NO801586L - GUANIDINES, PROCEDURES FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING SUCH COMPOUNDS AND THEIR USE - Google Patents

Description

The invention relates to new guanidine derivatives, further methods for their production as well as pharmaceutical preparations containing these new compounds, as well as their use.

The invention relates to new guanidine derivatives, especially heterocyclic, substituted guanidines of formula

in which R1 means an optionally substituted aliphatic or cycloaliphatic hydrocarbon residue, R- means hydrogen, an optionally substituted, aliphatic or cycloaliphatic hydrocarbon residue, or and R2 together means an optionally substituted, bivalent hydrocarbon residue of aliphatic character, in which the carbon atoms of the chain may be interrupted by a heteroatom . , Het means a heteroalkyl residue with 3 chain links which completes the group C-N to an optionally unsaturated, heterocyclic five-ring with 2 to 3 heteroatoms from the group oxygen, sulfur or nitrogen in the ring, respectively. Het means a heteroalkylene radical with 4-6 chain links which completes the group C-N to a heterocyclic six-to-eight ring which, in addition to the nitrogen atom, contains a further heteroatom of the group oxygen, sulphur, or nitrogen in the ring, and Ph means an optionally substituted phenyl radical, their tautomeric compounds and salts.

In the context of the present description, the residues and compounds designated as "lower" preferably contain

show up to 7, primarily up to 4 carbon atoms.

An aliphatic hydrocarbon residue R^ or R^, which may optionally be substituted, is primarily an alkyl and an alkenyl or alkynyl residue, especially a lower alkyl and lower alkenyl or lower alkynyl residue. Substituents of aliphatic hydrocarbon residues are e.g. free, esterified or etherified hydroxy groups, such as lower alkanoyloxy, lower alkoxy or lower alkenyloxy groups or halogen atoms, as well as optionally esterified carboxy groups such as lower alkoxycarbonyl.

Above as below, the general designations can have the following meaning: Lower alkyl groups are e.g. methyl and ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl or n-heptyl groups ; lower alkenyl groups are e.g. the allyl or 2-methylallyl groups and lower alkynyl groups are preferably propargyl groups. Substituted lower alkyl groups are, for example, the trifluoromethyl group or an optionally esterified carboxymethyl group such as e.g. a lower alkoxycarbonylmethyl-, e.g. methoxycarbonylmethyl group.

Low-area coke is e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or n-pentyloxy, and lower alkenyloxy are e.g. vinyloxy or allyloxy. Lower alkanoyloxy is e.g. acetoxy or propionyloxy.

Halogen atoms are primarily fluorine, chlorine or bromine atoms, but can also be iodine atoms.

A cycloaliphatic hydrocarbon residue is primarily a mono- and polycyclic cycloalkyl residue with e.g. up to 12 incl., preferably 3 to 10 ring carbon atoms.

A cycloalkyl group is e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or adamantyl group.

An optionally substituted phenyl residue can be substituted with one, two or three identical or different substituents. Such substituents are e.g. hydrocarbon residues such as lower aliphatic hydrocarbon residues, e.g. lower alkyl, substituted lower alkyl such as e.g. trifluoromethyl, optionally functionally converted hydroxy or mercapto as etherified hydroxy, e.g. lower alkoxy, lower alkenyloxy or lower alkylenedioxy, further lower alkylthio or halogen, nitro, amino including substituted amino, e.g. lower alkylamino or di-lower alkylamino, optionally functionally converted carboxy such as esterified carboxy, e.g. lower alkoxycarbonyl.

Lower alkylthio is especially methylthio, further also ethylthio, isopropylthio, n-propylthio or also straight or branched butylthio, loweralkylamino or diloweralkylamino are e.g. methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di-n-propylamino, isopropylamino, di-isopropylamino or n-butylamino or di-n-butylamino.

Both substituents R 1 and can together mean an optionally substituted bivalent, aliphatic hydrocarbon residue with 4-7 carbon atoms in the chain. The group -NR^R2 is, for example, a straight, branched or phenyl-substituted lower alkyleneamino, in which the lower alkylene chain can, for example, be interrupted by a heteroatom, which e.g. oxygen, sulfur or optionally with lower alkyl, phenyl or lower alkoxycarbonyl substituted nitrogen,

and indicates, for example, as lower alkyleneamino pyrrolidino, 2,5-dimethylpyrrolidino, piperidino, 2-methylpiperidino, 4-phenylpiperidino, hexahydroazepino or octahydroazocino, as oxa-lower alkyleneamino, for example morpholino, 2,6-dimethylmorpholino as thialaverealkylenamino, for example thiomorpholino or as azalaverealkylenamino f. e.g. piperazino, N-methyl-, N-phenyl or N-lower oxycarbonylpiperazino.

The heteroalkylene residue Het with 3 chain links that complete the group C-N together to form an optionally unsaturated, heterocyclic five-ring with 2-3 heteroatoms of the group oxygen, sulfur or nitrogen in the ring, forms with C-N

together, for example, an imidazoline, imidazolidine, oxa-

zolin-, oxazolidine-, thiazoline-, thiazolidine-, isoxazoline-, isoxazolidine-, isothiazoline-, isothiazolidine-, 1,2,4-oxadiazoline-, 1,2,4-oxadiazolidine-, 1,3,4-oxadiazoline, 1,3,4-oxadiazblidine, 1,2,4-thiazoline-, 1,2,4-thiazolidine-, 1,3,4-thiazoline-, 1,3,4-thiazolidine-, pyrazoline-, pyrazolidine-, 1,2,3-triazoline-, 1,2,3-triazolidine-, 1,2,4-triazoline-, or also 1,2,4-triazolidine ring.

Particular mention should be made of 4-imidazoline-, imidazolidine-, 4-oxazoline-, oxazolidine-, 4-thiazoline-, thiazolidine-, 4-(1,3,4)-thiadiazoline-, 4-(1,3,4)- the oxadiazoline, isoxazoline or also the isoxazolidine ring.

The heteroalkylene residue Het with 4-6 chain links that completes the group C-N to a heterocyclic six- to eight-membered ring, which in addition to the nitrogen atom also contains a heteroatom of the group oxygen, sulfur or nitrogen in the ring, forms for example a morpholine, thiomorpholine, 2H-3,4 ,5,6-tetrahydro-1,3-thiazine-, 2H-3,4,5,6-tetrahydropyrimidine-, piperazine-, hexahydro-1,3-thiazepine-, hexahydro-1,4-thiazepine -, the hexahydro-1,3-thiazocine or also the hexahydro-1,4-thiazocine ring. Both of the latter ring systems can be bound in 2- or 4- respectively. 3- or 5-position.

In particular, the morpholine, thiomorpholine, piperazine, 2H-3,4,5,6-tetrahydro-1,3-thiazine or also hexahydro-1,4-thiazepine ring should be mentioned.

The new compounds of the general formula I and their addition salts with inorganic or organic acids have valuable pharmacological properties, in particular hypoglycemic activity which can be demonstrated in metabolically normal rats after oral administration of doses from 3 mg/kg and also in rats as by injection of strepto-zotocin was put into a diabetes-like metabolic state (cf. A. Junod et al., Proe. Soc. Exp. Biol. Med. 126, 201-205 (1967)). The lowering of the blood sugar level is not accompanied by hyperlactatemia. The pharmacological findings characterize the new compounds of the general formula I and their pharmaceutically acceptable acid addition salts as antidiabetics, which can be used for the oral treatment of hyperglycemia in mammals, especially of diabetes mellitus.

Special mention must be made of compounds of formula I

in which R. means an optionally substituted aliphatic or cycloaliphatic hydrocarbon residue, R2 is hydrogen or an optionally substituted aliphatic hydrocarbon residue, or R^

and R2 together mean an optionally substituted, bivalent hydrocarbon residue of an aliphatic character, in which the carbon atoms of the chain may be interrupted by a heteroatom, R^ means hydrogen, lower alkyl, R^ means hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, dilower alkylamino, halogen, trifluoromethyl or optionally substituted phenyl or a single-bonded carbon atom on both sides, also oxo, R,- means hydrogen or lower alkyl, Het means a heteroalkylene residue with 3 chain members which completes the group C-N to an optionally unsaturated, heterocyclic pentaring with 2 to 3 heteroatoms of the group oxygen, sulfur or nitrogen in the ring, Ph means an optionally substituted phenyl residue, their tautomeric compounds and salts.

The invention primarily relates to compounds of formula I, in which R^ means lower alkyl or cycloalkyl, R 2 means hydrogen or lower alkyl or both together a lower alkylene chain, which may optionally be interrupted by an oxygen, sulfur or optionally by f .ex. lower alkyl or phenyl substituted nitrogen atom, R^ means hydrogen or lower alkyl, R^ means hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, dilower alkylamino, halogen, trifluoromethyl or a carbon atom singly bonded on both sides, also oxo, or optionally with lower alkyl, lower alkoxy or halogen substituted phenyl, Ri- means hydrogen or lower alkyl and Het means a hetero alkylene residue with 3 chain links which complements the group C-N to an optionally unsaturated, heterocyclic five-ring with 2 to 3 heteroatoms from the group oxygen, sulfur or nitrogen in the ring, and Ph means an optionally substituted phenyl radical, as well as their tautomeric compounds and salts.

In particular, the invention relates to such compounds of formula I, in which R 2 means lower alkyl or cycloalkyl, R 2 means hydrogen or lower alkyl or both together a lower alkylene chain which can optionally be interrupted by an oxygen or sulfur atom or optionally by e.g. lower alkyl or phenyl substituted nitrogen atom, e.g. lower alkyleneamino, e.g. pyrrolidino, 2,5-dimethylpyrrolidino, piperidino, 2-methylpiperidino, hexahydroazepino or octahydroazocino, oxalaverealkyleneamino, e.g. morpholino, thialaverealkyleneamino, e.g. thiomorpholino or azalaverealkyleneamino, e.g. piperazino, N-methyl or N-phenylpiperazino, R^ means hydrogen or lower alkyl, R^ means hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, dilower alkylamino, halogen, trifluoromethyl, or a carbon atom singly bonded on both sides, also oxo, or optionally with lower alkyl, lower alkoxy or halogen-substituted phenyl, R^ means hydrogen or lower alkyl and Het means a divalent heteroalkylene residue with 3 chain links which makes the group C-N a saturated or simple unsaturated and can be, for example, an imidazoline, imidazolidine, oxazoline, The oxazolidine, thiazoline, thiazolidine, isoxazoline, isoxazolidine, isothiazoline, isothiazolidine, oxadiazoline, oxadiazolidine, thiadiazoline, thiadiazolidine, pyrazoline, pyrazolidine or also triazoline ring and Ph means an optionally lower alkyl , lower alkoxy or halogen substituted phenyl radical, as well as their tautomeric compounds and salts.

Of particular interest are compounds of formula I,

in which R1 means lower alkyl or cycloalkyl, R2 means hydrogen or lower alkyl or the group -NR^R2 means, for example, lower alkyleneamino, in which the lower alkylene chain may be interrupted by an oxygen or sulfur atom, and

can be, for example, pyrrolidino, 2,5-dimethylpyrrolidino, piperidino, 2-methylpiperidino or also morpholino or thiomorpholino, R^ means hydrogen or lower alkyl, R^

means hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, trifluoromethyl or a single-bonded carbon atom on both sides, also oxo, or optionally with lower alkyl, lower alkoxy or halogen substituted phenyl, R^ means hydrogen or lower alkyl and Het means as divalent residue together with the group C-N an optionally single unsaturated, heterocyclic five-ring, such as e.g. imidazoline, imidazolidine, oxazoline, oxazolidine, thiazoline, thiazolidine, oxadiazoline, oxadiazolidine, triazoline, thiadiazoline or thiadiazolidine ring and Ph means a phenyl radical optionally substituted with lower alkyl, lower alkoxy or halogen, as also their tautomeric compounds and salts.

Of particular interest are compounds of formula I, in which R₂ means lower alkyl, e.g. methyl or ethyl, R2 means hydrogen or lower alkyl, e.g. methyl or ethyl or the group -NR^R2 is present as lower alkyleneimino interrupted optionally by an oxygen or sulfur atom, for example as pyrrolidino, piperidino, morpholino or thiomorpholino, R^ means hydrogen or lower alkyl, e.g. methyl or ethyl, R 1 means hydrogen, lower alkyl, e.g. methyl or ethyl, lower alkoxy, e.g. methoxy or ethoxy, lower alkylthio, e.g. methylthio or ethylthio, halogen, e.g. chlorine or bromine, trifluoromethyl or optionally with lower alkyl, e.g. methyl or ethyl, halogen, e.g. chlorine or bromine substituted phenyl, R,- means hydrogen or lower alkyl, e.g. methyl or ethyl and Het means, as a divalent heteroalkylene residue with the group C-N, an optionally single unsaturated, heterocyclic five-ring, such as e.g. 4-imidazoline-, 4-oxazoline-, 4-thiazoline-, 4-(1,3,4)-thiadiazoline-, 4-(1,3,4)-oxadiazoline- or also isoxazolidine ring, and Ph means an optionally with lower alkyl, such as methyl or ethyl, halogen, such as chlorine or bromine or lower alkoxy, such as methoxy or ethoxy, substituted phenyl radical, as well as their tautomeric compounds and salts.

Emphasis should also be placed on compounds of formula Ib

in which R^ and R2 mean an optionally substituted aliphatic or cycloaliphatic hydrocarbon residue or R^ and R2 together mean an optionally substituted, bivalent hydrocarbon residue of an aliphatic character, in which the carbon atoms in the chain may be interrupted by a heteroatom, R^ means hydrogen, lower alkyl, R^ means hydrogen, lower alkyl, lower alkoxy, lower alkylamino, dilower alkylamino, halogen, lower alkoxycarbonyl or optionally substituted phenyl, or a single-bonded carbon atom on both sides, also oxo, Het means a heteroalkylene residue with 4-6 chain links, which complements the group C-N to a heterocyclic six- to eight, which, in addition to the nitrogen atom, further contains a heteroatom of the group oxygen, sulfur or nitrogen in the ring, and Ph means an optionally substituted phenyl residue, their tautomeric compounds and salts.

The invention primarily relates to compounds of formula Ib, in which R., and R.sup.2 means lower alkyl or cycloalkyl or both together mean a straight, branched or substituted lower alkylene chain, which may optionally be interrupted by an oxygen, sulfur or optionally by e.g. e.g. lower alkyl, phenyl or lower alkoxycarbonyl substituted nitrogen atom, R^ means hydrogen or lower alkyl, R^ means hydrogen, lower alkyl, lower alkoxy, lower alkylamino, dilower alkylamino, halogen, lower alkoxycarbonyl or a single-bonded carbon atom on both sides, also oxo, or optionally with lower alkyl, lower alkoxy or halogen-substituted phenyl and Het means a heteroalkylene residue with 4-6 chain links which completes the group C-N to a heterocyclic six-membered ring which, in addition to the nitrogen atom, contains a further heteroatom of the group oxygen, sulfur or nitrogen in the ring and Ph means an optionally substituted phenyl residue, which also their tautomeric compounds and salts.

In particular, the invention relates to such compounds of formula Ib, in which R 1 and R 2 mean lower alkyl or cycloalkyl, or both together a straight, branched or substituted lower alkylene chain, which may optionally be interrupted by an oxygen or sulfur atom or optionally with e.g. lower alkyl, phenyl or lower alkoxycarbonyl substituted without nitrogen, such as lower alkyleneamino, for example pyrrolidino, 2,5-dimethylpyrrolidino, piperidino, 2-methyl-piperidiho, 4-phenylpiperidino, hexahydroazepino or octahydroazocino, such as oxalaverealkylenamino, for example morpholino, 2,6-dimethylmorpholino, such as thialaverealkylenamino, for example thiomorpholino or as aza-lower alkyleneamino, for example piperazino, N-lower alkoxycarbonyl, N-methyl or N-phenylpiperazino, R^ means hydrogen or lower alkyl, R4 means hydrogen, lower alkyl, lower alkoxy, lower alkylamino, di lower alkylamino, halogen, lower alkoxycarbonyl or optionally with lower alkyl, lower alkoxy or halogen substituted phenyl and Het means a divalent heteroalkylene residue with 4-5 chain links which completes the group C-N to a heterocyclic six- to seven-ring which, in addition to the nitrogen atom, contains a further heteroatom of the group oxygen, sulfur or nitrogen in the ring, and Ph . means a phenyl radical optionally substituted with lower alkyl, lower alkoxy or halogen, as well as their tautomeric compounds and salts.

Of particular interest are compounds of formula Ib, in which R 1 and R 2 are lower alkyl or the group

-NR1R2 together means a lower alkyleneamino, in which the straight, branched or phenyl-substituted lower alkylene chain may optionally be interrupted by an oxygen, sulfur or optionally with e.g. lower alkyl, phenyl or lower alkoxycarbonyl substituted nitrogen atom, and may be

for example as lower alkyleneamino pyrrolidino, 2,5-dimethylpyrrolidino, piperidino, 2-methylpiperidino, 4-phenylpiperidino, hexahydroazopino or octahydroazocino, as oxa-lower alkyleneamino e.g. morpholino, 2,6-dimethylmorpholino, as thialaverealkylenamino e.g. thiomorpholino or as aza-loweralkylenamino e.g. piperazino, N- ethoxycarbonyl-, N-methyl-, N-phenylpiperazino, R^ means hydrogen or lower alkyl, R^ means hydrogen, lower alkyl, lower alkoxy, lower alkylamino, halogen, lower alkoxycarbonyl or optionally with lower alkyl, lower alkoxy or halogen substituted phenyl and Het means a divalent heteroalkylene radical with 4-5 chain links, which complement the group C-N to a heterocyclic six- to seven-ring, which, in addition to the nitrogen atom, contains a further heteroatom of the group oxygen, sulfur or nitrogen in the ring, and can for example be a morpholine^, thiomorpholine-, 2H-3,4 ,5,6-tetrahydro-1,3-thiazine-, 2H-3,4,5,6-tetrahydropyrimidine-, piperazine- or also a hexahydr o-1,4-thiazepine ring, and Ph means a phenyl radical optionally substituted with lower alkyl, lower alkoxy or halogen, as well as their tautomeric compounds and salts.

Of particular interest are compounds of formula Ib, in which R 1 and R 2 mean lower alkyl, e.g. methyl or ethyl, or the group -NR^R2 together means a lower alkylene amino, in which the straight, branched or phenyl-substituted lower alkylene chain can be interrupted by an oxygen, sulfur or possibly lower alkyl, such as e.g. methyl or ethyl or lower alkoxycarbonyl, such as e.g. methoxy- or ethoxycarbonyl substituted nitrogen atom, and can for example be pyrrolidino, piperidino, 4-phenylpiperidino, morpholino, 2,6-dimethylmorpholino, thiomorpholino, piperazino, N-ethoxycarbonyl-piperazino, R^ means hydrogen or lower alkyl, e.g. . methyl or ethyl, R₂ means hydrogen, lower alkyl, e.g. methyl or ethyl, or lower alkoxycarbonyl, e.g. methoxy- or ethoxycarbonyl and Het means a divalent heteroalkylene residue which, with the group C-N, completes this to form a six-membered heterocyclic ring which, in addition to the nitrogen atom, contains a further heteroatom of the group oxygen, sulfur or nitrogen in the ring, and can be, for example, a morpholino, thiomorpholino or piperazine ring and Ph means an optionally with lower alkyl, such as e.g. methyl or ethyl, halogen, such as fluorine, chlorine or bromine or lower alkoxy, such as e.g. methoxy or ethoxy, substituted phenyl radical, as well as their tautomeric compounds and salts.

The new guanidines of formula I are obtained according to i

and known methods.

Thus, one can e.g. obtain the new compounds of formula I by reacting a compound of formula II

where X.j means the group. Ph-N= in which Ph means an optionally substituted phenyl residue or a leaving group, X2 means the group in which and R2 has the meaning given under formula I or a leaving group and X^ means the group

wherein R 3 , R 3 , R 3 , and Het are divalent

heteroalkylene residue with the group C-N has the meaning given under formula I, or means a cleavable group, with the proviso that only one of the substituents, X ? or X^ may be a leaving groupbg in which one of the groups X^, X2 and X^ is connected by a double bond with the carbon atom, with an amine or imine, which is identical to missing amino or imino group as defined under

X^ , X^ or X^, to replace the leaving group, and, if desired, carry out additional process steps, and/or, if desired, transfer obtained compounds in a salt, and/or, if desired, convert obtained salts into compounds of formula I in the free bases.

As cleavable groups X^, X^ and X3 come, for example, lower alkylthio groups, which e.g. methylthio or ethylthio, lower alkoxy, such as e.g. methoxy or ethoxy, or also.halogen, such as e.g. chlorine or bromine into consideration.

Compounds of the general formula II are, depending on what the cleavable groups X^, X^ or X^ mean, either compounds of formula IIa

in which X^ a leaving group, Ph, R^, R4, R^, Hét and C-N have the meanings given above,

compounds of the general formula IIb,

wherein X^ represents a leaving group, or compounds of formula lic wherein means a leaving group, their tautomeric forms or their acid addition salts. Depending on what is present as a cleavable group X^, X2 or X^ in a compound of formula II, a compound of formula IIa is reacted with an amine of formula HNR^R2, a compound of formula IIb with an imino compound of formula III

(III) or one trades one

compound of formula lic with an optionally substituted aniline of formula Ph-NH2. Compounds with the formulas IIa, IIb and Ic can also be used as acid addition salts, preferably as hydrohalides. In an analogous manner, the amines, imino compounds or also anilines used can also be reacted as acid addition salts, preferably as hydrohalides.

The reaction of a compound of formula II, i.e. in particular a compound of formula IIa, IIb or Ic, for example with a previously mentioned amine or imine as free base takes place using a stoichiometric excess of the amine or imine, for example in a molar ratio of 1: 1 to 1:2.0. When using only a small excess of the amine or imine as free base or when using the amine or imine as acid addition salts, it is appropriate to add a further stoichiometrically equivalent amount of a tertiary alkylamine, such as e.g. triethylamine or N-ethyldiisopropylamine.

If, for example, an imino compound of formula III is reacted as a free base with a compound of formula IIb, in which X represents a halogen, then preferably 2 molar equivalents or more of the free base of the above-mentioned imino compound are used. According to the following reaction scheme

an equivalent of the imino compound is formed as an acid addition salt. For this reason, the reaction is preferably carried out in an aprotic solvent, in which the obtained compound of formula I is soluble, where, in return, the addition salt of the hydrohalic acid is precipitated as an insoluble compound according to the above scheme.

In this way, the two reaction products obtained can easily be separated from each other by simple filtration. The obtained acid addition salt to the imino compound is transferred by basic hydrolysis, for example by adding alkali or alkaline earth hydroxide or carbonate to the free base and can thereby be recovered as a starting product for further use. Preferably, however, compounds of formula IIb and III are reacted as acid addition salts, for example as hydrohalides, as stated above in the presence of a further tertiary alkylamine, such as e.g. triethylamine or N-ethyldiisopropylamine.

The described reactions of compounds of formula IIb with an imino compound of formula III take place, as already mentioned above, preferably in aprotic solvents. Examples of preferred applicable solvents are ether, such as e.g. diethyl ether and tetrahydrofuran, low-real aliphatic ketones and esters, such as e.g. acetone, methyl ethyl ketone and ethyl acetate, aromatic hydrocarbons, such as benzene, toluene or xylene, as well as acetonitrile. Particularly preferably, however, the reaction is carried out in diethyl ether or acetonitrile. The turnover can. is carried out at a temperature between 0-150°C, preferably between room temperature and the reflux temperature of the reaction mixture.

One uses as starting compound with formula II, however, e.g. a compound of formula IIa

then X^ as a cleavable group preferably has the meaning of a lower alkoxy or lower alkylthio group. Starting compounds of formula IIa are reacted in the form of their salts, for example in the form of their acid addition salts with a hydrohalic acid with an amine of the formula HNR^ R 2 as a free base or as an acid addition salt, in which R^ and R 2 have the meaning indicated above.

The sales are carried out e.g. in an alcohol as solvent, preferably in a lower alcohol, such as e.g. ethanol, isopropanol or tert.-butanol, particularly preferred however in an ether, such as e.g. diethyl ether or tetrahydrofuran or in acetonitrile at temperatures from room temperature to preferably the reflux temperature of the reaction mixture. The reactions can, however, be carried out in a closed reaction vessel under pressure, such as e.g. in a bomb tube or in an autoclave, at higher temperatures. The guanidine derivatives of the general formula I are obtained in the form of their salts which can, for example, be transferred by alkaline hydrolysis into the corresponding free bases. In the reaction of compounds of the general formula IIa with the amine of the general formula HNR^R 2 , the amine is preferably used in stoichiometric excess, for example in a molar ratio of 1:1 to 1:2.0 or greater. When using only a small excess of the amine or an acid addition salt, it may be appropriate to add a further stoichiometrically equivalent amount of a tertiary alkyl amide, such as e.g. triethylamine or N-ethyldiisopropylamine, to increase the reaction rate.

The reaction of compounds of formula lic with a cleavable group, which next to the meaning of a halogen atom preferably means lower alkoxy or lower alkylthio, or their tautomeric forms with an optionally substituted aniline as free base takes place in the same way as described for the reaction of a compound of formula Ila with an amine of formula HNR^R2. The reaction is preferably also carried out in a stoichiometric excess of the optionally substituted aniline. When using only a small excess of the aniline or an acid addition salt thereof, it may be appropriate to add a stoichiometrically equivalent amount of a tertiary trialkylamine already defined above. The reactions are carried out in analogous solvents as previously described for the reaction of compound IIa with

III.

Compounds of the general formula I can also be prepared by reacting a guanidine compound of the general formula IV in which Ph, and R 2 have the meanings given under formula I, with a compound of the general formula V

in which Y means lower alkoxy, such as e.g. methoxy or ethoxy, lower alkylthio, such as e.g. methylthio or ethylthio, halogen, such as e.g. chlorine or bromine, or Y means two lower alkoxy groups which are. bound to the same C atom, and Z means a tetrafluoroborate-, a fluorosulfonate-, a lower alkylsulfate-, which e.g. methyl sulfate or lower alkane sulfonate, such as e.g. methanesulfonate anion or a halide, such as chloride or bromide, whereby when Y has the meaning of two lower alkoxy groups bound to the same C atom, Z is omitted as an anion, or, when R^ means hydrogen, the tautomeric form is present as a free base, and, if desired, further process steps are carried out and, if desired, transfer obtained compounds of formula I in a salt., and/or, if desired, transfer obtained salts to compounds of formula I in the free compounds.

The compounds of the general formula I are conveniently prepared in such a way that a lactam salt of the above-mentioned formula V is reacted with a guanidine derivative of the above-defined formula IV in stoichiometric amounts. The turnovers are carried out preferentially.

in an anhydrous organic solvent. Organic solvents are e.g. lower alkanols, such as e.g. methanol, ethanol, isopropanol, tert.-butanol, ether, such as e.g. diethyl ether, tetrahydrofuran or dioxane, lower, halogenated hydrocarbons, such as e.g. chloroform, methylene chloride or 1,2-dichloroethane and aromatic hydrocarbons, such as benzene, toluene or xylene. In general, the reaction is carried out at temperatures between -20°C and +50°C, preferably between 0°C and room temperature. The reaction product with the general formula I obtained in salt form is transferred by basic hydrolysis, for example by the addition of an alkali or alkaline earth hydroxide or

-carbonate in the free base.

The lactam fluoroborates or fluorosulfonates with the general formula V used in the process, in which Z ® for example denotes the tetrafluoroborate group with the formula BF^® or fluorosulfonate group with the formula OS02F ® , can be prepared according to usual methods, by reacting a lactam with the formula Va

with the corresponding trialkyloxonium fluoroborate or a fluorosulfonic acid lower alkyl ester to the corresponding lactam salt of the general formula V.

The reaction is carried out, for example, at temperatures between -20°C and +50°C, preferably at temperatures between 0°C and +25°C in an inert gas, such as e.g. nitrogen or argon, and in the presence of an inert, anhydrous organic solvent, for example in a lower halogen hydrocarbon, such as e.g. chloroform, 1,2-dichloroethane or preferably in methylene chloride. Examples of other applicable organic solvents are ether, such as e.g. diethyl ether, dioxane, tetrahydrofuran or 1,2-dimethoxyethane as well as aromatic hydrocarbons, such as e.g. benzene, toluene or xylene.

The 2-lower alkylthiolactimeter under the general formula V can be prepared by reacting the lactam of the general formula Va with phosphorus pentasulfide in an analogous manner according to R. Gomper et al., Org. Sight. Coll., Vol. V, pages 780-785. When this reaction is carried out, a thiolactam is first obtained, which, when reacted with an alkylating agent, gives the 2-alkylthiolactimether in the form of corresponding salts. An alkyl halide, for example methyl iodide, a fluorosulfonic acid alkyl ester, such as e.g. fluorosulphonic acid methyl ester, a lower alkanesulphonic acid alkyl ester, e.g. methanesulfonic acid alkyl esters such as e.g. methanesulfonic acid methyl ester, a toluenesulfonic acid alkyl ester, such as e.g. toluenesulfonic acid methyl ester or dialkyl sulfate, such as e.g. dimethyl sulfate. The reaction of the lactimeter salts with the guanidine derivative of the general formula IV gives the corresponding salts of the general formula

IN-

In the reaction of the above-described lactam fluorosulfonates of the general formula V with the guanidines of the general formula IV, quaternary ammonium salts of compounds of the general formula I can also be formed as side reactions.

Also those under the general formula V comprising methyl sulfate salts are obtained in an analogous manner as described by H. Bredereck et al., Chem. Ber., vol. 96, (1963), p

1350, for pyrrolidones, of lactams of the general formula Va by reaction with dimethyl sulfate. The reaction is preferably carried out in an anhydrous, inert organic solvent, for example in an aromatic hydrocarbon, which e.g. benzene, toluene or xylene, in an ether, such as diethyl ether, dioxane or tetrahydrofuran, or in a halogenated aliphatic hydrocarbon, such as e.g. 1,2-dichloroethane or chloroform. The obtained methyl sulfate of the general formula V is then transferred with the corresponding guanidine derivative of the general formula. IV in the manner described above to

corresponding lower alkyl sulfate salt, such as e.g. methyl sulfate salt to the compound with the general formula I. The obtained salts can be converted by treatment with an alkali or alkaline earth hydroxide or carbonate in corresponding free bases with the general formula I.

Of lower alkyl sulfate-, such as e.g. the methyl sulfate salt with the general formula V can, for example, be prepared by reaction with a metal alkoxide, preferably an alkali metal alkoxide such as e.g. sodium methoxide or ethoxide,

in the corresponding anhydrous alkanol corresponding to the lactam acetal of formula Vb

Of the lactam acetals, the free bases of the general formula I can be prepared, as described above, with the guanidine derivatives of the general formula IV.

The halide, especially chloride salts of the lactam of the general formula V used in the process can be prepared in an analogous manner as described by W. Jentsch and M. Seefelder, Chem. Ber., vol. 98 (1965), page 274, for .pyrrolidones, by reacting a lactam of the general formula Va with phosgene or thionyl chloride.

As already mentioned above, the free bases of the general formula V can also be used for the preparation of the compound of the general formula I, in which a hydrogen atom means. The reaction of the salts of the general formula V with a base, such as e.g. an alkali or alkaline earth hydroxide or carbonate, preferably in a halogenated aliphatic hydrocarbon as solvent, such as e.g. methylene chloride or chloroform, they give free bases

with the general formula Ve

Compounds of the general formula I can also be prepared according to a further method, reacting guanidine derivatives of the general formula VI or a tautomeric form thereof, in which Ph, , R 2 and R 3 have the meanings given above and have the meaning of an oxo-, thioxo - or NH group, with a compound of the general formula VII in which n^ or n2 means 0, 1, 2 or 3, with the proviso that n^ and n2 together do not mean more than 3, Z^ means a halogen atom, Z2 means a oxo group or together the group consists of hydrogen and halogen, whereby the hydrogen atom can be part of a methyl group, or Z^ and Z2 together over an imino group complete the bivalent alkylene residue

to an azirdine derivative, whereby R^ and R,- have meant-

the addition of hydrogen, and, if desired, carrying out further process steps, and/or, if desired, converting the obtained compound into a salt, and/or, if desired, converting the obtained salts into the compounds of formula I in the free bases.

For example, a compound of formula VI, in which means an oxo or thioxo group, is reacted with a haloacetaldehyde of formula VII, in which Z^ means a halogen, means an oxo group, n^ and n^ means 0 and Ri- means hydrogen, preferably in a solvent with or without the addition of an acid-binding agent.

Lower alkanols such as e.g. methanol, ethanol, isopropanol, butanol; ketones, such as acetone, butanone, methyl isopropyl ketone; ether, such as 1,2-dimethoxyethane, diisopropyl ether, tetrahydrofuran or dioxane; carbonic acid derivatives, such as e.g. acetonitrile, ethyl acetate, dimethylformamide; aromatics, such as benzene, toluene or xylene, aliphatics or cycloaliphates, such as e.g. petrol and ligroin with boiling ranges between 60°C to 180°C, cyclo-hexane; halogenated aliphatic hydrocarbons, such as methylene chloride, chloroform, tetrachloromethane or 1,2-dichloroethane.

For example, the following can be used as an acid-binding agent: Inorganic bases, such as e.g. sodium bicarbonate, sodium carbonate, potassium carbonate, trisodium phosphate, sodium hydroxide, potassium hydroxide or organic bases, such as e.g. triethylamine or benzyldimethylamine.

For the reaction of compounds of formula VI with halogenacetaldehydes or halogenacetaldehyde-cleavable compounds, such as e.g. corresponding acetals, preferably equimolar or approximately equimolar amounts of both components are used. In particular, it may be appropriate to use a small excess (1-15 mol-%) of haloacetaldehyde or haloacetaldehyde-releasing compounds. To this, the compound of formula VI is dissolved in a solvent or suspended and the halogen-acetaldehyde or the halogen-acetaldehyde-releasing compound is slowly added. The acid-binding agent kåh is thereby also applied or only added afterwards. The reaction is carried out at 0°C up to the boiling point of the solvent used, for example up to a temperature of 150°C; the preferred temperature range is from 20°C to 100°C.

In an analogous manner, a compound of formula VI, in which Y represents a thioxo group, can also be reacted with a dihaloethane compound of formula VII, in which Z^ means a halogen atom and Z_ means a halogen atom and hydrogen atom, to the same compounds of formula I. On in an analogous manner to that described above, the reactions are carried out in an organic solvent or in an excess of the used dihalogenethanfer compound with formula VII. Preferably, the conversion takes place in a lower alkanol, such as e.g. methanol, ethanol, isopropanol or butanol.

The aziridines under the formula VII, in which R^ and R,- mean hydrogen, can be reacted with a thiourea derivative of the formula VI in aqueous-acidic solution or preferably in a non-polar solvent, such as e.g. in one of the above-mentioned ketones at a temperature between 0°C and 100°C, preferably between 0°C and 30°C. However, if an aqueous-acidic solution is used as the solvent, the reaction mixture must be made alkaline after the reaction has been carried out in order to obtain the resulting compound of formula I as a free base.

The compounds according to the invention with formula I, in which Het means a heteroalkylene residue with 4-6 chain links which complements the group C-N to a heterocyclic six-membered ring, can be prepared by reacting compounds with formula

IV

in which R 1 , R 2 and Ph have the meanings given above, with a haloalkylene isothiocyanate of formula

in which Z^ means a halogen atom and the bivalent residue "alkylene" means an alkyl chain with 3-5 carbon atoms, whereby a hydrogen atom in the alkylene chain can be replaced by the substituent 1, which has the meaning given above for R^ with the exception of hydrogen, and, if desired, carry out further method steps, and/or, if desired, transfer obtained compounds in a salt, and/or, if desired, convert obtained salts into the compounds of formula I in the free bases.

The reaction is preferably carried out in an anhydrous, inert organic solvent, for example an aromatic hydrocarbon, which e.g. benzene, toluene or xylene, an ether, such as diethyl ether, dioxane or tetrahydrofuran. The reaction is carried out at a temperature of 0°C up to the boiling point of the solvent used, for example up to a temperature of 120°C; the preferred temperature range is at 20° to 100°C,

The compounds according to the invention with formula I, in which R^ has the meaning defined above and R 2 and/or R^ is hydrogen, can be converted according to a further method by reaction with a reactive ester of an aliphatic or cycloaliphatic alcohol in compounds with formula I , in which R 2 and/or R^ in the framework of the above-mentioned definition for R 2 and R^ is different from hydrogen, and, if desired, carry out further process steps, and/or, if desired, transfer obtained compounds of formula I in a salt, and/or, if desired, converts obtained salts into compounds of formula I in the free bases.

As a reactive ester, as a so-called alkylating agent, you can use e.g. an alkyl or cycloalkyl halide such as methyl or cyclohexyiodide, a corresponding fluorosulfonic acid alkyl ester such as, for example fluorosulfonic acid methyl ester, a corresponding lower alkanesulfonic acid ester such as e.g. methanesulfonic acid methyl ester, a corresponding toluenesulfonic acid alkyl ester such as e.g. toluenesulfonic acid methyl ester or a dialkyl sulfate such as e.g. dimethyl or

diethyl sulfate.

The compounds according to the invention with formula I, in which R 2 and/or R- means hydrogen, can also be prepared according to a further method, splitting off in compounds with the general formula IX

in which R^, R^, R^, Ph and Het have the meaning given under formula I and one of the substituents R2<1> and R^' has the meaning of R2 or R^ and the other means an amino protecting group, or R2<1> and R^1 means an amino protecting group, these and if desired carry out further method steps, and/or, if desired, transfer obtained compounds of formula I in a salt, and/or, if desired, convert obtained salts into compounds of formula I in the free bases.

An amino protecting group R2' or R^' is primarily an acyl group such as acyl of an aliphatic, aromatic or araliphatic carboxylic acid, especially lower alkanoyl, e.g. acetyl or propionyl, or aroyl., e.g. benzoyl or acyl of a formic acid or a carboxylic acid half-derivative, e.g. -ester such as formyl, lower alkoxycarbonyl, e.g. ethoxycarbonyl or tert.-butyloxycarbonyl or aryl laverealoxycarbonyl,. e.g. benzoyloxycarbonyl.

The cleavage of an amino protecting group R2' and/or R2' used acyl residue takes place in a manner known per se, e.g. by solvolysis, primarily by means of alcoholysis, further by. by means of hydrolysis. The alcohololytic cleavage of an acyl residue R2<1> and/or R^' can take place e.g. in the presence of a strong basic agent, at too high a temperature, e.g. at approx. 50°C to approx. 120°C. Thereby, a lower alkanol in particular is used, e.g. n-butanol or ethanol, and as a strong base an alkali metal, e.g. sodium or potassium lavereal alkanolate, e.g. -n-butylate or -ethylate or an alkali metal hydroxide, e.g. sodium or potassium hydroxide.

Amino-protecting groups 1 and 1/, for example lower alkoxycarbonyl groups such as tert.-butyloxycarbonyl, can be cleaved particularly gently acidolytically, e.g.

by treatment with trifluoroacetic acid.

A further, particularly mild cleavable amino protecting group is an ethoxycarbonyl group which in position carries a silyl group substituted with three hydrocarbon residues such as triphenylsilyl, dimethyl-butylsilyl or preferably trimethylsilyl. Such a 3-(trimethylsilyl)-ethoxycarbonyl group forms with the amino group to be protected, a corresponding 3-trimethylsilyl-ethoxy-carbonyl-amino group which can be cleaved under mild conditions under the influence of fluoride ions. As fluoride ion-releasing reagents, for example, fluorides of quaternary organic bases, such as tetraethylammonium fluoride, come into consideration.

It is therefore to be taken into account that as amino protecting group R^<1>and/or R^' only those which are selectively cleavable while maintaining the structure of the compounds of the general formula I are taken into consideration.

The starting materials are known, or if they are new, they can be prepared according to known methods. Where it has proven appropriate, the starting products used have already been described, in connection with the described method.

Compounds with the general formula IIa, in which X2 denotes a lower alkylthio group, can be prepared, for example, from corresponding thioureas with the general formula X by reacting this with one of the above-mentioned alkylating agents with the formula R x R , in which R means Jr a lower alkyl, for example methyl or ethyl group and Z means, for example, a p-toluenesulfonate, methanesulfonate, fluorosulfonate or a lower alkyl sulfate, which e.g. methyl sulfate group, preferably halogen, such as e.g. chlorine or bromine.

The reaction is carried out in one of the organic solvents already defined above. Preferably an ether is used as solvent, such as e.g. diethyl ether, tetrahydrofuran or dioxane, a ketone such as acetone or 2-butanone, a halogenated, aliphatic hydrocarbon such as e.g. chloroform or methylene chloride or a lower alkanol, such as e.g. methanol or ethanol. Particularly suitable is an alkyl halide in methanol or ethanol. In general, the alkylating agent is used in at least an equimolar amount. The alkylation can optionally be carried out at room temperature or at higher temperatures and, if necessary, in a closed reaction vessel.

Compounds with the general formula IX can further be prepared from the already mentioned and known imino compounds with formula III

by reaction with an optionally substituted phenyl isothiocyanate with the formula Ph - NCS in an inert already defined above,

organic solvent, preferably in benzene, methylene chloride or chloroform, at temperatures from 0°C to room temperature within 2-24 hours in approximately equimolar amounts.

Compounds of formula IIb, in which X^ as leaving group means halogen, preferably chlorine, are obtained according to that of E. Kiihle, Angew. Chem. , Intern. Ed., Volume 8

(1969), pages 24-26, described method, as one converts

an isocyanide dihalogenide of formula XI

with an amine of the formula HNR^R2 in the presence of a trialkylamine, such as e.g. triethylamine, in an inert, aprotic, anhydrous solvent. Compounds of formula X can also be present as immonium chlorides. As a solvent, e.g. an ether, for example diethyl ether, dioxane or tetrahydrofuran, a halogenated, aliphatic hydrocarbon, such as e.g. chloroform or methylene chloride, or an aromatic hydrocarbon, such as benzene, toluene or xylene. Compounds with the general formula X are known and can be prepared in an analogous manner as described in Angew. Chem., Intern. Oath. volume 6 (1967), page 649.

Compounds of the general formula IIb, in which the cleavable group X^ means, for example, halogen, can easily be converted in a known manner into compounds of formula IIb, in which X^ means a lower alkoxy group.

Output compounds with the general formula lic,

in which the cleavable group X^ means halogen, preferably chlorine, can be prepared by reacting an immonium chloride with the formula

with an imino compound of formula III

according to that of R.G. Glushkow, Khim.-Pharmasevt. Zh. 12, No. 6, 59-64/1978 described method.

The conversion takes place in an analogous manner to that described above for the conversion of a compound of formula X.

Output compounds of the general formula VI,

in which, for example, means an oxo or thioxo group and R^ is different from hydrogen, can be prepared by reacting a guanidine compound of formula IV

with a lower alkyl isothiocyanate or isocyanate. The reaction takes place in an organic solvent, preferably in an ether, such as e.g. diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, a carboxylic acid derivative such as e.g. acetonitrile, at a temperature between 0°C and the boiling point of the solvent, preferably at 20°C to 100°C.

Compounds with the general formula VI, in which, for example, Y^ means a thioxo group and R^ is hydrogen, can be prepared according to that of H. Hartmann et al., J. Prakt. Chem. 315 (1973), page-144, described method. Guanidine compounds of the general formula IV are reacted with a lower alkoxycarbonyl isothiocyanate to a compound of formula XII which is converted by hydrolysis with a mineral acid, preferably hydrochloric acid, to a compound of formula VI.

Compounds with the general formula IX can be prepared according to one of the above-described first three methods for preparing compounds with the general formula I, whereby, however, in the starting products used, R 2 and/or R 1 means an acyl residue. These acyl residues used as amino protecting groups are defined as above.

The described methods can be carried out in the usual way at room temperature, during cooling or heating, at normal pressure or elevated pressure and if necessary in the presence or absence of a diluent, catalysts or condensation agents. If necessary, the reactions can also take place in the atmosphere of an inert gas, e.g. nitrogen.

In the compounds obtained, substituents can be introduced, converted or split off within the framework of the definition of the end products.

The new starting materials and method for their production are likewise an object of the present invention.

Depending on the process conditions and the starting materials, the end products are obtained in free form or in the form of their salts, especially acid addition salts, which are likewise covered by the invention. The acid addition salts of the high compounds can be transferred in a manner known per se into the free compounds, e.g. with basic agents such as alkalis or ion exchangers. On the other hand, the free bases obtained with organic or inorganic acids can form salts.. For the preparation of acid addition ion salts

in particular such acids are used which are suitable for formation

of therapeutically useful salts. Examples of such acids should be mentioned: Hydrohalic acid, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carbonic or sulphonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxy-maleic or benzoic acid; phenylacetic, benzo-, p-amino-benzo-, anthranilic-, p-hydroxybenzo-, salicylic- or p-amino-salicylic acid, embonic acid, methanesulfonic, etahsulfonic, hydroxyethanesulfonic, ethylenesulfonic acid; halobenzenesulfonic, toluenesulfonic, naphthalene sulfonic or sulfanilic acid; methionine,

tryptophan, lysine or arginine.

These or other salts of the new compounds, such as e.g. the picrates, can also serve to purify the free bases obtained, as one transfers the free bases into salts, separates these and again frees the bases from the salts. Due to the close connection between the new compounds in free form and in the form of their salts, above and below the free compounds should logically and expediently also mean the corresponding salts.

The invention also relates to such embodiments

of a process in which one interrupts a process at any step or in which one starts from an obtainable compound as an intermediate at any step and carries out a missing step or forms a starting substance under reaction conditions or optionally uses a starting compound in the form of a salt . The invention also includes resulting new intermediates.

Also covered by the invention are therapeutic drug compositions which consist of a hypoglycemic active portion of the compound of the general formula I or an acid addition salt and a pharmacologically tolerable solid carrier or liquid diluents.

The pharmaceutical preparations according to the invention contain at least one compound of the general formula I or a salt thereof as active ingredient together with a common pharmaceutical carrier. The nature of the carrier largely depends on the area of application. The pharmaceutical compositions according to the invention which contain as active ingredient compounds of formula I can be administered orally, parenterally or rectally.

For the oral treatment of hyperglycemia, solid dosage unit forms such as tablets, dragées and capsules preferably contain between 10 and 90% of an active substance of the general formula I or a salt to enable the administration of daily doses between 1.5 and 100 mg are considered. /kg to warm-blooded beings. For the production of tablets and dragee cores, the compounds of the general formula I are combined with solid, powdered carriers such as lactose, sucrose, sorbitol, corn starch, potato starch or amylopectin, cellulose derivatives or gelatins, preferably with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weight. Dragon cores are coated in connection therewith, for example, with concentrated sugar solutions which may additionally contain e.g. Arabic gum, talc and/or titanium dioxide, or with a varnish dissolved in volatile organic solvents or solvent mixtures. Dyes can be added to these overcoats, e.g. for characterizing different active substance doses. Soft gelatin capsules and other closed capsules consist, for example, of a mixture of gelatin and glycerin and may contain e.g. mixtures. of a compound of formula I with polyethylene glycol. Stick capsules contain e.g. the granules of an active substance with solid, powdered carriers such as e.g. lactose, sucrose, sorbitol, mannitol; starches such as potato starch, corn starch or amylopectin, cellulose derivatives and gelatins as well as magnesium stearate or stearic acid.

As dosage unit forms for rectal use, e.g. suppositories in consideration, which consist of a combination of an active substance with a suppository matrix based on natural or synthetic triglycerides

(e.g. cocoa butter), polyethylene glycols or suitable higher fatty alcohols, and gelatin rectal capsules, which contain a combination of the active ingredient with polyethylene glycols.

Ampoule solution for parenteral, especially intramuscular or intravenous administration contains a compound of formula I or a salt thereof in a concentration of preferably 0.5 to 5% as aqueous, with the help of usual solubilizers and/or emulsifiers, as well as possibly of stabilizers prepared dispersion, or preferably an aqueous solution of a pharmaceutically acceptable, water-soluble acid addition salt of a compound of the general formula I.

For liquids for oral intake, such as syrups and elixirs, the concentration of the active ingredient is chosen so that a unit dose can be easily measured, e.g. as the contents of a teaspoon or a measuring spoon of e.g. 5 ml or a majority of these volumes.

The following examples a) to e) shall illustrate the production of some typical forms of application, but in no way indicate the only embodiments of such. a) 250.0 g of active substance is mixed with 550.0 g of lactose and 292.0 g of potato starch, the mixture is moistened with an alcoholic solution of 8 g of gelatin and granulated through a sieve. After drying, 60.0 g of talc, 10.0 g of magnesium stearate and 20.0 g of colloidal silicon dioxide are mixed and the mixture is pressed into 10,000 tablets, each weighing 125 mg and containing 25 mg of active ingredient, which, if desired, can be provided with partial slits for finer adjustment of the dosage.

b) From 100.0 g of active ingredient, 379.0 g of lactose and the alcoholic solution of 6.0 g of gelatins, one prepares

a granule which, after drying, is mixed with 10.0 g of colloidal silicon dioxide, 40.0 g of talc, 60.0 g of potato starch and 5.0 g of magnesium stearate and pressed into 10,000 dragon kernels. These are then coated with a concentrated syrup of 533.5 g crystal, sucrose, 20.0 g shellac, 75.0 g gum arabic, 250.0 g talc, 20.0 g colloidal

silicon dioxide and 1.5 g of dye and dried. The resulting dragées each weigh 150 mg and each contain 10 mg of active ingredient. c) 25.0 g of active substance and 1975 g of finely grated suppository base mass (e.g. cocoa butter) are thoroughly mixed and then melted. 1,000 suppositories of 2.0 g are cast from the melt, which is kept homogeneous by stirring. They each contain 25 mg of active ingredient. d) To prepare a syrup with 0.25% active ingredient content, dissolve in 3 liters of dist. water 1.5 liters glycerin, 42 g p-hydroxybenzoic acid methyl ester, 18 g p-hydroxy-benzoic acid n-propyl ester and, under slight heating, 25.0 g active ingredient, add 4 liters 70% sorbitol solution, 1000 g crystals, sucrose, 350 g of glucose and a flavoring agent, e.g. 250 g of "Orange Peel Soluble Fluid" from Eli Lilly and Co., Indianapolis, or each 5 g of natural lemon flavor and 5 g of "Halb und Halb" essence, both from the firm of Haarmann und Reimer, Holzminden, Germany, filters the solution obtained and supplements the filtrate with dist. water to 10 litres. e) To prepare a drop solution with .1.5% active substance content, dissolve 150.0 g of active substance and 30 g of sodium cyclamate in a mixture of 4 liters of ethanol (96%) and 1 liter of propylene glycol. On the other hand, you mix 3.5 liters of a 70% sorbitol solution with 1 liter of water and add the mixture to the above-mentioned active substance solution. A flavoring substance is then added, e.g. 5 g of throat tablet aroma or 30 g of grape fragrance essence, both from the company, a Haarmann und Reimer, Holzminden, Germany, all well mixed, filtered and supplemented with dist. water to 10 litres.

The following examples illustrate the preparation of the new compounds of the general formula I, but should not limit the scope of the invention in any way. The temperatures are indicated in °C.

<Example>_<1>_

To a solution cooled at 5° of 24.2 g (0.1 mol) of 2,5-dimethyl-3-isoxazoTidinimine hydroiodide {cf. Bull. Soc. Chim. Fr. 1 974,. 1651-1655} in 120 ml of acetonitrile, 21.25 g (0.21 mol) of triethylamine are added dropwise while stirring. During further cooling, 22.47 g (0.1 mol) of N-phenyl-4-morpholinecarboximidoyl chloride (cf. Chem. Ber. 105, 1 532-1539 (1 972)) are added in portions, whereby the reaction temperature is kept at 5- 10°. After the addition has been completed, the mixture is stirred for a further hour at 10° and 1 hour at room temperature. The reaction mixture is filtered, the filter residue is washed with a little acetonitrile and the filtrate is evaporated under vacuum. 2-n caustic soda is added to the residue and extracted several times with chloroform. The neutrally washed chloroform phases combined with water are evaporated after drying over sodium sulfate, whereby crude N-(2,5-dimethyl-3-isoxazolidinylidene)-N'-phenyl-4-morpholinecarboximidamide is obtained. The fumarate produced by reaction with fumaric acid melts after recrystallization from ethanol/ethyl acetate at 192-193°.

Example_el_2

Analogously to example 1, starting from 12.1 g (0.05 mol) of 2,5-dimethyl-3-isoxazolidinimine hydroiodide, 11.13 g (0.05 mol) of N-phenyl-1-piperidine carboximide is obtained -oyl chloride {cf. Organ metal. Chem. Pity. 1_, 23-30 (1970-71 )}, 10.63 g (0.105 mol) triethylamine and 60 ml acetonitrile crude N-(2,5-dimethyl-3-isoxazolidinylidene)-N'-phenyl-1-piperidine-carboximidamide . The fumarate produced therefrom with fumaric acid melts at 171.5-173° after recrystallization from isopropanol/ethyl acetate.

Example_el_3

Analogously to example 1, one obtains, starting from 11.4 g (0.05 mol) of 2-methyl-3-isoxazolidinimine hydroiodide {cf. Bull. Soc. Chim.. Fr. 1974, 1651-1655}, 11.23 g (0.05 mol) N-phenyl-4-mOrpholine carboximidoyl chloride, 10.63 g (0.105 mol) triethylamine and 60 ml acetonitrile crude N-(2-methyl-3- the isoxazolidinylidene)-N'-phenyl-4-morpholinecarboximidamide (m.p. 80-88°, of petroleum ether). The fumarate produced therefrom with fumaric acid melts at 167-168° after

recrystallization from ethanol/ether.

ExemjDél_4

Analogously to example 1, one obtains, starting from 12.8 g (0.05 mol) 2,5,5-trimethyl1-3-isoxazolidinimine hydroiodide (cf. Bull. Soc. Chim. Fr. 1974, 1651-1655), 11.23 g (0.05 mol) N-phenyl-4-morpholine carboximidoyl chloride, 10.63 g (0.105 mol) triethylamine and 60 ml acetonitrile crude N-(2,5,5-trimethyl-3-isoxazblidinylidene)- N'-phenyl-4-morpholinecarboximidamide. The fumarate produced therefrom with fumaric acid melts at 203-204° after recrystallization from ethanol/ether.

Example_5

To a solution of 12.26 g (0.05 mol) N,N-tetra-methylene-N<1->phenyl-chloroformamidinium chloride (respectively, phenylimino-chlorocarbonic acid-pyrrolidinylamide hydrochloride)

{cf. Chem. Pray. 97, 1232-1245 (1964)} and 12.1 g (0.05 mol) of 2,5-dimethyl-3-isoxazolidinimine hydroiodide in 50 ml of acetonitrile are added dropwise while stirring and cooling 15.18 g (0. 15 mol) of triethylamine, whereby the reaction temperature is kept at 5-10°. The reaction mixture is stirred for a further 15 hours at room temperature and then filtered. The filtrate is evaporated in vacuo and the residue is filtered with chloroform over silica gel with a grain size of 0.063-0.200 mm. The fractions containing it The desired product is combined and washed with ice-cold caustic soda and water. The chloroform phase is dried over sodium sulfate and evaporated in vacuo, whereby crude N-(2,5-dimethyl-3-isoxazolidinylidene)-N<1->phenyl-1 -pyrrolidinecarboximidamide. The maleate produced from it with maleic acid melts at 114-116° after recrystallization from ethyl acetate/isopropanol..

Eczema gel_6

a) 200 ml isopropanol with 19.5 g (0.05 mol) N-(1,3-dimethyl-2-imidazolidinylidene)-

N<1->phenylcarbamidothiomethyl ester hydroiodide and 10.66 g (0.15 mol) pyrrolidine. The reaction mixture is boiled for 36 hours under reflux and then evaporated. The residue is divided between chloroform and 1-n caustic soda. The water-washed and sodium sulfate-dried organic phase is evaporated, and the residue is filtered with a mixture of chloroform/methanol/conc. ammonia = 40:10:1 over silica gel with a grain size of 0.063 - 0.200 mm. The fractions containing the desired product are evaporated in a vacuum. The thus obtained crude N-(1,3-dimethyl-2-imidazolidinylidene)-N<1->phenyl-1-pyrrolidine-carboximidamide is transferred with maleic acid into the maleate, which melts at 126-127° after recrystallization from ethyl acetate/isopropanol .

The starting compound, N-(1,3-dimethyl-2-imidazol-idinylidene)-N'-phenylcarbamimido-thiomethyl ester hydroiodide, is prepared as follows: b) To a solution of 44.1 g (0.5 mol) N,N -dimethylethylenediamine in 300 ml of toluene, a solution of 52/9 g of cyanogen bromide in 1,300 ml of toluene is added dropwise with stirring over the course of 1 hour. The reaction mixture is stirred for a further 2 hours at 80°. Allow to cool to room temperature, filter and wash the residue with ether. The crude 1,3-dimethyl-2-imino-imidazolidine hydrobromide obtained after drying under vacuum melts at 153-160°. c) A suspension of 58.2 g (0.3 mol) 1,3-dimethyl-2-imino-imidazolidine hydrobromide in 470 ml chloroform is added while stirring at 5° 30.4 g (0.3 mol) triethylamine Man then drops a solution of 40.6 g (0.3 mol) of phenyl isothiocyanate in 235 ml of chloroform and refluxes the reaction mixture for 15 hours. After cooling, it is washed with water, dried over sodium sulphate and evaporated in vacuo. Crude N-(1,3-dimethyl-2-imidazolidin-ylidene)-N<1->phenyl-thiourinstbff is obtained, which after recrystallization from ethanol melts at 195-196°. d) To a suspension of 24.8 g (0.1 mol) N-(1,3-dimethyl-2-imidazolidinylidene)-N'-phenyl-thiourea in

165 ml of tetrahydrofuran are added dropwise while stirring

at room temperature a solution of 21.3 g (0.15 mol) of methyl iodide in 35 ml of tetrahydrofuran. The mixture is stirred for 15 hours at room temperature and then 160 ml of ether is added to the reaction mixture. The precipitate is filtered off, washed with ether and dried in a vacuum. The obtained N-(1,3-dimethyl-2-imidazolidinylidene)-N<1->phenylcarbamimido-thiomethyl ester hydroiodide melts at 157-158°.

Example_7

a) A solution of 19.6 g of N-{3-methyl-4-(1,3,4)-thiadiazolin-2-ylidene}-N<1->phenylcarbamimido-thiomethyl ester hydroiodide and 10.6 g of pyrrolidine in 150 ml isopropanol is heated for 15 hours under reflux. The reaction mixture is then evaporated to dryness and the residue chromatographed over a short column filled with silica gel. Elute first with chloroform and then with a chloroform/acetone mixture (95:5). The last fractions are combined, stirred with ether

and the hydroiodide thus obtained is transferred by means of an ion exchanger into the hydrochloride. The obtained N-{3-methyl-4-(1,3,4)-thiadiazolin-2-ylidene}-N<1->phenyl-1-pyrrolidine-carb-oximidamide hydrochloride melts at 217-218° (decomposition ).

, The N-{3-methyl-4-(1,3,4)-thiadiazolin-2-ylidene}-N<1->phenylcarbamimido-thiomethyl-ester-hydro iodide used as starting compound is obtained as follows:

b) A suspension of. 52.7 g of 2-imino-3-methyl-4-(1,3,4)-thiadiazoline hydriodide and 24.3 g of potassium tert.-butylate in 500 ml of tetrahydrofuran are stirred for 1 hour at room temperature. It is then filtered through a layer of diatomaceous earth. 29.3 g of phenylisothiocyanate are added dropwise to the filtrate over 5 minutes and stirred for 16 hours at room temperature. The reaction mixture is then evaporated to dryness, the residue is stirred with ether, filtered off and stirred once more with hot isopropanol. The N-{3-methyl-4-(1,3,4)-thiadiazolin-2-ylidene}-N'-phenylthiourea is thus obtained, melting point 174-175°. c) A solution of 25.5 g of the compound obtained in b) in 300 ml of acetonitrile is added with 43.4 g of methyl iodide. The solution is heated for 30 minutes under reflux. The crystals separated during cooling are filtered off, first washed with acetonitrile, then with ether and dried. The N-{3-methyl-4-(1,3,4)-thiadiazolin-2-ylidene}-N<1->phenylcarbamimido-thiomethyl ester hydroiodide is thus obtained, melting point 190° (decomposition).

Example_el_8

a) A solution of 17.6 g of 2-amino-5-methyl-1,3,4-thiadiazole in 350 ml of isopropanol is added with 65.1 g of methyl iodide. The solution is heated for 15 hours under reflux. The reaction mixture is then evaporated to dryness, the crystalline evaporation residue is stirred with acetic acid, and the solvent is filtered off. The crystalline residue is first washed with vinegar, then with ether and subsequently dried. Thus, 2-imino-3,5-dimethyl-4-(1,3,4)-thiadiazoline hydroiodide with a melting point of 208° (decomposition) is obtained.

Analogously, the following salts of 2-imino compounds can be prepared: b) 2-imino-3-methyl-5-ethyl-4-(1,3,4)-thiadiazoline hydroiodide, melting point 137-138° (decomposition). c) 2-imino-3-methyl-5-trifluoromethyl-4-(1,3,4)-thiadiazoline hydroiodide, melting point 187-188° (decomposition). d) 2-imino-3-methyl-5-methylmercapto-4-(1,3,4)-thiadiazoline hydroiodide, melting point 205-206°. e) 2-imino-3-methyl-4-phenyl-4-thiazoline hydroiodide, melting point 235° (decomposition). f) 2-imino-3,5-dimethyl-4-thiazoline hydroiodide, melting point 187-188°. g) 2-imino-1,3-dimethyl-4-imidazoline hydroiodide, melting point 126-127°. h) 2-imino-3-methyl-4-oxazoline hydroiodide, melting point 191-192°. (fission).

i) 2-imino-3,4,5-trimethyl-4-oxazoline hydroiodide, melting point 169-171°.

j) 2-imino-3,5-dimethyl-4-(1,3,4)-oxadiazoline-

hydroiodide, melting point 169° (decomposition).

Example_el_9

According to example 7 b), however, using an equivalent amount of the 2-imino compound obtained in example 8, the following thioureas are obtained by reaction with an equivalent amount of phenylisothiocyanate: a) N-{3,5-dimethyl-4-(1 ,3,4)-thiadiazolin-2-ylidene}-N<1->phenylthiourea, melting point 175-176°. b) N-{3-methyl-5-ethyl-4-(1,3,4)-thiadiazolin-2-ylidene}-N'-phenylthiourea, melting point 135-136°. c) N-{3-methyl-5-methylmercapto-4-(1,3,4)-thiadiazolin-2-ylidene}-N'-phenylthiourea, melting point 160-161°. d) N-(3-methyl-4-thiazolin-2-ylidene)-rN'-phenylthiourine substance f, melting point 174-175°. e) N-(3-methyl-4-phenyl-4-thiazplin-2-ylidene)-N<1->phenylthiourea, melting point 183-184°. f) N-(3,5-dimethyl-4-thiazolin-2-ylidene)-N<1->phenyl-thiourea f , melting point 185-186°. g) N-(1,3-dimethyl-4-imidazolin-2-ylidene)-N<1->phenylthiourea, melting point 221-222°. h) N-(3-methyl-4-oxazolin-2-ylidene)-N<1->phenylthiourea, melting point 169-170°.

i) N-(3,4,5-trimethyl-4-oxazolin-2-ylidene)-N1 - phenylthiourea, melting point 192-192.5°.

Analogously produced by:

j) 2-imino-3-allyl-4-thiazoline hydroiodide and phenyl isocyanate N-(3-allyl-4-thiazolin-2-ylidene)—N'-phenylthiourine substance fatty, melting point 129.5-130, 5° and

k) 2-imino-3-methyl-thiazolidine hydroiodide and phenyl isocyanate N-(3-methyl-thiazolidin-2-ylidene)-N<1->phenylthiourine substance f et, melting point 170-172°.

Example_el_1_0

According to example 7 c), however, using the thioureas specified above in example 9 in appropriate specific solvents, the methyl ester hydroiodides are obtained: a) in isopropanol N-{3,5-dimethyl-4-(1,3,4 )-thiadiazolin-2-ylidene}-N 1-phenylcarbamimido-thiomethyl ester hydroiodide, melting point 134-135.5°; b) in tetrahydrofuran N-{3-methyl-5-ethyl-4-(1,3,4)-thiadiazolin-2-ylidene}-N*-phenylcarbamimido-thiomethyl ester hydro iodide, crude oil; c) in tetrahydrofuran N-{3-methyl-5-methylmercapto-4-(1,3,4)-thiadiazolin-2-ylidene}-N1-phenylcarbamimido-thio-methyl ester hydro iodide, melting point 160-161°; d) in tetrahydrofuran N-(3-methyl-4-thiazolin-2-ylidene)-N'-phenylcarbamimido-thiomethyl ester hydroiodide, melting point 174-175°; e) . i. tetrahydrofuran N-(3-methyl-4-phenyl-4-thiazolin-2-ylidene)-N'-phenylcarbamimido-thiomethyl ester hydroiodide, melting point 183-184°; f). in tetrahydrofuran N-(3,5-dimethyl-4-thiazolin-2-ylidene)-N'-phenylcarbamimido-thiomethyl ester hydroiodide, melting point 185-186°; g) in acetonitrile N-(1,3-dimethyl-4-imidazolin-2-ylidene)-N<1->phenylcarbamimido-thiomethyl ester hydroiodide, melting point 221-222°; ;h) in isopropanol the N-(3-methyl-4-oxazolin-2-ylidene)-N'-phenylcarbamimido-thiomethyl ester hydroiodide, melting point ;140-141°; ;i) , in isopropanol N-(3,4,5-trimethyl-4-oxazolin-2-ylidene)-N<1->phenylcarbamimido-thiomethyl ester hydroiodide, melting point 192-192.5°; ;j) in isopropanol the N-(3-allyl-4-thiazolin-2-ylidene)-N'-phenylcarbamimido-thiomethyl ester hydroiodide, melting point 138-139°; ;k) in tetrahydrofuran N-(3,4,5-trimethyl-4-oxazolin-2-ylidene)-N'-phenylcarbamimido-thiomethyl ester hydroiodide, melting point 139-141°. ;Example 21;According to example 7 a) the corresponding methylthiohydroiodides from example 10 as well as the corresponding amides with the general formula HNR^F^ are reacted in a molar ratio of 1:3 in refluxing isopropanol, tert.-butanol or also ethanol to the new following compounds a - k in the form of the hydroiodides. The hydroiodides are isolated as such, transferred into the hydrochlorides by means of an anion exchange resin or optionally with aqueous alkali in the free bases. By reacting the free bases with a suitable acid, other salts can also be produced. a) N-{3,5-dimethyl-4-(1,3,4-thiadiazolin-2-ylidene}-N'-phenyl-1-pyrrolidine-carboximidamide as free base, melting point 98-99°; • b) N-{3-methyl-5-ethyl-4-(1,3,4)-thiadiazolin-2-ylidene}-N'-phenyl-1-pyrrolidine carboximidamide as free base, melting point 85-86°; c) N-{3-methyl-5-methylmercapto-4-(1,3,4)-thiadiazolin-2-ylidene}-N'-phenyl-1-pyrrolidine carboximidamide as free base, melting point 98-99°; d) N-(3-methyl-4-thiazolin-2-ylidene)-N<1->phenyl-1-pyrrolidine carboximidamide as free base, melting point 129-130°; e) N-(3-methyl-4-phenyl-4-thiazolin-2-ylidene)-N1-phenyl-1-pyrrolidine carboximidamide as hydrochloride, melting point 196-197°; f) as N-(3,5-dimethyl-4-thiazolin-2-ylidene)-N<1->phenyl-1-pyrrolidine-carboximidamide as hydrochloride, melting point 220.5-221.5°; g) as N-(1,3-dimethyl-4-imidazolin-2-ylidene)-N'-phenyl-1-pyrrolidine-carboximidamide • . 2HC1, melting point ;170°, (decomposition); ;h) N-(3-methyl--4-oxazolin-2-ylidene)-N 1 -phenyl-1-pyrrolidine carboximidamide as free base, melting point ;94.5-95.5°; ;i) N-(3,4,5-trimethyl-4-oxazolin-2-ylidene)-N'-phenyl-1-pyrrolidine carboximidamide as hydrochloride, melting point 161-163°; ;j) N-(3-allyl-4-thiazolin-2-ylidene)-N'-phenyl-1-pyrrolidine carboximidamide as free base, melting point 91-92°; ;k) N-(3,4,5-trimethyl-4-oxazolin-2-ylidene)-N'-phenyl-1-pyrrolidine carboximidamide as hydrochloride, melting point 225-226°; 1) N-{3,5-dimethyl-4-(1,3,5)-thiadiazolin-2-ylidene}-N<1->phenyl-dimethylamino-carboximidamide as hydrochloride, melting point 238-239.5° (fission); ;m) N-(3,4,5-trimethyl-4-oxazolin-2-ylidene)-N1 - phenyl-dimethylamino-carboximidamide as free base, melting point 84-86°. ;Example_12;A solution of 9.3 g of 2-imino-3-methyl-thiazolidine and 10.3 g of N-ethyldiisopropylamine in 50 ml of acetonitrile is added dropwise over 15 minutes at room temperature to a solution of 14.8 g of N -phenyl-4-morpholine-carboximidoyl chloride in 50 ml of acetonitrile. It is then stirred for 2 hours at room temperature and then a further 3 hours under reflux. The reaction mixture is evaporated to dryness, the crystalline residue is stirred with isopropanol, the solvent is filtered off and the solid product obtained is then stirred for 30 minutes with 50 ml of water, filtered off, washed first with water, then with isopropanol and dried. The N-(3-methyl-thiazolidin-2-ylidene)-N<1->phenyl-4-morpholine-carboximidamide thus obtained melts at 144.5-145.5°. ;Example_23;From 18.5 g of 2-imino-3-methyl-5-trifluoromethyl-4-(1,3,4)-thiadiazoline hydroiodide, the base is released with 10% caustic soda, taken up in methylene chloride, dried with anhydrous magnesium sulfate and evaporated. The thus obtained base and 7.6 g of N-ethyldiisopropylamine are dissolved in 50 ml of acetonitrile and added dropwise over 15 minutes to a solution of 11.9 g of N-phenyl-4-morpholine-carboximidoyl chloride in 50 ml of acetonitrile* In addition is stirred for a further 4 hours at room temperature, the reaction mixture is then evaporated to dryness, the residue is stirred with ether, filtered off, the ether extract is evaporated and the evaporation residue is chromatographed over a short column filled with silica gel. First eluted with methylene chloride, then with a methylene chloride-acetone mixture 97:3. The middle fractions are combined, stirred with a little hexane, filtered off, washed with hexane and dried. The N-{3-methyl-5-trifluoromethyl-4-(1,3,4)-thiadiazolin-2-ylidene}-N'-phenyl-4-morpholine-carboximidamide thus obtained melts at 110.5-112°.

Eczema gel_1_4

From 14.6 g of 2-imino-3-methyl-4-(1,3,4)-thiadiazoline hydroiodide, the base is released with 30% caustic soda, taken up in methylene chloride, dried with anhydrous magnesium sulfate and evaporated. The base thus obtained and 7.1 g of N-ethyldiisopropylamine are dissolved in 50 ml of acetonitrile and added dropwise over 15 minutes to a solution of 11.2 g of N-phenyl-4-morpholine-carboximidoyl chloride in 50 ml of acetonitrile. The mixture is then stirred for 1 hour at room temperature and then a further 3 hours under reflux. The reaction mixture is evaporated to dryness, and the evaporation residue is chromatographed over a column filled with silica gel. Elute with chloroform. The base thus obtained is transferred with alcoholic hydrochloric acid into the hydrochloride. After recrystallization from acetonitrile-acetic ester, pure N-{3-methyl-4-(1,3,4)-thiadiazolin-2-ylidene}-N'-phenyl-4-morpholine-carboxymidamide hydrochloride is obtained with a melting point of 201.5 -202.5°.

Example_el_25

Following the procedure described in example 14, 8.6 g of 2-imino-3-methyl-4-(1,3,4)-thiadiazoline and 16.7 g of N-phenyl-1-piperidine-carboximidoyl chloride N-{ 3-Methyl-4-(1,3,4)-thiadiazolin-2-ylidene}-N'-phenyl-^1-piperidinecarboximidamide, melting point 94.5-95.5°.

Example_el_1_6

Following the procedure described in example 14, 6.3 g of 2-imino-3-methyl-4-thiazoline and 11.2 g of N-phenyl-4-morpholine-carboximidoyl chloride N-(3-methyl-4-thiazoline- 2-ylidene)-N<1->phenyl-4-morpholine-carboximidamide hydrochloride, melting point 209-210°.

Example_el_22

12.0 g of 2-imino-3,5-dimethyl-4-(1,3,4)-oxadiazoline hydroiodide is reacted with 11.2 g of N-phenyl-4-morpholine-carboximidoyl chloride, as described in example 8. However, the reaction mixture is only stirred at room temperature and for less than 16 hours. The reaction mixture is evaporated and chromatographed over a column filled with silica gel. Elute first with chloroform, then with a chloroform-acetone mixture 95:5 and finally with chloroform-methanol 95:5. A hydrochloride is extracted from the latter fractions, which is stirred with 30% caustic soda. The initially oily base soon crystallizes. The N-{3,5-dimethyl-4-(1,3,4)-oxadiazolin-2-ylidene}-N<1->phenyl-4-morpholine-carboximidamide thus obtained melts at 117-118°.

Example_18

To 200 ml of tetrahydrofuran and 111 ml of a 20% solution of phosgene in toluene (0.21 mol) 4 3.3 g (0.21 mol) of N-phenyl-N<1>,N' are added with stirring -tetramethylene-thiourea {cf. J. Org. Chem. 23, 1760-1764 (1958)}, whereby care is taken that the temperature does not rise above 35 . It is stirred for a further 15 minutes at 20°, then cooled to 10° and the reaction mixture (suspension of N,N-tetramethylene-N1-phenyl-chloroformamidinium chloride) with 100 ml of acetonitrile and '50.8 g (0.21 mol) 2,5-dimethyl-3-isoxazolidinimine hydroiodide. After the dropwise addition of 64.8 g (0.64 mol) of triethylamine at 10-15°, the suspension is stirred for a further 12 hours. Filter, evaporate the filtrate under vacuum and dissolve the residue in ice-cold 2-N hydrochloric acid. The crude N-(2,5-dimethyl-3-isoxazolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide hydrochloride is extracted with chloroform and the chloroform extract is washed with 2-n sodium hydroxide solution and water, dried over sodium sulfate and evaporated. Crude N-(2,5-dimethyl-3-isoxazolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide is obtained. The maleate produced therefrom with maleic acid melts at 114-116° (from ethyl acetate).

Variant

A further simplification of the method consists in adding phenylisothiocyanate dropwise to a solution of pyrrolidine in ether or tetrahydrofuran, in

an equivalent amount of phosgene is introduced into the formed suspension of N-phenyl-N<1>,N<1->tetramethylenethiourea and the reaction mixture is further treated as described above.

Eczema gel_1_9

A mixture of 3.6 g (0.05 mol) pyrrolidine and 15.2 g (0.45 mol) of triethylamine. The reaction mixture is stirred for a further 15 minutes at 0° and then 12.1 g (0.05 mol) of 2,5-dimethyl-3-isoxazolidineimine hydroiodide are added, whereby care is taken that the temperature does not rise above 10°. The suspension is stirred for 1 hour at 20°. Filter, evaporate the filtrate and distribute the residue between chloroform and 2-n caustic soda. The chloroform phase washed neutrally with water and dried over sodium sulfate is evaporated, whereby crude N-(2,5-dimethyl-3-isoxa-zolidinylidene)-N<1->phenyl-1-pyrrolidinecarboximidamide is obtained. The crude maleate produced from this with maleic acid is purified by filtration over silica gel with a grain size of 0.063-0.2 mm with a solvent mixture of chloroform/methanol = 95:5. The pure N-(2,5-dimethyl-3-isoxazolidinylidene)-N'-phenyl-1-pyrrolidine carboximidamide maleate melts after recrystallization from ethyl acetate at 112-114°.

Eczema2<el>_<2>0

A suspension of 6.6 g of N-phenyl-4-morpholinecarboximidamide hydroiodide in 40 ml of acetonitrile is mixed with 3.5 g of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine. The mixture is heated on the water bath for 12 hours with vigorous stirring. The acetonitrile is evaporated under reduced pressure and the residue is recrystallized from a mixture of acetone-acetic acid ethyl ester. The N-(thiomorpholin-3-ylidene)-N'-phenyl-4-morpholinecarboximidamide hydroiodide is obtained with the formula

which melts at 220°.

The corresponding free base is prepared as follows: A suspension of 4.3 g of the above-mentioned hydroiodide

10 ml of 10% aqueous sodium hydroxide solution is added to 50 ml of methylene chloride. The organic phase is separated and after evaporation under reduced pressure the free base is obtained, which melts after recrystallization from a mixture of ethyl acetate-hexane at 80-81°.

The following salts are prepared as described:

El£oluensulfonate

A solution of 3 g of the free base in 30 ml of methyl-. encyclopedic acetone is added with stirring, with 1.8 g of p-toluenesulfonic acid. The product separates in the form of colorless crystals, which are recrystallized from a mixture of isopropanol-acetic acid ethyl ester. The N-(thiomorpholin-3-ylidene)-N'-phenyl-4-morpholinecarboximidamide-p-toluene-sulfonate is obtained, which melts at 172°.

Hydrochloride

A solution of 5 g of the free base in 40 ml of isopropanol is acidified with hydrochloric acid in isopropanol. The solvent is evaporated under reduced pressure, and the residue is recrystallized from a mixture of isopropanol-acetone. The N-(thiomorpholin-3-ylidene)-N<1->phenyl-4-morpholinecarboximidamide hydrochloride is obtained, which melts at 228°.

Sulfate

A solution of 3.1 g of the free base in 30 ml of methylene chloride-acetone is added while stirring with 2 g of sulfuric acid in methylene chloride. The product separates in the form of white crystals, which are recrystallized from a mixture of isopropanol-acetic acid ethyl ester. The N-(thio-morpholin-3-ylidene)-N1-phenyl-4-morpholinecarboximidamide sulfate is obtained, which melts at 220°.

Tartrate

A solution of 3.2 g of the free base in 40 ml of acetone is added with 2.1 g of a previously purified and dried d-tartaric acid in acetone. The separated product is washed several times with diethyl ether and acetone. The residue is recrystallized from acetone. The N-(thiomorpholin-3-ylidene)-N'-phenyl-4-morpholinecarboximidamide tartrate is obtained, which melts at 102°.

Methanesulfonate

A solution of 3.2 g of the free base in 30-40 ml of methylene chloride-acetone is added to 1.2 g of methanesulfonic acid in methylene chloride. The product separates in the form of white crystals, which are crystallized from a mixture of ethanol-acetone. The N-(thiomorpholin-3-ylidene)-N'-phenyl-4-morpholinecarboximidamide methanesulfonate is obtained, which melts at 182°.

Eczema Gel_21_

A suspension of 8.1 g of N,4-diphenyl-1-piperidine-carboximidamide hydroiodide in 35 ml of acetonitrile is added with 4 g of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine. The mixture is heated for 14 hours in the water bath and stirred vigorously. The acetonitrile is evaporated under reduced pressure and the residue crystallizes under the triturator with acetic acid ethyl ester. The product is crystallized from acetone-acetic acid ethyl ester. The N-(thiomorpholin-3-ylidene)-N<1>,4-diphenyl-1-piperidinecarboximidamide hydroiodide is obtained, which melts at 210°.

The starting material for the above-mentioned synthesis is prepared as follows: A suspension of 29 g of N-phenyl-S-methyl-isothiourea hydroiodide in 100 ml of acetonitrile is added with 20 g of 4-phenyl-piperidine. The mixture is boiled for 15 hours under reflux and the acetonitrile is evaporated under reduced pressure. The residue is recrystallized from a methylene chloride-acetone mixture. The N,4-diphenyl-1-piperidinecarboximidamide hydroiodide is obtained, which melts at 151°.

Example_el_22

A suspension of 6.5 g of N-phenyl-4-morpholinecarboximide-amide hydroiodide in 35 ml of acetonitrile is added with 4 g of 3-ethoxy-5,6-dihydro-2H-1,4-oxazine with stirring. The mixture is heated on the water bath for 12 hours with vigorous stirring. The acetonitrile is evaporated under reduced pressure, and the residue is recrystallized from a mixture of acetic acid ethyl ester-acetone. The N-(morpholin-3-ylidene)-N<1->phenyl-4-morpholine carboximidamide hydroiodide is obtained, which melts at 228°.

Example_23

A suspension of 9.8 g of N-phenyl-4-piperidinecarboximidamide hydroiodide in 40 ml of acetonitrile is added while stirring with 5.5 g of 3-ethoxy-5,6-dihydro-2H-1,4-oxazine. The mixture is heated with vigorous stirring for 12 hours

the water bath. The acetonitrile is evaporated under reduced pressure and the residue is recrystallized from a mixture of isopropanol-acetic acid ethyl ester. The N-(morpholin-3-ylidene)-N1-phenyl-4-piperidinecarboximidamide hydroiodide is obtained, which melts at 202°.

Example<el>_24

A suspension of 7.2 g of N-(4-methoxy-phenyl)-4-morpholinecarboximidamide hydroiodide in 35 ml of acetonitrile is added while stirring with 4 g of 3-ethoxy-5,6-dihydro-2H-1,4- thiazine with stirring. The mixture is heated for 12 hours on the water bath with vigorous stirring. The acetonitrile is evaporated under reduced pressure, and the residue is recrystallized from a mixture of isopropanol-acetic acid ethyl ester. The N-(thio-morpholin-3-ylidene)-N'-(4-methoxy-phenyl)-4-morpholinecarboximidamide hydroiodide is obtained, which melts at 172°.

Example_el_25

A suspension of 3.6 g of N-phenyl-4-(2,6-dimethyl-morpholine)-carboximidamide hydroiodide in 15 ml of acetonitrile is added while stirring with 1.8 g of 3-ethoxy-5,6-dihydro-2H- 1,4-oxazine. The mixture is boiled with stirring for 16 hours under reflux. The acetonitrile is evaporated under reduced pressure, and the residue is recrystallized from isopropanol-acetic acid ethyl ester. The N-(morpholin-3-ylidene)-N1-phenyl-2,6-dimethyl-4-morpholinecarboxymidamide hydroiodide is obtained, which melts at 230°.

Example_el_26

A suspension of 3.5 g of N-phenyl-4-(2,6-dimethyl-morpholine)-carboximidamide hydroiodide in 15 ml of acetonitrile is added while stirring with 2 g of 3-ethoxy-5,6-dihydro-2H-1, 4-thiazine. The mixture is boiled under reflux for 16 hours. The acetonitrile is evaporated under reduced pressure, and the residue is recrystallized from a mixture of acetone-acetic acid ethyl ester. The N-(thiomorpholin-3-ylidene)-N<1->phenyl-2,6-dimethyl-4-morpholinecarboximidamide hydroiodide is obtained, which melts at 246°.

Eczema|2el_27

A suspension of 6.2 g of N-phenyl-1-pyrrolidinecarboximidamide hydroiodide in 30 ml of acetonitrile is added with 3.8 g of 3-ethoxy-5,6-dihydro-2H-1,4-oxazine with stirring. The mixture is stirred vigorously on the water bath for 12 hours. The acetonitrile is evaporated under reduced pressure and the residue is recrystallized from a mixture of methylene chloride-ethyl acetate. The N-(morpholin-3-ylidene)-N<1->phenyl-1-pyrrolidinecarboximidamide hydroiodide is obtained, which melts at 226°.

Eczema gel_28

A suspension of 3.5 g of N-(4-fluorophenyl)-4-morpholine-carboximidamide hydroiodide in 15 ml of acetonitrile is added while stirring with 2 g of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine. The mixture is heated on the water bath for 12 hours with vigorous stirring. The acetonitrile is evaporated under reduced pressure,

and the residue is recrystallized from a mixture of acetone-acetic acid ethyl ester. The N-(thiomorpholin-3-ylidene)-N'-(4-fluorophenyl)-4-morpholinecarboximidamide hydroiodide is obtained, which melts at 212°.

Example_el_29

A suspension of 3.6 g of N-(4-fluorophenyl)-4-morpholine-carboximidamide hydroiodide in 15 ml of acetonitrile is added with stirring with 2 g of 3-ethoxy-5,6-dihydro-2H-1,4-oxazine; The mixture is heated on the water bath for 12 hours with vigorous stirring. The acetonitrile is evaporated under reduced pressure,

and the residue is recrystallized from a mixture of isopropanol-acetic acid ethyl ester. N-(morpholin-3-ylidene)-N<1-> is obtained

The (4-fluorophenyl)-4-morpholinecarboximidamide hydroiodide, which melts at 215°.

Eczema gel_30

A suspension of 8 g of N-(4-methyl-morpholin-3-ylidene)-N-phenyl-S-methyl-isothiourea hydroiodide in 15 ml of acetonitrile is added while stirring with 2.5 g of morpholine. The mixture is boiled in an oil bath for 36 hours under reflux. The acetonitrile is evaporated under reduced pressure, and the residue is recrystallized from a mixture of isopropanol-acetic acid ethyl ester. The N1 -(4-methyl-morpholin-3-ylidene)-N-phenyl-4-morpholine-carboximidamide hydroiodide is obtained, which melts after recrystallization from a mixture of acetone-acetic acid ethyl ester at 165°.

The starting material for the above-mentioned synthesis is prepared as follows: A solution of 23 g of 4-methyl-morpholin-3-one in 100 ml of anhydrous methylene chloride is added while cooling and stirring with 80 g of triethyloxonium fluoroborate in 100 ml of methylene chloride. The reaction mixture is stirred for 18 hours in a nitrogen atmosphere. Ammonia is then introduced into the mixture for 3 hours. The reaction mixture is allowed to stand for 30 hours at room temperature, and the solvent is evaporated under reduced pressure in a water bath at 40°. The crude 4-methyl-3-imino-morpholine is dissolved in 100 ml of acetonitrile and added with stirring at room temperature with 24 g of phenylisothiocyanate in 60 ml of acetonitrile. The mixture is stirred for 14 hours and concentrated, whereby a crystalline product separates. This is recrystallized from a mixture of isopropanol-acetic acid ethyl ester. N1 -(4-methyl-morpholin-3-ylidene)-N-phenyl-thiourea is obtained, which melts at 121-122°.

A solution of 15 g of N1 -(4-methyl-morpholin-3-ylidene)-N-phenylthiourea in 50 ml of dioxane is added dropwise while stirring with 10 g of methyl iodide in .30 ml of dioxane. The mixture is heated on the water bath for 3 hours. The dioxane is recovered under reduced pressure, and the residue is recrystallized from a mixture of acetone-acetic acid ethyl ester. The N'-(4-methyl-morpholin-3-ylidene)-N-phenyl-S-methyl-isothiourea hydroiodide is obtained, which melts at 155°.

Eczema gel_31

A suspension of 3.8 g of N-(p-toluene)-4-morpholine-carboximidamide hydro iodide in 15 ml of acetonitrile is added while stirring with 1.8 g of 3-ethoxy-5,6-dihydro-2H-1,4 -oxazine. The mixture is stirred vigorously on the water bath for 12 hours. The acetonitrile is evaporated under reduced pressure, and the residue is recrystallized from a mixture of acetic acid ethyl ester-acetone. The N-(morpholin-3-ylidene)-N1-(p-toluene)-4-morpholine carboximidamide hydroiodide is obtained, which melts at 192°.

Example_32

A suspension of 4 g of N-(p-toluene)-4-morpholinecarboximidamide hydro iodide in 20 ml of acetonitrile is added with 2 g of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine with stirring. The mixture is stirred vigorously on the water bath for 12 hours. The acetonitrile is evaporated under reduced pressure, and the residue is recrystallized from a mixture of isopropanol-acetic acid ethyl ester. The N-(thiomorpholin-3-ylidene)-N'-(p-toluene)-4-morpholinecarboximidamide hydroiodide is obtained, which melts at 225°.

Example_el_33

A suspension of 3.1 g of N-phenyl-1-pyrrolidinecarboximidamide hydroiodide in 7 ml of acetonitrile is added with 5 g of 4-carbethoxy-2-ethoxy-3,4,5,6-tetrahydropyrazine. The mixture is boiled for 12 hours under reflux, then diluted with acetic acid ethyl ester, and the precipitate obtained is filtered off. This is treated with potassium carbonate solution, washed with water and dried. When the product obtained is treated with hydrochloric acid in isopropanol, the N-(4-carbethoxy-piperazin-2-ylidene)-N'-phenyl-1-pyrrolidine carboximide-amide hydrochloride is obtained, which melts after recrystallization from acetonitrile-acetic acid ethyl ester at 246- 247°.

The starting material is produced as follows:

A cooled solution of 43 g of 4-carbethoxy-2-piperazinone

in 400 ml of methylene chloride is added with 120 g of triethyloxonium

fluoroborate in 150 ml methylene chloride. The reaction mixture is stirred under a nitrogen atmosphere for 16 hours and then made weakly basic (pH 7.5) with aqueous saturated potassium carbonate solution. The organic layer is separated and dried over anhydrous potassium carbonate. The solvent is evaporated and the residue distilled at 115°/0.1 mm Hg. 4-Carbethoxy-2-ethoxy-3,4,5,6-tetrahydropyrazine is obtained.

A mixture of 2 g of N-phenyl-1-(4-carbethoxy-piperazine)-carboximidamide hydroiodide in acetonitrile and 2.5 g of 3-methoxy-5,6-dihydro-2H-1,4-thiazine is heated for 1 hour more 70°. The reaction mixture is allowed to stand for 7 days at room temperature and is then diluted with diethyl ether. The precipitate obtained is recrystallized from a mixture of isopropanol-acetic acid ethyl ester. The N-(thiomorpholin-3-ylidene)-N<1->phenyl-4-carbethoxy-1-piperazine-carboxymidamide hydroiodide is obtained, which melts at 206°.

The starting material is produced as follows:

A suspension of 8.7 g of N-phenyl-5-methyl-isothiourea hydroiodide in 30 ml of isopropanol is added with 9.6 g of 1-carbethoxy-piperazine. The mixture is boiled with stirring for 18 hours under reflux and then evaporated under reduced pressure. The N-phenyl-4-carbethoxy-1-piperazine-carboximidamide hydroiodide is obtained, which melts after recrystallization from isopropanol-acetic acid ethyl ester at 218-219°.

Example_el_35

A mixture of 4 g of N-(p-toluene)-4-carbethoxy-1-piperazine carboximidamide hydroiodide in acetonitrile and 8 g of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine is heated for 1 hour at 80° . The obtained solution is stored for 15 days at room temperature. The solid material thus obtained is filtered off and washed with acetic acid ethyl ester. The N-(thiomorpholin-3-ylidene)-N'-(p-toluene)-4-carbethoxy-1-piperazinecarboximidamide hydroiodide is obtained, which melts after recrystallization from acetonitrile-acetone at 228-229°.

The starting material is produced as follows:

A mixture of 17.8 g of N-(p-toluene)-S-methyl-isothiourea hydroiodide and 18.9 g of 1-carbethoxy-piperazine in 50 ml of isopropanol is boiled with stirring for 18 hours under reflux. The solvent is then evaporated under reduced pressure and the residue triturated with ethyl acetate. The N-(p-toluene)-4-carbethoxy-1-piperazinecarboximide-amide hydroiodide is obtained, which melts after recrystallization from isopropanol-acetic acid ethyl ester at 201-202°.

Example_36

A mixture of 2.2 g of N-(p-methoxyphenyl)-4-carbethoxy-1-piperazinecarboximidamide hydroiodide and 1.5 g of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine in 5 ml of acetonitrile boiled for 10 hours under reflux. The clear solution is cooled and diluted with ethyl acetate. A precipitate is obtained which is filtered off and recrystallized from acetonitrile. The N-(thiomorpholin-3-ylidene)-N'-(p-methoxyphenyl)-4-carbethoxy-1-piperazinecarboximidamide hydroiodide is obtained, which melts at 203-204°.

The starting material is produced as follows:

A mixture of 10 g of p-anisidine hydrochloride and 12.25 g of potassium thiocyanate is heated for 16 hours in 100 ml of ethanol. The reaction mixture is cooled and filtered. The residue is washed with water and recrystallized from methanol. A solid material is obtained, which melts at 226° and consists of p-methoxy-phenylthiourea. 5.3 g of the latter compound are heated with 10 ml of methyl iodide in 20 ml of acetone for 8 hours at 50°. The reaction mixture is cooled, the precipitate obtained is filtered off and washed with acetone. S-methyl-p-methoxyphenyl isothiourea hydroiodide is obtained, which melts at 165-166°.

A mixture of 6.4 g of S-methyl-N-p-methoxyphenyl-iso-thiourea f-hydro iodide and 6.2 g of 1-carbethoxy-piperazine in 50 ml of acetonitrile is boiled for 10 hours under reflux. The solvent is evaporated under reduced pressure and

the residue obtained is triturated with acetic acid ethyl ester.

S-methyl-p-methoxyphenyl isothiourea hydroiodide is obtained, which melts at 165-166°.

A mixture of 6.4 g of S-methyl-N-p-methoxyphenyl-isothiourea f-hydro iodide and 6.2 g of 1-carbethoxy-piperazine in 50 ml of acetonitrile is boiled for 10 hours under reflux. The solvent is evaporated under reduced pressure and the residue obtained is triturated with acetic acid ethyl ester. The N-(p-methoxyphenyl)-4-carbethoxy-1-piperazine carboximidamide hydroiodide is obtained, which after recrystallization from acetonitrile melts at 156-157°.

Eczema gel_37

A suspension of 7.4 g of N-(p-chlorophenyl)-4-morpholine-carboxymidamide hydro iodide in 50 ml of acetonitrile is added with 4 g of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine. The mixture is boiled with stirring for 14 hours under reflux. The acetonitrile is evaporated under reduced pressure, and the residue is recrystallized from a mixture of isopropanol-acetic acid ethyl ester. The N-(thiomorpholin-3-ylidene)-N<1->(p-chlorophenyl)-4-morpholinecarboxymidamide hydroiodide is obtained.

The starting material is produced as follows:

A suspension of 32 g of N-(p-chlorophenyl)-S-methyl-isothiourea f-hydroiodide in 100 ml of acetonitrile is added with 12 g of morpholine. The mixture is boiled with stirring for 15 hours under reflux. The acetonitrile is evaporated under reduced pressure, and the residue is recrystallized from a mixture of methylene chloride-ethyl acetate. The N-(p-chlorophenyl)-4-morpholine carboximidamide hydroiodide is obtained, which melts at 185-187°.

Example_el_38

A suspension of 7 g of N-(p-chlorophenyl)-1-pyrrolidine-carboximidamide hydroiodide in 40 ml of acetonitrile is added with stirring with 4 g of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine. The mixture is stirred vigorously in a water bath for 12 hours. The acetonitrile is evaporated under reduced pressure, and the residue is recrystallized from a mixture of methylene chloride-acetic acid ethyl ester. The N-(thiomorpholin-3-ylidene)-N 1 -(p-chloro-phenyl)-1-pyrrolidine carboximidamide hydroiodide is obtained, which melts at 198°.

The starting material is prepared as follows: A suspension of 16 g of N-(4-chlorophenyl)-S-methyl-isothiourea hydroiodide in 50 ml of acetonitrile is added with 5 g of pyrrolidine. The mixture is boiled with stirring for 15 hours under reflux. The acetonitrile is evaporated under reduced pressure, and the residue is recrystallized from a mixture of ethyl acetate-isopropanol. The N-(4-chlorophenyl)-1-pyrrolidinecarboximidamide hydroiodide is obtained, which melts at 195-196°.

Eczema gel_39

A mixture of 1.9 g of N-phenyl-1-pyrrolidinecarboximidamide and 1.4 g of 3-chloropropyl isothiocyanate in 25 ml of anhydrous dioxane is heated for 3 hours at 80°. The solvent is evaporated under reduced pressure, the residue is washed with diethyl ether and recrystallized from acetone-methanol. The N-(thiomorpholin-3-ylidene)-N'-phenyl-1-pyrrolidine carboximide amide hydrochloride is obtained, which melts at 260-262°.

Eksemgel_4 0

A mixture of 5.5 g of N-phenyl-4-mbrfolinecarboximide-amide-hydro iodide and 3.8 g of 5-ethoxy-2,3,6,7-tetrahydro-1H-T,4-thiazepine in 20 ml of acetonitrile is heated with stirring for 6 hours at 80-90°. The solution is concentrated under reduced pressure, the solid material obtained is filtered off and recrystallized from acetonitrile. N-(hexa-hydro-5H-1,4-thiazepin-5-ylidene)-N'-phenyl-4-morpholinecarboximidamide hydro iodide is obtained, which melts during decomposition at 225°.

Example_41

A mixture of 3.6 g of N<1->phenyl-1-(4-morpholinyl)-S-methyl-isothiourea hydroiodide and 2 g of 2-amino-2-thiazoline in 30 ml of acetonitrile is boiled for 8 hours under reflux. The solvent is evaporated under reduced pressure, the residue is made basic with alkali and extracted with methylene chloride. The crude base is chromatographed on silica gel in acetic acid ethyl ester and the column is eluted with acetic acid ethyl ester containing increasing amounts of methanol. The later fractions give an oily base which is treated with hydrogen chloride in isopropanol. The 1-(4-morpholinyl)-N1-phenyl-N-(2-thiazolinyl)-formamidine hydrochloride is obtained, which melts after recrystallization from a mixture of methanol and diethyl ether at 225-227°.

Claims (6)

1. Process for the preparation of guanidine derivatives with formula in which R^ is an optionally substituted aliphatic or cycloaliphatic hydrocarbon residue, R2 is hydrogen, an optionally substituted aliphatic or cycloaliphatic hydrocarbon residue or R^ and R2 together mean an optionally substituted bivalent hydrocarbon residue of an aliphatic character, in which the carbon atoms in the chain may be interrupted by a heteroatom, R^ means hydrogen, lower alkyl, R^ means hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, dilower alkylamino, halogen, trifluoromethyl or optionally substituted phenyl or to a carbon atom singly bonded on both sides, also oxo, R,- means hydrogen or lower alkyl, Het means a heteroalkylene residue with 3 chain members which completes the group C-N to an optionally unsaturated, heterocyclic five-ring with 2 to 3 heteroatoms from the group oxygen, sulfur or nitrogen in the ring, resp. Het means a heteroalkylene residue with 4 to 6 chain links which completes the group C-N to a heterocyclic six- to eight-membered ring which, in addition to the nitrogen atom, further contains a heteroatom from the group oxygen, sulfur or nitrogen in the ring, and Ph means an optionally substituted phenyl residue, their tautomeric compounds and salts , characterized by a) reacting a compound with formula in which X^ means the group Ph-N=, in which Ph means an optionally substituted phenyl residue or a leaving group, X2 means the group in which R. and R.sub.2 have the meaning given under formula I or a leaving group, and X.sub.2 means the group in which R^ , R^ , R5 and Het as a divalent heteroalkylene residue with the group C-N have the meanings given under formula I or mean a leaving group, with the proviso that only one of the substituents X^ , X2 or X^ can be a leaving group and in which one of the groups X^ , X2 and X^ is connected by a double bond with. carbon atoms, with an amine or imine, which is identical to the missing amino or imino group defined under X^ , X2 or X^ , to replace the leaving group, or.b) reacts a guanidine compound of the general formula IV wherein Ph, R and R2 have the meanings given under formula I, with a compound of the general formula V in which Y means lower alkoxy, lower alkylthio, halogen, or Y means two lower alkoxy groups which are bound to the same C atom, and Z means a tetrafluoroborate-, a fluorosulfonate-, a lower alkylsulfate-, which e.g. methyl sulfate- or lower-alkanesulfonate-, such as e.g. methanesulfonate anion or a halide, such as chloride or bromide, whereby when Y has the meaning of two lower alkoxy groups bound to the same C atom, Z is omitted as an anion, or, when it means hydrohene, the tautomeric form is present as a free base, orc) reacts guanidine derivatives with the general formula VI or a tautomeric form thereof, in which Ph, R^ , R 2 and R^ have the above-mentioned meanings and Y^ has the meaning of an oxo-, thioxo- or NH group, with a compound of the general formula VII wherein n^ or n2 means 0, 1, 2 or 3, with the proviso that n 1 and n2 together do not mean more than 3, Z^ means a halogen atom, Z2 means an oxo group or together means the group consisting of hydrogen and halogen, whereby the hydrogen atom can be part of a methylene group, or Z^ and Z2 together complement over an imino group the bivalent alkyl rest to an aziridine derivative, whereby R. and. R- has the meaning of hydrogen, d) for the preparation of compounds of formula I, in which Het is a heteroalkylene residue with 4-6 chain links which complements the group C-N to a heterocyclic six-octet, react compounds of formula IV wherein , R 1 and Ph have the meanings given above, with a haloalkylene isothiocyanate of formula VIII in which Z^ means a halogen atom and the bivalent residue "alkylene" means an alkylene chain with 3-5 carbon atoms, whereby a hydrogen atom in the alkylene chain can be replaced by the substituent R^' which has the meaning of R^ with the exception of hydrogen, or e) converts compounds of formula I, in which R^ has the meaning defined above and R_ and/or R^ means hydrogen, by reaction with a reactive ester of an aliphatic or cycloaliphatic alcohol into compounds of formula I, in which R2 and/ or R^ in the framework of the above definitions for R^ and R^ is different from hydrogen, or f) in compounds of the general formula IX in which R.j , R^ , Rj-, Ph and Het have the meaning given under formula I and one of the substituents R 2 ' and R^ ' has the meaning of R 2 or R^ and the other means an amino protecting group, or R 2 ' and R^ ' both mean an amino protecting group, carry out these and, if desired, further process steps, and/or if desired, transfer obtained compounds of formula I in a salt, and/or, if desired, convert obtained salts into . compounds of formula I in the free bases. 2. Method according to claim 1, characterized in that a compound of formula Ila is reacted wherein X^ means a leaving group, with an amine of formula HNR1 R2 . 3. Method according to claim 1, characterized in that one converts a compound of formula IIb wherein X^ means a leaving group, with an imino compound of formula III 4. Method according to claim 1, characterized in that one reacts a compound with formula Ile in which X. means a leaving group, with an optionally substituted aniline of formula Ph-NF^ • 5. Method according to claims 1-4, characterized in that a cleavable residue in the compounds with the formulas II, Ila, Ilb and Ile means a lower alkylthio-, lower alkoxy- or a halogen. 6. Process according to claims 1-5, characterized in that a cleavable residue in the compounds with the formulas II, Ila, Ilb means a methylthio, methoxy or a chlorine or bromine atom.