (0.039 gr.at..) of sodium ic, 50 cc of methanol at a temoerature lho)ween 0 and 5 0 C; the mixture is stirred for 2 hours at 0 0 C then 4.2 g (0.0176 mole) of 2-chloromethyl 5,6-dihydro--4H-thieno [2,3-cl pyrrole hydrochloride is added at this temperature; stirring is continued for 42 hours at ambient temperature, after which '-he mixture is oveporated, the residue dissolved in a sufficiant amount of chloroform, the resulting solution is washed with aqueous sodium hydroxide, then water, the organic phase is dried on sodium sulfate, the solvent filtered and evaporated, the residue is dispersed in diisopropyl ether, drained and dried. Weight 3.3 g Yield 58% Mp 129-132'C.

Mp 142-143'C (isopropanol) NM.R (DMSO-d6) 1.3 3H (CH 3

CH

2 7H (CH 3

-CH

2 N, SCH 2 3.8-4.3 (in) 8H (CH 2 S, N-CH 2 6.8-7.3 (in) 3H (NH, aromatic H) Percentage analysis: Cl4H 2 lNS 2 MW 323.48 C H N S calculated 51.98 6.54 21.65 19.83 %found .52.02 6.55 ?1.81 19.5 EXAMPLE 2: N-i~Lhyl-2-[2-pyrrclyl-(5-ethyl 5p 2ir-HJ +EPr; e4- inethylthio1l l-'nethylthio 2-nitroethenainine (Formula 2) A mixtuire of 7.8 g (0.032 mole) of 2 ethyl 5,6',6hydro-4H-thierio f,2,3-cl) mnethyithiol] ethylamine and 1 114

I

I 4 14

I

f 4* I: '9 I 9 I I 9 41*1 I l4~

S

IIC

II4I~ I

I

*14441 4 **a*ae 9' I -26 5.3 g (0.032 mole) of bis-2,2'-mrethylthio 2-nitroethene in 100 cc oF acetonitrile is refluxed for 12 hours; then the reaction mixture is filtered, tha filtrate evaporated dry, the resulting residue is dispersed in a minimumt amount of ethyl acetate, the solid is drained, washed with dilsopropyl ether, then dried.

Weight 7 g Yield =61% Mp 85-878C Mp 93-94'C (diisopropyl ether -isopropanol, 1-1) NMR (CDC 13 1.2 3H- (CH3CH 2 1.8 lH (NH) 2.4 3H (CH 3 9) it2.6-3.1 (in) 4H

(SCH

2

CH

3 CH2N) 3.33-4.1 (mn) RH (CH2N, CH 2 S) 6.6 and 6.75 2H aromatic H) Analysis: C14H 2 1

N

3 0 2

S

3 MW 359.53 C Hi N S calculated 46.77 5.89 11.69 26. found 46.52 5.90 11.85 26 EXAMPLE 3: N-f ethyl-2- f2-pyrollyl- (5-ethyl 5,6-dihydro-4W>I4-e.i.e.

(Formula 3 A solution of 5.3 q (0.0147 Tnole) of the compound of example 2 in 19 cc of 33% methylamine solution in ethanol is *refluxed for 11 hours; then the m$,xture is evaporated, the 43sultinq residue is dispersed in a sufficient amount of ethyl1 4,41acetate, drained and dried. Weight 4.6 g Yield 92% MP= 96-101.

0

C

MP =99-101 0 C (ethyl acetate- isopropanol NMIR (CDCl 3 1.2 3H (CH 3

CH

2 2.6-4.08 tm) 15 Hj (Cl-i 2 6.6-7.3 (in) 3H NH) 10.1 (broadened s) 1H- (NH) Analysis: C14H 22

N

4 0 2

S

2 MW =342.48 C Hi N %calculated 490 .8 16.36 18,73 found 49.09 6.39 .16.19 18.90 EXAMPLE~ 4: N-cyano N'-Iethyl 2-r2-pyrrolyl-(9-ethyl 5,6- #sadihydro-4H-thieno (2,3-cl) Tnethylthioll N"-isopropyl guanidine (F'ormula 4) 7.2 g (0.0386 mole) of N-cyan,- N' -isopropyl T nercapt-oethyl) quanidine in solution in 85 cc of~ methanol is addto a methanol. solution, of sodium, methylater prepared by w 4 27 dissolving 1 g (0.0434 gr.at.) of sodium in S0 cc of methanol and cooled between 0 and 5 0 C; the mixture is stirred for 2 hours between 0 and 5'C then 4,6 q (0,0193 mole) of 2-chioromethyl 5,6dihydro-5-ethyl-4H-thieno [2,3-cl Ipyrrol(.- hydrochloride in 50 cc oE methanol are added T-hereto; stfiring of the mixture is continued for 24 hours at airthient temperature, then evaporated.

The residue is dissolved in of chloroform, the resulting solution is washed in aqueous sodium hydroxide, then water, the organic phase is dried on sodium sulfate, filtered, the solvent is evaporated and the residue is dispersed in ethyl acetate, drained and dried. Weight 6.8 g Yield =47% Nip =92-95'C 97- 99'C (diisopropyl ether-isopropanol, 5-1) Analysis: Cl6H25N5S 2 MW =351.53 C H N S calculated 54.66 I7cl7 19.93 1R.24 found 54.40 7.24 20.16 18.31 The compounds of following examples 5, 6 and 7 are prepared according to the method described in example 1 by using the appropriate 2-chloromethyl thieno 12,3-c] pyrrole.

XAMPt -c anm 1-felhyl 2-'2-pyrrolyl-(5,6-dihydro-5mty-4-,ti [23:)mtytil -methyl guanidine tit (Formula Nip *Lq5-147*fC (isopropanol) Analysis C 1 3Hj9N 5

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 -c NIfty 2-i2-pyrrolyl-(5,6-dihydro-5isoropl-4- ARM- r, thylthio]1 N"-methyl guanidine (Formula 6) Mp =120-121'C (diisopropyl ether -isopropanol, 2-1) Analyzis: Cl9HAt3N5S2 MW =337.50 C HN calculated 53.38 6.87 20.75 19.00 found 53.49 6.97 20.99 19.17 Ik

I

0 fl2 28 EXAMPLE 7: N-iet-hvl 2-[2-pyrrolyl-(5-henzyl-5,6-dihydro-4H- CS,4- n e+\rv.e- 4-ememethyithiol] N'-cyano N"-methyl guanidine (Formula 7) Mp ='122-123'C (diisopropyl ether isopropanol, 1-3) Analysis: C19H23N5S2 MW 385.54 C H N %calculated 59.19 6.01 18.17 16.63 found 59.02 6.10 17.0 16.58.

EXAMPLEI 8: 3-f2-pyrrolyl-(5-ethyl 5,-iyr- -RRt methyithiol N-sulfawoyl propanamidine (Formula 8) A mixture of 11.3 g (0.0397 Toole) of 3-r2-pyrrolyl-(5ethyl 5,6-dihydro-4H-thieno[2,3-c] meUthyithiol methyl propanimidate and 7.6 g (0.08 mole) of sulfamide in 100 cc of methanol is stirred in a reactor placed under nitrogen atmosphere for 48 hours, evaporated, the residue ic taken up with chloroform, filtered, the filtrate is evaporated and the residue crystallized in isopropanol. Weight 3.8 g Yield 28% Np- 124-13 0'C (isopropanol-ethanol, 4-1) This solid is dissolved in chloroform by adding thereto a little methanol and this solution is chromatographed on a silica gel column by using a 5% methanol solution in chloroform as eluent. Weight =1.1 g Mp 137-1391C (isopropanol ethanol, 4-1) NMR (DMSO-d6) 1 3H (CH 3 ;2.25-3 (in) 6H (CH 2 SCH2, CH 2 N) ,3-4 (in) 6H

(CH

2 S, NCH 2 -6.4 2H (NH2) 6.75 1H (theophene H) 7-8.2 (mn) 2H (NH 2 Analysis: C 12

H

20

N

4 0 2

S

3 MW =3,:9.51 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 N'[ethyl 2-[2-pyrrolyl(5-ethyl 5,6-dihydro- 4H-thieno [12,3-cl methylthioil ethylguanidine (Formula 9 A go2lution of 5g(017mole) of N-cyano N' rethyl 2- S methyl isothiourea and 19.9 g (0.441 mole) of ethylamine in cc of ethanol is refluxed for 5 h 30 min, then the solution is *4 9*

I.

I I I II I I C 4 4

A

A

29 evaporated and the resulting residue is crystallized in a sufficient amount of ethyl acetate, drained and dried. Weight =3.4 g Yield 68% Mp 91-93°C. This solid is recrystallized in a mixture of 20 cc of diisopropyl ether an'd 10 cc of isopropanol then in a mixture of 15 cc of diisopropyl ether and cc of ethyl acetate. Weight 2.4 g. Mp 95-96 0

C.

Analysis: C15H 2 3

N

5 2 MW 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'-fethyl 2-[2-pyrrolyl-(5-ethyl 5,6dihydro-4H-teinc methylthioll propargyl guanidine (Formula A mixture of 3 g (0.0088 mole) of N-cyano N'[ethyl 2- 5,6-dihydro-4H-thieno 2-pyrrolyl) methylthio]] S methyl isothiourea and 7.3 g (0.132 mole) of propargylamine in cc of methanol is refluxed for 8 hours; then the solution is evaporated, then the residue in solution in chloroform is chromatographed on a silica gel column by successively using as eluents: chloroform, ethyl acetate, chloroform with 5% methanol; the fractions eluted with ethyl acetate and chloroform-methanol are put together and evaporated dry; a solid is thus obtained.

Weight 1.7 g Yield 56% Mp 107-110°C Mp 112-114 0

C

(diisopropyl ether ethyl acetate, 1-3) NMR (CDC1 3 1.2 3H (CH 3 2.4 1H 2.6-3.3 4H (S-CH 2

CH

2 3.3-3.6 2H (CH 2 3.6-4.2 8H (NCH2, CH2S); 5.8-6.6 2H 6.7 1H (thiophene H).

Analysis: Ci6H21N 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 EXAMPLE 1 N-[ethyl 2-r2-pyrrolyl-(5-ethyl 5,6-dihydro-4Hthion methylthiol] 1-methyl-1H-triazole diamine (Formula 11) A solution of 4.25 g (0.0925 mole c f methylhydrazine and 6.75 g (0.0925 mole) of dry N,N-dimethylformamide in 60 cc of ±o 4 04 0 10 4 4 44 .4 4f 4 t 4 4 4

~I

9)i j 30 I 30 toluene is refluxed under a nitrogen atmosphere for 2 hours, then the solution is cooled to 30 0 C and 6.3 g (0.0185 mole) of Ncyano N'[ethyl 2-[2-pyrrolyl(5-ethyl 5,6-dihydro-4H-thieno [2,3c] methylthio]1 S methyl isothiourea is added; the mixture is refluxed for 7 hours then the solvent is evaporated, the residue is washed with water, extracted with chloroform, the chloroform phase is dried on sodium sulfate, concentrated and chromatographed on a silica gel column by successively using as eluents chloroform, ethyl acetate and a 5% chloroform solution in methanol. The fraction eluted with this latter mixture provides, after evaporation and crystallization of the residue in diisopropyl ether to which a few drops of acetone have been added, a solid that recrystallizes in ethyl acetate. Weight 1.8 g Yield 28% Mp 109-1120C (diisopropyl ether ethyl acetate). NMR (CDC 1 3 1.08 3H (CH3CH 2 2.4-3.1 4H 3.1-4.6 14H 6.7 (s) 1H (thiophene H) Analysis: C14H2 2 N6S 2 MW 338.5 C H N S S. calculated 49.67 6.55 24.83 18.95 found 49.62 6.52 24.50 18.81 XAMPLE 12: N N-cano.N'-[ethyl 2-[2-pyrrolyl-(5,6-dihydro- S* phenyl-4H-tiono [3,3 o methylthio l N"-methyl guanidine (Formula 12) A mixture of 2.5 g (0.0064 mole) of N-cyano N'[ethyl 2- 5,6-dihydro-4H-thieno [2,3-cl) methylthiol] S methyl isothiourea, 30 cc of a 33% methylamine solution in ethanol and 30 cc of DMF is refluxed and a current of methylamine Sis made to bubble through the reaction for 5 hours. The solvents are evaporated, the residue is dispersed in isopropanol and recrystallized in a sufficient amount of a water-DMF mixture (2- S Weignt 1.4 g Mp 164-168C Yield 58% NMR (DMSO-d6) SttC; 2.85-3 5H (CH 2 S, CH 3 N) 3 -3.6 2H (CH2NH) 3.8-4.2 (s) 2H (CH2S) 4.2-4.8 (CH 2 6.4-7.4 8H (aromatic H, NH) 4 Analysis: C18H21N5S 2 MW 371.52 C H N S calculated 58.19 5.70 18.85 17.26 58 found 58.19 5.73 19.01 17.18

%J

1 u w 2' 11 31 EXAMPLE 13: N-[ethyl 2-r2-pyrrolyl-(5-ethyl 5,6-dihydro-4Hthieno 12,3-cl) methyithioll 1-oxide thiadiazole [1,2,51 3,4diamine (Formula 13) A solution of 2.15 g (0.0089 mole) of 2-[2-pyrrolyl-5ethyl 5,6-dihydro-4H-thieno [2,3-cl) mnethyithiol ethylamine in cc of methanol is added to a solution of 1.7 g 90.0089 mole) of 3,4-diethoxy thiadiazole 1-oxide in 20 cc of methanol between 5 and 10'C. The mixture is stirred for 5 h 30 min at ambient temperature then an ammonia current is made to bubble therein for 10 min at 0 0 C. Stirring is continued for 4 hours at ambient temperature then the resulting solid is drained. weight 1.4 g Mp 1740C (decomposed), yield 60%, Mp 1750C (dec.) (MeOH-DMF, 3-1).

Analysis: C13Hl9N5OS 2 MW =357.52 C H N S %calculated 43.67 5.36 19.59 26. 19 %found 43.60 5.35 19.62 26.73 EXAMPLE 14:. N-11ethyl 2-[2-pyrrolyl-(5,6-dihydro-5 methvrl-4H- ~:hiz~ [3,3methylthioll N'-methyl 2-nitroethene 1,1-diamine it (Formula 14) I I A solution of 2.4 g (0.0105 mole) of bis-2,2'methylthio nitroethene and 1.75 g (0.0076 mole) of 2-12-pyrrolyl- (5,6-dihydro-5 rethyl-4H-thieno (2,3-cl) mnethylthioll Othylamihe in 30 cc of acetonitrile is refluxed for 11 h 30 min then cooled to -5 0 C, the resulting solid is drained (weight 2.4 g, Mp 112-1131C) and put in suspension in 15 cc of a solution of 33% methylamine in ethanol. This mixture is heated for 6 h min then the solvents are evaporated. A solid is isolated.

Weight 1.9 g, Yield 72%, Mp 108-112'C (ethyl acetate isopropanol, 5-1).

Analysis: C 13

H

19

.N

3 0 2

S

3 MW 345.5 44**tt

I

4 calculated found 47 .5 47 .6

H

6.14 5.98

N

17.*06 16. 89

S

19.52 19 .78 -1 -_1 32 EXAMPLE 15: N-[ethyl 2-[2-pyrrolyl-(5,6-dihydro-5 methyl-4H-furo methylthioll N'-methyl 2-nitroethene 1,1-diamine (Formula A solution of 3.3 g (0.0136 mole) of 2-[2-pyrrolyl-(5ethyl 5,6-dihydro-5 methyl-4H-furo [2,3-cl) methylthioll ethylamine and 2.25 g (0.0136 mo'e) of bis-2,2'-mehyththio nitroethene in 35 cc of acetonitrile is refluxed for 9 hours and min; it is evaporated dry then the residue is taken up with cc of a 33% methylamine solution in ethanol; this solution is refluxed for 8 hours, then evaporated and the resulting residue is chromatographed in solution in methanol on a column of 40 g of silica gel using methanol as eluent. The residue obtained after evaporation of the methanol is dispersed in ethyl acetate and drained. Weight 1.5 g, Yield 33%, Mp 103-110°C, Mp 110- 112 0 C (diisopropyl ether isopropanol, 5-4).

Analysis: C 1 4H22N403S MW 326.42 C H N S calculated 51.51 6.79 17.17 9.82 found 51.29 6.64 17.316 9.63 S* t XAMPLR 16: N-cyano N'[ethyl 2-[2-,pyrrolyl-(5-ethyl 5,6- S dihydro-4H-furo methylthio1 N" methyl guanidine S (Formula 16) A solution of 2.3 g of 2-(2-pyrrolyl-(5-ethyl 5,6methyl-4H-furo [2,3-cl) methylthioll ethylamine and 1.4 g (0.0095 mole) of dimethyl cyano dithio carbonate is refluxed for 6 hours; then the solvent is evaporated and the residue is dispersed in ether; the resulting solid is taken up with 30 cc of ethyl acetate, refluxed then allowed to crystallize. The resulting solid is drained and chromatographed in solution in an ethyl acetate-riethanol mixture on a column of g of silica gel using ethyl acetate followed by methanol as eluents; after evaporation, a solid is obtained. Weight 1.5 g, Mp 53-58 0 C. Then a solution of this solid in 20 cc of ethanol with 33% of methylamine is refluxed then evaporated dry, the i residue is dispersed in ether, drained and dried. Weight 1.3 g, Yield 44%, Mp 125-128 0 C, MP 129-131°CC (ethyl acetate r 1~~ -33 isopropanol, NMR (CDCl 3 1.2 (CH 3

CH

2 2.6-3.1 (in)

(S-CH

2

CR

3 CH3-CH 2 3.5 2H (CH,-NH) 3.8 6H

CCH

2 S, CH 2 N) 5.7 1H (NH) 6.1 (mn) IH (NH) 6. 2 1H (furan H) Analysis: Cl4H 2 lN5So 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-Ilethyl 2 2 -pyrrolyl- ethyl 5,6-dihydro-4H-furo 12,3-cl) methyithijol] l-rethylthio 2-nitroethenamine (Formula 17) A solution of 2.3 g (0.0095 mole) of 2-[2-pyrrolyl-(5ethyl 5,6-dihydro-5 methyl-4H-furo methyithia]] ethylainine and 1.6 g (0.0095 mole) of his-2,2'-methylthio nitroethene in 25 cc of acetonitrile is refluxed for 6 hours; then the solution is evaporated and the residue recrystallized in cc of ethyl acetate in the presence of Norit. The resulting solid is drained and dried. weight 1.4 g, Yield MP 77-79'C, Mp =80-821C (chromatography on 10 g of silica gel: eluents CH 2

C

12 then methanol).

NMR (CDCl3) 1.1 3H (CH 3

CH

2 2.4 3H (CH3S) 2.8 (in) 4H (SCR 2 CH2N) 3.3-3.9 (mn) 8H (CH, 2 Nf CH 2 S) ;6.1 1H (=CH-N0 2 6.5 1H (furan 10.5 Cs) 1H (NH).

Analysis: C141N 3 0 3

S

2 MW =343.46 t C.

t tt 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-Ilethyl 2-[2-pyrrolyl-(5,6-dihydro3 5-n-pentyl-4Hthieno (2,3-ci methylthio]] N'-methyl 2-nitroethene 1,l -diapiine (Formula 18) *eIBAt 4 4 4S~ 444 4 Prepared under the conditions of examp e 3 rom N- [ethyl 2-[2-pyrrolyl-(5,6-dihydro -petl4 I methylthiol I l-iethylthio 2-nitroethenainine and methylanine.

Weight 3.6 g, Yield 86%, Mp =90-93*C, MP 93-95*C (diisopropyl ether isopropanol, 1-2) d/k

'I

0 o, 47 A solution of 5. 9g (0.052 mole) of cysteamine hydrochloride in 50 cc of methanol is added to a sodium methylate methanolic solution prepared. by dissolving 2.6 g 2 34 Analysis: C17H 2 8N4O 2

S

2 MW 384.55 C H N S calculated 53.09 7.34 14.57 15. 68 found 53.24 7.26 17.44 16.75 EXAMPLE 19: N-[ethyl 2-[2-pyrrolyl-(5-ethyl 5,6-dihydro 3methyl-4H-4e4,._e4methylthio1 1 N '-methyl 2-nitroethene 1,1-diamine (Formula 19) Prepared under the conditions of example 3 from N- [ethyl 2-[.2--pyrrolyl-(5-ethyl 5,6-dihydro 3-methyl-4H-thieno 2,3methylthio] 1 -mnethylthio 2-nitroethenamine and methylamine. Mp =112-113'C (diisopropyl ether isopropanol) Analysis: C1 5

H

24

N

4 0 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 EXAMPThE 20:. N- rethyl 2- [2-pyrrolyl- (5-ethyl 5, 6-dihydro-4Ht~ioz [7i i)~methyltl-o.11 N'-methyl 1-oxide thiadiazole [1,2,51 3,4-diamin.e (Formula Prepared under the conditions of example 13 using methylamine instead of amnmonia. Mp =144-146C (isopropyl ether isopropanol, 1-4) NMR (CDC 13 1.16 3H (CH 3

CH

2 2.35-3.1 (in) 7H (SCH 2

CH

2 N, CH 3 N) 3.1-4 (in 8H (CH 2 NCH2) ;6.7 Ws JIF (thiophene H) 7t6-8.4 (broadened s) 2H (NH) Analysis: C14H2lN50Q 3 MW 371.55 C H N S *~calculated 42.25 5.70 18.85' 25.89 found 45.27 5.39 18.74 25.65 EXAMPLE 21:, N-rethyl 2-[2-pyrrolyl-(5-ethyl 5,6-dihydro -4H,hi01 N'-propargy. 1-oxide thiadiazole (1,2,51 3,4-diamine (Formula 21' A mixture of 1.7 g (0.0089 mole) of 3,4-diethoxy thiadiazole [1,2,51 1-oxide and 0.5 q (0.0089 mole) of propargylamine in solution in 20 cc of methanol is stirred at ambient temperature for 6 hours; it is evaporated dry then 2 e.

4 44 4. 4 4 4 4, 4

I

l~t I 4 -4 I t I t 2 35 (0&0089 mole) of 2-rF2-pyrrolyl--(5-ethyl 5,6-dihydro-4H-thieno methyithioll ethylamine in solution in 20 cc of methanol is added between 5 and 10 0 C; this solution is stirred at ambient temperature for 17 hours then the formed precipitate is drained. Weight 1.8 g Yield,= 51% MP 164-166C (decomposed) Mp 165-166'C (me-thanol-DMF, 1.8-1) Analysis: G16H2J.NSOS 3 MW =395.57 C H N S9 calculated 48.58 5.35 17.71 24 .32 found 48.58 5.41 17.63 24 RXAMPL' 22- N-fethyl 2-[2-pyrrolyl-(5,6-dihydro-5-n-propyl-4Hthin [13-1 methyithiol] 1-oxide thiadiazole 3,4diarnine (Formula 22) A solution of 3.25 g (0.0126 mole) of 2-112-pyrrolyl- (5,6-dihydro-5-n- propyl-4H-thieno methyithioll ethylamine in 25 cc of methanol is added to a solution of 2.4 g (0.0126 mole) of 3,4-diethoxy thiadiazole [1,2,51 1-oxide in cc o~f methanol between 5 and 10*C; this mixture is stirred for hours at ambient temperature then an ammonia current is made to bubble therethrough for 10 min between 0 and 5*C; stirring is continued for 4 hours at ambienit temperature, then the mixture is cooled to 0 0 C and the precipitate formed is drained. Weight 2.4 g Yield 51% MP? 178 0 C (decomposed) Mp= 1791C (mothanol DMF, 1-1) Analysis: C14H 2 lN 5 OS93 MW =371.55 calculated found 45.*25 45.41

H

5.70 5.*75

N

18.85 18.70 8 25 .89 25 .64 The compounds of following examples 23 and 24 are prepared according to the method descr bed in examle 2 from the tcappropriate 2-2proy-56dhdo4-rw 3 mnethylthiol ethylamines.

A

4- -36- EXAMPLE 2t.: [ethyl 2-2-pyrroyl-(5-ethyl 5,6-dihydro-3-rnethyl- 4H- Ti a 4-4.emethylthioll1l-methylthio, 2-nitroethenamine (Formula 23)

C

1 5H 23

N

3 0 2

S

3 MW =373.55, Mp 74-771C (diisopropyl etherisopropanol) NMP (CDC 13 :2.46 3H] (CH3S) EXAMLE -4.1 N-[ethyl 2-[2-pyrrolyl--(5,6-dihydro-6-n-pentyl-4H- (Formul~a 24)

C

17

H

27 Nq 3 0 2

S

3 MW =401.61, Mp =72-741C (isopropanol) NMR (CDC 13 2.46 3H (CH3S) RXAMPLE 25: N-cyano N'-[e,.hyl 2-[2-pyrrolyI-(5,6-dihydro-5p he nyl1 4HR tiz methylthiolI S-methyl isothiourea (Formul~a C18H2?0N 4

S

3 MW 388.57 A mixture of 2.6 q (0.0094 mole) of 2-[2-pyrrolyl-(5,6dihydro-4H-thieno methylthiol ethylamine and 1.4 g (0.0094 mole) of dimethyl cyano imido dithiocarhonate in 590 cc of acetonitrile is refluxed; the resulting solid is drained col.d, *washed with diisopropyl ether and dried. Weight =3 g Yield S82% MP- 189'-193 0 C Mp =195-197 0 C (H 2 0 DMF, 4-15) IR (KI~r) CN 2180 cm-l.

EXAMPLR 26: N-cy0n -[ethyl 2-f2-pyrrolyl-(5-ethyl 5,6dihydro-4H- Aao2 methylthiol] S-methyl isothiourea 14 (Formula 26) C14H 2 0N4S 3 MW =340.53 Prepared according to the method of example 25 from 2- [2-pyrrolyl-(5-ethyl-5,6-di',hydro-4H-thieno methyithiol ethylamine: Mp 11l2-114'C IR CN 2170 cm-I RXAMPLE 27: &ethyl 2-[2-pyrrolyl-(5-ethyl1 5,6-dlihydro-4Ht~io J2[3_ 31 methoxyl]1 -oxicde thiaditazole (1,2,51 3,4diamine (Formula 27) A solution of 3.8 g (Q.0168 mole) of 2-[2-pyrrolyl-(5p::ethyl 5,6-dihydro-414-thieno ethylamine in 20 cc of *~:methanol is added to a solution of 3.2 g (0.0168 mole) of 3,4diethoxy thiadia oe [1,2,51 1-oxide in 30 cc of methanol. between Uj -37 and l01C; the mixture is stirred for 9 hours at ambient ternperatu~re then an ammonia current is made to bubble therein for min between 0 and 5'C. Stirring is continued at ambient temperatu're For 5 hours then it is evaporated dry; the residue is extracted with water and chloroform, the organic phase is dried on sodium sulfate, the chloroform is evaporated, the residue is dispersed in a sufficient amount of isopropanol, drained, washed in diisopropyl ether and dried. weight 1.5 g Yield =26% Mp 144-1461C (decomposition) Mp =149-1501C (methanol) Analysis: Cl3Hl 9 N5O 2

S

2 MW =341.45 C HN calculated 45.73 5.61 20.51 18.78 %I found 46.01 5.49 20.25 18.68 EXAMPLI 28, N-fethyl 2-r2-pyrrolyI-(5-n-butvl 5,6-dihydro-4Hmehltil 1-oxide thiadiazole (1,2,51 3,4diamine (Formula 28) A sol~ution of 5.8 g (0.0214 mole) of 2-[2-pyrrolyl-(5n-butyl 5, 6-dihydro-4H-thieno 3-cl methylthiol ethylamine in cc of methanol is added to a solution of 4.1 g (0.0214 mole) Sof 3,4-diethoxy thiadiazole [1,2,51 1-oxide in 40 cc of t t mothanol; the mixture is stirred for 17 hours at ambient temperature then an ammonia current is made to bubble there for min between 0 and 5 0 C. Stirring is performed for 4 hours at ambient temperitvtrer the formed solid is drained and dried.

Weight =5.1 g Yield 62%1 Mp ~'183-184 0 C (C 2

H

5 OH-DMFf 2-1) Analysis: Cl5H 23 N5QS 3 MW 285.57 IC H M S W calculated 46.72 6.01 18.17 24.95 found 46.88 5.67 18.08 24.49 The compounds of following examples 29 to 33 are prepared according to the the method of example 28 fr I appropriate 2-[2-pyrrolyl-(5,6-dihydro-4H-f4iz4- .0 5 z' Smethylthiot alkylamines and 3,4-diethoxy thiadiazole Ioxide.

38 EXAM ,PLE2 N~-[ethyl 2- [2-pyrrolyl- isobutyl, 5, 6-dihydro-4H- LA&R A2PImeythoil 1--oxide thiadiazole [1.,2,51 3,4diamine (Formula 29) Yield 57% Mp 178-1791C (ethanol DMF, 7-4) Analysis: C, 9 H23N 5 0S 3 MW 385.57 C H NS calculated 46.72 6.01 18.17 24.95 found 46.91 6.06 17.93 24.67 U~AMPLFE 30. N-Iethyl 2-(2-pyrrolyl-(5-n-hexyl 5,6-dihydro-4H- '4methylthiol I 1-oxide thiadiazole [1,2,51 3,4diamine (Formula Mp =180-181'C (ethanol T)MF, 7-4) Yield =73% Analysis: r.17H2 7 NI5O,93 MWA 413 .63 C HNS calculated 49.36 6.58 16.93 23 .26 found 49.41 6.59 16.93 22.95 FRXAMPLE 31 N-[ethyl 2-2proy-56dhdo5-n-pentyl-4HthW io 2- me thylth io] 1 I-ox ide th i ad iazo 1e 2,f51 3, 4a*.diamine (Formula 31) at Mp =172-1731C (ethanol), Yield Analysis: Cl6H25N5OS 3 MW 399.60 C HN 19 calculated 48.09 6.31 17.53 24.07 forind 48.15 6.33 17.32 23.80 ERXAKPLR '32 .N-Epropyl 3-[2.-pyrrolyl-(5-eqthyl 5,6-dihydro-4H- [2 9-1 poyl 1-oxide thiadiazole 3,4-diamine (Formula 3.71 Mp =157-158 0 C (isopropanol) Yield 27% Analysis: C14H2lIN5OS3 MW 371.55 C 9 calculated 42.25 5.70 18.85 25.89 found 44.94 5.60 18.98 25.60 f8XAMPLE 33 N-[ethyl-, -proy- f5o6-dihydro 5-(2a o\pyrrolylI ehxyt,-I:4- Y il 1-oxide thiadiazole (1,2,51 3,4-diamine (Formula 33 Mp 174-176 0 C (ethanol) Yield =64% Analysis: Cl4fl 2 IN50 2

S

3 MW =387.55 -39 C HNS calculated 43,39 5.45 18.07 24 .82 fovnd 43.19 5.38 18.18 24 .84 RXAMPLE 34 3-amino 4-[ethylamnino-2-[(2-~pyrrolyl-5,6-ihy~ro n-propyl-4-in -ethylthio] cyclobutene-l, 2-diane (Formula 34) A solution of 1.4 g (0.01 mole) of 3,4-dimethoxy cyclobutene-l,2-dione in 20 cc of methanol is added to a solution of 2.6 g (0.01 mole) of N-2-[(2-pyrrolyl-5,f6-dihydro 4H-thieno methyithiol ethylamine in 20 cc of methanol in 20 cc of methanol between 5 and 10 0 C; the mixture is stirred at irbient temperature for 48 hours then an ammonia current is made tro bubble there for 15 min between 5 and 10'C, after which stirting is continued for 4 hours at ambient temperature. The resulting solid is filtered, washed with ether and dried then .11 recrystalli7.ed in a mixture of 20 ml of ethanol and ml of DMF.

UWeight =0.9 g Yield =25% Mp 320 0

C

UAnalysis: C 1 6

H

2 jN 3 0 2

S

2 MW 351.48 C HN S %calculated 54.67 6.02 11.96 18.25 %found 54.59 -5.92 11.94 18.52 RXAMPLE 35 :N-[ethyl 2-[2-pyrrolyI-[5,6-dihydro 5-n-propyl-4Hfuro mietylthiol] 1-oxide thiadiazole 3,4- (Formula 2 1N50 2

S

2 MW =355.48 A solution of 6.7 g (1.028 mole) of 2-U(2-pyrrolyI-5,6dihydro 5-n-propyl-4H-furo (2,3-cl) methylthia1 ethylamine in Scc of methanol is added to a solution of 5.3 g (0.028 mole) of Ct3,4-r,"iethoxy thiadiazole 1-oxide in 50 cc of methanol betwo'en 5 and 101C; the mixture is then stirred for 20 hours at ambi'ent temperature; then an ammonia current is made to bubble therethrough between 5 and lQOC; stirring is continued for 4 hours, at amhient temperature. The mixture is evaporated dry, the '..esutii,, residua sdspre in ether, drained and dried.

S W- ioht Yield 70% Mp 146-148 0 C, Mp m154-156'r, (after 3 chromatographies on a silica gel column with a mixture of AIhloroeorm-ethanol ,95-5 L:*en 90-10, as eluent) t1)4 S- Analysis: C H N S calculated for C14H 2 1

N

5 0 2

S

2 +1/2H 2 0 17.59 46.16 6.09 19.22 found 17.91 46.46 5.87 19.38 EXAMPLE 36 methyl 5-ethyl 5,6-dihydro-4H-furo 2-pyrrole carboxylate (Formula 36) A mixture of 44.8 g (0.167 mole) of methyl 4-chloromethyl 2-furan carboxylate and 22.6 g (0.502 mole) of ethylamine in solution in 5 liters of acetonitrile is stirred for 4 days under -'trogen atmosphere; then the solvent and the excess ethylamine that has not reacted are evaporated, the residue is taken up with hydrochloric acid, insolubles are eliminated by filtering, the filtrate is washed with ether then neutralized by addition of sodium bicarbonate. Extraction is performed with ether, this ether phase is washed with water then dried on sodium sulfate; successively, after evaporation, the residue is taken up with hexane, refluxed in the presence of Norit, filtered, an oil o is decanted, the hexane is partially evaporated, filtered and evaporated dry. Weight 13 g, Yield 40%, Mp 52-54°C a (diisopropyl ether)

NMR

I t t 1.1 3H CH 3

-CH

2 2.8 2H CH2N 3 CH 3 0 3-3.9 4H NCH2 7.1 aromatic H Analysis: C1OH1 3

NO

3 MW 195.21 C H N calculated 61.52 6.71 7.18 found 61.41 6.65 7.23 S EXAMPLE 37 5-ethyl 5,6-dihydro-4H-furo 2-pyrrole methanol (Formula 37) S11.7 g (0.06 mole) of meihyl 5,6-dihydco-4H-furo [2,3c] 2-pyrrole carboxylate in solution in 70 cc of ether is added 0 to a solution of 3 g (0.079 mole) of lithium and aluminum hydride in solution in 150 cc of ether at ambient temperature refluxing is performed for 2 hours 30 min, then water and dilute sodium I, ,lliuIA Ml ll IIIIII lII IIIilli i I I M I I liI1i II l l iiIl l i i i, i I i irn 14 hydroxide are added to the cooled mixture. The ether phase is decanted, the inorganic precipitate is extracted with ether; the various ether fractions are combined and dried on sodium sulfate then evaporated dry to provide a solid that is dispersed in diisopropy! ether. Weight =5.1 g, Mp 67-69*C, Yield 51% NMR (CDC 13 1.2 3H CR 3 2.8 2H (CH2CH3) 3.8 4H CH 2 -N 3.9 (in) 1H OH 4.6 2H CH 2 0 6.2 1H aromatic 9, Analysis: C 9H 13 N0 2 Mw 167.20 C HN calculated 64.65 7.83 8.73 9% found 64.43 '1.89 8.42 EXAMPLE~ 38 2-f2-pyrcrolyl-(5-ethyl 5,6-dihydro-4H-furo methyithioji ethylainine (Formula 38) CjjH 8

N

2 OS MW 242.34 5,6-dihydro-4H-furo [24,3-cl 2-pyrrole methanol is added b~y small portions, while cooling between 0 and 4 0 C, to a solution of 2.5 g (0.022 mole', of cysteamine hydrochloride in 8 c- off concentrated hydrochloric acid, then the mixture is ~.:stirred for 2 hours between 4 and 5'C, then it is kept at -5 0

C

for 48 hours, after which it is alkalized by addition of sodium bicarbonate and extracted with ether. After drying of the ether phase on sodium sulfate followed by evaporation, an oil is obtained that is used in the following stage Weight =3.3 g, Yield 62% EXAMPLE~ 39 methyl 5,6-dihydro-ri-5-propyl-furo 2--pr zrole carboxylate (Formoula 39 C 1 lH 15 N0 3 MW 209.24 A mixture of 69 g (0.258 mole) of methyl 4 4-chloromethyl 2-furan carboxylat,,e and 46 g (0.775 mole) of n.

propylamine in 1 .67 liters of acetoniltrile is stirred for 7 dlays at ambient temperature; the mixture is filtered then the filtrate is evaporated dry, the resulting residue is taken up with OV 4 hydrociiloric acidr the insolubles are eliminated by draining, the *~.filtrate is alkalized by addition of sodium bicarbonate. The filtrate is extracted with other, dried-on sodlium sulfate 4nd 53 3-C2-pyrrolo-(5-ethyl 5-dihydro-4H(3,4-b) thiophene) methyl thiol N-sulfamoyl p~opanamidine; 2-[2-pyrrolo-(5-ethyl 5,6-dihydro-4H (304-b) -42 evaporated dry. An oil is obtained that is used in the in synthesis sequence. Weight 31.4 g, Yield 58% EXAMPLE 40 5,6-dihydro-n-5-propyl-furo [2,3-cl 2-pyrrole methanol (Formula

CO

0

H

1 5 N0 2 MW =181.23 31.4 g (0.15 mole) of methyl 5,6-dihydro-n-5-propylfuro [2,3-cl 2-pyrrole carboxylate in solution in 176 cc of ether is added with reflux to a solution of 7 g (0.1845 mole) of lithium or aluminum hydride in 350 cc of ether; after which, the mixture is refluxed for 4 hours then treated as in example 37; thus a solid is isolated. Weight 11 g, Yield 40%, Mp 62 0

C

NMR (CDC 13 0.9 3H (CR 3 1.5 (sext.) 2H 2 CH3) 2.7 2H (NCH 2 CH2) 3.7 4H (CH 2 OH) 3.9 (OH) 4.5 2H (CH 2 0H) 6.1 aromatic 1H EXAMPLR 41 :2-[2-pyrrolyl-(5,6-dihydro-n-5-propyl-4H-furo [2,3ci) methylthioll ethylamine (Formula 41) C 12 20

N

2 0S Mw 240.37 Prepared under the conditions of example 38 from cysteamine hydrochloride and 5,6-dihydro-n-5-propyl-furo [2,3-c 2-pyrrole methanol; the reaction mixture is treated as follows: alkanization with O10N sodium l-ydroxide, extraction with ether, new extraction of the aqueous phase by an ether-methanol after saturation with sodium hydroxide in pellets; the two organic phases are combined, dried on sodium sulfate, evaporated and distilled. Bp2 148-150 0 C, Weight 6.7 g, Yield 46% NMR

(CDC

1 3 0.9 3H (CH3) 1.2-1.8 28 ((CH 3 CH2) 1.5 1H

(NH

2 2.5-3 6H (CH2) 3.7 (q s) 6H (CH 2 S and CH 2 N) 6.1 1H (arom.) Nn 1o0 0 EXAMPLE 42 5-ethyl 5,6-dihydro-4HR- en.e 2-pyrrole ethyl carboxylate (Formula 42) C 11

HI

15 N0 2 S, MW 225.3 126.6 g (0.5 mole) of bis-4,5-chloromethyl-2-thiophene ethyl carboxylate is dissolved in.15 liters of acetonitrile in a s.ee$ reactor placed under a nitrogen atmosphere, then 67.6 g mole) of ethylamine is added; the mixture is stirred for 8 days ~41 at ambient temperature then filtered. The filtrate is evaporated dry, the resulting residue is dissolved in a sufficient amount of 1.5N hydrochloric acid, washed with ether then alkalized by addit.on. of potassu carbonate; it is extracted with ether. After drying of the ether phase on sodium sulfate followed by evaporation, an oil is obtained that is distilled under low pressure. Bp 1 5 122-125-C, Weight 65.4g, Yield 58%, C.P.V. SE 30 1 meter T 230OC: 1 single peak The following esters are prepared, according to the mode of operation of example 42, from the appropriate amine and bis-4,5-chloromethyl-2-thiophene ethyl or methyl carboxylate: EXAMPLE 43 5,6-dihydro-5-met~hyl-4H-2-pyrrolo (3,4-b) thiophene ethyl carboxylate (Formula 43) C 10

H

13 NO2 MW 211.27 used raw in the following stage.

EXAMPLE 44 5-benzyl 5,6-dihydro-4H-2-pyrrolo (3,4-b) 0 thiophene ethyl carboxylate (Formula 44) C 16H 17NO 2S MW 287.8 223-224'C1672 2CJ EXAMPLE 4 5 5,6--dihydro-5-isopropyl-4H-2-pyrrolo (3,4-b) thiophene ethyl carboxylate (Formula 45) C 12

H

17 NO S MWA 239.33. Used raw in the following stage.

EXAMPLE 46 5,6-dihydro-5-phenyl-4H-2-pyrrolo (3,4-b) thiophene ethyl carboxylate (Formula 416) C 15 H 15

NO

2

S

MW =273.34 MP =147-150*C EXAMPLE 4 7 5,6-dihydro-5-n-pentyl-4H-2-pyrrolo (3,4-b) thiophene ethyl carboxylate (Formula 47) it, f C 1 4

H

2 N 0 S MW 267.38 BP 1 36-145 0

C

EXAMPLE 48 5,6-dihydro-5-n-propyl-4H-2 pyrrolo (3,4-b) thiophene ethyl carboxylate (Formula 48) C H N 14 1i 3 MW 239.44 Used raw in the following stage.1272 EXAMPLE 49 5-n-butyl-5,6-dihydro-4H-2 pyrrolo (3,4-b) thiophene methyl carboxylate (Formula 49) C 2

H

17 NO S MW 239.32 BP 2= 138-1450C EXAMPLE 50 isobutyl-5,6-dihydro-4H-2 pyrrolo (3,4-b) thiophene methyl carboxylate (Formula 50) C 12

H

17 N0)S MW 239.23 Bp 1 5 120-1250C 7 1"7 44 Ai

D

r

J

a cc r r ct EXAMPLE 51 5-n-hexyl-5,6-dihydro-4H-2 pyrrolo (3,4-b) thiophene methyl carboxylate (Formula 51) C 14

H

2 1 NO2S MW 267.33 Amorphous solid EXAMPLE 52 :5,6-dihydro-5-(2-methoxyethyl)-4H-2 pyrrolo thiophene methyl carboxylate (Formula 52) C11HI5NO3 S MW 241.30. Used raw.

EXAMPLE 53 5-ethyl-5,6-dihydro-4H-2 pyrrolo (3,4-b) thiophene methanol (Formula 53) A solution of 65.1g (0.289 mole) of 5-ethyl-5,6dihydro-4H-2 pyrrolo thiophene ethyl carboxylate in 400 cc of ether is added to a solution of 20g (0.527 mole) of lithium or aluminium hydride in 1 liter of ether placed under a nitrogen atmosphere and refluxed; reflux is continued for 4 hours, then the mixture is cooled and there is introduced there, drop by drop, 120 cc of water, then 100 cc of a 30% sodium hydroxide solution; the organic phase is decanted, and the extraction ether of the formed precipitated is combined with it, the whole is dried on sodium sulfate, evaporated dry and the solid residue 2'0 obtained under hexane is dispersed, drained and dried.

Weight 50g, Yield 88%, Mp 85-97 0 C (hexane isopropanol, 15-1) NMR (CDC 13 S 1.13 3H (CH 3 2.8 2H (CH 2

-CH

3 3.85 4H

(CH

2 4.65 2H (CH20) 5 1H (OH) 6.55 (s) 1H (thiophene H) 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 The following alcohols are prepared from the appropriate ester according to the method of example 53: EXAMPLE 54 5,6-dihydro-5-methyi-4H-2 pyrrolo (3,4-b) thiophene methanol (Formula 54) C H 11 NOS MW 169.24 Mp 105-1070C (diisopropyl ether isopropanol) EXAMPLE 55 :5,6-dihydro-5-isopropyl-4H-2 pyrrolo (3,4-b) thiophene methanol (Formula 55) C 10 H1 5 NOS Mw 197.29 Mp 118-120°C (chromatography on alumina, eluent CHC 13

IJ

EXAMPLE 56 5-br.,izyl-5,6-dihydro-4H-2 pyrrolo (3,4-b) thiophene methanol (Formula 56) C 1 4

H

15 NOS MW 245.33 Mp 132-133 0

C

EXAMPLE 57 5,6-dihydro-5-phenyl-4H-2 pyrrolo (3,4-b) thiophene methanol (Formula 57) Mp 197-198 0 C (THF) Analysis C 13H 13NOS 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-2 pyrrolo (3,4-b) thiophene methanol (Formula 58) C 1 0 H 5 NOS MW 197.29 Used raw.

EXAMPLE 5 9 5,6-dihydro-5-n-pentyl-4H-2 pyrrolo (3,4-b) thiophene methanol (Formula 59) C 2 H NOS MW 295.34 Used raw.

EXAMPLE 60 5.6-dihydro-3-methyl-4H-2 pyrrolo (3,4-b) thiophene methanol (Formula 60) C 0 H NOS MW =197.29 Used raw.

EXAMPLE 61 5-butyl-5,6-dihydro-4H-2 pyrrolo (3,4-b) 0, thiophene methanol (Formula 61) C 11 1 NOS MW 211.32 Mp 78-80 0

C

EXAMPLE 62 5-isobutyl-5, 6-dihydro-4H-2 pyrrolo (3,4-b) thiophene methanol (Formula 62) C 11H 17NOS MW 211.32 Mp =73-75 0

C

EXAMPLE 63 5-n-hexyl-5,6-dihydro-4H-2 pyrrolo (3,4-b) thiophene methanol (Formula 63) C 13

H

2 NOS MW 239.37 Mp 70-72 0

C

EXAMPLE 64 5, 6-dihydro-5-(2--methoxymethyl)-4H-pyrrolo thiophene methanol (Formula 64) C10 15O2 3u MW 213.29 Mp 76-78 0

C

EXAMPLE 65 2-chloromethyl 5-ethyl 5,6-dihydro-4HT--pyrrolo thiophene hydrochloride (Formula C 1 2 NS MW 238.17 (0.29 mole) of thionyl chloride is added at ambient temperature (use of a cooling %ixure) to a solution of 45g (0.245 mole) of 5-ethyl-5,6.-dihydro-4H-2 pyrrolo thiophene methanol in 500 cc of chloroform; then the solution is stirred for 2 hours at ambient temperature and fi n/ 46 the solvent and excess thionyl chloride that has not reached are evaporated. The resulting residue is dispersed in 200 cc of isopropanol, drained and dried. Weight 43.3g Yield 74% Mp 151-153 0 C (decomposition).

The corresponding halides of following examples 66 to 68 are prepared from appropriate alcohols according to the method of example EXAMPLE 66 2-chloromethyl-5,6-dihydro-5-methyl-4H-pyrrolo thiophene hydrochloride (Formula 66) alp C8H 1 C1 2 NS MW 224.15 Mp 173-176 0

C

(decomposition) (isopropanol methanol) o EXAMPLE 67 :5-benzyl-2-chloromethyl-5,6-dihydro-5-methylo,*o 4H-pyrrolo thiophene hydrochloride (Formula 67) S C14H15C12 NS MW 300.24 Mp 146-148 0

C

EXAMPLE 68 2-chloromethyl-5,6-dihydro-5-isopropyl-4Hpyrrolo thiophene hydrochloride (Formula 68) C1 H15 C2NS MW 252.12 Mp 148-150 0

C

EXAMPLE 69 2-[2-pyrrolyl (5-ethyl-5,6-dihydro-4H-(3,4-B) thiophene) methylthio] ethylamine (Formula 69) 2'P CIH8N2S 2 MW 242.40 36.1g (0.197 mole) of 5-ethyl-5,6-dihydro-4H-2 pyrrolo S thiophene methanol ii; slowly added between 0 and to a solution of 22.8g (.02 mole) of cysteamine hydrochloride in 400 cc of concentrated hydrochloric acid; then the mixture is stirred for 3 hours 30 min at ambient temperature then neutralized with sodium hydroxide and extracted with ether. The ether phase is dried on sodium sulfate and evaporated. An oil is obtained that is distilled under low pressure. Bp 149-155 0 C Weight 30.9g Yield NMR (CDC 13 1-1.4 5H (CH 3

HN

2 2.2-3.1 6H (S-CH 2

CH

2 N) 3.86 (broadened s) 6H (NCH 2

CH

2 S) 6.7 (s) 1H (thicphene H) EXAMPLE 70 2-[2-pyrrolyl (5,6-dihydro-5-methyl-4H-(3,4-b) thiophene) methylthio] ethylamine (Formula

C

1

OH

16

N

2

S

2 MW 228.38 i F'!i 1 t n f i 477 47 A solution of 5.9g (0.052 mole) of cysteamine hydrochloride in 50 cc of methanol is added to a sodium methylate methanolic solution prepared by dissolving 2.6 g of sodium in 50 cc of methanol; the mixture is stirred for 2 4 hours between 0 and 5 0 C then there is added to it a solution of 5.8g (0.0258 mole) of 2-chloromethyl 5,6-dihydro-5-methyl- 4H-pyrrolo thiophene hydrochloride in 60 cc of methanol; stirring is continued for 24 hours at ambient temperature, then the mixture is filtered, the filtrate evaporated, the residue is taken up with chloroform; the 0 0 chloroform phase is then washed with water and dried on sodium sulfate. The resulting oil is distilled under low o o, pressure after evaporation of the chloroform. Bp0.7 127-145 0 C Weight 2.4g Yield 41% EXAMPLE 71 2-[2-pyrrolyl (5-benzyl-5,6-dihydro-5-methyl- 4H-(3,4-b) thiophene) methylthio] ethylamine (Formula 71)

C

1 6

H

2 0

N

2

S

2 MW 304.47 Prepared according to example 70 from 5-benzyl-2chloromethyl-5,6-dihy' o-4H-pyrrolo thiophene 42,0 hydrochloride. Bp 155-210 0

C

0.7 The anines of following examples 72 to 79 are prepared from appropriate alcohols according to the method of example 69: EXAMPLE 72 2-12-pyrrolyl (5,6-dihydro-phenyl-4Hthiophene) methylthioj ethylamine (Formula 72) C 15

H

18

N

2 MW 276.43 MP 128-133 0 C (H2 DMF.1-3) EXAMPLE 73 2-C2-pyrrolyl (5,6-dihydro-5-n-pentyl-4Hthiophene) methylthio] ethylamine (Formula 73) C14H N 2S2 MW 284.48 Bp 2 188-199 0

C

14 24 2 22 EXAMPLE 74 2-2-pyrrolyl (5-ethyl-5,6-dihydro-3-methyl- 4H-(3,4-b) thiophene) methylthio] ethylamine (Formula 72)

C

1 2

H

2 0N 2

S

2 MW 256.43 BPl-1.5 150-156 0

C

EXAMPLE 75 2-[2-pyrrolyl (5,6-dihydro-5-propy1-4Hthiophene) methylthio ethylamine (Formula 012H20N2S2 MW 256.43 Bp 0 .5- 1 158-161 0

C

7r22 4 7A EXAMPLE 76 2-[2-pyrrolyl (5-butyl-5,6-dihydro-4Hthiopheie) methyithiol ethylarnine (Formula 76) c13 H22 N2s2MW 270.46 Bp 0 6 0 8 147-152 0

C

EXAMPLE 77 2-[2-pyrrolyl (5-isobutyl-5,6-dihydro-4Hthiophene) methylthio] ethylamine (Formula 77) C 13 H22 N2s2MW 270.46 Bp 0 7 0 9 -150-154 0

C

EXAMPLE 78 :2-[2-pyrrolyl (5-n-hexyl-5,6-dihydro-4Hthiophene) methylthio] ethylamine (Formula 78) C 15

H

26 N 2 2 MW 298.51 Bpl 1 1 5 185-190'C 99O XAPE79 2[yrrolyl (5,6-dihydro-5-(2-methoxyethyl)- 4H-(3,4-b) thiophene) 2-ethylene (Formula 79)

C

12

H

2

N

2 2S M 272.43 Bp 0 9 170-172 0

C

9 99t

L

9999,W -48- EXAMPLE 80 2-[2-pyrroly1 (5-ethyl-5,6-dihydro-4H ~hiene [grg3 -zl) methoxy]) ethylamine (Formtiia 80) CllHlRN 2 0S MW 226 .34 A mixture of 12.5 g (0.0525 mole) of ethyl-5,6--dihydro-4H-thieno pyrrole hydrochloride and 150 cc of 2-arninoethanol is heated at 100'C for 6 hours; then this mixturc- is evaporated dry, the residue is dissolved in water, this a7,queous solution is alkalized by addition of potassium Icarbonate and extracted with ether. The ether phase is dried on sodium sulfate and evaporated dry. An oil is isolated that is distil led under low pressure. Thp 1 155-1620C Weight =4 g, Yield 33.6% NMR (CoDC 3 1.15 3H (Cl1 3

-CH

2 ;2.3 2H (NH1 2 2.6-3.1 (in) 4H (CH 2

N)

;3.5-4.1 (in) 8H (N-C 2 HO 6.66 iohneH EXAMPLE 81 3-f2-pyrrolyl (5ehl56dhdo4 -~methylthio] propylamine (Formula R!l) C], 2

M

2 0N 2

S

2

MW

256.43 A solution of 12.4 g of (2-pvrrolyl 5,6-diAhydro-4H- 04 0 0 thieno methanethiol in 30 cc mnethanol is added between and 1 0'C to a sodium methylate solution prepared by dissolving not 0 403 g of sodium in 50 cc of methanol; the mixture is stirred for 2 4 0 000hours at ambient temperature, then there is added to it a Ssolution of 13.6 g 3-bromopropy..imine hydrochloride in 50 cc of methanol; stirring of the mixture is continued at ambient temperature for 18 hours, the it is evaporated dry, the residue is taken up in ether, the ether phase is washed with water, dried on sodium sulfate. The ether is evaporated. An oil is isolated that is distilled under low pressure. B3p 0 1 millibar 154- 1570C Weight =7.6 g Yield 48% NMR (cTD1 3 1-1.4 (in) 5Hf (CH 3

NH

2 1.45-2 (mn) 2H (CH2-CH 2

-CH

2 2.4-3.1 (in) 6H (S-CH 2 CH2N) 3.7-4.2 (in) 6H (N-CH2, CH 2 S) ;6.7 lH (thiophene H) v- XAMPLR 82 :(2-pyrrolyl (5-ethyl-5,6-dihydro-4H-10t-zo[, iethylthiol' (Formula 82) CqH 1 3

NS

2 OMW 199.33 N1/ -49 A mixture of 55.4 q (0.23 mole) of ethyl- 6-dihydro-4H-thieno [2,3-cl pyrrole hydrochloride and 17.7 g (0.23 ml)of thiourea in 650 cc of ethanol is refluxed for 4 hours; the mixture is allowed to cool, the precipitate is drained, washed with dilsopropyl ether and dried (weight =62.3 g) then it is dissolved in a solution of 28.5 g of sodium hydroxide in pellets in 250 cc of water. This solution is heated in a boiling water bath for 4 hours, filtered cold, acetic acid is added to the filtrate to PH =6 and extracted with chloroform. The chlorofonn phase is dried on sodium sulfate, then distilled. B3PO.

6 99--1151C Weight =25 g Yield 63% Hydrochloride CqH 1 4 ClNS 2 Mp 147-149*C (diisopropyl ether isopropanol, 1-4) NMR (CDC1 3 1.4 3H (CH 3 ,2 1H (SH) 3-5 (mn) 8H (CH 2 N, CH 2 ;6.6 IH (thiophene H) 13 (in) 1H Analysis: S C H N Cl c~adculated 45.84 5 .98 15.04 15.04 27.2 found 45.71 6 .02 5.92 ~4.qf 2.9 EXAMPLE 83 :3-[(2-pyrrolyl (5-ethyj-5r6-dihydro-4HR~~o[, -ej methylthiol (Formula 83) C12Hl 6

N

2

S

2 MW =252.40 A solutira' of Z2.9 9 of (5-ethyl-5,6-dihydro-4H-thierto [2,3-cl 2-pyrrolyl) .iethanolthiol in 100 cc of methanol is added between 0 and 10 0 C to a inethanolio solution of sodium methylate by dissolving 2.8 g of Sodium in 50 cc of Methanol; the mixture is stirred for 2 hours between Q and 10 0 C and there iss added to it 10.8 g of 3-chloropropane nitrile in solution in 100 cc of methanol; stirring is continued for 42 hours, then the ixIture is filtered, the filtrate is evaporated eiy the residue is dissolved in ether, the ether phase is washed with water, then dried on sodium sulfate. Upon evaporation of the ether an oil is obtained that is d .stilled. 13pl =175-176'C Weight =19.1 g **Yield =66% NMR (CDCl 3 1.1 Wt 3H (CH3) 2.15-3 (in) 6H (CH 2 N, SCH 2

CH-

2 CN) (mn) 6H (NCFI 2 CH2S) 6.6 31H (thtophene H) E XAMPLE 84 :3-1K2-pyrrolyl (5-ethyl-5, 6-bdio-Hdrt-4H-m m rethylthiol methyl propane imidate (Formula 84) Cl3H 2 ON2OS2 MW 284.44 4 A current oE hydrogen chloride and nitrogen is made to 4 bubble simultaneously for 4 hours between -5'C and +5'C in a solution of 10 g (0.0396 mole) of 3-[(2-pyrrolyl (5-ethyl-5,6dih1y1ro-4H-thieno [2,3-cl rnethylthiol propane nitrile in 40 cc of methanol and 80 cc of chloroform; the solvents are then evaporated and the residue is poured onto 32 g of potassium carbonate in solution in 2 liters of ice water. The ether is immediately extractedr the ether phase is dried on sodium sulfate and evaporated dry. An oil is obtained that is used as such in the synthesis sequence. Weight 11.3 g Ouantitative yield IR C =N :1650 cm- 1 EXKL 5 N[ty 2-[(2-pyrrolyl-5-ethyl, S,6-dihydro-4H- .4.45. a 1 4) ethylthio] 1-oxide thiadiazole [1,2,91 3,4diamine dihydrochloride (Formula 0 #0 An MCI current is made to bubble to dissolution in a .suspension of 2 q (0.0056 mole) of N-fethyl 2-II(2-pyrrolyl-5ethyl, 5,6-dihydro-4H--thieno [2,3-cl) methylthil 1-oxide thiadiazole r.1,2,51 3,4-diamine in 25 cc of methanol cooled between 0 and 5'C. Then it is stirred for two hours between 0 and 10 0 C, a precipitate appears which is filtered, washed with diisopropyl ether and dried. Weight =2 g, Yield 83%, Mp 168-170 0

C

Analysis: Cl3H2lC 2N50S3 mw 430.45 C H Cl N S calculated 36.27 4.92 16.27 16.47 22.34 %found 36.33 4. 057 16.23 16.40 22.14 EXAMPLE 86 N-[ethyl 2-[(2-pyrrolyl-,6-dihydro-5-n-propyl-4Hthieno [2,3-cl) methylthiol 1-oxide thiadiazole (1,2,51 3,4diamine dihydrochloride (Formula 86) Prepared u~nder the conditions of~ example A5 from Nmethyithiol 1-oxide thiadiazole r1,2,51 3, 4-diamlne Analysis: C1 4

H

2 3C 1 j 2 N5QS3 MW =444.47 ~51 C TICl N 19 calculated 37.83 5.22 15.9)5 15.76 21.64 found 37.66 5.21 15.64 16.'02 2.48 EXAMP! 5 qc: 3-mino 4-[ethylamino 2-[(2-pyrrolyl 5,6-dihydro-4iimethyithiol cyclobutene- 2-dione Formula 87) C16 H22 Cl N3 02 S2 MW =387.94 Prepared according to the method of example 85 from 3-amino 4-[ethylamino, 2-112-pyrrolyl 5,6-dihydro-5-n-propyl-4H-thieno [2,3-cl mnethyithiol cyclobutene-1 ,2-dione. Mp 145-147'C (ethanol) Analysis: C1 6

H

2 2 C1N 3 0 2

S

2 +1H20 C H Cl N S calculated 47.34 5.96 8.73 10.35 15.80 found 47.73 5.55 8.75 10.36 15.81 a I,

Claims (9)

1. 2. FP'rrolo thiophenes according to claim 1, N-cyano N'-[ethyl-2-(/5-ethyl-5,6 dihydro-4H-2-pyrrc-io thiophene) methylthio]] N" methylguariidie; N-Cethyl4-2-[(5-ethyl 5,6-dihydro-4H-2-pyrrolo (3,4-b) thiophene) methyl thioll) NI-methyl 2-nitroethene 1,1-diamine; *N-cyano N'-[oth'Dyl 2-[2-pyrrolo-(5,6-dihydro 4H-(3,4-b) thiophene) methyl thio]] N"l-methylguanidine; f jU <k MWA 53 i
2. 3-L2-pyrrolo-(5-ethyl 5,6-dihydro-4H(3,4-b) thiophene) methyl thia] N-sulfamoyl piopanamidine; 2-.[2-pyrrolo-(5-ethyl 5,6-dihydro-4H (3,4-b) thiophene) methyl thiol] methyl-i-iN triazole [1,2,41 3, *N-[ethyl 2-[2-pyrrolo-(5-ethyl 5,6-dihydro-4H (3,4-b) tiviophene) methyl thio 1-oxide thiadia7ole [1,2,5] 3, 4-diamine; *N-[ethyl 2-[2-pyrrolo-(5,6 dihydro 5-n pentyl-4H (3,4-b) G.s. thiophene) methyl thio]] N'-methyl nitrothene 1,1-diamine; 6 ethyl 2-]2-pyrrolo-r(5-ethyl 5,6-dihydro 3-methyl-4H ad. thiophene) methyl thio]] N'-methyl 2-nitroet:he~ie aa 1,1-diamline; *N-[ethyl 2-[2-pyrrolo-(5-ethyl 5,6-dihydro-4H (3,4-b) thiophene) methyl thio]] N'-methyl 1-oxide thiadiazole [1,2,51 3,4-diamine; Ii-ethyl 2-[2-pyrrolo-(5-ethyl 5,6-dihydro-4i (3,4-b) 'thiophenie) methyl thio]] N'-propargyl 1-oxide thiadiazole 3,4-diamin. 2 N-[ethyl 2-[(2-pyrrolo-(5,6 dihydro 5-n pentyl-4H-(3,4-b) It0 thiophene) mnethyl thio]] 1-uxide thiadiazole [1,2,5] iethyl-2-[2-pyrrolo-(5-n butyl 5,6-dihydro-4H (3,4-b) thiophene) methyl thiol] 1-oxide thiadiazole (1,2,5] 3 ,4-diarnine; *N-[etlhyl-2[2-pyrrolo-('5-isobutyl 5,6-dihydro-4H (3,4-b) t hiophene) methyl thio]] 1-oxide thiadiazole [1,2o51 3, 4-diamine; N-Lethyl--2-[2-pyrrolo-(5-n hexyl 5,6-dihydro-4H (3,4-b) t hiophene) methyl thio]] 1-oxide thiadiazole (1,2,51 3, 4-diamine; N-[ethyl-2-(2-pyrrolo-(5-n pentyl 5,6 dihydro-4H (3,4-b) thiophene) me~thyl thiol] 1-oxide thiadiazole [1,2,53 3 ,4-diamine; *N-[ethyl-2-[2-pyrrolo-(5-(2-methoxyethyl 5,6 dihydro-4H-(3,4-b) thiophene) methyl thio~] 1-oxide] thiadiazole 3,4 diamine; 3-amino-[4-ethylamino-2](2-piyrrolo 5-n propyl 5,6 dihydro-4H-(3,4-b) thiophene) cyclobuthene-1,2 dione. 54 ~&rL fl2 mmL -yh R- Pr ,py 3. Therapeutic addi:ion salts of the compounds according to claim l,said salts heing selected from the giroups consisting of hydrochlorides, hydrobromides, sulfates, phosphates, sulfonates, acetates, tartarates, citrates camphosulfates, maleates,. fumerates, and methanesulfates.
3. 4. A process for preparing the compounds of claimi, wherein U is selected from the group consisting of: I 90 C 9 0 O 90 0* p o z 0 I II I RIP P I I v-w N H R 3 0 -NH NHR 3 P pP p V P wherein an amine of the formula S CH S-(CR -NH R,2 2 M 2 R I III *PV 4 P F' -e 1 i- r I is made to react with a compound of the forumla O r CH 3 S CH 3 O 0 N N CH 3S O C 2 H 5 0C2H5CH30 and reacting the product so formed with an amine of the formula R 3 NH2' Intermediates for the preparation of compounds of claim 1, of the formula o 0* t t; Cr r" A Art I R 1 -CH2X2-(CH 2 )m-NH 2 R -N j 1- R 2 wherein X 1 is oxygen, R 2 is hydrogen, X 2 is sulfur, and m is 2.
4. 6. A process for preparing the compounds of claim 1 wherein X 1 and X 2 are sulfur, m 2, wherein a halogen derivative of the formula S CH2 X R 1 N I R 2 wherein X is halogen is made to react with a thiol of the formula V-W HSCH 2 CH 2 -NH N NHR 3 t t 55
5. 7. A process for preparing the compounds of claim 1, wherein X 1 and X 2 are sulfur, m 2, and U is aminosulfonyl which process comprises reacting an imino either of the formula NH RS CH 2 SCH 2 CH H 2 <ocH 3 1 OCH 3 R1 -N R2 with sulfamide.
6. 8. A process for preparing the compounds of claim 1 wherein R 2 is hydrogen and U is a l-H-diamino-l,2,4-triazole, which process comprises reacting a compound of the formula NCN CH2SCH2CH2NHCN R SCH 3 R -NR 1 with methylhydrazine.
7. 9. Intermediates Eor the preparation of the compounds of claim 1 where X is sulfur, of the formula CH 2 -Y 2 0 R 1 -N \R R where Y is selected from the groups consisting of OH, halogen, SH, -S(CH 2 )2CN, and <NH S (CH 2 2 OCH 3 WC 6 I Intermediates for the preparation of compounds of claim 1 where Xl is oxygen of the formula 0 Z R 1 -N wherein Z is selected from the group consisting of -COOCH 3 or -CH2OH.
8. 11. A pharmaceutical composition containing as active ingredient a compound according to claim 1, in admixture with a pharmaceutical carrier.
9. 12. A pharmaceutical composition according to claim 1 in a unit dosage form, wherein a unit dosage contains from 5 to 500 mg. active ingredient. S" 13. A compound according to any one of claims 1, 5, 9 or V I 10 substantially as hereinbefore described with reference to anyone of the examples. DATED: 9 October, 1985 4 PHILLIPS ORMONDE FITZPATRICK SAttorneys for: SLIPHA, LYONNAISE INDUSTRIELLE PHARACEUTIQUE i t r 1 W t WC 57 C "f CHN112 SCH 2 CH 2 -NNHH SS CU 2 2SCHHCCH2 H/CH Na0 CHIU 2 CH I-cf SUCH ge 3 CH 3 H 2 21, 1iY2 5* 4 CH H2J1/S]I-C 2 SCH 2 CH 2 NH-(HHCH3 SCH3 SCH 2 -SCH 2 CH 2 NH-<C NH CH Go 0 H Nz J S CII( -<NHCH 3 CHyCH2 NC~HK SNH 2 CH SCH CH N H 2 CH 3 CH 2 HN jT 2 2 H 2 SCH 2 CH 2 M3 /NCN CH3 CH 2 N1jI2 NH0U 2 P CHI A L NH 2 CH3 12 CHf CH 2 -N HH 2 SCHT-S-CHT-CH:-NH N 13 CH 2 N 14 CH 3 CH 2 2 I7~C 2 H{N.KH -Na2 NHCH 3 C1 3 CH 2 Na D25 C r H H C 16 CHTCH 2 NaH 3 ,(CCH-N0 SNHCH V 18 r~4.t10CH 3 -CH 2 C 2 1-NO(: 19 C~SC22N- HH CtIJH 2 H27INNHCH 3 2N 2 N- 4. C'3-C -N:::UlNH-CH 2 -C=CH CHC~i-Hi-*H N too N-S *0 a. NH 2 so* 22 SCH ~23 SH 9CH 3 -02H)r-Na l iiH--U-H- H__</CR-NO2 99 9,24 SCH3 4 '9'C CH 3 -CHf-Na AHCN SC 2~~7 S C HT CH rN H. N4 26 S Ht3 C 2 HB-N22 27 ,S ~i~(NH 0 CHi-S-CH2EHFNHH\ 28 N-S 9, .4 9 .4 .9 S 4 6 4 .4 4. 4 4 4,4 4 4* 4 9 9 9* *449 444* >H3CH 2 T-HI~7j1 N H 2 CH /1 S CH -S-ClH-CHf-NH ,\ZN 3 29 2 H -S'x 292 CH 3 5 -cI Ii N, Nw 0 31 CCH 3 i- ,SfSCH 2 CH 2 CHNH> NH 2 tH 3 OH 2 CfS CfHi 2 C 2 CH 2 2 0 YCAN NH 2 C 32 H("1I ii 'xl 41t f 1 CYVVIO yj. 0 yj yCH2CH Nl- CH :CH N 3- 2- o cHf-OH 0 COOCH3 c fflu C H 3 C 2 N 10 ao N 2 5 C 2 7 H 2 4 2 A -U, C u3C 2 Cl-([jli0 y i( 2 CHU 3 CH 3 CH 2 CH-N 1 1~j C39 C1- 40 0 CH 2 OH C~t~CU~ U O N''Tr .1(2 2 CH 2 NH 2 C 2 H S5(i-~ L.CO. 9, S. 99 9. *99 0 I. 9* 0 9. 9 9 99 S 9 I 9 t~ 9 9 99 9 9(99 94999 9 CH-N 43 CH 3 CH N CH3 S. COODt C 3 -(CH 2 )4-N 47 S COOEt 49 S COOme C 2 N-N2I S7iCl ~CH II CH2 "-Nar 1)CU 2 OH 57 C 2 O 41 42 44 Ot 46 Ot CU 3 -CU 2 -'CU 2-H~ 48 NS~ CODOt C-C 2-f2Iiso jS Coome CU 3 -0 H202 52 -024C Sa CHOH 56 58 s CH 4 OH 4 999,9* 4 r I,, t t t I ft C H 3 (CH 2 3 N" ~Ii( 61 INH-N I H0 IC X-H1, 71S I H CE UH CH3 S CH3 /61, CH 2 -M 62 CH30-CH2-CH2- 1= 1 64 S CH2 OH S CH2C' 'HC' 66 CH3,, CH3 Li I I 69 CH 2 C 70C 67C S CH CI H L tiI 3 -ES *CH2IS]NEH 2 2H 2 NclH-H2i 72 CHi 3 -EH 2 Na-t(7' 74 7S H 76S El 2 SEH 2 EI'2 NH 2