CS270592B2 - Method of 1,4-dihydropyridines production - Google Patents

Abstract

4-Aryl-5-carbamoyl-1,4-dihydropyridine cpds. of formula (I) and their salts are new. (R = phenyl opt. substd. or is phenyl fused to a dioxolane ring; R1, R2 = H or 1-6C alkyl, or R1 and R2 together complete a pyrrolidinyl, piperidono, morpholino, piperazinyl, N-(1-4C alkyl)piperazinyl or N-(2-4C alkanoyl)piperazinyl gp.; or R2 is H or 1-4C alkyl and R1 is CN, 3-7C cycloalkyl, aryl, heteroaryl or a 1-4C alkyl gp., the 1-4C alkyl gp. of R1 being substd.; Z = 1-6C alkoxy, aryl(1-4C)alkoxy OH or NR4R5; R4, R5 = H or 1-6C alkyl or R4 and R5 together complete a pyrrolidine, piperidino, morpholino, piperazinyl or N-(1-4C alkyl)piperazinyl gp.; Y = 1,4-phenylene or pyridine-2,5-diyl; X = a 5 or 6 membered aromatic heterocyclic gp. contg. N atom(s) in its ring, which ring may be fused to a benzene ring or to a further 5- or 6-membered aromatic heterocyclic ring contg. N atom(s), heterocyclic ring(s) opt. also contg. an O or S atom and being opt. substd.; aryl = phenyl opt. substd., heteroaryl in the definition of R1 = 5- or 6-membered aromatic heterocyclic gp. contg. heteroatom(s) selected from N, O and S and which may opt. be fused to a benzene ring and which may opt. be substd. in heterocyclic and fused benzene ring(s).

Description

(57) A process for the preparation of compounds of formula (I) wherein R is 2-chlorophenyl, 2-trifluoromethoxyphenyl, 2,4-difluorophenyl, 4-cyanophenyl or 1,3-benzodioxol-4-yl, R is hydrogen; _д -alkyl, pyridyl, thiazolyl, l- (phenyl) ethyl, 4- or 6-methylpyridin-2-yl, 4- or 5-methylthiazol-2-yl, 5-methylthiadiazol-2-yl, 5-3-methyloxadiazole yl, 5-methylisoxazole-3-yl, benzothiazol-2-yl, 5-ethoxybenzothiazol-2-yl or l-methylimidazol-2-yl, R ^a is hydrogen or С, _{д а1ку1,} X is an optionally substituted pyrióýlový, imidazole , p Y-: rimidylový, triazole, oxazoles or ^thi: azole radical, Y is 1,4-phenylene or pyridine-2,5-diyl radical and Z is C. * -alkoxy or aryl-C д-alkoxy, wherein the aryl is optionally substituted phenyl, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula II is reacted with an aldehyde of formula RCHO and a compound of formula III, or with a reaction product thereof corresponding to formula IV, and the resulting product optionally converted to a pharmaceutically acceptable salt thereof. The compounds produced act as antagonists of the platelet activating factor and can be used in medicine to treat allergic and inflammatory diseases.

(XIX) cm

CS 270 592 B2

The invention relates to dihydropyridines, in particular certain 4-aryl-5-carbamoyl-1,4-dihydropyridines, which can be used for the treatment of allergic or inflammatory diseases in human and veterinary medicine.

Ahtiischeeic and antihypertensive effects have been described for a number of 1,4-dihydropyridines. These compounds are capable of inhibiting the movement of calcium into cells and are therefore effective in the treatment and prevention of various heart diseases or as antihypertensive agents (see, for example, European Patent Application No. 100189). However, the compounds of the invention are potent and selective antagonists of the platelet activating factor and as such have clinical utility in a completely different field, namely for the treatment of allergic and inflammatory diseases such as asthma and respiratory diseases. arthritis. ”

Platelet activating factor (PAF) is an ether phospholipid. whose structure was first elucidated in 1979. It is 10-alkyl-2-acetyl-sn-glyceryl-3-piperphylcholine. This factor is produced, relaxed and reacts with numerous cells involved in the inflammatory response, platelets and kidneys. PAF, besides having a strong effect on platelet aggregation, exhibits a broad spectrum of biological activity. These effects act either directly or through the release of other active mediators such as thromboxane A ₂ or leukotrienes. In vitro, PAF stimulates the movement and aggregation of neutrophils and the release of neutrophils and the release of tissue damaging enzymes and oxygen radicals therefrom. These activities contribute to the effects of PAF in vivo and are consistent with the fact that PAF plays an important role in inflammatory and allergic processes. Thus, intradermal PAF has been shown to cause an inflammatory response associated with pain, inflammatory cell accumulation, and increased vascular permeability, comparable to an allergic reaction that occurs when the skin is exposed to an allergen. Similarly, both acute bronchoconstriction and chronic inflammatory reactions induced by allergens in asthma can be mimicked by intratracheal administration of PAF. Accordingly, agents that antagonize the effects of PAF and hence release of the mediator by PAF have clinical use in the treatment of a variety of allergic diseases, inflammatory and hypersecretory conditions such as asthma, arthritis, rhinitis, bronchitis and urticaria.

In addition to the cases mentioned above, PAF is implicated in a number of other disease states. Thus, PAF infusion can mimic the circulating Soc, which is characterized by systemic hypotension, pulmonary hypertension, and increased permeability of fungal vessels. This, together with evidence that the level of circulating PAF increases when endotoxins are infused, suggests that PAF is a major mediator in some forms of Sok. Intravenous infusion of PAF to rats at doses of 20 to 200 pmol / kg.min results in widespread hemorrhagic erosion of the gastric mucosa, making PAF the most effective steroid ulcer described so far, the endogenous release of which may cause or contribute to some forms of gastric ulcer disease. Psoriasis is an inflammatory and proliferative disease characterized by skin lesions. PAF contributes to inflammation and has been isolated from damaged areas of psoriasis patients, suggesting that PAF plays a role in psoriasis. Furthermore, PAF appears to be a potential pathophysiological cause of cardiac and vascular disease. Thus, recent studies of patients suffering from angina pectoris show that PAF is released by controlling atrial heart rate. Intracoronary injection of PAF causes a long-term reduction in blood flow in pigs in pigs and causes regional shunt and ischemia in guinea pigs. In addition, PAF has been found to initiate thrombus formation in arteria mesenterica. Both exogenous and endogenous release administration. Recently, PAF has been shown to play a role in brain ischemia induced in animal models of stroke.

Since the compounds of the present invention are capable of antagonizing the effects of PAFs.

they can be used to treat the above-described disease states.

CS 270 592 B2

Our related published European 4-aryl-5-carbamoyl-1,4-dihydropyridines patent applications Nos. 258033 and 266989 disclose PAF antagonists.

The present invention provides compounds of formula III

!

CD in which

R is 2-chlorophenyl, 2-trifluoromethoxyphenyl, 2,4-difluorophenyl, 4-cyanophenyl or 1,3-benzodioxol-4-yl,

R @ ¹ is hydrogen, C1 -C4 alkyl, pyridyl such as pyrid-2-yloy, thiazolyl such as thiazol-2-yl, 1- (phenyl) ethyl, 4- or 6 a methylpyrid-2-yl group, 4- or 4-methyl group;

5-methylthiazol-2'-yl, 5-methyloxadiazol-3-yl, 5-methylisoxazol-3-yl, benzothiazol-2-yl, 5-ethoxybenzothiazol-2-yl or 1-methylimidazol-2- a yl group,

R is hydrogen or alkyl of 1 to 4 carbon atoms,

X is 2-methylimidazo [4,5-c] pyrid-1-yl, imidazol-1-yl, benzimidazol-1-yl, 2-methylbenzimidazol-1-yl, 3,5-dimethyl-1, 2,4-triazol-4-yl, 2-trifluoromethylimidazo [4,5-c] pyrid-1-yl, 2-butylimidazo 5-c] pyrid-1-yl, 2-methylimidazo | 4,5-b] pyrid-3-yl, 2-methylimidazo [1,2-a] pyrid-3-yl, 2-ethylimidazo [4,5-c] pyrid-1-yl, 7-methoxy-2 methylimidazo [4,5-d] pyrimid-3-yl, 2-methylimidazof4,5- (3-pyrid-3-yl), 2,4,6-trimethylimidazo [4,5-c] pyrid-1-yl a group, 2,4-dimethylimidazol-1-yl, 2-methylimidazol-1-yl, 2,4,5-trimethylimidazol-1-yl, 4-methylimidazol-1-yl, 2-methylpyrid-3- yl, 2,6-dimethylpyrid-3-yl, 3,5-dimethyl-1,2,4-triazol-1-yl, 4-methyloxazol-5-yl, 2,4-dimethylthiazol-5- 6-methylimidazolyl, 2-b] thiazol-5-yl or 4-methyl hiazol-5-yl,

Y represents a 1,4-phenylene residue or a pyridine-2,5-diyl residue and

Z is C 1 -C 4 alkoxy or C 1 -C 4 arylalkoxy in the alkoxy moiety wherein the aryl moiety is a phenyl group optionally having one substituent selected from the group consisting of halogen atoms, trifluoromethyl, C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, sulfamoyl and cyano, and pharmaceutically acceptable salts thereof.

CS 270 592 B2

By the above-mentioned halo is meant fluorine, chlorine, bromine, or iodine. The alkyl and alkoxy groups of three or more carbon atoms can be straight or branched.

1

Preferably, R is hydrogen and R is hydrogen, C 1 -C 4 alkyl, pyridyl (most preferably 2-pyridyl), thiazolyl (most preferably 2-thiazolyl) or 1-phenylethyl.

According to a preferred embodiment, Z is ethoxy. methoxy or benzyloxy substituted on the ring by halogen.

The object of the present invention is a process for the preparation of compounds of formula I and their pharmaceutically acceptable salts, characterized in that the compound of formula II

is reacted with an aldehyde of the general formula

RCHO and a compound of formula III

(III)

or with the product of their mutual reaction corresponding to formula IV

(IV) in which the general formulas have the meanings given above, and the resulting product is optionally converted into its pharmaceutically acceptable salt.

The reaction of compounds of formulas II, III and RCHO represents a conventional Hantzch synthesis following the following reaction scheme:

CS 270 592 B2

(II)

According to a typical embodiment of the process, the aminocrotonamide (II), ketoester (III) and aldehyde are heated in a suitable organic solvent, for example a C 1 -C 4 alkanoate such as ethanol, to a temperature of 60 to 130 ° C, preferably boiling under. reflux, until virtually complete reaction completion, which usually takes 24 hours or less. A small amount of a lower alkanoic acid such as acetic acid may optionally be added to neutralize the solution. The resulting product of formula (I) may be isolated and purified in a conventional manner, for example by shaking, recrystallization or chromatography.

Alternatively, the ketoester of formula III and the aldehyde are reacted with each other, usually by stirring a slight excess of the ketoester with the aldehyde in an organic solvent, for example, isopropyl alcohol containing piperidine as a catalyst. The reaction mixture was stirred at room temperature for 4Θ hours. The reaction yields an intermediate of formula (IV) which may optionally be isolated, for example by evaporating the reaction mixture to an oily residue, triturating the same oil with water and purifying the product by filtration and recrystallization from ethyl acetate. The compound of formula (IV) may then be reacted with an aminocrotonamide of formula (II) by, for example, heating the compounds in an alcoholic solvent at a temperature of from 60 to 130 ° C, preferably at reflux. The product of formula (I) thus obtained may be isolated by conventional means.

The ketoesters of formula (III) above are either known or can be prepared by the following methods.

(I) The ketoesters of formula III may be prepared by Blaiee reaction according to a modification described by S. M. Hannick and Y. Kishi in J. Org. Спет., 1983, 48, 3833, according to the following reaction scheme:

CN

I Zn

X -, ------ C0CH ₂ C0Z

AND

X

I BCHCHCOCO

X X (III)

CS 270 592 B2

A cyano compound is added to a suspension of zinc dust and the corresponding bromoacetate in an inert solvent such as tetrahydrofuran. Additional bromoacetate was added at reflux, and after cooling the reaction mixture, an aqueous potassium carbonate solution was added. The resulting mixture is filtered and the filtrate is hydrolyzed for several hours at reflux with dilute hydrochloric acid or by stirring with 20% aqueous trifluoroacetic acid in a suitable solvent such as dichloromethane.

The reaction mixture is neutralized and the resulting ketoester of formula III is isolated and purified by conventional means, for example, by shaking, recrystallization or chromatography.

The cyano compounds used are either known or can be prepared by known methods described in the literature, for example in the work cited above.

(II) An alternative method of preparing certain ketoesters of formula III is by Gold-; berg and Claisen ester condensation according to the following reaction scheme:

KaH of ₂ co

(III)

The starting p-bromoacetophenone can be replaced by the corresponding fluoro, chloro or iodo derivative and the first reaction step of the above reaction sequence can be carried out in the presence of copper and copper (I) bromide catalyst.

According to a typical embodiment, a mixture of a compound of formula XH, p-bromoacetophenone, copper bronze, cuprous bromide and anhydrous potassium carbonate in a solvent such as dry N-methylpyrrolidinone is heated under an inert gas atmosphere for up to 6 hours. The solvent is then evaporated and the intermediate ketone is isolated and purified in a conventional manner.

The ketone intermediate was added to a suspension of sodium hydride under nitrogen. in a dry solvent such as tetrahydrofuran, then the appropriate dialkyl carbonate is added and the reaction mixture is heated to reflux for about 18 hours. Alternatively, the dialkyl carbonate can also be used as a solvent. The resulting ketoester (III) is isolated and purified in a conventional manner.

CS 270 592 B2

The aminocrotonamides of formula (II) are either known or can be prepared in conventional manner, for example, from ketoamide by reaction with ammonia.

Likewise, aldehydes of the formula RCHO are either known or can be prepared by known methods described in the literature. . -. ‘

The activity of the compounds of the invention is demonstrated by their ability to inhibit the platelet aggregation activity of PAF in vitro. The test for this effect is performed as follows.

Blood samples are taken from rabbit or human and mixed with 0.1 volumes of ethylenediaminetetraacetic acid disodium buffer and centrifuged for 15 minutes to obtain platelet-enriched plasma. This plasma is further centrifuged to give a platelet precipitate which is washed with a buffer solution (4 mM K 2 R 6, 6 mM Na ₂ HPO 4, 100 mM NaCl, 0.1% glucose and 0.1% bovine serum albumin, pH 7). 25) and then suspended in a buffer flow at a concentration of 2 × 10θ platelets / ml. A sample of this suspension (0.5 ml) was preincubated for 2 minutes at 37 ° C with stirring in a Paton aggregometer, either with the vehicle alone or with the vehicle containing the test compound. PAF is added at a concentration resulting in maximum aggregation in the absence of the test compound (10 M to ₄ 10 M) and platelet aggregation is measured by monitoring the increasing optical transmission of the solution. The experiment is repeated in the presence of the test compound at various concentrations, and the concentration of the test compound required to reduce the response to 50% of the maximum value is termed ΙΟ ^ θ.

The activity of the compounds of formula I can also be demonstrated in vivo by their ability to protect the mouse from the lethal effect of PAF injection. Mice are injected into the tail vein with 0.2 ml of a mixture of PAF (50 µg / kg) and DL-propranolol (5 mg / kg) in 0.9% (w / v) sodium chloride solution. The test compound is either injected into the tail vein immediately prior to the injection of a combination of PAF and propranolol, or administered orally 2 hours prior to this injection by gastric tube. The active substances are tested in several doses in groups of 5 mice each and the dose which reduces mortality to 50% is recorded as hodnota ^ θ.

The compounds of the invention are also tested for their ability to attenuate or suppress PAF-induced bronchoconstriction in anesthetized guinea pigs. This test calculates airway resistance and dynamic lung performance from airflow and transpleural pressure records and residual volume calculations. Bronchoconstriction induced by PAF at 100 ng / kg was determined. One hour after the initial dose of PAF, the test compound is administered and the test repeated. The ability of the test substance to reduce the bronchoconstrictor effect of PAF is calculated and recorded as a ratio.

For therapeutic use, the compounds of Formula I are generally administered in admixture with a pharmaceutical carrier selected taking into account the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing starch or lactose as carriers, or in the form of capsules or ovules containing either alone or in admixture with carriers or excipients, or in the form of elixirs or suspensions containing flavoring agents. or dyes. The disclosed compounds may also be administered by parenteral injection, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, the active compounds are best used in the form of a sterile aqueous solution which may contain other ingredients, such as salts or glucose, to render the solution isotonic with blood.

For administration to the curative or prophylactic treatment of allergic bronchial diseases and arthritis in human medicine, the compounds of the invention are orally administered in doses ranging from 2 to 1000 mg per day, calculated on an average adult patient (70 kg). A tablet or capsule intended for a typical adult patient obspCS 270 592 B2 comprises from 1 to 500 mg of active ingredient in a suitable pharmaceutically acceptable carrier or diluent. The dosage for intravenous administration and in the case of a unit dose usually ranges from 1 to 10 mg. For the treatment of allergic diseases and diseases caused by bronchial hyperreactivity, the preferred route of administration may be by inhalation using an inhaler or aerosol preparations. The dosage in this mode of administration ranges from 0.1 to 50 mg per single dose. In practice, the attending physician will determine a particular dose that will be most appropriate for a particular patient and which will vary depending on the age, weight, and response of the patient to the formulation. The above dosage is given only as an example, but in some circumstances higher or lower dosages may be required. However, such cases are also within the scope of the invention.

Accordingly, the invention also provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The invention further provides the use of the compounds of formula (I) or pharmaceutically acceptable salts thereof in medicine, particularly for the treatment of allergic and inflammatory diseases in human medicine.

The invention is illustrated by the following non-limiting examples.

Example 1

4- (2-chlorophenyl) 1,4-dihydro-3-ethoxycarbonyl-6-methyl-2- [4- (2-methylimidazo [4,5-c pyrid-1-yl) phenyl] -5- [N- ( 2-pyridyl) carbamoyl] pyridine. A mixture of 475 mg (1.47 mmol) of ethyl 4- (2-methylimidazo [4,5-c] pyrld-1-yl) benzoylacetate, 260 mg (1.47 mmol) of N- (2-pyridyl) -3- of aminocrotonamide and 207 mg of 2-chlorobenzaldehyde (1.47 mmol) in absolute ethanol were heated under reflux for 8 hours under nitrogen. The reaction solution was allowed to cool and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography using a gradient elution of 5% diethylamine in ethyl acetate and methanol. The product containing fractions were concentrated and the solid material was further purified by trituration with a mixture of diethyl ester and ethyl acetate. Filtration and drying in vacuo afforded 280 mg (31%) of the title compound as a solid, mp 226-22 ° C.

H, 4.92; N, 13.68. Found: C, 66.86; H, 4.76; N, 13.72.

Examples 2 to 28.

Further compounds prepared according to the procedure of Example 1 using the corresponding aldehyde, 4'-substituted benzoylacetic acid ester and N-substituted crotonamide are summarized in Table 1 below.

O R ¹ II R И 3 'co ₂ r ^j К 1 (Ia) 1 | l. CH ₃ sr and· H OL

<X (decomposition) (59.53 4.65 11.96)

к

CS 270 592 B2

_{Ί Ί} о · »temperature yield Analysis (%) example RR ^x R * R ^J X ~ found

CS 270 592 B2

сх «* · σ • н»> * φ Нч Ck. )

Η »

ί »

w «♦ u>

w Η <♦ С * οχ 00 flb φ Η 00 3 • d AND 1 Нч Η Η Η ο Ch 00 z-ч <♦ го \ Ο ο φ

04 / 04 / ОХ ох >> 4 · ч * ч · ч * οχ 00 * » го 00 -č н ХО CA 04 / чл чл * · ч · ч · ч · it о го о CJ -4 о Η * н » н н * го го >> чК <* w VI 04 / '· Чл н -4 о чК чК

CS 270 592 B2

FROM

СХ ΙΤΌ

СО Нч and Others

О О

го О по

I по о н СО чл

I н со оо

н

-ч

С * ах ь *

z-ч Cs z-ч. σ> сл а < -> 4 -4 0) Н · * · со. N VI <л ф and чл оо В Нч Ы < ЧЛ \ л Ф м • 4_z -0 чл со & н » σ> • ^ х ф а н » н ф по по о ЧЛ Ν) 4J н Фч

CS 270 592 B2

m.p. = 0 DEG C. Yield Analysis (%) cc R Ir- R ^J X _л found

CS 270 592 В2

ОМе

EXAMPLE Yield Temperature Analysis (%) Example RR ^x R * R ^J X found

Melting point (° C) (%) (calculated):

bd

ГО u> чл

I го Си со

4 »

04 го го

4 * 04

U>

о * чл чл со

А * К)

40

CS 270 592 B2

Cx

04 /

СО со

-4 04

СО 4 *>

чл чл ь> о ·

СО

pří-. _{9 ч} Temperature Yield Analysis (%).

example RR ^x R ^Z R ^J X _Λ found

CS 270 592 B2

(66.40 5.42 12.91)

inc., p -> temperature yield Analysis (%)

CS 270 592 B2

- 1 pri- _{Ί о} -> temperature yield analysis (%) Example RR ^Z R ^X R X ^J _л found

CS 270 592 B2

Axis Axis * 4 -Ч

W Μ axis σ> o чл * чл U> Μ ГО Η

OS

Η * ro * øo

LJ *

GJ's o

_{pří- Ί} ? Temperature Yield Analysis (%) of RR ^x and X found

1Б

CS 270 592 B2

ГО ГО

ГО cx

Yield Temperature Analysis Analysis (%) Example RR ^x R ^ R ^J X _л found

CS 270 592 B2

1?

ω кл

ΓΌ

w с *

К φ

• * 3 ΟΧ О \ о

W Μ

Η 00

4 * U>

кЛ чл

Н * U) -> J кЛ kO w *

VO

H * 04

pří- ·. at temperature yield Analysis (%) found RR ^x R ^ R ^J X ~ found

CS 27: 592 82 го -о го о fto • hCD НЧ

CL I

• н »

Н »

Ch по

СЬ 0 \ чл чл *

КО чл

ПО UI <h σ \ КО кО

CЛ CU го чл чл ··> LU 00 по кО ко ЧЛ> ►

LO ПО

Z-чЗ> 4® & н® • о Ф ь * О N << X ОФ н <♦ 3 Ф Ф О х-х

О

CS 270 592 B2 to

butyl group

• H · ® Hx Сь I

ro

LJ

Η <♦ С * 40 ΑΧ Ο 4Л 2 • ο 1 Нч Η Η Ο 40 ζ-χ С * 40 ο 0

σ \ σχ чл σχ ч »* ·

КО о α> ν ’\ ·

Μ «*

Η 00 <Κ 40

Η Η U> ΓΌ

W «*

-4 чО -4

CS 270 592 B2

Legend:

calculated for a solvate containing 1/4 mol of isopropyl alcohol with 1/2 mol of water

2Ί calculated for hemihydrate ³⁾ @ 1 H-NMR (CDCl3) .delta. 1.00 (3H, t, 37 Hz), 2.31 (3H, e), 3.93 (2H, m),

5.63 (1H, s), 5.99 (1H, s), 7.02 1H, dd, 3,6 and 7 Hz), 7.21 (2H, m), 7.28-7.37 (3H) m), 7.51 (2H, d, 3 = 9 Hz), 7.63 (1H, m), 7.66 (2H, d, 3 = 9 Hz), 8.15 (2H, m),

8.28 (1H, m), 8.55 (1H, d, 3-7 Hz), 9.31 (1H, δβ) calculated for hydrate containing 3/4 mol of water ⁵ ) calculated for hydrate

6) 1 H-NMR (CDCl 3; for a 1: 1 mixture of diastereomers): 0.96 (3H, t, = 7 Hz), 0.97 (3H, t, 3 = 7 Hz), 1.44 ( 2H, d, 3 = 7Hz), 1.45 (2H, d, 3 = 7Hz),

2.26 (3H, m), 2.34 (3H, s), 2.61 (6H, s), 3.90 (4H, m), 5.08 (2H, m), 5.45 (1 H, s),

5.48 (13, s), 5.74 (1H, s), 5.76 (1H, s), 6.03 (2H, m), 7.03-7.69 (32H, complex),

8.39 (2H, d, J = 7 Hz), 9.09 (2H, s).

calculated for a solvate containing 1/2 mol of ethyl acetate and 1/2 mol of water ⁾ H-NMR (CDCl3): 1.00 (3H, t, 3 → 7 Hz), 2.47 (3H, s), 2, 61 (3 H, s),

3.97 (2H, m), 5.23 (1H, s), 6.42 (2H, s), 7.03 (1H, d, 3 = 6 Hz), 7.10 (1H, d, 3) = 5 Hz)

7.42 (2H, d, 3-7 Hz), 7.60 (2H, d, 3 = 7 Hz), 7.66 (4H, m), 7.90 (1H, s), 8.19 ( 1H, d, 3-7 Hz), 8.24 (1H, d, 3-6 Hz), 8.29 (ΊΗ, d, 3 = 5 Hz, 9.04 (1H, s)) calculated for solvate containing 1/4 mol of ethyl acetate compound was isolated from the Hantzsch reaction as a covalent hydrate and converted to dihydropyridine calculated for the hydrate containing 5/4 mol of water by heating under reflux in toluene in the presence of p-toluenesulfonic acid.

Example 29

4- (2-chlorophenyl) -1,4-dihydro-2- [4- (3,5-dimethyl-1,2,4-triazol-1-yl) phenyl] -3-ethoxycarbonyl-6-methyl-5 - [N- (2-pyridyl) carbamoyl] pyridine.

(a) Ethyl 2- [4 * - (3,5-dimethyl-1,2,4-triazol-1-yl) -benzoyl] -3- (2'-chlorophenyl) propenoate

A mixture of 618 mg (2.15 mmol) of ethyl 4 '- (3,5-dimethyl-1,2,4-triazol-1-yl) benzoylacetate,

302 mg (2.15 mol) of 2-chlorobenzaldehyde and 2 drops of piperidine in 10 ml of isopropanol are stirred at room temperature for 72 hours. The volatiles were evaporated from the reaction mixture and the residue was purified by flash chromatography using ethyl acetate as eluent. This afforded 600 mg (68% yield) of the title compound.

CS 270 592 B2 (b) 4- (2-chlorophenyl) _-l> 4-dihydro-2-4- _{(3,5-dimethyl-1} 2 4-triazol-l-yl) phenyl-3-ethoxykacbony1- 6-methyl-5- [N- (2-pyridyl) carbamoylpyridine

A mixture of 566 mg (1.38 mmol) of the product of (a) and 245 mg (1.38 mmol) of N- (2-pyridyl) -3-aminocrotonamide in 10 ml of ethanol was refluxed for 8 hours under nitrogen. . The solvent was evaporated and the residue was purified by flash chromatography using diethylamine in ethyl acetate for 2 h as eluent. 50 mg (6%) of the title compound are obtained as a white solid, m.p. 130 ° C.

Analysis:

H, 5.01; N, 14.32.

Found: C, 63.36; H, 5.43; N, 13.96.

In this manner, but using ethyl 4 '- (2-methylimidazophyll, 5-c} pyrid-1-yl) benzoylacetate instead of ethyl 4' - (3,5-dimethyl-1,2,4-triazole-1 -) - yl) -benzoylacetate also yields the compound of Example 1. The analytical data of this product are identical to those given in Example 1.

Example 30 ⁴

4- (2-chlorophenyl) -1,4-dihydro-3-ethoxycarbonyl-6-methyl-2- [4- (4-methyloxazol-5-yl) phenyl] -5- [N- (2-pyridyl) carbamoyl] pyridine

A mixture of 260 mg (1.0 mmol) of ethyl 4 '- (4-methyloxazol-5-yl) benzoylacetate, 160 mg (1.1 mmol) of N- (2-pyridyl) -3-aminocrotonamide and 160 mg (1, 2-chlorobenzaldehyde was heated to reflux in 10 ml of ethanol containing 1 drop of acetic acid under nitrogen for 16 hours. The reaction solution was allowed to cool and all volatiles were evaporated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate as eluent. The light yellow oil obtained, after trituration with anhydrous diethyl ether, gave the title compound as a white solid, m.p. Deň: 32 ° C. Yield: 24 mg (5%).

Analysis: for hemietherate

calculated 66.90 4 C, 5.42 % H, 9.46 * N; found 66.56 % C, 5.22 * H, 9.29 % N. Ex 1 and d у 31 and ž 33

Table 2 below lists the other compounds prepared as in Example 30 using 2-chlorobenzaldehyde and the corresponding 4'-substituted benzoylacetate in each case.

CS 270 592 B2 «W го Η \ /

CS 27c 5 = 2 82

UJ ro o ΚΌ • h * * d <OD h4 O. I

X

H ·

X ro

W * * x LO

LO

AND

ГО o o

H Ch ФI H G \ 04 ►í O N <H Ф RН »ro

H ЧЛ

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CS 270 592 B2

Example 34

4- (2-Chloro-phenyl) -1,4-dihydro-3-ethoxycarbonyl-6-methyl-2- [2- (2-methyl-imidazo [4,5-c] pyrid-1-yl) -pyrid-5-y 1H-5- [N- (2-pyridyl) carbamoyl] pyridine;

A solution of 324 mg (1.0 mmol) of ethyl 2- (2-methylimidazo {[4,5-c] pyrid-1-yl) pyrid-5-oyl acetate, 178 mg (1.0 mmol) of 3-amino-N - (2-Pyridyl) -but-2-enamide and 140 mg (1.0 mmol) of 2-chlorobenzaldehyde in 4 ml of ethanol were heated under reflux for 5 hours under nitrogen. The resulting solution was cooled, concentrated under reduced pressure, and the residue purified first by flash chromatography eluting with ethyl acetate / methanol (6: 1; then eluting with ultrasonic stirring in a 3: 1 mixture of ether and ethyl acetate). 45 min The off-white solid was filtered and dried under vacuum to give 140 mg (23%) of the title compound, mp 242-243 ° C.

Analysis for C C ^ ^ gCl gNyO ^. % C, 63.96;% H, 4.79;% N, 15.82;

Found: C, 64.11; H, 4.56; N, 15.52.

The following preparations describe the preparation of intermediates used to produce the compounds of formula (I).

Preparation 1 Ethyl -4 '- (2-methylbenzimidazol-1-yl) benzoylacetate

A suspension of activated zinc dust (994 mg, 15.2 mmol) in dry tetrahydrofuran (10 mL) was stirred under ultrasound for 10 min under nitrogen and 3 drops of ethyl bromoacetate were added. The mixture was heated at reflux for 10 minutes, then 1- (4-cyanophenyl) -2-methylbenzimidazole (708 mg, 3.04 mmol) was added in one portion, followed by refluxing for 1 min. A solution of 1.35 mL (12.1 mmol) of ethyl bromoacetate in 4 mL of anhydrous tetrahydrofuran was added dropwise over 1 h. After a further 10 minutes, the mixture was cooled to room temperature, diluted with 19.5 ml of tetrahydrofuran, 4 ml of 50% aqueous potassium carbonate were added thereto, and the resulting mixture was stirred vigorously for 30 minutes. The organic solution is filtered through a filter aid and the filter cake is washed with 90 ml of tetrahydrofuran. The organic solutions were combined, dilute hydrochloric acid (10 ml) was added and the biphasic mixture was stirred at room temperature for 14 hours. The resulting mixture was neutralized with saturated aqueous sodium bicarbonate solution and concentrated under reduced pressure. The residue was partitioned between brine and dichloromethane, dried over magnesium sulfate and concentrated to a yellow oil. The crude product was purified by flash chromatography using a mixture of equal parts of diethyl ether and ethyl acetate as eluent to give 526 mg of the title compound as a pale yellow solid.

¹ H-NMR (CDCl 3): 1.33 (3H, t, 3 = 7 Hz, 2.59 (3H, s), 4.1 (2H, s), 4.29 (2H, q, 3 = 7) Hz, 7.15-7.35 (3H, m), 7.56 (2H, d, 3 = 9 Hz), 7.79 (1H, d, 3 = 8 Hz), 8.20 (2H, d , J = 9 Hz).

Preparations 2 to 20

According to the general procedure described in Preparation 1, additional ketoesters are summarized in Table 3 below from the corresponding nitriles.

CS 270 592 02

7 trifluoroacetic acid was stirred at room temperature for 15-20 minutes. The resulting products correspond to formula III (III).

X

CS 270 592 82

(1N, s)

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Preparation 21

Ethyl 4- (4-methylimidazol-1-yl) benzoylacetate

(a) 4'- (4-methylimidazol-1-yl) acetophenone

A mixture of 4'-fluoroacetophanone (13.8 g, 100 mmol), 4-methylimidazole (8.2 g, 100 mmol) and potassium carbonate (20.7 g, 150 mmol) was heated to 150 DEG C. in 190 ml of dry dimethylformamide for 23 hours. Most of the solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and aqueous sodium chloride solution. The organic layer was washed three times with brine, dried over magnesium sulfate and evaporated to a sticky solid which was purified by flash chromatography using 5% diethylamine in ethyl acetate as eluent. Recrystallization from ethyl acetate / hexane gave 4 g (204) of the title compound, melting at 100 ° C. ’

b) Ethyl-4-methylimidazol-1-yl) benzoylacetate

To a suspension of sodium hydride (0.44 g of a 60 * dispersion in mineral oil, washed with dry hexane) in 12 ml of diethyl carbonate, 2 g (10 mmol) of the product prepared in (a) is slowly added under reflux. After refluxing for one hour, an additional 500 mg of sodium hydride is added and refluxing is continued for 2 hours. Excess sodium hydride was decomposed by addition of ethanol and the resulting mixture was evaporated to dryness. The residue was dissolved in a minimum volume of 2M hydrochloric acid and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extract was dried over magnesium sulphate and evaporated to a gummy residue which, after flash chromatography using ethyl acetate as eluent, afforded 400 mg (15%) of the title compound as a white solid.

^X H-

NMR (CDCl3): 1.30 (3H, t, 3 = 6Hz) 2.33 (3H, with), 4.05 (2H, s), 4.25 (2H, q, 3 = 6Hz) 7.11 (1H, with), 7.52 (2H, d, 3 = 9) 7.90 (1H, s), 8.11 (2H, d, 3 = 9 Hz). Ex 1 p г a v a 22nd

Hz),

Ethyl 4- (3,5-dimethyl-1,2,4-triazol-1-yl) benzoylacetate

The procedure described in Preparation 21 was repeated except that an appropriate amount of 3,5-dimethyl-1,2,4-triazole was used instead of 4-methylimidazole. Step (a) yields 4 '- (3,5-dimethyl-1,2,4-triazol-1-yl) acetophenone in 42% yield. In step (b), ethyl 1-4 (yield 63%) is obtained. 3,5-dimethyl-1,2,4-triazol-1-yl) benzoylacetate.

1 H-NMR of the title ketoester (deuterochloroform):

1.30 (1H, t), 2.47 and 2.60 (3H, s each), 4.04 (2H, s), 4.25 (2H, q), 7.66 and 8.11 (each 2H, d, J = 9Hz).

Preparation 23

Ethyl-4 '- (1-benzimidazolyl) benzoylacetate (a) 4' - (1-benzimidazolyl) acetophenone

CS 270 592 02

A mixture of 3.98 g (20 mmol) of p-bromoacetophenone, 4.72 g (40 mmol) of benzimidazole, 1.27 g (20 mmol) of copper bronze, 5.52 g (40 mmol) of basic potassium carbonate and 290 mg (2 mmol) of copper bromide in 60 ml of dry N-methylpyrrolidinone was heated at 160 ° C under nitrogen for 6 hours. Most of the solvent was distilled off under reduced pressure, and the residue was stirred with 500 ml of dichloromethane and 200 ml of 2N sodium hydroxide. The organic layer was washed with 300 mL of water and, after drying over magnesium sulfate, concentrated to a dark brown oily residue which, after purification by flash chromatography using ethyl acetate as eluent, afforded 3.085 g of 4 '- (1-benzimidezolyl) acetoenone as a pale yellow solid. m.p. 133-135 ° C; 1 H-NMR (CDCl 3)? 2.73 (3H, e), 7.46 (2H, m), 7.65 (1H, m), 7.69 (2H , d, 8 Hz), 7.94 (1H, m), 8.21 (1H, s), 8.23 (2H, d, 3-8 Hz).

. (b) Ethyl 1-4 (1-benzimidazolyl) benzoylacetate,

The title compound was prepared by appropriate modification of the procedure described in U.S. Pat. No. 4,353,905. 132 mg (4.4 mmol) of a 60% sodium hydride dispersion in oil were washed with dry pentane, suspended under nitrogen in 10 mL of dry tetrahydrofuran as described above. a solution of 944 mg (4.0 mmol) of 4 '- (1-benzlimidazolyl) acetophenone in 20 mL of dry tetrahydrofuran was added dropwise. After stirring at room temperature for 1 hour, diethyl carbonate (1.21 mL, 10 mmol) was added. The reaction mixture was heated under reflux for 18 hours, then cooled and filtered. The solid material was suspended in water, acidified with acetic acid, and extracted with dichloromethane. The extracts were dried (MgSO 4) and the residue purified by flash chromatography (4: 1 ethyl acetate: hexane). 449 mg of ethyl 4 '- (1-benzimidazolyl) benzoylacetate is obtained as a colorless solid, m.p. 69-71 ° C.

^* H-NMR (CDCl₃) and 1.32 (3H, t, 3 «6 Hz), 4.08 (2H," a), 4.28 (2H, q, 3 = 6Hz), 7.41 ( 2H, m), 7.63 (1H, m), 7.71 (2H, m), 7.94 (1H, m),

8.22 (3H, m).

Methyl 4 '- (imidazol-1-yl) benzoylacetate was prepared as described in U.S. Patent 4,353,905.

¹ Preparation 24 l- (4-cyanophenyl) -2-methylbenzimidazole (a) N- (4-iodophenyl) -2-nitroaniline.

According to the method described by V. P. Chernetskii а А. I. Kuprianov in Zh. Obsch. Khim., 1956, 2.6, 3465, a mixture of 14.0 g (100 mmol) of 2-fluoronitrobenzene, 10.95 g (50 mmol) of p-iodoaniline and 13.9 ml (100 mmol) of triethylamine is heated at reflux for 42 hours. under reflux. The reaction mixture was cooled, diluted with 300 ml of ethyl acetate and washed successively with 100 ml of water, 100 ml of 2N sodium hydroxide and 100 ml of sodium chloride solution. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate. 10.03 g of N- (4-iodophenyl) -2-nitroaniline are obtained in the form of bright orange needle crystals, m.p. 171-172 ° C. ...

(b) N- (4-iodophenyl) -1,2-aminobenzene.

According to the method given in Chein. Abe., 1962, £ 7, 9840a, a solution of 24.74 g of 85% dithionium

CS 270 592 B2 sodium citrate (121 mmol) in 120 mL of water was added to a suspension of (4-iodophenyl) -2-nitroaniline in 500 mL of ethanol. The mixture was heated to reflux for 45 minutes, then cooled, 300 ml of dilute aqueous ammonia solution were added, and the resulting mixture was concentrated under reduced pressure. The resulting white suspension was added. 200 ml of dilute aqueous ammonia solution, the mixture is filtered and the residue on the filter is washed with 200 ml of water. The solid product, after drying in a vacuum desiccator at room temperature, affords 8.91 g of N- (4-iodophenyl) -1-2-diaminobenzene, which melts at 122-123 ° C and slowly darkens in light.

1 H-NMR (CDCl 3): 3.81 (2H, bs), 5.21 (1H, bs), 6.54 (2H, d, 3 = 8 Hz),

6.82 (2H, tn), 7.09 (2H, m), 7.48 (2H, d, 3 = 8 Hz).

(c) 1- (4-iodophenyl) -2-methylbenzimidazole

Ethyl acetimidate hydrochloride (6.757 g, 54.9 mmol) was added at room temperature to a suspension of N- (4-iodophenyl) -1,2-diaminobenzene (6.2 g, 22.0 mmol) in absolute ethanol (30 ml). After two hours, 50 ml of ice-cold 2N aqueous sodium hydroxide are added and the product is extracted twice with 100 ml of ethyl acetate each time. The extracts were washed with water (3.times.100 ml), dried (MgSO4) and concentrated under reduced pressure. There were obtained 6.695 g of 1- (4-iodophenyl) -2-methylbenzimidazole as a white solid, m.p. 137 ° C.

1 H-NMR (CDCl 3): 2.55 (3H, s), 7.14 (1H, d, J = 8Hz), 7.17 (2H, d, 3 = 8Hz), 7. 25 ( 1H, t, 3 = 8Hz), 7.31 (1H, t, 3 = 8Hz), 7.93 (1H, d, 3 = 8Hz), 7.95 (2H, d, 3 = 8Hz) ).

(d) 1- (4-cyanophenyl) -2-methylbenzimidazole.

To a mixture of 5.184 g (15.5 mmol) of 1- (4-iodophenyl) -2-methylbenzimidazole and 170 mg of palladium acetate in 15 ml of N, N &apos; -dimethyl-1,4,5,6-tetrahydro-2-pyrimidone was added. Copper cyanide (8.323 g, 93 mmol) was added and the resulting solution was heated to 100 ° C under nitrogen for 15 hours. The reaction mixture was cooled, poured into 150 ml of saturated aqueous ammonia solution and shaken to dissolve the salts. The resulting mixture was extracted with ether (3.times.150 ml), the combined extracts were washed successively with water (3.times.150 ml) and brine (150 ml), dried (MgSO4) and concentrated under reduced pressure. 941 mg of 1- (4-cyanophenyl) -2-methylbenzimidazole are obtained as a white solid.

1 H-NMR (CDCl 3): 2.58 (3H, s), 7.17 (1H, d, 3 = 8 Hz), 7.27 (1H, t, J = 8 Hz), 7.34 (1H t, 3 = 8Hz), 7.58 (2H, d, J = 1Hz), 7.79 (1H, d, J = 8Hz), 7.95 (2H, d, 3 = 8Hz) .

Preparation 25

4- (4-cyanophenyl) -3,5-dimethyl-1,2,4-triazole

To a solution of 5.43 g (30.9 mmol) of p -cyanthioacetanilide (prepared according to 3. Pharm. Soc. 3pn., 1952, 72, 739) in 50 ml of tetrahydrofuran, 1.64 ml (34 mmol) was added dropwise at room temperature. hydrazine hydrate. After 30 minutes, the resulting solution was concentrated under reduced pressure, and 40 ml of triethyl orthoacetate was added to the residue. The reaction mixture was heated at 80 ° C for 30 minutes, then cooled and excess reagent was evaporated under reduced pressure. The residue is stirred with 100 ml of ice cold dilute aqueous ammonia solution, the product is filtered off and, after washing with water, dried under vacuum. 4.85 g of the title triazole are obtained as an off-white solid melting above 230 ° C.

1 H-NMR (CDCl 3): 2.32 (6H, s), 7.42 (2H, d, 3-8 Hz), 7.92 (2H, d, 3 ^s 8 Hz).

Preparation 26 1- (4-Cyanophenyl) -2-methylimidazo [4,5-c] pyridine (a) N- (4-cyanophenyl) -4-amino-3-nitropyridine.

To a solution of 9.26 g (58.4 mmol) of 4-chloro-3-nitropyridine in 200 ml of ethanol, 6.894 g ( 58.4 mmol) of p-cyananiline and the mixture was stirred at room temperature for 18 hours. The resulting yellow suspension is poured into 500 ml of ice cold dilute ammonia, the solid material is filtered off, stirred with 150 ml of boiling ethanol and, after cooling in ice, filtered again. 12.15 g of N- (4-cyanophenyl) -4-amino-3-nitropyridine are obtained in the form of a bright yellow powder, melting at 210 DEG-211 DEG.

1 H-NMR (CDCl 3): 7.15 (1H, d, 3-6 Hz), 7.45 (2H, d, 3-9 Hz), 7.79 (2H, d, = 9 Hz), 8 43 (1H, d, 3-6 Hz), 9.36 (1H, e), 9.80 (1H, ee).

(b) 3-amino-4- (4'-cyanophenylaminopyridine)

In accordance with a modification of the method described in Pharm. Helv. Acta, 1975, 50, 188 was added to a suspension of 12.0 g (50 mmol) of N- (4-cyanophenyl) -4-amino-3-nitropyridine in 35 mL of 2N aqueous acid. hydrochloric acid, 150 ml of water and 75 ml of ethanol are added 56.4 g (250 mmol) of stannous chloride dihydrate and the resulting mixture is refluxed under nitrogen for 10 minutes. The reaction mixture was cooled in ice, poured into 400 ml of ice-cold 2N aqueous sodium hydroxide solution, and the resulting mixture was filtered. The cream colored solid was washed with 2N aqueous sodium hydroxide solution and water and dried in a vacuum desiccator. 9.31 g of 3-amino-4- (4'-cyanophenyl) aminopyridine is obtained, which gradually changes color to reddish-brown in the light and in the air.

¹ H-NMR (CDCl 3): 3.52 (2H, bs), 6.04 (1H, bs), 7.03 (2H, d, 3-9 Hz), 7.59 (2H, d, 3 = 9 Hz), 8.07 (1H, m), 8.20 (1H, s).

(c) 1- (4-cyanophenyl) -2-methylimidazo (4,5-c) pyridine

A mixture of 9.31 g (44.3 mmol) of 3-amino-4- (4'-cyanophenyl) aminopyridine, 40 ml of triethyl orthoacetate and 30 ml of acetic anhydride was heated under reflux for 2 hours under nitrogen, then cooled. and concentrated under reduced pressure. The brown residue was dissolved in 1M hydrochloric acid and the solution was washed with 200 ml of stoyl acetate. The aqueous layer was made basic with aqueous ammonia solution and extracted three times with 200 ml of dichloromethane each time. The combined extracts were washed with water and, after drying with magnesium sulfate, concentrated. 6.5 g of 1- (4-cyanophenyl) -2-methylimidazo [1,5-c] pyridine are obtained as a brown solid.

¹ H-NMR (CDCl 3): 2.61 (3H, s), 7.13 (1H, d, 3 = 6 Hz), 7.58 (2H, d, 3 = 9 Hz),

7.98 (2H, d, 3 = 9 Hz), 8.45 (1H, d, 3-6 Hz), 8.11 (1H, s).

CS 270 592 B2

Preparation 27

1- (4-cyanophenyl) -2-trifluoromethylimidazo [4,5-c] pyridine

A mixture of 420 mg (2.0 mmol) of the above-prepared 3-amino-4- (4'-cyanophenyl) aminopyridine, 232 mg (2.0 mmol) of trifluoroacetaldehyde hydrate and 475 mg (2.5 mmol) of sodium metabisulfite in 10 ml Ν The Ν-dimethylacetamide was heated to reflux for 16 hours. After cooling, the reaction mixture is diluted with 200 ml of ethyl acetate, washed with 50 ml of saturated aqueous sodium bicarbonate solution and five times with 50 ml of water each time. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate) to give 1- (4-cyanophenyl) -2-trifluoromethylimidazo [4,5-c] pyridine (337 mg).

¹ H-NMR (CDCl 3): 7.17 (1H, d, 3 = 5 Hz), 7.63 (2H, d, J = 8 Hz), 7.99 (2H, d, 3 = 8 Hz) 8.62 (1H, d, J = 5 Hz), 9.35 (1H, e).

Preparation 28

2-Butyl-1- (4-cyanophenyl) imidazo [4,5-c] pyridine

A mixture of 1.26 g (6.0 mmol) of 3-amino-4- (4'-cyanophenyl) aminopyridine [see Preparation 26 (ЬУ) and 10 ml of valeric anhydride was refluxed under nitrogen for 16 hours. The reaction mixture was cooled, poured into 100 ml of 2N aqueous sodium hydroxide and allowed to stand for 15 minutes. The resulting solution was extracted three times with 70 ml of dichloromethane each time, the extracts were dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography (9: 1 ethyl acetate: methanol) gave 947 mg of the title compound as a brown solid.

@ 1 H-NMR (CDCl3): 0.93 (3H, t, J = 8Hz), 1.4 (2H, p, J = 8Hz), 1.86 (2H, p, J = 8Hz) 2.2 Θ4 (2H, t, J = 8Hz), 7.10 (1H, d, J = 5Hz),

7.56 (2H, d, J = 8 Hz), 7.97 (2H, d, J = 8 Hz), 8.46 (1H, d, J = 5 Hz), 9.13 (1H> a) .

Preparation 29 1- (4-Cyanophenyl) -2-ethylimidazo [4,5-o] pyridine

A mixture of 2.00 g (9.5 mmol) of 3-amino-4- (4'-cyanophenyl) aminopyridine [see Preparation 26 (b)] and 12.2 ml (95 mmol) of propionic anhydride under nitrogen for 17 hours heats to reflux. Excess aqueous sodium bicarbonate solution was added to the resulting solution, and the product was extracted three times with 150 ml of dichloromethane each time. The combined extracts were dried over magnesium sulphate, concentrated under reduced pressure and the residue purified by flash chromatography using a gradient elution of ethyl acetate-methanol mixtures. This afforded 510 mg (22%) of the title compound as a brown solid.

@ 1 H-NMR (300 MHz, CDCl3): 1.45 (3H, t, J = 7 Hz), 2.87 (2H, q 7.10 (1H, d, J = 5 Hz), 7.55 (2H, d 7.96 (2H, d, J = 8 Hz), 8.44 (1H, d 9.13 (1H, with).

- 7 Hz),

J = 8Hz)

J = 5 Hz)

CS 270 592 B2

Preparation 30

9- (4-cyanophenyl) -6-methoxy-8-methylpurine (a) 5-amino-6-chloro-4- (4-cyanophenyl) amino-pyrimidine *)

A solution of 5-amino-4,6-dichloropyrimidine (7.00 g, 42.7 mmol) and 4-aminobenzonitrile (5.04 g, 42.7 mmol) in n-butanol (130 ml) was heated at reflux for 16 h. After cooling the reaction mixture, the precipitated solid material was filtered off and partitioned between 500 ml of dichloromethane and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to give 6.31 g (60%) of the title compound. ¹ H-NMR (300 MHz, CDCl 3): 7.72 (2H, d, 3 = 8) Hz), 7.99 (2H, d, 3 = 8 Hz), 8.02 (1H, s).

(b) 4- (acetyl- [4-cyanophenyl) amino] -6-chloro-5-diacetylaminopyrimidine

A mixture of 6.31 g (25.7 mmol) of 5-amino-6-chloro-4- (4-cyanophenyl) aminopyrimidine and 105 ml of acetic anhydride was heated at 120 ° C for 6 hours and then allowed to stand at 20 ° for 16 hours. C. Excess reagent was evaporated under reduced pressure and the residue was recrystallized from methanol. This gave 4.62 g (51%) of the title compound as a white solid.

@ 1 H-NMR (300 MHz, CDCl3): 2.15 (3H, a), 2.38 (6H, s), 7.40 (2H, d, = 8 Hz), 7.80 (2H, d, 3) = 8 Hz), 8.87 (1H, s).

(c) 6-chloro-9- (4-cyanophenyl) -8-methylpurine

2.50 g (6.73 mmol) of 4- (N-acetyl-N- (4-cyanophenyl) amino) -6-chloro-5- (N, N'-diacetylamino) pyrimidine was heated at 6 for 2 hours, 7 kPa to 240 ° C. The reaction melt was cooled and purified by flash chromatography using a 3: 1 mixture of ethyl acetate and dichloromethane as eluent. This afforded 1.10 g (61%) of the title compound. .

(d) 9- (4-cyanophenyl) -6-methoxy-8-methylpurine

160 mg (6.96 mmol) of sodium metal was treated with 5 ml of dry methanol under a nitrogen atmosphere until hydrogen evolution ceased, followed by the addition of 1.03 g (3.82 mmol) of 6-chloro-9- ( 4-cyanophenyl) -8-methylpurine and the resulting suspension was heated to reflux for 90 minutes. The solvent is evaporated under reduced pressure, the gummy residue is dissolved in 50 ml of dichloromethane, the solution is washed with 20 ml of sodium chloride solution and, after drying over magnesium sulphate, concentrated under reduced pressure. This afforded 840 mg (83%) of the title compound.

¹ H-NMR (300 MHz, CDCl 3): 2.63 (3H, s), 4.26 (3H, s), 7.63 (2H, d, 3 = 8 Hz),

7.95 (2H, d, J = 8 Hz), 8.52 (1H, s).

CS 270 592 B2

Preparation 31

3- (4-cyanophenyl) -2-methylimidazo 4,5-c pyridine J (a) 2-methylimidazo [4,5-c] pyridine

A mixture of 3,4-diaminopyridine (20.0 g, 183 mmol) and acetic anhydride (360 mL) was heated at 100 ° C for 16 h. Excess reagent was evaporated under reduced pressure and the residue purified by flash chromatography using a 3: 1 mixture of ethyl acetate and methanol as eluent. 15.5 g (64%) of the desired product are obtained as a brown solid. .

@ 1 H-NMR (300 MHz, CDCl3): 2.68 (3H, s), 7.58 (1H, d, .delta. = 6 Hz), 8.31 (1H, d, .delta. = 6 Hz), .delta. .80 (1H, s). ^:

B ‘(b) 2-methylimidazo [4,5- (4-pyridine-N-oxide)

In accordance with the procedure described in Chem. Pharm. Bull., 12, 866 (1964), a solution of 5.65 g (42.5 mmol) of 2-methylimidazo [4,5-c] pyridine in 15 ml of 30% aqueous hydrogen peroxide and glacial acetic acid is stirred at room temperature for 6 days. 60 ° C. The volatiles were evaporated under reduced pressure, the residue was dissolved in ethanol and solid anhydrous potassium carbonate was added to the solution. The solid material was filtered off, washed with ethanol and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using a 10-30% water in acetone solution. The fractions containing the desired product are concentrated under reduced pressure, the residue is redissolved in 200 ml of a mixture of equal parts of isopropanol and toluene and the solution is evaporated. This afforded 2.94 g (46%) of the title compound as a hygroscopic solid.

¹ H-NMR (300 MHz, CD OD): 2.69 (3H, s), 7.69 (2H, d, 3 = 6Hz), 8.23 (1H, d,

J = 6Hz), 8.72 (1H, s).

(c) 3- (4-cyanophenyl) -2-methylimidazo [4,5- c] pyridine

2.06 g (13.8 mmol) of 2-methylimidazo [4,5-c] pyridine-N-oxide, 1.67 g (13.8 mmol)

Of 4-fluorobenzonitrile and 13.8 mmol of anhydrous potassium carbonate in 35 ml of dry dimethylformamide was heated at 140 ° C under nitrogen for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a mixture of 1- and 3- (4-cyanophenyl) -2-methylimidazo [4,5-c] pyridine-N-oxides.

This mixture was dissolved in 40 ml of glacial acetic acid and 1.16 g (20.7 mmol) of iron powder was added. The reaction mixture was heated at 100 ° C for 30 minutes, then cooled and filtered through a filter aid. The filtrate is concentrated under reduced pressure, the residue is taken up in 150 ml of dichloromethane and the solution is washed with a saturated aqueous solution of sodium bicarbonate. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 9: 1 mixture of ethyl acetate and methanol as eluent. Three fractions were collected in this chromatography. 415 mg (13%) of 3- (4-cyanophenyl) -2-methylimidazo [4,5-c] pyridine was eluted first.

1 H-NMR (300 MHz, CDCl 3) δ 2.64 (3H, s), 7.62 (2H, d, 3 = 8 Hz), 7.70 (1H, d, = 5 Hz), 7., 98 (2H, d, 3 = 8Hz), 8.52 (1H, d, = 5Hz), 8.59 (1H, s). .

3) The second fraction was eluted with 410 mg (13%) of a mixture of 3- and 1- (4-cyanophenyl) -2-methylimidazo-4,5-c-pyridines and the third eluted with 350 mg (11%) of pure 1- (4- cyanophenyl) -2-methyllimidazo 4,5-c pyridine.

CS 270 592 B2

Preparation 32

1- (4-Cyanophenyl-2,4,6-triniethylimidazo [4,5-c] pyridine (a) 2,6-Dimethyl-3-nitro-4-pyridone

52.56 g (0.427 mmol) of 2,6-dimethyl-4-pyridone Chem. (1976) is dissolved at 50 ° C vs 100 ml of water and 40 ml of fuming nitric acid is added dropwise. The mixture was cooled in ice for 45 minutes, then the precipitated pale yellow-brown crystals were filtered off, washed with a small amount of water and sucked dry to give 46.79 g (59%) of 2,6-dimethyl-4-pyridone salt with nitric acid. . This material was added portionwise at room temperature to a mixture of 23 ml of fuming sulfuric acid and 31 ml of fuming nitric acid. The mixture was heated to 100 ° C, maintained at this temperature for 5.5 hours, then poured onto ice and scrolled with a saturated aqueous potassium carbonate solution. Precipitated light yellow solid ma. The material was filtered off, introduced into a Soxhlet extractor and extracted with boiling isopropanol. Evaporation of isopropanol under reduced pressure gave 26.5 g (63%) of the title compound.

¹ H-NMR (300 MHz, CDCl 3): 2.3B (3H, s), 2.45 (3H, s), 6.39 (1H, 3).

(b) 4-chloro-2,6-dimethyl-3-nitropyridine

11.23 g (66.8 mmol) of 2,6-dimethyl-3-nitro-4-pyridone together with 57 ml. of phosphorus oxychloride was heated to reflux for 1.5 hours. Excess reagent is evaporated under reduced pressure, the residue is dissolved in 150 ml of dichloromethane, dilute aqueous sodium bicarbonate solution is added to the solution until the aqueous layer has a pH of 7, then the organic phase is separated and dried over magnesium sulfate. This gave 9.8 g (79%) of a light yellow solid.

Warning: this, the compound strongly irritates the skin.

¹ H-NMR (300 MHz, CDCl 3): 2.58 (3H, 3), 2.61 (3H, s), 7.22 (1H, s).

(c) 4- (4-cyanienyl) amino-2,6-dimethyl-3-nitropyridine

A solution of 4-chloro-2,6-dimethyl-3-nitropyridine (9.82 g, 52.5 mmol) and 4-aminobenzonitrile (6.20 g, 52.5 mmol) in ethanol (160 ml) was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure, the residue was dissolved in 200 ml of dichloromethane and the solution was washed with 100 ml of a saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The gummy residue is crystallized by addition of ether (100 ml) and ultrasonic stirring for 5 minutes. Filtration and drying in vacuo gave 9.80 g (70%) of a yellow solid, m.p. 171-172 ° C.

¹ H-NMR (300 MHz, CDCl 3): 2.49 (ЗN, з), 2.76 (3H, s), 6.96 (1H, s), 7.35 (2H, d, 0 = 8 Hz) 7.74 (2H, d, 3-8 Hz), 8.69 (1H, bs).

(d) 3-amino-4- (4-cyanophenyl) amino-2,6-dimethylpyridine

A solution of 5.00 g (18.6 mmol) of 4- (4-cyanophenyl) amino-2,6-dimethyl-3-nitropyridine in a mixture of 20 mL of dichloromethane and 100 mL of ethanol was treated with 500 mg of 10% palladium on carbon for 3 hours it is hydrogenated at 20 DEG C. under a pressure of 138 kPa. The catalyst was filtered off and the solvent was evaporated under reduced pressure to give 4.20 g (94%) of the title compound as a brown solid, m.p.

CS 270 592 B2 ^X H-NMR (300 MHz, CD OD): 2.39 (3H, 8), 2.62 (3H, 8), 6.90 (1H, s), 7.11 (2H, d, J * V Hz), 7.62 (2H, d, 3.0 Hz) Λ (θ) 1- (1,4-cyanophenyl) -2,4,6-trimethylimidazo-4,5-c-pyridine

Sm6s 4.20 kg (17.6 mmol) of 3-amino-4- (4-cyanophenyl) amino-2,6-dimethylpyrldine, 12.6 mL of acetic anhydride and 12.6 mL of acetic acid are stirred at 100 ° C for 16 h. C, whereupon excess reagents were evaporated under reduced pressure. The resinous residue was dissolved in water and the solution basified by the addition of concentrated aqueous ammonia. The precipitated white solid was filtered off and dried in vacuo. 4.06 g (88%) of the title compound of melting point 260 DEG-262 DEG C. are obtained.

¹ H-NMR (300 MHz, CDCl 3): 2.60 (3H, s), 2.65 (3H, s), 2.90 (3H, s), 6.01 (1H, s), 55 (2H, d, 3 = 0 Hz), -7.96 (2H, d, 3 = 0 Hz).

Analysis calculated for: ^C 16 ^H 14 ^N 4: C, 73.26; H, 5.38; N, 21.36. Found: C, 73.57; H, 5.37; N, 21.53.

Preparation 33 (1S) -N- (1-Phenylethyl) -3-aminobut-2-enamide

4.20 g (20.5 mmol) of (1 * S) -N- (1-phenylethyl) -3-ketobutanamide (J. Chem. Eng. Data., 1954, 22, 229) was dissolved in 20 ml at room temperature. ml of ethanol and ammonia gas were added to the solution for 6 hours. The solvent was evaporated under reduced pressure to give 4.00 g (95%) of the title compound as a tan oil which can be used directly in the Hantzsch reaction without further purification.

Preparation 34

4- (2,4-Dimethylimidazol-1-yl) benzonitrile

A mixture of 3 g (25 mmol) of 4-fluorobenzonitrile, 3 g (25 mmol) of 2,4-dimethylimidazolium chloride and 7.2 g (52 mmol) of potassium carbonate in 50 ml of dimethylformamide was heated at 145 ° C for 16 h. Most of the solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate and evaporated to a yellow solid which crystallized from hexane-ether to give 2.6 g (57%) of a pale yellow solid.

@ 1 H-NMR (CDCl3): inter alia 2.25 and 2.41 (3H, s each), 6.78 (1H, s), 7.43 and 7.80 (2H, d, J each); 9 Hz).

Preparation 35

4- (2-Methylimidazol-1-yl) benzonitrile

The process described in Preparation 34 was repeated except that 25 mmol of 2-methylimidazolium chloride was used in place of 2,4-dimethylimidazolium CS 270 592 02 chloride. The title nitrile is obtained in 22% yield. J '.i i' ^X H NMK (CDCl₃), inter alia. 2.44 (3H, s), /, and 09 7> 8 (each 2H, d, J = 9Hz),

7.04 (2H, d, J = 8Hz). ' ¹ '. -PjPiI Preamble -36

4- (2,4,5-trimethylimidazol-1-yl) benzonitrile

The procedure described in Preparation 34 was repeated except that 25 mmol of 2,4,5-trimethylimidazolium chloride was used in place of 2,4-dimethylimidazolium chloride. The title nitrile is obtained in 7% yield. @ 1 H-NMR (CDCl3): inter alia 1.96, 2.10 and 2.23 (3H, s each), 7.34 and 7.84 (2H, d, J = 9 Hz each).

Preparation 37

3- (4-cyanophenyl) -2-methylpyridine

To a solution of 2.81 g (15.4 mmol) of 4-bromobenzonitrile in 100 ml of anhydrous tetrahydrofuran was added dropwise 18.1 ml (32.6 mmol) of a 1.8 M solution of tert-butanol at -60-5 ° C under stirring. butyllithium in pentane. ·

After stirring for 20 minutes at the above temperature, a solution of 4.62 g (33.8 mmol) of dry zinc chloride in 55 ml of tetrahydrofuran was added via a tube, the resulting solution was heated to +10 ° C with stirring over 10 minutes. 0.5 g (0.43 mmol) of tetrakis (triphenylphosphine) palladium and 3.19 g (18.5 mmol) of 3-bromo-2-methylpyridine were then added and the resulting clear red colored solution was stirred at reflux for 5.5 hours.

After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to a volume of about 50 ml and the concentrate was partitioned between 300 ml of methylene chloride and a solution of 8 g of ethylenediaminetetraacetic acid disodium salt and 10 g of sodium carbonate in 500 ml of water. The organic extract was separated, dried (MgSO4) and concentrated under reduced pressure to a dark oily residue.

The above oily residue is chromatographed on silica gel using a gradient of 0% to 100% ether in hexane. Product containing fractions were combined and concentrated under reduced pressure to give 0.6 g (20%) of the oily title compound which solidified on standing;

¹ H-NMR (CDCl 3): δ 2.52 (3H, s), 7.26 (1H, m), 7.48 (2H, d, J = 9 Hz), <7.53 (1H, m) 7.78 (2H, d, J = 9Hz), 8.58 (1H, m).

Preparation 38

Synthesis of 3- (4-cyanophenyl) -2,6-dimethylpyridine

To a stirred suspension of 0.8 g (33 mmol) of magnesium shavings and a single iodine crystal in 15 mL of anhydrous tetrahydrofuran, a solution of 5.58 g (30 mmol) of 3-bromo-2,6-dimethylpyridine was added under reflux under nitrogen. in 20 ml of anhydrous tetrahydrofuran and the mixture was refluxed for a further 1 hour with stirring.

CS 270 592 82

After cooling to room temperature, a solution of 4.1 g (30 mmol) of dry zinc chloride in 40 ml of anhydrous tetrahydrofuran and then 0.2 g (17 mmol) of tetrakis (triphenylphosphine) palladium and solution 2 is added to the mixture while stirring. 34 g (13 mmol) of 4-bromobenzonitrile in 5 ml of anhydrous tetrahydrofuran. The reaction mixture was then heated to reflux for 1 hour with stirring.

After cooling to room temperature, the reaction mixture was partitioned between 200 ml of methylene chloride and a solution of 8 g of disodium arylenediaminetetraacetic acid and 10 g of sodium carbonate in 500 ml of water. The organic extract was separated, dried and magnesium sulphate and concentrated under reduced pressure.

The oily residue was flash chromatographed on silica gel using ether: hexane / diethylamine (25: 75: 2) as eluent. The fractions containing the product were combined and concentrated to a volume of about 10 ml. The precipitated crystals are filtered off and, after washing with ether, dried to dryness. This gave 1.2 g (44%) of the title compound. .

@ 1 H-NMR (CDCl3): inter alia 2.50 and 2.62 (3H, s each), 7.12 and 7.43 (1H, d, J = 8 Hz each), 7.47 and 7, respectively. 77 (each 2H, d, J = 9 Hz).

Preparation 39

5- (4-cyanophenyl) -4-methyloxazole

A biphasic mixture of 0.6 ml (15 mmol) of formamide and 0.8 kg (3.4 mmol) of 4-tert-bromo-2-oxopropyl) benzonitrile was stirred at 120 ° C for 2 hours, then cooled and added. to 15 ml of dichloromethane and 10 ml of saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried and magnesium sulfate, and the solvent was evaporated under reduced pressure to give 0.4 g of an amorphous yellow solid which, after purification by silica gel chromatography eluting with dichloromethane gave 0.29 g (47%). ) of the title compound as a light yellow solid, m.p. 120-121 ° C.

• Preparation 40

5- (4-cyanophenyl) -6-methylimidazo 2,1-b thiazole,

To a hot (110 ° C) solution of 2-aminothiazole in 3 mL of n-butanol was added a solution of 1 g (4 mmol) of 4- (1-bromo-2-oxopropyl) -benzonitrile in 3 mL of n-butanol. After refluxing for 2 hours, 0.5 ml (4 mmol) of triethylamine is added and heating is continued for a further 2 hours. All volatiles were evaporated and the residue was chromatographed on silica gel using ethyl acetate / hexane / diethylamine (5: 14: 1) as eluent. There was obtained 0.34 g (35%) of an off-white solid, m.p. 88-91 ° C. ·

Preparation 41 *

5- (4-cyanophenyl) -2,4-dimethylthiazole

To a solution of 0.9 g (3.83 mmol) of 4- (1-bromo-2-oxopropyl) benzonitrile in 2 ml of toluene was first added 0.6 g (8 mmol) of thioacetamide and then 0.45 ml of pyridine. The mixture was heated at 100 ° C for 1 hour and then partitioned between ethyl acetate and brine. Organic layer

The solid was dried over magnesium sulphate and evaporated to a yellow oily residue which, after chromatography on silica gel using 5 4 ether in dichloromethane as eluent, gave a pale yellow oily product which crystallized. There was obtained 0.52 g (64%) of the desired product, m.p.

Preparation 42

5- (4-cyanophenyl) -4-methylthiazole (a) 5- (4-cyanophenyl) -4-methylthiszole-2-thiol

A solution of 4.65 was added to a stirred suspension of ammonium dithiocarbate 2.2 g (0.02 mmol) in 20 mL absolute ethanol at room temperature over 10 minutes. g (0.02 mol) of 4- (1-bromo-2-oxopropyl) benzonitrile in 20 ml of absolute ethanol is stirred for a further 24 hours, then 50 ml of water are added, most of the ethanol is evaporated under reduced pressure and the product was extracted with ethyl acetate. The organic extract was dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with ethanol and filtered to give 1.2 g (26%) of the title compound.

(b) 5- (4-cyanophenyl) -4-methylthiazole

To a solution of 1.2 g (5 mmol) of the product of (a) in 120 ml of absolute ethanol was added 1 g of Raney nickel, the mixture was heated to 80 ° C in an autoclave for 18 hours, then cooled to room temperature. An additional 1 g of Raney-Nickel was added and the resulting mixture was heated in an autoclave at 80 ° C for a further 6 hours. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to dryness. The residue was flash chromatographed on silica gel using ethyl acetate / hexane / diathylamine (25: 75: 2) as eluent. 0.35 g (35%) of the title compound is obtained as a resinous material which solidifies on standing and is directly used in Preparation 19.

Preparation 43

Ethyl 2- (2-methylimidazo-4,5-c pyrid-1-ylpyrid-4-oyl acetate (a) 4-chloro-1- (5-ethoxycarbonylpyrid-2-yl) -2-methylimidazole ZO 4,5- c pyridine

3.34 g (20 mmol) of 4-chloro-2-methylimidazo-4,5-c pyridine described in C.A. 79, 105515Z, but prepared according to Chem. Pharm. Bull ·, 12 (8) 866-872 (1964) and 3.71 g (26.2 mmol) of ethyl 6-chloro-clotinate are dissolved in 42 ml of Ν, Ν-dimethylformamide, 2.76 g (20 mmol) are added. ) of potassium carbonate, the reaction mixture is heated to reflux over noo. The mixture was then cooled and the solvent was evaporated under reduced pressure. The crude product was dried by flash chromatography using ethyl acetate as eluent. The fractions containing the product were evaporated and the foamy residue was triturated with ether. The solid material is filtered off and dried under reduced pressure to give 3.2 g (51%) of the compounds; title compound as a yellow solid.

¹ H-NMR (300 MHz, CDCl 3) δ 1.47 (3H, t, 3. 6 Hz), 2.84 (3H, s), 4.56 (2H, q, = 6 Hz), 7 38 (1H, d, J = 4 Hz),

7.59 (1H, d, 3 = 6Hz), 8.25 (1H, d, 3 = 4Hz), 8.63 (1H, d, 3 = 6Hz),

9.36 (1 H, s).

CS 270 592 02 (b) 1- (5-ethoxycarbonylpyrid-2-yl) -2-methylimidazo [4,5-c] pyridine

A solution of 4-chloro-1- (5-ethoxycarbonylpyrid-2-yl) 2-methylimidazo [4,5-o] pyridine in 100 mL of ethanol was treated with 3 g of 30% palladium on carbon and 0.8 g of magnesium oxide for 30 hours is hydrogenated at 50 mbar. The mixture is filtered through diatomaceous earth and the filter cake is washed six times with 50 ml of boiling ethanol each time. After concentration of the filtrate under reduced pressure, it is obtained

2.75 g (96 H) of the title compound as a white foam.

¹ H-NMR (300 MHz, CDCl 3): 1.51 (3H, t, 3 = 6 Hz), 2.83 (3H, s), 4.53 (2H, q, = 6Hz), 7.70 ( 1 H, d, 3 = 4 Hz), 7.92 (1H, d, 3 = 6 Hz), 8.43 (1H, d, 3 = 4 Hz), 8.72 (1H, d, 3 = = 6 Hz), 8.97 (1H, s), 9.32 (1H, s).

(c) 6- (2-methylimidazo [4,5-c] pyridin-1-yl pyridine-3-carboxylic acid)

2.75 g (9.75 mmol) of 1- (5-ethoxycarbonylpyrid-2-yl) methylimidazo [4,5-c] pyridine are dissolved in 15 ml of ethanol and 5.8 ml of 2N aqueous sodium hydroxide are added to the solution. . The mixture was stirred at room temperature for 3 days, the solvent was evaporated under reduced pressure, the residue was neutralized to pH 6 with dilute hydrochloric acid, the precipitate formed was filtered off and dried in vacuo. This gave 1.70 g (69%) of the title compound as a white solid.

¹ H-NMR (300 MHz, CDCl 3) δ 2.70 (3H, s), 7.58 (1H, d, 3-4 Hz), 7.93

1 H, d, 3 → 6 Hz), 8.36 (1 H, d, 3 = 4 Hz), 8.58 (1 H, d, J = 6 Hz), 8.96 (1 H, s), 9.18 (1 H, s).

(d) Ethyl-2- (2-methylimidazo [4,5- d] pyrld-1-yl) pyrid-5-oyl acetate 6- (2-methylimidazo [4,5-c] pyrid-1-yl) pyridine The 3-carboxylic acid is suspended in 1 ml of dry dichloromethane and 29 mg of oxalyl chloride and 1.5 mg of Ν, dl-dimethylformamide are added. The mixture was sonicated at room temperature for 1 hour to give a suspension of 6- (2-methylimidazo [4,5-c] pyridin-1-ylpyrid-3-oyl chloride in dichloromethane).

mg of ethyl ethyl malonate was suspended in 1 ml of dry tetrahydrofuran, 170 µl of a 2M solution of isopropylmagnesium chloride in tetrahydrofuran was added, and the suspension was sonicated for 0.5 h, turning to a homogeneous solution which was added to the 6- (2) suspension with stirring. methyl-imidazo [4,5-c-pyridin-1-yl] -pyrid-3-oyl chloride in dichloromethane. The reaction mixture was stirred at room temperature for 0.5 hour, then poured into 1N hydrochloric acid, stirred for 15 minutes, then adjusted to pH 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted twice with 10 ml of dichloromethane each time, the extracts combined , dried over magnesium sulfate and the solvent was evaporated under reduced pressure. 40 mg (63%) of the title compound are obtained as a light red oil consisting of a mixture of equal parts of tautomeric enol and ketophores.

1 H-NMR (CDCl 3): 1.40 (3H, m), 2.78 and 2.80 (3H, 2 xs), 4.10 (1H, s), 4.30 (2H, m), δ .80 (0.5H, s), 7.40 (1H, m), 7.57 (0.5H, d, 3 = 5 Hz), 7.62 (0.5H, d, 3 »5 Hz) ), 8.37 (0.5H, d, 3 = 5Hz),

8.42 (1H, m), 8.57 (0.5H, d, 3 = 5 Hz), 9.10 (1.5H, s),

9.25 (0.5H, s), 12.87 (0.5H, w). ·

CS 270 592 B2

Preparation 44

5- (4-cyanophenyl) -4-methylimidazo [1,2-a] pyridine.

(a) 4- (1-Bromo-2-oxopropyl) benzonitrile. ;

To 4- (2-oxopropyl) benzonitrile in 85 ml of dichloromethane at 25 ° C was added dropwise 5.28 g of bromine in 80 ml of dichloromethane over 1 hour. After the addition was complete, the reaction mixture was stirred for 0.5 h, then washed with brine (50 mL), dried (MgSO 4) and the solvent evaporated under reduced pressure. 7.55 g (96%) of the title compound are obtained. in the form of a light red oil.

¹H-NMR (CDCl₃): 2.41 (в, 3H), 5.24 (s, 1H), 7.61 (d, 3, ³ 4 Hz, 2H), 7.73 (d, 3 »4 Hz , 2H).

^(B) 5- (4-cyanophenyl) -4-methylimidazo [l, 2 and 3-pyridine

A mixture of 2-amino-pyrrolidine (178 mg) and 4- (1-bromo-2-oxopropyl) benzonitrile (450 mg) in ethanol (2 ml) was stirred and refluxed for 5 hours. The ethanol was then evaporated under reduced pressure. 15 ml of dichloromethane and 10 ml of saturated aqueous sodium bicarbonate solution are added to the residue, the organic phase is separated, dried over sodium sulphate and the solvent is evaporated off under reduced pressure. The product was purified by flash chromatography on eelica gel, eluting with ethyl acetate as eluent, to give 1.0 mg (41%) of the title compound as a white solid.

1 H-NMR (CDCl 3) δ 2.47 (β, 3H), 6.84 (t, 3 = 4 Hz, 1H), 7.25 (d, 3 = 4 Hz, 1H), 7.62 (d 3.55 Hz, 2H), 7.86 (d, 3-4 Hz, 2H), 8.17 (d, 3 = 4 Hz, 1H).

Preparation 45

2-Chlorobenzyl-4 '- (2-methylimidazo [4,5-c] pyridin-1-yl) -benzoylacetate

A mixture of 320 kg (1 mmol) of ethyl 4- (2-methylimidazo [4,5-c] pyrid-1-yl) benzoylacetate and 710 mg (5 mmol) of 2-chlorobenzyl alcohol in 5 ml of toluene was heated under reflux for 20 hours. reflux condenser. The reaction solution was evaporated and the residue was purified by flash chromatography using 10 4 methanol in ethyl acetate as eluent. 300 mg (72%) of a colorless, pan-like product melting below 40 ° C are obtained.

Calcd for Hemihydrate 64.41 4 C, 4.47 4 H, 9.80 4 N; found 64.14 4 C, 4.38 4 H, 9.55 4 N.

Preparation 46

3- (4-cyanophenyl) -2-methylimidazo [4,5-b] pyridine, (a) N- (4-cyanophenyl) -2-amino-3-nitropyridine

A mixture of 2.36 g of p-cyananiline and 3.17 g of 2-chloro-3-nitropyridine in 60 ml of ethanol was heated at reflux for 3 days. The resulting solid product was filtered off and partitioned between 50 ml of dichloromethane and 30 ml of saturated aqueous sodium bicarbonate solution.

CS 270 592 82

The organic layer was dried (MgSO 4) and concentrated to give a yellow solid which was recrystallized from ethyl acetate. Yield: 2.70 g.

1 H-NMR (CDCl 3) 7.03 (1H, dd, J = 4 and 8 Hz), 7.69 (2H, d, 3 = 9 Hz), 7.92 (2H, d, 3 = 9 Hz) 8.59 (1H, d, 3 = 4 Hz), 8.62 (1H, d, 3 = 8 Hz), 10.39 (1H, bs).

This product is converted to a process analogous to that described in (b) and (c) of Preparation 26 above. 3- (4-Cyanophenyl) -2-methylimidazo-4,5-b-pyridine.

(b) 3-amono-2- (4-cyanophenyl) aminopyridine.

@ 1 H-NMR (CDCl3) .delta. 6.92 (1H, dd, 3 = 4 and 8 Hz), 7.19 (1H, d, 3 = 8 Hz),

7.45 (2H, d, J = 9 Hz). 7.58 (2H, d, 3 = 9 Hz), 7.69 (1H, d, 3-4 Hz).

(c) 3- (4-cyanophenyl) -2-methylimidazo 4,5-b pyridine 1 H-NMR (CDCl 3): 2.66 (3H, s), 7.31 (1H, dd, 3, 5, and 8) Hz), 7.66 (2H, d, 3 = 9 Hz), 7.94 (2H, d, 3-9 Hz7, 8.07 (1H, d, 3 = 8 Hz), 8.34 (1H , d, 3 → 5 Hz).

Claims (3)

SUBJECT OF THE INVENTION 1. A process for the preparation of 1,4-dihydropyridines which is 2-chlorophenyl, 2-trifluoromethoxyphenyl, 2,4-difluorine of general formula I R is phenyl, 4-cyanophenyl or 1,3-benzodloxol-4-yl, R ¹ is hydrogen, alkyl having 1 to 4 carbon atoms, a pyridyl group such as pyrid-2-yl, thiazolyl, such as thiazol-2-yl, 1- (phenyl) -ethyl, 4- or 6-methylpyrid-2-yl, 4- or 5-methylthiazol-2-yl, 5-methylthiadiazol-2-yl, 5-methyl-oxadiazol-3-yl, 5-methylisoxazol-3-yl, benzothiazol-2-yl, 5-ethoxybenzothiazol-2-yl or 1-methylimidazol-2-yl, CS 270 592 82 R ² represents hydrogen or alkyl of 1 to 4 carbon atoms, is 2-methylimidazo [4,5-c] pyridin-l-yl, imidazol-yl, benzimidezol-l-yl, 2-methylbenzimidszol- 1-yl, 3,5-dimethyl-1,2,4-triazol-4-yl, 2-trifluoromethylimidazo [4,5-c] pyrid-1-yl, 2-butylimidazo [4,5-c] pyridine- 1-yl, 2-methylimidazo [4,5-b] pyrid-3-yl, 2-methylimidezo [1,2-a] pyrid-3-yl, 2-methylimidazo [4,5-c] pyridine; 1-yl, 7-methoxy-2-methylimidazo [4,5-d] pyrimid-J-yl, 2-methylimidazo [4,5-c] pyrid-3-yl, 2,4,6-trimethylimidazo [4,5-c] pyrid-1-yl, 2,4-dimethylimidazol-1-yl, 2-methylimidazol-1-yl,. 2,4,5-trimethylimidazol-1-yl, 4-methylimidazol-1-yl, 2,6-dimethylpyrid-3-yl, 3,5-dimethyl-1,2,4-triazol-1-yl is 4-methyl-oxazol-5-yl, 2,4-dimethylthiazol-5-yl, 6-methylimidazo [1,2-b] thiazol-5-yl, or 4-methylthiazol-5-yl, is 1 Or a 4-phenylene radical or pyridine-2,5-diyl radical and represents an alkoxy group having 1 to 4 carbon atoms or an arylalkoxy group having 1 to 4 carbon atoms in the alkoxy moiety, wherein the aryl moiety is a phenyl group optionally bearing one substituent selected from the group consisting of halogen, trifluoromethyl, C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy, sulfamoyl and cyano, pharmaceutically acceptable salts thereof, characterized by The method of claim 1, wherein the compound of formula II _______________— (П) is reacted with an aldehyde of the general formula and with the compound RCHO of formula III (III) or a product of their mutual reaction, corresponding to formula IV CS 270 592 B2 in which the general formulas have the meanings given above, and the resulting product is optionally converted into its pharmaceutically acceptable salt. • Г '2. The process of claim 1, wherein the compound RCHO, aloučsnina of formula II and formula III ketosstsr heated together in the ^OR, the organic solvent at 60 to 130 ° C. 3. A process according to claim 1, wherein the compound of formula RCHO and the catheter of formula III are stirred with isopropyl alcohol and piperidine at room temperature, the reaction mixture is evaporated, the oily residue is triturated with water, the solid material is filtered off and recrystallized. from ethyl acetate to give a compound of formula IV, which was converted to a compound of formula I by heating to 60-130 ° C with a compound of formula II in an organic solvent, which was filtered off, washed and dried in vacuo.