DD151167A5 - PROCESS FOR THE PREPARATION OF GUANIDINE DERIVATIVES - Google Patents

Abstract

The invention relates to novel guanidine derivatives, in particular substituted guanidines of the formula I with hypoglycaemic activities for the oral treatment of hyperglycemia in mammals, in particular diabetes mellitus.

Description

2 2 1 3 9 5 - ^{/ |} -

Berlin, 10.9.1980 AP C 07 D / 221 395 57 464/12

Process for the preparation of guanidine derivatives Field of application of the invention

The invention relates to a process for the preparation of novel guanidine derivatives.

The compounds prepared according to the invention are used for the preparation of pharmaceutical preparations containing these novel compounds. They serve as medicines, in particular for the treatment of diabetes

Characteristic of the known technical solutions

There is no information on which compounds have been used to treat diabetes mellitus.

There are also no data on methods for the production of guanidines known.

Object of the invention

The aim of the invention is to provide a simple and economical process for the preparation of guanidine derivatives with valuable pharmacological, in particular hypoglycanic activity «

29 ι Q 9 p

-1- 10.9.1980

AP C 07 D / 221 395 57 464/12

Explanation of the essence of the invention

The invention has for its object to find new guanidine derivatives with the desired properties and methods for their preparation.

According to the invention, novel guanidine derivatives, in particular heterocyclic substituted guanidines of the formula

, Ph - N = C - K = C Het J (I)

N \J ** (I)

^R 1 ^R 2 R

manufactured,

wherein R- is an optionally substituted aliphatic or cycloaliphatic hydrocarbon radical, Rp is hydrogen, an optionally substituted aliphatic or cycloaliphatic hydrocarbon radical or R ₁ and Rp taken together represent an optionally substituted bivalent hydrocarbon radical of aliphatic character in which the carbon atoms of the chain may be interrupted by a heteroatom, R ^ Hydrogen, lower alkyl, R. hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, di-lower alkylamino, halogen, trifluoromethyl or optionally substituted phenyl, or at one carbon atom easily bonded on both sides also oxo, R ₁ - hydrogen or lower alkyl, Het a heteroalkylene radical. 3 chain members of the group CN to an optionally unsaturated heterocyclic five-membered ring with 2 to 3 heteroatoms from the group oxygen, sulfur

2 2 13 9 5

or nitrogen in the ring, or Het a heteroalkylene radical with 4-6 chain members, the group CN to a heterocyclic six- to Achtring, which contains in addition to the nitrogen atom or a heteroatom selected from the group oxygen, sulfur or nitrogen in the ring, and Ph represents an optionally substituted phenyl radical, their tautomeric compounds and salts.

In the context of the present specification, the radicals and compounds designated "lower" preferably contain up to 7, primarily up to 4, carbon atoms.

An aliphatic hydrocarbon radical R.sup.1 or R.sup.1 which may optionally be substituted is primarily an alkyl and an alkenyl or alkynyl radical, in particular a lower alkyl and lower alkenyl or lower alkynyl radical. Substituents of aliphatic hydrocarbon radicals are e.g. free, esterified or etherified hydroxy groups, such as lower alkanoyloxy, lower alkoxy or lower alkenyloxy groups, or halogen atoms, and optionally esterified carboxy groups, such as lower alkoxycarbonyl.

As above, the general terms may have the following meaning:

Lower alkyl groups are e.g. preferably methyl and ethyl, n-propyl, isopropyl, η-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 group, and lower alkynyl groups preferably propargyl groups. ' Substituted. Lower alkyl groups are, for example, the trifluoromethyl group or an optionally esterified carboxymethyl group, such as. a lower alkoxycarbonylmethyl-, ζ.3. methoxycarbonylmethyl,

22 1395

Lower alkoxy is e.g. Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or n-pentyloxy, and lower alkenyloxy e.g. Vinyloxy or allyloxy. ,

Nicodalkanoyloxy is e.g. Acetoxy or propionyloxy.

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

A cycloaliphatic hydrocarbon radical is primarily a mono- as well as polycyclic cycloalkyl radical 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 radical may be substituted by one, two or three identical or different substituents. Such substituents are e.g. Hydrocarbon radicals, such as lower aliphatic hydrocarbon radicals, e.g. Lower alkyl, substituted lower alkyl, e.g. Trifluoromethyl, optionally functionally modified hydroxy or mercapto, such as etherified hydroxy, e.g. Lower alkoxy, lower alkenyloxy or lower alkylenedioxy, further lower alkylthio, or halo, nitro, amino including substituted amino, e.g. Lower alkylamino or di-lower alkylamino, optionally functional, modified carboxy, such as esterified carboxy, e.g. Lower alkoxycarbonyl.

Niederalkylthio is't in particular methylthio, and also ethylthio, isopropylthio, n-propylthio or straight or branched butylthio. Lower alkylamino or di-lower alkylamino is e.g. Methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di-n-propylamino, isopropylamino, diisopropylamino or n-butylamino or di-n-butylamino.

2 2 13 9 5 - 4 -

The two substituents R ₁ and R taken together may represent an optionally substituted bivalent aliphatic hydrocarbon radical having 4-7 carbon atoms in the chain. The group -NR.R_ is, for example, a straight, branched or phenyl-substituted lower alkylene amino in which the lower alkylene chain is substituted, for example, by a heteroatom such as oxygen, sulfur or optionally lower alkyl, phenyl or lower alkoxycarbonyl. Nitrogen f can be interrupted, and represents, for example, as Niederalkylenamino pyrrolidino, 2,5-dimethyl pyrrolidino, piperidino, 2-methylpiperidino, 4-phenylpiperidino, hexahydroazepino or octahydroazocino, as Oxaniederalkylenamino example, morpholino, 2,6-Dimethylmorpholino as Thianiederalkylenamino example Thiomorpholine or as Azaniederalkylenamino example, piperazino, N-methyl, N-phenyl or N-Niederalkoxycarbonylpiperazino.

The heteroalkylene radical Het with 3 chain members which together form the group CN to form an optionally unsaturated heterocyclic five-membered ring containing 2 to 3 heteroatoms from the group oxygen, sulfur or nitrogen in the ring together forms, for example, an imidazoline, imidazolidine, oxazoline, Oxazolidine, thiazoline, thiazolidine, isoxazoline, isoxazolidine, isothiazoline, isothiazolidine, 1,2,4-oxadiazoline, 1,2,4-oxadiazolidine, 1,3,4-oxadiazoline, 1, 3,4-oxadiazolidine, 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 1,2,4-triazole.

Particular mention may be made of 4-imidazoline, imidazolidine, 4-oxazoline, oxazolidine, 4-thiazoline, thiazolidine, 4- (l, 3,4) -thiadiazolinone, 4- (l, 3,4 ) -Oxadiazoline, isoxazoline or isoxazolidine ring.

The heteroalkylene radical Het with 4-6 chain members, which adds the group CN to a heterocyclic six- to eight-membered ring which, in addition to the nitrogen atom, also contains a heteroatom from the group oxygen, sulfur or nitrogen in the ring, forms, for example, a morpholine, thiomorpholine , 2H-3,4,5,6-tetrahydro-l, 3

22 1395

thiazine, 2H-3,4,5,6-TetΓahydropyrimidin-, piperazine, hexahydro-1,3-thiazepine, hexahydro-l.A-thiazepine, hexahydro-l ^ -thiazocin- or hexahydro-l.A-thiazocinring. The two latter ring systems may be bonded in the 2- or 4- or 3- or 5-position.

Particularly noteworthy are the morpholine, thiomorpholine, piperazine, 2H-3,4,5,6-tetrahydro-l, 3-thiazine or hexahydro-1,4-thiazepinring.

The novel compounds of the general formula I and their addition salts with inorganic or organic acids have valuable pharmacological properties, in particular hypoglycanic activity, such as in metabolism-normal rats after oral administration of doses from 3 mg / kg as well as on rats, by injection of Streptozotocin were placed in a diabetes-like metabolic state [vgl. A. Junod et al., Proc. Soc. Exp. Biol. Med. 126 , 201-205 (1967) 3, can be detected. The lowering of the blood sugar level is not accompanied by hyperlactatemia. The pharmacological findings characterize the novel compounds of general formula I and their pharmaceutically acceptable acid addition salts as antidiabetic agents which can be used for the oral treatment of hyperglycemia in mammals, in particular diabetes mellitus.

Particularly noteworthy are compounds of the formula I.

Het

Ph - N = C - N = C

wherein R 1 is an optionally substituted aliphatic or cycloaliphatic hydrocarbon radical, R "is hydrogen or an optionally substituted aliphatic hydrocarbon radical or R and R taken together represent an optionally substituted bivalent hydrocarbon radical of aliphatic character in which the carbon atoms of the" chain are interrupted by a heteroatom

2 2 13 9 5 - 6 -

R, hydrogen, lower alkyl, R can be hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, di-lower alkylamino, halogen, trifluoromethyl or optionally substituted phenyl, or on a carbon atom which is simply bonded on both sides also oxo, R ,. Is hydrogen or lower alkyl, Het a heteroalkylene radical with 3 chain members, the group CN to form an optionally unsaturated heterocyclic five-membered ring with 2 to 3 heteroatoms from the group oxygen, sulfur or nitrogen in the ring, and Ph represents an optionally substituted phenyl, their tautomeric compounds and salts ,

The invention relates in the first place to compounds of the formula I in which R, lower alkyl or cycloalkyl, R 1 is hydrogen or lower alkyl or both taken together, a lower alkylene chain which may be interrupted by an oxygen, sulfur or optionally substituted by, for example, lower alkyl or phenyl nitrogen atom R5 may be hydrogen, lower alkyl, lower alkylthio, lower alkylamino, di-lower alkylamino, halogeno, trifluoromethyl, or oxo mono or monosubstituted carbon; or oxo; or phenyl optionally substituted by lower alkyl, lower alkoxy or halogen; ₁ . Hydrogen or lower alkyl, and Het a heteroalkylene radical with 3 chain members, which adds the group CN to a saturated or monounsaturated heterocyclic five-membered ring with 2-3 heteroatoms from the group oxygen, sulfur or nitrogen in the ring, and Ph is an optionally substituted. Phenyl, as well as their tautomeric compounds and salts.

In particular, the invention relates to those compounds of the formula I in which R, lower alkyl or cycloalkyl, R _{2 is} hydrogen or lower alkyl or both taken together, a lower alkylene optionally interrupted by an oxygen or sulfur atom or, optionally substituted by, for example, lower alkyl or phenyl substituted nitrogen atom For example, lower alkyleneamino, for example pyrrolidino, 2,5-dimethylpyrrolidino, piperidino, 2-methylpiperidino, hexahydroazepino

22 1395

or Octahydroazoci.no, Oxaniederalkylenamino, e.g. Morpholino, thian-lower alkylene amino, e.g. Thiomorpholino or azan-lower alkylene amino, e.g. Piperazino, N-methyl or N-phenylpiperazino, R'o is hydrogen or lower alkyl, R, hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, di-lower alkylamino, halogen, trifluoromethyl, or oxo either at one end simply bound carbon also oxo, or optionally phenyl substituted by lower alkyl, lower alkoxy or halogen, R-hydrogen or lower alkyl, and Het is a bivalent heteroalkylene radical having 3-chain members, the group CN to a saturated or monounsaturated and, for example, an imidazoline, 'imidazolidine, oxazoline', 'oxazolidine May be, thiazoline, thiazolidine, isoxazoline, isoxazolidine, isothiazoline, isothiazolidine, oxadiazoline, oxadiazolidine, thiadiazoline, thiadiazolidine, pyrazoline, pyrazolidine or triazoline ring and Ph is optionally substituted by lower alkyl, Lower alkoxy or halogen substituted phenyl radical, as well as their tautomeric compounds and salts.

Of particular interest are compounds of formula T in which R is lower alkyl, or cycloalkyl, R is hydrogen or lower alkyl, or the group -NR.R_ is, for example, lower alkylene-amino in which the lower alkylene chain may optionally be interrupted by an oxygen or sulfur atom and, for example, pyrrolidino , 2,5-dimethylpyrrolidino, piperidino, 2-methylpiperidino or else morpholino or thiomorpholino, R, hydrogen or lower alkyl, R 1 'hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, trifluoromethyl or oxo also bonded to a carbon atom bonded on both sides, or optionally substituted by lower alkyl, lower alkoxy, or halogen-substituted phenyl, R_ is hydrogen or lower alkyl, and Het as a bivalent radical with the group CN together represents an optionally monounsaturated heterocyclic five-membered ring, such as Imidazoline, imidazolidine, oxazoline, oxazolidine, thiazoline, thiazolidine, oxadiazoline, oxadiazolidine, triazoline, thiadiazoline or thiadiazolidine ring, and Ph represents an optionally substituted by lower alkyl, 'lower alkoxy or halogen-substituted phenyl radical, as well their tautomeric compounds and salts.

22 13 95 -8-

Of very particular interest are compounds of the formula I in which R is lower alkyl, for example methyl or ethyl, R _{2 is} hydrogen or lower alkyl, for example methyl or ethyl or the group -NR ₁ R ₂ as optionally interrupted by an oxygen or sulfur atom lower alkylene, for example as pyrrolidino, piperidino _j morpholino or thiomorpholines, R is hydrogen or lower alkyl, for example methyl or ethyl, R ^, hydrogen, lower alkyl, for example methyl or ethyl, lower alkoxy, for example methoxy or ethoxy, lower alkylthio, for example methylthio or ethylthio, halogen, for example Chlorine or bromine, trifluoromethyl or optionally substituted by lower alkyl, for example methyl or ethyl, halogen, for example chlorine or bromine substituted phenyl, R, hydrogen or lower alkyl, for example methyl or ethyl and Het as a bivalent heteroalkylene radical with the group CN is an optionally monounsaturated heterocyclic five-membered ring, such as the 4-imidazoline, 4-oxazoline, 4-thiazoline, 4- (l, 3,4) thiadiazoline, 4- (l , 3,4) -oxadiazoline or Isoxazolidinring means, and Ph is optionally substituted by lower alkyl, such as methyl or ethyl, halogen, such as chlorine or bromine or lower alkoxy, such as methoxy or ethoxy, substituted phenyl, as well as their tautomers Compounds and salts.

Also to be emphasized are compounds of formula Ib

Ph-N-C-N-C Het

, V J (Ib),

in which R.sup.1 and R.sup.2 denote an optionally substituted aliphatic or cycloaliphatic hydrocarbon radical or R.sup.1 and R.sup.4 taken together represent an optionally substituted bivalent hydrocarbon radical of aliphatic character in which the carbon atoms of the chain may be interrupted by a heteroatom, R.sup.1 is hydrogen, lower alkyl, R, Hydrogen, lower alkyl, lower alkoxy, lower alkylamino, di-lower alkylamino, halogen, lower alkoxy

22 1395 -9-

carbonyl or unsubstituted or substituted phenyl, or oxo also bonded to a carbon atom bonded on both sides, or heteroalkylene radical having 4-6 chain members which forms the group CN to form a heterocyclic six- to eight-membered ring which, in addition to the nitrogen atom, is also a heteroatom selected from the group consisting of oxygen, Contains sulfur or nitrogen in the ring, and Ph represents an optionally substituted phenyl radical, their tautomeric compounds and salts.

The invention relates in the first place to compounds of the formula Ib in which R.sup.1 and R.sup.6 lower alkyl or cycloalkyl, or both taken together, are a straight, branched or substituted lower alkylene chain which may be replaced by an oxygen, sulfur or optionally by e.g. Lower alkyl, phenyl or lower alkoxycarbonyL.substituted nitrogen atom may be interrupted, R is hydrogen or lower alkyl, R ^, hydrogen, lower alkyl, lower alkoxy, lower alkylamino, di-lower alkylamino, halogeno, lower alkoxycarbony1, or oxo also attached to a carbon atom which is simply bonded on both sides, or optionally lower alkyl, Lower alkyl or halogen substituted phenyl, and Het a heteroalkylene radical with 4-6 chain members, the group CN to a heterocyclic six- to Achtring, which in addition to the nitrogen atom still contains a heteroatom selected from the group oxygen, sulfur or nitrogen in the ring, and Ph represents an optionally substituted phenyl radical, as well as their tautomeric compounds and salts.

In particular, the invention relates to those compounds of the formula Ib in which R ₁ and R are lower alkyl or cycloalkyl, or both taken together, a straight, branched or substituted lower alkylene chain optionally substituted by an oxygen or

2 2 13 3 5 - ίο -

Sulfur atom or optionally by e.g. Lower alkylene, for example, pyrrolidino, 2,5-dimethylpyrrolidino, piperidino, 2-methylpiperidino, 4-Phenylpiperidino, Hexahydroazepino or Octahydroazocino, as Oxaniederalkylenamino example, morpholino, 2,6-Dimethylmorpholino, as Thianiederalkylenamino example Thiomorpholino or as Azaniederalkylenamino example, piperazino, N-lower alkoxycarbonyl, N-methyl or N-phenylpiperazino, R. hydrogen or lower alkyl, R, hydrogen, lower alkyl, lower alkoxy, lower alkylamino, di-lower alkylamino, halogen, lower alkoxycarbonyl, or optionally by lower alkyl, lower alkoxy or Halogen-substituted phenyl, and Het is a divalent heteroalkylene radical having 4-5 chain members, which is the group CN to a heterocyclic six- to seven-membered ring, in addition to the nitrogen atom or a heteroatom from the group oxygen, sulfur or nitrogen, iia ring contains, and Ph represents an optionally substituted by lower alkyl, lower alkoxy or halogen substituted phenyl, as well as their tautomeric compounds and salts. , ·. , ·

Of particular interest are compounds of the formula Ib in which R ₁ and R 6-lower alkyl or the group -NR.R- together form a lower alkylene-amino in which the straight, branched or phenyl-substituted lower alkylene chain is optionally substituted by an oxygen, sulfur or optionally substituted by, for example, lower alkyl, phenyl or lower alkoxycarbonyl-substituted nitrogen atom, and for example as Niederalkylenamino pyrrolidino, 2,5-dimethyl pyrrolidino, piperidino, 2-methylpiperidino, 4-phenylpiperidino, hexahydroazepino or octahydroazocino, as Oxaniederalkylenamino example, morpholino, 2, 6-dimethylmorpholino, for example thiomorpholino as thianethoxyalkylene or, for example, as piperazino, N-ethoxycarbonyl, N-methyl-, N-phenylpiperazino as azanoweralkyleneamino, R. hydrogen or lower

2 2 1 3 9 p

- ι τ -

alkyl, R, hydrogen, lower alkyl, lower alkoxy, lower alkylamino, halogen, lower alkoxycarbonyl, or optionally substituted by lower alkyl, lower alkoxy or halogen substituted phenyl and Het a divalent heteroalkylene radical having 4-5 chain members, the group CN to a heterocyclic six to seven ring, the in addition to the nitrogen atom also contains a heteroatom from the group oxygen, sulfur or nitrogen in the ring, supplemented, and for example, a morpholine, thiomorpholine, 2H-3,4,5,6-tetrahydro-l, 3-thiazine, 2H- May be 3,4,5,6-tetrahydropyrimidine, piperazine or even a hexahydro-1,4-thiazepine ring, and Ph represents an optionally substituted by 'lower alkyl, lower alkoxy, or halogen-substituted phenyl, as well as their tautomeric compounds and salts.

Of particular interest are compounds of formula Ib in which R and R are lower alkyl, e.g. Methyl or ethyl, or the group -NR.R- together a Niederalkylenamino in which the straight, branched or substituted by phenyl lower alkylene chain optionally substituted by an oxygen, sulfur or optionally by Niederaikyl, such as. Methyl or ethyl or lower alkoxycarbonyl, e.g. For example, it may be pyrrolidino, piperidino, 4-phenylpiperidino, morpholino, 2,6-dimethylmorpho, NO, thiomorpholines, piperazino, N-ethoxycarbonylpiperazino, R.J. hydrogen or lower alkyl, e.g. Methyl or ethyl, R, hydrogen, lower alkyl, e.g. Methyl or ethyl, or lower alkoxycarbonyl, e.g. Methoxy- or ethoxycarbonyl and Het a divalent heteroalkylene radical, which with the group CN this to a heterocyclic six-membered ring which contains in addition to the nitrogen atom or a heteroatom selected from the group oxygen, sulfur or nitrogen in the ring, and, for example, a morpholine, thiomorpholine or may also be piperazine ring, and Ph is optionally substituted by lower alkyl, such as Methyl or ethyl, halogen, e.g. Fluorine, chlorine or bromine or lower alkoxy, e.g. Methoxy or ethoxy, substituted

'22 13 95 - ₁₂ -

substituted phenyl radical, as well as their tautomeric compounds and salts.

The novel guanidines of the formula I are obtained by methods known per se.

So you can, for example the novel compounds of the formula I are obtained by reacting a compound of the formula II

i: Λ

X ₃ · (ID

in X _1, the group Ph-N * ³ in the Ph represents an optionally substituted phenyl radical, or a cleavable group, X _{2 is} the group

Wherein R. and R. are listed under the formula I have 3edeutung ^X 2 X, or is a leaving group and X, the group

- N - ^^ -. C Het), where R,, R, Rr and Het are bivalent

R.

heteroalkylene

with the group CN have the meanings given under the formula I, or a cleavable group, with the proviso that only one of the substituents X, X or X can be a cleavable group, and in which one of the groups X, X and X by a double bond to the carbon atom is reacted with an amine or imine identical to the missing amino or imino group defined under X, X or X to replace the leaving group and, if desired, additional process steps is converted into a salt, and / or, if desired, obtained compounds in a salt, and / or, if desired, obtained salts of the compounds of formula I converted to the free bases.

22 13SS

As cleavable groups X ₁ , X, and X_ are, for example, lower alkylthio groups, such as methylthio or ethylthio, lower alkoxy, such as methoxy or ethoxy, or halogen, such as chlorine or bromine in question.

Compounds of the general formula II are, depending on the leaving group X ₁ , X ₂ or X -, either compounds of the formula Ha *

Ph-NCN -z ^ - ¹ · C .. Het ^) (Ha)

X ² R.

in which X. is a leaving group, Ph, R, R ,, R, Eet and C-N have the abovementioned meanings, compounds of general formula Hb,

Ph-NCX ₃

R ₁ H

wherein X. is a cleavable group, or compounds of the formula lic.

X. - C - N - ^ - ^ - C. Het ¹ ® ^ - Hal ^U ,

^R 3

where X _{1 is} a leaving group, their tautomeric forms, or their acid addition salts «

Depending on whether the cleavable group X, X- or X- is present in a compound of the formula II, a compound of the formula Ha is reacted with an amine of the formula HNR ₁ R-, a compound of the formula Hb with an imino compound of the formula III. ·

2 2 13 3 5

H-N =C het 1 (III) or a compound of the formula lic with

ι

^R 3

an optionally substituted aniline of the formula Ph-NH-. Compounds of the formulas Ha, Hb and Hc can also be used as acid addition salts, preferably as hydrohalides. In an analogous manner, the amines, imino compounds or anilines used can also be reacted as acid addition salts, preferably hydrohalides.

The reaction of a compound of formula II, i. in particular a compound of formula Ha, Hb or Hc, for example, with a previously mentioned amine or imine as the free base is carried out using a stoichiometric excess of the amine or imine, for example in a molar ratio of 1: 1 bos 1: 2.0. When using only a slight excess of the amine or imine as the free base, or when using the amine or imine as the acid addition salts, it is convenient to additionally add a stoichiometrically equivalent amount of a tertiary alkylamine, e.g. To add triethylamine or N-Aethyldiisopropylamin.

Substituting, for example, an imino compound of the formula HI as the free base ^ - ~ R

r> \ ⁴

HN -C Ret) _(m)

R.

with a compound of the formula Hb in which X- is a halogen, it is preferable to use 2 molar equivalents or more of the free base of the above-mentioned imino compound. According to the following reaction scheme

22 13 95

Ph-N-C-HaI + 2 H-N - C Het j ^ I

(lib) »(III)

H-N - C Het) HHaI

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 resulting compound of formula I is soluble, whereas the addition salt of the hydrohalic acid precipitates according to the above scheme as an insoluble compound. In this way, the two reaction products obtained can be easily separated by simple filtration. The resulting acid addition salt of the imino compound is converted to the free base by basic hydrolysis, for example by the addition of alkali or alkaline earth metal hydroxide or carbonate, and can hereby be recovered as a starting material for reuse. However, it is preferred to use compounds of formula Hb and III as acid addition salts, for example as hydrohalides, as indicated above, in the presence of an additional tertiary alkylamine, e.g. Trityhylamine or N-Aethyldiisopropylamin order.

The reactions of compounds of formula I described Hb carried out with an imino compound of the formula III, as already mentioned ^"vot ~ preferably in aprotic solvents. Examples of preferably usable solvents are ethers, such as diethyl ether and tetrahydrofuran, lower aliphatic ketones and esters, such as acetone, methyl ethyl ketone and ethyl acetate, aromatic hydrocarbons, such as benzene, toluene or xylene, and acetonitrile. Most preferably, however, the reaction is carried out in diethyl ether or acetonitrile. The implementations

2 2 13 9 5 - ie -

can be performed at a temperature between 0-15O ⁰ C, but preferably between room temperature and Rückflussteinperatur of the reaction mixture.

If, however, the starting compound of the formula II used is, for example, a compound of the formula Ha,

Fh-HC-HiTi c Hetl _(Ila )

. ' ^h η:

Thus, X- as a cleavable group preferably has the meaning of a lower alkoxy or lower alkylthio group. Starting compounds of the formula Ha 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 EHiR-R ₂ as the free base or as the acid addition salt, in which R 1 and R _{2 are} as defined above.

The reactions are z.3. in an alcohol as a solvent, preferably in a lower alkanol, such as z.3. Ethanol, isopropanol or tertiary-butanol, but more preferably in an ether, e.g. Diethyl ether or tetrahydrofuran or in acetonitrile at temperatures from room temperature to preferably the reflux temperature of the reaction mixture, but the reactions can be carried out in a closed reaction vessel under pressure, such as in a bomb tube or in an autoclave, at higher temperatures Formula I is obtained in the form of its salts, which can be converted, for example, by alkaline hydrolysis into the corresponding free bases. In the reaction of the compounds of general formula Ha with the amine of general formula HNR.R-, the amine is preferably in stoichiometric excess For example, in a molar ratio of 1: 1 to 1: 2.0 and more, using only a slight excess of the amine or an acid addition salt, it may be desirable to additionally add a stoichiometrically equivalent amount of a tertiary alkyl amine such as T riäthyl-

22 1395

amine. or N-ethyldiisopropylamine. to add to increase the reaction rate.

The reactions of compounds of the formula IIIa with a cleavable group X - which, in addition to the meaning of a halogen atom, preferably lower alkoxy or lower alkylthio, or their tautomeric form with an optionally substituted aniline as the free base, take place in the same manner as in the reaction of a compound of the formula Ha with an amine of the formula HNR. R_ described. The reactions are advantageously also carried out in a stoichiometric amount of optionally substituted anilines. If only a slight excess of the aniline or an acid addition salt thereof is used, it may be expedient to add a stoichiometrically equivalent amount of a tertiary trialkylamine already defined above. The reactions are described in analogous solvents as previously described in the reaction of the compound Ha with III , executed.

Compounds of the general formula I can also be prepared by reacting a guanidine compound of the general formula IV

Ph - N = C - NH, I

(IV)

wherein Ph, R and R ^ have the meanings given under the formula I, with a compound of the general formula V

€>

Y - ^ - ^ C. Het

Z Θ

wherein Y is lower alkoxy, e.g. Methoxy or ethoxy, lower alkylthio, e.g. Methylthio or ethylthio, "halogen, such as chlorine or bromine, or Y two lower alkoxy groups, sitting on the same carbon atom, and Z is a tetrafluoroborate, a fluorosulfonate, a lower alkyl sulfate, such as methyl sulfate or Niederalkansulfonat-, such as Methanesulfonate anion or a

2 2 13 9 5 _ ₁₈ .

Halide, e.g. Chloride or bromide, where when Y has the meaning of two lower alkoxy groups on the same C atom, Z is an anion, or, when R is hydrogen, the tautomeric form is in the form of free base, and, if desired, performs additional process steps and, if desired, converted compounds of formula I into a salt, and / or, if desired, obtained salts of the compounds of formula I converted into the free compounds.

The compounds of general formula I are advantageously prepared by reacting a lactam salt of formula V given above with a guanidine derivative of formula IV as defined above in stoichiometric amounts. The reactions are preferably carried out in an anhydrous organic solvent. Organic solvents are 2.3. lower alkanols, vie z.3. Methanol, .Aethanol, isopropanol, tert.-3-butanol, ether, much ζ.3. Diethyl ether, tetrahydrofuran or dioxane, lower halogenated hydrocarbons, such as 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 which are between -20 ⁰ C and + 50 ⁰ C, but preferably carried out between 0 ⁰ C and room temperature. The obtained in salt form reaction product of general formula I is converted by basic hydrolysis, for example by the addition of an alkali or alkaline earth metal hydroxide or carbonate in the free base.

The lactam fluoroborates or fluorosulfohates of the general formula V used in accordance with the process, in which Z represents, for example, the tetrafluoroborate group of the formula BF or fluorosulfonate group of the formula OSO.sup.-F, can be prepared by customary processes by reacting a lactam of the formula Va '.

/ -V ^E «

O = C HetJ (Va)

^R 3

22 1 3S

with the corresponding Trialkyloxoniumfluoroborat or a Fluorsulfonsäureniederalkylestar to the corresponding lactam salt of the general formula V is reacted.

The reaction is beispielsveise at temperatures between -20 ⁰ C and +50 ⁰ C, preferably at temperatures between 0 ⁰ C and +25 ⁰ C in an inert gas such as nitrogen or argon and in the presence of an inert, anhydrous organic solvent , For example, in a lower halogenated hydrocarbon, such as chloroform, 1,2-dichloroethane or preferably methylene chloride carried out. Examples of other useful organic solvents are ethers, such as z.3. Diethyl ether, dioxane, tetrahydrofuran or 1,2-dimethoxyethane, and aromatic hydrocarbons, such as z.3. Benzene, toluene or xylene.

The 2-lower alkyl thiol lactim ethers covered by the general formula V can be prepared by reacting the lactam of the general formula Va with phosphorus pentasulfide in a manner analogous to R. Gomper et al., Org. Syn. Coll., Vol. V, pp. 780-785. .With execution of this reaction is first obtained a thiolactam, which provides by reaction with an alkylating the 2-Alkylthiolactimäther in the form of the corresponding salts. As the alkylating agent, an alkyl halide, for example, methyl iodide, a fluorosulfonic acid alkyl ester, e.g. Fluorosulfonic acid methyl ester, a lower alkanesulfonic acid alkyl ester, e.g. Methanesulfonic acid alkyl esters, e.g. Methanesulfonic acid methyl ester, a toluenesulfonic acid alkyl ester, e.g. Toluenesulfonic acid methyl ester, or dialkylsulfate, e.g. Dimethyl sulfate can be used. The reaction of Lactimäthersalze with the guanidine derivative of the general formula IV provides the. corresponding salts of general formula I.

In the reaction of the previously described lactamfluorosulfonates of the general formula V with the guanidines of the general formula IV, quaternary ammonium salts of the compounds of the general formula I can also be formed as a side reaction.

22 1395

The methylsulfate salts also covered by the general formula V are prepared in an analogous manner as described by H. Bredereck et al., Cheat. 3er., Vol. 96, (1963), page 1350 described for pyrrolidones, obtained from lactams of general formula Va by reaction with dimethyl sulfate. The reaction is preferably carried out in an anhydrous inert organic solvent, for example an aromatic hydrocarbon, e.g. Benzene, toluene or xylene, an ether, e.g. Diethyl ether, dioxane or tetrahydrofuran, or a halogenated aliphatic hydrocarbon, such as 2.B. 1,2-dichloroethane or chloroform. The resulting methylsulfate of general formula V is then reacted with the corresponding guanidine derivative of general formula IV in the manner described above to give the corresponding lower alkyl sulphate salt, e.g. Methylsulfate salt of the compound of general formula I transferred. The salts obtained can be converted into corresponding free bases of general formula I by treatment with an alkali metal or alkaline earth metal hydroxide or carbonate.

From the lower alkyl sulphate, e.g. Methylsulfate salt of the general formula V can be, for example, by reaction with a metal alkoxide, preferably an alkali metal alkoxide, such as z.3. Sodium methoxide or ethoxide, in the corresponding anhydrous lower alkanol, the corresponding lactam acetal of the formula Vb

Niederalky1-0

) C. Hec) (Vb)

Niederalky1-0

produce.

From the lactam acetals can be _; As described above, with the guanidine derivatives of the general formula IV, the free bases of the general formula I produce.

22 13 95

The halide, in particular chloride salts of lactams of the general formula V used according to the process can be prepared in a manner analogous to that described by W. Jentsch and M. Seefelder, Chem. 3er., Vol. 98 (1965), as described for pyrrolidones, by reaction of a lactam of general formula Va with phosgene or thionyl chloride.

As already mentioned above, for the preparation of the compounds of general formula I in which R. a. Hydrogen atom, also the free bases of the general formula V are used. The reaction of the salts of general formula V with a 3ase, e.g. an alkali or alkaline earth metal hydroxide or carbonate, preferably in a halogenated aliphatic hydrocarbon as a solvent, such as z.3. Methylene chloride or chloroform, provides the free bases of the general formula Vc

Y-C Het 1 (Vc).

Compounds of the general formula .1 can also be prepared by a further process by reacting guanidine derivatives of the general formula VI

Ph-N-C-NH-C- ONLY (VI)

I ^J

Λ ^{1 2}

or a tautomeric form thereof, wherein Ph, R, R ₂ and R have the meanings given above and Y has the meaning of an oxo, thioxo or NH group, with a compound of general formula VII

Z- (CHj-CH-O- (CHJ = Z_ (VII)

1 / nl i nz L

in which η or η is 0, 1, 2 or 3, with the proviso that η. and n "together are not more than 3, Z _{1 is} a halogen atom, Z" is an oxo group or together the group consisting of hydrogen and halogen, where the hydrogen atom may be part of a methylene group,

2 2 13 9 5 _ ₂₂ _.

or Z and Z taken together via an imino group the bivalent

^R 4 ^R 5 alkylene radical -CH-CH- to give an aziridine derivative, wherein R, and R have the meanings of hydrogen, and if desired, performs additional process steps, and / or, if desired, obtained compounds in a salt , and / or, if desired, salts of the compounds of the formula I obtained are converted into the free bases.

For example, a compound of the formula VI in which Y is an oxo or thioxo group, with a haloacetaldehyde of the formula VII in which Z is a halogen, Z is an oxo group η and η 0 and R_ is hydrogen, preferably in a solvent with or without Addition of an acid-binding agent implemented.

Examples of suitable solvents are lower alkanols, such as, for example, methanol, ethanol, isopropanol, butanol; Ketones, such as acetone, butanone, methyl isopropyl ketone; Ethers, such as 1,2-dimethoxyethane, diisopropyl ether, tetrahydrofuran or dioxane; Carboxylic acid derivatives such as acetonitrile, ethyl acetate, dimethylformamide; Aromatics, such as benzene, toluene or xylene, aliphatic or cycloaliphatic, such as benzene and ligiroins with boiling ranges between 60 ⁰ C to 180 ⁰ C, cyclohexane; halogenated aliphatic hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride or 1,2-dichloroethane can be used.

As acid-binding agents, there may be used, for example, inorganic bases such as e.g. Sodium bicarbonate, sodium carbonate, potassium carbonate, trisodium phosphate, sodium hydroxide, potassium hydroxide or organic bases, e.g. Triethylamine or benzyl-dimethylamine.

For the reaction of compounds of the formula VI with haloacetaldehydes or haloacetaldehyde-releasing compounds such as z.3. corresponding acatals, preferably become equimolar or approximately equimolar amounts of the two

22 139 5

- Zj -

Components used. In particular, it may be appropriate to use a slight excess (1-15 mol-) of haloacetaldehyde or haloacetaldehyde-releasing compound. For this purpose, the compound of the formula VI is dissolved or suspended in a solvent and the halogenoacetaldehyde or the haloacetaldehyde-releasing compound is added slowly. The acid-binding agent can also be submitted with or added later. The reaction is carried out at ⁰ ° C to the boiling point of the solvent used, for example up to a temperature of 15O ⁰ C; the preferred temperature range is bSi 20 ⁰ C to 100 ⁰ C * * *

In an analogous manner, a compound of formula VI in which Y is a thioxo group, with a Dihalogenäthanverbindung of formula VII, in which Z is a htalogenatom and Z. a halogen atom and hydrogen atom, are reacted to aen same compounds of formula I. In an analogous manner as described above, the reactions are carried out in an organic solvent or in excess of the Dihalogenäthanverbindung used of the formula VII. Preferably, the reaction is carried out ih a lower alkanol, such as z.3. Methanol, ethanol, isopropanol or butanol.

The aziridines falling under the formula VII, in which R and R are 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 in one of the above ketones at a temperature between 0 ^a C to 100 ⁰ C, but preferably between ^{0 0} C and 30 ⁰ C implement. If, however, the solvent used is an aqueous-acidic solution, then the reaction mixture must be made alkaline after the reaction to obtain the resulting compound of the formula I as the free base.

2 2 13 9 5

The compounds of the formula I according to the invention in which Het is a heteroalkylene radical having 4-6 chain members which adds the group C-N to a heterocyclic 6-8 ring can be prepared by reacting compounds of the formula III

Ph - N = C - NH "

wherein R, R and Ph have the meanings given above, with a Halogenalkylenisothiocyanat of the formula

alkylenL

CS '(VIII),

wherein Z represents a halogen atom, and the bivalent radical "alkylene" means an alkylene chain having 3-5 carbon atoms, wherein a hydrogen in the alkylene chain replaced by the substituent R!, which has the abovementioned meaning for R, with the exception of hydrogen can be reacted, and if desired, additional process steps, and / or, if desired, compounds obtained in a salt, and / or, if desired, obtained salts of the compounds of formula... I converted into the free bases.

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

2 2 1 3 9 5 - 25 -

The novel compounds of formula I in which R has the meaning defined above and R 'and / or R, hydrogen, can be converted by a further process by reaction with a reactive ester of an aliphatic or cycloaliphatic alcohol in compounds of formula I. in which R and / or R- are different from hydrogen in the above definition for R and R_ and, if desired, carrying out additional process steps, and / or, if desired, obtaining compounds of formula I which have been converted into a salt, and or, if desired, salts of the compounds of the formula I obtained are converted into the free bases. ,

As a reactive ester, as a so-called alkylating agent, e.g. an alkyl or cycloalkyltelgenide such as e.g. Methyl or cyclohexyl iodide, a corresponding fluorosulfonic acid alkyl ester, e.g. Fluorosulfonic acid methyl ester, a corresponding lower alkanesulfonic acid ester, e.g. Methanesulfonic acid methyl ester, a corresponding toluenesulfonic acid alkyl ester, e.g. Toluenesulfonic acid methyl ester, or a dialkylsulfate, e.g. Dimethyl or diethyl sulfate. "

The compounds of the formula I according to the invention in which R and / or R are hydrogen may be prepared by a further process by reacting compounds of the general formula IX

Ph - Hf - C - N o C Het

wherein R, R, R ₅ , Ph and Het have the meaning given under the formula I, and one of the substituents R 'and R' has the meaning of R or R, and the other is an amino protecting group, or de R 'and R' represent an amino protecting group, these cleavage and, if desired, performs additional process steps, and / or, if desired, obtained compounds of formula I in a salt, and / or, if desired, obtained salts of the compounds of formula I in the converts free bases.

22 13 95 -26-

An amino-protecting group R '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, z.3. Benzoyl, or acyl of formic acid or a carbonic acid half derivative, e.g. esters, such as Fonayl, lower alkoxycarbonyl, z.3. Ethoxycarbonyl or tert-butyloxycarbonyl, or aryl-lower alkoxycarbonyl, e.g. Benzyloxycarbonyl.

The cleavage of an acyl radical used as amino-protecting group R 'and / or R' is carried out in a manner known per se, for example by solvolysis, primarily by alcoholysis, furthermore by hydrolysis The alcoholic cleavage of an acyl radical R 'and / or R' can be effected, for example .3 to about 120 ⁰ C, carried out in the presence of a strong basic agent, at elevated temperature, for example at about 5O ^e C. it is used in particular a lower alkanol, for example n-butanol or ethanol, and the strong base is an alkali metal, metal, for example, sodium or potassium lower alkoxide, for example -n-butylate or ethylate, or an alkali metal hydroxide, for example sodium or potassium hydroxide.

Amino-protecting groups Ri and R ', for example ITiederalko-xycarbonylgruppen such as tert-butyloxycarbonyl, can be particularly gently acidolytic, e.g. by treatment with trifluoroacetic acid.

Another, particularly gently cleavable amino protecting group is an Aethoxycarbonylgruppe in the ß-position with a three hydrocarbon radicals substituted silyl group, such as triphenylsilyl, Ditnethyl-butyl-silyl or especially trimethylsilyl carries. Such β- (trimethylsilyl) -ethoxycarbonyl group forms with the amino group to be protected a corresponding β-trimethylsilyl-ethoxycarbonyl-amino group which can be split off under mild conditions by the action of fluoride ions. Suitable fluoride ion donating reagents are, for example, fluorides of quaternary organic bases, such as tetraethylammonium fluoride in question.

2 2 13 9 5

 ".27 -

It should be noted that the amino protecting group R 1 and / or R 1 are only those which are selectively cleavable while retaining the structure of the compounds of the general formula I.

The starting materials are known or, if new, can be prepared by methods known in the art. Where appropriate, the starting products used have been described following the described process.

Compounds of the general formula Ha, in which X represents a lower alkylthio group, can be prepared, for example, from the corresponding thioureas of the general formula X.

Ph-HN-C-N-C Bet). (X)

S ι ³ . ^R 3

by reacting these with an alkylating agent of the formula R R listed above in which R is a lower alkyl, for example methyl or ethyl, group and Z is, for example, a p-toluenesulfonate, methanesulfonate, fluorosulfonate or lower alkylsulfate, e.g. Mylthyl sulfate group, preferably halogen, e.g. Chlorine or bromine, means, implements.

The reaction is carried out in an organic solvent already defined above. Preferably, the solvent used is an ether, e.g. Diethyl ether, tetrahydrofuran or dioxane, a ketone, e.g. Acetone or 2-butanone, a halogenated aliphatic hydrocarbon, e.g. Chloroform or methylene chloride or a lower alkanol, 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 may optionally be carried out at room temperature or at higher temperatures, and if necessary in a closed reaction vessel.

2 2 13 9 5

Compounds of the general formula IX in turn can be prepared from the already mentioned and known imino compounds of the formula III

H - N - C Het) (III)

S.

by reaction with an optionally substituted phenyl isothiocyanate of the formula Ph - NCS in an inert organic solvent already defined above, preferably in benzene, methylene chloride or chloroform, at temperatures of 0 ^e C to room temperature for 2-24 hours in approximately equimolar amounts.

Compounds of the formula Hb in which X.sup. As the cleavable group is halogen, preferably chlorine, are prepared according to the method described by S. Kuhle, Angew. Chem., Intern. Ed., 3d. 8 (1969), p. 24-26, by reacting an isocyanide dihalide of the formula XI

Ph-N-C-Cl

ι (χι)

Cl

with an amine of the formula HNR.R-, in the presence of a trialkyl amine, e.g. Triethylamine, reacted in an inert aprotic, anhydrous solvent. Compounds of the formula X can also be present as immonium chlorides. The solvent used is e.g. an ether, for example diethyl ether, dioxane or tetrahydrofuran, a halogenated aliphatic hydrocarbon, e.g. Chloroform or methylene chloride, or an aromatic hydrocarbon, e.g. Benzene, toluene or xylene. Compounds of general formula X are known and can be prepared in an analogous manner, as in Angew. Chem., -Intern. Ed. Bd. 6 (1967), p. 649.

Compounds of the general formula Hb, in which the leaving group X- represents, for example, halogen, can easily be converted in a known manner into compounds of the formula Hb in which X denotes a lower alkoxy group.

22 13S5

Starting compounds of the general formula IIIa in which the group X. which may be split off is a halogen, preferably chlorine, can be obtained by reacting an immonium chloride of the formula

R ₂ Cl

with an imino compound of the formula III

HN / He

according to R.G. Glushkov, Khim.-Farmatsevt. Zh. 12, no. 6, 59-64 / 1973.

The conversion takes place in analogue. As described above in the reaction of a compound of formula X. .... <

Starting compounds of the general formula VI, in which Y is, for example, an oxo or thioxo group and R_ is different from hydrogen, can be prepared by reacting a guanidine compound of the formula IV

Ph - N = »C - NH ₂

, Λ

1.2 ..

with a lower alkyl isothiocyanate or isocyanate. The reaction is carried out in an organic solvent, preferably in an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, a carboxylic acid derivative, such as 2.3. Acetonitrile, at a temperature which is between ^{0 0} C and the boiling point of the solvent, preferably at 2O ⁰ C to 100 ⁰ C.

22 1395

Compounds of the general formula VI in which, for example, Y ₁

is a thioxo group, and R, is hydrogen, can be prepared according to the procedure described by H. Hartmann et al., J. Prakt. Chem. 315 (1973), p. 144. Guanidine compounds of the general formula IV are reacted with a lower alkoxycarbonylisothiocyanate to give a compound of the formula XIII

Ph-Na-C-NH-C-NH-CO-lower alkyl (XII)

l V

^R l V

which is converted by hydrolysis with a mineral acid, preferably hydrochloric acid to a compound of formula VI.

Compounds of the general formula IX can be obtained by a first method described for the "preparation of compounds of the general formula I above", but in the starting product used R and / or R- represent an acyl radical. These acyl residues used as amino-protecting groups are as defined above.

The processes described can be carried out in the usual manner at room temperature, under cooling or heating, at atmospheric or elevated pressure, and if necessary in the presence or absence of a diluent, catalyst or condensing agent. If necessary, the reactions may also be carried out in the atmosphere of an inert gas such as e.g. Nitrogen, done.

In compounds obtained, it is possible within the definition of the end products to modify or eliminate substituents.

The new starting materials and processes for their preparation are also the subject of the present invention.

Depending on the process conditions and starting materials, the end products are obtained in free form or in the form of their salts, in particular acid addition salts, likewise included in the invention. The acid

2 2 13 9 5

addition salts of the new compounds can be converted into the free compound in a manner known per se, z.3. with basic agents, such as alkalis or ion exchangers. On the other hand, the obtained free 3asan can form salts with organic or inorganic acids. For the preparation of acid addition salts, in particular those acids are used which are suitable for the formation of therapeutically useful salts. Examples of such acids are: hydrogen halides, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, and Aepfel -, tartaric, citric, ascorbic -, maleic, hydroxymaleic or pyruvic acid; Phenylacetic, benzoic, p-atainobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulfonic, ethanesulfonic, hydroxyethylsulfonic, ethylenesulfonic acid; Halobenzenesulphonic, toluenesulphonic, naphthalenesulphonic or sulphanilic acid; Methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, such as 2.B. the

- -ΐ

Picrates, can also serve to purify the resulting free 3asen by converting the free 3aseu into salts, these separated and from the salts in turn frees the bases. Owing to the close relations between the new compounds in free form and in the form of their salts, the preceding and subsequent free compounds are to be understood as meaningful and expedient, and where appropriate also the corresponding salt.

The invention also relates to those embodiments of a process in which one terminates a process at any stage or starting from a compound obtainable at any stage as an intermediate product and carrying out the missing steps, or forming a starting material under the reaction conditions or optionally in the form a salt used. The invention also includes resulting new intermediates.

22 1395

Also encompassed by the invention are therapeutic compositions comprising a hypoglycemic portion of the compounds of general formula I or an acid addition salt and a pharmacologically acceptable 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 customary pharmaceutical carrier. The type of carrier depends largely on the field of application. The pharmaceutical compositions according to the invention, which contain compounds of the formula I as active ingredients, can be administered orally, parenterally or rectally.

For the oral treatment of hyperglycemia, solid dosage unit forms, such as tablets, dragees and capsules, which preferably contain between 10 and 902 of an active ingredient of the general formula I or a salt, are suitable for administration of daily doses of between 1.5 and 100 mg / kg of warm-blooded animals. For the preparation of tablets and dragee cores, the compounds of general formula I are combined with solid, pulverulent carriers, such as lactose, sucrose, sorbitol, corn starch, potato starch or amylopectin, cellulose derivatives or gelatin, preferably with the addition of lubricants, such as magnesium or calcium stearate, or Polyethylene glycols of suitable molecular weight. Dragee cores are then coated, for example, with concentrated sugar solutions, which are e.g. or Arabic rubber, talc and / or titanium dioxide, or with a lacquer dissolved in volatile organic solvents or solvent mixtures. Dye may be added to these coatings, e.g. for labeling different doses of active substance. Soft gelatin capsules and other closed capsules consist for example of a mixture of gelatin and glycerol and can

22 1395

e.g. Mixtures of a compound of formula I with polyethylene glycol. Capsules contain, for example, granules of an active ingredient with solid, powdery excipients, e.g. Lactose, sucrose, sorbitol, mannitol; Starches, such as potato starch, corn starch or amylopectin, cellulose derivatives and gelatin, and magnesium stearate or stearic acid.

As dosage unit forms for rectal use are e.g. Suppositories which consist of a combination of an active ingredient with a Supoositoriengrundmasse on the basis of natural odef synthetic triglycerides (z.3 .. cocoa butter), polyethylene glycols or suitable higher fatty alcohols, and gelatin rectal capsules containing a combination of the active ingredient with Polyethylene glycols included.

Ampoules solutions for parenteral, especially intramuscular or intravenous administration containing a compound of formula I or a salt thereof in a concentration of preferably 0.5 to SZ as aqueous, with the aid of customary Eosungsveraittlera and / or emulsifiers, and optionally stabilizing agents prepared dispersion, or preferably an aqueous solution of a pharmaceutically acceptable, water-soluble acid addition salt of a compound of general formula I.

For liquids for oral use, such as syrups and elixirs, the concentration of the drug is chosen so that a single dose can be easily measured, z.3. as the content of a teaspoon or a measuring spoon of e.g. 5 ml, or as a multiple of these volumes.

The following examples a) to e) are intended to illustrate the preparation of some typical forms of application, but by no means represent the only embodiments of such.

2 2 13 9 5 _ 34 -

a) 250.0 g of active compound are 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 silica are added and the mixture is compressed to 10 000 tablets of 125 mg each and 25 mg of active ingredient, optionally with partial grooves for finer adjustment the dosage can be provided.

b) 100.0 g of active ingredient, 379.0 g of lactose and the alcoholic solution of 6.0 g of gelatin are used to prepare a granulate which, after drying with 10.0 g of colloidal silica, 40.0 g of talc, Mix 60.0 g potato starch and 5.0 g magnesium stearate and squeeze to 10 * 000 drag cores. These are then mixed with a concentrated syrup of 533.5 g krist. Sucrose, 20.0 g shellac, 75.0 g arabic gumai, 250.0 g talc, 20.0 g colloidal silica and 1.5 g dye coated and dried. The coated tablets each weigh 150 mg and each contain 10 mg of active ingredient.

c) 25.0 g of active ingredient and 1975 g of finely ground suppository base (e.g., cocoa butter) are mixed thoroughly and then melted. From the melt, kept homogeneous by stirring, 1000 suppositories of 2.0 g are poured. They each contain 25 mg of active ingredient.

d) To prepare a syrup with 0.25% active ingredient dissolved in 3 liters of dist. Water 1.5 liters of glycerol, 42 g of p-hydroxybenzoic acid methyl ester, 18 g of p-hydroxybenzoic acid n-propyl ester and with gentle heating 25.0 g of active ingredient, add 4 liters of 70% sorbitol, 1000 g krist. Sucrose, 350 g glucose and a flavoring agent, e.g. 250 grams of "Orange Peel Soluble Fluid" from Eli Lilly and Co., Indianapolis, or 5 grams each of natural lemon flavor and 5 grams of "half and half" feeds2, both from Haarmann · and Reimer, Holzminden, Germany, to, filtered, the resulting solution and the filtrate is supplemented with dist. Water to 10 liters.

2 2 1 3 9 S -35- AP C 07 D / 221 395

57 464/12

e) In order to prepare a dropping solution containing 1.5 » active ingredient, 150.0 g of active ingredient and 30 g of sodium cyclamate are dissolved in a mixture of 4 liters of ethanol (36%) and 1 liter of propylene glycol. On the other hand, mix 3.5 liters of 70% sorbitol solution with 1 liter passer and add the mixture ^ to the above drug solution. Then a flavoring, z. B * 5 g cough sweet A-roma or 30 g grapefruit essence, both from the company Haarmann and Reimer, Holzminden, Germany, added, the whole well mixed, filtered and distilled with dist. Water added to 10 liters, ^ι

embodiment

The following examples illustrate the preparation of the novel compounds of general formula I, but are not intended to limit the scope of the invention in any way. The temperatures are given in degrees centigrade.

t '

Example 1: To a solution of 24.2 g (0.1 mol) of 2,5-dimethyl-3-iso2: azolidinimine hydroiodide cooled to 5 ° (see Bull. Soc. Chim. Pr. 1974, 1651-1655 ) in 120 acetonitrile is added dropwise with stirring 21.25 g (0.21 mol) of triethylamine. With further cooling, 22.47 g (0.1 mol) of K-phenyl-4-morpholinecarbo-2-imidoyl chloride (see Chem. Ber., 105, 1532-1539 (1972)) are added in portions, the reaction temperature being kept at 5 to 10 ° C becomes. After completion of the addition, the mixture is stirred for 1/2 hour at 10 ° and for one hour at room temperature. The reaction mixture is filtered, the filter residue washed with a little acetonitrile and the '' iltrat evaporated in vacuo. The residue is added ice-cold 2-n. , Sodium hydroxide solution and extracted several times with chloroform. The combined neutral with water washed chloroform phases are evaporated after drying over sodium sulfate to give crude ^ N- (2,5- ^u imethyl-3-isoxazolidinyliden) -N ^f -phenyl-4-morpholincarboximidamid receives. The Pumarat produced by reaction with fumaric acid melts after recrystallization from ethanol / ethyl acetate at 192 to 193 ⁰ C,

22 1395

Example 2 : 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 are obtained analogously to Example 1 -carboximidoyl chloride [cf. Organometal. · Chem. Sync. I, 23-30 (1970-71)], 10.63 g (0.105 mol) of triethylamine and 60 ml of acetonitrile, crude N- (2,5-dimethyl-3-isoxazolidinylidene) -N'-phenyl-1-piperidinecarboximidamide. The fumarate produced therefrom with fumaric acid melts at 171.5-173 ° after recrystallization from isopropanol / ethyl acetate.

Example 3 : Analogously to Example 1, aan is obtained, starting from 11.4 g (0.05 mol) of 2-methyl-3-isoxazolidinimine hydroiodide [cf. 3ull. Soc. Chiai. 1974, 1651-1655], 11.23 g (0.05 mol) of N-phenyl-4-morpholine-carboximidoyl chloride, 10.63 g (0.105 mol) of triethylamine and 60 ml of acetonitrile are crude N- (2-methyl-1-chloroethyl) 3-isoxazolidinylidene) -N'-phenyl-4-morpholinecarboximidamide [m.p. 80-88 °, from petroleum ether]. The fumarate produced therefrom with fumaric acid melts at 167-168 ° after recrystallization from Aethano VAether.

Example 4 : Starting from 12.8 g (0.05 mol) of 2,5,5-trimethyl-3-isoxazolidinimine hydroiodide (see Bull. Soc. Chim ), 11.23 g (0.05 mol) of N-heny 1, 4-morpho, noncarboximidoyl chloride, 10.63 g (0.105 mol) of triethylamine and 60 ml of acetonitrile, crude N- (2,5,5-trimethyl-3-) isoxazolidinyliden) -N '-? -phenyl-4-morpholincarboximidamid. The fumarate produced therefrom with fumaric acid melts at 203-204 ° after recrystallization from Aethano1 / ether.

Example 5 ; To a solution of 12.26 g (0.05 mol) of N, N-Te tr ame thy Ua-N'-phenyl-chlorononnamidiniumchlorid (brw., Phenylimino-chloro kihlensäurepyrrolidinylamid hydrochloride) [see. Chem. Ber. 97, 1232-1245 (1964)] and 12.1 g (0.05 mol) of 2,5-dimethyl-3-isoxazolidinimin-hydroiodide in 50 ml of acetonitrile is added dropwise with stirring and cooling 15.18 g (0.15 mol ) Triethylamine, wherein the reaction temperature is maintained at 5-10 °.

22 1395

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 of particle size 0.063-0.200 mm. The fractions containing the desired product are combined and washed with ice-cold sodium hydroxide solution and water. The chloroform phase is dried over sodium sulphate and concentrated by evaporation in vacuo to give crude N- (2,5-dimethyl-3-isoxazolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide. The maleate prepared therefrom with maleic acid melts at 114-116 ° after recrystallization from ethyl acetate / Isopröpanöl.

Example 6 ;

a) 200 ml of isopropanol are added, with stirring, to 19.5 g (0.05 mol) of N- (1,3-dimethyl-2-imidazolidinylidene) -N'-phenyl-carbamimidothiomethyl-ester-hydroiodide and 10.66 g (0, 15 moles) of pyrrolidine. The reaction mixture is refluxed for 36 hours and then evaporated. The residue is partitioned between chloroform and 1-n. Sodium hydroxide solution. The washed with water and dried over sodium sulfate organic phase is evaporated and the residue with a mixture of chloroform / methanol / conc. Ammonia = 40: 10: 1 filtered through kieselge l the grain size 0.063 - 0.200 mm. The fractions containing the desired product are evaporated in vacuo. The resulting crude N-djS-dimethyl-Z-imidazolidinylideni-N'-phenyl-l-pyrrolidincarboximidamid is converted with maleic acid in the maleate, which melts at 126-127 ° after recrystallization from ethyl acetate / isopropanol.

The starting compound, N- (1,3-dimethyl-2-imidazolidinylidene) -N'-phenylcarbamimido-thiomethyl ester hydroiodide, is prepared as follows:

b) To a solution of 44.1 g (0.5 mol) of Ν, Ν'-dimethylethylenediamine in 300 ml of toluene is added dropwise with stirring for 1 hour, a solution of 52.9 g of cyanogen bromide in 300 ml of toluene. The reaction mixture is stirred for a further two hours at 80 °. Allow to cool to room temperature.

22 ! 395

len, filtered and the residue washed with ether. The crude l, 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) of l, 3-dimethyl-2-iminoimidazolidin hydrobromide in 470 ml of chloroform is added with stirring at 5 ° with 30.4 g (0.3 mol) of triethylamine. A solution of 40.6 g (0.3 mol) of phenylisothiocyanate in 235 ml of chloroform is then added dropwise, and the reaction mixture is refluxed for 15 hours. After cooling, it is washed with water, dried over sodium sulfate and evaporated in vacuo. This gives crude N- (l, 3-dimethyl-2-imidazolidinyliden) -N'-phenyl-thioharastoff, which melts after recrystallization from ethanol at 195-196 °.

d) To a suspension of 24.8 g (0.1 mol) of N- (1,3-diaethyl-2-imidazolidinylidene) -M'-phenylthiourea in 165 ml of tetrahydrofuran, a solution of 21, with stirring at room temperature, 3 g (0.15 mol) of methyl iodide in 35 ml of tetrahydrofuran was added dropwise. The mixture is stirred for 15 hours at room temperature and then the reaction mixture is mixed with 160 ml of ether. The precipitate is filtered off, washed with ether and dried in vacuo. The resulting N- (1,3-dimethyl-2-imidazolidinylidene) -N'-phenylcarbamimido-thiomethyl ester hydroiodide melts at 157-158 °.

Example 7 :

a) A solution of 19.6 g of N- [3-methyl-4- (l, 3,4) -thiadiazolin-2-ylidene] -N'-phenylcarbamimido-thiomethyl ester hydroiodide and 10.7 g of pyrrolidine in 150 ml Isopropanol is refluxed for 15 hours. The reaction mixture is then evaporated to dryness and the residue is chromatographed on a short column filled with silica gel. It is eluted first with chloroform and then with a chloroform / acetone mixture (95: 5). The last fractions are combined, stirred with ether, and the resulting hydroiodide is converted into the hydrochloride by means of an ion exchanger. The resulting N-f3-methyl-1,4- (1,3,4) -thia-

22 1395

diazolin-2-ylidene] -N'-phenyl-1-pyrrolidinecarboxiaminideamide hydrochloride> melts at 217-218 ° '(c). '. '*

The starting N- [3-methyl-4- (l, 3,4) -thiadiazolin-2-ylidene] -N'-phenylcarbamimido-thiomethylestar-hydroiodide is obtained as follows:

b) A suspension of 52.7 g of 2-imino-3-methyl-4- (l, 3,4) -thiadiazolin-hydroiodide and 24.3 g of potassium tert-butoxide in 500 ml of tetrahydrofuran is added 1 hour stirred at room temperature. It is then filtered through a bed of diatomaceous earth. To the filtrate is added dropwise within 5 minutes 2 ^, 3 g phenyl isothiocyanate and stirred for 16 hours at -Raumtemperatur. The reaction mixture is then evaporated to dryness, the residue is stirred with ether, filtered off with suction and stirred again with hot isopropanol. This gives the N- [3-methyl-4- (l, 3,4) -thiadiazolin-2-ylidene J-N'-phenylthiourea, Smp.sup. 174-175 *.

c) A solution of 25.5 g of the compound obtained in b) in 300 ml of acetonitrile is mixed with 43.4 g of methyl iodide. The solution is refluxed for 30 minutes. The precipitated on cooling crystals are filtered off with suction, washed first with acetonitrile, then with ether and dried. There is thus obtained the N- (3-methyl-4- (l, 3,4) -thiadiazolin-2-ylidene] -N ^f -phenylcarbamateido-thiomethyl ester hydroiodide, m.p. 190 ° (decomposition).

Example 8

a) A solution of 17.6 g of 2-amino-5-methyl-l, 3,4-thiadiazole in 350 ml of isopropanol is treated with 65.1 g of methyl iodide. The solution is refluxed for 15 hours. Subsequently, the reaction mixture is evaporated to dryness, the crystalline evaporation residue is stirred with ethyl acetate and the solvent filtered off with suction. The crystalline residue is washed first with Ess-igestar, then with ether and then dried. This gives 2-imino-3,5-dimethyl-4- (l, 3,4) -thiadiazolin-hydroiodide of mp. 208 ° (dec.).

2 139 5

The following salts of the 2-imino compounds can be prepared analogously:

b) 2-Imino-3-methyl-5-ethyl-4- (l, 3,4) -thiadiazoline hydroiodide, Sep. 137-138 ° (decomp.)

c) 2-Imino-3-ethyl-5-trifluoro-2-ethyl-4- (l, 3,4) -thiadiazoline-hydroiodide, m.p. 187-188 ° (dec.)

d) 2-Imino-3-methyl-5-methylacercapto-4- (1,3,4) -thiadiazoline-hydroiodide, m.p. 205-206 °.

e) 2-Imino-3-methyl-4-phenyl-4-thiazoline-hydroiodide, mp 235 ° (dec.)

f) 2-Imino-3,5-dimethyl-4-thiazoline hydroiodide, mp 187-188 °

g) 2-Imino-1,3-dimethy4-imidazoline hydroiodide, mp 126-127 ° h) 2-Imino-3-methyl-4-oxazoline hydroiodide, mp 191-192 ° (dec. i) 2-Imino-3,4,5-trimethyl-4-oxazoline hydroiodide, m.p. 169-171 ° j) 2-Imino-3,5-dimethy1-4- (1,3,4) -oxadiazoline -hydrojodid,

M.p. 169 ° (decomp.).

Example 9 According to Example 7 b), but using an equivalent amount of the 2-imino compound obtained in Example 8, the following thioureas are obtained in the reaction with an equivalent amount of phenyl isothiocyanate:

a) N- [3,5-dimethyl-4- (l, 3,4) -thiadicLZolin-2-ylidene] -N'-phenylthiourea, mp 175-176 °

b) N- [3-Methyl-5-ethyl-4- (l, 3,4) -thiadiazolin-2-ylidene] -N'-phenylthioharomatic, m.p. 135-136 °

c) N- [3-methyl-5-methylmercapto-4- (l, 3,4) -thiadiazolin-2-ylidene

N'-phenyl thiourea, mp 160-161 °

d) N- (3-methyl-4-thiazolin-2-ylidene) -II'-phenylthiourea,

Mp. 174-175 °

_{e) N} - _{(3-M e} thyl-4-phenyl-4-thiazoline-2-ylidene) -N'-phenylthioham-

fabric, mp 183-184 °

f) N- (3,5-dimethyl-4-thiazoline-2-ylidene) -N ^t -phenylthiohamstoff,

M.p. 185-186 °

22 1395

g) N- (1-dimethyl-imidazoline-1-ylidene) -N'-phenyl thiourea, m.p. 221-222 °. "

h) N- (3-methyl-4-oxazolin-2-ylidene) -N'-phenylthiourea, mp 169-170 °

i) N- (3,4,5-trimethyl-4-oxazolin-2-ylidene) -iJi'-phenyl, urea, mp 192-192.5 °

In an analogous manner are prepared from:

j) 2-imino-3-allyl-4-thiazoline hydroiodide and phenyl isocyanate of N- (3-allyl-4-thiazolin-2-ylidene) -N'-phenylthiourea, m.p. 129.5-130.5 ° and , '

k) 2-Ixnino-3-methyl-thiazolidine hydroiodide and phenyl isocyanate of N- (3-methyl-thiazolidin-2-ylidene) -N'-phenylthiourea, mp 170-172 °.

Example 10 According to Example 7c), but using the thioureas listed above in Example 9 in specific solvents, the methyl ester hydroiodides are increased:

a) in isopropanol, the N- [3,5-dimethyl - ^ - (l, 3,4) -thiadiazolin-2-ylidene] -N'-phenylcarbamimido-thiomethyl ester hydroiodide, mp 134-135, 5 °;

b) in tetrahydrofuran, the N- {3-i-methyl-5-ethyl-4- (l, 3,4) -thiadiazolin-2-ylidene] -N'-phenylcarbamimido-thiomethyl ester hydroiodide, red OeI;

c) in tetrahydrofuran, the N- (3-methyl-5-methylmercapto-4- (l, 3,4) -thiadiazolin-2-ylidene] -N'-phenylcarbamoinido-thiomethyl ester hydroiodide, mp 160-161 °;

d) in tetrahydrofuran, the N- (3-methyl-4-thiazolin-2-ylidene) -N'-phenylcarbamimido-thiomethyl ester hydroiodide, mp 174-175 °;

e) in tetrahydrofuran, the N- (3-methyl-4-phenyl-4-thiazolin-2-ylidene) -N'-phenylcarbamimido-thiomethyl ester hydroiodide, mp 183-184 °;

f) in tetrahydrofuran, the N- (3,5-dimethyl-4-thiazolin-2-ylidene) -N'-phenylcarbamimido-thiomethyl ester hydroiodide, mp 185-186 °;

g) in acetonitrile, the N- (1,3-dimethyl-4-iiaidazolin-2-ylidene) -N'-phenylcarbamimido-thiomethyl ester hydroiodide, m.p. 221-222 °;

221395

h) in isopropanol, the N- (3-methyl-4-oxazolin-2-ylidene) -N'-phenylcarbamimido-thiomethyl ester hydroiodide, mp. 140-141 °;

i) in isopropanol, the N- (3,4,5-triaethyl-4-oxazolin-2-ylidene) -N'-phenylcarbamimido-thiomethyl ester hydroiodide, mp 192-192.5 °;

j) in isopropanol, the N- (3-allyl-4-thiazolin-2-ylidene) -iT-pheny 1-carbamimido-thiomethyl ester hydroiodide, m.p. 138-139 °;

k) in tetrahydrofuran, the N- (3,4,5-trimethyl-4-oxazolin-2-ylidene) -N'-phenylcarbamimido-thiomethyl ester hydroiodide, mp 139-141 °.

Example 11 According to Example 7a), the corresponding methylthio-hydroiodides of Example 10 and the corresponding amines of the general formula HNR ₁ R- in a molar ratio of 1: 3 in refluxing isopropanol, tert-3utanol or ethanol to the now following compounds a - k implemented in Fora of the hydroiodides. The hydroiodides are isolated as such, converted by means of an anion exchange resin in the hydrochlorides or optionally converted with aqueous alkali into the free 3asen. By reaction of the free bases with a suitable acid, other salts can also be prepared.

a) the N- [3,5-dimethyl-4- (l, 3,4) -thiadiazolin-2-ylidene] -M'-phenyl-1-pyrxolidine-carboximidamide as a free 3ase, mp. 98-99 °;

b) the N- (3-methyl-5-ethyl-4- (l, 3,4) -thiadiazolin-2-ylidene] -N'-phenyl-1-pyrrolidine-carboximidamide free 3ase, m.p. 85-86 °;

c) the N- (3-methyl-5-methylmercapto-4- (l, 3,4) -thiadiazolin-2-ylidene] -N'-phenyl-1-pyrrolidine-carboxy-alidamide as free 3ase, mp. 98-

d) the N- (3-methyl-4-thiazolin-2-ylidene) -N'-phenyl-1-pyrrolidine

carboximidamide as free base, mp 129-130 °;

e) the N- (3-methyl-4-phenyl-4-thiazolin-2-ylidene) -N'-phenyl-l-. pyrrolidine-carboximidamide hydrochloride, m.p. 196-197 °;

f) as N- (3,5-dimethyl-4-thiazolin-2-ylidene) -α'-phenyl-1-pyro-lidin-carfaoximidamide hydrochloride, m.p. 220.5-221.5 °;

g) as N- (1,3-dimethyl-4-imidazolin-2-ylidene) -N'-phenyl-1-pyrrolidine carboxamide · 2HCl, m.p. 170 ° (decomposition);

22 1395

h) the N- (3-methyl-4-oxazolin-2-ylidene) H! -phenyl-1-pyrrolidinecarboximidamide free base, mp 94.5-95.5 °;

i) the N- (3,4,5-trimethyl-4-oxazolin-2-ylidene) -N'-phenyl-1-pyrrolidine-carboxixaidamide hydrochloride, mp 161-163 °;

j) the N- (3-allyl-4-thiazolin-2-ylidene) -N'-phenyl-1-pyrrolidinecarboximidamide as a free base, mp 91-92 °;

k) N- (3,4,5-triaethyl-4-oxazolin-2-ylidene) .- N'-phenyl-1-pyrrolidine-carboximidamide hydrochloride, mp 225-226 °;

1) the N- [3,5-dimethyl-4- (l, 3,5) -thiadiazolin-2-ylidene] -N'-phenyldimethylamino-carboximidamide hydrochloride, m.p. 238-239.5 ° (decomposition);

m) N- (3,4,5-trimethyl-4-oxazolin-2-ylidene) -. * i ^f -phenyl-dimethylamino-carboximidamide free base, m.p. 84-86 °.

Example 12 : A solution of 9.3 g of 2-imino-3-methyl-chiazolidine and 10.3 g of N-ethyldiisopropylamine in 50 ml of acetonitrile is added within 15 minutes at room temperature to a solution of 14.8 g of N-phenyl 4-morpholine-carboxinidoyl chloride in 50 ml of acetonitrile. The mixture is then stirred at room temperature for 2 hours and then under reflux for a further 3 hours. The reaction mixture is evaporated to dryness, the crystalline residue is stirred with isopropanol, the solvent is filtered off with suction and the resulting solid product is then stirred for 30 minutes with 50 ml of water, filtered with suction, washed first with water, then with isopropanol and dried. The resulting N- (3-methyl-thiazolidin-2-ylidene) -N'-phenyl-4-morpholine-carboximidamide melts at 144.5-145.5 °.

Example 13 From 18.5 g of 2-imino-3-iaethyl-5-trifluoromethyl-4- (l, 3,4) -thiadiazolin-hydroiodide, the base is liberated with 10% sodium hydroxide solution, taken up in methylene chloride, dried with anhydrous magnesium sulfate and evaporated. The base thus obtained and 7.6 g of N-ethyldiisopropylamine are dissolved in 50 ml of acetonitrile and added dropwise within 15 minutes to a solution of 11.9 g of M-phenyl-4-morpholine-carboximidoyl chloride in 50 ml of acetonitrile. Subsequently, 4 hours at room temperature

2 2 13 9 5

stirred, the reaction mixture was then evaporated to dryness, the residue was stirred with ether, filtered off with suction, the ether extract was evaporated and the evaporation residue was chromatographed over a short column filled with silica gel. It is eluted first with methylene chloride, then with a methylene chloride-acetone mixture 97: 3. The middle fractions are combined, stirred with a little hexane, filtered with suction, washed with hexane and dried. The resulting N- [3-methyl-5-trifluoromethyl-4- (l, 3,4) -thiadiazolin-2-ylidene] -N'-phenyl-4-morpholine-carboximidamide melts at 110.5-112 °.

Example 14 From 14,6 g of 2-imino-3-methyl-4- (l, 3,4) -thiadiazolinhydrcjodid is liberated with 30Ziger sodium hydroxide solution, taken up in methylene chloride, dried with anhydrous magnesium sulfate and evaporated. The 3ase 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 for 3 hours under reflux. The reaction mixture is evaporated to dryness and the evaporation residue is chromatographed on a column filled with silica gel. It is eluted with chloroform. The base thus obtained is converted into the hydrochloride with alcoholic hydrochloric acid. After recrystallization from acetonitrile-ethyl acetate, pure N- [3-methyl-4- (l, 3,4) -thiadiazolin-2-ylidene] -N'-phenyl-4-morpholine-carboximidamide hydrochloride of the mp 201, 5 to 202.5 °.

Example 15 : The procedure described in Example 14 gives 8.6 g of 2-imino-3-methyl-4- (l, 3,4) -thiadiazoline and 16.7 g of N-phenyl-1-piperidine-carboximidoyl chloride the N- [3-methyl-4- (l, 3,4) -thiadiazolin-2-ylidene] -N'-phenyl-1-piperidinecarboximidainide, m.p. 94.5-95.5 °.

2 13 9

EXAMPLE 16 According to 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 are subjected to N- (3-methyl-4-thiazoline; Methyl-4-thiazolin-2-ylidene) -N'-phenyl-4-morpholine-carboximidamide hydrochloride, m.p. 209-210 °.

Example 17 : 12.0 g of 2-imino-3,5-dimethyl-4- (l, 3,4) -oxadiazoline hydroiodide are treated with 11.2 g of N-phenyl-4-morpholine-carboximidoyl chloride as in Example 8 described, implemented. However, the reaction mixture is stirred only at room temperature for 16 hours. The reaction mixture is evaporated and chromatographed on a column filled with silica gel. It is eluted first with chloroform, then with a 95: 5 chloroform-acecon mixture and finally with chloroform-methanol 95: 5. From the last fractions a * hydrochloride is obtained, which is stirred with 3OZiger sodium hydroxide solution. The first oily base soon crystallizes. The resulting N- [3,5-dimethyl-4- (1,3,4) oxadiazolin-2-ylidene-N'-phenyl-4-morpholine-carboximidamide melts at 117-118 °.

Example 18 : To 200 ml of tetrahydrofuran and 111 ml of a. 20Z-igen solution of phosgene in toluene (0.21 mol) is added with stirring 43.3 g (0.21 mol) of N-phenyl-N'.N'-tetramethylenethiourea [see J. Org. Chem. ^ 23, 1760-1764 (1958)], taking care that the temperature does not rise above 35 °. The mixture is stirred for 15 minutes at 20 °, then cooled to 10 ° and treated the reaction mixture (suspension of NN-tetramethylene-N'-phenyl-chloroformamidinium chloride) with 100 ml of acetonitrile and 50.8 g (0.21 mol) 2,5-dimethyl-3-isoxazolidiniminhydroiodid. After dropwise addition of 64.8 g (0.64 mol) of triethylamine at. 10-15 ", the suspension is stirred for a further 12 hours at 20 ° C. The mixture is filtered, the filtrate is evaporated in vacuo and the residue is dissolved in ice-cold 2N hydrochloric acid The crude N- (2,5-dimethyl-3-isoxazolidinylidene ) -N'-phenyl-1-pyrrolidinecarboximidamide hydrochloride is extracted with chloroform and the chloroform extract with 2N sodium hydroxide solution and water

2 2 13 9 5

washed, dried over sodium sulfate and evaporated. This gives crude N- (2,5-dimethyl-3-isoxazolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide.

The maleate produced therefrom with maleic acid melts at 114-116 ° (from ethyl acetate).

Variant ;

A further simplification of the method is that is added dropwise to a solution of pyrrolidine in ether or tetrahydrofuran phenyl isothiocyanate, in the resulting suspension of N-phenyl-N · ^1, N ^f tetramethylenthioharnstöff initiates an equivalent amount of phosgene and the reaction mixture as described above, further treated.

Example 19 : A mixture of 3.6 g (0.05 mol) of pyrrolidine and 15.2 g is added to a solution of 8.7 g (0.05 mol) of phenyl isocyanide dichloride in 120 ml of acetonitrile with stirring at -10 ° to 0 ° g (0.45 mol) of triethylamine was added dropwise. The reaction mixture is stirred for 15 minutes and then added to 12.1 g (0.05 mol) of 2,5-dimethyl-3-isoxazolidiniminhydroiodid, taking care that the temperature does not rise above 10 °. The suspension is stirred for 1 hour at 20 °. The mixture is filtered, the filtrate is evaporated and the residue is partitioned between chloroform and 2-n. Sodium hydroxide solution. The washed neutral with water and dried over sodium sulfate chloroform phase is evaporated to give crude N- (2,5-dimethyl-3-isoxazolidinyliden) -N'-phenyl-lpyrrolidincarboximidamid receives. The crude maleate prepared therefrom with maleic acid is purified by filtration through silica gel of particle size 0.063-0.2 mm with a solvent mixture of chloroform / methanol = 95: 5. The pure N- (2,5-dimethyl-3-isoxazolidinyliden) -N'-phenyl-l-pyrrolidincarboximidamidmaleat melts after ümkristallisation of ethyl acetate at 112-114 °.

22 1395

Example 20: 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-Essigsäureäthyläthylester. To yield the N- (thiomorpholine-3-ylidene) -N ^l -phenyl-4-morpholincarboximidamid hydroiodide of the formula

A • 3 = · V H ^ .- N = ON I .A 1 ί V

which melts at 220 °.

The corresponding free base is prepared as follows: A suspension of 4.3 g of the above hydroiodide in 50 ml of methylene chloride is treated with 10 ml of 10% aqueous sodium hydroxide solution. The organic phase is separated off and, after evaporation under reduced pressure, the free base is obtained, which after recrystallization from a mixture of ethyl acetate-hexane melts at 80-81 °. '

The following salts are prepared as described:

p-toluenesulfonate :

A solution of 3 × g of the free base in 30 ml of methylene chloride-acetone is mixed with 1.8 g of p-toluenesulfonic acid with stirring. The product is precipitated in the form of colorless crystals, which are recrystallized from a mixture of isopropanol-ethyl acetate. To yield the N- (Thiotnorpholin-3-ylidene) _{-N'-phenyl-4-i} morpholincarboximidamid p-toluenesulfonate, which melts at 172 ".

22 1395 _ ₄₈ _

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 recrystallized from a mixture of isopropanol-acetone. The N- (thiouriorpholine-3-ylidene) -N'-phenyl-4-tnorpholinecarboximidamide 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 with stirring 2 g of sulfuric acid in methylene chloride. The product is precipitated in the form of white crystals, which are recrystallized from a mixture of isopropanol-ethyl acetate. This gives the N- (thiomorpholin-3-ylidene) -N'-phenyl-4-morpholinearboximidamid sulfate, which melts at 220 °.

Tartrate :

A solution of 3.2 g of the free base in 40 ml of acetone is combined with 2.1 g of previously purified and dried d-tartaric acid in acetone The precipitated product is washed several times with diethyl ether and acetone The residue is recrystallized from acetone. to give N - "(thiomorpholine-3-ylidene) -N ^l -phenyl-4-morpholincarboximidamid-tartrate which melts at 102 °.

Methanesulfonate ;

A solution of 3.2 g of the free base in 30-40 ml of methylene chloride-acetone is treated with 1.2 g of methanesulfonic acid in methylene chloride. The product precipitates in the form of white crystals, which are recrystallized from a mixture of ethanol-acetone. This gives the N- (thiomorpholin-3-ylidene) -N'-phenyl-4-morpholinecarboximidamidethanesulfonate, which melts at 182 °.

2 2 13 9 5. ₄₉ .

Example 21: To a suspension of 8.1 g of N, 4-diphenyl-1-piperidinecarboximidamide hydroiodide in 35 ml of acetonitrile is added 4 g of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine. The mixture is heated for 14 hours on the water bath and stirred vigorously. The acetonitrile is evaporated under reduced pressure and the residue is crystallized while triturating with ethyl acetate. The product is recrystallized from acetone-ethyl acetate. The N ~ (thiomorpholin-3-ylidene) -N ', 4-diphenyl-1-piperidinecarboxiinidamide hydroiodide, which melts at 210 °.

The starting material for the above synthesis is prepared as follows:

A suspension of 29 g of N-phenyl-S-methyl-isothiourea hydroiodide in 100 ml of acetonitrile is combined with 20 g of 4-phenyl-piperidine. The mixture is refluxed for 15 hours and then the acetonitrile is evaporated under reduced pressure. The residue is recrystallized from a mixture of methylene chloride-acetone

 The N-diphenyl-1-piperidinecarboximidamide hydroiodide which melts at 151 ° C. is obtained.

EXAMPLE 22 A suspension of 6.5 g of N-phenyl-4-morpholinecarboximidamide hydroiodide in 35 ml of acetonitrile is mixed with 4 g of 3-ethoxy-5,6-dihydro-2H-1,4-oxazine with stirring. The mixture is heated on the water bath with vigorous stirring for 12 hours. The acetonitrile is evaporated under reduced pressure and the residue is recrystallized from a mixture of ethyl acetate-acetone. This gives the N- (morpholin-3-ylidene) -N'-phenyl-4-morpholinecarboximidamide hydroiodide, which melts at 228 °.

Example 23: A suspension of 9.8 g of N-phenyl-4-piperidinecarboximidamide hydroiodide in 40 ml of acetonitrile is combined with 5.5 g of 3-ethoxy-5,6'-dihydro-2H-1,4-oxazine with stirring , The mixture is heated with vigorous stirring for 12 hours on the water bath. The acetonitrile is evaporated under reduced pressure and the residue from a

22 1395 _ ₅₀ _

Recrystallized mixture of isopropanol-ethyl acetate. The N- (morpholin-3-ylidene) -N ^f -phenyl-4-piperidinecarboximidamidehydroiodide which melts at 202 ° C. is obtained.

Example 24: A suspension of 7.2 g of N- (4-methoxyphenyl) -4-morpholinecarboximidamide hydroiodide in 35 ml of acetonitrile is treated with 4 g of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine added 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-ethyl acetate. The N- (thiomorpholin-3-ylidene) -N '- (4-methoxyphenyl) -4-morpholinecarboximidamide hydroiodide which melts at 172 ° is obtained.

EXAMPLE 25 A suspension of 3.6 g of N-phenyl-4- (2,6-dimethyl-B-morpholine) -carboximidamide-hydroiodide in 15 ml of acetonitrile is stirred with 1.8 g of 3-ethoxy-5,6- dihydro-2H-l, 4-oxazine added. The Geaisch is refluxed with stirring for 16 hours. The acetonitrile is evaporated under reduced pressure and the residue is recrystallized from isopropanol-ethyl acetate. The N- (morpholin-3-ylidene) -N'-phenyl-2,6-dimethyl-4-morpholinecarboximidamide hydroiodide, which melts at 230 °, is obtained.

Example 26: A suspension of 3.5 g of N-phenyl-4- (2,6-dimethylmorpholine) -carboximidamide hydroiodide in 15 ml of acetonitrile is added under stirring to 2 g of 3-ethoxy-5,6-dihydro-2H-1 , 4-thiazine added. The mixture is refluxed for 16 hours under reflux. The acetonitrile is evaporated under reduced pressure and the residue is recrystallized from a mixture of acetone-ethyl acetate. This gives the N- (thiomorpholin-3-ylidene) -N'-phenyl-2,6-dimethyl-4-morpho-linearboximidamid-hydroiodide, which melts at 246 °.

Example 2 7: A suspension of 6.2 g of N-phenyl-1-pyrrolidinecarboximidamide hydroiodide in 30 ml of acetonitrile is charged with 3.8 g of 3-ethoxy-

2 2 1 3 9 p

5,6-dihydro-2H-l, 4-oxazine added 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'-phenyl-1-pyrrolidinecarboximidamide hydroiodide which melts at 226 ° C. is obtained.

Example 28 ; A suspension of 3.5 g of N- (4-fluorophenyl) -4-morpholinecarboximidamide hydroiodide in 15 ml of acetonitrile is added with stirring 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. recrystallized from a mixture of acetone-ethyl acetate. The N- (thiomorpholin-3-ylidene) -N '- (4-fluorophenyl) -4-morpholinecarboximidamide hydroiodide, which melts at 212 °.

Example 29 : A suspension of 3.6 g of N- (4-fluorophenyl) -4-morpholinecarboximidamide hydroiodide in 15 ml of acetonitrile is added under stirring to 2 g of 3-ethoxy-5,6-dihydro-2H-1,4-oxazine added 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 recrystallised from a mixture of isopropanol-ethyl acetate. "The N- (morpholinyl-3-ylidene) -N '- (4-fluorophenyl) -4-morpholinecarboximidamide hydroiodide which is obtained 215 "melts.

Example 30: A suspension of 8 g of N '- (4-methyl-morpholin-3-ylidene) -N-phenyl-S-methylisothiourea hydroiodide in 25 ml of acetonitrile is added with stirring with 2.5 g of morpholine. The mixture is refluxed in an oil bath for 36 hours. The acetonitrile is evaporated under reduced pressure and the residue from • a mixture of isopropanol-ethyl acetate recrystallized. The N '- (4-methyl-morpholin-3-ylidene) -N-phenyl-4-morpholinecarboximidamid-hydroiodide obtained after recrystallization from a

2 2 13 9 5

Mixture of acetone-ethyl acetate at 165 ° melts.

The starting material for the above 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 with cooling and stirring with 80 g of triethyloxonium fluoroborate in 100 ml of methylene chloride. The reaction mixture is stirred in a nitrogen atmosphere for 18 hours. Then introduce 3 hours of ammonia into the mixture. The reaction mixture is allowed to stand at room temperature for 30 hours and the solvent is evaporated off under reduced pressure on a 40 ° C water bath. The crude 4-methyl-3-imino-mprpholine is dissolved in 100 ml of acetonitrile and treated with stirring at room temperature with 24 g of phenyl isothiocyanate in 60 ml of acetonitrile. The mixture is stirred for 14 hours and concentrated to precipitate a crystalline product. This is recrystallized from a mixture of isopropanol-ethyl acetate. The N '- (4-methyl-morpholin-3-ylidene) -N-phenyl-thiourea, which melts at 121-122 °.

A solution of 15 g of N '- (4-methyl-morpholin-3-ylidene) -N-phenylthiourea in 50 ml of dioxane is added dropwise with stirring 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 recrystallized from a mixture of acetone-ethyl acetate. This gives the N '- (4-methyl-morpholine-S'-ylidene) -N-phenyl-S-methyl-isothiourea hydroiodide, which melts at 155 °.

Example 31 : A suspension of 3.8 g of N- (p-tolyl) -4-morpholinecarboximidamide hydroiodide in 15 ml of acetonitrile is added under stirring to 1.8 g of 3-ethoxy-5,6-dihydro-2H-1,4 oxazine added. 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 ethyl acetate-acetone. This gives the N- (morpholin-3-ylidene) -N '- (p-tolyl) -4-morpholinecarboximidamide hydroiodide, which melts at 192 °.

2 2 13 9 5. ₅₃ .

Example 32: To a suspension of 4 g of N- (p-tolyl) -4-morpholinecarboximidamide hydroiodide in 20 ml of acetonitrile is added 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-ethyl acetate. This gives the N- (thiomorpholin-3-ylidene) -N ^f - (p-tolyl) -4-morpholinecarboximidamide hydroiodide, which melts at 225 °.

Example 33: A suspension of 3.1 g of N-phenyl-1-pyrrolidinecarboxlidamide hydroiodide in 7 ml of acetonitrile is treated with 5 g of 4-carbethoxy-2-ethoxy-3,4,5,6-tetrahydropyrazine. The mixture is refluxed for 12 hours, then diluted with ethyl acetate and the resulting precipitate is filtered off. This is treated with potassium carbonate solution, washed with water and dried. By treating the resulting product with hydrochloric acid in isopropanol, the N- (4-Carbethoxy-piperazin-2-ylidene) -N'-phenyl-l-pyrrolidincarboximidamid hydrochloride, which melts after recrystallization from acetonitrile-ethyl acetate at 246-247 ° ,

The starting material is prepared as follows:

A cooled solution of 43 g of 4-carbethoxy-2-piperazinone in 400 ml of methylene chloride is mixed with 120 g of triethyloxonium fluoroborate in 150 ml of methylene chloride. The reaction mixture is stirred in a nitrogen atmosphere for 16 hours and then rendered 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 is distilled at 115 ° / 0.1 mmHg »4-Carbethoxy-2-ethoxy-3,4,5,6-tetrahydropyrazine is obtained.

22 13 95

Example 34 : A mixture of 2 g of N-phenyl-1-C4-carbethoxy-piperazine) -carboximideamide hydroiodide in acetonitrile and 2.5 g of 3-methoxy-5,6-dihydro-2H-1,4-thiazine becomes Hours heated to 70 °. The reaction mixture is allowed to stand at room temperature for 7 days and then diluted with diethyl ether. The resulting precipitate is recrystallized from a mixture of isopropanol-ethyl acetate. The N- (thiomorpholin-3-ylidene) -N'-phenyl-4-carbethoxy-1-piperazinecarboximidamide hydroiodide which melts at 206 ° C. is obtained.

The starting material is prepared as follows:

A suspension of 8.7 g of N-phenyl-5-methyl-isothiourea hydroiodide in 30 ml of isopropanol is treated with 9.6 g of 1-carbethoxy-piperazine. The mixture is refluxed with stirring for 18 hours and then evaporated under reduced pressure. This gives the N-phenyl-4-carbethoxy-l-piperazincarboximidamid-hydroiodide, which melts after recrystallization from isopropanol-ethyl acetate at 218-219 °.

Example 35 ; A mixture of 4 g of N-Cp-tolyl) -4-carbethoxy-1-piperazinecarboximidamide hydroiodide in acetonitrile and 8 g of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine is heated at 80 ° for one hour , The resulting solution is allowed to stand for 15 days at room temperature. The resulting solid material is filtered off and washed with ethyl acetate. The N- (thiomorpholin-3-ylidene) -N '- (p-tolyl) -4-carbethoxy-1-piperazinecarboximidamide hydroiodide is obtained, which, after recrystallization from acetonitrile-acetone, melts at 228-229 °.

The starting material is prepared as follows:

A mixture of 17.8 g of N-Cp-tolyl) -S-methyl-isothiourea hydroiodide and 18.9 g of 1-carbethoxy-piperazine in 50 ml of isopropanol is refluxed with stirring for 12 hours. The solvent is then evaporated under reduced pressure and the residue is triturated with ethyl acetate. This gives the N-Cp-tolyl) -4-carbethoxy-lpiperazincarboximidamid-hydroiodide, which melts after recrystallization from isopropanol-ethyl acetate at 201-202 °.

22 1395

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 5 ml of acetonitrile is refluxed for 10 hours. 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'-Cp-methoxyphenyl) O-carbethoxy-1-piperazinecarboximidamide hydroiodide is obtained which melts at 203-204 °.

The starting material is prepared as follows:

A mixture of 10 g of p-anisidine hydrochloride and 12.25 g of potassium thiocyanate is heated in 100 ml of ethanol for 16 hours. 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 resulting precipitate is filtered off and washed with acetone. This gives the S-methyl-p-methoxyphenyl isothiourea hydroiodide, which melts at 165-166 °.

A mixture of 6.4 g of S-methyl-N-p-methoxyphenylisothiourea hydroiodide and 6.2 g of 1-carbethoxy-piperazine in 50 ml of acetonitrile is refluxed for 10 hours. The solvent is evaporated under reduced pressure and the residue obtained triturated with ethyl acetate. The N- (p-methoxyphenyl) -4-carbethoxy-1-piperazinecarboximidamide hydroiodide is obtained which, after recrystallization from acetonitrile, melts at 156-157 °.

Example 37 : To a suspension of 7.4 g of N- (p-chlorophenyl) -4-taorpholinecarboximidamide hydroiodide in 50 ml of acetonitrile is added 4 g of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine. The mixture is refluxed with stirring for 14 hours. The acetonitrile is evaporated under reduced pressure and the residue is recrystallized from a mixture of isopropanol-ethyl acetate. You get that

22 13 95

N- (thiomorpholin-3-ylidene) -N ¹ - (p -chlorophenyl) -4-morpholinecarboxiiaidamide hydriodide.

The starting material is prepared as follows:

A suspension of 32 g of N - (p-chlorophenyl) -S-methyl-isothioureahydroiodide in 100 ml of acetonitrile is treated with 12 g of morpholine. The mixture is refluxed with stirring for 15 hours. The acetonitrile is evaporated under reduced pressure and the residue is recrystallized from a mixture of methylene chloride-ethyl acetate. This gives the N- (p-chlorophenyl) -4-morpholinecarboximidamide hydroiodide, which melts at 185-187 °.

Example 38 ; A suspension of 7 g of N- (p-chlorophenyl) -l-pyrrolidine-carboximidamide-hydroiodide in 40 ml of acetonitrile is treated while stirring with ig 3-ethoxy-5,6-dihydro-2H-l, 4-thiazine. The mixture is stirred vigorously on a 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- (thiomorpholin-3-ylidene) -N '- (p-chlorophenyl) -1-pyrrolidinecarboxime, idamido-hydroiodide, which melts at 198 °.

The starting material is prepared as follows:

A suspension of 16 g of N- (4-chlorophenyl) -S-methyl-isothioureahydroiodide in 50 ml of acetonitrile is treated with 5 g of pyrrolidine. The mixture is refluxed with stirring for 15 hours. Acetone acetonitrile is evaporated under reduced pressure and the residue is recrystallized from a mixture of ethyl acetate-isopropanol. The N- (4-chlorophenyl) -l-pyrrolidinecarboximidamide hydroiodide, which melts at 195-196 °, is obtained.

Example 39 : A mixture of 1.9 g of N-phenyl-1-pyrrolidinecarboximidamide and 1.4 g of · S-chloropropyl isothiocyanate in 25 ml of anhydrous dioxane is heated at 80 ° for 3 hours. The solvent is evaporated off under reduced pressure Residue was washed with diethyl ether and recrystallized from acetone-methanol. You get that

2 2 13 9 5

N- (thiomorpholin-3-ylidene) -N ¹ -phenyl-1-pyrrolidinecarboximidane-1-ol hydrochloride which melts at 260-262 °.

Example 40 : A mixture of 5.5 g of N-phenyl-4-morpholinecarboximidamide hydroiodide and 3.8 g of 5-ethoxy-2,3,6,7-tetrahydro-lH-1,4-thiazepine in 20 ml of acetonitrile with stirring for 6 hours at 80-90 ° heated. The solution is concentrated under reduced pressure, the resulting solid material is filtered off and recrystallized from acetonitrile. The N- (hexahydro-5H-1,4-thiazepin-5-ylidene) -N'-phenyl-4-morpholinecarboximidamide hydroiodide is obtained, which melts with decomposition at 225 °.

Example 41: A mixture of 3.6 g of N'-phenyl-1- (4-morpholinyl) ~ S -methyl-isothiourea hydroiodide and 2 g of 2-amino-2-thiazoline in 30 ml of acetonitrile is refluxed for 8 hours * The solvent is evaporated under reduced pressure, the residue basified with alkali and extracted with methylene chloride. The crude base is chromatographed on silica gel in ethyl acetate and the column is eluted with ethyl acetate containing increasing amounts of methanol. The late fractions give an oily base which is treated with hydrogen chloride in isopropanol. This gives the 1- (4-morpholinyl) -N'-phenyl-N- (2-thiazolinyl) -fonnamidinhydrochlorid, which melts after recrystallization · from a mixture of methanol and diethyl ether at 225-227 °.

Claims (11)

22 1395 _ ₅₈ _ Claim 1. A process for the preparation of guanidine derivatives of the formula CD, where R | an optionally substituted aliphatic or cycloaliphatic hydrocarbon radical, Rp is hydrogen, an optionally substituted aliphatic or cycloaliphatic hydrocarbon radical or R .. and Rp taken together represent an optionally substituted bivalent hydrocarbon radical of aliphatic character in which the carbon atoms of the chain may be interrupted by a heteroatom, R ^ Yfesserstoff , Lower alkyl, R ^ is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, di-lower alkylamino, halogeno, 'rifluoromethyl or optionally substituted phenyl, or oxo, R, - hydrogen or lower alkyl, or heteroalkylene radical with 3 chain members, on one carbon atom bonded on both sides which adds the group CN to an optionally unsaturated heterocyclic ring containing 2 to 3 heteroatoms from the group (oxygen, sulfur or nitrogen in the ring, or Het a heteroalkylene radical with 4 to Mean 6 chain links, the roup CN to form a heterocyclic six- to eight-membered ring, which in addition to the nitrogen atom, a hetero atom .from the ^ roup is oxygen, sulfur or nitrogen in the ring, complements the ^G, and Ph is an optionally substituted phenyl radical, their tautomeric compounds and salts, characterized in that "a) a compound of the formula 22 13 95 οι: (II) wherein X _{1 is} the group Ph-N =, in which Ph represents an optionally substituted phenyl radical, or a leaving group, X- the group ~ \ _ ^'Wor in R ₁ and R_ are as defined under the formula I 2
have, or a cleavable group and X- the group - N - ^ - C. Het wherein R-, R ,, R ₁ . and Hef as bivalent heteroalkylene radical having the group CN have the meanings given under the formula I, or a leaving group, with the proviso that only one of the substituents X., X or X can be a cleavable group, and wherein one of the groups X., X- and X is linked through a double bond to the carbon atom, with an amine or imine identical to the missing amino or imino group defined under X., X or X - to the leaving group replace, or b) a guanidine compound of general formula IV Ph-N-C-I Λ. (IV) wherein Ph, R ₁ and R_ have the meanings given under the formula I, with a compound of general formula V Z Θ C. Het 2 2 13 9 5 - 6o -. wherein Y is lower alkoxy, lower alkylthio, halo, or Y is two lower alkoxy groups which reside on the same C-Acom, and Z is a tetrafluoroborate, a fluorosulfonate, a lower alkyl sulfate, e.g. Methylsulfate or lower alkanesulfonate, e.g. Methanesulfonate anion or a. Halide, e.g. Chloride or bromide, wherein when Y has the meaning of two lower alkoxy groups on the same carbon atom, Z is omitted as the anion, or when R 1 is hydrogen, the tautomeric form is present as the free base, or c) guanidine derivatives of the general formula VI Ph-N-C-NH-C-NHR (VI) or a tautomeric form thereof, wherein. Ph, R, R and R have the abovementioned meanings and Y has the meaning of an oxo, thioxo or NH group, with a compound of general formula VII ^R 4 ^R 5 - - r ι Z- (CH ₀₎ -CH-C- (CHJ -Z (VII) 1 2 2 al 2 TLZ in which n or n is 0, 1, 2 or 3, with the proviso that η. and η together are not more than 3, Z is a halogen atom, Z is an oxo group or together the group consisting of hydrogen and halogen, where the hydrogen atom may be part of a methylene group, or Z. and Z taken together via an imino ^R 4 ^R 5 II group to supplement the bivalent alkylene radical -CH-CH- to an aziridine derivative, wherein R and R have the meanings of hydrogen, 2 2 13 9 5 - egg - d) for the preparation of compounds of the formula I in which Het is a heteroalkylene radical having 4-6 chain members which adds the group C-N to a heterocyclic 6-8 ring, compounds of the formula IV Ph-N = C-NH (IV), wherein R ₁ , R_ and Ph have the meanings given above with a Halogenalkylenisothiocyanat of formula VIII (VIII) n.
N CS wherein Z represents a halogen atom, and the bivalent radical "alkylene" means an alkylene chain having 3-5 carbon atoms, wherein a hydrogen atom in the alkylene chain may be replaced by the substituent Rl, which has the meaning for R, with the exception of hydrogen replaced , or e) compounds of the formula I in which R.sup.1 has the meaning defined above and R.sup.1 and R.sup.2 denote hydrogen, by reaction with a reactive ester of an aliphatic or cycloaliphatic alcohol to compounds of the formula I in which R.sup.1 and / or or R in the above definitions for R. and R are different from hydrogen, or f) in compounds of general formula IX Ph NCNC Het J ( _IX ) VV V 22 1395 _62- 10.9.1980  AP C 07 D / 221 57 464 7 12 wherein R _1, R, R _n., Ph, and Het have the meanings given under formula I, and one of the substituents Ri and RA the meaning of Ro or R ~ has, and the other represents a minoschutzgruppe ^A, or both RX and RX represents an amino protecting group, these and enf desired alls additional ^v out steps carried out, and / or, if desired, converting compounds of the formula I obtained into a ^ü alz, and / or, if desired, obtained ^ AIZ e of the compounds of Formula I converts to the free bases. 2 · Method according to item 1, characterized in that a compound of the formula Ha (IIa) wherein Xo ^e i ^ne means cleavable ^ü roup with an amine of the formula R _{2 1} HHR reacted. 3. The method according to item 1, characterized by reacting a compound of formula Hb Ph-H = C-X. ₁ R ₂ 13 95 -63- '10.9.1980 AP C 07 D / 221 395 57 464/12 wherein X ^ represents a cleavable group, with an imino compound of the formula III HN = C Het) ^{(III) R} 3. ' implements © , »* * · - * 4. The method according to item 1, characterized in that a compound of Pormel Hc 0 X ₁ -C- u i -lU-c ^ Het / \ Hal O , / \ · Ro ^R 1 ^R 2 in which Σ- represents a cleavable group, with an optionally substituted aniline of the Pormel Ph-IfHp. 5φ Process according to items 1 to 4, characterized in that a cleavable ^K est in the compounds of the formulas II, Ha, Hb and Hc is a Nlteralkylthio, Hiederalkoxy- or a halogen. 2.2 1395 -64- 10.9.1980 AP C 07 D / 221 395 57 464/12 6. The method according to item 1, characterized in that a cleavable - ^ est X-, X ₂ ^ ⁰¹ ^ - ^ 3 i ⁿ ^ ^en compounds of the formula II is a lower alkylthio, Niedefalkoxygruppe or a halogen. 7 · Process according to items 1 to 6, characterized in that compounds of the formula I Ph - N = C - N = R ₁ R ₂ wherein R-. an optionally substituted aliphatic or cycloaliphatic hydrocarbon radical, R _{2 is} hydrogen or an optionally substituted aliphatic hydrocarbon radical, or R ₁ and R _? taken together, an optionally substituted bivalent hydrocarbon radical of aliphatic character in which the carbon atoms of the chain may be interrupted by a heteroatom, R-, hydrogen, lower alkyl, R. hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, di-lower alkylamino, halogen, trifluoromethyl or optionally substituted phenyl or, on a carbon atom which is simply bonded on both sides, also oxo, Rc is hydrogen or lower alkyl, Het is a heteroalkylene radical with 3 chain members, the group CN to an optionally unsaturated heterocyclic five-membered ring with 2 to 3 heteroatoms from the ^u group oxygen, sulfur or nitrogen in% ng he- 22 13 95 -65- 10.9.1980 AP C 07 D / 221 57 464/12 and Ph represents an optionally substituted phenyl radical, their tautomeric compounds and salts. Process according to items 1 to 6, characterized in that compounds of the formula I, in which R 1 is lower alkyl or cycloalkyl, R p is hydrogen or lower alkyl or both are taken together, a lower alkylene chain optionally substituted by an oxygen, sulfur or optionally substituted by z _e B. lower alkyl nitrogen atom may be interrupted, R ~ is hydrogen or lower alkyl, R. hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, di-lower alkylamino, halogen, trifluoromethyl, or simply bonded on both sides. Carbon atom also oxo, or phenyl optionally substituted by lower alkyl, lower alkoxy or halogen, R, - hydrogen or lower alkyl, and Het a heteroalkylene radical with 3 chain members, the group CN to a saturated or monosaturated heterocyclic five-membered ring with 2 to 3 Heteroatoraen from the group oxygen, sulfur or nitrogen in ^R ing supplements, and Ph represents an optionally substituted phenyl radical, as well as their tautomeric compounds and s
alze, manufactures. 9. A process according to items 1 to 6, characterized in that compounds of the formula I in which R _{1 is} lower alkyl or cycloalkyl, R p is hydrogen or lower alkyl or both taken together are a lower alkylene chain optionally substituted by an oxygen or sulfur atom or 2 2 1.395 -66- 10.9.1980 AP C 07 D / 221 395 57 464/12 if necessary by z. B. lower alkyl substituted nitrogen atom may be interrupted, for. B. Niederalkyleiamino, z. B, pyrrolidino, 2,5 - ^D imethylpyrrolidino, piperidino, 2-methylpiperidino, hexahydroazepino or octahydroazocino, oxanoweralkyleneamino, e.g. B-. Morpholino, thian-lower alkylene-amino, e.g. B. thiomorpholines or Azaniederalkylamino, z. B. piperazino, N-methyl or N-phenylpiperazino, R ^, hydrogen or lower alkyl, R. hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylamino, di-lower alkylamino, halogen, trifluoromethyl, or on a both sides simply bonded carbon atom and oxo, or phenyl optionally substituted by lower alkyl, lower alkoxy or halogen, R _{1 is} hydrogen or lower alkyl, and Het is a bivalent heteroalkylene radical having 3 chain members, which _{adds the} ring CN to a saturated or monounsaturated heterocyclic five-membered ring containing 2 to 3 heteroatoms in% ng and for example, an imidazoline, imidazolidine, oxazoline, oxazolidine, ^IJ -'hiazoline, thiazolidine, isoxazoline, isoxazolidine, isothiazoline, isothiazolidine, oxadiazoline, oxadiazolidine, thiadiazoline, thiadiazolidine, pyrazoline, Py may be pyrazolidine or iriazoline ring, and Ph is an optionally substituted by lower alkyl, lower alkoxy or halogen phenyl mean, as well as their tautomeric compounds and salts. 10. ^v experienced according to item 1 · to 6, characterized in that compounds of formula I in which R ^ Niederalkyl.oder cycloalkyl, R _{2 is} hydrogen or lower alkyl 2 2 13 9 $ -67- 10.9.1980 AP C 07 D / 221 57 464/12 or the group -NTLRp example ITiederalkyl enamino in which the ITiederalkylenkette may be optionally interrupted by one ^u auerstoff- or sulfur atom, and is, for example, pyrrolidino, 2,5- imethyl ~ ^u pyrrolidino, 2,5-dimethylpyrrolidino, piperidino, 2-methylpiperidino , Morpholino or thiomorpholines, R _{3 is} hydrogen or lower alkyl, R. hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, trifluoromethyl or carbon on one or both sides also oxo, or optionally substituted by ITiederalkyl, Mederalkoxy or halogen-substituted phenyl, R, - Hydrogen or ITiederalkyl, and Het as a bivalent heteroalkylene radical with the group C-IT together an optionally monounsaturated heterocyclic five-membered ring, such as, for example, imidazoline, imidazolidine, oxazoline, oxazolidine, thiazoline, thiazolidine, oxadiazoline, oxadiazolidine -, Triazolin-, Thiadiazolin- or i'hiadiazolidinring, and Ph is a given N-substituted by lower alkyl, lower alkoxy or halogen-substituted phenyl radical, as well as their tautomeric compounds and salts. Process according to items 1 to 6, characterized in that compounds of formula I in which R _{1 is} lower alkyl, z, B is methyl or ethyl, Rp is hydrogen or lower alkyl, for. B represents methyl or ethyl, or · the ^above-roup -ITR Rp as being optionally interrupted by an oxygen or sulfur atom ITiederalkylenamino, for example as pyrrolidino, piperidino, · Morpholini 22 1 395 -68- 10.9.1980 AP C 07 D / 221 395 57 464/12 or thiomorpholino, R ^ is hydrogen or lower alkyl, e.g. Methyl or A _e methyl, R. is hydrogen, lower alkyl, Z ₀ as methyl or ethyl, Hiederalkoxy, z. Methoxy or ethoxy, alkylthio, for example methylthio or ethylthio, halogen, for example chlorine or bromine, trifluoromethyl or optionally lower alkyl, eg. Methyl or ethyl, halogen, e.g. B, chloro or bromo substituted phenyl, R ₁ - hydrogen or lower alkyl, e.g. As methyl or ethyl and Het as divalent heteroalkylene radical with the group C-IT an optionally monounsaturated heterocyclic five-membered ring, such as. B. 4-imidazoline, 4-oxazoline, 4- ^IJL 'hiazolin-, 4- (1,3,4) -Thiadiazolin-, 4- (1,3,4> - oxadiazoline or Isoxasolidinring means, and Ph is optionally substituted by lower alkyl, such as methyl or ethyl, halogen such as Cj ₁ I _{01 o} the - means ^ rom or Hiederalkoxy, such as methoxy or ethoxy, substituted phenyl radical, as well as its.... tautomeric compounds and ^ 'ales, manufactures. 12. The method according to item 1 to 6, characterized in that one prepares the Ef- (2,5-dimethyl-3-isoxazolidinyliden) -li ^l phenyl-4-morpholine-carboximidamide and their tautomeric Erbindungen and ^ü alze. 13 · Method according to items 1 to 6, characterized by. that the li _! O-methyl-4- (1,3,4) -thiadiazolin-2-ylidene-U- ^t- phenyl-4-morpholine-carboximidamide hydrochloride, as well as their tautomeric compounds and salts. 22 13 95 -69- 1Ο · 9.198Ο AP C 07 D / 221 395 57 464/12 14 · Process according to items 1 and 6, characterized in that compounds of the formula Ib R ₁ R ₂ in which IL and Rp denote an optionally substituted aliphatic or cycloaliphatic hydrocarbon radical or R ₁ and Rp taken together represent an optionally substituted bivalent hydrocarbon radical of aliphatic character in which the carbon atoms of the chain can be interrupted by a heteroatom, R 1 is hydrogen, lower alkyl, R is hydrogen, lower alkyl, lower alkoxy, lower alkylamino, di-lower alkylamino, halogen, lower alkoxycarbonyl or optionally substituted phenyl, or a both sides simply "bound carbon atom also oxo, Het is a heteroalkylene having from 4 to 6 members of the ^above roup CN to form a heterocyclic six- to eight-membered ring, in addition to the nitrogen atom, a hetero atom also contains oxygen, sulfur or nitrogen, ^and when Ph represents an optionally substituted phenyl radical, produces its tautomeric compounds and salts, Process according to items 1 and 6, characterized in that compounds of the formula Ib in which R ₁ and Rp are lower alkyl or cycloalkyl, or both taken together, are straight, branched or substituted 22 13 95 -70- '' '10.9.1980 AP C 07 D / 221 395 57 464/12 Lower alkylene chain, optionally substituted by an oxygen, sulfur or optionally by z. B. lower alkyl, phenyl or lower alkoxycarbonyl-substituted nitrogen atom may be interrupted, R ^ is hydrogen or lower alkyl, R. hydrogen, lower alkyl, lower alkoxy, Niederalkylainino, di-lower alkylamino, halogen, lower alkoxycarbonyl, or on a double-sided easily bonded carbon atom also oxo, or optionally lower alkyl, Lower alkyl or halogen substituted phenyl, and Het a heteroalkylene radical having 4 to 6 chain members, the aie öruppe CN to a heterocyclic six- to Achtring, which in addition to the nitrogen atom or a heteroatom from the group oxygen, sulfur or nitrogen in the ring contains, and Ph represents an optionally substituted phenyl radical. as ai
manufactures. as well as their tautomeric compounds and alze, Verfahrenβ »Process according to item 1 and 6, characterized in that compounds of the formula Ib, in which R and Rg are lower alkyl or cycloalkyl, or both taken together a straight, branched or substituted lower alkylene chain optionally substituted by an oxygen or sulfur atom or optionally by z. B. lower alkyl ₇ phenyl or lower alkoxycarbonyl substituted nitrogen atom may be interrupted, as Niederalkylenamino example Pyrrolidiono, 2,5-dimethylpyrrolidino, piperidino, 2-methylpiperidino, 4-Phenylpiperidino, hexa- 22 13 95 «γι-10.9.1980 AP C 07 D / 221 57 464/12 hydroazepino or octahydroazocino, as Oxaniederalkylenamino, for example, morpholino, 2,6-Dimethylmorpholino, as Thianiederalkylenamino "example, thiomorpholino or as Azaniederalkylenamino, for example, piperazino, N-lower alkoxycarbonyl, N-methyl or N-phenylpiperazino, R ~ hydrogen or lower alkyl, R. Hydrogen, lower alkyl, lower alkoxy, lower alkylamino, di-lower alkylamino, halo, lower alkoxycarbonyi or optionally lower alkyl, lower alkoxy or halogen substituted phenyl, and Het is a divalent heteroalkylene radical having 4 to 5 chain members, _forming the G _rii pp _e CN into a heterocyclic six- to _{seven-membered} ring, which in addition to the nitrogen atom also contains a heteroatom from the group consisting of oxygen, sulfur or nitrogen in the ring, and Ph represents a phenyl radical which is unsubstituted or substituted by lower alkyl, lower alkoxy or halogen and also produces their tautomeric compounds and salts, 17. The method according to item 1 and 6, characterized in that compounds of the formula Ib, in which R ₁ and R _{2 is} lower alkyl or the group -NR _- -R ₂ together a lower alkylamino in which the straight, branched or substituted by phenyl Lower alkylene optionally by an oxygen, sulfur or optionally by an oxygen, sulfur or optionally by z. Be lower alkyl, phenyl or H'iederalkoxycarbonyl substituted nitrogen atom may be interrupted, and for example as Niederalkylenamino pyrrolidino, 2,5-dimethylpyrrolidino, piperidino, 2.2.13 95 _ _72- 10.9.1980 AP C 07 D / 221 57 464/12 2-methylpiperidino, 4 ~ phenylpiperidino, hexahydroazepino or Octahydroazocino as Oxaniederalkylenamino beispielsv / else morpholine), 2,6-dimethylmorpholino, as Ihianiederalkylenamino example, '^' hioraorpholino or ^A zaniederalkylenamino example piperazino, IT-ethoxycarbonyl ^, U-methyl-, N-phenylpiperazino, R-, hydrogen or lower alkyl, R. Y / acid, lower alkyl, lower alkoxy, lower alkylamino, halogen, lower alkoxycarbonyl, or phenyl optionally substituted by lower alkyl, lower alkoxy or halogen and Het is a divalent heteroalkylene radical having 4 to 5 chain members, which adds the group CN to a heterocyclic-to-di-seven-membered ring which, in addition to the nitrogen atom, also contains a heteroatom from the group oxygen, sulfur or nitrogen in the ring, and for example a morpholine, thiomorpholine, 2H-3,4, 5,6-tetrahydro-1,3-thiazine, 2H-3,4,5,6-tetrahydropyrimidine, piperazine or hexahydro-1,4-thiazzepine ring and Ph represents an optionally substituted by lower alkyl, lower alkoxy, or halogen-substituted phenyl, as well as their tautomeric compounds and ^ alze prepared. 18 "according to Puniit, I and 6, characterized in that compounds of formula Ib, in which R ₁ and Rp lower alkyl, z. As methyl or ethyl, or ^G roup -NR-Rp. together a Niederalkylenamino in which the straight, branched or substituted by phenyl lower alkylene optionally by an oxygen, sulfur or optionally by lower alkyl, such as *. *. ^f ^ ~ ^ -73- 10.9.1980 AP C 07 D / 221 395 57 464 ./12 z, B, methyl or ethyl or lower alkoxycarbonyl, such as ζ. B. methoxy or ^A thoxycarbonyl-substituted nitrogen atom may be interrupted, and for example pyrrolidino, piperidino, 4-phenylpiperidino, morpholino, 2,6-dimethylmorpholino, thiomorpholines, piperazino, Ji-A-ethoxycarbonylpiperazino may be, R ^ is hydrogen or Liiederalkyl , z, B is methyl or ethyl, R is hydrogen, lower alkyl, e.g. Methyl or ethyl, or lower alkoxycarbonyl, e.g. For example, methoxy or Aethoxycarbonyl and Het a zv / eiv / ertigen heteroalkyl: enrest, with the group C-Ii this to a heterocyclic six-membered ring, in addition to the nitrogen atom or a heteroatom from the _GrU ppe oxygen, sulfur or nitrogen in the ring contains,. Complemented, and may be, for example, a morpholine, Thiomorpholin-, or piperazine ring, and Ph is optionally substituted by lower alkyl, such as methyl or ethyl, halogen, such as. B, * luor, chlorine or bromine or Hiederalkoxy, such as. B, methoxy or ethoxy, substituted phenyl radical, as well as their tautomeric compounds and salts, Process according to items 1 and 6, characterized in that the N- (thiomorpholin-3-ylidene) -N ^f -phenyl-4-morpholinecarboximidamide and also its tautomeric compounds and salts are prepared. 20. The method according to item 1 and 6, characterized in that one prepares the H- (morpholine-3- ^r liden) -N ^l -phenyl-4-morpholincarboximidamid as well as theirautautomeren connections and ^ö alze produces »