KR100484599B1 - Cathecol acetonitrile derivatives, process for preparing the same and pharmaceutical composition containing the same - Google Patents

Abstract

The present invention provides a catechol hydrazone derivative represented by the following general formula (I) having an inhibitory action on cyclic adenosine 3 ′, 5′-monophosphate phosphodiesterase IV or TNF and pharmaceutically acceptable Salts, methods for their preparation and pharmaceutical compositions containing them:

Wherein R ¹ is methyl or ethyl and R ² is C ₁ -C ₇ alkyl or C ₃ -C ₇ cycloalkane; R ³ is an oxadizolone containing a nitrile, amide, carboxylic acid, C (NH) = NOR ⁵ , carbonyl or thiocarbonyl group, R ⁴ is hydrogen, CO ₂ R ⁶ , C ₂ -C ₅ containing N Heteroaryl or C ₂ -C ₅ heterocycloalkane, phenyl, benzyl, 2-phenethyl, or a benzene ring with a halogen group, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, nitrile, trifluoromethyl, A C ₁ -C ₆ alkyl, azido, substituent with one or two carboxylic acid groups; X is carbon, nitrogen, oxygen or sulfur; R ⁵ represents hydrogen, amide or CO ₂ R ⁷ ; R ⁶ and R ⁷ are each hydrogen or C ₁ -C ₆ alkyl.

Description

Catecol acetonitrile derivatives, methods for preparing the same and pharmaceutical compositions containing the same {Cathecol Acetonitrile Derivatives, Process for Preparing the Same and Pharmaceutical Composition Containing the Same}

The present invention is directed to phosphodiesterase IV or tumor necrosis factor (TNF) and to asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction, psoriasis, allergic rhinitis, dermatitis and AIDS, HIV, Crohn's disease, Novel catechol acetonitrile derivatives useful for the treatment of diseases including sepsis, septic shock, other inflammatory diseases such as atherosclerosis, and production of TNF, and methods for their preparation and pharmaceutical compositions containing them .

Phosphodiesterases are enzymes that hydrolyze cyclic nucleotides as one of the chemical delivery agents. In particular phosphodiesterase IV is an enzyme that selectively hydrolyzes cyclic adenosine 3 ', 5'-monophosphate to inactive adenosine 3', 5'-monophosphate and is a cyclic adenosine 3 ', 5'-monophosphate Is a second messenger responsible for regulating the response of cells to external cellular stimuli, which relaxes and contracts the bronchial muscles.

Inhibition of phosphodiesterase IV can prevent bronchial spasms by maintaining the concentration of cyclic adenosine 3 ', 5'-monophosphate and, in addition, anti-inflammatory action. Thus compounds that inhibit phosphodiesterase IV are useful as therapeutic agents for asthma and the like.

TNF has been known to be associated with many infections, including atherosclerosis, and autoimmune diseases, which have been shown to be the major mediators of the inflammatory response seen in sepsis and septic shock.

As inhibitors for phosphodiesterase IV or TNF, compounds having structures similar to the present invention have been disclosed. For example, materials having oxime-carbamate and oxime-carbonate structures represented by the following formula (A) have been reported in EP 470,805 (American Home Product).

Wherein, R is C ₃ - ₇ alkyl or C ₃ - ₇ cycloalkyl, and, R ¹ is a halogen or a lower alkyl group, R ² is amino, lower alkylamino, arylamino, lower ahkok during or aryloxy.

In addition, phenylalkyl oxamide-based compounds represented by formula (B) are described in USP 5,393,788 (SmithKline Beecham Corporation):

Wherein R 1 is C _4-6 cycloalkyl, X is YR ² halogen or lower alkyl group, Y is oxygen or sulfur, R ₃ or R ₅ are each hydrogen or OR ⁷ , and R ₄ is hydrogen or C _{1 -2} alkyl, R ₆ is OR ₇ or NR ₇ OR ₇ , and R ₇ is hydrogen or C _1-3 alkyl.

Also described in US Pat. No. 5,128,358 (Pfizer Inc.) are diimidazolone-based compounds represented by the following formula (C):

Wherein R ¹ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, benzyl or phenethyl, and R ² is hydrogen, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkanoyl or benzoyl to be.

The inventors have developed novel compounds which are structurally different from the above known compounds.

The present invention provides a catechol acetonitrile derivative represented by the following formula (I) and a pharmaceutically acceptable salt thereof:

In the above formula,

R ¹ is buckwheat or ethyl;

R ² is C ₁ -C ₇ alkyl or C ₃ -C ₇ cycloalkane;

R ³ is an oxadizolone including a nitrile, amide, carboxylic acid, C (NH) = NOR ⁵ , carbonyl or thiocarbonyl group;

R ⁴ is hydrogen, CO ₂ R ⁶ , C ₂ -C ₅ heteroaryl containing N, or C ₂ -C ₅ heterocycloalkane, phenyl, benzyl, 2-phenethyl, or a halogen group in the benzene ring, C _1- C ₆ alkoxy, C ₁ -C ₆ alkylthio, nitrile, trifluoromethyl, C ₁ -C ₆ alkyl, azido, substituents having one or two carboxylic acid groups;

X is carbon, nitrogen, oxygen or sulfur;

R ⁵ represents hydrogen, amide or CO ₂ R ⁷ ;

R ⁶ and R ⁷ are each hydrogen or C ₁ -C ₆ alkyl

Compounds (I) of the present invention may exist in the form of optical isomers or geometric isomers, and the present invention includes these isomers and mixtures thereof.

The present invention also provides a pharmaceutical composition having an inhibitory action against phosphodiesterase IV or TNF by containing the novel catechol acetonitrile derivative of the present invention described above together with a pharmaceutically acceptable carrier.

The novel compounds represented by formula (I) of the present invention are prepared by the following scheme (I).

Scheme I

Some derivatives target the cyclization reaction of aminooximes (J. Med. Chem., 1996, 39, 5228) using phenylacetonitrile synthesized by known methods (J. Org. Chem., 1961, 26, 4741). Compound (I) was obtained.

The present invention is explained in detail by the following examples. However, these examples are only intended to illustrate the invention and should not be understood as limiting the invention to these examples.

Reference Example 1

3-cyclopentyloxy-4-methoxybenzaldehyde

A suspension of isovanillin (100 g, 0.66 mol), anhydrous potassium carbonate (136.2 g, 0.99 mol), potassium iodide (3 g) and anhydrous dimethylformamide (650 mL) was stirred at 65 ° C., and the suspension was then subjected to cyclopentyl bromide ( 127.3 g, 0.85 mol) was slowly added dropwise for 1 hour, stirred at 65 ° C. for 1 day, and then the temperature was lowered to room temperature. Toluene (2.0 L) was added to the mixed solution and diluted, followed by 1M sodium hydroxide (2 × 1.5). Washed with L). The obtained aqueous layer solution was extracted with toluene (0.5 L), and the obtained organic layer was washed with distilled water (2 × 1.5 L). The organic layer was dried and concentrated to give a light brown oily title compound (117 g).

¹ H NMR (CDCl ₃ , δ): 9.84 (s, 1H) 7.42 (m, 2H) 6.95 (d, 1H, J = 9 Hz) 4.87 (m, 1H) 3.93 (s, 3H) 2,1-1.6 ( m, 8H)

Example 1

2- [3-cyclopentyloxy-4-methoxyphenyl] -2-morpholinoacetonitrile

Morpholine (5.3 mL) and sodium cyanide (2.96 g) were added dropwise to the ethanol solution of the title compound (10 g) in Reference Example 1, followed by the addition of water (50 mL) to make the reaction solution uniform, followed by sodium bisulfite ( 6.95 g) was added and stirred at room temperature for 1 day. The resulting solid was filtered and then recrystallized with ether to give a white solid title compound (11.8 g).

Melting Point (℃): 114-115

¹ H NMR (CDCl ₃ , δ): 7.05 (m, 2H) 6.83 (d, 1H) 4.81 (m, 1H) 4.76 (s, 1H) 3.80 (s, 3H) 3.70 (m, 4H) 2.57 (m, 4H) 1.80 (m, 8H)

Example 2

2- [3-cyclopentyloxy-4-methoxyphenyl] -2-piperidinoacetonitrile

Piperidine (0.61 mL) and sodium cyanide (0.30 g) were added dropwise to the ethanol solution of the title compound (1 g) in Reference Example 1, followed by the addition of water (10 mL) to make the reaction solution uniform, followed by sodium bisulfite. (0.70 g) was added thereto, and the resultant was stirred at room temperature for 1 day. The resulting solid was filtered and then recrystallized with hexane: isopropyl ether (20: 1) to give a white solid title compound (1.51 g).

Melting Point (℃): 101 ~ 103

¹ H NMR (DMSO-d6, δ): 7.01 (m, 3H) 5.20 (s, 1H) 4.77 (m, 1H) 3.76 (s, 3H) 2.40 (m, 4H) 1.90 (m, 2H) 1.70 (m , 4H) 1.50 (m, 6H) 1.50 (m, 2H)

Example 3

2- [3-cyclopentyloxy-4-methoxyphenyl] -2- (1,4-thiazinan-4-yl) acetonitrile

Thiomorpholine (0.31 mL) and sodium cyanide (0.15 g) were added dropwise to the ethanol solution of the title compound (0.5 g) in Reference Example 1, and then water (5 mL) was added dropwise to make the reaction solution uniform. Sodium sulfate (0.35 g) was added thereto, followed by stirring at room temperature for 30 hours. The resulting solid was filtered and then recrystallized with isopropyl ether to give a pale yellow solid title compound (0.45 g).

Melting Point (℃): 88 ~ 90

¹ H NMR (DMSO-d6, δ): 6.99 (m, 3H) 5.02 (s, 1H) 4.73 (m, 1H) 3.78 (s, 3H) 2.64 (m, 8H) 1.90 (m, 2H) 1.70 (m 4H) 1.60 (m, 2H)

Example 4

2- [3-cyclopentyloxy-4-methoxyphenyl] -2-pyrrolidinylacetonitrile

Pyrrolidine (0.25 mL) and sodium cyanide (0.15 g) were added dropwise to the ethanol solution of the title compound (0.5 g) in Reference Example 1, and then water (5 mL) was added dropwise to make the reaction solution uniform. Sodium sulfate (0.35 g) was added thereto and stirred at room temperature for 1 day. The resulting solid was filtered and then recrystallized with isopropyl ether to give a white solid title compound (0.83 g).

Melting Point (℃): 76 ~ 77

¹ H NMR (DMSO-d6, δ): 7.01 (m, 3H) 5.37 (s, 1H) 4.79 (m, 1H) 3.78 (s, 3H) 2.64 (m, 2H) 2.50 (m, 2H) 1.90 (m , 2H) 1.70 (m, 8H) 1.60 (m, 2H)

Example 5

Ethyl-1-cyano- [3-cyclopentyloxy-4-methoxyphenyl] -methyl-4-piperidinecarboxylate

To the ethanol solution of the title compound (0.5 g) of Reference Example 1 was added dropwise ethyl isonipetate (0.44 mL) and sodium cyanide (0.14 g), followed by the addition of water (10 mL) to make the reaction solution uniform. , Sodium bisulfite (0.30 g) was added thereto, and stirred at room temperature for 4 hours. Sodium cyanide (0.14 g) and ethyl isonipekotate (0.44 mL) were further added thereto, followed by stirring for one day. The resulting solid was filtered and then recrystallized with isopropyl ether to give a white solid title compound (0.74 g).

Melting Point (℃): 82 ~ 83

¹ H NMR (DMSO-d6, δ): 6.99 (m, 3H) 5.25 (s, 1 H) 4.78 (m, 1 H) 4.05 (q, 2H, J = 7.1 Hz) 3.76 (s, 1H) 2.90 (m, 1H) 2.50 (m, 1H) 2.35 (m, 2H) 2.04 (m, 1H) 1.84 (m, 4H) 1.68 (m, 5H) 1.57 (m, 2H) 1.43 (m, 1H) 1.18 (t, 3H, J = 7.1 Hz)

Example 6

2- [3-cyclopentyloxy-4-methoxyphenyl] -2- (4-phenylpiperidino) acetonitrile

To the ethanol solution of the title compound (0.5 g) of Reference Example 1, 4-phenylpiperidine (0.49 mg) and sodium cyanide (0.15 g) were added dropwise, followed by dropwise addition of water (10 mL) to make the reaction solution uniform. Then, sodium bisulfite (0.35 g) was added thereto and stirred at room temperature for 4 hours. After the resulting solid was filtered, the white solid title compound (0.70 g) was obtained.

Melting Point (° C): 117-119

¹ H NMR (DMSO-d6, δ): 7.28 (m, 3H) 7.20 (m, 2H) 7.00 (m, 3H) 5.29 (s, 1H) 4.79 (m, 1H) 3.77 (s, 3H) 3.18 (m , 1H) 2.64 (m, 1H) 2.44 (m, 2H) 2.10 (m, 1H) 1.83 (m, 3H) 1.70 (m, 6H) 1.50 (m, 3H)

Example 7

2- [3-cyclopentyloxy-4-methoxyphenyl] -2- (4-piperidinopiperidino) acetonitrile

4-piperidinopiperidine (0.48 mg) and sodium cyanide (0.14 g) were added dropwise to the ethanol solution of the title compound (0.5 g) in Reference Example 1, and then the reaction solution was uniformly added dropwise with water (10 mL). After adding sodium bisulfite (0.30 g), the mixture was stirred at room temperature for 4 hours. Sodium cyanide (0.14 g) and 4-piperidino piperidine (0.48 mg) were further added dropwise, stirred at room temperature for 1 day, and then the resulting solid was filtered and then the white solid title compound (0.68) was added. g) was obtained.

Melting Point (℃): 117 ~ 119

¹ H NMR (DMSO-d6, δ): 6.99 (m, 3H) 5.23 (s, 1H) 4.77 (m, 1H) 3.75 (s, 3H) 3.03 (m, 1H) 2.57 (m, 1H) 2.43 (m , 4H) 2.27 (m, 1H) 2.20 (m, 1H) 1.90 (m, 3H) 1.70 (m, 6H) 1.50 (m, 7H) 1.36 (m, 3H)

Example 8

2- [3-cyclopentyloxy-4-methoxyphenyl] -2- [4- (2-pyridyl) piperazino] acetonitrile

To the ethanol solution of the title compound (0.5 g) of Reference Example 1, 1- (2-pyridyl) piperazine (0.43 mg) and sodium cyanide (0.14 g) were added dropwise, followed by dropwise addition of water (10 mL). After homogenizing, sodium bisulfite (0.30 g) was added thereto, and the mixture was stirred at room temperature for 4 hours. Sodium cyanide (0.14 g) and 1- (2-pyridyl) piperazine (0.43 mg) were further added dropwise thereto, stirred at room temperature for 1 day, and then the resulting solid was filtered and then an off-white solid title compound. (0.76 g) was obtained.

Melting Point (℃): 126 ~ 127

¹ H NMR (DMSO-d6, δ): 8.08 (m, 1 H) 7.50 (dt, 1 H, J = 2.0, 8.6 Hz) 6.98 (m, 3H) 6.76 (d, 1H, J = 8.6 Hz) 6.59 (m) , 1H) 5.25 (s, 1H) 4.48 (m, 1H) 3.70 (s, 3H) 3.42 (m, 4H) 2.54 (m, 2H) 2.46 (m, 2H) 1.85 (m, 2H) 1.66 (m, 4H ) 1.53 (m, 2H)

Example 9

N-hydroxy-2- [3- (cyclopentyloxy) -4-methoxyphenyl] -2-morpholinoethimidamide

Triethylamine (8.81 ml) was added dropwise to a dimethylsulfoxide (30 ml) solution of hydroxyamine hydrochloride (4.40 g) to precipitate an insoluble solid, which was filtered off and washed with tetrahydrofuran (60 ml). The filtrate was concentrated to remove tetrahydrofuran, and then the title compound (4 g) of Example 1 was added dropwise and stirred at 75 ° C. for 15 hours. After lowering the temperature to room temperature, ethyl acetate was added to precipitate a solid, which was filtered to obtain a white solid title compound (3.98 g).

Melting Point (℃): 191 ~ 192

¹ H NMR (CDCl 3, δ): 6.98 (m, 2H) 6.80 (dd, 1H) 4.85 (s, 1H) 4.79 (m, 1H) 3.80 (s, 3H) 3.74 (m, 4H) 3.62 (s, 1H ) 2.60 (s, 1H) 2.44 (m, 4H) 1.80 (m, 8H)

Example 10

1-amino-2- (3-cyclopentyloxy-4-methoxyphenyl) -2-morpholinoethane-O- (aminocarbonyl) oxime

To the suspension of tetrahydrofuran (20 ml) of the title compound (0.5 g) of Example 9 was slowly added dropwise chlorosulfonyl isocyanate (0.19 ml) at 0 ° C., stirred for 30 minutes, and further chlorosulfonyl isocyanate (0.19 ml). ) Was added dropwise and stirred for 3 hours. The reaction mixture was concentrated, water (30 ml) was added thereto, washed with saturated sodium bicarbonate solution (15 ml), and the solid obtained was filtered to yield a white solid title compound (0.34 g).

Melting Point (℃): 195 ~ 197

¹ H NMR (DMSO-d6, δ): 8.97 (s, 2H) 7.08 (s, 1H) 6.88 (m, 2H) 5.21 (brs, 2H) 4.79 (m, 1H) 3.67 (s, 3H) 3.60 (m , 4H) 3.50 (s, 1H (m, 4H) 1.80 (m, 8H)

Example 11

2- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1,4-oxazin-4-yl) acetamide

To the concentrated sulfuric acid (10 ml) solution was added dropwise the title compound of Example 1 (0.5 g) at 0 ℃ and stirred for 2 hours at room temperature. The reaction solution was poured into ice water, stirred for 30 minutes, and the pH was adjusted to pH 8 with ammonia water. The resulting solid was filtered and then column chromatographed in methanol: dichloromethane = 1: 20 to give a white solid title compound (0.32 g).

Melting Point (° C): 53 to 55

¹ H NMR (BMSO-d6, δ): 8.90 (brs, 1H) 7.86 (d, 1H) 6.90 (d, 1H) 6.84 (d, 1H) 6.75 (dd, 1H) 3.94 (m, 1H) 3.70 (s , 3H) 3.50 (m, 4H) 3.48 (s, 1H) 2.25 (m, 5H) 1.80 (m, 8H)

Example 12

3- [3-cylopentyloxy-4-methoxyphenyl (1,4-oxazin-4-yl) methyl] -4,5-dihydro-1,2,4-oxadiazole-5- Tion

The title compound of Example 9 (0.5 g), 1,1-thiocarbonyldiimidazole (0.31 ml), DBN (0.75 ml) and acetonitrile (10 ml) were stirred at room temperature for 4 hours, and then the reaction solution was concentrated. After dilution with water (10 ml) and pH adjusted to pH 4.5 using 1N hydrochloric acid.

After washing with ether (30ml × 3), the resulting solid compound was filtered to yield an off-white solid title compound (0.20 g).

Melting Point (℃): 145 ~ 147

¹ H NMR (DMSO-d6, δ): 7.24 (d, 1H, J = 2.0 Hz) 7.10 (dd, 1H, J = 8.4, 2.0 Hz) 6.96 (d, 1H, J = 8.4 Hz) 5.20 (s, 1H) 4.78 (m, 1H) 3.76 (m, 7H) 2.80 (m, 4H) 1.80 (m, 8H)

The following experiments were conducted to evaluate the pharmacological effects induced by the compounds of the present invention.

Experiment method

PDE IV partially purified from human U 937 cells, the test compound, and 1.0 μM cAMP containing 0.01 μM [ ³ H] cAMP were incubated at 30 ° C. for 20 minutes. The PDE reaction, in which cAMP was changed to AMP, was completed by boiling for 2 minutes. Toxic nucleotidase was added and incubated at 30 ° C. for 10 minutes to change AMP to adenosine. Unhydrolyzed cAMP was bound to AG1-X2 resin and the remaining [ ³ H] adenosine in aqueous solution was quantified by scintillation counting. The results are shown in Table 1 below.

TABLE 1

Claims (5)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: In the above formula, R ¹ is methyl or ethyl; R ² is C ₃ -C ₇ cycloalkane; R ³ is an oxadizolone including a nitrile, amide, carboxylic acid, C (NH) = NOR ⁵ , carbonyl or thiocarbonyl group; R ⁴ is hydrogen, CO ₂ R ⁶ , 2,3,4-pyridyl, piperidine, phenyl, benzyl, 2-phenethyl; X is carbon, nitrogen, oxygen or sulfur; R ⁵ represents hydrogen, amide or CO ₂ R ⁷ ; R ⁶ and R ⁷ are each hydrogen or C ₁ -C ₆ alkyl. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl and R ² is cyclopentyl. The compound of claim 1 selected from the group of compounds: 2- [3-cyclopentyloxy-4-methoxyphenyl] -2-morpholinoacetonitrile; 2- [3-cylopentyloxy-4-methoxyphenyl] -2-periferdinoacetonitrile; 2- [3-cyflopentyloxy-4-methoxyphenyl] -2- (1,4-thiazinan-4-yl) acetonitrile; 2- [3-cyflopentyloxy-4-methoxyphenyl] -2-pyrrolidinylacetonitrile; Ethyl-1-cyano- [3-cyclopentyloxy-4-methoxyphenyl] -methyl-4-piperidinecarboxylate; 2- [3-cyclopentyloxy-4-methoxyphenyl] -2- (4-phenylpiperidino) acetonitrile; 2- [3-cyclopentyloxy-4-methoxyphenyl] -2- (4-piperidinopiperidino) acetonitrile; 2- [3-cyclopentyloxy-4-methoxyphenyl] -2- [4- (2-pyridyl) piperazino] acetonitrile; N-hydroxy-2- [3- (cyclopentyloxy) -4-methoxyphenyl] -2-morpholinoethimidamide; 1-amino-2- (3-cyclopentyloxy-4-methoxyphenyl) -2-morpholinoethane-0- (aminocarbonyl) oxime; 2- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1,4-oxazin-4-yl) acetamide; And 3- [3-cyclopentyloxy-4-methoxyphenyl (1,4-oxazin-4-yl) methyl] -4,5-terhydro-1,2,4-oxadiazole-5-thione. C ₃ -C ₇ cycloalkane represented by R ² is reacted with a compound of formula (II) to produce a compound of formula (III), and the product is reacted with a compound of formula (IV) A process for preparing a compound of formula (I) characterized by producing a compound of V) and obtaining the desired compound of formula (I) from this product: In which R ¹ is methyl or ethyl; R ² is C ₃ -C ₇ cycloalkane; R ³ is an oxadizolone including a nitrile, amide, carboxylic acid, C (NH) = NOR ⁵ , carbonyl or thiocarbonyl group; R ⁴ is hydrogen, CO ₂ R ⁶ , 2,3,4-pyridyl, piperidine, phenyl, benzyl, 2-phenethyl; X is carbon, nitrogen, oxygen or sulfur; R ⁵ represents hydrogen, amide or CO ₂ R ⁷ ; R 6 and R 7 are each hydrogen or C ₁ -C ₆ alkyl. For the treatment of diseases selected from the group consisting of asthma, arthritis, bronchitis, chronic airway obstruction, psoriasis, allergic rhinitis, dermatitis, Crohn's disease and sepsis containing the compound of any one of claims 1 to 3 as an active ingredient Pharmaceutical compositions.