DE10055713A1 - New diaryl-substituted azole compounds, useful in human or veterinary medicine as broad spectrum antifungal agents effective against fluconazole-resistant strains - Google Patents

Abstract

Diaryl-substituted imidazole, thiazole, thiadiazole, oxazole or oxadiazole derivatives (I) are new. Azoles of formula (I) and their salts are new. Ar = phenyl, thienyl or pyridyl; R1, R2 (substituents on Ar) = H, halo, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, aryloxy, alkylthio, acylamino or NH2, OH, CN, NO2, COOH, CONH2, SO2NH2, mono- or dialkylamino, acylamino or mono- or dialkylaminosulfonyl; or R1 + R+2 = OCH2O or OCH2CH2O; V = N, O or S; R3, R4 = H, alkyl (optionally substituted by NH2, mono- or dialkylamino, OH, CN or COOH), alkenyl, alkynyl or acyl (one of R3 and R4 being absent if X = O or S); or R3 + R4 = -(CH2)-Q-(CH2)m-; or VR3R4 = pyrrole, imidazole, 1,3,4-triazole, 1,2,4-triazole or pyrazole (all bonded via N); Q = CH2, O, S(O)n or NR7; n = 0-2; R7 = lower alkyl; m = 2, or one m may also = 1 if Q = CH2; R5 = H, halo, OR, OH, NO2, NH2 or NHCOR; R = alkyl or aryl; X = N, O or S; Y = N or S; Z' = N or CR8; R8 = H, halo, lower alkyl or alkoxycarbonyl; p = 1-3; provided that (i) Y = N if X = O or S and (ii) X, Y and Z are not all N. An Independent claim is included for the preparation of (I).

Description

The invention relates to a new class of substituted azoles and in particular special diaryl-substituted thiazoles, diaryl-substituted thiadiazoles and diaryl-substituted oxadiazoles, compounds that are useful for the Treatment of fungal infections in mammals including humans. the These compounds are active against a wide range of fungi (Mushrooms), e.g. B. Candida albicans, Candida parpsilosis, Candida tropicalis, Can dida krusei, Cryptococcus neoformans, Aspergillus fumigatus and Torulopsis glabrata. In addition, connections within these rows are also ak active against fluconazole-resistant strains and isolates.

Background of the Invention

Opportunistic fungal infections are responsible for the increased morbidity and mortality among patients suffering from AIDS and other immunodeficiency disorders diseases suffer including infections that result from neutropenia Cancer chemotherapy and organ transplantation result ("Annals N. Y. Acad. Sc. ", 544: 1-3).

In addition, until recently, the treatment of deep-seated mushroom limped after the treatment of bacterial infections and just a few few systemic means are available to combat this invasive patho gene available.  

Current therapy involves the administration of polyenes such as ampho tericin B, allylamines such as naftafin and terbinafine, and azoles such as fluconazole, Itraconazole and ketoconazole. Amphotericin B, formerly the treatment of choice, is no longer recommended due to the acute and chronic toxicities that associated with its use.

In addition, the antifungal azoles are fungistatic and not fungicidal and it has led to the formation of azole-resistant fungi, d. H. of mushroom stems and Isolates that have been compared to treatment with fluconazole and others ten antifungal agents are resistant ("New Engl. J. Med.", 1944, 330: 263-272).

Known state of the art

Azole compounds in which hydroxyl and / or carboxy groups are the moles cooling structure, are known for fighting pa thogene fungi (mushrooms) can be used.

For example, fluconazole is described in British Patent No. 2,099,818 and US Patent No. 4,440,216

a triazole derivative that protects against a variety of fungi played an important role.

In addition, DE-41 24 942 describes azoles with the following structure, which have antithrombotic and fibrinogen-binding activities:

Q ¹ = ABCN <
Q ² = ABC-CH <
Q ³ = ABCC =
Q ⁴ = FEDN <
Q ⁵ = FED-CH <
Q ⁶ = FEDC =
in which mean:
one of the radicals X ¹ to X ⁵ Q ¹ -Q ³ , a second Q ⁴ -Q ⁶ , a third S, SO, N, R ¹ N, R ² C, (R ² ) ₂ C, a fourth O, S , N, SO ₂ , R ² C, CO and a fifth R ² C, (R ² ) ₂ C, N;
A cyano, (substituted) phenylene, pyridinylene, pyrazinylene, triazinylene, C (substituted) phenylene, pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene, triazinylene, cycloalkylene-cycloalkylene;
D (substituted) alkylene, alkenylene and the like;
E is a bond, alkylene and the like,
F carboxy, (substituted) alkoxycarbonyl;
R ^{1 is} H, alkyl, aralkyl, aryl, heteroaryl;
RH, Cl, Br, alkyl, aralkyl, aryl, heteroaryl, alkoxy, R ¹ O ₂ C, (R ¹ ) ₂ N, and the like.

It states that these compounds are antithrombotic and Have fibrinogen binding activity. The closest related example is 4- (4-amidinophenyl) -2- [4- (2-carboxyethyl) phenyl] thiazole.

WO-92/09 586 (EP-A-0 513 387) describes thiazole derivatives with the following structure, which can be used as superoxide radical inhibitors:

in which mean:
R ¹ substituted phenyl, pyridyl, thienyl, carbostyryl, pyrazyl, pyrrolyl, quinolyl, 3,4-dihydrocarbostyryl;
R ^{2 is} hydrogen, halogen, alkyl, phenyl, alkoxycarbonyl, alkylamino and the like;
X sulfur or oxygen;
R ³ Q (see above), wherein R is hydroxyl, carboxylic acid, alkyl, alkenyl and m can be a number from 0 to 2 or R ³ can be T (see above), where R ^{4 is} hydrogen or alkyl and R is Aminoalkyl stand.

The structure-activity relationship (SAR) of the series mentioned above was published in "J. Med. Chem." 1995, 38, 353-358, in which the following general formula is given:

WO-93 24 472 (EP-A-0 600 092) describes compounds of the following structure as an active oxygen inhibitor:

in which mean:
R ¹ Ph, which can be substituted by 1 to 3 alkoxy groups; and
R ² substituted pyridylcabonyl, which can be substituted by alkoxy carbonyl, carboxyl, a 5 to 15-membered mono-, di- or tricyclic heterocyclo ring radical having 1 to 3 N, O or S atoms or a phenyl Rest of the formula

wherein R ³ represents carboxyl, lower alkoxycarbonyl, hydroxyl-substituted lower alkyl, lower alkoxy, tri-lower alkyl-substituted silyloxy, hydroxy or hydrogen; R ⁴ represents hydrogen, lower alkenyl or lower alkyl; R ⁵ represents amino-lower alkoxycarbonyl, which may be further substituted by lower alkyl, amino-lower alkoxy or lower alkoxy or the like.

U.S. Patent No. 4,791,200 describes compounds having the following structure which are useful as antisecretory agents:

in which mean:
RC ₁ -C ₄ alkyl, phenyl, phenyl which is substituted by CF ₃ , halogen selected from I, Br or Cl, C ₁ -C ₃ alkyl, alkoxy, acetamido, nitro, cyano, alkylamino or dialkylamino with 1 to 4 carbon atoms or pyridyl,
R ¹ H or C ₁ -C ₄ alkyl,
R ² H, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkoxy or Cl; Br or I;
R ³ or R ⁴ -O- (CH ₂ ) _m -NR ⁵ R ⁶ , where m = 1-3.

Patel and Colah describe in "Bull Haff. Inst." (1977), 5, 72-74, p- (2-substituted-4-thiazolyl) phenylacetic acid and p- (2-substituted-4-thiazolyl) phenoxyacetic acids, which can be used for the treatment of tuberculosis and against fungi (fungi) :

wherein R ^{1 is} CH ₂ COOH or OCH ₂ COOH and Ar is phenyl, substituted phenyl or benzyl and the like.

Kirke et al describe in "Bull. Haffkine Inst." (1977), 5, 75-77 and (1974), 2, 28-31, a series of thiazolyl-phenoxyacetic acids and derivatives, one in vitro antituberculosis and antifungal activity against T. rubrum and T. have mentagrophytes.

Anne et al describe in "Antimicrob. Agents Chemother." (1980), 18 (2), 231-239, diaryloxadiazole derivatives which have only a very weak activity against Candida albicans (MIC ₅₀ <60 µg / ml), such as. B.

Summary of the invention

The invention relates to diaryl-substituted azoles and pharmaceutically acceptable Salts thereof which can be used as antifungal agents.

The invention also relates to processes for the production of said Azoles and antifungal compositions containing these compounds or a pharmaceutically acceptable salt thereof as an active ingredient contain.

The azoles according to the invention are compounds of the general formula

in which mean:
Ar phenyl, thienyl, pyridyl which is substituted by R ¹ R ² , where R ¹ and R ² independently of one another are hydrogen or halogen such as F, Cl, Br and I; Alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, alkylthio, amino, hydroxyl, cyano, nitro, COOH, aminocarbonyl or aminosulfonyl, alkylamino, dialky lamino, acylamino, dialkylaminosulfonyl, alkylaminosulfonyl, alkylamino, dial kylamino, acylamosulfonyl, or aminosulfonyl, R ¹ and R ² together form a ring -O- (CH ₂ ) _n -O-, where n = 1, 2, can form;
R ³ , R ⁴ independently of one another are hydrogen, C ₁ -C ₁₆ -alkyl, which may optionally be substituted by amino, dialkylamino, hydroxy, cyano, carboxy; Alkenyl, alkynyl, acyl or R ³ and R ⁴ can together represent - (CH ₂ ) _m -Q- (CH ₂ ) _{m '} - where m' = m = 2, Q = CH ₂ , O, S (O) _n , n = O-2, NR ⁷ , wherein R ⁷ stands for C ₁ -C ₃ alkyl with the proviso that when Q = CH ₂ , m 'can also be 1;
R ^{5 is} H, halogen as defined above, OR, OH, NO ₂ , NH ₂ or NHCOR, wherein R is lower alkyl, alkyl or aryl and the like;
XN, O or S;
YN or S, with the proviso that if X = O or S, YN;
ZN or CR ⁸ , wherein R ^{8 is} hydrogen, halogen, e.g. B. Cl, Br or I, lower res alkyl or alkoxycarbonyl, with the proviso that X, Y and Z cannot all simultaneously represent N;
VN, O or S and, if V = N, V can also be combined with R ³ and R ^{4 to} form a heterocycle, such as pyrrole, imidazole-1,2,4-triazole, 1,3,4-triazole and pyrazole , and when V = O or S, R ³ and R ⁴ can be combined to form a single substituent which has only the definition of R ⁴ alone; and
p is an integer from 1 to 3.

The invention particularly relates to thiazoles of the formula

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , p and V are each as defined in formula (I) above and R ^{6 represents} hydrogen, halogen, carboxy, alkoxycarbonyl, lower alkyl, hydroxy and lower alkoxy , and their non-toxic pharmacologically acceptable salts.

The invention also relates to thiadiazoles of the following formula:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , p and V are each as defined in formula (I) above, and their non-toxic pharmaceutically acceptable salts.

The invention also relates to thiadiazoles of the formula

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ p and V are as defined in formula (I) above and their non-toxic pharmaceutically acceptable salts.

The invention also relates to oxadiazoles of the formula

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , p and V are as defined in formula (I) above, and their non-toxic pharmaceutically acceptable salts.

The invention particularly relates to thiazoles of the formula

wherein R ¹ , R ² , R ³ , R ^{4 are} as defined in formula (I) above, and their non-toxic pharmaceutically acceptable salts.

The invention also relates to diazoles of the formula

wherein R ¹ , R ² , R ³ , R ^{4 are} as defined above and X is O or S, and their pharmaceutically acceptable salts.

Alternatively, and according to another embodiment, the preferred ones Products according to the invention are those which are indicated by the following Formulas VIII-XIII are presented.

In general, the preferred products are those corresponding to Formula VIII and Formula IX:

in which mean:
A _{R is} selected from pyridyl, halogen-substituted pyridyl and

wherein R ^{8 is} hydrogen, halogen, nitro, amino, trifluoromethoxy, pyrrolyl, lower alkoxy, trifluoromethyl, cyano, lower alkynyl and trimethylsilyl-lower alkynyl and R ^{9 is} hydrogen, nitro, lower alkoxy or cyano;
XS or O;
Y is CH or N;
Z CH or N;
B lower alkylene or lower alkynylene;
D SR ¹⁰ , OR ¹¹ or N (R ¹² R ¹³ ), wherein R ^{10 is} di-lower alkylaminoalkyl; R ^{11 represents} di-lower alkylaminoalkyl, lower alkenyl, lower Al kinyl or lower alkoxyalkyl; R ¹² and R ^{13 are the} same or different and stand for hydrogen, lower alkyl, lower alkenyl, lower alkynyl, furfuryl, lower alkoxyalkyl, lower cycloalkyl, never their dialkylaminoalkyl, hydroxy-lower alkyl, lower alkylaminoalkyl, mononuclear lower alkyl, lower-alkylaminoalkylcarbonyl or what R ¹² and R ¹³ can be combined to form -CH ₂ CH ₂ N (R ¹⁴ ) CH ₂ CH ₂ - or -CH ₂ CH ₂ SCH ₂ -CH ₂ -, wherein R ^{14 is} lower alkyl; and
R ^{15 is} hydrogen, nitro, amino, lower alkanamido or hydroxy;
as well as their non-toxic pharmacologically acceptable salts.

Another preferred embodiment is the thiazole compounds of the formula X:

in which mean:
R ^{8 is} hydrogen, halogen, nitro, amino, trifluoromethoxy, pyrrolyl, lower alkoxy, trifluoromethyl, cyano, lower alkynyl, trimethylsilyl, lower alkynyl;
R ^{9 is} hydrogen, nitro, lower alkoxy or cyano;
R ¹² and R ¹³ , which are the same or different, are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, furfuryl, lower alkoxyalkyl, lower res cycloalkyl, lower dialkylaminoalkyl, hydroxy-lower alkyl, lower res alkylaminoalkyl, mononuclear lower alkyl, lower-alkylaminoalkylcarbonyl or wherein R ¹² and R ¹³ can be combined to form -CH ₂ CH ₂ N (R ¹⁴ ) CH ₂ CH ₂ - or -CH ₂ CH ₂ SCH ₂ -CH ₂ -, wherein R ^{14 is} lower alkyl;
R ^{15 is} hydrogen, nitro, amino, lower alkanamido or hydroxy; and
n is an integer with a value from 1 to 3,
as well as their non-toxic pharmacologically acceptable salts.

Yet another preferred embodiment are thiazoles of the following formula

in which mean:
R ^{16 is} hydrogen, halogen, nitro, lower alkoxy, cyano, trifluoromethyl or lower alkyl;
R ^{17 is} hydrogen, nitro, halogen or cyano;
R ¹⁸ and ¹⁹ , which are the same or different, are hydrogen, lower alkyl, lower alkenyl, lower lower alkylamino alkyl, lower hydroxy alkyl and lower alkylaminoalkyl; and
R ^{20 is} hydrogen or hydroxy,
as well as their non-toxic pharmacologically acceptable salts.

Another embodiment relates to diazoles of the formula

in which mean:
R ^{21 is} selected from hydrogen and lower alkoxy;
R ^{22 is} selected from hydrogen and nitro; and
R ²³ and R ²⁴ lower alkyl
as well as their non-toxic pharmacologically acceptable salts.

The preferred embodiments also include thiadiazoles of the formula XIII:

in which E represents SR ²⁶ or? NR ²⁷ R ²⁸ in which R ^{26 represents} lower alkylaminoalkyl and R ²⁷ and R ²⁸ , which are the same or different, represent lower alkyl and lower Al kenyl,
and their non-toxic, pharmacologically acceptable salts.

The above compounds are suitable for the treatment of a wide range of yeast infections and they are also active against one Variety of fungi (fungi) and fungi isolates including the fluconazole resistant isolates and strains. These connections are for this purpose  suitable if it is in a concentration in the range of 250 µg / ml and used below.

Suitable compounds of the formulas I to XIII can be used in the free Base form, in the form of the base salts where possible and in the form of the acid readditionssalze. In practice, the use of the salt form is equivalent to Using the base shape.

Pharmaceutically acceptable salts within the scope of this invention are those of mineral acids such as hydrochloric acid and sulfur acid and the like., and organic acids, such as ethanesulfonic acid, benzenesul fonic acid, p-toluenesulfonic acid and the like. These each result the corresponding hydrochloride, sulfate, ethanesulfonate, benzenesulfonate, p- Hydrochloride and the like; the invention is based on the above compounds however, not limited, as equivalent to those skilled in the art Salts are readily apparent.

Examples of the pharmaceutically acceptable base addition salts include organic bases that are non-toxic and have such strength that they form usable salts. These organic bases form one Class, the limits of which for the expert in this field without further ado and for the purposes of illustration, they include mono-, di- and trialkylamines such as methylamine, dimethylamine and triethylamine; Mono, di or trihydroxyalkylamines such as mono-, di- or triethanolamine, amino acids such as arginine and lysine; guanidine; N-methyl-glucosamine; N-methylglucamine; L- glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-Benzylphenethyl amine; Tris (hydroxymethyl) aminomethane and the like (see, e.g., "Pharmaceutical Salts "in" J. Pharm. Sci. ", 66 (1): 1-19 (1977)). About the salts of the inorganic bases include sodium, potassium, calcium or the like.

The acid addition salts of the basic compounds mentioned are obtained placed either by dissolving the free base of the compound (I) to (XIII) in  aqueous or aqueous-alcoholic solution or in other suitable solvents solvents containing a suitable acid and isolating the salt by evaporating the solution or by reacting the free base Compound (I) to (XIII) which carries an acid group with such a base, that the reactions take place in an organic solvent, whereby in in this case the salt separates out directly or by concentrating the solution can be obtained. Salts can also be made by adding a base to an aqueous-alcoholic solution of another salt.

In general, the compounds of formulas (I) to (XIII) under An using methods 1 to 9 identified below.

Procedure 1 (Scheme 1)

Scheme 1

In this process (Scheme 1) the substituted thiobenzamide (2) is prepared by the literature method ("Tetrahedron", 41, (22), 5061, 1985, by M. Cava and M. Levinson) by heating under reflux of benzamide (1) with a Lawesson reagent in dry benzene or toluene (M. Levinson). A condensation reaction between the thiobenzamide and α-halo acetophenone derivatives in a solvent, e.g. B. in a lower alcohol, THF, CH ₃ CN and the like, gives 2,4-diarylthiazole compounds (3) ("Organic Synthesis", Coll. III, 332). The NBS bromination of compound (3) gives the bromomethyl products (4a) and / or (4b), which by reaction with a suitable nucleophile, as indicated in Scheme 1, respectively in compounds (5) and ( 6) be converted. Compound (5) can also be debrominated by catalytic hydrogenation to form compound (6).

Procedure 2 (Scheme 2)

Scheme 2

An alternative synthetic route is shown in Scheme 2, which includes the Bromination of ethyl 4-acetylbenzoate with bromine in ether in the presence of a catalytic amount of aluminum chloride. The α-bromoacetophenone ver Bond (7) is then treated with a suitable thiobenzamide (2) as above described, condensed to form the diarylthiazole derivatives (8). The on final reduction of the ester with LAH and the subsequent bromination with carbon tetrabromide and triphenylphosphine gives the bromide (4a) which results in the target product (6) after nucleophilic substitution. The Compound (6) can also be prepared via the mesylated intermediate product (9), which is obtained by reducing the compound (8) with LAH and then ßende Mesylierung with methanesulfonyl chloride is prepared.

A compound of the general formula (II), in which p = 2-3, can be prepared according to the Methods are prepared as shown in Scheme 3 and Scheme 4 is.  

Procedure 3 (Scheme 3)

Scheme 3

Compound (11) is obtained by condensation and cyclization of Thiobenzamide (2) and α-bromoacetophenone (10) by the above described bromination reaction is prepared. By heating the ver bond (11) under reflux in acetone with an excess amount of Nal the iodine analogue (12) is obtained, which is the result of the reaction with a nucleo phil gives the product (13).

Procedure 4 (Scheme 4)

For the preparation of a compound of the general formula (II) in which p = 3 a palladium-catalyzed C-C coupling reaction between the 4- (p- Bromophenyl) thiazole derivatives (14) and an acetylene reactant applied.  The catalytic hydrogenation of the coupling product (15) gives the extended three carbon side chain links (16) in very good Yield (Scheme 4).

Scheme 4

Method 5 (Scheme 5)

Scheme 5

The primary amine side chain compounds (18) can be prepared from the bromine compounds (4a) by using methenamine and subsequent cleavage of the resulting quaternary amine salts with ethanolic HCl ("Organic Synthesis", Coll. "V, 212). The secondary amine side chain compounds (21) (Scheme 5) are prepared by acetylation of the compounds (18) with trifluoroacetic anhydride with quantitative formation of the amide analogues (19), treatment of the compound (19) with NaH in anhydrous DMF and Subsequent alkylation with alkyl halide gives compound (20), which can be converted into secondary amine products (21) by cleavage of the trifluoroacetyl group in a basic medium, and compound (21) is treated by treatment with a base such as K ₂ CO ₃ and a suitable alkyl halide leads into the target compounds (6).

Method 6 (Scheme 6)

Scheme 6

The α-bromoacetophenones with the desired dialkylaminoalkyl groups (23) are synthesized and coupled with substituted thiobenzamides (2) to form the target compounds (Scheme 6). 4'-Methyl acetophenone or derivatives thereof are treated with NBS in CCl ₄ under reflux conditions, giving the corresponding benzyl bromides (22), which are then treated with the required dialkylamines at room temperature to form the dialkylaminoalkyl derivatives (23). These compounds are purified by flash chromatography, converted into the corresponding HCl salt and brominated with Br ₂ to form α-bromoacetophenones (24). The compounds (24) are reacted with substituted thiobenzamides (2) in refluxing EtOH or a similar solvent to form the target compounds (25) in the form of a mixture of the HCl and HBr salts. These are converted into the free base and, if necessary, purified by flash chromatography. The compounds in which R ^{7 is} not hydrogen are further derivatized to further target compounds. For example, compound (25) (R ⁷ = NH ₂ ) is optionally treated with Ac ₂ O to form the N-acetylamino compound (27) (R ⁷ = NHCOCH ₃ ).

Method 7 (Scheme 7)

Scheme 7

According to the process described in process 1, the desired thiobenzamide (2) is reacted with 3'-methoxy-α-bromoacetophenone in refluxing EtOH to form the thiazole (28). This compound is demethylated with BBr ₃ under standard conditions to give the corresponding phenol (29). This is treated with a mixture of paraform aldehyde and the required dialkylamine in refluxing EtOH to form the desired dialkylaminomethyl compounds (30).

Method 8 (Scheme 8)

A compound of the general formula (III) can be prepared according to the in the scheme 8 specified processes can be produced:

Scheme 8

Based on a known method ("Adv. Heterocycl. Chem.", 1982, 32, 285) p-methylbenzimidate hydrochloride (31) is prepared by Hin passing hydrochloric acid gas through a cooled solution of p- Tolunitrile in a mixed solvent (chloroform and methanol 1: 1). By treating the benzimidate (31) with an ammonia / methanol solution the amidine hydrochloride (32) is obtained and with an ammonia / methanol The amidine hydrochloride (32) is obtained quantitatively. Amidine (32) is then treated with 1 equivalent of perchloromethyl mercaptan in the presence of Trie implemented at 0 ° C, whereby a cyclized product, the 5-chloro- 1,2,4-thiadiazole (33), in the form of a yellow solid. By domes of 5-chloro-1,2,4-thiadiazole with substituted aryl Grignard reagents in dry THF gives the desired diaryl-1,2,4-thiadiazoles (34) ("J. At the. Chem. Soc. ", 1985, 107, 2033, and" Organometallics ", 1993, 12, 3468). The subsequent bromination, followed by nucleophilic substitution, as described in Manufacturing Process 1, gives the final product (36).

Method 9 (Scheme 9)

A compound of general formula (IV) and (V) can follow after the processes are made:  

Scheme 9

The N, N'-diacylhydrazine compound ("J. Chem. Soc." (C), 1970, 1397) (37) is produced by acylation of the substituted benzhydrazide at 0 ° C with p-methylbenzoyl. The N, N'-diacylhydrazine compound (37) is heated either with thionyl chloride to produce the cyclized product 1,3,4- Oxadiazole (38a) or with the Lawesson reagent (Lawesson reagent = (2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-disulfide and the use of the reagent in various processes is described by M.D. Cara and M.I. Levinson in "Tetrahedron"; Volume 41: Pages 5061 ff. (1985).) To counter oxygen Exchange sulfur, and then cyclized to 1,3,4-thiadiazoles (38b). The cyclized products (38a and 38b) are made with N-bromosuccinimide treated to give bromomethyl compounds (39a and 39b) which be reacted with suitable nucleophiles to form the desired ones Products (40a) or (40b).

It is readily apparent to those skilled in the art that Ab Changes in the reaction sequence and changes in the appropriate reaction conditions compared to the analog reactions as indicated or otherwise known, suitably in the above methods can be used to produce the verb according to the invention formulas (I) to (XIII)  

example 1 2- (4'-Fluorophenyl) -4- [4 "- (N-methyl-N-allylaminomethyl) phenyl] thiazole (VI: R ¹ = H, R ² = 4-F, R ³ = Me, R ⁴ = Allyl, V = N (Method 1, Scheme 1)

4-Fluorobenzamide (5.0 g, 35.9 mmol) in benzene (100 ml) is added to the Lawes son reagent (7.27 g, 18.0 mmol) and the resulting solution is heated under reflux for 1 h. The solution is cooled to room temperature, concentrated and water (150 ml) is added. The mixture is refluxed for 3 hours and cooled to room temperature. The precipitate is filtered off and dried under vacuum, giving 4-fluorothio benzamide in the form of a yellow solid (4.1 g, 71%).
¹ H NMR (CDCl ₃ ): δ 7.09 (t, 2H), 7.90 (dd, 2H).

2-Bromo-4'-methylacetophenone (2.75 g, 12.9 mmol) is added to a solution of the crude product of 4-fluorothiobenzamide (2.0 g, 12.9 mmol) in EtOH (30 ml). The mixture is heated under reflux for 24 hours. The course of the reaction is followed by thin layer chromatography. After the reaction is complete, the solution is cooled to room temperature and the white precipitate is filtered off and dried under vacuum to give 2- (4'-fluorophenyl) -4- (p-tolyl) thiazole (1.54 g, 54%) ,
¹ H NMR (DMSO _d6 ): δ 62.35 (s, 1H), 7.28 (d, 2H), 7.38 (t, 2H), 7.94 (d, 2H), 8.08 (dd , 2H), 8.11 (s, 1H).

To a solution of 2- (4'-fluorophenyl) -4- (p-tolyl) thiazole (1.49 g, 5.5 mmol) in CCl ₄ (50 ml) are added NBS (1.09 g, 6.1 mmol) and benzoyl peroxide (50 mg) are added and the reaction mixture is heated under reflux. Another 50 mg of benzoyl peroxide are added every hour for 4 hours. The mixture is heated under reflux for 24 h and then filtered through Celite. The mother liquor is concentrated to give a yellow oil, which is triturated with pentane and filtered to give 2- (4'-fluorophenyl) -4- [p- (bromomethyl) phenyl)] thiazole (1.45 g, 75%).
¹ H NMR (DMSO _d6 ): δ 4.77 (s, 2H), 7.39 (t, 2H), 7.58 (d, 2H), 8.08 (m, 2H), 8.22 (s , 1H).

To a solution of 2- (4'-fluorophenyl) -4- (p-bromomethylphenyl) thiazole (1.00 g, 2.87 mmol) in EtOH (20 ml) is added N-methylallylamine (0.45 g, 6 , 00 mmol) in EtOH (10 ml) was added dropwise. The solution is stirred at room temperature for 12 hours and the solvent is removed under reduced pressure to give a green oil. The oil is taken up in CH ₂ Cl ₂ (30 ml) and washed with 1N NaOH (30 ml) and brine (30 ml). The organic layer is dried over anhydrous K ₂ CO ₃ and concentrated. The residue is chromatographed on a silica gel column and eluted with MeOH: CHCl ₃ (5:95) to give a yellow oil. The resulting oil is dissolved in MeOH (5 ml), to which an excess of HCl / MeOH solution (10 w / w%, 1 ml) is added and stirred for 1 h. The solvent is removed under reduced pressure and the residue is recrystallized from isopropanol to give the title compound in the form of an HCl salt as a brown solid (0.43 g, 40%).
¹ H NMR (DMSO _d6 ): δ 2.60 (d, 3H), 3.70 (m, 2H), 4.35 (m, 2H), 5.51 (s, 1H), 5.59 (d , 1H), 6.08 (m, 1H), 7.40 (t, 2H), 7.72 (d, 2H), 8.12 (m, 4H), 8.30 (s, 1H).

Example 1a 2- (4'-Chlorophenyl) -4 - [[4 '- (2-N, N-dimethylaminoethyl) thio] methyl] phenyl] thiazole (II: R ¹ = H, R ² = 4-Cl, V = S , R ³ , R ⁴ = CH ₂ CH ₂ NMe ₂ , R ⁶ = H)

If 4-fluorobenzamide is replaced by 4-chlorobenzamide in the above experiment, the compound 2- (4'-chlorophenyl) -4 - [(p-bromomethyl) phenyl] thiazole is obtained. To a slurry of NaH (60%, 0.44 g, 11 mmol) in THF (20 ml), 2-dimethylaminoethanethiol hydrochloride (0.7 g, 5.0 mmol) is added and the suspension is stirred for 1 hour. A solution of the above bromomethyl compound (1.82 g, 5.0 mmol) in THF (20 ml) is added with stirring and the reaction mixture is stirred for 4 hours. The THF is distilled off, the residue is poured into water and the mixture is extracted with EtOAc. The EtOAc extract is washed with brine, dried, stripped and the residue is chromatographed (3102, 100 g, CHCl ₃ / CHCl ₃ / MeOH 5%) to give the title compound as a soft solid (0.75 g ), Mp 51-52 ° C.
¹ H NMR (CDCl ₃ ): 2.20 (s, 6H), 2.40-2.60 (m, 4H), 3.80 (s, 2H), 7.35-7.50 (m, 5H) ), 7.85-8.00 (m, 4H).

Example 1b 2- (4'-Chlorophenyl-4 - [[4 '- (N-methylpiperazinyl) methyl] phenyl] thiazole (II: R ¹ = H, R ² = 4-Cl, V = N, R ³ R ⁴ = ( CH ₂ CH ₂ ) ₂ NMe, R ⁶ = H)

To a suspension of 2- (4'-chlorophenyl) -4 - [(p-bromomethyl) phenyl] thiazole (1.0 g, 2.74 mmol) and anhydrous K ₂ CO ₃ (0.83 g, 6 mmol) in DMF (15 ml), a solution of N-methyl-piperazine (0.3 ml, 2.74 mmol) in DMF (1 ml) is added with stirring. The reaction mixture is stirred at room temperature for 18 h. It is poured into water (100 ml) and the organic material is extracted with EtOAc. The EtOAc layer is washed with a sodium chloride solution, dried, stripped and the residue is chromatographed (SiO ₂ , 30 g, CHCl ₃ / CHCl ₃ / MeOH 5%) to give the title compound (0.43 g), F. 110 to 111 ° C.
¹ H NMR (CDCl ₃ ): 2.25 (s, 6H), 2.35-2.60 (br s, 8H), 3.55 (s, 2H), 7.35-7.50 (m, 5H), 7.90-8.05 (m, 4H).

Further examples are given in Table I.  

Example 2 2- (4'-Methoxyphenyl) -4- [4 "- (N-allyl-N-methylaminomethyl) phenyl] thiazole (VI: R ¹ = H, R ² = 4 MeO, R ³ = Me, R ⁴ = allyl ) (Method 2, Scheme 2)

To a solution of ethyl 4-acetylbenzoate (5.12 g, 26.6 mmol) in ether (50 ml) containing aluminum chloride (0.025 g, 0.19 mmol), bromine is added (1.31 ml, 26 , 6 mmol) and the reaction mixture is stirred for 2 h. The reaction mixture is poured into a saturated NaHCO ₃ solution and stirred for 30 minutes and the layers are separated. The organic layer is washed with NaHCO ₃ , H ₂ O, dried over MgSO ₄ , concentrated to half its volume and placed in the refrigerator overnight. The resulting solid is filtered off to give ethyl 4- (2'-bromoacetyl) benzoate (5.89 g, 81.6%) in the form of white crystals.
¹ H NMR (CDCl ₃ ): δ 1.42 (t, 3H), 4.42 (q, 2H), 4.48 (s, 3H), 8.04 (d, 2H), 8.16 (d , 2H).

Ethyl 4- (2'-bromoacetyl) benzoate (2.43 g, 8.97 mmol) is added to a solution of 4-methoxythiobenzamide (1.50 g, 8.97 mmol) in ethanol (50 ml) and the The reaction mixture is heated under reflux for 4 h. The reaction mixture is cooled to room temperature and the precipitate is filtered off, giving ethyl p- [2- (4'-methoxy) phenylthiazol-4-yl] benzoate (2.15 g, 70.1%) in the form of a light yellow solid.
¹ H NMR (CDCl ₃ ): δ 1.42 (t, 3H), 3.87 (s, 3H), 4.40 (q, 3H), 6.98 (d, 2H), 7.53 (s , 1H), 7.96-8.14 (m, 6H).

To a slurry of LAH (167 mg, 4.41 mmol) in dry THF (10 ml) is added a solution of ethyl p- [2- (4'-methoxyphenyl) thiazol-4-yl] benzoate (500 mg, 1.47 mmol) in dry THF (10 ml) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. A saturated (NH ₄ ) ₂ SO ₄ solution (20 ml) is added to the reaction mixture and stirred for 30 minutes. The precipitate is filtered off and the aqueous layer is washed thoroughly with ethyl acetate. The combined organic layer is washed with H ₂ O and a brine, dried over MgSO ₄ and concentrated in vacuo to give 2- (4'-methoxyphenyl) -4- (4 "-hydroxy methylphenyl) thiazole (360 mg, 82 , 2%) in the form of a white solid he holds.
¹ H NMR (CDCl ₃ ): δ 3.89 (s, 3H), 4.76 (s, 2H), 6.98 (d, 2H), 7.42 (s, 1H), 7.46 (d , 2H), 7.97-8.02 (m, 4H).

To a solution of 2- (4'-methoxyphenyl) -4- (4 "-hydroxymethylphenyl) thiazole (355 mg, 1.13 mmol) in dry THF (10 ml) triphenylphosphine (446 mg, 1.70 mmol) and carbon tetrabromide (564 mg, 1.70 mmol) are added and the reaction mixture is stirred for 17.5 h at 0 ° C. The precipitate is filtered off and the filter cake is washed with THF concentrated and purified by column chromatography, eluting with 10% ethyl acetate / hexane, giving 2- (4'-methoxyphenyl) -4- (4 "-bromomethylphenyl) thiazole (285 mg, 70%) in the form of a white Solid receives.
¹ H NMR (CDCl ₃ ): δ 3.88 (s, 3H), 4.56 (s, 2H), 6.98 (d, 2H), 7.43 (s, 1H), 7.46 (d , 2H), 7.95-8.01 (m, 4H).

The above-mentioned bromomethyl compound is aminated according to the procedure described in Example 1, the title compound being 2- (4'-methoxyphenyl) -4- [4 "- (N-allyl-N-methylaminomethyl) phenyl] thiazole in 95% yield is obtained.
¹ H NMR (CDCl ₃ ): δ 2.51 (s, 3H), 3.56-3.90 (m, 2H), 3.85 (s, 3H), 4.19-4.46 (m, 2H), 5.51-5.60 (m, 2H), 5.98-6.29 (m, 1H), 7.11 (d, 2H), 7.70 (d, 2H), 7.98 (d, 2H), 8.12 (d, 2H), 8.20 (s, 1H), 11, 12 (br s, 1H).

Example 2a Method 2, Scheme 2 2- (4-pyridyl) -4 - [[4 "- (N-methyl-N-propylamino) methyl] phenyl] thiazole (I: R ¹ R ² -Ar = 4-Py, R ³ = propyl, R ⁴ = Me, R ⁵ = H, p = 1, V = N)

2- (4-Pyridyl) -4 - [(4 "-hydroxymethyl) phenyl] thiazole is obtained according to the above procedure ren produced in Example 2.

A solution of methanesulfonyl chloride (0.75 ml, 9.11 mmol) in THF (5 ml) becomes an ice-cold solution of the above alcohol (0.83 g, 3.09 mmol) in THF (70 ml) with stirring. containing Et ₃ N (0.92 ml, 9.11 mmol) was added. After the addition is complete, the reaction mixture is allowed to warm to room temperature and, if necessary, heated under reflux for 2 hours to complete the reactions. The reaction mixture is cooled and filtered. The residue is washed with CHCl ₃ and dried to give the desired compound in the form of a yellow solid (0.45 g).
¹ H NMR (DMSO _d6 ): δ 2.35 (s, 3H), 4.84 (s, 2H), 7.59 (d, 2H), 8.13 (d, 2H), 8.43 (d , 2H), 8.95 (d, 2H).

A solution of the above mesylate (0.45 g, 1.3 mmol) and of N-methyl-N-propylamine (0.33 ml, 3.25 mmol) in THF (50 ml) is kept at 55 ° for 18 h C. heated. The reaction mixture is stripped and flash chromatographed (SiO ₂ , CHCl ₃ / MeOH 5%) to give 0.238 g of the title compound.
¹ H NMR (CDCl ₃ ): δ 0.86 (t, 3H), 1.38-1.60 (m, 2H), 2.13 (s, 3H), 2.30 (t, 2H), 3 , 49 (s, 2H), 7.40 (d, 2H), 7.95-8.04 (dd, 4H), 8.32 (s, 1H), 8.75 (d, 2H). It was converted to the dihydrochloride salt, mp 192-195 ° C.

Further examples are given in Table I.

Example 3 Method 3, Scheme 3 2- (4'-Methoxyphenyl) -4- [4Ó- [2- (N, N-dimethylamino) ethyl] phenyl] thiazole (II: R ¹ = H, R ² = 4-CH ₃ O, R ³ = R ⁴ = CH ₃ , R ⁵ = H, R ⁶ = H, V = N, p = 2)

To a solution of 4 '- (2-chloroethyl) acetophenone (5.00 g, 27.37 mmol) and aluminum chloride (0.30 g, 2.73 mmol) in anhydrous diethyl ether (75 ml) is bromine (4.37 g, 27.37 mmol) was added dropwise. After 18 h the solution is concentrated and the residue is taken up in CHCl ₃ (75 ml) and washed with water (75 mf). The organic layer is dried over MgSO ₄ and concentrated, giving 7.91 g of crude bromine product in the form of a dark oil, which is used as is without further purification.

A mixture of α-bromo-4 '- (2-chloroethyl) acetophenone (1.56 g, 5.98 mmol) and 4-methoxythiobenzamide (1.00 g, 5.98 mmol) is placed in EtOH for 2 h (25 ml) heated under reflux. Then the mixture is cooled to 5 ° C and the precipitate is filtered off and dried, 2- (4Õ- Methoxyphenyl) -4- [4Ó- (2-chloroethyl) phenyl] thiazole (0.90 g, 46%).

A solution of 2- (4'-methoxyphenyl) -4- [4Ó- (2-chloroethyl) phenyl] thiazole (0.30 g, 0.71 mmol) and excess (2 ml) dimethylamine / EtOH solution (19 wt ./Wew.-%) in THF (10 ml) are placed in a sealed reaction container and heated to 80 ° C for 20 h. The solution is then concentrated and the residue is taken up in CHCl ₃ (20 ml) and washed with saturated NaHCO ₃ (20 ml). The organic layer is dried over MgSO ₄ and concentrated to give an oil which is purified on a silica gel column, eluting with 10% MeOH / CHCl ₃ , giving the title compound as an off-white solid (90 mg , 37%) receives.
¹ H NMR (CDCl ₃ ): δ 2.33 (s, 6H), 2.60 (m, 2H), 2.80 (m, 2H), 3.86 (s, 3H), 6.97 (i.e. , 2H), 7.27 (d, 2H), 7.35 (s, 1H), 7.89 (d, 2H), 7.97 (d, 2H).

Further examples are given in Table I.

Example 4 Method 4, Scheme 4 2- (4'-fluorophenyl) -4- [4 '- [3- (N, N-dimethylamino) propyl] phenyl] thiazole (II: R ¹ = H, R ² = 4-F, p = 3, V = N, R ³ = R ⁴ = CH ₃ )

To a solution of p-fluorothiobenzamide (0.39 g, 2.5 mmol) in 20 ml abs. EtOH, 2,4'-dibromoacetophenone (0.7 g, 2.5 mmol) is added all at once. The reaction mixture is stirred at room temperature for 3 hours and then cooled in an ice bath. The precipitate is collected by filtration, washed with cold EtOH (5 ml x 2) and dried in vacuo to give 2- (4'-fluorophenyl) -4- (4'-bromophenyl) thiazole as a white fluffy crystalline solid ( 1.55 g, 93%), mp 158-159 ° C.
¹ H NMR (CDCl ₃ ): δ 7.16 (t, 2H), 7.47 (s, 1H), 758 (d, 2H), 7.87 (d, 2H), 8.02 (m, 2H) ).

Triphenylphosphine (80 mg, 10%), PdCl ₂ (40 mg, 5%) and 2- (4'-fluorophenyl) -4- (4'-bromophenyl) thiazole (0.98 g, 2.9 mmol) introduced in 20 ml of diethylamine. After stirring for 15 minutes under an N ₂ atmosphere, CuI (30 mg, 5%) and 1-dimethylamino-2-propyne (0.27 g, 3.18 mmol) in 20 ml of acetonitrile are added to the mixture. After heating for 18 hours, the solvent is evaporated under reduced pressure and the residue is filtered through a pad of silica gel (50 g) using CHCl ₃ (400 ml) and 2% MeOH in CHCl ₃ (400 ml). A large portion of unreacted 2- (4'-fluorophenyl) -4- (4'-bromophenyl) thiazole is recovered after removal of the chloroform filtrate (0.55 g, 56%). The second part of the filtrate (2% MeOH in CHCl ₃ ) is concentrated and the remaining solid is then purified on a silica gel column, eluting with 2% MeOH in CHCl ₃ . After concentration and trituration with hexane, 2- (4'-fluorophenyl) -4- [4 '- (3-dimethylamino-2-propin-1-yl) phenyl] thiazole (0.25 g, yield 27%) is obtained. , Mp 98-99 ° C.
¹ H NMR (CDCl ₃ ): δ 2.39 (s, 6H), 3.50 (s, 2H), 7.16 (t, 2H), 7.48 (s, 1H), 7.51 (i.e. , 2H), 7.93 (d, 2H), 8.03 (m, 2H).

A warm solution of 2- (4'-fluorophenyl) -4- [4 '- (1-dimethylamino-2-propyn-3-yl) phenyl] thiazole (0.2 g, 0.6 mmol) in abs. EtOH (20 ml) containing a catalytic amount of palladium on charcoal (5%, 20 mg) is shaken under a hydrogen atmosphere (30 psi) for 2 h. After removing the catalyst by filtration, the filtrate is concentrated to give 2- (4'-fluorophenyl) -4- [4 '- (3-N, N-dimethylaminopropyl) phenyl] thiazole as the desired product (0.18 g , 89%) receives.
¹ H NMR (CDCl ₃ ): δ 1.65 (m, 2H), 2.24 (s, 6H), 2.32 (t, 2H), 2.69 (t, 2H), 7.14 (t , 2H), 7.27 (d, 2H), 7.40 (s, 1H), 7.89 (d, 2H), 8.02 (m, 2H).

Further examples are given in Table I.

Example 5 Method 5, Scheme 5 2- (4'-Chlorophenyl-4 - [[4 '- (N-pentyl) aminomethyl] phenyl] thiazole (VI: R ¹ H, R ² = 4-Cl, R ³ = n-pentyl, R ⁴ = H )

A solution of 2- (4'-chlorophenyl) -4- [4'-bromomethyl) phenyl] thiazole is added to a boiling solution of methenamine (1.1 g, 7.85 mmol) in CCl ₄ (80 ml) (Scheme 1; 2.6 g, 7.13 mmol) in CHCl ₃ (40 ml) was added dropwise. The reaction mixture was refluxed for 3 hours under N ₂ and cooled. The white precipitate is filtered off and the residue is washed with a small volume of CHCl ₃ and air dried to give the quaternary salt (2.7 g). Concentrated HCl (4 ml) is added dropwise to a suspension of the above salt (2.7 g) in EtOH (30 ml) and the reaction mixture is heated under reflux for 3 h. It is cooled, filtered and the residue is washed with a small volume of EtOH and dried to give the desired amine hydrochloride (1.97 g), mp <320 ° C.
¹ H NMR (DMSO _d6 ): δ 4.05 (s, 2H), 7.43-7.63 (m, 4H), 7.95-8.13 (m, 5H).

An aqueous solution of NaOH (6 N) up to pH 12 is added to an aqueous suspension of the above-mentioned salt and the free base is extracted with CH ₂ Cl ₂ . The extract is dried and evaporated to give the corresponding amine 2- (4'-chlorophenyl) -4- [4 '- (aminomethyl) phenyl] thiazole (1.4 g).
¹ H NMR (DMSO _d6 ): δ 3.75 (s, 2H), 7.43 (d, 2H), 7.60 (d, 2H), 7.98 (d, 2H), 8.06 (d , 2H), 8.16 (s, 1H).

A solution of trifluoroacetic anhydride (0.85 ml, 6 mmol) in THF (5 ml) is added dropwise to a solution of the above amine (1.4 g, 4.7 mmol) in THF (15 ml) and the reaction mixture turns 18 stirred at room temperature for h. The THF is evaporated and the residue is triturated with a small volume of ether. The solid is filtered off, washed with hexane and dried to give 2- (4'-chlorophenyl) -4- [4'-trifluoroacetylamino-methyl) phenyl] thiazole (1.56 g), mp 174-175 ° C.
¹ H NMR (CDCl ₃ ): δ 4.58 (d, 2H), 6.58 (br s, 1H), 7.30-7.48 (m, 4H), 7.51 (s, 1 H) , 7.91-8.05 (m, 4H).

A solution of the above compound (0.59 g, 1.48 mmol) in DMF (5 ml) is added to a slurry of NaH (60%, 70 mg, 1.77 mmol) in DMF (2 ml) under nitrogen , The reaction mixture is stirred at room temperature until the gas evolution ceases (∼ 1 h). N-iodo-pentane (0.5 g, 2.5 mmol) is added and the reaction mixture is heated to 100 ° C. (oil bath) for 3 hours. The reaction mixture is cooled, poured into water (50 ml) and the organic material is extracted with EtOAc. The EtOAc layer is washed with brine, dried and stripped to give a solid which is chromatographed (SiO ₂ , 0-5% MeOH / CH ₂ Cl ₂ ), giving the desired compound (0.5 g ) receives.
¹ H NMR (CDCl ₃ ): δ 0.88 (t, 3H), 1.10-1.41 (m, 4H), 1.45-1.80 (m, 2H), 3.34 (t, 2H), 4.68 (d, 2H), 7.33 (d, 2H), 7.40-7.60 (m, 3H), 7.92-8.22 (m, 4H).

A solution of the above trifluoroacetylamide (1.05 g, 2.25 mmol) and aqueous KOH (25%, 6 ml, 2.68 mmol) in acetone (30 ml) are refluxed for 18 h. The acetone is distilled off and the residue is partitioned between water (15 ml) and EtOAc (25 ml). The organic layer is separated and the aqueous layer is extracted with EtOAc (3.20 ml). The combined organic extract is washed with a saline solution, dried and chromatographed (SiO ₂ , 0-5% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.8 g), melting point 70 to 72 ° C.
¹ H NMR (CDCl ₃ ): 0.88 (t, 3H), 1.12-1.45 (m, 4H), 1.45-1.80 (m, 2H), 2.64 (t, 2H) ), 3.55 (br s, 1H), 3.85 (s, 2H), 7.32-7.52 (m, 5H), 7.83-8.13 (m, 4H).

Example 5a 2- (4'-Chlorophenyl-4 - [[4 '- (N-cyclopropyl, N-methyl) amino-methyl] phenyl] thiazole (VI: R ¹ = H, R ² = 4-Cl, R ³ = c-propyl, R ⁴ = Me).

Iodomethane (0.1 ml, 2.1 mmol) is added to a stirred mixture of 2- (4'-chlorophenyl-4 - [[4 '- (N-cyclopropyl) aminomethyl] phenyl] thiazole (prepared as in Example 5) (0.2 g, 0.6 mmol) and anhydrous K ₂ CO ₃ (0.2 g, 1.4 mmol) in THF (15 ml) were added, stirred and filtered for 16 h and the residue was washed with CH ₂ Cl ₂ washed, the washing water and the filtrate are evaporated and the remaining oil is chromatographed (SiO ₂ , 0 to 2% MeOH / CH ₂ Cl ₂ ), whereby 50 mg of the title compound is obtained.

Further examples are given in Table I below.

Example 6 Method 6, Scheme 6 2- (4'-Cyanophenyl-4 - [[4 '- (N, N-dimethyl) aminomethyl] phenyl] thiazole (VI: R ¹ = H, R ² = 4-CN, R ³ = R ⁴ = Me)

0.2 g of benzoyl peroxide is added to a mixture of 4'-methyl acetophenone (30 g, 0.22 mol) and NBS (39.9 g, 0.22 mol) in CCl ₄ (200 ml) and the reaction mixture is stirred for 6 h heated under reflux. Additional benzoyl peroxide (0.2 g) is added and the mixture is heated under reflux for 16 h. It is cooled and filtered. The filtrate is stripped to give an oil (47.9 g). The ¹ H NMR spectrum gives ∼75% of the desired bromide, which is used as it is for the next step.

Dimethylamine (19% in EtOH, 21.2 g, 0.47 mol) becomes a solution of the above bromide (47.8 g, 0.22 mol) in CH ₂ Cl ₂ (100 ml) with stirring at 0 ° C dripped. When the addition is complete, the ice bath is removed and the solution is stirred at room temperature for 16 hours. The solvent is evaporated and the residue is taken up in CHCl ₃ . The chloroform solution is washed successively with saturated NaHCO ₃ , a saline solution, dried and stripped. The residue is chromatographed (SiO ₂ , 2 to 10% MeOH / CH ₂ Cl ₂ ), giving 15 g of 4 '- (N, N-dimethylamino) methylacetophenone. The amine is converted into the corresponding HCl salt.

Bromine (1.36 ml, 26.5 mmol) is added dropwise to a solution of the above HCl salt (5.6 g, 26.5 mmol) in CHCl ₃ (60 ml) with stirring at 0 ° C. The reaction mixture is stirred at room temperature for 2 hours and the solvent is evaporated to give a brown solid (9 g).
¹ H NMR (CDCl ₃ ): δ 2.81 (s, 6H), 4.26 (s, 2H), 4.44 (s, 2H), 7.89 (d, 2H), 8.07 (d , 2H).

A mixture of the above phenacyl bromide (1.54 g, 4.57 mmol) and 4-cyanothiobenzamide (0.74 g, 4.57 mmol) in EtOH (15 ml) is heated under reflux for 2 h. It is cooled and filtered to give a yellow solid (1.17 g). The solid is partitioned between CHCl ₃ and a saturated NaHCO ₃ solution. The organic layer is separated, washed with brine, dried and evaporated to give 0.77 g of a solid. This is purified by column chromatography (SiO ₂ , 0 to 2% MeOH / CH ₂ Cl ₂ ), giving 0.46 g of the title compound, mp 121-122 ° C.
¹ H NMR (CDCl ₃ ): δ 2.37 (s, 6H), 3.47 (s, 2H), 7.42 (d, 2H), 7.57 (s, 1H), 7.77 (d , 2H), 7.92 (d, 2H), 8.13 (d, 2H).

Example 6a 2- (4'-Fluorophenyl-4 - [[[4 '- (N, N-dimethyl) aminomethyl] -3Õ-nitro] phenyl] thiazole (II: R ¹ = H, R ² = 4-F, R ³ = R ⁴ = Me, R ⁶ = H, R ⁵ = 3-NO ₂ , V = N, p = 1)

If you replace 4'-methyl-acetophenone with 4'-methyl-3'-nitroacetophenone and following the above-mentioned procedure, the compound 4 '- (N, N- Dimethylamino) methyl-3'-nitroacetophenone. This is transferred into the HCl salt leads and brominated, giving α-bromo-4'-methyl-3'-nitroacetophenone.

A mixture of α-bromo-4 '- [N, N-dimethylaminomethyl) -3'-nitroaceto phenone (2.38 g, 6.23 mmol) and 4-fluorothiobenzamide (0.97 g, 6.23 mmol) in EtOH (150 ml) is heated under reflux for 6 h. The EtOH is stripped and the residue is taken up in EtOAc. The EtOAc solution is washed one after the other with saturated Na ₂ CO ₃ and a saline solution, dried and stripped. The residue is triturated with isopropyl alcohol and filtered to give 1.37 g of the title compound, mp 112 ° C.
¹ H NMR (CDCl ₃ ): δ 2.25 (s, 6H), 3.75 (s, 2H), 7.17 (t, 2H), 7.57 (s, 1H), 7.69 (i.e. , 1H), 7.98-8.18 (m, 3H), 8.45 (d, 1H).

Example 6b 2- (4'-Fluorophenyl-4 - [[[4 '- (N, N-dimethyl) aminomethyl] -3'-amino] phenyl] thiazole (II: R ¹ = H, R ² = 4-F, R ³ = R ⁴ = Me, R ⁶ = H, R ⁵ = NH ₂ , V = N, p = 1)

A solution of the above nitro compound (Example 6a, 0.65 g) in EtOH (80 ml) and HCl (0.2 ml) are reduced under catalytic conditions (5% Pd / C, 250 mg). After the reduction has ended (18 h), the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is partitioned between CH ₂ Cl ₂ and saturated Na ₂ CO ₃ . The organic layer is washed with water, dried and stripped to give 0.47 g of the title compound, mp 108-109 ° C.
¹ H NMR (CDCl ₃ ): δ 2.21 (s, 6H), 3.45 (s, 2H), 7.05 (t, 2H), 7.14 (s, 1H), 7.18-7 , 23 (d, 1H), 7.31 (d, 1H), 7.40 (s, 1H), 7.97-8.08 (dd, 2H).

Example 6c 2- (4'-Fluorophenyl-4 - [[[4 '- (N, N-dimethyl) aminomethyl] -3'-acetylamino] phenyl] thiazole (II: R ¹ = H, R ² = 4-F, R ³ = R ⁴ = Me, R ⁶ = H, R ⁵ = NHCOCH ₃ , V = N, p = 1)

Acetic anhydride (0.4 ml) is added to a solution of the above amine (Example 6b, 0.47 g) in anhydrous THF (10 ml) and the solution is stirred at room temperature for 18 hours. The THF is evaporated and the residue is taken up in CHCl ₃ . The CHCl ₃ solution is washed thoroughly with water, dried and stripped to give a soft solid. It is triturated with ether and filtered to give 0.21 g of the title compound in the form of a white solid, mp 128.5 ° C.
¹ H NMR (CDCl ₃ ): δ 2.15 (s, 3H), 2.30 (s, 6H), 3.50 (s, 2H), 7.10-7.20 (m, 3 H), 7.50 (s, 1H), 7.65-7.75 (d, 1H), 8.00-8.10 (dd, 2H), 8.80 (s, 1H), 10.75 (br s , 1H).

Further examples are given in Table I below.

Example 7 Method 7, Scheme 7 2- (3'-nitrophenyl-4 - [[[4 '- (N, N-dimethylamino) methyl] -3'-hydroxy] phenyl] thiazole (II: R ¹ = H, R ² = 3-NO ₂ , R ³ = R ⁴ = CH ₃ , R ⁵ = 3-OH, R ⁶ = H, V = N, p = 1)

A mixture of 3-nitrobenzenethioamide (2.73 g, 15 mmol) and 3-methoxy-α-bromoacetophenone (3.43 g, 15 mmol) in EtOH (30 ml) is heated under reflux for 18 h. It is cooled and filtered, giving 4 g of 2- (3'-nitrophenyl) -4 - [(3'-methoxy) phenyl] thiazole in the form of a yellow solid, mp 122-123 ° C.
¹ H NMR (CDCl ₃ ): δ 3.94 (s, 3H), 6.90-7.01 (dd, 1H), 7.32-7.48 (t, 1H), 7.50-7, 75 (m, 4H), 8.22-8.45 (dd, dd 2H), 8.90 (dd, 1H).

A solution of BBr ₃ in CH ₂ Cl ₂ (1 M, 4.9 ml) is added to an ice-cold solution of the above-mentioned methyl ether (0.77 g, 2.46 mmol) in CH ₂ Cl ₂ (10 ml) , The solution is stirred at 0 ° C for 0.5 h and then stirred at room temperature for 18 h. It is quenched with 12 ml of water and the mixture is stirred for 0.5 h and filtered. The residue is washed thoroughly with water, then with ether and dried, yielding 0.55 g of 2- (3-nitrophenyl) -4 - [(3'-hydroxy) phenyl] thiazole.

A mixture of the above hydroxy compound (0.55 g, 1.93 mmol), of p-formaldehyde (0.3 g), (Me) ₂ NH / EtOH (19%, 2.2 ml) in EtOH ( 7 ml) is heated under reflux for 8 h. The EtOH is evaporated and the residue is poured into water and the solution is taken up in CH ₂ Cl ₂ . The organic layer is washed with brine, dried, stripped and the residue is chromatographed (SiO ₂ , MeOH / CH ₂ Cl ₂ 2%) to give 0.15 g of the title compound, mp 157-160 ° C.
¹ H NMR (CDCl ₃ ): δ 2.32 (s, 6H), 3.67 (s, 2H), 7.00-7.01 (dd, 1H), 7.40-7.48 (m, 2H), 7.53 (s, 1H), 7.65 (t, 1H), 8.22-8.45 (dd, dd 2H), 8.85 (m 1H).

Further examples are given in Table I below.  

Example 8 Method 8, Scheme 8 5- (4-Fluorophenyl) -3- [4 "- (N-methyl-N-allylaminomethyl) phenyl] -1,2,4-thiadiazole (III: R ¹ = H, R ² = 4-F, R ³ = CH ₃ , R ⁴ = allyl, R ⁵ = H, V = N, p = 1)

HCl is passed into a solution of p-tolunitrile (10.1 g, 86.21 mmol) in 100 ml of CHCl ₃ : MeOH (1: 1), which has been cooled to 5 ° C. in an ice water bath, for 1 h. to achieve saturation. The solution is stirred at 10 ° C for 43 h, then concentrated under reduced pressure, keeping p-methyl benzimidate hydrochloride in the form of pale yellow crystals (15.98 g, 99%).
¹ H NMR (CDCl ₃ ): δ 2.44 (s, 3H), 4.52 (s, 3H), 7.36 (d, 2H), 8.29 (d, 2H).

An NH ₃ / MeOH solution (2.68 M, 24.12 ml, 64.64 mmol) is added to a solution of p-methylbenzimidate hydrochloride (8.00 g, 43.09 mmol) in MeOH (100 ml). added. After the addition of the NH ₃ , the mixture has a pH of about 8.5. Ammonium chloride (2.30 g, 43.09 mmol) is added to this solution. The reaction mixture is stirred at room temperature for 20 hours, then cooled in a refrigerator and the precipitate is removed by filtration. The mother liquor is concentrated to give the crude product, which is taken up in a limited amount of cold EtOH, and then the white precipitate is filtered off. The two filtrates are concentrated to give p-methylbenzamidine hydrochloride in the form of an off-white solid (7.15 g, 97%).
¹ H NMR (DMSO _d6 ): δ 2.41 (s, 3H), 7.43 (d, 2H), 7.78 (d, 2H), 9.24-9.39 (broad d, 3H).

To a mixture of p-methylbenzamidine hydrochloride (5.1 g, 30.0 mmol) in CHCl ₃ (100 ml) is added triethylamine (15.12 g, 20.9 ml, 150.0 mmol) and in an ice water bath cooled to 5 ° C. Perchloromethyl mercaptan (95%, 6.16 g, 31.5 mmol) in CHCl ₃ (10 ml) is slowly added to the mixture over a period of 1 h. The yellow solution is allowed to warm to room temperature. After 2 h the mixture is washed with water (2 × 100 ml) and a saline solution (100 ml). The organic layer is dried over MgSO ₄ and the solvent is removed under reduced pressure to give a brown oil. The oil is purified on a silica gel bed, eluting with CHCl ₃ / hexanes (1: 1) to give 3- (p-tolyl) -5-chloro-1,2,4-thiadiazole in the form of a yellow Solid (2.78 g, 44%).
¹ H NMR (CDCl ₃ ): δ 2.41 (s, 3H), 7.30 (d, 2H), 8.13 (d, 2H).

A mixture of 3- (p-tolyl) -5-chloro-1,2,4-thiadiazole (0.50 g, 2.37 mmol) and [1,3-bis (diphenylphosphino) propane] nickel (II) chloride -Catalyst (1.41 g, 2.61 mmol) in anhydrous THF (20 ml) is cooled in an ice water bath. 4-Fluorophenyl-magnesium bromide (1.0 M in THF, 2.5 ml, 2.49 mmol) is slowly added to this mixture with the exclusion of both moisture and oxygen. The mixture is allowed to warm to room temperature and stirred under N _{2 for} 18 h. The mixture is filtered through Celite and concentrated. The residue is taken up in CHCl ₃ (50 ml) and washed with a saline solution (2 × 50 ml). The organic layer is dried over magnesium sulfate and concentrated. The residue is purified on a silica gel column, eluting with CHCl ₃ / hexanes (3: 7), giving 5- (4'-fluorophenyl) -3- (p-tolyl) -1,2,4-thiadiazole (0.20 g, 31%).
¹ H NMR (CDCl ₃ ): δ 2.43 (s, 3H), 7.21-7.32 (m, 4H), 8.06 (m, 2H), 8.24 (d, 2 H).

To a solution of 5- (4'-fluorophenyl) -3- (p-tolyl) -1,2,4-thiadiazole (0.16 g, 0.59 mmol) in CCl ₄ (20 ml), NBS (0 , 11 g, 0.59 mmol) are added and the mixture is heated under reflux for 36 h. The mixture is cooled to room temperature and filtered through Celite. The mother liquor is concentrated. The residue is taken up in chloroform (30 ml) and washed with water (30 ml). The organic layer is dried over MgSO ₄ and concentrated to give 5- (4'-fluorophenyl) -3- (p-bromomethylphenyl) -1,2,4-thiadiazole (0.22 g) as a crude product how it is obtained is used without further purification.
¹ H NMR (CDCl ₃ ): 64.55 (s, 2H), 7.19 (d, 2H), 7.54 (d, 2H), 8.06 (m, 2H), 8.35 (d, 2H).

To a solution of 5- (4'-fluorophenyl) -3- (4 "-bromomethylphenyl) -1,2,4-thiadiazole (0.19 g, 0.54 mmol) in chloroform (15 ml) becomes N-methylallylamine (0.14 g, 1.62 mmol) in chloroform (5 ml) is slowly added. The solution is stirred for 12 h at room temperature and washed with water (30 ml). The organic layer is dried over K ₂ CO ₃ and concentrated The resulting oil is chromatographed on a silica gel column, eluting with ethyl acetate / hexanes (30:60) to give the title compound as an oil (0.10 g, 55%).
¹ H NMR (CDCl ₃ ): δ 2.23 (s, 3H), 3.05 (d, 2H), 3.57 (s, 2H), 5.12-5.30 (m, 2 H), 5.85-6.05 (m, 1H), 7.19 (d, 2H), 7.45 (d, 2H), 8.07 (m, 2H), 8.32 (d, 2H).

Further examples are given in Table I below.

Example 9 Method 9, Scheme 9 1,3,4-thiadiazoles and 1,3,4-oxadiazoles 2- (3'-nitrophenyl) -5- [4 "- (N, N-dimethylaminomethyl) phenyl] -1,3,4-thiadiazole (IV: R ¹ = H, R ² = 3-NO ₂ , R ³ = R ⁴ = CH ₃ , R ⁵ = H, V = N, p = 1)

To a solution of 3-nitrobenzhydrazide (2.16 g, 11.92 mmol) in pyridine (40 ml), which has been cooled to 0 ° C. in an ice bath, p-toluoyl chloride (1.94 g, 11.92 mmol) was added dropwise. The mixture is allowed to warm to room temperature and stirred for 12 hours. The mixture is quenched with 350 ml of water and stirred for 30 minutes. The precipitate is filtered off and dried in a vacuum oven, giving 1 - [(4-methyl) benzoyl] -2- (3-nitrobenzoyl) hydrazine in the form of a pale yellow solid (2.94 g, 82%).
¹ H NMR (DMSO _d6 ): δ 2.40 (s, 3H), 7.35 (d, 2H), 7.86 (d, 2H), 7.87 (t, 1H), 8.37 (d , 1H), 8.45 (d, 1H), 8.76 (s, 1H), 10.58 (s, 1H), 10.90 (s, 1H).

A mixture of 1 - [(4-methyl) benzoyl] -2- (3-nitrobenzoyl) hydrazine (1.40 g, 4.68 mmol) and Lawesson's reagent (0.95 g, 2.34 mmol) in benzene (25 ml) is slowly heated to 60 ° C. After 3 h, the solution is concentrated, quenched with 35 ml of water and heated under reflux for a further 12 h. Then the mixture is cooled to room temperature and the precipitate is collected by filtration. The precipitate is then taken up in chloroform (100 ml) and the insoluble portion is removed by filtration. The filtrate is then dried over MgSO ₄ and concentrated to give 2- (3'-nitrophenyl) -5- (p-tolyl) -1,3,4-thiadiazole in the form of a pale yellow solid (0.67 g, 48 %).
¹ H NMR (CDCl ₃ ): δ 2.45 (s, 3H), 7.35 (d, 2H), 7.73 (t, 1H), 7.92 (d, 2H), 8.38 (t , 2H), 8.81 (s, 1H).

To a solution of 2- (3'-nitrophenyl) -5- (p-tolyl) -1,3,4-thiadiazole (0.66 g, 2.22 mmol) in CCl ₄ (75 ml), NBS (0 , 43 g, 2.44 mmol) were added and the mixture was heated under reflux for 12 h. The mixture is then concentrated and the residue is taken up in chloroform (50 ml) and washed with a saturated NaHCO ₃ solution (50 ml) and brine (50 ml). The organic layer is dried over MgSO ₄ and concentrated to give 2- (3'-nitrophenyl) -5- (p-bromomethylphenyl) -1,3,4-thiadiazole in the form of a light brown solid (0.69 g, 83%).
¹ H NMR (CDCl ₃ ): δ 4.51 (s, 2H), 7.55 (d, 2H), 7.72 (t, 1H), 8.01 (d, 2H), 8.39 (t , 2H), 8.80 (s, 1H).

To a suspension of 2- (3'-nitrophenyl) -5- (p-bromomethylphenyl) -1,3,4-thiadiazole (0.69 g, 1.83 mmol) in warm EtOH (25 ml) in excess Dimethylamine / EtOH solution ( ^∼ 19 w / w%, 3 ml) is added and the mixture is stirred at room temperature. After 12 h the solution is concentrated and the residue is taken up in chloroform (50 ml) and washed with a saturated NaHCO ₃ solution (50 ml) and a saline solution (50 ml). The organic layer is dried over K ₂ CO ₃ and concentrated to give a brown solid, which is chromatographed on a silica gel column, eluting with 10% MeOH / CHCl ₃ and giving the title compound in the form of a light yellow solid ( 0.26 g, 37%)
¹ H NMR (CDCl ₃ ): δ 2.29 (s, 6H), 3.50 (s, 2H), 7.50 (d, 2H), 7.72 (t, 1H), 7.97 (d , 2H), 8.39 (t, 2H), 8.82 (s, 1H).

Example 9a 2- (3'-nitrophenyl) -5- [4 "- (N, N-dimethylaminomethyl) phenyl] -1,3,4-oxadiazole (V: R ¹ = H, R ² = 3-NO ₂ , R ³ = R ⁴ = CH ₃ , R ⁵ = H, V = N, p = 1)

A suspension of 1 - [(4-methyl) benzoyl)] - 2- (3-nitrobenzoyl) hydrazine (1.37 g, 4.58 mmol) in 20 ml of thionyl chloride is heated under reflux for 12 h. The solution is concentrated and the residue is taken up in chloroform (50 ml) and washed with water (50 ml) and a brine (50 ml). The organic layer is dried over MgSO ₄ and concentrated to give 2- (3'-nitrophenyl) -5- (p-tolyl) -1,3,4-oxadiazole in the form of a yellow solid (1.12 g, 87 %).
¹ H NMR (CDCl ₃ ): δ 2.47 (s, 3H), 7.39 (d, 2H), 7.76 (t, 1H), 8.07 (d, 2H), 8.42 (d , 1H), 8.80 (d, 1H), 8.95 (s, 1H).

To a solution of 2- (3'-nitrophenyl) -5- (p-tolyl) -1,3,4-oxadiazole (1.00 g, 3.56 mmol) in CCl ₄ (25 ml), NBS (0 , 43 g, 3.74 mmol) are added and the mixture is heated under reflux. After 24 h the solution is concentrated and the residue is taken up in chloroform (100 ml) and washed with a saturated NaHCO ₃ solution (50 ml) and a saline solution (50 ml). The organic layer is dried over MgSO ₄ and concentrated to give 2- (3'-nitrophenyl) -5 - [(p-bromomethyl) phenyl] -1,3,4-oxadiazole in the form of a light brown solid (0.69 g, 83%).
¹ H NMR (CDCl ₃ ): δ 4.55 (s, 2H), 7.59 (d, 2H), 7.78 (t, 1H), 8.16 (d, 2H), 8.45 (d , 1H), 8.52 (d, 1H), 8.96 (s, 1H).

To a suspension of 2- (3'-nitrophenyl) -5 - [(p-bromomethyl) phenyl] -1,3,4-oxadiazole (0.50 g, 1.39 mmol) in warm EtOH (25 ml) An excess of a dimethylamine / EtOH solution ( ^∼ 19 w / w%, 3 ml) is added and the mixture is stirred at room temperature for 12 h. The solution is then concentrated and the residue is taken up in chloroform (30 ml) and washed with a saturated NaHCO ₃ solution (30 ml) and a saline solution (30 ml). The organic layer is dried over K ₂ CO ₃ and concentrated, where a brown oil is obtained which is chromatographed on a silica gel column, eluting with 10% MeOH / CHCl ₃ and the title compound being in the form of a light brown solid obtained (0.22 g, 49%).
¹ H NMR (CDCl ₃ ): δ 2.25 (s, 6H), 3.52 (s, 2H), 7.54 (d, 2H), 7.77 (t, 1H), 8.12 (d , 2H), 8.40 (d, 1H), 8.54 (d, 1H), 8.95 (s, 1H).

Following the procedure described in the previous examples also made the following connections.  

Table I

organisms

Three strains of Candida (Candida parpsilosis, Candida tropicalis, Candida albicans-ATCC 36082) and Cryptococcus neoformans for the An catch test used. Then active compounds against Flucona zol-resistant Candida albicans, Candida krusei, and Torulopsis glabrata Cryptococcus neoformans together with Sporothrix shenkii and Aspergillus flavus tested in the second round of testing. All ver in this investigation Clinical strains used were clinical microbial blood culture isolates logistics labs at Harbor-UCLA Medical Center, Torrance, California. The Or ganisms were grown on a Sabouraud Dextrose Inclined Agar at 4 ° C tet. Singlet suspensions were used for each experiment Organism produced by growing the yeast overnight at 27 ° C on a spinning drum in a yeast nitrogen base broth (YNB) with Ami nonacids (Difco, Detroit, MI), at pH 7.0 with 0.05 M morpholine propane sulfonic acid right (MOPS). The suspension was then centrifuged and twice at 0.85 % NaCl washed. This was followed by an ultrasound treatment from gewa cell suspension for 4 s (Branson Sonifer, Model 350, Danbury, CT). The singlet blastopores were counted in a hemocytometer and counted the desired concentration is set in 0.85% NaCl.  

Antifungal activity

The antifungal activity of the compounds and fluconazole against the Candida and Cryptococcus strains was determined using a modification of a broth micro-dilution technique. The test compounds were diluted in DMSO to a ratio of 1.0 mg / ml and then in the YNB broth to 64 µg / ml, pH 7.0, with MOPS (fluconazole was used as a control). This served to get a working solution for each connection. Using a 96-well spotting plate, wells 1 and 3 to 12 were made with a YNB broth, then 10-fold dilutions of the linking solution in wells 2 to 11 were made (the concentration ranges were 64 to 0.125 µg / ml ). The deepening 1 served as a sterility control and blank for the spectrophotometric determinations. The depression 12 served as a growth control. The microtiter plates were inoculated 2 to 11 in each of the wells (the final inoculum size was 10 ⁴ organisms / ml). The inoculated plates were incubated at 35 ° C for 48 hours. By measuring the absorbance at 420 nm (Automatic Microplate Reader, DuPont Instruments, Wilmington, DE) after stirring the plates for 2 minutes with a vortex mixer (Vorte-Genie 2 Mixer, Scientific Industries, Inc., Bolemia, NY) MIC values determined spectrophotometrically. The MIC endpoint was defined as the lowest drug concentration that resulted in a growth decrease of approximately 50% (or more) compared to the control well. In the turbidity test, this was defined as the lowest drug concentration at which the turbidity occurring in the well was <50% of the control (IC ₅₀ ). The minimum cytolytic concentrations (MCC) were determined by subculturing all wells of the 96 well plate on a Sabouraud Dextrose Agar (SDA) plate and incubating for 1 to 2 days at 35 ° C and viability was checked.

The following Table II shows the antifungal activities of a selected An number of examples.  

Table II

Claims (20)

1. Compound of the formula
in which mean:
Ar is phenyl, thienyl or pyridyl which is substituted by R ¹ and R ² ;
R ¹ and R ² , which are the same or different, are hydrogen, halogen, alkyl, al kenyl, alkynyl, aryl, alkoxy, aryloxy, alkylthio, amino, hydroxy, cyano, nitro, carboxy, aminocarbonyl or aminosulfonyl, alkylamino, dialkylamino, acy lamino, dialkylaminosulfonyl or alkylaminosulfonyl or in which R ¹ and R ² together form -O- (CH ₂ ) -O-, in which n is an integer with the value 1 or 2;
R ³ and R ⁴ , which are the same or different, are hydrogen, alkyl, which may optionally be substituted by amino, alkylamino, dialkylamino, hydroxy, cyano, carboxy, alkenyl, alkynyl or acyl or in which R ³ and R ⁴ together - (CH ₂ ) _m -Q- (CH ₂ ) _{m '} -, where Q is selected from CH ₂ , O, S (O) _n or NR ⁷ , where n is an integer with the value 0, 1 or 2 stands; R ^{7 stands} for lower alkyl and m and m 'stand for integers with the value 2, with the proviso that if Q stands for CH ₂ , m' can also have the value 1;
R ^{5 is} H, halogen, OR, OH, NO ₂ , NH ₂ and NHCOR, where R is alkyl, lower alkyl or aryl;
XN, O or S,
YN or S;
with the proviso that if X is O or S, then Y must be;
ZN or CR ⁸ , in which R ^{8 represents} hydrogen, halogen, lower alkyl or alkoxycarbonyl,
with the proviso that X, Y and Z cannot all mean N at the same time;
VR ³ R ⁴ heterocyclic rings selected from pyrrole, imidazole, 1,3,4-triazole-1,2,4-triazole and pyrazole, which are bonded via the nitrogen atom;
VN, O or S, and
p has a value from 1 to 3;
as well as their non-toxic, pharmacologically acceptable salts. 2. A compound according to claim 1 of the formula
wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , p and V are each as defined in claim 1 and R ^{6 represents} hydrogen, halogen, carboxy, alkoxycarbonyl, lower alkyl, hydroxy and lower alkoxy,
as well as their non-toxic, pharmaceutically acceptable salts. 3. A compound according to claim 1 of the formula
wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , p and V are as defined in claim 1, and their non-toxic, pharmaceutically acceptable salts. 4. A compound according to claim 1 of the formula
wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , p and V are as defined in claim 1, and their non-toxic, pharmaceutically acceptable salts. 5. A compound according to claim 1 of the formula
wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , p and V are as defined in claim 1, and their non-toxic, pharmaceutically acceptable salts. 6. A compound according to claim 2 of the formula
wherein R ¹ , R ² , R ³ , R ^{4 are} as defined in claim 1, and their non-toxic, pharmaceutically acceptable salts. 7. A compound according to claim 4 of the formula
wherein R ¹ , R ² , R ³ , R ^{4 are} as defined in claim 1 and X is O or S, and their non-toxic, pharmaceutically acceptable salts. 8. A compound according to claim 5 of the formula
wherein R ¹ , R ² , R ³ , R ^{4 are} as defined in claim 1, and their non-toxic, pharmaceutically acceptable salts. 9. Azole according to claim 1, selected from the group consisting of
in which mean:
A _R selected from pyridyl, halogen-substituted pyridyl and
wherein R ^{8 is} hydrogen, halogen, nitro, amino, trifluoromethoxy, pyrrolyl, lower alkoxy, trifluoromethyl, cyano, lower alkynyl and trimethylsilyl-lower alkynyl and R ^{9 is} hydrogen, nitro, lower alkoxy or cyano;
XS or O;
Y is CH or N;
Z CH or N;
B lower alkylene or lower alkynylene;
D SR ¹⁰ , OR ¹¹ or N (R ¹² R ¹³ ), wherein R ^{10 is} lower alkylaminoalkyl; R ^{11 is} lower alkenyl, lower alkynyl or lower alkoxyalkyl; R ¹² and R ¹³ , which are the same or different, represent hydrogen, lower alkyl, lower alkenyl, lower alkynyl, furfuryl, lower alkoxyalkyl, lower res cycloalkyl, lower dialkylaminoalkyl, hydroxy-lower alkyl, lower alkylaminoalkyl, mononuclear lower alkyl, lower alkylaminoalkylcarbonyl or wherein R ¹² and R ¹³ together can form -CH ₂ CH ₂ N (R ¹⁴ ) CH ₂ CH ₂ - or -CH ₂ CH ₂ SCH ₂ -CH ₂ -, wherein R ^{14 is} lower alkyl; and
R ^{15 is} hydrogen, nitro, amino, lower alkanamido or hydroxy;
as well as its non-toxic, pharmacologically acceptable salts. 10. Azole according to claim 9 of the formula
in which mean:
R ^{8 is} hydrogen, halogen, nitro, amino, trifluoromethoxy, pyrrolyl, lower alkoxy, trifluoromethyl, cyano, lower alkynyl, trimethylsilyl-lower alkynyl; and
R ^{9 is} hydrogen, nitro, lower alkoxy or cyano;
R ¹² and R ¹³ , which are the same or different, are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, furfuryl, lower alkoxyalkyl, lower res cycloalkyl, lower dialkylaminoalkyl, hydroxy-lower alkyl, lower alkylaminoalkyl, mononuclear lower alkyl, lower-alkylaminoal kylcarbonyl or in which R ¹² and R ¹³ together can form -CH ₂ CH ₂ N (R ¹⁴ ) CH ₂ CH ₂ - or -CH ₂ CH ₂ SCH ₂ -CH ₂ -, wherein R ^{14 is} lower alkyl;
R ^{15 is} hydrogen, nitro, amino, lower alkanamido or hydroxy; and
n is an integer from 1 to 3;
as well as its non-toxic, pharmacologically acceptable salts. 11. Thiazole according to claim 10 of the formula
in which mean:
R ^{16 is} hydrogen, halogen, nitro, lower alkoxy, cyano, trifluoromethyl or lower alkyl;
R ^{17 is} hydrogen, nitro, halogen or cyano;
R ¹⁸ and ¹⁹ , which are the same or different, are hydrogen, lower alkyl, lower alkenyl, lower lower alkylamino alkyl, lower hydroxy alkyl and lower alkylaminoalkyl; and
R ^{20 is} hydrogen or hydroxy,
as well as its non-toxic, pharmacologically acceptable salts. 12. Azole according to claim 9 of the formula
in which mean:
XS or O;
R ^{21 is} selected from hydrogen and lower alkoxy;
R ^{22 is} selected from hydrogen and nitro; and
R ²³ and R ²⁴ lower alkyl,
as well as its non-toxic, pharmacologically acceptable salts. 13. Azole according to claim 9 of the formula
in which E represents SR ²⁶ or NR ²⁷ R ²⁸ , in which R ²⁶ denotes lower-alkylamino-alkyl and R ²⁷ and R ²⁸ , which are the same or different, mean lower alkyl and lower alkenyl,
as well as its non-toxic, pharmacologically acceptable salts. 14. [(Allylaminomethyl) phenylthiazole-2- (4'-nitrophenyl) -4- [4 "- (N-methyl-N- Allylaminomethyl) phenyl] thiazole. 15. 2- (3'-nitrophenyl) -4- [4 "- (N-methyl-N-allylamino-methyl) phenyl] thiazole. 16. 2- (4'-Methoxy-3-nitrophenyl) -4- [4 "- (dimethylaminomethyl) phenyl] thiazole. 17. 2- (4'-methoxy-3-nitrophenyl) -4- [4 "-N-methyl-N-allylaminomethyl) phenyl] - thiazole. 18. Pharmaceutical composition containing an effective amount of one Compound according to claim 1 in combination with a pharmaceutically acceptable contains tablen carrier. 19. A method of treating a fungal infection (fungi infection) that occurs around comprises administering an effective amount of the compound according to the method saying 1 in a unit dosage form to a mammalian host. 20. A process for the preparation of the compounds according to claim 1, wherein the process schemes described are applied.