TW200410936A - Amides of cyclic amino acids as PDE 4 inhibitors - Google Patents

Abstract

The invention relates to novel amides of cyclic amino acids, their use as inhibitors of phosphodiesterase 4 and processes for preparing them.

Description

200410936 (1) 发明 Description of the invention [Technical field to which the invention belongs] The present invention relates to substituted cyclic amidoamines, to a method for preparing them, to pharmaceutical preparations containing these compounds, and to medical uses of these compounds These compounds are inhibitors of phosphodiesterase 4 and are active compounds for treating diseases which can be affected by the inhibition of phosphodiesterase 4 activity by the compounds according to the invention in immune component cells such as macrophages and lymphocytes. [Prior Art] Activation of the receptor by a conductive substance in the cell membrane results in activation of the second messenger system. Adenylate cyclase synthesizes active cyclic AMP (cAMP) and cyclic GMP (cGMP) from AMP and GMP, respectively. cAMP and cGMP cause, for example, the relaxation of smooth muscle cells or the inhibition of mediator release or synthesis in inflammatory cells. The second messengers c A M P and c G M P are cleaved by phosphodiesterases (PDEs). So far, 11 families of PDE enzymes have been known (PDE1-11), and their substrate-specificity (cAMP, cGMP, or both) and their dependence on other substrates (such as calcitonin) different. These isoenzymes have different functions in the body and to varying degrees in individual cell types (Beavo JA, Conti M, and Heaslip RJ. Multiple Cyclic Nucleotide Phosphodiesterases, Molecular Medicine, 1994, 46: 399-405 HaU IP · Isozyme Selective Phosphodiesterase Inhibitors: Potential Clinical Use, Br J. clin. Pharmacol. 1993, 35: 1-7). Inhibition of different types of PDE isoenzymes causes cAMP or / and cGMP to accumulate in cells (2) (2) 200410936, some of which are therapeutically used (Torphy TT, Livi GP, Christensen SB. Novel phosphodiesterase inhibition for asthma Agents, Drug News and Far Cultivation 1-993, 6: 203 — 2 1 4). In cells (leukocytes, mast cells, eosinophils, and macrophages) that are important for allergic inflammation, the main PDE isoenzyme is type 4 (Torphy, J.T. and Undem, B.J. Phosphodiesterase inhibitors: a new opportunity for the treatment of asthma. Thorax 1991, 46: 5 1 2 — 523). The use of appropriate inhibitors to inhibit P D E 4 is considered to be an important method for treating many allergic-induced diseases (Schudt Ch, Dent G, Rabe K phosphodiesterase inhibitors, A c a d e m i c p r e s s London 1 996). An important property of phosphodiesterase inhibitors 4 is that they inhibit the release of tumor necrosis factor alpha (TNA) from inflammatory cells. TNF alpha is an important pre-inflammatory cytokine that exerts influence on many biological processes. For example, ' TNFa is released in the brain from activated macrophages, activated T lymphocytes, mast cells, basophils, fibroblasts, endothelial cells and stellate cells. It itself has an activating effect on neutrophils, eosinophils, fibroblasts and endothelial cells, resulting in the release of a variety of tissue-damaging mediators. In monocytes, macrophages and T lymphocytes, TNFα causes an increase in the production of other pro-inflammatory cytokines such as GM-CSF (granulocyte-macrophage colony-stimulus factor) or interleukin-8. Because of its inflammation-promoting and catabolic effects, TNFα plays a central role in many diseases such as airway inflammation, joint inflammation, endotoxin shock, tissue rejection, AID S, and many other immune diseases. The results of inhibitors of phosphodiesterase 4 are also suitable for treating these TNFα-related diseases. -6-(3) (3) 200410936 The spread of chronic obstructive pulmonary disease (COPDs) in the population is also economically important. Therefore, COPD disease in developing countries causes approximately 10-15% of all disease costs, and approximately 25% of all deaths in the United States can be attributed to this cause (Norman P .: COPD: New Development and Treatment Opportunities, Drug News and Far Cultivation, 1 1 (7), 43 1 — 43 7, 1 998), although these patents usually expire more than 55 years (Nolte D ·: chronische Bronchitis — eine Volkskrankheit multifaktorieller Genese [Chronic Bronchitis A Multi-Factor Origin of the universal disease]. Atemw · —Lungenkrkh. 20 (5), 260—267, 1994). WHO estimates that COPD will be the third leading cause of death in the next 20 years. The Chronic Obstructive Pulmonary Disease (COPD) syndrome includes the clinical condition of chronic bronchus with various symptoms including cough and sputum, as well as lung function progression and irreversible deterioration (exhalation is particularly affected). The disease stage progresses and is often exacerbated by the outbreak of bacterial infections (Rennard SI: COPD: Overview of definitions, epidemiology, and factors that influence other developments. Chest, 113 (4) Supp] ·, 23 5 S-241 S , 1 998). During the course of the disease, lung function steadily decreases, the lungs gradually become emphysema, and the patient's dyspnea becomes apparent. The disease significantly impairs patients' quality of life (shortness of breath, low load capacity) and significantly reduces their life expectancy. In addition to environmental factors, the main risk factor is smoking (Kiimmer F .: Asthma and COPD [Asthma and COPD]. Atemw.-Lungenkrkh. 20 (5), 299 — 302, 1 994; Rennard SI: Definition affecting other developments Overview of epidemiology and factors. Chest, 113 (4) Suppl., 235S-241S, (4) (4) 200410936 1 9 9 8) and therefore men are often affected more than women. However, this situation will change in the future due to changes in lifestyle and the increase in the number of female smokers. ’Current treatment is only aimed at reducing symptoms without the progression of causative intervention. J ο ng — the use of a cold 2 activator (such as salmeterol (sa 1 meter ο 1)), if appropriate with a niucarinergic antagonist (such as ipratropium) Combination, which improves lung function as a result of bronchiectasis, and is routinely used (Norman P ·: COPD: new development and treatment opportunities, Drug News Outlook, 1 1 (7), 43 1-43 7, 199 8 ). Bacterial infection, which must be treated with antibiotics, plays an important role in the stage of COPD (Wilson R .: The role of infection in COPD, Chest 113 (4) Suppl., 242S-248S, 1 99 8; Grossman RF: the price of antibiotics And the results of antibacterial treatment in the degeneration of COPD. Chest, 1 1 3 (4) Suppl., 249S — 255S, 1 998) ° Currently the treatment of this disease is still unsatisfactory, especially regarding the stable decline of lung function . Novel treatments against inflammatory mediators, protein enzymes or adhesion molecules will be very promising (Barnes PJ: Chronic obstructive disease: new opportunities for drug development, TiPS 10 (19), 415-42 3, 1 998 ). The independence of bacterial infections of chronic diseases (chronic inflammation, which is dominated by neutrophils) is found in the bronchi. These mediators and enzymes released by neutrophils are immobilized, particularly in response to structural changes (emphysema) observed in the airways. Inhibition of neutrophils -8- (5) (5) 200410936 Granulocyte activity is therefore a reasonable method to prevent or delay the progression of COPD (deterioration of lung function parameters). The pro-inflammatory cytokine TNF α (tumor necrosis factor) is an important stimulus for activating granulocytes. Therefore, it is generally known that TNF α stimulates the formation of oxygen free radicals from neutrophils (Jersmann 5 Η. P. A., Rathjen, DA ·, and Ferrante A: LPS — induced neutrophil oxygen free radical production is enhanced by TNF , Infection and Immunity, 4, 1 744 1 747, 1 99 8). PDE4 suppressed! 1 g is very effective in inhibiting the release of TNFα from many cells and consequently inhibiting the activity of neutrophils. The non-specific PDE inhibitor pentoxifylline is able to inhibit the formation of oxygen free radicals and the ability of neutrophil phagocytosis (Wenisch, C .; Zedtwitz — Licbenetein, KK; Parschalk, B. and Graninger W .: Borrow The effect of pentoxifylline on the ability of neutrophil reactive oxygen to produce and swallow cells in vitro is assessed by flow cytometry, Clin. Drug Invest., 13 (2): 99 — 1 04, 1997). Known Multiple PDE4 inhibitors. The most important in this regard are xanthine derivatives, rolipram analogs and nitraquazone derivatives (Overview: Karlsson J-A, Aldos D phosphodiesterase 4 inhibition for asthma treatment Agent, Exp Opin. Ther. Patent 1 997, 7: 98 9 — 1 003). It has not been possible to bring any of these compounds into clinical use to date. It must be concluded that these known PDE4 inhibitors also have various side effects, such as nausea and vomiting, which have hitherto not been sufficiently inhibited. For this reason, it is necessary to find novel PDE4 inhibitors with a superior therapeutic range or / and fewer side effects. There have been quite few developments of novel active compounds with different indications. -9-(6) (6) 200410936 Previous reports of the use of cyclic amines. Patent specification U S 3, 1 2 9, 2 5 8 Application for substituted hydrazinomine P 0 of the following general formula

NN N—R Η II R2 where A is Η or fluorenyl, Z is C] to C5 alkyl, R] is Η, or lower; U and R2 are academic, flammable, cyclic, aryl, or aryl Heteroaryl. These compounds differ from the compounds according to the invention, in particular with respect to the noble chain of Z and a hydrogen substituent on a hydrazine nitrogen atom. The requested compound has therapeutic properties for treating depression. The reaction of unsubstituted piperidine-1-ylamine with substituted benzaldehyde to produce phenylg-methylamino-D-diamine has been described by Zimmer et al. In J. Amei *

Chem. Soc., 77; 1955; 790-792 and interpolated by R. Brohme in Chem. Ber .; 123; 10; 1 990; 2039-2046. In Eur. J. Med. Chem .; 24; 1 9 8 9; 313-315, F · D · P o pp describes substituted piperidine-1-ylamine or pyrrolidine. Carbaldehydes reaction. In Synthesis, (7), 5 2-5 3 3; 1988, F. Szurdoki and colleagues disclosed a simple method for N-aminated peptides. In Eur. J. Med. Chem .; 22; 1 98 7; 1 47-1 52, Ch G hig 1 ieri — Bertez discloses the condensation of an unsubstituted piperidine-1 1-amine and acetophenone This produces 1- (1-phenylethyleneiminyl) piperidine. In Helv. Chim. Acta; 41, 1958, 22-25, p R inderspacher explains the use of substituted isonicotinyl chloride from unsubstituted piperidine- 1-yl radical of -10- (7) (7) 200410936 Preparation of N- (piperidine-l-yl) -isonicotinamine amine in J, Org. Chem. (1989), 54 (23), 5632-5 6 3 5, T · E · D'Ambra And MR Bell described pyridin-2-carboxamidine synthesized by the amidation of an aryl isocyanate with an α-amino anion. In Zh. Prikl. Khin (189 8 7), 60 (11), 2511-2515, A · I · Kazika et al. Investigated the synthesis and stereoselective properties of palmyl benzyl pipecolyl amine benzophenone. . Z. Physiol. Chem. At HoppeSeyier; 3 22; 1960; 1 0 1 — 11 1. S. Fittkaul describes N- (phenyl) cyclod-D- 2 -residue acid without any amine group at the 1 position. amine. In J. Chem. S oc. Perkin Trans. 1; 17; 1996; 2117 — 2 1 28, P. O'Brien describes the pure mirror isomerism of N- (aryl)- Pyrrolidine- 2-carboxamide. SPECS and Bio SPECS DV sell compounds N- (3-isobutoxy-4-methoxyphenyl)-1- (3,4-dimethoxymethoxybenzyl) piperidine- 1 as screening compounds 2 —residual amine. No biological activity was revealed. NL-6 603 8 20 describes N-fluorenyl acridine derivatives as antitumor and antiviral agents. One of these compounds is m-chloro-N- [2-[[9,9-dimethyl-1-10-acridanyl] carbonyl- 1-] pyrrolidinyl] benzamide. No prior knowledge of cyclic amidoamines as inhibitors of PDE4. -11-200410936 [Summary of the Invention] The present invention relates to substituted cyclic amidoamines of the general formula I

X 〇 where η can be 1 or 2, X can be a νη2;-N = C (R3)-R4 (E or Z configuration, ipsilateral or contralateral) '-NH-CH (R3)-R4,- N (R3)-CHR "-r4, one NH-CH2-R4, or one NH-(C = 0)-R4, R] and R4 may be the same or different and may be a single with 3 to 14 ring members Ring or polycyclic saturated or monounsaturated or polyunsaturated carbocyclic ring, having 5 to 15 ring members and 1 to 6 heteroatoms, preferably monocyclic or polycyclic saturated or monounsaturated N, 0 or S Or polyunsaturated heterocycles, in which the carbocyclic or heterocyclic ring is partially substituted by one or more of the following groups: -F, -C1, -Br, -I, -0H, -N02, One NH — CO — c] — C6 —alkyl, straight or branched, one COOH, one COOC] — C6 one alkyl, straight or branched, one c!-C6 —alkyl, straight or branched .Chain, —c] —c6—alkoxy, straight or branched, —C3—c7 —cycloalkyl, — c3 —C7 —cycloalkoxy, —n (r3) 2, —c0N ( R3) 2 or 1 200410936 〇) where each alkyl or alkoxy group, and a part thereof, may be substituted once or More than once: one F, —C1, —Br, one I, —c3—C7_cycloalkyl or —C7—cycloalkyloxy and each cycloalkyl or cycloalkoxy, some of which may be substituted by the following groups One or more times: one F, one C1, one Br, one I, one OH, one C] —C6—alkyl or / and one (:! — (: 6—alkoxy R3 may be in each case Independently fluorene or alkyl (—Cl-c6), straight or branched chain, in which each alkyl group can be arbitrarily substituted once or more than once, and R2 can be independently fluorene or alkyl in each case (a Cl — c6), linear or branched or benzyl, in which each alkyl or benzyl group can be arbitrarily substituted one or more times as described above, and R1-N — R2 can also be an N-containing hetero Ring system, in which the heterocyclic ring system can be substituted once or more arbitrarily as described above, for example, 8-chloro-5,10-dihydrodibenzo [b, eH1,4] diazepine-n-one, 10, n —dihydro-5H —dibenzo [b, f] nitrogen, 9 Η —carbazole or 10 thiophenanthrene's prerequisite is that the compound (,) is not N — (3 —isobutyl Oxy-4-methoxy Group ~ (3,4-mono-methoxy-benzylamino) fixed a 2-residual acid amine or m ~ chloro-N — [2 — [(9,9-dimethyl-1 10-D y Iodine) fluorenyl ~ 1-]-D than slightly D]] benzamidine. Within the meaning of this application, an 'alkyl, alkoxy, cycloalkyl or cycloalkoxy group may also contain one or more C = C or / and bonds, if appropriate, preferably NH2 or- N = C (R3)-R4. X is especially good — -13- (10) ^ '200410936 N = C (R3)-R4. Preferred are monocyclic aromatic or heteroaromatic ring systems having (particularly) 6 ring members, such as phenyl or pyridyl, such as pyridin-4-yl, or bicyclic aromatics having 9-10 ring members Family or heteroaromatic ring systems, such as naphthyl, such as naphthyl-l- or naphthyl-2-yl, d-indolyl or quinolyl. The ring system R1 preferably has from 0 to 3 substituents, and uses a group having, in particular, —F, —C1 ′ — — — —OH — —C6 —C6_alkoxy, such as Oxy, ethoxy, propoxy, isopropoxy, butoxy,

Isobutoxy, or allyloxy, -Cl-C6-alkyl 'straight or branched chain, such as methyl or ethyl, substituted C6-alkyl, such as CF2H or ispropylmethyl,- Cs—C7 —cycloalkyl, such as cyclopentyl or cyclohexyl ′ —C3 — C7 —cycloalkoxy, —coOH, —C00Ci — C6 —alkyl, straight or branched chain, such as methoxycarbonyl or Ethoxycarbonyl,

NHC 0—Ci—C6—Cycloyl, straight or branched, such as N Η monoethylfluorenyl, mono CON (R3) 2, such as aminocarbonyl, N (r3) 2, such as dimethylamino or diamine Ethylamino or S02NH2 as a substituent. Particularly preferred is to give i-3 presences such as 4 early replacement, 2, 6-or 3, 4-2 or 2, 4 '6-, 2, 3' 4-or 3, 4 '5-tri-substituted pyridine Or a substituent in a phenyl ring, which is selected from the group consisting of -F, -C1'-Bι ,, 1] [, 10H, -Ci-C6 ~ alkoxy, straight or branched, -c〇〇. H, a COOG — C6-alkyl, straight or branched chain, a Ci—C6 —alkyl, —C0NH2, —NH — CO — C] —C6 —alkyl, S02H2 5, and each alkyl or Alkoxy, its part, is straight or branched, straight or branched, or may be substituted one or more times by halogen, 0H, and / or cycloalkyl. -14-(11) (11) 200410936 monocyclic aromatic or heteroaromatic ring system, such as phenyl or pyridine-4 ~ yl, or bicyclic aromatic or heteroaromatic ring system, such as naphthalene-1 monoyl or naphthalene ~ 2 ~ base, especially for R1. The ring system has 0 to 3 substituents, which may be the same or different and may be one F, one C1, one Br, one I, one OH, one co-c] -C6-alkyl, linear or branched Chain, one COOH, —CONH2, —COOC] —C6-alkyl, straight or branched, —Ci—C6 ~ alkyl, straight or branched, —10—Ci—C6-institution, straight or Branches, —Cq ~ L / Cycloalkyl, —c3-C7-Cycloalkoxy, —NH2, —NH (Cl—alkyl, straight or branched chain), or —N (Ci— C6 —Institute Group, straight or branched chain) 2, or a S02nh2, preferably each alkyl or alkoxy group, a part of which may be optionally substituted with one of the following; less than one time: halogen, OH,-C3 -C7 —Cyclocyclyl or / and ~ c —C 7 —Cycloalkoxy, and the total number of substituents therein may be 0 to 3. Preferably, R2 is fluorene or methyl or together with R1 to form an n-heterocyclic system. Preferably R3 is administered as fluorene or methyl. R4 is preferably a monocyclic aromatic or heterocyclic ring system having, in particular, 5 or 6 ring members, such as phenyl, pyridyl, such as pyridin-2-yl, pyridin-2-yl, or pyridin-4 Radical, furanyl, such as furan-2-yl, furan-3-yl, or furan ~ 4-yl, thiophenyl, such as thiobenzene-2-yl, thiobenzene-3-yl, or thiobenzene-4-yl, Pyrrolyl, such as pyrrol-2-yl, or a ring aromatic or heteroaromatic ring system having 9-10 ring members, such as naphthyl, such as naphthyl-1 or naphthyl-2, quinolyl or Indole. The ring system R4 preferably has up to 3 substituents, and is used in particular having -ρ,--15- (12) 200410936

Cl, -Br, -I, -0H, -c] -c6 -alkoxy, linear or branched, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy 'or bupropoxy, -c] -c6-institution, straight or branched, one C3-C7-cycloalkyl, such as cyclopentyl or cyclohexyl, -C3-C7 monocycloalkane Oxy, mono-COOH, —COOC] -c6-alkyl, straight or branched, such as methoxycarbonyl, mono-CON (R3) 2 such as amine carbonyl, mono-NH — CO — C] — C 6 —alkyl , Straight or branched chain, such as n Η -ethenyl,

N (R3) 2, such as dimethylamino, or S02NH2, as a substituent, and each alkyl or alkoxy group, a portion thereof may be substituted one or more times by the following groups: halogen, —0H, — C3 — C7 —Cyclocyclyl or / and —C3— C7 A cycloalkoxy group and each cycloalkyl or cycloalkoxy group, some of which may be substituted one or more times by the following groups: halogen, —0H, —c] — C6 —alkyl or / and —C! ~ C6 —alkoxy, such as cyclopropylmethoxy. Particularly preferred are 1 to 3 selected from the group consisting of phenyl rings present in, for example, 4-mono-substituted, 2,6- or 3,4-di-substituted, or 2,4, ό—or 3,4,5-tri-substituted. -F, -C1, -Br, -I,-and -C] -C4 -alkoxy substituents. A monocyclic aromatic or heteroaromatic ring system, such as phenyl or pyridin 4-yl 'or a two-earth aromatic or heteroaromatic ring system, such as naphthalene-1, or naphthalene-2, is specific for R4 good. The ring system has 0 to 3 substituents, which may be the same or different and may be one F, -C1, one Br, one I, one OH,-CC >-Cl ~ -alkyl, straight or branched chain, -COOH, CONH2, -cooc ^, C6-alkyl, straight or branched, -monoalkyl, straight or branched, ~ 0-Cl-C6-alkoxy, straight or branched, -NH2 , (C) —C6—Yuanji's straight or branched bond), or—N (C] —C6 —-16- (13) (13) 200410936 Yuanji's straight or branched chain), or s〇2nh2 And each of the alkyl or alkoxy groups, a portion thereof may be substituted one or more times by: halogen, -OH, -C3-C7-cycloalkyl or / and C3-C7-cycloalkoxy, and Each cycloalkyl group or cycloalkoxy group, part of it, may be substituted one or more times by the following groups: halogen, OH or / and a Cl-C6-alkyl group, and the total number of substituents may be 0 to 3 . Among them, two adjacent substituents on R] or R4 may be bridged with each other if appropriate, for example, to form a 5-ring or a 6-ring. Bridging is generated using methylene (-C C 2-) or ethylene (-CH2CH2-) units. A particularly good example of bridging is methylenedioxy. The invention further relates to salts of the compounds according to formula 1, particularly physiologically tolerable salts. Physiologically tolerable salts are obtained by neutralizing bases with inorganic or organic acids, and / or by neutralizing acids with inorganic or organic bases. Examples of suitable inorganic acids are hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, while examples of suitable organic acids are carboxylic acids, su 1 ph 0 or sulfonic acids such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, Malonic acid, maleic acid, trans maleic acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, Mandelic acid, citric acid, malic acid, salicylic acid, 3-aminosalicylic acid, ascorbic acid, pamoic acid, nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2 monohydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzoic acid '4 monomethylbenzoic acid or naphthalene-1 2-sulfonic acid. Examples of suitable inorganic bases are sodium hydroxide, potassium hydroxide, and ammonia, and examples of suitable organic bases are amines, but tertiary amines are preferred, such as-(14) (14) 200410936 such as trimethylamine, triethyl Amine, pyridine, N, N-dimethylaniline, D-quinoline, isoquinoline, α-methylpyridine, / 3-methylpyridine, τ-methylpyridine, quinalidine or pyrimidine. Besides, the physiologically tolerable salt of the compound according to Formula 1 can be obtained by converting a derivative having a tertiary amine group into a corresponding quaternary ammonium salt by a known method using a quaternary agent. Examples of suitable quaternizing agents are haloalkanes, such as iodoform, bromoethyl, and n-chloropropane compounds, and halogenated compounds, such as phenyl chloride or 2-phenethyl bromide. The invention further relates to compounds of formula 1 containing one or more asymmetric carbon atoms in the form of their optical isomers or mixtures of optical isomers, such as D-form, L-form and D, L mixtures, and in several In the case of the presence of an asymmetric carbon atom, it is related to the non-mirromeric form. Compounds of formula 1 containing asymmetric carbon atoms and generally naturally occurring racemates can be resolved into optically active isomers in a manner known per se (for example by using optically active acids). However, it is also possible to use an optically active starting material and then obtain the corresponding optically active or non-mirromeric compound in the final product. The compounds according to the invention have been found to have pharmacologically important properties that can be used therapeutically. The compounds according to the invention are inhibitors of TNF alpha release. Part of the present invention is therefore a compound of formula 1 and their salts according to the present invention, as well as pharmaceutical preparations containing these compounds or their salts, which can be used for the prevention or treatment of diseases in which the inhibitory effect of TNFα is a valuable disease. These diseases include ' for example ' inflammation of joints including arthritis and rheumatoid arthritis and other arthritic diseases such as rheumatoid spondylitis and osteoarthritis. Other possible applications are septicemia, septic shock, K-18-18 (15) (15) 200410936 Ran-negative sepsis, toxic shock syndrome, dyspnoea syndrome, asthma and other chronic lung diseases, bone wasting Or transplant rejection or other autoimmune diseases, such as lupus erythematosus, multiple sclerosis, filamentous nephritis and uveitis, insulin-dependent diabetes, and chronic myelination. In addition to this, the compounds according to the invention can also be used for the treatment of infections, such as viral infections and parasitic infections, for example for the treatment of malaria, fevers infecting Baiguan, infection-related muscle pain, AIDS and cachexia. The compounds according to the invention are inhibitors of phosphodiesterase 4. Therefore, another part of the object of the present invention is the compounds of formula 1 and their salts according to the present invention, as well as the pharmaceutical preparations of these compounds or their salts, which can be used to treat the inhibitory effect of phosphodiesterase 4 in which it is valuable. disease. Therefore, the compound according to the present invention can be used as a bronchodilator and for asthma prevention. In addition, the compound of formula 1 according to the present invention inhibits the accumulation and activity of eosinophils. As a result, the compounds according to the present invention can also be used in diseases in which eosinophils play a role. These include 'for example' inflammatory airway diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic vasculitis, inflammation of eosinophilic mediators, such as eosinophilic keratitis, Erythrocyte pneumonia and PIE syndrome (pulmonary infiltration with eosinophils), measles, ulcerative colitis, Crohn's disease, and proliferative skin diseases such as psoriasis or keratosis. The treatment of chronic obstructive pulmonary disease (C OPDs) is particularly good. Another aspect of the present invention is still the formula according to the present invention] Compounds 19- (16) (16) 200410936 and their salts are capable of inhibiting lipopolysaccharide (LPS) -induced TNF alpha in human blood in vitro Release and in vivo LP.S-induced pulmonary neutrophil infiltration in mice. In summary, these discovered pharmacologically important properties are empirically based on the compounds of Formula 1 and their salts, as well as pharmaceutical formulations containing these compounds or their salts, which are therapeutically used for the treatment of chronic obstructive pulmonary disease. In addition to this, the compounds according to the invention have neuroprotective properties and can be used for the treatment of diseases in which neuroprotection is of value. Examples of these diseases are Alzheimer's disease (Alzheimer's disease), memory loss, Parkinson's disease, depression, stroke, and intermittent sickness. Other possible applications of the compounds according to the invention are the prevention and treatment of prostate diseases, such as benign prostate proliferation, ρ 11 akiria and nocturnal disease, as well as the treatment of incontinence, urinary stone-induced colic, and sexual dysfunction in men and women. . Finally, the compounds according to the invention can also be used to inhibit the development of drug dependence associated with repeated use of analgesics (e.g. morphine) and to reduce the development of tolerances associated with repeated use of these analgesics. Effective doses of the compounds according to the invention or their salts are used in the preparation of medicaments with conventional adjuvants, carrier substances and additives. The dosage of the active compound may vary depending on the route of administration, the age and weight of the patient, the nature and severity of the disease to be treated, and similar factors. The daily dose can be administered in a single dose, which is a daily dose to be divided into two or more times and is usually 0.001 to 100 mg, such as 0.01 to 50 mg. Examples of suitable administration forms are oral, non-menstrual Intestinal, intravenous, transdermal-20- (17) (17) 200410936, topical, inhaled and intranasal preparations. Conventional Galen formulations are used, such as lozenges, dragees, capsules, dispersible powders, granules, aqueous solutions, water or oil suspensions, syrups, juices and drops. The solid pharmaceutical form may contain inert ingredients and carrier materials such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginate, gelatin, guar gum, magnesium stearate, aluminum stearate, methyl Cellulose, talc, highly dispersible silicic acid, silicone oil, high molecular weight fatty acids (such as stearic acid), gelatin, agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol) ; Formulations suitable for oral administration may include additional flavoring agents and / or sweeteners if necessary. Liquid pharmaceutical forms can be sterilized or / and, if appropriate, contain auxiliary substances such as preservatives, stabilizers, wetting agents, penetrants, emulsifiers, dispersants, solubilizers, salts for regulating osmotic pressure or buffering , Sugar or sugar alcohol 'or / and and viscosity modifiers. Examples of these additives are tartrate buffers and citrate buffers, ethanol and chelating agents (such as ethylene diamine tetraacetic acid and its non-toxic salts). High molecular weight polymers, such as liquid polyepoxide, microcrystalline cellulose, carboxymethylvidin, polyvinylpyrrolidone, W polysaccharide or gelatin, are suitable for adjusting viscosity. Examples of solid carrier materials are reduced powder, lactose, mannitol, cellulose methyl ether, talc, highly dispersible silicic acid, high molecular weight fatty acids (such as stearic acid), gelatin, agar, golden phosphate, magnesium stearate, Animal and vegetable fats and solid high molecular weight polymers, such as polyethylene glycol. Parenteral or topical oil suspensions can be plant-based synthetic or semi-synthetic oils', e.g. in each case 8 to 22 in the fatty acid chain -21-(18) (18) 200410936 C Liquid fatty acid esters such as palmitic acid, lauric acid, tridecanoic acid, heptadecanoic acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid , Maleic acid, erucic acid or oleic acid in units having 1 to 6 C atoms to triols, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, diols or Glycerol esterification. Examples of such fatty acid esters are the commercial products mi glyo Is, isopropyl myristate, isopropyl palmitate 'isopropyl stearate, P RG 6-decanoic acid, caprylic acid / decane of saturated fatty alcohols Esters, polyoxyethylene triglycerides, ethyl oleate, waxy fatty acid esters, such as artificial duck tail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate , Ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, and the like. Varying viscosity ketone oils or fatty alcohols such as isotridecanol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, and fatty acids such as oleic acid are also suitable. It is also possible to use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil, or soybean oil. Examples of suitable solvents are alcohols such as ethanol or isopropanol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipic acid, propylene glycol, glycerol, dione or Tripropylene glycols' waxes, methyl cellosolvents, cellosolvents, esters, morpholine, monooxane, methylformone, dimethylformamide, tetrahydro Diffran, cyclohexanone and the like. The film-forming agents that can be used are celluloses that are soluble or swellable in water and organic solvents, such as hydroxypropyl methylcellulose, methyl cellulose, • 22-(19) (19) 200410936 B Cellulose or soluble starch. A type representing a mixture of a gelling agent and a film-forming agent is also completely possible. In this case, special ionic macromolecules are used, such as sodium carboxymethyl vitamin D, polyacrylic acid, polymethacrylic acid and its salts, sodium starch glycolate, alginic acid or propylene glycol alginates such as sodium salts , Acacia, xanthan, guar or carrageenin. Further formulation aids that can be used are: glycerol, paraffin waxes of different viscosities, triethanolamine, collagen, allantoin, and phenylbenzimidazole sulfonic acid. Surfactants, emulsifiers or wetting agents may also be necessary in the formulation, such as sodium lauryl sulfate, fatty alcohol ether sulfate, N-lauryl P-iminodipropionate, polyoxyethylation Castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (such as Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearin Acid esters, alkylphenol polyglycol ethers, cetanetrimethylammonium chloride or mono- / dialkyl polyglycol ether orthophosphate monoethanolamine salts. Stabilizers, such as microcrystalline kaolinite or colloidal silicic acid, may be required to prepare the formulation, if appropriate, to stabilize the emulsion or prevent dissociation of active substances such as antioxidants such as tocopherol or butylhydroxyanisole, Or preservatives, such as P-hydroxybenzoate. Preparations for parenteral administration may also be presented in separate dosage unit forms, such as ampoules or vials. Preference is given to using solutions of the active compounds, preferably aqueous solutions and, in particular, isotonic solutions, and suspensions. These injection forms can be prepared as a stand-alone agent or only before use by mixing the active compound, such as a lyophilizate, with other solid carrier materials, if appropriate, directly with the desired solvent or suspending agent. -23- (20) 200410936 The internal preparation can be present in water or oil solution or as a water or oil suspension. They can also be lyophilized and prepared using a suitable solvent or suspending agent before use. Produce formulations, aliquots and seal under conventional antimicrobial and antiseptic conditions. Compounds according to the invention or pharmaceutical formulations containing these compounds can also be administered in combination with other pharmacologically active compounds (such as other phosphodiesterase inhibitors). I. The invention further relates to a method for preparing a compound according to the invention. According to the present invention, the compound of the general formula 1 has the meanings of X and R 1 and R 2 described above and wherein n = 1 or 2,

X 〇 is the same as that of aromatic or heterocyclic by making 1-aminopyrrolidine- 2 -residamine or 1-aminopiperidine- 2 -carboxamide of formula 2 the same meaning as R 2 and R 2 Aromatic aldehydes, ketones or fluorenyl chlorides are prepared by reaction.

2 ο The reaction of the methylforminogen reducing agent with the fluorenyl chloride is advantageously carried out in the presence of an auxiliary base. Excess amines used as co-reactants, tertiary amines, preferably pyridine or / and triethylamine, and an inorganic base ', preferably alkali metal hydroxide or alkali metal hydride, can be used as auxiliary bases. • 24-(21) (21) 200410936 1-Aminopiperidinecarboxamide or 1-amino-pyrrolidinecarboxamide of formula 2 by using in a suitable solvent (such as alcohols, such as n-butanol) Reaction of 2-bromo-5-chlorohexamidineamine or 2-yl-5chlorochloropentamidine with hydrazine and 2-bromo-5-chlorohexamidineamine or 2-bromo-5-chloro Prepared by pentamidine. In addition, the present invention will be illustrated by the following examples. [Embodiment] An example of a method for preparing a compound of formula 3 according to the present invention: Example 1: N-(3-isobutoxy-4 -methoxyphenyl)-1 -aminopiperidine-2 -carboxyl 20 g of N- (3-isobutoxy-4 4-methoxyphenyl) -bromo-6-chlorohexamidine (49 mmol) and 36 g of hydrazine hydrate (720 mmol) Mol) was heated under reflux in 140 ml of n-butanol for 13 hours and then 40 ml of n-butanol was distilled off. After the mixture was cooled, 100 ml of water, 100 ml of toluene and 20 ml of ammonia solution (25% strength) were added, and all were stirred for 30 minutes. The organic phase was separated, washed with 50 ml of water, dried over sodium sulfate and distilled to dryness. The residue was crystallized from ethanol. Yield: 1 1 · 8 g (75% of theory)

Melting point: 1 4 5 — 1 4 6 ° C It is also possible to prepare many other compounds of formula -25- (22) 200410936 3 using the instructions given in Example I, where η and R1 can have the following meanings, and list the following Chemicals as examples:

Η

I Example η R] Melting point rc] 2 1 2,4,6-trimethylphenyl 20 8 -2 1 0 (HC1) 3 1 3,4-dimethoxyphenyl 141-142 (formate) 4 1 2,6-dichlorophenyl 144-145 5 1 phenyl 165-166 (formate) 6 1 4-ethoxycarbonylphenyl 104-105 7 2 3,4-dimethoxyphenyl 145 -146 8 2 2,6-dichlorophenyl 149-150 9 2 4-ethoxycarbonylphenyl 114-115 10 2 pyridine-4 -yl 131-132 11 2 4 -aminocarbonylphenyl 242-243 12 2 1-naphthyl 137-138 13 2 2 -naphthyl 148-149 An example of a method for preparing a compound of formula 4 according to the present invention: Example 1 4: Ν— (2,6-dichlorophenyl) (E) -1 — [(3,4-dimethoxybenzylidene) amino] pyrrolidine-1 2-carboxamide 4.85 g of N— (2,6-dichlorophenyl) -1 monoaminopyrrole Pyridine-26- (23) (23) 200410936 ~ 2-Carboxamide (18 mmol) and 3.66 g of 3,4-dimethoxy ~ benzaldehyde (22 mmol) in 50 ml of 2 propane The alcohol was heated at reflux for 4 hours. After the mixture was cooled, the precipitate was filtered by suction and recrystallized from methanol. Yield: 6.3 g (84% of theory)

Melting point: 1 6 7 — 1 6 8 ° C Various substituted aromatic aldehydes are commercially available or can be prepared similarly to the preparation of 3-isobutoxy-8-methoxybenzaldehyde. 3-Isobutoxy-4-methoxybenzaldehyde 120 g (0.876 mole) of 1-bromo-2-methylpropane was added dropwise to 65-75 ° C while stirring for 30 minutes 100 g (0.657 mol) of 3-hydroxy-4-methoxymethoxybenzaldehyde, 138 g (1.0 mol) of potassium carbonate and 3 g of potassium iodide in 600 ml of anhydrous N'N-di A mixture in methylformamide. After stirring at 80 to 85 ° C for 25 hours, the organic phase was separated and thoroughly mixed with 400 ml of a 10% sodium hydroxide solution and 400 ml of benzene. The benzene solution and the aqueous phase were further extracted twice with 300 ml of benzene in each case. The combined organic phases were shaken with 2000 ml of a 100% sodium hydroxide solution and in each case twice with 300 ml of water. The benzene was distilled off and the crane residue was evaporated in vacuo. Yield: 91.2 g (66.5% of theory)

Boiling point: 1 4 0 — 1 4 3 ° C / 5 mmHg Melting point: 48 — 49 ° C Example of use] 4, many other -27- 200410936 \ 1 / (24

'T is listed below and examples R1 R4 Melting point [° C] 15 3,4-dimethoxyphenyl 3-isobutoxy-4-methoxyphenyl 112.3-113.7 Amend A 16 3,4 -Dimethoxyphenyl 3-isobutoxy-4-methoxyphenyl 136.0-137.3 modified B 17 2,6-dichlorophenyl 3-isobutoxy-4-methoxyphenyl 135 -136 18 4-ethoxycarbonylphenyl 3-isobutoxy-4-methoxyphenyl 135-136 19 2-bromophenyl 3,4-dimethoxyphenyl 154-155 20 2-bromo Phenyl-4,5-dimethoxyphenyl 3,4-dimethoxyphenyl 147-148 21 2,4,6-trimethylphenyl 3,4-dimethoxyphenyl 147-148 22 4-ethoxycarbonylphenyl 3,4-dimethoxyphenyl 153-154 23 3-isobutoxy-4-methoxyphenyl 3,4-dimethoxyphenyl 128-129 24 3-isobutoxy-4-methoxyphenyl 2,6-dichlorophenyl 114-115 25 4-ethoxycarbonylphenyl 3-hydroxy-4-methoxyphenyl 159-160 -28- (25) (25) 200410936 Example R] R4 Melting point [° C] 26 3 '4-_. Methoxy 3,4-dimethoxyphenyl 153-154 27 3,4-dimethoxy Phenyl 2,6-dichlorophenyl 108-109 28 Phenyl 3-isobutoxy-4-methoxyphenyl 108-110 29 3,4-dimethoxyphenyl 4-methoxy-Cai-1 -yl 137-138 30 3,4-dimethoxyphenyl 2-methoxy-naphthyl 141-142 31 3,4-dimethoxyphenylpyridinyl 148-149 32. 3,4-dimethoxyphenyl 3-difluoromethoxy-'methoxyphenyl 119-121 3,4- Dimethoxyphenyl 3-propanyl-4-methoxyphenyl 122-124 34 3,4-dimethoxyphenyl 4-difluoromethoxy-3-methoxyphenyl 132 -133 35 3 5 4-methoxymethoxy 3-cyclopropyl-methoxy-4-methoxyphenyl 151-152 36 3,4- (methylenedioxy) phenyl 3-cyclopropyl Methoxy-methoxy-4-methoxyphenyl 127-128 37 3,4- (methylenedioxy) phenyl 4-* per / methoxy-3 -methoxyphenyl 124-125 38 3,4-dimethoxyphenyl 4-ethylaminoaminophenyl 203-204 39 3,4- (methylenedioxy) phenyl 4-ethylamidophenyl 219-221 40 3, 4-dimethoxyphenyl 3-isobutoxy-4-methoxyphenyl 1221-122 In compound N- (3,4-dimethoxyphenyl) — (E) —l— [(3 —Isobutoxy-4 monomethoxyphenylbenzylidene) -amino] pyrrolidine-2 2-carboxamide To two different amendments. Example 1 5 ·· Correction A: Melting point 1 1 2.3 — 1 1 3 · 7 ° C. Example 16: Correction B ·· Melting point 1 3 6.0 — 1 3 7.3 t. X-ray diffraction analysis of modified A and B shows different reflection patterns. The IR spectrum is different, and the NMR spectrum is the same. (26) (26) 200410936 The two crystal types can be prepared by dissolving Example 15 in hot 2-propanol and modifying the selectivity of A or B seed crystals. An example of a method for preparing a compound of formula 5 according to the present invention: Example 4 1: (3 -isobutoxy-4 -methoxymethoxyphenyl)-(E) — 1-[(3 '4 ~ dimethoxy Monobenzylidene) amino; piperidine-2-carboxamide 4.8 g of N- (3-isobutoxy-4 4-methoxyphenyl) -1-amino-piperidine-2- Carboxamide (15 mmol) and 2.9 g of 3,4-dimethoxybenzaldehyde (18 mmol) were heated under reflux in 25 ml of 2-propanol for 4 hours. After the mixture was cooled, the precipitate was filtered by suction and recrystallized twice from 2-isopropanol. Yield: 3.1 g (44% of theory)

Melting point: 1 3 3 — 1 3 4 ° C It is also possible to prepare many other compounds of formula 5 using the instructions given in Example 41, where R1 and r4 can have the following meanings, and the following compounds are listed as examples: -30 -200410936

Example R1 R4 Melting point [° C] 42 3-isobutoxy-4-methoxyphenyl 3-isobutoxy-4-methoxyphenyl 62-62.5 43 2,6-dichlorophenyl 3 -Isobutoxy-4-methoxyphenyl 143-144 44 3-isobutoxy-4-methoxyphenyl 4-hydroxy-3-methoxyphenyl 123-124 45 3,4- Dimethoxybenzene 3-isobutoxy-4-methoxyphenyl 113-114 46 2,6-dichlorophenyl 3,4-dimethoxybenzene 151-152 47 3-isobutoxy 4-methoxyphenyl 3-hydroxymethoxyphenyl 139-140 -31-(28) 200410936 Example R] R4 Melting point [° C] 48 3-isobutoxy-4-methoxyphenyl 2,6-dichlorophenyl 130-130.5 49 3,4-dimethoxyphenyl 2,6-dichlorophenyl 133-134 50 3,4-dimethoxybenzene 2-fluorophenyl 122-123 51 4-ethoxycarbonylphenyl 3-isobutoxy-4-methoxyphenyl 105 · 107 52 4-ethoxycarbonylphenyl 3-hydroxy-4-methoxyphenyl 148-150 53 4- Ethoxycarbonylphenyl 3,4-dimethoxyphenyl 115-117 54 3-isobutoxy-4-methoxyphenyl 4-methoxyfluorenylphenyl 146-147 55 3-isobutoxy Phenyl-4-methoxyphenyl 3,4-dihydroxyphenyl 179-180 56 3-isobutoxy-4-methoxyphenyl 4-hydroxy Phenyl163-164 57 3-isobutoxy-4-methoxyphenylphenyl 159-160 58 3-isobutoxy-4-methoxyphenylpyran-2-yl 128-129 59 3-isobutoxy-4-methoxyphenylthiophen-2-yl 116.5- 117.5 60 3-isobutoxy-4-methoxyphenylpyridin-4-yl 134-135 (29) 200410936 Example R1 R4 Melting point [° C] 61 3-Isobutoxy-4-methoxyphenylpyrrole-4-yl 144-145 62 HexaBdin-4-yl 3-isobutoxy-4-methoxy Phenyl 156-157 63 3-isobutoxy-4-methoxyphenylpyridyl 176-177 64 3-isobutoxy-4-methoxyphenylpyridin-3-yl 168-169 65 Port D D-4-yl 3-isobutoxy-4-methoxyphenyl 101-102 (monohydrate) 66 Port D 4--4-yl 3,4,5-trimethoxyphenyl 158 -159 67 3-isobutoxy-4-methoxyphenyl 2,3,4-trimethoxyphenyl 145-146 68 3-isobutoxy-4-methoxyphenyl 3,4, 5-trimethoxyphenyl 108-109 69 pyridin-4-ylpyridin-4-yl 167-168 70 3,4-dimethoxybenzene 3,4-methylenedioxy-6-nitrophenyl 173-174 71 3,4-dimethoxybenzene 3-nitrophenyl 125-126 72 3,4-dimethoxybenzene 4-dimethylamino- Phenyl 146-148 73 3,4-dimethoxybenzene 1-naphthyl 132-133 (30) 200410936 Example R] R4 Melting point [° C] 74 3-isobutoxy-4-methoxyphenyl Naphthyl 117-118 75 4-aminocarbonylphenyl 3,4-dimethoxybenzene 244-245 76 4-aminocarbonylphenyl 3-isobutoxy-4-methoxyphenyl 218-220 77 4 -Aminocarbonylphenyl 2,3,4-trimethoxyphenyl 211-213 78 4-aminocarbonylphenyl 3,4,5-trimethoxyphenyl 227-226 79 1-naphthyl 3,4-di Methoxybenzene 142-143 80 1-naphthyl 3-isobutoxy-4-methoxyphenyl 129-130 81 1-naphthyl 3,4,5-trimethoxyphenyl 143-144 82 2 -Naphthyl 3,4-dimethoxybenzene 145-147 83 Zeinyl 3-isobutoxy-4-methoxyphenyl 129-131 84 2-naphthyl 3,4,5-trimethoxybenzene Group 132-133 85 3,4-dimethoxybenzene 3- — * di / methoxy-4-methoxyphenyl 119-121 86 3,4-dimethoxybenzene 3-propanyloxy 4-methoxyphenyl 139-141 87 3,4-dimethoxybenzene 3-difluoromethoxy-4-methoxyphenyl 159-160 88 3,4-dimethoxybenzene 3 -Cyclopropyl-methoxy-4-methoxyphenyl 150-152 89 3,4-dimethoxybenzene 4-acetamidamine Phenyl 172-173 An example of a method for preparing a compound of formula 6 according to the present invention: Example 9 0: -34-(31) (31) 200410936 N— (2,4,6-trimethylphenyl) -i- (3,4-dimethoxyaniline) pyrrolidine-2-carboxamide hydrochloride 3.95 g of N— (2,4,6-trimethylphenyl) —1 — [(3, 4— Dimethoxy-benzylidene) amino] pyrrolidine-2-carboxamide (} mM) in the presence of 0.5 g of added charcoal (10% Pd) in 100 ml In methanol at 20 ° C. After the absorption of hydrogen was completed, the catalyst was filtered by suction and the methanol was distilled off. The residue was dissolved in anhydrous diethyl ether 'and a slight excess of HC1 diethyl ether solution was added; after the crystallization was completed, the crystals were filtered by suction and recrystallized from 2-propanol. Yield: 1.8 g (42% of theory)

Melting point · 1 7 7-1 7 9 ° C It is also possible to prepare many other compounds of formula 6 using the instructions given in Example 90, where n, r], R3 and r4 may have the following meanings and list the following compounds As an example:

Example η R1 R3 R4 Melting point [° C] 91 2 3-isobutoxy-cardiomethoxyfluorene 3,4-dimethoxy-benzene 153-154 phenylmethyl (oxalate) 92 2 3, 4-Dimethoxy · phenyl · fluorene 3-isobutoxy-4-methoxy130-137ylphenyl (oxalate) Example of a method for preparing a compound of formula 7 according to the invention: Example 93: » 35- (32) 200410936 N — (2,6-dichlorophenyl) (E) — 1- [1 ((3,4-dimethoxyphenyl) -ethyleneimine]) 5.5 grams of N- (2, ό-dichlorophenyl), 1-aminopyrrolidine, 2-carboxamide (20 millimolar), and 4.5 grams of 3,4-one Methoxyacetophenone was heated in 50 ml of n-butanol under reflux for 15 hours and the mixture was then distilled to dryness. 30 ml of water and 5 ml of ammonia (25% strength) were added to the residue and the mixture was extracted with benzene. The organic phase was washed with water, dried over sodium sulfate and distilled to dryness. The residue was dissolved in 8 ml of 2-propanol and neutralized. After the crystallization was completed, the crystals were filtered by suction and recrystallized from 90% 2-propanol. Yield: 3.0 grams (34% of theory)

Melting point: 1 2 4 — 1 2 5 ° C It is also possible to prepare many other compounds of formula 7 using the instructions given in Example 9 3, where η, R] and R4 can have the following meanings, and the following compounds are listed as examples :

R 7 Example η 1 R] R4 Melting point 丨 ° C 1 94 2 3_isobutoxy-4 -methoxyphenyl 3,4-dimethoxy_benzyl 1 40 · 141 _ Prepared according to the invention An example of a method for the compound of formula 8: -36- (33) (33) 200410936 Example 9 5: N — (3-isobutoxy-4—methoxyphenyl) 1 — [(1 Fluorenyl) amino] piperidine-2-carboxamide 3.2 g of N- (3-isobutoxy-4-methoxybenzyl)-1-aminopiperidine- 2-carboxamide (1 0 millimolar) and 3.5 grams of potassium carbonate in 100 milliliters of acetone and 10 milliliters of water were stirred and 1.9 grams of benzamidine chloride (1.3 milliliters) was added dropwise at 20 ° C. Moore). After stirring for 1 hour, 1.9 g of benzamidine chloride (13 mmol) was added dropwise again and the mixture was stirred at 20 ° C for 3 hours, then 100 ml of water was added and the mixture was stirred for 3 hours. Hours and then let stand for 20 hours. The precipitate that had settled was filtered by suction and recrystallized from methanol. Yield: 2.0 g (48% of theory)

Melting point: 1 7 0 — 1 7 1 ° C It is also possible to prepare many other compounds of formula 8 using the fingertips given in Example 9 5 where R] and R4 may have the following meanings ’and the following compounds are listed as examples:

Example R1 R4 Melting point [° C] 96 2,6-dichlorophenyl 3,4,5-trimethoxyphenyl 267-269 97 2,6-dichlorophenyl 3,4-dimethoxy-benzene Methyl 240-241 98 3,4-dimethoxy-benzyl 3,4-dimethoxy-benzyl 222-223 99 ------ 3,4-dimethoxy-benzene Methyl 3,4,5-trimethoxyphenyl 218-219 > 37- (34) (34) 200410936 An example of a method for preparing compound 9 according to the present invention: Example 1 00: Ν '-( Group)-(E) — 1 — [(3 —isobutoxy-4 —methoxybenzylidene) amino] piperidine-2 —carboxamide 10.7 g (0.1 mole) of N-formyl A mixture of phenylaniline and 32.2 g (0.13 mol) of ^ -bromo-omega-chlorodecanyl chloride in 150 ml of toluene was heated under reflux for 6 hours. After the mixture was cooled, the toluene phase was washed with 10% potassium carbonate solution and with water and distilled to dryness. The residue was dissolved in 300 ml of 2-propanol and heated with 60 ml of hydrazine hydrate under reflux for 10 hours. 200 ml of 2-propanol and the residue were then distilled off and extracted with 100 ml of water and chloroform; the chloroform phase was washed twice with water and distilled to dryness. After the crystallization was completed, the 'N-amino- 2-卩 -fixed residual acid N'-aniline was washed with heptane. Yield: 20.1 g

Melting point: 74-75 ° C 2 · 33 g (0.01 mol) of N-amino-2-piperidinecarboxylic acid N, monoaniline and 2.7 g (0.013 mol) of 3-isobutoxy The methyl-4-methoxybenzaldehyde was heated in 20 ml of 2-propanol under reflux for 4 hours. The 2-propanol was distilled off and the residue was dissolved in toluene / heptane (1/3) and the solution was placed at 0 ° C. Isolate the oil layer and stand in heptane until crystallization occurs. The precipitate was filtered by suction and recrystallized from heptane. Yield: 2.1 g (49.6% of theory). Melting point: 9 3-9 5 ° C. (35) 200410936 Using the instructions given in Example 100, it is also possible to prepare many other compounds of formula 9, where R1 and R4 may have the following meanings, and the following examples are listed as working compounds.

9 cases

R

Chromatographic separation of 4 R-based phenyloxymethyl p-melting enantiomers: Example 1 0 2: N— (3,4-dimethoxyphenyl) — (E) — (—) —} — [(3 -isobutoxy-4 -methoxymethoxymethylene) amino] piperidine- 2 -carboxamidin 0.5 g of N-(3,4-dimethoxybenzylidene)- (E) — (1) 1-[(3-isobutoxy-4, 4-methoxybenzylidene) amino] piperidine- 2 -carboxamide (Example 36) was dissolved in 2.5 ml N-hexane / ethanol / diethylamidamine-80 / 20 / 0.1; and with the aid of a palm HP LC column (Chiralpack AD; 250 x 50 mm; 20 μM) and using eluent n-hexane / ethanol / Diethylamine = 80/20 / 〇]] separated into two parts, the first eluted part contains 0.2 g of N (3,4-dimethoxyphenyl) -39- (36) (36) 200410936 — (E) · — (—) 1 — [(3 —Isobutoxy-4 monomethoxybenzylidene) amino] pyrimidin-2-carboxylic acid. Optical rotation: —194 · 0 (82.55 mg in 100 ml of ethanol) Melting point: 1 1 3 — 1 1 4 t Example 103: N— (3,4-dimethoxyphenyl) (E) — (+) 1 — [(3—Isobutoxy-4 monomethoxybenzylidene) amino] piperidine-2 2-carboxamide The second part of the lysis according to the instructions given in Example 102 contains 0.2 Grams of N— (3,4-dimethoxyphenyl) — (E) —1 (+) — [(3-isobutoxy-4—methoxybenzylidene) amino] piperidine -2-Carboxamide. Optical rotation: +1 86.6 (82.55 mg in 100 ml of ethanol)

Melting point: 1 1 3 — 11 4 ° C Using the instructions given in Examples 1 02 and 103, it is possible to prepare many other compounds of formula 1 0 or 1 1 as mirror-isomeric compounds, in which η, X and R1 may have the following meanings The following compounds are listed as examples: -40- 200410936

Example η X R1 Melting point rc] Optical rotation [α] 104 1 (3-isobutoxy-4-methoxyphenyl-phenylmethylene) amino 3,4-dimethoxyphenyl 123-125 -276.7 105 1 (3-isobutoxy-4-methoxyphenyl-benzylidene) amino 3,4-dimethoxyphenyl 122-125.5 +260.0 Example 1 0 4: Excess () One enantiomer 9 9.8% ee Example 105: Excess (+) -enantiomer 97.3% ee It is also possible to prepare compounds of formula 12 using the instructions given, and the following compounds are presented as examples: -41 ^ 12 (38) 200410936

Example η R] -N-R2 X Melting point [° C] 106 2 8-Chloro-11-one-10,11-dihydrodibenzo [b, e] diazol-5-yl NH2 X HC1 237-239 107 2 8-chloro-11-keto-10,11-dihydrodibenzo [b, e] diazol-5-yl 3,4-dimethoxy-benzylidene 243-245 108 2 8-chloro-11-keto-10,11-dihydrodibenzo [b, e] diazol-5-yl 3-isobutoxy-4-methoxybenzoyl Methylamino 191-193 109 2 8-chloro-11-keto-10,11-dihydrodibenzo [b, e] diazol-5-yl 3-difluoromethoxy- 4-methyl Oxy-benzylidene group 174-176 110 2 8-oxyl-11-alanyl-10 '1-dibenzo [b, e] diazol-5-yl 3-cyclopropyl-4- Methoxy-4-methoxybenzylidene 182-184

-42-(39) (39) 200410936 Example η R, N-R2 X Melting point [° c] 111 2 8-chloro-11-keto-10,11-dihydrodibenzo [b, e] di Nitro-5-yl 3-isopentyloxy-4-methoxybenzylidene 153-155 112 2 8-amino-11-amyl-10,11-dihydrodibenzo [b, e] Diazet-5-yl 3-cyclopentyloxy + methoxybenzylidene group 233-234 113 2 8-Gasyl-11-amyl-10,11-dihydrodibenzo [b , E] diazol-5-yl 3-allyloxy-4-methoxybenzylidene 222-325 114 2 8-chloro-11-amyl-10,11-dihydrodiphenyl Benzo [b, e] diazeth-5-yl 4-difluoromethoxy-3-methoxybenzylidene 192-194 115 2 sulfamidinoanilide NH2 X HC1 224-226 116 2 10 , 11-dihydrodibenzo [b, e] —Aza-5--5-4-difluoromethoxy-3-methoxy-benzylidene group 172-173 117 2 4-Ethylamido group Aniline nh2 169-171 118 1 3,4- (methylenedioxy) -aniline nh2 114-116 119 2 10,11-dihydrodibenzo [b, e] —breath-5-yl nh2 151- 153 The compounds according to the invention are potent inhibitors of phosphodiesterase 4 and TNF alpha release. Their therapeutic potential has been demonstrated in vivo, for example, by inhibiting guinea pigs' late-stage asthma response (hypereosinophils) and by affecting allergen-induced vascular permeability in brown Norwegian rats sensitized by activity. Phosphodiesterase inhibitory PDE 4 activity was measured in an enzyme-43-(40) (40) 200410936 agent obtained from human multinuclear leukocytes (PMNLs), and PED2, 3, and 5 activities were measured using human platelet-derived PDE . Human blood is anticoagulated with citrate. The blood-rich platelet plasma in Shangcheng tincture was separated from red blood cells and white blood cells by centrifugation at 7000 x g for 20 minutes at room temperature (RT). Platelets are lysed by ultrasound and used in PDE 3 and PDE 5 tests. In order to determine PDE 2 activity, the c y t 0 s ο 1 i c platelet fraction was purified on an anion exchange column using a Na C 1 gradient and the PDE 2 peak was isolated for analysis. PMNLs for the PDE 4 assay were isolated by subsequent dextran sedimentation, which was then followed by centrifugation using a gradient of F i c ο 11 P a q u e. After washing the cells twice, lyse them at 4 ° C and within 6 minutes by adding 10 ml of hy ρ ο nic buffer (155 mM NH4C1, 10 mM NaHC03, 0.1 mM EDTA, pH = 7.4). Red blood cells still present. The original PMNLs were washed twice with PBS, and then dissolved by ultrasound. The supernatant solution obtained by centrifugation at 4 ° C and 4 000 X g for 1 hour contains a cytosolic PDE 4 fraction and is used for PDE 4 measurement. Phosphodiesterase activity is measured using a method, a modified SPA (scintillation approach assay) assay provided by Amersham Pharmacia Biotech.

The reaction mixture contains 50 mM Tris-HCl (pH 7.4), 5 mM

MgCl2, various concentrations of inhibitors, appropriate enzyme preparations, and additional ingredients needed to detect individual isoenzymes (see below). The reaction starts by adding a substrate 0.5 // M [3H] — cAMP or [3H]-cGMP. The final volume was 100 microliters. The test substance was prepared as a stock solution in D M S 0. The concentration of D M S 0 in the reaction mixture was 1% V / V. The D M S 0 concentration had no effect on the (41) (41) 200410936 PDE activity. After the reaction has started by adding a substrate, the sample is incubated at 37 ° C for 30 minutes. The reaction was stopped by adding a defined amount of SPag and the samples were measured in a beta counter. [3H] -cAMP was used as a substrate for measuring PDE 4 activity, PDE 3 resistance, and PDE 2 activity, and [3H] -cGMP was used for determining PDE s knowledge. Non-specific enzyme activity In each case, the wish for PDE4 was in the presence of 100 // m rolipram, and when purchased & PDE 3 and PDE 5, at 100 μm IB M X was determined in the presence of, and subtracted from test 値. The incubation mix for the PDE 4 assay contained 100 μm cGMp in order to suppress any possibility of contamination with PDE 3. PDE 2 activity was measured in the presence of a PDE 2 activator (5 μm cGMP). It was found that the inhibitory effect on phosphodiesterase 4 of the compound according to the present invention has an I C 50% in the range of 10-9 to 10-5M. Its tendency to selectivity for p d E 2, 3, and 5 yields a factor from 100 to 100,000.

-45- (42) 200410936 Inhibition of human PMNL PDE 4 Example concentration [Nemole / liter] η% Inhibition 15 154 4 50 17 265 4 5 0 26 7 82 4 50 28 506 4 50 3 2 47 5 4 50 3 3 345 4 50 34 257 4 50 3 5 23 8 4 50 4 1 360 4 50 42 523 4 50 43 447 4 50 44 1000 4 5 1 45 168 4 50 60 4460 4 50 65 257 4 50 7 5 723 4 50 76 133 4 50 7 9 54 1 4 50 80 559 4 50 83 282 4 50 85 248 4 50 86 258 4 50 8 7 86.6 4 50 88 15 8 4 50 102 114 4 50 103 479 4 50 104 127 4 50 105 1000 4 42.7 107 5 000 4 79.6 108 1000 4 48.9 109 1000 4 39.7 110 529 4 50 112 1000 4 32.4 113 10 0 0 4 48.2 114 1 000 4 4 3.4

-46- (43) (43) 200410936 The inhibition of late-phase eosinophilia in brown-sensitized Norwegian rats that were sensitized to anti-oval protein (OVA) after 48 hours after inhalation of egg protein challenge The ability of the substance according to the invention to inhibit pulmonary eosinophil infiltration was tested in male brown Norwegian rats (250-350 grams). Sensitization was performed by subcutaneously injecting a suspension of 10 micrograms of OVA in each animal on days 1, 14, and 21, together with 20 mg of aluminum hydroxide as an adjuvant, and 0.5 ml of physiological sodium chloride solution. produce. At the same time, these animals were additionally injected with Bordet ell si pertussis vaccine dilution at a rate of 0.25 ml i.p per animal. On the 28th day of the experiment, these animals were individually placed in an open 1 liter resin glass (Plexiglass) box connected to a head and nose exposure device. The animals were exposed to an aerosol consisting of a 1.0% suspension of egg protein (allergen stimulus). The egg protein aerosol is produced using compressed air (0.2 MPa) -operated sprayer (Bird Micro Sprayer, Palm Springs, CA, USA). The exposure period was 1 hour and an aerosol spray consisting of a 0.9% solution of sodium chloride was used in the normal control group.

48 hours after allergen stimulation, a large number of eosinophils migrated into the animal's lungs. At this time, the animals were anesthetized with an overdose of ethyl carbamate (1.5 g / kg body weight ip ·) and the lungs were rinsed with 3x4 ml of Hank's balanced solution (tracheal and alveolar lavage, BAL). The total number of cells in the collected BAL fluid and the number of eosinophils were then determined using an automated cell discrimination device (Bayer Diagnostic Technicon H1E). Calculate the number of eosinophils (Ε Ο S) in BAL fluid per animal, 10 6 / animal · · Ε Ο S / microliter XBAL (44) (44) 2 | 00410936 Recovery (ml) = EOS / animal. Two control groups were included in each test (sprayed with physiological sodium chloride solution and sprayed with OVA · solution). The percentage inhibition of excessive eosinophils in the substance-treated experimental group was calculated according to the following formula: {((OVAD-SC)-(OVAD-SC)) / (OVAD- SC)} X 1 0 0%-% inhibition ( SC = control group treated with vehicle and stimulated with 0.9% sodium chloride solution; OVAC == control group treated with vehicle and stimulated with 1% egg protein suspension; OVAD = treated with substance and 1% egg protein Experimental group stimulated by suspension. Two hours before stimulation with allergens, the test substance was administered intraperitoneally or orally with 10% polyethylene glycol 300 and a suspension of 0.5% 5-hydroxyethyl cellulose. In a manner corresponding to the test substance administered therein, the 'control group was treated with a vehicle. The compound according to the present invention inhibited 30% to 100% after intraperitoneal administration of 10 mg / kg and 3 orally. After 0 mg / kg 'inhibits late eosinophilia from 30% to 70%. The results of the compounds according to the invention are particularly suitable for the preparation of a medicament for the treatment of diseases related to eosinophil activity. By way of example, the inhibition Excessive eosinophils obtained after allergic induction The results are edited in the following table: -48- (45) 200410936 Example dose (mg / kg) Administration of n% inhibition 15 1 i · p-2 h 6 3 6 15 10 i · p.-2 h 5 50 15 0.1 p .-2 h 6 17 15 1 p.-2 h 12 47 15 10 p · 〇.-2 h 6 70 17 10 i. P. — 2 h 6 50 17 10 p. O. — 2 h 5 47 45 10 i · p.-2 h 5 34 45 10 p..-2 h 5 6 5 1 10 i. p ·-2 h 5 8 5 1 10 p..-2 h 5 17

Affects allergen-induced vascular permeability in active-sensitized brown Norwegian rats. Male brown Norwegian rats weighing 2 800-300 grams are suspended in 1 ml with 1 mg of egg protein together with 100 mg of argon oxide. Liquid intraperitoneal injection / animal sensitization of activity for 2 consecutive days. After three weeks of sensitization, the rats were anesthetized with sodium thiobarbiturate and fixed in a dorsal position. In order to fill the nasal cavity, a polyethylene catheter advances the inner hole in the trachea of each animal as high as the posterior nostril of the perfusion solution in a retrograde manner. As a result of the pump advancement, it can drip from the nostril after flowing through the nasal cavity. A short tracheal tube is coupled to the trachea in an ortho grade for breathing. For perfusion, a peristaltic pump was used to continuously pump -49- (46) (46) 200410936 into the phosphate-buffered sodium chloride solution (p BS) through the nasal cavity at a rate of 0.5 ml / min in a retrograde manner and by Partial collectors collect liquid dripping from the nostrils. Evans blue was used as a plasma marker and injected intravenously via a catheter placed in the jugular vein (in each case 1 ml / animal 1% solution in PS). The substance is administered locally or systemically. In the case of local administration, the test substance is added to a perfusion medium (PBS). Nasal mucosa was perfused for 30 minutes with a solution containing pDE 4 inhibitor. Plasma labeled Evans Blue was then injected intravenously immediately before the nasal mucosa began to perfuse the egg protein-containing solution (10 mg / ml egg protein dissolved in PBS). During egg protein challenge, the perfusate was partially collected in a partial collector every 15 minutes. The total period of egg protein challenge was 60 minutes. The Evans blue concentration in the perfusate was measured using a D i g i s c a η photometer at a wavelength of 6 2 0 nm. Related to this, the blank 値 is automatically subtracted. Use the ATJ C program to calculate the effect in 60 minutes. The effect of the compound group on the vehicle-treated control group animals was calculated (the content of Evans blue in the perfusate from the control animals = 100%). When administered systemically, one hour before the challenge with the allergen, the test substance is administered via the catheter to the upper duodenum of the animal as a suspension in 10% PEG and 0.5% hydroxyethyl cellulose. Effective concentrations of the compounds according to the invention are determined to be in the range from 10 -8 to 10-5 M. When the compounds are administered prophylactically, these concentrations avoid the vascular permeability of the nasal mucosa as a result of allergen perfusion. -50- (47) 200410936 Example dosage · n% inhibition 15 0.001 μ.m perfusion 0.5 h 3 6 15 0.01 ji m perfusion 0.5 h 4 43 15 0.1 / m perfusion 0 0.5 h 3 54 15 0.1 mg / kg id · — lh 3 14 1 5 1 mg / kg i. d · — 1 h 4 3 0 15 1 0 mg / kg id 1 h 3 59 15 30 mg / kg id- 1 h 3 62

Inhibition of lipopolysaccharide (LP S) -induced pulmonary neutropenia in Lewis rats The substance according to the invention was tested in male Lewis rats (250-350 grams) to inhibit pulmonary neutrophil infiltration Ability. On the day of the experiment, the animals were individually placed in an open 1 liter Plexiglas box connected to a head and nose exposure device. The animals were exposed to an aerosol (LPS-initiated) consisting of a lipopolysaccharide suspension (100 μg LPS / ml 0.1% hydroxylamine solution) in PBS. LPS / -Hydroxyamine aerosols are produced using compressed air (0.2 MPa) -operated sprayers (Bird micro-sprayers, Palm Springs, CA, USA). The exposure period was 40 minutes, and the aerosol spray normal control group consisting of a 0.1% hydroxylamine solution in PBS was also 40 minutes. Six hours after LPS challenge, there was a large amount of neutrophil migration into the animal's lungs. At this time, the animals were anesthetized with an overdose of ethyl carbamate (1.5 g / kg body weight i. · P.) And used 3 x 4 -51-(48) (48) 200410936 ml of Hank Equilibrium solution was used for tracheal and alveolar lavage (BAL). The total number of cells in the collected BAL fluid and the number of neutrophils were then determined using an automated cell discrimination device (Bayer Diagnostic Technicon 1 E). Calculate the number of neutrophils (NEUTRO) in BAL per animal, 106 / animal: NEUTRO / microliter x BAL recovery (ml) = NEUTRO / animal. Two control groups were included in each test (sprayed with 0.1% hydroxylamine solution in PBS and 100 micrograms of LPS / ml 0.1% hydroxylamine solution in PBS). The percentage inhibition of neutrophils in the experimental group treated with substances was calculated according to the following formula: {((LPSC-SC)-(LPSD-SC)) / (LPSC-SC)} x 1 0 0% =% ίΦ 芾! J Action sc = Control group treated with vehicle and excited with 0.1% hydroxylamine solution; LPSC = Control group treated with vehicle and stimulated with LPS (100 μg / ml 0.1% hydroxylamine solution); LPSD = treated with substance And the experimental group excited with LPS (100 μg / ml 0.1% hydroxylamine solution). Two hours before challenge with L PS, the test substance was administered orally as a suspension of 10% polyethylene glycol 300 and 0.5% 5-hydroxyethyl cellulose. In a manner corresponding to the test substance administered therein, the control group was treated with a vehicle. After the oral administration of 1 mg / kg, the compound according to the present invention inhibited from 40% to 90% of neutropenia and The results are particularly suitable for the preparation of a medicament for treating diseases related to the action of neutrophils. By example, select application examples to obtain neutropenia suppression -52- (49) 200410936 (49)

The results are compiled in the following table: Example dose (mg / kg) administration of n% inhibits 15 10 ρ. 〇.-2 h 6 69 15 30 ρ. 〇.-2 h 6 77 17 1 ρ. Ο.-2 h 5 7 17 10 ρ. Ο. ~ 2 h 5 53 45 1 p. O.-2 h 4 23 45 10 p. O.-2 h 5 33 5 1 1 p. O.-2 h 4 47 5 1 10 p . o.-2 h 5 52

-53-

Claims (1)

200410936 ⑴ Pickup, patent application scope • A general formula 1, substituted by 环状 / 4 ^ Τχ cyclic amino acid amines (° Η2) η-ι R2 Where η can be 1 or 2, X can be -ΝΗ2;-N = C (R3 ^ 1; (E or Z configuration, ipsilateral or contralateral), NH-CH (R3)-R4,-N ( R3) one chr3) _ r4, one NH-CH2-R4, or one NH-(C = 0)-R4, R and R4 can be the same or different and can be single or multiple with 3 to 14 ring members Ring-saturated or mono-unsaturated or poly-unsaturated carbocyclic ring, having 5 to 15 ring members and 1 to 6 heteroatoms, preferably mono- or poly-ring saturated or mono-unsaturated or poly-unsaturated with n, 0 or / and S Saturated heterocyclic ring, in which the carbocyclic ring or heterocyclic ring is partially substituted by one or more of the following groups: -F, -C1, -B r '-I,-Ο Η'-Ν Ο 2 '-ΝΗ — CO-C] — C6 -alkyl, straight or branched, —COOH, a COOC! — C6-alkyl, straight or branched, one (6-alkyl, straight or branched) , One Cl — C6-alkoxy, straight or branched, one C3 — c7-cycloalkyl, one C3 — c7 —cycloalkoxy, —N (R3) 2, one CON (R3) 2 or — S02N (R3) 2, and each alkyl or alkoxy group, and part thereof, -54 »(2) 2004 10936 may be substituted one or more times by the following groups: halogen, 1,0H'C7-cycloalkyl or / and -C3-C7-cycloalkoxy and each cycloalkyloxy, some of which can be replaced by Substituents one or more times: -OH, _C] _C6 -alkyl or / and -Ci -C6 -alkoxy, where two adjacent substituents of R1 or R4 are bridged if appropriate, R2 in each case China may be independently fluorene or acryl (a Ci- chain or branched chain or benzyl, in which each alkyl group may be substituted more than once by the following groups: halogen, 0H, a C3 — C7 — ring acryl or / and C7 -cycloalkoxy and each benzyl group may be substituted once or one by: -F, -C1, -Br, -I, -0Η, -N02 '-NΗc! -C6-alkyl, straight chain Or branched '—C00H, — COOCj alkyl, straight or branched, one c] -c6-alkyl, straight or branched — c6 —alkoxy, straight or branched, one c3 — c7 ring Alkyl, c7—cycloalkoxy, —N (R3) 2, or / and —C0N (R3: each of the alkyl or alkoxy groups may be partially substituted by the following groups more than once: halogen, —0H , A C3—C7-ring Academic group or / and C7-cycloalkoxy group and each cycloalkyl group or cycloalkoxy group, part of which may be substituted one or more times with a group of one, one 0H, one Cj-c6 or / and one C 】 —C6-alkoxy, R—N — R2 can be an N-containing heterocyclic system, in which the system can be arbitrarily substituted one or more times by the following group ... -F, -Br, -I, -OH, One No2, one NH—C0—C] —C6—a chain or branched chain, —C00H '— COOC] —C6—alkyl, straight chain—C 3 — or a naphthenic halogen, can be mutually;), straight One or one C 3 more than one time C0 — one c6 —, —Cl one C 3 —) 2, and one or more —C3 — is supported by the following monoalkyl heterocyclic system CI, — group, straight or branched (3 ) (3) 200410936, one G—C6-alkyl, straight or branched, one c] —c6 —alkoxy, straight or branched, —C3-C6 —Cyclocyclyl ', one C3-C7 -Opionyloxyl, N (R3) 2 or / and -CON (R3) 2, and each of the alkyl or alkoxy groups, some of which may be substituted one or more times by the following groups: halogen , 10H, one C3-C7-cycloalkyl or / and one C3-C 7-Cycloalkoxy and each cycloalkyl or cycloalkoxy group, some of which may be substituted one or more times by the following groups ... dentin, -0H, -Cl-C6 -sinyl or / and -Cl —C6 —alkoxy, R3 in each case may be independently fluorene or alkyl (—C! — C6), straight or branched, in which each alkyl group, part thereof, may be optionally substituted once or More than one time: halogen, -OH, C3-C7-cycloalkyl or / and `` C3-C7-cycloalkoxy, and their salts, the prerequisite is that compound (1) is not N-(3-isobutyl Oxy-4 monomethoxyphenyl) -1 1- (3,4-dimethoxy-benzylamino) pididine-2-carboxamide or m-chloro-N — [2 — [ (9,9 dimethyl-1 10-acridanyl) carbonyl-1 1]] pyrrolidine] benzamide. 2 · If the compound in the scope of patent application No. 1 is a type of physiologically tolerable salt, it can be obtained by neutralizing the base with an inorganic or organic acid 'or / and by using an inorganic or organic base Obtained by neutralizing the acid or / and by quaternizing the tertiary amine to produce a quaternary ammonium salt. 3. The compound according to item 1 or 2 of the patent application scope, which is a type of an optical isomer or a mixture of optical isomers. 4 · If the compound in the third item of the patent application scope, it has D-56- (4) (4) 200410936, L-type and asymmetric carbons of D and L mixtures, and non-asymmetric carbons when several asymmetric carbons are present. Enantiomeric form. 5. The compound according to item 1 or 2 of the application scope, characterized in that X is ~~~ ^ N Η 2. 6. If the compound in the scope of patent application 1 or 2 is characterized by X is -N = C (R3)-R4 〇7. If the compound in the scope of patent application 1 or 2 is characterized by R 1 is single A cyclic or bicyclic aromatic or heteroaromatic ring system, particularly selected from phenyl, D to D amidyl, naphthyl, indolyl, or quinolinyl, which may optionally contain up to 3 substituents. 8. The compound according to item 1 or 2 of the application scope, characterized in that R4 is a monocyclic or bicyclic aromatic or heteroaromatic ring system, especially selected from phenyl, naphthyl, Dl ± pyridyl, furanyl, Thiophenyl, pyrrolyl, indolyl or orthoquinolinyl 'may optionally contain up to 3 substituents. 9 · If the compound in the scope of patent application No. 1 or 2 is characterized in that R] and R4 independently have 0 to 3 substituents in each case, the substituents may be the same or different and may be -F, -C1 -Br, -I, -OH;-ΝΗ-CO-dagger alkyl, straight or branched, -COOH, a conh2, -coocrc,-alkyl, straight or branched,-C] —C6 —alkyl, straight or branched, 10—Ci—C6 —alkyl, straight or branched, 1nh2, —nh (c) —c6—alkyl, straight or branched), 1 N (Ci — c6 — courtyard-based 'straight-chain or branched-chain') 2 or ―s〇2nh2, in which each alkyl group, part of it ”may be substituted one or more times by the following groups: halogen, one or / and one C3 — C7-cycloalkyl. -57-200410936 (5) 10. The compound according to item 1 or 2 of the scope of patent application, which is selected from the group consisting of N-(3-isobutoxy-4 -methoxyphenyl)-1-aminoquinone Pyridinyl-2 -carboxamidine, N-(2,4,6-trimethylphenyl) -1-aminopyrrolidine -2 -carboxamidine, N-(3,4-dimethoxyphenyl) ) 1-aminopyrrolidine- 2 -carboxamidine, N-(2,6-dichlorophenyl)-1-amino group D Pyrrolidine-2 -carboxamidine, N-(4-ethoxycarbonylphenyl) -1 monoaminopyrrolidine-2 -carboxamidine, N-(3,4-dimethoxyphenyl) -1 Monoaminopiperidine-2-carboxamide, N- (2,6-dichlorophenyl) -1 monoaminopiperidine-2 carboxamido N- (4-ethoxycarbonylphenyl) -1 —Aminopiperidine- 2 -carboxamido N — (D than D—4—one group) — 1—amino group — —2—amidine—N— (4-aminoaminocarbonylphenyl) —1 Monoaminopiperidine-2 -carboxamidine N-(1-naphthyl) -1 monoaminopiperidine-2 -carboxamidine, N-(2-naphthyl) 1 —Amino group, 2—Residamine, -58- (6) (6) 200410936 N— (2,6-dichlorophenyl) — (E) — 1— [(3,4 —Two Methoxymonophenylmethylene) amino] pyrrolidine-2, carboxamidine, N— (3,4-dimethoxyphenyl) — (E) — 1— [(3 —isobutoxy -4 -methoxymethoxymethylene) amino] pyrrolidine-2 -carboxamide modified A, N — (3,4-dimethoxyphenyl) — (E) — 1 — [(3 —Isobutoxy-4 monomethoxybenzylidene) amino] pyrrolidine-2 2-carboxamide Amendment B, N— (2,6-dichlorophenyl) — (E) — 1— [ (3-Isobutoxy-4 monomethoxy-benzylidene) amino] pyrrolidine-2 monocarboxamidine, N- (4-ethoxyoxyphenyl)-(E) — 1 — [(3 -Isobutoxy-4 4-methoxybenzylidene) amino] oxopyridine-1 2-carboxamide, N— (2-bromophenyl) — (E) — 1— [ (3,4-dimethoxybenzylidene) -amino] pyrrolidine-2 -carboxamidine, N-(2-bromo-4,5-dimethoxyphenyl)-(E) — 1 one [(3, 4 — Methoxy-benzylidene) amino] pyrrolidine- 2-carboxamide, 1 ^-(2,4,6-trimethylphenyl)-(ugly)-1-[(3,4- a Dimethoxymonobenzylidene) amino] pyrrolidine-2 -carboxamidine, N-(4-ethoxyphenyl)-(E)-1-[(3,4 -dimethylformamide) Oxy-benzylidene) amino] pyrrolidine-2 -carboxamide, N-(3 -isobutoxy-4 -methoxyphenyl)-(E) —] — [-59- ( 7) (7) 200410936 (3,4-di-methoxybenzylidene) amino] pyrrolidine- 2 -carboxamide N-(3 -isobutoxy-4 -methoxyphenyl) Mono (E) — 1- [(2,6-dichloromonobenzylidene) amino] oxopyridine-1 2-carboxamide, N— (3-ethoxycarbonylphenyl)-(E) -1- [(3-Hydroxy-4-methoxy-benzylidene) amino] pyrrolidine-2 -carboxamide, N- (3,4-dimethoxyphenyl)-(E) —L — [(3,4-dimethoxymonobenzylidene) amino] oxopyridine—2-carboxamide, N— (3,4-dimethoxyphenyl) — (E) — 1 a [(2,6 — dichloromonobenzylidene ) Amino] pyrrolidine-2-carboxamide, N- (4-phenyl- (E) — 1-[(3 -isobutoxy-4-methoxy-benzylidene) amino ] D than pyrrolidine- 2-carboxamide, N- (3,4-dimethoxyphenyl)-(E) — 1- [(4-methoxynaphthalene- 1-methylene) amine Yl] pyrrolidine- 2-carboxamide, N- (3,4-dimethoxyphenyl)-(E) — 1- [(2-methoxynaphthalene-1-ylmethylene) amine [Methyl] pyrrolidine- 2-carboxamide, N- (3,4-dimethoxyphenyl)-(E) -l-[(l-pyridine- 4-yl-methylene) amino] Dtt-pyridine- 2-carboxamidine, N-(3- isobutoxy-4 -methoxyphenyl)-(E)-1- [(3,4-dimethoxy-phenylmethylene ) Amino] piperidine- 2-carboxamide, N- (3- isobutoxy-4 -methoxyphenyl)-(E) — 1- [(3-isobutoxy-4 -methyl Oxyphenylmethylene) amino] piperidine- 2-carboxamide, N- (2,6-dichlorophenyl)-(E) — 1 — [(3 —isobutoxy-60- (8 ) (8) 200410936 group-4 monomethoxy- Phenylmethylene) amine] piperidine-2-carboxamide, N— (3-isobutoxy-4 4-methoxyphenyl)-(E) — 1- [(4-hydroxy-1 —Methoxybenzylidene] amino] piperidine- 2—carboxamide N— (3,4-dimethoxyphenyl) — (E) — 1— [(3 — isobutoxy— 4 monomethoxymonophenylmethylene) amino] piperidine- 2-carboxamide N- (2,6-dichlorophenyl)-(E) — 1- [(3,4-dimethoxy -Phenylbenzylidene) amino] piperidine- 2-carboxamide, N — (3-isobutoxy-4 4-methoxyphenyl) — (E) — 1 — [(3-hydroxyl 4-monomethoxybenzylidene) amino] piperidine- 2-carboxamide N-(3-isobutoxy-4 -methoxyphenyl)-(E) — 1- [(2, 6-dichloro-benzylidene) amino] piperidine- 2-carboxamide, N- (3,4-dimethoxyphenyl)-(E) — 1-[(2,6 — Dichloromonophenylmethylene) amino] piperidine- 2-carboxamide, N- (3,4-dimethoxyphenyl)-(E) — 1- [(2-fluorophenylene Methyl) monoamino] piperidine-2-carboxyl Amine, N— (4-ethoxycurylphenyl)-(E) — 1 — [(3-isobutoxy-4—methoxybenzylidene) amino] piperidine—2-carboxamidine Amine, N — (4-Ethoxyoxyphenyl)-(E) — 1-[(3-Ethyl-4—methoxy-benzylidene) amino] piperidine-2—carboxamide , N — (4-ethoxycarbonylphenyl)-(E) — 1 — [(3,4-dimethoxymonophenylmethylene) amino] piperidine-2—carboxamide, -61- (9) (9) 200410936 N — (3-isobutoxy-4 monomethoxyphenyl) — (E) — 1 — [(4-monomethoxycarbonylbenzylidene) amino] piperidine— 2-carboxamidine, N— (3-isobutoxy-4—methoxyphenyl)-(E) — 1 — [(3,4-dihydroxymonophenylmethylene) amino] piperidine —2 —Carboxamide, N — (3-isobutoxy—4-methoxyphenyl) — (E) — 1 — [(4-hydroxy-benzylidene) amino] piperidine—2 -Carboxamide, N- (3-isobutoxy-4-methoxyphenyl)-(E) -1-[(benzylidene) -amino] -pyridine-2-carboxamide, N- (3-isobutoxy- 4-monomethoxyphenyl) — (E) — 1 — [(furan-2-yl-methyleneamino] piperidine-2-carboxamide, N— (3-isobutoxy-1— (Methoxyphenyl) — (E) — 1-[(thiophenyl-2—yl-methylene) amino] piperidine-2—carboxamide, N— (3-isobutoxy-4— Methoxyphenyl)-(E) -1-((pyridine-2-yl-methylene) amino] piperidine-2-carboxamidine, N- (3-isobutoxy-4-methyl Oxyphenyl) — (E) — 1 — [(pyrrole-2-yl-methylene) amino] piperidine-2-2-carboxamide, N- (pyridine-4-yl)-(E) One; [one [(3-isobutoxy-4-methoxy-benzylidene) amino] piperidine-2-carboxamide, N-(3-isobutoxy-4-methoxy Phenyl) — (E) — 1-[(pyridine- 4-methylidene) amino] piperidine- 2 -carboxamide, N — (3-isobutoxy-4 -methoxy Phenyl)-(E) — 1-[(pyridin-3-ylmethylene) amino] piperidine-2-carboxamide, N- (amidin-4-yl)-(E) — 1 — [1 1 (3 —isobutoxy-4 Monomethoxymonobenzylidene) amino] piperidine- 2-carboxamidine, -62-(10) (10) 200410936 N-(H D D -4 -yl)-(E) — 1 — [1 — (3,4,5 —trimethoxybenzylidene) amino] piperidine-2 -carboxamide, N — (3-isobutoxyphenyl)-(E) — 1— [ 1- (2,3,4-trimethoxyphenylmethylene) amino] piperidine-2-carboxamide, N — (3-isobutoxy-4 4-methoxyphenyl) — ( E) — 1-[(3,4,5-trimethoxybenzylidene) amino] piperidine-2-carboxamide, N— (0 than a 4-amino group) — (E) — 1 — [(1—D butylated 4-methylidene) -amino] piperidine-2-carboxamide, N— (3,4-dimethoxyphenyl) — (E) — 1— [1— (3,4-methylenedioxy-6-nitrobenzylidene) amino] piperidine-2—carboxamide, N— (3,4-dimethoxyphenyl ) — (E) — 1— [1— (3-nitrobenzylidene) -amino] piperidine-2-carboxamide, N— (3,4-dimethoxyphenyl) — ( E) — 1— [1— (4 — dimethylamino Monophenylmethylene) amino] piperidine- 2-carboxamide, ^ ((3,4-dimethoxyphenyl)-(£)-1- [naphthalene 1-yl-yl (Methyl) amino] -pyridinyl 2-carboxamidine, N — (3-isobutoxy-4 —methoxyphenyl) — (E) — ΙΕ 1 — (naphthalene 1 -yl-methylene ) Amine] Piperidine-2-carboxamide, &gt; 1- (4-Amine-based phenyl)-(£) -1- [1- (3,4-dimethoxy-phenylmethylene) ) Amine] -pyridin-2-aminocarboxamide, N-(4-aminocarbonylphenyl)-(E)-1-[1-(3-isobutoxybenzylidene) amino] piperidine -2-Carboxamide, -63- (11) (11) 200410936 N — (4-aminocarbonylphenyl)-(E) — 1— [1-(2,3,4-trimethoxyoxybenzene Methylene) amino] piperidine-2-carboxamide, N — (4-aminoamine base) — (E) — 1 — [1 — (3,4,5-trimethoxy-phenylene (Methyl) amino] piperidine- 2-carboxamidine, N — (1-naphthyl) — (E) — 1 — [1 (3,4-dimethoxybenzylidene) -amino ] Piperidine-2 -carboxamide, N-(1-naphthyl) — (E) — 1— [1— (3 —isobutoxy-4 4-methoxymethoxybenzylidene) amino] piperidine-2 2-carboxamide, N — (1 —Czeki) — (E) — 1 — [1— (3,4,5 —dimethoxybenzylidene) —amino] piperidine—2—carboxamide, N— (2 —Naphthyl) — (E) — 1 — [1— (3,4-dimethoxybenzylidene) —amino] piperidine—2-carboxamide, N— (2-naphthyl) — (E) — 1— [1— (3 —isobutoxy-4 4-methoxy-benzylidene) amino] piperidine-1 2-carboxamidine, N— (2—Chaiki) — ( E) — 1— [1— (3,4,5-trimethoxybenzylidene) -amino] piperidine-2-carboxamide, N— (2,4,6-trimethylphenyl) )-1- (3,4-dimethoxybenzylamino) pyrrolidine- 2-carboxamidine hydrochloride, N-(3-isobutoxy-4 -methoxymethoxyphenyl) -1 Mono (3,4-dimethoxy-benzylaminopiperidine-2-carboxamidate oxalate, N- (3,4-dimethoxyphenyl)-1- (3-isobutoxy 4-A-methoxy-benzene Amino-piperidine 13-di-2-residue glucosamine oxalate, N — (2 '6 —chlorophenyl) — (E) — 1 — [1 — (3, 4 — -64-(12) ( 12) 200410936 Dimethoxyphenyl ·) -Ethyleneimine] Xantrolidine-2—Carboxamidine, N— (3-Isobutoxy-4—methoxyphenyl) — <E) — 1- [1-((3,4-dimethoxyphenyl) ethyleneamino]] pyrrolidin-2-carboxamide, N- (3-isobutoxy-4-methoxyphenyl )-1-[(1-benzylamido) amino] -piperidine- 2-carboxamide, N- (2,6-dichlorophenyl) -1-(3,4,5-trimethoxy Benzamidine-amino) piperidine-2-carboxamide, N- (2,6-dichlorophenyl) -1- (3,4-dimethoxybenzylamino) -piperidine Pyridin-2-carboxamide, N- (3,4-dimethoxyphenyl) -1 1- (3,4-dimethoxybenzylamino) -piperidine-2-carboxamide, N- (3,4-dimethoxyphenyl)-1- (3,4,5-trimethoxybenzylidene-amino) piperidine-2 -carboxamide, N, monomethyl- ( E) — 1-[(3-isobutoxy-4 4-methoxybenzylidene) -amino] piperidine-1 2-carboxamide, N, —methyl— (E) —1 a [ (3,4-dimethoxybenzylidene) amino] -H-di-2-amine, N— (3,4-dimethoxyphenyl) — (E) — (―) 1-[(3-isobutoxy-4 -methoxybenzylidene) amino] piperidine- 2-carboxamide, N- (3,4-dimethoxyphenyl)-(E ) — (+) 1-[(3 -isobutoxy-4 -methoxymethoxymethylene) amino] piperidine-2 -carboxamide, -65- (13) (13) amine 2 200410936 N — (3,4-dimethoxyphenyl) — (E) — (—) 1 — [(3 —isobutoxy—4—methoxybenzylidene) amino] pyrrolidine—2 —Carboxamide and 1 ^-(3,4-dimethoxyphenyl) — (£) — (+) 1 — [(3 —Isobutoxy-4—methoxybenzylidene) Amine] D (t-pyridine-2-carboxamide and physiologically acceptable salts and optical isomers thereof. 1 1 · A method for preparing a compound of formula 1 according to any one of items 1 to 10 of the scope of patent application, characterized in that the compound of formula 1 (having the meaning of X, R above) and R2 and n = 1 or 2 ) Is determined by making a 1-amino group of formula 2 a 2-residue amine or a 1-amino group_D a 2-residue. R RIN has the same meaning as R1 and R2, and reacts with aromatic or heteroaromatic aldehydes, ketones, or fluorenyl chlorides, and the aromatic or heteroaromatic aldehydes, ketones, or fluorenyl chlorides include R4 having the aforementioned meaning And, where appropriate, a double bond or carbonyl group formed by using a suitable reducing agent is reduced to methylene. 12. The method according to item 11 of the scope of patent application, characterized in that the reaction with fluorenyl chloride is performed in the presence of an auxiliary base and the auxiliary base used is an excess of amine, tertiary amine, which is used as a co-reactant. Preference is given to pyridine or / and triethylamine, or / and an inorganic test, preferably a metal hydroxide test or a metal hydride test. -66-(14) (14) 200410936 1 3.-A compound of formula 1 in any one of claims 1 to 10 (without application. Please refer to the prerequisites for item 1 in the patent scope) as a therapeutic activity The compounds are useful in the preparation of a medicament for the prevention or / and treatment of which the inhibitory effect of TNFα is a therapeutically active compound with therapeutic value. 14 · A compound of formula 1 according to any one of claims 1 to 10 (without prerequisites for claim 1) as a therapeutically active compound for the preparation of a medicament for the prevention or / and treatment of phosphoric acid therein The inhibitory effect of diesterase 4 is useful for therapeutic purposes. 15 · A compound of formula 1 as claimed in any one of claims 1 to 10 (without the prerequisites of claim〗) as a therapeutically active compound for the preparation of a medicament for the prevention or / and treatment of Uses of diseases related to eosinophil activity. 16. A drug comprising one or more compounds of any one of the scope of claims 1 to 10 (without the prerequisites of the scope of claims of the scope of patent application 1) as the active compound, and the conventionally physiologically acceptable Tolerated excipients, diluents or auxiliary substances. 17 · —A method for preparing a drug as claimed in item 16 of the patent scope ', characterized by one or more compounds of any one of the scope of patent applications 1 to 10 (there is no prerequisite for the scope of patent application 1) (Conditions) and conventional physiologically tolerable excipients, diluents or / and auxiliary substances are processed into a medicinal preparation or a form that is therapeutically available. 1 · · A compound of general formula 1 in any one of the scope of patent applications 1 to 10 (without the prerequisites for the scope of patent application in category 1) or / and medicines and other applications in scope of patent scope 16 Use of physiologically active compound combination -67- (15) 200410936. -68-200410936 柒, (1), the designated representative figure in this case is ... Figure _ (2), the component representative symbols of this representative figure are simply explained: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: -4-