7-azaindoles, use thereof as phosphodiesterase 4 inhibitors and method for producing the same

1. A compound selected from the group consisting of:

N-(4-pyridylmethyl)-1-cyclopropylmethyl-7-azaindole-3-carboxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-1-isobutyl-7-azaindole-3-carboxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-1-hexyl-7-azaindole-3-carboxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-1-cyclopropylmethyl-7-azaindole-3-carboxylic acid amide;

N-(4-pyridylmethyl)-1-(4-fluorobenzyl)-7-azaindole-3-carboxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-1-(4-fluorobenzyl)-7-azaindole-3-carboxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-1-(4-methoxybenzyl)-7-azaindole-3-carboxylic acid amide;

N-(4-pyridylmethyl)-1-(4-chlorobenzyl)-7-azaindole-3-carboxylic acid amide;

1-(4-fluorobenzyl)-7-azaindole-3-carboxylic acid morpholide;

N-(2,6-dichlorophenyl)-1-(2-methylpropene-3-y)-7-azaindole-3-carboxylic acid amide; and

N-(3,5-dichloropyridine-4-yl)-1-(4-pyridylmethyl)-7-azaindole-3-carboxylic acid amide.

2. A compound selected from the group consisting of:

N-(3,5-dichloropyridine-4-yl)-(1-(3-methoxybenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

N-(4-pyridyl)-(1-(4-fluorobenzyl)-7-azaindole-3-yl)-glyoxylic acid amide hydrochloride;

N-(3,5-dichloropyridine-4-yl)-(1-(4-fluorobenzy 1)-7-azaindole-3-yl)-glyoxylic acid amide;

N-(4-pyridyl)-(1-(4-chlorobenzyl)-7-azaindole-3-yl)-glyoxylic acid amide hydrochloride;

N-(3,5-dichloropyridine-4-yl)-(1-(4-chlorobenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-(1-(4-methoxybenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

N-(2,6-dichlorophenyl)-(1-(4-chlorobenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

N-(4-carboxyphenyl)-(1-(4-fluorobenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

N-(4-ethoxycarbonylphenyl)-(1-(4-fluorobenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

N-(3,4-dimethoxyphenyl)-(1-(4-fluorobenzyl)-7-azaindole-3-yI)-glyoxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-(1-(4-methylbenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-(1-(4-hydroxybenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-(1-(3-hydroxybenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-(1-cyclopropylmethyl-7-azaindole-3-yl)-glyoxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-(1-hexyl-7-azaindole-3-yl)glyoxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-(1-isobutyl-7-azaindole-3-yl)-glyoxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-(1-(2-methylproperie-3-yl)-7-azaindole-3-yl)glyoxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-(1-(2-methoxyethyl)-7-azaindole-3yl)glyoxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-(1-(1-naphthylmethyl)-7-azaindole-3-yl)-glyoxylic acid amide;

N-(3,5-dichloropyndine-4-yl)-(1-(4-pyridylmethyl)-7-azaindole-3-yl)glyoxylic acid amide;

N-(3,5-dichloropyridine-4-yl)-(1-(3,5-dimethylisoxazole-4-ylmethyl)-7-azaindole-3-yl) glyoxylic acid amide;

N,N-bis(2-methoxyethyl)-(1-(4-fluorobenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

(1-(4-fluorobenzyl)-7-azaindole-3-yl)-glyoxylic acid morpholide;

(1-(4-fluorobenzyl)-7-azaindole-3-yl)-glyoxylic acid (S, S-dioxo-thiomorpholide);

(1-(4-fluorobenzyl)-7-azaindole-3-yl)-glyoxylic acid (4-methylpiperazide);

N-(6-methyluracil-5-yl)-(1-(4-fluorobenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

N-(3,6-dimethyluracil-5-yl)-(1-(4-fluorobenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

N-1,3,6-trimethyluracil-5-yl)-(1-(4-fluorobenzyl)-7-azaindole-3-yl)-glyoxylic acid amide;

and

N-1,2,4-4H-triazole-3-yl)-(1-(4-fluorobenzyl)-7-azaindole3-yl)-glyoxylic acid amide.

3. A 7-Azaindole of the formula 1

or a physiologically tolerated salt thereof

wherein n is 2;

R 1 is a —C 1 to —C 10 linear or branched alkyl; which may be unsubstituted or substituted with at least one of —OH, —SH, —NH 2 , —NHC 1 to NHC 6 alkyl, —N(C 1 to C 6 -alkyl) 2 , —NHC 6 to —NHC 14 aryl, —N(C 6 to C 14 aryl) 2 , —N(C 1 to C 6 alkyl)(C 6 to C 14 aryl), —NO 2 , —CN, —F, —Cl, —Br, —I, —O—C 1 to —O—C 6 alkyl, —O—C 6 to —O—C 14 aryl, —S—C 1 to —S—C 6 alkyl, —S—C 6 to —S—C 14 aryl, —SO 3 H, —SO 2 C 1 to —SO 2 C 6 alkyl, —SO 2 C 6 to —SO 2 C 14 aryl, —OSO 2 C 1 to —OSO 2 C 6 alkyl, —OSO 2 C 6 to —OSO 2 C 14 aryl —COOH, —(CO)C 1 to —(CO)C 5 alkyl, with mono-, bi- or tri-cyclic, saturated or monounsaturated or multi-unsaturated carbocyclic compounds with 3 to 14 ring elements, with mono-, bi- or tricyclic saturated or monounsaturated or multi-unsaturated heterocyclic groups with 5 to 15 ring elements and 1 to 6 hetero atoms selected from the group consisting of N, O and S, or a —C 2 to —C 10 alkenyl, monounsaturated, multiunsaturated, linear, branched, unsubstituted, monosubstituted or multi-substituted with at least one of —OH, —SH, —NH 2 , to —NHC 1 to —NHC 6 alkyl, —N(C 1 to C 6 -alkyl) 2 , —NHC 6 to —NHC 14 aryl, —N(C 6 to C 14 aryl) 2 , —N(C 1 to C 6 alkyl)(C 6 to C 14 aryl), —NO 2 , —CN, —F, —Cl, —Br, —I, —O—C 1 to —O—C 6 alkyl, —O—C 6 to —O—C 14 aryl, —S—C 1 to —S—C 6 alkyl, —S—C 6 to —S—C 14 aryl, —SO 3 H, —SO 2 C 1 to —SO 2 C 6 alkyl, —-SO 2 C 6 to —SO 2 C 14 aryl, —OSO 2 C 1 to —OSO 2 C 6 alkyl, —OSO 2 C 6 to —OSO 2 C 14 aryl, —COOH, —(CO)C 1 to —(CO)C 5 alkyl, with mono-, bi- or tri-cyclic, saturated or monounsaturated or multi-unsaturated carbocyclic compounds with 3 to 14 ring elements, with mono-, bi- or tri-cyclic saturated or monounsaturated or multi-unsaturated heterocyclic groups with 5 to 15 ring elements and 1 to 6 hetero atoms selected from N, O and S, wherein said C 6 to C 14 aryl groups and the carbocyclic and heterocyclic substituents may optionally be substituted at least once with R 4 ;

R 2 and R 3 are independently selected from the group consisting of —H, —C 1 –C 5 alkyl, unsubstituted or monosubstituted or multi-substituted with —OH, —SH, —NH 2 , —NHC 1 to —NHC 6 alkyl, —N(C 1 to C 3 -alkyl) 2 , —NO 2 , —CN, —F, —Cl, —Br—, —I, —O—C 1 to —O—C 6 alkyl, —S—C 1 to —S—C 6 alkyl, -phenyl, -pyridyl, or -phenyl, unsubstituted or monosubstituted or multi-substituted with —OH, —SH, NH 2 , —NHC 1 , to —NHC 3 alkyl, —N(C 1 to C 3 -alkyl) 2 , —NO 2 , —CN, —COOH, to —COOC 1 -alkyl, —F, —Cl, —Br—, —O C 1 to —O—C 3 alkyl, —S—C 1 to —S—C 3 alkyl,

or pyridyl, unsubstituted or monosubstituted or multisubstituted with NO2, —CN 1 —COOH 1 —COOC 1 to —COOC 3 alkyl, —C 1 , —Br, —O—C 1 to —OC 3 alky, —S—C 1 to S—C 3 alkyl, or

wherein —-NR 2 R 3 can be

R 4 is —H, —OH, —NH 2 , —NHC 1 to —NHC 6 alkyl, —N(C 1 to C 6 alkyl) 2 , —NCH 6 to —NHC 14 aryl, —N(C 6 to C 14 aryl) 2 , —N(C 1 to C 6 alkyl) (C 6 to C 14 aryl), —NHCOC 1 to —NHCOC 6 alkyl, —NO 2 , —CH, —COOH, —COOC 1 to —COOC 6 alkyl, —(CO)C 1 to —(CO)C 6 alkyl, —(CS)C 1 to —(CS)C 6 alkyl, —F, —Cl, —Br, —I, —O—C 1 to —O—C 6 alkyl, —O—C 6 to —O—C 14 aryl, —S—C 1 to —S—C 6 alkyl, —S—C 6 to —S—C 14 aryl, —SOC 1 to SOC 6 alkyl, —SO 2 C 1 to —SO 2 C 6 alkyl.

4. A physiologically tolerated salt of the 7-azaindole of claim 3 , wherein basic substituents of said 7-azaindole are neutralized with inorganic or organic acids or acidic groups are neutralized with inorganic or organic bases or tertiary amines are quatemized to quaternary ammonium salts.

5. A method of preparing the 7-azaindole of claim 3 by reacting 7-azaindole with oxalyl chloride to resultant product is reacted with a primary or secondary amine to form the 7-azaindale, wherein n=2.

6. The method of preparing a 7-azaindole of claim 3 comprising reacting 7-azaindole-3-yl-glyoxylic acid chloride with a primary or secondary amine in the presence of an inorganic base.

7. A method comprising administering a therapeutically effective amount of a 7-azaindole of claim 3 to a subject afflicted with at least one condition selected from the group COPD and asthma to treat the condition by inhibiting phosphodiesterase 4.

8. The method of claim 7 , wherein said condition is COPD.

9. The method of claim 7 , wherein said condition is asthma.

10. A pharmaceutical composition comprising a 7-azaindole of claim 3 and at least one conventional, physiologically tolerated carrier, diluent or adjuvant.

11. The compound of claim 3 that is N-(3,5-dichloropyridine-4-yl)-[(1-(4-fluorobenzyl)-7-azaindole-3-yl]glyoxylic acid amide.