1,3-dioxolan-2-yl\methyl\-1H-imidazoles and 1H-1,2,4-triazoles

$: 1,3-dioxolan-2-yl\methyl\-1H-imidazoles and 1H-1,2,4-triazoles$
8>

uropaisches Patentamt

uropean Patent Office

ffice europeen des brevets

p Publication number: 3 1

D iUROPEAN PATENT SPECIFICA I iuim

6) Date of publication of patent specification: l4.Ub.83

a) Application number: 84200092.9

g) Date of filing: 24.01.84

Sp IntCI*: UU/ U W O / C 07 D 4 1 3 / 1 4 , C 07 D 4 1 7 / 1 4 , A 61 K 31/495, A 01 N 43 /60 , A 01 N 43/64, A 01 N 43 /76 , A 01 N 43/78 / / ( C 0 7 D 4 0 5 / 1 4 , 2 4 9 : 0 8 , 3 1 7 : 2 8 , 295 :12) , (C07D405 /14 , 2 3 3 : 6 1 , 317:28, 2 9 5 : 1 2 , 249 :08) , (C07D413/14 , 2 3 3 : 6 1 , 317:28, 2 9 5 : 1 2 , 271 :06) , (C07D417/14, 2 4 9 : 0 8 , 317:28, 295:12, 2 8 5 : 0 8 )

g) ((4.(4-(4-PhenYl-1-piperazinyl)phenoxymetnyl)-i,3-aioxoian--:-yiim8tnyi;- in-imiua^uies a..u .n- triazoles.

D Priority: 28.02.83 US 470405 ® Proprietor: JANSSEN PHARMACEUTICA N.V. 09 01.84 US 569122 Turnhoutsebaan 30

B-2340 Beerse (BE)

§) Date of publication of application: 12.09.84 Bulletin 84/37 Q?) Inventor: Heeres,Jan

Leemskuilen 18 B-2350Vosselaar(BE)

S) Publication of the grant of the patent: Inventor: Stokbroekx, Raymond A. 14.06.89 Bulletin 89/24 Rode Kruisstraat 13

B-2340 Beerse (BE) Inventor: Backx, Leo J.J.

8) Designated Contracting States: Broekstraat 92 AT BE CH DE FR GB IT LI LU NL SE B-2370 Arendonk (BE)

References cited: EP-A-0 006712 EP-A-0007 696 DE-A-2803 870 US-A-4267179 US-A-4402957

The file contains technical information submitted after the application was filed and not included in this specification

CO

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0 0

CL LU

Note: Within nine months trom tne puDiicaxion ot me menuun ui uieyiauiu. u.= K- «••■». - r r----- - give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been

paid. (Art. 99(1) European patent convention).

courier rress, Leammyiun o(ja, unyianu.

:P 0 1 1 8 1 3 8 B1

description

In US— A-4 144,346 there are described a number of 1-(1,3-dioxolan-2-ylmethyl)-1/y-imidazoles and

HA 2 4-triazoles and in US-A-4,267,179 there are described a number of heterocyclic derivatives of (4- ,hen'yM-piperazinyl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1//-imidaZoles and 1tf-1,2,4-tr.azoles, which

ire taught to have antifungal and antibacterial properties. ,Qn,.7n . Structually similar compounds are also described in EP-A-6712, EP-A-7695, DE-A-2803870 and

JS — A — 4402957 having all antifungal and antibacterial activity. In comparison with the prior art compounds, the subject compounds of the present invention differ

herefrom not only by their chemical structure but also by their increased effectiveness which effectiveness

nakes them useful in the treatment of vaginal candidosis by topical and/or systemic administration. This invention is concerned with 1W-imidazoles and 1W-1,2,4-triazoles having the formula (I)

5

>0

the pharmaceutical^ acceptable acid-addition salts and the stereochemicaliy isomeric Torms tnereoT, is wherein

Q is — N= or— CH=; Ar is phenyl or substituted phenyl, said substituted phenyl having from 1 to 3 substituents each

independently selected from the group consisting of halo; R is hydrogen or C, — C6 alkyl; and

jo Y is a radical having the formula (a)

60

or a radical having the formula (b)

40 X— B

I— A (b ) ;

wherein 45 Z is 0 or NR1; said R1 being hydrogen; C3 — C6 alkenyl; C3— C6 alkynyl; Ar; C3— C6 cycloalkyl; — C6

alkyl optionally substituted with a member selected from the group consisting of Ar, C,— C6 alkyloxy and C3 — C6 cycloalkyl; pyrimidine, optionally substituted with halo,

X is 0, S or NR2; said R2 being hydrogen or G, — C6 alkyl; , A is >C=0, NR3 or methylene, optionally substituted with up to two radicals selected from the group

so consisting of C, — C6 alkyl and Ar; said R3 being hydrogen or C, — C6 alkyl, or R1 and R3, taken together form a Cn — C6 alkanediyl radical; provided that, when A is NR3, Z is other than oxygen; and

B is >C=0 or methylene optionally substituted with up to two radicals selected from the group consisting of C, — C6 alkyl and C, — C6 alkyloxy; or A and B, taken together, form a bivalent radical of formula:

55 — CH2— CH2— CH2— (C)

or — C(O) — N — C(O) — (d)

R4

wherein R4 is hydrogen or d — C6 alkyl; or

65

U 110 130 0 1

where Y is a radical of formula (b), A and B, when taken together, can also form a bivalent radical of formula

— CH=CH— (e) or

- — n=ch— (f);

wherein one hydrogen in the said radical (f) and up to two hydrogens in the said radicals (c), or (e) may be

replaced by a C,— C6 alkyl radical; provided that when — A— B— is a radical of formula (f), said radical is connected to Z by its nitrogen atom

o and said Z is other than 0. In the foregoing definitions the term "halo" is generic to fluoro, chloro, bromo and lodo, the term

"Ci— C8 alkyl" is meant to include straight and branched hydrocarbon radicals having from 1 to 6 carbon

atoms such as, for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 1-methylpropyl, 2-

methylpropyl, butyl, pentyl, hexyl; "C3-C6 alkenyl" refers to alkenyl radicals having from 3 to about 6

,5 carbon atoms, such as, for example, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl; C3-C6 alkynyl refers

to alkynyl radicals having from 3 to about 6 carbon atoms, such as, for example, 2-propynyl, 2-butynyl, 3- butynyl 2-pentynyl; "C3— C6 cycloalkyl" embraces cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and "C3— C6 alkanediyl" stands for bivalent straight or branch chained alkanediyl radicals having from 3 to 6 carbon a t o m s . . . . ,

,0 The compounds of formula (I) may contain in their structure a tautomeric system and consequently these compounds may be present in each of their tautomeric forms.

Preferred compounds within the invention are those wherein Y is a radical of formula (a) or (b), wherein X, Z, A and B are as described hereinabove, provided that A and B, taken together, do not form a radical of formula (e) or (f) when Y is a radical of formula (b).

25 The most preferred compounds within the invention are: c/s-1-butyl-3-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-

yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-imidazolidinedione; , c/s-1-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1//-1,2,4-triazol-1-ylmethyl]-1,3-dioxolan-4-yl]methoxy]- phenyl]-1-piperazinyl]phenyl]-3-propyl-2-imidazolidinone; the pharmaceutical^ acceptable acid addition

30 salts and the stereochemical^ isomeric forms thereof. In order to simplify the structural representations of the compounds (I) and of certain starting materials

and intermediates used in the preparation thereof, the 2-Ar-2-(1tf-imidazol-1-ylmethyl or 1W-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl group, wherein Ar is as previously defined, will hereafter be represented by the symbol D:

35 „

45

— n J

CH, — C— Ar

i I

The compounds of formula (I) can generally be prepared by o-alkylating an appropriately suDstitutea phenol of formula (III) with a reactive ester of formula (II).

D-CH -W + HO— V V-N N*\ / Y *- ( I ) \ — / \ / \ — / r e a c t i o n 50 »»» II I I I

In formula (II), W has the meaning of a reactive ester residue such as, for example, halo, preferably chloro, bromo or iodo, or a sulfonyloxy group such as, for example, methylsulfonyloxy or 4- m e t h y l p h e n y l s u l f o n y l o x y . .

55 The said O-alkylation reaction is conveniently conducted in a suitable reaction-inert solvent of a mixture of such solvents. Suitable reaction-inert solvents are an aromatic hydrocarbon, e.g., benzene, methylbenzene or dimethylbenzene; a lower alkanol, e.g., methanol, ethanol or 1-butanol; a ketone, e.g., 2-

propanone or 4-methyl-2-pentanone; an ether, e.g., 1,4-dioxane, 1,1'-oxybisethane or tetrahydrofuran; /V,/V-dimethylformamide (DMF); /V,/V-dimethylacetamide (DMA); hexamethylphosphorictriamide (HMPT);

6o dimethyl sulfoxide (DMSO); nitrobenzene or 1-methyl-2-pyrrolidinone. The addition of an appropriate base such as, for example, an alkali metal carbonate or hydrogen carbonate, sodium hydride or an organic base such as, for example, /V,/V-diethylethanamine or W-(1-methylethyl)-2-propanamine may be utilized to pick up the acid which is liberated during the course of the reaction. It may be advantageous previously to convert the substituted phenol (III) into a metal salt thereof, preferably the sodium salt, in the usual manner,

65 e.g., by the reaction of (III) with metal bases such as sodium hydride or sodium hydroxide, and to use

■3

EP 0 1 1 8 1 3 8 B1

thereafter said metal salt in the reaction with (II). Somewhat elevated temperatures are appropriate to enhance the reaction rate and most preferably the reaction is carried out at from 80°C to 130°C.

Additionally, the compounds of formula (I) may also generally be prepared by cyclizing an intermediate of formula (IV) with an amine of formula (V) or by cyclizing an amine of formula (VI) with an

5 intermediate of formula (VII).

20 The reaction is carried out by stirring the reactants together in the presence of an appropriate polar solvent, e.g., water, in admixture with an appropriate water-miscible organic solvent such as, for example, 2-propanol or 2-propanone, preferably at an elevated temperature, in order to enhance the rate of the reaction, and, most preferably, in the presence of an appropriate alkali- or earth alkali metal iodide such as, for example, potassium iodide.

25 The compounds of formula (I) can also be prepared by N-alkylating a piperazine of formula (VIII) with an appropriately substituted benzene of formula (IX) or by N-alkylating a piperazine of formula (XI) with a benzene of formula (X).

30

35

40

45

50

D-CH2-0- \ s = / \ / ' \ = / r e a c t i o n

VIII IX

2 X — / \ / \ = / reaction 3 ( I )

X XI

Said N-alkylation reaction may be carried out in the usual manner, e.g., by stirring the reactants together, preferably at somewhat elevated temperatures in an appropriate organic solvent such as, for example, dimethylsulfoxide or /V,/V-dimethylformamide, in the presence of an appropriate base such as, for example, an alkali metal hydride or carbonate.

The compounds of formula (I) may also be derived from a compound of formula (XII)

R X

wherein R5 is hydrogen and R6 is an appropriate leaving group or R5 and R6, when taken together, represent 55 a direct bond, by cyclizing a said compound of formula (XII) with a derivative of formula XIII

H— Z— A— B— L XI 1 1

wherein L is an appropriate leaving group. 60 The said cyclization-reaction can generally be conducted in a suitable reaction-inert solvent such as, for

example, an alcohol, e.g. butanol, an ether, e.g., tetrahydrofuran or 1,4-dioxane. Although the cyclization reaction may be conducted at room temperature, somewhat elevated temperatures are appropriate to enhance the rate of the reaction. Preferably the reaction is conducted at the reflux temperature of the reaction mixture. Suitable catalysts, e.g., /V,/V-dimethyl-4-pyridinamine, may also enhance the rate of the

65 reaction.

4

>

0

EP 0 118 138 B1

In some cases it may be advantageous to conduct the hereinabove-described cyclization reaction with a derivative of formula (XIV)

H— Z— A— B— L' XIV

* wherein L' is a precursor of a leaving group, e.g. an alcohol function, to isolate the thus formed intermediate of formula (XV)

R _L , X

D - C H 2 - 0 ^ ) - N ^ ^ ^ - N H - l : - Z - A - B - L ' XV

to convert the L'-group into a suitable leaving group L, e.g. by converting an alcohol into a chloride

<s function, and, finally, to cyclize the thus obtained intermediate of formula (XVI)

R X

D . C H 2 H ) H Q . N ^ t ) ^ - ^ - A - B - L XVI

The compounds of formula (I) wherein Y is a radical of formula (a) wherein Z is NR1, said compounds being represented by the formula (l-a), can also be prepared by cyclizing an intermediate of formula (XVII) with an appropriate reagent of formula (XVIII).

»5 R X

D . C H 2 _ 0 _ ^ ^ ^ ^ ^ N - ^ ^ - N H - S - N H - R 1 + W-A-B-W »-

XVII XVIII

20

25

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35

45

50

60

D-CH2~0-

(I-a) B— A/

The said cyclization reaction is generally conducted following the same proceaures as previously aescnueu herein for the preparation of (I) starting from (Xil) and (XIII).

40 The compounds of formula (I), wherein Y is a radical of formula (b) wherein X is NR and Z is NR1, said compounds being represented by the formula (l-b) may be prepared by a cyclodesulfurization reaction of an intermediate of formula (XIX).

D-CH2-0-

41 S - ^ ^ N ^ ^ - ^ ^ ^ - C - N - A - B - N R ^

xix R

cycxoaesuxrur- izat ion r e a c t i o n

R R

R2 55 . R

Said cyclodesulfurization reaction may be carried out by the reaction of (XIX) with an appropriate alkyl halide, preferably iodomethane in an appropriate reaction-inert organic solvent, e.g., a lower alkanol such as methanol, ethanol or 2-propanol. Otherwise, the cyclodesulfurization reaction may be carried out by the reaction of (XIX) with an appropriate metal oxide or salt in an appropriate solvent according to art-known

60 procedures. For example, the compounds of formula (I) can easily be prepared by the reaction of (XIX) with an appropriate Hg(ll) or Pb(ll) oxide or salt, such as, for example HgO, HgCI2, Hg(OAc)2, PbO or Pb(OAc)2. In certain instances it may be appropriate to supplement the reaction mixture with a small amount of sulfur. Even so methanediimines, especially /V,/V'-methanetetraylbis[cyclohexanamine] may be used as

„ cyclodesulfurizing agents. 65

EP 0 1 1 8 1 3 8 B1

The compounds of formula (I) wherein Y is a radical of formula (b), wherein — AB — is a bivalent radical of formula (f), said compounds being represented by the formula (l-c), can be prepared by reacting an intermediate of formula (XX) in an acidic aqueous solution, e.g. an aqueous hydrochloric, hydrobromic, sulfuric and the like acidic solution with a carbonyl-generating agent, e.g., formic acid.

carbonyl-genera t ing agent —

15 ' - - 2 - < K i > - G - « = a I - c

20 The compounds of formula (I) wherein Z is NH, said compounds being represented by the formulae

(l-d-1) respectively (l-d-2) can be converted into a compound of formula (I) wherein R1 is other than hydrogen, said R1 being represented by the formula R1-a and said compounds by the formulae (l-e-1) respectively (l-e-2), by reacting the former with a reagent of formula (XXI), wherein W represents a reactive

25 leaving group, following art-known N-alkylation reactions.

R X

D - C H 2 - 0 H f " ^ N ^ ^ N - / — V - N ^ _ fH + R1_a-W N-a lky la t ion 30 N / \ = / VB_A r e a c t i o n

l-d-1 XXI

35

40

45

50

55

60

2 w \ _ y " w "nb j

I - e - l

R

D - C H 2 - o Y ^ V n / ^ V N - / ~ \ N = / X j + R ^ ^ w N-a lky la t ion \ = / \ / \ = z / XN_A reaction '

H XXI I -d -2

R v r h \ / r ^ \ /X-b

« K X > < K !

I - e - 2

Said N-alkylation reaction may be carried out in the usual manner, e.g., by stirring the reactants together, preferably at somewhat elevated temperatures in an appropriate organic solvent such as, for example, dimethyl sulfoxide or /V,/V-dimethylformamide, in the presence of an appropriate base such as,

65 for example, an alkali metal hydride or carbonate.

6

P 0 I I S 138 0 1

The 1tf-imidazole- and 1W-1,2,4-tnazole-denvatives ot rormuia u», oDiameu in uase .uim m u.c foregoing preparations, may be converted to their therapeutically active non-toxic acid addition salt forms by treatment with appropriate acids, such as, for example, inorganic acids, such as hydrohalic acid, e.g. hydrochloric or hydrobromic, and sulfuric acid, nitric acid or phosphoric acid; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic or 4-amino-2-hydroxybenzoic.

The salts are in turn converted to the corresponding free bases in the usual manner, e.g., by reaction

j with alkali such as sodium or potassium hydroxide. From formula (I) it is evident that the compounds of this invention have at least two asymmetric carbon

atoms in their structures, namely those located in the 2- and 4-position of the dioxolane nucleus, and consequently they can exist under different stereochemically isomeric forms. The stereochemically isomeric forms of (I) and the pharmaceutically acceptable acid addition salts thereof are intended to be

5 embraced within the scope of this invention. The diastereomeric racemates of (I), denoted as cis and trans forms respectively, according to the rules

described in J. Org. Chem. 35(9), 2849—2867 (1970), may be obtained separately by conventional methods. Appropriate methods which may advantageously be employed therefore include, for example, selective crystallization and chromatography separation, e.g., column-chromatography.

o Since the stereochemical configuration is already fixed in a number of intermediate compounds, e.g., in intermediates of the formulas (II), (IV), (VI), (VIII), (X), (XII), (XV), (XVI), (XVII), (XIX) and (XX), it is also possible to separate cis and trans forms at this or even an earlier stage, whereupon the corresponding forms of (I) may be derived therefrom in the previously indicated manner. The separation of cis and trans forms of such intermediates may be performed by conventional methods as described hereabove for the

>5 separation of cis and trans forms of the compounds (I). It is evident that the cis and trans diastereomeric racemates may be further resolved into their optical

isomers, cis(+), cis(-), trans(+) and trans(-) by the application of methodologies known to those skilled in the art.

A number of the intermediates and starting materials used in the foregoing preparations are known

,o compounds, others may be prepared according to art-known methodologies of preparing similar compounds and some of them are novel and consequently their preparation will be described hereafter.

The intermediates of formula (III) can generally be derived from an intermediate of formula (XXII), wherein P is an appropriate protective group, following art-known procedures.

j l lmination or protective group

1 45

50 The procedures for eliminating the protective group P depend upon the nature of P. For example,

where P is a methyl group the reaction can be conducted in an acidic hydrolyzmg medium, containing a

strong non-oxidizing mineral acid, e.g., hydrobromic acid in glacial acetic acid. The intermediates of formula (XXII) can be obtained by cyclizing an intermediate of formula (XXIII) with

55 an amine of formula (V) following the same procedure as described for the preparation of (I) starting from

(IV) and (V).

60

65

7

EP 0 1 1 8 138 B1

The starting materials of formula (V), wherein Y is a radical of formula (a) or (b) wherein Z is NR1, said Y being represented by Y' and said (V) by (V-a), may be prepared by cyclizing a reagent of formula (XXIV) with a reagent of formula (XXV) following the cyclization reaction which is previously described herein for the preparation of the compounds of formula (I) starting from (XII) and (XIII).

5 x

Y'

P ' -NH— NH-B-A-L + R^-N-G-R^ ^

0 8,5

XXIV XXV V-a

In (XXIV) P' represents hydrogen or an appropriate protective group, in which case the said protective '5 group should be eliminated after the cyclization reaction.

The starting materials of formula (V) may also be derived from the corresponding nitro-derivatives following art-known nitro-to-amine reducing procedures.

The intermediates of formula (XXII) may also be derived from an intermediate of formula (XXVI)

» R X

?0

40

50

55

'L"K XXVI e

* by reacting the latter with a reagent of formula (XIII) following the previously described cyclizat.on

procedures for the preparation of compounds of formula (I) starting from (XII) and (XII . The intermediates of formula (XII) may be derived from an amine of formula (XXVII) by reacting the

latter with a reagent of formula (XXVIII) or carbon disulfide thus yielding an intermediate of formula (Xll-a), respectively an intermediate of formula (Xll-b).

» L-C-S6 OTIII 2 \ = / V - / W

D-CH2-0-^ / \ XXVII

Xl i -a

K

XI I- b

The intermediates of formula (XVII), (XIX) and (XX) can conveniently be prepared by reacting an intermediate of formula (XII) with an appropriate amine derivative.

The intermediates of formula (Xll-a), wherein R6 is a radical of formula Z1 — R7, said intermediates being represented by the formula (XII-a-1)

X D h : H 2 - 0 - - ^ ~ ^ ~ N ^ ~ ^ N - ^ - ^ - N H - C - Z 1 R 7 XII-a-1

wherein Z1 is 0 or NR8, said R8 being hydrogen, Ar or C,— C6 alkyl optionally substituted by Ar, and

65 R7 is hydrogen, Ar, amino or C-,— C6 alkyl optionally substituted by a member selected from the group

8

:P 0 118 138 B1

consisting of hydroxy, Ar-amino, C,— U6 alkyiamino or carooxy or suDsmuieu wuu up iu ™ ^—^6 alkyloxy radicals, provided that:

— Z1 is other than 0 where R7 is hydrogen; and — where R7 is amino, Z1 is other than NH or O;

said intermediates, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof display strong antimicrobial properties themselves and both as useful intermediates herein and as antimicrobial substances they constitute an additional feature of this invention.

It is evident from the structure of the intermediates of formula (XII-a-1) that the stereochemical isomery o as described hereinabove for the compounds of formula (I) applies also for the said intermediates and acid

addition salts thereof. The compounds of formula (I), the intermediates of formula (XII-a-1), the pharmaceutically acceptable

acid addition salts and stereochemically isomeric forms thereof are useful agents in combatting fungi and bacteria. For example, said compounds are found to be highly active against a wide variety of fungi such

5 as, for example, Microsporum canis, Ctenomyces mentagrophytes, Trichophyton rubrum, Phialophora verrucosa, Cryptococcus neoformans, Candida tropicalis, Candida albicans, Mucor species, Aspergillus fumigatus, Sporotricum schenckii and Saprolegnia species, and against bacteria such as, for exmaple, Erysipelotrix indidiosa. Staphylococci such as Staphylococcus hemolyticus and Streptococci such as Streptococcus pyogenes. In view of their potent, local as well as systemic, antimicrobial activity the

o compounds of this invention constitute useful tools for the destruction or prevention of the growth of fungi and bacteria and more particularly they can effectively be used in the treatment of subjects suffering from such microorganisms.

The strong antimicrobial activity of the compounds (I) and the intermediates (XII-a-1) is clearly evidenced by the data obtained in the following experiments, which data are only given to illustrate the

;s useful antimicrobial properties of all the compounds (I) and the intermediates (XII-a-1).

Experiment A: Oral treatment of vaginal candidosis in rats Female Wistar rats of ±100 g body weight were used. They were ovariectomized and hysterectomized

and after three weeks of recovery, 100 ug of oestradiol undecylate in sesame oil was given subcutaneously w once a week for 3 consecutive weeks. The thus induced pseudo-oestrus was controlled by microscopic

examination of vaginal smears. Food and water were left available ad libitum. The rats were infected intravaginally with 8.10s cells of Candida albicans, grown on Sabouraud broth for 48 hours at 37°C and diluted with saline. The date of infection varies from day +25 to day +32 after surgical intervention, depending on the appearance of signs of induced pseudo-oestrus.

w The drugs under investigation were administered orally once a day for three days starting from the third day after infection. For each experiment there were placebo treated controls. The results were assessed by taking vaginal smears with sterile swabs on several days after the infection. The swabs were put into Sabouraud broth in petri-dishes and incubated for 48 hours at 37°C. If no growth of Candida albicans occurs, i.e., when the animals were negative at the end of the experiment, this was due to drug

10 administration because it never happens in placebo-treated controls. The first column in the Tables I, II and III gives the lowest oral dose in mg/kg of the drug under

investigation which is found active at the 14th day after infection.

Experiment B: Topical treatment of vaginal candidosis in rats 45 Female Wistar rats of +100 g body weight were used. They were ovariectomized and hysterectomized

and after three weeks of recovery, 100 ug of oestradiol undecylate in sesame oil was given subcutaneously once a week for 3 consecutive weeks. The thus induced pseudo-oestrus was controlled by microscopoic examination of vaginal smears. Food and water were left available ad libitum. The rats were infected intravaginally with 8.105 cells of Candida albicans, grown on Sabouraud broth for 48 hours at 37°C and

50 diluted with saline. The date of infection varies from day +25 to day +32 after surgical intervention, depending on the appearance of signs of inducing pseudo-oestrus.

The drugs under investigation were administered topically twice a day for three consecutive days starting from the third day after infection. For each experiment there were placebo treated controls. The results were assessed by taking vaginal smears with sterile swabs on several days after the infection. The

55 swabs were put into Sabouraud broth in petri-dishes and incubated for 48 hours at 37°C. If no growth of Candida albicans occurs, i.e., when the animals were negative at the end of the experiment, this was due to drug administration because it never happens in placebo-treated controls.

The second column in the Tables I, II and III give the lowest concentration of the drug under investigation which is found active at the 7th day after the last topical administration of the drug.

so Experiment C: Oral treatment of Microsporum cams infections in guinea pigs

Adult Albino guinea pigs were prepared by clipping their backs and infected on the scarified skin by scratching five 3 cm long transverse cuts with Microsporum canis (strain RV 14314). The animals were housed individually in wire mesh cages and food and water were available ad libitum. The drugs under

es investigation were administered orally once a day for 14 consecutive days starting 24 hours before

a

EP 0 1 1 8 1 3 8 B1

infection. For each experiment there were placebo treated controls. The animals were evaluated 21 days after infection by microscopic examination of the skin and by

cultures on Sabouraud agar comprising a suitable bacterial antibiotic and a suitable agent to eliminate contaminating fungi.

s The third column in Tables, I, II and III give the lowest oral dose in mg/kg of the drug under investigation at which no lesions were observed and at which there was no culture growth.

Experiment D: Topical treatment of Microsporum canis infections in guinea pigs Adult Albino guinea pigs were prepared by clipping their backs and infected on the scarified skin by

10 scratching five 3 cm long transverse cuts with Microsporum canis (strain RV 14314). The animals were housed individually in wire mesh cages and food and water were available ad libitum. The drugs under investigation were administered topically once a day for 14 consecutive days starting the third day after infection. For each experiment there were placebo treated controls.

The animals were evaluated 21 days after infection by microscopic examination of the skin and by is cultures on Sabouraud agar comprising a suitable bacterial antibiotic and a suitable agent to eliminate

contaminating fungi. The fourth column in Tables, I, II and ill gives the lowest concentration of the drug under investigation

at which no lesions were observed and at which there was no culture growth. The compounds listed in Tables I, II and III are intended to illustrate and not to limit the scope of the

20 present invention.

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26

:P 0 118 138 B1

In view of their antifungal and antibacterial properties tnis invention provides vaiuauie uumuusmuno comprising the compounds of formula (I), (XII-a-1 ), acid addition salts or stereochemically isomeric forms thereof, as the active ingredient in a solvent or a solid, semi-solid or liquid diluent or carrier; these compounds and compositions can be used for combatting fungal or bacterial growth by use of an effective

5 antifungal or antibacterial amount of such compound (I), (Xll-a-1) or salts thereof. Antifungal and antibacterial compositions comprising an effective amount of an active compound (I) or (XII-a-1), either alone or in combination with other active therapeutic ingredients, in admixture with suitable carriers may be readily prepared according to conventional pharmaceutical techniques for the usual routes of a d m i n i s t r a t i o n . . .

o Preferred compositions are in dosage unit form, comprising per dosage unit an effective quantity of the active ingredient in admixture with suitable carriers. Although the amount of the active ingredient per unit dosage may vary within rather wide limits, dosage units comprising from 1 to 500 mg and more particularly from 10 to 250 mg of the active ingredient are preferred.

To prepare the pharmaceutical compositions of this invention an antimicrobially effective amount of 5 the particular compound or compounds, in base or acid-addition salt form, as the active ingredients, is

combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, preferably, for administration orally, rectally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual

<0 pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously

>5 employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Acid addition salts of (I), due to their increased water solubility over the corresponding base form, are obviously more

io suitable in the preparation of aqueous compositions. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage

unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in

15 association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof. The amount of active ingredient per dosage unit is from about 0.25 mg to about 100 mg and, preferably from about 0.5 to about 20 mg.

w The following formulations exemplify compositions typical for the treatment of vaginal candidosis in dosage unit form suitable for systemic or topical administration to animal and human subjects in accordance with the instant invention.

Oral drops: . 45 The following formulation provides 50 liters of an oral-drop solution comprising 10 milligrams of as -

1 - butyl - 3 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1# - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl] - 2,4 - imidazolidinedione (A.I.) per milliliter.

A.l. 500 grams 50

2-hydroxypropanoic acid 0.5 liter

Sodium saccharin i/ougr_ms>

ss Cocoa flavor 2.5 liters

Purified water 2.5 liters

Polyethylene glycol q.s. aa ou iuer& 60

The A.I. was dissolved in the 2-hydroxypropanoic acid and 1.5 liters of the polyethylene glycol at 60— 80°C. After cooling to 30— 40°C there were added 35 liters of polyethylene glycol and the mixture was stirred well. Then there was added a solution of the sodium saccharin in 2.5 liters of purified water and while stirring there were added the cocoa flavor and polyethylene glycol q.s. ad volume. The resulting

65 solution was filled into suitable containers.

2 /

EP 0 1 1 8 1 3 8 B1

Injectable solution: The following formulation provides 20 liters of a parenteral solution comprising 2 milligrams of cis -

1 .[4 -[4 -[4 -[[2 -(2,4 - dichlorophenyl) -2 -(1/V -1,2,4 -triazol -1 -ylmethyl) -1,3 -dioxolan -4 - yl]methoxy]phenyl] - 1 - piperazinyljphenyl] - 3 - propyl - 2 - imidazolidinone per milliliter.

10

is

20

30

35

40

45

50

55

A.I.

2,3-dihydroxybutanedioic acid

methyl 4-hydroxybenzoate

propyl 4-hydroxybenzoate

water for injection q.s. ad 20 liters.

40 grams

20 grams

36 grams

4 grams

The methyl and propyl 4-hydroxybenzoates were dissolved in about 10 liters of boiling water for injection. After cooling to about 50°C there were added while stirring the 2,3-dihydroxybutanedioic acid and thereafter the A.I. The solution was cooled to room temperature and supplemented with water for injection q.s. ad volume. The solution was sterilized by filtration (U.S.P. XVII p. 811) and filled in sterile containers.

Oral solution: The following formulation provides 20 liters of an oral solution comprising 5 milligrams of cis -1 -[4 -

[4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1W - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yljmethoxyjphenyl] - 1 - piperazinyljphenyl] - 3 - propyl - 2 - imidazolidinone per teaspoonful (5

25 milliliters).

A.I. 20 grams

2,3-dihydroxybutanedioic acid 10 grams 30

Sodium saccharin 40 grams

1,2,3-propanetriol 12 liters

35 Sorbitol 70% solution 3 liters

Methyl 4-hydroxybenzoate 9 grams

Propyl 4-hydroxybenzoate 1 gram 40

Raspberry essence 2 milliliters

Gooseberry essence 2 milliliters

45 Purified water q.s. ad 20 liters.

The methyl and propyl 4-hydroxybenzoates were dissolved in 4 liters of boiling purified water. In 3 liters of this solution were dissolved first the 2,3-dihydroxybutanedioic acid and thereafter the A.I. The latter solution was combined with the remaining part of the former solution and the 1,2,3-propanetriol and the

50 sorbitol solution were added thereto. The sodium saccharin was dissolved in 0.5 liters of water and the raspberry and gooseberry essences were added. The latter solution was combined with the former, water was added q.s. ad volume and the resulting solution was filled in suitable containers.

Film-coated tablets: 55 10,000 Compressed tablets, each containing as the active ingredient 10 milligrams of cis -1 -butyl -

3 -[4 -[4 -[4 -[[2 -(2,4 -dichlorophenyl) -2 -(1/V -1,2,4 -triazol -1 -ylmethyl) -1,3 -dioxolan -4 - yl]methoxy]phenyl] -1 -piperazinyljphenyl] -2,4 - imidazolidinedione, were prepared from the following formulation:

60

65

28

P 0 118 138 B1

ablet core:

Lactose 570 Qrams

Starch 200 grams

: Polyvinylpyrrolidone (Kollidon K90) 10 grams

Microcrystalline cellulose (Avicel) 100 grams

Sodium dodecyl sulfate 5 grams

Hydrogenated vegetable oil (Sterotex) 15 grams

0

>s

10

?5

40

45

50

55

60

65

loatmg:

Methyl cellulose iivieinocei ou nu/ iu aiaiMO

Ethyl cellulose (Ethocel 22 cps) 5 grams

1,2,3-propanetriol 2.5 milliliters

Polyethylene glycol 6000 10 grams

Concentrated colour suspension (Opaspray K-1-2109) 30 milliliters

Polyvinylpyrrolidone (Povidone) 5 grams

Magnesium octadecanoate 2.5 grams

^ T m l x t u r e ^ l t h e T L , " the lactose and the starch was mixed well and thereafter humidified with a solution of the sodium dodecyl sulfate and the polyvinylpyrrolidone in about 200 milliliters of water. The

wet powder was sieved, dried and sieved again. Then there was added the microcrystalline cellulose and

the hydrogenated vegetable oil. The whole was mixed well and compressed into tablets.

C°atTo9a solution of the methyl cellulose in 75 milliliters of denaturated ethanol there was added a solution

of the ethyl cellulose in 150 milliliters of dichloromethane. Then there were added 75 milliliters of

dichloromethane and 1,2,3-propanetriol. The polyethylene glycol was molten and dissolved in 75 millihters

of dichloromethane. The latter solution was added to the former and then there were added the

magnesium octadecanoate, the polyvinylpyrrolidone and the concentrated colour suspension and the

whole was homogenized. The tablet cores were coated with the thus obtained mixture in a coating apparatus.

SUPHuSntjYedSsuppositories each containing 3 milligrams cis - 1 - but^ - 3 - [4 - [4 - [4 - [[2 - (2,4 - di-

chlorophenyl) - 2 - (1tf - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yljmethoxylphenyl] - 1 - piperazinyljphenyl] - 2,4 - imidazolidinedione were prepared from the following formulations:

A.I. 0-3 grams

2,3-dihydroxybutanedioic acid 3 grams

Polyethylene glycol 400 2 milliliters

Surfactant (Span) 12 grams

Triglycerides (Witepsoi 555) q.s. ad 300 grams

The A I was dissolved in a solution of the 2,3-dihydroxybutanedioic acid in polyethylene glycol 400.

The surfactant and the triglycerides were molten together. The latter mixture was mixed well with the

Z3

EP 0 1 1 8 1 3 8 B1

former solution. The thus obtained mixture was poured onto moulds at a temperature of 37 — 38 C to form the suppositories.

In view of the antimicrobial properties of the compounds of formula (I) or (XII-a-1), it is evident that the present invention provides a method of inhibiting and/or eliminating the development of fungi and bacteria

5 in warm-blooded animals suffering from diseases caused by these fungi and/or bacteria by the systemic or topical administration of an antimicrobially effective amount of a compound of formula (I), (XII-a-1), pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.

The following examples are intended to illustrate and not to limit the scope of the present invention. - Unless otherwise stated all parts therein are by weight.

10 Examples

A. Preparation of Intermediates Example I

To a stirred solution of 13.5 parts of phenyl carbonochloridate in 100 parts of pyridine and 390 parts of 15 dichloromethane were added dropwise 47 parts of c/s-4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1W-1,2,4-triazol-1-

ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl]-1-piperazinyl]benzenamine. Upon completion, stirring was continued for 3 hours at room temperature. 200 Parts of water and 140 parts of petroleumether were added. The precipitated product was filtered off, washed successively with water, 2-propanol, 2,2'-oxybispropane and dichloromethane, and dried, yielding 49 parts (86%) of c/s-phenyl [4-[4-[4-(2-(2,4-dichlorophenyD-

20 2-(1/V-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl]-1-piperazinyl]phenyl]carbamate; mp. 203.1 °C (1).

In a similar manner there were also prepared: c/s-phenyl [4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1W-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl]-1- piperazinyl]phenyl]carbamate; mp. 198.8°C (2);

25 phenyl c/s-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]- phenyl]-3-methyl-1-piperazinyl]phenyl]carbamate; mp. 168.5°C (3); and

phenyl c/s-[4-[4-[4-[[2-(4-chlorophenyl)-2-(1A/-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]- phenyl]-1-piperazinyl]phenyl]carbamate; mp. 215.5°C (4).

30 Example II To a stirred and cooled (ice-bath) mixture of 12.6 parts of carbon disulfide, 2.1 parts of /V,/V'-methane-

tetraylbis[cyclohexaneamine] and 30 parts of pyridine were added 5.8 parts of c/s-4-[4-[4-[2-(2,4- dichlorophenyl)-2-(1/y-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl]-1-piperazinyl]benzenamine and stirring was continued first for 2 hours while cooling in an ice-bath and then for 1 hour at room

35 temperature. 42 Parts of 2,2'-oxybispropane were added and the product was allowed to crystallize. It was filtered off and purified by filtration over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 3.8 parts (61%) of c/s-1-[4-[[2-(2,4-dichlorophenyl)-2- (1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(4-isothiocyanatophenyl)piperazine; mp.

40 165.4°C (5). In a similar manner there were also prepared: c/s-1-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-

(4-isothiocyanatophenyl)-piperazine; mp. 149.1°C (6).

45 Example III A mixture of 21 parts of 1-(4-nitrophenyl)-2-imidazolidinone, 16 parts of iodomethane, 10 parts of

potassium hydroxide and 200 parts of dimethyl sulfoxide was stirred for 3 hours at room temperature. Another portion of 16 parts of iodomethane and 10 parts of potassium hydroxide were added. Stirring was continued overnight. 300 Parts of water were added to the reaction mixture and the whole was stirred. The

so precipitated product was filtered off and crystallized from 4-methyl-2-pentanone, yielding 16.5 parts (74%) of 1-methyl-3-(4-nitrophenyl)-2-imidazolidinone; mp. 214.1— 21 5.5°C (7).

In a similar manner there were also prepared: 1-ethyl-3-(4-nitrophenyl)-2-imidazolidinone; mp. 175.2°C (8);

55 1-(1-methylethyl)-3-(4-nitrophenyl)-2-imidazolidinone; mp. 161.7°C (9); 1-butyl-3-(4-nitrophenyl)-2-imidazolidinone; mp. 130.0°C(10); and 1-(4-nitrophenyl)-3-propyl-2-imidazolidinone; mp. 128.2°C(11).

Example IV 60 A mixture of 2.7 parts of ethyl 2-[(4-aminophenyl)amino]acetate hydrochloride, 1 .1 parts of acetic acid

anhydride, 0.98 parts of sodium hydrogen carbonate, 65 parts of dichloromethane and 50 parts of water was stirred for 30 minutes at room temperature. The organic phase was separated, washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 1.9 parts (68%) of ethyl 2-[[4-(acetylamino)phenyl]amino]acetate; mp. 119.5°C

65 (12).

30

EP 0 1 1 8 1 3 8 B1

Example V A mixture of 25 parts of ethyl 2-[[4-(acetylamino)phenyl]amino]acetate, 20 parts of 1-isocyanatobutane,

! parts of /V,/V-dimethyl-4-pyridinamine and 300 parts of trichloromethane was stirred and refluxed for 48 lours. The reaction mixture was evaporated and the residue was stirred and refluxed for 8 hours in 180 )arts of dimethylbenzene. After cooling, the precipitated product was filtered off, washed with 2-propanol ind dried, yielding 25.5 parts (83%) of /V-[4-(3-butyl-2,4-dioxo-1-imidazolidinyl)phenyl]acetamide; mp. I92.8°C (13).

In a similar manner there were also prepared: /V-[4-(3-methyl-2,4-dioxo-1-imidazolidinyl)phenyl]acetamide; mp. 262.7°C; (14) /V-[4-[3-(1-methylethyl)-2,4-dioxo-1-imidazolidinyl]phenyl]acetamide; mp. 215°C; (15) /V-[4-(3-ethyl-2,4-dioxo-1-imidazolidinyl)phenyl]acetamide; mp. 250.5°C (16); and /V-[4-(2,4-dioxo-3-propyl-1-imidazolidinyl)phenyl]acetamide; mp. 212.3°C (17).

Example VI A mixture of 12 parts of 1-ethyl-3-(4-nitrophenyl)-2-imidazolidinone, 1 part of a solution of thiophene in

sthanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with I parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the :atalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 2,2'- Dxybispropane. The product was filtered off and dried, yielding 9.6 parts (93%) of 1-(4-aminophenyl)-3- 3thyl-2-imidazolidinone (18).

In a similar manner there were also prepared: 1-(4-aminophenyl)-3-(1-methylethyl)-2-imidazolidinone (19); 1-(4-aminophenyl)-3-butyl-2-imidazolidinone (20); 1-(4-aminophenyl)-3-propyl-2-imidazolidinone (21); and 1-(4-aminophenyl)-3-methyl-2-imidazolidinone (22).

Example VII A mixture of 19.5 parts of /V-[4-(2,4-dioxo-3-propyl-1-imidazolidinyl)phenyl]acetamide and 480 parts of

Doncentrate hydrochloric acid was stirred and refluxed for 5 hours. The reaction mixture was cooled, the precipitated product was filtered off and dissolved in a mixture of methanol and water. The solution was neutralized with a sodium hydrogen carbonate solution and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 15 parts (90%) of 1-(4-aminophenyl)- 3-propyl-2,4-imidazolidinedione; mp. 133.2°C (23).

In a similar manner there were also prepared: 1-(4-aminophenyl)-3-(1-methylethyl)-2,4-imidazolidinedione; mp. 109.4°C (24); 1-(4-aminophenyl)-3-methyl-2,4-imidazolidinedione; mp. 201.5°C (25); 1-(4-aminophenyl)-3-ethyl-2,4-imidazolidinedione; mp. 149.3°C (26); and 1-(4-aminophenyl-3-butyl-2,4-imidazolidinedione; mp. 114.8°C (27).

Example VIII A mixture of 16.5 parts of /V,/V-bis(2-chloroethyl)-4-methoxybenzenamine, 12.5 parts of 1-(4-

aminophenyl)-3-methyl-2-imidazolidinone, 11 parts of sodium hydrogen carbonate and 240 parts of 1- butanol was stirred and refluxed for 24 hours. After cooling, 100 parts of water were added and the whole was stirred. The precipitated product was filtered off, washed with water and with 1-butanol and dried, yielding 17.5 parts (73%) of 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-methyl-2-imidazolidine; mp. 240.9— 241. 0°C (28).

In a similar manner there were also prepared: 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-(1-methylethyl)-2,4-imidazolidinedione; mp.

214.2°C (29); 3-ethyl-1-[4-f4-(4-methoxyphenyl)-1-piperazinyl]phenyi]-2,4-imidazolidinedione; mp. 228.0°C (30); 3-butyl-1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2,4-imidazolidinedione; mp. 206.7°C; (31) 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-methyl-2,4-imidazolidinedione; mp. 258.7°C; (32) 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-propyl-2,4-imidazolidinedione; mp.200.8°C; (33) 1-ethyl-3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-imidazolidinedione; mp. 246.3°C; (34) 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-(1-methylethyl)-2-imidazolidinone; mp. 234.5°C;

(35) 1-butyl-3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-imidazolidinone; mp. 240.4°C; (36) and 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-propyl-2-imidazolidinone; mp. 252.0°C (37)

Example IX A mixture of 5 parts of phenyl [4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate, 3 parts of

ethyl [(1-methylethyl)amino]acetate, 1 part of /V,/V-dimethyl-4-pyridinamine and 100 parts of 1,4-dioxane was stirred and refluxed overnight. The warm solution was saturated with water and allowed to cool. The solution was poured onto water and extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of

31

EP 0 1 1 8 1 3 8 B1

trichloromethane and methanol (98:2 by volume) as eluent. The filtrate was evaporated and the residue was crystallized from methylbenzene, yielding 3.7 parts (73%) of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]- phenyl]-1-(1-methylethyl)-2,4-imidazolidinedione; mp. 193.7°C (38).

A mixture of 24 parts of phenyl [4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate, 15.9 parts of 5 ethyl /V-butylglycine, 2 parts of /V,/V-dimethyl-4-pyridinamine and 200 parts of 1,4-dioxane was stirred and

refluxed overnight. Then water was added and stirring was continued for a while. The reaction mixture was cooled, poured onto water and the whole was stirred. The precipitated product was filtered off, washed with water and dissolved in 150 parts of trichloromethane. This solution was stirred for 30 minutes with 3 parts of silica gel. The latter was filtered off and the filtrate was evaporated. The residue was crystallized

io from butanol. The product was filtered off and dried in vacuo at 60°C, yielding 2.3 parts of 1-butyl-3-[4-[4-(4- methoxyphenyl)-1-piperazinyl]phenyl]-2,4-imidazolidinedione; mp. 183.7°C (39).

Example X A mixture of 15 parts of 1-(4-isothiocyanatophenyl-4-(4-methoxyphenyl)piperazine, 6.5 parts of 2,2-

15 dimethoxy-/V-methylethanamine and 195 parts of dichloromethane was stirred for 1 hour at room temperature. The reaction mixture was evaporated and the residue was triturated in 4-methyl-2-pentanone. The product was filtered off and dried, yielding 19.4 parts (95%) of /V-(2,2-dimethoxyethyl)-/V'-[4-[4-(4- methoxyphenyl)-1-piperazinyl]phenyl]-/V-methylthiourea; mp. 155.0°C (40).

In a similar manner there were also prepared: 20 /V-(2,2-dimethoxyethyl)-/V-ethyl-/V'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea (41);

/V-(2,2-dimethoxyethyl)-/V'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-/V-(1-methylethyl)thiourea; mp. 139.7°C (42); and

/V-(2,2-dimethoxyethyl)-/V'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-/V-(1-methylpropyl)thiourea; mp.140°C(43).

25 Example XI

a. A mixture of 10 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 6.3 parts of 3- (butylamino)-l-propanol and 130 parts of dichloromethane was stirred for 3 hours at room temperature. The reaction mixture was evaporated and the residue was triturated in 2-propane. The product was filtered

30 off and dried, yielding 12.7 parts (92%) of A^-butyl-/V-(3-hydroxypropyl)-/V'-[4-[4-(4-methoxyphenyl)-1- piperazinyl]phenyl]thiourea; mp. 153.9°C (44).

b. To 75 parts of a hydrobromic acid solution 48% in water was added a small amount of sodium hydrogen sulfite. Then there were added 1.7 parts of /V-butyl-/V-(3-hydroxypropyl)-/V'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea. The whole was stirred and refluxed for 3 hours. The reaction

35 mixture was evaporated. The residue was dissolved in a mixture of methanol and water. The solution was neutralized with a sodium hydrogen carbonate solution. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from

40 2-propanol. The product was filtered off and dried, yielding 0.6 parts (38%) of 4-[4-[4-[(3-butyltetrahydro- 1,3-thiazin-2-ylidiene)amino]phenyl]-1-piperazinyl]phenol; mp. 143.0°C (45).

Example XII A mixture of 7 parts of 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-propyl-2-imidazolidinone

45 and 225 parts of a hydrobromic acid solution 48% was stirred and refluxed for 5 hours. After cooling, the precipitated product was filtered off, washed with 2-propanol and dissolved in a mixture of methanol and water. The solution was neutralized with a sodium hydrogen carbonate solution. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was triturated in dichloromethane. The product was filtered off and dried, yielding 6 parts (89%) of 1-[4-[4-(4-

so hydroxyphenyi)-1-piperazinyl]phenyl]-3-propyl-2-imidazolidinone (46). In a similar manner there were also prepared: -- 1-ethyl-3-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-imidazolidinone; mp. +300°C (dec); (47) 1-butyl-3-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-imidazolidinone; mp. 217.5°C; (48) 1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3-(1-methylethyl)-2-imidazolidinone; mp. 250.0°C (49);

55 1-butyl-3-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2,4-imidazolidinedione(50); 3-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-1-(1-methylethyl)-2,4-imidazolidinedione; mp. 244.1°C

(51); 1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3-propyl-2,4-imidazolidinedione; mp. 210.9°C (52); 1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3-(1-methylethyl)-2,4-imidazolidinedione; mp. 249°C;

eo (53) 3-ethyl-1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2,4-imidazolidinedione; mp. 287. 1°C; (54) 3-butyl-1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2,4-imidazolidinedione; mp. 212.2°C; (55) 1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3-methyl-2,4-imidazolidinedione (56); and 1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3-methyl-2-imidazolidinone (57).

32

K U HO lOO B l

txampie aim Gazeous hydrogen bromide was bubbled through 150 parts of cold a hydrobromic acid solution 48 /o in

water. 18.3 Parts of /V-(2,2-dimethoxyethyl)-/V'-[4-[4-(4-methoxyphenyl)-1-piperaz.nyl]phenyl]-/V-(1-methyl- ethyllthiourea were added and the whole was stirred first for 1 hour at room temperature and for 2 hours at

reflux. After cooling overnight, the precipitated product was filtered off '.washed with 2-propano J and

dissolved in a mixture of methanol and water. The solution was neutralized with a sodium hydrogen

carbonate solution. The product was extracted with dichloromethane The extrac was dried, f. I e ed and

evaporated. The residue was boiled in methanol. After cooling the, product was f « " ^ ^ " ^ J * *

column chromatography over silica gel using a mixture of trichloromethane and methanol (98.2 by

, volume) as eluent The pure fractions were collected and the eluent was evaporated^ The residue was crystallized from 1-butanol. The product was filtered off and dried yielding 10.5 , parts ; (68%) of 4-[4-[4-[[3- (1-methylethyl)-2(3W)-thiazolyliden]amino]phenyl]-1-piperazinyl]phenol; mp. 215.7 C (58).

Example XIV ; Gazeous hydrogen bromide was bubbled through a stirred mixture of 150 parts of a hydrobromic acid

solution 48% in water and 1 part of sodium sulfite. 16.5 Parts of /V-(2,2-dimethoxyethyl)-/V -[4-[4-(4- methoxyphenyl)-1-piperazinyl]phenyl]-/V-methylthiourea were added and the whole was stirred and refluxed for 3 hours. After cooling, the precipitated product was filtered off, washed with 2-propanol and dissolved in a mixture of methanol and water. The solution was treated with sodium hydrogen carbonate.

o The product was extracted with dichloromethane. The precipitated product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was triturated in dichloromethane. The product was filtered off and dried, yielding 6 parts (44 M of 4-[4-l4-l(3- methyl-2(3tf)-thiazolyliden)amino]phenyl]-1-piperazinyl]phenol; mp. 225°C (59).

5 In a similar manner there were also prepared: 4-[4-[4-[(3-ethyl-2(3/y)-thiazolyliden)amino]phenyl]-1-piperazinyl]phenol; mp. 198.6 C (60); ana 4-[4-[4-[[3-(1-methylpropyl)-2(3W)-thiazolyliden)amino]phenyl]-1-piperazinyl]phenol; mp. 160 C (61).

Example XV <o A mixture of 456 parts of 1-[[2-(2-bromo-4-chlorophenyl)-1,3-dioxolan-2-yl]methyl]-1W-1,2,4-triazole

and 1 584 parts of concentrate hydrochloric acid was stirred and refluxed for 4 hours. The whole was treated with a sodium hydroxide solution 50%. After stirring for a while, the precipitated product I was-filtered off, washed with water and set aside. The filtrate was extracted first twice with 4-methyl-2-pentanone and then three times with trichloromethane. The 4-methyl-2-pentanone layers were dried, filtered and evaporated.

is The residue was stirred in 2-propanol. The precipitated product II was filtered off and set aside. The trichloromethane-layers were dried, filtered and evaporated. The residue was stirred in 2-propanol. The

precipitated product was filtered off and purified, together with product I and product II which were set aside, by column chromatography over silica gel using a mixture of dichloromethane, ethanol and ammonium hydroxide (98.5:1 :0.5 by volume) as eluent. The pure fractions were collected and the eluent

to was evaporated. The residue was crystallized from 2,2'-oxybispropane and 2-propanol. The product was filtered off and dried, yielding 17 parts of 1-(2-bromo-4-chlorophenyl)-2-(1W-1,2,4-triazol-1-yl)ethanone (62).

Example XVI A mixture of 30 parts of 1,2,3-propanetriol, 25 parts of 1-(2-bromo-4-chlorophenyl)-2-(1//-1,2,4-triazol-1-

45 yDethanone, 296 parts of methanesulfonic acid and 180 parts of benzene was stirred and refluxed for 5 hours The whole was stirred overnight at room temperature. The reaction mixture was added dropwise to

a sodium hydrogen carbonate solution. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of trichloromethane, hexane and methanol (46:46:8 by volume) as

50 eluent. The pure fractions were collected and the eluent was evaporated, yielding 13 parts (43%) of c/s-2-(2- bromo-4-chlorophenyl)-2-[1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol; mp. 150°C (63).

In a similar manner there were also prepared: (c/s+?ra/7s)-2-(4-bromophenyl)-2-(1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol as residue

55 (64)'c/s-2-(4-chlorophenyl)-2-(1/V-1,2,4-triazol-1-ylmethyl-1,3-dioxolane-4-methanol as a residue (65).

Example XVII To a stirred mixture of 37 parts of (c/s+r/-a/7s)-2-(2-chlorophenyl)-2-(1W-1,2,4-triazol-1-ylmethyl-1,3-

dioxolane-4-methanol, 500 parts of pyridine and 650 parts of dichloromethane were added dropwise 37

eo parts of benzoyl chloride at a temperature below 20°C. Upon completion, stirring was continued for 3 hours at room temperature. The reaction mixture was poured onto water and the solution was treated with sodium hydrogen carbonate. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified twice by column chromatography (HPLC) over silica gel using first a mixture of hexane, trichloromethane and methanol (60:38:2 by volume)

65 and then a mixture of trichloromethane and methanol (98:5:1.5 by volume) as eluent. The pure fraction

oo

EP 0 1 1 8 138 B1

(cis-isomer) was collected and the eluent was evaporated, yielding 19 parts (38%) of c/s-2-(2-chlorophenyl)- 2-(1/7-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol benzoate(ester) as a residue (66).

In a similar manner there was also prepared: c/s-2-(4-bromophenyl)-2-(1/V-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol benzoate(ester) (67).

Example XVIII A mixture of 17 parts of c/s-2-(2-chlorophenyl)-2-(1/V-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-

methanol benzoate(ester), 35 parts of a sodium hydroxide solution 50%, 150 parts of water and 300 parts of 1,4-dioxane was stirred and refluxed for 30 minutes. After cooling, the reaction mixture was poured onto water. The product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was triturated in 2,2'-oxybispropane. The product was filtered off and dried, yielding 11 parts (88%) of c/s-2-(2-chlorophenyl)-2-(1/V-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol; mp. 87.2°C (68).

In a similar manner there was also prepared: c/s-2-(4-bromophenyl)-2-(1/V-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol ethanedioateO :1);

mp. 165.5°C (69).

Example XIX To a stirred mixture of 11 parts of c/s-2-(2-chlorophenyl)-2-(1//-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-

4-methanol, 150 parts of pyridine and 195 parts of dichloromethane were added 6 parts of methanesulfonyl chloride. Stirring was continued for 3 hours at room temperature. The reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was triturated in 2,2'-oxybispropane and 4-methyl-2-pentanone. The product was filtered off and dried, yielding 13.6 parts (98%) of c/s-2-(2-chlorophenyl)-2-(1W-1,2,4-triazol-1- ylmethyl)-1,3-dioxolane 4-methanol methanesulfonate(ester); mp. 100.0°C (70).

In a similar manner there were also prepared: c/s-2-(4-chlorophenyl)-2-(1A/-1,2,4-triazol-1-ylmethyl-1,3-dioxolane-4-methanol methanesulfonate

(ester); (71) c/s-2-(4-bromophenyI)-2-(1/V-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate

(ester) ethanedioateO :1) (72); c/s-2-(2-bromo-4-chlorophenyl)-2-(1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methane-

sulfonate (ester) (73); c/s-2-(2-chloro-4-fluorophenyl)-2-(1/V-imidazol-1-ylmethyl)-1,3-dioxolane-4-methanol methane-

sulfonate (ester) (74); and c/s-2-(4-fluorophenyl)-2-(1/i/-imidazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate (ester)

ethanedioate (1:1) (75).

Example XX a) To 11.9 parts of water was added dropwise 11.5 parts of sulfuric acid with stirring and while cooling.

Then there was added portionwise 4.6 parts of dl-1-(4-methoxyphenyl)-2-methyl-4-(4-methylphenyl- sulfonyOpiperazine and after addition was complete, the whole was stirred and refluxed for 20 hours. After cooling the reaction mixture was poured onto crushed ice. The whole was alkalized with sodium hydroxide solution 1 5N and extracted three times with 4-methyl-2-pentanone. The combined extracts were dried over potassium carbonate and evaporated. The oily residue was distilled to vacuo, yielding 1 .7 parts of oily 1-(4- methoxyphenyl)-2-methylpiperazine; bp. 144— 147°C at 0.3 mm pressure; ml0 = 1.5633; d|§ = 1.0782 (76).

b) A mixture of 43 parts of 1-(4-methoxyphenyl)-2-methylpiperazine and 375 parts of a hydrobromic acid solution 48% in water was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 72 parts (97%) of 4-(2-methyl-1-piperazinyl)phenol dihydrobromide (77).

c) To a stirred mixture of 69 parts of 4-(2-methyl-1-piperazinyl)phenyl dihydrobromide, 50 parts of sodium hydrogen carbonate, 500 parts of water and 450 parts of trichloromethane were added 21 parts of acetic acid anhydride. Stirring was continued for 1 hour at room temperature. The organic phase was separated, dried, filtered and evaporated. The residue was dissolved in a dilute sodium hydroxide solution and stirred overnight. The whole was neutralized with acetic acid and sodium hydrogen carbonate. The precipitated product was filtered off and triturated in 4-methyl-2-pentanone. The product was filtered off and crystallized from 2-propanol, yielding 22.8 parts of 1-acetyl-4-(4-hydroxyphenyl)-3-methylpiperazine; mp. 175.9°C (78).

d) A mixture of 19 parts of 1-acetyl-4-(4-hydroxyphenyl-3-methylpiperazine, 36 parts of c/s-2-(2,4- dichlorophenyl)-2-(1/Y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate(ester), 6.5 parts of potassium hydroxide and 200 parts of dimethyl sulfoxide was stirred overnight at room temperature. The reaction mixture was poured onto water and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The filtrate was evaporated and the residue was crystallized from a mixture of 4-methyl-2- pentanone and 1,1'-oxybisethane, yielding 23.3 parts (52%) of c/s-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-

34

:P 0 118 138 B1

(1tf-1,2,4-triazol-1-ylmethyl)-1,3-dio^ mP- '^■D-lo'-J ° (79)

e) A mixture of 21.3 parts of c/s-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-1,2,4-triazol-1-ylmethyl)- 1,3-dioxoian-4-yi]methoxy]phenyl]-3-methylpiperazine and 200 parts of a hydrochloric acid solution 1N was stirred for 5 hours at 80°C. The reaction mixture was cooled and neutralized with sodium hydrogen carbonate. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 1,1'-oxybisethane, yielding 11.7 parts (59%) of c/s-1-[4-[[2- (2,4-dichlorophenyl)-2-(1/i/-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-2-methylpiperazine; mp. 125°C (80). rtn , . , M U

9 f) A mixture of 4.2 parts of 1-fluoro-4-nitrobenzene, 14 parts of c/s-1-[4-[[2-(2,4-dichlorophenyl)-2-(1tf- 1 2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-2-methylpiperazine, 2 parts of potassium carbonate and 150 parts of dimethyl sulfoxide was stirred for 1 hour at 100°C. The reaction mixture was cooled and poured onto water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from a small amount of 4-methyl-2-

5 pentanone and 1,1'-oxybisethane, yielding 14 parts (80%) of c/s-1-[4-[[2-(2,4-dichlorophenyl)-2-(1W-1,2,4- triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-2-methyl-4-(4-nitrophenyl)piperazine; mp. 133.7 C (81)

g) A mixture of 12 parts of c/s-1-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxoIan- 4-yl]methoxy]phenyl]-2-methyl-4-(nitrophenyl)piperazine, 1 part of a solution of thiophene in ethanol 4%

o and 300 parts of 2-methoxyethanol was hydrogenated at normal pressure and at 50°C with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 1 1 .4 parts (100%) of c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)- 2-(1W-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-3-methyl-1-piperazinyl]benzenamine as a residue (82).

'5 Example XXI A mixture of 4.1 parts of l-butyl-3-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2,4-imidazolidine-

dione, 6.2 parts of c/s-2-(4-chlorophenyl)-2-(1/V-1,2,4-triazol-1-ylmethyl-1,3-dioxolane-4-methanol methanesulfonate (ester) ethanedioateO :1), 10.0 parts of potassium carbonate and 180 parts of 1-propanol was

30 stirred and refluxed for 1 week. After cooling, the reaction mixture was diluted with water. The product was extracted three times with dichloromethane. The combined extracts were dried, filtered and evaporated in vacuo. The residue was triturated in acetonitrile. The precipitated product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was

35 crystallized from 4-methyl-2-pentanone, yielding 2.5 parts (39%) of propyl c/s-[4-[4-[4-[[2-(4-chlorophenyl)- 2-(1/7,-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]carbamate; mp. 210.7°C (83).

In a similar manner there was also prepared: propyl c/s-[4-[4-[4-[[2-(4-bromophenyl)-2-(1/V-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

40 phenyl]-1-piperazinyl]phenyl]-carbamate; mp. 214.4°C (84).

Example XXII A mixture of 2 parts of 2-(methylamino)ethanol, 10 parts of c/s-phenyl [4-[4-[4-[2-(2,4-dichlorophenyD-

2-(1/V-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]carbamate and 150 45 parts of 1,4-dioxane was stirred and refluxed for 4 hours. To the reaction mixture were added 35 parts of

2,2'-oxybispropane. The product was allowed to crystallize. It was filtered off and triturated in 2-propanone. The product was filtered off and dried, yielding 9 parts (93%) of cis - N - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) -2 - {IH -1,2,4 - triazol - 1 '- ylmethyl) -1,3 - dioxolan -4 - yl]methoxy]phenyl] -1 - piperazinyljphenyl] - N' - (2 - hydroxyethyl) - N' - methylurea; mp. 185.4°C. (85).

so Following the same procedure and using equivalent amounts of the appropriate starting materials there were also prepared:

55

60

65

ob

EP 0 118 138 B1

I n t . No. Q Ar R ' mp. in °C

(86) CH 2, 4- dichlorophenyl 137.4 (87) N 2,4-dichlorophenyl C2H5 159.8 (88) N 2,4-dichlorophenyl n.C3H- 157.8 (89) N 2,4-dichlorophenyl n.C4H9 151.9 (90) N 2,4-dichlorophenyl (CH3)2CH 176.8 (91) N 2,4-dichlorophenyl C2H5(CH3)CH 176.5 (92) N 2,4-dichlorophenyl i.C4Hg 136.5 (93) N 2,4-dichlorophenyl (CH3)2CHCH2CH2 162.7

I n t . 1o. Q Ar R 1 mp. in °C

[94) N 2 ,4-dichlorophenyl C2H5(CH3)CHCH2 136.8 [95) N 2,4-dichlorophenyl. (C2H5)2CH 174.3 [96) N 2,4-dichlorophenyl n.C3H?( CH3)CH 139.4 [97) CH 2,4-dichlorophenyl C ^ C H ^ C H 190.0 [98) N 2,4-dichlorophenyl n.C5Hn 159.5 [99) CH 2,4-dichlorophenyl H 201.2 [100) CH 2,4-dichlorophenyl n.C4Hg 168.6 [101) CH 2,4-dichlorophenyl n.^H- 166.2 [102) CH 2,4-dichlorophenyl CH3 170.2 [103) N 2,4-dichlorophenyl C ^ 106.1-120.2

i similar manner there were also prepared!

!6

■P 0 1 1 8 138 B1

.nt . No. Q Ar R 1 mp. in °C

104) CH 2,4-dichlorophenyl C2H5 145.2

105) N 2,4-dichlorophenyl C2H5

Example xxm ?5 A mixture of 5 parts of 2,2-dimethoxyethanamine, 22 parts of cis - phenyl [4 - [4 - [4 - [2 - (2,4 -

dichlorophenyl) - 2 - (1/V - 1 ,2,4-triazol - 1 - ylmethyl) - 1,3-dioxolan - 4 - ylmethoxylphenyl] - 1 - piperazinyllphenyllcarbamate and 250 parts of 1,4-dioxane was stirred and refluxed overnight. The reaction mixture was cooled to about 50°C and treated with activated charcoal. The latter was filtered off and the filtrate was saturated with 2,2'-oxybispropane. The precipitated product was filtered off and

30 crystallized from 2-propanol, yielding 16 parts (71%) of cis - phenyl [4 - [4 - [4 - [2 - (2,4 - dichlorophenyl) - 2 - (1/V - 1,2,4 - triazol - 1 - ylmethyl) - 1,3-dioxolan - 4 - ylmethoxylphenyl] - 1 - piperazinyi]phenyl] - N' - (2,2-dimethoxyethyl)urea; mp. 151.7°C (106).

In a similar manner there was also prepared: c/s-/V-[4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1/V-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl]-1-

35 piperazinyl]phenyl]-/V'-(2,2-dimethoxyethyl)urea (107).

Example XXIV A mixture of 2.2 parts of 2-(phenylamino)ethanol, 10 parts of phenyl cis - [4 - [4 - [4 - [2 - (2,4 -

dichlorophenyl) - 2 - (1W - 1,2,4 - triazol - 1 - ylmethyl) - 1,3-dioxolan - 4 - ylmethoxylphenyl] - 1 - 40 piperazinyllphenyllcarbamate, 2 parts of /V,/V-dimethyl-4-pyridinamine and 200 parts of 1,4-dioxane was

stirred and refluxed overnight. The reaction mixture was cooled and poured onto water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The

45 residue was crystallized twice from 4-methyl-2-pentanone (activated charcoal), yielding 3.8 parts (36%) of 2-(phenylamino)ethyl c/s-[4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1/V-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]- methoxy]phenyl]-1-piperazinyl]phenyl]carbamate; mp. 188.1°C (108).

Example XXV 50

' A mixture of 1.8 parts of 2-(ethylamino)ethanol, 10 parts of c/s-1-[4-[[2-(2,4-dichlorophenyi)-2-(1W- imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(4-isothiocyanatophenyi)piperazine and 160 parts of ethanol was stirred till all solid entered solution. Upon stirring, the reaction mixture was allowed to cool. The crystallized product was filtered off and dried, yielding 9 parts (79%) of cis-N - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) -2 -(1tf - imidazol -1 -ylmethyl) -1,3 - dioxolan -4 -yl]methoxy]phenyl] -1 -

55 piperazinyllphenyl] - N' - ethyl - N' - (2-hydroxyethyl)thiourea; mp. 171. 5°C (109). In a similar mannerthere was also prepared: c/s-yV-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1//-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-

1-piperazinyl]phenyl]-/V'-(2-hydroxyethyl)-/V'-(1-methylpropyl)thiourea; mp. 173.4°C (110).

60 Example XXVI A mixture of 5 parts of 2-[(3-methylbutyl)amino]ethanol, 20 parts of c/s-1-[4-[[2-(2,4-dichlorophenyl)-2-

(1/V-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(4-isothiocyanatophenyl)piperazineand 390 parts of dichloromethane was stirred for 1 hour at room temperature. The reaction mixture was evaporated and the residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried,

65 yielding 19.7 parts (81%) of cis - N' - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1W - imidazol - 1 -

37^

EP 0 1 1 8 1 3 8 B1

ylmethyl) -1,3-dioxolan -4 - yl]methoxy]phenyl] -1 -piperazinyljphenyl] -N -(2 - hydroxyethyl) -N - (3-methylbutyl)thiourea; mp. 166.0°C (111).

Following the same procedure and using equivalent amounts of the appropriate starting materials there were also prepared:

10

15

20 int. Q n R1 mp. in "C Nn.

(112) CH 2 (CH3)2CH 137.7 (113) CH 2 n.C3H? 155.1

25 (114) CH 2 i.C4HQ 170.0 (115) N 2 C2H5 179.6 (116) N 2 C2H5(CH3)CH 169.3

30 (117) CH 2 n.C4Hg 180.4 (118) N 2 n.C3H- 178.5-178.9

(119) N 2 (CH3)2CH 190.0 (120) CH 2 CH, 153.5 35 3 (121) N 2 n*C5HH 154'7

(122) N 2 (CH3)2CHCH2 180.0 (123) CH 2 n.C.H.. 153.1

40 J 11 (124) N 2 CH3 175.2

(125) CH 2 (C2H5)2CH 181.4 (126) CH 2 C2H5(CH3)CHCH2 165.0

45 (127) N 2 (C2H5)2CH ' 162.8

(128) N 2 n.C4_9 144.9

(129) N 2 n.C3H_(CH3)CH 116.7 50 (130) N 2 C2H5(CH3)CHCH2. 120.0

(131) N 2 1-C5HH (132) N 3 C2H5 166.6

6S (133) CH 3 C2H5 165.0

(134) N 3 n.C4H9 147.5

(135) CH 3 n.C4H9 172.9

60 (136) CH 3 i.C3H- 156.4

£75

38

P U 110 1JO D l

txampie aavii A mixture of 4 parts of 2-(phenylamino)ethanol, 10 parts of c/s-1-[4-[[2-(2,4-dichlorophenyl)-2-(1/7'-

f1idazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(4-isothiocyanatophenyl)piperazme, 1 part of ' /V-dimethyl-4-pyridinamine and 39 parts of dichloromethane was stirred overnight at room temperature, he reaction mixture was evaporated. The residue was crystallized from 2-propanone. The product was Itered off and dried, yielding 10.5 parts (86%) of cis - N - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - H - imidazol -1 - ylmethyl) -1,3 - dioxolan -4 - yl]methoxy]phenyl] -1 - piperazinyljphenyl] -N - l-hydroxyethyl) - N' - phenylthiourea; mp. 131.7°C (137).

Example XXVIII A mixture of 10 parts of 2-(phenylamino)ethanol and 10 parts of cis-1-[4-[[2-(2,4-dichlorophenyl)-2-(1//-

2 4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(4-isothiocyanatophenyl)piperazine was tir'red and heated till all entered solution. The whole was stirred overnight at 50°C. The residue was taken

pin a mixture of trichloromethane and methanol (90:10 by volume). The solution was washed twice with dilute hydrochloric acid solution and once with a sodium hydrogen carbonate solution. The mixture was vaporated. The residue was purified by column chromatography over silica gel using a mixture of ■ichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the luentwas evaporated, yielding 10 parts (82%) of cis - N' - [4 - [4 - [4 - [[2 -(2,4 - dichlorophenyl) - 2 - \H - 1,2,4-triazol - 1 -yl - methyl) -1,3 - dioxolan -4 - yl]methoxy]phenyl] -1 - piperazmyUphenylJ - I - (2 - hydroxyethyl) - N - phenylthiourea as a residue (138).

Example XXIX A solution of 17 parts of 1H-imidazole-2-methanamine dihydrochloride, 10.7 parts of benzaldehyde, 2

arts of a solution of thiophene in methanol 4%, 20 parts of potassium acetate and 200 parts of methanol

/as hydrogenated at normal pressure and at 50°C with 2 parts of platinum-on-charcoal catalyst 5 /o. After he calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was vaporated The residue was dissolved in water and the solution was treated with ammonium hydroxide, he product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 5 parts (80%) of /V-(phenylmethyl)-1/V-imidazole-2-methanamine as a residue (139).

In a similar manner there was also prepared: c/s-/V'-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

ihenyl]-1-piperazinyl]phenyl]-/V-ethyl-/V-[2-(ethylamino)ethyl]thiourea; mp. 149.6°C (140) . . Example XXX

A mixture of 2.1 parts of 2,2-dimethoxy-/V-methylethanamine, 10 parts of cis - 1 - [4 - [[2 - (2,4 - iichlorophenyl) - 2 - (IH - imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl - 4 - (4 - sothiocyanatophenyDpiperazine and 130 parts of dichloromethane was stirred for 2 hours at room

emperature. The reaction mixture was evaporated and the residue was crystallized from methanol. The

jroduct was filtered off and dried, yielding 11. 6 parts (97.8%) of cis -N' -[4 -[4 - [4 -[[2 - (2,4 -dichloro-

jhenyl) - 2 - (1tf - imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 -

Diperazinyllphenyl - N - (2,2 - dimethoxyethyl) - N - methylthiourea; mp. 164.6°C (141). In a similar manner there were also prepared: c/s-/V'-[4-[4-[4-[[2-(2,4-dicW^

Dhenyl]-1-piperazinyl]phenyl]-/V-(2,2-dimethoxyethyl)-/V-phenylmethylthiourea; mp. 129.7 C (142 ; c!fe-/V'-[4-[4-t4-[[2-(2,4-dichlorophenyl)-2-(1/V-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-

l-piperazinyl]phenyl]-/V-(2,2-dimethoxyethyl)-/V-ethylthiourea;mp.115.4°C(143); c/s-/V'-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-

1-piperazinyl]phenyl]-/V-(2,2-dimethoxy)-/V-(1-methylpropyl)thiourea;mp. 141.0°C (144); c/s-/V'-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

phenyl]-1-piperazinyl]phenyl]-/V-(2,2-dimethoxyethyl)-/V-methylthiourea; mp. 139.2°C (145); c/s-/V'-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

phenyl]-1-piperazinyl]phenyl]-/V-(2,2-dimethoxyethyl)-/V-ethylthiourea;mp.139.5°C(146); c/s-/V'-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-

1-piperazinyi]phenyl]-yV-(2,2-dimethoxyethyl)-/V-(1-methylethyl)thiourea; mp. 143.9°C (147); c/s-/V'-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methox^y]-

phenyl]-1-piperazinyl]phenyi]-/V-(2,2-dimethoxyethyl)-/V-(1-methylpropyl)thiourea as a residue (148); and c/s-/V'-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1//-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

phenyl]-1-piperazinyl]phenyl]-/V-(2,2-dimethoxyethyl)-/V-(1-methylethyl)thiourea monohydrate; mp. 128.1°C(149).

Example XXI To a stirred mixture of 0.91 parts of methylhydrazine in 195 parts of cis - N - [4 - [4 - [4 - [[2 - (2,4 -

dichlorophenyl) -2 -(1tf -1,2,4 -triazol -1 -ylmethyl) -1,3 -dioxolan -4 -yl]methoxy] - phenyl] -1 - piperazinyljphenyl -1 - methylhydrazinecarbothioamide were added 10 parts of as -1-14 - U2 - (2,4 - dichlorophenyl) - 2 - (IH - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yljmethoxyjphenyl] - 4 - (4 - isothiocyanatophenyDpiperazine. The whole was stirred for 1 hour. The reaction mixture was

EP 0 1 1 8 1 3 8 B1

evaporated. The residue was triturated in methanol. The product was filtered off and crystallized from 1 - butanol. The product was filtered off and dried yielding 7.2 parts (67%)ofc/s -/V -[4 -[4 -[4 -[[2 -{2,4 - dichlorophenyl) - 2 - [1/V - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl - 1 - piperazinyljphenyl] - 1 - methylhydrazinecarbothioamide; mp. 171.3°C (150).

5 Example XXXII

A mixture of 5.2 parts of N,N - dimethyl - N' -(1 - methylpropyDmethanehydrazonamide, 12.5 parts of cis -1 -[4 -[[2 -(2,4 - dichlorophenyl) -2 - (1/V -1,2,4 - triazol -1 -ylmethyl) -1,3 - dioxolan -4 - yl]methoxy]phenyl] - 4 - (4-isothiocyanatophenyl)piperazine and 300 parts of trichloromethane was

10 stirred for 5 hours at room temperature. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (resp. 99:1 and 97.5:2.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from methanol, yielding 7.2 parts (53%) of cis - N' - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) -2 - (1/V -1,2,4 - triazol -1 -ylmethyl) -1,3 - dioxolan -4 - yl]methoxy]phenyl] -1 -

75 piperazinyljphenyl] - N,N - dimethylthiourea; mp. 185.0°C (151).

Example XXXIII To a stirred solution of 5 parts of c/s-4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1/V-imidazol-1-ylmethyl)-1,3-

dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]benzenamine in 50 parts of pyridine were added dropwise 20 0.85 parts of methyl carbonochloridate. Upon completion, stirring was continued for 1 hour. Another 0.85

parts of methyl carbonochloridate was added dropwise and stirring was continued for 2 hours at room temperature. The reaction mixture was poured onto water. The precipitated product was filtered off and dried. It was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The

25 residue was crystallized from 1-butanol, yielding 4.5 parts (82%) of cis - methyl [4 - [4 - [4 - [2 - (2,4 - dichlorophenyl) - 2 - ("iH - imidazol - 1 - ylmethyl] - 1,3 - dioxolan - 4 - ylmethoxylphenyl - 1 - piperazinyl]phenyl]carbamate; mp. 208.6°C (152).

Example XXXIV 30 To a stirred solution of 5 parts of c/s-4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1A/-imidazol-1-ylmethyl)-1,3-

dioxolan-4-ylmethoxy]phenyl]-1-piperazinyl]benzenamine in 130 parts of dichloromethane were added successively 0.8 parts of ethyl chloroformate and 1 part of sodium hydrogen carbonate in 50 parts of water. The whole was stirred for one hour at room temperature. 140 Parts of petroleumether were added to the reaction mixture. The precipitated product was filtered off, washed with water and 2-propanol, and purified

35 by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 1,4-dioxane and 2,2'-oxybispropane, yielding 4.6 parts of cis - ethyl [4 - [4 - [4 - [2 - (2,4 - dichlorophenyl) - 2 - (1/V - imidazol - 1 - ylmethyl] - 1,3 - dioxolan - 4 - ylmethoxylphenyl] - 1 - piperazinyl]phenyl]carbamate; mp. 206.7°C (153).

40 In a similar mannerthere were also prepared: c/s-ethyl [4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1/v'-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

phenyl]-1-piperazinyl]phenyl]carbamate; mp. 202°C (154); and c/s-methyl [4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1A/-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

phenyl]-1-piperazinyl]phenyl]carbamate; mp. 205.5°C (155). 45"

Example XXXV A mixture of 0.73 parts of isothiocyanatomethane, 5 parts of cis - 4 - [4 - [4 - [2 - (2,4 -

dichlorophenyl) - 2 - (1// - imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - ylmethoxylphenyl] - 1 - piperazinyl]benzenamine, 130 parts of dichloromethane and 100 parts of 1,4-dioxane was stirred and

so refluxed for 4 hours. Another 0.73 parts of isothiocyanatomethane were added and stirring at- reflux temperature was continued overnight. The reaction mixture was evaporated and the residue was crystallized from 2-propanol. The product was filtered off and recrystallized from 1-butanol (activated charcoal), yielding 3.2 parts (57%); of cis - N - [4 - [4 - [4 - [2 - (2,4 - dichlorophenyl) - 2 - (1/V - imidazol -1 -ylmethyl) -1,3 - dioxolan -4 - ylmethoxylphenyl] -1 - piperazinyljphenyl] - N' - methyi-

55 thiourea; mp. 172.5°C (156). Example XXXVI

A mixture of 0.9 parts of 1-isocyanatopropane, 5.8 parts of cis - 4 - [4 - [4 - [2 - (2,4 - dichlorophenyl) - 2 - (1/V - imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - ylmethoxylphenyl] - 1 - piperazinyljbenzenamine and 260 parts of dichloromethane was stirred overnight at room temperature.

eo The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone (activated charcoal), yielding 3.4 parts (51%)ofc/s -N -[4 -[4 -[4 -[2 -(2,4 -dichlorophenyl) -2 -(IH - imidazol - 1 - ylmethyl) - 1,3-dioxolan - 4 - ylmethoxylphenyl] - 1 - piperazinyljphenyl] - N' -

65 propylurea; mp. 228.6°C (157).

40

■P 0 118 138 B1

In a similar manner there were also prepared: c/s-/V-[4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1W-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenylJ-1-

piperazinyl]phenyl]-N'-methylurea; mp. 192.6°C; (158) c/s-/V-[4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1^-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenylJ-

r 1-piperazinyl]phenyl]-N'-methylurea; mp.203.4°C; (159) c/s-/V-[4-[444-[2-(2,4-dichlorophenyl)-2-(1/V-1,2Atriazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl]-

1-piperazinyl]phenyl]-N'-ethylurea; mp. 164.4°C; (160) c/s-/V-[4-[4-[4-[2-(2,4-dichloroph

piperazinyl]phenyl]-N'-ethylurea; mp. 217.2°C (161); and o c/s-/V-[4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

phenyl]-1-piperazinyl]phenyl]-N'-propylurea; mp. 194°C (162). Following the same procedure and using equivalent amounts of the appropriate starting materials,

there were also prepared:

5

>.0

is Int . No. Q R1 mp. in °C

30 (163) CH 4-N02-C6H4 219.2

(164) CH 2-Cl-C6H4 203.4

(165) N (C2H5)2CH 163.8

(166) CH (C-H,)-CH 201.9 35 1 1 1

(167) CH CH3(C2H5)CH

(168) CH CH3(C3H?)CH 191.4

40 (169) CH 4-CH3-C6H4 234.4

(170) CH C6H5 224.0

(171) CH (CH3)2CH(CH2)2 209.4

(172) CH CH3(CH2)4 203.6

(173) CH t.C4Hg 216.9

(174) N CH3(C2H5)CH 161.6

(175) N (CH3)2CH(CH2)2 196.6 50 (176) N C'C4H9 208,1

(177) N (CH3)2CHCH2 201.8

(178) N CH3(CH2)4 171.1 55 (179) CH (CH3)2CHCH2 221.5

(180) N a.C4H9 196-°

(181) N i.C3H? 198.9

60 (182) CH i'C3H7 248,9

(183) CH n-CAH9 196'9 anc

(184) CH 3-Cl-C6H4 186.9

65 1 — — '

41

EP 0 1 1 8 1 3 8 B1

Example XXXVII A mixture of 4 parts of cis - 3 - [4 - [4 - [4 - [[2 -(2,4 - dichlorophenyl) -2 -(IH - imidazol -1 -yl-

nethyl] - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyljphenyl - 5,5 - dimethyl - 2,4 - midazolidinedione, 4 parts of potassium hydroxide and 80 parts of ethanol was stirred and refluxed till all solid entered solution. After cooling, the product was filtered off and dissolved in a mixture of methanol and water. The acid was liberated with acetic acid. The product was filtered off, washed with water and nethanol and dried, yielding 3 parts (73%) of cis -2 -[[[4 -[4 -[4 -[[2 -(2,4 -dichlorophenyl) -2 -[1tf - midazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yljmethoxyjphenyl] - 1 - piperazinyl]phenyl]amino- :arbonyl]amino] - 2 - methylpropanoic acid; mp. 199.3°C (185).

Example XXXVIII A mixture of 1.92 parts of thionyl chloride, 5 parts of cis -N - [4 - [4 - [4 - [2 -(2,4 - dichlorophenyl) -

2 - (IH - imidazol -1 -ylmethyl) -1,3 -dioxolan -4 -ylmethoxylphenyl] -1 - piperazinyljphenyl] -N' - [2 - hydroxyethyl)urea and 225 parts of trichloromethane was stirred and refluxed for 2 hours. The reaction mixture was evaporated and the residue was stirred in 80 parts of methanol. 2 Parts of potassium hydroxide were added and the whole was stirred till the product was precipitated. It was filtered off and purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol [99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from methanol, yielding 1 part (20%) of cis -N -(2 - chloroethyl) -N' - [4 - [4 - [4 - [2 - (2,4 - dichlorophenyl) -2 - (1/V - imidazol -1 -ylmethyl) -1,3 - dioxolan -4 - yl]methoxy]phenyl] -1 - piperazinyl]phenyl]urea; mp. 204.6°C (186).

B. Preparation of Final Compounds Example IXL

A mixture of 40 parts of phenyl cis - [4 - [4 - [4 - [2 - (2,4 - dichlorophenyl) - 2 - (IH - imidazol - 1 - ylmethyl) -1,3 - dioxolan -4 -ylmethoxylphenyl] -1 - piperazinyl]phenyl]carbamate, 11.3 parts of ethyl 2-aminopropanoate hydrochloride, 3 parts of /V,/V-dimethyl-4-pyridinamine, 8 parts of sodium hydrogen carbonate and 300 parts of 1,4-dioxane was stirred and refluxed for 4 hours. The reaction mixture was saturated with water and stirring and heating was continued for 30 minutes. The mixture was allowed to cool. The precipitated product was filtered off, washed with water and with 2-propanol and dried in a dry- pistol at 120°C, yielding 37.4 parts (97%) of cis - 3 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1W - imidazol -1 -ylmethyl) -1,3 -dioxolan -4 - yl]methoxy]phenyl] -1 - piperazinyljphenyl] -5 - methyl - 2,4 - imidazolidinedione; mp. 260.3°C (compound 1).

In a similar manner there were also prepared: c/s-3-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/V-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]phenyl]-2,4-imidazolidinedione; mp. 253.6°C (compound 2). c/s-3-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/V-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]phenyl]-5,5-dimethyl-2,4-imidazolidinedione; mp. 226.3°C (compound 3); and c/s-3-[4-[4-[4-[[2-(4-chlorophenyl)-2-(1A/-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]phenyl]-5,5-dimethyl-2,4-oxazolidinedione; mp. 223.6°C (compound 4).

Example XL A mixture of 1.5 parts of ethyl 2-[(1-methylethyl)amino]acetate, 5 parts of c/s-phenyl [4 - [4 - [4 - [2 -

(2,4 - dichlorophenyl) -2 -(\H -1,2,4 - triazol -1 -ylmethyl -1,3 - dioxolan -4 - ylmethoxylphenyl] - 1 - piperazinyl]phenyl]carbamate, 1 part of /V,/V-dimethyl-4-pyridinamine and 100 parts of 1,4-dioxane was stirred and refluxed overnight. Water was added followed by the addition of 4-methyl-2-pentanone and 2,2'-oxybispropane. The whole was stirred till the product was crystallized. It is filtered off and recrystallized from 4-methyl-2-pentanone, yielding 4.5 parts (89%) of cis - 3 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) -2 - (IH -1,2,4 - triazol -1 -ylmethyl) -1,3 - dioxolan -4 - yl]methoxy]phenyl] -1 - piperazinyl]phenyl] - 1 - (1 - methylethyl) - 2,4 - imidazolidinedione; mp. 178.0°C (compound 5).


42

EP 0 1 1 8 1 3 8 B1

5 z is

20

Compound No. Q R 1 R'.R" mp. in °C

6 N CH3 H,H 197.6 7 CH CH3 H,H 212.7

8 N n.C4H- H,H 145.0

9 N n.C3H- H,H 150.8

10 CH n.C3H? H,H 170.2

11 N C2H5 H,H 165.1

12 CH n.C4Hg H,H 135.6

13 N H CH3,H 192.3-202.9 and

14 N H (CH3)2 178.5-202.5

In a similar manner there were also prepared:

35

40

c i s

50

Compound

No. Q R' R" mp. in °C

15 N CH3 H 188.5

16 N CH3 CH3 203.4

17 CH CH3 CH3 214.1

18 N 2,4-Cl2-C6H3 H 136.5

19 CH CH3 H 173.6

20 CH 2,4-Cl2-C6H3 H 142.0

21 N C2H5 C2H5 157.8

22 CH C2H5 CH3 193.2

23 N C2H5 CH3 144.9

and 24 CH C2H5 C2H5 140.4

43

EP 0 1 1 8 1 3 8 B1

Example XLI A mixture of 4.2 parts of 3 - [4 - [4 - [4 - (4 - hydroxyphenyl) - 1 - piperazinyl]phenyl] - 1 - (1 -

methylethyl) -2,4 - imidazolidinedione, 4.3 parts of cis -2 -(2,4 - dichlorophenyl) -2 - (1/V - imidazol - 1 -ylmethyl) -1,3 -dioxolane -4 - methanol methanesulfonate (ester), 1.4 parts of potassium carbonate

5 and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 72 hours. The reaction mixture was cooled and poured onto water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99.5:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone.

10 The product was filtered off and dried at 120°C, yielding 1.9 parts (25%) of cis - 3 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1/V - imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl]phenyl] - 1 - (1 - methylethyl) - 2,4 - imidazolidinedione; mp. 177.6°C (compound 25).

Example XLII 15 A mixture of 3.4 parts of 1 -[4 -[4 -(4 - hydroxyphenyl) -1 - piperazinyljphenyl] -3 -methyl -2,4 -

imidazolidinedione, 5.6 parts of cis -2 -(2,4 - dichlorophenyl) -2 - (1/V -1,2,4 - triazol -1 -ylmethyl) - 1,3 - dioxolane - 4 - methanol methanesulfonate (ester), 2.8 parts of potassium carbonate, 20 parts of dimethyl sulfoxide and 64 parts of 1-butanol was stirred and refluxed for 3 hours. After cooling, 200 parts of water were added. The precipitated product was filtered off, washed with water and with 1 -butanol, dried

20 and purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (99.5:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 160 parts of 1-butanol, yielding 2.1 parts (33%) of cis - 1 - [4 - [4 - [4 - [[2 - (2,4 -dichlorophenyl) -2 - [1/V -1,2,4 -triazol -1 -ylmethyl) -1,3 -dioxolan -4 -yl]methoxy]phenyl] - 3 - methyl - 2,4 - imidazolidinedione; mp. 236.8°C (compound 26).

25 In a similar manner there were also prepared: c/s-1-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]phenyl]-3-methyl-2,4-imidazolidinedione; mp. 237.9°C (compound 27).

Example XLIII 30 A mixture of 3.6 parts of 1 - [4 - [4 - (4 - hydroxyphenyl) - 1 - piperazinyljphenyl] - 3 - (1 - methyl-

ethyl) -2,4 -imidazolidinedione, 5.5 parts of cis -2 -(2,4 -dichlorophenyl) -2 -{Mi -1,2,4 -triazol -1 - ylmethyl) - 1,3 - dioxolane - 4 - methanol methanesulfonate (ester), 2 parts of potassium carbonate and 160 parts of 1-butanol was stirred and refluxed for 3 hours. Then there was added another portion of 2.5 parts of cis - 2 - (2,4 - dichlorophenyl) - 2 - (1/V - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolane - 4 -

35 methanol methanesulfonate (ester) and stirring at reflux was continued for 2 hours. The reaction mixture was cooled and 200 parts of water were added. Upon stirring, the precipitated product was filtered off and crystallized from 1-butanol, yielding 4.2 parts (65%) of cis - 1 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - {IH - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yljmethoxyjphenyl] - 1 - piperazinyljphenyl] - 3 - (1 - methylethyl) - 2,4 - imidazolidinedione; mp. 227.1°C (compound 28).

40 Following the same procedure and using equivalent amounts of the appropriate starting materials there were also prepared:

45

50

c i s

mp. in °C

232.2 180.7

235.4 228.6 195.4 and 199.5

Compound

55

60

65

No. Q R1

29 CH (CH3)2CH 30 N n-C4H9 31 CH C2H5 32 N C2H5 33 N n.C3H? 34 CH n.C-jH-

44

EP 0 1 1 8 1 3 8 B1

Example XLIV A mixture of 5 parts of 1 - [4 - [4 - (4 - hydroxyphenyl) - 1 - piperazinyljphenyl] - 3 - methyl - 2 -

imidazolidinone, 8.7 parts of cis - 2 - (2,4 - dichlorophenyl) - 2 - (1/V - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolane - 4 - methanol methanesulfonate (ester), 3 parts of potassium carbonate and 160 parts of

5 1-butanol was stirred and refluxed overnight. The reaction mixture was cooled and 100 parts of water were added. The precipitated product was filtered off, dried and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1-butanol, yielding 7.8 parts (82%) of cis -1 -[4 -[4 - [4 -[[2 -(2,4 - dichlorophenyl) -2 - (1/V -1,2,4 - triazol -1 -ylmethyl) -1,3 -

10 dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyljphenyl] - 3 - methyl - 2 - imidazolidinone; mp. 205.8°C (compound 35).


20

c i s

25 i— — — Compound

No. Q mP- in °C

30 36 N C2H5 198.3

37 CH C2H5 205.3

38 CH n.C4Hg 159.5

35 39 N n.C3H- 179.8-181.0

40 CH n.C3H- 189.2-191.3

41 CH i.C3H7 209.8-217.5

40 42 N i.C3H? 199.0-200.0

43 CH CH3 215.4

45


45

EP 0 1 1 8 1 3 8 B1

c i s

Comp. No. Q Ar R1 mp. in °C

44 N 2,4-Cl2-C6H3 n._4_g 152.2 45 N 4-Cl-C6H4 n.C3H? 194.3 46 N 2-Br,4-Cl-C6H3 n.C.H- 181.0 47 CH 4-F-CgH4 n . C ^ 175.1 48 N 2-Cl-C6H4 n.C3H? 162.2 49 N 4-Br-CgH4 n*C3H7 201«5 an<i 50 CH 2-Cl,4-F-C6H3 n . C ^ 161.6

Example XLV A mixture of 3.3 parts of 4 -[4 -[4 -[(3 - butyltetra hydro -1,3 -thiazin -2 -ylidene)amino]phenyl] -

1 - piperazinyljphenol, 4.2 parts of cis - 2 - (2,4 - dichlorophenyl) - 2 - (1/V - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolane - 4 - methanol methanesulfonate (ester), 1.4 parts of potassium carbonate and 160 parts of 2-propanol was stirred and refluxed for 3 days. Another portion of 2.1 parts of cis - 2 - (2,4 - dichlorophenyl) - 2 - {IH - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolane - 4 - methanol methanesulfonate (ester) was added and stirring was continued for 2 days at reflux temperature. After cooling, 300 parts of water were added. The precipitated product was filtered off, washed with water and 2-propanol, dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 3.8 parts (66%) of cis - 4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1/V - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl] - N - (3 - butyltetrahydro - 2/V - 1,3 - thiazin -2 -ylidene)benzenamine; mp. 190.8°C (compound 51).

Example XLVI A mixture of 3 parts of 4 - [4 - [4 - [(3 - methyl - 2(3/V) - thiazolyliden)amino]phenyl] - 1 -

piperazinyljphenol, 3.5 parts of cis -2 -(2,4 - dichlorophenyl) -2 - (1/V - imidazol -1 -ylmethyl) -1,3 - dioxolane - 4 - methanol methanesulfonate (ester), 1.4 parts of potassium carbonate and 160 parts of 2- propanol was stirred and refluxed over week-end. Another portion of 3.5 parts of cis - 2 - (2,4 - dichlorophenyl) -2 -(1/V -imidazol -1 -ylmethyl) -1,3 -dioxolane -4 - methanol methanesulfonate (ester) and 1.4 parts of potassium carbonate was added and stirring was continued for 24 hours at reflux. After cooling, 200 parts of water were added. The precipitated product was filtered off, washed with water and 2-propanol and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1-butanol, yielding 4.1 parts (74%) of cis - 4 -[4 -[4 -[[2 -(2,4 - dichlorophenyl) - 2 - (1W - imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yljmethoxyjphenyl] - 1 - piperazinyl] - N - (3 - methyl - 2(3/V) - thiazolylidene)benzenamine; mp. 192.3°C (compound 52).

In a similar manner there were also prepared: c/s-4.[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-

1-piperazinyl]-/V-(3-ethyl-2(3W)-thiazolylidene)benzenamine; mp. 196.8°C (compound 53); c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]-/V-(3-ethyl-2(3/V)-thiazolylidene)benzenamine; mp. 163.0°C (compound 54); c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1//-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-

1-piperazinyl]-/V-(3-methyl-2(3A/)-thiazolylidene)benzenamine; mp. 177.5°C (compound 55); c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]-/V-(3-(1-methylpropyl)-2(3/y)-thiazolylidene)benzenamine; mp. 160.4°C (compound 56); c/s-4.[4.[4-[[2-(2,4-dichlorophenyl)-2-(1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-

46

p u n o 100 d i

1-piperazinyl]-/v-(3-0-methylp^ mw- lul-'f v iwhikUu„u- .„ c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1tf-1^^

1-piperazinyl]-/V-[3-(1-methylethyl)-2(3A/)-thiazolylidene]benzenamine; mp. 176.1X (compound 58); and c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/V-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]ph

; piperazinyl]-/V-[3-(1-methylethyl)-2(3W)-thiazolylidene]benzenamine; mp. 178.6°C (compound 59).

Example XLVII A mixture of 0.5 parts of bromoethane, 4 parts of cis - 3 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) -

2 - (1W - imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - ylmethoxylphenyl] - 1 - piperazinyl]phenyl] - 3 2 4 - imidazolidinedione, 0.7 parts of potassium hydroxide and 100 parts of dimethyl sulfoxide was stirred

for one hour at room temperature. The reaction mixture was poured onto water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using mixture of trichloromethane and methanol (99.5—0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The

5 residue was crystallized from 4-methyl-2-pentanone, yielding 1 .8 parts (43%) of cis - 3 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) -2 - (1/Y - imidazol -1 -ylmethyl) -1,3 - dioxolan -4 -yl]methoxy]phenyl] -1 - piperazinyl]phenyl] - 1 -ethyl - 2,4 - imidazolidinedione; mp. 199.6°C (compound 60).

Example XLVIII o A mixture of 5 parts of cis -3 -[4 -[4 -[4 -[[2 -(2,4 -dichlorophenyl) -2 -(1tf -1,2,4 -triazol -1 -

ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyljphenyl] - 5 - methyl - 2,4 - imidazolidinedione, 0.38 parts of a sodium hydride dispersion 50% and 100 parts of dimethyl sulfoxide was stirred till foaming had ceased. 1.01 Parts of 1-bromopropane were added and stirring was continued for 1 hour at room temperature. The reaction mixture was poured onto water. The product was extracted with

5 dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel using first a mixture of trichloromethane and methanol (99:1 by volume) and then a mixture of trichloromethane and methanol (99.5:0.5 by volume) as eluent The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol, yielding 2.4 parts (44%) of cis - 3 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1W - 1,2,4 -

■o triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl]phenyl] - 5 - methyl - 1 - propyl - 2,4 - imidazolidinedione mp. 133.7°C (compound 61).

In a similar manner there were also prepared: , , . „ „ . . , „ n c/s-1-butyl-3-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/V-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]- methoxy]phenyl]-1-piperazinyl]phenyl]-5-methyl-2,4-imidazolidinedione; mp. 132.1T compound 62);

t5 c/si.[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1- piperazinyl]phenyl]-1-ethyl-5-methyl-2,4-imidazolidinedione; mp. 159.6°C (compound 63).

c,s-3-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methox phenyl]-1-piperazinyl]phenyl]-1,5-dimethyl-2,4-imidazolidinedione; mp. 171.8°C (compound 64)

cW[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy- m phenyl]-1-piperazinyl]phenyl]-1-ethyl-5-methyl-2,4-imidazolidinedione; mp. 154.5°C (compound 65).

Js-3-[M4-[4-[[2-(2^^ piperazinyi]phenyl]-5-methyl-1-propyl-2,4-imidazolidinedione; mp. 142.0oC (compound 66);

c/s-1-butyl-3-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]- phenyl]-1-piperazinyl]phenyl]-5-methyl-2,4-imidazolidinedione; mp. 123.8°C (compound 67); and

,5 c/s.3-[4.[4-[4-[[2-(2,4-dichlorophenyl)-2-(1«-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1- piperazinyl]phenyl]-1,5-dimethyl-2,4-imidazolidinedione; mp. 194.3°C (compound 68).

Example IL A mixture of 1 part of bromoethane, 3.5 parts of cis - 3 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 -

so (1W - 1 2 4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yi]methoxy]phenyl] - 1 - piperazmyl]phenyl] - 5 5 - dimethyl - 2,4 - imidazolidinedione, 0.5 parts of potassium hydroxide and 50 parts of dimethyl sulfoxide was stirred overnight at room temperature. The reaction mixture was poured onto water. The

product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from methanol, yielding 3.2 parts (88%) of cis - 3 - [4 - [4 - 14 -

55 [[2 - (2,4 - dichlorophenyl) - 2 - (1/V - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]- phenyl] - 1 - piperazinyl]phenyl] - 1 - ethyl - 5,5 - dimethyl - 2,4 - imidazolidinedione; mp. 165.0 C (compound 70).


60

65

EP 0 118 138 B1

Comp. No. Q mp. in °C

70 N i.C3H7 129.6 71 N CH3 180.7 72 N n.C3H? 203.4 73 N n.C4Hg 182.6

74 CH CH3 228.5 75 CH C2H5 190.6 76 CH n.C3H? 103.0 77 CH i.C3H? 125.6 78 CH n.C4Hg 133.0 79 CH C2H50(CH2)2 133.0 80 CH CH30(CH2)2 152.6

81 CH n.C3H70(CH2)2 145.6 82 CH i.C3H70(CH2)2 149.7 83 CH i.C3H?-CH2 144.1 84 CH n*C5Hll 79,2 85 CH CH3OCH2 122.1 86 CH C2H5(CH3)CH 109.9 87 CH C3H7(CH3)CH 129.1

88 CH i.C3H7(CH2)2 187.4 89 CH C3H5 111.1

90 N CH30(CH2)2 179.5

91 N n.C3H?-(CH2)2 163.0

92 CH CH2=CH-CH2 119.7

93 N i.C3H70(CH2)2 126.8

94 CH i.C2H50(CH2)2 151.2

95 CH 2-Cl-4-pyrimidinyl 190.6 96 N C2H5(CH3)CH 150.1

97 N 2-Cl-4-pyrimidinyl 196.5

98 N C3H5CH2 186.1

99 N i.C3HyCH2 193.2

100 CH CH30CH2 122.1

1-8

p o u s 130 m

omp . *Jo. Q R 1 mp. in °C

01 N i.C3H7(CH2)2 176.9

02 N n.C5Hn 163.0 and

03 CH HC=C-CH2 l " - 8

,s txampie l A mixture of 1 part of ethyl hydrazinecarboxylate, 5 parts of cis - phenyl [4 - [4 - [4 - [2 - (2,4 -

dichlorophenyl) - 2 - (1/V - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - ylmethoxylphenyl] - 1 - piperazinyllphenyllcarbamate, 1 part of N,N - dimethyl - 4 - pyridinamine and 100 parts of 1,4 - dioxane was stirred and refluxed overnight. The reaction mixture was cooled and poured onto water. The product

>0 was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and stirred in a mixture of 40 parts of 2-propanol and 75 parts of water with 7.5 parts of a sodium hydroxide solution 50 k till all solid enters solution. The solution was neutralized with acetic acid and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column

>5 chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent The pure fractions were collected and the eluent was evaporated. The residue was triturated in 2- propanone.The product was filtered off and dried for 48 hours at 140°C, yielding 2.5 parts (53%) of cis -4 - [4 -[4 -[4 -[[2 -(2,4 - dichlorophenyl) -2 -(1tf -1,2,4 - triazol -1 -ylmethyl) -1,3 -dioxolan -4 -yljmethoxylphenyl] - 1 - piperazinyl]phenyl] - 1,2,4 - triazolidine - 3,5 - dione; mp. 210.8°C (compound

io 104). In a similar manner there was also prepared: c/s-4.[4.[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/V-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]phenyl]-1,2,4-triazolidine-3,5-dione; mp. 256.0°C (compound 105).

?5 Example LI A mixture of 1.46 parts of A, 4 parts of cis - 4 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1W -

imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyljphenyl] - 1,2,4 - triazolidine - 3,5 - dione, 1 part of potassium hydroxide and 100 parts of dimethyl sulfoxide was stirred for 2 hours at room temperature. The reaction mixture was poured onto water and the product was extracted

to with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99.5:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 2.2 parts (51%) of cis -4 - [4 - [4 - [4 - [[2 - (2 4 - dichlorophenyl) -2 - (1W - imidazol -1 -ylmethyl) -1,3 - dioxolan -4 - yl]methoxy]phenyl] -1 -

K piperazinyl]phenyl] - 1,2 - diethyl - 1,2,4 - triazolidine - 3,5 - dione; mp. 180.4X (compound 106). Following the same procedure and using equivalent amounts of the appropriate starting materials

there were also prepared: c/s-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1Ay-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenylJ-1-

piperazinyl]phenyl]-1,2-dipropyl-1,2,4-triazolidine-3,5-dione; mp. 150.7°C (compound 107); so c/s-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

phenyl]-1-piperazinyl]phenyl]-1,2-diethyl-1,2,4-triazolidine-3,5-dione; mp. 163.5°C (compound 108); c/s-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

phenyl]-1-piperazinyl]phenyl]-1,2-dimethyl-1,2,4-triazolidine-3,5-dione; mp. 199.8°C (compound 109); c?/s-1,2-dibutyl-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/V-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]-

55 methoxy]phenyl]-1-piperazinyl]phenyl]-1,2,4-triazolidine-3,5-dione; mp. 141.4°C (compound 110); c/s-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

phenyl]-1-piperazinyl]phenyl]-1,2-dipropyl-1,2,4-triazolidine-3,5-dione;mp.139.1°C (compound 111); c/s-1,2-butyl-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/V-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yi]-

methoxy]phenyl]-1-piperazinyl]phenyl]-1,2,4-triazolidine-3,5-dione; mp. 120.1°C (compound 112); and

so c/s-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1- piperazinyl]phenyl]-1,2-dimethyl-1,2,4-triazolidine-3,5-dione; mp. 204.7°C (compound 113).

Example Lll To a stirred mixture of 8.5 parts of cis - 4 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) -2 -{IH - 1,2,4 -

65 triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyljphenyl] - 1,2,4 -

EP 0 1 1 8 1 3 8 B1

triazolidine - 3,5 - dione, 1.2 parts of potassium hydroxide and 100 parts of dimethyl sulfoxide were added dropwise 2.5 parts of 1,3-dibromopropane. Upon completion, stirring was continued for 30 minutes. The reaction mixture was poured onto water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography

5 over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1-butanol, yielding 5.1 parts of cis - 2 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1tf - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl]phenyl]dihydro - 1A/,5/y - pyrazolo[1,2-a][1,2,4]triazole - 1,3(2W) - dione; mp. 223.8°C (compound 114).

m In a similar manner there were also prepared: c/s-2-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]phenyl]dihydro-1//,5//-pyrazolo[1,2-a][1,2,4]triazole-1,3(2W)-dione; mp.249.2°C; (compound 115);

c7/s-2-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1//-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]- is phenyl]-1-piperazinyl]phenyl]5,6,7,8-tetrahydro-1/y-[1,2,4]triazolo[1,2-a]pyridazine-1,3(2/y)-dione; mp.

194.7°C (compound 116); and c/s-2-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1A/-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]phenyl]-5,6,7,8-tetrahydro-1/y-[1,2,4]-triazolo[1,2-a]pyridazine-1,3(2ry)-dione; mp. 200.5°C (compound 117).

20 Example Llll

To a stirred suspension of 5.4 parts of cis - N - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1A/ - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyljphenyl] - N' - (2 - hydroxyethyl) - N' - methylthiourea in 260 parts of dichloromethane was added dropwise a solution

25 of 1.92 parts of thionyl chloride in 130 parts of dichloromethane. The temperature was kept below 0°C by cooling in an ice/salt-bath. Upon completion, stirring was continued for 2 hours at room temperature. The reaction mixture was neutralized with a sodium hydrogen carbonate solution. The layers were separated. The organic layer was purified by filtration over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The

30 residue was crystallized from ethanol, yielding 4.7 parts (89%) of cis - 4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1W - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl] -N -(3 - methyl -2 - thiazolidinylidene)benzenamine; mp. 164.5°C (compound 118).


35

40 c i s

45 R.

Compound Salt or

No. Q S.1 base mp. in °C

I form

60

119 CH C2H5 base 142.7

120 CH i.C3H7 base 183.1

121 N C2H5 C2H5OH 148.1

122 N C2H.(CH3)CH base 125.5

123 CH i.C5H1;L base 104.9-108.4

124 CH n.C4H9 base 64.9-73.6

125 N n.C3H? base 173.3-175.6

126 N i'C3H7 base 179.1-180.1

65

50

:P 0 118 138 B1

Compound Salt or

No. Q R"1 base mp. in °C 5

form

127 CH CH3 base 152.8

128 N i.C;H9 base 189.7 10 129 CH n.C3H? base 149.2

130 N n-C5Hu base 167-7

131 CH n-C5Hn base 117 • 7 w 132 CH (C2H5)2CH base 86.3

133 CH C2H5(CH3)CHCH2 base 126.4

134 N (C2H5)2CH base 123.2

20 135 N n.C4H9 base 176.6

136 N C2H5(CH3)CHCH2 base 172.1

137 N l - ^ l l base 183,5

2g 138 N n.C3H?(CH3)CH base 166.1

139 N C6H5 base 165.2 and

140 CH C6H5 H20 97.7

!0

Example Llv To a stirred and cooled (ice-bath) solution of 5 parts of cis - N - [4 - [4 - [4 - [[2 - (2,4 - dichloro-

phenyl) - 2 - (1/V - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - 35 piperazinyllphenyl] - N' -(1 - ethylpropyl) - N' -(2 - hydroxyethyUurea in 130 parts of dichloromethane

were added 2.4 parts of thionyl chloride and the whole was stirred for 1 hour at room temperature. The reaction mixture was neutralized with a sodium hydrogen carbonate solution and the layers were separated. The organic phase was filtered over silica gel using a mixture of trichloromethane and methanol (99.5:0.5 by volume) as eluent. The filtrate was evaporated and the residue was crystallized from ethanol,

40 yielding 4.3 parts (89%) of cis - 4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1tf - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl] - N - [3 - (1 - ethylpropyl) - 2 - oxazolidinyiidene]benzenamine; mp. 178.1°C (compound 141).


45

51

EP 0 1 1 8 1 3 8 B1

CIS

sase

Compound

js No. Q It* mp. in "C

142 CH C2H5 192.5

143 N CH, 187.0 20 3

144 N C2H5 149.1

145 N n.C3H? 144.0

146 N Q-C4H9 135.6 25

147 N i ' 0 ^ ! 189°1

148 N C2H5(CH3)CH 175.8

149 N i'C5EU 149 " 7 30 150 N C2H5(CH3)CHCH2 119.1

151 N i.C4H9 149.8

152 N n.C3H?(CH3)CH 150.1 and

35 153 CH C2H5(CH3)CH 143.3

40 Example LV To a stirred and cooled (ice/salt bath) mixture of 8 parts of thionyl chloride and 195 parts of

dichloromethane were added portionwise 8.8 parts of cis - N - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (IH - imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl]phenyl] - N' - (2 - hydroxyethyl) - N' - (1 - methylpropyDthiourea at a temperature below 0°C. Upon completion,

45 stirring was continued for 1 hour. The reaction mixture was neutralized with a sodium hydrogen carbonate solution and the layers were separated. The organic phase was filtered over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The filtrate was evaporated and the residue was purified by column-chromatography (HPLC) over silica gel using a mixture of methylbenzene and ethanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The

so residue was separated by HPLC over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent.

— The first fraction was collected and the eluent was evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 0.8 parts (10%) of cis -1 -[4 -[4 -[4 - [[2 -(2,4 -dichlorophenyl) -2 -(1tf -imidazol -1 -ylmethyl) -1,3 -dioxolan -4 -yl]methoxy]phenyl] -

55 1 - piperazinyljphenyl] - 3 - (1 - methylpropyl) - 2 - imidazolidinethione; mp. 161.8°C (compound 154). — The second fraction was collected and the eluent was evaporated. The residue was crystallized from

a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 0.8 parts (10%) of cis - N - [3 - (1 - methylpropyl) -2 -thiazolidinylidene] -4 -[4 -[4 -[[2 -(2,4 - dichlorophenyl) -2 -(1W - imidazol -1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl]benzenamine; mp. 121.0°C

60 (compound 155). In a similar manner there were also prepared: c/s-1-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1r/-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]phenyl]-3-(2-methylpropyl)-2-imidazolidinethione; mp. 165.3°C (compound 156); and c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

55 piperazinyl]-/V-[3-(2-methylpropyl)-2-thiazolidinylidene]benzenamine; mp. 134.6°C (compound 157).

« 52

:P 0 118 138 B1

txampie lvi To a stirred solution of 3.2 parts of thionyl chloride in 130 parts of dichloromethane was added

dropwise a solution of 5.5 parts of cis - N' - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1W - 1,2,4 - triazol -1 -ylmethyl) -1,3 -dioxolan -4 -yl]methoxy]phenyl] -1 - piperazinyllphenyl] -N - ethyl -N -

> (3 - hydroxypropyDurea in 260 parts of C while cooling in an ice/salt bath at a temperature below 0°C. Upon completion, stirring was continued for 1 hour and the whole was allowed to reach room temperature. The mixture was neutralized with a sodium hydrogen carbonate solution and the layers were separated. The organic layer was purified twice by column chromatography over silica gel using first a mixture of trichloromethane and methanol (98:2 by volume) and a mixture of trichloromethane and methanol (95:5 by

o volume) and then a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol, yielding 2.6 parts (45%) of cis -4 -[4 -[4 -[[2 -(2,4 -dichlorophenyl) -2 -(1/V -1,2,4 -triazol -1 -yl -methyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl] - N - (3 - ethyl - tetrahydro - 2/V - 1,3 - oxazin -2 - ylidene)benzenamine ethanol (1:1); mp. 101 .5°C (compound 158).

5 Example LVII

To a stirred solution of 2.4 parts of thionyl chloride in 130 parts of dichloromethane was added dropwise a solution of 7.3 parts of cis - N' - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (IH - 1,2,4 - triazol -1 -ylmethyl) -1,3 -dioxolan -4 - yl]methoxy]phenyl] -1 -piperazinyllphenyl] -N - ethyl -N -

>o (3 - hydroxypropyUthiourea in 260 parts of dichloromethane while cooling in an ice/salt bath at a temperature below 0°C. Upon completion, stirring was continued for 1 hour. The mixture was neutralized with a sodium hydrogen carbonate solution and the layers were separated. The organic layer was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The second fraction was collected and the

>5 eluent was evaporated. The residue was crystallized from ethyl acetate. The product was filtered off and dried in a dry-pistol at 90°C, yielding 3.1 parts (43%) of cis - 4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1tf - 1,2,4 - triazol - 1 - yl - methyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl) - N - (3 - ethyl' - tetrahydro - 2H - 1,3 - thiazin - 2 - ylidene)benzenamine; mp. 160.4°C (compound 159).

In a similar manner there were also prepared: w c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]-/V-(3-ethyl-tetrahydro-2/V-1,3-thiazin-2-ylidene)benzenamine; mp. 131 .5°C (compound 160);

c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-imidazol-1-ylmethyl).-1,3-dioxolan-4-yl]methoxy]phenyl]-1- piperazinyl]-/V-(3,4,5,6-tetrahydro-3-(1-methylethyl)-2A/-1,3-thiazin-2-ylidene)benzenamine; mp. 180.3°C

?5 (compound 161).

Example LVIII To a stirred solution of 3.2 parts of thionyl chloride in 130 parts of dichloromethane was added

dropwise a solution of 8 parts of cis -N - butyl -N' -[4 -[4 -[4 -[[2 -(2,4 - dichlorophenyl) - 2 - (1/V - to 1,2,4 - triazol -1 -yl - methyl) -1,3 - dioxolan -4 - yl]methoxy]phenyl] -1 - piperazinyllphenyl] -N -

(3 - hydroxypropyDthiourea in 260 parts of C at a temperature below 10°C. Upon completion, stirring was continued for one hour. The reaction mixture was neutralized with a sodium hydrogen carbonate solution. The layers were separated. The organic phase was evaporated. The residue was purified twice by column chromatography over silica gel using first a mixture of trichloromethane and methanol (99:1 by volume)

45 and then a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol. The product was filtered off and dried, yielding 2.7 parts (34%) of cis - 1 - butyl - 3 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1/V - 1,2,4 - triazol - 1 - yl - methyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyllphenyl] -3,4,5,6 - tetrahydro - 2(1W) - pyrimidinethione; mp. 159.1°C (compound 162).

so In a similar manner there were also prepared: c/s-1-[4-[4-t4-[[2-(2,4-dichlorophenyl)-2-(1/V-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]phenyl]-3-ethyltetrahydro-2(1/V)-pyrimidinethione; mp. 168.8°C (compound 163); c/s-1-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

phenyl]-1-piperazinyl]phenyl]-3-ethyltetrahydro-2(1W)-pyrimidinethione; mp. 194.2°C (compound 164);

55 and c/s-1-butyl-3-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1W-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

phenyl]-1-piperazinyl]phenyl]tetrahydro-2(1/y)-pyrimidinethione; mp. 163.7°C (compound 165).

Example LIX 60 A solution of 7 parts of cis - N' - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) -2 - (1/V - imidazol - 1 -

ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyljphenyl] - N - (2,2 - dimethoxyethyl) - N - ethylthiourea in 60 parts of formic acid was stirred for 1 hour. The whole was evaporated. The residue was dissolved in dichloromethane. The reaction mixture was neutralized with a sodium hydrogen carbonate solution. The layers were separated. The organic layer was dried, filtered and evaporated. The

65 residue was crystallized from 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 6 parts (89%) of cis -

OJ

EP 0 1 1 8 1 3 8 B1

4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1// - imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]- methoxyjphenyl] - 1 - piperazinyl] - N - (3 - ethyl - 5 - methoxy - 2 - thiazolidinylidene)benzenamine; mp. 155.0°C (compound 166).

In a similar manner there were also prepared: c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-

1-piperazinyl]-/V-[5-methoxy-3-(phenylmethyl)-2-thiazolidinylidene]benzenamine; mp. 86.8°C (compound 167);

c/s-4-[4-[4-I[2-(2,4-dichlorophenyl)-2-(1/y-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl] -1 - piperazinyl]-/V-(5-methoxy-3-methyl-2-thiazolidinylidene)benzenamine; mp. 156.6°C (compound 168);

c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phe 1-piperazinyl]-/V-(5-methoxy-3-methyl-2-thiazolidinylidene)benzenamine; mp. 127.6°C (compound 169);

c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]1- piperazinyl]-/V-[5-methoxy-3-(1-methylpropyl)-2-thiazolidinylidene]benzenamine 1-butanol (1:1); mp. 88.1°C (compound 170);

c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1//-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]- 1-piperazinyl]-/V-(5-methoxy-3-ethyl-2-thiazolidinylidene)benzenamine; mp. 134.5°C (compound 171);

c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1A/-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]- 1-piperazinyl]-/V-[5-methoxy-3-(1-methylpropyl)-2-thiazolidinylidene]benzenamine; mp. 131.3°C (compound 172);

c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]- 1-piperazinyl]-/V-[5-methoxy-3-(1-methylethyl)-2-thiazolidinylidene]benzenamine; mp. 164.0°C (compound 173) ; and

c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/V-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1- piperazinyl]-/V-[5-methoxy-3-(1-methylethyl)-2-thiazolidinylidene]benzenamine; mp. 137.0°C (compound 174) .

Example LX A mixture of 4.1 parts of 1 - butyl - 3 -[4 -[4 -(4 - hydroxyphenyl) -1 - piperazinyl]phenyl] -2,4 -

imidazolidinedione, 6.5 parts of cis -2 -(4 - bromophenyl) -2 -{IH -1,2,4 -triazol -1 -ylmethyl) -1,3 - dioxolane - 4 - methanol methanesulfonate (ester) ethanedioate (1:1), 6.0 parts of potassium carbonate, 160 parts of 1-propanol and 25 parts of 1,4-dioxane was stirred and refluxed for 3 days. The reaction mixture was diluted with water and the product was extracted three times with dichloromethane. The combined organic layers were washed with water, dried and evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 1.7 parts (25%) of propyl cis - [4 - [4 - [4 - [[2 - (4 - bromophenyl) - 2 - (1 H - 1,2,4 - triazol - 1 - ylmethyl) - 1 , 3 - dioxolan - 4 - yl]methoxy]phenyl] -1 - piperazinyl]phenyl]carbamate; mp. 214.4°C (compound 175).

In a similar manner there were also prepared: c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1//-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-

1-piperazinyl]-/V-(1-methyl-2-imidazolidinylidene)benzenamine; mp. 161 .9°C (compound 176); and c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1A/-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-.

1-piperazinyl]-/V-(1-ethyl-2-imidazolidinylidene)benzenamine; mp. 184.0°C (compound 177).

Example LXI A mixture of 5 parts of cis - N' - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1/V - 1,2,4 - triazol -

1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy] phenyl] - 1 - piperazinyllphenyl] - N - ethyl - N - [2 - (ethylamino)ethyl]thiourea, 2.2 parts of mercury (II) oxide and 160 parts of acetonitrile was stirred and refluxed for 20 hours. Another portion of 0.8 parts of B were added and stirring at reflux was continued for 24 hours. The reaction mixture was filtered hot over Hyflo and the filtrate was evaporated. The residue was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile (activated charcoal), yielding 2.9 parts (61%) of cis -4 -[4 -[4 -[[2 -(2,4 -dichlorophenyl) -2 -(1tf -1,2,4 -triazol -1 -ylmethyl) - 1,3 - dioxolan -4 - yl]methoxy]phenyl] -1 - piperazinyl] -N -(1,3 - diethyl -2 - imidazolidinylidene)- benzenamine; mp. 91.7°C (compound 178).

In a similar manner there were also prepared: c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/V-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-

1-piperazinyll-/V-(3-phenyl-2-oxazolidinylidene)benzenamine; mp. 133.2°C (compound 179); and c/s-4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/y-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]-/V-(1,3-diethyl-2-imidazolidinylidene)benzenamine; mp. 178.0°C (compound 180).

Example LXI I To a stirred solution of 5.1 parts of ethanedioyl dichloride in 300 parts of trichloromethane was added

dropwise a warm solution of 6.4 parts of cis - N - butyl - N' - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) -

54

EP 0 1 1 8 1 3 8 B1

2 -\\H - 1,2,4 - triazol - 1 - yl - methyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyljphenyl]urea in 150 parts of trichloromethane. Upon completion, the whole was heated to reflux and stirring was continued for 1 hour at reflux temperature. Another 2.9 parts of ethanedioyl dichloride was added and stirring at reflux was continued for 2 hours. After cooling, 30 parts of potassium carbonate were added and

s water was added dropwise carefully (foaming). The organic layer was separated. The aqueous phase was extracted with trichloromethane. The combined organic layers were washed with water, dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of methylbenzene and ethanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1-butanol. The product was filtered off and dried in vacuo at 60°C, yielding 5.8

to parts (83%) of cis -1 - butyl - 3 - [4 - [4 - [4 - [[2 -(2,4 - dichlorophenyl) -2 -(1tf -1,2,4 - triazol -1 - yl - methyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyllphenyl] - 2,4,5 - imidazolidinetrione; mp. 150.4°C (compound 181).


'5

20 z i s

base

Compound No. Q R1 mp. in °C

30 182 CH CH3 209.3 183 N CH3 .208.8

35 184 N C2H5 171.8 185 N n*C3H7 152,4

186 N i'C3H7 191,6 187 CH i.C.H- 212.3

40 4 9 188 N i.C4Hg 172.7

189 N n,C5HH 150,2

190 CH n.C3H7 198.7 45 191 N i,C5Hll 164,6

192 CH i,C5Hll 145,3

193 CH t.C4Hg 206.8 50 194 N C2H5(CH3)CH 159.7

195 CH n,C5Hll 169,7

196 CH C3H7(CH3)CH 137.0

55 and

197 CH (C2H5)2CH 157.4

Example LXIII To a stirred mixture of 6.5 parts of cis - N - [4 - [4 - [4 - [2 - (2,4 - dichlorophenyl) - 2 - (1tf -

imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - ylmethoxylphenyl] - 1 - piperazinyllphenyl] - N' - ethylurea, 0.5 parts of /V,/V-dimethyl-4-pyridinamine, 50 parts of pyridine and 65 parts of dichloromethane were added dropwise 1.57 parts of ethanedioyl dichloride at room temperature. Upon completion, stirring was continued overnight at reflux temperature. Another portion of 0.75 parts of ethanedioyl dichloride was

55

EP 0 1 1 8 1 3 8 B1

added and the whole was stirred and refluxed. The reaction mixture was poured onto buu parts ot water. The organic layer was separated. The aqueous phase was extracted with dichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was stirred in 2-propanone. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by column

s chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was stirred in 4-methyl- 2-pentanone. The product was filtered off and dried in vacuo at 60°C, yielding 1.4 parts (19%) of cis - 1 - [4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1// - imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]- methoxylphenyl] - 1 - piperazinyllphenyl] - 3 - ethyl - 2,4,5 - imidazolidinetrione; mp. 212.5°C

to (compound 198). In a similar manner there were also prepared: c/s-1-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1/7,-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]

piperazinyl]phenyl]-3-(1-methylethyl)-2,4,5-imidazolidinetrione; mp. 218.2°C (compound 199); c/s-1-butyl-3-[4-[444-[[2-(2,4-dichlorophenyl)-2-(1//H'midazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-

is phenyl]-1-piperazinyl]phenyl]-2,4,5-imidazolidinetrione; mp. 173.5°C (compound 200).

Example LXIV Toastirredmixtureof60partsofformicacidand50partsofwaterwereadded10partsofc/s -N -[4 -

[4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1// - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]- 10 methoxylphenyl] - 1 - piperazinyllphenyl] - 1 - methylhydrazinecarbothioamide. The whole was stirred

overnight at room temperature. This solution was added dropwise to 240 parts of concentrate hydrochloric acid. Upon completion, stirring was continued for 1 hour. The whole was neutralized with sodium hydrogen carbonate. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of

?5 trichloromethane and methanol (99.5:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 4.4 parts (43%) of cis - 4 - [4 - [4 - [[2 - (2,4 - dichlorophenyl) - 2 - (1// - 1,2,4 - triazol - 1 - yl - methyl) - 1,3 - dioxolan - 4 - yl]methoxy] - phenyl] - 1 - piperazinyl] - N - (3 - methyl - 1,3,4 - thiadiazol - 2(3//) - ylidene)benzenamine; mp. 175.2°C (compound 201).

30 Claims

1. A chemical compound having the formula (I)

35

40

a pharmaceutically acceptable acid-addition salt or a stereochemically isomeric form thereof, wnerein

AMs~phenyl or substituted phenyl, said substituted phenyl having from 1 to 3 substituents each

independently selected from the group consisting of halo; R is hydrogen or C,— C6 alkyl; and Y is a radical having the formula (a)

55 or a radical having the formula (b)

r B eo -N=( | (b) ;

Z_A

wherein

« s a i d ^ being hydrogen; C3-C6 alkenyl; C3-C6 alkynyl; Ar; C3-C6 cycloalkyl; C,-C6 alkyl optionally

56

bK u n a 138 m

substituted with a member selected from the group consisting of Ar, C,— C6 alkyloxy and C3— C6 cycloalkyl; pyrimidine, optionally substituted with halo,

X is 0, S or NR2; said R2 being hydrogen or C,— C6 alkyl;

A is >C=0, NR3 or methylene, optionally substituted with up to two radicals selected from the group consisting of C,— C6 alkyl and Ar; said R3 being hydrogen or C6 alkyl, or R1 and R3, taken together form a C,— C6 alkanediyl radical; provided that, when A is NR3, Z is other than oxygen; and

B is >C=0 or methylene optionally substituted with up to two radicals selected from the group consisting of C,— C6 alkyl and C,— C6 alkyloxy;

i or A and B, taken together, form a bivalent radical of formula:

— CH2— CH2— CH2— (c)

0r — C(0) — N — C(0) — (d) I

o

4b

50 -

where Y is . " r X T S f c ^ u W i and B,when taken together, can also form a bivalent radical of formula

_CH=CH- (e)

— N=CH— (f);

>5 wherein one hydrogen in the said radical (f) and up to two hydrogens in the said radicals (c), or (e) may be

provided Sat w h ^ - A - B ^ t a V a d i c a l of formula (f), said radical is connected to Z by its nitrogen atom

f t chlmfaf compound according to claim 1 wherein Y is a radical of formula (a) or (b), wherein X, Z

30 A and B are as defined in said claim 1, provided that A and B, taken together, do not form a radical of

f 0 ^ A ( : n ~ wherein the compound is selected from the group

y K S ^ e ^ and the Pharmaceutically acceptable

55 ^ T c T e n t S compound according to claim 1 wherein the compound is selected from the group

consistino of y S o ^ and the Pharmaceut,cally acceptable

i0 ^ t ^ S ^ ^ ^ microorganisms comprising an inert -arr ier^ter ia . and as an active

ingredient an antimicrobially effective amount of a compound as cla.med m any of claims 1 to 4.

6. A chemical compound having the formula

J I P CH.— C — Ar | X

a pharmaceutically acceptable acia-aaamon sau or a &ieieui.iici...^a..y —

55 Ar'ls phenyl or substituted phenyl, said substituted phenyl having from 1 to 3 substituents each

independently selected from the group consisting of halo; R is hydrogen or C6 alkyl; and X is 0, S or NR2, said R2 being hydrogen or C6 alkyl; , Z1 is 0 or NR8, said R8 being hydrogen, Ar or C,— C6 alkyl, optionally substituted by Ar, and R7 is hydrogen, Ar, amino or Cn-C6 alkyl optionally substituted by a member selected from the group

consisting of hydroxy, Ar-amino, C,-C6 alkylamino or carboxy or substituted with up to two C,-C6 alkyloxy radicals, provided that

— Z1 is other than 0 where R7 is hydrogen; and _ where R7 is amino, Z1 is other than NH or 0.

o /

EP 0 1 1 8 138 B1

7. A composition for combatting microorganisms comprising an inert carrier material and as an active ingredient an antimicrobially effective amount of a compound as claimed in claim 6.

8. A process for preparing a chemical compound as claimed in claim 1, characterized by a) O-alkylating a phenol of formula (III)

5 K

H 0 \ = 7 ~ N\ / \ — 7~Y 111

with a reagent of formula (II)

D — CH2 — W II 75

wherein W has the meaning of a reactive ester residue in a suitable reaction-inert medium; or b) N-alkylating an amine of formula (V) or (VI)

20 H 2 N - ^ ^ - Y V D-CH2-0-^r~^-NH2 VI

with a reagent of formula (IV) or (VII)

25 R R

^CH-^-CH-tf W-CH-^-CH D-CH2-0-^ y-N H H X N - ^ M

30 X CrL-CH.-W W-CH,-CH,/

2 2 2 2 y

IV VII

in a suitable reaction-inert medium; or 35 c) N-alkylating a piperazine of formula (VIII) or (XI)

R R

40 d - c h 2 - o - c ^ ~ ^ / ~ ^ \ h v i i i h / ~ ^ \ - ^ * ~ ^ - Y XI

with a reagent of formula (IX) or (X)

45

W - ^ ^ - Y IX ' D-CH2-0-^^) -W X

in a suitable reaction-inert medium; or 50 d) cyclizing an intermediate of formula (XII)

D - C H 2 - 0 ^ / ^ N ^ ^ N - C - R 6

R5

60 wherein R5 is hydrogen and R6 is an appropriate leaving group or R5 and R6, taken together, represent a direct bond with, a reagent of formula (XIII) or (XIV)

H— Z— A— B— L XIII

65 H— Z— A— B— L' XIV

58

P 0 118 138 B1

wherein L is an appropriate leaving group and L is a precursor or an appropriate leaving group in a suitable reaction-inert medium, optionally after converting L' into L where an intermediate of formula (XV)

j R f X

D-CH2-0-^ / \ f \ y-NH~c~z~A-B-L ' XV

o is formed, or e) cyclizing an intermediate of formula (XVII)

R

5 3-CH2-0-^ f \ f \ /

NH"C_NH~r1 x v i t

with a reagent of formula (XVIII)

20 W— A— B— W XVIII

in a suitable reaction-inert medium, thus yielding a compound of formula (l-a)

» I X.N 1

30 or

f) cyclodesulfurizing an intermediate of formula XIX R

/ ~ \ A \ / - \ U 35 ^ C H 2 ^ ^ ^ N ^ ^ N - ^ ^ - NH-C-N-A-B— NR2H XIX

R1

^ in the presence of an appropriate alkyl halide or an appropriate metal oxide or salt in a suitable medium, thus yielding a compound of formula (l-b)

R1 ■ i

D-CH„-0 45 Tl-CH.-O N N

g) cyclizing an intermediate of formula (XX) R

^-NH-C-N-NH2 XX 2 W V - / W L

55 Rl

in an acidic medium containing a carbonyl-generating agent, thus yielding a compound of formula (l-c)

R

65

r

59

EP 0 1 1 8 1 3 8 B1

optionally, if desired, N-alkylating a compound of formula (l-d-1) or (l-d-2) R

D - C H 2 - 0 - ^ y - N ^ f ~ \ ^ — | I - d -1

H 15

with a reagent of formula (XXI)

R1~a— W XXI

20 said R1_a having the previously defined meaning of R1 provided that hydrogen is excluded, in a suitable reaction-inert medium, thus yielding a compound of formula (l-e-1)

R

_ | ^ R1_a

D-CH2-0-^ y-N^ / \ / \ I I - e -1

30 respectively a compound of formula (l-e-2)

R

f. TV /~\~\ f, T\ X~B

R1

40 wherein D represents a radical of the formula

45 I C H _ C — Ar

0 0 I L

50 and optionally, if desired, converting the compounds of formula (I) into a therapeutically active non-toxic acid- addition salt form by treatment with an appropriate acid or, conversely, converting the acid-addition salt into the free base form with alkali; and/or preparing stereochemically isomeric forms thereof.

5S 9. A method of preparing a pharmaceutical composition as claimed in any one of claims 5 or 7, characterized by mixing an effective amount of a compound as claimed in any one of claims 1 to 4 or 6 with an inert carrier.

10. A compound as claimed in any one of claims 1 to 4 or 6 for use as an antimicrobial agent:

60

65

60

c r 0 118 138 b l

11. A process for preparing a chemical compound as claimed in claim 6, characterized by reacting an nine of formula (XXVII)

-V-H--U-\' t-N ti-U /NM_ XXVI 1 2 \ = / w \ = / 2

wherein D represents a radical of the formula

i N

J :h2— c s r A r

o 0

o with a reagent of the formula

l — u — n >5

wherein R6 is a radical of formula — Z1— R7 said Z1 and R7 being as claimed in claim 6; and optionally, if desired, converting said prepared compounds into a therapeutically active non-toxic acid-

addition salt form by treatment with an appropriate acid or, conversely, converting the acid-addition salt

» into the free base form with alkali; and/or preparing stereochemically isomeric forms thereof.

Patentanspruche

1. Chemische Verbindung mit der Formel (I)

is |, N >° ll 1 1

4S ein pharmazeutisch annehmbares saureaaomonssaiz ouer o».w«.- . . . . - worin

A/TOrP^enyf od l r^u^SSer t e s Phenyl steht, wobei das genannte subs t i tu te Phenyl 1 bis 3 Subsmuente! J auteist, die jewei.s unabhangig voneinander aus der aus Halogen bestehenden Gruppe

50 gewahlt sind; R fur Wasserstoff oder C,— C6Alkyl steht; und Y einen Rest mit der Formel (a)

55

oder einen Rest mit der i-ormei id; 60

65

-N | (a) \B — A

- K i V A Z_A

EP 0 1 1 8 1 3 8 B1

bedeutet; worin Z fur O oder NR1 steht;

worin der genannte Rest R1 Wasserstoff; C3— C6Alkenyl; C3— C6Alkinyl; Ar; C3— C6Cycloalkyl; C,— C6Alkyl, das gegebenenfalls durch einen Vertreter, ausgewahlt aus der aus Ar, C,— C6Alkyloxy und C3— C6Cycloalkyl

s bestehenden Gruppe, substituiert ist; Pyrimidin, das gegebenenfalls durch Halogen substituiert ist, bedeutet;

X fur 0, S oder NR2 steht; worin der Rest R2 Wasserstoff oder C, — C6Alkyl bedeutet;

A fur >C=0, NR3 oder Methylen steht, das gegebenenfalls mit bis zu 2 Resten, ausgewahlt aus der aus io C, — C6Alkyl und Ar bestehenden Gruppe, substituiert ist;

worin der Rest R3 Wasserstoff oder C, — C6Alkyl bedeutet oder R1 und R3 zusammen einen C3 — C6Alkandiylrest ausbilden; mit der MaSgabe, dal3 dann, wenn A fur NR3 steht, Z eine andere Bedeutung als Sauerstoff aufweist; und

B fur >C=0 oder Methylen steht, das gegebenenfalls mit bis zu 2 Resten, ausgewahlt aus der aus is C, — C6Alkyl und G, — QjAlkyloxy bestehenden Gruppe, substituiert ist;

oder A und B zusammen einen zweiwertigen Rest mit der Formel:

— CH2— CH2— CH2— (c)

20 °der

- C ( 0 ) - N - C ( 0 ) - (d)

25 wenn Y einen Rest der Formel (b) darstellt, A und B zusammen auch einen zweiwertigen Rest der Formel

— CH=CH— (e) oder

— N=CH— (f) 30

ausbilden konnen; worin ein Wasserstoff in dem Rest (f) und bis zu 2 Wasserstoffatome in den Resten (c) oder (e) durch einen C - -CgAlkylrest ersetzt sein konnen; mit der Mafcgabe, dalS dann, wenn — A— B— einen Rest der Formel (f) darstellen, dieser Rest iiber sein

35 Stickstoffatom an Z gebunden ist und Z eine andere Bedeutung als Sauerstoff aufweist. 2. Chemische Verbindung nach Anspruch 1, worin Y einen Rest der Formel (a) oder (b) darstellt, worin

X, Z, A und B wie in diesem Anspruch 1 definiert sind, mit der MalSgabe, daB A und B zusammen nicht einen Rest der Formel (e) oder (f) ausbilden, wenn Y einen Rest der Formel (b) darstellt.

3. Chemische Verbindung nach Anspruch 1, worin die Verbindung ausgewahlt ist aus der aus cis - 1 - 40 Butyl - 3 - [4 - [4 - [4 - [[2 - (2,4 - dichlorphenyl) - 2 - (1//- 1,2,4 - triazol - 1 - ylmethyl) - 1,3 -

dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl] phenyl]2,4 - imidazolidinon und den pharmazeutisch annehmbaren Saureadditionssalzen hievon bestehenden Gruppe.

4. Chemische Verbindung nach Anspruch 1, worin die Verbindung ausgewahlt ist aus der aus cis - 1 - [4 -[4 -[4 -[[2 -(2,4 - Dichlorphenyl) -2 - (1/V -1,2,4 -triazol -1 -ylmethyl) -1,3 - dioxolan -4 -yl]-

45 methoxyjphenyl] - 1 - piperazinyl]phenyl] - 3 - propyl - 2 - imidazolidinon und den pharmazeutisch annehmbaren Saureadditionssalzen hievon bestehenden Gruppe.

5. Zusammensetzung zur Bekampfung von Mikroorganismen, umfassend ein inertes Tragermaterial und als einen wirksamen Bestandteil eine antimikrobiell wirksame Menge einer Verbindung, wie in einem der Anspriiche 1 bis 4 beansprucht.

so 6. Chemische Verbindung mit der Formel

20 oder

— C(O) — N — C(O) —

R4 ausbilden; worin R4 fur Wasserstoff oder C1 — C6Alkyl steht; oder,

25 wenn Y einen Rest der Formel (b) darstellt, A und B zusammen auch einen ;

ein pharmazeutisch annehmbares Saureadditionssalz oder stereochemisch isomere Formen hievon, worin Q fur — N= oder — CH= steht; Ar Phenyl oder substituiertes Phenyl bedeutet, wobei das substituierte Phenyl 1 bis 3 Substituenten

65 aufweist, die jeweils unabhangig voneinander aus der aus Halogen bestehenden Gruppe ausgewahlt sind;

62

EP 0 1 1 8 138 B1

R fur Wasserstoff oder C,— C6Alkyl steht; und X fur 0, S oder NR2 steht, worin R2 Wasserstoff over C,— C6Alkyl bedeutet; Z1 fur 0 oder NR8 steht, worin R8 Wasserstoff, Ar oder C,— C6Alkyl, das gegebenenfalls durch Ar

iubstituiert ist, bedeutet; und R7 Wasserstoff, Ar, Amino oder C,— C6Alkyl, das gegebenenfalls durch einen Vertreter, ausgewahlt aus

ier aus Hydroxy, Ar-amino, d— C6Alkylamino oder Carboxy bestehenden Gruppe, oder durch bis zu zwei C6Alkyloxyreste substituierte ist, bedeutet, mit der MalSgabe, daB: — Z1 eine andere Bedeutung als 0 hat, wenn R7 fur Wasserstoff steht; und — wenn R7 Amino bedeutet, Z1 eine andere Bedeutung als NH oder 0 aufweist. 7. Zusammensetzung zur Bekampfung von Mikroorganismen, umfassend ein inertes Tragermaterial

jnd als einen wirksamen Bestandteil eine antimikrobiell wirksame Menge einer Verbindung, wie in \nspruch 6 beansprucht.

8. Verfahren zur Herstellung einer chemischen Verbindung, wie in Anspruch 1 beansprucht, jekennzeichnet durch

a) O-Alkylieren eines Phenols der Formel (III)

R

mit einem Reagenz der Formel (II)

D— CH2— W II,

worin W die Bedeutung eines reaktiven Ester-Restes aufweist, in einem geeigneten reaktions-inerten Medium; oder

b) N-Alkylieren eines Amins der Formel (V) oder (VI)

H 2 N - ^ ~ ^ - Y V oder D-CH2-0-^^ -NH2 VI

mit einem Reagenz der Formel (IV) oder (VII)

R R

. ^CH-^-CH-W W-CH-A-CH

3-CH2-0-(/ \)-N H oder h X N - / v 2 W \

CH2-CH2-W W-CH2-CH2 i

IV VII

in einem geeigneten reaktions-inerten Medium; oder c) N-Alkylieren eines Piperazins der Formel (VIII) oder (XI)

R R

D - C H 2 - 0 - ^ ~ ^ / ~ H m VIII oder H N ^ ^ N - ^ J ^ - Y XI

mit einem Reagenz der Formel (IX) oder (X)

W - ^ ^ - Y IX oder T i - C E ^ O - ^ ^ V W 1 W

in einem geeigneten reaktions-inerten Medium; oder

63

EP 0 1 1 8 138 B1

d) Cyklisieren einer Zwischenverbindung der Formel (XII)

D-CH.

n.

^ . ^ 1 , ' H I

R5

to worin R5 Wasserstoff bedeutet und R6 eine geeignete Leaving-Gruppe darstellt oder R5 und R6 zusammen eine direkte Bindung darstellen, mit einem Reagenz der Formel (XIII) oder (XIV)

H— Z— A— B— L XIII oder

75 H— Z— A— B— L' XIV,

worin L eine geeignete Leaving-Gruppe darstellt und L' einen Vorlaufer einer geeigneten Leaving-Gruppe bedeutet, in einem geeigneten reaktions-inerten Medium, gegebenenfalls nach Uberfuhrung von L' in L, wo eine Zwischenverbindung der Formel (XV)

20 R

J u . > X

D-CH2-0-T y-N N-T -y-NH-C-Z-A-B-L ' XV 25

^ gebildet wird, oder

e) Cyklisieren einer Zwischenverbindung der Formel (XVII)

R

30 / " ^ " i d-ch2-o-^ y-N /N~\__y NH"C-NH"R XVIT

mit einem Reagenz der Formel (XVIII)

35 W— A— B— W XVIII

in einem geeigneten reaktions-inerten Medium, unter Ausbildung einer Verbindung der Formel (l-a)

} X 40 A-X 1

D-CH„-0-</ \>N IK' *>-N I - a 2 \ = y V_V \ = y NB-A

45 oder f) Cyclodesulfurieren einer Zwischenverbindung der Formel (XIX)

/ r \ r k

R L _ s

d - c h 0 - o - ^ ~ V n n -^~^V- nh-c-n-a-b— nr2h XIX 2 W w w L R

in Anwesenheit eines geeigneten Alkylhalogenids oder eines geeigneten Metalloxids oder Salzes in einem geeigneten Medium, unter Ausbildung einer Verbindung der Formel (l-b)

„1

55 geeigneten Medium, unter Ausbildung einer Verbindung der Formel (l-b)

? r r » / t i - b

i i R

65 oder

64

EP 0 118 138 B1

g) Cyklisieren einer Zwischenverbindung der Formel (XX)

D - C H 2 - 0 - ^ ~ ^ / ~ ^ N - ^ ~ ^ - NH-C-N-NH2. XX 1 W \ _ 7 \ = J | 1

R in einem sauren waSrigen Medium, das ein Carbonyl-bildendes Mittel enthalt, unter Ausbildung einer

w Verbindung der Formel (l-c) R

gegebenenfalls, falls erwunscht, N-Alkyklieren einer Verbindung der Formel (l-d-1) oder (l-d-2)

20 R Y I X.v

D-CH2-0-^ y-N^ K-j | I - d - 1

25

I - d - 2 30 2 \ — / \ / \ = J N— A

H

mit einem Reagenz der Formel (XXI)

35 R1"a-W, XXI

worin R1_a die zuvor definierte Bedeutung von R1 mit der MaBgabe hat, dalS Wasserstoff ausgenommen ist, in einem geeigneten reaktions-inerten Medium, unter Ausbildung einer Verbindung der Formel (l-e-1)

R Y 40 j > \ _ 1-a D-CH2-r>(r^_N |~R I - e - 1

45 Rl

bzw. einer Verbindung der Formel (I-e-2)

R

55 worin D einen Rest der Formel

60

65

■Ar

65

■P 0 1 1 8 1 3 8 B1

edeutet; und . . . gewunschtenfalls Uberfuhren der Verbindungen der Formel (I) in eine therapeutisch wirksame nicnt-

axische Saure-Additionssalzform durch Behandlung mit einer geeigneten Saure, oder umgekehrt, Jmwandeln des Saure-Additionssalzes in die freie Basenform mit Alkali; und/oder Herstellen tereochemisch isomerer Formen hievon.

9. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung, wie in einem der Anspruche i oder 7 beansprucht, gekennzeichnet durch Vermischen einer wirksamen Menge einer Verbindung, wie in inem der Anspruche 1 bis 4 oder 6 beansprucht, mit einem inerten Trager.

10. Verbindung, wie in einem der Anspruche 1 bis 4 oder 6 beansprucht, zur Anwendung als ein intimikrobielles Mittel.

11. Verfahren zur Herstellung einer chemischen Verbindung, wie in Anspruch 6 beansprucht, jekennzeichnet durch Umsetzen eines Amins der Formel (XXVII)

R

.AVll

vorin D fur einen Rest der Formel

steht, mit einem Reagenz der Formel X II

L — C- — R6,

worin R6 einen Rest der Formel — Z1— R7 darstellt, worin Z1 und R7 wie in Anspruch 6 beansprucht sind; und

gewunschtenfalls Uberfuhren der hergestellten Verbindungen in eine therapeutisch wirksame nicht- toxische Saure-Additionssalzform durch Behandlung mit einer entsprechenden Saure, oder umgekehrt, Uberfuhren des Saure-Additionssalzes in die freie Basenform mit Alkali; und/oder Herstellen stereochemisch isomerer Formen hievon.

Revendications

1. Un compose chimique repondant a la formule (I)

un sel d'addition d'acide convenant en pharmacie ou une forme isomere stereochimique de celui-ci, ou Q est— N= ou — CH=, Ar est un phenyle ou un phenyle substitue, ledit phenyle substitue ayant un a trois substituants choisis

chacun independamment dans le groupe constitue d'halogeno; R est un hydrogene ou un alkyle en O, — Cs; et Y est un radical de formule (a)

bb

:P 0 118 138 B1

ou un radical de formule (b)

x— a -NK I (b) ;

5 NZ_A

Z est 0 ou NR1; » . „ . ledit R1 etant un hydrogene; un alcenyle en C3— C6; un alcynyle en C3— C6; Ar; un cycloalkyle en

C«— CB- un alkyle en d— C6 facultativement substitue par un composant choisi dans le groupe constitue par

jo Ar, un' alcoxy en d - C . et un cycloalkyle en C3-C6; un pyrimidinyle, facultativement substitue par halogeno;

X est 0, S ou NR2; ledit R2 etant un hydrogene ou un alkyle en d— C6; . . A est >C=0, Nr3 ou un methylene, facultativement substitue par jusqu'a deux radicaux choisis dans le

75 groupe constitue par un alkyle en d— C6 et Ar; ledit R3 etant un hydrogene ou un alkyle en d— C6, ou R1 et R3 pns ensemble forment un radical

alcanediyle en C3 — C6; . sous reserve que, lorsque A est NR3, Z est autre qu'un oxygene; et B est >C=0 ou un methylene facultativement substitue par jusqu'a deux radicaux choisis dans le

20 groupe constitue par un alkyle en d— d et un alcoxy en C,— C6; ou A et B pris ensemble forment un radical bivalent de formule:

— CH2— CH2— CH2— (c)

25

— ■ C 1 OU

— c(0) — n — c(0) — W);

)Ci R7 est un hydrogene ou un alkyle en d— W. ou, orsque Y est un radical de formule (b), A et B pris ensemble peuvent egalement former un radical bivalent ie formule

— CH=CH— iej

- n = c h - (f); 35

ou un hydrogene dudit radical (f) et jusqu'a deux hydrogenes desdits radicaux (c) ou (e) peuvent etre remplaces par un radical alkyle en d — Ce'r sous reserve que lorsque — A— B— est un radical de formule (f), ledit radical est raccorde a Z par son atome d'azote et ledit Z est autre que 0.

40 2. Un compose chimique selon la revendication 1 ou Y est un radical de formule (a) ou (b) ou X, Z, A et B sont comme defini dans ladite revendication 1, sous reserve que A et B pris ensemble ne forment par un radical de formule (e) ou-(f) lorsque Y est un radical de formule (b).

3. Un compose chimique selon la revendication 1, lequel compose est choisi dans le groupe constitue par la cis - 1 - butyl - 3 - [4 - [4 - [4 - [[2 - 2 - (2,4 - dichlorophenyl) - 2 - (1H - 1,2,4 - triazole - 1 :

45 ylmethyl) -1,3 -idoxolanne -4 -yljmethoxyjphenyl] -1 -piperazinyljphenyl] -2,4 - imidazolidinedione et les sels d'addition d'acides convenant en pharmacie de celle-ci.

4. Un compose chimique selon la revendication 1, lequel compose est choisi dans le groupe constitue par la cis - 1 - [4 - [4 - [4 - [[2 - 2 - (2,4 - dichlorophenyl) - 2 - (1H - 1,2,4 - triazole - 1 - ylmethyl) - 1,3 - idoxolanne -4 - yljmethoxyjphenyl] -1 - piperazinyllphenyl] -3 -propyl -2 - imidazolidinone et

so les sels d'addition d'acides convenant en pharmacie de celle-ci. 5. Un composition pour lutter contre les micro-organismes comprenant une matiere support inerte et

comme ingredient actif une quantite antimicrobienne efficace d'un compose comme revendique dans I'une quelconque des revendications 1 a 4.

6. Un compose chimique repondant a la formule

60

65

0 /

EP 0 1 1 8 1 3 8 B1

un sel d'addition d'acide convenant en pharmacie ou les formes isomeres stereochmiques de celui-ci, ou Q est — N= ou — CH=; Ar est un phenyle ou un phenyle substitue, ledit phenyle substitue ayant un a trois substituants choisis

chacun independamment dans le groupe constitue d'halogeno; 5 R est un hydrogene ou un alkyle en C, — C6; et

X est 0, S ou NR2, ledit R2 etant un hydrogene ou un alkyle en Ct — C6; Z1 est 0 ou NR8, ledit R8 etant un hydrogene, Ar ou un alkyle en C,— C6, facultativement substitue par

Ar, et R7 est un hydrogene, Ar, un amino ou un alkyle en d— C6 facultativement substitue par un composant

io choisi dans le groupe constitue par hydroxy, Ar-amino, alkylamino en C,— C6 ou carboxy ou substitue par jusqu'a deux redicaux alcoxy en C3 — C6, sous reserve que:

— Z1 est autre que 0 lorsque R7 est un hydrogene; et — lorsque R7 est un amino, Z1 est autre que NH ou 0. 7. Une composition pour lutter contre les micro-organismes comprenant une matiere support inerte et

75 comme ingredient actif une quantite antimicrobienne efficace d'un compose comme revendique dans la revendication 6.

8. Un procede pour preparer un compose chimique comme revendique dans la revendication 1, caracterise par

a) l'O-alkylation d'un phenol de formule (III) 20

R

25

avec un compose reagissant de formule (II)

D — CH2 — W II

ou W est le reste d'un ester reactif dans un milieu reactionnel inerte approprie; ou b) la N-alkylation d'une amine de formule (V) ou (VI)

35

avec un compose reagissant de formule (IV) ou (VII)

40

45

IV VII

dans un milieu reactionnel inerte approprie; ou so c) la N-alkylation d'une piperazine de formule (VIII) ou (XI)

R R

55

avec un compose reagissant de formule (IX) ou (X)

60

65 dans un milieu reactionnel inerte approprie; ou

68

EP 0 118 138 B l

I la cyclisation d'un intermediaire de formule (XII)

K.

2 W W V = / | , R

dans laquelle R5 est un hydrogene et R6 est un groupe labile approprie ou R5 et R6 pris ensemble ro represented une liaison directe,

avec un compose reagissant de formule (XIII) ou (XIV)

H - Z - A - B - L XIII

,5 H— Z— A— B— L' XIV

oCi L est un groupe labile approprie et L' est un precurseur d'un groupe labile approprie, dans un milieu reactionnel inerte approprie, facultativement apres conversion de L' en L lorsqu'un intermediaire de formule (XV)

10 R

25 D-CH2-0-r' y-N N-^ ^-NH-C-Z-A-B-L '

est forme, ou e) la cyclisation d'un intermediaire de formule (XVII)

R 30 ^_f^ X

D-CH2-0-^ y-N y - NH-C-NH-R1

avec un compose reagissant de formule (XVIII) 35

W — A — B — W XVIII

dans un milieu reactionnel inerte approprie, pour obtenir un compose de formule (l-a)

' \ = z J \ / ^ = J XB-A 45

OU f) la cyclodesulfuration d'un intermediaire de formule (XIX)

R

~ f/ ^ ^ / " K j - / ^ - ^ - mh-c-m-a-B- D - r a 2 - 0 - ^ ^ N ^ N - ^ ^ N H - C - N - A - B - N R H

R1

55 en presence d'un halogenure d'alkyle approprie ou d'un oxyde ou se. metamque apo,uu„c ^ ~

approprie pour obtenir un compose de formule (l-b)

60

65 OU

69

SP 0 118 138 B1

3) la cyclisation d'un intermediaire de formule (XX) R

_ ... _ / r \ - C H 2 - 0 - ^ ~ ^ - ^ / N " ^ ~ ^ ~

NH-C-|-NH2 * \ = / \ _ v w U R

dans un milieu aqueux acide contenant un agent generateur de carbonyle, ro pour former un compose de formule (l-c)

D-CH0- '5 1

facultativement, si on le desire, la N-alkylation d'un compose de formule (l-d-1) ou (l-d-2) 20

R X / r ^ \ / ~ K / 7 ~ \

» W W W

R

H

ivec un compose reagissant de formule (XXI)

Ri"a— W XXI

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ledit R1_a ayant la signification precedemment mentionnee pour R a I exclusion ae I nyarogene, dans un milieu reactionnel inerte approprie, pour obtenir ainsi un compose de formule (l-e-1)

R X

D - C H 2 - C - ^ ^ - N ^

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ou respectivement un compose de formule (l-e-2)

R

\ 1 XB-A

50

D-

55 R

ou D represente un radical de formule

60 4>V»N I CH, — — C Ar ; et

0 ^ 0 1 — - L

70

EP 0 118 138 B1

facultativement, si on le desire, la conversion des composes de formule (I) en un sel d'addition d'acide non toxique a activite therapeutique par traitement avec un acide approprie, ou inversement la conversion du sel d'addition d'acide en la base libre avec un alcali; et/ou la preparation des formes isomeres stereochimiques correspondantes.

9. Un procede de preparation d'une composition pharmaceutique comme revendique dans I'une quelconque des revendications 5 ou 7, caracterise par le melange d'une quantite efficace d'un compose comme revendique dans I'une quelconque des revendications 1 a 4 ou 6 avec un support inerte.

10. Un compose comme revendique dans I'une quelconque des revendications 1 a 4 ou 6 pour ('utilisation comme agent antimicrqbien.

1 11. Un procede de preparation d'un compose chimique comme revendique dans la revendication 6, caracterise par

la reaction d'une amine de formule (XXVII)

s

lans laquelle D represente un radical de tormuie

'5

avec un compose reagissant de tormuie

X

L-— C — R6

is dans laquelle R6 est un radical de formule —Z'—R , . . . . . . lesdits Z1 et R7 etant comme defini dans la revendication 6; et facultativement, si on le desire, la conversion de ces composes prepares en un sel d'addition d'acide non toxique a activite therapeutique par traitement

avec un acide approprie, ou inversement la conversion du sel d'addition d'acide en la base libra avec un alcali; et/ou la preparation des formes isomeres stereochimiques correspondantes.

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65

n

1,3-dioxolan-2-yl\methyl\-1H-imidazoles and 1H-1,2,4-triazoles

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