Derivatives of amide, methods for their preparing, pharmaceutical composition, method of treatment

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of amide of the general formula (I)

wherein X means -CH; Y means -CH or nitrogen atom (N); m = 1 or 2; R1 means (C1-C6)-alkyl, (C1-C)-alkoxy-group, N,N-di-[(C1-C6)-alkyl]-amino-group, heterocyclyl-(C1-C6)-alkyl wherein heterocyclyl represents piperazinyl or homopiperazinyl; n = 3; R2 means halogen atom, (C1-C6)-alkyl; R3 means hydrogen atom; Q means phenyl optionally substituted with cyano-group, or pyridyl optionally substituted with morpholino-group, or their pharmaceutically acceptable salts, to methods for synthesis of indicated compounds, pharmaceutical compositions containing thereof and their using in treatment of diseases or states mediated by cytokines.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and pharmaceutical compositions.

10 cl, 2 tbl, 7 ex

 

This invention relates to amide derivative, useful as inhibitors cytokineproducing diseases. The invention also relates to methods for amide derivatives of the invention, pharmaceutical compositions containing these compounds and to their use in methods of treatment, for example, inhibition cytokineproducing disease.

Derivative amide described in the present invention are inhibitors of the production of cytokines, such as tumor necrosis factor (hereinafter TNF)such as TNFαand various representatives of the family of interleukins (hereinafter IL)such as IL-1, IL-6 and IL-8. Accordingly, the compounds of the invention are useful in the treatment of diseases or conditions in which excessive production of cytokines, such as excessive production of TNFα or IL-1. It is known that cytokines are produced by a wide range of cells such as monocytes and macrophages, and that they cause a variety of physiological actions, which are believed to be important in diseases or conditions, such as inflammation and immunoregulation. For example, TNFα and IL-1 are involved in the cascade of cell signaling, which is believed to contribute to the pathology of painful conditions, such as inflammatory and allergic diseases, and cytokine-induced toxi is ness. It is also known that in some cellular systems, the production of TNFα precedes and mediates the production of other cytokines, such as IL-1.

Abnormal levels of cytokines are also involved, for example, in the production of physiologically active eicosanoids, such as prostaglandins and leukotrienes, stimulation of allocation of proteolytic enzymes such as collagenase, activation of the immune system, for example, by stimulation of helper T cells, activation osteoclastic activity, leading to resorption of calcium, stimulate release of proteoglycans from cartilage, stimulation of cell proliferation and angiogenesis.

Also suppose that the cytokines implicated in the emergence and development of painful conditions such as inflammatory and allergic diseases such as inflammation of the joints (in particular, rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (in particular, inflammatory bowel, ulcerative colitis, Crohn's disease and gastritis), skin disease (in particular, psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis, allergic rhinitis, respiratory distress syndrome of adults and chronic obstructive pulmonary disease), and in the emergence and development of various cardiovascular and cerebrovascular castroist is, such as congestive heart failure, myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, Alzheimer's disease, by reperfusion injury, vascular injury including restenosis and peripheral vascular disease, and, for example, various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteoporosis), Paget's disease, bone metastases, hypercalcemia, hyperparathyroidism, osteosclerosis, osteoporosis and periodontitis, and the abnormal changes in bone metabolism which may accompany rheumatoid arthritis and osteoarthritis. Cytokines with excess production is also involved in mediating some of the complications of bacterial, fungal and/or viral infections, such as endotoxin shock, septic shock and toxic shock, and in mediating some complications during surgery on the Central nervous system or injury, such as neurotrauma and ischemic stroke. Cytokines with excess production is also involved in mediating or exacerbation of the disease, including resorption of cartilage or muscles, pulmonary fibrosis, cirrhosis, kidney fibrosis, cachexia, found in some chronic diseases, such as malignant disease and acquired immunodeficiency syndrome (AIDS), the tumor is th invasiveness and tumor metastases and multiple sclerosis.

The proof of the Central role of TNFαperformed by them in the chain of transmission of cellular signals that lead to the emergence of rheumatoid arthritis, is efficacy in clinical trials of antibody TNFα (The Lancet, 1994,344, 1125 and the British Journal of Rheumatology, 1995,34, 334).

Thus, I believe that cytokines, such as TNFα and IL-1 are important mediators of a large number of diseases and illnesses. Accordingly, it is expected that the inhibition of the production and/or activity of these cytokines will be a favorable factor for the prevention, control or treatment of such diseases and conditions.

If you don't want to argue on the basis of only one biological process that the compounds described in the present invention possess pharmacological activity, it is assumed that on the basis of inhibition of the enzyme kinase R compounds inhibit the action of cytokines. Kinase R, otherwise known as cytokine-suppressor binding protein (hereinafter CSBP) and reactivating kinase (hereinafter RK), is a member of a family of enzymes kinase - mitogenactivated proteins (MAP), which are known to be activated by physiological stress, such as stress caused by ionizing radiation, cytotoxic substances and toxins such as endotoxins, such as bacteria the capacity lipopolysaccharide, and in many substances, such as cytokines, for example TNFα and IL-1. It is known that the kinase R phosphorylate some intracellular proteins involved in the cascade of enzymatic steps, leading to the biosynthesis and secretion of cytokines, such as TNFα and IL-1. A review of known kinase inhibitors R provides G.J. Hanson in Expert Opinions on Therapeutic Patents, 1997,7, 729-733. It is known that the kinase R exist in isoforms identified as Rα and Rβ.

Compounds described in the present invention are inhibitors of the production of cytokines, such as TNF, in particular TNFαand various interleukins, in particular IL-1.

In accordance with its first aspect the present invention relates to a compound of formula I

where X represents CH or N;

Y represents CH or N;

m is 0, 1, 2 or 3;

R1represents hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbarnoyl, formyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino, (C1-C6)alkoxycarbonyl,N-(C1-C6)allylcarbamate,N,Ndi-[(C1 -C6)alkyl]carbarnoyl, (C2-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkanolamine,N-(C1-C6)alkylsulfonyl,N,Ndi-[(C1-C6)alkyl]sulfamoyl, (C1-C6)alkanesulfonyl,N-(C1-C6)alkyl-(C1-C6)alkanesulfonyl, halogen-(C1-C6)alkyl, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, cyano-(C1-C6)alkyl, amino-(C1-C6)alkyl, (C1-C6)alkylamino-(C1-C6)alkyl, di-[(C1-C6)alkyl]amino-(C1-C6)alkyl, carboxy-(C1-C6)alkyl, (C1-C6)alkoxycarbonyl-(C1-C6)alkyl, carbarnoyl-(C1-C6)alkyl,N-(C1-C6)allylcarbamate-(C1-C6)alkyl,N,Ndi-[(C1-C6)alkyl] carbarnoyl-(C1-C6)alkyl, halogen-(C2-C6)alkoxy, hydroxy-(C2-C6)alkoxy, (C1-C6)alkoxy-(C2-C6)alkoxy, cyano-(C1-C6)alkoxy, carboxy-(C1-C6)alkoxy, (C1-C6)alkoxycarbonyl-(C1-C6)alkoxy, carbarnoyl-(C1-C6)alkoxy,N-(C1-C6)allylcarbamate-(C1-C6)alkoxy,N,Ndi-[(C1-C6)alkyl]carbarnoyl-(C1/sub> -C6)alkoxy, amino-(C2-C6)alkoxy, (C1-C6)alkylamino-(C2-C6)alkoxy, di-[(C1-C6)alkyl]amino-(C2-C6)alkoxy, halogen-(C2-C6)alkylamino, hydroxy-(C2-C6)alkylamino, (C1-C6)alkoxy-(C2-C6)alkylamino, cyano-(C1-C6)alkylamino, carboxy-(C1-C6)alkylamino, (C1-C6)alkoxycarbonyl-(C1-C6)alkylamino, carbarnoyl-(C1-C6)alkylamino,N-(C1-C6)allylcarbamate-(C1-C6)alkylamino,N,Ndi-[(C1-C6)alkyl]carbarnoyl-(C1-C6)alkylamino, amino-(C2-C6)alkylamino, (C1-C6)alkylamino-(C1-C6)alkylamino, di-[(C1-C6)alkyl]amino-(C2-C6)alkylamino,N-(C1-C6)alkylhalides-(C1-C6)alkylamino,N-(C1-C6)alkylperoxy-(C2-C6)alkylamino,N-(C1-C6)alkyl-(C1-C6)alkoxy-(C2-C6)alkylamino,N-(C1-C6)alkylene-(C1-C6)alkylamino,N-(C1-C6)alkylcarboxylic-(C1-C6)alkylamino,N-(C1-C6)alkyl-(C1-C6)alkoxycarbonyl-(C1-C6)alkylamino,N-(C1-C6)allylcarbamate-(C1- 6)alkylamino,N-(C1-C6)alkyl-N-(C1-C6)allylcarbamate-(C1-C6)alkylamino,N-(C1-C6)alkyl-N,Ndi-[(C1-C6)alkyl]carbarnoyl-(C1-C6)alkylamino,N-(C1-C6)alkylamino-(C2-C6)alkylamino,N-(C1-C6)alkyl-(C1-C6)alkylamino-(C2-C6)alkylamino,N-(C1-C6)alkyl, di-[(C1-C6)alkyl]amino-(C2-C6)alkylamino, halogen-(C2-C6)alkanolamine, hydroxy-(C2-C6)alkanolamine, (C1-C6)alkoxy-(C2-C6)alkanolamine, cyano-(C2-C6)alkanolamine, carboxy-(C2-C6)alkanolamine, (C1-C6)alkoxycarbonyl-(C2-C6)alkanolamine, carbarnoyl-(C2-C6)alkanolamine,N-(C1-C6)allylcarbamate-(C2-C6)alkanolamine,N,Ndi-[(C1-C6)alkyl]carbarnoyl-(C2-C6)alkanolamine, amino-(C2-C6)alkanolamine, (C1-C6)alkylamino-(C2-C6)alkanolamine or di-[(C1-C6)alkyl]amino-(C1-C6)alkanolamine,

or R1represents aryl, aryl-(C1-C6)alkyl, aryl-(C1-C6)alkoxy, aryloxy, arylamino,N-(C1-C6)alkylsilanes is, aryl-(C1-C6)alkylamino,N-(C1-C6)alkylaryl-(C1-C6)alkylamino, aroylamino, arylsulfonamides,N-arylsulfonyl, aryl-(C2-C6)alkanolamine, heteroaryl, heteroaryl-(C1-C6)alkyl, heteroaromatic, heteroaryl-(C1-C6)alkoxy, heteroallyl,N-(C1-C6)alkyldiethanolamine, heteroaryl-(C1-C6)alkylamino,N-(C1-C6)alkylglycerol-(C1-C6)alkylamino, heteroarylboronic, heteroarylboronic,N-heteroarylboronic, heteroaryl-(C2-C6)alkanolamine, heteroaryl-(C1-C6)alkoxy-(C1-C6)alkyl, heteroaryl-(C1-C6)alkylamino-(C1-C6)alkyl,N-(C1-C6)alkylglycerol-(C1-C6)alkylamino-(C1-C6)alkyl, heterocyclyl, heterocyclyl-(C1-C6)alkyl, heterocyclic, heterocyclic-(C1-C6)alkoxy, heterocyclisation,N-(C1-C6)alkyldiethanolamine, heterocyclyl-(C1-C6)alkylamino,N-(C1-C6)alkylglycerol-(C1-C6)alkylamino, geterotsiklicheskikh, heterocyclization,N-heterocyclisation, heterocyclyl-(C2-C6)alkanolamine, heterocyclyl-(C1-C6)alkoxy-(C1 -C6)alkyl, heterocyclyl-(C1-C6)alkylamino-(C1-C6)alkyl, orN-(C1-C6)alkylglycerol-(C1-C6)alkylamino-(C1-C6)alkyl,

or (R1)mis (C1-C3)alkylenedioxy,

and where any of the substituents R1with the above values, containing SN2-group associated with the 2 carbon atoms, or CH3-group associated with the carbon atom, may optionally contain each of the specified CH2or CH3group Deputy selected from hydroxy, amino, (C1-C6)alkoxy, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino and heterocyclyl,

and where any aryl, heteroaryl or heterocyclyl group in the substituent R1may optionally contain 1 or 2 substituent selected from hydroxy, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, carboxy, (C1-C6)alkoxycarbonyl,N-(C1-C6)allylcarbamate,N,Ndi-[(C1-C6)alkyl]carbamoyl, (C2-C6)alkanoyl, amino, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino, halogen-(C1-C6)alkyl, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, cyano-(C1-C6)Alki is a, amino-(C1-C6)alkyl, (C1-C6)alkylamino-(C1-C6)alkyl, di-[(C1-C6)alkyl]amino-(C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl,

n is 0, 1, 2 or 3;

R2represents hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, (C1-C6)alkoxy, (C1-C6)alkylamino or di-[(C1-C6)alkyl]amino;

R3represents hydrogen, halogen, (C1-C6)alkyl or (C1-C6)alkoxy;

q is 0, 1, 2, 3 or 4; and

Q is aryl, aryloxy, aryl-(C1-C6)alkoxy, arylamino,N-(C1-C6)alkylamino, aryl-(C1-C6)alkylamino,N-(C1-C6)alkylaryl-(C1-C6)alkylamino, aroylamino, arylsulfonamides,N-arylcarbamoyl,N-arylsulfonyl, aryl-(C2-C6)alkanolamine, (C3-C7)cycloalkyl, heteroaryl, heteroaromatic, heteroaryl-(C1-C6)alkoxy, heteroallyl,N-(C1-C6)alkyldiethanolamine, heteroaryl-(C1-C6)alkylamino,N-(C1-C6)alkylglycerol-(C1-C6)alkylamino, heteroarylboronic, heteroarylboronic,Nheteroarylboronic, N-heteroarylboronic, heteroaryl-(C2-C6)alkanolamine, heterocyclyl, heterocyclic, geherally-(C1-C6)alkoxy, heterocyclisation,N-(C1-C6)alkyldiethanolamine, heterocyclyl-(C1-C6)alkylamino,N-(C1-C6)alkylglycerol-(C1-C6)alkylamino, geterotsiklicheskikh, heterocyclization,N-heterocyclisation,N-heterocyclisation or heterocyclyl-(C2-C6)alkanolamine,

and Q is optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, trifloromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)quinil, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino, (C1-C6)alkoxycarbonyl,N-(C1-C6)allylcarbamate,N,Ndi-[(C1-C6)alkyl]carbamoyl, (C2-C6)alkanoyl, (C2-C6)alkanoyloxy, (C1-C6)alkanolamine,N-(C1-C6)alkylsulfonyl,N,Ndi-[(C1-C6)alkyl]sulfamoyl, (C1-C6)alkanesulfonyl, N-(C1 -C6)alkyl-(C1-C6)alkanesulfonyl, halogen-(C1-C6)alkyl, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, cyano-(C1-C6)alkyl, amino-(C1-C6)alkyl, (C1-C6)alkylamino-(C1-C6)alkyl, di-[(C1-C6)alkyl]amino-(C1-C6)alkyl, carboxy-(C1-C6)alkyl, (C1-C6)alkoxycarbonyl-(C1-C6)alkyl, carbarnoyl-(C1-C6)alkyl,N-(C1-C6)allylcarbamate-(C1-C6)alkyl,N,Ndi-[(C1-C6)alkyl]carbarnoyl-(C1-C6)alkyl, halogen-(C2-C6)alkoxy, hydroxy-(C2-C6)alkoxy, (C1-C6)alkoxy-(C2-C6)alkoxy, cyano-(C1-C6)alkoxy, carboxy-(C1-C6)alkoxy, (C1-C6)alkoxycarbonyl-(C1-C6)alkoxy, carbarnoyl-(C1-C6)alkoxy,N-(C1-C6)allylcarbamate-(C1-C6)alkoxy,N,Ndi-[(C1-C6)alkyl] carbarnoyl-(C1-C6)alkoxy, amino-(C2-C6)alkoxy, (C1-C6)alkylamino-(C2-C6)alkoxy, di-[(C1-C6)alkyl]amino-(C2-C6)alkoxy, halogen-(C2-C6)alkylamino, hydroxy-(C2-C6)alkylamino, (C1-C6 2-C6)alkylamino, cyano-(C1-C6)alkylamino, carboxy-(C1-C6)alkylamino, (C1-C6)alkoxycarbonyl-(C1-C6)alkylamino, carbarnoyl-(C1-C6)alkylamino,N-(C1-C6)allylcarbamate-(C1-C6)alkylamino,N,Ndi-[(C1-C6)alkyl]carbarnoyl-(C1-C6)alkylamino, amino-(C2-C6)alkylamino, (C1-C6)alkylamino-(C2-C6)alkylamino, di-[(C1-C6)alkyl]amino-(C2-C6)alkylamino,N-(C1-C6)alkylhalides-(C1-C6)alkylamino,N-(C1-C6)alkylperoxy-(C2-C6)alkylamino,N-(C1-C6)alkyl-(C1-C6)alkoxy-(C2-C6)alkylamino,N-(C1-C6)alkylene-(C1-C6)alkylamino,N-(C1-C6)alkylcarboxylic-(C1-C6)alkylamino,N-(C1-C6)alkyl-(C1-C6)alkoxycarbonyl-(C1-C6)alkylamino,N-(C1-C6)allylcarbamate-(C1-C6)alkylamino,N-(C1-C6)alkyl-N-(C1-C6)allylcarbamate-(C1-C6)alkylamino,N-(C1-C6)alkyl-N,Ndi-[(C1-C6)alkyl]carbarnoyl-(C1-C6)alkylamino,N-(C1-C6)alkylamino-(C2-C6)alkylamino,N-C 1-C6)alkyl-(C1-C6)alkylamino-(C2-C6)alkylamino,N-(C1-C6)alkyl, di-[(C1-C6)alkyl]amino-(C2-C6)alkylamino, halogen-(C2-C6)alkanolamine, hydroxy-(C2-C6)alkanolamine, (C1-C6)alkoxy-(C2-C6)alkanolamine, cyano-(C2-C6)alkanolamine, carboxy-(C2-C6) alkanolamine, (C1-C6)alkoxycarbonyl-(C2-C6)alkanolamine, carbarnoyl-(C2-C6)alkanolamine,N-(C1-C6)allylcarbamate-(C2-C6)alkanolamine,N,Ndi-[(C1-C6)alkyl]carbarnoyl-(C2-C6)alkanolamine, amino-(C2-C6)alkanolamine, (C1-C6)alkylamino-(C2-C6)alkanolamine, di-[(C1-C6)alkyl]amino-(C2-C6)alkanolamine, aryl, aryl-(C1-C6)alkyl, aryl-(C1-C6)alkoxy, aryloxy, arylamino,N-(C1-C6)alkylamino, aryl-(C1-C6)alkylamino,N-(C1-C6)alkylaryl-(C1-C6)alkylamino, aroylamino, arylsulfonamides,Narylsulfonyl, aryl-(C2-C6)alkanolamine, heteroaryl, heteroaryl-(C1-C6)alkyl, heteroaromatic, heteroaryl-(C1-C6)alkoxy, heteroallyl,N-(C1-C6)alkyl is triarylamine, heteroaryl-(C1-C6)alkylamino,N-(C1-C6)alkylglycerol-(C1-C6)alkylamino, heteroarylboronic, heteroarylboronic,Nheteroarylboronic, heteroaryl-(C2-C6) alkanolamine, heteroaryl-(C1-C6)alkoxy-(C1-C6)alkyl, heteroaryl-(C1-C6)alkylamino-(C1-C6)alkyl,N-(C1-C6)alkylglycerol-(C1-C6)alkylamino-(C1-C6)alkyl, heterocyclyl, heterocyclyl-(C1-C6)alkyl, heterocyclic, heterocyclic-(C1-C6)alkoxy, heterocyclisation,N-(C1-C6)alkyldiethanolamine, heterocyclyl-(C1-C6)alkylamino,N-(C1-C6)alkylglycerol-(C1-C6)alkylamino, geterotsiklicheskikh, heterocyclization,Ngeterotsiklicheskikh, heterocyclyl-(C2-C6)alkanolamine, heterocyclyl-(C1-C6)alkoxy-(C1-C6)alkyl, heterocyclyl-(C1-C6)alkylamino-(C1-C6)alkyl andN-(C1-C6)alkylglycerol-(C1-C6)alkylamino-(C1-C6)alkyl,

or substituted Q (C1-C3)alkylenedioxy,

and where any substituents for Q having values above containing SN2-group associated with the 2 atoms is of Pereda, or CH3-group associated with the carbon atom, can optionally contain each of the specified CH2or CH3group Deputy selected from hydroxy, amino, (C1-C6)alkoxy, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino and heterocyclyl,

and where any aryl, heteroaryl or etracycline group Deputy for Q may optionally contain 1 or 2 substituent selected from hydroxy, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, carboxy, (C1-C6)alkoxycarbonyl,N-(C1-C6)allylcarbamate,N,Ndi-[(C1-C6)alkyl]carbamoyl, (C2-C6)alkanoyl, amino, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino, halogen-(C1-C6)alkyl, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, cyano-(C1-C6)alkyl, amino-(C1-C6)alkyl, (C1-C6)alkylamino-(C1-C6)alkyl, di-[(C1-C6)alkyl]amino-(C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl,

or its pharmaceutically acceptable salt or its complex ether, biodegradable in vivo.

In accordance with another aspect, the present invention relates to a compound of formula I, where each of X, Y, R1, R2, m, n, and Q has any of the above meanings and R 3selected from halogen and (C1-C6)alkyl; or its pharmaceutically acceptable salt or its complex ether, biodegradable in vivo.

In this description, the term "(C1-C6)alkyl" vklyuchayuschimisya group with a linear or branched chain, such as propyl, isopropyl and tert-butyl, and (C3-C6)cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. However references to individual alkyl groups such as "propyl", characteristic only for the version with a linear chain, references to individual alkyl groups branched chain, such as isopropyl", characteristic only for version with branched chain, and links to individual cycloalkyl groups, such as "cyclopentyl", characteristic only for 5-membered rings. A similar approach applies to other common terms such as (C1-C6)alkoxy includes methoxy, ethoxy, cyclopropylamine, cyclopentyloxy, (C1-C6)alkylamino includes methylamino, ethylamino, cyclobutylamine, cyclohexylamine, and di-[(C1-C6)alkyl]amino include dimethylamino, diethylamino,N-cyclobutyl-N-cyclobutylamine andN-cyclohexyl-N-ethylamino.

It should be borne in mind that since some of the compounds of formula I, described above may exist in optically active or racemic Faure is Oh, due to the presence of one or more asymmetric carbon atoms, the invention in its definition includes any such optically active or racemic form, having the property of inhibiting cytokines, in particular TNF. Synthesis of optically active forms can be accomplished by conventional methods of organic chemistry well known in this field, for example by synthesis from optically active starting compounds or by splitting of racemic forms. Similarly inhibiting properties against TNF can be estimated using standard laboratory methods listed below.

Suitable values for the radicals mentioned above are the values listed below.

A suitable value of "aryl" in the definition of R1and Q when they represent aryl, in the definition of substituent on Q when it is an aryl, or in the definition of aryl groups in the substituent R1or Q group, or the substituents on Q is, for example, phenyl, indenyl, indanyl, naphthyl, tetrahydronaphthyl or fluorenyl, more preferably phenyl.

A suitable value heteroaryl" in the definition of R1or Q when they are heteroaryl, in the definition of heteroaryl groups in the substituent R1or the group Q, in the definition of substituent on Q when such Deputy represents heteroaryl, or in the definition of heteroaryl groups in the substituents on Q is, for example, an aromatic 5 - or 6-membered monocyclic ring, a 9 - or 10-membered bicyclic ring or a 13 - or 14-membered tricyclic ring, each containing up to five heteroatoms in the ring selected from atoms of oxygen, nitrogen and sulphur, such as furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuranyl, indolyl, benzothiazyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazoles, benzofurazanyl, hinely, ethanolic, hintline, honokalani, cinnoline, naphthyridine, carbazolyl, dibenzofurans, dibenzothiophenes,S,S-deoxidisation, xantener, dibenzo-1,4-dioxines, phenoxathiin, phenoxazines, dibenzothiazyl, phenothiazinyl, thianthrene, benzofuranyl, peridontal, acridines or phenanthridine, more preferably furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazoles, benzofurazanyl, hinely, ethanolic, hintline, honokalani, naphthyridine, carbazolyl, dibenzofurans, Deeb is sociogenic or xantener, more preferably furyl, thienyl, isoxazolyl, thiazolyl, pyridyl, benzothiazyl, benzofurazanyl, hinely, carbazolyl, dibenzofurans or dibenzothiophene.

A suitable value heterocyclyl" in the definition of R1or Q when they are heterocyclyl, in the definition of substituent on Q when a Deputy is heterocyclyl, or heterocyclyl group in the substituent R1or the group Q, or substitute for Q is, for example, non-aromatic saturated or partially saturated 3 to 10-membered monocyclic or bicyclic ring with up to five heteroatoms selected from atoms of oxygen, nitrogen and sulfur, such as oxiranyl, oxetanyl, azetidine, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrrolidinyl, 1,1-dioxothiazolidine, morpholinyl, tetrahydro-1,4-thiazines, 1,1-dioxotetrahydrofuran-1,4-thiazines, piperidinyl, homopiperazine, piperazinil, homopiperazine, dihydropyridines, tetrahydropyridine, dihydropyrimidine or tetrahydropyrimidines, or, for example, imidazolyl, imidazolidinyl, pyrazolines, pyrazolidine, or, for example, their lansoprozole, such as 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl, indolinyl, isoindolyl, bromanil and isopropanol, preferably heterocyclyl group represents pyrrolidin-1-yl, pyrrolidin-2-the l morpholino, piperidino, piperazine-1-yl or homopiperazin-1-yl.

A suitable value of Q when Q is (C3-C7)cycloalkyl is, for example, non-aromatic mono - or bicyclic 3-7-membered carbon ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2,1]heptyl, preferably cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, more preferably cyclohexyl.

The appropriate values of the different groups of R1, R2or R3or different substituents on Q or on an aryl, heteroaryl or heterocyclyl groups in R1or aryl, heteroaryl or heterocyclyl groups in the substituents on Q include:

for halogen: fluorine, chlorine, bromine and iodine;

for (C1-C6)alkyl: methyl, ethyl, propyl, isopropyl,tert-butyl, cyclobutyl, cyclopentyl and cyclohexyl;

for (C2-C6)alkenyl: vinyl and allyl;

for (C2-C6)quinil: ethinyl and 2-PROPYNYL;

for (C1-C6)alkoxy: methoxy, ethoxy, propoxy, isopropoxy, cyclopropylamine, butoxy, cyclobutylamine, cyclopentyloxy;

for (C1-C6)alkylamino: methylamino, ethylamino, propylamino, cyclobutylamine, cyclohexylamine;

for di-[(C1-C6)alkyl]amino: dimethylamino, diethylamino andN-ethyl-N-methylamino;

for (C1-C6)alkoxycarbonyl: methoxycarbonyl, etoxycarbonyl, propoxycarbonyl andtert-butoxycarbonyl;

forN-(C1-C6)allylcarbamate:N-methylcarbamoyl,N-ethylcarbamate andN-propellerblades;

forN,Ndi-[(C1-C6)alkyl]carbamoyl:N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl andN,N-diethylcarbamoyl;

for (C2-C6)alkanoyl: acetyl and propionyl;

for halogen-(C1-C6)alkyl: vermeil, chloromethyl, methyl bromide, deformity, dichloromethyl, dibromomethyl, 2-foretel, 2-chloroethyl and 2-bromacil;

for hydroxy-(C1-C6)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl;

for (C1-C6)alkoxy-(C1-C6)alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;

for cyano-(C1-C6)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and 3-cyanopropyl;

for amino-(C1-C6)alkyl: aminomethyl, 2-amino-ethyl, 1-amino-ethyl and 3-aminopropyl;

for (C1-C6)alkylamino-(C1-C6)alkyl: methylaminomethyl, ethylaminomethyl, 1-methylaminomethyl, 2-methylaminomethyl, 2-ethylaminomethyl and 3-methylaminopropyl;

for di-[(C1-C6)alkyl]amino-(C1-C6)alkyl: dimethylaminomethyl, diethylaminomethyl, 1-dim is delaminates, 2-dimethylaminoethyl and 3-dimethylaminopropyl.

The appropriate values of R1or Q and the appropriate values of the substituents for R1or Q include:

for aryl-(C1-C6)alkyl: benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl;

for aryl-(C1-C6)alkoxy: benzyloxy and 2-phenylethane;

for aryloxy: phenoxy and 2 naphthyloxy;

for arylamino: aniline;

forN-(C1-C6)alkylamino:N-methylaniline andN-ethylaniline;

for aryl-(C1-C6)alkylamino: benzylamino, 2-phenylethylamine, 2-phenylpropylamine and 3 phenylpropylamine;

forN-(C1-C6)alkylaryl-(C1-C6)alkylamino:N-benzyl-N-methylaniline;

for aroylamino: benzamide and 2 naphthylamine;

for arylsulfonamides: benzosulfimide;

forNarylcarbamoyl:N-phenylcarbamoyl;

forNarylsulfonyl:N-phenylsulfonyl;

for aryl-(C2-C6)alkanolamine: phenylacetamido and 3 phenylpropionamide;

for heteroaryl-(C1-C6)alkyl: heteroaromatic, 2-heteroaromatic, 2-heteroarylboronic and 3-heteroaromatic;

for heteroaryl-(C1-C6)alkoxy: heteroaromatics and 2 heteroaromatics;

forN-(C1-C6)alkyldiethanolamine:N-methylethanolamine;

for heteroaryl-(C1-C6)alkylamino: heteros is arylmethylidene, 2 heterotrimetallic and 3 heteroarylboronic;

forN-(C1-C6)alkylglycerol-(C1-C6)alkylamino: N-methylethanolamine andN-methyl-2-heteroarylboronic;

for heteroaryl-(C2-C6)alkanolamine: heteroalicyclic and 3 heteroarylboronic;

for heteroaryl-(C1-C6)alkoxy-(C1-C6)alkyl: heteroeroticism, 2-heteroepitaxial and 3-heteroaromatic;

for heteroaryl-(C1-C6)alkylamino-(C1-C6)alkyl: heteroarylboronic, 2-heteroarylboronic and 3-heteroarylboronic;

forN-(C1-C6)alkylglycerol-(C1-C6)alkylamino-(C1-C6)alkyl:N-heteroaromatic-N-methylaminomethyl,N-(2-heteroaromatic)-N-methylaminomethyl andN-(3-heteroaromatic)-N-methylaminomethyl;

for heterocyclyl-(C1-C6)alkyl: heterocyclyl, 2-heterocyclisation, 2-heterocyclisation and 3-heterocyclisation;

for heterocyclyl-(C1-C6)alkoxy: heterocyclisation and 2 heterocyclics;

forN-(C1-C6)alkyldiethanolamine:N-methylethanolamine;

for heterocyclyl-(C1-C6)alkylamino: heterocyclisation, 2-heterocyclisation and 3 heterocyclisation;

for -(C1-C6)alkylglycerol-(C1-C6)alkylamino:N-methylselenocysteine andN-methyl-2-heterocyclisation;

for heterocyclyl-(C2-C6)alkanolamine: heterocyclization and 3 heterocyclisation;

for heterocyclyl-(C1-C6)alkoxy-(C1-C6)alkyl: heterocyclisation, 2-heterocyclisation and 3-heterocyclization;

for heterocyclyl-(C1-C6)alkylamino-(C1-C6)alkyl: getprocessimagefilenamea, 2-getprocessimagefilenamea and 3-getprocessimagefilenamea;

forN-(C1-C6)alkylglycerol-(C1-C6)alkylamino-(C1-C6)alkyl:N-heterocyclyl-N-methylaminomethyl,N-(2-heterocyclisation)-N-methylaminomethyl andN-(3-heterocyclisation)-N-methylaminomethyl;

for (C1-C3)alkylenedioxy: methylenedioxy, Ethylenedioxy, trimethylenediamine;

for (C1-C6)alkylthio: methylthio, ethylthio, propylthio;

for (C1-C6)alkylsulfonyl: methylsulfinyl, ethylsulfinyl and propylsulfonyl;

for (C1-C6)alkylsulphonyl: methylsulphonyl, ethylsulfonyl and propylsulfonyl;

for (C2-C6)alkanoyloxy: acetoxy, propionyloxy;

for (C1-C6)alkanolamine: formamido, and is atamido, propionamido;

forN-(C1-C6)alkylsulfanyl:N-methylsulfonyl andN-ethylsulfanyl;

for N,Ndi-[(C1-C6)alkyl]sulfamoyl:N,N-dimethylsulphamoyl;

for (C1-C6)alkanesulfonyl: methanesulfonamido, ethanolgasoline;

forN-(C1-C6)alkyl-(C1-C6)alkanesulfonyl:N-methylmethanesulfonamide andN-methylethanolamine;

for carboxy-(C1-C6)alkyl: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 3-carboxypropyl and 4-carboxybutyl;

for (C1-C6)alkoxycarbonyl-(C1-C6)alkyl: methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropionyl and 3-ethoxycarbonylphenyl;

for carbarnoyl-(C1-C6)alkyl: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylmethyl;

forN-(C1-C6)allylcarbamate-(C1-C6)alkyl:N-methylcarbamoylmethyl,N-ethylcarboxylate,N-propylgallate, 1-(N-methylcarbamoyl)ethyl, 1-(N-ethyl-carbarnoyl)ethyl, 2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamate)ethyl and 3-(N-methylcarbamoyl)propyl;

forN,Ndi[(C1-C6)alkyl]carbarnoyl-(C1With 6)alkyl:N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoylmethyl,N,N-diethylcarbamoyl, 1-(N,N-dimethylcarbamoyl)ethyl, 1-(N,N-diethylcarbamoyl)ethyl, 2-(N,N-dimethylcarbamoyl)ethyl, 2-(N,N-diethylcarbamoyl)ethyl, 3-(N,N-dimethylcarbamoyl)propyl and 4-(N,N-dimethylcarbamoyl)butyl;

for halogen-(C2-C6)alkoxy: 2-chloroethoxy, 2-bromoethoxy, 3 chloropropoxy, 1,1,2,2-tetrafluoroethoxy and 2,2,2-triptoreline;

for hydroxy-(C2-C6)alkoxy: 2-hydroxyethoxy, 3 hydroxypropoxy, 2-hydroxy-1-methylethoxy, 2-hydroxy-2-propoxy and 4-hydroxybutane;

for (C1-C6)alkoxy-(C2-C6)alkoxy: 2-methoxyethoxy, 2-ethoxyethoxy, 3 methoxypropane, 2-methoxy-1-methoxyethoxy and 4 amoxibiotic;

for cyano-(C1-C6)alkoxy: cyanoethoxy, 2-cyanoethoxy and 3 cyanopropionic;

for carboxy-(C1-C6)alkoxy: carboxymethoxy, 1 carboxymethoxy, 2-carboxymethoxy and 3 carboxypropyl;

for (C1-C6)alkoxycarbonyl-(C1-C6)alkoxy: ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, tert-butoxycarbonylmethyl, 2-ethoxycarbonylmethoxy and 3 ethoxycarbonylmethoxy;

for carbarnoyl-(C1-C6)alkoxy: carbamoylphenoxy and 2 carbamoylphenoxy;

forN-(C1-C6)ancillary mail-(C 1-C6)alkoxy:N-methylcarbamoylmethyl, 2-(N-ethyl-carbarnoyl)ethoxy and 3(N-methylcarbamoyl)propoxy;

forN,Ndi-[(C1-C6)alkyl]carbarnoyl-(C1-C6)alkoxy:N,N-dimethylcarbamoyl, 2-(N,N-dimethylcarbamoyl)ethoxy and 3-(N,N-diethylcarbamoyl)propoxy;

for amino-(C2-C6)alkoxy: 2-aminoethoxy, 2-amino-1-methylethoxy, 3 aminopropoxy, 2-amino-2-methylpropoxy and 4 aminobutoxy;

for (C1-C6)alkylamino-(C2-C6)alkoxy: 2-methylaminoethanol, 2-methylamino-1 methylethoxy and 3 Ethylenedioxy;

for di-[(C1-C6)alkyl]amino-(C2-C6)alkoxy: 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-dimethylaminopropoxy, 2-dimethylamino-2-methylethoxy, 3 dimethylaminopropoxy and 4 dimethylaminoethoxy;

for halogen-(C2-C6)alkylamino: 2-foretelling, 2-chloroethylamine, 2-bromethalin, 3 forprofile and 3 chloropropylamine;

for hydroxy-(C2-C6)alkylamino: 2-hydroxyethylamino, 3 hydroxypropylamino, 2-hydroxy-2-methylpropylamine and 4 hydroxyethylamino;

for (C1-C6)alkoxy-(C2-C6)alkylamino: 2-methoxyethylamine, 2-ethoxyethylene, 3 methoxypropylamine and 3 ethoxypropylamine;

for cyano-(C1-C6)alkylamino: cyanomethylene, 2-cyanoethylene and 3-cyanoprop is ylamino;

for carboxy-(C1-C6)alkylamino: carboxymethylamino, 1 carboxymethylamino, 2-carboxymethylamino and 3 carboxymethylamino;

for (C1-C6)alkoxycarbonyl-(C1-C6)alkylamino: methoxycarbonylmethylene, 2-(etoxycarbonyl)ethylamino and 3-(tert-butoxycarbonyl)Propylamine;

for carbarnoyl-(C1-C6)alkylamino: carbamoylmethyl and 2 carbamoylation;

forN-(C1-C6)allylcarbamate-(C1-C6)alkylamino:N-methylcarbamoylmethyl,N-ethylcarbodiimide and 2(N-methylcarbamoyl)ethylamino;

forN,Ndi-[(C1-C6)alkyl]carbarnoyl-(C1-C6)alkylamino:N,N-dimethylcyclohexylamine,N,N-diethylcarbamoyl and 2(N,N-dimethylcarbamoyl)ethylamino;

for amino-(C2-C6)alkylamino: 2-aminoethylamino, 3 aminopropylene, 2-amino-2-methylpropylamine and 4 aminoethylamino;

for (C1-C6)alkylamino-(C2-C6)alkylamino: 2-methylaminoethanol, 2-ethylaminoethanol, 2-Propylenediamine, 3 methylaminopropane, 3 ethylenepropylene, 2-methylamino-2-methylpropylamine and 4 methylaminopropane;

for di-[(C1-C6)alkyl]amino-(C2-C6)alkylamino: 2-diethylaminoethylamine, 2-(N-ethyl-N-methylamino)ethylamino, 2-diethylam is neutralino, 2 dipropylenetriamine, 3 dimethylaminopropylamine, 3 diethylaminopropylamine, 2-dimethylamino-2-methylpropylamine and 4 diethylaminoethylamine;

forN-(C1-C6)alkylhalides-(C2-C6)alkylamino:N-(2-chloroethyl)-N-methylamino,N-(2-bromacil)-N-methylamino andN-(2-bromacil)-N-ethylamino;

forN-(C1-C6)alkylperoxy-(C2-C6)alkylamino:N-(2-hydroxyethyl)-N-methylamino,N-(3-hydroxypropyl)-N-methylamino andN-ethyl-N-(2-hydroxyethyl)amino;

forN-(C1-C6)alkyl-(C1-C6)alkoxy-(C2-C6)alkylamino:N-methyl-N-(2-methoxyethyl)amino,N-methyl-N-(3-methoxypropyl)amino andN-ethyl-N-(2-methoxyethyl)amino;

forN-(C1-C6)alkylene-(C1-C6)alkylamino:N(cyanomethyl)-N-methylamino;

forN-(C1-C6)alkylcarboxylic-(C1-C6)alkylamino:Ncarboxymethyl- N-methylamino andN-(2-carboxyethyl)-N-methylamino;

forN-(C1-C6)alkyl-(C1-C6)alkoxycarbonyl-(C1-C6)alkylamino:N-methoxycarbonylmethyl-N-methylamino,N-(2-ethoxycarbonylethyl)-N-ethylamino andN-(2-tert-butoxycarbonylmethyl)-N-methylamino;

forN-(C1-C6)allylcarbamate-(C1- 6)alkylamino:N-carbamoylmethyl-N-methylamino andN-(2-carbamoylethyl)-N-methylamino;

forN-(C1-C6)alkyl-N-(C1-C6)allylcarbamate-(C1-C6)alkylamino:N-(N-methylcarbamoylmethyl)-N-methylamino,N-(N-ethylcarboxylate)-N-methylamino andN-[2-(N-methylcarbamoyl)ethyl]-N-methylamino;

forN-(C1-C6)alkyl-N,Ndi-[(C1-C6)alkyl]carbarnoyl(C1-C6)alkylamino:N-(N,N-dimethylcarbamoyl)-N-methylamino andN-[2-(N,N-dimethylcarbamoyl)ethyl]-N-methylamino;

forN-(C1-C6)alkylamino-(C2-C6)alkylamino:N-(2-aminomethyl)-N-methylamino,N-(3-aminopropyl)-N-methylamino andN-(4-aminobutyl)-N-methylamino;

forN-(C1-C6)alkyl-(C1-C6)alkylamino-(C2-C6)alkylamino:N-(2-methylaminomethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminomethyl)-N-ethylamino andN-(4-methylaminomethyl)-N-methylamino;

forN-(C1-C6)alcalde-[(C1-C6)alkyl]amino-(C2-C6)alkylamino:N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino andN-(4-dimethyl shall aminobutyl)- N-methylamino;

for halogen-(C2-C6)alkanolamine: 2-chloracetamide and 3 chlorpropamide;

for hydroxy-(C2-C6)alkanolamine: 2-hydroxyacetamido and 3 hydroxypropylamino;

for (C1-C6)alkoxy-(C2-C6)alkanolamine: 2-methoxyacetate and 3 methoxypropionate;

for cyano-(C2-C6)alkanolamine: 2-cyanoacetamide and 3 cyanopropionic;

for carboxy-(C2-C6)alkanolamine: 2-carboxylated and 3 carboxypropyl;

for (C1-C6)alkoxycarbonyl-(C2-C6)alkanolamine: 2-methoxycarbonylethyl, 2-(tert-butoxycarbonyl)acetamido and 3-methoxycarbonylpropionyl;

for carbarnoyl-(C2-C6)alkanolamine: 2-carbamoylated, 3 carbamoylphosphate and 4 carbamoylating;

forN-(C1-C6)allylcarbamate-(C2-C6)alkanolamine: 2-(N-methylcarbamoyl)acetamido and 3-(N-ethylcarbamate)propionamido;

forN,Ndi-[(C1-C6)alkyl]carbarnoyl-(C2-C6)alkanolamine: 2-(N,N-dimethylcarbamoyl)acetamido, 2-(N,N-diethylcarbamoyl)acetamido and 3-(N,N-dimethylcarbamoyl)propionamido;

for amino-(C2-C6)alkanolamine: 2-aminoacetyl, 2-aminopropionic and 3 aminopropionic;

for (C1-C6 2-C6)alkanolamine: 2-methylaminoethanol, 2-ethylaminoethanol, 2-methylaminopropane and 3 methylaminopropane;

for di-[(C1-C6)alkyl]amino-(C2-C6)alkanolamine: 2-dimethylaminoacetyl, 2-diethylaminoacetate, 2-dimethylaminopropylamine and 3 dimethylaminopropylamine.

When, as defined here previously, any of the substituents in R1or Q containing SN2-group associated with the 2 carbon atoms, or CH3-group associated with the carbon atom, may contain, optionally, in each of the specified CH2or CH3group Deputy selected from hydroxy, amino, (C1-C6)alkoxy, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino and heterocyclyl, suitable substituents formed in this manner are, for example, substituted heterocyclyl-(C1-C6)alkoxygroup, such as 2-hydroxy-3-piperidinyloxy and 2-hydroxy-3-morpholinopropan, substituted amino-(C2-C6)alkoxygroup, such as 3-amino-2-hydroxypropoxy, substituted (C1-C6)alkylamino-(C2-C6)alkoxygroup, such as 2-hydroxy-3-methylaminopropane, substituted di-[(C1-C6)alkyl]amino-(C2-C6)alkoxygroup, such as 3-dimethylamino-2-hydroxypropoxy, 3-[N-(3-dimethylaminopropyl)-N-methylamino]propoxy and 3-[ N-(3-dimethylaminopropyl)-N-methylamino]-2-hydroxypropoxy, substituted heterocyclyl-(C1-C6)alkylamino, such as 2-hydroxy-3-piperidinophenyl and 2-hydroxy-3-morpholinopropan, substituted amino-(C2-C6)alkylamino, such as 3-amino-2-hydroxypropylamino, substituted (C1-C6)alkylamino-(C2-C6)alkylamino, such as 2-hydroxy-3-methylaminopropane, substituted di-[(C1-C6)alkyl]amino-(C2-C6)alkylamino, such as 3-dimethylamino-2-hydroxypropylamino, 3-[N-(3-dimethylaminopropyl)-N-methylamino]Propylamine and 3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-hydroxypropylamino, and substituted (C1-C6)alkylamino-(C2-C6)alkyl groups such as 2-diethylaminoethylamine, 3-dimethylaminopropylamine, 3-dimethylamino-2,2-dimethylpropylene, 2-morpholinomethyl, 2-piperazine-1-ylethylamine and 3-morpholinepropanesulfonic.

In order to avoid any misunderstanding, it should be borne in mind that, when X or Y represents a CH group, and the ring, which includes groups X and Y, contains one or more substituents R1Deputy R1can be located in any convenient place on the ring, including the position of the carbon atom of X or Y.

Suitable in pharmaceutical preparations is automatic acceptable salt of the compounds of formula I is for example, the additive salt of the acid compounds of formula I which is sufficiently basic, for example an additive salt of inorganic or organic acids, such as hydrochloric, Hydrobromic, sulfuric, triperoxonane, citric or maleic acid; or a salt of the compounds of formula I which is sufficiently acidic, for example, salts of alkaline or alkaline-earth metal such as calcium or magnesium salt, or ammonium salt, or salt of organic bases such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or Tris-(2-hydroxyethyl)amine.

In the art there are known various forms of prodrugs. As examples, describing such proletarienne derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985) and Methods in Enzvmology. Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H.Bundgaard p.113-191 (1991);

c) H.Bundgaard, Advanced Drug Delivery Reviews,8, 1-38 (1992);

d) H.Bundgaard. el al., Journal of Pharmaceutical Sciences,77, 285 (1988); and

e) N.Kakeya. el al., Chem. Pharm. Bull.,32, 692 (1984).

Examples of such prodrugs are formed esters of compounds of formula I, cleaved in vivo. Cleaved in vivo ester compounds of the formula I containing carboxypropyl represents, for example, pharmaceutically acceptable words is cent ether, which is cleaved in the human or animal with the formation of the original acid. Suitable pharmaceutically acceptable esters for carboxy (C1-C6)alkoxymethyl esters, for example methoxymethyl ether; (C1-C6)alkanoyloxy esters, for example pivaloyloxymethyl ether; palidrome esters; and (C3-C8)cycloalkylcarbonyl-(C1-C6)alkalemia esters, for example 1-cyclohexyloxycarbonyloxy ether; 1,3-dioxolane-2-ylmethylene esters, for example 5-methyl-1,3-dioxolane-2-ymetray ether; and (C1-C6)alkoxycarbonylmethyl esters, for example 1-methoxycarbonylmethylene ether; and such esters may be formed by any carboxypropyl in the compounds of the present invention.

Specific new compounds according to the first aspect of the invention are, for example, amide derivatives of the formula I or their pharmaceutically acceptable salts, where

(a) R3represents hydrogen, halogen (such as fluorine, chlorine or bromine) or (C1-C6)alkyl (such as methyl, ethyl, propyl and isopropyl), preferably R3represents hydrogen, chlorine, methyl or ethyl, more preferably hydrogen, chlorine or methyl; and X, Y, R1, R2, Q, m, n and q have any of the values of the above or in this section relating to the new JV is civicism compounds of the invention;

(b) Q is phenyl or a heteroaromatic 5 - or 6-membered monocyclic ring or 9 - or 10-membered bicyclic ring with up to five heteroatoms selected from atoms of oxygen, nitrogen and sulphur containing the main Deputy, selected from the substituents for Q above; and X, Y, R1, R2, R3, m, n and q have any of the values of the above or in this section relating to new specific compounds of the invention;

(c) Q is phenyl, indenyl, indanyl or fluorenyl, which optionally contain 1, 2 or 3 substituent selected from the substituents for Q, referred to here above; and X, Y, R1, R2, R3, m, n and q have any of the values of the above or in this section relating to new specific compounds of the invention;

(d) Q is phenyl or a heteroaromatic 5 - or 6-membered monocyclic ring or 9 - or 10-membered bicyclic ring with up to five heteroatoms selected from atoms of oxygen, nitrogen and sulphur containing the main Deputy, selected from amino, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino, amino-(C1-C6)alkyl, (C1-C6)alkylamino-(C1-C6)alkyl, di-[(C1-C6)alkyl]amino-(C1-C6)alkyl, amino-(C2-C6)alkoxy, (C1-C6)and is calamine-(C 2-C6)alkoxy, di-[(C1-C6)alkyl]amino-(C2-C6)alkoxy, amino-(C2-C6)alkylamino, (C1-C6)alkylamino-(C2-C6)alkylamino, di-[(C1-C6)alkyl]amino-(C2-C6)alkylamino,N-(C1-C6)alkylamino-(C2-C6)alkylamino,N-(C1-C6)alkyl-(C1-C6)alkylamino-(C2-C6)alkylamino,N-(C1-C6)alkyl, di-[(C1-C6)alkyl]amino-(C2-C6)alkylamino, amino-(C2-C6)alkanolamine, (C1-C6)alkylamino-(C2-C6)alkanolamine, di-[(C1-C6)alkyl]amino-(C2-C6)alkanolamine, heteroaryl, heteroaryl-(C1-C6)alkyl, heteroaryl-(C1-C6)alkoxy, heterocyclyl, heterocyclyl-(C1-C6)alkyl and heterocyclyl-(C1-C6)alkoxy, and where any heteroaryl or heterocyclyl group in the main Deputy on Q may optionally contain 1 or 2 substituent selected from a halogen, (C1-C6)alkyl, (C2-C6)alkanoyl, amino, (C1-C6)alkylamino and di-[(C1-C6)alkyl]amino; and X, Y, R1, R2, R3, m, n and q have any of the values of the above or in this section relating to new specific compounds of the invention;

(e) Q is predstavljaet phenyl or a heteroaromatic 5 - or 6-membered monocyclic ring or 9 - or 10-membered bicyclic ring with up to five heteroatoms, selected from atoms of oxygen, nitrogen and sulfur containing, optionally, 1, 2 or 3 substituent selected from hydroxy, halogen, trifloromethyl, cyano, nitro, amino, carboxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino, (C1-C6)alkoxycarbonyl, (C2-C6)alkanoyl, halogen-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, amino-(C1-C6)alkyl, (C1-C6)alkylamino-(C1-C6)alkyl, di-[(C1-C6)alkyl]amino-(C1-C6)alkyl, halogen-(C2-C6)alkoxy, hydroxy-(C2-C6)alkoxy, (C1-C6)alkoxy-(C2-C6)alkoxy, cyano-(C1-C6)alkoxy, carboxy-(C1-C6)alkoxy, (C1-C6)alkoxycarbonyl-(C1-C6)alkoxy, amino-(C2-C6)alkoxy, (C1-C6)alkylamino-(C2-C6)alkoxy, di-[(C1-C6)alkyl] amino-(C2-C6)alkoxy, pyridyl, imidazolyl, pyridyl-(C1-C6)alkyl, imidazolyl-(C1-C6)alkyl, pyridyl-(C1-C6)alkoxy, imidazolyl-(C1-C6)alkoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-(C1-C6)alkylpiperazine, 4-(C2-C6)alkanolamines is, pyrrolidinyl-(C1-C6)alkyl, piperidinyl-(C1-C6)alkyl, morpholinyl-(C1-C6)alkyl, piperazinil-(C1-C6)alkyl, 4-(C1-C6)alkylpiperazine-(C1-C6)alkyl, 4-(C2-C6)alkanolamine-(C1-C6)alkyl, pyrrolidinyloxy, piperidinyloxy, 1-(C1-C6)alkylpiperidines, pyrrolidinyl-(C2-C6)alkoxy, piperidinyl-(C2-C6)alkoxy, morpholinyl-(C2-C6)alkoxy, piperazinil-(C2-C6)alkoxy, 4-(C1-C6)alkylpiperazine-(C2-C6)alkoxy and 4-(C2-C6)alkanolamine-(C2-C6)alkoxy, or Q contains a Deputy (C1-C3)alkylenedioxy; and X, Y, R1, R2, R3, m, n and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(f) Q is phenyl, indenyl, indanyl, fluorenyl or heteroaromatic 5 - or 6-membered monocyclic ring with up to three heteroatoms selected from atoms of oxygen, nitrogen and sulfur containing, optionally, 1, 2 or 3 substituent selected from hydroxy, halogen, trifloromethyl, cyano, nitro, amino, carboxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylamino, di-[(C1-C6)is lcil]amino, (C1-C6)alkoxycarbonyl, (C2-C6)alkanoyl, (C1-C6)alkanolamine, (C1-C6)alkanesulfonyl,N-(C1-C6)alkyl-(C1-C6)alkanesulfonyl, phenyl, furil, teinila, azetidine, pyrroline, pyrrolidine, 1,1-dioxothiazolidine, piperidinyl, homopiperazine, morpholine, piperazinil, homopiperazine, pyrrolidinyl-(C1-C6)alkyl, piperidinyl-(C1-C6)alkyl, morpholinyl-(C1-C6)alkyl and piperazinil-(C1-C6)alkyl, and where any phenyl, furilla, thienyl or heterocyclyl group in the substituents on Q may optionally contain 1 or 2 substituent selected from a halogen, (C1-C6)alkyl, (C1-C6)alkoxy and (C2-C6)alkanoyl; and X, Y, R1, R2, R3, m, n and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(g) Q is phenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazoles, benzofurazanyl, hinely, ethanolic, hintline, honokalani or naphthyridine, which is optional, is the may contain 1 or 2 substituent, selected from the substituents listed above in paragraphs (b), (d) or (e); and X, Y, R1, R2, R3, m, n and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(h) Q is phenyl, 2 - or 3-furyl, 2 - or 3-thienyl, 2-, 4 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl, 2-, 4 - or 5-imidazolyl, 3 - or 4-pyrazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 2-, 3 - or 4-pyridyl, 3 - or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 2-, 3-, 5 - or 6-benzofuranyl, 2-, 3-, 5 - or 6-indolyl, 2-, 3-, 5 - or 6-benzothiazyl, 2-, 5 - or 6-benzoxazolyl, 2-, 5 - or 6-benzimidazolyl, 2-, 5 - or 6-benzothiazolyl, 3-, 5 - or 6-indazole, 5-benzofurazanyl, 2-, 3-, 6-or 7-chinolin, 3-, 6 - or 7-ethanolic, 2-, 6 - or 7-hintline, 2-, 6 - or 7-honokalani or 1.8-naphthiridine-2-yl or 1,8-naphthiridine-3-yl, which optionally contain 1 or 2 substituent selected from the substituents listed above in paragraphs (b), (d) or (e); and X, Y, R1, R2, R3, m, n and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(i) Q represents a heteroaromatic 5 - or 6-membered monocyclic ring or 9 - or 10-membered bicyclic ring or a 13 - or 14-membered tricyclic ring with up to five heteroatoms selected from atoms of oxygen, nitrogen and sulphur, soda is official optional 1, 2 or 3 substituent selected from hydroxy, halogen, trifloromethyl, cyano, nitro, amino, carboxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C3)alkylenedioxy, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino and (C1-C6)alkoxycarbonyl; and X, Y, R1, R2, R3, m, n and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(j) Q represents a heteroaromatic 13 - or 14-membered tricyclic ring with up to five heteroatoms selected from atoms of oxygen, nitrogen and sulfur containing, optionally, 1, 2 or 3 substituent selected from hydroxy, halogen, trifloromethyl, cyano, nitro, amino, carboxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C3)alkylenedioxy, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino and (C1-C6)alkoxycarbonyl; and X, Y, R1, R2, R3, m, n and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(k) Q represents furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazyl, benzoxazolyl, benzie azolyl, benzothiazolyl, indazoles, benzofurazanyl, hinely, ethanolic, hintline, honokalani, naphthyridine, carbazolyl, dibenzofurans, dibenzothiophenes or xantener, which optionally contain 1 or 2 substituent selected from the substituents listed above in paragraph (i); and X, Y, R1, R2, R3, m, n and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(l) Q is 1-, 2 - or 3-carbazolyl, 1-, 2-, 3 - or 4-dibenzofuran or 1-, 2-, 3 - or 4-dibenzothiophenes, which optionally contain 1 or 2 substituent selected from the substituents listed above in paragraph (i); and X, Y, R1, R2, R3, m, n and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(m) n is 0 and X, Y, R1, R3, Q, m and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(n) n is 1 and R2represents halogen or (C1-C6)-alkyl; and X, Y, R1, R3, Q, m and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(o) q is 0 and X, Y, R1, R2, R3, Q, m and n have any of the values of the above or in this section shall Le, related to specific new compounds of the invention;

(p) m is 1 and R1represents amino, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino, amino-(C1-C6)alkyl, (C1-C6)alkylamino-(C1-C6)alkyl, di-[(C1-C6)alkyl]amino-(C1-C6)alkyl, amino-(C2-C6)alkoxy, (C1-C6)alkylamino-(C2-C6)alkoxy, di-[(C1-C6)alkyl]amino-(C2-C6)alkoxy, amino-(C2-C6)alkylamino, (C1-C6)alkylamino-(C2-C6)alkylamino, di-[(C1-C6)alkyl]amino-(C2-C6)alkylamino,N-(C1-C6)alkylamino-(C2-C6)alkylamino,N-(C1-C6)alkyl-(C1-C6)alkylamino-(C2-C6)alkylamino,N-(C1-C6)alcalde-[(C1-C6)alkyl]amino-(C2-C6)alkylamino, heteroaryl, heteroaryl-(C1-C6)alkyl, heteroaryl-(C1-C6)alkoxy, heterocyclyl, heterocyclyl-(C1-C6)alkyl, heterocyclic or heterocyclic-(C1-C6)alkoxy, and where any heteroaryl or heterocyclyl group in the substituent R1may contain, optionally, 1 or 2 substituent selected from hydroxy, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C2 -C6)alkanoyl, amino, (C1-C6)alkylamino and di-[(C1-C6)alkyl]amino; and X, Y, R2, R3, Q, n and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(q) m is 1 and R1represents amino, (C1-C6)alkyl-amino, di-[(C1-C6)alkyl]amino, amino-(C1-C6)alkyl, (C1-C6)alkylamino-(C1-C6)alkyl, di-[(C1-C6)alkyl] amino-(C1-C6)alkyl, amino-(C2-C6)alkoxy, (C1-C6)alkylamino-(C2-C6)alkoxy, di-[(C1-C6)alkyl]amino-(C2-C6)alkoxy, amino-(C2-C6)alkylamino, (C1-C6)alkylamino-(C2-C6)alkylamino, di-[(C1-C6)alkyl] amino-(C2-C6)alkylamino,N-(C1-C6)alkylamino-(C2-C6)alkylamino,N-(C1-C6)alkyl-(C1-C6)alkylamino-(C2-C6)alkylamino,N-(C1-C6)alcalde-[(C1-C6)alkyl]amino-(C2-C6)alkylamino, pyridyl, imidazolyl, pyridyl-(C1-C6)alkyl, imidazolyl-(C1-C6)alkyl, pyridyl-(C1-C6)alkoxy, imidazolyl-(C1-C6)alkoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-(C1-C6)alkyle erzini, homopiperazine, 4-(C1-C6)acylhomoserine, 4-(C2-C6) alkanolamines, pyrrolidinyl-(C1-C6)alkyl, piperidinyl-(C1-C6)alkyl, morpholinyl-(C1-C6)alkyl, piperazinil-(C1-C6)alkyl, 4-(C1-C6)alkylpiperazine-(C1-C6)alkyl, 4-(C2-C6)alkanolamine-(C1-C6)alkyl, pyrrolidinyloxy, piperidinyloxy, 1-(C1-C6)alkylpiperidines, pyrrolidinyl-(C2-C6)alkoxy, piperidinyl-(C2-C6)alkoxy, morpholinyl-(C2-C6)alkoxy, piperazinil-(C2-C6)alkoxy, 4-(C1-C6)alkylpiperazine-(C2-C6)alkoxy or 4-(C2-C6)alkanolamine-(C2-C6)alkoxy; and X, Y, R2, R3, Q, n and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(r) m is 1 and R1represents hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, carboxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl or (C1-C6)alkoxy; and X, Y, R2, R3, Q, n and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(s) m equals 2, and first Deputy R1selected issuetitle, previously described in paragraph (q), and the second substituent R1selected from the substituents described earlier in paragraph (r); and X, Y, R2, R3, Q, n and q have any of the values of the above or in this section relating to particular new compounds of the invention;

(t) each of X and Y represents a CH group; and R1, R2, R3, Q, m, n and q have any of the values of the above or in this section relating to particular new compounds of the invention; and

(u) one or both of X and Y are N-group; and R1, R2, R3, Q, m, n and q have any of the values of the above or in this section relating to particular new compounds of the invention.

Special new compounds according to the second aspect of the invention are, for example, amide derivatives of the formula I or their pharmaceutically acceptable salts, where

(a) R3represents a halogen (such as fluorine, chlorine or bromine) or (C1-C6)alkyl (such as methyl, ethyl, propyl and isopropyl), preferably R3represents chlorine, methyl or ethyl, more preferably chlorine or methyl; and X, Y, R1, R2, Q, m, n and q have any of the above values.

A preferred compound according to the first aspect of the invention is an amide derivative of the formula I, where

X represents CH or N;

Y represents CH or N

R3represents hydrogen, fluorine, chlorine, bromine, methyl or ethyl;

m is 0, 1 or 2;

R1represents hydroxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3 aminopropoxy, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-aminoethylamino, 3 aminopropylene, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropyl 3 ethylenepropylene, 2-diethylaminoethylamine, 2-diethylaminoethylamine, 3 dimethylaminopropylamine, 3 diethylaminopropylamine,N-(2-amino-ethyl)-N-methylamino,N-(3-aminopropyl)-N-methylamino,N-(2-methylaminomethyl)-N-methylamino,N-(2-ethylaminomethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminomethyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, pyridyl, pyridylmethyl, pyridyloxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-methylpiperazine, homopiperazine, 4-IU is algomarine, 4-acetylpiperidine, pyrrolidinyl, piperidinylmethyl, morpholinylmethyl, piperidinylmethyl, 4-methylpiperazine, 4-acetylpiperidine, pyrrolidinyloxy, 1 methylpyrrolidinone, piperidinyloxy, 1 methylpiperidine, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinil) ethoxy, 3-(piperazinil)propoxy, 2-(4-methylpiperazine) ethoxy, 3-(4-methylpiperazine)propoxy, 2-(4-acetylpiperidine)ethoxy or 3-(4-acetylpiperidine)propoxy;

n is 0 or 1;

R2represents fluorine, chlorine, bromine, methyl or ethyl;

q 0;

Q represents phenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazoles, benzofurazanyl, hinely, ethanolic, hintline, honokalani or naphthyridine, which optionally contain 1 or 2 substituent selected from hydroxy, fluorine, chlorine, trifloromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3 hydroxypropoxy, 2-metoxi is hydroxy, 2 ethoxyethoxy, 3 methoxypropane, 3 ethoxypropane, 2-aminoethoxy, 3 aminopropoxy, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, pyridyl, pyridylmethyl, pyridyloxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-methylpiperazine, homopiperazine, 4-methylhomopiperazine, 4-acetylpiperidine, pyrrolidinyl, piperidinylmethyl, morpholinylmethyl, piperidinylmethyl, 4-methylpiperazine, 4-acetylpiperidine, pyrrolidinyloxy, 1-methylpyrrolidinone, piperidinyloxy, 1-methyl-piperidinyloxy, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinil)ethoxy, 3-(piperazinil)propoxy, 2-(4-methylpiperazine)ethoxy, 3-(4-methylpiperazine)propoxy, 2-(4-acetylpiperidine)ethoxy and 3-(4-acetylpiperidine)propoxy;

or its pharmaceutically acceptable salt.

Another preferred compound according to the first aspect of the invention is an amide derivative of the formula I, where

X represents CH;

Y represents CH or N;

R3represents hydrogen, chlorine or methyl;

m is 0, 1 or 2;

R1represents hydroxy, fluorine, chlorine, bromine, crypto is methyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3 aminopropoxy, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-aminoethylamino, 3 aminopropylene, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 ethylenepropylene, 2-diethylaminoethylamine, 2-diethylaminoethylamine, 3 dimethylaminopropylamine, 3 diethylaminopropylamine,N-(2-amino-ethyl)-N-methylamino,N-(3-aminopropyl)-N-methylamino,N-(2-methylaminomethyl)-N-methylamino,N-(2-ethylaminomethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminomethyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, 2-pyridyl-methyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridyloxy, 3 pyridyloxy, 4-pyridyloxy, pyrrolidin-1-yl, piperidino, morpholino, piperazine-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazine-1-yl, 4-acetyl-piperazine-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morph is linoleyl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperidine-1-ylmethyl, pyrrolidin-3-yloxy, 1 methylpyrrolidine-3-yloxy, piperidine-4-yloxy, 1 methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-piperazine-1-ylethoxy, 3-piperazine-1 ipropose, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperidine-1-yl)-ethoxy or 3-(4-acetylpiperidine-1-yl)propoxy;

n 0;

q is equal to 0, and

Q represents phenyl, 2-furyl, 2-thienyl, 4-oxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-isothiazole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-benzofuranyl, 2-indolyl, 2-benzothiazyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-benzothiazolyl, 4-benzofuranyl, 2-chinolin, 6-chinolin, 7-chinolin, 3-ethanolic, 6-hintline, 7-hintline, 6-honokalani or 7-honokalani, which optionally contain 1 or 2 substituent selected from hydroxy, fluorine, chlorine, trifloromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3 hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3 methoxypropane, 3 ethoxypropane, 2-aminoethoxy, 3 aminopropoxy, 2-methylaminoethanol, 2-ethylaminoethanol is, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridyloxy, 3 pyridyloxy, 4-pyridyloxy, pyrrolidin-1-yl, piperidino, morpholino, piperazine-1-yl, 4-methyl-piperazine-1-Il, homopiperazin-1-yl, 4-methylhomopiperazine-1-yl, 4-acetylpiperidine-1-yl, pyrrolidinyl, piperidinomethyl, morpholinomethyl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperidine-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylindolin-3-yloxy, piperidine-4-yloxy, 1 methylpiperidin-4-yloxy, 2-pyrrolidin-1 ylethoxy, 3-pyrrolidin-1 ipropose, 2-piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-piperazine-1 ylethoxy, 3-piperazine-1-ylpropionic, 2-(4-methyl-piperazine-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl) propoxy, 2-(4-acetylpiperidine-1-yl)ethoxy and 3-(4-acetylpiperidine-1-yl)-propoxy;

or its pharmaceutically acceptable salt.

Another preferred compound according to the first aspect of the invention is an amide derivative of the formula I,

where X represents CH;

Y represents CH or N;

R3represents hydrogen, chlorine or methyl;

m is 0, 1 or 2;

R1represents hydroxy, fluorine, chlorine, bromine, trifluoromethyl, tzia is about, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3 aminopropoxy, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-aminoethylamino, 3 aminopropylene, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 ethylenepropylene, 2-diethylaminoethylamine, 2-diethylaminoethylamine, 3 dimethylaminopropylamine, 3 diethylaminopropylamine,N-(2-amino-ethyl)-N-methylamino,N-(3-aminopropyl)-N-methylamino,N-(2-methylaminomethyl)-N-methylamino,N-(2-ethylaminomethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminomethyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridyloxy, 3 pyridyloxy, 4-pyridyloxy, pyrrolidin-1-yl, piperidino, morpholino, piperazine-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazine-1-yl, 4-acetylpiperidine-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinol the sludge, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperidine-1-ylmethyl, pyrrolidin-3-yloxy, 1 methylpyrrolidine-3-yloxy, piperidine-4-yloxy, 1 methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-piperazine-1-ylethoxy, 3-piperazine-1 ipropose, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperidine-1-yl)ethoxy or 3-(4-acetylpiperidine-1-yl)propoxy;

n 0;

q is equal to 0, and

Q represents phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, which optionally contain 1 or 2 substituent selected from hydroxy, fluorine, chlorine, trifloromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3 hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3 methoxypropane, 3 ethoxypropane, 2-aminoethoxy, 3 aminopropoxy, 2 methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridyloxy, 3 pyridyloxy, 4-pyridyloxy, pyrrol the DIN-1-yl, piperidino, morpholino, piperazine-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazine-1-yl, 4-acetylpiperidine-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazine-1-ylmethyl, 4-methyl-piperazine-1-ylmethyl, 4-acetylpiperidine-1-ylmethyl, pyrrolidin-3-yloxy, 1 methylpyrrolidine-3-yloxy, piperidine-4-yloxy, 1 methylpiperidin-4-yloxy, 2-pyrrolidin-1 ylethoxy, 3-pyrrolidin-1 ipropose, 2-piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-piperazine-1-ylethoxy, 3-piperazine-1-ylpropionic, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperidine-1-yl)ethoxy and 3-(4-acetylpiperidine-1-yl)propoxy;

or its pharmaceutically acceptable salt.

Another preferred compound according to the first aspect of the invention is an amide derivative of the formula I,

where X represents CH;

Y represents CH or N;

R3represents hydrogen, chlorine or methyl;

m is 1 or 2;

R1represents hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, dimethylaminomethyl, diethylaminomethyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-dimethylamino-2-hydroxypropoxy, 3 diethylamino-2-hydroxypropoxy, 2-aminoethylamino, 3 aminopropylene, 4-aminoethylamino, 3-methylaminopropyl is, 2 diethylaminoethylamine, 2-diethylaminoethylamine, 3 dimethylaminopropylamine, 4-diethylaminoethylamine, 3-amino-2-hydroxypropylamino, 3-dimethylamino-2-hydroxypropylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazine-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, homopiperazin-1-yl, 4-methylhomopiperazine-1-yl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazine-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidine-1-ylmethyl, 3-hydroxypyrrolidine-1-ylmethyl, 4-(2-hydroxyethyl)piperazine-1-ylmethyl, pyrrolidin-3-yloxy, 1 methylpyrrolidine-3-yloxy, piperidine-4-yloxy, 1 methylpiperidin-4-yloxy, 1-benzylpiperidine-4-yloxy, 2-pyrrolidin-1 ylethoxy, 3-pyrrolidin-1 ipropose, 2-piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-piperazine-1-ylethoxy, 3-piperazine-1 ipropose, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-hydroxy-3-pyrrolidin-1 ipropose, 2-hydroxy-3-piperidinyloxy, 2-hydroxy-3-morpholinopropan, piperidine-4-ylamino, 1 methylpiperidin-4-ylamino, 1-benzylpiperidine-4-ylamino, 2-pyrrolidin-1 ylethylamine, 3-pyrrolidin-1 iproplatin, 2-morpholinoethyl 3 morpholinopropan, 2-piperidinoethyl, 3-piperid is Dobropillya, 2-piperazine-1-ylpropionic, 3-piperazine-1-ylpropionic, 2-(4-methylpiperazin-1-yl)ethylamino, 3-(4-methylpiperazin-1-yl)propylamino, 2-(1-methylpyrrolidine-2-yl)ethylamino, 3-(1-methylpyrrolidine-2-yl) propylamino, 2-diethylaminoethylamine, 3-dimethylaminopropylamine, 3-dimethylamino-2,2-dimethylpropylene, 2-(1-methylpyrrolidine-2-retil)aminomethyl, 3-pyrrolidin-1-improvisationally, 2-morpholinomethyl, 3-morpholinepropanesulfonic, 2-piperazine-1-ylethylamine, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl or 2-pyridyloxy;

n 0;

q is equal to 0, and

Q is 2-pyridyl, 3-pyridyl or 4-pyridyl, which optionally contain a Deputy selected from pyrrolidin-1-yl, 3-hydroxypyrrolidine-1-yl, 2-hydroxyethylpyrrolidine-1-yl, morpholino, piperidino, 4-hydroxypiperidine-1-yl, piperazine-1-yl and 4-methylpiperazin-1-yl;

or its pharmaceutically acceptable salt.

A particularly preferred compound according to the first aspect of the invention is an amide derivative of the formula I,

where X represents CH;

Y represents CH or N;

R3represents hydrogen, chlorine or methyl;

m is 1 and R1selected from diethylaminomethyl,N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazine-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, homepipe the Zin-1-yl, 4-methylhomopiperazine-1-yl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-methylhomopiperazine-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidine-1-ylmethyl, 3-hydroxypyrrolidine-1-ylmethyl, pyrrolidin-3-yloxy, pyrrolidin-4-yloxy, 2-pyrrolidin-1 ylethoxy, 2-piperidinoethyl, 2-morpholinoethoxy, 3-dimethylaminopropylamine, 3-dimethylamino-2,2-dimethyl-propylaminoethyl, 2-(1-methylpyrrolidine-2-ileti)aminomethyl, 3-pyrrolidin-1-improvisational, 2-morpholinoethyl-methyl, 3-morpholinepropanesulfonic, 2-piperazine-1-ylethylamine, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl and 2 pyridyloxy;

n 0;

q is equal to 0, and

Q is 3-pyridyl or 4-pyridyl, which optionally contain a Deputy selected from pyrrolidin-1-yl, morpholino, piperidino, piperazine-1-yl and 4-methylpiperazin-1-yl;

or its pharmaceutically acceptable salt.

Another particularly preferred compound according to the first aspect of the invention is an amide derivative of the formula I,

where X represents CH;

Y represents CH or N;

R3represents hydrogen, chlorine or methyl;

m is 1 and R1isN-(3-dimethylaminopropyl)-N-methylamino, 4-methylpiperazin-1-yl, 4-methylhomopiperazine-1-yl, 4-methylpiperazin-1-ylmethyl or pyrrolidin-3-yloxy;

n 0;

q is equal to 0, and

Q is 2-Mohali opioid-4-yl;

or its pharmaceutically acceptable salt.

Specific preferred compounds of the invention are, for example,

N-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)benzamide,

N-[6-(4-ethylpiperazin-1-yl)pyrid-3-yl]-2-chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzamide,

N-[6-(4-methylpiperazin-1-yl)pyrid-3-yl]-2-chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzamide or

N-{6-[N-(3-dimethylaminopropyl)-N-methylamino]pyrid-3-yl}-2-chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzamide;

or their pharmaceutically acceptable salts.

A preferred compound according to the second aspect of the invention is an amide derivative of the formula I,

where X represents CH or N;

Y represents CH or N;

R3represents fluorine, chlorine, bromine, methyl or ethyl;

m is 0, 1 or 2;

R1represents hydroxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, methyl, ethyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3 aminopropoxy, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-aminoethylamino, 3 aminopropylene, 2-IU is iluminatului, 2 Ethylenediamine, 3 methylaminopropane, 3 ethylenepropylene, 2-diethylaminoethylamine, 2-diethylaminoethylamine, 3 dimethylaminopropylamine, 3 diethylaminopropylamine,N-(2-amino-ethyl)-N-methylamino,N-(3-aminopropyl)-N-methylamino,N-(2-methylaminomethyl)-N-methylamino,N-(2-ethylaminomethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminomethyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, pyridyl, pyridylmethyl, pyridyloxy, 3-pyrroline, pyrrolidine, piperidinyl, homopiperazine, morpholine, piperazinil, 4-methylpiperazine, 4-ethylpiperazine, homopiperazine, 4-methylhomopiperazine, 4-acetylpiperidine, pyrrolidinyl, piperidinylmethyl, morpholinylmethyl, piperidinylmethyl, 4-methylpiperazine, homopiperazine, 4-methylhomopiperazine, 4-acetylpiperidine, pyrrolidinyloxy, 1 methylpyrrolidinone, piperidinyloxy, 1 methylpiperidine, homopiperazine, 1 methylhomopiperazine, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinil)ethoxy, 3-(piperazinil)propox is, 2-(4-methylpiperazine)ethoxy, 3-(4-methylpiperazine)propoxy, 2-(4-acetylpiperidine)ethoxy, 3-(4-acetylpiperidine)propoxy, 3-dimethylaminopropylamine, 3-dimethylamino-2,2-dimethylpropylene, 2-(1-methylpyrrolidinyl)aminomethyl, 3-pyrrolidinylcarbonyl, 2-morpholinylmethyl, 3-morpholinylmethyl, 2-piperidinylmethyl, 3-(4-methylpiperazine)aminomethyl, pyridyloxy, imidazolylidene, thiazoleacetate and 2 methylthiazolidine;

n is 0 or 1;

R2represents fluorine, chlorine, bromine, methyl or ethyl;

q is equal to 0, and

Q represents phenyl, indenyl, indanyl, tetrahydronaphtyl, fluorenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazoles, benzofurazanyl, hinely, ethanolic, hintline, honokalani, naphthyridine, carbazolyl, dibenzofurans, dibenzothiazyl or xantener, which optionally contain 1 or 2 substituent selected from hydroxy, fluorine, chlorine, trifloromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopentyloxy, methylendioxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, methanesulfonamido,N-matilla is sulfonamide, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3 hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3 methoxypropane, 3 ethoxypropane, 2-aminoethoxy, 3 aminopropoxy, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, phenyl, furil, teinila, pyridyl, pyridylmethyl, pyridyloxy, azetidine, 3-pyrroline, pyrrolidine, piperidinyl, homopiperazine, morpholine, the piperazinil, 4-methylpiperazine, homopiperazine, 4-methylhomopiperazine, 4-acetylpiperidine, pyrrolidinyl, piperidinylmethyl, morpholinylmethyl, piperidinylmethyl, 4-methylpiperazine, 4-acetylpiperidine, pyrrolidinyloxy, 1 methylpyrrolidinone, piperidinyloxy, 1 methylpiperidine, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinil)ethoxy, 3-(piperazinil)propoxy, 2-(4-methylpiperazine)ethoxy, 3-(4-methylpiperazine)propoxy, 2-{4-acetylpiperidine)ethoxy and 3-(4-acetyl-piperazinil)propoxy, and where any phenyl, furilla, thienyl, perederina or heterocyclyl group Deputy Q may optionally contain 1 Il the 2 Deputy selected from fluorine, chlorine, methyl and methoxy;

or its pharmaceutically acceptable salt.

Another preferred compound according to the second aspect of the invention is an amide derivative of the formula I, where

X represents CH;

Y represents CH or N;

R3represents chlorine or methyl;

m is 0, 1 or 2;

R1represents hydroxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3 aminopropoxy, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-aminoethylamino, 3 aminopropylene, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropyl 3 ethylenepropylene, 2-diethylaminoethylamine, 2-diethylaminoethylamine, 3 dimethylaminopropylamine, 3 diethylaminopropylamine,N-(2-amino-ethyl)-N-methylamino,N-(3-aminopropyl)-N-methylamino,N-(2-methylaminomethyl)-N-methylamino,N-(2-ethylaminomethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminomethyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-<> N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridyloxy, 3 pyridyloxy, 4-pyridyloxy, pyrrolidin-1-yl, piperidino, morpholino, piperazine-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-acetylcoumarin-1-yl, 4-acetylpiperidine-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetyl-piperazine-1-ylmethyl, pyrrolidin-3-yloxy, 1 methylpyrrolidine-3-yloxy, piperidine-4-yloxy, 1 methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-piperazine-1-ylethoxy, 3-piperazine-1-yl-propoxy, 2-(4-methylpiperazin-1-Il)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperidine-1-yl)ethoxy or 3-(4-acetylpiperidine-1-yl)propoxy;

n 0;

q is equal to 0, and

Q represents phenyl, 2-furyl, 2-thienyl, 4-oxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-isothiazole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-benzofuranyl, 2-indolyl, 2-benzothiazyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-benzothiazolyl, 4-benzo-furutani, 2-chinolin, 6-chinolin, 7-chinolin, 3-ethanolic, 6-hintline, 7-hintline or 7-honokalani that, optionally contain 1 or 2 substituent selected from hydroxy, fluorine, x is ora, trifloromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3 hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3 methoxypropane, 3 ethoxypropane, 2-aminoethoxy, 3 aminopropoxy, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridyloxy, 3 pyridyloxy, 4-pyridyloxy, pyrrolidin-1-yl, piperidino, morpholino, piperazine-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazine-1-yl, 4-acetylpiperidine-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperidine-1-ylmethyl, pyrrolidin-3-yloxy, 1 methylpyrrolidine-3-yloxy, piperidine-4-yloxy, 1 methylpiperidin-4-yloxy, 2-pyrrolidin-1 ylethoxy, 3-pyrrolidin-1 ipropose, 2-piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-piperazine-1-ylethoxy, 3-piperazine-1-ylpropionic, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperidine-1-yl)ethoxy and 3-(4-acety the piperazine-1-yl)propoxy;

or its pharmaceutically acceptable salt.

Another preferred compound according to the second aspect of the invention is an amide derivative of the formula I, where

X represents CH;

Y represents CH or N;

R3represents chlorine or methyl;

m is 0, 1 or 2;

R1represents hydroxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3 aminopropoxy, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminoethoxy, 2-aminoethylamino, 3 aminopropylene, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropyl 3 ethylenepropylene, 2-diethylaminoethylamine, 2-diethylaminoethylamine, 3 dimethylaminopropylamine, 3 diethylaminopropylamine,N-(2-amino-ethyl)-N-methylamino,N-(3-aminopropyl)-N-methylamino,N-(2-methylaminomethyl)-N-methylamino,N-(2-ethylaminomethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminomethyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl is)- N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridyloxy, 3 pyridyloxy, 4-pyridyloxy, pyrrolidin-1-yl, piperidino, morpholino, piperazine-1-yl, 4-methylpiperazin-1-yl, homepipe-Razin-1-yl, 4-methylhomopiperazine-1-yl, 4-acetylpiperidine-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperidine-1-ylmethyl, pyrrolidin-3-yloxy, 1 methylpyrrolidine-3-yloxy, piperidine-4-yloxy, 1 methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-piperazine-1-ylethoxy, 3-piperazine-1-ylpropionic, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperidine-1-yl)ethoxy or 3-(4-acetylpiperidine-1-yl)propoxy;

n 0;

q is equal to 0, and

Q represents phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, which optionally contain 1 or 2 substituent selected from hydroxy, fluorine, chlorine, trifloromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3 hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3 methoxypropane, 3-e is oxopropoxy, 2 aminoethoxy, 3 aminopropoxy, 2-methylaminoethanol, 2-ethylaminoethanol, 3 methylaminopropane, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridyloxy, 3 pyridyloxy, 4-pyridyloxy, pyrrolidin-1-yl, piperidino, morpholino, piperazine-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazine-1-yl, 4-acetylpiperidine-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperidine-1-ylmethyl, pyrrolidin-3-yloxy, 1 methylpyrrolidine-3-yloxy, piperidine-4-yloxy, 1-methyl-piperidine-4-yloxy, 2-pyrrolidin-1 ylethoxy, 3-pyrrolidin-1 ipropose, 2 piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-piperazine-1-ylethoxy, 3-piperazine-1-ylpropionic, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperidine-1-yl)ethoxy and 3-(4-acetylpiperidine-1-yl)propoxy;

or its pharmaceutically acceptable salt.

Another preferred compound according to the second aspect of the invention is an amide derivative of the formula I, where

X represents CH;

Y represents CH or N;

R3represents chlorine or methyl;

m is 1 or 2;

R1represents hydroxy, fluorine, chlorine, methyl, ethyl, propyl, methoxy, dimethylaminomethyl, diethylaminomethyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminoethoxy, 3-dimethylamino-2-hydroxypropoxy, 3 diethylamino-2-hydroxypropoxy, 2-aminoethylamino, 3 aminopropylene, 4-aminoethylamino, 3 methylaminopropyl, 2-diethylaminoethylamine, 2-diethylaminoethylamine, 3 dimethylaminopropylamine, 4-diethylaminoethylamine, 3-amino-2-hydroxypropylamino, 3-dimethylamino-2-hydroxypropylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazine-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, homopiperazin-1-yl, 4-methylhomopiperazine-1-yl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazine-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidine-1-ylmethyl, 3-hydroxypyrrolidine-1-ylmethyl, 4-(2-hydroxyethyl)piperazine-1-ylmethyl, pyrrolidin-3-yloxy, 1 methylpyrrolidine-3-yloxy, piperidine-4-yloxy, 1 methylpiperidin-4-yloxy, 1-benzoperylene-4-yloxy, 2-pyrrolidin-1 ylethoxy, 3-pyrrolidin-1 ipropose, 2-piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-piperazine-1-ylethoxy, 3-piperazine-1 ipropose, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)PR is poxi, 2-hydroxy-3-pyrrolidin-1 ipropose, 2-hydroxy-3-piperidinyloxy, 2-hydroxy-3-morpholinopropan, piperidine-4-ylamino, 1 methylpiperidin-4-ylamino, 1-benzylpiperidine-4-ylamino, 2-pyrrolidin-1 ylethylamine, 3-pyrrolidin-1 iproplatin, 2-morpholinoethyl, 3 morpholinopropan, 2-piperidinoethyl, 3-piperidino-propylamino, 2-piperazine-1-ylpropionic, 3-piperazine-1-ylpropionic, 2-(4-methylpiperazin-1-yl)ethylamino, 3-(4-methylpiperazin-1-yl)propylamino, 2-(1-methylpyrrolidine-2-yl)ethylamino, 3-(1-methylpyrrolidine-2-yl)propylamino, 2-diethylaminoethylamine, 3-dimethylaminopropylamine, 3-dimethylamino-2,2-dimethylpropylene, 2-(1-methylpyrrolidine-2-retil)aminomethyl, 3-pyrrolidin-1-improvisationally, 2-morpholinomethyl, 3-morpholinepropanesulfonic, 2-piperazine-1-ylethylamine, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl or 2-pyridyloxy;

n 0;

q is equal to 0, and

Q is 2-pyridyl, 3-pyridyl or 4-pyridyl, which contains a Deputy selected from pyrrolidin-1-yl, 3-hydroxypyrrolidine-1-yl, 2-hydroxyethylpyrrolidine-1-yl, morpholino, piperidino, 4-hydroxypiperidine-1-yl, piperazine-1-yl and 4-methylpiperazin-1-yl;

or its pharmaceutically acceptable salt.

A particularly preferred compound according to the second aspect of the invention is an amide derivative of the formula I, where

X represents CH;

Y represents CH or N;

R3represents chlorine or methyl;

m is 1 and R1selected from diethylaminomethyl,N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazine-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazine-1-yl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-methylhomopiperazine-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidine-1-ylmethyl, 3-hydroxypyrrolidine-1-ylmethyl, pyrrolidin-3-yloxy, piperidine-4-yloxy 2-pyrrolidin-1 ylethoxy, 2-piperidinoethyl, 2-morpholinoethoxy, 3-dimethylaminopropylamine, 3-dimethylamino-2,2-dimethylpropylene, 2-(1-methylpyrrolidine-2-retil)aminomethyl, 3-pyrrolidin-1-improvisational, 2-morpholinosydnonimine, 3-morpholinepropanesulfonic, 2-piperazine-1-ylethylamine, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl and 2 pyridyloxy;

n 0;

q is equal to 0, and

Q is 3-pyridyl or 4-pyridyl, which contains a Deputy selected from pyrrolidin-1-yl, morpholino, piperidino, piperazine-1-yl and 4-methylpiperazin-1-yl;

or its pharmaceutically acceptable salt.

Another particularly preferred compound according to the second aspect of the invention is an amide derivative of the formula , where

X represents CH;

Y represents CH or N;

R3represents chlorine or methyl;

m is 1 and R1selected from diethylaminomethyl,N-(2-di-methylaminomethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino, homopiperazin-1-yl, piperazine-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazine-1-yl, piperazine-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazine-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidine-1-ylmethyl, 3-hydroxypyrrolidine-1-ylmethyl, pyrrolidin-3-yloxy,N-methylpyrrolidine-3-yloxy, piperidine-4-yloxy,N-methylpiperidin-4-yloxy, homopiperazin-4-yloxy,N-methylhomopiperazine-4-yloxy, 2-pyrrolidin-1 ylethoxy, 2-piperidinoethyl, 2-morpholinoethoxy, 3-dimethylaminopropylamine, 3-dimethylamino-2,2-dimethylpropylene, 2-(1-methylpyrrolidine-2-retil)aminomethyl, 3-pyrrolidin-1-improvisational, 2-morpholinosydnonimine, 3-morpholinepropanesulfonic, 2-piperazine-1-ylethylamine, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl, 2-pyridyloxy, 4-thiazoleacetate and 2-methylthiazole-4-ylethoxy;

n 0;

q is equal to 0, and

Q represents phenyl containing 1 or 2 substituent selected from fluorine, chlorine, trifloromethyl, methoxy,cyclopentyloxy, acetamido,N-methylmethanesulfonamide, 2-furil, azetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino, homopiperazine, piperazine-1-Il, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylhomopiperazine-1-yl;

or Q is 1-fluorenyl or 4-dibenzofuran, or Q is 3-pyridyl or 4-pyridyl, which contains a Deputy selected from azetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino, homopiperazine, piperazine-1-Il, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylhomopiperazine-1-yl;

or its pharmaceutically acceptable salt.

Another particularly preferred compound according to the second aspect of the invention is an amide derivative of the formula I, where

X represents CH;

Y represents CH or N;

R3represents chlorine or methyl;

m is 1 and R1isN-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-methylhomopiperazine-1-yl or 4-methylpiperazin-1-ylmethyl;

n 0;

q is equal to 0, and

Q is 2-(pyrrolidin-1-yl)pyrid-4-yl, 2-(3-pyrrolin-1-yl)pyrid-4-yl, 2-piperidinomethyl-4-yl, 2-morpholinomethyl-4-yl, 1-fluorenyl, dibenzofuran-4-yl, 3-acetamidophenyl or 3-(2-furyl)phenyl;

or its pharmaceutically acceptable salt.

More particularly n is edocfile connection according to the second aspect of the invention is an amide derivative of the formula I, where

X represents CH;

Y represents CH or N;

R3represents chlorine or methyl;

m is 1 and R1isN-(3-dimethylaminopropyl)-N-methylamino, 4-methylpiperazin-1-yl, 4-methylhomopiperazine-1-yl or 4-methylpiperazin-1-ylmethyl;

n 0;

q is equal to 0, and

Q is 2-morpholinomethyl-4-yl;

or its pharmaceutically acceptable salt.

Derived amide of formula I or its pharmaceutically acceptable salt or its cleaved in vivo ester can be obtained by any known method, which is used for production of chemically related compounds. Such methods are used to obtain a new amide derivative of the formula I, is given as another feature of the invention and are illustrated by the following typical variations of ways in which, unless otherwise stated, X, Y, R1, R2, R3, m, n, q and Q have any of these values. The necessary starting materials can be obtained by standard methods of organic chemistry. The receipt of such starting compounds are described in connection with the following characteristic variations of the methods described in the examples. Alternatively, the necessary source materials produced by methods (similar to the illustrated methods), standard for professionals in the field of organic chemistry.

(a) Compound of formula I or its Pharma is efticiency acceptable salt, or cleaved in vivo ester can be obtained by the interaction of aniline of the formula II

with a benzoic acid of formula III or its activated derivative

in standard conditions of formation of amide linkages, where the changing of the groups have the meanings indicated above, and where any functional group is optionally protected,

(i) removing any protective groups; and

(ii) optional, education pharmaceutically acceptable salt or cleaved in vivo complex ether.

Suitable reactive derivative of carboxylic acid of the formula III is, for example, allalone, such as acyl chloride formed by the reaction of interaction between the acid and the acid chloride inorganic acid, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of interaction between acid and chloroformiate, such as isobutylparaben; and an active ester, for example an ester formed by the interaction of the acid with a phenol such as pentafluorophenol, complex ether, such as pentaftorosilikata, or with alcohol, such asN-hydroxybenzotriazole; acylated, such as azide formed by the interaction of the acid and azide such as diphenylphosphoryl; achilleid, such as cyanide, education is the interaction of acid and cyanide, such as diethylphosphoramidite; or the product of the interaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide.

Standard conditions for the formation of amide linkages typically include the presence of a suitable base, such as, for example, carbonate, alkoxide, hydroxide or hydride of an alkaline or alkaline-earth metal, for example sodium carbonate, potassium carbonate, ethoxide sodium, butoxide potassium, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an ORGANOMETALLIC base such as alkylate, for example n-utility, or dialkylaminomethyl, such as sitedisability, or, for example, an organic amine, such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, research or diazabicyclo [5.4.0]undec-7-ene.

Interaction is also carried out, preferably, in a suitable inert solvent or diluent, such as, for example, methanol, ethanol, tetrahydrofuran, methylene chloride, 1,2-dimethoxyethan,N,N-dimethylformamide,N,N-dimethylacetamide,N-methylpyrrolidine-2-it, dimethylsulfoxide or acetone, and at a temperature in the range of, for example, 0-100°C, preferably at ambient temperature or close to it.

As a rule, carbodiimide reagent combination used in the presence of an organic solution of the dye (preferably, anhydrous polar aprotic organic solvent) at low temperatures, for example in the range from -10 to 40°Since, as a rule, when the ambient temperature is about 20°C.

Typical standard conditions for the formation of amide linkages include activating carboxypropyl, for example, by treatment with halogen-containing reagent (e.g., oxalylamino) with the formation of allhelgona, in an organic solvent at ambient temperature and subsequent interaction of the activated compound with aniline. If necessary to protect any functional group and remove the protective group. Suitable use of carbodiimide reagent combinations in the presence of an organic solvent (preferably anhydrous polar aprotic organic solvent) at low temperatures, for example in the range from -10 to 40°Since, as a rule, when the ambient temperature is about 20°C.

Protective group, as a rule, you can choose from any of the groups described in the literature or known to specialists as appropriate to protect the interest of the group, and you can enter them in the usual ways. The protective group can be removed with a suitable method described in the literature or known in the art as suitable for the removal of the protective group of the stand is engaged interest groups, moreover, such methods chosen to carry out the removal of the protective group with minimal impact on other groups present in the molecule.

Specific examples of the protective groups is shown for convenience, where "lower", as for example, in the definition of "lower alkyl", means that the group belongs to the definition, contains, preferably, 1-4 carbon atoms. It should be borne in mind that these examples are not exhaustive. Below are specific examples of methods for removing protective groups is not exhaustive. The use of protective groups and methods of removal are not specifically mentioned protective groups, of course, also included in the scope of the invention.

The protective group for carboxypropyl may be a remnant afrobrazil aliphatic or arylaliphatic alcohol or afrobrazil of silanol (moreover, these alcohol or silanol combined with caffeine, preferably containing 1-20 carbon atoms). Examples of the carboxy protective groups are linear or branched (C1-C12)alkyl groups (for example, isopropyl, tert-butyl); (lower alkoxy) (lower alkyl) group (for example, methoxymethyl, ethoxymethyl, isobutoxide); (lower aliphatic, acyloxy) (lower alkyl) group (for example, acetoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl) (lower alkoxycarbonyl) (lower alkyl) group (for example, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl); aryl(lower alkyl) group (for example, benzyl,p-methoxybenzyl,about-nitrobenzyl,p-nitrobenzyl, benzhydryl and phthalidyl); three(lower alkyl) silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); three(lower alkyl) silyl-(lower alkyl) group (for example, trimethylsilylmethyl) and (C2-C6)alkeneamine group (for example, allyl and vinylaryl). Methods that are suitable, in particular, for removal of the carboxy protective groups include, for example, acidic and basically catalyzed by the metal or enzyme hydrolysis.

Examples of the hydroxy protective groups are lower alkyl groups (for example,tert-butyl), lower alkeneamine group (e.g. allyl); lower alcoholnye groups (for example acetyl); lower alkoxycarbonyl group (for example,tert-butyloxycarbonyl); lower altneratively group (for example, allyloxycarbonyl); aryl-(lower alkoxycarbonyl) group (for example, benzyloxycarbonyl,p-methoxybenzeneboronic,about-nitrobenzisoxazole,p-nitrobenzenesulfonyl); three(lower alkyl)-silili (for example, trimethylsilyl,tert-butyldimethylsilyl) and aryl(lower alkyl) (e.g., benzyl) group.

Examples of amino protective groups are formyl, kalkilya group (for example, gasoline and substituted benzyl, p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl and triphenylmethyl); di-p-anthimeria and purimetla group; a lower alkoxycarbonyl (for example,tert-butyloxycarbonyl); lower alkenylbenzenes (for example, allyloxycarbonyl); aryl (lower alkoxycarbonyl) group (for example, benzyloxycarbonyl,p-methoxybenzeneboronic,about-nitrobenzisoxazole,p-nitrobenzenesulfonyl); trialkylsilyl (for example, trimethylsilyl andtert-butyldimethylsilyl); alkylidene (for example, methylidene); benzylidene and substituted benzylidene group.

Methods appropriate for removal of hydroxy and amino protective groups include, for example, acidic and alkaline catalyzed by the metal or enzyme hydrolysis for bands such asp-nitrobenzisoxazole, hydrogenation in the case of groups such as benzyl, and photolytic cleavage in the case of groups such asabout-nitrobenzisoxazole.

You should contact Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & Sons, 1992, as General guidance on the interaction conditions and reagents, and Protective Groups in Organic Synthesis, 2nd Edition, by Green et al., published by John Wiley & Sons, as a General guide protective groups.

Benzoic acid of formula III can be obtained by splitting its corresponding ester, which, in turn, can be obtained by the interaction of nilina formula IV

where R is, for example, nishiuchi or benzyl,

with a carboxylic acid of formula V or its activated derivative indicated earlier,

under standard amide formation conditions, specified above, where the changing of the groups have the meanings indicated above, and where the functional group is optionally protected.

(b) a Compound of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo ether, can be obtained by the interaction of aniline of the formula VI

with a carboxylic acid of formula V or its reactive derivative mentioned above,

under standard amide formation conditions, specified above, where the changing of the groups have the meanings indicated above, and where the functional group is optionally protected, and

(i) removing any protective groups; and

(ii) optional, education pharmaceutically acceptable salt or cleaved in vivo ether.

Aniline of the formula VI can be obtained by recovery of the corresponding nitrobenzene of the formula VII

where changing groups have the meanings indicated above, and where the functional group is optionally protected.

Typical slavestate during recovery include the use of ammonium formate or hydrogen gas in the presence of a catalyst, for example, a metal catalyst such as palladium-on-charcoal grill. Alternatively, you can perform the recovery of metal by dissolving, for example, using iron in the presence of acids, for example inorganic or organic acids, such as hydrochloric, Hydrobromic, sulfuric or acetic acid. Interaction is good to exercise in the presence of an organic solvent (preferably, proton polar solvent and, preferably, while heating, for example, up to about 60°C. If necessary, to protect any functional group and otscheplaut protective group.

The nitrobenzene of the formula VII can be obtained by the interaction of aniline of the formula II

with a carboxylic acid of formula VIII or its reactive derivative, the above

under standard amide formation conditions, specified above, where the changing of the groups have the meanings indicated above, and where the functional group is optionally protected.

(C) a Compound of formula I, where R1or Deputy on Q is (C1-C6)alkoxy or substituted (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino or substituted (C1-C6 )alkylamino, can be obtained by alkylation, usually in the presence of a suitable base, the above amide derivative of the formula I, where R1or Deputy on Q is hydroxy, mercapto or amino as appropriate.

The interaction is carried out, preferably, in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, simple ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, or a bipolar aprotic solvent, such asN,N-dimethylformamide,N,N-dimethylacetamide,N-methylpyrrolidine-2-one or dimethylsulfoxide. Interaction conveniently be carried out at a temperature in the range of, for example, 10-150°C, preferably in the range of 20-80°C.

A suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy to alkoxy or substituted alkoxy, or for the alkylation of mercaptopropyl to allylthiourea, or for the alkylation of amino to alkylamino or substituted, alkylamino, for example, alkyl or substituted alkylhalogenide, for example, (C1-C6)alkylchloride, -bromide or-iodide or a substituted (C1-C6)alkylchloride, -bromide or-iodide, presets is provided a suitable base, above, in a suitable inert solvent specified above, and at a temperature in the range of, for example, 10-140°or, preferably, at ambient temperature or close to it.

(d) Compound of formula I where the substituents on Q is amino, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino, substituted (C1-C6)alkylamino, substitutedN-(C1-C6)alkyl-(C2-C6)alkylamino or attached N heterocyclyl group, can be conveniently obtained by the interaction in the presence of a suitable base indicated above, the amide derivative of the formula I where the substituents on Q represents a suitable tsepliaeva group with an appropriate amine.

Suitable tsepliaeva group represents, for example, galactography, such as fluorine, chlorine or bromine, (C1-C6)alkanesulfonyl, such as methanesulfonamido, or arylsulfonate, such as 4-toluensulfonate.

Interaction conveniently be in the presence of a suitable inert diluent or carrier, above, and at a temperature in the range of, for example, 20-200°C, preferably in the range of 75-150°C.

(e) Compound of formula I, where R1or Deputy in Q is (C1-C6)alkanolamine or substituted (C2-C6alkanolamine, can be obtained by acylation of compounds of formula I, where R1or Deputy on Q represents an amino group.

Suitable allermuir agent is, for example, an agent that is known in this area for the acylation of amino to acylamino, such as allalone, for example (C1-C6)alcoholclone or-bromide, usually in the presence of a suitable base, as specified above, anhydride alanovoy acid or a mixed anhydride, for example anhydride (C1-C6)alanovoy acid, such as acetic anhydride, or mixed anhydride formed by the interaction alanovoy acid and (C1-C6)alkoxycarbonylmethyl, for example (C1-C6)alkoxycarbonylmethyl, in the presence of a suitable base, above. Typically, the acylation is carried out in a suitable inert solvent or diluent as above, and at a temperature in the range of, for example, from -30 to 120°C, preferably at ambient temperature or close to it.

(f) Compound of formula I, where R1or Deputy on Q is (C1-C6)alkanesulfonyl, can be obtained by the coupling of compounds of formula I, where R1or Deputy on Q is amino, (C1-C6)alkanesulphonic acid or its activated derivative.

Appropriate aktivirovani derivative (C 1-C6)alkanesulphonic acid is, for example, alkanesulfonyl, such as alkanesulfonyl obtained by the interaction between sulfonic acid and acid chloride inorganic acid, such as thionyl chloride. The interaction is preferably carried out in the presence of a suitable base, as specified above, in particular pyridine, in a suitable inert solvent or diluent, mentioned above, in particular methylene chloride.

(g) Compound of formula I, where R1or Deputy on Q represents carboxy, carboxy-(C1-C6)alkyl, carboxy-(C1-C6)alkoxy, carboxy-(C1-C6)alkylamino,N-(C1-C6)alkylcarboxylic-(C1-C6)alkylamino or carboxy-(C2-C6)alkanolamine, can be obtained by splitting the compounds of formula I, where R1or Deputy on Q is (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl-(C1-C6)alkyl, (C1-C6)alkoxycarbonyl-(C1-C6)alkoxy, (C1-C6)alkoxycarbonyl-(C1-C6)alkylamino,N-(C1-C6)alkyl-(C1-C6)alkoxycarbonyl-(C1-C6)alkylamino or (C1-C6)alkoxycarbonyl-(C2-C6)alkanolamine that fits.

The cleavage reaction can be conveniently about usestat, for example, by hydrolysis in an acidic or alkaline environment. A suitable base is, for example, a carbonate or hydroxide of an alkali metal, alkaline earth metal or ammonium, for example sodium carbonate, sodium hydroxide, potassium hydroxide or ammonium hydroxide. The interaction is preferably carried out in the presence of water and a suitable solvent or diluent, such as methanol or ethanol. Interaction conveniently be carried out at a temperature in the range of 10-150°C, preferably at ambient temperature or close to it.

(h) Compound of formula I, where R1is amino-(C1-C6)alkyl, (C1-C6)alkylamino-(C1-C6)alkyl, di-[(C1-C6)alkyl]amino-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, can be obtained by the interaction, usually in the presence of a suitable base indicated above, the compounds of formula IX

where X, Y, R2, R3, n, q and Q have the above meanings and Z represents a suitable tsepliaeva group, with a suitable amine or heterocyclic compound.

Suitable tsepliaeva group Z is, for example, galactography, such as fluorine, chlorine or bromine, (C1-C6)alkanesulfonyl, such as methanesulfonate, or arils heiligengrabe, such as 4-toluensulfonate.

Interaction conveniently be in the presence of a suitable inert diluent or carrier, as specified above, and at a temperature in the range of, for example, 20-200°C, preferably in the range of 50-150°C.

The following biological tests and examples serve to illustrate the present invention.

Biological assays

To determine the inhibitory effect of compounds of the present invention to kinase R and TNF and antiaritmicheskogo steps, you can use the following tests.

Enzymatic analysis of in vitro

Assess the ability of compounds of the invention inhibit the enzyme kinase R. Determine the activity of test compounds against each of the isoforms of the enzyme Rα and Rβ.

Recombinant MCC human (GenBank, inventory number G1209672) was isolated from the clone Image 45578 (Genomics, 1996,33, 151) and is used to produce protein in the form of a GST-fused protein in the vector pGEX using procedures similar to those described in J. Han et al., Journal of Biological Chemistry, 1996,271, 2886-2891. Allocate RA (GenBank, inventory number G529039) and p38β (GenBank, inventory number G1469305) by PCR-amplification of cDNA lymphoblastoid human (GenBank, inventory number GM1416) and cDNA fetal brain [synthesized from mRNA (Clontech, catalogue No. 6525-1) using the set is for the synthesis of cDNA Gibko], accordingly, using oligonucleotides designed for 5'- and 3'-ends of genes Rα and Rβ man, using procedures similar to those described in J. Han et al., Biochimica et Biophisica Acta, 1995,1265, 224-227, and Y. Jiang et al.. Journal of Biological Chemistry, 1996,271, 17920-17926.

Both protein isoforms R expressed in E. coli in PET vectors. Recombinant isoforms Rα and Rβ people get labeled 5' c-myc, 6His proteins. As MCC and proteins R cleaned using standard schemes: GST MCC purified using column glutathioneperoxidase and proteins R purified using columns with Nickel chelate complex.

Enzymes R activate before use by incubation with MCC for 3 hours at 30°C. Inactivated expressed in E. coli MCC retain sufficient activity for the full activation of both isoforms R. Activated by incubation mixture contains Rα (10 μl solution of 10 mg/ml) or Rβ (10 μl solution of 5 mg/ml) together with MCC (10 μl solution of 1 mg/ml), "buffer for kinase" [100 μl; pH 7.4, buffer contains Tris (50 mm), EGTA (0.1 mm), orthovanadate sodium (0.1 mm) and β-mercaptoethanol (0,1%)] and MgATP (30 μl of a solution of 50 mm Mg(ASON3)2and 0.5 mm ATP). This is sufficient for activation of the enzyme R 3 titration microplate.

Test compounds dissolved in DMSO in the wells tiralongo microplan the ETA add 10 ál of the sample, diluted 1:10 "buffer for kinase". In the case of tests with a single dose of a compound was tested at 10 μm. Then add the mixture to analyze kinase" [30 µl; contains myelin basic protein (Gibco BRL, cat. No. W-010; 1 ml of 3.33 mg/ml solution in water), the activated enzyme R (50 μl) and buffer for kinase" (2 ml)] and then labeled ATP" [10 µl of a solution containing 50 μm ATP, 0.1 ám CI33P ATP (Amersham International, cat. No. BF1000) and 50 mm Mg(ASON3)2]. Tablets incubated at room temperature with gentle stirring. Tablets containing Rα, incubated for 90 min, and tablets containing Rβ, incubated for 45 minutes Incubation is stopped by adding 50 μl of 20% trichloroacetic acid (TCA). Fallen in sediment phosphorylate protein kinase R and evaluate test compounds for their ability to inhibit this phosphorylation. Tablets filtered using filter Canberra Packard Unifliter and washed with 2% TCA, dried over night and perform counting with a scintillation counter Thor Count.

Compounds are first tested at one dose and active compounds have again to determine the values of the IC50.

Cellular analysis of in vitro

(i) PBMC

The ability of compounds of this invention inhibit the production of TNFα evaluate, using mononuclear cells prefer the risk of human blood, which synthesize and secrete TNFα when stimulated by lipopolysaccharide.

Mononuclear cells from peripheral blood (PBMC) isolated from heparinized (10 units/ml heparin) human blood by centrifugation in a density gradient (Lymphoprep™; Nycomed). Mononuclear cells resuspended in the medium for cultivation [medium RPMI 1640 (Gibco) supplemented with 50 units/ml penicillin, 50 μg/ml streptomycin, 2 mm glutamine and 1% thermoinactivation serum AB person (Sigma H-1513)]. Compounds dissolved in DMSO at a concentration of 50 mm, diluted 1:100 with medium for the cultivation and then perform a serial dilution in the environment for cultivation, containing 1% DMSO. RVMS (2,4×105cells in 160 μl of medium for cultivation) incubated with 20 μl of solutions of the test compounds at various concentrations (three repetitions) or 20 μl of media for culturing containing 1% DMSO (control wells)for 30 minutes at 37°wet (5% CO2/95% air) chamber (Falcon 3072; 96-well plates to the cultivation of tissues with flat-bottomed holes). In appropriate wells add 20 μl of lipopolysaccharide [LPS E. coli 0111:B4 (Sigma L-4130)to a final concentration of 10 μg/ml], dissolved in the medium for cultivation. In the control wells ""one environment" add 20 µl of media for culturing. In each 96-well tablet features the Yat six holes to control one LPC and four holes for control "one environment". In each test include various concentrations of known inhibitor of TNFαi.e. inhibitor of the enzyme PDE type IV (for example, see Seromler, J. Wachtel. N. and Enders, S., Int. J. Immunopharmac. (1993),15(3), 409-413) or an inhibitor of Pro-TNFα-convertase (for example, see McGeehan, G.M., et al., Nature (1994),370, 558-561).

Tablets incubated for 7 hours at 37° (humid chamber), and then from each hole to remove 100 ál of supernatant and store at -70° (96-well tablets with round-bottomed wells; Corning 25850). The content of TNFα in each sample determined using ELISA method for TNFa (see WO 92/10190 and Current Protocols in Molecular Biology, vol.2, Frederick M. Ausbel et al., John Wiley and Sons Inc.).

(ii) Whole human blood

The ability of compounds of this invention inhibit the production of TNFα also assessed in the analysis of whole human blood. Whole human blood secretes TNFα upon stimulation with LPS. This property of blood creates the basis for analysis, which is used as a secondary test compounds proved to be active when tested with RVMS.

Heparinized (10 units/ml) blood taken from volunteers. In wells of 96-well plates with round-bottomed wells (Corning 25850) add 160 µl of whole blood. Compounds are dissolved and serially diluted in RPMI medium 1640 (Gibco) supplemented with 50 units/ml penicillin, 50 µg/mistreatin and 2 mm glutamine, as described in detail above. In appropriate wells add 20 µl of a solution of the test compound at each concentration (three repetitions). In the control wells add 20 µl of RPMI medium 1640 with the addition of antibiotics and glutamine. Tablets incubated for 30 minutes at 37° (humid chamber) before adding 20 μl LPS (final concentration 10 μg/ml). In the control wells add medium RPMI 1640. Each tablet assign six holes to control one LPS and four holes for control "one environment". In each test also includes a known inhibitor of the synthesis/secretion of TNFα. Tablets incubated for 6 hours at 37° (humid chamber). Tablets centrifuged (2000 rpm for 10 minutes), remove 100 μl of plasma and stored at -70° (tablets Corning 25850). The content of TNFα determined by ELISA method (see WO 92/10190 and Current Protocols in Molecular Biology, vol.2, Frederick M. Ausbel et al., John Wiley and Sons Inc.). Paired antibodies used in ELISA, R&D Systems (cat. No. MAB, anti-human antibody shell against TNFα, BAF210, biotinylated anti-human antibodies for detection of TNFα).

Evaluation of ex vivo/in vivo

The ability of compounds of this invention as ex vivo inhibitors of TNFα evaluate on rats or mice. Briefly, groups of male Wistar rats Alderley Park (AP) (180-210 g) introducing the compound (6 rats) or storage of medicinal environments is TBA (10 rats) in a suitable way, for example, oral (r.o.), administered intraperitoneally (I.P. Pavlova.) or subcutaneously (s.c.). After nine minutes of rats killed with the use of CO2in increasing concentration and lower blood from the posterior Vena cava in heparinate (5 units per ml of blood). Blood samples immediately placed on ice and centrifuged at 2000 rpm for 10 min at 4°collected and the plasma frozen at -20°for subsequent analysis of its effect on the production of TNFα human blood stimulated by LPS. Plasma samples thawed rats and add 175 ál of each sample according to the established pattern in 96-well plates with round-bottomed wells (Corning 25850). Then to each well was added 50 μl of heparinized human blood, stirred and the plate is incubated for 30 min at 37° (humid chamber). In wells add LPS (25 μl; final concentration 10 μg/ml) and continue incubation for another 5.5 hours. In the control wells before incubation placed only 25 µl of the same environment. Then the tablets centrifuged for 10 min at 2000 rpm and 200 μl of supernatant transferred into a 96-well plate and frozen at -20°for subsequent analysis of the content of TNF by ELISA method.

Data analysis with the help of a special program count for each connection on the dose:

Alternative, described in the th above procedure instead of rats, you can use the mouse.

Test compounds as antiaritmichesky funds

The potency of the compound as antiaritmicheskogo tools evaluated as follows. Trentham et al. [1] showed that native collagen type II, acid-soluble, is arthritogenic for rats; it causes arthritis in the introduction in incomplete Freund's adjuvant. Now this phenomenon is known as kollageninducyruemuyu arthritis (CIA), and this condition can cause in mice and primates. Recent studies have shown that monoclonal antibodies against TNFα [2] and fused proteins of the TNF receptor and IgG [3] improves upon the established CIA, which indicates that TNF plays a key role in the pathophysiology of CIA. Moreover, discovered in recent clinical studies, significant efficiency in the case of monoclonal antibodies against TNF shows that TNF plays a major role in the specified chronic inflammatory disease. Thus, the CIA in mice DBA/1, as described in [2] and [3] is a basic model that can be used to demonstrate antiaritmicheskoi the activity of the connection. Cm. also [4].

Although the pharmacological properties of the compounds of formula I, as expected, vary with the structure, as a rule, the compound of formula I leads to the inhibition Rα and/or Rβgreater than 30% at concentrations up to 10 MCDS tested compounds of the present invention unacceptable toxicity at effective dose is not found.

For example, the connectionN-{6-[N-(3-dimethylaminopropyl)-N-methylamino]pyrid-3-yl}-2-chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzamide has IC50about 0.05 μm against Rα and IC50approximately 5 µm when tested with whole human blood.

In accordance with another aspect of the invention relates to pharmaceutical compositions containing the amide derivative of the formula I or its pharmaceutically acceptable salt, or its cleaved in vivo ester, as defined above, in combination with a pharmaceutically acceptable diluent or carrier.

Compositions of the invention can be in a form suitable for oral use (for example, in the form of tablets, pellets, hard and soft gelatin capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, in the form of creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example, in the form of finely ground powder or a liquid aerosol), for administration by insufflation (for example, in the form of finely ground powder) or for parenteral administration (for example, in the form of a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dose or in the form of a suppository on what I rectal administration).

Compositions of the invention can be obtained by conventional methods using conventional pharmaceutical excipients, well known in this field. Thus, compositions intended for oral use may contain, for example, one or more dyes, podslushivala, corrigentov and/or preservatives.

The amount of active ingredient that is combined with one or more excipients to obtain a separate dosage forms, of course, will vary depending on the recipient, which is treated and the particular route of administration. For example, a composition intended for oral administration to man, as a rule, will contain, for example, from 0.5 mg to 0.5 g of the active substance, United with an appropriate and convenient amount of excipients, the content of which may vary from about 5 to about 98 wt.% by weight of the entire composition.

The magnitude of the doses of the compounds of formula I for therapeutic and prophylactic purposes, of course, will vary according to the nature and severity of the condition, age and sex of the animal or patient and the route of administration in accordance with known in medicine rules.

When using the compounds of formula I for therapeutic or prophylactic purposes it generally imposed at the rate to get your daily dose intervals is f, for example, from 0.5 mg to 75 mg per kg of body weight, which is given, if necessary, in small doses. Generally, parenteral method of administration will be administered a smaller dose. For example, in the case of intravenous administration, as a rule, will be used dose in the range, for example, from 0.5 mg to 30 mg per kg of body weight. Similarly, for administration by inhalation is used dose in the range, for example, from 0.5 mg to 25 mg per kg of body weight. However, preferably oral administration, in particular in the form of tablets. As a rule, a standard dosage forms will contain from about 1 mg to about 500 mg of the compounds of this invention.

In accordance with another aspect of the invention relates to amide derivative of the formula I or its pharmaceutically acceptable salt, or its cleaved in vivo complex ether, as defined above, for use in the method of treatment of the human or animal.

In accordance with another aspect of the invention relates to amide derivative of the formula I or its pharmaceutically acceptable salt, or its cleaved in vivo complex ether, as defined above, for use in the manufacture of a medicine for use in the treatment of diseases or conditions mediated by cytokines.

In another aspect, the present invention relates to a method Leche is of diseases or conditions, mediated by cytokines, including the introduction of a warm-blooded animal an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo complex ether.

In another aspect, the present invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo of ester in the manufacture of a medicine for use in the treatment of diseases or conditions mediated by TNF, IL-1, IL-6 or IL-8.

In another aspect, the present invention relates to a method of treating diseases or conditions mediated by TNF, IL-1, IL-6 or IL-8, including the introduction of a warm-blooded animal an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo complex ether.

In another aspect, the present invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo of ester in the manufacture of a medicine for use in the treatment of diseases or conditions mediated by TNF.

In another aspect, the present invention relates to a method of treating diseases or conditions mediated by TNF, including the introduction of a warm-blooded animal an effective amount of the compounds of formula I or farmacevtichesky acceptable salt, or cleaved in vivo complex ether.

In another aspect, the present invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo of ester in the manufacture of a medicine for inhibiting TNF, IL-1, IL-6 or IL-8.

In another aspect, the present invention relates to a method of inhibiting TNF, IL-1, IL-6 or IL-8, including the introduction of a warm-blooded animal an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo complex ether.

In another aspect, the present invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo of ester in the manufacture of a medicinal product for use in the inhibition of TNF.

In another aspect, the present invention relates to a method of inhibiting TNF, including the introduction of a warm-blooded animal an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo complex ether.

In another aspect, the present invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo of ester in the manufacture of a medicinal product for use in Leche the research Institute for diseases or conditions, mediated by kinase R.

In another aspect, the present invention relates to a method of treating diseases or conditions mediated by kinase R, including the introduction of a warm-blooded animal an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo complex ether.

In another aspect, the present invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo of ester in the manufacture of a medicine for use in preparation of inhibitory effect on the kinase R.

In another aspect, the present invention relates to a method of providing inhibitory effect on the kinase R, including the introduction of a warm-blooded animal an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo complex ether.

In another aspect, the present invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo of ester in the manufacture of a medicinal product for use in the treatment of rheumatoid arthritis, asthma, mucous colitis, multiple sclerosis, AIDS, septic shock, ischaemic heart disease or psoriasis.

In another aspect, the present is sabreena relates to a method of treatment of rheumatoid arthritis, asthma, mucous colitis, multiple sclerosis, AIDS, septic shock, ischaemic heart disease or psoriasis involving the introduction of a warm-blooded animal an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo complex ether.

The compounds of this invention can be used in combination with other drugs and treatments used in the treatment of painful conditions that can help the inhibition of cytokines, in particular TNF and IL-1. For example, the compounds of formula I can be used in combination with medicaments and methods of treatment of rheumatoid arthritis, asthma, mucous colitis, multiple sclerosis, AIDS, septic shock, coronary heart disease, psoriasis and other painful conditions specified above in this description.

For example, due to its ability to inhibit cytokines, the compounds of formula I are of value in the treatment of certain inflammatory and non-inflammatory diseases which are currently treated any abscopal cyclooxygenase nonsteroidal anti-inflammatory drugs (NSAID)such as indomethacin, Ketorolac, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of compounds of formula I and NSAID mo is et to reduce the amount of last resort, required for therapeutic action. Through this reduces the possibility of harmful side effects of NSAIDs, such as effects on the gastrointestinal tract. Thus, in accordance with another distinctive feature, the invention relates to pharmaceutical compositions containing a compound of formula I or its pharmaceutically acceptable salt, or its cleaved in vivo ester in combination or mixed with inhibiting cyclooxygenase non-steroidal anti-inflammatory drug and a pharmaceutically acceptable diluent or carrier.

Compounds of the invention can also be used with anti-inflammatory drugs, such as inhibitors of the enzyme 5-lipoxygenase.

The compounds of formula I can also be used in the treatment of conditions such as rheumatoid arthritis, in combination with protivoallergicheskimi means, such as gold, methotrexate, steroids and penicillinases, and conditions such as osteoarthritis, in combination with steroids.

Compounds of the invention can also be administered in diseases associated with degradation, for example osteoarthritis, cartilage protectors, antidegradable and/or reducing means, such as diacerein, composition with hyaluronic acid, such as Gilan, Romulan, arteparon, and salts of glucosamine, such as Tril.

The compounds of formula I can be used in the treatment of asthma in combination with asthma means, such as bronchodilators and leukotriene antagonists.

If the composition is created in the form of a fixed dose, such combination products the compounds of this invention are used within the range of doses described herein and the other pharmaceutically active agent is used within approved for his range of doses. It is assumed consistent use, not suitable when combined composition.

Although the compounds of formula I, in the first place, are of value as therapeutic agents for application to warm-blooded animals (including man), they are also useful in any case, when you want the inhibition of cytokines. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the study of new pharmacological agents.

Now the invention will be illustrated below by examples, which are not restrictive, in which, if there are no other instructions,

(i) the operation is carried out at ambient temperature, i.e. in the range of 17-25°and in the atmosphere of inert gas, such as argon, unless otherwise indicated;

(ii) the evaporation is performed with the use of the rotary evaporator in vacuum, and procedures post-processing is carried out after the removal of the remaining solids by filtration;

(iii) column chromatography (flash method) and the liquid medium pressure chromatography (MPLC) carried out on silica Merck Kieselgel (art. 9385) or Merck Lichroprep RP10 (art. 9303) for chromatography with reversed phase obtained from Emagic, Darmstadt, Germany, or liquid chromatography high pressure (HPLC) performed on silica for chromatography with reversed phase C18, for example Dynamax C-18, 60 Å preparative column for chromatography with reversed phase;

(iv) the outputs are given for illustration only and is not necessarily the maximum attainable outputs;

(v) generally, the end products of the formula I give satisfactory results when microanalysis, and their structure confirmed by the method of nuclear magnetic resonance (NMR) and/or mass spectral techniques; mass spectral data with the fast atom bombardment (FAB) is obtained using the spectrometer Platform and, where appropriate, collect data with positive or negative ions; the magnitude of chemical shift in NMR is measured on the Delta scale [proton spectrum magnetic resonance determined using a spectrometer Varian Gemini 2000, operating at a field strength of 300 MHz, or Bruker spectrometer AM, running PR the field strength of 250 MHz]; and the following abbreviations are used: s - singlet; d - doublet; t - triplet; m - multiplet; ush - broadened;

(vi) intermediate compounds, as a rule, do not fully characterize and assess their purity when analyzed by thin layer chromatography, HPLC, infrared spectrometry (IR) and/or NMR;

(vii) the melting temperature is not correct and to determine whether use of the device for the automatic determination of the melting temperature Mettler SP62 or device with an oil bath; the melting temperature of the final products of formula I is determined after recrystallization from common organic solvents such as ethanol, methanol, acetone, ether or hexane, as such or mixtures thereof; and

(viii) the following abbreviations are used:

DMF - dimethylformamide,

DMSO - dimethyl sulfoxide,

THF is tetrahydrofuran.

Example 1

N-(4-Propylphenyl)-5-(4-cyanobenzoyl)-2-methylbenzamide

4-n-Propylaniline (0.11 g) is added to a stirred suspension of 5-(4-cyanobenzoyl)-2-methylbenzonitrile (0,224 g), triethylamine (of 0.21 ml) and methylene chloride (5 ml) and the resulting mixture stirred at ambient temperature for 16 hours. The mixture is filtered and the filtrate is evaporated. The residue is purified column chromatography on dioxide, silica using as eluent mixtures of methylene chloride and methanol with age is the fact that polarity. So get named in the title compound (0,049 g). An NMR spectrum: (d6) of 0.87 (t, 3H), and 1.56 (m, 2H), 2,33 (s, 3H), 2,48 (m, 2H), 7,13 (d, 2H), 7,28 (d, 1H), 7,63 (m, 2H), 7,83 (m, 3H), 8,01 (d, 1H), 8,1 (m, 2H). Mass spectrum: M+N+398.

5-(4-Cyanobenzoyl)-2-methylbenzoate used as a starting compound, obtained as follows.

4-Cyanobenzoate (4,50 g) is added to a stirred suspension of methyl 5-amino-2-methylbenzoate (J. Med. Chem., 1991, 34, 2176-2186; 3 g), triethylamine (2,54 ml) and methylene chloride (100 ml) and the resulting mixture stirred at ambient temperature for 16 hours. The mixture is acidified by adding 1 N hydrochloric acid, and the mixture was stirred at ambient temperature for 30 minutes. The obtained solid substance is separated and dried in vacuum at 40°receiving methyl 5-(4-cyanobenzoyl)-2-methylbenzoate (5.32 g). An NMR spectrum: (d6) 2,47 (s, 3H), 3,83 (s, 3H), 7,31 (d, 1H), 7,88 (d, 1H), 8.0 a (d, 2H)and 8.1 (d, 2H), of 8.27 (s, 1H), 10,57 (s, 1H). Mass spectrum: M+N+295.

A mixture of a portion (3 g) thus obtained substance, 2 N aqueous sodium hydroxide solution (20.4 ml), water (10 ml) and methanol (80 ml) was stirred at ambient temperature for 16 hours and then heated at 50°C for 5 hours. The resulting solution is evaporated and the residue treated with ethyl acetate and water. The aqueous phase is acidified to pH 5 by adding 1 N hydrochloric sour is, and the obtained solid substance is separated and dried in vacuum at 40°C. are Thus obtained 5-(4-cyanobenzoyl)-2-methylbenzoic acid (1,79 g). An NMR spectrum: (d6) of 2.45 (s, 3H), 7,24 (d, 1H), to 7.84 (m, 1H), 8,02 (m, 4H), compared to 8.26 (s, 1H), 10,41 (d, 1H). Mass spectrum: M+H+279.

Oxalicacid (0.104 g g) is added dropwise to a stirred mixture of 5-(4-cyanobenzoyl)-2-methylbenzoic acid (0.21 g), DMF (few drops) and methylene chloride (10 ml), cooled to 0°C. the Mixture is heated to ambient temperature and stirred for 4 hours. The mixture is evaporated, obtaining the required starting material, which is used without further purification.

Example 2

Using a procedure similar to that described in example 1, the corresponding benzoyl chloride is subjected to interaction with the corresponding aniline, getting the connections described in table 1.

4-cyanophenyl
Table 1

No.(R1)mR3QNote
14-propylmethylphenyland
23,4-dimethoxymethylphenylb
33,4-dimethoxymethyl

Notes

a) the Product has the following data: NMR spectrum: (d6) of 0.87 (t, 3H), 1,52-of 1.56 (m, 2H), 2,32 (s, 3H), 2,48 of $ 2.53 (m, 2H), 7,13 (d, 2H), 7,26 (d, 1H), 7,51-7,63 (m, 5H), and 7.8 (d, 1H), 7,86 (S, 1H), 7,95 (d, 2H), of 10.21 (s, 1H), 10,29 (s, 1H); mass spectrum: M+N+373.

5-Benzamido-2-methylbenzoate used as the starting material, is obtained from methyl 5-amino-2-methylbenzoate and benzoyl chloride using procedures similar to those described under example 1, on receipt of the original substances. Thus receive, alternately,

methyl 5-benzamido-2-methylbenzoate, an NMR spectrum: (d6) 2,43 (S, 3H), 3,83 (s, 3H), 7,29 (d, 1H), 7,49-to 7.61 (m, 3H), 7,88 (d, 1H), 7,95 (d, 2H), 8,29 (s, 1H), 10,33 (s, 1H); mass spectrum: M+N+270;

5-benzamido-2-methylbenzoate, an NMR spectrum: (d6) 2,43 (s, 3H), 7,24 (d, 1H), 7,44 and 7.6 (m, 3H), to 7.84 (d, 1H), 7,94 (d, 2H), of 8.25 (s, 1H), accounted for 10.39 (s, 1H), 12,80 (s, 1H); mass spectrum: M+H+254; and

5-benzamido-2-methylbenzoate, which is used without further purification.

b) After stirring at ambient temperature for 16 hours, the reaction mixture was filtered and the filtrate is successively washed with 1 N hydrochloric acid and saturated aqueous sodium bicarbonate. The organic phase is evaporated and the residue triturated with a mixture of isohexane and ethyl acetate. The obtained solid substance was separated, washed Dyatlov the m ether and dried. Thus obtained product has the following data: NMR spectrum: (d6) of 2.33 (s, 3H), and 3.72 (s, 6N)and 6.9 (d, 1H), 7,25 (d, 2H), 7,43-7,58 (m, 4H), 7,78 (d, 1H), 7,87 (s, 1H), 7,95 (d, 2H), 10,13 (s, 1H), 10,29 (s, 1H); mass spectrum: M+H+391.

c) After stirring at ambient temperature for 16 hours, the reaction mixture was filtered and the filtrate is successively washed with 1 N hydrochloric acid and saturated aqueous sodium bicarbonate. The organic phase is evaporated and the residue triturated with a mixture of isohexane and ethyl acetate. The obtained solid substance was separated, washed with diethyl ether and dried. Thus obtained product has the following data: mass spectrum: M+N+416.

Example 3

N-[3-(4-Methylpiperazin-1-ylmethyl)phenyl]-2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)benzamide

Using a procedure analogous to the procedure described in example 1, 2-morpholinopropan-4-carbonylchloride subjected to interaction withN-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-5-amino-2-methylbenzamide. The residue is purified column chromatography on ion-exchange column (column with isolat-SCX from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using as eluent initially methanol and then a mixture of 99:1 methanol and a saturated aqueous solution of ammonium hydroxide. So get named in the title compound with a yield of 2%. Mass spectrum: M+H+529.

2-Morpholinopropan-4-carbonylchloride used as the starting material, was obtained as follows.

2-Chloropyridin-4-carbonylchloride (11.2 g) is added to a stirred mixture of tert-butoxide potassium (7,15 g) and THF (50 ml), cooled to 0°C. the Mixture is heated to ambient temperature and stirred for 16 hours. The mixture is evaporated and the residue treated with ethyl acetate and water. The organic phase is washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and evaporated. Thus obtained tert-butyl 2-chloropyridin-4-carboxylate (10.5 g). An NMR spectrum: (CDCl3in ) 1.6 (s, N), 7,72 (d, 1H), 7,82 (s, 1H), 8,51 (d, 1H).

After repetition of the previous interaction of the mixture thus obtained pyridine-4-carboxylate (18.3 g) and research (30 ml) is stirred and heated at 100°C for 40 hours. The mixture was poured into water and extracted with methylene chloride. The organic phase is evaporated and the residue purified column chromatography on silica using as eluent first mixture 5:1 isohexane and ethyl acetate and then a mixture of 10:3 of the same solvent. Thus obtained tert-butyl 2-morpholinopropan-4-carboxylate (15 g). An NMR spectrum: (d6) of 1.52 (s, N), 3.46 in-3,55 (m, 4H), 3,62 to 3.7 (m, 4H), to 7.09 (d, 1H), 7,13 (s, 1H), 8,24 (d, 1H).

The mixture thus obtained substance, in which s (10 ml) and triperoxonane acid (90 ml) was stirred at ambient temperature for 3 hours. The mixture is evaporated and the residue is treated with a mixture of isohexane and ethyl acetate. The obtained solid substance was separated, washed with ethyl acetate and dried, obtaining 2-morpholinopropan-4-carboxylic acid (13,2 g). An NMR spectrum: (d6) of 3.46-3,51 (m, 4H), 3,62 to 3.7 (m, 4H), 7,07 (d, 1H), 7,25 (s, 1H), 8,24 (d, 1H).

Thus obtained substance is subjected to interaction with oxalylamino using a procedure analogous to the procedure described in the last paragraph of example 1, on receipt of the original substances. Thus obtained 2-morpholinopropan-4-carbonylchloride, which is used without further purification.

N-[3-(4-Methylpiperazin-1-ylmethyl)phenyl]-5-amino-2-methylbenzamide used as the starting material, was obtained as follows.

A mixture of 3-nitrobenzaldehyde (1 g) andN-methylpiperazine (3 ml) is stirred and heated at 100°C for 4 hours. The mixture is cooled to ambient temperature and treated with methylene chloride and water. The organic phase is evaporated, obtaining 3-(4-methylpiperazin-1-ylmethyl) nitrobenzene (1,05 g). An NMR spectrum: (d6) and 2.14 (s, 3H), 2,31-of 2.38 (m, 8H), of 3.57 (s, 2H), and 7.6 (t, 1H), 7,54 (d, 1H), 8.07-a 8,13 (m, 2H).

To a stirred suspension thus obtained substance in a mixture of ethanol (30 ml), water (2 ml) and acetic acid (0.5 ml) is added iron powder (2,47 g). The mixture is stirred and Ki is Atat under reflux for 4 hours. The mixture is cooled to ambient temperature. Add water (30 ml) and the resulting mixture is alkalinized by adding sodium carbonate. The mixture is filtered and the filtrate is evaporated. The residue is treated with water. The obtained solid substance is separated and dried in vacuum at 40°C. are Thus obtained 3-(4-methylpiperazin-1-ylmethyl)aniline (0.51 g). An NMR spectrum: (d6) 2,11 (s, 3H), 2,24-of 2.36 (m, 8H), of 3.28 (s, 2H), 4.92 in (s, 2H), 6,37-6,41 (m, 2H), of 6.49 (s, 1H), 7,9 (t, 1H).

Oxalicacid (0.31 g) is added dropwise to a stirred mixture of 2-methyl-5-nitrobenzoic acid (0.4 g), DMF (few drops) and methylene chloride (25 ml), cooled to 0°C. the Mixture is heated to room temperature and stirred for five hours. The mixture is evaporated, obtaining 2-methyl-5-nitrobenzoate which is dissolved in methylene chloride (10 ml) and the resulting solution is added dropwise to a stirred mixture of 3-(4-methylpiperazin-1-ylmethyl) aniline (0,44 g), triethylamine (0,49 g) and methylene chloride (10 ml). The mixture was stirred at ambient temperature for 16 hours. The mixture was washed with saturated aqueous sodium bicarbonate. The organic phase is evaporated and the residue purified column chromatography on ion-exchange column isolute-SCX, using as eluent initially methanol and then a mixture of 99:1 methanol and a saturated aqueous solution of ammonium hydroxide. So what are square N-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-methyl-5-nitrobenzamide (0,46 g). Mass spectrum: M+N+369.

The mixture thus obtained 5-nitrobenzamide, iron powder (2,79 g), water (1 ml), acetic acid (0.25 ml) and ethanol (15 ml) is stirred and heated to boiling under reflux for 5 hours. The mixture is cooled to ambient temperature. Add water (50 ml) and the mixture is alkalinized by adding sodium carbonate. The resulting mixture was filtered and the filtrate is evaporated. The residue is treated with methylene chloride and water. The organic phase is evaporated and the residue purified column chromatography on ion-exchange column isolute-SCX, using as eluent initially methanol and then a mixture of 99:1 methanol and a saturated aqueous solution of ammonium hydroxide. So getN-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-5-amino-2-methylbenzamide (0,194 g). An NMR spectrum: (CDCl3) of 2.28 (s, 3H), is 2.37 (s, 3H), 2,42-of 2.58 (m, 8H), and 3.5 (s, 2H), 3,64 (broadened s, 2H), from 5.29 (s, 1H), 6,67-for 6.81 (m, 2H), 7,02 (t, 1H), 7,10 (d, 1H), and 7.3 and 7.6 (m, 1H). Mass spectrum: M+N+339.

Example 4

N-[6-(4-Ethylpiperazin-1-yl)pyrid-3-yl]-2-chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzamide

2-Chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzoic acid (rate £ 0.162 g) is added to a stirred mixture of 5-amino-2-(4-ethylpiperazin-1-yl)pyridine (0,093 g), diisopropylethylamine (0,232 g), hexaflurophosphate (V) 2-(7-and benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (0,176 g) and DMF (10 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture is treated with ethyl acetate and water. The organic phase is washed with saturated aqueous sodium bicarbonate and evaporated. The residue is treated with a mixture of isohexane and ethyl acetate. The obtained solid substance is separated and dried in vacuum at 40°With, getting named the title compound (0,071 g). An NMR spectrum: (d6) of 1.02 (t, 3H), of 2.34 (m, 2H), 2,4-of 2.46 (m, 4H), 3,38-of 3.42 (m, 4H), 3,5-of 3.53 (m, 4H), 3,69-3,71 (m, 4H), PC 6.82 (d, 1H), was 7.08 (d, 2H), 7,22 (s, 1H), 7.62mm (d, 1H), 7,82-7,98 (m, 3H), of 8.28 (d, 1H), 8,39 (s, 1H). Mass spectrum: M+H+550 and 552.

2-Chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzoic acid used as the starting material, was obtained as follows.

Using procedures similar to those described in the last paragraph of example 3, on receipt of original substances, restore methyl 2-chloro-5-nitrobenzoate, receiving methyl 5-amino-2-chlorobenzoate with 38%. An NMR spectrum: (d6) 3,79 (s, 3H), 5,46 (s, 2H), 6,66 (d, 1H), 6,97 (s, 1H), and 7.1 (d, 1H).

Using a procedure similar to that described in example 1, 2-morpholinopropan-4-carbonylchloride subjected to interaction with methyl 5-amino-2-chlorobenzoate. The reaction product is treated with a mixture of isohexane and ethyl acetate. The obtained solid substance was separated and washed with diethyl ether. Thus obtained methyl 2-chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzoate with the release of 63%. When ECTR NMR: (d 6) 3,49-of 3.53 (m, 4H), 3,69-and 3.72 (m, 4H), 3,86 (S, 3H), to 7.09 (d, 1H), 7.23 percent (s, 1H), 7,56 (d, 1H), of 7.96 (d, 1H), 8,25-of 8.28 (m, 2H), 10,55 (s, 1H). Mass spectrum: M+H+376 and 378.

The mixture thus obtained methylbenzoate (3 g), 2 N aqueous sodium hydroxide solution (16 ml), water (25 ml) and methanol (100 ml) was stirred at ambient temperature for 16 hours. The resulting solution is evaporated and the residue acidified to pH 1 by adding 1 N hydrochloric acid. Add water (1 ml) and methanol (1 ml) and the mixture is stirred for 1 hour. The obtained solid substance is separated and dried in vacuum at 40°receiving the required starting material (2.83 g). An NMR spectrum: (d6) 3,62-3,74 (m, 8H), 7,21 (d, 1H), 7,53 (d, 1H), 7,63 (s, 1H), 8,01 (d, 1H), 8,21 (d, 1H), 8,28 (s, 1H), 10,98 (s, 1H). Mass spectrum: M+H+360 and 362.

5-Amino-2-(4-ethylpiperazin-1-yl)pyridine used as the starting material, was obtained as follows.

A mixture of 2-chloro-5-nitropyridine (1 g) andN-ethylpiperazine (4 ml) is stirred and heated at 100°C for 16 hours. The mixture is cooled to ambient temperature and poured into water. The obtained solid substance was separated, washed successively with water and diethyl ether and dried in vacuum at 40°C. are Thus obtained 2-(4-ethylpiperazin-1-yl)-5-nitropyridine (0,22 g). An NMR spectrum: (d6) a 1.01 (t, 3H), 2,33-to 2.41 (m, 2H), 2,42 is 2.44 (m, 4H), 3,71 of 3.75 (m, 4H), 6,91 (d, 1H), 8,17 (d, 1H), of 8.92 (s, 1H).

The mixture according to the scientists thus substances, 10% palladium-on-coal (0,095 g) and methanol (20 ml) is stirred in hydrogen atmosphere. After cessation of hydrogen absorption, the catalyst is removed by filtration and the filtrate is evaporated. Thus obtained the required starting material (0.18 g). An NMR spectrum: (d6) and 1.0 (t, 3H), 2,28-of 2.36 (m, 2H), 2,38-to 2.41 (m, 4H), 3.15 and 3.21-in (m, 4H), 4,5 (broadened s, 2H), return of 6.58 (d, 1H), 6,85 (d, 1H), EUR 7.57 (s, 1H). Mass spectrum: M+N+207.

Example 5

Using a procedure analogous to the procedure described in example 4, the corresponding 5-aminopyridine is subjected to interaction with 2-chloro-5-(2-metroliner-4-ylcarbonyl)benzoic acid, obtaining the compounds described in table II.

Table II

No.R1R3Note
1N-(2-dimethylaminoethyl)-N-methylaminochlorineand
2N-(3-dimethylaminopropyl)-N-methylaminochlorineb
34-methylpiperazin-1-ylchlorine
44-methylhomopiperazine-1-ylchlorined

Notes

a) the Product has the following data: NMR Spectrum: (d6) of 2,4-2,49 (m, 8H), 2,98 (s, 3H), 3,48-of 3.53 (m, 4H), 3,66-and 3.72 (m, 6N), is 6.61 (m, 1H), and 7.1 (d, 1H), 7.23 percent (s, 1H), 7,53 (d, 1H), 7,78-of 7.82 (m, 1H), 7,88-to 7.93 (m, 1H), 8,27 is 8.38 (m, 2H), 10,26 (s, 1H), 10,51 (s, 1H). Mass spectrum: M+H+538 and 540.

5-Amino-2-[N-(2-dimethylaminoethyl)-N-methylamino]pyridine used as starting substances are obtained from 2-chloro-5-nitropyridine andN-(2-dimethylaminoethyl)-N-methylamine using procedures similar to the procedures described in example 4, for obtaining 5-amino-2-(4-ethylpiperazin-1-yl)pyridine. The required starting material has the following data: NMR Spectrum: (d6) to 2.35 (t, 2H), 2,48 (C, 6N), 2,82 (s, 3H), 3,32-3,44 (m, 6N), 6.4 (m, 1H), 6,84-6,9 (m, 1H), 7,53-7,56 (m, 1H). Mass spectrum: M+N+195.

b) the Product is purified column chromatography on ion-exchange column isolute-SCX using as eluent initially methanol and then a mixture of 99:1 methanol and a saturated aqueous solution of ammonium hydroxide. The product has the following data: Mass spectrum: M+N+552 and 554.

5-Amino-2-[N-(3-dimethylaminopropyl)-N-methylamino]pyridine used as starting substances are obtained from 2-chloro-5-nitropyridine andN-(3-dimethylaminopropyl)-N-methylamine using procedures similar to the procedures described in example 4, for obtaining 5-amino-2-(4-ethylpiperazin-1-yl)pyridine. The required starting material has a footprint is the following data: NMR Spectrum: (d 6) 1,48-of 1.56 (m, 2H), 2,08 (C, 6N), of 2.16 (t, 2H), 2.49 USD (s, 3H), 3,29-to 3.36 (m, 2H), 4,28 (broadened s, 2H), 6,37-6.42 per (m, 1H), 6,84-6,9 (m, 1H), 7,53 (s, 1H). Mass spectrum: M+H+209.

c) the Product has the following data: NMR Spectrum: (d6) 2,19 (s, 3H), 2,36-2,39 (m, 4H), 3,39-of 3.43 (m, 4H), 3,39-to 3.52 (m, 4H), 3,68-3,71 (m, 4H), at 6.84 (d, 1H), was 7.08 (d, 1H), 7.23 percent (s, 1H), 7,52 (d, 1H), 7,84-7,94 (m, 3H), of 8.27 (d, 1H), 8,39 (s, 1H). Mass spectrum: M+N+536 and 538.

5-Amino-2-(4-methylpiperazin-1-yl)pyridine used as starting substances are obtained from 2-chloro-5-nitropyridine andN-methylpiperazine using procedures similar to the procedures described in example 4, for obtaining 5-amino-2-(4-ethylpiperazin-1-yl) pyridine. The required starting material has the following data: NMR Spectrum: (d6) and 2.26 (s, 3H), 2,47-2,49 (m, 4H), 3,21-of 3.25 (m, 4H), and 6.6 (d, 1H), 6,9 (d, 1H), EUR 7.57 (s, 1H). Mass spectrum: M+N+193.

d) the Product is purified column chromatography on ion-exchange column isolute-SCX using as eluent initially methanol and then a mixture of 99:1 methanol and a saturated aqueous solution of ammonium hydroxide. The product has the following data: Mass spectrum: M+N+550 and 552.

5-Amino-2-(4-methylhomopiperazine-1-yl)pyridine used as starting substances are obtained from 2-chloro-5-nitropyridine andN-methylhomopiperazine using procedures similar to the procedures described in example 4, CAS is the existing obtain 5-amino-2-(4-ethylpiperazin-1-yl) pyridine. The required starting material has the following data: mass spectrum: M+N+207.

Example 6

N-[3-(4-Methylpiperazin-1-ylmethyl)phenyl]-2-chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzamide

Using a procedure similar to that described in example 4 3-(4-methylpiperazin-1-ylmethyl)aniline is subjected to interaction with 2-chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzoic acid, getting named the title compound with a yield of 32%. An NMR spectrum: (d6) to 2.13 (s, 3H), 2,31 to 2.35 (m, 8H), 3,42 (s, 2H), 3,49-of 3.53 (m, 4H), 3,69-and 3.72 (m, 4H), 7,02 (d, 1H), and 7.1 (d, 1H), 7,22-to 7.3 (m, 2H), EUR 7.57-the 7.65 (m, 3H), 7,84-7,94 (m, 2H), 8,28 (d, 1H), 10,47 (s, 1H), 10,52 (, 1H). Mass spectrum: M+N+549 and 551.

Example 7

Pharmaceutical compositions.

The following are typical pharmaceutical dosage forms of the invention, as defined here (the active ingredient referred to as the "Compound X"), for therapeutic or prophylactic use in humans.

(a) Tablet Img tablet
Connection X100
Lactose (eurofarm.)182,75
Crosscarmeloseto 12.0
The paste of maize starch (5% paste, wt./about.)2,25
Magnesium stearate3,0
(b) Tablet II mg tablet
Compound X50
Lactose (eurofarm.)223,75
Crosscarmelose6,0
Maize starch15,0
Polyvinylpyrrolidone (5% paste, wt./about.)2,25
Magnesium stearate3,0
(C) Tablet IIImg tablet
Compound X1,0
Lactose (eurofarm.)93,25
Crosscarmelose4,0
The paste of maize starch(5% paste, wt./about.)0,75
Magnesium stearate1,0
(d) Capsulemg/capsule
Compound X10
Lactose (eurofarm.)488,5
Magnesium stearate1,5
(e) Injection I(50 mg/ml)
Connection X5,0% (wt./about.)
1 M sodium hydroxide solution15,0% (vol./about.)
0.1 M hydrochloric acid (to bring the pH to 7.6)
The polyethylene glycol 4004,5% (wt./about.)
Water for injection to 100%
(f) Injects the I II (10 mg/ml)
Compound X1,0% (wt./about.)
Sodium phosphate, BP3,6% (wt./about.)
0.1 M solution of sodium hydroxide15,0% (vol./about.)
Water for injection to 100%
(g) Injection III(1 mg/ml, sabut. to pH 6)
Connection X0,1% (wt./about.)
Sodium phosphate, BPof 2.26% (wt./about.)
Citric acid0,38% (wt./about.)
The polyethylene glycol 4003,5% (wt./about.)
Water for injection to 100%
(h) Aerosol Img/ml
Connection X10,0
Trioleate sorbitan13,5
Trichlorofluoromethane910,0
DICHLORODIFLUOROMETHANE490,0
(i) Aerosol IImg/ml
Compound X0,2
Trioleate sorbitan0,27
Trichlorofluoromethane70,0
DICHLORODIFLUOROMETHANE280,0
Dichlorotetrafluoroethane1094,0
(j) Aerosol IIImg/ml
Connection X2,5
Trioleate sorbitan3,38
Trichlorofluoromethane67,5
DICHLORODIFLUOROMETHANE1086,0
Dichlorotetrafluoroethaneto 191.6
(k) Aerosol IVmg/ml
Compound X2,5
Soy lecithin2,7
Trichlorofluoromethane67,5
DICHLORODIFLUOROMETHANE1086,0
Dichlorotetrafluoroethaneto 191.6
(l) Ointmentml
Compound X40 mg
Ethanol300 ál
Water300 ál
1-Dodecylsulfate-2-he50 µl
Propylene glycolto 1 ml

Note

The above composition can be obtained with conventional procedures known in the pharmaceutical field. The tablets (a)-(C) can be applied intersolubility coverage of the easy ways, for example, to form a coating of acatitla cellulose. Aerosol composition (h)-(k) can be used in combination with valves, measuring the standard dose aerosol, and suspendresume agents trioleate sorbitan and soya lecithin may be replaced by other suspen yousie agents, such as monooleate sorbitan, sesquioleate sorbitan, Polysorbate 80, of the polyglycerol oleate or oleic acid.

Sources of information

1. Trentham, D.E. etc al. (1997), J. Exp.Med.,146, 857.

2. Williams, R.O. et al. (1992), Proc. Natl. Acad. Sci.89,9784.

3. Williams, R.O. et al. (1995), Immunoiogy,84, 433.

4. Badger, M,B. et al (1996), The Jornal of Pharmacology and Experimtntal Therapeutics,279, 1453-1461.

1. Derived amide of the formula I

where X represents CH;

Y represents CH or N;

m is 1 or 2;

R1is (C1-C6)alkyl, (C1-C6)alkoxy, N,N-di[(C1-C6)alkyl]amino, heterocyclyl-(C1-C6)alkyl, where heterocyclyl is piperazinil or homopiperazine, and

any of the substituents R1with the above values, containing SN2-group associated with the 2 carbon atoms, or CH3-group associated with the carbon atom, may optionally contain each of the specified CH2or CH2group Deputy selected from di[(C1-C6)alkyl]amino;

R2represents halogen, (C1-C6)alkyl;

n is equal to 3;

R3represents hydrogen;

Q represents phenyl optionally substituted by cyano, or pyridyl, optionally substituted, morpholino, or their pharmaceutical the ski acceptable salt.

2. Derived amide of the formula I according to claim 1, where

X represents CH;

Y represents CH or N;

m is 1 or 2;

R1represents propyl, methoxy, N-(2-dimethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino, 4-methylpiperazine, 4-methylhomopiperazine;

R2represents methyl, chlorine;

Q is phenyl, optionally substituted by cyano, or pyridyl, substituted morpholino, or their pharmaceutically acceptable salts.

3. Derived amide of the formula I according to claim 1, where

X represents CH;

Y represents CH or N;

m is equal to 1;

R1selected from N-(3-dimethylaminopropyl)-N-methylamino, 4-methylpiperazin-1-yl and 4-methylhomopiperazine-1-yl;

R2represents methyl, chlorine;

Q is 4-pyridyl, substituted morpholino, or their pharmaceutically acceptable salts.

4. Derived amide of the formula I according to claim 1, where X represents CH;

Y represents CH or N;

m is equal to 1;

R is selected from N-(3-dimethylaminopropyl)-N-methylamino, 4-methylpiperazin-1-yl and 4-methylhomopiperazine-1-yl;

R2represents methyl, chlorine;

Q is 2-morpholinomethyl-4-yl, or their pharmaceutically acceptable salts.

5. Derived amide of the formula I according to claim 1, selected from

N-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-meth is l-5-(2-morpholinomethyl-4-ylcarbonyl)benzamide,

N-[6-(4-ethylpiperazin-1-yl)pyrid-3-yl]-2-chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzamide,

N-[6-(4-methylpiperazin-1-yl)pyrid-3-yl]-2-chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzamide and

N-{6-[N-(3-dimethylaminopropyl)-N-methylamino]pyrid-3-yl}-2-chloro-5-(2-morpholinomethyl-4-ylcarbonyl)benzamide, or its pharmaceutically acceptable salt.

6. The method of obtaining the amide derivative of the formula I or its pharmaceutically acceptable salts, including the interaction of aniline of the formula II

with a benzoic acid of formula III or its activated derivative

in standard conditions of formation of amide linkages, where the changing of the groups have the meanings indicated in claim 1, and where any functional group is optionally protected, and

(i) removing any protective groups; and

(ii) optionally, the formation of pharmaceutically acceptable salts.

7. The method of obtaining the amide derivative of the formula I or its pharmaceutically acceptable salts, including the interaction of aniline of the formula VI

with a carboxylic acid of formula V or its reactive derivative

under standard amide formation conditions the Oh communication where changing groups have the meanings indicated in claim 1, and where any functional group is optionally protected, and

(i) removing any protective groups; and

(ii) optionally, the formation of pharmaceutically acceptable salts.

8. Pharmaceutical composition for treating diseases or conditions mediated by cytokines R and TNFαcontaining amide derivative of the formula I or its pharmaceutically acceptable salt according to claim 1 in combination with a pharmaceutically acceptable carrier or diluent.

9. Derived amide of formula I or its pharmaceutically acceptable salt according to claim 1 for use in the manufacture of a medicinal product for the treatment of diseases or conditions mediated by cytokines R and TNFα.

10. A method of treating diseases or conditions mediated by cytokines R and TNFαinvolving the introduction of a warm-blooded animal an effective amount of the compounds of formula I or its pharmaceutically acceptable salt according to claim 1.



 

Same patents:

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to anthranylamide derivative selected from compound of formula I or N-oxides thereof, wherein R1 represents methyl, F, Cl, Br; R2 represents F, Cl, Br, I, CF3; R3 represents CF3, Cl, Br, OCH2CF3; R4a represents C1-C4-alkyl; R4b represents H, CH3; and R5 represents Cl, Br, and agriculturally acceptable salt thereof. Also disclosed are composition for pest controlling containing biologically effective amount of formula I and at least one additional component selected from group comprising surfactants, solid and liquid diluents; composition for invertebrate insect controlling containing biologically effective amount of formula I and at least one additional biologically active compound or agent. Also disclosed are method for insect controlling as well as intermediates such as benzoxazinone and parasolocarboxylic acid derivatives.

EFFECT: compounds with insecticide activity, useful in insect controlling.

20 cl, 16 tbl, 33 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new sulfonamide derivatives possessing anti-tumor activity, namely to compounds of the formula (I): wherein R6 means hydroxyl; R7 means methyl, isopropyl, isobutyl, benzyl or indole-3-ylmethyl; R8 means hydrogen atom; R9 means phenylene; R10 means thienyl, furyl or pyridyl optionally substituted with lower alkyl or halogen atom. Also, invention relates to their derivatives or pharmaceutically acceptable salts or solvates. Invention describes medicinal agents used in treatment or prophylaxis of cancer and for prophylaxis of metastasis. Also, invention describes a case for treatment of cancer in mammal.

EFFECT: improved treatment method, valuable medicinal properties of agent.

5 cl, 17 tbl, 112 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes using 2-morpholyl-6-piperidyl-4-[(4'-(ethoxycarbonyl-5'-1',2',3'-triazol)-1'-yl]-1,3,5-triazine of the formula: as an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyacetic acid on sunflower germinated seeds. The proposed substance allows significant increasing roots and hypocotyls length of seedlings and to expand assortment of the known antidotes.

EFFECT: improved and valuable properties of antidote.

2 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (II): or their pharmaceutically acceptable salts wherein Xa means -C(R13)2-, -C(R13)(R19)-, -C(O)-, and others; Ra means R6a-phenyl or phenyl substituted with methylsulfonyl; R1 means hydrogen atom or (C1-C6)-alkyl; R2 means R7-, R8-, R9-phenyl wherein R7-, R8 and R9 mean substituted 6-membered heteroaryl and others; R3 means R10-phenyl, pyridyl and others; R4 means hydrogen atom, (C1-C6)-alkyl, fluoro-(C1-C6)-alkyl; R6a means from 1 to 3 substitutes taken among the group involving hydrogen, halogen atom, -CF3 and CF3O-; R7 and R8 mean (C1-C6)-alkyl and others; R9 means R7, hydrogen atom, phenyl and others; R10 means (C1-C6)-alkyl, -NH2 or R12-phenyl wherein R12 means hydrogen atom, (C1-C6)-alkyl and others; R13, R14, R15 and R16 mean hydrogen atom or (C1-C6)-alkyl; R17 and R18 in common with carbon atom to which they are bound form spirane ring comprising from 3 to 6 carbon atoms; R19 means R6-phenyl wherein R6 means R6a or methylsulfonyl; R20, R21 and R22 mean hydrogen atom or (C1-C6)-alkyl; R23 means (C1-C6)-alkyl under condition that if Ra means phenyl substituted with methylsulfonyl then Xa can mean the group only. Compounds of the formula (II) possess properties of CCR5-antagonist and can be used in medicine in treatment of HIV-infection.

EFFECT: improved method for treatment, valuable medicinal properties of compounds and composition.

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention describes a new compound 4,6-bis-(morpholyl)-2-[(2'-ethoxyacetyltetrazolyl)-5'-yl]-1,3,5-triazine of the formula: that represents an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyacetic acid on germinating sunflower seeds and seedlings.

EFFECT: valuable properties of compound.

2 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to derivatives of piperazine and piperidine of the formula (I): wherein ---Z represents =C or -N; Q means benzyl or 2-, 3- or 4-pyridylmethyl that can be substituted with one or more substitutes taken among group comprising halogen atom, cyano-group, (C1-C3)-alkoxy-group, CF3, OCF3, SCF3, (C1-C4)-alkyl, (C1-C3)-alkylsulfonyl and their salts, and to a method for their preparing also. It has been found that these compounds elicit valuable pharmacological properties owing to combination of (partial) agonism with respect to members of dopamine receptors subtype and affinity with respect to corresponding serotonin and/or noradrenergic receptors and can be useful in preparing compositions used in treatment of fear and/or depression or Parkinson's disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 3 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

The invention relates to a new process for the preparation of 5-chloro-4-aminosilane derivative 3(2H)-pyridazinone formula (I) and its pharmaceutically acceptable acid additive salts

The invention relates to a method for producing 6-aryl-5-arylazo-3,4-dihydro-3,4-pyridazinedione General formula I, where AG1denotes phenyl or p-chlorophenyl, AG2denotes phenyl

The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions containing an effective amount of the compounds in the mixture

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bis-aryl compounds of the formula (I): wherein one among A1-A4 means nitrogen atom and others mean -CH or -CR5; A5-A8 mean -CH or -CR5; R5 means halogen atom or (C1-C)-alkyl; R(1) means -C(O)OR(9), -COR(11); R(9) and R(11) mean CxH2x-R(14); x means 0, 1,2, 3 or 4 and x can't mean 0 if R(14) means -OR(15); R(14) means (C1-C6)-alkyl or phenyl; R(15) means (C1-C5)-alkyl; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y means 0, 1, 2, 3 or 4 and y can't mean 0 if R(16) means -OR(17); R(16) means (C1-C6)-alkyl, phenyl or pyridyl; R(17) means hydrogen atom, (C1-C5)-alkyl, phenyl or pyridyl, or R(3) means -CHR(18)R(19); R(18) means hydrogen atom or CzH2z-R(16) wherein R(16) means abovementioned values; z means 0, 1, 2 or 3; R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and to their pharmaceutically acceptable salts also. Compounds of the formula (I) possess anti-arrhythmic activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

11 cl, 30 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention relates to compounds of the formula (1) , their N-oxides and salts that can be used in agriculture wherein values A, B, J, R1, R3, R4 and n are given in the invention claim. Also, invention describes a method for control of arthropoda pests to provides high productivity that comprises applying the effective dose of compound of the formula (1) on arthropoda pests and in medium of their habitation, and a the composition with arthropocide activity comprising compounds of the formula (1).

EFFECT: valuable properties of compounds and composition.

23 cl, 34 tbl, 759 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-phenylpyridine of the general formula: (I) wherein R means halogen or halogen atom; R1 means -(C≡C)mR1' or -(CR'=CR'')mR1'; X means -C(O)N(R8)-, -N(R8)C(O)- or -N(R8)-(CH2)p- wherein m = 0-4 and p = 1-2; values of radicals R1', R2, R3', R3, R4, R4', R8, R' and R'' are given above, and to their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. New compounds are neurokinine-1 antagonists and can be used as medicinal agents in treatment of diseases mediated by neurokinine-1 receptors.

EFFECT: valuable medicinal properties of derivatives.

13 cl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 4-phenylpyridine of the following general formulae: (IA)

and (IB) wherein R1 means and , or -NH(CH2)2OH, -NR3C(O)CH3 or -NR3C(O)-cyclopropyl; R2 means methyl or chlorine atom; R3 means hydrogen atom or methyl; R means hydrogen atom or -(CH2)2OH; n = 1 or 2, and their pharmaceutically acceptable acid-additive salts. Also, invention describes a medicinal agent possessing effect of agonist of NK-1 receptors based on these compounds. Proposed compounds show good affinity degree to NK-1 receptors and can be used in treatment or prophylaxis of diseases associated with these receptors.

EFFECT: valuable medicinal properties of compounds and agent.

10 cl, 1 tbl, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active ortho-substituted nitrogen-containing bis-aryl compounds. Invention describes compounds of the formula (I): wherein A1, A2, A3, A4, A5, A6, A7 and A8 mean independently of one another nitrogen atom or -CH and wherein at least one or two (not above) these groups mean nitrogen atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x has a value 0, 1, 2, 3 or 4 and R(14) means alkyl c 1, 3, 4, 5 or 6 carbon atoms, phenyl or isoxazolyl wherein phenyl and isoxazolyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J, CF3, OCF3, alkyl with 1, 2, 3 or 4 carbon atoms and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y has a value 0, 1, 2, 3 or 4but y can't mean 0 if R(16) means -OR(17), and R(16) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3 carbon atoms, -OR(17), phenyl or pyridyl wherein phenyl and pyridyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(17) means hydrogen atom; or R(3) means -CHR(18)R(19) wherein R(18) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms and R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition showing effect that inhibits K+-channel and comprising the effective amount of at least compound of the formula (I) and using compounds of the formula (I). Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 8 tbl, 35 ex

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