ADENOSINE A2B RECEPTOR ANTAGONISTS

Abstract

The present invention provides compounds of the formula

Description

EXAMPLE 1

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-phenyl-acetamide

A. 2-Bromo-N-phenylacetamide

A solution of aniline (0.016 mol) in 40 mL of dichloromethane is cooled on ice, and 1.0 equivalent of bromoacetyl bromide in 3 mL of dichloromethane is added dropwise, followed by 0.019 mol of triethylamine (TEA). The solution turns dark and a precipate forms, as the reaction mixture is warmed to RT over 3 h. The mixture is concentrated and taken up in ethyl acetate (EtOAc) and washed three times with water. The organic phase is dried over anhydrous sodium sulphate (Na₂SO₄), filtered and concentrated. The residue is purified by crystallization from EtOAc to afford 2-bromo-N-phenylacetamide: m.p. 131-135° C.; ¹H-NMR (CDCl₃) δ 4.01 (s, 2H), 7.18 (m, 1H), 7.36 (m, 2H), 7.54(2H), 8.09 (s, 1H).

B. 5-Methyl-1-phenylcarbamoylmethyl-1H-pyrazole-3-carboxylic acid ethyl ester

To a magnetically stirred mixture of ethyl 5-methyl-1H-pyrazole-3-carboxylate (0.02 mol) and sodium ethoxide (0.22 mol) in ethanol (20 mL) is added the title A compound, 2-bromo-N-phenyl-acetamide (0.02 mol). The resulting suspension is stirred at RT for 3 h. After concentration in vacuo, EtOAc is added and the resulting solution is washed twice with water and dried over anhydrous Na₂SO₄. After filtration and concentration, the residue is purified by flash chromatography (ethyl acetate/hexane) to afford 5-methyl-1-phenylcarbamoyl-methyl-1H-pyrazole-3-carboxylic acid ethyl ester: m.p. 139-140° C.; ¹H-NMR (DMSO-d₆)δ 1.26-1.29 (t, 3H J=72 Hz), 2.28 (s, 3H), 4.23-4.25 (q, 2H J=72 Hz), δ 06 (s, 2H), δ 56 (s, 1H), 7.07 (m, 1H), 7.32 (m, 2H), 7.57 (m, 2H), 10.41 (s, 1H).

C. 5-Methyl-1-phenylcarbamoylmethyl-1H-pyrazole-3-carboxylic acid

To a magnetically stirred mixture of the title B compound, 5-methyl-1-phenylcarbamoyl-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (3.0 mmol), in dioxane (50 mL) is added aqueous 2 N KOH (5 mL) and the resulting mixture is stirred at RT for 3 h to give a solution. After concentration in vacuo, the residue is cooled and acidified with a 10% HCl solution to precipitate 5-methyl-1-phenylcarbamoylmethyl-1H-pyrazole-3-carboxylic acid as a white solid: m.p. 273-275° C.; ¹H-NMR (DMSO-d) δ 2.28 (s, 3H), δ 06 (s, 2H), δ 56 (s, 1H), 7.07 (m, 1H), 7.32 (m, 2H), 7.57 (m, 2H), 10.41 (s, 1H), 12.50 (s, 1H).

D. 2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-phenyl-acetamide

To a solution of 1,3-dipropyl-5,6-diaminouracil (2.20 mmol), in MeOH (10 mL), is added an equimolar amount of the title C compound, 5-methyl-1-phenylcarbamoylmethyl-1H-pyrazole-3-carboxylic acid, and EDCl (2.21 mmol). The reaction mixture is stirred at RT for 4-5 h while being monitored by TLC. The solvent is concentrated in vacuo and the amide intermediate is precipitated by the addition of water. After filtration, the solid is dissolved in MeOH (10 mL) and aqueous NaOH (2.5 N, 15 mL) and the mixture is stirred at 50-60° C. for 1 h. The MeOH is distilled off, and the residue is taken up in H₂O and acidified with HCl to pH 4-5. The precipitate is collected by filtration, washed with water, and purified by flash chromatography (ethyl acetate-petroleum ether) to afford 2-[3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-phenyl-acetamide: m.p. 255-257° C.; ¹H-NMR (DMSO-d₆) δ 0.87 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.32 (s, 3H), 3.84 (m, 2H), 3.98 (m, 2H), δ0.08 (s, 2H), 6.74 (s, 1H), 7.08 (m, 1H), 7.33 (m, 2H), 7.59 (m, 2H), 10.41 (s, 1H), 13.85 (s, 1H).

EXAMPLE 2

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-iodophenyl)-acetamide

The title compound is prepared analogously to Example 1: m.p 286-289° C.; ¹H-NMR (DMSO-d₆) δ 0.87 (m, 6H), 1.56 (q, 2H), 1.71 (q, 2H), 2.30 (s, 3H), 3.84 (t, 2H), 3.97 (t, 2H), 507 (s, 2H), 67.4 (s, 1H), 7.42 (d, 2H J=8.8 Hz), 7.66 (d, 2H J=88 Hz), 10.52 (s, 1H), 13.69 (s, 1H).

EXAMPLE 3

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-bromophenyl)acetamide

The title compound is prepared analogously to Example 1: m.p. 270-273° C.; ¹H-NMR (DMSO-d₆) δ 0.87 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.31 (s, 3H), 3.85 (m, 2H), 3.98 (m, 2H), 5.08 (s, 2H), 675 (s, 1H), 751 (d, 2H J=8.0 Hz), 7.57 (d, 2H J=80 Hz), 1056 (s, 1H), 13.68 (s, 1H).

EXAMPLE 4

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-chlorophenyl)-acetamide

The title compound is prepared analogously to Example 1: m.p. 261-265° C.; ¹H-NMR (DMSO-d₆) δ 0.87 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.31 (s, 3H), 3.82 (m, 2H), 3.95 (m, 2H), 5.07 (s, 2H), δ 7.73 (s, 1H), 7.37 (d, 2H J=82 Hz), 7.60 (d, 2H J=82 Hz), 10.55 (s, 1H), 1368(s, 1H).

EXAMPLE 5

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-fluoro-phenyl)-acetamide

The title compound is prepared analogously to Example 1: m.p. 205-207° C.; ¹H-NMR (DMSO-d₆) δ 0.87 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.31 (s, 3H), 3.84 (t, 2H), 3.97 (t, 2H), 07 (s, 2H), 6.74 (s, 1H), 7.17 (d, 2H J=8.8 Hz), 7.61 (d, 2H J=8.8 Hz), 10.48 (s, 1H), 13.80 (s, 1H).

EXAMPLE 6

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-methoxyphenyl)-acetamide

The title compound is prepared analogously to Example 1: m.p. 293-296° C.; ¹H-NMR (DMSO-d₆) δ 0.87 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.31 (s, 3H), 3.71 (s, 3H), 3.84 (t, 2H), 3.97 (t, 3H), 5.03 (s, 2H), 6.72 (s, 1H), 7.90 (d, 2H J=8.2 Hz), 7.49 (d, 2H J=8.2 Hz), 10.28 (s, 1H), 13.80 (s, 1H).

EXAMPLE 7

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl}-5-methyl-pyrazol-1-yl]-N-(3,4-dimethylphenyl)-acetamide

The title compound is prepared analogously to Example 1: m.p. 261-265° C.; ¹H-NMR (DMSO-d₆) δ 0.87 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.17 (m, 6H), 2.31 (s, 3H), 3.84 (t, 2H), 3.97 (t, 2H), δ 5.03 (s, 2H), 6.70 (s, 1H), 7.06 (d, 1H), 7.29 (d, 1H), 7.37 (s, 1H), 10.24 (s, 1H), 13.80(s, 1H).

EXAMPLE 8

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(3,4-dimethoxyphenyl)-acetamide

The title compound is prepared analogously to Example 1: m.p. 285-290° C.; ¹H-NMR (DMSO-d₆) δ 0.88 (m, 6H), 1.57 (q, 2H), 1.70 (q, 2H), 2.32 (s, 3H), 3.71 (s, 6H), 3.84 (t, 2H), 3.88 (t, 2H), δ 5.03 (s, 2H), δ 6.73 (s, 1H), 6.90 (d, 1H), 7.05 (d, 1H), 7.32 (s, 1H), 10.29 (s, 1H), 1388 (s, 1H).

EXAMPLE 9

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-6-ethyl-pyrazol-1-yl]-N-(4-chlorophenyl)acetamide

The title compound is prepared analogously to Example 1: m.p. 256-257° C.; ¹H-NMR (DMSO-d₆) δ 0.88 (m, 6H), 1.25 (m, 3H), 1.55 (q, 2H), 1.70 (q, 2H), 2.66 (q, 2H), 3.84 (t, 2H), 3.99 (t, 2H), 5.08 (s, 2H), 6.77 (s, 1H), 7.40 (d, 2H J=7.6 Hz), 7.63 (d, 2H J=8.2 Hz), 10.56 (s, 1H), 13.67(s, 1H).

EXAMPLE 10

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-pyrazol-1-yl]-N-(4-chloro-phenyl)-acetamide

The title compound is prepared analogously to Example 1: m.p 283-285° C.; ¹H-NMR (DMSO-d) δ 0.87 (m, 6H), 1.52 (q, 2H), 1.66 (q, 2H), 3.85 (t, 2H), 3.98 (t, 2H), 5.14 (s, 2H), 6.94(d, 1H J=24 Hz), 7.37 (d, 2H J=88 Hz), 7.60 (d, 2H J=88 Hz), 7.89 (d, 1H J=2.6 Hz), 10.57 (s, 1H), 13.69 (s, 1H).

EXAMPLE 11

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-dimethylaminophenyl)-acetamide

The title compound is prepared analogously to Example 1: m.p.>300° C.; ¹H-NMR (DMSO-d₆) δ 0.88 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.31 (s, 3H), 2.84 (s, 6H), 3.85 (t, 2H), 3.94 (t, 2H), δ 5.01 (s, 2H), 6.67 (s, 1H), δ 6.72 (d, 2H J=9 Hz), 7.42 (d, 2H J=9 Hz), 10.11 (s, 1H), 13.70 (s, 1H).

EXAMPLE 12

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-sec-butylphenyl)-acetamide

The title compound is prepared analogously to Example 1: m.p 268-271° C.; ¹H-NMR DMSO-d₆δ0.74 (t, 3H); 0.88 (m, 6H); 1.15 (q, 3H); 1.48-1.55 (m, 7H); 2.31 (s, 3H); 3.85 (t, 2H); 3.97 (t, 2H); 5.06 (s, 2H); 6.74 (s, 1H); 7.14 (d, 2H); 7.49 (d, 2H); 10.33 (s, 1H); 13.75(s, 1H).

EXAMPLE 13

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(naphthalen-1-yl)-acetamide

The title compound is prepared analogously to Example 1: m.p.>300° C.; ¹H-NMR (DMSO-d₆) δ 0.89 (m, 6H)₁ 1.59 (q, 2H), 1.72 (q, 2H), 2.36 (s, 3H), 3.85 (t, 2H), 3.97 (t, 2H), δ 30 (s, 2H), δ0.76 (s, 1H), 7.46-7.81 (m, 5H), 7.93-78.19 (m, 2H), 10.36 (s, 1H), 13.72 (s, 1H).

EXAMPLE 14

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(3-methoxylphenyl)-acetamide

The title compound is prepared analogously to Example 1: m.p 274-277° C.; ¹H-NMR (DMSO-d₆) δ 0.87 (m, 6H), 1.58 (q, 2H), 1.68 (q, 2H), 2.31 (s, 3H), 3.71 (s, 3H), 3.84 (t, 3H), 3.97 (t, 2H), δ0.06 (s, 2H), 6.63-6.68 (m, 1H), δ 72 (s, 1H), 7.08-7.31 (m, 3H), 10.48 (s, 1H), 13.80(s, 1H).

EXAMPLE 15

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1 yl]-N-(3-chlorophenyl)-acetamide

The title compound is prepared analogously to Example 1: m.p. 304-307° C.; ¹H-NMR (DMSO-d₆) δ 0.87 (m, 6H), 1.56 (q, 2H), 1.70 (q, 2H), 2.31 (s, 3H), 3.84 (t, 2H), 3.95 (t, 2H), 5.09 (s, 2H), 6.73 (s, 1H), 7.15-7.80 (m, 4H), 10.48 (s, 1H), 13.80 (s, 1H).

EXAMPLE 16

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(3,4-dichlorophenyl)-acetamide

The title compound is prepared analogously to Example 1: m.p. 298° C.; ¹H-NMR (DMSO-d₆) δ 0.87 (m, 6H), 1.57 (q, 2H), 1.73 (q, 2H), 2.31 (s, 3H), 3.86 (t, 2H), 3.95 (t, 2H), 5.01 (s, 2H), 6.75 (s, 1H), 7.47-7.59 (m, 2H), 7.97 (d, 1H), 10.73 (s, 1H), 13.75 (s, 1H).

EXAMPLE 17

2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-p-tolyl-acetamide

The title compound is prepared analogously to Example 1: m.p.>300° C.; ¹H-NMR (DMSO-d₆) δ 0.88 (m, 6H), 1.57 (q, 2H), 1.72 (q, 2H), 2.25 (s, 3H), 2.31 (s, 3H), 3.84 (t, 2H), 3.99 (t, 2H), 5.05 (s, 2H), 6.73 (s, 1H), 720 (d, 2H J=8.8 Hz), 746 (d, 2H J=88 Hz), 1032 (s, 1H), 13.85 (bs, 1H).

EXAMPLE 18

2-[4-Chloro-3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-chlorophenyl)-acetamide

A. 4-Chloro-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester

To a magnetically stirred solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (3 mmol) in 10 mL of anhydrous DMF at 0° C. is added N-chlorosuccinimide (4 mmol). The solution is stirred at RT for 5 h. The solvent is concentrated to a half of the original volume, water is added and the reaction mixture is allowed to cool over ice. The solid that precipitates is collected by filtration and purified by crystallization to afford 4-chloro-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid: m.p. 106-107° C.; ¹H-NMR (DMSO-d₆) δ 1.25-1.32 (t, 3H J=7 Hz), 2.21 (s, 3H), 4.22-4.32 (q, 2H J=7.2), 13.59 (s, 1H).

B. 4-Chloro-1-[(4-chloro-phenylcarbamoyl)-methyl]-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester

The title B compound is prepared as described for the title B compound of Example 1: m.p. 208-210° C.; ¹H-NMR (DMSO-d₈) δ 1.26-1.29 (t, 3H J=72 Hz), 2.25 (s, 3H), 4.26-4.28 (q, 2H J=7.2 Hz), 5.14 (s, 2H), 7.39 (d, 2H J=88 Hz), 7.60 (d, 2H J=8.8 Hz), 10.60 (s, 1H).

C. 4-Chloro-1-[(4-chloro-phenylcarbamoyl)-methyl]-5-methyl-1H-pyrazole-3-carboxylic acid

The title C compound is prepared as described for the title C compound of Example 1: m.p 244-245° C.; ¹H-NMR (DMSO-d₆) δ 2.24 (s, 3H), 5.11 (s, 2H), 7.39 (d, 2H J=88 Hz), 7.60 (d, 2H J=8.8 Hz), 10.60 (s, 1H), 12.98 (s, 1H).

D. 2-[4-Chloro-3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-chloro-phenyl)-acetamide

The title D compound is prepared as described for the title D compound of Example 1: m.p. 297-298° C.; ¹H-NMR (DMSO-d₆) δ 0.88 (m, 6H), 1.62 (q, 2H), 1.70 (q, 2H), 2.31 (s, 3H), 3.85 (t, 2H), 4.00 (t, 2H), 5.15 (s, 2H), 7.39 (d, 2H J=9 Hz), 7.61 (d, 2H J=9 Hz), 10.59 (s, 1H), 13.89 (s, 1H).

EXAMPLE 19

2-[4-Bromo-3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-chlorophenyl)-acetamide

The title compound is prepared analogously to Example 18: m.p. 298-299° C.; ¹H-NMR (DMSO-d₆) δ 0.88 (m, 6H), 1.57(q, 2H), 1.72 (q, 2H), 2.321 (s, 3H), 3 91 (t, 2H), 4.02 (t, 2H), 5.19 (s, 2H), 7.39 (d, 2H J=9 Hz), 7.61 (d, 2H J=9 Hz), 10.68 (s, 1H), 13.79 (s, 1H).

EXAMPLE 20

2-[4-Iodo-3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-chlorophenyl)-acetamide

The title compound is prepared analogously to Example 18: m.p 296-297° C.; ¹H-NMR (DMSO-d₆) δ 0.90 (m, 6H), 1.59 (q, 2H), 1.74 (q, 2H), 2.35 (s, 3H), 3.87 (t, 2H), 4.03 (t, 2H), 5.19 (s, 2H), 7.40 (d, 2H J=9 Hz), 7.59 (d, 2H J=9 Hz), 10.58 (s, 1H), 13.87 (s, 1H).

Claims

1. A compound of the formula

2. A compound according to claim 1, wherein R3 is hydrogen;

3. A compound according to claim 2, wherein R5 is hydrogen;R6 is monocyclic aryl which may be optionally substituted by 1-3 substituents selected from the group consisting of C1-C6 alkyl, trifluoromethyl, C3-C6 cycloalkyl, halo, hydroxy, C1-C6 alkoxy, methylenedioxy, ethylenedioxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C3-C10 aryloxy, amino, C1-C6alkylamino, di(C1-C6 alkyl)amino, thiol, C1-C6alkylthio, C6-C10 arylthio, nitro, cyano, carboxy, C1-C6alkoxycarbonyl, carbamoyl, C1-C6 alkylthiono, C1-C6 alkylsulfonyl or C6-C10 arylsulfonyl;

4. A compound according to claim 3, wherein R1 and R2 are, independently from each other, C1-C3 alkyl optionally substituted by cyclopropyl, —CH═CH2, —C≡CH or phenyl;

5. A compound according to claim 4, wherein R4 is methyl;

6. A compound according to claim 1 selected from the group consisting of:

7. A method of treating a medical condition in a mammal which is mediated by the A2B receptor activity comprising administering to the mammal, in need thereof, a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. A method according to claim 7, wherein the medical condition is selected from the group consisting of inflammatory diseases involving degranulation of mast cells, conditions involving impaired sensitivity to insulin, diseases in which angiogenesis is a key component of pathogenesis, apnea of preterm infants, myocardial reperfusion injury, inflammatory bowel disease, autoimmune diseases, diseases involving microvascular abnormalities of the retina and cardiac diseases.

9. A method according to claim 8, wherein the inflammatory disease involving degranulation of mast cells is selected from the group consisting of asthma, allergic rhinitis and allergic dermatitis.

10. A method according to claim 8, wherein the condition involving impaired sensitivity to insulin is selected from the group consisting of type 2 diabetes, non-insulin dependent diabetes, pre-diabetic state and impaired glucose tolerance.

11. A method according to claim 8, wherein the disease in which angiogenesis is a key component of pathogenesis is selected from the group consisting of solid tumors and angiogenic retinopathies.

12. A method according to claim 8, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis and lupus erythematosis.

13. A method according to claim 8, wherein the disease involving microvascular abnormalities of the retina is selected from the group consisting of retinopathy of prematurity, macular degeneration and diabetic retinopathy.

14. A method according to claim 8, wherein the cardiac disease is selected from the group consisting of hyperplasia consequent to hypertension, heart attack and arteriosclerosis.

15. A method according to claim 7, wherein the condition mediated by the A2B receptor activity is selected from the group consisting of asthma and diabetes.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable carriers.

17. A pharmaceutical composition according to claim 16 for the treatment of inflammatory diseases involving degranulation of mast cells, conditions involving impaired sensitivity to insulin, diseases in which angiogenesis is a key component of pathogenesis, apnea of preterm infants, myocardial reperfusion injury, inflammatory bowel disease, autoimmune diseases, diseases involving microvascular abnormalities of the retina and cardiac diseases.

18. A pharmaceutical composition according to claim 17, wherein the inflammatory disease involving degranulation of mast cells is selected from the group consisting of asthma, allergic rhinitis and allergic dermatitis.

19. A pharmaceutical composition according to claim 17, wherein the condition involving impaired sensitivity to insulin is selected from the group consisting of type 2 diabetes, non-insulin dependent diabetes, pre-diabetic state and impaired glucose tolerance.

20. A pharmaceutical composition according to claim 17, wherein the disease in which angiogenesis is a key component of pathogenesis is selected from the group consisting of solid tumors and angiogenic retinopathies.

21. A pharmaceutical composition according to claim 17, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis and lupus erythematosis.

22. A pharmaceutical composition according to claim 17, wherein the disease involving microvascular abnormalities of the retina is selected from the group consisting of retinopathy of prematurity, macular degeneration and diabetic retinopathy.

23. A pharmaceutical composition according to claim 17, wherein the cardiac disease is selected from the group consisting of hyperplasia consequent to hypertension, heart attack and arteriosclerosis.

24. A pharmaceutical composition according to claim 16 for the treatment of asthma and diabetes.