2-AMINO-HETEROCYCLES AND THERAPEUTIC USES THEREFOR

The invention relates to the use of 2-amino-heterocycles for the preparation of medicaments, in particular for the treatment of airway diseases and inflammatory diseases, new active compounds and process or for their preparation.

Leukotrienes are arachidonic acid metabolites produced by the 5-lipoxygenase pathway in activated phagocytes and are important mediators of bronchial asthma and acute inflammation. The pathophysiological importance of leukotrienes suggests that selective inhibitors of leukotriene synthesis may be useful anti¬ allergic and an ti -inflammatory therapeutic agents.

Urea,N,N-bis[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]- N'[[3,5-bis(l, ldimeth>'l- ethyl)-4-hydroxyphenylmethyl] and derivatives having an inhibiting effect as antioxidants are described in the publication Neftekhimiya (1987), 27 (5), 703-9.

Also N,N'-diphenyl-N-(2-pyridinyl)urea derivatives are known as herbicides and plant growth regulators, cholinergic agents, acetylcholine releasing agents as cog¬ nition activator or as objects for crystallorgraphic and spectroscopic investigations (J. Crystallorg. Spectrosc. Res. (1988), 18 (6), 729-45; Bioorg. Med. Chem. Lett. (1992), 2(8), 855-60; EP 401 168 A2 or US 4 782 071],

It has been found that 2-amino-heterocycles of the general formula (I)

R ¹

,2/ M N. W ^v CO-R ³ wherein

R represents hydrogen or methyl or represents a 6 membered aromatic hetero- cycle having up to 2 nitrogen, atoms and to which a phenyl ring can be fused and wherein the rings optionally monosubstituted or disubstituted by identical or different substituents are from the series comprising cyano, halogen, carboxyl, nitro, trifluormethyl, by a straight-chain or branched alk- oxycarbonyl having up to 6 carbon atoms or by a group or a formula -(CO) _a -NR ⁴ R ⁵ or -NH-CO-R ⁶

wherein

a denotes a number 0 or 1,

R ⁴ , R ⁵ and R ⁶ are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, which optionally are monosubstituted or disubstituted by pyridyl, benzyl, hydroxyl and/or phenyl, which is optionally substituted by halogen or straight chain or branched alkoxy having up to 4 carbon atoms,

R ² represents adamantyl, cycloalkyl having 3 to 6 carbon atoms, pyridyl, phenyl or benzyl, which optionally are monosubstituted to trisubstituted by halogen, phenyl, carboxyl, cyano, trifluoromethoxy or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or by a residue of a formula -CO-NH-CH(CH ₃ )C ₆ H ₅ , -CO-NH-

adamantyl, -NH-(CO) ₂ -NH-C ₆ H ₅ or , or

represents a group of a formula

or

R and R including the nitrogen atom form together a residue of a formula

and

3 7 ft

R represents a group of the formula -A-NR R ,

R

wherein

A, D, D' and E are identical or different and denote a bond or straight- chain or branched alkyl having up to 6 carbon atoms,

L denotes a nitrogen atom or the CH-group,

or

A denotes a C=O group,

T and T are identical or different and denote halogen or methyl,

R ⁷ and R ⁸ are identical or different and denote hydrogen, cycloalkyl having up to 6 carbon atoms, phenyl, adamantyl, biphenyl or quinidinyl

or denote straight-chain or branched alkyl having up to 8 carbon atoms, which optionally are up to trisubstituted by identical or different substituents from the series comprising hydroxyl, cyclo¬ alkyl having 3 to 6 carbon atoms, pyridyl, thienyl or phenyl, which is optionally up to trisubstituted by identical or different substituents from the series comprising hydroxyl, amino, phenyl, halogen, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 7 carbon atoms, or by a group of a formula -CO-NR ¹⁰ R ⁿ or -SO ₂ -NH ₂ ,

in which

R ¹⁰ and R ^{1 1} have the abovementioned meanin 'g3 of R ⁴ and R ⁵ ,

and/or alkyl optionally is substituted by a residue of a formula

R and R are identical or different and denote phenyl, which optionally is monosubstituted or disubstituted by halogen, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or

R ⁹ denotes carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or denotes a residue of the formula -CHR R ,

in which

R ¹² and R ^lj denote phenyl, which is optionally monosubstituted or disubstituted by halogen,

or

R ⁹ denotes a residue of the formula -CHR ¹² R ^{1 '} ' ,

in which

R ¹² and R ^lj are identical or different and have the abovementioned meaning of R ¹² and R ^lj ,

or

R and R including the nitrogen atom form together a residue of a formula

and their salts,

suφrisingly have a high activity as inhibitors of leukotriene synthesis and thus and suitable for control and treating airway diseases and inflammatory diseases.

Heterocycle in general represents a 6-membered aromatic ring which can contain up to 2 nitrogen atoms as heteroatoms and to which further aromatic ring can be fused.

The following are mentioned as preferred: pyridyl, pyrimidyl, pyrazinyl, pyridazi- nyl, quinolyl or isoquinolyl.

Preferably used are those compounds of the general formula (I),

wherein

R ¹ represents hydrogen or methyl or represents isoquinolyl, pyrazinyl, pyridyl or pyrimidinyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising cyano, fluorine, chlorine, bromine, trifluormethyl, carboxyl, nitro or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or by a group of the formula -(CO) _a -NR ⁴ R ⁵ or -NH-CO-R ⁶ ,

in which

a denotes a number 0 or 1,

R ⁴ , R ³ and R ⁶ are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each

having up to 5 carbon atoms, which are optionally are monosub¬ stituted or disubstituted by pyridyl, benzyl, hydroxyl and/or phenyl, which is optionally substituted by fluorine, chlorine, bromine or straight chain or branched alkoxy having up to 4 carbon atoms,

R" represents adamantyl, cyclopentyl, cyclohexyl, pyridyl, phenyl or benzyl, which optionally are monosubstituted to trisubstituted by fluorine, chlorine, bromine, carboxyl, trifluoromethoxy, phenyl, cyano or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or by a residue of a formula -CO-NH-CH(CH ₃ )C ₆ H ₅ or -CO-NH-

adamantyl, -NH-(CO) ₂ -NH-C ₆ H ₅ or or

represents a group of a formula

or

R ¹ and R ² including the nitrogen atom form together a residue of a formula

and

R ^J represents a group of a formula -A-NR 7r R> 8

in which

A, D, D' and E are identical or different and denote a bond or a straight- chain or branched alkyl one chain having up to 4 carbon atoms,

L denotes a nitrogen atom or the CH-group,

or

A denotes a C=O group,

T and T' are identical or different and denote hydrogen or methyl,

R ⁷ and R ⁸ are identical or different and denote hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, adamantyl, biphenyl or quinudinyl,

or denote straight-chain or branched alkyl having up to 6 carbon atoms, which optionally are up to trisubstituted by identical or different substituents from the series comprising hydroxyl, cyclo¬ propyl, cyclopentyl, cyclohexyl, pyridyl, thienyl or by phenyl, which optionally is up to trisubstituted by identical or different substituents from the series comprising hydroxyl, amino, fluorine, chlorine, bromine, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 6 carbon atoms, or by a group of a formula -CO-NR ¹⁰ R ⁿ or SO ₂ -NH ₂ ,

in which

R ¹⁰ and R ^{1 1} have the abovementioned meaning of R ⁴ and R^,

and/or alkyl optionally is substituted by a residue of a formula

0 0'

R and R are identidal or different and denote phenyl, which optionally is monosubstituted or disubstituted by fluorine, chlorine, bromine, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or

R denotes carboxyl or straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, or denotes a residue of a formula -CHR ^, R ^" \

in which

R ⁿ and R ¹² denote phenyl, which optionally is monosubstituted or disubstituted by fluorine, chlorine or bromine,

or

R ⁹ denotes a residue of the formula -CHR ^! R ^lj

in which

R and R are identical or different and have the abovementioned meaning of R ¹² and R ¹³ ,

or

R' and R ⁸ including the nitrosen atom form together a residue of a formula

and their salts.

Particularly preferred used are compounds of the general formula (I),

wherein

R ¹ represents hydrogen or methyl or represents chinolyl, isoquinolyl, pyra¬ zinyl, pyridyl or pyrimidinyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising cyano, fluorine, chlorine, bromine, trifluormethyl, carboxyl, nitro, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or by a group of a formula -(CO) _a -NR ⁴ R ⁵ or -NH-CO-R ⁶ ,

in which

a denotes a number 0 or 1,

R ⁴ , R ⁵ and R ⁶ are identical or different and denote hydrogen, biphenyl, phenyl or adamantyl, straight-chain or branched alkyl or acyl each having up to 3 carbon atoms, which optionally ore monosubstituted or disubstituted by pyridyl, benzyl, hydroxyl and/or phenyl, which is optionally substituted by fluorine, chlorine or methoxy,

R ² represents adamantyl, cyclopentyl, cyclohexyl, pyridyl, phenyl or benzyl, which optionally are monosubstituted to trisubstituted by fluorine, chlorine, bromine, carboxyl, phenyl, cyano, trifluoromethoxy or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon

atoms, or by a residue of a formula -CO-NH-CH(CH ₃ )C ₆ H ₅ , -CO-NH-

adamantyl, -NH-(CO) ₂ -NH-C ₆ H ₅ or -O or

represents a group of the formula

or

1 "-

R and R" including the nitrogen atom form together a residue of a formula

R ^"5 represents a group of a formula -A-NR 7 Rτ, 8 ,

in which

A, D, D' and E are identical or different and denote a bond or a straight- chain or branched alkyl having up to 4 carbon atoms,

L denotes a nitrogen atom or the CH-group,

or

A denotes a C=O group,

T and T are identical or different and denote hydrogen or methyl,

R ⁷ and R ⁸ are identical or different and denote hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, adamantyl, biphenyl or quinu- clidinyl or denote straight-chain or branched alkyl having up to 5 carbon atoms, which optionally are up to trisubstituted by identical or different substituents from the series comprising hydroxyl, cyclo¬ propyl, cyclopentyl, cyclohexyl, pyridyl, thienyl or by phenyl, which optionally is up to trisubstituted by identical or different sub¬ stituents from the series comprising hydroxyl, amino, fluorine, chlorine, bromine, nitro, carboxyl, straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or acyl each having up to 5 carbon atoms, or by a group of a formula -CO-NR ¹⁰ R ⁿ or -SO- H-,

in which

R ¹⁰ and R ¹¹ have the abovementioned meaning of R ⁴ and R ³ ,

and/or alkyl optionally is substituted by a residue of a formula

R ⁹ and R ^9' are identical or different and denote phenyl, which optionally is monosubstituted or disubstituted by fluorine, chlorine, bromine, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or

R ⁹ denotes carboxyl or straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, or denotes a residue of a formula -CHR "R ^" \

in which

R ¹² and R ¹³ denote phenyl, which is optionally monosubstituted to disubstituted by fluorine,

or

R ⁹ denotes a residue of the formula -CHR ¹ R ¹³ .

in which

R ^~ and R are identical or different and have the abovementioned meaning of R 12 a _„nd., R n l3

or

7 8 R and R including the nitrosen atom form together a formula

and their salts.

The invention additionally relates to new compounds of the formula (X).

wherein the substituents are of the following meaning:

I NH-AtJamanryi

- 11 -

28

- 23 -

Continuation of new compounds:

Structure

Structure

Structure

Structure

Structure

Structurc

Structure

Structure

-32

- _>_> -

Structure

H.CO

Structure

Structure

Structure

Structure

Structure

- J 9 -

Structure

Structure

H ₃ C

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

œtructure

Structure

Structure

Structure

5S -

Structure

Structure

Cl

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

Structure

I

Structure

I

Structure

Structure

Structure

Structure

Structure

S4 -

Structure

H,C.

Structure

Structure

Structure

Structure

H,C,

Structure

H H

H ₃ <Y Ύ ^N

Structure

Structure

Structure

Structure

The compound of the general formula (I) can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.

Physiologically acceptable salts are preferred in the context of the present invention. Physiologically acceptable salts of the 2-amino-heterocycles and the new compounds can be metal or ammonium salts of the substances according to the invention, which contain a free carboxylic group. Those which are particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or tri ethanol amine, dicyclo- hexylamine, dimethylaminoethanol, arginine, lysine or ethyl enedi amine.

Physiologically acceptable salts can also be salts of the compounds according to the invention with inorganic or organic acids. Preferred salts here are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.

Plot as a function of respective substituents compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image

(enantiomers), or which do not behave as image and mirror image (di aster eomers). The invention relates both to the antipodes and to the racemate forms, as well as the diastereomer mixtures. The racemate forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.

A process for the preparation of the compounds of the general formula (I) has additionally been found, characterized in that

[A] compounds of the general formula (II)

R ¹

| (II)

R — NH

in which

R ¹ and R ² have the abovementioned meaning

are reacted first with trichloromethylchloroformate and compounds of the general formula (III)

R ³ -H (III)

in which

R ³ has the abovementioned meaning

or

[B] compounds of the general formula (II) are

directly reacted with compounds of the general formula (IV)

X-CO-R ³ (IV)

in which

X denotes halogen, preferably chlorine

and

R ^J has the abovementioned meaning,

in inert solvents, if appropriate in the presence of a base and/or in the presence of an auxiliary,

and in the case of amides the carbon acids are reacted with the corresponding amines optionally in the presence of a base and/or an auxiliary,

and in the case of esters the corresponding acids are etherified,

and in the case of carbon acid esters are hydrolysed by customary method and in the case of diamides (-NR R ) the monoamides are reacted with the halogenides in the presence of KHMDS.

The process according to the invention can be illustrated by way of example by the following equations:

[A]

NH trichloromethylchloroformate

HN(CH ₂ -C ₆ H ₅ ) ₂

H ₃ CO -

Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofurane, acetone, dimethylsυlfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as di- chlormethane, trichlorom ethane or tetrachloromethane. Dioxane is preferred.

Suitable bases are generally inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide, sodium hydrogencarbonate or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkaline metal, or kaliumhexamethyldisilazid or organic amines (trialky^C _j -C^amines) such as tri ethyl amine, or heterocycles such as 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or amides such as sodium amides, lithium butyl amide or butyllithium, pyridine or methylpiperidine. It is also possible to employ alkali metals, such as sodium or its hydrides such as sodium hydride, as bases. Potassium carbonate, tri ethyl amine, sodium hydrogencarbonate, sodiumhydroxide or kaliumhexamethyldisilazid are preferred.

The process is in general carried out in a temperature range from 0°C to +100°C, preferably from room temperature to +80°C.

The process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).

The base is employed in an amount from 1 mol to 10 mol, preferably from 1.0 mol to 4 mol, relative to 1 mol of the compounds of the general formulae (III) or (IV).

The compounds of the general formula (II) are known or can be prepared by reacting compounds of the general formula (V)

R'-Y (V)

in which

R ¹ has the abovementioned meaning

and

Y represents halogen, preferably chlorine,

with amines of the general formula (VI)

R ² -NH ₂ (VI)

in which

R ² has the abovementioned meaning,

where the corresponding amines react as solvents simultaneous.

The process is in general carried out in a temperature range from +60°C to +200°C, preferably from +100°C to +160°C.

The process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).

The compounds of the general formulae (III), (IV), (V) and (VI) are known and in some cases new and can be prepared by customary methods.

The 2-amino-heterocycles of the general formula (I) and the new compounds according to the invention can be employed as active compounds in medicaments. The substances can act as inhibitors of enzymatic reactions in the context of arachidonic acid metabolism.

The compounds of the general formula (I) surprisingly exhibit a high activity as inhibitors of leukotriene synthesis, specifically inhibit the production of leukotriene B ₄ by polymorphonuclear leucocytes (PMN).

They are therefore preferably suitable for the treatment and prevention of diseases of the respiratory passages, such as allergies/asthma, bronchitis, emphysema, shock lung, pulmonary hypertension, inflammations/rheumatism and oedemas, throm¬ boses and thromboembolism, ischaemis (disturbances in peripheral, cardiac and cerebral circulation), cardiac and cerebral infarctions, disturbances in cardiac rhythm, angina pectoris and arterioscleoris, in the event of tissue, transplants, dermatoses, such as psoriasis, inflammatory dermatoses, for example eczema, dermatophyte infection, infections of the skin by bacteria, metastases and for cytoprotection in the gastrointestinal tract.

Test description

1. Preparation of human PMN

Blood was taken from healthy subjects by venous puncture and neutrophils were purified by dextran sedimentation and resuspended in the buffered medium.

2. Inhibition of thaspsigargin-induced leuktoriene B ₄ generation Neutrophils (4 x 10 ⁵ cells/ml) were placed in a 96 well microtitre plate and prewarmed to 37°C. Compounds according to the invention were added in dimethyl sulphoxide (DMSO). Compound concentration ranged from 0.3 to

30 μM, the DMSO concentration was < 0.3% v/v. The plate was incubated for 5 min at 37°C. Neutrophils were then stimulated by addition of 1 μM thapsigargin followed by 1.3 mM Ca~ . The reaction was stopped after 5 minutes and supernatants assayed for the presence of leukotriene (LT) B ₄ using an LTB ₄ -specific radioimmunoassay kit supplied by Amersham

Internationl pic. Percentage inhibition was determined by comparison with vehicle-containing controls.

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceuti¬ cally suitable excipients or solvents. In this connection, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.

The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, organic solvents can be used as auxiliary solvents if appropriate.

Administration is carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously.

In the case of parenteral administration, solutions of the active compound can be employed using suitable liquid vehicles.

In general, it has proved advantageous on intravenous administration to administer amounts from about 10 to 100 mg/kg, preferably about 10 to 50 mg kg of body weight to achieve effective results, and on oral administration the dosage is about

10 to 100 mg/kg, preferably 10 to 50 mg/kg of body weight.

In spite of this, it may be necessary to depart from the amounts mentioned, in particular depending on the body weight or the type of application route, on individual behaviour towards the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be sufficient to manage with less than the abovementioned minimum amount,

while in other cases the upper limit mentioned must be exceeded. In the case of administration of relatively large amounts, it is advisable to divide these into several individual doses over the course of the day.

Starting compounds

Example I

2-(4-Methoxyanilino)pyridine

A mixture of 1.05 ml (1 1.2 mmol) 2-chloropyridine and 9.5 g (77 mmol) 4- methoxyaniline were heated to 150°C. After 1 hr another 6.15 ml (65.2 mmol) 2- chloropyridine were added. 3 hrs. later the crude product was purified by chromatography (gradient eluation: PE/EE 20:1, 10: 1, 5: 1, 2:1) yielding 12.7 g of the title compound, which was recrystallized from ethylacetate (8.8 g = 57.8% of theory).

Η-NMR (250 MHz, D ₆ -DMSO): δ = 3.71 (s, 3H); 6.62 - 6.67 (ddd, 1H); 6.72 (d, 1H); 6.84 - 6.89 (m, 2H); 7.45 - 7.57 (m, 3H); 8.07 (dt, 1H), 8.75 (s, 1H).

MS (70 eV): m/z (%) = 200 (100) [JvT].

Preparation Examples:

Example 1

N-(l-(4-Methoxyphenyl)-N-2-pyridyl-N'-dibenzyl-urea

To a solution of 500 mg (2.5 mmol) of example I in 25 ml dioxane were added 166 μl (0 55 eq) chlorotrichloromethylformate dropewise. This mixture was kept at 60°C for 17 hrs, followed by addition of 0.58 ml (3.0 mmol) dibenzylamine. After another 24 hrs at 60°C the mixture was cooled to room temperature, the solvent removed under reduced pressure and the residue dissolved in ethylacetate. Aqueous work up yielded an oil, which was purified by chromatography (PE / EA = 5: 1) yielding 302 mg (46.1%) of chloro-N-(4-methoxyphenyl)-N-2-pyridyl- formamide and 1 12 mg (10.5%) of N-(l-(4-Methoxyphenyl)-N-2-pyridyl-N'- dibenzyl-urea.

Example 1 1H-NMR (250 MHz, CDC1 ₃ ): δ = 3.80 (s, 3H); 4.43 (s, 4H), 6.68 (d, 1H), 6.83 -

6.92 (m, 3H); 7.02 - 7.08 (m, 2H); 7.20 - 7.32 (m, 10H); 7.49 (m, 1H); 8.33 - 8.37 (ddd, 1H). MS (FAB)- m/z (%) = 424 (100) [MYl].

chloro-N-(4-methoxyphenyl ,-N-2-pyridylformamide: 1H-NMR (250 MHz, CDC1 ₃ ): δ = 3.81 (s, 3H); 6 84 - 6.97 (m, 2H); 7 18 - 7 23

(ddd, 1H), 7.26 - 7 34 (m, 2H); 7.51 (dd, 1H), 7.77 (ddd, 1H), 8.45 (ddd, 1H) MS (FAB) m/z (%) 263 (55) [MYl].

The compounds shown in Table 1 are prepared in analogy to the procedure of example 1 or by the way of the indicated methods.

Table 1:

R ¹

I • N,

^' CO-R ^'

17

IS

13:

142

CH ₂ C1 ₂ : MeOH = Methylene chloride: Methanol

Cycl. : EE = Cyclohexane : Acid ester

a) in analogy to example 1 b) starting compounds diamine/KHDMS/benzylbromide c) starting compounds

/TBTU/dii sopropyl ethylamin e

d) starting compounds

H ₂ N carbon acid chloride

C ₆ H ₅ - -N — CO — N(CH _-C _B 6H' V ₅ ) ₂ e) starting compounds ester LiOH

f) starting compounds /Buli/Cl-CO-N(CH,C ₆ H ₅ ), H

g) starting compounds amine/Cl-CO-CH ₂ -Cl/ — D-N N — E-R a

h) starting compounds amine/Cl-(CO) ₂ -Cl/H ₂ N(CH ₂ C ₆ H ₅ ) ₂

i) starting compounds amine enzylisocyanate.