NO891293L - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE IMIDAZOLE AND TRIAZOL DERIVATIVES. - Google Patents

Description

The invention relates to methods for the production of new 2,3,4-substituted imidazoles and 3,4,5-trisubstituted 1,2,4-triazoles which can be used as pharmaceuticals.

The new compounds have the formula

where

A stands for N or CH;

B for a 1- or 2-membered ring part of a mononuclear or polynuclear aromatic or heteroaromatic ring system, especially a system where B means CH=CH, S, 0, NR16;

Q, Q\ Q", Q'"

stands for a single bond or C₁-C₂ alkylene,

Q also for 0 or NR16;

R1 for

where

R4, R5: H, halogen, R11(0R117aryl, O-aryl, aralkyl, O-aralkyl, NiRuJj,

R4 and R5 together also stand for an optionally substituted fused C5-C7 cycloalkene ring, or fused benzene ring, or a group

-N=CH-NH-, -N=CH-CH=CH-, -0-CH2-CH2-, -0-CH2-CH2-CH2-, 0-(CH2) 1-3-0-, -NH -CO-NH-, -N=CH-CH=N-, -HN-C0-C(R16)2-0-, -HN-CO-0-, -NH-C0-CH2, -HN-C0- CH=CH-, -HN-C0-CH2-CH2-;

which is bonded to C atoms adjacent to the benzene ring;

R6: H, halogen, R11#0R1X or aryl;

R7: H, halogen, RX1, ORn, aryl or aralkyl;

R8: H, halogen, R11;0R117 aryl, aralkyl, N(RU)2,

R7 and R8 together also a condensed optionally substituted C5-C7 cycloalkene or benzene ring,

R9, R10: H, halogen, R11#0R11; N(<R>11)2, aryl, O-aryl,

aralkyl, 0-aralkyl,

Rg and R10 together also stand for an optionally substituted fused C5-C7 cycloalkene or benzene ring;

D: S, 0, NR16;

E, E<1>, E", E<1>":

CH, N, where in the case of Group III, not more than two, and in the case of Group IV, not more than three of the symbols E - E'" stand for N;

Rii= H, C^-C^-alkyl, which may be interrupted by oxygen or substituted with up to 5 halogen atoms, N(R16)2, aryl, O-aryl, a C3-C7 cycloaliphate

or an N-heterocycle, which may be attached to

the alkyl group via the ring nitrogen, and as further heteroring members may contain 0, S or NR16; alkenyl or alkynyl with a total of up to 6 C atoms; R2 stands for H, OH, O-acyl (with up to 7 C atoms), a saturated or unsaturated aliphatic residue with up to 8 C atoms, which may be interrupted by 0-, S- or NR16- and be substituted by up to 5 halogen atoms, OH, O-acyl, oxo, aryl or O-aryl, or also be bonded via oxygen to imidazole or the triazole ring; for an optionally via R16, OH, oxo, N(Ri6)2/substituted, saturated or unsaturated, optionally via oxygen or C1-C4-alkylene, C3-C7-cycloaliphatic ring bound to imidazole-resp. the triazole ring; or for a group (CH2)n-NRaRb(n=0, 1, 2 or 3); Ra °9 Rb can be H, or a saturated or unsaturated aliphatic residue with up to 6 C atoms which can optionally be interrupted by oxygen and which can also be OH- or N(Ri6)2-substituted; Ra can also stand for a C3-C7 cycloaliphatic residue; the entire group NRaRbogså for a 5-7-membered ring which may contain 0, S or NR16 as additional ring members; R3 stands for a mononuclear or polynuclear, optionally substituted, preferably, aromatic carbocyclic or nitrogenous heterocyclic residue, where the latter may be bound to -Q'"-Y- over a nitrogen or carbon atom, especially for

where

G: is S, O, CH, CH=CH, N=CH, CH=N, N=N, NR16;

L, L* : is N, CR16;

R 12 : is H, (0) (C 1 -C 4 -alkyl), aryl, O-aryl,

aralkyl, halogen, OH,

R13: is H, (0) q^-(C^C^)alkyl), where the respective alkyl chains may be substituted with OH or up to 5 times with halogen, or is alkenyl or alkynyl with up to 6 C atoms or

halogen, R12 and R13 together also form an optionally substituted fused benzene ring,

R14: is H, halogen, CN, OH, (0)0_1-(C1-C4-alkyl) (where the alkyl group may be substituted with up to 5 halogen atoms), N(R16)2, alkenyl or alkynyl radicals with up to 6 C- atoms, CO-(C1-C4-alkyl), CO-aryl, aralkyl, aryl, O-aryl, a residue of formula III or IV;

R15: is H, halogen, OH, (O)O_!-(C1-C6 alkyl),

optionally substituted with OH or with up to 5 halogen atoms, R14 and R15 together can also form an optionally substituted condensed homocyclic or heterocyclic 5- to 7-ring, under which up to two ring members can be heteroatoms from the group N, NR16, 0 and S;

R 16 : is H, C 1 -C 4 alkyl;

R 17 stands for H, (O)O_1-C1-C4-alkyl, halogen;

X-Y for a single bond, a double bond bridging group of formula C0NR16, CSNR16, C(NH)NR16, NR16C0, S02NR16NR16S02, C0NR16NR16, NR16CONR16, NR16C(NR16)NR16, NR16C0NR16NR16, CO (CH2 ) 1_3NH, NH(CH2)1_3C0, S02( CH2)i-3NH, NH( CH2 ) 1_3S02 , and

when the residue R3 is connected to Q"<1> via a carbon atom and at least one of the groups Q" and Q"'

stands for a single bond, also CO or 0.

The compounds may optionally exist in the form of separate stereoisomers and their mixtures and/or acid addition salts.

Preferably, the symbols within the definition given above have the following meaning: B: CH=CH, S, NR 16 or 0;

R1: a group of formula II, wherein

R 4 , R 5 , R 6 mean H, C 1 -C 4 alkyl,

C1-C4-Alkoxy or Halogen,

R4 in addition to aryl, aralkyl, aryloxy or N(R16)2 as well as C5-C12-alkyl or -alkyloxy when R5 and R6 are H, furthermore R4 and R5 together can constitute condensed C5-C7-cycloalkene, 0-(CH2)1_3-0 or N=CH- NH (bonded to the adjacent C atom) and, when R6 is hydrogen, also a fused benzene ring;

a group of formula III, wherein

D has the above meaning, where at most one of the symbols E, E', E", E<1>" means N and the others are CH;

R7, R8 is H, C1-C6 alkyl,

C1-C4-Alkoxy, halogen, furthermore when R8 is H, R7 can also mean C5-C12-alkyl or aryl, R7 and R8 together also mean a fused C5-C7 cycloalkene or benzene ring;

a group of formula IV, where no more than two of the symbols E, E', E", E"' stand for N;

R9, R10 means halogen, R16, 0R16, N(R16)2,

R9 also means aryl, O-aryl, aralkyl and R9 and R10 together can also stand for a fused C5-C7 cycloalkene ring or benzene ring;

R2: is H, OH, a saturated or unsaturated aliphatic residue with up to 8 C atoms, C3-C6 cycloalkyl, up to five halogen-substituted C1-C3 alkyl or CH30CH2CH2,

R3: is a group of formula V, V, V", V", VII or IX,

where

G, L, L<1>, R16 and R17 have the meaning indicated above;

Rn: is R16;

Ri2: is R16, aryl or halogen,

R13: is R16, alkenyl with up to 4 C atoms,

R12 and R13 together can also mean a fused benzene ring;

R14: is R16, halogen, CN, CF3, CO-(C1-C4-alkyl),

OR 16 ;

R15: is R16, halogen or 0R16;

R4: has the above-mentioned preferred meaning;

A, Q, Q', Q", Q'" and XY are defined as above.

If the compounds produced according to the invention comprise a pyridine ring, especially in R3, the nitrogen atom in this may be present in quaternary form. As an additional group, the N atom carries a lower alkyl or aralkyl residue. In this connection, C1-C4-alkyl and benzyl must be emphasized, so that there can be, for example, compounds which

where A has the above meaning, Alk e.g. is CH3, n-C3H7 and R2 have the previously stated meanings, e.g. 5-bromo- or 5-methylthienyl or 3-chloro-, 3,5-dichloro- or 3,5-dimethoxyphenyl.

Within the scope of the definitions given above, connections where

A and D have the above meaning;

B stands for CH=CHor S;

Q and Q' form a single bond or CH2;

Q" is C 1-03 alkylene, but preferably a single bond;

Q'" is a single bond or, if XY is CO, also CH2; Rx stands for groups II and III, where

R 4 , R 5 and R 6 have the above-mentioned preferred meanings, likewise D, E, E' , E", G, L, L", R 3 , R n , R 14 / Ri 5 / Ri 6 /

R 7 , R 8 is H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, R 8 also aryl, R 7 and R 8 together can also form a fused benzene ring or C 5 -C 7 cycloalkene ring;

R 2 stands for H, C 1 -C 8 alkyl, cyclopropyl, phenyl, CF 3 or

allyl;

R3 stands for one of the groups V, V, V", V", VII or IX, where V is preferably

R12 stands for R16, phenyl, halogen;

R13 stands for R16 or together with R12 also for a condensed benzene ring;

R17 is H, CH3, OCH3 or Cl,

XYQ1 " stands for CONR16, NR16CO, S02NR16, NR16S02, NR16CONR16,

CO(CH2)1_3-NH, COCH2or 0.

The new compounds can exist as free bases or as acid addition salts.

In addition to this, the following connections must be highlighted:

A: CH, N; B: CH=CH, S; Q, Q', Q": a single bond, CH2;

R 1 : C 1 -C 4 alkyl, Cl, Br, C 3 -C 7 cycloalkyl;

Rk: fused C5-C6 cycloalkene or benzene ring;

K n , R o :

H, Cl, CH3, C1-C4-Alkoxy, CF3, N(R16)2, and if RQ is H, Rm and Rn together are also a fused benzene ring or OCH20, bonded to adjacent C atoms;

R16: H, C1-C4 alkyl, N(R16)2 primarily N(CH3)2 and N(C2H5)2;

R 2 : CH 3 , C 2 H 5 ;

XY: CONH, NHCO, SO 2 NH, NHCONH, COCH 2 , CH 2 O;

R3:

where one of the symbols L,L<1>, L" stands for N and the others for CH and Rp are H or CH3.

In addition, the following connections should be highlighted:

where

R1: naphthyl or

A: N or CH;

R'i: C1-C4-alkyl#Cl, Br,

R'k: fused cyclopentene or cyclohexene ring;

R'm: H, Cl, CH 3 O, CF 3 , CH 3 ;

R'n: H, CH 3 O, Cl, CH 3 ; both together form OCH20 wood

neighboring C atoms;

R'O: H, CH 3 O, CH 3 .

The following applies to the above definitions:

To the extent that symbols occur several times in a formula, they may have the same or different meanings.

The hydrocarbon chains may, unless otherwise stated, be unbranched or branched. "Halogen" means fluorine, chlorine, bromine and also iodine. Fluorine and chlorine should be highlighted as halogen atoms in aliphatic residues. Corresponding residues are e.g. CF3, OCF3, CF2CF3/CCIF3. "Aryl" is preferably phenyl or naphthyl. "Heteroaryl" should also be considered such residues which are composed of aromatic and heteroaromatic rings, e.g. quinoline, quinazoline. "Aralkyl" refers to aryl or hetero-aryl groups which are linked via a straight chain or branched alkylene bridge.

The aromatic, resp. heteroaromatic groups may be single or polysubstituted and may each have the same or different substituents. Substituents are halogen, ^-4-alkyl, C1-C4-alkoxy (which may also be halogen-substituted), N(R16)2, N02, lower alkenyl or alkynyl residues, CN, aryl, C3-C7-cycloalkyl, C00R16, CON (R16)2, SO2N(R16)2, O-aryl, O-aralkyl, NHS02-(C!-C4-alkyl) , OH, NR16C0R16(where R18 denotes an aliphatic or cycloaliphatic residue with up to 7 C atoms, N( R 16 ) 2 or H. By "lower" are meant residues with up to 6, preferably up to 4, C atoms.

While halogen, alkyl or alkoxy can occur as substituents up to three times on a ring (exceptionally, phenyl is also possible with 4 or 5 substituents), the other substituents usually occur only once or twice. The total number of substituents on one ring is generally no more than 3.

In the case of halogen atoms, optionally in admixture with alkyl or olefinic acid residues, up to 5 substituents may optionally also occur on a ring. The substitution possibilities can of course be reduced by the heteroatom in the ring. When, for example, group IV means the rest

only one substituent (ie R9) can occur.

As substituents according to what is stated above, the following should be mentioned in particular: F, Cl, Br, CH3, C2H5, t-C4H9, n-C3-H7, i-C3H7, OCH3, OC2H5, CF3, 0CF3, benzyl, cyclopropyl , phenyl, allyl, propargyl, C00CH3, COOC2H5, CON(C2H5)2, SO2N(CH3)2/ NHS02CH3, NHC0CH3, NHCONH2, phenoxy.

Alkenyl and alkynyl residues are usually bound via a saturated C atom.

To the extent that R16 is included in the groups indicated for X-Y, the meaning of this is preferably H.

If RX1 occurs as a substituent in groups II, III

and IV next to other substituents, the chain length is preferably limited to 4 members. If RX1 comprises a heterocycle, this is a 5- to 7-membered, preferably non-aromatic, ring, e.g. pyrrolidine, piperidine, piperazine, morpholine, under which these rings can be e.g. lower alkyl-substituted.

Typical representatives of groups II to IV should be mentioned:

phenyl, benzyl, 3-methoxy, dimethylamino or 3-chlorophenyl, 3,5-dimethoxy, 3,5-dimethyl, 3-methoxy-5-trifluoromethyl, trimethoxy or 3,5-dichlorophenyl; thienyl-2-yl and 5-lower alkyl, 5-phenyl, 4-cyclopentyl, 5-cyclohexyl, 5-chloro or 5-bromothien-2-yl, 5-allyltien-2-yl;

where these ring systems can optionally also contain further substituents, especially halogen atoms, lower alkyl and alkoxy groups, as well as N(R16)2. Representative groups for R2 are lower alkyl and alkoxy residues, C3-C6 cycloalkyl groups, halogen-substituted alkyl and alkoxy groups such as CF3, OCF3, C2F5,

OC2F5, also CH2N(E16)2 and e.g. methoxyethyl, ethoxyethoxy, allyl and propargyl.

The group R3 can be particularly diverse. Some simpler ring systems from which R3 is derived should be mentioned: pyrrole, pyrazole, N-methylpyrrole, imidazole, thiazole, triazole, tetrazole, 1,2,4- and 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazole, among which these the rings can also be substituted, e.g. with lower alkyl groups or halogen atoms.

In addition, the following must be mentioned:

phenyl, phenylphenyl, phenoxyphenyl, under which these residues may be substituted, e.g. with lower alkyl, lower alkoxy, (NR 16 ) 2 , CF 3 , halogen; residues derived from condensed systems, such as theophylline, benzimidazole,

The condensed systems can also contain additional substituents, such as e.g. OH, CH3, OCH3, Cl.

If the groups II to X<1> constitute fused ring systems, they can also be bound via the fused ring.

The new compounds can be produced according to known methods. Such methods are described for 1,2,4-triazoles, for example, in "Chemistry of Heterocyclic Compounds", Vol. 21_, S. 34 ff and 66 ff (J. A. Montgomery (Ed.), "1,2,4-Triazoles", New York, Willey (1981) and for the imidazoles in Rodd's Chemistry of Carbon Compounds, 2nd Edition, Vol. IV, Part C, pp. 119 ff (M.F. Ansell, New York, Elsevier (1986)).

The procedures are detailed below:

1. Compounds with formula

is obtained by heating acyl amide razones of formula

where R1#R2, R3, B, Q, Q', Q", Q"', X and Y have the meanings given above and, as indicated, R1 and R2Qn as in the other formulas, can exchange positions, without solvent or in an inert solvent. The reaction temperature is preferably 150-200°C. As a solvent

those that have a boiling point in the aforementioned range are suitably used, so that turnover can take place during reflux cooling.

Compounds of formula XI can e.g. is achieved in the following way:

(a) Imidic acid esters (XII) are reacted with carboxylic acid hydrazides (XIII) to carboxylic acid hydrazone esters (XIV), which with the amino compounds (XV) give acylamidorazones.

In the formulas given above, R stands for a lower alkyl residue, the other symbols have the meanings given above. R1 and R2Q can, as before and in the following, be interchanged, i.e. instead of R1 in the formulas R2Q can be written, while instead of R2Q correspondingly R: is written. (b) Corresponding amidrazines are reacted with carboxylic acid halides, carboxylic acid anhydrides, resp. orthoesters: (c) Thioamides, resp. S-methylisothiamides, resp. chlorimides are reacted with hydrazides: 2. Compounds of formula Ia, resp. Ib, where A stands for CH, is obtained by reacting N-chloramidines XXI with enamines, resp. silylenol ethers XXII:

The turnover takes place in inert organic solvents, e.g. chlorinated hydrocarbons such as chloroform, in the presence of a tertiary base, e.g. pyridine, in the temperature range 30-60°C. The N-chloramidines XXI are obtained from the corresponding amidines and N-chlorosuccinimide. The enamines, resp. silylenol ethers XXI can be obtained from corresponding aldehydes with amines, resp. silyl chlorides. 3. Compounds with formula Ia, resp. Ib, where H stands for CH, is obtained by reacting substituted amides XXIII with amines of formula XXIV in the presence of PC13 on heating,

The reaction takes place in an inert solvent such as chlorobenzene, e.g. at 100 to 150°C. The amides (XXIII) can, for example, be obtained from corresponding acid chlorides and α-amino ketones.

4. Compounds of formula Ia/Ib, where -X-Y- means CONH, CSNH, C0(CH2)1_3NH, SO2NH or SO2(CH2)^NH, can be obtained from compounds XXV and amines XXVI:

In this case, A, B, R1; R2 and R3 have the meanings given above, X' stands for CO, CO(CH2)1_3, SO2 or SO2(CH2)1_3, SO2 and Z for OH, halogen, lower alkoxy, lower acyloxy. The turnover takes place under normal conditions, e.g. as described in Houben-Weyl VIII, 653ff and E5, 941ff.

5. For the preparation of compounds of formula I, where X-Y-means NH-CO or NH-CO-NH, amines XXVII can be reacted with carboxylic acids, resp. carboxylic acid derivatives XXVIII, resp. with the isocyanate XXIX by usual methods according to procedure 4:

A, B, Q, Q", Q", Q"', r1#R2, R3 and Z below have the meanings indicated above.

The starting materials for methods 4 and 5 are prepared according to usual methods. XXV and XXVII can e.g. is achieved analogously to methods 1 to 3.

If desired, bases can be obtained according to methods 1 to 5,

in the usual way are transferred in acid addition salts, or first obtained salts are transferred in free bases.

The compounds produced according to the invention have PAF-antagonistic action. As is known, PAF (platelet-activating factor) is the phospholipid acetyl-glyceryl-ether-phosphoryl-choline (AGEPC), which is known as a potent lipid mediator, which is released from animal and human proinflammatory cells. Among this type of cells there are mainly basophilic and neutrophilic granulocytes, macrophages (from blood and tissue) and thrombocytes, which are involved in inflammatory reactions.

In pharmacological experiments, PAF exhibits bronchoconstriction, lowering of blood pressure, release of platelet aggregations as well as a proinflammatory effect.

These experimentally detectable effects of PAF point directly or indirectly to possible functions of this mediator in anaphylaxis, in the pathophysiology of bronchial asthma and in inflammation in general.

PAF antagonists are necessary both to elucidate pathophysiological functions of this mediator in animals and humans and to treat pathological conditions and diseases in which PAF is involved, especially inflammatory and allergic reactions. Examples of possible indications for a PAF antagonist are inflammatory processes in the trachea, bronchial tree (acute and chronic bronchitis, bronchial asthma) or the kidney (glomerulonephritis), joints (rheumatic arthritis), anaphylactic conditions, allergies and inflammation in mucosal areas (rhinitis, conjunctivitis) and in the skin (e.g. psoriasis), as well as in shock conditions due to sepsis, endotoxins and burns. Other important indications for a PAF antagonist are lesions and inflammation in the stomach and intestinal mucosa area, such as e.g. shock ulcer, ulcerative colitis, Crohn's disease, stress ulcer, in general peptic ulcer and especially ventriculi and duodenal ulcers;

obstructive lung disorders, such as bronchial hyperreactivity, lung infections, such as chronic bronchitis; cardiovascular diseases, such as polytrauma, anaphylaxis, arterio-sclerosis, intestinal inflammation, EPH-gestosis (edema-proteinuria-hypertension), diseases of the extracorporeal circuit, e.g. heart failure, heart attack, organ damage due to hypertension, ischemic diseases, inflammation and immunological diseases, immunomodulation in transplants of foreign tissue, for example rejection of kidney, liver and other transplants, immunomodulation in leukaemia. Metastases (e.g. in bronchial neoplasia), diseases of the CNS, such as e.g. migraine, multiple

sclerosis, endogenous depression, agarophobia (panic disorder). Moreover, the new compounds prove to be cyto- and organo-protective, e.g. for neuroprotection, e.g. in liver cirrhosis, DIC (disseminated intravascular coagulation).

Side effects of drug therapy, e.g. anaphylactoid circulatory reactions, contrast agent complications, side effects of tumor therapy;

incompatibility of blood transfusions; fulminant liver failure

(CCl4 intoxication)

Amanita phalloides intoxication (fly poisoning)

Symptoms of parasitic diseases (e.g. intestinal worms) Autoimmune diseases (e.g. Werlhof's disease);

Autoimmune hemolytic anemias,

autoimmune glomerulonephritis,

Hashimoto's thyroiditis

primary myxoedema

pernicious anemia

autoimmune atrophic gastritis

Add i s on's disease

juvenile diabetes

Goodpasture Syndrome,

idiopathic leukopenia,

primary biliary cirrhosis

active or chronic aggressive hepatitis (HBsAg-neg.),

ulcerative colitis and systemic lupus erythematosus (SLE), idiopathic thrombocytopenic purpura (ITP).

Immune function in AIDS, diabetes, juvenile diabetes, diabetic retinopathy, polytraumatic shock, hemorrhagic shock; PAF-associated interactions with tissue hormones (autocoid hormones), lymphokines and other mediators.

They can also be used in combinations where PAF antagonists are suitable, such as e.g. with S-adrenergics, parasympatholytics, corticosteroids, antiallergics, secretolytics. In combination with TNF (Tumor Necrosis Factor), a better tolerability of TNF is achieved (removal of disturbing side effects); TNF can therefore also possibly be used in higher doses than when used alone.

(By "combination" here is also meant the use of both active substances in separate preparations and with a certain time

space). By the simultaneous use of the new compounds together with β-adrenergics, a synergistic effect can be achieved, e.g. in broncholysis.

As a measure of the PAF-antagonistic effect, the inhibitory concentrations (IC50) of the PAF-induced platelet aggregation are indicated here:

Compounds with formula

The new compounds can be administered topically, orally, transdermally, parenterally or by inhalation. The compounds are present below as active ingredients in normal forms of administration, e.g. in compositions which essentially consist of an inert pharmaceutical carrier and an effective dose of the active ingredient, e.g. such as tablets, dragees, capsules, wafers, powders, solutions, suspensions, inhalation aerosols, ointments, emulsions, syrups, suppositories.

The therapeutic and prophylactic dose depends on the nature and degree of the disease.

An effective dose of the compounds produced according to the invention, when used orally is between 1 and 100, preferably between 10 and 80 mg/dose, when used intravenously or intramuscularly between 0.001 and 50, preferably between 0.1 and 30 mg/dose. For inhalation, solutions containing 0.01 to 1.0, preferably 0.1 to 0.5% active substance, as well as powders and suspensions in condensed propellant gases are used.

Formulation examples

1. Tablets

The components are processed in the usual way into tablets with a weight of 600 mg. If desired, the active substance content can be increased or decreased and the amount of dextrose reduced or increased accordingly.

2. Suppositories

The components are processed in the usual way into suppositories with a weight of 1.7 g.

3. Inhalation powder

Micronized active ingredient powder (compound with formula I; Particle size approx. 0.5 to 7 mm) is filled onto hard gelatin capsules in an amount of 0.02 mg together with 10 mg of micronized lactose, and possibly together with suitable amounts of additional active ingredients. The powder is inhaled from ordinary inhalation devices, e.g. according to DE-A 3345 722.

4. Dosing aerosol

The mixture is refilled in standard aerosol dosing devices. The dosing device is set, for example, so that 0.05 ml of the mixture is released with each release.

Example 1

3-methyl-5-(5-methyl-2-thienyl)-4-[4-[N-(3-pyridyl)-carbamoyl]-phenyl]-4H-1,2,4-triazole

2.9 g acetic acid [2-(5-methyl-2-thenoyl)-hydrazonide] ethyl ester, m.p. 110-113°C (prepared from 5-methylthiophene carboxylic acid hydrazide, m.p. 102-104°C, by reaction with acetimidic acid ethyl ester hydrochloride), and 2.1 g of p-aminobenzoic acid-N-(3-pyridyl) -amide, m.p. 200-202°C (prepared from p-nitrobenzoyl chloride by reaction with 3-aminopyridine and catalytic reduction of the nitro compound (m.p. 182-184°C, with Raney nickel), was heated to 170-190°C for 2 hours The oily residue was dissolved in

150 ml of chloroform, the insoluble components filtered off, the chloroform phase was washed with dilute acetic acid and dilute ammonia solution, dried and evaporated. The residue was dissolved in 20 ml of ethyl acetate and cooled, after which the precipitated title compound (1.2 g; 32% of theory) was suctioned off and recrystallized from ethanol;

M.p.: 206-208°C.

Example 2

3-methyl-5-methyl-4-[4-[N-(3-pyridyl)-carbamoyl]-phenyl]- 4H- 1, 2, 4- triazole

1.7 g of 4-(4-carboxyphenyl)-3-methyl-5-phenyl-4H-1,2,4-triazole, m.p. >270°C (prepared from acetic acid-(2-phenyl-hydrazonide)-ethyl ester by reaction with p-aminobenzoic acid ethyl ester and hydrolysis of the ester (m.p. 140-142°C)), was slurried in 6.3 ml of dimethylformamide and 25 ml of tetrahydrofuran and added 0.91 ml of triethylamine. The solution was cooled to 10°C and with stirring added dropwise a mixture of 2.5 ml

tetrahydrofuran/10.59 ml chloroformic acid ethyl ester. After 30 minutes, the precipitated triethylamine hydrochloride was filtered off, sucked off, washed with 5 ml of tetrahydrofuran and the solution added with 0.58 g of 3-aminopyridine dissolved in 5 ml of tetrahydrofuran. The tetrahydrofuran was then distilled off, the residue heated for 11 hours to 80-90°C, the dimethylformamide distilled off, the residue dissolved in 100 ml of chloroform and washed once with water, dried and evaporated. The residue was dissolved in 10 ml of ethyl acetate and the precipitated title compound (1 g; 46% of theory) filtered off and recrystallized (mp. 194-196°C) from acetonitrile.

Example 3

3-methyl-4-[4-(1-imidazolyl)-acetamidophenyl]-5-(2-thienyl)-4H- 1,2,4-triazole

6.4 g of 4-(4-aminophenyl)-3-methyl-5-(2-thienyl)-4H-1,2,4-triazole (m.p. 226-228°C) [prepared from acetic acid[2-( 3-thenoyl)-hydrazonide]ethyl ester by reaction with 4-aminoacetanilide and hydrolysis of the amide (m.p. 210-212°C)] was reacted with 2.1 ml of chloroacetyl chloride under the addition of 2.2 ml of pyridine in 100 ml of ethylene chloride.

3.6 g of chloroacetyl compound (m.p. >280°C) was added portionwise to a mixture of 25 ml of dimethylformamide, 0.75 g of imidazole, 0.55 g of sodium hydride dispersion (approx. 55%) and stirred for 2 hours at 80 -100°C. The solution was then diluted with water and stirred for 30 minutes while adding 20 ml of ethyl acetate. The precipitated crystals were sucked off and recrystallized from methanol.

Yield 2.5 g (61% of theoretical);

Temp. 190-193°C (hydrate).

Example 4

1-[4-(N-pyridyl)carbamoyl]-2-methyl-5-(3,5-dimethoxy-phenyl)-imidazole 2 g 1-(4-carbethoxyphenyl)-2-methyl-5-(3,5 -dimethoxyphenyl)-imidazole [prepared from 3,5-dimethoxy-α-acetaminoacetophenone by reaction with 4-aminobenzoic acid ethyl ester], was hydrolyzed to the acid in 50 ml of ethanol and 20 ml of 10% caustic soda.

The acid was then refluxed in 500 ml of chloroform and 2 ml of thionyl chloride for 2 hours, after which the chloroform was distilled off and the acid chloride in 50 ml of dioxane was added to a solution of 2.5 g of 3-aminopyridine in 50 ml of dioxane. The solution was heated to 80°C for 30 minutes and then diluted with 200 ml of ice water. The product was extracted with chloroform and purified over a silica gel column (eluent, chloroform/ethanol, 8:2).

The title compound was then obtained in a yield of

0.6 g (26.5% of the theoretical);

Temp. 179-181°C (from chloroform/petroleum ether).

Example 5

4-[3-(3,5-dimethoxyphenyl)-5-methyl-4H-1,2,4-triazol-4-yl]-N-(3-pyridyl)benzamide

3,5-dimethoxybenzoic acid in chloroform was treated with thionyl chloride

at reflux temperature transferred into the acid chloride, which was then, under heating, reacted with 4-aminobenzoic acid ethyl ester in the presence of triethylamine to the amide, m.p. 133-135°C. During reflux treatment in toluene, the amide was reacted with phosphorus pentachloride. The reaction product in toluene was refluxed with acethydrazide and triethylamine. The reaction product was then isolated, dissolved in methanol, diluted caustic soda was added and boiled under reflux for 30 minutes. The solution was acidified and the reaction product isolated and recrystallized from dimethylformamide;

Temp. >250°C.

A cooled mixture of 4.25 g of the obtained acid in 70 ml of dimethylformamide and tetrahydrofuran (1:1) and 2 g of triethylamine was added dropwise to an excess of chloroformic acid ethyl ester in tetrahydrofuran and stirred further for approx. 1 hour. The precipitated triethylamine hydrochloride was suctioned off and 1.5 g of 3-aminopyridine was added to the solution and boiled under reflux for 1 hour. After removal of the solvent, an oily residue was obtained which was taken up in chloroform. The chloroform phase was washed with dilute caustic soda and dilute acetic acid, dried with sodium sulfate, after which a significant portion of the solvent was distilled off. Upon cooling, crystals were obtained which, after further purification, melted at 245°C; yield approx. 50% of the theoretical.

In a similar way as in the previous examples, the compounds in the following table can also be obtained:

Claims (6)

1. Process for the preparation of therapeutically active compounds of formula where A stands for N or CH; B for a 1- or 2-membered ring part of a single or multi-core aromatic or heteroaromatic ring system, especially a system where B means CH=CH, S, 0, NR 16 ; Q, Q\ Q", Q'" stands for a single bond or Ci-Ca-alkylene, Q also for 0 or NR16; Rx for where R4, R5: H, halogen, R11f0R11(aryl, O-aryl, aralkyl, 0- aralkyl, N(RX1)2, R4 and R5 together also stand for an optionally substituted fused C5-C7 cycloalkene ring, or fused benzene ring, or a group -N=CH-NH-, -N=CH-CH=CH-, -0-CH2-CH2-, -0 -CH2-CH2-CH2-, O-CC^J^s-O-, -NH-CO-NH-, -N=CH-CH=N-, -HN-C0-C(R16)2-0-, - HN-CO-O-, -NH-CO-CH2, -HN-CO-CH=CH-, -HN-CO-CH2-CH2-; which is bonded to C atoms adjacent to the benzene ring; R6: H, halogen, R1lf0RU or aryl; R7: H, halogen, R1X, ORn, aryl or aralkyl; R8: H, halogen, R1X, 0R11#aryl, aralkyl, N(RX1)2, R7 and R8 together also a condensed optionally substituted C5-C7 cycloalkene or benzene ring, R9, R10: H, halogen, RX1, 0RX1, N(RX1)2, aryl, O-aryl, aralkyl, 0-aralkyl, Rg and R10 together also stand for an optionally substituted fused C5-C7 cycloalkene or benzene ring; D: S, 0, NR16; E, E', E", E'": CH, N, where in the case of Group III, not more than two, and in the case of Group IV, not more than three of the symbols E - E'" stand for N; Rn: H, C 1 -C 4 -alkyl, which may be interrupted by oxygen or substituted with up to 5 halogen atoms, N(R16)2, aryl, O-aryl, a C3-C7 cycloaliphate or an N-heterocycle, which may be attached to the alkyl group via the ring nitrogen, and which further heteroring members may contain 0, S or NR16; alkenyl or alkynyl with a total of up to 6 C atoms; R2 stands for H, OH, O-acyl (with up to 7 C atoms), a saturated or unsaturated aliphatic residue with up to 8 C atoms, which may be interrupted by 0-, S- or NR16- and be substituted by up to 5 halogen atoms, OH, O-acyl, oxo, aryl or O-aryl, or also be bonded via oxygen to imidazole or the triazole ring; for an optionally via R16, OH, oxo, N(R16)2, substituted, saturated or unsaturated, optionally via oxygen or C1-C4-alkylene, C3-C7-cycloaliphatic ring bound to imidazole-resp. the triazole ring; or for a group (CH2)n-NRaRb(n=0, 1, 2 or 3), Ra and Rb can be H, or a saturated or unsaturated aliphatic residue with up to 6 C atoms which can optionally be interrupted by oxygen and which can also be OH- or N(Ri6 ) 2~ substituted; Ra can also stand for a C3-C7 cycloaliphatic residue; the entire group NRaRbogså for a 5-7-membered ring which may contain 0, S or NR16 as additional ring members; R3 stands for a mononuclear or polynuclear, optionally substituted, preferably, aromatic carbocyclic or nitrogenous heterocyclic residue, where the latter may be bound to -Q'"-Y- over a nitrogen or carbon atom, especially for where G: is S, O, CH, CH=CH, N=CH, CH=N, N=N, NR16; L, L' : is N, CR16; Ri2: is H, (O)O_x-(Cx-C4)-alkyl), aryl, O-aryl, aralkyl, halogen, OH, R 13 : is H, (O)O_1-(C 1 -C 4 )alkyl), where the respective alkyl chains can be substituted with OH or up to 5 times with halogen, or is alkenyl or alkynyl with up to 6 C atoms or halogen, R12 and R13 together also form an optionally substituted fused benzene ring, Ri4: is H, halogen, CN, OH, (O)q^-(Ci-C^alkyl) (where the alkyl group may be substituted with up to 5 halogen atoms), N(R16)2, alkenyl or alkynyl radicals with up to 6 C atoms, C0-(C1-C4 alkyl), CO-aryl, aralkyl, aryl, O-aryl, a residue of formula III or IV; Ri5: erH, halogen, OH, (O)q^-(Ci-C^alkyl), optionally substituted with OH or with up to 5 halogen atoms, R14 and R15 together can also form an optionally substituted condensed homocyclic or heterocyclic 5- to 7-ring, under which up to two ring members can be heteroatoms from the group N, NR16, 0 and S; R 16 : is H, C 1 -C 4 -alkyl; R 17 stands for H, (O)O_1-C1-C4-alkyl, halogen; X-Y for a single bond, a double bond bridging group of formula C0NR16, CSNR16, C(NH)NR16, NR16C0, S02NR16NR16S02, CONR16NR16, NR16C0NR16, N<R>16C(NR16)NR16, NR16C0NR16NR16, C0(CH2) 1_3NH, NH(CH2) 1_3C0, S02(CH2)1_3NH, NH ( CH2 ) i-3S02 , and when the residue R3 is connected to Q"' via a carbon atom and at least one of the groups Q" and Q"' represents a single bond, also CO or 0, optionally in the form of separate stereoisomers and their mixtures and/or acid addition salts and/or if R3 comprises a pyridine ring, in the form of quaternary compounds, where the further groups in the pyridinium structure are lower alkyl or aralkyl, characterized by a) acyl amide razones of formula where RlfR2/R3, B, Q, Q<1>, Q", Q'"7 X and Y have the meanings given above, heated without solvent or in an inert solvent, or that b) N-chloramidines XXI are reacted with enamines, resp. silylenol ethers XXII: or that c) substituted amides XXIII are reacted with amines of formula XXIV in the presence of PC13 upon heating, or that d) compounds XXV are reacted with amines XXVI: or that e) amines XXVII are reacted with carboxylic acids, resp. carboxylic acid derivatives XXVIII, resp. with isocyanates XXIX by usual methods according to method 4: (A, B, Q, Q', Q", Q'", RlfR2, R3 and Z have the meanings given above), and that bases obtained according to methods a) to e) are transferred in the usual way into acid addition salts, first obtained salts are transferred into free bases, and/or that quaternary compounds are prepared from such compounds where R3 comprises a pyridine ring, possibly in the usual way in the pyridine nitrogen with lower alkyl or aralkyl. 2. Process according to claim 1, for the production of compounds of formula Ia, for example Ib, where B: is CH=CH, S, NR16 or 0; R 1 : is a group of formula II, wherein R 4 , R 5 , R 6 mean H, C 1 -C 4 -alkyl, C1-C4-Alkoxy or Halogen, R4 in addition to aryl, aralkyl, aryloxy or N(R16)2 as well as C5-C12-alkyl or -alkyloxy when R5 and R6 are H, furthermore R4 and R5 together can constitute condensed C5-C7-cycloalkene, 0-(CH2)1_3-0 or N=CH- NH (bonded to the adjacent C atom) and, when R6 is hydrogen, also a fused benzene ring; a group of formula III, wherein D has the above meaning, at most one of the symbols E, E<1>, E", E'" means N and the others are CH; R7, R8 is H, C1-C4 alkyl, C1-C4-Alkoxy, halogen, furthermore when R8 is H, R7 can also mean C5-C12-alkyl or aryl, R7 and R8 together also mean a fused C5-C7 cycloalkene or benzene ring; a group of formula IV, where no more than two of the symbols E, E', E", E'" stand for N; Rg, R10 means halogen, R16, 0R16, N(R16)2, R9 also means aryl, O-aryl, aralkyl and R9 and R10 together can also stand for a fused C5-C7 cycloalkene ring or benzene ring; R2: is H, OH, a saturated or unsaturated aliphatic residue with up to 8 C atoms, C3-C6 cycloalkyl, up to five times halogen-substituted C1-C3 alkyl or CH3OCH2CH2, R3: is a group of formula V, V, V", V", VII or IX, where G, L, L', R16 and R17 have the meaning indicated above; Rn: is R16; R12: is R16, aryl or halogen, R13: is R16, alkenyl with up to 4 C atoms, R12 and R13 together can also mean a fused benzene ring; R14: is R16, halogen, CN, CF3, C0-(C1-C4-alkyl), OR 16 ; R 15 : is R 16 , halogen or 0R 16 ; R4: has the above-mentioned preferred meaning; A, Q, Q', Q", Q<1>" and XY are defined as above, characterized by corresponding output connections being used. 3. Process according to claim 1, for the production of compounds of formula Ia or Ib, where A and D have the above meaning; B stands for CH=CHor S; Q and Q<*>constitute a single bond or CH2; Q" is C 1-03 alkylene, but preferably a single bond; Q'" is a single bond or, if XY is CO, also CH 2 ; R: stands for groups II and III, where R4, R5 and R6 have the above-mentioned preferred meanings, likewise D, E, E', E", G, L, L", R3, Rn, R14, R15/R16/R7, R8 is H, C1-C4-alkyl, C1-C4-Alkoxy, R8 also aryl, R7 and R8 together can also form a fused benzene ring or C5-C7 cycloalkene ring; R 2 stands for H, C 1-0 3 alkyl, cyclopropyl, phenyl, CF 3 or allyl; R3 stands for one of the groups V, V,V", V", VII or IX, where V preferably is R12 stands for R16; phenyl, halogen; R13 stands for R16 or together with R12 also for a condensed benzene ring; R17 is H, CH3, 0CH3 or Cl, XYQ' " stands for CONR16, NR16C0, S02NR16, NR16S02, NR16CONR16, COCCHzJ^a-NH, COCH2or 0, characterized in that corresponding output connections are used. 4. Process according to claim 1, for the production of compounds with formula A: CH, N; B: CH=CH, S; Q, Q', Q": a single bond, CH2; Rx: R^: C1-C4-alkyl, Cl, Br, C3-C7-cycloalkyl; Rk: fused C5-C6 cycloalkene or benzene ring; Rm in Rn / Ro : H, Cl, CH3, C1-C4-Alkoxy, CF3, N(R16)2, and if R0 is H, Rm and Rn together are also a condensed benzene ring or OCH20, bonded to neighboring C atoms; Ri6: H, C1-C4-alkyl, N(R16)2 primarily N(CH3)2 and N(C2H5)2; R 2 : CH 3 , C 2 H 5 ; XY: CONH, NHCO, SO 2 NH, NHCONH, COCH 2 , CH 2 O; R3: where one of the symbols L,L',L" stands for N and the others for CH and Rp are H or CH3, characterized in that corresponding output connections are used. 5. Process according to claim 1, for the production of compounds with formula where Rx: naphthyl or A: N or CH; R'i: C1-d-alkyl, Cl, Br, R'k: fused cyclopentene or cyclohexene ring; R'm: H, Cl, CH 3 O, CF 3 , CH 3 ; R'n: H, CH 3 O, Cl, CH 3 ; both together form OCH20 wood neighboring C atoms; R'O: H, CH3O, CH3, characterized in that corresponding output connections are used. 6. Process according to claim 1, for the production of compounds with formula where A is CH or N, Rx means where R"a is C 1-4 alkyl, Cl or Br; R" 4 is H, CH 3 , OCH 3 , Cl, CF 3 ; R"5 is H, CH3, OHCH3, Cl; R"6 is H, 0CH3; R"12 is H, CH3, Cl, in the case of thiazole also a fused benzene ring, characterized in that corresponding output connections are used.