Amide derivatives, method for production thereof (variants), pharmaceutical composition and inhibition method

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

 

This invention relates to certain derivatives of amide, which are useful as inhibitors mediasound cytokine diseases. This invention also relates to methods for amide derivatives of the present invention, the containing pharmaceutical compositions and their use in therapeutic methods, for example, due to their ability to inhibit mediasound cytokine disease.

Derivative amide described in this invention are inhibitors of the production of cytokines, such as Tumor Necrosis Factor Tissue (hereinafter TNF)such as TNFαand various representatives of the family of interleukin (hereinafter IL)such as IL-1, IL-6 and IL-8. Accordingly, the compounds of this invention may be useful in the treatment of diseases or clinical conditions, in which there is a surplus production of cytokines, such as excessive production of TNFα or IL-1. It is known that cytokines are produced by various cells, such as monocytes and macrophages, and that they cause the development of many physiological effects, which are believed to play an important role in the disease or medical conditions, such as inflammation and immunoregulation. For example, TNFα and IL-1 is involved in cell signaling cascade, which is believed to contribute to patol the Gia painful condition such as inflammation and allergic diseases, and cytokineinduced toxicity. It is also known that in some cellular systems, the production of TNFα precedes and mediium 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, stimulating allocation of proteolytic enzymes such as collagenase, activation of the immune system, for example, stimulation of T-helper cells, the activation steps of osteoclasts, leading to resorbtive calcium, stimulating allocation proteoglycans, for example, cartilage, promoting cell proliferation and angiogenesis.

Also believe that cytokines are involved in the generation and development of painful conditions such as inflammation and allergic diseases, such as inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel, ulcerative colitis, Crohn's disease and gastritis), skin diseases (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis, allergic rhinitis, respiratory distress syndrome in adults and chronic obstructive pulmonary disease), and in the generation and time is United of various cardiovascular and cerebral-vascular disorders, such as congestive heart failure, myocardial infarction, atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, Alzheimer's disease, disorders associated with reperfusion injury, vascular damage, including restenosis and disease of the peripheral blood vessels, and, for example, various disorders of bone metabolism such as osteoporosis (including age and postmenopausal osteoporosis), Paget's disease, metastases to bone, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteoporosis and periodontitis, and the abnormal changes in bone metabolism which may accompany rheumatoid arthritis and osteoarthritis. Excessive production of cytokine is also involved in MediaLounge some complications in bacterial, fungal and/or viral infections, such as the syndrome of bacterial endotoxin-toxic shock, septic shock and toxic shock, and in MediaLounge certain complications of surgery or injury of the CNS, such as neurotrauma or ischemic stroke. Excessive production of cytokine is also involved in MediaLounge or exacerbation of the disease, including resorption of cartilage or muscles, pneumosclerosis, cirrhosis, renal fibrosis, cachexia, found in certain chronic diseases, such as slocate the state of the disease and acquired immunodeficiency syndrome (AIDS), the invasiveness of tumors and tumor metastases, and multiple sclerosis.

Evidence that TNFα plays a Central role in the signaling cascade of cells, which leads to rheumatoid arthritis, is the efficiency of clinical research with antibodies to TNFα (The Lancet, 1994, 344, 1125, and the British Journal of Rheumatology, 1995, 34, 334).

Thus, cytokines, such as TNFα and IL-1 are important mediators significant range of diseases and clinical conditions. Accordingly, suppose that the inhibition of the production and/or activity of these cytokines may be useful in the prevention, control or treatment of such diseases and clinical conditions.

Not arguing that the compounds of this invention have pharmacological action only because of the effect on a single biological process, suppose that the compounds inhibit the action of cytokines through inhibition of the enzyme R kinase. R Kinase, also known as binding the cytokine suppressor protein (hereinafter CSBP) and reactivating kinase (hereinafter RK)are a family of enzymes mitogenactivated protein (next MAP) kinases, about which we know that they are activated under physiological stress, such as caused by ionizing radiation, cytotoxic agents, and toxins such as endotoxins, such as bacterial shall lipopolysaccharide, and a number of agents, such as cytokines, for example TNFα and IL-1. It is known that R kinase phosphorylates some intracellular proteins that are involved in the cascade of enzymatic steps, which leads to the biosynthesis and secretion of cytokines, such as TNFα and IL-1. Known inhibitors R kinase described by G.J. Hanson in Expert Opinions on Therapeutic Patents, 1997, 7, 729-733. It is known that R kinase exists in the form of isoforms identified as Rα and Rβ.

The compounds of this invention are inhibitors of the production of cytokines, such as TNF, in particular TNFαand various interleukins, in particular IL-1.

Some derivatives of 3-(5-benzamido-2-were)-3,4-dihydroquinazolin-4-it is described in Chemical Abstracts, volume 77, abstract 19599. Disclosed compounds include 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-one, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-one and 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-one.

According to one aspect of the present invention represented by the compound of formula Ia

in which X is-NHCO - or-CONH-;

m is 0, 1, 2 or 3;

R1is hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphonyl is, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)allylcarbamate,N,Ndi[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (1-6C)alkanolamine,N-(1-6C)alkyl-(1-6C)alkanolamine,N-(1-6C)alkylsulfonyl,N,Ndi[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonyl,N-(1-6C)alkyl-(1-6C)alkanesulfonyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di[(1-6C)alkyl] amino-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl, carbarnoyl-1-6C)alkyl,N-(1-6C)allylcarbamate-(1-6C)alkyl,N,Ndi[(1-6C)alkyl]carbarnoyl-(1-6C)alkyl, halogen-(2-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-6C)alkoxy(2-6C)alkoxy, cyano-(1-6C)-alkoxy, carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)-alkoxy, carbarnoyl-(1-6C)alkoxy, N-(1-6C)allylcarbamate-(1-6C)-alkoxy,N,Ndi[(1-6C)alkyl]carbarnoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di[(1-6C)alkyl]-amino-(2-6C)alkoxy, halogen-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-6C)alkoxy(2-6C)alkylamino, cyano-(1-6C)-alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino, carbarnoyl-(1-6C)alkylamino,N-(1-6C)allylcarbamate-(1-6C)alkylamino,N,Ndi[(1-6C)alkyl]carbarnoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino, (1-6C-alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkylhalides-(1-6C)alkylamino,N-(1-6C)alkylperoxy-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxy(2-6C)alkylamino,N-(1-6C)alkylene-(1-6C)alkylamino,N-(1-6C)alkylcarboxylic-(1-6C)alkylamino,N-(1-6C)alkyl-(1-6C)-alkoxycarbonyl-(1-6C)-alkylamino,N-(1-6C)allylcarbamate-(1-6C)alkylamino,N-(1-6C)-alkyl-N-(1-6C)allylcarbamate-(1-6C)-alkylamino,N-(1-6C)alkyl-N,Ndi[(1-6C)alkyl]carbarnoyl-(1-6C)-alkylamino,N-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino-(2-6S) -alkylamino,N-(1-6C)alkyl, di[(1-6C)alkyl]amino-(2-6C)alkylamino, halogen-(2-6C)alkanolamine, hydroxy-(2-6C)alkanolamine, (1-6C)alkoxy(2-6C)-alkanolamine, cyano-(2-6C)alkanolamine, carboxy-(2-6C)alkanolamine, (1-6C)alkoxycarbonyl- (2-6S)-alkanolamine, carbarnoyl-(2-6C)alkanolamine,N-(1-6C)allylcarbamate-(2-6C) alkanolamine,N,Ndi[(1-6C)alkyl]carbarnoyl-(2-6C)alkanolamine, amino-(2-6C)alkanolamine, (1-6C)alkylamino-(2-6S)-alkanolamine or di-[(1-6C)alkyl]amino-(2-6C)alkanolamine,

or R1is aryl, aryl-(1-6C)alkyl, aryl-(1-6C)-alkoxy, aryloxy, arylamino,N-(1-6C)alkylamino, aryl-(1-6C)alkylamino,N-(1-6C)alkylaryl-(1-6C)alkylamino, aroylamino, arylsulfonamides,N-arylsulfonyl, aryl-(2-6C)alkanolamine, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaromatic, heteroaryl-(1-6C)alkoxy, is heteroarenes, N-(1-6C)alkyldiethanolamine, heteroaryl-(1-6C)alkylamino,N-(1-6C)alkylglycerol-(1-6C)alkylamino, heteroarylboronic, heteroarylboronic,N-heteroarylboronic, heteroaryl-(2-6C)alkanolamine, heteroaryl-(1-6C)alkoxy-(1-6C)alkyl, heteroaryl-(1-6C)alkylamino-(1-6C)alkyl,N-(1-6C)alkylglycerol-(1-6C)alkylamino-(1-6C)alkyl, heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclic, heterocyclic-(1-6C)alkoxy, heterocyclisation,N-(1-6C)alkyldiethanolamine, heterocyclyl-(1-6C)alkylamino,N-(1-6C)-alkylglycerol-(1-6C)alkylamino, geterotsiklicheskikh, heterocyclization,N-heterocyclisation, heterocyclyl-(2-6C)alkanolamine, heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl, heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl, orN-(1-6C)alkylglycerol-(1-6C)alkylamino-(1-6C)alkyl,

or (R1)mis (1-3C)alkylenedioxy,

and where any of the substituents R1defined above, which contains a CH2the group, which is attached to 2 carbon atoms, or CH3group that is attached to the carbon atom, may not necessarily be on each of the specified CH2or CH3group Deputy selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl,

and where any aryl, heteroaryl or g is teracycline group in the substituent R 1can optionally have 1 or 2 substituent selected from hydroxy, halogen, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)allylcarbamate,N,Ndi-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[ (1-6C)alkyl]amino, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl,

and where any heterocyclyl group in the substituent R1may optionally have 1 or 2 substituent selected from oxo or tocography;

n is 0, 1 or 2;

R2is hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino or di-[(1-6C)alkyl]amino;

R3is hydrogen, halogen, (1-6C)alkyl or (1-6C)alkoxy;

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

Q is aryl, aryloxy, aryl-(1-6C)alkoxy, arylamino,N-(1-6C)alkylamino, aryl-(1-6C)alkylamino,N-(1-6C)alkylaryl-(1-6C)alkylamino, aroylamino, arylsulfonamides,N-arylcarbamoyl,N-arylsulfonyl, aryl-(2-6C}-alkanolamine, (3-7C)cycloalkyl, heteroaryl, heteroaromatic, heteroaryl-(1-6C)alkoxy, heteroallyl,N-(1-6C)alkyldiethanolamine, heteroaryl-(1-6C)alkilani what about the, N-(1-6C)alkylglycerol-(1-6C)alkylamino, heteroarylboronic, heteroarylboronic,N-heteroarylboronic,N-heteroarylboronic, heteroaryl-(2-6C)alkanolamine, heterocyclyl, heterocyclic, heterocyclic-(1-6C)alkoxy, heterocyclisation,N-(1-6C)alkyldiethanolamine, heterocyclyl- (1-6C)alkylamino,N-(1-6C)alkylglycerol-(1-6C)-alkylamino, geterotsiklicheskikh, heterocyclization,N-heterocyclization,N-heterocyclisation or heterocyclyl- (2-6C)alkanolamine,

and Q is optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, trifloromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfonyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)allylcarbamate,N,Ndi[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (1-6C)alkanolamine,N-(1-6C)alkyl-(1-6C)alkanolamine,N-(1-6C)alkylsulfonyl,N,Ndi-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonyl,N-(1-6C)alkyl-(1-6C)alkanesulfonyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl is, (1-6C)alkoxycarbonyl-(1-6C)alkyl, carbarnoyl-(1-6C)alkyl,N-(1-6C)allylcarbamate-(1-6C)alkyl,N,Ndi-[(1-6C)alkyl]-carbarnoyl-(1-6C)alkyl, halogen-(2-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-6C)alkoxy(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbarnoyl-(1-6C)alkoxy,N-(1-6C)allylcarbamate-(1-6C)alkoxy,N,Ndi-[(1-6C)alkyl]carbarnoyl-(1-6C)alkoxy, amino-(2-6C)-alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]-amino-(2-6C)alkoxy, halogen-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-6C)alkoxy(2-6C)alkylamino, cyano-(1-6C)-alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino, carbarnoyl-(1-6C)alkylamino,N-(1-6C)-allylcarbamate-(1-6C)alkylamino,N,Ndi-[(1-6C)alkyl]carbarnoyl(1-6C)alkylamino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkylhalides-(1-6C)alkylamino,N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxy(2-6C)alkylamino,N-(1-6C)alkylene-(1-6C)alkylamino,N-(1-6C)alkylcarboxylic-(1-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)-alkylamino,N-(1-6C)allylcarbamate-(1-6C)alkylamino,N-(1-6C)alkyl-N-(1-6C)allylcarbamate-(1-6C)alkylamino,N-(1-6C)-alkyl-N,Ndi-[(1-6C)alkyl]carbarnoyl-(1-6C)alkylamino,N-(1-6C)-alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino, -(1-6C)alkyl, di-[(1-6C)alkyl]amino-(2-6S)-alkylamino, halogen-(2-6C)alkanolamine, hydroxy-(2-6S)-alkanolamine, (1-6C)alkoxy(2-6C)alkanolamine, cyano-(2-6C)alkanolamine, carboxy-(2-6C)alkanolamine, (1-6C)-alkoxycarbonyl-(2-6C)alkanolamine, carbarnoyl-(2-6S)alkanolamine,N-(1-6C)allylcarbamate-(2-6C)alkanolamine,N,Ndi[(1-6C)alkyl]carbarnoyl-(2-6C)alkanolamine, amino-(2-6S) -alkanolamine, (1-6C)alkylamino-(2-6C)alkanolamine, di-[(1-6C)alkyl]amino-(2-6C)alkanolamine, aryl, aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, aryloxy, arylamino,N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino,N-(1-6C)alkylaryl-(1-6C)-alkylamino, aroylamino, arylsulfonamides,Narylsulfonyl, aryl-(2-6C)alkanolamine, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaromatic, heteroaryl-(1-6C)alkoxy, heteroaryl a melamine,N-(1-6C)alkyl-heteroarenes, heteroaryl-(1-6C)-alkylamino,N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylboronic, heteroarylboronic,N-heteroaryl-sulfamoyl, heteroaryl-(2-6C)alkanolamine, heteroaryl-(1-6C)alkoxy-(1-6C)alkyl, heteroaryl-(1-6C)alkylamino-(1-6C) alkyl,N-(1-6C)alkylglycerol-(1-6C)alkylamino-(1-6C)alkyl, heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclic, heterocyclic-(1-6C)alkoxy, heterocyclisation,N-(1-6C)alkyl-heterocyclisation, heterocyclyl-(1-6C)alkylamino,N-(1-6C)alkylglycerol-(1-6C)Ala is laminitis, geterotsiklicheskikh-Mino, heterocyclization,Ngeterotsiklicheskikh, heterocyclyl-(2-6C)alkanolamine, heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl, heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl, andN-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl,

or Q is replaced by (1-3C)alkylenedioxy,

and where any Deputy radical Q defined above, which contains a CH2the group, which is attached to 2 carbon atoms, or CH3group that is attached to the carbon atom, may not necessarily be on each of the specified CH2or CH3group Deputy selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl,

and where any aryl, heteroaryl or heterocyclyl group Deputy radical Q may optionally have 1 or 2 substituent selected from hydroxy, halogen, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)allylcarbamate,N,Ndi-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl,

and where Q, if it is heterocyclyl group or contains heterocyclyl group or Liu is th heterocyclyl group Deputy radical Q may optionally have 1 or 2 substituent, selected from oxo or tocography;

or its pharmaceutically acceptable salt or in vivo degradable ester

with the exception of 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it.

According to another aspect of the present invention represented by the compound of formula Ib

where m is 0, 1, 2 or 3;

R1is hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfonyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)allylcarbamate,N,Ndi[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (1-6C)alkanolamine,N-(1-6C)alkylsulfonyl,N,Ndi[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonyl,N-(1-6C) alkyl-(1-6C)alkanesulfonyl, halogen-(1-6C) alkyl, hydroxy-(1-6C)alkyl, (1-6C)-alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)-alkyl]-amino-(1-6C)by alkyl, carboxy-(1-6C)alkyl, (1-6C)-alkoxycarbonyl-(1-6C)alkyl, carbarnoyl-(1-6C)alkyl,N-(1-6C)allylcarbamate-(1-6C)alkyl,N,Ndi(1-6C)alkyl]carbarnoyl-(1-6C)alkyl, halogen-(2-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-6C)alkoxy(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbarnoyl-(1-6C)alkoxy,N-(1-6C)allylcarbamate-(1-6C)alkoxy,N,Ndi[(1-6C)alkyl]carbarnoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di[(1-6C)alkyl]amino-(2-6C)-alkoxy, halogen-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-6C)-alkoxy-(2-6C)alkylamino, cyano-(1-6C)alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino, carbarnoyl-(1-6C)alkylamino,N-(1-6C)allylcarbamate-(1-6C)-alkylamino,N,Ndi[(1-6C)alkyl] carbarnoyl-(1-6C)alkylamino, amino-(2-6S)-alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]-amino-(2-6C) alkylamino,N-(1-6C)alkylhalides-(1-6C)alkylamino,N(1-6C)alkylperoxy-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)-alkoxy-(2-6C)alkylamino,N-(1-6C)alkylene-(1-6C)alkylamino,N-(1-6C)alkylcarboxylic-(1-6C)alkylamino,N-(1-6C)alkyl- (1-6C) -alkoxycarbonyl-(1-6C)alkylamino,N-(1-6C)allylcarbamate-(1-6C)-alkylamino,N-(1-6C)alkyl-N-(1-6C)-allylcarbamate-(1-6C)alkylamino,N-(1-6C)alkyl-N,Ndi[(1-6C)-alkyl]carbarnoyl-(1-6C)alkylamino,N-(1-6C)alkylamino-(2-6S)-alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl, di[(1-6C)alkyl]amino-(2-6C)alkylamino, halogen-(2-6C)alkanolamine, hydroxy-(2-6S)-alkanolamine, (1-6C)-alkoxy-(2-6C)alkanoyl the Mino, cyano-(2-6S)-alkanolamine, carboxy-(2-6C)alkanolamine, (1-6C)alkoxycarbonyl-(2-6S)-alkanolamine, carbarnoyl-(2-6C)alkanolamine,N-(1-6C)-allylcarbamate-(2-6C)alkanolamine,N,Ndi[(1-6C)alkyl]-carbarnoyl-(2-6C)alkanolamine, amino-(2-6C)alkanolamine, (1-6C)alkylamino-(2-6C)alkanolamine or di-[(1-6C)alkyl]amino-(2-6C)alkanolamine,

or R1is aryl, aryl-(1-6C)alkyl, aryl-(1-6C)-alkoxy, aryloxy, arylamino,N-(1-6C)alkylamino, aryl-(1-6C)alkylamino,N-(1-6C)alkylaryl-(1-6C)alkylamino, aroylamino, arylsulfonamides,N-arylsulfonyl, aryl-(2-6S)-alkanolamine, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaromatic, heteroaryl-(1-6C)alkoxy, heteroallyl,N-(1-6C)alkyldiethanolamine, heteroaryl-(1-6C)alkylamino,N-(1-6C)alkylglycerol-(1-6C)alkylamino, heteroarylboronic, heteroarylboronic,N-heteroarylboronic, heteroaryl-(2-6C)alkanolamine, heteroaryl-(1-6C)alkoxy-(1-6C)alkyl, heteroaryl-(1-6C)alkylamino-(1-6C)alkyl,N-(1-6C)-alkylglycerol-(1-6C)alkylamino-(1-6C)alkyl, heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclic, heterocyclic-(1-6C)alkoxy, heterocyclisation,N-(1-6C)alkyldiethanolamine, heterocyclyl-(1-6C)alkylamino,N-(1-6C)-alkylglycerol-(1-6C)alkylamino, geterotsiklicheskikh, heterocyclization,N-heterocyclisation the Ohm, heterocyclyl-(2-6C)alkanolamine, heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl, heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl, orN-(1-6C)alkylglycerol-(1-6C)alkylamino-(1-6C)alkyl,

or (R1)mis (1-3C)alkylenedioxy,

and where any substituent R1defined above, which contains a CH2the group, which is attached to 2 carbon atoms, or CH3group that is attached to the carbon atom, may not necessarily be on each of the specified CH2or CH3group Deputy selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl, and where any aryl, heteroaryl or heterocyclyl group in the substituent R1may optionally have 1 or 2 substituent selected from hydroxy, halogen, (1-6C)alkyl, (1-6C) alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)allylcarbamate,N,Ndi-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)-alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl;

n is 0, 1 or 2;

R2is hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl is, (1-6C)-alkoxy, (1-6C)alkylamino or di-[(1-6C)alkyl]amino;

R3is hydrogen, halogen, (1-6C)alkyl or (1-6C)alkoxy;

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

Q is aryl, aryloxy, aryl-(1-6C)alkoxy, arylamino,N- (1-6C)alkylamino, aryl-(1-6C)alkylamino,N-(1-6C)alkylaryl-(1-6C)alkylamino, aroylamino, arylsulfonamides,N-arylcarbamoyl,N-arylsulfonyl, aryl-(2-6S)-alkanolamine, (3-7C)cycloalkyl, heteroaryl, heteroaromatic, heteroaryl-(1-6C)alkoxy, heteroallyl,N-(1-6C)-alkyldiethanolamine, heteroaryl-(1-6C)alkylamino,N-(1-6C)-alkylglycerol-(1-6C)alkylamino, heteroarylboronic, heteroarylboronic,N-heteroarylboronic,N-heteroarylboronic, heteroaryl-(2-6C)alkanolamine, heterocyclyl, heterocyclic, heterocyclic-(1-6C)alkoxy, heterocyclisation,N-(1-6C)alkyldiethanolamine, heterocyclyl-(1-6C)alkylamino,N-(1-6C)alkylglycerol-(1-6C)-alkylamino, geterotsiklicheskikh, heterocyclisation a melamine,N-heterocyclization,N-heterocyclisation or heterocyclyl-(2-6C)alkanolamine,

and Q is optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, trifloromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)Alky is the sulfinil, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)allylcarbamate,N,Ndi[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (1-6C)-alkanolamine,N-(1-6C)alkylsulfonyl,N,Ndi-[(1-6C)-alkyl]sulfamoyl, (1-6C)alkanesulfonyl,N-(1-6C)alkyl-(1-6C)alkanesulfonyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl, carbarnoyl-(1-6C)alkyl,N-(1-6C)allylcarbamate-(1-6C)alkyl,N,Ndi-[(1-6C)alkyl]-carbarnoyl-(1-6C)alkyl, halogen-(2-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-6C)alkoxy(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbarnoyl-(1-6C)alkoxy,N-(1-6C)allylcarbamate-(1-6C)alkoxy,N,Ndi-[(1-6C)alkyl]carbarnoyl-(1-6C)alkoxy, amino-(2-6C)-alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]-amino-(2-6C)alkoxy, halogen-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-6C)alkoxy(2-6C)alkylamino, cyano-(1-6C)-alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino, carbarnoyl-(1-6C)alkylamino,N-(1-6C)allylcarbamate-(1-6C)alkylamino,N,Ndi-[(1-6C)alkyl]carbarnoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]and the eno-(2-6C)alkylamino, N-(1-6C)alkylhalides-(1-6C)alkylamino,N-(1-6C)alkylperoxy-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxy(2-6C)alkylamino,N-(1-6C)alkylene-(1-6C)alkylamino,N-(1-6C)alkylcarboxylic-(1-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino,N-(1-6C)allylcarbamate-(1-6C)alkylamino,N-(1-6C)alkyl-N-(1-6C)allylcarbamate-(1-6C)alkylamino,N-(1-6C)alkyl-N,Ndi[(1-6C)alkyl]carbarnoyl-(1-6C)alkylamino,N-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)-alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl, di-[(1-6C)alkyl]-amino-(2-6C)alkylamino, halogen-(2-6C)alkanolamine, hydroxy-(2-6C)alkanolamine, (1-6C)alkoxy(2-6C)alkanolamine, cyano-(2-6C)alkanolamine, carboxy-(2-6C)alkanolamine, (1-6C)alkoxycarbonyl-(2-6C)alkanolamine, carbarnoyl-(2-6S)-alkanolamine,N-(1-6C)allylcarbamate-(2-6C)alkanolamine,N,Ndi-[(1-6C)alkyl]carbarnoyl-(2-6C)alkanolamine, amino-(2-6C)alkanolamine, (1-6C)alkylamino-(2-6C)alkanolamine, di[(1-6C)alkyl]amino-(2-6C)alkanolamine, aryl, aryl-(1-6C)-alkyl, aryl-(1-6C)alkoxy, aryloxy, arylamino,N-(1-6C)alkylamino, aryl-(1-6C)alkylamino,N-(1-6C)alkylaryl-(1-6C)alkylamino, aroylamino, arylsulfonamides,Narylsulfonyl, aryl-(2-6C)alkanolamine, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaromatic, heteroaryl-(1-6C)-alkoxy, heteroallyl,N-(1-6C)alkyldiethanolamine, heteroaryl-(1-6C)Alky is amino, N-(1-6C)alkylglycerol-(1-6C)-alkylamino, heteroarylboronic, heteroarylboronic,Nheteroarylboronic, heteroaryl-(2-6C)alkanolamine, heteroaryl-(1-6C)alkoxy-(1-6C)alkyl, heteroaryl-(1-6C)-alkylamino-(1-6C)alkyl,N-(1-6C)alkylglycerol-(1-6C)-alkylamino-(1-6C)alkyl, heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclic, heterocyclic-(1-6C)alkoxy, heterocyclisation,N-(1-6C)alkyldiethanolamine, heterocyclyl-(1-6C)alkylamino,N-(1-6C)alkylglycerol-(1-6C)alkylamino, geterotsiklicheskikh, heterocyclization,Ngeterotsiklicheskikh, heterocyclyl-(2-6C)alkanolamine, heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl, heterocyclyl-(1-6C)-alkylamino-(1-6C)alkyl, andN-(1-6C)alkylglycerol-(1-6C)-alkylamino-(1-6C)alkyl,

or Q is replaced by (1-3C)alkylenedioxy,

and where any Deputy radical Q defined above, which contains a CH2the group, which is attached to 2 carbon atoms, or CH3group that is attached to the carbon atom, may not necessarily be on each of the specified CH2or CH3group Deputy selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl,

and where any aryl, heteroaryl or heterocyclyl group Deputy radical Q may optionally have 1 or 2 to cover the El, selected from hydroxy, halogen, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,N-(1-6C)allylcarbamate,N,Ndi-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)-alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl;

or its pharmaceutically acceptable salt or in vivo degradable ester;

with the exception of 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it.

In this description, the term (1-6C)alkyl includes alkyl groups with straight or branched chain, such as propyl, isopropyl and tert-butyl, (3-6C)cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. However references to individual alkyl groups such as "propyl", is only defined for compounds with a straight chain, references to specific branched alkyl groups, such as "isopropyl", is only defined for compounds with branched chain and references to specific cycloalkyl groups, such as "cyclopentyl", defined only for 5-membered rings. Similar conditions apply for the other General terms for example, (1-6C)alkoxy includes methoxy, ethoxy, cyclopropylamine, cyclopentyloxy, (1-6C)alkylamino includes methylamino, ethylamino, cyclobutylamine, cyclohexylamine and di-[(1-6C)alkyl]amino include dimethylamino, diethylamino,N-cyclobutyl-N-methylamino andN-cyclohexyl-N-ethylamino.

It is clear that because of some of the compounds of the formula I defined above may exist in optically active or racemic forms by one or more asymmetric carbon atoms, the invention includes any such optically active or racemic forms, which have the property to inhibit cytokines, in particular TNF. Synthesis of optically active forms can be carried out by standard methods of organic chemistry well known in this field, for example by synthesis from optically active starting materials or by separating racemic forms. Also inhibiting properties against TNF can be estimated using standard laboratory methods presented in this description.

The appropriate values of common radicals, described above, are presented below.

A suitable value for R1or Q, if he is aryl, Deputy radical Q, if it is aryl or for the aryl group in the substituent R1or Q radical or the Deputy the radical Q is for example, phenyl, indenyl, indanyl, naphthyl, tetrahydronaphthyl or fluorenyl, preferably phenyl.

A suitable value for R1or Q, if it is heteroaryl, for the heteroaryl group in the substituent R1or Q groups for the substituent of the radical Q, if it is heteroaryl or heteroaryl group Deputy radical 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 of which has up to 5 heteroatoms in the ring selected from 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, thianthrenes, benzofuranyl, peridontal, acridines or phenanthridine, 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, dibenzothiophenes or xantener, more preferably furyl, thienyl, isoxazolyl, thiazolyl, pyridyl, benzothiazyl, benzofurazanyl, hinely, carbazolyl, dibenzofurans or dibenzothiophene.

A suitable value for R1or Q, if it is heterocyclyl, Deputy radical Q, if it is heterocyclyl, or for heterocyclyl group in the substituent R1or Q is a radical or Deputy radical Q is, for example, non-aromatic saturated or partially saturated 3-to 10-membered monocyclic or bicyclic ring containing up to 5 heteroatoms selected from oxygen, nitrogen and sulfur, such as oxiranyl, oxetanyl, azetidine, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidine, 1,1-dioxothiazolidine, morpholinyl, tetrahydro-1,4-thiazines, 1,1-dioxotetrahydrofuran-1,4-thiazines, piperidinyl, homopiperazine, piperazinil, homopiperazine, dihydropyridines, tetrahydropyridine, or dihydropyrimidine tetrahydropyrimidines or b is soproizvodnje, such as 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl, indolinyl, isoindolyl, bromanil and isopropanol, preferably azetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, 1,1-dioxothiazolidine-2-yl, morpholino, 1,1-dioxotetrahydrofuran-4H-1,4-thiazin-4-yl, piperidine-3-yl, piperidine-4-yl, homopiperazin-1-yl, piperidino, piperazine-1-yl or homopiperazin-1-yl. A suitable value for such a group which has 1 or 2 substituent selected from oxo or tocography is, for example, 2-oxopyrrolidin, 2-dioxopyrimidine, 2-Oxymetazoline, 2-dioxoimidazolidin, 2-oxopiperidine, 2.5-dioxopyrimidine, 2.5-dioxoimidazolidin or 2,6-dioxopiperidin.

A suitable value for Q when it is (3-7C)-cycloalkyl is, for example, non-aromatic mono - or bicyclic ring containing 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl, preferably cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, more preferably cyclohexyl.

Suitable values for R1, R2or R3groups, or different substituents of the radical Q or aryl, heteroaryl or heterocyclyl group in R1or aryl, heteroaryl or heterocycles group substituent on Q is Vlada:

for halogen: fluorine, chlorine, bromine and iodine;

for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl or cyclohexyl;

for (2-6C)alkenyl: vinyl and allyl;

for (2-6C)quinil: ethinyl and 2-PROPYNYL;

for (1-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy, cyclopropylamine, butoxy, CYCLOBUTANE, cyclopentyloxy;

for (1-6C)alkylamino: methylamino, ethylamino, propylamino, cyclobutylamine, cyclohexylamine;

for di-[(1-6C)alkyl]amino: dimethylamino, diethylamino andN-ethyl-N-methylamino;

for (1-6C)alkoxycarbonyl: methoxycarbonyl, etoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl;

forN-(1-6C)allylcarbamate:N-methylcarbamoyl,N-ethylcarbamate andN-propellerblades;

forN,Ndi-[(1-6C)alkyl]carbamoyl:N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl andN,N-diethylcarbamoyl;

for (2-6C)alkanoyl: acetyl and propionyl;

for halogen-(1-6C)alkyl: vermeil, chloromethyl, methyl bromide, deformity, dichloromethyl, dibromomethyl, 2-foretel, 2-chloroethyl and 2-bromacil;

for hydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl;

for (1-6C)alkoxy-(1-6C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;

for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1 canoe the silt and 3-cyanopropyl;

for amino-(1-6C)alkyl: aminomethyl, 2-amino-ethyl, 1-amino-ethyl and 3-aminopropyl;

for (1-6C)alkylamino-(1-6C)alkyl: methylaminomethyl, ethylaminomethyl, 1-methylaminomethyl, 2-methylaminomethyl, 2-ethylaminomethyl and 3-methylaminopropyl;

for di-[(1-6C)alkyl]amino-(1-6C)alkyl: dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylaminopropyl.

Suitable values for R1or Q and suitable values for substituents on R1or Q are:

for aryl-(1-6C)alkyl: benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl;

for aryl-(1-6C)alkoxy: benzyloxy and 2-phenylethane;

for aryloxy: phenoxy and 2 naphthyloxy;

for arylamino: aniline;

forN- (1-6C)alkylamino:N-methylaniline andN-ethylaniline;

for aryl-(1-6C)alkylamino: benzylamino, 2-phenethylamine, 2-phenylpropylamine and 3 phenylpropylamine;

forN-(1-6C)alkylaryl-(1-6C)alkylamino:N-benzyl-N-methylamino;

for aroylamino: benzamide and 2 naphthylamine;

for arylsulfonamides: benzosulfimide;

forNarylcarbamoyl:N-phenylcarbamoyl;

forNarylsulfonyl:N-phenylsulfonyl;

for aryl-(2-6C)alkanolamine: phenylacetamido and 3 phenylpropionamide;

for heteroaryl-(1-6C)alkyl: heteroaromatic, 2-heteroaromatic, 2-heteroarylboronic and 3-heteroaromatic;

for heteroa the Il-(1-6C)alkoxy: heteroaromatics and 2 heteroaromatics;

forN-(1-6C)alkyldiethanolamine:N-methylethanolamine;

for heteroaryl-(1-6C)alkylamino: heterotrimetallic, 2-heteroarylboronic and 3 heteroarylboronic;

forN-(1-6C)alkylglycerol-(1-6C)alkylamino:N-methylethanolamine andNmethyl-2-heteroarylboronic;

for heteroaryl-(2-6C)alkanolamine: heteroalicyclic and 3 heteroarylboronic;

for heteroaryl-(1-6C)alkoxy-(1-6C)alkyl: heteroeroticism, 2-heteroepitaxial and 3-heteroaromatic;

for heteroaryl-(1-6C)alkylamino-(1-6C)alkyl: heteroarylboronic, 2-heteroarylboronic and 3-heteroarylboronic;

forN-(1-6C)alkylglycerol-(1-6C)alkylamino-(1-6C)alkyl:N-heteroaromatic-N-methylaminomethyl,N-(2-heteroaromatic)-N-methylaminomethyl andN-(3-heteroaromatic)-N-methylaminomethyl;

for heterocyclyl-(1-6C)alkyl: heterocyclyl, 2-heterocyclisation, 2-heterocyclisation and 3-heterocyclisation;

for heterocyclyl-(1-6C)alkoxy: heterocyclisation and 2 heterocyclics;

forN-(1-6C)alkyldiethanolamine:N-methylethanolamine;

for heterocyclyl-(1-6C)alkylamino: heterocyclisation, 2-heterocyclisation and 3 heterocyclisation;

forN-(1-6C)alkylglycerol-(1-6C)alkylamino:N-methylglutaronitrile the Mino and N-methyl-2-heterocyclisation;

for heterocyclyl-(2-6C)alkanolamine: heterocyclization and 3 heterocyclisation;

for heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl: heterocyclisation, 2-heterocyclisation and 3-heterocyclization;

for heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl: getprocessimagefilenamea, 2-getprocessimagefilenamea and 3-getprocessimagefilenamea;

forN-(1-6C)alkylglycerol-(1-6C)alkylamino-(1-6C)alkyl:N-heterocyclyl-N-methylaminomethyl,N-(2-hetero-cyclicity)-N-methylaminomethyl andN-(3-heterocyclisation)-N-methylaminomethyl;

for (1-3C)alkylenedioxy: methylenedioxy, Ethylenedioxy, trimethylenediamine;

for (1-6C)alkylthio: methylthio, ethylthio, propylthio;

for (1-6C)alkylsulphonyl: methylsulphonyl, ethylsulfinyl and propylsulfonyl;

for (1-6C)alkylsulphonyl: methylsulphonyl, ethylsulfonyl and propylsulfonyl;

for (2-6C)alkanoyloxy: acetoxy, propionyloxy;

for (1-6C)alkanolamine: formamido, acetamido, propionamido;

forN- (1-6C)alkyl-(1-6C)alkanolamine:N-methylacetamide andN-methylpropionamide;

forN-(1-6C)alkylsulphonyl:N-methylsulfonyl andN-ethylsulfanyl;

forN,Ndi-[(1-6C)alkyl]sulfamoyl:N,N-dimethylsulphamoyl;

for (1-6C)alkanesulfonyl: methanol is enamide, acanalonia;

forN-(1-6C)alkyl-(1-6C)alkanesulfonyl:N-methylmethanesulfonamide andN-methylethanolamine;

for carboxy-(1-6C)alkyl: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 3-carboxypropyl and 4-carboxybutyl;

for (1-6C) alkoxycarbonyl-(1-6C)alkyl: methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropionyl and 3-ethoxycarbonylphenyl;

for carbarnoyl-(1-6C)alkyl: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylmethyl;

forN-(1-6C)allylcarbamate-(1-6C)alkyl:N-methylcarbamoylmethyl,N-ethylcarboxylate,N-propylgallate, 1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamate)ethyl, 2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamate)ethyl and 3-(N-methylcarbamoyl)propyl;

forN,Ndi-[(1-6C)alkyl]carbarnoyl-(1-6C)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-(2-6C)alkoxy: 2-chloroethoxy, 2-bromoethoxy, 3 chloropropoxy, 1,1,2,2-is eraftineense and 2,2,2-triptoreline;

for hydroxy-(2-6C)alkoxy: 2-hydroxyethoxy, 3 hydroxypropoxy, 2-hydroxy-1-methylethoxy, 2-hydroxy-2-propoxy and 4-hydroxybutane;

for (1-6C)alkoxy(2-6C)alkoxy: 2-methoxyethoxy, 2-ethoxyethoxy, 3 methoxypropane, 2-methoxy-1-methylethoxy and 4 amoxibiotic;

for cyano-(1-6C)alkoxy: cyanoethoxy, 2-cyanoethoxy and 3 cyanopropionic;

for carboxy-(1-6C)alkoxy: carboxymethoxy, 1 carboxymethoxy, 2-carboxymethoxy and 3 carboxypropyl;

for (1-6C)alkoxycarbonyl-(1-6C)alkoxy: ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, tert-butoxycarbonylmethyl, 2-ethoxycarbonylmethoxy and 3 ethoxycarbonylmethoxy;

for carbarnoyl-(1-6C)alkoxy: carbamoylphenoxy and 2 carbamoylphenoxy;

forN-(1-6C)allylcarbamate-(1-6C)alkoxy:N-methylcarbamoylmethyl, 2-(N-ethylcarbamate)ethoxy and 3(N-methylcarbamoyl)propoxy;

forN,Ndi[((1-6C)alkyl]carbarnoyl-(1-6C)alkoxy:N,N-dimethylcarbamoyl, 2-(N,N-dimethylcarbamoyl)ethoxy and 3(N,N-diethylcarbamoyl)propoxy;

for amino-(2-6C)alkoxy: 2-aminoethoxy, 2-amino-1-methylethoxy, 3 aminopropoxy, 2-amino-2-methoxypropane and 4 aminobutoxy;

for (1-6C)alkylamino-(2-6C)alkoxy: 2-methylaminoethanol, 2-methylamino-1 methylethoxy and 3 Ethylenedioxy;

for di-[(1-6C)alkyl]amino-(2-6C)alkoxy: 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-dimethylamino what robaxi, 2-dimethylamino-2-methylethoxy, 3 dimethylaminopropoxy and 4 dimethylaminoethoxy;

for halogen-(2-6C)alkylamino: 2-foretelling, 2-chloroethylamine, 2-bromethalin, 3 forprofile and 3 chloropropylamine;

for hydroxy-(2-6C)alkylamino: 2-hydroxyethylamino, 3 hydroxypropylamino, 2-hydroxy-2-methylpropylamine and 4 hydroxyethylamino;

for (1-6C)alkoxy(2-6C)alkylamino: 2-methoxyethylamine, 2-ethoxyethylene, 3 methoxypropylamine and 3 ethoxypropylamine;

for cyano-(1-6C)alkylamino: cyanomethylene, 2-cyanoethylene and 3 cyanopropionic;

for carboxy-(1-6C)alkylamino: carboxymethylamino, 1 carboxymethylamino, 2-carboxymethylamino and 3 carboxymethylamino;

for (1-6C)alkoxycarbonyl-(1-6C)alkylamino: methoxycarbonylmethylene, 2-(etoxycarbonyl)ethylamino and 3-(tert-butoxycarbonyl)Propylamine;

for carbarnoyl-(1-6C)alkylamino: carbamoylmethyl and 2 carbamoylation;

forN-(1-6C)allylcarbamate-(1-6C)alkylamino:N-methylcarbamoylmethyl,N-ethylcarbodiimide and 2(N-methylcarbamoyl)ethylamino;

forN,Ndi-[(1-6C)alkyl]carbarnoyl-(1-6C)alkylamino:N,N-dimethylcyclohexylamine,N,N-diethylcarbamoyl and 2(N,N-dimethylcarbamoyl)ethylamino;

for amino-(2-6C)alkylamino: 2-aminoethylamino, 3 aminopropylene, 2-amino-2-methylpropylamine and 4-aminobutyl the but;

for (1-6C)alkylamino-(2-6C)alkylamino: 2-methylaminoethanol, 2-ethylaminoethanol, 2-Propylenediamine, 3 methylaminopropane, 3 ethylenepropylene, 2-methylamino-2-methylpropylamine and 4 methylaminopropane;

for di - [(1-6C)alkyl]amino-(2-6C)alkylamino: 2-diethylaminoethylamine, 2-(N-ethyl-N-methylamino)ethylamino, 2-diethylaminoethylamine, 2-dipropylenetriamine, 3 dimethylaminopropylamine, 3 diethylaminopropylamine, 2-dimethylamino-2-methylpropylamine and 4 diethylaminoethylamine;

forN-(1-6C)alkylhalides-(2-6C)alkylamino:N-(2-chloroethyl)-N-methylamino,N-(2-bromacil)-N-methylamino andN-(2-bromacil)-N-ethylamino;

forN-(1-6C)alkylperoxy-(2-6C)alkylamino:N-(2-hydroxyethyl)-N-methylamino,N-(3-hydroxypropyl)-N-methylamino andN-ethyl-N-(2-hydroxyethyl)amino;

forN-(1-6C)alkyl-(1-6C)alkoxy(2-6C)alkylamino:N-methyl-N-(2-methoxyethyl)amino,N-methyl-N-(3-methoxypropyl)amino andN-ethyl-N-(2-methoxyethyl)amino;

forN-(1-6C)alkylene-(1-6C)alkylamino:N(cyanomethyl)-N-methylamino;

forN-(1-6C)alkylcarboxylic-(1-6C)alkylamino:Ncarboxymethyl- N-methylamino andN-(2-carboxyethyl)-N-methylamino;

forN-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino:N-methoxycarbonylmethyl-N-methylamino,N-(2-ethoxycarbonyl later)- N-ethylamino andN-(2-tert-butoxycarbonylmethyl)-N-methylamino;

forN-(1-6C)allylcarbamate-(1-6C)alkylamino:N-carbamoylmethyl-N-methylamino andN-(2-carbamoylethyl)-N-methylamino;

forN-(1-6C)alkyl-N-(1-6C)allylcarbamate-(1-6C)alkylamino:N-(N-methylcarbamoylmethyl)-N-methylamino,N-(N-ethylcarboxylate)-N-methylamino andN-[2-(N-methylcarbamoyl)ethyl]-N-methylamino;

forN-(1-6C)alkyl-N,Ndi-[(1-6C)alkyl]carbarnoyl-(1-6C)-alkylamino:N-(N,N-dimethylcarbamoyl)-N-methylamino andN-[2-(N,N-dimethylcarbamoyl)ethyl]-N-methylamino;

forN-(1-6C)alkylamino-(2-6C)alkylamino:N-(2-amino-ethyl)-N-methylamino,N-(3-aminopropyl)-N-methylamino andN-(4-aminobutyl)-N-methylamino;

forN-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino:N-(2-methylaminomethyl)-N-methylamino,N-(2-methylaminomethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminomethyl)-N-ethylamino andN-(4-methylaminomethyl)-N-methylamino;

forN-(1-6C)alkyl, di((1-6C)alkyl]amino-(2-6C)alkylamino:

N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino andN-(4-dimethylaminomethyl)-N-methylamino;

for halogen-(2-6C)alkanoyl the Mino: 2-chloracetamide and 3 chlorpropamide;

for hydroxy-(2-6C)alkanolamine: 2-hydroxyacetamido and 3 hydroxypropylamino;

for (1-6C)alkoxy(2-6C)alkanolamine: 2-methoxyacetate and 3 methoxypropionate;

for cyano-(2-6C)alkanolamine: 2-cyanoacetamide and 3 cyanopropionic;

for carboxy-(2-6C)alkanolamine: 2-carboxylated and 3 carboxypropyl;

for (1-6C)alkoxycarbonyl-(2-6C)alkanolamine: 2-methoxycarbonylethyl, 2-(tert-butoxycarbonyl)acetamido and 3-methoxycarbonylpropionyl;

for carbarnoyl-(2-6C)alkanolamine: 2-carbamoylated, 3 carbamoylphosphate and 4 carbamoylating;

forN-(1-6C)allylcarbamate-(2-6C)alkanolamine: 2-(N-methylcarbamoyl)acetamido and 3-(N-ethylcarbamate)propionamido;

forN,Ndi-[(1-6C)alkyl]carbarnoyl-(2-6C)alkanolamine: 2-(N,N-dimethylcarbamoyl)acetamido, 2-(N,N-diethylcarbamoyl)acetamido and 3-(N,N-dimethylcarbamoyl)propionamido;

for amino-(2-6C)alkanolamine: 2-aminoacetyl, 2-aminopropionic and 3 aminopropionic;

for (1-6C)alkylamino-(2-6C)alkanolamine: 2-methylaminoethanol, 2-ethylaminoethanol, 2-methylaminopropane and 3 methylaminopropane;

for di-[(1-6C)alkyl]amino-(2-6C)alkanolamine: 2-dimethylaminoacetyl, 2-diethylaminoacetate, 2-dimethylaminopropylamine and 3 dimethylaminopropylamine.

When, as defined above, shall uboy of the substituents of the radicals R 1or Q, which contains a CH2the group, which is attached to 2 carbon atoms, or CH3group that is attached to the carbon atom, may not necessarily be on each of the specified CH2or CH3group Deputy selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl such suitable substituents are, for example, substituted heterocyclyl-(1-6C)alkoxygroup, such as 2-hydroxy-3-piperidinyloxy and 2-hydroxy-3-morpholinopropan, substituted (1-6C)alkylamino-(2-6C)alkoxygroup, such as 2-hydroxy-3-methylaminopropane, substituted di-[(1-6C)alkyl]amino-(2-6C)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-(1-6C)alkylamino, such as 2-hydroxy-3-piperidinophenyl and 2 hydroxy-3-morpholinopropan, substituted amino(2-6C)alkylamino, such as 3-amino-2-hydroxypropylamino, substituted (1-6C)alkylamino-(2-6S)-alkylamino, such as 2-hydroxy-3-methylaminopropane, substituted di-[(1-6C)alkyl]-amino-(2-6C-alkylamino, such as 3-dimethylamino-2-hydroxy-propylamino, 3-[N-(3-dimethylaminopropyl)-N-methylamino]Propylamine and 3-[N-(3-dimethylaminopropyl) N-methylamino]-2-hydroxypropylamino, and substituted (1-6C)alkylamino-(1-6C)alkyl groups such as 2-diethylaminoethylamine, 3-dimethylaminopropylamine, 3-dimethylamino-2,2-dimethylpropylene, 2-morpholinomethyl, 2-piperazine-1-ylethylamine and 3-morpholinepropanesulfonic.

A suitable pharmaceutically acceptable salt of the compounds of formula Ia or Ib is, for example, an acid additive salt of the compounds of formula Ia or Ib which is sufficiently basic, for example an acid additive salt with an organic or inorganic acid, such as hydrochloric, Hydrobromic, sulfuric, triperoxonane, citric or maleic acid, or, for example, the salt of the compounds of formula Ia or Ib, which is sufficiently acidic, for example, salts with alkali or alkaline earth metal such as calcium or magnesium salt, or ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or Tris-(2-hydroxyethyl)amine.

In the art there are known various forms of prodrugs. Examples of such prodrugs can be found in the

a) Design of Prodrugs, edited by H.Bundgaard (Elsevier, 1985) and Methods in Enzymology, volume 42, pp. 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.Bungaard, Chapter 5 "Design and Application of Prodrugs", by H. Bndgaard, pp. 113-191 (1991);

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

d) H.Bungaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988), and

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

Examples of such prodrugs can be used for education, in vivo biodegradable esters of compounds of formula Ia or Ib. In vivo cleaved the ester compounds of the formula Ia or Ib, containing carboxyl group is, for example, pharmaceutically acceptable ester which is cleaved in the human or animal with the formation of the parent acid. Suitable pharmaceutically acceptable esters for carboxy include (1-6C)-alkoxymethyl esters, such as methoxymethyl; (1-6C)-alkanoyloxy esters, such as pivaloyloxymethyl; palidrome ester; (3-8C)cycloalkylcarbonyl(1-6C)-alkalemia esters, for example 1-cyclohexylcarbodiimide; 1,3-dioxolane-2-ylmethylene esters, for example 5-methyl-1,3-dioxolane-2-ylmethyl; (1-6C)alkoxycarbonylmethyl esters, for example 1-methoxycarbonylmethyl, and can be formed at any carboxy group in the compounds of the present invention.

The particular new compounds of this invention include, for example, suitable amide derivatives of the compounds of the formula Ia or Ib or pharmaceutically acceptable salts, where

(a) R3is hydrogen or (1-6C)alkyl, such as methyl, ethyl, PR is drank and isopropyl, preferably R3is hydrogen, stands or ethyl, more preferably hydrogen or stands, and X, R1, R2, Q, m, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(b) Q is phenyl or a heteroaromatic 5 - or 6-membered monocyclic ring or 9 - or 10-membered bicyclic ring containing up to five heteroatoms in the ring selected from oxygen, nitrogen and sulfur, which are the main Deputy, selected from the substituents for Q, as defined above, and X, R1, R2, R3, m, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(c) Q is phenyl, indenolol, indayla or fluorenyl, which optionally has 1, 2 or 3 substituent selected from the substituents for Q, as defined above, and X, R1, R2, R3, m, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(d) Q is phenyl or a heteroaromatic 5 - or 6-membered monocyclic ring or 9 - or 10-membered bicyclic ring containing up to five heteroatoms in the ring selected from oxygen, nitrogen and the career, which are the main Deputy, selected from amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]-amino-(2-6C)alkoxy, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl- (1-6C)-alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl, di-[(1-6C)alkyl]-amino-(2-6C)alkylamino, amino-(2-6C)alkanolamine, (1-6C)-alkylamino-(2-6C)alkanolamine, di-[(1-6C)alkyl]amino-(2-6C)-alkanolamine, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyl-(1-6C)-alkyl and heterocyclyl-(1-6C)alkoxy, and where any heteroaryl or heterocyclyl group in the main Deputy on Q may optionally have 1 or 2 substituent selected from halogen, (1-6C)alkyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and X, R1, R2, R3, m, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(e) Q is phenyl or a heteroaromatic 5 - or 6-membered monocyclic ring or 9 - or 10-membered bicyclic ring containing up to five heteroatoms in the ring selected from oxygen, nitrogen and sulfur, which is s not necessarily have a 1, 2 or 3 substituent selected from hydroxy, halogen, trifloromethyl, cyano, nitro, amino, carboxy, (1-6C) alkyl, (1-6C) alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, (2-6C)alkanoyl, halogen-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)-alkyl, halogen-(2-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-6C)alkoxy(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]-amino-(2-6C)alkoxy, pyridyl, imidazolyl, pyridyl-(1-6C)alkyl, imidazolyl-(1-6C)alkyl, pyridyl-(1-6C)alkoxy, imidazolyl-(1-6C)alkoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-(1-6C)alkylpiperazine, 4-(2-6C)alkanolamine, pyrrolidinyl-(1-6C)alkyl, piperidinyl-(1-6C)alkyl, morpholinyl-(1-6C)alkyl, piperazinil-(1-6C)alkyl, 4-(1-6C)alkylpiperazine-(1-6C)alkyl, 4-(2-6C)-alkanolamine-(1-6C)alkyl, pyrrolidinyloxy, piperidin-yloxy, 1-(1-6C)alkylpiperidines, pyrrolidinyl-(2-6C)-alkoxy, piperidinyl-(2-6C)alkoxy, morpholinyl-(2-6C)alkoxy, piperazinil-(2-6C)alkoxy, 4-(1-6C)alkylpiperazine-(2-6C) -alkoxy and 4-(2-6C)alkanolamine-(2-6C)alkoxy or Q is (1-3C)alkylethoxysulfates, and X, R1, R2, R3, m, n and q as appropriate have any of the values defined above or in this PA is the agraffe for a particular new compounds of the present invention;

(f) Q is phenyl, indenolol, indenolol, fluorenyl or heteroaromatic 5 - or 6-membered monocyclic ring containing up to 3 heteroatoms in the ring selected from oxygen, nitrogen and sulphur which optionally have 1, 2 or 3 substituent selected from hydroxy, halogen, trifloromethyl, cyano, nitro, amino, carboxy, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, (2-6C)alkanoyl, (1-6C)-alkanolamine,N-(1-6C)alkyl-(1-6C)alkanolamine, (1-6C)-alkanesulfonyl,N-(1-6C)alkyl-(1-6C)alkanesulfonyl, phenyl, furil, teinila, azetidine, pyrroline, pyrrolidine, 1,1-dioxothiazolidine, piperidinyl, homopiperazine, morpholine, piperazinil, homopiperazine, pyrrolidinyl-(1-6C) alkyl, piperidinyl-(1-6C)alkyl, morpholinyl-(1-6C)alkyl and piperazinil-(1-6C)alkyl, and where any phenyl, furilla, thienyl or heterocyclyl group in the substituents on Q may optionally have 1 or 2 substituent, selected from halogen, (1-6C)alkyl, (1-6C)alkoxy and (2-6C)alkanoyl, and X, R1, R2, R3, m, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(g) Q is phenyl, fullam, teinila, oxazolium, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, and what thiazolium, pyridium, pyridazinyl, pyrimidinyl, pyrazinium, benzofuranyl, indolium, benzothieno, benzoxazolium, benzimidazolium, benzothiazolium, indusrial, benzofurazanyl, chinaillon, ethanolism, hinazolinam, khinoksalinona or naphthyridine that do not have 1 or 2 substituent selected from the substituents defined above in paragraphs (b), (d) or (e), and X, R1, R2, R3, m, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(h) Q is phenyl, 2 - or 3-fullam, 2 - or 3-tanila, 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-isothiazoline, 2-, 3 - or 4-pyridium, 3 - or 4-pyridazinyl, 2-, 4 - or 5-pyrimidinyl, 2-pyrazinium, 2-, 3-, 5 - or 6-benzofuranyl, 2-, 3-, 5 - or 6-indolium, 2-, 3-, 5 - or 6-benzothieno, 2-, 5 - or 6-benzoxazolyl, 2-, 5 - or 6-benzimidazolyl, 2-, 5 - or 6-benzothiazolyl, 3-, 5 - or 6-indazolinone, 5-benzofurazanyl, 2-, 3-, 6 - or 7-chinaillon, 3-, 6 - or 7-ethanolism, 2-, 6 - or 7-hinazolinam, 2-, 6 - or 7-khinoksalinona or 1.8-naphthiridine-2-yl or 1,8-naphthiridine-3-yl, which optionally have 1 or 2 substituent selected from the substituents defined above in paragraphs (b), (d) and (e), and X, R1, R2, R3, m, n very lovely and q as appropriate have any of the values, defined above or in this paragraph for the particular new compounds of the present invention;

(i) Q is a heteroaromatic 5 - or 6-membered monocyclic ring, a 9 - or 10-membered bicyclic ring or a 13 - or 14-membered tricyclic ring containing up to five heteroatoms in the ring selected from oxygen, nitrogen and sulphur which optionally have 1, 2 or 3 substituent selected from hydroxy, halogen, trifloromethyl, cyano, nitro, amino, carboxy, (1-6C)alkyl, (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and (1-6C) alkoxycarbonyl, and X, R1, R2, R3, m, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(j) Q is a heteroaromatic 13 - or 14-membered tricyclic ring containing up to five heteroatoms in the ring selected from oxygen, nitrogen and sulphur which optionally have 1, 2 or 3 substituent selected from hydroxy, halogen, trifloromethyl, cyano, nitro, amino, carboxy, (1-6C)alkyl, (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)-alkylamino, di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl, and X, R1, R2, R3, m, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of this izaberete the Oia;

(k) Q is fullam, teinila, oxazolium, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolines, pyridium, pyridazinyl, pyrimidinyl, pyrazinium, benzofuranyl, indolium, benzothiophene, benzoxazolium, benzimidazolium, benzothiazolium, indusrial, benzofurazanyl, chinaillon, ethanolism, hinazolinam, khinoksalinona, naphthyridine, carbazolyl, dibenzofurans, dibenzothiophenes or xanterra that do not have 1 or 2 substituent selected from the substituents defined above in paragraph (i), and X, R1, R2, R3, m, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(l) Q is 1-, 2 - or 3-carbazolyl, 1-, 2-, 3 - or 4-dibenzofurane or 1-, 2-, 3 - or 4-dibenzothiophenes that do not have 1 or 2 substituent selected from the substituents defined above in paragraph (i), and X, R1, R2, R3, m, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(m) n is 0 and X, R1, R3, Q, m and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(n) n is 1 and R 2is halogen or (1-6C)alkyl and X, R1, R3, Q, m and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(o) q is 0 and X, R1, R2, R3, Q, m and n as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(p) m is 1 and R1is amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]-amino-(2-6C)alkoxy, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkylamino- (2-6C)alkylamino,N-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclic or heterocyclyl-(1-6C)alkoxy, and where any heteroaryl or heterocyclyl group in the substituent R1may optionally have 1 or 2 substituent selected from hydroxy, halogen, (1-6C)alkyl, (1-6C)alkoxy, (2-6C)alkanoyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and X, R2, R3, Q, n and q as appropriate have any of the values, determine the Lenna or above in this paragraph for the particular new compounds of the present invention;

(q) m is 1 and R1is amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, amino-(2-6C)-alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]-amino-(2-6C)alkoxy, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino,N-(1-6C)alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl-(1-6C)-alkylamino-(2-6C)alkylamino,N-(1-6C)alkyl, di-[(1-6C)alkyl]-amino-(2-6C)alkylamino, pyridium, imidazolyl, pyridyl-(1-6C)alkyl, imidazolyl-(1-6C)alkyl, pyridyl-(1-6C)alkoxy, imidazolyl-(1-6C)alkoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-(1-6C)alkylpiperazine, homopiperazine, 4-(1-6C)acylhomoserine, 4-(2-6C)alkanolamines, pyrrolidinyl-(1-6C)alkyl, piperidinyl-(1-6C)alkyl, morpholinyl-(1-6C)alkyl, piperazinil-(1-6C)alkyl, 4-(1-6C)alkylpiperazine-(1-6C)alkyl, 4-(2-6C)alkanolamine-(1-6C)alkyl, pyrrolidinyloxy, piperidinyloxy, 1-(1-6C)alkylpiperidines, pyrrolidinyl-(2-6C)-alkoxy, piperidinyl-(2-6C)alkoxy, morpholinyl-(2-6C)alkoxy, piperazinil-(2-6C)alkoxy, 4-(1-6C)alkylpiperazine-(2-6C)-alkoxy or 4-(2-6C)alkanolamine-(2-6C)alkoxy, and X, R2, R3, Q, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;/p>

(r) m is 1 and R1is hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkyl or (1-6C)alkoxy, and X, R2, R3, Q, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(s) m is 2 and the first R1Deputy selected from the substituents defined above in paragraph (q) and the second R1Deputy selected from the substituents defined above in paragraph (r), and X, R2, R3, Q, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of the present invention;

(t) X is-NHCO -, and R1, R2, R3, Q, m, n and q as appropriate have any of the values defined above or in this paragraph for the particular new compounds of this invention.

The preferred compound of this invention is an amide derivative of the formula Ib, in which R3is hydrogen, stands or ethyl;

m is 0,1 or 2;

R1is hydroxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, stands, ethyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-Amin is propoxy, 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)methylamino,N-(2-dimethyl-amino-ethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, pyridium, pyridylmethyl, pyridyloxy, pyrrolidinium, piperidinium, morpholinium, piperazinil, 4-methylpiperazine, homopiperazine, 4-methylhomopiperazine, 4-acetylpiperidine, pyrrolidineethanol, piperidinylmethyl, morpholinylmethyl, piperidinylmethyl, 4-methylpiperazine, 4-acetylpiperidine, pyrrolidinyloxy, 1 methylpyrrolidinone, piperidinyloxy, 1 methylpiperidine, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)-propoxy, 2-(piperidinyl)ethoxy, 3-(p is pyridinyl)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;

R2is fluorine, chlorine, bromine, stands or ethyl;

q is 0, and

Q is phenyl, fullam, teinila, oxazolium, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolines, pyridium, pyridazinyl, pyrimidinyl, pyrazinium, benzofuranyl, indolium, benzothieno, benzoxazolium, benzimidazolium, benzothiazolium, indusrial, benzofurazanyl, chinaillon, ethanolism, hinazolinam, khinoksalinona or naphthyridine that do not have 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, pyridyl, PI is Edelmetalle, 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 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-acetylpiperidine)propoxy;

or its pharmaceutically acceptable salt.

Another preferred compound of the present invention is an amide derivative of the formula Ia in which X is-NHCO - or-CONH-;

R3is hydrogen, stands or ethyl;

m is 0, 1 or 2;

R1is hydroxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, stands, 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-dimethylamino is hydroxy, 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, pyridium, pyridylmethyl, pyridyloxy, 3-pyrrolidino, pyrrolidinium, piperidinium, homopiperazine, morpholinium, piperazinil, 4-methylpiperazine, 4-ethylpiperazine, homopiperazine, 4-methylhomopiperazine, 4-acetylpiperidine, pyrrolidineethanol, piperidinylmethyl, morpholinylmethyl, piperidinylmethyl, 4-methylpiperazine, homopiperazine, 4-methylhomopiperazine, 4-acetylpiperidine, pyrrolidinyloxy, 1 methylpyrrolidinone, piperidinyloxy, 1 methylpiperidine, homopiperazine, 1 methylhomopiperazine, 2-(Pirro is idini)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, 3-(4-acetylpiperidine)propoxy, 3-dimethylaminopropylamine, 3-dimethylamino-2,2-dimethylpropylene, 2-(1-methylpyrrolidinyl)aminomethyl, 3-pyrrolidinylcarbonyl, 2-morpholinylmethyl, 3-morpholinepropanesulfonic, 2-piperidinylmethyl, 3-(4-methylpiperazine)-aminomethan, pyridyloxy, imidazolylidene, thiazoleacetate and 2 methylthiazolidine;

n is 0 or 1;

R2is fluorine, chlorine, bromine, stands or ethyl;

q is 0, and

Q is phenyl, indenolol, indenolol, tetrahydronaphthyl, fluorenyl, fullam, teinila, oxazolium, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolines, pyridium, pyridazinyl, pyrimidinyl, pyrazinium, benzofuranyl, indolium, benzothieno, benzoxazolium, benzimidazolium, benzothiazolium, indusrial, benzofurazanyl, chinaillon, ethanolism, hinazolinam, khinoksalinona, naphthyridine, carbazolyl, dibenzofurans, dibenzothiophenes or xanterra that do not have 1 or 2 substituent, wybran the x from hydroxy, fluorine, chlorine, trifloromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopentyloxy, methylendioxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido,N-methylacetamide, methanesulfonamido,N-methylmethanesulfonamide, 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, morpholinyl, 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-(piperaz the Nile)propoxy, 2-(4-methylpiperazine)ethoxy, 3-(4-methylpiperazine)propoxy, 2-(4-acetylpiperidine)ethoxy and 3-(4-acetylpiperidine)-propoxy, and where any phenyl, furilla, thienyl, perederina or heterocyclyl group in the substituents on Q may optionally have 1 or 2 substituent selected from fluorine, chlorine, methyl and methoxy;

or its pharmaceutically acceptable salt.

More preferred compound of this invention is an amide derivative of the formula Ib, in which R3is hydrogen or stands;

m is 0, 1 or 2;

R1is hydroxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, stands, 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-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-methylamino-this is l)- 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-elmetron, piperidinomethyl, morpholinomethyl, piperazine-1-elmetron, 4-methylpiperazin-1-elmetron, 4-acetylpiperidine-1-elmetron, 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 is 0 or 1;

R2is fluorine, chlorine or stands;

q is 0, and

Q is phenyl, 2-fullam, 2-tanila, 4-oxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-isothiazoline, pyridium, 3-pyridium, 4-pyridium, 2-benzofuranyl, 2-indolium, 2-benzothieno, 2-benzoxazolyl, 2-benzimidazolyl, 2-benzothiazolyl, 4-benzofurazanyl, 2-chinaillon, 6-chinaillon, 7-chinaillon, 3-ethanolism, 6-hinazolinam, 7-hinazolinam, 6-khinoksalinona or 7-khinoksalinona that do not have 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, 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-ilox is, 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.

More preferred compound of this invention is an amide derivative of the formula Ib, in which R3is hydrogen or stands;

m is 0, 1 or 2;

R1is hydroxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, stands, 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-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-elmetron, piperidinomethyl, morpholinomethyl, piperazine-1-elmetron, 4-methylpiperazin-1-elmetron, 4-acetylpiperidine-1-elmetron, 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 is 0 or 1;

R2is fluorine, chlorine or stands;

q is 0, and

Q is phenyl, 2-pyridium, 3-pyridi the Ohm or 4-pyridium, that may not necessarily have 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, 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-piperidino-propoxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-piperazine-1-ylethoxy, 3-piperazine-1-ylpropionic, 2-(4-methylpiperazin-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.

More preferred compound of this invention is an amide derivative of the formula Ib, in which R3is hydrogen or stands;

m is 1 or 2;

R1is hydroxy, fluorine, chlorine, stands, methoxy, dimethylaminomethyl, diethylaminomethyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 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-elmetron, 4-methylpiperazin-1-elmetron, homopiperazin-1-elmetron, 4-methylhomopiperazine-1-elmetron, morpholinomethyl, 3-aminopyrrolidine-1-elmetron, 3-hydroxypyrrolidine-1-elmetron, 4-(2-hidroxi who yl)piperazine-1-elmetron, 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-ylpropionic, 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 piperidinophenyl, 2-piperazine-1-ylethylamine, 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-impropriation, 2-morpholinosydnonimine, 3-morpholinepropanesulfonic, 2-piperazine-1-lateralisation, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl or 2-pyridyloxy;

n is 0 or 1;

R2is chlorine or stands;

q is 0, and

Q one is SJ 2-pyridium, 3-pyridium or 4-pyridium that have 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.

Especially preferred compound of the present invention is an amide derivative of the formula Ib, in which R3is hydrogen or stands;

m is 1 and R1choose from diethylaminomethyl,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 is 0 or 1;

R2is stands;

q is 0, and

Q is 3-pyridium or 4-pyridium that have a Deputy selected from pyrrolidin-1-yl, morpholino, piperidino, piperazine-1-yl and 4-methylpiperazin-1-yl;

or its pharmaceutically acceptable salt.

Even more preferred compound of this invention is an amide derivative of the formula Ib, in which R3is hydrogen or stands;

m is 1 and R1choose from diethylaminomethyl,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-ylpropyl)aminomethyl, 2 pyridyloxy, 4-thiazoleacetate and 2-methylthiazole-4-ylethoxy;

n is 0 or 1;

R2is stands;

q is 0, and

Q is phenyl which has 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, homopiperazin-1-yl, piperazine-1-Il, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylhomopiperazine-1-yl, or Q is 1-fluorenyl or 4-dibenzofurane, or Q is 3-pyridium or 4-pyridium that have 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.

Even more preferred compound of this invention is an amide derivative of the formula Ib, in which R3is hydrogen or stands;

m is 1 and R1is a 4-methylpiperazin-1-yl orN-(3-dimethylaminopropyl)-N-methylamino;

n is 0 or 1;

R2is 6-stands;

q is 0, and

Q is 2-morpholinomethyl-4-yl;

or its pharmaceutically acceptable salt.

Even more preferred compound of this invention is the I amide derivative of the formula Ib, in which R3is hydrogen or stands;

m is 1 and R1is a 4-methylpiperazin-1-yl, 4-methylhomopiperazine-1-yl orN-(3-dimethylaminopropyl)-N-methylamino;

n is 0 or 1;

R2is 6-stands;

q is 0; and

Q is 2-pyrrolidin-1-inpired-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.

Even more preferred compound of this invention is an amide derivative of the formula Ib, in which R3is hydrogen;

m is 1 and R1is piperazine-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazine-1-yl orN-(3-dimethylaminopropyl)-N-methylamino;

n is 0 or 1;

R2is 6-stands or 6-fluorine;

q is 0, and

Q is 2-azetidin-1-inpired-4-yl, 2-pyrrolidin-1-inpired-4-yl, 2-(3-pyrrolin-1-yl)pyrid-4-yl, 2-piperidinomethyl-4-yl, 2-morpholinomethyl-4-yl, 1-fluorenyl, dibenzofuran-4-yl, 5-(4-chlorophenyl)furan-2-yl, 4-(4-chlorophenyl)-Tien-2-yl, 2-methoxyphenyl, 3-ethoxyphenyl, 3-(1,1,2,2-tetrafluoroethoxy)phenyl, 3,4-methylenedioxyphenyl, 3-acetamidophenyl, 3-(4-forfinal)phenyl, 3-(2-furyl)phenyl, 3-fluoro-5-pyrrolidin-1-inveniam, 3-fluoro-5-piperidinophenyl, 3-fluoro-5-morford what nofemela or 3-morpholino-5-cryptomaterial;

or its pharmaceutically acceptable salt.

Specific preferred compounds of this invention are, for example:

6-[N-(3-dimethylaminopropyl)-N-methylamino]-3-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-one,

6-[N-(3-dimethylaminopropyl)-N-methylamino]-2-methyl-3-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-one,

6-[N-(3-dimethylaminopropyl)-N-methylamino]-3-[5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-one,

6-(4-methylpiperazin-1-yl)-3-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-one

or 8-[N-(3-dimethylaminopropyl)-N-methylamino]-3-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-one

or their pharmaceutically acceptable salt.

More preferred compounds of this invention are, for example:

3-[2-methyl-5-(2-pyrrolidin-1-inpired-4-ylcarbonyl)phenyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one,

3-[2-methyl-5-(2-piperidinophenyl-4-ylcarbonyl)phenyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one,

3-{2-methyl-5-[2-(3-pyrrolin-1-yl)pyrid-4-ylcarbonyl]phenyl)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one,

3-[5-dibenzofuran-4-ylcarbonyl-2-were]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one,

p> 3-{5-[3-(2-furyl)benzamido]-2-were}-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one, or

3-[5-(acetamidobenzoyl)-2-were]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one

or its pharmaceutically acceptable salt.

Derived amide of the formula Ia or Ib or its pharmaceutically acceptable salt or in vivo degradable ester can be obtained by any known method for producing chemically related compounds. Such methods, when used to obtain new amide derivatives of the formula Ia or Ib, is presented as another feature of the present invention and proillyustrirovany following exemplary variant of the method, in which, unless otherwise stated, X, R1, R2, R3, m, n, q and Q have any of the values defined above. The necessary starting materials may be obtained by standard methods of organic chemistry. The receipt of such starting materials is described in conjunction with the following illustrative manner and in the following examples. Alternative necessary starting materials may be obtained by methods similar to those presented as illustrative of what is within the competence of the specialist in the field of organic chemistry.

(a) Compound of formula Ia or pharmaceutically acceptable salt orin vivobiodegradable ester which may be obtained by interaction N-phenyl-2-aminobenzamide formula II

with a carboxylic acid of formula III or its reactive derivative

where group variables have the meanings defined above, and where any functional group is protected if necessary, and

(i) removing the existing protective groups and

(ii) optional education or its pharmaceutically acceptable salt or in vivo splitting of ester.

Suitable reactive derivative of carboxylic acid of the formula III is, for example, galoyanized, for example the acid chloride, obtained by the interaction of acid and chloride inorganic acid, for example thionyl chloride; a mixed anhydride, for example an anhydride, obtained by the interaction of the acid and chloroformiate, such as isobutylparaben; an active ester, for example an ester, obtained by the interaction of the acid with a phenol such as pentafluorophenol, complex ether, such as pentaftorosilikata or with alcohol, such asN-hydroxybenzotriazole; acid azide, such as azide, obtained by the interaction of the acid and azide such as diphenylphosphoryl; nitrile, Clonakilty, such as cyanide, obtained by the interaction of the acid and a cyanide such as diethylphosphoramidite; or the product wsimages is via acid and carbodiimide, such as dicyclohexylcarbodiimide. Preferred reactive derivative of carboxylic acid of the formula III is, for example, ester corresponding ortability carboxylic acid of the formula III, for example trialkylsilyl ether, such as timetravel or tritherapy ether. For carboxylic acids of the formula III in which R3is hydrogen, a suitable complex ester ortability is triethylorthoformate and carboxylic acids of the formula III in which R3is stands, suitable complex ester ortability is triethylorthoformate.

The reaction can be carried out in the presence of a suitable base, such as, for example, carbonate, the anion, hydroxide or hydride of an alkaline or alkaline-earth metal, for example sodium carbonate, potassium carbonate, sodium ethylate, potassium butyl, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an ORGANOMETALLIC base such as alkylate, for example, n-utility, or dialkylaminomethyl, such as diisopropylamide lithium, or, for example, the Foundation of the organic amine, such as, for example, pyridine, 2,6-lutidine, kallidin, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene.

The reaction can also be carried out in the presence of a suitable acid, such as, for example, inorganic or organic is Aya acid, such as hydrochloric, Hydrobromic, sulfuric, acetic, triperoxonane, citric or maleic acid.

The reaction is also preferably carried out in a suitable inert solvent or diluent, for example methanol, ethanol, tetrahydrofuran, methylene chloride, 1,2-dimethoxyethane,N,N-dimethylformamide,N,N-dimethylacetamide,N-methylpyrrolidine-2-one, dimethyl sulfoxide or acetone, and at a temperature in the range of, for example, from 0 to 150°C, preferably at about 75°C.

Protective groups in General can be selected from any of the groups described in the literature or known to experts in the field of chemistry as appropriate to protect the interest of the group and can be introduced by conventional methods. The protective group may be removed by any convenient methods described in the literature or known to experts in the field of chemistry as podhodjashee to remove interest of the protective group, such methods are selected to effectively remove the protective group with minimal impact on other groups of the molecule.

Specific examples of the protective groups is given below for convenience, where the term "lower", for example, in the term lower alkyl means that the group to which it belongs, preferably has 1-4 carbon atoms. It is clear that the presented examples are not limiting the who. Similarly, when examples of methods for removing protective groups, presented below, are not limiting. The use of protective groups and methods for removal are sewn, of course, not included in the scope of this invention.

Carboxyl protective group may be the residue afrobrazil aliphatic or arylaliphatic alcohol or afrobrazil of silanol (specified alcohol or silanol combined with caffeine, preferably containing 1-20 carbon atoms). Examples of carboxyl protective groups include straight or branched chain (1-12C)alkyl groups (for example, isopropyl, tert-butyl); lower alkoxy lower alkyl groups (for example, methoxymethyl, ethoxymethyl, isobutoxide); lower aliphatic, acyloxy lower alkyl groups (for example, acetoxymethyl, propionylacetate, butyrylacetate, pivaloyloxymethyl); lower alkoxycarbonyl lower alkyl groups (for example, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl); aryl lower alkyl groups (e.g. benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); three(lower alkyl)silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); three(lower alkyl)silyl lower alkyl groups (for example, trimethylsilylmethyl) and (2-6C)-alkeline group (for example, allyl and vinylaryl). The methods are particularly suitable for removing arboxylic protective groups, include, for example, hydrolysis with acid, basic, metal or enzyme catalyst.

Examples of hydroxyl protective groups include lower alkyl groups (for example tert-butyl), lower alkeneamine group (e.g. allyl); lower alcoholnye group (e.g. acetyl; lower alkoxycarbonyl group (e.g. tert-butoxycarbonyl); lower altneratively group (for example, allyloxycarbonyl; aryl lower alkoxycarbonyl group (for example, benzyloxycarbonyl, p-methoxybenzenesulfonyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl); three(lower alkyl)silyl groups (for example trimethylsilyl, tert-butyldimethylsilyl) and aryl lower alkyl groups (e.g. benzyl).

Examples aminosidine groups include formyl, kalkilya groups (e.g. benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-untilmately and furylmethyl group; a lower alkoxycarbonyl (for example, tert-butoxycarbonyl); lower alkenylbenzenes (for example, allyloxycarbonyl); aryl lower alkoxycarbonyl group (for example, benzyloxycarbonyl, p-methoxybenzenesulfonyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl); trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example, methylide is); benzylidene and substituted benzylidene group.

Methods appropriate for removal of hydroxy and aminosidine groups include, for example, hydrolysis with acid, basic, metal or enzyme catalyst for groups such as p-nitrobenzenesulfonyl, hydrogenolysis for groups such as benzyl, and photolytic method for groups such as o-nitrobenzenesulfonyl.

Reaction conditions and reagents are presented in Advanced Organic Chemistry, 4thEdition by Jerry March, published by John Wiley & Sons 1992. General information about protective groups are given in Protective Groups in Organic Synthesis, 2ndEdition by Green et al., published by John Wiley & Sons.

N-Phenyl-2-aminobenzamide formula II can be obtained by reduction of the corresponding nitro compounds of formula IV

The usual reaction conditions include the use of ammonium formate or hydrogen gas in the presence of a catalyst, for example a metal catalyst such as palladium on carbon. Alternative solvent metal recovery can be performed, for example, using iron in the presence of acid, for example, inorganic or organic acids, such as hydrochloric, Hydrobromic, sulfuric or acetic acid. The reaction is usually carried out in the presence of an organic solvent (preferably field the aqueous proton solvent and preferably by heating, for example, at a temperature of 60°C. Any functional groups may be protected and not protected if necessary.

The nitrobenzene of the formula IV in which X is-NHCO-, can be obtained by the interaction of aniline of formula V

with a carboxylic acid of formula VI, or its reactive derivative such as defined above,

in standard conditions of formation of amide linkages, where the variables group such as defined above, and where any functional group is protected if necessary.

Normal conditions include activating the carboxy group of the compounds of formula VI, for example, treatment with a halogen reagent (for example, oxalylamino) to produce acylhomoserine in an organic solvent at ambient temperature and then the interaction of the activated compound with aniline of formula V. Any functional groups may be protected and not protected if necessary. Usually use a condensing agent carbodiimide in the presence of an organic solvent (preferably anhydrous polar aprotic organic solvent) at a lower temperature, for example in the range from -10 to 40°C, typically at ambient temperature, about 20°C.

Aniline of formula V can be recip is N. the interaction of benzoic acid of formula VII or its activated derivative, such as defined above,

with an aniline of the formula VIII

under conditions suitable for the formation of amide linkages, as defined above.

The nitrobenzene of the formula IV, where X is-NHCO-, can also be obtained by the interaction of the benzoic acid of formula VII or its activated derivative, as defined above, with an aniline of formula IX

under conditions suitable for the formation of amide linkages, as defined above.

Corresponding reactions are shown in the examples, is used for nitrobenzene of the formula IV, where X is-CONH-.

(b) Compound of formula Ia in which X is-NHCO - or its pharmaceutically acceptable salt or in vivo degradable ester can be obtained by the interaction of aniline of the formula X

with a carboxylic acid of formula VI, or its reactive derivative, as defined above,

in standard conditions of formation of amide linkages, as defined above, where the variables group such as defined above, and where any functional group is protected if necessary, and

(i) removing any protective groups;

(ii) optional formation of pharmaceutically acceptable salts or in vivo split the Fira.

The reaction is preferably carried out in the presence of a suitable base as defined above. The reaction is preferably carried out in a suitable inert solvent or diluent, for example tetrahydrofuran, methylene chloride, 1,2-dimethoxyethane,N,N-dimethylformamide,N,N-dimethylacetamide,N-methylpyrrolidine-2-one, dimethyl sulfoxide or acetone, and at a temperature in the range of, for example, from -78 to 150°C, preferably at ambient temperature.

Usually carbodiimide condensing agent is used in the presence of an organic solvent (preferably anhydrous polar aprotic organic solvent) at a moderate temperature, for example in the range from -10 to 40°C, preferably at ambient temperature, about 20°C.

Aniline of formula X can be obtained by reduction under standard conditions, as described above, the corresponding compounds of formula XI

Nitrosoaniline formula XI can be obtained by interactionN-phenyl-2-aminobenzamide formula XII

with a carboxylic acid of formula III or its reactive derivative

where variable group such as defined above, and where any functional group protection is placed if necessary.

(C) a Compound of the formula Ia, in which R1or Deputy radical Q is (1-6C)alkoxy or substituted (1-6C)-alkoxy, (1-6C)alkylthio, (1-6C)alkylamino, di-[(1-6C)alkyl]-amino or substituted (1-6C)alkylamino can be obtained by the alkylation, preferably in the presence of a suitable base as defined above, the amide derivative of the formula Ia, in which R1or Deputy radical Q is hydroxy, mercapto or amino, respectively.

The reaction is preferably carried out 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 dipolar aprotic solvent, such asN,N-dimethylformamide,N,N-dimethylacetamide,N-methylpyrrolidine-2-one or dimethylsulfoxide. The reaction is preferably carried out at a temperature in the range of, for example, from 10 to 150°C, preferably in the range from 20 to 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 mercapto to alkylthio, or for the alkylation of amino to Ala is a melamine or substituted, alkylamino, for example, alkyl or substituted alkylhalogenide, for example (1-6C)alkylchloride, bromide or iodide or a substituted (1-6C)alkylchloride, bromide or iodide, in the presence of a suitable base as defined above, in a suitable solvent or diluent as defined above, and at a temperature in the range of, for example, from 10 to 140°C, preferably at ambient temperature or so.

(d) Compound of formula Ia, in which Deputy radical Q is amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, substituted (1-6C)alkylamino, substitutedN-(1-6C)alkyl-(2-6S)-alkylamino orN-related heterocyclyl group, can be obtained by interaction, preferably in the presence of a suitable base as defined above, the amide derivative of the formula Ia, in which Deputy radical Q is a suitable leaving group, with a suitable amine.

A suitable leaving group is, for example, a halogen group such as fluorine, chlorine or bromine, (1-6C)-alkanesulfonyl, such as methanesulfonate, or arylsulfonate, such as 4-toluensulfonate.

The reaction is preferably carried out in the presence of a suitable inert diluent or carrier as defined above, and at a temperature in the range of, for example, from 20 to 200°C, preferably in the range from 75 to 150°C.

(e) the unity of formula Ia, in which R1or Deputy radical Q is (1-6C)alkanolamine or substituted (2-6C)alkanolamine, can be obtained by acylation of compounds of formula Ia, in which R1or Vice radical Q is amino.

Suitable allermuir agent is, for example, any agent known in the art for the acylation of amino to acylamino, such as allalone, for example (1-6C)alcoholclone or bromide, in the presence of a suitable base as defined above, anhydride alanovoy acid or a mixed anhydride, for example an anhydride (1-6C)alanovoy acid, such as acetic anhydride, or mixed anhydride obtained by the interaction alanovoy acid and (1-6C)-alkoxycarbonylmethyl, for example (1-6C)alkoxycarbonyl, in the presence of a suitable base as defined above. Typically, the acylation is carried out in a suitable solvent or diluent as defined above, and at a temperature in the range of, for example, from -30 to 120°C, preferably at ambient temperature.

(f) Compound of formula Ia, in which R1or Deputy radical Q is (1-6C)alkanesulfonyl can be obtained by the coupling of compounds of formula Ia, in which R1or Deputy radical Q is amino, (1-6C)-alkanesulfonyl or its activated derivative.

<> A suitable activated derivative of (1-6C)alkanesulphonic is, for example, alkanesulfonyl, such as alkanesulfonyl obtained by the interaction between sulfonic acids and chloride inorganic acid, such as thionyl chloride. The reaction is preferably carried out in the presence of a suitable base as defined above, in particular pyridine, in a suitable inert solvent or diluent as defined above, in particular methylene chloride.

(g) Compound of formula Ia, where R1or Deputy radical Q is carboxy, carboxy-(1-6C)alkyl, carboxy-(1-6C)alkoxy, carboxy-(1-6C)alkylamino,N-(1-6C)alkylcarboxylic-(1-6C)alkylamino or carboxy-(2-6C)alkanolamine, can be obtained by splitting the compounds of formula Ia, in which R1or Deputy radical Q is (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl-(1-6C)-alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkylamino,N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino or (1-6C)-alkoxycarbonyl-(2-6C)alkanolamine respectively.

The cleavage reaction may preferably be carried out by any of numerous methods known in the art for such a transformation. The reaction may represent, for example, hydrolysis under acidic or basic conditions. A suitable base is, for the example, the carbonate or hydroxide of an alkali metal, alkaline earth metal or ammonium, for example sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or ammonium hydroxide. The reaction is preferably carried out in the presence of water and a suitable solvent or diluent, such as methanol or ethanol. The reaction is usually carried out at a temperature in the range from 10 to 150°C, preferably at ambient temperature.

(h) Compound of formula Ia, in which R1is amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di[(1-6C)alkyl]amino-(1-6C)alkyl or heterocyclyl-(1-6C)alkyl, can be obtained by the coupling of compounds of formula XIII is preferably in the presence of a suitable base as defined above,

where X, R2, R3, n, q and Q have any of the values defined above, and Z is a suitable leaving group,

with the appropriate amine or heterocycle.

A suitable leaving group Z is, for example, a halogen group such as fluorine, chlorine or bromine, (1-6C)-alkanesulfonyl, such as methanesulfonate or arylsulfonate, such as 4-toluensulfonate.

The reaction is preferably carried out in the presence of a suitable inert diluent or carrier as defined above, and at a temperature in the range of, for example, from 20 to 200°C, preferably in the range from 50 to 150°C.

The following biological studies and examples are given to illustrate this invention.

Biological studies

These studies can be used to determine the ability of inhibition R kinase, inhibition of TNF and antiarthritic action of the compounds of this invention are:

Enzyme study iv vitro

Assessment of the ability of the compounds of this invention inhibit the enzyme R kinase. Is determined by the activity of compounds against each Rα and Rβ isoforms of the enzyme.

Recombinant MCC human (GenBank AccesionNumber G1209672) was isolated from the clone Image 45578 (Genomics, 1996, 33, 151) and is used to produce protein in the form of a fused protein GST in pGEX vector using methods similar to those described in J.Han et al., Journal of Biological Chemistry, 1996, 271, 2886-2891. p38α (GenBank Accesion Number G529039) and p38β (GenBank Accesion Number G1469305) was isolated by PCR amplification lymphoblastic human cDNA (GenBank Accesion Number GM1416) and cDNA brain of the human embryo [synthesized from mRNA (Clontech, catalog No. 6525-1) using the kit for cDNA synthesis Gibco superscript], respectively, using oligonucleotides designed for 5' and 3' ends of Rα and p38β human genes using methods similar to the methods described in J.Han et al., Biochimica et Biophysica Act a, 1995, 125, 224-227, and Y.Jiang et al., Journal of Biological Chemistry, 1996, 271, 17920-17926.

Both protein isoforms R Express in E. coli in vector PET. Recombinant isoforms Rα and p38β people receive in the form of 5' c-myc, 6His tagged proteins. Both MCC and R protein purified using standard protocols: GST MKK6 purified using column glutathioneperoxidase, and R proteins purified using columns with a chelate of Nickel.

Enzymes R activate before use by incubation with MKK6 for 3 hours at a temperature of 30°C. Not activated, expressed in E.coli MKK6 retains significant activity in order to fully activate both isoforms R. Incubat to activate contains Rα (10 μl, 10 mg/ml) or p38β (10 μl, 5 mg/ml) together with MKK6 (10 μl of 1 mg/ml), buffer kinase" [100 μl; pH 7.4 buffer containing Tris (50 mm), EGTA (0.1 mm), orthovanadate sodium (0.1 mm) and β-mercaptoethanol (0,1%)] and Mgatp (30 μl of 50 mm Mg (ASON3)2and 0.5 mm ATP). The method provides a sufficiently activated R enzyme for 3 titration microplate.

Test compounds dissolved in DMSO and 10 μl diluted 1:10 sample in the buffer kinase" add to cell tiralongo microplate. To determine the single dose of the compounds tested at 10 μm. Then add "Kinase Assay Mix" [30 μl; containing Myelin Basic Protein (Gibco BRL, catalog No. 1322B-010; 1 ml of 3.33 mg/ml solution in water)Akti the new R enzyme (50 μl) and buffer kinase" (2 ml)] with subsequent dobavleniem "Labeled ATP" [10 μl; containing 50 μm ATP, 0.1 to MX33P ATP (Amersham International, catalog No. BF1000) and 50 mm Mg(ASONC)2]. Tablets incubated at room temperature under mild 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). Precipitated precipitated protein phosphorylate R kinase and the test compounds is evaluated on the ability to inhibit this phosphorylation. The contents of the tablets is filtered using a Canberra Packard Unifilter and washed with 2% TCA, dried overnight and counted on a scintillation counter Thor Count.

The tested compounds have first dose and active connection re-test to identify IC50.

Cell-based in vitro studies

(i) RVMS

The ability of the compounds of the present invention to inhibit the formation of TNFα evaluate using mononuclear cells of peripheral blood, which synthesize and secrete TNFα upon stimulation by lipopolysaccharide.

Mononuclear cells from peripheral blood (RVMS) was isolated from heparinized (10 units/ml heparin) human blood by centrifugation in a density gradient (LymphoprepTM; Nycomed). Mononuclear cells re suspe dirout in culture medium [RPMI medium 1640 (Gibco) supplemented with 50 units/ml penicillin, 50 µg/ml streptomycin, 2 mm glutamine and 1% heat inactivating human AB serum (Sigma N-1513)]. Compounds dissolved in DMSO at a concentration of 50 mm, diluted 1:100 in culture medium and then spend serial dilution in culture medium containing 1% DMSO. RVMS (2,4×105cells in 160 µl of culture medium) incubated with 20 μl of test compounds at various concentrations (performed three repetitions of culture) or 20 ál of culture medium containing 1% DMSO (control cells) for 30 minutes at a temperature of 37°C incubator with humidity (5% CO2/95% air) (Falcon 3072; 96-cell tablet with a flat bottom for the cultivation of tissues). In appropriate wells add 20 μl of lipopolysaccharide [LPS E. coli 0111:B4 (Sigma L-4130)to a final concentration of 10 μg/ml], solubilizing in culture medium. 20 μl of Culture medium added to the control cells with "one environment". Six controls with one FSC" and four with "one environment" included in each 96-cell tablet. In each test include various concentrations of known inhibitors of TNFαi.e. the Inhibitor of the enzyme PDE Type IV (for example, see Semmler,J., Wachtel.H. and Endres, S., Int. J. Immunopharmac. (1993), 15(3), 409-413) or inhibitor Pro TNFα convertase (for example, see McGeehan, G.M. et al., Nature (1994), 370, 558-561). Tablets incubated for 7 hours at a temperature of 37° (incubator with SWL what jnanam), then 100 µl nagadoches liquids removed from each cell and stored at -70° (96-cell tablet with a round bottom; Corning 25850). The levels of TNFα determined in each sample using ELISA kit for human TNFα (see WO 92/10190 and Current Protocols in Molecular Biology, volume 2, Frederick M. Ausbel et al., John Wiley and Sons Inc.).

(ii) Whole human blood

The ability of the compounds of the present invention to inhibit the formation of TNFα it was also estimated in the study of whole human blood. Whole human blood secretes TNFα upon LPS stimulation. This property forms the blood is the basis of the study, which is used as a secondary test for compounds that have proved effective in the test with RVMS.

Heparinized (10 units/ml) human blood get from volunteers. 160 μl of whole blood added to 96-cell tablet with cells with a round bottom (Corning 25850).

Compounds are dissolved and serially diluted in RPMI medium 1640 (Gibco) supplemented with 50 units/ml penicillin, 50 µg/ml streptomycin and 2 mm glutamine, as described above. 20 μl of each test concentration added to the appropriate wells (performed three repetitions of culture). 20 µl of RPMI medium 1640, supplemented with antibiotherapy and glutamine, add in the control cells. Tablets Incubus who enjoy for 30 minutes at a temperature of 37° C (incubator with humidity) before adding 20 μl LPS (final concentration 10 μg/ml). Six controls with one FSC" and four with "one environment" include in each tablet. In each test include known inhibitors of the synthesis/separation, TNFα. Tablets incubated for 6 hours at a temperature of 37° (incubator with humidity). Tablets centrifuged (2000 rpm for 10 minutes) and 100 µl of plasma removed and stored at -70° (tablets Corning 25850). The levels of TNFα measured by ELISA (see WO 92/10190 and Current Protocols in Molecular Biology, volume 2, Frederick M. Ausbel et al., John Wiley and Sons Inc.). Paired antibodies used in ELISA, R&D Systems (catalogue No. MAB anti-human TNFα covering antibodies, BAF210 biotinylated anti-human TNFα detecting antibodies).

Ex vivo/in vivo evaluation

The ability of the compounds of the present invention to inhibit TNFα ex vivo evaluated in mice or rats. Briefly, groups of male Wistar rats Alderley Park (AP) (180-210 g) injected dose of the compound (6 rats) or media drugs (10 rats) suitable manner, for example orally (P.O.), intraperitoneal (V.B.) or subcutaneous (P.K.). After 19 minutes to kill rats by increasing the concentration of CO2and let the blood through the posterior Vena cava in 5 units of sodium heparin/ml of blood. Blood samples immediately placed on ice and centrifuged at 000 rpm for 10 minutes at a temperature of 4° With, and the collected plasma was frozen at -20°for further investigation of their influence on the formation of TNFα LPS-stimulated human blood. Plasma samples of rats thawed and 175 μl of each sample type according to the specified method in 96-cell tablet with cells with a round bottom (Corning 25850). Then in cabut cell add 50 ál of heparinized human blood, mixed and tablets incubated for 30 min at 37 ° ° (incubator with humidity). In cell type LPS (25 μl; final concentration 10 μg/ml) and incubation continued for a further 5.5 hours. Control cells incubated with 25 μl of the same environment. Then the tablets centrifuged for 10 minutes at 2000 rpm, 200 ál nagadoches liquid is transferred into a 96-cell tablet and frozen at -20°for subsequent analysis of concentration of TNF by ELISA.

Data analyzed by using intended for this purpose software for each connection/dose:

Alternative to the above method instead of rats can be used a mouse.

Test antiarthritic actions

The action of the compounds as antiarthritic agents tested as follows. Trentham et al [1] showed that acid-soluble native colligative II is the latter for rats; it causes arthritis in the introduction in incomplete Freund's adjuvant. Currently, it is known as induced by collagen arthritis (CIA), and this condition can be induced in mice and primates. Recent studies have shown that anti-TNF monoclonal antibodies [2] and TNF receptor-IgG fused proteins [3] improve the established CIA, noting that TNF plays a key role in the pathophysiology of CIA. Moreover, remarkable efficiency was observed in anti-TNF monoclonal antibodies in the course of recent clinical trials of rheumatoid arthritis shows that TNF plays a major role in these chronic inflammatory diseases. Thus, the CIA in DBA/l mice, as described in references 2 and 3, represents a tertiary model that can be used to demonstrate antiarthritic activity of a compound. Also see reference 4.

1. Trentham, D.E. et al., (1977) 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) Immunology, 84, 433.

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

Although, as expected, the pharmacological properties of the compounds of formula Ia vary with structural change, in General the compounds of formula Ia to give more than 30% inhibition Rα and/or Rβ at concentrations up to 10 μm. For the tested compounds of this invention in effective the x doses was not observed in any physiologically acceptable toxicity.

For example:

(i) 6-[N-(3-dimethylaminopropyl)-N-methylamino]-3-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-he has the IC50approximately 0.2 μm in respect of p38α and IC50approximately 2 μm according to testing with whole human blood;

(ii) 6-[N-(3-dimethylaminopropyl)-N-methylamino]-3- [5- (2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-he has the IC50about 0.05 μm against Rα and IC50approximately 5 μm according to testing with whole human blood and

(iii) 8-[N-(3-dimethylaminopropyl)-N-methylamino]-3-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-he has the IC50approximately 0.1 μm against Rα and IC50approximately 7 μm according to testing with whole human blood.

According to another aspect of the present invention presents a pharmaceutical composition, which contains an amide derivative of the formula Ia or Ib, or its pharmaceutically acceptable salt or in vivo degradable ester as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-Z,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it, in combination with the pharmaceutically acceptable diluent or carrier.

The compositions of this invention can be in a form suitable for oral use (for example, in the form of tablets, lozenges, hard or soft 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 fine powder or a liquid aerosol), for administration pneumatically (e.g., in the form of a fine powder) or for parenteral administration (for example, in the form of sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular injection or in the form of suppositories for rectal administration).

The compositions of this invention can be obtained by conventional methods using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and/or preservatives.

The amount of active ingredient that is combined with one or more excipients to obtain a single dosage form, necessarily depends on taking treatment of the patient and specific pic is BA introduction. For example, the composition for oral administration person usually contains, for example, from 0.5 mg to 0.5 g of active compound with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 wt.%. by weight of the entire composition.

The magnitude of the dose for therapeutic or prophylactic purposes of a compound of formula Ia naturally depends on the nature and severity of the condition, age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

When using the compounds of formula Ia for therapeutic or prophylactic purposes it is normally administered so that a daily dose of, for example, from 0.5 to 75 mg per 1 kg of body weight, if necessary, divided into several doses. Usually when parenteral use lower doses. Thus, for example, for intravenous administration, the dose of, for example, from 0.5 to 30 mg per 1 kg of body weight. Also, for administration by inhalation, used dose in the range, for example, from 0.5 to 25 mg per 1 kg of body weight. However, preferably oral administration, particularly in the form of tablets. Typically, the unit dosage form contains from about 1 mg to about 500 mg of the compounds of this invention.

According to another aspect of the present invention presents a new amide derivative of formula or its pharmaceutically acceptable salt or in vivo degradable ester, as defined above, for use in a method of therapeutic treatment of the human or animal.

According to another aspect of the present invention presents the use of amide derivative of the formula Ia or Ib or its pharmaceutically acceptable salt or in vivo splitting of ester, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it is for the manufacture of a medicinal product for use in the treatment of diseases or clinical conditions, mediasound cytokines.

In another aspect, the invention provides a method of treatment of diseases or clinical conditions, mediasound cytokines, which includes the introduction of a warm-blooded animal an effective amount of amide derivative of the formula Ia or Ib or its pharmaceutically acceptable salt or in vivo splitting of ester, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it.

In another aspect of this image is eenie represents the application of the amide derivative of the formula Ia or pharmaceutically acceptable salts, or in vivo splitting of ester, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3, 4-dihydroquinazolin-4-it for production medicines for use in the treatment of diseases or clinical conditions, mediasound TNF, IL-1, IL-6 or IL-8.

In another aspect, the invention provides a method of treatment of diseases or clinical conditions, mediasound TNF, IL-1, IL-6 or IL-8, which includes the introduction of a warm-blooded animal an effective amount of amide derivative of the formula Ia or Ib, or its pharmaceutically acceptable salt or in vivo splitting of ester, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide) -2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it.

In another aspect of this invention is the use of amide derivative of the formula Ia or pharmaceutically acceptable salt or in vivo splitting of ester, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-one, 3- [5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it is for the manufacture of a medicinal product for use in the treatment of diseases or clinical conditions, mediasound TNF.

In another aspect, the invention provides a method of treatment of diseases or clinical conditions, mediasound TNF, which includes the introduction of a warm-blooded animal an effective amount of amide derivative of the formula Ia, or pharmaceutically acceptable salt or in vivo splitting of ester, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4 she and 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it.

In another aspect of this invention is the use of amide derivative of the formula Ia or pharmaceutically acceptable salt or in vivo splitting of ester or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4, as defined above, for the manufacture of a medicinal product for p is imeneniya for inhibition of TNF, IL-1, IL-6 or IL-8.

In another aspect, the invention provides a method of inhibiting TNF, IL-1, IL-6 or IL-8, which includes the introduction of a warm-blooded animal an effective amount of amide derivative of the formula Ia, or pharmaceutically acceptable salt or in vivo splitting of ester, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3- [5-(4-methylbenzamide)-2-were]-2-methyl 3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it.

In another aspect of this invention is the use of amide derivative of the formula Ia or pharmaceutically acceptable salt or in vivo splitting of ester, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-Z,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it is for the manufacture of a medicinal product for use for inhibiting TNF.

In another aspect, the invention provides a method of inhibiting TNF, which includes the introduction of a warm-blooded animal an effective amount of amide derivative of the formula Ia, or pharmaceutically acceptable salt or in vivo degradable layer is aqueous ether, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it.

In another aspect of this invention is the use of amide derivative of the formula Ia or pharmaceutically acceptable salt or in vivo splitting of ester, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it is for the manufacture of a medicinal product for use in the treatment of diseases or clinical conditions, mediasound R kinase.

In another aspect, the invention provides a method of treatment of diseases or clinical conditions, mediasound R kinase, which includes the introduction of a warm-blooded animal an effective amount of amide derivative of the formula Ia, or pharmaceutically acceptable salt or in vivo splitting of ester, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydr the hinzelin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it.

In another aspect of this invention is the use of amide derivative of the formula Ia or pharmaceutically acceptable salt or in vivo splitting of ester or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydro-hinzelin-4-it is for the production of medicines used to generate inhibitory effect against R kinase.

In another aspect, the invention provides a method of generating inhibitory effect against R kinase, which includes the introduction of a warm-blooded animal an effective amount of amide derivative of the formula Ia, or pharmaceutically acceptable salt, orin vivosplitting of ester, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it.

In another aspect of this invention is the use of amide derivative of the formula Ia or pharmaceutically acceptable salts, orin vivosplitting of ester, as defined above, or production is one amide, selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it is for the manufacture of a medicinal product for use in the treatment of rheumatoid arthritis, asthma, irritable bowel syndrome, multiple sclerosis, AIDS, septic shock, ischaemic heart disease or psoriasis.

In another aspect, the invention provides a method of treatment of rheumatoid arthritis, asthma, irritable bowel syndrome, multiple sclerosis, AIDS, septic shock, ischaemic heart disease or psoriasis, which includes the introduction of a warm-blooded animal an effective amount of amide derivative of the formula Ia, or pharmaceutically acceptable salt, orin vivosplitting of ester, as defined above, or amide derivative selected from 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it.

The compounds of this invention can be used in combination with other drugs and therapeutic methods used in the treatment of painful conditions that facilitated when and what generowanie cytokines, in particular TNF and IL-1. For example, the compounds of formula Ia can be used in combination with medicines and therapeutic methods for the treatment of rheumatoid arthritis, asthma, irritable bowel syndrome, 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 Ia are valuable in the treatment of certain inflammatory and non-inflammatory diseases which are both treated any abscopal cyclooxygenase nonsteroidal anti-inflammatory drugs (spit), such as indomethacin, Ketorolac, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of compounds of formula I with spit may reduce the number of the last agent needed to obtain a therapeutic effect. Thus, the likelihood of side effects if used spit, such as gastrointestinal effects, is reduced. According to another features of the present invention presents a pharmaceutical composition, which contains an amide derivative of the formula Ia or pharmaceutically acceptable salt or in vivo splitting of ester or in combination with EXT is vcoi inhibiting cyclooxygenase nonsteroidal anti-inflammatory agents and a pharmaceutically acceptable carrier or diluent.

The compounds of this invention can also be used with anti-inflammatory agents, such as inhibitors of the enzyme 5-lipoxygenase.

The compounds of formula Ia can also be used to treat conditions such as rheumatoid arthritis, in combination with antiarthritis agents such as gold, methotrexate, steroids and penicillinases, and conditions such as osteoarthritis together with steroids.

The compounds of this invention can also be entered in degenerative diseases such as osteoarthritis, with chondro-protective, antidegradation and/or reparative agents such as Diacerhein, formulations of hyaluronic acid, such as Gilan, Rumalon, Arteparon and salts of glucosamine, such as Antril.

The compounds of formula Ia can be used in the treatment of asthma in combination with anti-asthma agents such as bronchodilators and leukotriene antagonists.

When the existence of a fixed dose, such combined products of the compounds of this invention are used in the dose described above, and other pharmaceutically active agents within the approved dose. If you cannot obtain a combined formulation use consistent application.

Although the compounds of formula Ia more valuable as a therapeutic agent is for use on warm-blooded animals (including humans), they are also useful when you want inhibiting the action of cytokines. Thus, they are used as pharmacological standards for the development of new biological tests and the search for new pharmacological agents.

Further, the invention is illustrated is not limiting its scope by the examples in which, unless stated otherwise:

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

(ii) the evaporation is performed on a rotary evaporator under vacuum and the processing procedure is carried out after removal of residual solids by filtration;

(iii) chromatography on a column (flash chromatography) and liquid chromatography medium pressure (GHSD) is performed on a column of reversed phase silica Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) from Emagic, Darmstadt, Germany, or liquid chromatography high pressure (ghvd) is performed on a column of reversed phase silica C18, for example on a preparative column with reversed phase Dynamax C-18 60Å;

(iv) the output is given for illustration only and is not necessarily the maximum achievable;

(v) in General, the end products of the formula Ia have a satisfactory microanalysis and their structures confirmed by the methods of nuclear magnetic rez is the mission (NMR) and/or mass spectrum; mass spectral data of fast atom bombardment (the Belarusian library Association) obtained using the spectrometer Platform and, if possible, receive data positive ion data or negative ion; the values of chemical shift NMR was measured on a scale Delta [range proton magnetic resonance is determined using an spectrometer Varian Gemini 2000, operating at a field strength of 300 MHz, or Bruker spectrometer AM operating at a field strength of 250 MHz]; the following abbreviations: s, singlet; d, doublet; t, triplet; m, multiplet; W, wide;

(vi) intermediate compounds usually do not have full features and their purity assessed by means of thin layer chromatography, HPLC, infrared spectrum (IR) and/or NMR analysis;

(vii) the melting temperature was not adjusted and determined by automatic apparatus for determining the melting temperature Mettler SP62 or apparatus with oily-water bath; the temperature of melting for the final products of formula Ia were determined after crystallisation from a conventional organic solvent, such as ethanol, methanol, acetone, ether or hexane, pure or in mixture, and

(viii) used the following abbreviations:

DMFN,N-dimethylformamide
DMSOthey shall tranfixed.

Example 1

3-(5-Benzamido-2-chlorophenyl)-7-methoxy-3,4-dihydroquinazolin-4-one

Triethylorthoformate (0,189 ml) are added to stir the mixtureN-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide (0.15 g), ethanol (10 ml) and glacial acetic acid (0,022 ml) and the resulting mixture is heated at a temperature of 70°C for 16 hours. The mixture is evaporated. The residue is distributed between methylene chloride and saturated aqueous sodium bicarbonate. The organic phase is dried (MgSO4) and evaporated, and the residue triturated under a mixture of ethyl acetate and diethyl ether. The compound obtained is further purified by chromatography on ion-exchange column (column isolute SCX from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous solution of ammonium hydroxide as eluent. So get listed in the header are connected (0,054 g).

An NMR spectrum: (MCOd6) to 3.92(s, 3H), 7,12-7,22 (m, 2H), of 7.48 and 7.6(m, 3H), 7,68(d, 1H), 7,88 to 8.0(m, 3H), 8,04-to 8.12(m, 2H), 8,28(m, 1H), 10,06(s, 1H). Mass spectrum: M+N+406 and 408.

N-(5-Benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide used as a starting compound, obtained as follows.

The benzoyl chloride (5.2 ml) is added to a stirred mixture of 2,4-diaminoanisole (6.42 per g), triethylamine (12.5 ml) and methylene chloride (100 ml), which is cooled to a tempera is URS 0° C. the Mixture is heated under ambient temperature and stirred for 16 hours. The mixture is evaporated and the residue triturated under water saturated solution of sodium bicarbonate. The obtained solid substance emit, washed successively with water and isohexane and dried in a vacuum at a temperature of 55°C. Thus getN-(3-amino-4-chlorophenyl)benzamide in the form of solids (10,38 g). An NMR spectrum: (d6) 5,32 (s, 2H), 6,9(m, 1H), and 7.1(d, 1H), 7,37(d, 1H), 7,52(m, 3H), 7,9(d, 2H), of 10.05(s, 1H).

Oxalicacid (0,781 ml) is added dropwise to a stirred mixture of 4-methoxy-2-nitrobenzoic acid (1.6 g), DMF (few drops) and methylene chloride (30 ml)which was cooled to a temperature 0°C. the Mixture allow to warm to ambient temperature and stirred for 4 hours. The mixture is evaporated. The residue is dissolved in methylene chloride (10 ml) and added dropwise to a stirred mixtureN-(3-amino-4-chlorophenyl)benzamide (2.0 g), triethylamine, (2,49 ml) and methylene chloride (30 ml). The resulting mixture was stirred at ambient temperature for 16 hours. The sediment out, washed with 1N aqueous solution of hydrochloric acid and methanol and dried in vacuum at a temperature of 40°C. Thus getN-(5-benzamido-2-chlorophenyl)-4-methoxy-2-nitrobenzamide (2,49 g). An NMR spectrum: (d6) a 3.9 (s, 3H), 7,39(d, 1H), 7,47 to 7.62(m, 5H), 7,72(d, 1H), 7,78(d,1H), of 7.97(d, 2H), 8,14(s, 1H), 10,28(s, 1H), 10,46(s, 1H). Mass spectrum: M+H+426 and 428.

Iron powder (2,79 g) is added to a stirred suspension parts (2,13 g) obtained above compounds in a mixture of ethanol (100 ml), water (20 ml) and acetic acid (4 ml). The mixture is stirred and heated at boiling temperature under reflux for 6 hours. The mixture is cooled to ambient temperature. Add water (50 ml) and the resulting mixture was alkalinized by addition of sodium carbonate. The mixture is filtered and the filtrate is evaporated. The residue is triturated under water. The obtained solid is isolated and dried in a vacuum at a temperature of 40°C. Thus receive the desired source connection (0,911 g). An NMR spectrum: (d6) and 3.72(s, 3H), 6,09(d, 1H), 6,27(s, 1H), 6,62(s, 2H), 7,45-to 7.61(m, 4H), 7,66-7,72(m, 2H), 7,95(d, 2H), 8,07(s, 1H), 9,52(s, 1H), 10,37(s, 1H). Mass spectrum: M+H+396 and 398.

Example 2

3-(5-Benzamido-2-chlorophenyl)-7-methoxy-2-methyl-3,4-dihydroquinazolin-4-one

According to the method of example 1 triethylorthoformate subjected to interaction withN-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide. The obtained compound purified column chromatography on isolute SCX ion exchange column using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous solution of ammonium hydroxide as eluent. Get listed in the title compound with a 27% yield.

An NMR spectrum: (DM is d 6) to 2.15(s, 3H), 3,91(s, 3H), 7,09-7,14(m, 2H), 7,46 and 7.6(m, 3H), 7,71(d, 1H), 7,87-of 8.06(m, 5H), 10,57(s, 1H). Mass spectrum: M+H+420 and 422.

Example 3

Using the methods of examples 1 and example 2, suitable 2-aminobenzamide subjected to interaction with triethylorthoformate or triethylorthoformate with obtaining the compounds described in table 1.

Table I
No.(R1)m(R2)nR3Approx.
16-[N-(3-dimethylaminopropyl)-N-methylamino]6-methylhydrogenand
26-[N-(3-dimethylaminopropyl)-N-methylamino]6-methylmethylb
36-[N-(3-dimethylaminopropyl)-N-methylamino]hydrogenhydrogen
46-[N-(3-dimethylaminopropyl)-N-methylamino]hydrogenmethyld
56-(4-methylpiperazin-1-yl)6-methylhydrogene
66-(4-methylpiperazin-1-yl)6-methylmethyl f
76-(4-methylpiperazin-1-yl)hydrogenhydrogen9
86-(4-methylpiperazin-1-yl)hydrogenmethylh
98-[N-(3-dimethylaminopropyl)-N-methylamino]6-methylhydrogeni
106-[N-(3-methylaminopropyl)-N-methylamino]6-methylhydrogenj

Notes

a) the Product has the following characteristics. An NMR spectrum: (d6) 1,73 of-1.83(m, 2H), of 1.88(s, 3H), of 2.23(s, 6N), and 2.26-of 2.34(m, 2H), of 3.07(s, 3H), 3,44-3,55(m, 6N), 3,67-3,71(m, 4H), to 7.0(d, 1H), to 7.09(s, 1H), 7,19(d, 1H), 7,31(d, 1H), 7,43(s, 1H), 7,54(s, 1H), 7,66(d, 1H), of 7.75(d, 2H), 8,23(d, 1H), 8,69 (s, 1H). Mass spectrum: M+H+556.

N-[2-Methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-2-Mino-5-[N-(3-dimethylaminopropyl)-N-methylamino]benzamide used as a starting compound, obtained as follows.

The triethylamine (31.8 ml) is added to a stirred mixture of 4-methyl-3-nitroaniline (15,8 g), 2-chloropyridin-4-carbonylchloride (20 g) and methylene chloride (1 liter) and the resulting mixture stirred at ambient temperature for 16 hours. The sediment out, washed with saturated aqueous restaura sodium bicarbonate and methylene chloride and dried in in the cosmology vacuum at a temperature of 40° C. Obtain 2-chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide (10.2 g). The organic filtrate was washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and evaporated. The residue is triturated under methylene chloride and the resulting solid is isolated and dried in a vacuum at a temperature of 40°C. Receive a second portion (8,13 g), 2-chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide. An NMR spectrum: (d6) 2,48(s, 3H), 7,51(d, 1H), 7,86(m, 1H), of 7.96(m, 2H), 8,49(m, 1H), 10,85(s, 1H). Mass spectrum: M+H+292 and 294.

The mixture obtained pyridine-4-carboxamide and research (250 ml) is stirred and heated at a temperature of 100°C for 18 hours. The mixture was poured into water (250 ml) and stirred for 10 minutes. Add methylene chloride and the resulting mixture is stirred for 30 minutes. The obtained solid substance emit, washed with methylene chloride and dried in a vacuum oven at a temperature of 40°C for 18 hours. GetN-(4-methyl-3-nitrophenyl)-2-morpholinopropan-4-carboxamid (17,34 g). An NMR spectrum: (d62,48 (s, 3H), 3,52(m, 4H), 3,71(m, 4H), and 7.1(d, 1H), 7,25(s, 1H), 7,49(d, 1H), 7,97(m, 1H), 8,29(m, 1H), 8,49(m, 1H), to 10.62(s, 1H). Mass spectrum: M+H+343.

A mixture of part (8.5 g) of the obtained compound, catalyst (5% palladium on carbon (0.85 grams) and methanol (600 ml) is stirred under atmospheric pressure of hydrogen for 18 hours. Add methylene chloride, reactio the ing the mixture is filtered through diatomaceous earth. The filtrate is evaporated to obtainN-(3-amino-4-were)-2-morpholinopropan-4-carboxamide (6,41 g). An NMR spectrum: (d6) a 2.01(s, 3H), 3,52(m, 4H), to 3.73(m, 4H), of 4.83(s, 2H), 6,78(d, 1H), at 6.84(d, 1H),? 7.04 baby mortality-was 7.08(m, 2H), 7,2(s, 1H), 8,24(d, 1H), 9,95 (s, 1H). Mass spectrum: M+N+313.

Oxalicacid (0.55 g) is added dropwise to a stirred mixture of 5-chloro-2-nitrobenzoic acid (0,726 g), DMF (few drops) and methylene chloride (25 ml), cooled down to 0°C. the Mixture is heated under ambient temperature and stirred for 5 hours. The mixture is evaporated. The residue is dissolved in methylene chloride (10 ml) and added dropwise to a stirred mixtureN-(3-amino-4-were)-2-morpholinopropan-4-carboxamide (0,933 g), triethylamine (1,12 ml) and methylene chloride (25 ml). The resulting mixture was stirred at ambient temperature for 16 hours. The precipitate allocate, washed successively with water, methylene chloride and diethyl ether and dried in vacuum at a temperature of 40°C. ReceiveN-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-5-chloro-2-nitrobenzamide (1.12 g). An NMR spectrum: (d6) of 2.23 (s, 3H), 3,5-of 3.54 (m, 4H), 3,69-to 3.73(m, 4H), 7,12(d, 1H), 7,2-7,25(m, 2H), 7,58(d, 1H), 7,81(d, 1H), 7,87 to 7.9(m, 2H), 8,15(d, 1H), compared to 8.26(d, 1H). Mass spectrum: M+H+496 and 498.

A mixture of a portion (0.2 g) of the obtained compound, andN-(3-dimethylaminopropyl)-N-methylamine (1.5 ml) is stirred and nagrevaete temperature of 100° C for 16 hours. The mixture is cooled and poured into water. The precipitate allocate, washed successively with water and diethyl ether and dried in vacuum at a temperature of 40°C. ReceiveN-(2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-5-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide (0,223 g). An NMR spectrum: (d6) 1,62-of 1.74(m, 2H), 2,12(C, 6N), 2,18-of 2.26(m, 5H), is 3.08(s, 3H), 3,50-of 3.54(m, 6N), 3,69-3,71(m, 4H), 6.75 in(s, 1H), 6,84(s, 1H), 7,12(d, 1H), 7,2(d, 1H), 7,26(s, 1H), 7,68(d, 1H), and 7.9(s, 1H), of 8.04(d, 1H), compared to 8.26(d, 1H), 9,82(s, 1H), 10,04(s, 1H).

Mass spectrum: M+H+576.

A mixture of the compounds obtained, 10% palladium on carbon (0.02 g) and methanol (15 ml) is stirred in hydrogen atmosphere. After cessation of hydrogen absorption, the catalyst is removed by filtration through diatomaceous earth and the filtrate is evaporated. Get the required parent compound (0.15 g). Mass spectrum: M+H+546.

a) the Compound has the following characteristics. An NMR spectrum: (d6) 1,58 is 1.7(m, 2H), of 1.97(s, 3H), of 2.06(s, 3H), 2,12(C, 6N), of 2.23(t, 2H), 2,96(s, 3H), 3,39-of 3.48(m, 2H), 3,48-to 3.52(m, 4H), 3,68-3,71(m, 4H), was 7.08(d, 1H), 7,15(s, 1H), 7,22(s, 1H), 7,32(m, 1H), 7,42(d, 1H), 7,51(d, 1H), to 7.67(s, 1H), 7,74(d, 1H), compared to 8.26(d, 1H), 10,42(s, 1H). Mass spectrum: M+H+570.

b) the Compound has the following characteristics. An NMR spectrum: (d6) of 1.66(m, 2H), 2,12(C, 6N), 2,22(m, 2H), 2,99(s, 3H), 3,51(m, 6N), 3,71(t, 4H), and 7.1(d, 1H), from 7.24(m, 3H), 7,35(m, 1H), 7,55(m, 2H), a 7.85(m, 2H), with 8.05(s, 1H), 8,27(d, 1H), 10,51(broad s, 1H). Mass spectrum: M+H+ 542.

N-[3-(2-Morpholinomethyl-4-ylcarbonyl)phenyl]-2-amino-5-[N-3-dimethylaminopropyl)-N-methylamino]benzamide used as a starting compound, obtained as follows.

The triethylamine (6,7 ml) is added to a stirred mixture of 3-nitroaniline (3 g), 2-chloropyridin-4-carbonylchloride (4.6 g) and methylene chloride (50 ml) and the resulting mixture stirred at ambient temperature for 40 hours. The mixture is evaporated and the residue triturated under water. The obtained solid substance emit, washed with saturated aqueous sodium bicarbonate and dried in a vacuum at a temperature of 55°C. Receive 2-chloro-N-(3-nitrophenyl)pyridine-4-carboxamide (6,03 g). An NMR spectrum: (d6) to 7.68(t, 1H), 7,88 (t, 1H), 7,99(m, 2H), 8,16(d, 1H), 8,63(d, 1H), 8,73 (t, 1H), 10,95 (broad s, 1H); Mass spectrum: M+N+278.

The mixture obtained pyridine-4-carboxamide and research (100 ml) is stirred and heated at a temperature of 130°C for 3.5 hours and up to a temperature of 150°C for 2 hours. The mixture was poured into water (250 ml) and stirred for 10 minutes. The obtained solid substance emit, washed successively with water and isohexane and dried in a vacuum at a temperature of 55°C. ReceiveN-(3-nitrophenyl)-2-morpholinopropan-4-carboxamid (6.8 g). An NMR spectrum: (d6) to 3.52 (t, 4H), 3,71(t, 4H), 7,12(d, 1H), 7,25(s, 1H), 7,66(t, 1H), of 7.97(d, 1H), 8,15(d, 1H), 8,29(d, 1H), 8,t, 1H), of 10.72(broad s, 1H). Mass spectrum: M+N+329.

A mixture of the obtained compound, the catalyst is 10% palladium on carbon (0.68 g), ammonium formate (13 g) and methanol (150 ml) is stirred and heated at boiling temperature under reflux for 2 hours. The reaction mixture is filtered through diatomaceous earth. The filtrate is evaporated and the residue triturated under water. The obtained solid substance emit, washed successively with water and isohexane and dried in a vacuum at a temperature of 55°C. ReceiveN-(3-AMINOPHENYL)-2-morpholinopropan-4-carboxamid (5,38 g). An NMR spectrum: (d6) 3,51(t, 4H), 3,71(t, 4H), 5,07(broad s, 2H), 6,33(d, 1H), for 6.81(d, 1H), 6,95(t, 1H), 7,05(m, 2H), 7,2(s, 1H), 8,24(d, 1H), 9, 96 (broad s, 1H). Mass spectrum: M+N+299.

Oxalicacid (0,66 ml) was added dropwise to a stirred mixture of 5-chloro-2-nitrobenzoic acid (1.22 g), DMF (few drops) and methylene chloride (20 ml). The mixture was stirred at ambient temperature for 4 hours. The mixture is evaporated. The residue is dissolved in methylene chloride (10 ml) and added to stir the mixtureN-(3-AMINOPHENYL)-2-morpholinopropan-4-carboxamide (1.5 g), triethylamine (1.75 ml) and methylene chloride (20 ml). The resulting mixture was stirred at ambient temperature for 16 hours. The mixture is evaporated and the residue triturated under water. The obtained solid substance was separated, washed on sledovatelno 2N aqueous solution of sodium hydroxide and diethyl ether. The compound obtained purified by ion exchange column (isolute SCX, using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous solution of ammonium hydroxide as eluent. GetN- [3-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-5-chloro-2-nitrobenzamide (1,96 g). An NMR spectrum: (d6) 3,51(t, 4H), 3,71(t, 4H), and 7.1(d, 1H), 7.23 percent(s, 1H), was 7.36(m, 2H), 7,51(d, 1H), 7,82(d, 1H), to 7.93(s, 1H), 8,18(m, 2H), compared to 8.26(d, 1H), 10,37(broad s, 1H), of 10.73(broad s, 1H). Mass spectrum: M+H+482.

A mixture of part (0,384 g) of the obtained compound, andN-(3-dimethylaminopropyl)-N-methylamine (4 ml) is stirred and heated at a temperature of 120°C for 4 hours. The mixture is cooled and poured into a mixture of ice and water. The obtained precipitate out, washed with isohexane and dried in a vacuum at a temperature of 55°C. ReceiveN-[3-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-5-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide (0,376 g). An NMR spectrum: (d6) to 1.67(m, 2H), 2,11 (C, 6N), 2,2(t, 2H), of 3.07(s, 3H), 3,51(m, 6N), 3,71(t, 4H), 6,77(d, 1H), 6,84(m, 1H), and 7.1(d, 1H), 7,24(s, 1H), 7,31(m, 2H), of 7.48(d, 1H), 8,04(d, 1H), 8,17(s, 1H), compared to 8.26(d, 1H), 10,34 (broad s, 1H), 10,42 (broad s, 1H). Mass spectrum: M+N+562.

A mixture of the compounds obtained, 10% palladium on uglevodoroda (0.036 g), ammonium formate (0.4 g) and methanol (4 ml) is stirred and heated at boiling temperature under reflux for 2 hours. The mixture is filtered through diat the MoEHE the ground. The filtrate is evaporated and the residue purified by chromatography on a column using the column obrashenii phase C18 with silicon dioxide and a mixture of water and methanol with decreasing polarity as eluent. Get the desired source connection (0,256 g). An NMR spectrum: (d6) to 1.59(m, 2H), and 2.14(s, 6N), and 2.26(t, 2H), 2,11 (s, 3H), 3,18(t, 2H), 3,52(t, 4H), 3,71(t, 4H), to 6.67(d, 1H), PC 6.82(m, 1H), 6,93(d, 1H), 7,11(d, 1H), 7,29(m, 2H), 7,39(d, 1H), 7,46(d, 1H), 8.17 and(s, 1H), compared to 8.26(d, 1H), of 10.05(broad s, 1H), 10,31(broad s, 1H).

Mass spectrum: M+N+532.

C) the Compound has the following characteristics. An NMR spectrum: (d6) of 1.64(m, 2H), 2,11(s, N), of 2.21(m, 2H), 2,96(s, 3H), 3.43 points(t, 2H), 3,51(m, 4H), and 3.7(m, 4H), to 7.09(d, 1H), 7,15(m, 2H), 7.23 percent(s, 1H), 7,33(m, 1H), of 7.48(m, 2H), 7,73(s, 1H), 7,83(d, 1H), 8,27(d, 1H), 10,49 (broad s, 1H). Mass spectrum: M+H+556.

d) Compound has the following characteristics. Mass spectrum: M+N+540.

N-[2-Methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamide used as a starting compound, obtained as follows.

According to the method described in the fifth paragraph of the portion of note a)relating to the acquisition of the initial compounds,N-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-5-chloro-2-nitrobenzamide subjected to interaction with 1-methylpiperazine with gettingN-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl-amino)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzene the A.

An NMR spectrum: (d6) of 2.21(s, 3H), 2,24(s, 3H), 2,41-2,47(m, 4H), 2,63-2,69(m, 2H), 3.46 in-of 3.53(m, 8H), 3,69-and 3.72(m, 4H), 7,0(s, 1H),? 7.04 baby mortality for 7.12(m, 2H), 7,19(d, 1H), 7,25(s, 1H), EUR 7.57(d, 1H), 7,88(s, 1H), 8,04(d, 1H), compared to 8.26(d, 1H), 9,83(s, 1H), 10,33(s, 1H). Mass spectrum: M+H+560.

According to the method described in the sixth paragraph of part of the notes (a)relating to the acquisition of the initial compounds,N-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide restore with obtaining the required parent compound. Mass spectrum: M+N+530.

e) the Compound has the following characteristics. Mass spectrum: M+N+554.

f) Connection has the following characteristics. An NMR spectrum: (d6) 2,22(s, 3H), 2,4(m, 4H), 3,3(m, 4H), 3,51(t, 4H), 3,71(t, 4H), and 7.1(d, 1H), 7,25(m, 2H), 7,47(s, 1H), 7,54(t, 1H), 7,6(c, 2H), 7,87(m, 2H), 8,14(s, 1H), 8,28(d, 1H), 10,52(broad s, 1H). Mass spectrum: M+H+526.

N-[3-(2-Morpholinomethyl-4-ylcarbonyl)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamide used as a starting compound, obtained as follows.

According to the method described in the fifth paragraph of part of the notes)relating to the acquisition of the initial compounds,N-[3-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-5-chloro-2-nitrobenzamide subjected to interaction with 1-methylpiperazine with gettingN-[3-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide with 89% yield. Spec is p NMR: (d 6) 2,2(s, 3H), 2,41(m, 4H), 3,5(m, 8H), 3,71(t, 4H), 7,07(m, 3H), 7,31(m, 3H), of 7.48(d, 1H), 8,03(d, 1H), 8,16(s, 1H), compared to 8.26(d, 1H), 10,35(broad s, 1H), 10,44(broad s, 1H). Mass spectrum: M+N+546.

According to the method described in the sixth paragraph of part of the notes)relating to the acquisition of the initial compounds,N-[3-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide restore. The compound obtained purified by chromatography on ion-exchange column (isolute SCX using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous solution of ammonium hydroxide as eluent. Get the required initial connection to 50% output. An NMR spectrum: (d6) 2,2 (s, 3H), 2,4(m, 2H), 3,0 (t, 4H), 3,52(t, 4H), 3,71(t, 4H), of 6.68(d, 1H), of 6.96(d, 1H), and 7.1(m, 2H), 7,25(m, 2H), and 7.4(m, 2H), 8,15(s, 1H), compared to 8.26(d, 1H), 10,01(broad s, 1H), 10,31(broad s, 1H). Mass spectrum: M+N+516.

g) the Compound has the following characteristics. An NMR spectrum: (d6) a 2.12 (s, 3H), of 2.21 (s, 3H), 2,5(m, 4H), up 3.22(m, 4H), 3,51(m, 4H), and 3.7(m, 4H), to 7.09(d, 1H), 7,18(m, 2H), 7,37(s, 1H), 7,54(m, 3H), 7,74(s, 1H), 7,83(d, 1H), 8,27(d, 1H), and 10.5(broad s, 1H). Mass spectrum: M+N+540.

h) Compound has the following characteristics. Mass spectrum: M+N+556.

N-[2-Methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-2-amino-3-[N-(3-dimethylaminopropyl)-N-methylamino]benzamide used as a starting compound, obtained as follows.

According to the method described in the fourth paragraph of the portion of note a)relating to the acquisition of the initial compounds, 3-chloro-2-nitrobenzoate (obtained by the interaction of 3-chloro-2-nitrobenzoic acid and oxalylamino) is subjected to interaction withN-(3-amino-4-were)-2-morpholinopropan-4-carboxamido with gettingN-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3-chloro-2-nitrobenzamide. An NMR spectrum: (d6) 2,2(s, 3H), 3,49-of 3.53(m, 4H), 3,69-to 3.73(m, 4H), and 7.1(d, 1H), 7.18 in-7,24(m, 2H), 7,58(d, 1H), 7.68 per for 7.78(m, 2H), 7,58(d, 1H), 7.68 per for 7.78(m, 2H), 7,84 to 8.0(m, 2H), of 8.25(d, 1H). Mass spectrum: M+N+496 and 498.

According to the method described in the fifth paragraph of the portion of note a)relating to the acquisition of the initial compounds,N-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3-chloro-2-nitrobenzamide subjected to interaction withN-(3-dimethylaminopropyl)-N-methylamine with gettingN-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide. An NMR spectrum: (d6) 1,44 is 1.58(m, 2H), 2.06 to(C, 6N), of 2.15(t, 2H), of 2.21(s, 3H), 2,69(s, 3H), to 3.02(t, 2H), 3,48-of 3.53(m, 4H), 3,69-to 3.73(m, 4H), and 7.1(d, 1H), 7,19-7,25(m, 2H), 7,44 to 7.62(m, 3H), 7,74-to 7.64(m, 1H), 7,94(d, 1H), compared to 8.26(d, 1H), 10,13(s, 1H), 10,32(s, 1H). Mass spectrum: M+N+576.

According to the method described in the sixth paragraph of part of the notes (a)relating to the acquisition of the initial compounds,N-[2-methyl-5-(2-morpholinomethyl-4-ilıca is Beniamino)phenyl]-3-[ N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide catalytically restore with obtaining the required parent compound. Mass spectrum: M+N+546.

i) Compound has the following characteristics. An NMR spectrum: (d6) 1,6-of 1.75(m, 2H), 2.05 is(s, 3H), of 2.28(s, 3H), 2,47-2,52(m, 2H), 2,99(s, 3H), 3,49-of 3.53(m, 6N), 3,69-to 3.73(m, 4H), was 7.08(d, 1H), 7,22(s, 2H), 7,34-7,24(m, 2H), and 7.6(d, 1H), 7,75 one-7.8(m, 2H), 7,97(, 1H),8,28(d, 1H), 10,42(s, 1H). Mass spectrum: M+N+542.

N-(2-Methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-2-amino-5-[N-(3-methylaminopropyl)-N-methylamino]benzamide used as a starting compound, obtained as follows.

According to the method described in the fifth paragraph of the portion of note a)relating to the acquisition of the initial compounds,N-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-5-chloro-2-nitrobenzamide subjected to interaction withN-(3-methylaminopropyl)-N-methylamine with gettingN-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-5-[N-(3-methylaminopropyl)-N-methylamino]-2-nitrobenzamide. An NMR spectrum: (d6) 1,61-of 1.74(m, 2H), 2,35(s, 3H), and 2.26(m, 3H), 2,38 is 2.44(m, 2H), to 3.09(s, 3H), 3,5-3,55(m, 6N), 3,7-3,74(m, 4H), 6,78(s, 1H), at 6.84(d, 1H), 7,14(d, 1H), 7,21(d, 1H), 7,27(s, 1H), and 7.6(d, 1H), of 7.9(s, 1H), 8,04(d, 1H), 8,27(d, 1H), 9,83(s, 1H), 10,55 (s, 1H). Mass spectrum: M+H+562.

According to the method described in the sixth paragraph of part of the notes (a)relating to the acquisition of the initial connection is on, N-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3-[N-(3-methylaminopropyl)-N-methylamino]-2-nitrobenzamide catalytically restore with obtaining the required parent compound.

An NMR spectrum: (d6) 1,57-of 1.62(m, 2H), 2,2(s, 3H), of 2.25(s, 3H), 2,47-2,5(m, 2H), 2,77 (s, 3H), 3,19 is 3.23(m, 2H), 3,5-of 3.54(m, 4H), 3,69-to 3.73(m, 4H), 5,6(s, 2H), of 6.68(d, 1H), PC 6.82(d, 1H),? 7.04 baby mortality(s, 1H), and 7.1(d, 1H), 7,2-of 7.23(m, 2H), 7,54(d, 1H), 7,83(d, 1H), compared to 8.26(d, 1H), 9,75(s, 1H), 10,28(s, 1H). Mass spectrum: M+H+532.

Example 4

Using a technique similar to that described in example 1 suitable 2-aminobenzamide subjected to interaction with triethylorthoformate with obtaining the compounds described in table II.

Table II
No.(R1)m(R)pApprox.
16-(4-methylpiperazin-1-yl)3 morpholino-5-trifluoromethyland
26-[N-(3-dimethylaminopropyl)-N-methylamino]3 morpholino-5-trifluoromethylb
38-[N-(3-dimethylaminopropyl)-N-methylamino]3 morpholino-5-trifluoromethyl
46-methoxy3-fluoro-5-morpholino d

Notes

a) as a reagent use triethylorthoformate and the compound obtained has the following characteristics. An NMR spectrum: (d6) was 2.05 (s, 3H), of 2.23 (s, 3H), 2,5(m, 4H), 3,3 (m, 8H), 3,76(t, 4H), 7,44(M, 3H), 7,72(m, 6N)and 8.1(s, 1H), 10,52(W s, 1H). The mass spectrum. M+H+607.

N-[2-Methyl-5-(3-morpholino-5-triptoreline)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamide used as a starting compound, obtained as follows.

Ethyl-3-morpholino-5-cryptomelane obtained from ethyl-3-fluoro-5-triftoratsetata according to the method described in Brown et al., Tetrahedron Lett., 1999, 40, 1219. The compound obtained has the following characteristics. An NMR spectrum: (CDCl3) of 1.36(t, 3H), 3,19(t, 4H), 3,81(t, 4H), 4,34(m, 2H), 7,22(d, 1H), 7,72(d, 1H), 7,76(s, 1H).

A mixture of ethyl-3-morpholino-5-triftoratsetata (0,67 g), 1N aqueous sodium hydroxide solution (3.3 ml) and ethanol (6 ml) is stirred and heated to boiling point under reflux for 15 minutes and then left for 16 hours. The ethanol is evaporated and the residue is dissolved in water (6 ml). Add hydrochloric acid (1 M, 3.3 ml) and the resulting solid is washed with water and dried. Get 3 morpholino-5-triftorperasin acid solids (0,464 g). An NMR spectrum: (d6) of 3.25(t, 4H), to 3.73(t, 4H), and 7.4(s, 1H), 7,53(s, 1H), 7,65(s, 1H), and 13.3(s, 1H).

A solution of 3-morpholino-5-trifloromethyl orida (11,43 g, obtained by the interaction of benzoic acid with oxalylamino using conventional techniques) in methylene chloride (200 ml) is added to a stirred mixture of 4-methyl-3-nitroaniline (vs. 5.47 g), triethylamine (10 ml) and methylene chloride (200 ml). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous sodium bicarbonate, dried (MgSO4) and evaporated. The obtained solid is stirred with diethyl ether (300 ml) for 16 hours. The obtained solid is collected, washed with diethyl ether and dried. GetN-(4-methyl-3-nitrophenyl)-3-morpholino-5-perbenzoic in the form of a solid (10.4 g). An NMR spectrum: (CDCl3) of 2.58 (s, 3H), up 3.22 (t, 4H), 3,83 (t, 4H), 7,21 (s, 2H), 7,32 (d, 1H), 7,41 (s, 1H), 7,58 (s, 1H), 7,82 (m, 1H), 8,02 (s, 1H), 8,23 (d, 1H).

The compound obtained is dissolved in ethyl acetate (500 ml) and hydronaut over the catalyst 10% palladium on uglevodoroda (1.1 g) under hydrogen pressure of 3 atmospheres until then, until there is no further absorption of hydrogen. The catalyst was removed by filtration and the filtrate is evaporated. The residue is triturated under ethyl acetate to obtainN-(3-amino-4-were)-3-morpholino-5-cryptomelane 8.1 (d). An NMR spectrum: (COCl3) a 2.01(s, 3H), 3,23(t, 4H), of 3.75(t, 4H), to 4.81(s, 2H), 6,77(m, 1H), 6,83(d, 1H), 7,02(d, 1H), 7,25(s, 1H), 7,58(s, 1H), 7,63(s, 1H), 9,9(s, 1H).

Diisopropylate the Lamin (0,918 ml) is added to the mixture N-(3-amino-4-were)-3-morpholino-5-cryptomelane (1 g), 5-chloro-2-nitrobenzoic acid (0,584 g), 2-(7-asobancaria-1-yl)-1,1,3,3-tetramethylethylenediamine(V) (1.2 g) and DMF (6 ml) and the reaction mixture stirred at ambient temperature for 16 hours. The mixture is then poured into a mixture of ice and water and the resulting precipitate out, washed successively with methanol and isohexane and dried in a vacuum at a temperature of 55°C. ReceiveN-[2-methyl-5-(3-morpholino-5-triptoreline)phenyl]-5-chloro-2-nitrobenzamide (0,965 g). An NMR spectrum: (d6) 2,24 (s, 3H), 3,3(m, 4H), 3,76(m, 4H), of 7.23(d, 1H), was 7.36(s, 1H), and 7.6(d, 1H), 7,65(s, 1H), 7,72(s, 1H), 7,82(d, 1H), of 7.90(m, 2H), 8,17(d, 1H), 10,17 (s, 1H), 10, 38 (s, 1H). Mass spectrum: M+N+563.

A mixture of part (0.45 g) of the obtained compound, andN-methylpiperazine (2 ml) is stirred and heated at a temperature of 120°C for 16 hours. The reaction mixture was poured into a mixture of ice and water. The obtained solid substance out, washed with water and dried in a vacuum at a temperature of 55°C. the Obtained solid is purified by chromatography on ion-exchange column (column isolute SCX)using initially methanol and then a mixture of methanol and 1% aqueous ammonium hydroxide solution as eluent. GetN-[2-methyl-5-(3-morpholino-5-triptoreline)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide (0.29 grams). An NMR spectrum: (d6)of 2.21 (s, 3H), 2,24 (s, 3H), of 2.5-3.3 (m, 8H), of 3.48 (m, 4H), 3,76 (m, 4H), to 7.0 (d, 1H), 7,07 (d, 1H), 7,2 (d, 1H), was 7.36 (s, 1H), 7,6 (m, 3H), 7,88 (s, 1H), 8,04 (d, 1H), 9,84 (s, 1H), 10,37 (s, 1H). Mass spectrum: M+N+627.

A mixture of the obtained compound, ammonium formate (0,146 g), catalyst (10% palladium on carbon (0,029 g) and methanol (5 ml) is stirred and heated at a temperature of 65°C for 2 hours. The resulting mixture was filtered and the filtrate is evaporated. The residue is triturated under methylene chloride and filtered. The filtrate is evaporated to obtainN-[2-methyl-5-(3-morpholino-5-triptoreline)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamide, which was used without further purification.

b) as a reagent use triethylorthoformate and the product has the following characteristics. An NMR spectrum: (d6) to 1.67(m, 2H), 2.05 is(s, 3H), 2.13 and(C, 6N), and 2.27(m, 2H), 3.0 a(s, 1H), 3,3(m, 4H), 3,47(m, 2H), 3,76(W s, 4H), 7,25(d, 1H), 7,39(m, 3H), a 7.62(m, 3H), 7,73(d, 1H), 7,81(d, 1H), and 8.0(s, 1H), 10,51(W s, 1H). Mass spectrum: M+H+623.

N-[2-Methyl-5-(3-morpholino-5-triptoreline)phenyl]-2-amino-5-[N-(3-dimethylaminopropyl)-N-methylamino]benzamide used as starting material was obtained as follows.

The mixture ofN-[2-methyl-5-(3-morpholino-5-triptoreline)phenyl]-5-chloro-2-nitrobenzamide (0.45 g),N-(3-dimethylaminopropyl)-N-methylamine (2 ml) and DMSO (1 ml) is stirred and heated at a temperature of 120°C for 16 hours is. The reaction mixture was poured into a mixture of ice and water. The obtained solid substance out, washed with water and dried in a vacuum at a temperature of 55°C. ReceiveN-[2-methyl-5-(3-morpholino-5-triptoreline)phenyl]-5-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide (0.51 g). An NMR spectrum: (d6) was 1.69(m, 2H), 2,12(C, 6N), 2,24(m, 5H), is 3.08(s, 3H), 3,3(m, 4H), 3,52(t, 2H), 3,76(m, 4H), 6,76(S, 1H), 6,83(d, 1H), 7,2(d, 1H), was 7.36(s, 1H), 7,66(m, 3H), 7,89(s, 1H), 8,04(d, 1H), 9,82(s, 1H), 10,37(s, 1H).

A mixture of the obtained compound, ammonium formate (0.24 g), catalyst (10% palladium on carbon (0.05 g) and methanol (10 ml) is stirred and heated at a temperature of 65°C for 7 hours. The resulting mixture was filtered and the filtrate is evaporated. The residue is triturated under methylene chloride and filtered. The filtrate is evaporated to obtainN-[2-methyl-5-(3-morpholino-5-triptoreline)phenyl]-2-amino-5-[N-(3-dimethylaminopropyl)-N-methylamino]benzamide, which is used without further purification.

(C) as a reagent use triethylorthoformate and the product has the following characteristics. An NMR spectrum: (d6) 1,72(m, 2H), 2.06 to(m, N), 2,19(t, 2H), equal to 2.94(s, 3H), 3,3(m, 4H), 3,49(t, 2H), 3,76(W s, 4H), 7,26(d, 1H), 7,42(m, 3H), 7,68(m, 3H), and 7.8(m, 2H), 8,21(s, 1H), 10,49(W s, 1H). Mass spectrum: M+N+623.

N-[2-Methyl-5-(3-morpholino-5-triptoreline)phenyl]-2-amino-3-[N-(3-dimethylaminopropyl)-N-methylamino]Benza the ID, used as starting material was obtained as follows.

Diisopropylethylamine (0,46 ml) is added to the mixtureN-(3-amino-4-were)-3-morpholino-5-cryptomelane (0.5 g), 3-chloro-2-nitrobenzoic acid (0,292 g), 2-(7-asobancaria-1-yl)-1,1,3,3-tetramethylethylenediamine(V) (0.6 g) and DMF (3 ml) and the reaction mixture stirred at ambient temperature for 16 hours. The mixture is then poured into a mixture of ice and water and the resulting precipitate out, washed successively with methanol and isohexane and dried in a vacuum at a temperature of 55°C. ReceiveN-[2-methyl-5-(3-morpholino-5-triptoreline)phenyl]-3-chloro-2-nitrobenzamide (0.45 g). An NMR spectrum: (d6) 2,22 (s, 3H), 3,3 (m, 4H), 3,76(m, 4H), 7,25(d, 1H), 7,37(s, 1H), 7,71(m, 5H), of 7.96(d, 2H), 10,36(W s, 1H), 10,38(W s, 1H). Mass spectrum: M+H+563.

A mixture of the obtained compound,N-(3-dimethylaminopropyl)-N-methylamine (2 ml) and DMSO (1 ml) is stirred and heated at a temperature of 120°C for 16 hours. The reaction mixture was poured into a mixture of ice and water. The obtained solid substance out, washed with water and dried in a vacuum at a temperature of 55°C. ReceiveN-[2-methyl-5-(3-morpholino-5-triptoreline)phenyl]-3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide (0.51 g). An NMR spectrum: (d6) of 1.52(m, 2H), 2.06 to(C, 6N), of 2.15(m, 2H), 2,22(s, 3H), 2,69(s, 3H), 3,03(t, 2H), 3,3(m, 4H), 3,76(who, 4H), 7,22(d, 1H), was 7.36(m, 2H), 7,53(m, 4H), 7,73(d, 2H), 10,14(W s, 1H), 10,35(W s, 1H).

A mixture of the obtained compound, ammonium formate (0.24 g), catalyst (10% palladium on carbon (0.05 g) and methanol (10 ml) is stirred and heated at a temperature of 65°C for 7 hours. The resulting mixture was filtered and the filtrate is evaporated. The residue is triturated under methylene chloride and filtered. The filtrate is evaporated to obtainN-[2-methyl-5-(3-morpholino-5-triptoreline)phenyl]-2-amino-3-[N-(3-dimethylaminopropyl)-N-methylamino]benzamide, which is used without further purification.

d) as a reagent use triethylorthoformate and the product has the following characteristics. An NMR spectrum: (d6) to 2.06(s, 3H), 3,21(m, 4H), to 3.73(m, 4H), to 3.89(s, 3H), 6,97(d, 1H), 7,11(d, 1H), 7,29(s, 1H), 7,42(d, 1H), 7,49(d, 1H), 7,58(d, 1H), 7,72(d, 1H), 7,78(m, 2H), 8,17(s, 1H), 10,33(s, 1H). Mass spectrum: M+H+489.

N-[2-Methyl-5-(3-fluoro-5-morpholinomethyl)phenyl]-2-amino-5-methoxybenzamide used as starting material was obtained as follows.

A solution of 3,5-differentiald (2,82 g) in methylene chloride (20 ml) is added to a stirred mixture of 4-methyl-3-nitroaniline (2.28 g), triethylamine (4,35 ml) and methylene chloride (80 ml). The resulting mixture was stirred at ambient temperature for 16 hours. The sediment out, washed with methylene chloride and dried. GetN-(4-methyl-3-nitrophenyl)for 3,5-d is fermentated. An NMR spectrum: (d6) 2,43(s, 3H), 7,43(m, 2H), 7,63(m, 2H), 7,95(m, 2H), 8,43(d, 1H), 10,42(s, 1H).

Mass spectrum: M+H+293.

A mixture of part (1 g) of the obtained compound and the research (5 ml) is stirred and heated at a temperature of 100°C for 48 hours and up to a temperature of 120°C for 24 hours. The reaction mixture is cooled and poured into water (100 ml). The obtained solid substance out, washed with water and dried. The compound obtained purified by chromatography on a column of silica using a 1:1 mixture of isohexane and ethyl acetate as eluent. GetN-(4-methyl-3-nitrophenyl)-3-fluoro-5-morpholinomethyl in the form of solids (0,53 g). An NMR spectrum: (d6) to 2.46(s, 3H), up 3.22(t, 4H), of 3.75(t, 4H), 6,98(m, 1H), 7,12(d, 1H), 7,27(s, 1H), 7,46(d, 1H), of 7.96(m, 1H), 8,43(d, 1H), 10,48 (s, 1H). Mass spectrum: M+N+360.

Part (0,483 g) of the obtained compound was dissolved in ethyl acetate (40 ml) and hydronaut over the catalyst 10% palladium on carbon (0.6 g) in an atmosphere of hydrogen until then, until there is no further absorption of hydrogen. The catalyst was removed by filtration and the filtrate is evaporated. The residue is triturated under diethyl ether (25 ml). The obtained solid substance Siberut, washed with diethyl ether and dried. GetN-(3-amino-4-were)-3-fluoro-5-morpholinomethyl (0,341 g). An NMR spectrum: (d6) to 1.99(s, 3H), 3,19(t, 4H), 3,76(t, 4H), and 4.8(s, 2H), 6.75 in(d, 1H), PC 6.82(d, 1H), 6,9(d, 1H), 7,02(s, 1H),? 7.04 baby mortality(d,1H), of 7.23(s, 1H), 9,81(s, 1H).

Oxalicacid (0,523 ml) is added to a stirred mixture of 5-methoxy-2-nitrobenzoic acid (0,99 g), DMF (few drops) and methylene chloride (30 ml) and the mixture was stirred at ambient temperature for 3.5 hours. The mixture is evaporated and the residue is dissolved in methylene chloride (30 ml) and successively addN-(3-amino-4-were)-3-fluoro-5-morpholinomethyl (1.65 g) and triethylamine (0,697 ml). The resulting mixture was stirred at ambient temperature for 2 hours. The mixture is evaporated and the residue triturated under water. The obtained solid substance emit, washed sequentially with saturated aqueous sodium bicarbonate solution, water and diethyl ether and dried in vacuum at a temperature of 55°C. ReceiveN-[2-methyl-5-(3-fluoro-5-morpholinomethyl)phenyl]-5-methoxy-2-nitrobenzamide (to 2.29 g). An NMR spectrum: (d6) 2,24(s, 3H), 3,23(m, 4H), of 3.75(m, 4H), of 3.95(s, 3H), of 6.96(d, 1H), 7,17(m, 4H), 7,32(s, 1H), 7,58(d, 1H), 7,89(s, 1H), 8,18(d, 1H), 10.0 g(s, 1H), 10,22(s, 1H). Mass spectrum: M+N+509.

A mixture of part (1.28 g) of the obtained compound, the catalyst is 10% palladium on carbon (0,128 g) and methanol (60 ml) is stirred under an atmosphere of hydrogen for 20 hours. Add ethyl acetate (30 ml) and the reaction mixture stirred for another 2 hours in hydrogen atmosphere. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in the minimum to which icesto ethyl acetate and the solid precipitated by adding diethyl ether. The solid is isolated and dried in a vacuum at a temperature of 55°C. ReceiveN-[2-methyl-5-(3-fluoro-5-morpholinomethyl)phenyl]-2-amino-5-methoxybenzamide (0,98 g).

An NMR spectrum: (d6) 2,2 (s, 3H), up 3.22(m, 4H), 3,74(m, 7H), 5,93(W s, 2H), 6,72(d, 1H), 6,92(m, 2H), 7,12(d, 1H), 7,22(d, 1H), 7,27(m, 2H), 7,54(d, 1H), to 7.77(s, 1H), RS 9.69(s, 1H), 10,14(s, 1H). Mass spectrum: M+H+479.

Example 5

3-[5-(2-Chloropyrid-4-ylcarbonyl)-2-were]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one

2-Chloropyridin-4-carbonylchloride (0,61 g) is added to a stirred mixture of 3-(5-amino-2-were)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-it (1 g), triethylamine (1 g) and methylene chloride (15 ml) and the resulting mixture stirred at ambient temperature for 18 hours. The mixture was washed with saturated aqueous sodium bicarbonate and the organic phase is evaporated. Get listed in the title compound (1.28 g). An NMR spectrum: (d6) was 2.05(s, 3H), 2,22(s, 3H), 2,46-2,5(m, 4H), 3.25 to or 3.28(m, 4H), 7,42-7,47(m, 2H), 7.62mm(s, 1H), 7,76-7,79(m, 2H), a 7.85(d, 1H), 7,98(s, 1H), 8,07(s, 1H), 8,61(d, 1H), 10,65(s, 1H). Mass spectrum: M+H+489 and 491.

3-(5-Amino-2-were)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one used as starting compound, obtained as follows.

Oxalicacid (8.5 ml) is added dropwise to a stirred solution of 5-chloro-2-nitrobenzoic acid (15.1 g) in a mixture of methylene chloride (200 ml) and few drops of DMF), cooled to a temperature of 0°C. the Mixture is heated under ambient temperature and stirred for another 4 hours. The solvent is evaporated. The residue is dissolved in methylene chloride (300 ml) and added dropwise to a stirred mixture of 2-methyl-5-nitroaniline (10.6 g), triethylamine (27,2 ml) and methylene chloride (300 ml). The resulting mixture was stirred at ambient temperature for 16 hours. The sediment out, washed successively with water and diethyl EPROM and dried in a vacuum at a temperature of 40°C. ReceiveN-(2-methyl-5-nitrophenyl)-5-chloro-2-nitrobenzamide (24,9 g). An NMR spectrum: (d6) was 2.34(s, 3H), 7,46(D, 1H), of 7.75(s, 1H), 7,88(d, 1H), 8,03-8,16(m, 2H), 8,56(s, 1H). Mass spectrum: M+H+335.

A mixture of part (15 g) of the obtained compound, andN-methylpiperazine (24,8 ml) is stirred and heated at a temperature of 100°C for 16 hours. The reaction mixture was cooled to ambient temperature and poured into water. The obtained precipitate out, washed with water and dried in a vacuum at a temperature of 40°C. ReceiveN-(2-methyl-5-nitrophenyl)-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide (14.8 g). An NMR spectrum: (d6) 2,22(s, 3H), of 2.38(s, 3H), 2,41 at 2.45(m, 4H), 3,48-of 3.53(m, 4H), was 7.08(d, 1H), 7,17(s, 1H), 7,53(d, 1H), 7,98(d, 1H), 8,07(d, 1H), 8,53 (s, 1H), 10,15 (s, 1H). Mass spectrum: M+N+400.

A mixture of the obtained compound, the catalyst is 10% palladium on carbon (1.48 g) and methanol (500 ml) displacement is more in the atmosphere of hydrogen until until there is no further absorption of hydrogen. The catalyst is filtered off and the filtrate is evaporated. GetN-(5-amino-2-were)-2-amino-5-(4-methylpiperazin-1-yl)benzamide (10,11 g). An NMR spectrum: (d6) 2,02(s, 3H), 2,2 (s, MN), 2,4-of 2.45(m, 4H), 2,97 to 3.0(m, 4H), 4,84(s, 2H), of 5.82(s, 2H), 6,36(d, 1H), to 6.57(s, 1H), 6,66(d, 1H), 6,85(d, 1H), 6,92(d, 1H), 7,18 (s, 1H), and 9.4(s, 1H). Mass spectrum: M+H+340.

A mixture of part (of 8.27 g) of the material obtained, triethylorthoformate (8,27 ml), glacial acetic acid (0.7 ml) and ethanol (150 ml) is stirred and heated at a temperature of 70°C for 16 hours. Add 1N aqueous solution of hydrochloric acid (24 ml) and the mixture is stirred at a temperature of 60°C for 1 hour. The resulting mixture is evaporated. The residue is dissolved in water, alkalinized by adding sodium bicarbonate and extracted with methylene chloride. The organic extract is evaporated to obtain 3-(5-amino-2-were)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-it (8,29 g). An NMR spectrum: (d6) to 1.86(s, 3H), 2,22(s, 3H), 2,42 at 2.45(m, 4H), 3,24 of 3.28(m, 4H), 5,14(s, 2H), 6,47(s, 1H), is 6.61(d, 1H), 7,02(d, 1H), 7,45(s, 1H), to 7.59 (s, 1H), of 7.96(s, 1H). Mass spectrum: M+H+350.

Example 6

3-[2-Methyl-5-(2-pyrrolidin-1-inpired-4-ylcarbonyl)phenyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one

A mixture of 3-[5-(2-chloropyrid-4-ylcarbonyl)-2-were]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-it (0.18 g) and pyrrolidine (2 ml) is stirred and Renaut at a temperature of 100° C for 16 hours. The mixture is cooled to ambient temperature and poured into water. Received tverdova substance emit, washed with water and dried in a vacuum at a temperature of 40°C. Receive specified in the title compound (0.11 g).

An NMR spectrum: (d6) 1,94-of 1.97(m, 4H), 2,04(s, 3H), 2,22(s, 3H), of 2.45-2.49 USD(m, 4H), 3.25 to or 3.28(m, 4H), 3,4-of 3.45(m, 4H), 6,85(s, 1H), of 6.96(d, 1H), 7,42(d, 1H), 7,42(d, 1H), 7,44(s, 1H), 7.62mm(s, 2H), to 7.77-7,79(m, 2H), 8,07(s, 1H), and 8.2(s, 1H), 10,42(s, 1H). Mass spectrum: M+N+524.

Example 7

Using a technique similar to that described in example 6, the appropriate 6-substituted 3-[5-(2-chloropyrid-4-ylcarbonyl)-2-were]-3,4-dihydroquinazolin-4-one is subjected to interaction with a suitable amine with obtaining the compounds described in table III.

Table III
No.(R1)mRApprox.
16-(4-methylpiperazin-1-yl)piperidinoand
26-(4-methylpiperazin-1-yl)3-pyrrolin-1-ylb
36-(4-methylpiperazin-1-yl)homopiperazin-1-yl
46-(4-methylpiperazin-1-yl)azetidin-1-yld
56-(4-methylhomopiperazine-1-yl)piperidinoe
66-(4-methylhomopiperazine-1-yl)pyrrolidin-1-ylf
76-(4-methylhomopiperazine-1-yl)morpholino9

Notes

a) the Compound has the following characteristics. An NMR spectrum: (d6) 1,5-of 1.64(m, 6N), 2,04(s, 3H), 2,2(s, 3H), of 2.45-2.49 USD(m, 4H), 3,26 be 3.29(m, 4H), 3,55-3,59(m, 4H), 6,98(d, 1H), 7,19(s, 1H), 7,42(d, 1H), 7,47(s, 1H), 7.62mm(s, 2H), 7,76 for 7.78(m, 2H), 8,07(s, 1H), 8,21(s, 1H), 10,42(s, 1H). Mass spectrum: M+N+538.

b) the Compound has the following characteristics. An NMR spectrum: (d6) 2,04(s, 3H), 2,22(s, 3H), 2,47-2,5(m, 4H), 3.25 to and 3.31(m, 4H), to 4.23(s, 4H), 6,03(s, 2H), 6.87 in(s, 1H), 7,01(d, 1H), 7,42(d, 1H), 7,47(s, 2H), a 7.62(d, 2H), 7,76-7,81(m, 2H), 8,07(s, 1H), 8,23(d, 1H), 10,45(s, 1H). Mass spectrum: M+H+522.

c) Connection has the following characteristics. An NMR spectrum: (d6) of 1.45 to 1.47(m, 4H), 1,54-of 1.56(m, 4H), 2,04(s, 3H), 2,22(s, 3H), 2,45-2,5(m, 4H), 3.25 to 3.27 to(m, 4H), 3,62-to 3.64(m, 4H), 6,91(d, 1H), of 6.96(s, 1H), 7,02(d, 1H), 7,42(d, 1H), 7,47(s, 1H), 7.62mm(s, 2H), 7,76-7,81(m, 2H), 8,07(s, 1H), 8,18(d, 1H), 10,42(s, 1H). Mass spectrum: M+H+552.

d) Compound has the following characteristics. Mass spectrum: M+H+510.

e) the Compound has the following characteristics. An NMR spectrum: (CDCl3) 1,42 of 1.46(m, 6N), of 1.78 (s, 3H), 1,92-2,04(m, 2H), 2,48(s, 3H), 2,48-of 2.56(m, 2H), 2,64-of 2.72(m, 2H), 3,44-to 3.58(m, 6N), 3,6-to 3.64(m, 2H), 6,78(d, 1H), 7,01(s, 1H), 7,15-7,2m, 2H), 7,38(s, 1H), and 7.5(s, 1H), 7,58-to 7.68(m, 3H), 8,12(d, 1H), and 8.4(s, 1H). Mass spectrum: M+H+552.

f) Connection has the following characteristics. An NMR spectrum: (CDCl3) 1,84-2,04(m, N), 2,32(s, 3H), 2,48-of 2.58(m, 2H), 2,64 is 2.7(m, 2H), 3,32-3,44(m, 4H), 3,5-to 3.58(m, 2H), 3,6-to 3.64(m, 2H), 6,72-6,79(m, 2H), 7,14-to 7.2(m, 2H), 7,38(s, 1H), 7,52 to 7.62(m, 3H), of 7.64(s, 1H), 8,12(d, 1H), 8,44(s, 1H). Mass spectrum: M+N+538.

g) the Compound has the following characteristics. An NMR spectrum: (CDCl3) to 1.98(s, 3H), 2,02-2,12(m, 2H), 2,39(s, 3H), 2,58-2,62(m, 2H), 2,74-2,8(m, 2H), 3,5-to 3.58(m, 4H), 3,6-3,66(m, 2H), 3,66-of 3.78(m, 6N), 6,98(d, 1H), was 7.08(s, 1H), 7,2-7,26(m, 2H), 7,44(s, 1H), 7,58(S, 1H), to 7.64(d, 1H), 7,72 for 7.78(m, 2H), 8,24(d, 1H), 8,44(s, 1H). Mass spectrum: M+H+554.

Example 8

3-[5-(3,5-Differentaite)-2-were]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one

3,5-Differentiald (0,91 g) is added to a stirred mixture of 3-(5-amino-2-were)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-it (1.5 g), triethylamine (1.04 g) and methylene chloride (50 ml) and the resulting mixture stirred at ambient temperature for 18 hours. The mixture was washed with saturated aqueous sodium bicarbonate and the organic phase is evaporated. Get listed in the title compound (2,04 g). An NMR spectrum: (d6) was 2.05 (s, 3H), 2,22(s, 3H), 2,45-2,5(m, 4H), 3,24-3,3(m, 4H), 7,41-7,56(m, 3H), to 7.61-to 7.68(m, 4H), 7,75-7,79(m, 2H), of 8.06(s, 1H), and 10.5(s, 1H). Mass spectrum: M+N+490.

Example 9

According to the method described in example 6, 3-[5-(3,5-differentaite)-2-were]-6-(4-m is teleperson-1-yl)-3,4-dihydroquinazolin-4-one, 3-[5-(3-fluoro-4-triptoreline)-2-were]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one or 3-[5-(3,5-differentaite)-2-were]-6-(4-methylhomopiperazine-1-yl)-3,4-dihydroquinazolin-4-it is accordingly subjected to interaction with a suitable amidon with obtaining the compounds described in table IV.

Table IV
No.(R1)m(R)pApprox.
16-(4-methylpiperazin-1-yl)3-fluoro-5-pyrrolidin-1-yland
26-(4-methylpiperazin-1-yl)3-fluoro-5-piperidinob
36-(4-methylpiperazin-1-yl)3 azetidin-1-yl-5-fluoro
46-(4-methylpiperazin-1-yl)3-fluoro-5-(3-pyrrolin-1-yl)d
56-(4-methylpiperazin-1-yl)3-fluoro-3-morpholinoe
66-(4-methylpiperazin-1-yl)3 morpholino-5-trifluoromethylf
76-(4-methylhomopiperazine-1-yl)3-fluoro-5-pyrrolidin-1-ylg
86(4-methylhomopiperazine-1-yl) 3-fluoro-5-piperidinoh

Notes

a) the Compound has the following characteristics. An NMR spectrum: (d6) 1,95-2,0(m, 4H), 2,04 (s, 3H), of 2.18(s, 3H), 2,0-of 2.23(m, 4H), 2,47-2,5(m, 4H), 3.25 to 3,3(m, 4H), at 6.84-6.89 in(m, 2H), 7,22(d, 1H), and 7.4(d, 1H), 7,47(s, 1H), 7,6 to 7.62(m, 2H), 7,76-of 7.82(m, 2H), 8,07 (s, 1H), 10,27(s, 1H). Mass spectrum: M+H+541.

b) the Compound has the following characteristics. An NMR spectrum: (d6) 1,22 is 1.58(m, 6N), 2,04(s, 3H), 2,2(s, 3H), 2,45-2,5(m, 4H), 3.25 to be 3.29(m, 4H), 6,91(d, 1H), 7,02(d, 1H), 7,26(s, 1H), and 7.4(d, 1H), 7,47(s, 1H), 7.62mm(s, 2H), 7,76-7,81(m, 2H), of 8.06(s, 1H), to 10.3(s, 1H). Mass spectrum: M+N+555.

c) Connection has the following characteristics. Mass spectrum: M+N+527.

d) Compound has the following characteristics. Mass spectrum: M+N+539.

e) the Compound has the following characteristics. Mass spectrum: M+N+557.

f) 3-[5-(3-Fluoro-4-triptoreline)-2-were]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one and morpholine are heated together at a temperature of 130°C for 4 days. The connection has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), 2,22(s, 3H), 2,4-2,6(m, 4H), 2,86-2,96(m, 4H), 3,22-of 3.32(m, 4H), 3,64-3,74(m, 4H), 7,4-of 7.48(m, 2H), 7.62mm(s, 2H), 7,76-7,86(m, 4H), of 8.06(d, 2H), 10,53(s, 1H). Mass spectrum: M+N+607.

g) 3-[5-(3,5-Differentaite)-2-were]-6-(4-methylhomopiperazine-1-yl)-3,4-dihydroquinazolin-4-one and pyrrolidine heated together at a temperature of 95°C for 16 hours and at tempera is ur 105° C for 4 days. The connection has the following characteristics. An NMR spectrum: (CDCl3) 1,98-2,1(m, N), are 2.19(s, 3H), 2,58-2,62(m, 2H), 2,72-2,8(m, 2H), 3,24-of 3.32(m, 4H), to 3.58-3,62(m, 2H), 3,68-and 3.72(m, 2H), 6,32(d, 1H), 6,76(d, 1H), PC 6.82(s, 1H), 7,2-7,3(m, 2H), 7,44(s, 1H), 7,6-to 7.68(m, 3H), 7,78(s, 1H), 8,19(s, 1H). Mass spectrum: M+N+555.

h) Compound has the following characteristics. An NMR spectrum: (CDCl3) 1,52-of 1.74(m, 6N), 2,02-2,1(m, 5H), and 2.4(s, 3H), 2,58 to 2.6(m, 2H), was 2.76 and-2.8(m, 2H), 3,18 of 3.28(m, 4H), to 3.58-3,62(m, 2H), 3,68-and 3.72 (m, 2H), of 6.68(d, 1H), to 6.88(d, 1H), 7,18(s, 1H), 7,2-to 7.32(m, 2H), 7,44(s, 1H), 7,6-to 7.68(m, 3H), 7,78(s, 1H), 8,17 (s, 1H). Mass spectrum: M+N+569.

Example 10

3-[5-Dibenzofuran-4-ylcarbonyl-2-were]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one

A solution of 3-(5-amino-2-were)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-it (0,165 g) in DMF (0.5 ml) are added to stir the mixture dibenzofuran-4-carboxylic acid (0.1 g), diisopropylethylamine (0,164 ml), 2-(7-asobancaria-1-yl)-1,1,3,3-tetramethylethylenediamine(V) (0,214 g) and DMF (0.5 ml) and the reaction mixture stirred at ambient temperature for 16 hours. The mixture is diluted with water and the resulting solid is allocated, washed successively with water and diethyl ether and dried in vacuum at a temperature of 55°C. Receive specified in the header connection (0,228 g). An NMR spectrum: (d6) 2,07(s, 3H), of 2.25(s, 3H), of 2.5-3.3(m, 8H), at 7.55(m, 7H), 7,83(m, 4H), to 8.12(s, 1H), 8,21(d, 1H), 8.34 per(d, 1H), 10,59(s, 1H). Mass spec is p: M+N +544.

Example 11

According to the method similar to that described in example 10, 3-(5-amino-2-were)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one, 3-(5-amino-2-were)-6-(4-methylhomopiperazine-1-yl)-3,4-dihydroquinazolin-4-one or 3-(5-amino-2-were)-8-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-he is subjected to interaction with the appropriate carboxylic acid to obtain the compounds described in table V.

Table V
No.(R1)m(R)pApprox.
16-(4-methylpiperazin-1-yl)2-methoxy-3-phenyland
26-(4-methylpiperazin-1-yl)3-(4-forfinal)b
36-(4-methylpiperazin-1-yl)3-(2-furyl)
46-(4-methylpiperazin-1-yl)3 cyclopentyloxyd
56-(4-methylpiperazin-1-yl)3 cyclopentyloxy-4-methoxye
66-(4-methylpiperazin-1-yl)3-acetamidof
76-(4-methylpiperazin-1-yl)3-(N-matilla is sulphonamido) g
86-(4-methylpiperazin-1-yl)3-(1,1-dioxothiazolidine-2-yl)h
96-(4-methylpiperazin-1-yl)3 morpholinoi
106-(4-methylpiperazin-1-yl)3-fluoro-4-trifluoromethylj
116-(4-methylpiperazin-1-yl)3 tetrahydropyranyloxyk
126-(4-methylpiperazin-1-yl)2-methoxyl
136-(4-methylpiperazin-1-yl)3 ethoxym
146-(4-methylpiperazin-1-yl)3-(1,1,2,2-tetrafluoroethoxy)n
156-(4-methylhomopiperazine-1-yl)3 morpholinoabout
166-(4-methylhomopiperazine-1-yl)3-fluoro-5-morpholinop
176-(4-methylhomopiperazine-1-yl)3 morpholino-5-trifluoromethylq
186-(4-methylhomopiperazine-1-yl)3-(2-furyl)r
198-(4-methylpiperazin-1-yl)3 morpholinos
208-(4-IU reparacin-1-yl) 3-fluoro-5-morpholinot
218-(4-methylpiperazin-1-yl)3 morpholino-5-trifluoromethylu
228-(4-methylpiperazin-1-yl)3-(2-furyl)v
238-(4-methylpiperazin-1-yl)3-(4-forfinal)w

Notes

a) the reaction Product is purified by chromatography on a column of reversed phase silica using water first and then a mixture of methanol and water with decreasing polarity as eluent. Get the required connection 33% yield. An NMR spectrum: (d6) 2,04(s, 3H), and 2.27(s, 3H), of 2.5-3.3(m, 8H), 3,42(s, 3H), 7,54(m, 13H), 7,72(d, 1H), of 8.09(s, 1H), 10,52(s, 1H). Mass spectrum: M+H+560.

2-Methoxy-3-phenylbenzene acid used as the starting compound, obtained as follows.

Methyliodide (0,409 ml) is added to a stirred mixture of methyl 2-hydroxy-3-phenylbenzoate (0.5 g), potassium carbonate (0,606 g) and acetone (5 ml) and the reaction mixture is stirred at a temperature of 55°C for 2.5 hours. The mixture is evaporated and the residue is divided between ethyl acetate and water. The organic phase is dried (MgSO4) and evaporated with a mixture of starting compound and methyl 2-methoxy-3-phenylbenzoate. The resulting mixture was dissolved in DMF and added carbonate feces is I (0,606 g) and dimethylsulfate (0,207 ml) and the resulting reaction mixture is stirred at a temperature of 80° C for 16 hours. The mixture was separated between ethyl acetate and water. The organic phase is dried (MgSO4) and evaporated to obtain methyl 2-methoxy-3-phenylbenzoate (0,458 g) as oil. An NMR spectrum: (d6) of 3.48(s, 3H), of 3.94(s, 3H), 7,21(m, 1H), and 7.4(m, 6N), 7,73(d, 1H).

A mixture of the compounds obtained, 2N aqueous sodium hydroxide solution (5 ml), methanol (10 ml) and THF (3 ml) was stirred at ambient temperature for 16 hours. The organic solvent is evaporated and the aqueous reaction mixture is acidified by adding 2N aqueous solution of hydrochloric acid. The sediment out, washed with water and dried in a vacuum at a temperature of 55°C. Receive 2-methoxy-3-phenylbenzene acid (0,395 g). An NMR spectrum: (d6) to 3.4(s, 3H), 7,25(m, 1H), and 7.4(m, 6N), a 7.62(d, 1H), 12,92(W s, 1H).

b) the Original compound, 3-(4-forfinal)benzoic acid as described in Tetrahedron, 1997, 53, 14437-14450. The connection has the following characteristics. An NMR spectrum: (d6) 2,02(s, 3H), 2,32(s, 3H), 2,42-2,49(m, 4H), 3.25 to be 3.29(m, 4H), 7,28-7,38(m, 2H), 7,41-of 7.48(m, 2H), EUR 7.57-to 7.84(m, 3H), 7,84-7,88(m, 5H), 7,92(d, 1H), of 8.06(s, 1H), 8,19(s, 1H). Mass spectrum: M+H+548.

c) the Original compound, 3-(2-furyl)benzoic acid as described in Tetrahedron Letters, 1998, 39, 4175-4178. The product was then purified by chromatography on ion-exchange column (isolute SCX, using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous solution of ammonium hydroxide as eluent, obtaining follow what their characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), of 2.23(s, 3H), 2,45-2,5(m, 4H), 3,2-to 3.35(m, 4H), 6,62(s, 1H), 7,06(s, 1H), 7,42(s, 1H), of 7.48(s, 1H), EUR 7.57-7,63(m, 3H), 7,78-to 7.84(m, 4H), 7,9(d, 1H), 8,08(s, 1H), 8,24(s, 1H), 10,49(s, 1H). Mass spectrum: M+H+520.

d) Compound has the following characteristics. An NMR spectrum: (d6) 1,69-1,8 (m, 6N), 1,84-1, 98 (m, 2H), 2,04 (s, 3H), 2,24(s, 3H), 2,45-2,5(m, 4H), 3.25 to be 3.29(m, 4H), 4,86 to 4.92(m, 1H), 7,05(d, 1H), 7,37-of 7.48(m, 5H), 7,63(s, 2H), 7,79(d, 2H), 8,07(s, 1H), 10,32(s, 1H). Mass spectrum: M+H+538.

3-Cyclopentylacetic acid used as the starting compound, obtained as follows.

1,1'-Azodicarbonamide (6,64 g) are added to stir the mixture of Cyclopentanone (1,59 ml), ethyl-3-hydroxybenzoate (4,37 g), tributylphosphine (6,48 ml) and THF (100 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 by chromatography on a column of silica, using isohexane as eluent. Get ethyl-3-cyclopentylacetic (4.3 g). Mass spectrum: M+N+235.

A mixture of part (1 g) the compounds obtained, 2N aqueous sodium hydroxide solution (4,27 ml), methanol (20 ml) and water (5 ml) was stirred at ambient temperature for 4 hours. The mixture is evaporated and the residue is distributed between methylene chloride and water. The aqueous phase is acidified by addition of 1N aqueous solution of hydrochloric acid and extra is irout with methylene chloride. The organic extract is evaporated. Get 3-cyclopentylacetic acid (0,864 g). An NMR spectrum: (d6) 1,51 is 1.75(m, 6N), 1,8-2,0(m, 2H), 4,8-a 4.86(m, 1H), 7,12(d, 1H), 7,34-7,49(m, 2H), 7,46-7,49(m, 1H), 12,89(s, 1H).

e) the reaction Product is purified by chromatography on a column of reversed phase silica using water first and then a mixture of methanol and water with decreasing polarity as eluent. The purified compound has the following characteristics. An NMR spectrum: (d6) 1,48-of 1.62(m, 2H), 1,64-of 1.78(m, 4H), 1,8-of 1.95(m, 2H), 2,04(s, 3H), of 2.23(s, 3H), 2,45-2,5(m, 4H), 3,2-to 3.35(m, 4H), 3,81(s, 3H), 7,06(d, 1H), 7,39(d, 1H), of 7.48(d, 2H), EUR 7.57-7,63(m, 3H), to 7.77-7,82(m, 2H), 8,07(s, 1H), 10,17 (s, 1H). Mass spectrum: M+H+568.

3 Cyclopentyloxy-4-methoxybenzoic acid used as starting material, commercially available from Maybridge International, Tintagel, Cornwall, United Kingdom, or can be obtained from ethyl-3-hydroxy-4-methoxybenzoate according to methods analogous to the methods of the notes (d) above, is used to obtain 3-cyclopentylacetic acid.

f) the reaction Product is purified by chromatography on a column of reversed phase silica using water first and then a mixture of methanol and water with decreasing polarity as eluent. The purified compound has the following characteristics. An NMR spectrum: (MCOd6) 2,04(s, 3H), of 2.05 (s, 3H), 2,22(s, 3H), 2,45-2,5(m, 4H), 3,2-to 3.35(m, 4H), 7,38-7,47(m, 3H), 7,58 to 7.62(m, 3H), 7,75-7,81(m 3 is), 8,05-8,08(m, 2H), accounted for 10.39 (s, 1H). Mass spectrum: M+N+511.

g) the reaction Product is purified by chromatography on a column of reversed phase silica using water first and then a mixture of methanol and water with decreasing polarity as eluent. The purified compound has the following characteristics. An NMR spectrum: (d6) 2,02(s, 3H), 2,22(s, 3H), 2,43-2,5(m, 4H), 2,98(s, 3H), 3,21-3,3(m, 4H), 7,4-of 7.48(m, 2H), 7,52 to 7.62(m, 4H), 7,78-of 7.82(m, 2H), 7,88(d, 1H), 7,92(s, 1H), of 8.06(s, 1H), 10,55(s, 1H). Mass spectrum: M+H+561.

3-(N-Methylmethanesulfonamide)benzoic acid used as starting compound, obtained as follows.

Methanesulfonanilide (12.1 ml) is added to a stirred mixture of ethyl-3-aminobenzoate (RUB 24.55 g), pyridine (14,42 ml) and methylene chloride (300 ml) and the reaction mixture stirred at ambient temperature for 18 hours. The mixture is washed successively with water, 1N aqueous solution of hydrochloric acid and water. The organic phase is dried (MgSO4) and evaporated. Get ethyl-3-methanesulfonamide (35.2 g). An NMR spectrum: (d6) to 1.3 (t, 3H), 3.0 a(s, 3H), 4,3(m, 2H), 7,46(m, 2H), 7,66(m, 1H), 7,8(m, 1H), 9,95(s, 1H). Mass spectrum: M-H-242.

Methyliodide (4,23 ml) is added to a stirred mixture of ethyl-3-metasulphobenzoate (15 g), cesium carbonate (22,12 g) and DMF (60 ml) and the reaction mixture stirred at ambient temperature for 18 cha is impressive. The mixture is distributed between ethyl acetate and water. The organic phase is washed with water, dried (MgSO4) and evaporated. Get ethyl-3-(N-methylmethanesulfonamide)benzoate (14,87 g). An NMR spectrum: (d6) to 1.32(t, 3H), 2.95 and(s, 3H), 3,26(s, 3H), 4,32(m, 2H), 7,55(t, 1H), 7,68(m, 1H), 7,87(m, 1H), 7,92(m, 1H). Mass spectrum: M+H+258.

A mixture of the obtained compound, 10N aqueous sodium hydroxide solution (11.5 ml), ethanol (150 ml) and water (30 ml) was stirred at ambient temperature for 4 hours. The mixture is evaporated and to the residue add 1N aqueous solution of hydrochloric acid (125 ml), which leads to the formation of a white precipitate, which is marked, washed successively with water and diethyl ether and dried in vacuum at a temperature of 60°C. Receive 3-(N-methylmethanesulfonamide)benzoic acid (9,72 g). An NMR spectrum: (d6) to 2.94(s, 3H), 3,26(s, 3H), 7,52(t, 1H), 7,65(m, 1H), to 7.84(m, 1H), to $ 7.91(m, 1H). Mass spectrum: M-H-228.

h) the reaction Product is purified by chromatography on a column of reversed phase silica using water first and then a mixture of methanol and water with decreasing polarity as eluent. The purified compound has the following characteristics. An NMR spectrum: (d6) 2,04(s, 3H), of 2.23(s, 3H), 2,4-2,5(m, 6N), 3.25 to be 3.29(m, 4H), 3,53(t, 2H), 3,81(t, 2H), 7,39-7,58(m, 4H), to 7.61(s, 1H), to 7.67-to 7.68(m, 2H), 7,78-7,79(m, 2H), 8,07 (s, 1H), 10,43(s, 1H). Mass spectrum: M+H+573.

3-(1,1-Dioxothiazolidine-yl)benzoic acid, used as the starting compound, obtained as follows.

3-Chloropropanesulfonyl (5,1 g) is added dropwise to a stirred mixture of ethyl-3-aminobenzoate (4.5 g), pyridine (2,423 ml), 4-dimethylaminopyridine (0.03 g) and methylene chloride (100 ml) and the reaction mixture stirred at ambient temperature for 48 hours. The mixture was washed with 2N aqueous solution of hydrochloric acid and the organic phase is dried (MgSO4) and evaporated. Get ethyl-3-(3-chloropropanesulfonyl)benzoate (8,19 g). An NMR spectrum: (d6) of 1.29 (t, 3H), 2,19(m, 2H), 3,24(t, 2H), and 3.72(t, 2H), or 4.31(m, 2H), 7,47(m, 2H), 7,68(m, 1H), 7,83(m, 1H), 10,12 (s, 1H). Mass spectrum: (M-N)-303 and 305.

A mixture of the compounds, triethylamine (7.3 ml) and ethanol (120 ml) is stirred and heated at boiling temperature under reflux for 6 hours. The mixture is evaporated. The residue is distributed between methylene chloride and water. The organic phase is dried (MgSO4) and evaporated. Get ethyl-3-(1,1-dioxothiazolidine-2-yl)benzoate (6,99 g). An NMR spectrum: (d6) to 1.3(t, 3H), 2,42(m, 2H), 3,53(t, 2H), of 3.78(t, 2H), 4,32(m, 2H), 7,43(m, 1H), 7,52(t, 1H), 7,66(m, 1H), 7,78(m, 1H). Mass spectrum: M+H+269.

A mixture of part (6,87 g) of the obtained compound, 10N aqueous sodium hydroxide solution (5.1 ml), ethanol (80 ml) and water (14 ml) was stirred at ambient temperature for 18 hours. The mixture is evaporated and to the residue to ablaut 1N aqueous solution of hydrochloric acid (160 ml), that gives the appearance of a white precipitate, which is marked, washed successively with water and diethyl ether and dried in vacuum at a temperature of 60°C. Receive 3-(1,1-dioxothiazolidine-2-yl)benzoic acid (of 5.45 g). An NMR spectrum: (d6) 2,43(m, 2H), 3,5 (t, 2H), of 3.78(t, 2H), 7,39(m, 1H), of 7.48(t, 1H), 7,66(m, 1H), 7,78(m, 1H), 13,06(s, 1H). Mass spectrum: M-H-239.

i) Compound has the following characteristics. An NMR spectrum: (d6) 2,04(s, 3H), 2,48(s, 3H), 2,78-is 2.88(m, 4H), 3,15-3,19(m, 4H), 3,28-of 3.42(m, 4H), to 3.73-of 3.77(m, 4H), a 7.1 to 7.18(m, 1H), 7,35-7,42(m, 4H), 7,51(s, 1H), 7,65(s, 2H), 7, 77-7, 8 (m, 2H), and 8.1 (s, 1H), 10, 29 (s, 1H). Mass spectrum: M+N+539.

3-Morpholinomethyl acid used as the starting compound, obtained as follows.

A mixture of ethyl-3-bromobenzoate (1,92 ml), research (1.25 ml), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0,336 g), tert-butoxide sodium (near 1.615 g) and Tris(dibenzylideneacetone)-diplodia (0) (0.33 g) and toluene (25 ml) is stirred and heated at a temperature of 90°C in argon atmosphere for 18 hours. Realizando the mixture is cooled to ambient temperature and extracted with a 1N aqueous hydrochloric acid. The aqueous phase is alkalinized with concentrated sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried (MgSO4) and evaporated. The residual oil purified by chromatography on a column of silica gel, using 47:3 mixture of methylene chloride and met the Nola as eluent. GetN-(3-morpholinomethyl)morpholine (0.45 g).

A mixture of the obtained compound, 5M sodium hydroxide solution (2.5 ml) and butanol (2 ml) is stirred and heated at a temperature of 115°C for 18 hours. The mixture is evaporated and the residue is acidified by adding 1N aqueous solution of hydrochloric acid (12.5 ml). The obtained precipitate out, washed with water and dried to obtain 3-morpholinomethyl acid (0.15 g).

An NMR spectrum: (d6) 3,1(t, 4H), to 3.73(t, 4H), 7,19(d, 1H), 7,32(d, 1H), 7,38(m, 1H), 7,42(s, 1H).

(j) the Compound has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), and 2.26(s, 3H), 2,47 of $ 2.53(m, 4H), 3,2-3,3(m, 4H), 7,42-of 7.48(m, 2H), 7.62mm(s, 2H), 7,76 one-7.8(m, 2H), 7,93-8,07(m, 4H), to 7.93-8,07(m, 4H), at 10.64(s, 1H). Mass spectrum: M+H+540.

k) the Compound has the following characteristics. An NMR spectrum: (d6) of 1.97(s, 3H), 2,18-of 2.28(m, 2H), of 2.38 (s, 3H), 2,62-2,78(m, 4H), 3,2-to 3.41(m, 4H), 3,7-to 3.92(m, 4H), 5,04-5,14(m, 1H), 7,14(d, 1H), 7,39-EUR 7.57(m, 5H), to 7.64(s, 2H), to 7.77-of 7.82(m, 2H), 8,08(s, 1H), 10,35(s, 1H). Mass spectrum: M+N+540.

3-Tetrahydropyranyloxy acid used as the starting compound, get a technique similar to the technique notes (d)described above, except that instead of Cyclopentanol use 3-hydroxyether-hydrofuran.

l) Compound has the following characteristics. An NMR spectrum: (d6) was 2.05 (s, 3H), of 2.25 (s, 3H), 2,5(m, 4H), of 3.28(m, 4H), 3,88(s, 3H), 7,06(t, 1H), 7,18(d, 1H), and 7.4(d, 1H), 7.5(m, 2H), 7.62mm(m,3H), 7,74-7,81(m, 2H), and 8.1(s, 1H), 10,29(s, 1H). Mass spectrum: M+H+484.

m) Connection has the following characteristics. An NMR spectrum: (d6) of 1.34(t, 3H), of 2.05(s, 3H), of 2.25(s, 3H), 2,5(m, 4H), of 3.25(m, 4H), 4,08(kV, 2H), 7,14(m, 1H), 7,39-of 7.55(m, 5H), to 7.64(m, 2H), and 7.8(m, 2H), and 8.1(s, 1H), 10,36(s, 1H). Mass spectrum: M+H+498.

n) Connection has the following characteristics. An NMR spectrum: (d6) was 2.05 (s, 3H), of 2.25 (s, 3H), of 2.5-3.3(m, 8H), 6,85(m, 1H), 7,40-of 7.55(m, 3H), of 7.65(m, 3H), and 7.8(m, 3H), 7,98(m, 1H), and 8.1(s, 1H), 10,55(s, 1H). Mass spectrum: M+H+570.

a) the Compound has the following characteristics. An NMR spectrum: (d6) 1,86-to 1.98(m, 2H), 2,04(s, 3H), of 2.25(s, 3H), 2,42-2,5(m, 2H), 2,62-of 2.66(m, 2H), 3,15-3,19(m, 4H), 3,53(t, 2H), to 3.58-to 3.64(m, 2H), 3.72 points is 3.76(m, 4H), a 7.1 to 7.18(m, 1H), 7,24(s, 1H), 7,34-7,44(m, 5H), 7,58(d, 1H), 7,76-of 7.82(m, 2H), of 7.96(s, 1H), 10,29(s, 1H). Mass spectrum: M+N+553.

R) Connection has the following characteristics. An NMR spectrum: (d6) 1,86-to 1.98(m, 2H), 2,04(s, 3H), of 2.25(s, 3H), 2,42-2,5(m, 2H), 2,62-of 2.66(m, 2H), 3,19 is 3.23(m, 4H), 3,53(t, 2H), to 3.58-to 3.64(m, 2H), 3,71 of 3.75(m, 4H), 6,98(d, 1H), 7,12(d, 1H), 7,24(s, 1H), 7,28(, 1H), 7,32-7,44(m, 2H), 7,58(d, 1H), 7,74-of 7.82(m, 2H), of 7.96(s, 1H), 10,32(s, 1H). Mass spectrum: M+H+571.

3-Fluoro-5-morpholinomethyl acid used as the starting compound, obtained as follows.

A mixture of ethyl-3-fluoro-5-morpholinomethyl (Tetrahedron, 1999, 55, 13285-13300; 6.7 g), 10 M sodium hydroxide solution (to 13.6 ml), water (to 13.6 ml) and ethanol (67 ml) was stirred at ambient temperature for 20 hours. The mixture is concentrated Lipari what W and the residue is acidified by adding concentrated hydrochloric acid. The obtained precipitate out, washed with water and dried to obtain 3-fluoro-5-morpholinomethyl acid (5.7 g). An NMR spectrum: (d6) and 3.16(t, 4H), 3,71(t, 4H), 7,01(m, 2H), 7,27(s, 1H).

q) the Compound has the following characteristic NMR Spectrum: (d6) 1,86-to 1.98(m, 2H), 2.05 is(s, 3H), of 2.25(s, 3H), 2,42-2,5(m, 2H), 2,62-of 2.66(m, 2H), 3,24-to 3.34(m, 4H), 3,53(t, 2H), to 3.58-to 3.64(m, 2H), of 3.73-of 3.77(m, 4H), 7,24(s, 1H), 7,32-the 7.43(m, 3H), 7,58(d, 1H), 7,63(s, 1H), and 7.7(s, 1H), 7,74(s, 1H), and 7.8(d, 1H), of 7.97(s, 1H), 10,45(s, 1H); Mass spectrum: M+H+621.

r) Connection has the following characteristics. An NMR spectrum: (d6) 1,86-to 1.98(m, 2H), 2.05 is(s, 3H), of 2.25(s, 3H), 2,42-2,5(m, 2H), 2,62-of 2.66(m, 2H), 3,53(t, 2H), to 3.58-to 3.64(m, 2H), is 6.61(s, 1H),? 7.04 baby mortality(s, 1H), 7,24(s, 1H), 7,38(d, 1H), 7,42(d, 1H), 7,52 and 7.6(m, 2H), 7,78-a 7.92(m, 5H), 7,98(s, 1H), 8,24(s, 1H), 10,49(s, 1H). Mass spectrum: M+H+534.

s) the Remainder of the reaction mixture is purified by chromatography on ion-exchange column (isolute SCX, using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous solution of ammonium hydroxide as eluent. The compound obtained is dissolved in acetone and precipitated by adding isohexane. The compound obtained has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), of 2.25(s, 3H), 3,3-3,4(m, 4H), of 3.7-3.8(m, 4H), 7,1-7,2(m, 1H), and 7.3-7.5(m, 7H), 7,75-a 7.85(m, 3H), of 8.25(s, 1H), 10,3(s, 1H). Mass spectrum: M+N+539.

3-(5-Amino-2-were)-8-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one used as starting compound, obtained as about the time.

Oxalicacid (8.5 ml) is added dropwise to a stirred solution of 3-chloro-2-nitrobenzoic acid (15.1 g) in a mixture of methylene chloride (200 ml) and DMF (few drops), ohlazhdeniya to a temperature of 0°C. the Mixture is heated under ambient temperature and stirred for another 16 hours. The solvent is evaporated. The residue is dissolved in methylene chloride (300 ml) and added dropwise to a stirred mixture of 2-methyl-5-nitroaniline (10.6 g), triethylamine (27,2 ml) and methylene chloride (300 ml). The resulting mixture was stirred at ambient temperature for 16 hours. The sediment out, washed sequentially with saturated aqueous sodium bicarbonate solution and diethyl ether and dried in vacuum at a temperature of 40°C. ReceiveN-(2-methyl-5-nitrophenyl)-3-chloro-2-nitrobenzamide (14.2 g). An NMR spectrum: (d6) is 2.37 (s, 3H), EUR 7.57(d, 1H), 7,8-a 7.85(m, 1H), 7.95 is-with 8.05(m, 3H), 8,35(m, 1H). Mass spectrum: M+N+335.

A mixture of the compounds obtained andN-methylpiperazine (24.5 ml) is stirred and heated at a temperature of 100°C for 16 hours. The reaction mixture was cooled to ambient temperature and poured into water. The obtained precipitate out, washed with water and dried in a vacuum at a temperature of 40°C. ReceiveN-(2-methyl-5-nitrophenyl)-3-(4-methylpiperazin-1-yl)-2-nitrobenzamide (11.8 g). An NMR spectrum: (d6) 2,2 (s, 3H), 2,35 at 2.45(m, 7H), of 2.9-3.0(m, 4H), 7,5-7,7(who, 4H), 8,0-with 8.05(m, 1H), and 8.3(s, 1H). Mass spectrum: M+H+400.

A mixture of the obtained compound, the catalyst is 10% palladium on carbon (1.2 g) and methanol (600 ml) is stirred under an atmosphere of hydrogen until then, until there is no further absorption of hydrogen. The catalyst is filtered off and the filtrate vyparivat. The compound obtained purified by chromatography on a column of silica using 4:1 mixture of methylene chloride and methanol as eluent. GetN-(5-amino-2-were)-2-amino-3-(4-methylpiperazin-1-yl)benzamide (of 7.36 g). An NMR spectrum: (d6) 2,0(s, 3H), 2,2(s, 3H), of 2,75 2,85(m, 4H), around 4.85(s, 2H), 6,0(s, 2H), 6,35-6.4(m, 1H), to 6.57(m, 2H), 6,85(d, 1H), 7,07(d, 1H), 7,45(d, 1H), 9,35(s, 1H). Mass spectrum: M+N+340.

A mixture of part (4 g) of the obtained compound, triethylorthoformate (to 3.92 mg), glacial acetic acid (0,34 ml) and ethanol (72 ml) is stirred and heated at a temperature of 80°C for 2 days. The reaction mixture is cooled and evaporated. The residue is dissolved in water, alkalinized by adding sodium bicarbonate and extracted with methylene chloride. The organic extract is evaporated and the residue purified by chromatography on a column of silica, using a 20:1 mixture of methylene chloride and methanol as eluent. Get 3-(5-amino-2-were)-8-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one (4.1 g). An NMR spectrum: (d6) of 1.85(s, 3H), 2,2 (s, 3H), 2,5-2,6(m, 4H), of 5.15(s, 2H), and 6.5(d, 1H), 6,6-of 6.65(m, 1H),7,0(d, 1H), and 7.3(d, 1H), 7,42(t, 1H), of 7.75(d, 1H), 8,15(s, 1H). Mass spectrum: M+H+350.

t) Connection has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), of 2.25(s, 3H), 3,2-of 3.25(m, 4H), of 3.7-3.8(m, 4H), 6,95-7,0(m, 1H), 7,1-to 7.15(m, 1H), 7.3 to 7.4(m, 2H), and 7.4-7.5(m, 2H), 7,75 one-7.8(m, 3H), of 8.25(s, 1H), 10,33(s, 1H). Mass spectrum: M+N+557.

u) Compound has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), of 2.25(s, 3H), of 3.7-3.8(m, 4H), 7.3 to 7.5(m, 4H), 7,6-a 7.85(m, 5H), to 8.25(s, 1H), 10,48(s, 1H). Mass spectrum: M+N+607.

v), the Compound has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), of 2.25(s, 3H), 6,6-of 6.65(m, 1H), 7,05(m, 1H), and 7.3-7,35(m, 1H), and 7.4-7.5(m, 2H), 7.5 to about 7.6(m, 1H), 7,75-to 7.95(m, 6N), 8,25 to 8.3(m, 2H), and 10.5(s, 1H). Mass spectrum: M+H+520.

w) Connection has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), of 2.25(s, 3H), 7.3 to 7.4(m, 3H), of 7.4-7.5(m, 2H), 7,55-the 7.65(m, 1H), 7,75-to 7.95(m, 7H), 8,18(s, 1H), and 8.3 (s, 1H), 10,48(s, 1H). Mass spectrum: M+H+548.

Example 12

According to the method of example 1 or example 2 suitable 2-aminobenzamide subjected to interaction with triethylorthoformate or triethylorthoformate obtaining soedinenii presented in table VI.

8 morpholino
Table VI
No.(R1)m(R2)nR3(R)pApprox.
14-methylN3-(4-methylpiperazin-1-and
yl)methyl
28 morpholino4-methylmethyl3-(4-methylpiperazin-1 -b
yl)methyl

Notes

a) the Reaction mixture is heated at a temperature of 70°C for 48 hours. The connection has the following characteristics :

An NMR spectrum: (d6) 2,1(s, 3H), 2,2-of 2.45(m, 11N), and 3.5(s, 2H), of 3.7-3.8(m, 4H), 7.3 to 7,35(m, 2H), 7,4-of 7.55(m, 4H), 7,55-7,6(m, 1H), and 7.8(d, 1H), 7,8-7,9(m, 2H), and 8.3(s, 1H), 10.0 g(s, 1H). Mass spectrum: M+N+553.

N-{3-[3-(4-Methylpiperazin-1-ylmethyl)benzamido]-4-were)-2-amino-3-morpholinomethyl used as a starting compound, obtained as follows.

3-Chlorodibenzofuran (24,8 ml) is added to a stirred mixture of 2-methyl-5-nitroaniline (26,6 g), triethylamine (49 ml) and methylene chloride (800 ml) and the mixture was stirred at ambient temperature for 16 hours. The sediment out, washed with 1N aqueous solution of hydrochloric acid and diethyl ether and dried in vacuum at a temperature of 40°C. Receive 3-chloromethyl-N-(2-what ethyl-5-nitrophenyl)benzamide (43,5 g). An NMR spectrum: (d6) of 2.38(s, 3H), 2,85(s, 2H), 7,53-7,58(m, 2H), to 7.67(d, 1H), 7,95(d, 1H), 8,01-of 8.04(m, 2H), 8,32(s, 1H), 10,19(s, 1H). Mass spectrum: M+N+305.

1-Methylpiperazine (8,03 ml) are added to stir the mixture of part (20 g) of the obtained compound, potassium carbonate (18.2 g) and acetone (750 ml) and the mixture is heated at a temperature of 54°C and stirred for 16 hours. The resulting solution is evaporated and the residue is dissolved in methylene chloride. The organic solution is washed with water and evaporated. GetN-(2-methyl-5-nitrophenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide (26,4 g).

An NMR spectrum: (d6) to 2.06(s, 3H), 2,12(s, 3H), 2,31-is 2.37(m, 8H), 3,52(s, 2H), of 7.48-EUR 7.57(m, 3H), 7,87(d, 2H), 8,01(m, 1H), with 8.33(s, 1H). Mass spectrum: M+N+369.

Iron powder is added to stir the mixture of part (18.0 g) of the obtained compound, ethanol (500 ml), water (50 ml) and acetic acid (10 ml). The resulting mixture is stirred and heated at boiling temperature under reflux for 5 hours. Add water (50 ml) and the mixture is alkalinized by addition of sodium carbonate. The mixture is filtered and the filtrate is evaporated to dryness. The residue is triturated under water and the resulting solid is isolated and dried in a vacuum at a temperature of 40°C. ReceiveN-(5-amino-2-were)-3-(4-metapopulation-1-ylmethyl)benzamide (11.1 g). An NMR spectrum: (d6) 2,03(s, 3H), 2.13 and(s, 3H), 2,24-2,4(m, 8H), and 3.5(s, 2H), a 4.86(s, 2H), 6.35mm(d, 1H), to 6.57(s, 1H), 6,86(d 1H), 7,40-of 7.48(m, 2H), 7,78-7,83(m, 2H), to 9.57(s, 1H). Mass spectrum: M+N+339.

Oxalicacid (0,83 ml) is added to a mixture of 3-chloro-2-nitrobenzoic acid (1.45 g), methylene chloride (30 ml) and few drops of DMF, cooled to a temperature of 0°C. the Reaction mixture was stirred at ambient temperature for 4 hours. The mixture is evaporated. The residue is dissolved in methylene chloride (10 ml) and add a portion (5 ml) solution to the mixtureN-(5-amino-2-were)-3-(4-metapopulation-1-ylmethyl)benzamide (1.01 g), triethylamine (1 ml) and methylene chloride (20 ml). The resulting mixture was stirred at ambient temperature for 16 hours. The mixture is evaporated and the residue is divided between methylene chloride and saturated aqueous sodium bicarbonate. The organic phase is dried (MgSO4) and evaporated. GetN-{3-[3-(4-methylpiperazin-1-ylmethyl) benzamido] -4-were}-3-chloro-2-nitrobenzamide (1,69 g). An NMR spectrum: (d6) to 2.15(s, 3H), 2,2(s, 3H), 2,2-2,4(m, 8H), and 3.5(s, 2H), 7,2-7,3(m, 1H), and 7.4-7.5(m, 3H), 7,7-to 7.95(m, 6N), to 9.9(s, 1H), 10,78(s, 1H). Mass spectrum: M+N+522.

A mixture of the compounds obtained and research (2,71 ml) is stirred and heated at a temperature of 105°C for 16 hours. The mixture is cooled to ambient temperature and poured into water. The sediment out, washed with water and partitioned between saturated aqueous sodium bicarbonate and methylene chloride. Organicheskoi the phase is dried (MgSO 4) and evaporated. GetN-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-were}-2-nitro-3-morpholinomethyl (1.47 g). An NMR spectrum: (d6) to 2.15(s, 3H), 2,2(s, 3H), 2,2-of 2.45(m, 8H), 2,85-2,95(m, 4H), and 3.5(s, 2H), up 3.6-3.7(m, 4H), 7,2(d, 1H), and 7.4-7.5(m, 3H), 7.5 to about 7.6(m, 1H), about 7.6 to 7.7(m, 2H), of 7.75(s, 1H), 7,8-7,9(m, 2H), 9,9(s, 1H), to 10.62(s, 1H). Mass spectrum: M+N+573.

A mixture of the obtained compound, iron powder (1,435 g), ethanol (25,7 ml), water (to 2.57 ml) and glacial acetic acid (0,52 ml) is stirred and heated at a temperature of 95°C for 8 hours. The resulting mixture was cooled to ambient temperature and alkalinized to pH 9 by adding sodium bicarbonate. The mixture is filtered and the filtrate is evaporated. The residue is distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase is dried (MgSO4) and evaporated. The resulting material was dissolved in ethyl acetate and precipitated by adding isohexane. The solid is isolated. GetN-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-were}-2-amino-3-morpholinomethyl (0.95 g). An NMR spectrum: (d6) 2,1(s, 3H), 2,2(s, 3H), 2,2-2,4(m, 8H), of 2.75 to 2.8(m, 4H), and 3.5(s, 2H), of 3.7-3.8(m, 4H), equal to 6.05(s, 2H), and 6.6(t, 1H), and 7.1(d, 1H), 7,2(d, 1H), AND 7.4-7.5(M, 4H), and 7.8(d, 1H), 7,8-7,9(m, 2H), 9,85(s, 1H), 9,95(s, 1H). Mass spectrum: M+H+543.

b) the Reaction mixture is heated to 70° within 48 hours. The connection has the following characteristics. An NMR spectrum: (d6) 2,1(s,3H), 2,2(s, 3H), 2,2-2,4(m, MO), and 3.5(s, 2H), 3,7-of 3.85(m, 4H), 7,2-7,3(m, 2H), 7.3 to 7.5(m, 5H), the 7.65(d, 1H), 7,8-7,9(m, 2H), 10.0 g(s, 1H). Mass spectrum: M+H+567.

Example 13

Using a technique similar to the method of example 1 or example 2, suitable 2-aminobenzamide subjected to interaction with triethylorthoformate or triethylorthoformate with obtaining the compounds described in table VII. In each case, the reaction product is purified by chromatography on ion-exchange column (isolute SCX, using initially methanol and then a 99:1 mixture of ethanol and a saturated aqueous solution of ammonium hydroxide as eluent.

Table VII

No.(R1)mR3(R)pApprox.
16-(4-methylpiperazin-1-yl)methyl3-fluoro-5-morpholinoand
26-(4-methylpiperazin-1-yl)N3-fluoro-5-morpholinob
36-[N-(3-dimethylaminopropyl)-N-methylamino]methyl3-fluoro-5-morpholino
46-[N-(3-dimethylaminopropyl)-N-methylamino]N3-fluoro-5-morpholinod
56-(3 - dimethylaminopropylamine)methyl3-fluoro-5-morpholinoe
66-(3-dimethylaminopropylamine)N3-fluoro-5-morpholinof
76-[N-(3-methylaminopropyl)-N-methylamino]methyl3-fluoro-5-morpholinog
86-[N-(3-methylaminopropyl)-N-methylamino]N3-fluoro-5-morpholinoh

Notes

a) Compound has the following characteristics. Mass spectrum: M+N+591.

3-[2-Amino-5-(4-methylpiperazin-1-yl)benzamido]-4-chloro-N-(3-fluoro-5-morpholinomethyl)benzamide used as a starting compound, obtained as follows.

A mixture of 3,5-deformirovannoe (31.1 grams) and research (to 85.2 g) is stirred and heated at a temperature of 100°C for 66 hours. The mixture is evaporated and the residue purified by chromatography on a column of silica gel using 4:1 mixture of isohexane and ethyl acetate as eluent. Get 3-fluoro-5-morpholinopropan (33.3 g). An NMR spectrum: (d6) of 3.2 to 3.3(m, 4H), 3,6-3,8(m, 4H), 7,25(m, 1H), 7,37(m, 1H), 7.5(m, 1H).

A mixture of the compounds obtained, 10% palladium on carbon (3.3 grams) and ethanol (1400 ml) is stirred under atmospheric pressure of hydrogen for 6 hours. The mixture is filtered and the filtrate is evaporated to obtain 3-fluoro-5-morpholinopropan (27.5 g).

An NMR spectrum: (d6) of 2.9 was 3.05(m, 4H), up 3.6-3.7(m, 4H), of 5.15(s, 2H), 5,75-5,9(m, 3H).

A solution of 4-chloro-3-nitrobenzotrifluoride (41,2 g) in methylene chloride (120 ml) is added to a mixture of 3-fluoro-5-morpholinopropan (27 g), triethylamine (52,6 ml) and methylene chloride (600 ml), cooled in an ice bath. The resulting mixture was stirred at ambient temperature for 16 hours. The mixture is evaporated. Add methylene chloride and saturated aqueous sodium bicarbonate solution and the resulting precipitate was separated, washed with diethyl ether and dried in vacuum. Get 4-chloro-3-nitro-N-(3-fluoro-5-morpholinomethyl)benzamide (36,1 g). An NMR spectrum (d6) 3,05 is 3.15(m, 4H), 3,7-of 3.75(m, 4H), 6,5-6,6(m, 1H), 7,1-7,2(m, 2H), 7,95(d, 1H), and 8.2 to 8.3(m, 1H), and 8.6(s, 1H).

A mixture of the obtained compound, iron powder (50.6 g), glacial acetic acid (19 ml), water (95 ml) and ethanol (600 ml) is stirred and heated at boiling temperature under reflux for 6 hours. The mixture is cooled to ambient temperature and add water. The mixture gently alkalinized to pH 9 by addition of saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to obtain 3-amino-4-chloro-N-(3-fluoro-5-morpholinoethyl)benzamide (24.3 g). An NMR spectrum: (d6 ) 3,0-3,1(m, 4H), 3,7-of 3.75 (m, 4H), 5,6 (s, 1H), 6,45-6,55(m, 1H), 7,0-7,2(m, 3H), 7.3 to 7,35(m, 2H), to 10.09(W s, 1H). Mass spectrum: M+N+350.

Oxalicacid (1,05 ml) was added dropwise to a stirred mixture of 5-chloro-2-nitrobenzoic acid (2,08 g), methylene chloride (100 ml) and DMF (few drops)was cooled to a temperature 0°C. the Mixture is heated under ambient temperature and stirred for 4 hours. The mixture is evaporated and the residue is dissolved in methylene chloride (10 ml) and added dropwise to a stirred mixture of 3-amino-4-chloro-N-(3-fluoro-5-morpholinoethyl)benzamide (3.0 g) and pyridine (40 ml). The resulting mixture is heated at a temperature of 80°C for 16 hours. The solvent is evaporated and the residue is dissolved in methylene chloride (50 ml) and water (50 ml) and stirred for 1 hour. The obtained solid is filtered, washed with water and diethyl ether and dried in vacuum at a temperature of 40°C. Obtain 4-chloro-3-(5-chloro-2-nitrobenzamide)-N-(3-fluoro-5-morpholinomethyl)benzamide (1.07 g). An NMR spectrum: (d6) 3,09-3,14(m, 4H), 3,69-3,74(m, 4H), to 6.58(d, 1H), 7,15 to 7.2(m, 2H), 7,71(d, 1H), 7,82-a 7.92(m, 3H), and 8.2(d, 1H), 8,29(s, 1H), 10,37(s, 1H), 10,61(s, 1H). Mass spectrum: M+H+533 and 535.

A portion (0.8 g) of the obtained compound was dissolved in 1-methylpiperazine (3 ml) and the mixture is stirred and heated at a temperature of 100°C for 16 hours. The mixture is cooled and poured into water. The obtained solid substance emit, p is washed successively with water and diethyl ether and dried in vacuum at a temperature of 40° C. Obtain 4-chloro-N-(3-fluoro-5-morpholinomethyl)-3-[5-(4-methylpiperazin-1-yl)- 2-nitrobenzamide]benzamide (0,803 g). An NMR spectrum: (d6) of 2.21(s, 3H), 2,4-of 2.45(m, 4H), is 3.08-3,13(m, 4H), 3.46 in, and 3.5(m, 4H), 3,69-3,74(m, 4H), to 6.58(d, 1H), 6,84(s, 1H), 7,0-7,2(m, 4H), to 7.68(d, 1H), 7,80(d, 1H), 8,04(d, 1H), at 8.36 (s, 1H). Mass spectrum: M+H+597.

Iron powder (0,726 g) is added to a stirred suspension of 4-chloro-N-(3-fluoro-5-morpholinomethyl)-3-[5-(4-methylpiperazin-1-yl)-2-nitrobenzamide]benzamide (0,76 g), water (2 ml), acetic acid (0.5 ml) and ethanol (15 ml) and the resulting mixture is stirred and heated at boiling temperature under reflux for 1 hour. The mixture is cooled to ambient temperature. Add water (80 ml) and the mixture is alkalinized by addition of sodium carbonate. The resulting mixture was filtered through diatomaceous earth and the separated solids are washed successively with methylene chloride and methanol. The combined filtrate is evaporated and the residue triturated under ethyl acetate. The mixture is filtered and the filtrate is evaporated to obtain 3-[2-amino-5-(4-methylpiperazin-1-yl)benzamido]-4-chloro-N-(3-fluoro-5-morpholinoethyl)benzamide (0,385 g). Mass spectrum: M+N+567.

b) the Compound has the following characteristics. Mass spectrum: M+N+577.

c) Connection has the following characteristics. An NMR spectrum: (d6) to be 1.6-1.7(m, 2H), 2,09 (s, 3H), 2,11 (C, 6N), of 2.21(t, 2H), 2,96(s, 3H), 3,06-3,14(m, 4H), 3,37-of 3.43(m, 2H),3,69 to 3.8(m, 4H), 6,56(d, 1H), to 7.09(s, 1H), 7,15-7,19(m, 2H), 7,32-7,38(m, 1H), 7,53(d, 1H), 7,9(d, 1H), of 8.09(d, 1H), 8,16 (s, 1H), 10,31(s, 1H). Mass spectrum: M+N+607.

3-{2-Amino-5-[N-(3-dimethylaminopropyl)-N-methylamino]benzamido}-4-chloro-N-(3-fluoro-5-morpholinomethyl)benzamide used as a starting compound, obtained as follows.

A mixture of 4-chloro-3-(5-chloro-2-nitrobenzamide)-N-(3-fluoro-5-morpholinoethyl)benzamide (0.8 g) andN-(3-dimethylaminopropyl)-N-methylamine (3 ml) is stirred and heated at a temperature of 100°C for 16 hours. The mixture is cooled and poured into water. The obtained solid substance emit, washed successively with water and diethyl ether and dried in vacuum at a temperature of 40°C. Obtain 4-chloro-3-{5-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide}-N-(3-fluoro-5-morpholinomethyl)benzamide. An NMR spectrum: (d6) 1,62-of 1.74(m, 2H), 2,12(C, 6N), of 2.21(t, 2H), is 3.08(s, 3H), 3,1-3,13(m, 4H), 3,52(t, 2H), 3,71-3,74(m, 4H), of 6.68(d, 1H), 6,78(s, 1H), at 6.84(d, 1H), 7,16-7,20(m, 2H), 7,68(d, 1H), 7,82(d, 1H), of 8.04(d, 1H), 8,31(s, 1H). Mass spectrum: M+H+613 and 615.

Using a technique similar to the method of the last paragraph of notes (a)above, in part, on obtaining raw materials, 4-chloro-3-{5-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide}-N-(3-fluoro-5-morpholinomethyl)benzamid restore with 3-{2-amino-5-[N-(3-dimethyl shall aminopropyl)- N-methylamino]benzamido}-4-chloro-N-(3-fluoro-5-morpholinoethyl)benzamide. An NMR spectrum: (d6) 1,54-of 1.62(m, 2H), 2,1(s, 6N), 2,18-2,22(m, 2H), 2,77(s, 3H), 3,09-and 3.16(m, 4H), 3,18-up 3.22(m, 2H), 3,7-3,74(m, 4H), to 6.57(d, 1H), 6,7(d, 1H), at 6.84(d, 1H), 7,08-7,24(m, 3H), 7.7(d, 1H), 7,8(d, 1H), of 8.27 (s, 1H). Mass spectrum: M+H+583.

d) Compound has the following characteristics. Mass spectrum: M+N+593.

e) the Compound has the following characteristics. Mass spectrum: M+N+593.

3-[2-Amino-5-(3-dimethylaminopropylamine)benzamido]-4-chloro-N-(3-fluoro-5-morpholinomethyl)benzamide used as a starting compound, obtained as follows.

Using a technique similar to that described in the sixth paragraph of part of the notes (a)above relating to raw materials, 4-chloro-3-(5-chloro-2-nitrobenzamide)-N-(3-fluoro-5-morpholinomethyl)benzamid subjected to interaction with 3-dimethylaminopropylamine to obtain 4-chloro-3-[5-(3-dimethylaminopropylamine)-2-nitrobenzamide]-N-(3-fluoro-5-morpholinoethyl)benzamide with 76% yield. An NMR spectrum: (d6) 1,62-of 1.74(m, 2H), 2,12(C, 6N), and 2.27(t, 2H), is 3.08-3,13(m, 4H), 3,18-up 3.22(m, 2H), 3,69-3,74(m, 4H), to 6.58(d, 1H), 6,67(m, 2H), 7,15 to 7.2(m, 2H), 7,42(t, 1H), 7,69(d, 1H), 7,68(d, 1H), 7,82(d, 1H), of 8.04(d, 1H), compared to 8.26(s, 1H), 10,32(s, 1H). Mass spectrum: M+N+599.

Using a technique similar to the method of the last paragraph of notes (a), above, regarding the floor the treatment of source materials, 4-chloro-3-[5-(3-dimethylaminopropylamine)-2-nitrobenzamide]-N-(3-fluoro-5-morpholinomethyl)benzamid restore with obtaining the required parent compound. An NMR spectrum: (d6) 1,62-of 1.78(m, 2H), 2,15(C, 6N), of 2.33(t, 2H), 2,99(t, 2H), 3,09-3,13(m, 4H), 3,69-3,74(m, 4H), 6,56(d, 1H), 6,66(s, 2H), 6,94(s, 1H), 7,15-7,22(m, 3H), 7,68(D, 1H), 7,78(d, 1H), 8,32(s, 1H), 10,29 (s, 1H). Mass spectrum: M+N+569.

f) Connection has the following characteristics. Mass spectrum: M+N+579.

g) the Compound has the following characteristics. Mass spectrum: M+H+593.

3-{2-Amino-5-[N-(3-methylaminopropyl)-N-methylamino]benzamido}-4-chloro-N-(3-fluoro-5-morpholinomethyl)benzamide used as a starting compound, obtained as follows.

Using a technique similar to that described in the sixth paragraph of part of the notes (a)above relating to raw materials, 4-chloro-3-(5-chloro-2-nitrobenzamide)-N-(3-fluoro-5-morpholinomethyl)benzamid subjected to interaction withN-(3-methylaminopropyl)-N-methylamine to obtain 4-chloro-3-(5-chloro-2-nitrobenzamide)-N-(3-fluoro-5-morpholinoethyl)benzamide. An NMR spectrum: (d6) 1,62-of 1.74(m, 2H), of 2.25(s, 3H), 2,46-2,49(m, 2H), of 3.07(s, 3H), of 3.12(t, 2H), 3,55(t, 2H), 3,69-3,74(m, 4H), to 6.58(d, 1H), 6,79(s, 1H), 6,86(d, 1H), 7,16 to 7.2(m, 2H), 7,69(d, 1H), 7,82(d, 1H), to 8.12(s, 1H). Mass spectrum: M+H+599.

Using a technique similar to the method of the last paragraph of the lock notes (a), above, in part, on obtaining raw materials, 4-chloro-N-(3-fluoro-5-morpholinomethyl)-3-{5-[N-(3-methylaminopropyl)-N-methylamino]-2-nitrobenzamide}benzamide restore with 3-{2-amino-5-[N-(3-methylaminopropyl)-N-methylamino]benzamido}-4-chloro-N-(3-fluoro-5-morpholinoethyl)benzamide. Mass spectrum: M+H+569 and 571.

h) Compound has the following characteristics. Mass spectrum: M+N+579.

Example 14

3-{3-[N-(3-Fluoro-5-morpholinomethyl)carbarnoyl]VHI]Od}-8-[N-(3-dimethylaminopropyl)-N-methylamino]-3,4-dihydroquinazolin-4-one

Using a technique similar to the technique of example 1, 3-{2-amino-3-[N-(3-dimethylaminopropyl)-N-methylamino]benzamido}-N-(3-fluoro-5-morpholinomethyl)benzamid subjected to interaction with triethylorthoformate. The reaction product is purified by chromatography on ion-exchange column (isolute SCX, using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous solution of ammonium hydroxide as eluent. Get listed in the header connection. Mass spectrum: M+N+559.

3-{2-Amino-3-[N-(3-dimethylaminopropyl)-N-methylamino]benzamido}-N-(3-fluoro-5-morpholinomethyl)benzamide used as a starting compound, obtained as follows.

Oxalicacid (0.51 g) is added dropwise to a stirred mixture of 3-chloro-2-nor what robinsonii acid (0,694 g), of methylene chloride (50 ml) and DMF (few drops)was cooled to a temperature 0°C. the Mixture is heated under ambient temperature and stirred for 4 hours. The mixture is evaporated and the residue is dissolved in methylene chloride (10 ml) and added dropwise to a stirred mixture of 3-amino-4-chloro-N-(3-fluoro-5-morpholinoethyl)benzamide (1.0 g) and pyridine (20 ml). The resulting mixture is heated at a temperature of 80°C for 16 hours. The solvent is evaporated and the residue is dissolved in methylene chloride (50 ml) and water (50 ml) and stirred for 1 hour. The obtained solid is filtered, washed with water and diethyl ether and dried in vacuum at a temperature of 40°C. Obtain 4-chloro-3-(3-chloro-2-nitrobenzamide)-N-(3-fluoro-5-morpholinomethyl)benzamide (1.07 g). An NMR spectrum: (d6) 3,09-3,13(m, 4H), 3,5-3,74(m, 4H), 6.48 in(d, 1H), 7,14-7,21(m, 2H), 7,63(d, 1H), 7,7-to 7.77(m, 2H), 7,89(d, 1H), 8,04(d, 1H), 8,14(s, 1H), 10,27(s, 1H), and 10.8 (s, 1H). Mass spectrum: M+H+533 and 535.

A mixture of 4-chloro-3-(3-chloro-2-nitrobenzamide)-N-(3-fluoro-5-morpholinoethyl)benzamide (0.51 g) andN-(3-dimethylaminopropyl)-N-methylamine (2 ml) is stirred and heated at a temperature of 100°C for 16 hours. The mixture is cooled and poured into water. The obtained solid substance emit, washed successively with water and diethyl ether and dried in vacuum at a temperature of 40°C. Obtain 4-chloro-3-{3-(N-(3-dimethylaminopropyl) N-methylamino]-2-nitrobenzamide}-N-(3-fluoro-5-morpholinomethyl)benzamide (0.45 g) is an NMR Spectrum: (d6) 1,48 is 1.58 (m, 2H), 2,07 (C, 6N), of 2.15(t, 2H), 2,69(s, 3H), 3,03(t, 2H), is 3.08-3.15 in(m, 4H), 3,7-of 3.75(m, 4H), 6,74(d, 1H), 7,15 to 7.2(m, 2H), 7,44(d, 1H), 7,52-to 7.64(d, 2H), 7.7(d, 1H), 7,82(d, 1H), 8,08(s, 1H), 10,32(s, 1H). Mass spectrum: M+H+613 and 615.

A mixture of part (0.25 g) the compounds obtained, 10% palladium on carbon (0.025 g) and methanol (25 ml) is stirred in hydrogen atmosphere. After cessation of hydrogen absorption, the catalyst is removed by filtration through diatomaceous earth and the filtrate is evaporated. The reaction product is purified by chromatography on ion-exchange column (isolute SCX, using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous solution of ammonium hydroxide as eluent. Get 3-{2-amino-3-[N-(3-dimethylaminopropyl)-N-methylamino]benzamido}-N-(3-fluoro-5-morpholinomethyl)benzamide (is 0.102 g). An NMR spectrum: (d6) 1,58-of 1.62(m, 2H), 2,09(s, 6N in), 2.25(t, 2H), has 2.56(s, 3H), 2,77(t, 2H), 3,09-3,13(m, 6N), 3,7-to 3.73(m, 4H), to 6.39(s, 1H), 6.48 in-only 6.64(m, 3H), 7,08-7,24(m, 4H), of 7.4-7.5(m, 1H), 7.62mm(d, 1H), 7,92(d, 1H), compared to 8.26(s, 1H), 10,14(s, 1H), 10,22(s, 1H). Mass spectrum: M+N+549.

Example 15

3-[5-(2-Chloropyrid-4-ylcarbonyl)-2-were]-6-(4-methylhomopiperazine-1-yl)-3,4-dihydroquinazolin-4-one

Using a technique similar to the technique of example 5, 3-(5-amino-2-were)-6-(4-methylhomopiperazine-1-yl)-3,4-dihydroquinazolin-4-one is subjected to interaction with 2-harp ridin-4-carbonylchloride obtaining specified in the connection header. An NMR spectrum: (d6) 1,84 is 1.96 (m, 2H), 2.06 to(s, 3H), to 2.29(s, MN), 2,42-2,49(m, 2H), 2,62 of 2.68(m, 2H), 3,53(t, 2H), to 3.58-to 3.64(m, 2H), 7,22(d, 1H), 7,34(m, 1H), 7,44(m, 1H), 7,58(d, 1H), 7,73 for 7.78(m, 2H), 7,82-7,86(m, 1H), of 7.96-7,98(m, 2H), 8,50-to 8.62(m, 1H), is 10.68(s, 1H). Mass spectrum: M+N+503 and 505.

3-(5-Amino-2-were)-6-(4-methylhomopiperazine-1-yl)-3,4-dihydroquinazolin-4-one used as starting compound, obtained as follows.

The mixture ofN-(2-methyl-5-nitrophenyl)-5-chloro-2-nitrobenzamide (5 g)N-methylhomopiperazine (9.28 are ml) and DMSO (4 ml) is stirred and heated at a temperature of 80°C for 4 hours. The reaction mixture was cooled to ambient temperature and poured into water. The precipitate is separated, washed with water and diethyl ether and dried in vacuum at a temperature of 40°C. ReceiveN-(2-methyl-5-nitrophenyl)-5-(4-methylhomopiperazine-1-yl)-2-nitrobenzamide (5,42 g). An NMR spectrum: (d6) 1,82 is 1.96(m, 2H), and 2.26(s, 3H), of 2.38(s, 3H), 2,42-2,52(m, 2H), 2,61-to 2.65(m, 2H), 3,59-3,63(m, 2H), 3,67-3,71(m, 2H), 6,84-6,93(m, 2H), 7,52(d, 1H), 7,98(d, 1H), with 8.05(d, 1H), 8,55(s, 1H), 10,13(, 1H); Mass spectrum: M+H+414.

A mixture of the obtained compound, the catalyst is 10% palladium on carbon (0.54 g) and methanol (150 ml) is stirred under an atmosphere of hydrogen until then, until there is no further absorption of hydrogen. The catalyst is filtered off and the filtrate is evaporated. GetN-(5-amino-2-were)-2-amino-5-(4-methylhomopiperazine-1-yl)benzamide (of 3.64 g) Range of I Is P: (d 6) 1,8-of 1.92(m, 2H), 2,04(s, 3H), of 2.25(s, 3H), 2,42-2,48(m, 2H), 2.57 m-2,60(m, 2H), 3,34-3,39(m, 2H), 3,4-of 3.45(m, 2H), around 4.85(s, 2H), 5,46(s, 2H), 6,37(d, 1H), 6,62-6,74(m, 3H), at 6.84(d, 1H), 6,94(, 1H), 9,46(d, 1H). Mass spectrum: M+N+354.

A mixture of the obtained compound, triethylorthoformate (3,41 ml), glacial acetic acid (0.3 ml) and ethanol (75 ml) is stirred and heated at a temperature of 70°C for 16 hours. Add 1N aqueous solution of hydrochloric acid (20,6 ml) and the mixture is stirred at a temperature of 60°C for 3 hours. The resulting mixture is evaporated. The residue is dissolved in water, alkalinized by adding sodium bicarbonate and extracted with methylene chloride. The organic extract is evaporated to obtain 3-(5-amino-2-were)-6-(4-methylhomopiperazine-1-yl)-3,4-dihydroquinazolin-4-it (of 3.78 g). An NMR spectrum: (d6) to 1.86(s, 3H), 1,89-of 1.92(m, 2H), 2,24(s, 3H), of 2.44-2.49 USD(m, 2H), 2,6-2,63(m, 2H), 3,49-of 3.53(m, 2H), to 3.58-3,62(m, 2H), 5,14(s, 2H), 6,46(s, 1H), and 6.6(d, 1H), 7,01(d, 1H), 7,22(s, 1H), 7,32(d, 1H), at 7.55(d, 1H), 7,86(d, 1H). Mass spectrum: M+H+364.

Example 16

3-[5-(3,5-Differentaite)-2-were]-6-(4-methylhomopiperazine-1-yl)-3,4-dihydroquinazolin-4-one

Using the methodology of example 5, 3-(5-amino-2-were)-6-(4-methylhomopiperazine-1-yl)-3,4-dihydroquinazolin-4-one is subjected to interaction with 3.5-differentiaion obtaining specified in the connection header. An NMR spectrum: (d6) 1,84 is 1.96(m, 2H), 2.05 is(s, 3H), of 2.25(s, 3H), 2,42-2,5(m, 2H), 2,62-of 2.64(m, 2H), 3,53(t, 2H), to 3.58-to 3.64(m, 2H),7,24(d, 1H), 7,38(m, 1H), 7,40-7,44(m, 1H), of 7.48-rate of 7.54(m, 1H), 7,58(d, 1H), of 7.64-to 7.67(m, 2H), 7,75 for 7.78(m, 2H), of 7.96(s, 1H), 10,49(s, 1H). Mass spectrum: M+N+504.

Example 17

Using the method of example 10, a suitable 3-(5-amino-2-were)-3,4-dihydroquinazolin-4-one is subjected to interaction with the appropriate carboxylic acid to obtain the compounds described in table VIII.

Table VIII
(R1)mQApprox.
16-(4-methylpiperazin-1-yl)1-fluorenyland
26-(4-methylpiperazin-1-yl)3,4-methylenedioxyphenylb
36-(4-methylpiperazin-1-yl)3,4-trimethylhexanal
46-(4-methylpiperazin-1-yl)2,3-dihydrobenzofuran-7-yld
56-(4-methylpiperazin-1-yl)2-methyl-2,3-dihydrobenzofuran-7-yle
66-(4-methylpiperazin-1-yl)2,2-DIMETHYLPROPANE-6-ylf
76-(4-methylhomopiperazine-1-yl)dibenzofuran-4-ylg
8/td> 6-(4-methylhomopiperazine-1-yl)1-fluorenylh
96-(4-methylpiperazin-1-yl)5-(3-chlorophenyl)furan-2-yli
106-(4-methylpiperazin-1-yl)5-(4-chlorophenyl)furan-2-ylj
116-(4-methylpiperazin-1-yl)5-(4-chlorophenyl)Tien-2-ylk
126-(4-methylpiperazin-1-yl)4-(4-chlorophenyl)Tien-2-yll
136-(4-methylpiperazin-1-yl)4-(4-methoxyphenyl)Tien-2-ylm
146-(4-methylpiperazin-1-yl)3-finalization-5-yln
158-(4-methylpiperazin-1-yl)dibenzofuran-4-ylabout
168-(4-methylpiperazin-1-yl)1-fluorenylp
176-piperazine-1-Il1-fluorenylq
186-piperazine-1-Ildibenzofuran-4-ylr

Notes

a) the Compound has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), of 2.23(s, 3H), 2,47-2,5(m, 4H), 3,2-3,3(m, 4H), 4,18(s, 2H), 7,3-of 7.48(m, 4H), 7.5 to 7,63(m, 4H), of 7.75(d, 1H), and 7.8(d, 1H), 7,87(s, 1H, of 7.95(d, 1H), 8,08-8,11(m, 2H), 10,49(s, 1H). Mass spectrum: M+N+542.

b) the Compound has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), of 2.25(s, 3H), of 2.50(m, 4H), 3,26(m, 4H), 6,12(s, 2H), 7,06(d, 1H), 7,41(d, 1H), 7,49(d, 2H), 7,58(m, 1H), 7,65(d, 2H), 7,88(m, 2H), 8,08(s, 1H), 10,23(s, 1H). Mass spectrum: M+N+498.

c) Connection has the following characteristics. An NMR spectrum: (d6) was 2.05 (s, 3H), of 2.15(m, 2H), of 2.25 (s, 3H), 2,5-at 3.35(m, 8H), 4,2(m, 4H), and 7.6(d, 1H), and 7.4(d, 1H), of 7.48(s, 1H), 7,55-the 7.65(m, 4H), 7,76-a 7.85(m, 2H), and 8.1(s, 1H), 10,26(s, 1H).

Mass spectrum: M+N+526.

d) Compound has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), 2,3(s, 3H), by 2.55(m, 4H), of 3.25(m, 2H), 3,3(m, 4H), 4.75 V(t, 2H), 6,98(m, 1H), 7,39-7,49(m, 3H), 7,58-7, 65 (m, 3H), and 7.8(m, 2H), and 8.1 (s, 1H), 9, 9 (s, 1H). Mass spectrum: M+N+496.

e) 2-Methyl-2,3-dihydrobenzofuran-7-carboxylic acid used as starting compound, receive, as described in Monatschefte fur Chemie, 1990, 121, 883-891. The connection has the following characteristics. An NMR spectrum: (d6) a 1.50(m, 3H), of 2.05(s, 3H), of 2.25(s, 3H), by 2.55(m, 4H), of 3.28(m, 4H), 3,39(m, 2H), 5,12(m, 1H), 6,98(s, 1H), 7,41(d, 2H), 7,49(c, 1H), to 7.61(m, 3H), and 7.8(m, 2H), and 8.1(s, 1H), 9,87(s, 1H). Mass spectrum: M+N+510.

f) 2,2-DIMETHYLPROPANE-6-carboxylic acid used as starting compound, receive, as described in Tetrahedron, 1982, 38, 3673-3677. The connection has the following characteristics. An NMR spectrum: (d6) of 1.30(m, 6N), to 1.79(m, 2H), 2.05 is(s, 3H), of 2.25(s, 3H), 2,5(m, 4H), 2,8(m, 2H), 3,3(m, 4H), 6,8(d, 1H), 7,38(m, 1 is), 7,46(m, 1H), 7.62mm(m, 2H), 7,69-7,98(m, 4H), of 8.09(s, 1H), 10,18(s, 1H). Mass spectrum: M+N+538.

g) the Compound has the following characteristics. An NMR spectrum: (d6) 1,84-of 1.94(m, 2H), 2,07(s, 3H), of 2.25(s, 3H), 2,42-2,5(m, 2H), 2,62-of 2.66(m, 2H), 3,53(t, 2H), to 3.58-to 3.64(m, 2H), 7,26(s, 1H), 7,38(d, 1H), and 7.4-7.5(m, 2H), 7,51-to 7.61(m, 3H), 7,78-7,86(m, 4H), 8,01(s, 1H), 7,92-to 7.99(m, 2H), by 8.22(d, 1H), scored 8.38(d, 1H), 10,59(s, 1H). Mass spectrum: M+H+558.

h) Compound has the following characteristics. An NMR spectrum: (d6) 1,86-1, 98 (m, 2H), 2.06 to (s, 3H), of 2.25 (s, 3H), 2,42-2,5(m, 2H), 2,62-of 2.66(m, 2H), 3,53(t, 2H), to 3.58-to 3.64(m, 2H), 4,12(s, 2H), 7,24(s, 1H), 7,32-the 7.43(m, 4H), 7,52-to 7.61(m, MN), 7,72(d, 1H), 7,8(d, 1H), a 7.85(s, 1H), 7,92-to 7.99(m, 2H), 8,18(d, 1H), 10,49 (s, 1H). Mass spectrum: M+N+556.

i) 5-(3-Chlorophenyl)furan-2-carboxylic acid used as starting compound, receive, as described in Chem. Pharm. Bull., 1981, 29, 2420-2430. The connection has the following characteristics. An NMR spectrum: (d6) was 2.05 (s, 3H), 2,22(s, 3H), 2,47-2,5(m, 4H), of 3.25 to 3.35(m, 4H), 7,28(d, 1H), 7,38-of 7.48(m, 5H), a 7.62(s, 2H), 7,76(s, 1H), to 7.84(m, 1H), 7,9(d, 1H), 8,08(s, 2H), 10,38(s, 1H). Mass spectrum: M+H+554 and 556.

j) 5-(4-Chlorophenyl)furan-2-carboxylic acid used as starting compound, receive, as described in Chem. Pharm. Bull., 1981, 29, 2420-2430. The connection has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), 2,22(s, 3H), 2,47-2,5(m, 4H), 3,2-3,3(m, 4H), 7,2(d, 1H), 7,39-of 7.48(m, 3H), 7,54(d, 2H), 7,63(s, 2H), of 7.75(s, 1H), to 7.84(m, 1H), 7,98(m, 2H), 8,08(s, 1H), 10,34(s, 1H). Mass spectrum: M+N+554 and 556.

k) Connecting them is et the following characteristics. An NMR spectrum: (d6) 2,04(s, 3H), of 2.46(s, 3H), 2,47-2,5(m, 2H), 3,2-3,3(m, 4H), 7,41(d, 1H), of 7.48-7,51(m, 3H), 7,6-the 7.65(m, 3H), 7,73 one-7.8(m, 4H), 8,01(d, 1H), 8,07(s, 1H), and 10.5(s, 1H). Mass spectrum: M+N+570 and 572.

l) Compound has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), 2,22(s, 3H), 2,47-2,5(m, 2H), 3,2-3,3(m, 4H), 7,38-7,53(m, 4H), to 7.61-the 7.65(m, 2H), 7,72 one-7.8(m, 4H), 8,08(s, 1H), they were 8.22(s, 1H), of 8.47(s, 1H), and 10.5(s, 1H). Mass spectrum: M+H+570 and 572.

m) Connection has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), of 2.23(s, 3H), 2,47-2,5(m, 2H), 3,2-3,3(m, 4H), and 3.7(s, 3H), 7,01(d, 2H), 7,43(d, 1H), of 7.48(s, 1H), 7,6-7,66(m, 4H), 7,74 one-7.8(m, 2H), 8,02(s, 1H), 8,08(s, 1H), and 8.4 (s, 1H), 10,41(s, 1H). Mass spectrum: M+N+566.

n) 3-Finalization-5-carboxylic acid used as starting compound, receive, as described in Helv. Chim. Acta, 1966, 49, 2466-2469. The connection has the following characteristics. An NMR spectrum: (d6) 2,03(s, 3H), 2,22(s, 3H), 2,47-2,5(m, 4H), of 3.25 to 3.35(m, 4H), 7,35(d, 1H), 7,44-7,52(m, 5H), a 7.62(s, 1H), of 7.64-7,73(m, 2H), 7,98(d, 2H), of 8.06(s, 1H), and 8.4(s, 1H), 10,38(s, 1H). Mass spectrum: M+H+537.

a) the Compound has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), 2,2(s, 4H), 7.3 to 7,35(m, 1H), 7,4-7,6(m, 5H), of 7.75 to 7.9(m, 5H), and 8.2(d, 1H), 8,3 an 8.4(m, 2H), or 10.6(s, 1H). Mass spectrum: M+N+544.

R) Connection has the following characteristics. An NMR spectrum: (d6) was 2.05(s, 3H), 2,3 (s, 3H), 2.5 to approximately 2.65(m, 4H), 4,18(s, 2H), 7.3 to the 7.65(m, 7H), of 7.7 to 7.8(m, 3H), and 7.9(s, 1H), 7,95(d, 1H)and 8.1(d, 1H), and 8.3 (s, 1H), and 10.5(s, 1H). Mass spectrum: M+N+542.

q) 3-(5-Am is but-2-were)-6-(4-tert-butoxycarbonylmethyl-1-yl)-3,4-dihydroquinazolin-4-one used as starting compound. The initial reaction product is 3-[5-fluoren-1 ylcarbonyl-2-were]-6-(4-tert-butoxycarbonylmethyl-1-yl)-3,4-dihydroquinazolin-4-one, which is treated with a saturated solution of hydrogen chloride in ethanol for removal of tert-butoxycarbonyl protective group. The resulting product has the following characteristics. An NMR spectrum: (d6) 2,07(s, 3H), 3,26(m, 4H), 3,5(m, 4H), 4,18(s, 2H), 7,32-7.5(m, 4H), 7,55-7,63(m, 3H), 7,69-7,81(m, 4H), to $ 7.91 to 8.0(m, 3H), 8,11(s, 1H), 8,87(s, 1H). Mass spectrum: M+H+528.

3-(5-Amino-2-were)-6-(4-tert-butoxycarbonylmethyl-1-yl)-3,4-dihydroquinazolin-4-one used as starting compound, obtained as follows.

The mixture ofN-(2-methyl-5-nitrophenyl)-5-chloro-2-nitrobenzamide (5,02 g), piperazine (5,13 g) and DMSO (15 ml) is stirred and heated at a temperature of 100°C for 2 hours. The mixture is cooled to ambient temperature and poured into water. The obtained solid substance emit, washed successively with water and diethyl ether and dried in vacuum at a temperature of 55°C. ReceiveN-(2-methyl-5-nitrophenyl)-2-nitro-5-piperazine-1-ylbenzene (4,88 g). An NMR spectrum: (d6) of 2.38(s, 3H), 2,8(m, 4H), 3.43 points(m, 4H),? 7.04 baby mortality(m, 1H), 7,14(d, 1H), 7,52(d, 1H), 8,01(m, 1H), of 8.06(d, 1H), 8,53(d, 1H), 10,14(s, 1H). Mass spectrum: M+N+386.

2-(tert-Butoxycarbonyloxyimino)phenylacetonitrile (2.55 g) is added to the mixtureN-(2-methyl-5-nitrophenyl)2-nitro-5-piperazine-1-ilasamaja (2.5 g), triethylamine (1.7 ml), water (30 ml) and 1,4-dioxane (30 ml) and the resulting mixture stirred at ambient temperature in techenie 16 hours. The mixture is diluted with water and the resulting solid is isolated and washed successively with water and diethyl ether. GetN-(2-methyl-5-nitrophenyl)-5-(4-tert-butoxycarbonylmethyl-1-yl)-2-nitrobenzamide (2.85 g). An NMR spectrum: (CDCl3) to 1.48(s, N), is 2.37(s, 3H), of 3.48(m, 4H), 3,61(m, 4H), 6,77(m, 1H), 6.87 in(m, 1H), 7,33(d, 1H), 7,56(s, 1H), 7,95(m, 1H), 8,04(d, 1H), 8, 68 (s, 1H). Mass spectrum: M+H+484.

The compound obtained hydronaut in the presence of a catalyst 10% palladium on carbon, using a technique similar to that described in the third paragraph of example 5, related to raw materials. GetN-(5-amino-2-were)-2-amino-5-(4-tert-butoxycarbonylmethyl-1-yl)benzamide with 96% yield. An NMR spectrum: (CDCl3) 1,5 (, N), of 2.21(s, 3H), 3.0 a(m, 4H), 3,6(m, 4H), of 3.65(s, 2H), to 4.98(s, 2H), 6,47(m, 1H), 6.73 x(d, 1H), 7,01(m, 2H), 7,11(d, 1H), 7,41(d, 1H), and 7.8(s, 1H). Mass spectrum: M+H+426.

A mixture of the obtained compound (2,12 g), triethylorthoformate (1.7 ml), glacial acetic acid (0,07 ml) and ethanol (50 ml) is stirred and heated at a temperature of 70°C for 16 hours. Add a solution of sodium hydroxide (1 M, 5.0 ml) and the mixture is stirred and heated at a temperature of 60°C for 16 hours. Add another portion of the solution hydrocyanate (1M, 2.5 ml) and the mixture is again heated at a temperature of 60°C for 16 hours. The resulting mixture was cooled to ambient temperature and evaporated. The residue is dissolved in water and extracted with methylene chloride. The organic phase is dried and evaporated. The compound obtained purified by chromatography on a column of silica, using a 20:1 mixture of methylene chloride and methanol. Get 3-(5-amino-2-were)-6-(4-tert-butoxycarbonylmethyl-1-yl)-3,4-dihydroquinazolin-4-one (1.51 g). An NMR spectrum: (CDCl3) 1,5 (, N), to 2.06(s, 3H), of 3.27(m, 4H), 3,62(m, 4H), and 3.72(s, 2H), return of 6.58(d, 1H), 6,74(m, 1H), 7,15(d, 1H), 7,44(m, 1H), 7,68(m, 2H), 7,86(s, 1H). Mass spectrum: M+N+436.

g) 3-(5-Amino-2-were)-6-(4-tert-butoxycarbonylmethyl-1-yl)-3,4-dihydroquinazolin-4-one used as starting compound. The initial reaction product is 3-[5-dibenzofuran-4-ylcarbonyl-2-were]-6-(4-tert-butoxycarbonylmethyl-1-yl)-3,4-dihydroquinazolin-4-one, which is treated with a saturated solution of hydrogen chloride in ethanol for removal of tert-butoxycarbonyl protective group. The resulting product has the following characteristics. An NMR spectrum: (d6) 2,07(s, 3H), 3,29(m, 4H), 3,5(m, 4H), 7,42-7,6(m, 6N), to 7.67(m, 1H), 7,8-7,9(m, 4H), 7,95(s, 1H), 8,20-of 8.27(m, 2H), at 8.36(d, 1H), cent to 8.85(s, 1H). Mass spectrum: M+H+530.

Example 18

3-[2-Fluoro-5-(3-fluoro-5-morpholinomethyl)phenyl]-6-(4 - methylpiperazin-1-yl)-3,4-dihydro shall insulin-4-one

Triethylorthoformate (0,123 ml) are added to stir the mixtureN-[2-fluoro-5-(3-fluoro-5-morpholinomethyl)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamide (0.31 g), glacial acetic acid (0,016 ml) and ethanol (4 ml) and the resulting mixture is heated at a temperature of 76°C for 18 hours. The mixture is evaporated and the residue is distributed between methylene chloride and saturated aqueous sodium bicarbonate. The organic solution is washed with water and saturated aqueous sodium chloride, dried (MgSO4) and evaporated. The residue is purified by chromatography on a column of silica, using a mixture with increasing polarity of methylene chloride and methanol as eluent. Get listed in the title compound (0,119 g). An NMR spectrum: (d6) of 2.23 (s, 3H), up 3.22(m, 4H), and 3.72(m, 4H), of 6.99(d, 1H), 7,12(d, 1H), 7,29(s, 1H), 7,47(m, 2H), 7,63(s, 1H), 7,89(m, 1H), 7,97(m, 1H), 8,18(s, 1H), 10,44 (s, 1H). Mass spectrum: M+H+561.

N-[2-Fluoro-5-(3-fluoro-5-morpholinomethyl)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamide used as a starting compound, obtained as follows.

Oxalicacid (0.55 g) is added dropwise to a stirred mixture of 3-fluoro-5-morpholinomethyl acid (6,36 g), DMF (few drops) and methylene chloride (200 ml), cooled down to 0°C. the Mixture is allowed to warm to ambient temperature and stirred for 4 hours. mesh is evaporated. The residue is dissolved in methylene chloride (100 ml) and added dropwise to a stirred mixture of 4-fluoro-3-nitroaniline (of 4.05 g), triethylamine (12.0 ml) and methylene chloride (100 ml). The resulting mixture was stirred at ambient temperature for 20 hours. The mixture is evaporated and the residue is distributed between methylene chloride and water. The organic phase is washed with saturated aqueous sodium chloride, dried (MgSO4) and evaporated. GetN-(4-fluoro-3-nitrophenyl)-3-fluoro-5-morpholinomethyl (7,06 g). An NMR spectrum: (d6) 3,24(m, 4H), to 3.73(m, 4H), 7,0(m, 1H), 7,13(d, 1H), and 7.3(s, 1H), 7,58(t, 1H), 8,11(m, 1H), 8,63(m, 1H), 10,56(s, 1H). Mass spectrum: M-H-362.

A mixture of part (4,34 g) of the obtained compound, 30% palladium on carbon (0.68 g) and methanol (500 ml) is stirred in hydrogen atmosphere. After cessation of hydrogen absorption, the catalyst is removed by filtration and the filtrate is evaporated. GetN-(3-amino-4-forfinal)-3-fluoro-5-morpholinomethyl (3,49 g).

An NMR spectrum: (d6) 3,22(m, 4H), of 3.75(m, 4H), 5,12(s, 2H), for 6.81(m, 1H), 6.89 in-of 6.96(m, 2H), was 7.08(d, 1H), 7,24(m, 2H), 9,92(s, 1H). Mass spectrum: M+H+334.

Diisopropylamine (3,13 ml) is added to the mixtureN-(3-amino-4-forfinal)-3-fluoro-5-morpholinomethyl (1,99 g), 5-chloro-2-nitrobenzoic acid (1.45 g), 2-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium of hexaflurophosphate(V) (2,74 g) in DMF (12 ml) and the reaction mixture stirred at ambient temperature the Reda for 18 hours. The mixture was poured into water and the precipitate is separated, washed with water and dried in a vacuum at a temperature of 55°C. ReceiveN-[2-fluoro-5-(3-fluoro-5-morpholinomethyl)phenyl]-5-chloro-2-nitrobenzamide (1.64 g). An NMR spectrum: (d6) 3,22(m, 4H), 3,74(m, 4H), 6,97(d, 1H), 7,15(d, 1H), 7,25-to 7.32(m, 2H), 7,66(m, 1H), 7,82(m, 2H), 7,88(s, 1H), 8,18(d, 1H), 8.34 per(m, 1H), 10,32(s, 1H), of 10.58(s, 1H). Mass spectrum: M+H+517 and 519.

A mixture of part (0.55 g) of the obtained compound, andN-methylpiperazine (2 ml) is stirred and heated at a temperature of 80°C for 18 hours. The reaction mixture was cooled to ambient temperature and poured into water. The obtained precipitate out, washed with water and dried in a vacuum at a temperature of 55°C. ReceiveN-[2-fluoro-5-(3-fluoro-5-morpholinomethyl)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide (0.55 g).

An NMR spectrum: (d6) 2,2(s, 3H), 2,41(m, 3H), up 3.22(m, 4H), of 3.48(m, 4H), and 3.72(m, 4H), 6,93(m, 2H), 7,07(m, 1H), 7,16(d, 1H), 7,25(m, 1H), 7,32(s, 1H), 7,63(m, 1H), 8,14(d, 1H), at 8.36(m, 1H), 10,26(s, 1H), 10,3(s, 1H). Mass spectrum: M+H+581.

A mixture of the obtained compound, 30% palladium on carbon (0.075 g) and ethanol (500 ml) is stirred in hydrogen atmosphere. After cessation of hydrogen absorption, the catalyst is removed by filtration and the filtrate is evaporated. GetN-[2-fluoro-5-(3-fluoro-5-morpholinomethyl)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamide (0.52 g). An NMR spectrum: (d6) 2,22(s, 3H), 2,44(m, 4H), 2,98(m, 4H), 3,21(m, 4H) and 3.72(m, 4H), 5,93(W s, 1H), 6,69(d, 1H), 6,94-7,01(m, 2H), 7,12(d, 1H), 7,2-7,3(m, 3H), to 7.59(m, 1H), 7,97(m, 1H), 10,24(s, 1H). Mass spectrum: M+N+551.

Example 19

3-[2-Fluoro-5-(3-fluoro-5-morpholinomethyl)phenyl]-6-(4-methylhomopiperazine-1-yl)-3,4-dihydroquinazolin-4-one

Using the method of example 18,N-[2-fluoro-5-(3-fluoro-5-morpholinomethyl)phenyl]-2-amino-5-(4-methylhomopiperazine-1-yl)benzamid subjected to interaction with triethylorthoformate obtaining specified in the connection header with 63% yield. An NMR spectrum: (d6) of 1.92(m, 2H), of 2.25(s, 3H), 2,46(m, 2H), 2,64(m, 2H), 3,21(t, 4H), 3,53(t, 2H), 3,6(m, 2H), and 3.72(t, 4H), of 6.99(d, 1H), 7,12(d, 1H), 7.23 percent(m, 1H), and 7.3(s, 1H), was 7.36(m, 1H), of 7.48(t, 1H), 7,58(d, 1H), 7,87(m, 1H), of 7.96(m, 1H), of 8.06 (s, 1H), 10,43 (s, 1H). Mass spectrum: M+H+575.

N-[2-Fluoro-5-(3-fluoro-5-morpholinomethyl)phenyl]-2-amino-5-(4-methylhomopiperazine-1-yl)benzamide used as a starting compound, obtained as follows.

The mixture ofN-[2-fluoro-5-(H-fluoro-5-morpholinomethyl)phenyl]-5-chloro-2-nitrobenzamide (0.55 g) andN-methylhomopiperazine (2 ml) is stirred and heated at a temperature of 80°C for 18 hours. The reaction mixture was cooled to ambient temperature and poured into water. The precipitate is separated, washed with water and dried in a vacuum at a temperature of 55°C. ReceiveN-[2-fluoro-5-(3-fluoro-5-morpholinomethyl)phenyl]-5-(4-methylhomopiperazine-1-yl)-2-nitrobenzamide (0,58 g). An NMR spectrum: (d6 ) 1,89(m, 2H), of 2.25(s, 3H), 2,44(m, 2H), 2.63 in(m, 2H), up 3.22(t, 4H)and 3.59(t, 2H), 3,66(m, 2H), 3,74(t, 4H), 6,72(d, 1H), 6.87 in(m, 1H), 6,97(d, 1H), 7,16(d, 1H), 7.23 percent(t, 1H), 7,31(s, 1H), 7,63(m, 1H), 8,02(d, 1H), 8.34 per(m, 1H), 10,3(s, 1H). Mass spectrum: M+N+595.

A mixture of the obtained compound, 30% palladium on carbon (0.08 g) and ethanol (500 ml) is stirred in hydrogen atmosphere. After cessation of hydrogen absorption, the catalyst is removed by filtration and the filtrate is evaporated. GetN-[2-fluoro-5-(3-fluoro-5-morpholinomethyl)phenyl]-2-amino-5-(4-methylhomopiperazine-1-yl)benzamide (0,48 g). An NMR spectrum: (d6) to 1.86(m, 2H), 2,24(s, 3H), 2,44(m, 2H), 2,59(m, 2H), up 3.22(t, 4H), to 3.38(t, 2H), 3.43 points(m, 2H), and 3.72(t, 4H), of 6.68(d, 1H), 6,76(m, 1H), 6,98(m, 2H), 7,12(m, 1H), 7,22-7,31(m, 2H), 7,58(m, 1H), 8,08(m, 1H), of 10.25(W s, 1H). Mass spectrum: M+H+565.

Example 20

The pharmaceutical composition

The following illustrates examples of pharmaceutical dosage forms of the present invention (active ingredient is designated as "Compound X"), for therapeutic and prophylactic human use.

(a) Tablet Img tablet
Compound X100
Lactose Ph.Eur.182,75
Croscarmellose sodiumto 12.0
Pasta corn starch (5% wt./about paste)2,25
Magnesium stearate3,0
(b) Tablet IImg tablet
Compound X50
Lactose Ph.Eur.223,75
Croscarmellose sodium6,0
Corn starch15,0
Polyvinylpyrrolidone (5% wt./about paste)2,25
Magnesium stearate3,0
(c) Tablet IIImg tablet
Compound X1,0
Lactose Ph.Eur.93,25
Croscarmellose sodium4,0
Pasta corn starch (5% wt./about paste)0,75
Magnesium stearate1,0
(d) Capsulesmg/capsule
Compound X10
Lactose Ph.Eur.488,5
Magnesium1,5
(e) injection I(50 mg/ml)
Compound X5,0% wt./about
1M sodium hydroxide solution15,0% V/V
0,1M hydrochloric acid to bring pHto 7.6
The polyethylene glycol 4004.5% wt./about
Water for injection to100%
(f) RAS is a thief for injection II (10 mg/ml)
Compound X1.0% wt./about
Sodium phosphate BP3,6% wt./about
0,1M sodium hydroxide solution15,0% V/V
Water for injection to100%

(g) injection III (1 mg/ml, buffered to pH 6)

Compound X0.1% wt./about
Sodium phosphate BPof 2.26% wt./about
Citric acid0,38% wt./about
The polyethylene glycol 400a 3.5% wt./about
Water for injection to100%
(h) Aerosol Img/ml
Compound X10,0
Sorbitan trioleate13,5
Trichlorofluoromethane910,0
DICHLORODIFLUOROMETHANE490,0
(i) Aerosol IImg/ml
Compound X0,2
Sorbitan trioleate0,27
Trichlorofluoromethane70,0
DICHLORODIFLUOROMETHANE280,0
Dichlorotetrafluoroethane1094,0
(j) Aerosol IIImg/ml
The connection is 2,5
Sorbitan trioleate3,38
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 glycol1 ml

Note

The above formulation receive conventional methods, well known in the pharmaceutical field. The tablets (a)-(C) can be intersolubility membrane, applied by conventional means, for example, to get a shell from phthalate cellulose acetate. Aerosol formulations of (h)to(k) can be entered using standard aerosol for inhalation with a metering device, and suspendiruemye agents, sorbitan trioleate and soy is th lecithin may be replaced by alternative suspendium agent, such as sorbitan monooleate, sorbitan sesquioleate, Polysorbate 80, polyglycerol the oleate or oleic acid.

1. Derived amide of the formula Ia

in which X is-NHCO - or-CONH-;

m is 0, 1, 2 or 3;

R1is halogen, (1-6C)alkoxy, N-(1-6C)alkyl, di[(1-6C)alkyl]amino-(2-6S)-alkylamino

or R1is heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclic, heterocyclic-(1-6C)alkoxy, heterocyclisation, N-(1-6C)alkyl-heterocyclisation, heterocyclyl-(1-6C)alkylamino, N-(1-6C) -alkylglycerol-(1-6C)alkylamino, geterotsiklicheskikh, heterocyclization, N-heterocyclization, heterocyclyl-(2-6C)alkanolamine, heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl, heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl or N-(1-6C)alkylglycerol-(1-6C)alkylamino-(1-6C)alkyl,

and where any heterocyclyl group in the substituent R1may optionally have 1 or 2 substituent selected from halogen, (1-6C)alkyl and (1-6C)alkoxy,

and where any heterocyclyl group in the substituent R1may optionally have 1 or 2 substituent selected from oxo or tocography;

n is 0, 1 or 2;

R2is halogen or (1-6C)alkyl;

R3is hydrogen, halogen, (1-6C)alkyl or (1-6C)Alcock and;

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

Q is aryl, aryloxy, aryl-(1-6C)alkoxy, arylamino, N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino, (3-7C)cycloalkyl, heteroaryl, heteroaromatic, heteroaryl-(1-6C)alkoxy, heteroallyl, N-(1-6C)alkyldiethanolamine, heteroaryl-(1-6C)alkylamino, N-(1-6C)alkylglycerol-(1-6C)alkylamino, heterocyclyl, heterocyclic, heterocyclic-(1-6C)alkoxy, heterocyclisation, N-(1-6C)alkyldiethanolamine, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkylglycerol-(1-6C)alkylamino, optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, trifloromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfonyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)allylcarbamate, N,N-di[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (1-6C)alkanolamine, N-(1-6C)alkyl-(1-6C)alkanolamine, N-(1-6C)alkylsulfonyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonyl, N-(1-6C)alkyl-(1-6C)alkanesulfonyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl, carbarnoyl-(1-6) - Rev.)alkyl, N-(1-6C)allylcarbamate-(1-6C)alkyl, N,N-di-[(1-6C)alkyl]-carbarnoyl-(1-6C)alkyl, halogen-(2-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-6C)alkoxy(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbarnoyl-(1-6C)alkoxy, N-(1-6C)allylcarbamate-(1-6C)alkoxy, N,N-di-[(1-6C)alkyl]carbarnoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)-alkoxy, halogen-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-6C)alkoxy(2-6C)alkylamino, cyano-(1-6C)alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino, carbarnoyl-(1-6C)alkylamino, N-(1-6C)allylcarbamate-(1-6C)-alkylamino, N,N-di-[(1-6C)alkyl]carbarnoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, N-(1-6C)alkylhalides-(1-6C)alkylamino, N-(1-6C)alkylperoxy-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino, N-(1-6C)alkylene-(1-6C)alkylamino, N-(1-6C)alkylcarboxylic-(1-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino, N-(1-6C)-allylcarbamate-(1-6C)alkylamino, N-(1-6C)alkyl-N-(1-6C)allylcarbamate- (1-6C)alkylamino, N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]-carbarnoyl-(1-6C)alkylamino, N-(1-6C)alkylamino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino, N-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, halogen-(2-6C)alkanolamine, hydroxy-(2-6C)alkanolamine, (1-6C)alkoxy(2-6C)alkanolamine, cyano-(2-6C)alkanolamine is, carboxy-(2-6C)alkanolamine, (1-6C)alkoxycarbonyl-(2-6C)alkanolamine, carbarnoyl-(2-6C)alkanolamine, N-(1-6C)allylcarbamate-(2-6S)-alkanolamine, N,N-di-[(1-6C)alkyl]carbarnoyl-(2-6C)alkanolamine, amino-(2-6C)alkanolamine, (1-6C)alkylamino-(2-6S)-alkanolamine, di-[(1-6C)alkyl]amino-(2-6C)alkanolamine, aryl, aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, aryloxy, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaromatic, heteroaryl-(1-6C)-alkoxy, heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclic and heterocyclyl-(1-6C)alkoxy,

or Q is replaced by (1-3C)alkylenedioxy;

and where any aryl, heteroaryl or heterocyclyl group Deputy radical Q may optionally have 1 or 2 substituent selected from hydroxy, halogen, (1-6C)alkyl, (1-6C)alkoxy;

and where Q, if it is heterocyclyl group or contains heterocyclyl group, or any heterocyclyl group Deputy radical Q may optionally have 1 or 2 oxo or toxopneustes;

where aryl, when Q is an aryl group or contains an aryl group, or when aryl is Deputy radical Q, or contained in the Deputy radical Q is a phenyl, indenyl, indanyl, naphthyl, tetrahydronaphthyl or fluorenyl;

where heteroaryl, when Q is a heteroaryl group or contains heteroaryl the th group, or when heteroaryl is Deputy radical Q, or contained in the Deputy radical Q is an aromatic 5 - or 6-membered monocycle, 9 - or 10-membered bicyclic system or 13 - or 14-membered tricyclic system, which can have up to 5 heteroatoms selected from oxygen, nitrogen and sulfur;

and where heterocyclyl, when R1and Q are heterocyclyl group or contain heterocyclyl group, or when heterocyclyl is Deputy radical Q, or contained in the Deputy radical, Q represents a non-aromatic saturated or partially saturated 3 - to 10-membered monocycle or bicyclic system, which can have up to 5 heteroatoms selected from oxygen, nitrogen and sulfur;

or its pharmaceutically acceptable salt or in vivo degradable ester,

with the exception of 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it.

2. Derived amide of formula Ib

where m is 0, 1, 2 or 3;

R1is (1-6C)alkoxy, N-(1-6C)alkyl, di[(1-6C)alkyl]amino-(2-6S)-alkylamino,

or R1is heterocyclyl, heterocyclyl-(1-6C)alkyla is, heterocyclics, heterocyclyl-(1-6C)alkoxy, heterocyclisation, N-(1-6C)alkyldiethanolamine, heterocyclyl-(1-6C)alkylamino, N-(1-6C)-alkylglycerol-(1-6C)alkylamino, geterotsiklicheskikh, heterocyclization, N-heterocyclization, heterocyclyl-(2-6C)alkanolamine, heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl, heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl or N-(1-6C)alkylglycerol-(1-6C)alkylamino-(1-6C)alkyl,

and where any heterocyclyl group in the substituent R1may optionally have 1 or 2 substituent selected from halogen, (1-6C)alkyl and (1-6C)alkoxy,

n is 0 or 1;

R2is halogen or (1-6C)alkyl;

R3is hydrogen, halogen, (1-6C)alkyl or (1-6C)alkoxy;

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

Q is aryl, aryloxy, aryl-(1-6C)alkoxy, arylamino, N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino, N-(1-6C)alkylaryl-(1-6C)alkylamino, (3-7C)cycloalkyl, heteroaryl, heteroaromatic, heteroaryl-(1-6C)alkoxy, heteroallyl, N-(1-6C)alkyldiethanolamine, heteroaryl-(1-6C)alkylamino, N-(1-6C)alkylglycerol-(1-6C)alkylamino, heterocyclyl, heterocyclic, heterocyclic-(1-6C)alkoxy, heterocyclisation, N-(1-6C)alkyldiethanolamine, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkylglycerol-(1-6C)alkylamino,

and Q is optionally substituted by 1, 2 or 3 replacement is a Fort worth, selected from hydroxy, halogen, trifloromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfonyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)allylcarbamate, N,N-di[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (1-6C)alkanolamine, N-(1-6C)alkyl-(1-6C)alkanolamine, N-(1-6C)alkylsulfonyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonyl, N-(1-6C)alkyl-(1-6C)alkanesulfonyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl, carbarnoyl-(1-6C)alkyl, N-(1-6C)allylcarbamate-(1-6C)alkyl, N,N-di-[(1-6C)alkyl]-carbarnoyl-(1-6C)alkyl, halogen-(2-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-6C)alkoxy(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbarnoyl-(1-6C)alkoxy, N-(1-6C)allylcarbamate-(1-6C)alkoxy, N,N-di-[(1-6C)alkyl]carbarnoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)-alkoxy, halogen-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-6C)alkoxy(2-6C)alkylamino, cyano-(1-6C)alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino, carbarnoyl-(1-6C)alkylamino, N-(16C)allylcarbamate-(1-6C)-alkylamino, N,N-di-[(1-6C)alkyl]carbarnoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, N-(1-6C)alkylhalides-(1-6C)alkylamino, N-(1-6C)alkylperoxy-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkoxy(2-6C)alkylamino, N-(1-6C)alkylene-(1-6C)alkylamino, N-(1-6C)alkylcarboxylic-(1-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino, N-(1-6C)-allylcarbamate-(1-6C)alkylamino, N-(1-6C)alkyl-N-(1-6C)allylcarbamate- (1-6C)alkylamino, N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]-carbarnoyl-(1-6C)alkylamino, N-(1-6C)alkylamino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, halogen-(2-6C)alkanolamine, hydroxy-(2-6C)alkanolamine, (1-6C)alkoxy(2-6C)alkanolamine, cyano-(2-6C)alkanolamine, carboxy-(2-6C)alkanolamine, (1-6C)alkoxycarbonyl-(2-6C)alkanolamine, carbarnoyl-(2-6C)alkanolamine, N-(1-6C)allylcarbamate-(2-6S)-alkanolamine, N,N-di-[(1-6C)alkyl]carbarnoyl-(2-6C)alkanolamine, amino-(2-6C)alkanolamine, (1-6C)alkylamino-(2-6S)-alkanolamine, di-[(1-6C)alkyl]amino-(2-6C)alkanolamine, aryl, aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaromatic, heterocyclyl, heterocyclyl-(1-6C)alkyl, heterocyclic,

or Q is replaced by (1-3C)alkylenedioxy,

and where any aryl, heteroaryl or heterocyclyl group Deputy radical Q may neobyazatel is to have 1 or 2 substituent, selected from hydroxy, halogen, (1-6C)alkyl, (1-6C)alkoxy;

or its pharmaceutically acceptable salt or in vivo degradable ester;

with the exception of 3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it, 3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it 3-[5-(4-methoxybenzamido)-2-were]-2-methyl-Z,4-dihydroquinazolin-4-it.

3. Derived amide of the formula Ia according to claim 1, in which X is-NHCO - or-CONH-;

R3is hydrogen, stands or ethyl; m is 0, 1 or 2; R1is methoxy, ethoxy, N-(2-dimethylaminoethyl)-N-methylamino, N-(2-diethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino, N-(3-diethylaminopropyl)-N-methylamino, 3-pyrrolidino, pyrrolidinium, piperidinium, homopiperazine, morpholinium, piperazinil, 4-methylpiperazine, 4-ethylpiperazine, homopiperazine, 4-methylhomopiperazine, 4-acetylpiperidine, pyrrolidineethanol, 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)-PR is poxi, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinil)ethoxy, 3-(piperazinil)propoxy, 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-morpholinepropanesulfonic, 2-piperazinylmethyl, 3-(4-methylpiperazine)aminomethyl, pyridyloxy, imidazolylidene, thiazoleacetate and 2 methyldiethanolamine; n is 0 or 1; R2is fluorine, chlorine, bromine, stands or ethyl; q is 0; and Q is phenyl, indenolol, indenolol, tetrahydronaphthyl, fluorenyl, fullam, teinila, oxazolium, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolines, pyridium, pyridazinyl, pyrimidinyl, pyrazinium, benzofuranyl, indolium, benzothieno, benzoxazolium, benzimidazolium, benzothiazolium, indusrial, benzofurazanyl, chinaillon, ethanolism, hinazolinam, khinoksalinona, naphthyridine, carbazolyl, dibenzofurans, dibenzothiophenes or xanterra that do not have 1 or 2 substituent selected from hydroxy, fluorine, chlorine, trifloromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, p is epoxy, isopropoxy, cyclopentyloxy, methylendioxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, N-methylacetamide, methanesulfonamide, N-methylmethanesulfonamide, 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, 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 the Il)ethoxy and 3-(4-acetylpiperidine)propoxy, and where any phenyl, furilla, thienyl, perederina or heterocyclyl group Deputy radical Q may optionally have 1 or 2 substituent selected from fluorine, chlorine, methyl and methoxy; or its pharmaceutically acceptable salt.

4. Derived amide of the formula Ib according to claim 2, in which R3is hydrogen or stands; m is 1 and R1choose from 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 is 0 or 1; R2is stands; q is 0 and Q is 3-pyridium or 4-pyridium that have a Deputy selected from pyrrolidin-1-yl, morpholino, piperidino, piperazine-1-yl and 4-methylpiperazin-1-yl; or its pharmaceutically who ramlila salt.

5. Derived amide of the formula Ib according to p. 2, in which R3is hydrogen or stands; m is 1 and R1choose from 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-yl-propylaminoethyl, 2-morpholinosydnonimine, 3-morpholinepropanesulfonic, 2-piperazine-1-ylethylamine, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl, 2-pyridyloxy, 4-thiazoleacetate and 2-methylthiazole-4-ylethoxy; n is 0 or 1; R2is stands; q is 0 and Q is phenyl which has 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-Il, is morpholino, piperidino, homopiperazin-1-yl, piperazine-1-Il, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylhomopiperazine-1-yl, or Q is 1-fluorenyl or 4-dibenzofurane, or Q is 3-pyridium or 4-pyridium that have a Deputy selected from azetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino, homopiperazine, piperazine-1-Il, homopiperazin-1-silt, 4-methylpiperazin-1-yl and 4-methylhomopiperazine-1-yl; or its pharmaceutically acceptable salt.

6. Derived amide of the formula Ib according to p. 2, in which R3is hydrogen or stands; m is 1 and R1is a 4-methylpiperazin-1-yl, 4-methylhomopiperazine-1-yl or N-(3-dimethylaminopropyl)-N-methylamino; n is 0 or 1; R2is 6-stands; q is 0 and Q is 2-pyrrolidin-1-inpired-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.

7. Derived amide of the formula Ib according to claim 2, in which R3is hydrogen; m is 1 and R1is piperazine-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazine-1-yl or N-(3-dimethylaminopropyl)-N-methylamino; n is 0 or 1; R2is 6-stands or 6-fluorine; q is 0 and Q is 2-azetidin-1-inpired-4-yl, 2-pyrrolidin-1-inpired-4-yl, 2-(3-Pierre is Lin-1-yl)pyrid-4-yl, 2-piperidinomethyl-4-yl, 2-morpholinomethyl-4-yl, 1-fluorenyl, dibenzofuran-4-yl, 5-(4-chlorophenyl)furan-2-yl, 4-(4-chlorophenyl)-Tien-2-yl, 2-methoxyphenyl, 3-ethoxyphenyl, 3-(1,1,2,2-tetrafluoroethoxy)phenyl, 3,4-methylenedioxyphenyl, 3-acetamidophenyl, 3-(4-forfinal)phenyl, 3-(2-furyl)phenyl, 3-fluoro-5-pyrrolidin-1-inveniam, 3-fluoro-5-piperidinophenyl, 3-fluoro-5-morpholinopropan or 3-morpholino-5-cryptomaterial; or its pharmaceutically acceptable salt.

8. Derived amide of the formula Ia according to claim 1, selected from the group comprising 6-[N-(3-dimethylaminopropyl)-N-methylamino]-3-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-one,

6-[N-(3-dimethylaminopropyl)-N-methylamino]-2-methyl-3-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-one,

6-[N-(3-dimethylaminopropyl)-N-methylamino]-3-[5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-one,

6-(4-methylpiperazin-1-yl)-3-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-one,

8-[N-(3-dimethylaminopropyl)-N-methylamino]-3-[2-methyl-5-(2-morpholinomethyl-4-ylcarbonyl)phenyl]-3,4-dihydroquinazolin-4-one,

3-[2-methyl-5-(2-pyrrolidin-1-inpired-4-ylcarbonyl)-phenyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one,

3-[2-methyl-5-(2-piperidinophenyl-4-ylcarbonyl)-phenyl]-6-(4-methylpiperazin the-1-yl)-3,4-dihydroquinazolin-4-one,

3-{2-methyl-5-[2-(3-pyrrolin-1-yl)pyrid-4-ylcarbonyl]-phenyl}-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one,

3-[5-dibenzofuran-4-ylcarbonyl-2-were]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one,

3-{5-[3-(2-furyl)benzamido]-2-were}-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one

3-[5-(3-acetamidobenzoic)-2-were]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one,

or its pharmaceutically acceptable salt.

9. The method of obtaining the amide derivative of the formula Ia or Ib, or its pharmaceutically acceptable salt or in vivo splitting of ester according to claim 1 or 2, which includes

the interaction of N-phenyl-2-aminobenzamide formula II

with a carboxylic acid of formula III or its reactive derivative

where X, R1, R2, R3, m, n, q and Q have the meanings defined in claim 1, and where any functional group is protected if necessary, and:

(i) removing any protective groups and

(ii) optional education or a pharmaceutically acceptable salt or in vivo splitting of ester.

10. The method of obtaining the amide derivative of the formula Ia or Ib, or its pharmaceutically acceptable salt or in vivo splitting of ester according to claim 1 or 2 which includes

the interaction of aniline of the formula X

with a carboxylic acid of formula VI, or its reactive derivative,

in the conditions of formation of amide linkages,

where R1, R2, R3, m, n, q and Q have the meanings defined in claim 1, and where any functional group is protected if necessary, and

(i) removing any protective groups and

(ii) the optional formation of a pharmaceutically acceptable salt or in vivo splitting of ester.

11. The pharmaceutical composition inhibiting the production of cytokines by inhibiting the action of the enzyme R kinase, which contains amide derivative of the formula Ia or Ib, or its pharmaceutically acceptable salt or in vivo degradable ester as defined in claim 1 or 2, or amide derivative selected from the

3-(5-benzamido-2-were)-2-methyl-3,4-dihydroquinazolin-4-it,

3-[5-(4-methylbenzamide)-2-were]-2-methyl-3,4-dihydroquinazolin-4-she

3-[5-(4-methoxybenzamido)-2-were]-2-methyl-3,4-dihydroquinazolin-4-it,

in combination with a pharmaceutically acceptable diluent or carrier.

12. Derived amide of the formula Ia or Ib, or its pharmaceutically acceptable salt or in vivo split complex EPE is, as defined in claim 1 or 2, having the properties of an inhibitor of the production of cytokines by inhibiting the action of the enzyme R kinase.

13. Method of inhibiting the production of cytokines TNFα by inhibiting the action of the enzyme R kinase, which includes the introduction of a warm-blooded animal an effective amount of amide derivative of the formula Ia or Ib, or its pharmaceutically acceptable salt or in vivo splitting of ester as defined in claim 1 or 2.

Priorities:

17.03.1999 - claim 2, 4, 8, 9-12;

11.11.1999 - claims 1, 3, 5, 6.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

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EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 94 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new heterocyclic compounds corresponding to general formulas: (I) , (II) , (Ia) and (Ib) wherein substitutes have values given in the description. Such compounds are reversible inhibitors of cathepsins S, K, F, L and B. Also, invention relates to a method for preparing these compounds, pharmaceutical composition eliciting inhibitory activity with respect to cysteine proteases and to a method for modulation of autoimmune diseases, treatment of Alzheimer's disease and osteoporosis.

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

42 cl, 106 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to new substituted thienyl(amino)sulfonylureas of formula I ,

wherein A represents nitrogen or methane; Q represents direct bond or imino; R1 represents fluorine, chlorine, bromine, unsubstituted C1-C4-alkyl, C1-C4-alkoxyl optionally substituted with halogen, unsubstituted C1-C4-alkylthio, or di(C1-C4-alkyl)amino; R2 represents hydrogen or C1-C4-alkyl. Compounds of present invention are useful as herbicide agents.

EFFECT: new compounds with herbicide activity.

5 cl, 11 tbl, 5 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to new substituted thien-3-yl-sulfonylamino(thio)carbonyl-triazolin(thi)ons of general formula I

(wherein Q represents oxygen or sulfur; R1 represents unsubstituted alkyl; R2 represents hydrogen, halogen, unsubstituted alkyl; R3 represents hydrogen, halogen, alkyl optionally substituted with alkoxy, alkoxy or arylthio, optionally substituted with alkoxy or halogen, unsubstituted cycloalkyl or cycloalkyloxy, or unsubstituted arylalkoxy or aryloxy; R4 represents unsubstituted alkyl, alkoxy, dialkylamino, cycloalkyl) and their salts. Compounds of present invention are useful as herbicide agents. Also disclosed is herbicide composition and new synthetic intermediates for compounds of formula I.

EFFECT: new compounds and intermediates thereof with herbicide activity.

16 cl, 13 tbl, 67 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

The invention relates to organic chemistry and can find application in medicine

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new 4-piperazinyl-(8-quinolinyl)-methyl)-benzamides of general formula I

1, wherein R1 is phenyl, pyridinyl, thiophenyl, furanyl, and inidazolyl, and each phenyl or heteroaromatic ring is optionally and independently substituted with 1, 2 or 3 substituents, selected from linear or branched C1-C6-alkyl, NO2, CF3, C1-C6-alkoxy, halogen, or pharmaceutically acceptable salts thereof. Compounds of present invention are useful in therapy, in particular for pain alleviation. Also disclosed are pharmaceutical composition based on compounds of formula I and method for pain treatment.

EFFECT: new compounds and compositions for pain treatment.

12 ck, 19 ex, 3 tbl

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