CA1112648A

CA1112648A - 2-[3,4-disubstituted-phenylimino]-imidazolidines

Info

Publication number: CA1112648A
Application number: CA342,041A
Authority: CA
Inventors: Helmut Stahle; Herbert Koppe; Werner Kummer; Alexander Walland
Original assignee: Boehringer Ingelheim GmbH
Current assignee: Boehringer Ingelheim GmbH
Priority date: 1978-12-18
Filing date: 1979-12-17
Publication date: 1981-11-17
Also published as: DK146821B; ES8100272A1; EP0012822A1; DE2854659A1; EP0012822B1; DE2964166D1; AU526539B2; NZ192426A; ES486967A0; ZA796832B; FI68814C; ES486971A0; IE792447L; NO794114L; PH22130A; ES8102100A1; FI68814B; ES486970A0; AU5389379A; PT70592A

Abstract

ABSTRACT
Novel 2- [3,4-disubstituted-phenylimino] -imidazolidines This invention related to 2- [ 3,4-disubstituted-phenyli-mino ] -imidazolidine compounds of general formula (I) I
[ wherein Z represents a phenyl group substituted in one of the 3- and 4- positions by a fluorine atom and in the remaining 3- or 4- position by a chlorine atom or a methyl, nitro or amino group] and acid addition salts thereof, their preparation and pharmaceutical compositions containing such compounds or salts. In that the compounds of general formula (I) and their acid addition salts possess presynaptic and .alpha.-adrenergic activity they are suitable for use in the treatment of migraine.

Description

NOVEL 2-~3,4-DISUBSTITUTED-PHENYLIMINO~ IDAZOLIDINES

This invention relates to noYel 2-[3,4-disubstituted-phenylimino~-imidazolidine compounds and their acid addition salts, their preparation and pharmaceutical compositions thereof.

As a result of their pharmacological and therapeutic properties, 2-phenylimino-imida701idines have long been of interest. Conse~uently, compounds of this type have frequently been described in the literature and have been disclosed in, for example, Belgian Patent Specifi-cations Nos.623 305,653 933, 687 656, 687 657 and 705 944. In these references the essential processes for the production of 2-phenylimino-imidazolidines have also been described.

Previously the major interest has been in the 2-[2,6-disubstituted-phenylimino]- imidazolidines and their action upon the central nervous system.

However, it has now been found that a number of 2-[3,4-disubstituted - phenylimln~-imida~olidines surprisingly effect practically no central stimulation , instead predominantly effecting a peripheral pre-synaptic ~-adrenergic stimulation.

According to one aspect of the present invention we therefore provide 2- E 3,4-disubstituted-phenylimino]-imi-dazolidine compounds of general formu]a (I) H
/~ - , Z -N ~
N
H
[wherein Z represents a phenyl grou~ substituted in one of the 3- and 4- positions by a Eluorine atom and in the ,. ..
,, ~; ...

~:, ~ ' : " .
~,'' 26~

remaining 3- or 4- position by a chlorine atom or a methyl, nitro or amino group and acid addition salts thereof.
According to a further aspect of the present invention there are provided processes for the preparation of compounds of general formula (I) (as hereinbefore defined) which comprise reacting ethylene diamine with a compound of formula Il:

/x Z N _ C II
\Y
[wherein Z is as hereinbefore defined and X and Y, which may be the same or diEferent, each represents a halogen atom or a hydrothio, hydroxy, amino or nitroamino group or an alkylthio or alkoxy group containing 1 to 4 carbon atoms], or ~b) reacting an aniline of formula (III) Lwherein Z is as hereinbefore defined] with a compound of formula (IV) :
;
:`, N
:~ R ~ IV

f.' ~,~ R2 [wherein Rl represents a group susceptible to nucleophilic exchange and R2 represents a hydrogen atom or an aliphatic acyl group~ and, when R2 represents :~
.
:; ~ other than a hydrogen atom, subsequently splitting off the acyl group hydro-lytically; and

- 2 -~ ~, ,. . .
,. . .

' :' `' , ' (c) ~for the preparation of 2-I~-fluoro-3-aminophenylimino]-imida-zolidine hydrogenating 2-14-fluoro-3-nitro phenylimino]-imidazolidine.
Compounds of formula ~II) used in process ~a) according to the invention are preferably isocyanide dihalides ~more preerably the dichlorides),thioureas, carbaminic acid esters, thiocarbaminic acid chlorides, guanidines (or acid addition salts thereof) or nitroguanidines or 0-alkylureas (or acid addition salts thereof), S-alkyl thioureas (or acid addition salts thereof) or alkyl thiocarbaminic acid chlorides in which the said alkyl groups contain 1 to 4 carbon atoms.
The reaction (a) is conveniently effected at temperatures between 0 and 200C, the precise temperature depending upon the groups X and Y. Polar protic, polar aprotic and non-polar solvents may be used. Depending upon groups X and Y, the reaction may also be effected at an elevated temperature without a solvent. Where one or both of groups X and Y represents a halogen atom, it is recommended to use an acid-binding agent for the reaction. The ~ .
; reaction time is determined by the reactivity of the reagents used and ranges from several minutes to several hours.
In process (b) according to the invention, a compound of formula ,, ~;~ (IV) is preferably used in which the nucleophilically exchangeable group re-presented by Rl is a halogen atom ~more preferably a chlorine atom) or a methyl-; ~
thio, methoxy or hydroxyl group. When R' is a hydroxyl group the compound of formul IV may be present in the tautomeric keto-form.
- In the case where R represents a hydroxyl group, R is advant-ageously an acyl group such as, for example, an acetyl group. The reaction ~: taking place in this case between an aniline of formula (III~ and an 1-acylimidazolidin-2-one is appropriately effected in the presence of phosphorus oxychloride at a temperature of from 50 to _ 3 -" ~ , . :

.. , : ~

100C. The reaction lasts advantageously ~rom several hours to several days~ In order to produce compounds of formula (I~, hydrolytic deacylation is required, which may be achieved by, for example, refluxiny with lower alcohols such as, for exa~ple, methanol.

The reaction of anilines of formula (III) with 2-methylt-hioimidazol-2-ines or 2-chloroimidazol-2-ines re~uires the use of elevated temperatures (100 to 180C). Solvents, though not required, may,if desired, be used. Preferable as solvents are those of polar protic or polar aprotic character.

The reduction of process (c~ above may be effected by hydrogenation in the presence of finely dispersed metal catalysts such as, for example, palladium, platinum, Raney-nickel at normal or excess pressure or by means of "nascent" hydrogen, for example produced by hydrazine in the presence of Raney-nickel.
:~ .
The starting products of the processes (a) and (b) above can all be derived from anilines of fo~mula (III) and, as such, are readily accessible followin~ methods des-cribed in the literature.
.
The 2-phenyl-iminoimidazolidines of formula (I) according to theinvention may be converted into their physiologi-cally acceptable acid addition salts in a conventional manner. Acids suitable for salt formation are, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, -_-hydroxybenzoic acid, p-amino~enzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methane-sulfonic acid, ethanephosphonic acid and 8-chlorotheo-phylline.

I-t should be noted that acid addition salts of compounds of general formula (I) (as hereinbefore defined) other than those classified as physiologically acceptable may be useful in the preparation of compounds of general formula (I~ and the physiologically acceptible acid addition salts thereof.

The novel compounds as well as their acid addition salts possess valuable therapeutic properties. In pharmacolog-ical examinations of rats and cats it was found that they effect a pre-synaptic stimulation of the peripheral ~ --adreno~receptors and thus exert a peripheral neuros-ympathic and ~vagal transmission inhibition. As there are practically no central activities, an influence on blood pressure is not observed. The novel compounds may be used, for example, for the treatment of migraine.

Preferred compounds of general formula (I) by virtue of ~heirespecially favourable pharmacological properties are the following:
2- [3-fluoro-4-methylphenylimino] -imidazolidine, 2- [4-fluoro-3-methylphenylimino] -imidazolidine, 2- [4-fluoro 3-chlorophenylimino] -imidazolidine, 2 ¦4-fluoro--3~nitrophenylimino ] -imidazolidine and 2- [4-fluoro-3-aminophenylimino ] -imidazolidine and acid addition salts of the aforesaid compounds.

According to a still further aspect of the present inven-tion we therefore provide pharmaceutical compositions comprising at least one compound of formula (I) (as here-inbefore defined) or a physiologically acceptable acid 6~

addition salt thereof as active ingredient in association with a pharmaceutical carrier or excipient.

The compounds of genQral formula (I) and the physiologi-cally accepta~le acid addition salts thereof may be used either enterally or else parenterally. Pharmaceutical compositions in dosage unit form, for example for oral administration, conveniently contain from 0.5 -to 50 mg, preferably from 1 to lO mg, of the active ingredient acc-ording -to the invention.
The compounds of formula (I) and their physiologically acceptable acid addition salts may also be used together with other physiologically active substances. Suitable forms for pharmaceutical preparations are, for example, tablets (including coated tablets), capsules, supposit-ories, solutions, aerosol sprays or powders; together with conventional adjuvants, excipients, carriers, disintergrants or lùbricants or substances for obtain-ing sustained release.
The following Examples serve to illustrate the invention without restricting its scope.
xample l 2-(3~Fluoro-4-methylphenylimino)-imidazolidine 14.33 g (o.043 mol) of N-(3- luoro-4-methylphenyl)-S-methyl-thiouronium-iodide are refluxed together with 4.35 ml (~150%) of ethylenediamine in 58 ml of methanol for 8 hours while stirring. The solvent is then distilled off in vacuo and the residue is dissolved in 1 N hydrochloric acid. The hydrochloric acid solution is buffered to pH 7 with 5N KOH
and extracted twice with ether (the ether extracts being abandoned) and subsequently made alkaline with 50~ potas-sium hydro~ide solution. This causes the precipitation of an oil, which crystallizes within a short time. After vacuum filtration, the residue, the title compound, is washed :: ;
'~ :

, ~%~

with water a~d dried.
Yield: 6.1 g = 73.41% o theory Melting point: 109.5 - 110.5 C
Rf: 0.1 system: benzene 50, dioxan 40, ethanol 5, conc.
NH~O~ 5 Carrier: silicagel G ~ luminous pigmen-t,made visihle by:
UV and potassium iodoplatinate Elemental analysis:
C H F ~l Calcn 62.16 6.26 9.8321.75 %
~ound: 62.44 ~.44 9.8422.04 %

Example 2 2-(4-Fluoro-3-methylphen~limino1-imi~azolidine . .
46 g (0.141 mol~ of N-(4-fluoro-3-methylphenyl?-S-methylth-iouronium iodiae are refluxed together with 14.1 ml (~150%) of ethylenediamine in 190 ml of methanol for 5 hours while stirring. The solvent is then distilled off in vacuo and the residue is dissolved in lN hydrochloric acid. The hydrochloric acid solution is buffered to pH 7 with 5N KOH and extracted twice with ether (the ether extracts being abandoned1. ~fter admixing with active charcoal and subsequent filtration, the filtrate is made alkaline with 50% KOX. At first, the base precipiates as an oil, then, after covering with petroleum-ether at at a temperature of from 40 to 80C and with vigourous stirring it crystallizes. After vacuum filtration the residue, the title compound, is washed with water and dried.
Yield: 9.4 g = 34.50% of theory Melting point: 113-114 C
Rf: 0.3 system: benzene 50, dioxan 40, ethanol 5, conc.

Carrier: silicagel G ~ luminous pigment, made visible by UV and potassium iodoplatinate.

.. . .

~2~

Elemental Analysis:
C H F N
Calc: 62.16 6.26 9.83 21.75 %
Found 62.04 6.13 9.85 21.78 %
_xample 3 2-(4-Fluoro-3-nitrophenylimino~-imidazolidine A mixture consis~ing of 16.6 g (0.1 mol) of 4-fluoro-3-nitroaniline and 12.54 g (0.11 mol) of l-acetyl-imidazolidin-~-one in 145 ml of phosphorus oxychloride are heated for 70 hours at 50 degr. C while stirring. The excess of phosphorus oxychloride is then removed by distillation in vacuo. The residue is treated with ice/water until complete solution. The solution is made alkaline with 4N NaOH while cooling with ice and then extracted four .- times with ethylacetate. The organic layer is dried over anhydrous sodium sulfate and evaporated. The crude material is recrystallized from toluene to ~ ,;~, , yield 23.1 g (88.1 % of theory) 1-acetyl-(4-fluor-3-nitrophenyl-imino)-imida-zolidine having a melting point of 150 to 151 degr. C.
, .
4.5 g (0.0173 mol) of 1-acetyl-2-(4-fluoro-3-nitrophenylimino)-imidazolidine, m.p. 150 - 151C, are refluxed for lO hours in 66 ml of methanol while stirring. After cooling, the insoluble remnant is filtered off, the - 20 solvent is distilled off in vacuo and the residue remaining is dissolved in 1 N hydrochloric acid. The hydrochloric acid solution is extracted at rising pH-values (made alkaline by the stepwise addition of 2 N sodium hydroxide solution) with ether, fractionated from pH 8.5, precipitated and vacuum fil-tered. The solid fractions, the title compound, are united and dried.
Yicld: 1.7 g = 43.81% of theory Melting point: 146 - 147C
Rf: 0.4 system: benzene 50, dioxan 40, ethanol 5, conc.
NH4OH 5. Carrier: silicagel G + luminous pigment, .," -, . . .
.. ,: : . . .; .
: , . , . . ~ . . ,, :

~2~

Detector: W; potassium iodoplatinate.
Elemental Analysis:
C H F N
Calc.: 48.21 4.05 8.48 24.99 %
Found: 47.55 4.02 8.71 24.41 %
Example 4 2-(4-Fluoro-3-chloroph nylimino)-imidazolidine ,~` 20.8 g ~0.06 mol~ of N-(3-chloro~4-fluorophenyl)-S-methyl-thio-`~ uronium iodide are refluxed together with 6 ml (nv150%) of ethylenediamine ~ ~ , ~ ' 10 in 82 ml of methanol for 4 hours, while s~, ~:~
~,~, ,",~

. :~

; .
.~ .

- 8a -, :, - :-' ..

~2~
g stirring. The solvent is then distilled off in vacuo and the residue dissolved in 1 N hydrochloric acid. The hydrochloric acid solution is extracted twice with ether (the ether phases being abandoned1 and subsequently made alkaline with 50% KOH~ This results in the precipitation of an oil, which crystallizes within a short time. After vacuum filtration the residue, the title compound, is washed with water and dried.
Yield: 7.2 g = 56.17% of theory Melting point: 118.5 - 119.5 C
Rf: 0.5, system: benzene 50, dioxan 40, ethanol 5, conc.

Carrier: silicagel G + luminous pigment Detector: UV, potassium iodoplatinate Elemental Analysis:
C H Cl F N
Calc.: 50.59 4.2516.60 8.89 19~67 %
Found: 49.80 4.6416.57 ~.25 19.42 %
Example 5 2-(4-Fluoro-3-aminophenylimino)-imidazolidine ~ . .
5.5 g (0.0225 mol) of 2-(4-fluoro-3-nitrophenylimino)-imidaæolidine are dissolved in 40 ml of methanol and hydrogenated under normal pressure over Raney-nickel until the theoretical uptake of h~ydrogen is reached. Then the Raney-nickel is removed by vacuum filtration over active charcoal and the filtrate is evaporated in vacuo. For purification the residue is eluted in fractions over a 400 g silicagel column. (Mixture of eluents: ethylacetate 7, isopropanol 3, conc. NH~OH 1). The thin-layer chromato-graphically uniform fractions are united and evaporated in vacuo up to constant weight. The remaining thick oil is dissolved in a little methanol and admixed with etheric hydrochloric acid to form the acid salt of the title compound. Subsequently, it is precipated with ether and :

the precipitated salt is vacuum filtered, washed with ether and dried.
Yield: 3.7 g = 61.56% of theory Melting point: 222 C
Rf: 0.08; system: benzene 50, dioxan 40, ethanol 5, conc. NH40H 5.
Carrier: silicagel G ~ luminous pigment, Detectox: UV, potassium iodoplatinate Elemental Analysis:
C H Cl F N
Calc.: 40.46 ~.90 26.55 7.11 20.57 %
Found: 39.53 5.18 26.26 6.5S 20.37 ~ :;

: ~
, ,, Example 6: Tablets Active ingredient according to the invention 5 mg corn starch 160 mg sec. calcium phosphate 250 mg magnesium stearate 5 mg total 420 mg Production:
The individual components are admixed intensely and the mixture is granulated in the conventional manner and sub-.
sequently pressed to form tablets,each o F which weighs 420 mg and contains S mg of the active ingredient accor-ding to the invention.

Example 7: Gelatin Capsules The content of each capsule is as follows:
Active ingredient according to the invention 3 mg corn starch 172 mg total 175 mg Production:
__ .
The components are admixed intensely and portions of 175 mg of the mixture are filled into gelatin capsules of suitable size. Each capsule thus contains 3 mg of the active ingredient according to the invention.

Example 8: Inje_tible Soultion The solution is produced of the following components:
Active ingredient according to capsule is as follows:
the invention l.0 part by weight sodium salt o~ ethylene-dia~ine tetra-acetic acid 0.2 parts by weight distilled water ad l000.0 parts by weight . , .

Production:
The active ingredient according to the invention and the sodium salt of ethylene-diamine tetra-acetic acid are dissolved in sufficient distilled water and made up with distilled water to the desired volume. The solution is filtered free from suspended particles and 2 ml fractions are filled into ampoules under aseptic conditions. ~ubs-equently the ampoules are sterilized and sealed. Each ampoule thus contains 2 mg of the active substance.
Exam~le 9: Drops L
Active ingredient according to the invention 0.20 g methyl p-hydroxybenzoate 0.07 g propyl ~-hydroxybenzoate 0.03 g demineralized water ad lO0 ml The active ingredient according to the invention and the methyl p-hydroxybenzoate and propyl p-hydroxybenzoate are dissolved in sufficient demineralized water and made up with demineralized water to the desired volume.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing 2-[3,4-disubstituted-phenylimino]-imida-zolidine compounds of general formula (I) I
[wherein Z represents a phenyl group substituted in one of the 3- and 4-positions by a fluorine atom and in the remaining 3- or 4- position by a chlorine atom or a methyl, nitro or amino group] and pharmaceutically accept-able acid addition salts thereof, which process comprises:
(a) reacting ethylene diamine with a compound of formula (II) II
[wherein Z is as defined above and X and Y, which may be the same or different, each represents a halogen atom or a hydrothio, hydroxy, amino or nitroamino group or an alkylthio or alkoxy group containing 1 to 4 carbon atoms];
(b) reacting an aniline of formula (III) [wherein Z is defined above] with a compound of formula (IV) IV
[wherein R1 represents a group susceptible to nucleophilic exchange and R2 represents a hydrogen atom or an aliphatic acyl group] and, when R2 represents other than a hydrogen atom, subsequently splitting off the acyl group hydro-lytically; or (c) for the preparation of 2-[4-fluoro-3-aminophenylamino]-imida-zolidine, reducing 2-[4-fluoro-3-nitrophenylimino]-imidazolidine and, if required, converting a compound of formula I into a pharmaceutically accept-able acid addition salt.

2. A process as claimed in claim 1, wherein process (a) is used and the compound (II) is an isocyanide dihalide, thiourea, carbaminic acid ester, thiocarbaminic acid chloride, guanidine (or acid addition salt thereof) or nitroguanidine or an O-alkylurea (or acid addition salt thereof), S- alkyl-thiourea (or acid addition salt thereof) or alkyl thiocarbaminic acid chloride in which the said alkyl groups contain 1 to 4 carbon atoms.

3. A process as claimed in claim 2, wherein the compound (II) is an isocyanide dichloride.

4. A process as claimed in claim 1 when process (a) is used, 2 or 3 wherein the reaction is effected at a temperature between 0 and 200°C.

5. A process as claimed in claim 1 when process (a) is used, 2 or 3 wherein a compound of formula (II) is used in which X and Y both represent halogen atoms and the reaction is effected in the presence of an acid binding agent.

6. A process as claimed in claim 1, wherein process (b) is used and in the compound of formula (IV) R1 represents a halogen atom or a methylthio, methoxy or hydroxyl group.

7 A process as claimed in claim 6, wherein in the compound of formula (IV) R1 represents a chlorine atom.

8. A process as claimed in claim 6, wherein in the compound of formula (IV) R1 represents a hydroxyl group and R2 represents an aliphatic acyl group.

9. A process as claimed in claim 8, wherein the reaction is effected in the presence of phosphorous oxychloride at a temperature of 50 to 100°C.

10. A process as claimed in claim 1 when process (b) is used, 6 or 7 wherein a compound of formula (IV) is used in which R2 represents an acetyl group.

11. A process as claimed in claim 1 when process (b) is used, in the compound of formula IV R2 represents an aliphatic acyl group and subsequent deacylation is effected by refluxing with a lower alcohol.

12. A process as claimed in claim 11, wherein the said lower alcohol is methanol.

13. A process as claimed in claim 1, wherein process (c) is used and the reduction is carried out by hydrogenation in the presence of a metal catalyst.

14. A process as claimed in claim 13, wherein the said metal catalyst comprises palladium, platinum or Raney-nickel.

15. A compound of formula I as defined in claim 1 when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

16. A process according to claim 1 wherein Z is a phenyl group sub-stituted in the 3-position by a fluorine atom and in the 4-position by a methyl group.

17. A process for preparing 2-[3-fluoro-4-methylphenylimino]-imida-zolidine which comprises reacting N-(3-fluoro-4-methylphenyl)-5-methyl-thio-uronium iodide with ethylene diamine.

18. 2-[3-Fluoro-4-methylphenylimino]-imidazolidine when prepared by a process according to claim 17 or an obvious chemical equivalent thereof.

19. A process according to claim 1 wherein Z is a phenyl group sub-stituted in the 3-position by a methyl group and in the 4-position by a fluorine atom.

20. A process for preparing 2-[4-fluoro-3-methylphenylimino]-imida-zolidine which comprises reacting N-(4-fluoro-3-methylphenyl)-S-methylthio-uronium iodide with ethylene diamine.

21. 2-[4-Fluoro-3-methylphenylimino]-imidazolidine when prepared by a process according to claim 20 or an obvious chemical equivalent thereof.

22. A process according to claim 1 wherein Z is a phenyl group sub-stituted in the 3-position by a nitro group and in the 4-position by a fluorine atom.

23. A process for preparing 2-[4-fluoro-3-nitrophenylimino]-imida-zolidine which comprises deacetylating 1-acetyl-2-(4-fluoro-3-nitrophenyl-imino]-imidazolidine.

24. A process according to claim 23 wherein the 1-acetyl-2-(4-fluoro-3-nitrophenylimino)-imidazolidine is obtained by reacting 4-fluoro-3-nitro-aniline with 1-acetyl-imidazolidin-2-one to obtain 1-acetyl-(4-fluoro-3-nitrophenyl-imino)imidazolidine and subsequently deacetylating to obtain the required compound.

25. 2-[4-Fluoro-3-nitrophenylimino]-imidazolidine when prepared by a process according to claim 23 or 24 or by an obvious chemical equivalent thereof.

26. A process according to claim 1 wherein Z is a phenyl group sub-stituted in the 3-position by a chlorine atom and in the 4-position by a fluorine atom.

27. A process for preparing 2-[4-fluoro-3-chlorophenylimino]-imida-zolidine which comprises reacting N-(3-chloro-4-fluorophenyl)-5-methylthio-uronium iodide with ethylene diamine.

28. 2-[4-Fluoro-3-chlorophenylimino]-imidazolidine when prepared by a process according to claim 27 or an obvious chemical equivalent thereof.

29. A process according to claim 1 wherein Z is a phenyl group sub-stituted in the 3-position by an amino group and in the 4-position by a fluorine atom.

30. A process for preparing 2-[4-fluoro-3-aminophenylimino]-imida-zolidine which comprises reducing 2-(4-fluoro-3-nitrophenylimino)-imidazol-idine.

31. A process according to claim 1 wherein the reduction is carried out by hydrogenation in the presence of a Raney-nickel catalyst.

32, A process according to claim 30 wherein the 2-[4-fluoro-3-nitro-phenylimino]-imidazolidine is obtained by a process according to claim 22.

33. 2-[4-Fluoro-3-aminophenylimino]-imidazolidine when prepared by a process according to claim 30 or 31 or an obvious chemical equivalent thereof.