Pyridinone pyridazinone derivatives as inhibitors of poly(adp-ribose) polymerase (parp)


FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

 

The present invention relates to a derivative of pyridinone and pyridazinone, which are inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), previously known as poly(ADP-ribose)synthase and poly(ADP-ribosyl)transferase. Compounds of the present invention can be used for monotherapy of tumors with specific abnormalities in pathways of DNA repair, and as reinforcing agents for certain damaging DNA agents, such as anticancer tools and radiotherapy. Further compounds according to the present invention can be applied for the treatment of cellular necrosis (in case of shock and myocardial infarction), reduce inflammation and tissue damage, the treatment of retroviral infections and protection against toxicity of chemotherapy.

Poly(ADP-ribose)polymerase (PARP) is formed by a superfamily of eighteen proteins containing the catalytic domains of PARP (Bioassays (2004) 26:1148). These proteins include PARP-1, PARP-2, PARP-3, tankyrase-1, tankyrase-2, vaultPARP and TiPARP. PARP-1, the main representative of the superfamily consists of three domains: the amino (N)-terminal DNA-binding domain (DBD)containing two zinc-containing fragment, automotivegrade domain and carboxy-(C)-terminal catalytic domain.

PARP represent nuclear and cytoplasmic enzymes that break down NAD+to nicotinamide and ADP-ribose to get on the other and branched polymers of ADP-ribose on the target protein, including topoisomerases, histones and specific PARP (Biochem. Biophys. Res. Commun. (1998) 245:1-10).

Poly-ADP-ribosylating participates in several biological processes, including DNA repair, gene transcription, progression of the cell cycle, cell death, chromatin function and stability of the genome.

The catalytic activity of PARP-1 and PARP-2 has been shown to be directly activated by DNA strand breaks (seePharmacological Research (2005) 52:25-33). In response to DNA damage PARP-1 binds to single-stranded and donativum by DNA breaks. In normal physiological conditions, the activity of PARP is minimal, however, when DNA damage is immediate activation of PARP activity, increasing up to 500 times. As PARP-1 and PARP-2 find the thread breakages of DNA, acting as a cofactor break DNA, providing a quick stop signals of transcription and inflow of enzymes required for DNA repair at the point of damage. Because radiotherapy and many chemotherapeutic treatments for cancer are influenced by inducing DNA damage, PARP inhibitors can be used as chemo - and radio sensibilizators in the treatment of cancer. PARP inhibitors, as reported, are effective in radiosensibility hypoxic tumor cells (patents US 5032617, 5215738 and 5041653).

Most of the biological effects of PARP include the I to this process of poly-ADP-ribosylate, which affects the properties and functions of the target proteins; PAR-oligomers, which, when hatshepsuts from poly-ADP-ribosylating proteins, create different cellular effects; physical Association with PARP nuclear proteins with the formation of functional complexes and reduce the cellular level of the substrate, NAD+(Nature Review (2005) 4:421-440).

In addition to participating in DNA repair, PARP may also act as a mediator of cell death. Its over-activation in pathological conditions such as ischemia and reperfusion injury, can lead to a significant decrease in the level of intracellular NAD+that can lead to the weakening of several NAD+dependent metabolic pathways and lead to cell death (seePharmacological Research (2005) 52:44-59). As a result of activation of PARP levels of NAD+drop dramatically. Extensive activation of PARP leads to a significant decrease in the levels of NAD+in cells suffering from major damage to DNA. Short half-life of poly(ADP-ribose) leads to a high speed cycle, once poly(ADP-ribose) is formed, it is rapidly degraded always active poly(ADP-ribose) glycohydrolase (PARG). PARP and PARG form a loop, which converts a large number of NAD+in ADP-ribose, causing the fall of the NAD+and ATP to less than 20% of the normal level. So the scenario is particularly detrimental during ischemia, when the oxygen loss is significantly undermines the release of cellular energy. The subsequent production of free radicals during reperfusion, as expected, is a major cause of tissue damage. Part of the decline in ATP, which is typical of many organs during ischemia and reperfusion may be associated with reduced NAD+thanks to the circulation of poly(ADP-ribose). Thus, the inhibition of PARP, as expected, saves the level of cellular energy, thus potentsiruya survival of ischemic tissue after stroke. Compounds that are inhibitors of PARP, therefore, can be used to treat conditions that arise from mediated PARP cell death, including neurological conditions such as stroke, trauma and Parkinson's disease.

PARP inhibitors, as has been shown, can be applied for the specific destruction of BRCA-1 and BRCA-2 deficient tumors (Nature (2005) 434:913-916 and 917-921; and the Cancer Biology &Therapy (2005) 4:934-936).

PARP inhibitors have been shown are for selective destruction of cells with defects in ATM, DNRC or KU80 (Nucleic Acid Research (2006) 34: 1685-1691).

PARP inhibitors have been shown to enhance the efficacy of anti-cancer drugs (Pharmacological Research (2005) 52:25-33), including platinum compounds such as cisplatin and carboplatin (Cancer Chemther. Pharmacol. (1993) 33:157-162 and Mol. Cancer Ther. (2003) 2:371-382). PARP inhibitors have been shown to enhance the antitumor activity of inhibitors of topoisomerase I, such as irinotecan and topotecan (Mol. Cancer Ther. (2003) 2:371-382; and Clin. Cancer Res. (2000) 6:2860-2867), and it was demonstrated on models in vivo (J. Natl. Cancer Inst. (2004) 96:56-67).

PARP inhibitors have been shown to return sensitivity to the cytotoxic and antiproliferative effects temosolomida (TMZ) (seeCurr. Med. Chem. (2002) 9:1285-1301andMed. Chem. Rev. Online (2004) 1: 144-150). It was demonstrated in several in vitro models (Br. J. Cancer (1995) 72:849-856; Br J. Cancer (1996) 74:1030-1036;Mol Pharmacol (1997) 52:249-258;Leukemia (1999) 13:901-909; Glia (2002) 40:44-54;andClin. Cancer Res. (2000) 6:2860-2867 and (2004) 10:881-889and models in vivo (Blood (2002) 99:2241-2244; Clin. Cancer Res. (2003) 9:5370-5379 and J. Natl. Cancer Inst. (2004) 96:56-67). As shown, the PARP inhibitors also prevent the appearance of necrosis induced selective N3-actinotrichida agents such as MeOSO2(CH2-lexitropsin (Me-Lex) (Pharmacological Research (2005) 52:25-33).

PARP inhibitors have been shown to act as radiation sensitizers. PARP inhibitors, as reported, are effective against radiosensibility (hypoxic) of tumor cells and is effective in preventing the recovery of tumor cells after potentially lethal (Br. J. Cancer (1984) 49 (Suppl. VI):34-42; andInt. J. Radat Bioi. (1999) 75:91-100and close to lethal (Clin. Oncol. (2004) 16(l):29-39damage of DNA after radiation therapy, presumably by their ability to prevent connection of DNA strand breaks and by strong effects on multiple signaling pathways in DNA damage.

PARP inhibitors, as has been shown, can be applied for the treatment of acute and chronic myocardial diseases (seePharmacological Research (2005) 52:34-43). For example, it was demonstrated that a single injection of PARP inhibitors reduce the size of infarction caused by ischemia and reperfusion of the heart or skeletal muscle in rabbits. In these studies, a single injection of 3-aminobenzamide (10 mg/kg), for one minute before occlusion or one minute before reperfusion causes a corresponding reduction in infarct size in the heart (32-42%), while the 1.5-dihydroxyethylene (1 mg/kg), another PARP inhibitor, reduces infarct size in a comparable degree (38-48%). These results make the correct assumption that PARP inhibitors can restore previously damaged by ischemia heart or reperfusion injury of skeletal muscle tissue (PNAS (1997) 94:679-683). Similar results were also installed on the pigs (Eur. J. Pharmacol. (1998) 359:143-150 and Ann. Thorac. Surg. (2002) 73:575-581)and on dogs(Shock. (2004) 21:426-32).

PARP inhibitors, as has been shown, can be applied is for the treatment of certain vascular diseases, septic shock, ischemic damage and neurotoxicity (Biochim. Biophys. Acta (1989) 1014:1-7; J. Clin. Invest. (1997) 100: 723-735). DNA damage by oxygen radicals, which leads to rupture of the strands in DNA, which is then identified PARP, is a major factor contributing to such a painful condition, as shown by studies of PARP inhibitor (J. Neurosci. Res. (1994) 39:38-46 and PNAS (1996) 93:4688-4692). Also, it has been demonstrated that PARP plays a role in the pathogenesis of hemorrhagic shock (PNAS (2000) 97:10203-10208).

PARP inhibitors, as has been shown, can be applied for the treatment of inflammatory diseases (seePharmacological Research (2005) 52:72-82 and 83-92).

It was also demonstrated that efficient retroviral infection of mammalian cells is blocked by inhibition of PARP activity. This inhibition of recombinant retroviral vector infection, as has been shown in various cell types (J. Virology, (1996) 70(6):3992-4000). Thus, PARP inhibitors are investigated for use as an antiviral therapies for the treatment of cancer (WO 91/18591).

Experiments in vitro and in vivo have demonstrated that PARP inhibitors can be used for treating or preventing autoimmune diseases such as type I diabetes and complications from diabetes (Pharmacological Research (2005) 52:60-71).

Inhibition of PARP has been suggested as the reasons of the postponement of aging characteristics in human fibroblasts ( Biochem. Biophys. Res. Comm. (1994) 201(2):665-672 and Pharmacological Research (2005) 52:93-99). This may be due to the role PARP plays in controlling telomere function (Nature Gen., (1999) 23(l):76-80).

The vast majority of PARP inhibitors, published to date, interacts with the nicotinamide-binding domain of the enzyme behaves as a competitive inhibitor against NAD+(Expert Opin. Ther. Patents (2004) 14:1531-1551). Structural analogues of nicotinamide, such as benzamide and derivatives, were among the first compounds have been studied as inhibitors of PARP. However, these molecules have weak inhibitory activity and have other effects that are not related to inhibition of PARP. Thus, there is a need to find potent inhibitors of the enzyme PARP.

US 2005/0234236 describes a method for the synthesis of pyridazinones, WO 2004/085406 describes benzylpyridine as reverse transcriptase inhibitors and EP 0810218 describes benzylpyridine as inhibitors of COX I and COX II.

Now suddenly for the first time found that derivatives of pyridinone and pyridazinone of the present invention exhibit a high degree of inhibition of PARP activity.

Compounds of the present invention can be applied for inhibition of poly(ADP-ribose)polymerase (PARP). In particular, they can be used as inhibitors of PARP-1 and/or PARP-2. The present invention provides the use of compounds of formula I:

,

where

a is 0 or 1;

b is 0, 1, 2 or 3;

c is 0, 1, 2, 3, 4, 5 or 6;

d is 0 or 1;

e is 0 or 1;

f is 0 or 1;

g is 0 or 1;

h is 0, 1, 2, 3, 4, 5 or 6;

i is 0 or 1;

j is 0 or 1;

X represents N or CH;

Y represents a C6-10-aryl, 5-membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, but not more than one of whom represents O or S or a 6 membered unsaturated heterocycle containing 1, 2, 3 or 4 nitrogen atom;

Z represents C or SO;

R1each independently represents a C1-6-alkyl, halogen-(C1-6-alkyl, halogen or cyano;

R2each independently represents hydroxy, halogen, cyano, nitro, C1-6-alkyl, halogen-(C1-6-alkyl, C1-6-alkoxy, halogen-(C1-6-alkoxy or NRaRb;

R3represents hydrogen or C1-6-alkyl;

R4represents hydrogen or C1-6-alkyl;

R5represents hydrogen, hydroxy, cyano, oxo, halogen, C1-6-alkyl, C2-10alkenyl, halogen-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-alkylsulphonyl, C1-6-alkoxy, halogen-(C1-6-alkoxy, C1-6/sub> -alkoxycarbonyl, carboxy, nitro or cycle, which is a C6-10-aryl; C6-10-arylcarbamoyl; C3-10-cycloalkyl; a 4 membered saturated heterocyclic ring containing one N atom; a 5 - or 6-membered saturated or partially saturated heterocyclic ring containing one, two or three N atom and zero or one O atom; a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which represents O or S; a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atom; or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of the above rings is optionally substituted by one or more groups independently selected from A-(CR9R10)qR6;

A, each independently, represents a simple bond, O, C=O (C=O)NR7, NR7(C=O), (C=O)O, O(C=O), (C=S)NR7, NR7or S(O)r;

q, each independently, 0, 1, 2, 3 or 4;

r is 0, 1 or 2;

R6each independently represents hydroxy, oxo, cyano, halogen, nitro, C1-6-alkyl, C2-10alkenyl, halogen-C1-6-alkyl, NRaRbor cycle, which is: C3-10-cycloalkyl; C6-10-aryl; C6-10-aryloxy; a 4 membered saturated heterocyclic ring containing one N atom; a 5-, 6 - or 7-membered saturated or partially saturated heterocyclic ring containing one, two or three atoms independently selected from N, O and S; a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which represents O or S; a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atom; or a 7-10 membered unsaturated or partially saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of the above rings is optionally substituted by one or more groups independently selected from R8;

R7represents hydrogen or R6;

R8each independently represents hydroxy, oxo, cyano, halogen, nitro, C1-6-alkyl, C1-6-alkoxy, C2-10alkenyl, halogen-C1-6-alkyl, halogen-(C1-6-alkoxy, -O(C=O)C1-6-alkyl, -(C=O)OC1-6-alkyl, NRaRbor cycle, which is a C3-10-cycloalkyl, C6-10-aryl, C6-10-aryl-C1-6-alkyl, C6-10-arylcarbamoyl, C6-10-aryloxyalkyl, C6-10-aryl-C1-6-alkoxycarbonyl, 5-membered heteroaromatic ring containing 1, 2, 3 or 4 hetaeras the atom, independently selected from N, O and S, not more than one heteroatom of which represents O or S; or a 6-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atom; any of the above rings is optionally substituted by one or more groups independently selected from halogen, C1-6-alkyl or halogen-C1-6-alkyl;

each of R9and R10independently represents hydrogen, halogen, C1-6-alkyl or halogen-C1-6-alkyl;

each of Raand Rbindependently represents hydrogen, C1-6-alkyl, C3-10-cycloalkyl, C3-10-cycloalkyl-C1-6-alkyl, C6-10-aryl or C6-10-aryl-C1-6-alkyl;

or its pharmaceutically acceptable salt or tautomer for the preparation of drugs for treatment or prevention of conditions that can be improved by inhibition of poly(ADP-ribose)polymerase (PARP).

The present invention also provides a method of treatment or prevention of conditions that can be improved by inhibition of poly(ADP-ribose)polymerase (PARP), where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

In the embodiment, a condition that can is to be treated by inhibition of poly(ADP-ribose)polymerase (PARP), include inflammatory diseases; reperfusion injury; ischemic condition; stroke; chronic and acute renal failure; vascular diseases other than cardiovascular diseases; cardiovascular diseases; diabetes; cancer, particularly a cancer which is deficient in respect of dependent homologous recombination (HR) Repartee activity against double-strand break DNA, such as BRCA-1 or BRCA-2 deficient tumors; neurodegenerative diseases, retroviral infection; damage to the retina; skin aging; induced by UV-light skin damage and premature aging.

In the embodiment, a condition in which can be achieved improved by inhibition of poly(ADP-ribose)polymerase (PARP), are selected from reperfusion injury; ischemic conditions; stroke; chronic and acute renal failure; vascular diseases other than cardiovascular diseases; cardiovascular diseases; diabetes; cancer, especially cancer, which is scarce in relation to the dependent homologous recombination (HR) Repartee activity against double-strand break DNA, such as BRCA-1 or BRCA-2 deficient tumors; neurodegenerative diseases, retroviral infections, damage to the retina; aging of the skin; and dozirovannogo UV light damage to the skin and premature aging.

In the embodiment, for each of the above embodiments

R2each independently represents hydroxy, halogen, cyano, nitro, C1-6-alkyl, halogen-(C1-6-alkyl, C1-6-alkoxy or halogen-(C1-6-alkoxy;

R5represents hydrogen, hydroxy, cyano, oxo, halogen, C1-6-alkyl, C2-10alkenyl, halogen-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-alkylsulphonyl, C1-6-alkoxy, halogen-(C1-6-alkoxy, C1-6-alkoxycarbonyl, carboxy, nitro or cycle, which is a C6-10-aryl; C6-10-arylcarbamoyl; C3-10-cycloalkyl; a 4 membered saturated heterocyclic ring containing one N atom; a 5-, 6 - or 7-membered saturated or partially saturated heterocyclic ring containing one, two or three N atom and zero or one O atom; a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which represents O or S; a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atom; or 7-10 membered unsaturated or partially saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of the above rings is optionally substituted by one or more groups, independent is selected from A-(CH 2)qR6;

R6each independently represents hydroxy, oxo, cyano, halogen, nitro, C1-6alkyl, C2-10alkenyl, halogen-C1-6is alkyl or cycle, which is a C6-10-aryl; a 4 membered saturated heterocyclic ring containing one N atom; a 5-, 6 - or 7-membered saturated or partially saturated heterocyclic ring containing one, two or three N atom and zero or one O atom; a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which represents O or S; a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atom; or 7-10 membered unsaturated or partially saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of the above rings is optionally substituted by one or more groups independently selected from R8;

R8each independently represents hydroxy, oxo, cyano, halogen, nitro, C1-6-alkyl, C1-6-alkoxy, C2-10alkenyl, halogen-C1-6-alkyl, halogen-(C1-6-alkoxy, -O(C=O)C1-6-alkyl, -(C=O)OC1-6-alkyl, amino, C1-6-alkylamino, di(C1-6-alkyl)amino, C6-10-aryl, 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms, independently researched the performance of selected from N, O and S, not more than one heteroatom of which represents O or S; or a 6-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atom.

The present invention also provides new compounds of formula I:

,

in which

a, b, c, d, e, f, g, h, i, j, X, Y, Z, R1, R2, R3, R4and R5defined above; provided that:

(a) if (CH2)c(CO)d(NR3)e(Z=O)f(O)g(CH2)h(NR4)iis an O-bridge, R2represents fluorine, X represents N and Y represents a phenyl, R5is optionally substituted cycle, selected from C6-10-aryl, 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring or a 7-15 membered unsaturated or partially saturated heterocyclic ring;

(b) if X represents N and Y represents a phenyl, naphthyl or 9 - or 10-membered unsaturated or partially saturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, R5not represents a C1-6-alkyl, halogen-(C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-alkoxy, halogen-(C1-6-alkoxy, C1-6-alkylaryl or optionally substituted C3-10-cycloalkyl, phenyl, naphthyl, pyridinyl, pyrid the n-N-oxide, indole, indole N-oxide, quinoline, quinoline-N-oxide, pyrimidinyl, pyrazinyl or pyrrolyl; and

(c) if (CH2)c(CO)d(NR3)e(Z=O)f(O)g(CH2)h(NR4)iis a CO-bridge, X represents N and Y represents a phenyl, R5is not optionally substituted phenyl, pyridinyl, tanila or fullam;

or their pharmaceutically acceptable salts or tautomers.

In a variant implementation:

(a) if (CH2)c(CO)d(NR3)e(Z=O)f(O)g(CH2)h(NR4)iis an O-bridge, R2represents fluorine, X represents N and Y represents a phenyl, R5is optionally substituted cycle, selected from C6-10-aryl, 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring or a 7-10 membered unsaturated or partially saturated heterocyclic ring;

(b) if X represents N and Y represents a phenyl, naphthyl or 9 - or 10-membered unsaturated or partially saturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, R5not represents a C1-6-alkyl, halogen-(C1-6-alkyl, hydroxy-C1-6is alkyl or optionally substituted C3-10-cycloalkyl, phenyl, naphthyl, pyridi the sludge, pyridine-N-oxide, indole, indole N-oxide, quinoline, quinoline-N-oxide, pyrimidinyl, pyrazinyl or pyrrolyl; and

(c) if (CH2)c(CO)d(NR3)e(Z=O)f(O)g(CH2)h(NR4)iis a CO-bridge, X represents N and Y represents a phenyl, R5is not optionally substituted phenyl, pyridinyl, tanila or fullam.

In the embodiment, the sum of a and j is 1 or 2.

In the embodiment, b is 0 or 1. In another embodiment, b is 1.

In the embodiment, c is 0.

In the embodiment, d is 1.

In the embodiment, e is 0.

In the embodiment, f is 0.

In the embodiment, g is 0.

In the embodiment, h is 0.

In the embodiment, i is 0.

In the embodiment, j is 0. In another embodiment, j is 1.

In the embodiment, X is N. In another embodiment, X represents CH.

In the embodiment, Y is phenyl, pyridinyl, pyrimidinyl, furyl or thienyl.

In another embodiment, Y represents C6-10-aryl.

In particular, the group Y represents phenyl.

In the embodiment, R1represents a fluorine-C1-3-alkyl, halogen or C1-6-Ala is L. In another embodiment, R1represents a C1-6-alkyl.

Preferred R1the group represents ethyl. More preferred R1groups are methyl and isopropyl.

In the embodiment, R2represents halogen, C1-6-alkoxy, amino, C1-6-alkylamino or di(C1-6-alkyl)amino.

In another embodiment, R2represents a fluorine-C1-3-alkyl or halogen.

In another embodiment, R2represents a halogen, for example fluorine or chlorine.

Preferably, R2the group is a fluorine. More preferred R2groups are dimethylamino, isopropoxy and methoxy.

In the embodiment, R5represents hydrogen, hydroxy, cyano, halogen, C2-10alkenyl,1-6-alkylsulphonyl, C1-6-alkoxy, C1-6-alkoxycarbonyl, carboxy, nitro or cycle, which is a 4-membered saturated heterocyclic ring containing one N atom; or a 5-, 6 - or 7-membered saturated or partially saturated heterocyclic ring containing one, two or three N atom and zero or one O atom; any of the above rings is optionally substituted by one or more groups independently selected from A-(CH2)qR6.

In each the m embodiment, R 5is a 4-membered saturated heterocyclic ring containing one N atom, a 5 - or 6-membered saturated or partially saturated heterocyclic ring containing one, two or three N atom and zero or one O atom, or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of the above rings is optionally substituted by one or more groups independently selected from A-(CR9R10)qR6.

In another embodiment, R5is a 4-membered saturated heterocyclic ring containing one N atom, a 5 - or 6-membered saturated or partially saturated heterocyclic ring containing one, two or three N atom and zero or one O atom, or a 7-15 membered partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of the above rings is optionally substituted by one or more groups independently selected from A-(CR9R10)qR6.

In another embodiment, R5is a 4-membered saturated heterocyclic ring containing one N atom or a 5-, 6 - or 7-membered saturated or partially saturated heterocyclic ring, which contains the ASEE one, two or three N atom and zero or one O atom; any of the above rings is optionally substituted by one or more groups independently selected from A-(CH2)qR6.

In the embodiment, R5is diazepan, piperidinyl, piperazinil, pyrrolidinyl, spirobisindane, tetrahydrobiopterin, tetrahydrothiopyran, desesperation, tetrahydropyrimidines, diazepinones, imidazolidinyl, azetidine or tetrahydroaminoacridine; any of the above rings is optionally substituted by one or more groups independently selected from A-(CR9R10)qR6.

In the embodiment, when R5is a cycle, the cycle is optionally substituted by one, two or three independently selected of A-(CR9R10)qR6groups. In the embodiment, when R5is a cycle, the cycle is unsubstituted or monosubstituted.

In the embodiment, when R6is a cycle, he is optionally substituted one, two or three groups independently selected from R8. In another embodiment, when R6is a cycle, it is unsubstituted, monosubstituted or disubstituted.

In the embodiment, when the R 8is a cycle, it is optionally substituted with one, two or three groups independently selected groups. In another embodiment, when R8is a cycle, it is unsubstituted, monosubstituted or disubstituted.

In the embodiment, R7represents hydrogen.

In the embodiment, A represents a direct bond, O, CO or NH.

In another embodiment, A represents a direct bond, CO or NH. In another embodiment, A represents a direct bond or a carbonyl. Preferred A group is a CO.

In the embodiment, q is 0, 1 or 2. In another embodiment, q is 0.

In the embodiment, R6represents oxo, C1-6-alkyl, halogen-(C1-6-alkyl, amino, C1-6-alkylamino, (dis1-6-alkyl)amino or cycle, which is pyrimidinyl, pyridinyl, pyrazolyl, phenyl, pyrazinyl, tetrahydroisoquinoline, cyclopentyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, hintline, phenoxy, furyl, benzodioxolyl, thienyl, cyclopropyl or azetidine; any of the above rings is optionally substituted by one or more groups independently selected from R8.

In another embodiment, R6represents a C1-6-alkyl./p>

In the embodiment, R8represents cyano, halogen, C1-6-alkyl, halogen-(C1-6-alkyl, C1-6-alkoxy, amino, C1-6-alkylamino, di(C1-6-alkyl)amino, (C3-10-cycloalkyl-C1-6-alkyl)amino, C6-10-arylamino, (C6-10-aryl-C1-6-alkyl)amino or cycle, which is a C6-10-aryl, C6-10-aryl-C1-6-alkyl, C6-10-arylcarbamoyl, C6-10-aryloxyalkyl or C6-10-aryl-C1-6-alkoxycarbonyl; any of the above rings is optionally substituted by one or more groups independently selected from halogen and C1-6-alkyl.

Preferred R8groups include methoxy, chlorine, methyl, trifluoromethyl, fluorine, cyano, methylamino, propyl, dimethylamino, benzyl, menthoxycarbonyl, phenylamino, amino, benzylamino, (cyclopropylmethyl)amino, isobutylamino, tormentil, methylbenzyl, naphthylmethyl and ethyl.

In the embodiment, each of R9and R10independently represents hydrogen, methyl, fluorine or trifluoromethyl.

In another embodiment, each of R9and R10represents a hydrogen atom.

Preferred R6the group is a methyl. More preferred R6groups include pyrimidinyl, pyridinyl, methoxypyridine, dimethylamino, pyrazolyl, chloropyridinyl, FeNi is, dimethylpyrazine, methoxyphenyl, tetrahydroisoquinoline, cyclopentyl, trifluoromethyl, methylamino, deformity, isopropyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, hintline, were, (trifluoromethyl)phenyl, fervency, cyanopyridine, differenl, furyl, methylpyrrolidinyl, benzodioxolyl, thienyl, cyclopropyl, oxo, diversityinc, (methylamino)cyclopentyl, propylpyrrolidine, methylpiperidine, (dimethylamino)cyclopropyl, benzylpyrrolidine, (methylamino)cyclopropyl, methylaziridinyl, (menthoxycarbonyl)methylpiperidine (phenylamino)cyclopentyl, aminocyclopent (benzylamino)cyclopentyl, [(cyclopropylmethyl)amino]cyclopentyl, (isobutylamino)cyclopentyl, (tormentil)pyrrolidinyl, (methylbenzyl)pyrrolidinyl, (naphthylmethyl)pyrrolidinyl and ethylpyrrolidin.

Thus, the preferred R5groups represent diazepan and acetildenafil. More preferred R5groups represent pyrimidinediamine, pyridinylmethyl, [(pyridinylmethyl)oxy]piperidine, (methoxypyridine)piperazinil, pyridiniomethyl, [(dimethylamino)methyl]piperidinyl, spirobisindane, (personility)piperidinyl, (chloropyridinyl)piperazinil, benzylacrylamide, (dimethylpyrazine)piperazinil, vinyltetrahydrofuran, (methoxybenzo the l)piperazinil, tetrahydroaminoacridine, piperazinil, phenylpiperazines, benzylpiperazine, (pyridinylmethyl)piperazinil, (cyclopentanecarbonyl)diazepan, (trifluoromethyl)tetrahydrothiopyran, propenylbenzene, [(methyl)(methylamino)propanol]piperazinil, (divercity)piperazinil, (tryptophanol)piperazinil, isobutylpyrazine, (pyridylcarbonyl)piperazinil, (tetrahydrofuranyl)piperazinil, [(methyl)(dimethylamino)propanol]piperazinil, (pentafluoropropanol)piperazinil, (pyrrolidinylcarbonyl)piperazinil, (TRIFLUOROACETYL)piperazinil, piperidinylmethyl, pyrrolidinylcarbonyl, hinatainternational, pyrimidinylpiperazine, desesperation, (were)tetrahydrothiopyran, [(trifluoromethyl)phenyl]tetrahydrothiopyran, [(forfinance)methyl]tetrahydrothiopyran, (cyanopyridine)piperazinil, (methyl)desesperation, (differenl)tetrahydrothiopyran, [(dimethylamino)methyl]tetrahydrothiopyran, filteradministratortoken, (pentafluoroethyl)tetrahydrothiopyran, {[(trifluoromethyl)phenyl]amino}tetrahydrothiopyran, (methylpropyl)piperazinil, vinyltetrahydrofuran, benzodiazepinecarisoprodol, teeninterracialporn, cyclopropylacetylene, (thrift rmutil)tetrahydropyrimidine, pyridineacetonitrile, diazepinones, methyldeoxycytidine, (pyrrolidinyl)azetidine, (diversityinc)piperidinyl, (triptorelin)tetrahydroaminoacridine, {[(methylamino)cyclopentyl]carbonyl}piperazinil, methyldiethanolamine, [(propylpyrrolidine)carbonyl]piperazinil, (piperidinylcarbonyl)piperazinil, [(methylpiperidine)carbonyl]piperazinil, {[(dimethylamino)cyclopropyl]carbonyl}piperidinyl, [(dimethylamino)propanol]piperidinyl, [(benzylpyrrolidine)carbonyl]piperazinil, (pyrrolidinylcarbonyl)piperazinil, {[(methylamino)cyclopropyl]carbonyl}piperazinil, [(methylaziridinyl)carbonyl]piperazinil, [(methylpyrrolidinyl)carbonyl]piperidinyl, [(dimethylamino)tryptophanyl]piperazinil, [(methylpiperidine)carbonyl]piperidinyl, {[(menthoxycarbonyl)methylpiperidine]carbonyl}piperidinyl, [(dimethylamino)methylethyl]tetrahydrothiopyran, (triptorelin)tetrahydroaminoacridine, [(pyrrolidinyl)acetyl]piperidine, ethyldiethanolamine, (cyclopropylmethyl)desesperation, [(onlinestromectol)carbonyl]piperazinil, [(aminocyclopent)carbonyl]piperazinil, {[(benzylamino)cyclopentyl]carbonyl}piperazinil, ({[(cyclopropylmethyl)amino]cyclopentyl}carbonyl)piperazinil, {[(isobutylamino)cyclopentyl]carbonyl}piperazinil, [(tormentil)prolyl]piperazine is, [(methylbenzyl)prolyl]piperazinil, [(naphthylmethyl)prolyl]piperazinil and (ethylpropyl)piperazinil.

Preferred R5groups are 1,4-diazepan-1-yl and 4-acetyl-1,4-diazepan-1-yl. More preferred R5groups are 4-(pyrimidine-2-yl)-1,4-diazepan-1-yl, 4-(pyridin-4-yl)piperidine-1-yl, 4-[(pyridine-2-ylmethyl)oxy]piperidine-1-yl, 3-[(pyridine-2-ylmethyl)oxy]piperidine-1-yl, 4-(5-methoxypyridine-2-yl)piperazine-1-yl, 4-(4-methoxypyridine-2-yl)piperazine-1-yl, 3-pyridin-4-iparralde-1-yl, 3-[(dimethylamino)methyl]piperidine-1-yl, 1'H-Spiro[1-benzofuran-3,4'-piperidine]-1'-yl, 4-(1H-pyrazole-1-retil)piperidine-1-yl, 4-(5-chloropyridin-2-yl)piperazine-1-yl, 4-(6-methoxypyridine-2-yl)piperazine-1-yl 3-benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl, 4-(3,6-dimethylpyrazine-2-yl)piperazine-1-yl, 3-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl, 4-(3-methoxybenzyl)piperazine-1-yl, 4-(1,2,3,4-tetrahydroisoquinoline-2-yl)piperidine-1-yl, piperazine-1-yl, 2-phenylpiperazin-1-yl, 2-benzylpiperazine-1-yl, 3-(pyridine-3-ylmethyl)piperazine-1-yl, 4-(cyclopentanecarbonyl)-1,4-diazepan-1-yl, 3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, 4-propenylbenzene-1-yl, 4-[2-methyl-2-(methylamino)propanol]piperazine-1-yl, 4-(divercity)piperazine-1-yl, 4-(3,3,3-tryptophanol)piperazine-1-yl, 4-isobutylpyrazine-1-yl, 4-(pyridine-2-ylcarbonyl)piperazine-1-yl, 4-(tetrahydrofuran-2-ylcarbonyl)is piperazin-1-yl, 4-[2-methyl-2-(dimethylamino)propanol]piperazine-1-yl, 4-(2,2,3,3,3-pentafluoropropanol)piperazine-1-yl, 4-(pyrrolidin-1-ylcarbonyl)piperazine-1-yl, 4-(TRIFLUOROACETYL)piperazine-1-yl, 4-(piperidine-1-yl)piperidine-1-yl, 4-(pyrrolidin-1-yl)piperidine-1-yl, 4-(hinzelin-4-yl)piperazine-1-yl, 4-(pyrimidine-2-yl)piperazine-1-yl, 8-Aza-1-Sonisphere[4,5]Decan-8-yl, 3-(3-were)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 3-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 3-[(4-pertenece)methyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 4-(3-cyano-2-yl)piperazine-1-yl, 1-methyl-8-Aza-1-Sonisphere[4,5]Decan-8-yl, 3-(3,5-differenl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 3-[(dimethylamino)methyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 3-(2-furyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 3-(pentafluoroethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 3-{[4-(trifluoromethyl)phenyl]amino}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 4-(2-methylpropyl)piperazine-1-yl, 3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 3-(1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3,-a]pyrazin-7-yl, 3-(2-thienyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 3-cyclopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-6-yl, 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-6-yl, 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-yl, 3-pyridin-3-yl-5,6,7,8-tetrahydro[1,2,4]Tr is azolo[4,3-a]pyrazin-7-yl, 7-Aza-1-Sonisphere[3,5]nonan-7-yl, 4-methyl-2,5-dioxoimidazolidin-1-yl, 3-(pyrrolidin-1-ylmethyl)azetidin-1-yl, 4-(3,3-diversecity-1-yl)piperidine-1-yl, 1-(2,2,2-triptorelin)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-yl, 4-{[1-(methylamino)cyclopentyl]carbonyl}piperazine-1-yl, 1-methyl-7-Aza-1-Sonisphere[3,5]nonan-7-yl, 8-Aza-2-Sonisphere[4,5]Decan-8-yl, 4-[(2-propylpyrrolidine-2-yl)carbonyl]piperazine-1-yl, 2-methyl-8-Aza-2-Sonisphere[4,5]Decan-8-yl, 4-(piperidine-3-ylcarbonyl)piperazine-1-yl, 4-[(1 methylpiperidin-3-yl)carbonyl]piperazine-1-yl, 4-{[1-(dimethylamino)cyclopropyl]carbonyl}piperidine-1-yl, 4-[3-(dimethylamino)propanol]piperidine-1-yl, 4-[(2-benzylpyrrolidine-2-yl)carbonyl]piperazine-1-yl, 4-(pyrrolidin-3-ylcarbonyl)piperazine-1-yl, 4-{[1-(methylamino)cyclopropyl]carbonyl}piperazine-1-yl, 4-[(2-methylaziridine-2-yl)carbonyl]piperazine-1-yl, 4-[(1-methylpyrrolidine-3-yl)carbonyl]piperidine-1-yl, 4-[2-(dimethylamino)-3,3,3-tryptophanyl]piperazine-1-yl, 4-[(2-methylpiperidin-2-yl)carbonyl]piperidine-1-yl, 4-{[1-(menthoxycarbonyl)-2-methylpiperidin-2-yl]carbonyl}piperidine-1-yl, 3-[1-(dimethylamino)-1-methylethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, 1-(2,2,2-triptorelin)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine-5-yl, 4-[(2S)-pyrrolidin-2-ylacetic]piperidine-1-yl, 1-ethyl-8-Aza-1 Sonisphere[4,5]Decan-8-yl, 1-(cyclopropylmethyl)-8-Aza-1-Sonisphere[4,5]Decan-8-yl, 4-[(1-aniline cyclopentyl)carbonyl]piperazine-1-yl, 4[(1-aminocyclopent]carbonyl}piperazine-1-yl, 4-{[1-(benzylamino)cyclopentyl]carbonyl}piperazine-1-yl, 4-({1-[(cyclopropylmethyl)amino]cyclopentyl}carbonyl)piperazine-1-yl, 4-{[1-(isobutylamino)cyclopentyl]carbonyl}piperazine-1-yl, 4-[2-(4-terbisil)prolyl]piperazine-1-yl, 4-[2-(4-methylbenzyl)prolyl]piperazine-1-yl, 4-[2(naphthylmethyl)prolyl]piperazine-1-yl and 4-(2-ethylpropyl)piperazine-1-yl.

In the embodiment, each of Raand Rbindependently represents hydrogen, methyl, phenyl, benzyl or cyclopropylmethyl.

In another embodiment, each of Raand Rbindependently represents hydrogen or C1-6-alkyl, for example methyl.

The present invention also provides compounds of formula II:

,

where

a, b, j, q, A, X, Y, R1, R2, R6, R9and R10defined above;

t is 0, 1, 2 or 3;

if t is 0, B is CH2;

if t is 1, 2 or 3, B represents CH2, NH or O;

w is 0, 1, 2 or 3;

or their pharmaceutically acceptable salts or tautomers.

In order to avoid ambiguous interpretation of A-(CR9R10)qR6can be attached to the loop containing B, at any substitutable position.

Preferred embodiments of with reference to formula II defined previously for formula I, with the necessary amendments.

In VA ante implementation of each of R 9and R10represents hydrogen.

In the embodiment, t is 3.

In the embodiment, B represents NH.

In the embodiment, w is 0.

The present invention also provides compounds of formula III:

,

where

a, b, c, d, e, f, g, h, i, j, X, Y, Z, R1, R2, R3, R4and R5defined above;

provided that

(a) if (CH2)c(CO)d(NR3)e(Z=O)f(O)g(CH2)h(NR4)iis an O-bridge, R2represents fluorine and X represents N, R5is optionally substituted cycle, selected from C6-10-aryl, 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring or a 7-15 membered unsaturated or partially saturated heterocyclic ring;

(b) if X represents N, R5not represents a C1-6-alkyl, halogen-(C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-alkoxy, halogen-(C1-6-alkoxy, C1-6-alkylaryl or optionally substituted C3-10-cycloalkyl, phenyl, naphthyl, pyridinyl, pyridine-N-oxide, indole, indole N-oxide, quinoline, quinoline-N-oxide, pyrimidinyl, pyrazinyl or pyrrolyl; and

(c) if (CH2)c(CO)d(NR3)e(Z=O)f(O)g(CH2 h(NR4)iis a CO-bridge, and X represents N, R5does not represent optionally substituted phenyl, pyridinyl, thienyl or furyl; or their pharmaceutically acceptable salts or tautomers.

The present invention also provides compounds of formula IV:

,

where

a, b, c, d, e, f, h, i, j, X, Y, Z, R1, R2, R3and R4defined above;

R5is a 4-membered saturated heterocyclic ring containing one N atom, a 5 - or 6-membered saturated or partially saturated heterocyclic ring containing one, two or three N atom and zero or one O atom, or a 7-15 membered partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of the above rings is optionally substituted by one or more groups independently selected from A-(CR9R10)qR6;

or their pharmaceutically acceptable salts or tautomers.

The present invention also provides compounds of formula V:

,

where

a, b, d, i, j, X, Y, R1, R2, R4and R5defined above; provided that

(a) if X represents N, R5not represents a C1-6-alkyl, halogen-(C1-6-Alki is, hydroxy-C1-6-alkyl, C1-6-alkoxy, halogen-(C1-6-alkoxy, C1-6-alkylaryl or optionally substituted C3-10-cycloalkyl, phenyl, naphthyl, pyridinyl, pyridine-N-oxide, indole, indole N-oxide, quinoline, quinoline-N-oxide, pyrimidinyl, pyrazinyl or pyrrolyl; and

(b) if d is 1, i is 0, and X represents N, R5does not represent optionally substituted phenyl, pyridinyl, thienyl or furyl;

or its pharmaceutically acceptable salt or tautomer.

The present invention also provides new compounds of formula VI:

,

where

a, b, c, d, e, f, h, i, j, X, Y, Z, R1, R2, R3and R4defined above;

R5is a 4-membered saturated heterocyclic ring containing one N atom, a 5 - or 6-membered saturated or partially saturated heterocyclic ring containing one, two or three N atom and zero or one O atom, or a 7-15 membered partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of the above rings is optionally substituted by one or more groups independently selected from A-(CR9R10)qR6;

or its pharmaceutically acceptable salt or tautomer.

The present invention also provides is soedineniya formula VII:

,

where

a, b, j, i, X, R1, R2and R4defined above;

R5is a 4-membered saturated heterocyclic ring containing one N atom, a 5 - or 6-membered saturated or partially saturated heterocyclic ring containing one, two or three N atom and zero or one O atom, or a 7-15 membered partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of the above rings is optionally substituted by one or more groups independently selected from A-(CR9R10)qR6; or its pharmaceutically acceptable salt or tautomer.

The present invention also provides compounds of formula VIII:

,

where

a, b, d, Y, R1and R2defined above;

C is a 4-membered saturated heterocyclic ring containing one N atom, a 5 - or 6-membered saturated or partially saturated heterocyclic ring containing one, two or three N atom and zero or one O atom, or a 7-15 membered partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;

or their pharmaceutically acceptable salts or tautomers.

The present invention also p is dostavljaet the compounds of formula IX:

,

where

a, b, d, q, j, A, R1, R2, R6, R9, R10defined above;

C is a 4-membered saturated heterocyclic ring containing one N atom, a 5 - or 6-membered saturated or partially saturated heterocyclic ring containing one, two or three N atom and zero or one O atom, or a 7-15 membered partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;

or their pharmaceutically acceptable salts or tautomers.

Preferred C group represent diazepan, piperidinyl, piperazinil, pyrrolidinyl, spirobisindane, tetrahydrobiopterin, tetrahydrothiopyran, desesperation, tetrahydropyrimidines, diazepinones, imidazolidinyl, azetidine or tetrahydroaminoacridine.

In the embodiment, provided compounds according to any one of formulas II-XI in which X represents n

In the embodiment, provided compounds according to any one of formulas II-XI, in which b is 0 or 1 and R represents fluorine.

In the embodiment, provided compounds of formula II, X and XI, w is 0 or 1.

Preferred embodiments of with reference to formula III, IV, V, VI, VII, and VIII identified previously for four the street I and II with the necessary amendments.

The present invention also includes, within its scope, the N-oxides of compounds of formula I above. In General, the N-oxides can be obtained from any available nitrogen atom. N-oxides can be obtained by traditional methods, such as the interaction of the compounds of formula I with axonom in the presence of wet alumina.

The present invention includes, within its scope, prodrugs of compounds of formula I above. In General, such prodrugs will be functional derivatives of the compounds of formula I, which are readily convertible in vivo into the required compound of formula I. Conventional methods for selecting and obtaining suitable prodrugs are described, for example, in"Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

The prodrug may be a pharmacologically inactive derivative of a biologically active substance (source drug" or "original molecule"), which require conversion in the body to release the active drug, and that have improved delivery properties compared to the parent molecule drugs. The transformation in vivo can take place, for example, the result of some metabolic process, such as chemical or enzymatic hydrolysis of carboxylic, phosphate or sulphate of ester, or when the sun is declared or oxidation sensitive functional groups.

The present invention includes, within its scope, the solvate of the compounds of formula I and their salts, for example hydrates.

Compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described inE.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190and be present as racemates, racemic mixtures and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers are included in the present invention.

Connection, first described herein may exist as tautomers and both tautomeric forms are intended for inclusion in the scope of the invention, even if only a picture of one tautomeric structure. For example, the compounds of formula I can turn into the tautomers of the compounds with the following structure:

The compounds can exist in various isomeric forms, all of which are included in the scope of the present invention.

The compounds can exist in various polymorphic forms.

When any variable (for example, R1and R2and so on) occurs more than one time in any component, its definition in each case is independent from every other case. Also, combinations of substituents and change the s are valid, only if such combinations result in stable compounds. A line drawn to cyclic systems from substituents indicate that the indicated bond may be attached to any of the ring atoms that are valid for accommodation of deputies.

It is clear that the deputies and the type of substitution in the compounds of the present invention may be selected by the expert in the field of technology to produce compounds that are chemically stable and that can be easily synthesized by methods known in the art, as well as by the methods described below, from readily available starting materials. If the Deputy is itself substituted by more than one group, it is clear that these multiple groups can be on the same carbon atom or on different carbon atoms, if the result is a stable structure. The phrase "optionally substituted" shall be considered equivalent to the phrase "unsubstituted or substituted by one or more substituents", and in such cases the preferred option implementation will have from zero to three substituents. More preferably, there are from zero to two substituents. Deputy in a saturated, partially saturated or unsaturated heterocycle may be attached at any substitutable position.

Skin is Amy herein, the term "alkyl" is intended to include both branched, lineynoye, and cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-6-alkyl" is defined as including groups having 1, 2, 3, 4, 5 or 6 carbon atoms, linear, branched or cyclic structure. For example, "C1-6-alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and so forth. Preferred alkyl groups are methyl and ethyl. The term "cycloalkyl" refers to monocyclic, bicyclic or polycyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "C3-7-cycloalkyl" includes cyclopropyl, methylcyclopropyl, 2,2-dimethylcyclobutyl, 2-ethylcyclopentane, cyclohexyl, and so forth. In the embodiment of the invention, the term "cycloalkyl" includes the groups described immediately above, and further includes a monocyclic unsaturated aliphatic hydrocarbon group. For example, "cycloalkyl", as defined in this embodiment, includes cyclopropyl, methylcyclopropyl, 2,2-dimethylcyclobutyl, 2-ethylcyclopentane, cyclohexyl, cyclopentenyl, cyclobutenyl, 7,7-dimethylbicyclo[2,2,1]heptyl, and so forth. Preferably the e cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Used here, the term "C2-6alkenyl" refers to non-aromatic hydrocarbon radical, linear or branched, containing from 2 to 6 carbon atoms and at least one carbon-carbon double bond. Preferably, there is one carbon-carbon double bond, and may be present up to four non-aromatic carbon-carbon double bonds. Alkeneamine groups include ethynyl, propenyl, butenyl and 2-methylbutanal. Preferred alkeneamine groups include ethynyl and propenyl.

Used here, the term "C2-6-quinil" refers to a hydrocarbon radical, linear or branched, containing from 2 to 6 carbon atoms and at least one carbon-carbon triple bond. Can contain up to three carbon-carbon triple bonds. Alkyline group include ethinyl, PROPYNYL, butynyl, 3-methylbutanal and so on. Preferred alkyline group include ethinyl and PROPYNYL.

"Alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. "Alkoxy", therefore, includes the definition of alkyl above. Examples of acceptable alkoxygroup include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, qi is apropiate, cyclobutylamine, cyclopentyloxy. Preferred alkoxygroup represent methoxy, ethoxy. The term "C6-10-aryloxy" can be considered similarly. Preferred examples of such groups is phenoxy.

The terms "halogen-C1-6-alkyl and halogen-(C1-6-alkoxy" refers to C1-6-alkyl or C1-6-alkoxygroup, in which one or more (in particular, 1 to 3) hydrogen atoms are replaced by halogen atoms, especially fluorine atoms or chlorine. Preferred are fluorine-C1-6-alkyl and fluoro-C1-6-alkoxygroup, in particular fluorine-C1-3-alkyl and fluoro-C1-3-alkoxygroup, for example, CF3, CHF2CH2F, CH2CH2F, CH2CHF2CH2CF3, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2or OCH2CF3and most preferably CF3, OCF3and OCHF2.

Used here, the term "hydroxy-C1-6-alkyl" refers to a group in which one or more (in particular, 1 to 3) hydrogen atoms are replaced by hydroxy-group. Preferred are CH2OH, CH2CHOH and CHOHCH3.

Used here, the term "C1-6-alkylaryl" or "C1-6-alkoxycarbonyl" represents C1-6-alkyl or C1-6-CNS radicals, respectively, attached via a carbonyl (C=O) for the al. Acceptable examples1-6-alkylcarboxylic groups include methylcarbamyl, ethylcarboxyl, propylmalonic, isopropylcarbonate and tert-butylcarbamoyl. Examples of C1-6-alkoxycarbonyl include methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. The term "C6-10-arylcarbamoyl" can be interpreted in the same way.

The cycles present in the compounds of the present invention, may be monocyclic or polycyclic, especially bicyclic. Polycyclic rings may be condensed, bridged or spirolactone.

Used here, the term "C6-10aryl" is intended to designate any stable monocyclic or bicyclic carbon cycle, having from 6 to 10 atoms, where at least one cycle is aromatic. Examples of such aryl fragments include phenyl, naphthyl, tetrahydronaphthyl, indanyl, tetrahydrobenzo[7]annulen. The preferred aryl group is a phenyl or naphthyl, especially phenyl.

7-15-membered heterocycles include 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14 - and 15-membered heterocycles.

Examples of preferred compounds of the present invention are benzimidazolyl, benzofuranyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzotriazolyl, benzothiazyl, isoxazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzodioxolyl, benzoxadiazole, benzisoxazole, benzisothiazole, bromanil, bromanil, isopropanol, carbazolyl, carbolines, cinnoline, epoxides, furyl, furutani, imidazolyl, indolinyl, indolyl, indolizinyl, indolinyl, isoindolyl, indazoles, isobenzofuranyl, isoindolyl, ethanolic, isothiazolin, isoxazolyl, naphthyridine, oxadiazole, oxazole, oxazoline, isoxazoline, oxetanyl, purinol, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyrimidines, pyridazinyl, pyridinyl, pyrimidinyl, triazinyl, tetrazines, pyrrolyl, hintline, chinoline, honokalani, hemolysins, tetrahydropyranyl, tetrahydropyranyl, tetrahydroisoquinoline, tetrazolyl, tetrasulphides, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidine, 1,4-dioxane, hexahydroazepin, piperazinil, piperidyl, pyridine-2-IMT, pyrrolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrrolyl, morpholinyl, thiomorpholine, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydroisoxazole, dihydrofurane, dihydroimidazole, dihydroindole, dihydroisoxazole, dihydroisoxazole, dihydroimidazole, dihydrooxazolo, dihydropyrazine, dihydropyrazolo, dihydropyridines, dihydropyrimidines, dihydropyrrole, dihydroquinoline, dihydro shall thinline, dihydrotetrazolo, dihydrothiazolo, dihydrothiazolo, dehydration, dihydrotriazine, dihydroisocodeine, dihydroisocoumarin, dihydrobromide, dihydroimidazole, dihydrotriazine, dihydroergotoxine, dihydroisocodeine, dihydroimidazolium, methylenedioxybenzyl, tetrahydrofuranyl, tetrahydrothieno, tetrahydroquinoline, thiazolidinones, imidazolyl, isoindolyl, octahydrophenanthrene, activitiesunder, imidazopyridines, azabicycloalkanes, chromanones, triazolopyrimidines, dihydroisoxazole, thiazoleethanol, azoniabicyclo, azoniabicyclo, phthalazine, naphthyridine, hintline, pteridinyl, dihydroquinazolines, dihydrophenazine, benzisoxazole, tetrahydronaphthalene, dibenzo[b,d]furanyl, dihydrobenzofuranyl, imidazothiazoles, tetrahydroindazole, tetrahydrobenzene, hexahydropyridine, tetrahydroaminoacridine, tetrahydrobiopterin, pyrrolopyridine, diazepan and their N-oxides. Additional examples include spirobisindane, tetrahydrothiopyran, desesperation, tetrahydropyrimidines, diazepinones and tetrahydroaminoacridine.

Preferred 4-membered saturated the heterocycle is azetidine. Join heterocyclic substituent may be the future place via a carbon atom or through a heteroatom.

Preferred 5-, 6 - or 7-membered saturated or partially saturated heterocycles are pyrrolidine, piperidinyl, piperazinil, morpholinyl, tetrahydrofuran, thiomorpholine and diazepamin. The preferred cycle is imidazolidinyl.

Preferred 5-membered heteroaromatic rings are thienyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolin, imidazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, furyl and pyrrolyl.

Preferred 6-membered heteroaromatics cycles are pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.

Preferred 7-10-membered partially saturated or unsaturated heterocyclic rings are tetrahydroquinoline, chinoline, indolyl, imidazopyridines, benzothiazolyl, honokalani, benzothiadiazoles, benzoxazolyl, dihydroergotoxine, benzotriazolyl, benzodioxolyl, dihydroisoquinolyl, dihydroindole, tetrahydroisoquinoline, ethenolysis, benzothiazolyl, dihydroimidazolium, benzothiazyl, benzoxadiazole, thiazoleethanol, dihydroisocodeine, dihydroisoxazole, dihydrobenzofuranyl, benzimidazolyl, benzofuranyl, dihydroisoxazole, dihydroquinazolines, dihydrophenazine, indazoles, benzisoxazole, tetrahydronaphthalene, triazolopyrimidines, Deeb is the site, located between[b,d]furanyl, naphthyridines, dihydroquinoline, dihydroisocoumarin, dihydrobromide, dihydrobenzofuran, imidazothiazoles, tetrahydroindazole, tetrahydrobenzene, hexahydropyridine, tetrahydroaminoacridine, tetrahydrobiopterin, pyrrolopyridine, hintline and indolizinyl. Additional 7-15 membered unsaturated, partially saturated or saturated heterocyclic rings include spirobisindane, tetrahydrothiopyran, desesperation, tetrahydropyrimidines, diazepinones and tetrahydroaminoacridine.

Used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.

Preferred compounds within the scope of the present invention are

triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s;

triptorelin 4-{5-[(4-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s;

6-{3-[(4-acetyl-1,4-diazepan-1-yl)carbonyl]-4-terbisil}-4-ethylpyridine-3(2H)-he;

1-acetyl-4-{5-[(6-chloro-4-ethylpyridine-3-yl)methyl]-2-perbenzoic}-1,4-diazepan;

and their pharmaceutically acceptable salts, free bases and tautomers.

Especially preferred compounds within the scope of the present invention are

4-ethyl-6-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)pyridazin-3(2H)-he;

triptorelin 4-{5-[(5-ethyl-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s;

triptorelin 4-{5-[(4-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s;

triptorelin 4-{2-fluoro-5-[(5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzoyl}-1,4-diazepan-1-s;

triptorelin 4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s;

triptorelin 1-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-N,2-dimethyl-1-oxopropyl-2-ammonium;

triptorelin 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-8-Aza-1-Sonisphere[4,5]decane;

bis(triptorelin) 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-2-s-3-yl)methyl]-2-perbenzoic}-1-methyl-8-Aza-1-Sonisphere[4,5]decane;

triptorelin 4-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-N,N-dimethyl-2-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}of benzolamide;

triptorelin 6-(4-isopropoxy-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;

6-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4,5-dimethylpyridin-3(2H)-he;

6-(4-fluoro-3-{[4-(2-methylpropyl)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethylpyridin-3(2H)-he;

triptorelin 6-[4-fluoro-3-(4-methyl-2,5-dioxoimidazolidin-1-yl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;

triptorelin 6-(3-{[3-[1-(dimethylamino)-1-methylethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}-4-terbisil)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;

triptorelin (2R)-2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-methylaziridine;

triptorelin 6-{4-fluoro-3-[(4-{[1-(isobutylamino)cyclopentyl] carbonyl}piperazine-1-yl)carbonyl]benzyl}-4,5-dimethylpyridin-3(2H)-he;

triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-yl)pyrimidine-1-s;

triptorelin 4-(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)pyridinium;

triptorelin 2-{[(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)oxy]methyl}pyridinium;

triptorelin 2-{[(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-3-yl)oxy]methyl}pyridinium;

triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-5-methoxypyridine;

triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-4-methoxypyridine;

Triforce is at 4-(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}pyrrolidin-3-yl)pyridinium;

triptorelin 1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-3-yl)-N,N-dimethylethanamine;

4-ethyl-6-[4-fluoro-3-(1'Η-Spiro[1-benzofuran-3,4'-piperidine]-1'-ylcarbonyl)benzyl]pyridazin-3(2H)-he;

triptorelin 1-[2-(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)ethyl]-1H-pyrazole-2-s;

triptorelin 5-chloro-2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)pyridinium;

triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-6-methoxypyridine;

triptorelin 3-benzyl-7-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-1-s;

triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-3,6-dimethylpyrazine-1-s;

triptorelin 4-ethyl-6-{4-fluoro-3-[(3-phenyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)carbonyl]benzyl}-3-oxo-2,3-dihydropyridin-1-s;

triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1-(3-methoxybenzyl)piperazine-1-s;

triptorelin 2-(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)-1,2,3,4-tetrahydroisoquinoline;

triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-s;

triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-yl)methyl]-2-perbenzoic}-3-phenylpiperazin-1-s;

triptorelin 3-benzyl-4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-s;

bis(triptorelin) 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-2-(pyridine-3-ylmethyl)piperazine-1-s;

6-(3-{[4-(cyclopentanecarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-terbisil)-4,5-dimethylpyridin-3(2H)-he;

6-(3-{[4-(cyclopentanecarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-terbisil)-4-ethylpyridine-3(2H)-he;

triptorelin 4-{5-[(4,5-diethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s;

triptorelin 4-{2-fluoro-5-[(5-isopropyl-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzoyl}-1,4-diazepan-1-s;

triptorelin 4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-s;

6-{4-fluoro-3-[(4-propenylbenzene-1-yl)carbonyl]benzyl}-4,5-dimethylpyridin-3(2H)-he;

6-(3-{[4-(divercity)piperazine-1-yl]carbonyl}-4-terbisil)-4,5-dimethylpyridin-3(2H)-he;

6-(4-fluoro-3-{[4-(3,3,3-tryptophanol)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethylpyridin-3(2H)-he;

triptorelin 6-{4-fluoro-3-[(4-isobutylpyrazine-1-yl)carbonyl]benzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;

triptorelin 2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]pyridinium;

6-(4-fluoro-3-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethylpyridine is -3(2H)-he;

triptorelin 1-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-N,N,2-trimethyl-1-oxoprop-2-ammonium;

triptorelin 6-(4-fluoro-3-{[4-(2,2,3,3,3-pentafluoropropanol)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;

triptorelin 6-(4-fluoro-3-{[4-(pyrrolidin-1-ylcarbonyl)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;

triptorelin 6-(4-fluoro-3-{[4-(TRIFLUOROACETYL)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;

triptorelin 1-(1-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)piperidine;

triptorelin 1-(1-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)pyrrolidine;

triptorelin 4-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)hinzelin-1-s;

triptorelin 2-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)pyrimidine-1-s;

bis(triptorelin) 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(3-were)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1,4-die;

triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;

triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-Digi copyrightin-3-yl)methyl]-2-perbenzoic}-3-[(4-pertenece)methyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-2-s;

triptorelin 3-cyano-2-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)pyridinium;

triptorelin 3-(3,5-differenl)-7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;

bis(triptorelin) 3-[(dimethylammonio)methyl]-7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-2-s;

triptorelin (7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-N,N-dimethylethanamine;

triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(2-furyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;

triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(pentafluoroethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;

triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-{[4-(trifluoromethyl)phenyl]amino}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;

chloride 2-[(4-{2-fluoro-5-[(6-hydroxy-4,5-dimethylpyridin-3-yl)methyl]benzoyl}piperazine-1-yl)carbonyl]-2-methylpyrrolidine;

triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;

triptorelin 3-(1,3-benzodioxol-5-yl)-7-{5-(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;

triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(2-thienyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;

triptorelin 3-cyclopropyl-6-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-2-s;

triptorelin 6-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-2-s;

triptorelin 5-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-2-s;

bis(triptorelin) 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-pyridine-3-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-2-s;

triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-7-Aza-1-Sonisphere[3,5]nonane;

triptorelin 1-[(1-{3-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}azetidin-3-yl)methyl]pyrrolidine;

triptorelin 1-(1-{3-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)-3,3-diversative;

triptorelin 5-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1-(2,2,2-triptorelin)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-3-s;

triptorelin 1-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-the l)carbonyl]-N-methylcyclopentanone;

triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1-methyl-7-Aza-1-Sonisphere[3,5]nonane;

triptorelin 6-(4-methoxy-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;

triptorelin 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-8-Aza-2-Sonisphere[4,5]decane;

triptorelin 2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-propylpyrrolidine;

triptorelin 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-2-methyl-8-Aza-2-Sonisphere[4,5]decane;

triptorelin 3-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]piperidine;

triptorelin 3-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-1-methylpiperidine;

triptorelin 1-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-N,N-dimethylcyclopropane;

triptorelin 3-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-N,N-dimethyl-3-oxoprop-1-ammonium;

triptorelin 2-benzyl-2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]pyrrolidine;

triptorelin 4,5-di is ethyl-6-(3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)pyridazin-3(2H)-he;

triptorelin 6-[3-(1,8-diazaspiro[4,5]Dec-8-ylcarbonyl)-4-terbisil]-4-ethyl-3-oxo-2,3-dihydropyridin-1-s;

triptorelin 3-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]pyrrolidine;

triptorelin 1-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-N-methylcyclopropane;

triptorelin 3-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-1-methylpyrrolidine;

triptorelin 3-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-1,1,1-Cryptor-N,N-dimethyl-3-oxoprop-2-amine;

triptorelin 2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-methylpiperidine;

benzyl 2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-methylpiperidin-1-carboxylate;

4-ethyl-6-(4-fluoro-3-{[1-(2,2,2-triptorelin)-1,4,6,7-tetrahydro-5h-[1,2,3]triazolo[4,5-c]pyridine-5-yl]carbonyl}benzyl)pyridazin-3(2H)-he;

triptorelin 4-ethyl-6-{4-fluoro-3-[(1-methyl-1,8-diazaspiro[4,5]Dec-8-yl)carbonyl]benzyl}-3-oxo-2,3-dihydropyridin-1-s;

triptorelin (2S)-2-[2-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-2-oxoethyl]pyrrolidine;

triptorelin 8-{5-[(4,5-dimethyl-6-oxo-1,6-digit pyridazin-3-yl)methyl]-2-perbenzoic}-1-ethyl-8-Aza-1-Sonisphere[4,5]decane;

triptorelin 1-(cyclopropylmethyl)-8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-8-Aza-1-Sonisphere[4,5]decane;

6-[3-({4-[(1-onlinestromectol)carbonyl]piperazine-1-yl}carbonyl)-4-terbisil]-4,5-dimethylpyridin-3(2H)-he;

6-[3-({4-[(1-aminocyclopent)carbonyl]piperazine-1-yl}carbonyl)-4-terbisil]-4,5-dimethylpyridin-3(2H)-he;

triptorelin 6-{3-[(4-{[1-(benzylamino)cyclopentyl]carbonyl}piperazine-1-yl)carbonyl]-4-terbisil}-4,5-dimethylpyridin-3(2H)-he;

triptorelin 6-(3-{[4-({1-[(cyclopropylmethyl)amino]cyclopentyl}carbonyl)piperazine-1-yl]carbonyl}-4-terbisil)-4,5-dimethylpyridin-3(2H)-he;

triptorelin 6-[4-fluoro-3-({4-[2-(4-terbisil)prolyl]piperazine-1-yl}carbonyl)benzyl]-4,5-dimethylpyridin-3(2H)-he;

triptorelin 6-[4-fluoro-3-({4-[2-(4-methylbenzyl)prolyl]piperazine-1-yl}carbonyl)benzyl]-4,5-dimethylpyridin-3(2H)-he;

triptorelin 6-[4-fluoro-3-({4-[2-(1-naphthylmethyl)prolyl]piperazine-1-yl}carbonyl)benzyl]-4,5-dimethylpyridin-3(2H)-he;

triptorelin 6-(3-{[4-(2-ethylpropyl)piperazine-1-yl]carbonyl}-4-terbisil)-4,5-dimethylpyridin-3(2H)-he;

and their pharmaceutically acceptable salts, free bases and tautomers.

In the present invention includes compounds of formula I in the form of free bases, as well as their pharmaceutically acceptable salts and stereoisomers. Compounds of the present invention can be PR is tinted on the atom(s) of the amine nitrogen and/or containing the nitrogen atom of the heterocyclic fragment with the formation of salts. The term "free base" refers to amine compounds in mesolevel form. Included pharmaceutically acceptable salt not only include a salt represented by the examples described herein of specific compounds, but also all the typical pharmaceutically acceptable salts of the free forms of the compounds of formula I. freeform specific salts of the above compounds can be separated using techniques known in the art. For example, the free form may be regenerated by treating the salt with a suitable dilute aqueous solution of a base, such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. Available forms may to some extent differ from their respective salt forms in certain physical properties such as solubility in polar solvents, but the salts of joining acids and bases are pharmaceutically equivalent to their respective free forms for the purposes of the invention.

Pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from the compounds of the present invention, which contain a basic or acidic fragment, traditional chemical methods. In General, salts of the basic compounds are prepared, or by ion-exchange chromatography or by reaction freedoms is wow Foundation with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, salts of acidic compounds are prepared by reaction with an appropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention, as formed by the reaction of the compound of the present invention with inorganic, organic or polymeric acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, Hydrobromic, uudistoodetena, sulfur, sulfuric, sulfamic, phosphoric, phosphorous, nitrogen and the like, and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, Panova, maleic, hydroxymaleimide, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonate, methanesulfonate, ethicality, oxalic acid, sotynova, palmitic, gluconic, ascorbic, phenylacetic acid, aspartic, cinnamic acid, pyruvic acid, econsultancy, ethicality, Valerian, triperoxonane and the like. Examples of suitable polymeric salts include those that produced the from polymeric acids, such as tannic acid, carboxymethyl cellulose. Preferably, the pharmaceutically acceptable salt of the present invention contains 1 equivalent of the compound of formula (I) and 1, 2 or 3 equivalents of an inorganic or organic acid. More preferably, the pharmaceutically acceptable salt of the present invention are trifenatate or chloride salts, especially trifenatate salt.

When the compound of the present invention is acidic, the term suitable "pharmaceutically acceptable salts" refers to salts derived from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, salts of trivalent manganese, divalent manganese, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and anionic ion-exchange resin, such the AK arginine, lysine, betaine caffeine, kalinovye, N,N1-dibenzylethylenediamine, ethylamine, diethylamine, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, diethanolamine, ethylendiamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, his-tag, geranamine, Isopropylamine, lysine, methylglucamine, morpholine, pieperazinove, piperidine, polianinova resin, procainamide, purine, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine, dicyclohexylamine, butylamine, benzylamine, phenylbenzimidazole, tromethamine and the like.

Getting pharmaceutically acceptable salts described above, and other typical pharmaceutically acceptable salts is more fully described inBerg et al. (1977) J. Pharm. Sci., "Pharmaceutical Salts", 66:1-19.

It may also be noted that the compounds of the present invention are potentially internal salts or zwitterions, as in physiological conditions deprotonirovannym acid fragment in the connection, such as a carboxyl group may be anionic, and this electrical charge can then inside the molecule to balance the cationic charge of the protonated or alkylated main fragment, such as a Quaternary nitrogen atom.

Connection to izopet the tion can be applied in the method of treatment of a human or animal with the help of drug therapy.

The invention provides compounds for use for the treatment and prevention of conditions that can be improved by inhibition of poly(ADP-ribose)polymerase (PARP) (see, for example,Nature Review Drug Discovery (2005) 4:421-440).

Thus, the present invention provides a compound of formula I used in the making of a medicinal product for the treatment or prevention of conditions that can be improved by inhibition of poly(ADP-ribose)polymerase (PARP).

The present invention also provides a method of treatment or prevention of conditions that can be improved by inhibition of poly(ADP-ribose)polymerase (PARP), where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

The PARP inhibitors of the present invention can be applied to treatment of diseases defined in WO 2005/082368.

Compounds according to the invention can be applied to treatinflammatory diseases, including conditions resulting from rejection of the transplant organ, such as chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased resorption to the tee; inflammatory bowel diseases, such as ility, ulcerative colitis, Barrett syndrome and Crohn's disease; inflammatory lung diseases such as asthma, respiratory distress in adults and chronic obstructive pulmonary syndrome; inflammatory diseases of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic inflammation of the eyes and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidneys, including complications in the kidneys, glomerulonephritis and nephrosis; inflammatory diseases of the skin, including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the Central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, due to AIDS degeneration of the nervous tissue and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; complications of diabetes, including, without limitation, immune complex vasculitis, systemic lupus erythematosus (SLE); inflammatory diseases of the heart, such as cardiomyopathy, ischemic heart disease, hypercholesterolemia, and atherosclerosis; as well as various other diseases that the cat is who can have significant components of inflammation, including preeclampsia, chronic liver failure, brain injury and spinal cord syndrome and multiple organ dysfunction (MODS) (multiple failure of authorities (MOF)). The inflammatory disease may also be a systemic inflammation of the body, presents examples of gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock caused by cancer chemotherapy in response to Pro-inflammatory cytokines, e.g., shock associated with Pro-inflammatory cytokines. Such a shock may be caused, for example, chemotherapeutic drug, which is administered to treat cancer.

Thus, the present invention provides a compound of formula I, intended for the preparation of drugs for treating or preventing inflammatory diseases.

The present invention also provides a method of treating or preventing inflammatory diseases, where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

Compounds of the present invention can also be applied for treating or preventingreperfusion injuryobtained from naturally occur is odasi episodes and for surgical interventions, such as intestinal reperfusion injury; myocardial reperfusion injury; reperfusion injury in heart surgery under extracorporeal circulation surgery on an aneurysm in the aorta, surgical endarterectomy for carotid artery or hemorrhagic shock; and damage during recovery of oxygen saturation obtained by transplantation of organs such as heart, lung, liver, kidney, pancreas, intestine and the cornea.

Thus, the present invention provides a compound of formula I, intended for the preparation of drugs for treating or preventing reperfusion injury.

The present invention also provides a method of treating or preventing reperfusion injury, where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

Compounds of the present invention can also be applied in the treatment and prevention ofischemic conditionsincluding those obtained by transplantation of an organ, such as stable angina, unstable angina, myocardial ischemia, hepatic ischemia, mesenteric artery ischemia, intestinal ischemia, critical ischemia horse is ness, chronic critical limb ischemia, cerebral ischemia, acute cardiac ischemia, ischemic kidney disease, ischemic liver disease, ischemic disorders of the retina, septic shock and ischemic disease of the Central nervous system such as stroke or cerebral ischemia.

Thus, the present invention provides a compound of formula I, intended for the preparation of drugs for treating or preventing ischemic conditions.

The present invention also provides a method of treating or preventing ischemic conditions, where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

The present invention provides a compound of formula I used in the making of a medicinal product for the treatment or prevention of stroke.

The present invention also provides a method of treating or preventing stroke, where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

Compounds of the present invention can also be applied for treating or preventingchronic or acute renal defects in the exactly .

Thus, the present invention provides a compound of formula I, intended for the preparation of drugs for treating or preventing renal failure.

The present invention also provides a method of treating or preventing renal failure, where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

Compounds of the present invention can also be applied for treating or preventingvascular diseases other than cardiovascular diseasessuch as peripheral occlusal lesion artery, obliterating thrombovascular, disease and syndrome Raynaud, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema, lipedema.

Thus, the present invention provides a compound of formula I, intended for the preparation of drugs for treating or preventing vascular diseases other than cardiovascular diseases.

The present invention also provides a method of treating or preventing vascular diseases other than cardiovascular diseases, where the method comprises the administration to a patient in need so the m treatment effective amounts of compounds of formula I or a composition comprising the compound of formula I.

Compounds of the present invention can also be applied for treating or preventingcardiovascular diseasessuch as chronic heart failure, atherosclerosis, congestive heart failure, circulatory shock, cardiomyopathy, heart transplantation, myocardial infarction and cardiac arrhythmia, such as atrial fibrillation, supraventricular tachycardia, atrial flutter and paroxysmal supraventricular tachycardia.

Thus, the present invention provides a compound of formula I, intended for the preparation of drugs for treating or preventing cardiovascular diseases.

The present invention also provides a method of treating or preventing cardiovascular disease, where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

Compounds of the present invention can also be applied to treatment and preventiondiabetesincluding diabetes type I (insulin-dependent diabetes mellitus), type II diabetes (independent from insulin diabetes), diabetes in pregnancy, out the immune diabetes, insulinopenia, diabetes, caused by disease of the pancreas, diabetes associated with other endocrine diseases (such as Cushing's syndrome, acromegaly, chromafenozide, glucagonoma, primary aldosteronism or somatostatinoma), the syndrome of resistance to insulin type A syndrome of resistance to insulin type B, lipotropics diabetes and diabetes caused by 3-cell toxins. Compounds of the present invention can also be applied for the treatment or prevention of the complications of diabetes, such as diabetic cataract, glaucoma, retinopathy, nephropathy (such as microalbuminuria and progressive diabetic nephropathy), polyneuropathy, gangrene of the feet, atherosclerotic coronary artery disease peripheral artery disease, nemetona hyperglycemic-hyperosmotic coma, mononeuropathy, autonomic neuropathy, leg ulcers, joint diseases and complications on the skin or mucous membranes (such as infection, spots on legs, candidal infection or local lipoid necrosis in diabetic obesity, hyperlipidemia, hypertension, syndrome sustainability to insulin, coronary artery disease, retinopathy, diabetic neuropathy, polyneuropathy, mononeuropathy, autonomic neuropathy, foot ulcer, a disease of a joint, fungal infection, bacterial infections the Oia and cardiomyopathy.

Thus, the present invention provides a compound of formula I used in the making of a medicinal product for the treatment or prevention of diabetes.

The present invention also provides a method of treating or preventing diabetes, where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

Compounds of the present invention can also be applied for treating or preventingcancerincluding solid tumors such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angioplasticheskih sarcoma, ehotelier.com, lymphangiosarcoma, lymphangiosarcoma, sinovioma, mesothelioma, Ewing's sarcoma, leimyosarcoma, rhabdomyosarcoma, a cancer of the colon, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, cancer of the nasal cavity, larynx cancer, this form may cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, carcinoma of the sebaceous glands, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, carcinoma of the brain, bronchogenic carcinoma, pochernkletocny carcinoma, g is Paloma, carcinoma of the bile ducts, horiokartsinoma, spermatocyte, embryonal carcinoma, Wilms ' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, lung carcinoma, bladder carcinoma, epithelial carcinoma, skin cancer, melanoma, neuroblastoma, and retinoblastoma; blood cancers such as acute lymphoblastic leukemia ("ALL"), acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia ("AML"), acute promyelocytic leukemia ("APL"), acute monolistra leukemia, acute erythroleukemia leukemia sharp megakaryoblastic leukemia, acute myelomonocytic leukemia, acute limfocitna leukemia, acute undifferentiated leukemia, chronic malacitana leukemia ("CML"), chronic lymphocytic leukemia ("CLL"), Volokolamskaya leukemia and multiple myeloma; acute and chronic leukemias, such as lymphoblastic, myelogenous, lymphocytic, malacitana leukemia; lymphomas such as Hodgkin's disease, non-jackinsky lymphoma, multiple myeloma, macroglobulinemia Waldenstrom, heavy chain disease, and polycythemia of Wakasa-Osler; cancer of the Central nervous system and brain cancer, such as glioma, polodna astrocytoma, astrocytoma, anaplastic astrocytoma multiple glioblastoma, medulloblastoma, craniopharyngioma, apandi the social glioma, adenoma of the pineal body, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, vestibular Sanoma, adenoma, metastatic brain tumor, meningioma, spirulina tumor and medulloblastoma.

Thus, the present invention provides a compound of formula I, intended for the preparation of drugs for treating or preventing cancer.

The present invention also provides a method of treating or preventing cancer, where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

Compounds of the present invention can also be used for treatment of cancer which is deficient in respect of dependent homologous recombination (HR) Repartee activity against double-strand break DNA (see WO 2006/021801).

Dependent on HR Reparata function in relation to the double-strand break DNA restores double strand breaks (DSB) in DNA through homologous mechanisms for continuous recovery of the DNA helix (Nat. Genet. (2001) 27(3):247-254). Components dependent on HR Repartee activity against double-strand break DNA include, without limitation, ATM (NM-000051), RAD51 (NM-002875), RAD51 L1 (NM-002877), RAD51C (NM-002876), RAD51L3 (NM-002878), DMCl (NM-007068), XRCC2 (NM7005431), XRCC3 (NM-005432), RAD52 (NM-02879), RAD54L (NM-003579), RAD54B (NM-012415), BRCA-1 (NM-007295), BRCA-2 (NM-000059), RAD50 (NM-005732), MREI 1A (NM-005590), NBSI (NM-002485), ADPRT (PARP-1), ADPRTL2 (PARP-2), CTPS, RPA, RPA1, RPA2, RPA3, XPD, ERCC1, XPF, MMS19, RAD51p, RAD51D, DMC1, XRCCR, RAD50, MRE11, NB51, WRN, BLMKU70, RU80, ATRCHKl, CHK2, FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, RAD1 and RAD9. Other proteins involved in dependent HR Repartee activity against double-strand break DNA include regulatory factors, such as EMSY (Cell (2003) 115:523-535).

Cancer which is deficient in respect of dependent HR Repartee activity against double-strand break DNA, may include or consist of one or more cancer cells that have reduced or disabled compared with normal cells ability to repair double-strand DNA breaks in this way, the activity-dependent HR Repartee activity against double-strand break DNA can be reduced or disabled in one or more cancer cells.

The activity of one or more components is dependent on HR Repartee activity against double-strand break DNA can be disabled in one or more cancer cells of the individual having a cancer which is deficient in relation dependent on HR's ability to repair double-strand DNA breaks. Components dependent on HR Repartee system for double-strand break DNA is well characterized is in the prior art (see, for example,Science (2001) 291:1284-1289and include the components listed above.

The present invention provides a compound of formula I, intended for the preparation of drugs for treating or preventing cancer which is deficient in respect of dependent HR Repartee activity against double-strand break DNA.

The present invention also provides a method of treating or preventing cancer which is deficient in respect of dependent HR Repartee activity against double-strand break DNA, where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

In the embodiment, the cancer cells are deficient in dependent HR Repartee activity against double-strand break DNA for one or more phenotypes selected from ATM (NM-000051), RAD51 (NM-002875), RAD51 L1 (NM-002877), RAD51C (NM-002876), RAD51L3 (NM-002878), DMCl (NM-007068), XRCC2 (NM7005431), XRCC3 (NM-005432), RAD52 (NM-002879), RAD54L (NM-003579), RAD54B (NM-012415), BRCA-1 (NM-007295), BRCA-2 (NM-000059), RAD50 (NM-005732), MREI 1A (NM-005590), NBSl (NM-002485), ADPRT (PARP-1), ADPRTL2 (PARP-2), CTPS, RPA, RPA1, RPA2, RPA3, XPD, ERCC1, XPF, MMS19, RAD51p, RAD51D, DMC1, XRCCR, RAD50, MRE11, NB51, WRN, BLMKU70, RU80, ATRCHK1, CHK2, FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, RAD1 and RAD9.

In another embodiment, the cancer cells have BRCAl and/or BRCA2 deficient phenotype. R is the lateral cells with this phenotype may be scarce in relation to BRCA1 and/or BRCA2, that is, the expression and/or activity of the BRCA1 and/or BRCA2 may be reduced or turned off in cancer cells, for example, by mutation or polymorphism in the coding nucleic acid, or by means of amplification, mutation or polymorphism in a gene encoding a regulatory factor, such as EMSY gene, which encodes a regulatory factor BRCA2 (Cell (2003) 115:523-535).

BRCA-1 and BRCA-2 are known tumor suppressors whose alleles nematanthus type frequently lost in tumors heterozygous carriers (Oncogene, (2002) 21(58):8981-93; Trends Mol Med., (2002) 8(12):571-6). The relationship BRCA-1 and/or BRCA-2 mutations with breast cancer was characterized by good (Exp. Clin. Cancer Res., (2002) 21 (S Suppl):9-12). Amplification of EMSY gene, which encodes a BRCA-2-binding factor, as it is known, is associated with breast cancer and ovarian cancer. Carriers of mutations in BRCA-1 and/or BRCA-2 are also at an increased risk of cancer of the ovary, prostate and pancreas. Determining variations in BRCA-1 and BRCA-2 is well known in the technical field and are described, for example, in EP 699754, EP 705903,Genet. Test (1992) 1:75-83; Cancer Res Treat (2002) 107:29-59; Neoplasm (2003) 50(4):246-50; Ceska Gynekol (2003) 68(1): 11-16). The definition of amplification BRCA-2-binding factor EMSY described inCell 115:523-535. PARP inhibitors, as has been shown, can be applied to specific killing BRCA-1 and BRCA-2 deficient tumors (Nature (2005) 434:913-916 and 917-920)./p>

Thus, the present invention provides a compound of formula I used in the making of a medicinal product for the treatment or prevention of BRCA-1 or BRCA-2 deficient tumors.

The present invention also provides a method of treating or preventing BRCA-1 or BRCA-2 deficient tumors, where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

In the embodiment, the PARP inhibitors of the present invention can be applied as a preventive therapy for removal of BRCA2-deficient cells (seeCancer Res. (2005) 65: 10145).

Compounds of the present invention can be applied for the treatment or preventionneurodegenerative diseasesincluding indirect polyglutamine growth degeneration of nervous tissue, horey of Huntington's disease, Kennedy disease, spinocerebellar ataxia, dentatorubral and pallidoluysian atrophy (DRPLA) - mediated protein aggregation degeneration of nervous tissue disease Machado-Joseph disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spongy encephalopathy, prion disease and multiple sclerosis (MS).

Thus, the present invention provides a compound of formula I, is the second for the preparation of drugs for treatment or prevention of neurodegenerative diseases.

The present invention also provides a method for the treatment or prevention of neurodegenerative diseases, where the method comprises the administration to a patient in need of such treatment, an effective amount of the compounds of formula I or a composition comprising the compound of formula I.

Compounds of the present invention can also be applied for treating or preventing retroviral infection (U.S. patent 5652260), retinal damage (Curr. Eye Res. (2004), 29:403), aging and induced by ultraviolet light damage to the skin (U.S. patent 5589483 andBiochem. Pharmacol (2002) 63:921).

Compounds according to the invention can be applied for the treatment or prevention of premature aging and delay the beginning of age-related cellular dysfunction (Pharmacological Research (2005) 52:93-99).

According to standard pharmaceutical practice the compounds of the present invention can be introduced mammal, preferably human, or separately, or in combination with pharmaceutically acceptable carriers, excipients, diluents, adjuvants, fillers, buffers, stabilisers, preservatives, lubricants, pharmaceutical compositions.

Compounds of the present invention can be administered to the individual in any convenient way of introduction, or systemically/perifericheskie, or in place of the desired action, the key, without limitation, oral (e.g. by ingestion); local (including, for example, percutaneous, intranasal, eyes, cheek, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, for example, aerosol, e.g. through mouth or nose); rectal; vaginal; parenteral (e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, vnutrispinalnaya, intracapsular, subcapsular, ocular, intraperitoneal, vnutritraheinogo, Podkolokolny, intraarticular, subarachnoid, and intrasternal); and by implantation depot (for example, subcutaneously or intramuscularly).

An individual may represent a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a Guinea pig, hamster, rat, mouse), belonging to the family of murine (e.g. a mouse), related to canids (e.g., dog), belonging to the family feline (e.g. a cat), belonging to the family equine (e.g. a horse), belonging to the family of primates belonging to the family of monkeys (e.g., a monkey or APE), a monkey (e.g., marmoset, baboon), anthropoid APE (e.g., gorilla, chimpanzee, orangutan, Gibbon), or a man.

The invention also provides pharmaceutical compositions comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example in the form of tablets, lozenges, pellets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use can be obtained by any method known in the field of machinery for the production of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and acceptable organoleptic properties of the product. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets. These fillers can represent, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and dezintegriruetsja agents, for example, mikroC istoricheskoe cellulose, sodium crosscarmellose, corn starch or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or the Arabian gum, and lubricating agents, for example magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of drugs, or to delay disintegration and absorption in the gastrointestinal tract and thereby provide prolonged action over a longer period. For example, can be used water-soluble masking the taste of a substance, such as hypromellose or hydroxypropylcellulose, or substance, delaying the commencement of the action, such as ethylcellulose, acetylbutyrate pulp.

Compositions for oral administration can also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or white clay, or as soft gelatin capsules where the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active substance in MESI with fillers, suitable for the production of aqueous suspensions. Such fillers are suspendresume agents, for example sodium carboxymethylcellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum Arabic; dispersing or wetting agents may be a phospholipids of natural origin, for example lecithin, or condensation products of accelerated with fatty acids, such as polyoxyethylenesorbitan, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and exit, such as monooleate of polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of exit for example monooleate polyethylenimine. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl para-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more podcastalley, such as sucrose, saccharin or aspartame.

Oil suspensions can be formulated by active suspension to mponent in vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Podcastalley, such as those indicated above, and flavoring agents may be added to provide acceptable organoleptic properties of oral medication. These compositions may be preserved by adding an antioxidant such as bottled hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for receiving the aqueous suspension by the addition of water provide the active ingredient in a mixture with dispersing or wetting agent, suspenders agent and one or more preservatives. Suitable dispersing or wetting agents and suspendresume agents presents examples as those mentioned above. Additional excipients, for example sweetening, gives taste and coloring agents may also be present. These compositions may be preserved by adding an antioxidant such as ascorbic acid.

The pharmaceutical compositions according to the invention may also be present in the form of emulsions of oil-in-water. The oil phase may represent particularly the vegetable oil, for example olive oil or peanut oil, or mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers agents can represent phospholipids of natural origin, such as soybean lecithin, and esters or partial esters derived from fatty acids and anhydrides of exit, such as monooleate sorbitol, and the condensation products mentioned partial esters with ethylene oxide, such as monooleate of polyoxyethylenesorbitan. The emulsion may also contain sweeteners, flavouring agents, preservatives and antioxidants.

Syrups and elixirs may be retseptoriani with sweeteners, such as glycerin, propylene glycol, sorbitol or sucrose. Such compositions may also contain a demulcent, preservative agents for flavor, coloring agents and antioxidants.

The pharmaceutical compositions can be in the form of a sterile injectable aqueous solutions. Acceptable carriers and solvents that can be used are water, ringer's solution and isotonic sodium chloride solution.

Sterile injectable drugs may also be a sterile injectable microemulsion of the oil-in-water, where the active component is dissolved in the oil phase. For example, the active ingredient mo is et to be first dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into water and glycerin mixture and processed before the formation of the microemulsion.

Injectable solutions or microemulsions can be introduced into the blood stream of the patient local bolus injection. Alternatively, it may be beneficial to introduce the solution or microemulsion in such a way as to maintain constant the concentration of circulating compounds of the present invention. In order to maintain such a constant concentration, can be applied to the device constant intravenous delivery. An example of such device is the model of intravenous pump Deltec CADD-PLUS™ 5400.

The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous injection. This suspension may receptorrelated ways known in the art, using those suitable dispersing or wetting agents and suspendida agents such as those mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol. In addition, sterile, fixed oils are typically used as a solvent or suspendida cf the water. For this purpose, can be used any soft fixed oils, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable solutions.

The compounds of formula I can also be entered in the form of suppositories for rectal administration of medicinal means. These compositions can be obtained by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such substances include coconut oil, treated with glycerol gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of different molecular masses and esters of fatty acids with polyethylene glycol.

For local application apply creams, ointments, jellies, solutions or suspensions, etc. containing the compound of formula I. For purposes of this invention, the local application will include lotions for the mouth and the liquid for rinsing.)

Compounds of the present invention can be introduced in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or percutaneous routes, with the use of f the RM percutaneous surface patches, well-known to specialists in this field of technology. With the introduction in the form of a percutaneous delivery system, the introduction of drug dose will, of course, are continuous rather than at intervals during the dosing regime. Compounds of the present invention can also be applied in the form of suppositories, using a base, such as coconut oil, and treated with glycerol gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of different molecular masses and esters of fatty acids with polyethylene glycol.

When the connection according to this invention is administered to an individual, the selected dosage level will depend upon a variety of factors, including, without limitation, the activity of the specific compound, the severity of indywidualnych symptoms, route of administration, time of administration, rate of excretion of the compound, the duration of the treatment, other drugs, compounds and/or substances used in combination, and the age, sex, weight, condition, General health and prior medical history of the patient. The number of connections and route of administration will ultimately be at the discretion of the treating physician, although generally the dosage will be to achieve local concentrations at the point of action that achieves the desired effect without causing substantial harmful or dangerous adverse is known.

Introduction in vivo may be effected in one dose, continuously or intermittently (for example, in divided doses at appropriate intervals of time) during treatment. How to determine the most effective methods and dosages of the introduction of well-known specialists in this field and will vary depending on the composition used for therapy, the goals of therapy, the target cells exposed to treatment, and the individual undergoing treatment. Can be performed by single or multiple injections level dose and mode selected by the treating physician.

In General, a suitable dose of the active compound is in the range from about 100 μg to about 250 mg per kilogram body weight of individual per day. If the active compound is a salt, ester, prodrug or similar, the entered number is calculated based on the parent compound, and thus used the actual weight increases accordingly.

Compounds of the present invention can also be applied in combination with anticancer drugs or chemotherapeutic drugs.

Compounds of the present invention can be used as chemo - and radio sensibilizators for cancer treatment. They can be applied for the treatment of mammals, which RA is it passed or currently undergoing treatment for cancer. Such pre-treatments include prior chemotherapy, radiation therapy, surgery or immunotherapy, such as cancer vaccines.

Thus, the present invention provides the combination of the compounds of formula I and anticancer means for simultaneous, separate or sequential administration.

The present invention also provides a compound of formula I used in the making of the medicinal product for use as an adjunct in cancer therapy or to enhance the action on tumor cells to ionizing radiation or chemotherapeutic drugs.

The present invention also provides a method of chemotherapy or radiotherapy, where the method comprises the administration to a patient in need, an effective amount of the compounds of formula I or a composition comprising the compound of formula I in combination with ionizing radiation or chemotherapeutic drugs.

In combination therapy, the compound of the present invention can be introduced before (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks), concurrently with, or after (e.g., 5 minutes, 15 minutes, 30 m of the nut, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks) administration of another anti-cancer means to the individual in need of such treatment. In various embodiments, the communication according to the present invention and other anti-cancer tools are introduced every 1 minute, every 10 minutes, every 30 minutes, with an interval of less than 1 hour intervals from 1 hour to 2 hours, with an interval from 2 hours to 3 hours, every 3 hours up to 4 hours, with an interval of 4 hours up to 5 hours, with an interval of 5 hours up to 6 hours, with an interval of 6 hours up to 7 hours, with a range from 7 hours to 8 hours, with the interval from 8 hours to 9 hours, with an interval from 9 hours to 10 hours, with an interval of from 10 hours to 11 hours, with a range from 11 hours to 12 hours, with an interval of not more than 24 hours or at intervals of not more than 48 hours.

Compounds of the present invention and another anti-cancer agent can act additively or synergistically. The synergistic combination of these compounds and other anti-cancer tools may allow the use of lower dosages of one or both of these tools, and/or less frequent dosing of one or both compounds of the present invention and other anti-cancer tools, and/or less frequent is the introduction of funds may reduce any toxicity, associated with the introduction of agents to the individual, without reducing the effectiveness of the effectiveness of cancer treatment. In addition, a synergistic effect can result in improved efficacy of such agents in the treatment of cancer and/or reduce any adverse or unwanted side effects associated with use of each of the funds separately.

Examples of anti-cancer tools or chemotherapeutic agents for use in combination with compounds of the present invention can be found inCancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6thedition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Specialist in the art should be able to recognize what combination of tools could be applied based on the specific characteristics of drugs and the presence of cancer. Such anti-cancer tools include, without limitation, the following: HDAC inhibitors, modulators of the estrogen receptor, the receptor modulators, androgen modulators, retinoid receptor, cytotoxic/cytostatic agents, antiproliferative agents, inhibitors prenyl-proteincenter, inhibitors of HMG-CoA reductase inhibitor, an HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors, inhibitors of cell proliferation and Akti is the purpose of life-support systems, inducing apoptosis agents, and agents that affect checkpoints of the cell cycle. Compounds of the present invention are particularly applicable when used in conjunction with radiation therapy.

Examples of HDAC inhibitors include suberoylanilide acid (SAHA), LAQ824, LBH589, PXD101, MS275, FK228, valproate acid, butyric acid and CI-994.

The term "modulators of the estrogen receptor" refers to compounds that interact with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of modulators of the estrogen receptor include, without limitation, tamoxifen, raloxifene, idoxifene, LY353381, LY1 17081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646.

The term "modulators of the androgen receptor" refers to compounds that interact with or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of modulators of androgen receptor include finasteride and other inhibitors of 5α-reductase, nilutamide, flutamide, bikalutamid, liarozole and acetate abiraterone.

The term "modulators, retinoid receptor" refers to compounds that interact with or inhibit the CBE is ivanie of retinoids to the receptor, regardless of the mechanism. Examples of such modulators, retinoid receptor include bexarotene, tretinoin, 13-CIS-retinova acid, 9-CIS-retinova acid, α-deformational, ILX23-7553, TRANS-N-(4'-hydroxyphenyl)retinamide, and N-4-carboxyaniline.

The term "cytotoxic/cytostatic funds" refers to compounds which cause cell death or inhibit cell proliferation primarily by direct interaction with the functioning of cells, or inhibit or affect mitosis cells, including alkylating agents, tumor necrosis, intercalatory, activating hypoxia compounds, inhibitors of microtubules/stabilizing microtubules agents, inhibitors of mitotic kinesins, inhibitors of kinases involved in the development of mitosis, antimetabolites, biological response modifiers; hormonal/protivokomarinye therapeutic drugs, hematopoietic growth factors, therapeutic agents directed action based on monoclonal antibodies, topoisomerase inhibitors, proteasome inhibitors and inhibitors ubicacin ligase.

Examples of cytotoxic means include, without limitation, cyclophosphamide, chlorambucil, carmustine (BCNU), lomustin (CCNU), busulfan, treosulfan, serene, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamin, prednis the Steen, dibromodulcitol, ranimustine, fotemustine, nedaplatin, aroplatin, oxaliplatin, temozolomide, methyl methanesulfonate, procarbazine, dacarbazine, heptaplatin, estramustin, toilet improsulfan, trofosfamide, nimustine, chloride of dibromide, punitive, lobaplatin, satraplatin, propiomazine, cisplatin, irofulven, Taxifolin, CIS-amindian(2-methylpyridine)platinum, benzylguanine, glufosfamide, GPX100, (TRANS, TRANS, TRANS)-bis-µ-(hexane-1,6-diamine)-µ-[diaminopurine(II)]bis[diamine(chloro)platinum(II)]tetrachloride, dianisidines, arsenic trioxide, 1-(11-dodecylamino-10-hydroxyphenyl)was 3.7-dimethylxanthine, zorubicin, idarubitsin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinfed, valrubicin, amrubicin, doxorubicin, epirubicin, pirarubicin, antineoplaston, 3'-deamino-3'-morpholino-13 desoxo-10-hydroxylaminopurine, annamycin, galarubicin, alienated, MEN 10755 and 4 dimethoxy-3-deamino-3-aziridinyl-4-methylsulfonylbenzoyl (see WO 00/50032).

In the embodiment, compounds of the present invention can be applied in combination with alkylating agents.

Examples of alkylating means include, without limitation, nitrogen mustard oil: cyclophosphamide, ifosfamide, trofosfamide and chlorambucil; nitrosoanatabine: carmustin (BCNU) and lomustin (CCNU); alkyl sulphonates: busulfan and treosulfan; triazine: dacarbazine, procarbazine and temozolomide; containing platinum complexes, cisplatin, carboplatin, paraplatin and oxaliplatin.

In the embodiment, the alkylating agent is a dacarbazine. The dacarbazine can be administered to the individual at dosages in the range from about 150 mg/m2(the surface area of an individual's body) to about 250 mg/m2. In another embodiment, the dacarbazine is administered intravenously to the individual once a day consecutively for five days with a dose in the range from about 150 mg/m2to about 250 mg/m2.

In the embodiment, the alkylating agent is a procarbazine. Procarbazine can be administered to the individual at dosages in the range from about 50 mg/m2(the surface area of an individual's body) to approximately 100 mg/m2. In another embodiment, procarbazine is administered intravenously to the individual once a day consecutively for five days with a dose in the range from about 50 mg/m2to about 100 mg/m2.

In the embodiment, the alkylating agent is temozolomide. Temozolomide can be administered to the individual at dosages in the range from about 150 mg/m2(the surface area of an individual's body) to approximately 200 mg/m2. In another variationbetween temozolomide introduced orally to the animal once a day consecutively for five days with dose, in the range from about 150 mg/m2to about 200 mg/m2.

Examples antimitoticescoy agents include alocalized, halichondrin B, colchicine, a derivative of colchicine, dolastatin 10, maytansine, rhizoxin, thiocolchicine, trityl-cysteine.

Example activates the hypoxia connection is tirapazamine.

Examples of proteasome inhibitors include, without limitation, lactacystin, bortezomib, Apoksiomen and peptide aldehydes, such as MG-132, MG 115 and PSI.

Examples of inhibitors of microtubule/stabilizing microtubule agents include paclitaxel sulphate vindesine, vincristine, vinblastine, vinorelbine, 3',4'-didehydro-4'-deoxy-8'-nonventilatory, docetaxol, rhizoxin, dolastatin, isethionate of mesobolin, auristatin, cemadotin, RPR1 09881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pendaftar-N-(3-fluoro-4-methoxyphenyl)benzosulfimide, anhydrovinblastine, N,N-dimethyl-L-poured-L-poured-N-methyl-L-poured-L-prolyl-L-Proline-tert-butylamide, TDX258, epothilone (see, for example, U.S. patent No. 6284781 and 6288237) and BMS 188797.

Some examples of topoisomerase inhibitors are topotecan, gcaptain, irinotecan, rubitecan, exatecan, gimatecan, diflomotecan, silyl-camptothecin, 9-aminocamptothecin, camptothecin, Kristol, mitomycin C, 6-ethoxypropanol-3',4'-O-aktenzeichen-Chartreuse, 9-methoxy-N,N-dimethyl-5-nitropyrazole[3,4,5-l]acridine-2-(6H)propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':b,7]-indolizino[1,2-b]quinoline-10,13(9H,15H)Dion, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'-dimethylamino-2'-desocialised, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide, Bulacan, (5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-acid]-5,5a,6,8,8a,9-hexahydrofuro(3',4':6,7)oil(2,3-d)-1,3-dioxol-6-he, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]- phenanthridinium, 6,9-bis[(2-amino-ethyl)amino]benzo[g]isoquinoline-5,10-dione, 5-(3-aminopropylene)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridine-6-he, N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinoline-7-he demesne; necompetitive inhibitors topoisomerase-1, such as indolocarbazole; and dual inhibitors of topoisomerase-1 and II, such as benzophenone, XR20 115761MLN 576 and banteringly.

In the embodiment, the topoisomerase inhibitor is an irinotecan. Irinotecan can be administered to the individual at dosages in the range from about 50 mg/m2(the surface area of an individual's body) to priblizitelen is 150 mg/m 2. In another embodiment, irinotecan is administered intravenously to the individual once a day consecutively for five days with a dose in the range from about 50 mg/m2to about 150 mg/m2during days 1-5, then intravenously once a day consecutively for five days in a period of 28-32 days with a dose in the range from about 50 mg/m2to about 150 mg/m2then again intravenously once a day consecutively for five days within 55-59 days with a dose in the range from about 50 mg/m2to about 150 mg/m2.

Examples of inhibitors of mitotic kinesins, in particular the mitotic kinesin human KSP described in PCT publications WO 01/30768, WO 01/98278, WO 02/056880, WO 03/050064, WO 03/050122, WO 03/049527, WO 03/049679, WO 03/049678, WO 03/039460, WO 03/079973, WO 03/099211, WO 2004/039774, WO 03/105855, WO 03/106417, WO 2004/087050, WO 2004/058700, WO 2004/058148 and WO 2004/037171 and patent applications U.S. 2004/132830 and USA 2004/132719. In the embodiment, inhibitors of mitotic kinesins include, without limitation, inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E, inhibitors of MCAK, inhibitors Kif14, inhibitors of Mphosph1 and inhibitors of Rab6-KIFL.

The definition of "inhibitors of kinases involved in the completion of mitosis" includes, without limitation, inhibitors of Aurora kinases, inhibitors of Polo-similar kinases (PLK) (in particular, inhibitors of PLK-I)inhibitors of bub-1 and inhibitors of bub-Rl.

the Ermin "antiproliferative agents" include antisense RNA and DNA oligonucleotides, such as G3139, ODN698, RVASKRAS, GEM231, INX3001, and antimetabolites, such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, Galitsin, cytarabine ocfosfate, fosterin hydrate of sodium, raltitrexed, raltitrexed, Amateur, tianfuan, decitabine, nolatrexed, pemetrexed, nelarabine, 2'-deoxy-2'-matricectomy, 2'-permatile-2'-deoxycytidine, N-[5-(2,3-dihydro-benzofuran)sulfonyl]-N'-(3,4 - dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecanoyl]glycylamino]-L-glycero-B-L-managedproperty]adenine, aplidin, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidine[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-toenail-L-glutamic acid, aminopterin, 5-flurouracil, alanosine, ether 11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-desaturacia(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl acetic acid, swainsonine, lometrexol, dexrazoxane, methionine, 2'-cyano-2'-deoxy-N4-Palmitoyl-1-B-D-arabinofuranosylcytosine and thiosemicarbazone 3-aminopyridine-2-carboxaldehyde.

Examples of therapeutic agents directed action based on monoclonal antibodies include those therapeutic agents which contain cytotoxic agents or radioisotopes attached to monoclonal antibodies specific to cancer cells or specific to the target cell. An example of the include Bexar.

The term "inhibitors of HMG-CoA reductase inhibitor" refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA-reductase. Examples of inhibitors of HMG-CoA-reductase, which can be used include, without limitation, lovastatin (MEVACOR®; see U.S. patent No. 4231938, 4294926 and 4319039), simvastatin (ZOCOR®; see U.S. patent No. 4444784, 4820850 and 4916239), pravastatin (PRAVACHOL®; see U.S. patent No. 4346227, 4537859, 4410629, 5030447 and 5180589), fluvastatin (LESCOL®; see U.S. patent№ 5354772, 4911165, 4929437, 5189164, 5118853, 5290946 and 5356896) and atorvastatin (LIPITOR®; see U.S. patent No. 5273995, 4681893, 5489691 and 5342952). Structural formulas of these and additional inhibitors of HMG-CoA-reductase, which can be used in the methods of the present invention, described on page 87M. Yalpani, "Cholesterol Lowering Drugs", Chemistry &Industry, p. 85-89 (5 February 1996)and in U.S. patent No. 4782084 and 4885314. Used here, the term "inhibitor of HMG-CoA reductase inhibitor" includes all pharmaceutically acceptable forms of the lactone and open-acid (that is, if the lactone ring cycle opens with the formation of the free acid), and salt and essential forms of compounds which have inhibitory activity against HMG-CoA reductase, and therefore, the use of such forms, salts, esters, acids with an open circuit and the lactone is included in the scope of the present invention.

The term "inhibitor prenyl-proteincenter" refers to the connection to the which inhibits or one, or any combination of the enzymes prenyl-proteincenter, including farnesyl-proteincenter (FPTase), geranylgeranyl-proteincenter type I (GGPTase-I) and geranylgeranyl-proteincenter type-II (GGPTase-II, also called Rab GGPTase).

Examples of inhibitors prenyl-proteincenter can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. patent No. 5420245, U.S. patent No. 5523430, U.S. patent No. 5532359, U.S. patent No. 5510510, U.S. patent No. 5589485, U.S. patent No. 5602098, publication of the European patent 0618221, publication of the European patent 0675112, publication of the European patent 0604181, publication of the European patent 0696593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. patent No. 5661152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S. patent No. 5571792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436 and U.S. patent No. 5532359. As an example of the influence of inhibitor prenyl-proteincenter on angiogenesis, seeEuropean J. of Cancer (1999), 35(9): 1394-1401.

The term "angiogenesis inhibitors" refers to compounds that inhibit the formation of new blood vessels, regardless of the mechanism. An example of the inhibitors of angiogenesis include, without limitation, inhibitors tyrosinekinase, such as inhibitors tyrosinekinase receptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors of growth factors, epidermal, fibroblast or platelet inhibitors of MMP (metalloprotease matrix), integrin blockers, interferon-α, interleukin-12, polysulphate of pentosan, cyclo-oxygenase inhibitors, including nonsteroidal anti-inflammatory drugs (NSAIDs), like aspirin and ibuprofen as well as selective inhibitors of cyclooxygenase-2, similar to celecoxib and rofecoksib (PNAS (1992) 89:7384; JNCI (1982) 69:475; Arch. Opthalmol. (1990) 108:573; Anat. Rec. (1994) 238:68; FEBS Letters (1995) 372:83; Clin. Orthop. (1995) 313:76; J. Mol. Endocrinol. (1996) 16:107; Jpn. J. Pharmacol. (1997) 75:105;Cancer Res. (1997) 57:1625 (1997); Cell (1998) 93:705; Intl. J. Mol. Med. (1998) 2:715; J. Biol. Chem. (1999) 274:9116)), steroid anti-inflammatory drugs (such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxamidates, combretastatin A-4, squalamine, 6-O-chloracetophenone)fumakilla, thalidomide, angiostatin, troponin-1, antagonists of angiotensin II (seeJ. Lab. Clin. Med. (1985) 105:141-145), antibodies to VEGF (seeNature Biotechnology (1999) 17:963-968; Kim et al. (1993)Nature 362:841-844; WO 00/44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the present invention include agents that cat is that modulate or inhibit the blood coagulation system and fibrinolysis (see review inClin. Chem. La. Med. (2000) 38:679-692). Examples of such agents that modulate or inhibit the pathway of coagulation and fibrinolysis include, without limitation, heparin (seeTHRomb. Haemost. (1998) 80:10-23), low molecular weight heparins and inhibitors of carboxypeptidase U (also known as active inhibitors of thrombin, the inhibitor activatable fibrinolysis [TAFIa]) (seeThrombosis Res. (2001) 101:329-354). The TAFIa inhibitors are described in PCT publication WO 03/013526 and U.S. patent No. 60/349925 (published 18 January 2002).

The definition of "funds, which interact with the control points of the cell cycle" refers to compounds that inhibit protein kinases that convert signals checkpoint of the cell cycle, thus sensibiliser cancer cells by damaging DNA means. Such agents include inhibitors of ATR, ATM, Chk1 and Chk2 kinases and cdk inhibitors and cdc kinases and specifically presents examples 7-hydroxystaurosporine, staurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

The definition of "inhibitors of cell proliferation and pathways of activation systems" refers to pharmaceutical agents which inhibit the surface receptors of cells and output stream cascades of signal transduction of these surface receptors. Such agents include inhibitors of EGFR (for example, gefitinib and erlotinib), inhibitors of ERB- (for example, trastuzumab), inhibitors of IGFR (for example, those first described in WO 03/059951), inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K (for example LY294002), serine/treoninove kinases (including, without limitation, inhibitors of Akt such as described in WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO 02/083138, inhibitors of Raf kinase (for example BAY-43-9006), inhibitors of MEK (for example CI-1040 and PD-098059), and inhibitors of mTOR (for example, Viet has CCI-779 and Ariad AP23573). Such agents include compounds of low molecular weight inhibitors and antagonists based on antibodies.

The term "inducing apoptosis means" includes activators members of the TNF family receptor (including TRAIL-receptors).

The invention also includes the combination with NSAIDs that are selective COX-2 inhibitors. For the purposes of this description NSAIDs that are selective COX-2 inhibitors, are defined as those that have at least 100-fold specificity in relation to inhibition of COX-2 compared to COX-1, which is measured through the ratio of the IC50for COX-2 to the IC50for COX-1, identified through cell or microsomal studies. Such compounds include, without limitation, those that were first described in U.S. patent 5474995, U.S. patent 5861419, U.S. patent 6001843, U.S. patent 6020343, U.S. patent 5409944, U.S. patent 5436265, U.S. patent 5536752, U.S. patent 5550142, U.S. patent 5604260, U.S. patent 568584, U.S. patent 5710140, WO 94/15932, U.S. patent 5344991, U.S. patent 5134142, U.S. patent 5380738, U.S. patent 5393790, U.S. patent 5466823, U.S. patent 5633272 and U.S. patent 5932598, all of which are included in this description by reference.

COX-2 inhibitors that are particularly applicable to the treatment in the method according to the present invention are 5-chloro-3-(4-methylsulphonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine or its pharmaceutically acceptable salt.

Compounds that have been described as specific inhibitors of COX-2 and, therefore, which can be used in the present invention include, without limitation, parecoxib, CELEBREX®and BEXTRA®or their pharmaceutically acceptable salt.

Other examples of angiogenesis inhibitors include, without limitation, endostatin, Ukraine, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]Oct-6-yl(chloroacetyl)carbamate, azetidinone, 5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, phosphate sulfated mandamentos, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrroloquinoline[N-methyl-4,2-pyrrole]carbylamine]bis-(1,3-naphthalenedisulfonate) and 3-[(2,4-dimethylpyrrole-5-yl)methylene]-2-indolinone (SU5416).

As described above, the term "integrin blockers" refers to compounds that selectionprotected, inhibit or prevent the binding of a physiological ligand with αvβ3-integrin, to compounds which selectively resist, inhibit or prevent the binding of a physiological ligand with αvβ5-integrin, to compounds which counteract, inhibit or prevent the binding of a physiological ligand with αvβ3-integrin and αvβ5-integrin, and to compounds which counteract, inhibit or interfere with the activity of the particular integrin(s)expressed by(s) in edothelial cells of capillaries. The term also refers to antagonists of αvβ6-, αvβ8-, α1β1-, α2β1-, α5β1-, α6β1and α6β4-integrins. The term also refers to antagonists of any combination of αvβ3-, αvβ5-, αvβ6-, αvβ8-, α1β1-, α2β1-, β5α1-, α6β1and α6β4-integrins.

Some specific examples tyrosinekinase inhibitors include N-(triptoreline)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrole-5-yl)methylidene)indolin-2-he, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-forgenerating)-7-methoxy-6-[3-(4-morpholinyl)propoxy]chinasol is h, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-hinazolinam, BIBX1382, 2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-vindaloo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazepin-1-he SH268, genistein, STI571, CEP2563, sulfonate 4-(3-chlorpheniramine)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinone, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinone and EMD121974.

In the embodiment, compounds of the present invention can be applied for treating or preventing outward signs of necrosis caused by selective N3-adenine mahilyouski means, such as MeOSO2(CH2-lexitropsin (Me-Lex).

Combination with compounds other than cancer funds also include in the methods of the present invention. For example, the combination claimed in the present invention compounds with PPAR-γ (i.e. PPAR-gamma) agonists and PPAR-δ (i.e. PPAR-Delta) agonists can be used in the treatment of certain malignant tumors. PPAR-γ and PPAR-δ are nuclear peroxisome proliferative activated γ - and δ-receptors. The expression of PPAR-γ in endothelial cells and its involvement in angiogenesis has been described in the literature (seeJ. Cardiovasc. Pharmacol. (1998) 31:909-913; J. Biol. Chem. (1999) 274:9116-9121; Invest. Ophthalmol Vis. Sci. (2000) 41:2309-2317). Was is shown, that PPAR-γ agonists inhibit the angiogenic response to VEGF in vitro; as troglitazone and maleate of rosiglitazone inhibit the development of retinal neovascularization in mice (Arch. Ophthalmol. (2001) 119:709-717). Examples of PPAR-γ agonists and PPAR-γ/α agonists include, without limitation preparations, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionic acid (first described in USSN 09/782856) and 2(R)-7-(3-(2-chloro-4-(4-pertenece)phenoxy)propoxy)-2-ethylpropane-2-carboxylic acid (first described in USSN 60/235708 and 60/244697).

Another variant of implementation of the present invention is applied for the first time described in the present invention compounds in combination with antiviral agents such as nucleoside analogues, including ganciclovir for the treatment of cancer, see WO 98/04290).

Another variant of implementation of the present invention is applied for the first time described in the present invention compounds in combination with gene therapy for cancer treatment. For an overview of genetic approaches to cancer treatment, seeHall et al. (Am. J. Hum. Genet. (1997) 61:785-789) and Kufe et al. (Cancer Medicine, 5th Ed, p.876-889, BC Decker, Hamilton 2000). Gene therapy can be applied to release any of talauega tumor gene. Examples of such genes include, without limitation, p53, which can be released by the recombinant virus-mediated gene transfer (see, for example, U.S. patent No. 6069134), uPA/uPAR antagonist (Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August (1998) 5(8): 1105-13), gamma interferon (J. Immunol. (2000) 164:217-222).

Compounds of the present invention can also be administered in combination with an inhibitor of innate multilocational resistance (MDR), in particular MDR associated with high levels of expression of transport proteins. Such MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853, verapamil and PSC833 (valspodar).

The compound of the present invention can be applied in combination with antiemetic means to treat nausea or emesis, including acute, delayed, latent ahead and vomiting that may occur when using the compounds of the present invention, alone or with radiation therapy. To prevent or treat vomiting connection according to the present invention can be applied in combination with other antiemetic agents, particularly antagonists of the receptor neirokinina-1, antagonists of 5-HT3-receptor, such as ondansetron, granisetron, tropisetron and zatosetron, agonists of GABA -receptor, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Prepared, Benecare or others, such as those first described in U.S. patents№ 2789118, 2990401, 3048581, 3126375, 3929768, 3996359, 3928326 and 3749712, antidopaminergics means, such as the phenothiazines (eg, prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In the embodiment, the antiemetic agent is selected from receptor antagonist neirokinina-1, an antagonist of 5-HT3-receptor and steroid, is introduced as an adjuvant to treat or prevent vomiting, which may occur with the introduction of the compounds of the present invention.

Antagonists of the receptor neirokinina-1 for use in combination with compounds of the present invention have been fully described, for example, in U.S. patent№ 5162339, 5232929, 5242930, 5373003, 5387595, 5459270, 5494926, 5496833, 5637699, 5719147; the publication of the European patent # EP 0360390, 0394989, 0428434, 0429366, 0430771, 0436334, 0443132, 0482539, 0498069, 0499313, 0512901, 0512902, 0514273, 0514274, 0514275, 0514276, 0515681, 0517589, 0520555, 0522808, 0528495, 0532456, 0533280, 0536817, 0545478, 0558156, 0577394, 0585913, 0590152, 0599538, 0610793, 0634402, 0686629, 0693489, 0694535, 0699655, 0699674, 0707006, 0708101, 0709375, 0709376, 0714891, 0723959, 0733632 and 0776893; publication of international patent application PCT no WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 3/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and in the publication of a patent in the UK№ 2266529, 2268931, 2269170, 2269590, 2271774, 2292144, 2293168, 2293169 and 2302689. The compounds described in the aforementioned patents and publications, which are incorporated in this description by reference.

In the embodiment, the receptor antagonist neirokinina-1 for use in combination with compounds of the present invention is selected from 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-forfinal)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)of the research or its pharmaceutically acceptable salt described in U.S. patent No. 5719147.

The compound of the present invention can also be administered in combination with a tool that can be used to treat anemia. This treatment for anemia represents, for example, activator receptor continuous erythropoiesis (such as epoetin Alfa).

Connected to the e of the present invention can also be administered in combination with a tool, which can be applied for the treatment of neutropenia. This treatment for neutropenia is, for example, hematopoietic growth factor, which regulates the production and function of neutrophils, such as colony-stimulating factor in human granulocytes (G-CSF). Examples of G-CSF include filgrastim.

The compound of the present invention can also be entered with immunoactivity, such as levamisole, isoprinosine and zadaxin.

The compound of the present invention can also be applied for treating or preventing cancer, including bone cancer, in combination with bis-phosphonates (of course, include bis-phosphonates, diphosphonates, bis-phosphonic acids and diphosphonic acids). Examples of bis-phosphonates include, without limitation: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), encadrant or comadronas, clodronate, EB-1053, minodronate, meridional, Piedmont and tiludronate, including any and all of their pharmaceutically acceptable salts, derivatives, hydrates and mixtures.

Thus, the scope of the present invention includes the use claimed in the present invention compounds in combination with ionizing radiation and/or in combination with a second compound selected from the HDAC inhibitors, estrogen receptor modulator, modulator of androgen receptor, mo is ulator retinoid receptor, cytotoxic/cytostatic agent, an antiproliferative agent, an inhibitor of prenyl-proteincenter, an inhibitor of HMG-CoA reductase inhibitor, an inhibitor of angiogenesis, PPAR-γ agonist, a PPAR-δ agonist, an anti-virus agent, an inhibitor of innate multilocational sustainability, antiemetic agent, an agent that can be applied in the treatment of anemia, an agent that can be applied in the treatment of neutropenia, immunoactive drug, an inhibitor of cell proliferation and activation systems, an agent that affects the checkpoint of the cell cycle, causing apoptosis agent and bis-phosphonate.

The term "introduction" and its variants (e.g., "assignment" compound) in reference to the connection according to the invention means introducing the compound or prodrug of the compound into the body of the animal in need of such treatment. When the connection according to the invention or a prodrug is provided in combination with one or more other active agents (e.g., cytotoxic agent, etc.), the term "introduction" and its variants, each, as understood to include concurrent and sequential introduction of the compound or its prodrug, or other agents.

Used herein, the term "composition" includes a product consisting of certain components in certain to the icestar, as well as any product which arises, directly or indirectly, from the combination of certain components in certain amounts.

Used here, the term "therapeutically effective amount" means an amount of active compound or pharmaceutical agent that causes the tissue, system, animal or human biological or medical response that is desirable for the researcher, veterinarian, family physician or Clinician.

The term "treatment" refers to treatment of a mammal subject a pathological condition, and refers to the effect that improves the condition by killing cancer cells, but also to the effect that slows down the progression of the condition and includes a reduction in the speed of progression, retention rate of progression, improvement and recovery. Also included is a treatment as a preventive measure (i.e. prevention).

The term "pharmaceutically acceptable"as used here, refers to compounds, substances, compositions and/or dosage forms which are, within the scope of voiced medical diagnosis, suitable for use in contact with tissues of an individual (e.g., human) without excessive toxicity, irritation, allergic response, or other problem is we or complications the term is correlated with an acceptable ratio of benefit/risk. Each carrier, filler, etc. must also be "acceptable" in the sense of compatibility with other components of the composition.

The term "additive" refers to the use of compounds in combination with known therapeutic methods. Such methods include cytotoxic modes of administration of drugs and/or ionizing radiation that is used to treat various types of cancer. In particular, the active compounds known as potentiation of a number of anticancer chemotherapy, which include topoisomerases class of toxins (e.g., topotecan, irinotecan, rubitecan), the most well-known alkylating agents (e.g., DTIC, temozolomide) and based on platinum drugs (e.g., carboplatin, cisplatin), used in the treatment of cancer.

In the embodiment, the inhibitor of angiogenesis, is used as the second compound is selected from an inhibitor of tyrosinekinase, inhibitor of growth factor epidermis, an inhibitor of fibroblast growth factor, an inhibitor of platelet growth factor, an inhibitor of MMP (metalloprotease matrix), an integrin blocker, interferon-α, interleukin-12, polysulfate of pentosan, an inhibitor of cyclooxygenase, carboxamidates, combretastatin A-4, wells is amine, 6-O-chloracetophenone)fumakilla, thalidomide, angiostatin, troponin-1, or antibodies to VEGF. In the embodiment, the modulator of the estrogen receptor is a tamoxifen or raloxifene.

Also included in the scope of the claims is a method of treating cancer, which consists in injecting a therapeutically effective amount of the compounds of formula I in combination with radiation therapy and/or in combination with a compound selected from the HDAC inhibitors, estrogen receptor modulator, modulator of androgen receptor, a modulator, retinoid receptor, a cytotoxic/cytostatic agent, an antiproliferative agent, an inhibitor of prenyl-proteincenter, an inhibitor of HMG-CoA reductase inhibitor, an inhibitor of angiogenesis, PPAR-γ agonists, PPAR-δ agonists, an antiviral agent, an inhibitor of innate multilocational sustainability, antiemetic agent, an agent that can be used for the treatment of anemia, an agent that can be applied for the treatment of neutropenia, immunoactivity, an inhibitor of cell proliferation and activation systems, an agent that interacts with the control points of the cell cycle, the agent that causes apoptosis, and bis-phosphonate.

The following variant of the invention is a method of treating cancer, which includes the century is seeing a therapeutically effective amount of the compounds of formula I in combination with paclitaxel or trastuzumab.

Further, the invention includes a method of treating or preventing cancer, which includes the introduction of therapeutically effective amounts of compounds of formula I in combination with a COX-2 inhibitor.

The present invention also includes a pharmaceutical composition that can be used for treating or preventing cancer that comprises a therapeutically effective amount of the compounds of formula I and compounds selected from the HDAC inhibitors, modulators of the estrogen receptor, a modulator of androgen receptor, a modulator, retinoid receptor, cytotoxic/cytostatic tools, antiproliferative agent, an inhibitor of prenyl-proteincenter, an inhibitor of HMG-CoA reductase inhibitor, an inhibitor of HIV protease, reverse transcriptase inhibitors, inhibitors of angiogenesis, agonist of PPAR-γ agonist of PPAR-δ, antiviral agent, an inhibitor of cell proliferation and activation systems, agent interacts with the control points of the cell cycle, causing apoptosis agent and bis-phosphonate.

These and other aspects of the invention will be apparent from the present discussion.

Abbreviations used in the description of the reactions in the following examples:

AcOH (acetic acid); DCM (methylene chloride); DIPEA (N,N'-diisopropylethylamine); DMA (N,N-dimethylacetamide); DAP (4-dimethylaminopyridine); DMF (dimethylformamide); DMSO (dimethylsulfoxide); eq. (equivalent); EtOAc (ethyl acetate); HBTU (hexaphosphate O-benzotriazole-N,N,N',N'-tetramethyl-Urania); NaH (sodium hydride); NMR (nuclear magnetic resonance); PyBOP (1H-benzotriazol-1-electroparadise); RP-HPLC (ortofena liquid chromatography high resolution); RT (room temperature); sat. aq. (saturated water); TBTU (tetrafluoroborate O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylurea); TEA (triethylamine); TFA (triperoxonane acid), and THF (tetrahydrofuran).

The compounds of formula I, where c is 0 and d is 1, can be obtained by condensation of compounds of formula IA with a compound of formula IB:

,

where a, b, e, f, g, h, i, j, X, Y, Z, R1, R2, R3, R4and R5defined above. The reaction can usually be carried out in the presence of crosslinking agents such as HBTU and DIPEA in a solvent such as DMA, at a temperature close to the room. Can also be used crosslinking agent, such as TBTU, and a solvent, such as DMF. Similar conditions for the combination can be applied at any stage in the synthesis of compounds of formula I using the appropriate combinations of the original substances.

The compounds of formula IA can be obtained by simultaneous hydrolysis and decarboxylation of compounds of formula IC:

,

where a, b, j, R1, R2X and Y are defined above, E represents an electron-withdrawing group such as cyano, and L represents a leaving group such as halogen, for example fluorine or chlorine. The reaction is usually carried out in acidic or basic conditions. For example, a base such as NaOH, can be used at a temperature of about 90°C. the Reaction can be conducted in solvents such as AcOH and HCl, while boiling under reflux.

The compounds of formula IC can be obtained by reaction of compounds of formula ID with a compound of formula IE:

,

where a, b, j, R1, R2X, Y, E, and L2each independently defined above. The reaction is usually conducted in the presence of a base, such as NaH, in a solvent such as DMF, at a temperature from about 0°C. to room temperature.

Alternatively, the compounds of formula I can be obtained by simultaneous hydrolysis and decarboxylation of the compounds of formula IF:

,

where a, b, c, d, e, f, g, h, i, j, X, Y, Z, R1, R2, R3, R4, R5L2and E defined above. The reaction is usually carried out in acidic or basic conditions.

The compounds of formula IF can be obtained by reaction of compounds of formula ID with a compound of formula IG:

b> ,

where b, c, d, e, f, g, h, i, Y, Z, R2, R3, R4, R5and E defined above. The reaction is usually conducted in the presence of a base, such as NaH, in a solvent such as DMF, at a temperature from about 0°C. to room temperature.

If the synthesis of intermediates and starting compounds is not described, these compounds are commercially available or can be prepared from commercially available compounds by standard methods or by expanding on the examples.

The compounds of formula I can be converted into other compounds of formula I by known methods or by methods described in the examples.

When carrying out any of the synthetic sequences described herein, may be necessary and/or desirable to protect sensitive or reactive groups on any of the participating molecules. This can be achieved by a conventional protective groups such as those described inProtecting Groups in Organic Synthesis, 3rd Edition, Greene, T. W. and Wuts, P. G. M.; Wiley Interscience, 1999, and Kocienski, P. J. Protecting Groups, Thieme, 1994. Protective groups can be removed at a suitable subsequent stage using methods known from the prior art. For example, if there is a protective group Boc, it can be removed by adding TFA in the solvents such as DCM and/or MeCN, at a temperature close to matnog. An alternative can be applied EtOAc in the presence of HCl and 1,4-dioxane at a temperature close to the room. Benzylcarbamoyl protective group can be removed by hydrogenation using standard methods, such as the effect of a catalyst such as Pd/C, in a solvent such as methanol, in an atmosphere of hydrogen.

Compounds of the present invention was obtained according to the following schemes. All variables are within the above defined formula.

Scheme 1

Compounds described in this invention can be obtained using the methods described below. For example, 3,6-dichloro-4-alkylpyridine and 3,6-dichloro-4,5-dialkylimidazolium can be obtained as described below by radical join dichloropyridazine corresponding radicals are generated by decarboxylation of the corresponding alanovoy acid by the action of ammonium peroxodisulfate in the presence of Ag(I), as described in Org. Prep. + Proc. Int. 1988,20, 117. The reaction of substituted derivatives of 3,6-dichloropyridazine with (hetero)aromatic group bearing an activated methylene group activated electron-withdrawing group, such as ester or nitrile, in the presence of a base, allows the substitution of chlorine groups, which leads to a mixture of two regioisomeric 3-((hetero)arylmethyl)pyridazines. Hydrolysis of this isomeric mixtures and with simultaneous decarboxylation and hydrolysis aminofluorene group leads to the formation of the desired block. At this stage, the mixture of isomers can be separated (scheme 1).

Scheme 1

where

E represents an electron-withdrawing group such as-CO2-alkyl, -CN;

R* represents (CH2)c(CO)d(NR3)e(Z=O)f(O)g(CH2)h(NR4)iR5;

R1represents a C1-6-alkyl; and

all variables are defined above.

Scheme 2

In certain circumstances (hetero)aromatic group can carry the workpiece functional groups, which can then be converted with the formation of other derivatives. For example, (hetero)aromatic nitrile may remain unchanged when passing through the synthetic sequence. This functional group may be hydrolyzed during the reaction decarboxylation to obtain the corresponding carboxylic acid. In turn, it can be introduced in combination with various amines to obtain the desired PARP inhibitors (scheme 2).

Scheme 2

where

E represents an electron-withdrawing group such as-CO2-alkyl, -CN;

R** = (NR3)c(Z=O)f(O)g(CH2)h(NR4)iR5; and

all variables are defined above.

The inhibitors according to the present invention can be transformed into other related derivatives of standard transformations, known to specialists in this field, for example by reaction of a combination of amino groups with carboxylic acids using reagent combinations, similar HBTU, HATU, TBTU and PyBoP, or with activated acyl groups; reactions of sulfonylurea using sulphonylchloride; or reactions reductive amination using carbonyl derivative and an amino group using a reducing reagent, such cyanoborohydride sodium.

Scheme 3

3,6-dichloro-4-alkylpyridine can be obtained by attaching alkyl radical to dichloropyridazine, as described previously. Then can be obtained asymmetric 3,6-dichloro-4-alkyl-5-alkyl*-pyridazine, by reaction with a second alkyl radical by decarboxylation of the corresponding alanovoy acid with peroxodisulfate ammonium in the presence of Ag(I), as described in Org. Prep. + Proc. Int. 1988,20, 117. The reaction sequence described above, allow you to create the desired PARP inhibitors (scheme 3).

Scheme 3

where

E represents an electron-withdrawing group such as-CO2-alkyl, -CN;

R* represents (CH2)c(CO)d(NR3)e(Z=O)f(O)g(CH2)h(NR4)iR5;

R1and R1'represents the t of a C 1-6-alkyl; and

all variables are defined above.

Scheme 4

An alternative way to convert these PARP inhibitors in related compounds is to apply the reaction kurzius. The compound containing a carboxylic acid group, can be processed by diphenylphosphorylacetate in an alcohol solvent boiling under reflux and can undergo a rearrangement of kurzius, leading to the corresponding carbamate. The carbamate can then be hydrolyzed in acidic conditions to the corresponding derivative of (hetero)aniline, which can then be processed into the desired PARP inhibitors by means of combination reaction under standard conditions (scheme 8). Similarly, the derivative of (hetero)aniline can also be introduced in combination with allamerican and then next cyklinowanie in the corresponding imide by adding interactive reagent, such as TBTU. Alternatively, a (hetero)analed can be introduced in the interaction with the carboxylic acid containing urethane fragment, and then subjected to microwave irradiation in the presence of DMAP, which makes possible the cyclization to the corresponding cyclic urea.

Scheme 4

where

R and R1represent lower alkyl and

all variables are defined above;

Scheme 5

The following way to convert one type of inhibitor in the other consists in the reaction of nucleophilic aromatic substitution in Y-ring. For example, the group of halogen, such as fluoride, (hetero)aromatic ring may be substituted alkoxide ion or an amino group. Treatment with sodium alkoxide in boiling under reflux alcohol solvent can be alkoxygroup in the Y-ring. Alternatively, vigorous heating of the substrate in a solution of amine in a polar solvent like DMF in a sealed reaction vessel allows alkylamino and dialkylamino in the Y-ring. Subsequent operations with functional groups, such as the hydrolysis of nitrile groups in strong environments while boiling under reflux and interaction, lead to the desired PARP inhibitors (scheme 5).

Scheme 5

where

X = halogen, for example fluorine;

R* represents (CH2)c(CO)d(NR3)e(Z=O)f(O)g(CH2)h(NR4)iR5;

R, R', R1and R1'represents a C1-6-alkyl;

all variables are defined above.

Compounds described examples presented here, was tested in the following studies and, as it was found, had IC50in the guises of less than 5 microns.

The study of PARP-1 with the analysis of scintillation proximity (SPA)

Reagents

Buffer for research: 100 mm Tris, pH 8, 4 mm MgCl2, 4 mm spermine, 200 mm KCl, 0.04% Of Nonidet P-40.

The enzyme mixture: buffer for research (12,5 μl), 100 mm DTT (0,5 μl), PARP-1 (5 nm, Trevigen 4668-500-01), H2O (35 ml).

A mixture of nicotinamide - adaminaby dinucleotide(NAD)/DNA: [3H-NAD] (250 MX/ml, and 0.4 μl, counter, Perkin-Elmer NET-443H), NAD (1.5 mm, 0.05 µl, SIGMA N-1511), biotinylated-NAD (250 μm to 0.03 μl, Trevigen 4670-500-01), activated calf thymus (1 mg/ml, 0.05 µl, from Amersham Biosciences 27-4575), H2O (up to l0 µl).

Mix for symptoms of: streptavidine SPA-beads (5 mg/ml from Amersham Biosciences RPNQ 0007), dissolved in 500 mm EDTA.

The experiment

The reaction was carried out in 96-well-microplate with a final volume of 50 μl/well. After adding 5 μl of a 5% solution of the compound in DMSO was added to the enzyme mixture (35 ml), the reaction is initiated by adding a mixture of NAD/DNA (10 μl) and incubation for 2 hours at room temperature. The reaction was stopped by adding a mixture of (25 μl) and incubation for 15 min at room temperature. The measurement was carried out on the device Packard TOP COUNT.

EXAMPLE 1

Triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s (A4)

Stage 1: 5-[(6-chloro-5-ethylpyridine-3-yl)(cyano)methyl]-2-perbenzoate (A1) and 5-[(6-chloro-4-ethylpyridine-3-yl)(cyano)methyl]-2-perbenzoate (A2)

To a cooled with ice to a solution of 5-(cyanomethyl)-2-perbenzoate (1 EQ.) and 3,6-dichloro-4-ethylpyridine (1.9 EQ.) (Reference: Org. Prep. + Proc. Int. 1988,20, 117 and U.S. patent 4628088, 1986) in DMF portions was added NaH (2.1 EQ.). The reaction mixture was stirred at 0°C for 15 min, then warmed to room temperature and was stirred for 2 hours. The reaction was extinguished with saturated aqueous NaHCO3and was extracted with EtOAc. The combined organic fractions were washed with saturated salt solution, dried (Na2SO4) and concentrated under reduced pressure. The mixture of isomers of 4 - and 5-ethylpyridine were separated by chromatography on silica gel, was suirable a mixture Hexane:EtOAc 9:1, which gave the first 5-substituted isomer (A1) and then 4-substituted isomer (A2).

5-[(6-chloro-5-ethylpyridine-3-yl)(cyano)methyl]-2-perbenzoate (A1):1H-NMR (300 MHz, CDCl3) δ: 7,80 for 7.78 (2H, m), of 7.48 (1H, s), 7,31-7,29 (1H, m), 5,63 (1H, s), of 2.81 (2H, CVD, J=7.6 and 3.1 Hz), is 1.31 (3H, t, J=7,6 Hz). MS (ES) for C15H10ClFN4calculated: 300/302 found: 301/303 (M+H)+.

5-[(6-chloro-4-ethylpyridine-3-yl)(cyano)methyl]-2-perbenzoate (A2):1H-NMR (400 MHz, CDCl3) δ: 7,75-to 7.67 (2H, m), 7,45 (1H, s), 7,30 (1H, t, J=8.6 Hz), 5,74 (1H, s), 2,80-2,70 (1H, m), 2,60-of 2.50 (1H, m)of 1.26 (3H, t, J=7,3 Hz). MS (ES)for C 15H10ClFN4calculated: 300/302 found: 301/303 (M+H)+.

Stage 2: 5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-Formentera acid (A3)

The mixture A1 (1 EQ.) in AcOH, concentrated HCl and H2O (1:2:1, 0,065 M), was heated at the boil under reflux overnight, then cooled to room temperature and diluted with H2O and EtOAc, then was separated. The aqueous phase is washed with EtOAc and the combined extracts were washed with saturated salt solution, dried (Na2SO4) and concentrated under reduced pressure. The crude product was dissolved in AcOH was added NaOAc (2 EQ.). The resulting solution was heated at the boil under reflux for 1 hour. The reaction mixture was cooled and the mixture was extracted with EtOAc. The organic phase is washed twice with saturated salt solution, dried (Na2SO4) and the solvent was removed under reduced pressure. The residue is suspended in H2O and to the resulting suspension was added an aqueous solution of 23 M NaOH (8 EQ.) and they were heated to 90°C for 30 minutes the Reaction solution was cooled, then acidified to pH 4 by the action of 2 M HCl. The mixture was stirred for 10 min and filtered. The obtained solid substance was washed successively H2O, hexane, Et2O, EtOAc, and dried under high vacuum, giving specified in the title compound in the form of poorly-the ìנאםזוג} powder.

1H-NMR (300 MHz, DMSO-d6) δ: 13,30 (0,5H, users), 12,74 (1H, s), 7,78 to 7.75 (1H, m), 7,53 (1H, m), 7,31-of 7.25 (1H, m), 7,72 (1H, s), of 3.94 (2H, s), a 2.45 (2H, J=7.5 Hz), is 1.11 (3H, t, J=7.5 Hz). MS (ES) for C14H13FN2O3calculated: 276, found: 277 (M+H)+.

Stage 3: triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s (A4)

To a solution of A3 (1 EQ.) in DMA was added HBTU (2 EQ.), tert-butyl 1-homopiperazines (1.9 EQ.) and DIPEA (3.4 EQ.). The mixture was stirred over night at room temperature, then the reaction mixture was concentrated, the crude product was dissolved in DCM, washed twice with H2O, dried (Na2SO4) and concentrated under reduced pressure. The obtained orange oil was dissolved in a mixture of 6 M HCl/EtOH (2:1) and the mixture was stirred at room temperature for 1 hour. The solution was concentrated, podslushivaet concentrated aqueous solution of NH3to pH 9, then the organic matter was extracted with DCM. The combined organic fractions were washed H2O, saturated salt solution, dried (Na2SO4) and the solvent was removed under reduced pressure. The residue was purified by the method of preparative RP-HPLC, using H2O with 0.1% TFA) and MeCN (0.1% of TFA) as eluents (column: Water X-Terra C18), the combined fraction of the product liofilizirovanny that gave specified in the header link is, in the form of colorless powder.1H-NMR (300 MHz, DMSO-d6) δ: of 12.76 (1H, s), 8,79 (2H, users), 7,45-7,27 (3H, m), 7,19 (1H, s), 3,93 (2H, s), 3,85-3,74 (2H, m), of 3.56 (1H, m), 3,39-3,20 (5H, m), of 2.45 (2H, J=7.5 Hz), 2,08 is 1.91 (2H, m), is 1.11 (3H, t, J=7.5 Hz). MS (ES) for C19H23FN4O2calculated: 358, found: 359 (M+H)+.

EXAMPLE 2

Triptorelin 4-{5-[(4-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s (B3)

Stage 1: 5-[(6-chloro-4-ethylpyridine-3-yl)methyl]-2-Formentera acid (B1)

The solution from example 1, A2 (1 EQ.) in AcOH:concentrated HCl:H2O (1:10:1, 0,065 M) was heated at boiling under reflux overnight. The reaction mixture was then cooled to room temperature and was diluted with water/EtOAc. The organic phase was washed with saturated saline solution, dried (Na2SO4) and concentrated under reduced pressure. MS (ES) for C14H12ClFN2O2calculated: 294/296 found: 295/297 (M+H)+.

Stage 2: triptorelin 4-{5-[(6-chloro-4-ethylpyridine-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s (B2)

To a solution of B1 (1 EQ.) in DMA was added HBTU (2 EQ.), tert-butyl 1-homopiperazines (2 EQ.) and DIPEA (3.1 EQ.) and the mixture was stirred over night at room temperature. The reaction mixture was concentrated under reduced pressure and the crude product was dissolved in DCM, washed with H2O (2×), dry the Ali (Na 2SO4) and the solvent was removed under reduced pressure. The resulting crude product was dissolved in a solution of 6 M HCl:EtOH (3:1) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, podslushivaet aqueous ammonia to pH 9 and the mixture was extracted with DCM. The combined organic fractions were washed with water, saturated salt solution, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by the method of preparative RP-HPLC, using H2O with 0.1% TFA) and MeCN (0.1% of TFA) as eluents (column: Water X-Terra C18). Combined fractions of the product liofilizirovanny that gave specified in the title compound, as a yellow oil. MS (ES) for C19H22ClFN4O calculated: 376/378 found: 377/379 (M+H)+.

Stage 3: triptorelin 4-{5-[(4-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s (B3)

The mixture B2, NaOAc (2 EQ.) and AcOH (0,16 M) was heated at the boil under reflux for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by the method of preparative RP-HPLC, using H2O with 0.1% TFA) and MeCN (0.1% of TFA) as eluents (column: Water X-Terra C18). Combined fractions of the product liofilizirovanny that gave specified in the header of the connection.1H-NMR (00 MHz, DMSO-d6) δ: 12,80 (1H, m), 8,84 (2H, s), 7,38-7,28 (3H, m), of 6.66 (1H, s)to 4.01 (2H, s), 3,85-3,7 (2H, m), 3,55 (1H, m), 3,36-of 3.32 (2H, m), with 3.27 (1H, m), 3,20 (1H, m), and 3.16 (1H, m), 2,45-to 2.42 (2H, m)to 2.06 (1H, m,), 1,90 (1H, m), 1,11-of 1.07 (3H, m). MS (ES) for C19H23FN4O2calculated: 358, found: 359 (M+H)+.

EXAMPLE 3

6-{3-[(4-Acetyl-1,4-diazepan-1-yl)carbonyl]-4-terbisil}-4-ethylpyridine-3(2H)-he (C1)

To a solution of Example 1, A4 (1 EQ.) in DCM:DMF (2:1. 0.5 M) was added DIPEA (3 EQ.) with the subsequent addition of AcCl (1.2 EQ.). After stirring for 30 min at room temperature the solvent was removed under reduced pressure and the crude substance was re-dissolved in EtOAc, washed with 1 M HCl, dried (Na2SO4) and concentrated under reduced pressure. The resulting crude product was dissolved in TΗF:Η2O (1:1) was added LiOH (2 EQ.), after stirring for 40 min at room temperature, the reaction mixture was extracted with EtOAc. The combined organic fractions were washed with saturated salt solution, dried (Na2SO4) and concentrated under reduced pressure, which gave specified in the title compound as a yellow powder.1H-NMR (400 MHz, DMSO-d6) δ: 12,6 (1H, s), 7,38 (1H, m), 7,28-7,17 (3H, m)to 3.92 (2H, m), 3,82-3,66 (3H, m), 3,60-of 3.48 (3H, m), 3,43-3,30 (2H, m), 2,46 (2H, square, J=7,3 Hz), 2.05 is (1,5H, s), 1,89 (1,5H, s), 1,88-1,49 (2H, m), 1,12 (3H, t, J=7,3 Hz). MS (ES) for C21H25FN4O3RASSC the Eastern Europe and Caucasus: 400, found: 401 (M+H)+.

EXAMPLE 4

1-Acetyl-4-{5-[(6-chloro-4-ethylpyridine-3-yl)methyl]-2-perbenzoic}-1,4-diazepan (D1)

Specified in the title compound was obtained as described in example 3, from the product of example 2, B3. The compound was obtained as a white powder.1H-NMR (400 MHz, DMSO-d6) δ: 12,78 (1H, s), 7,32-7,14 (3H, m), of 6.65 (1H, s), 4,01-3,99 (2H, m), 3,79-3,63 (3H, m), 3,53-of 3.48 (3H, m), 3,40-of 3.27 (2H, m), 2,48 - to 2.41 (2H, m), 2,04-2,02 (3H, m), 1,86-of 1.78 (1H, m), 1,55 of 1.46 (1H, m), 1,11-of 1.06 (3H, m). MS (ES) for C21H25FN4O3calculated: 400 found: 401 (M+H)+.

EXAMPLE 5

4-Ethyl-6-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)pyridazin-3(2H)-he (E1)

To a solution of example 1, A3 (1 EQ.) in DMF (0.2 ml, of 0.28 M) was added ΗBTU (1.2 EQ.) and DIPEA (1 EQ.). The resulting solution was stirred 10 min at room temperature. Then to the solution was added a solution of chloride of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-Iya (PTC Int. Appl., WO 2005020929) (1.1 EQ.) and DIPEA (1.2 EQ.) in DMF (0.2 ml, of 0.28 M). The reaction mixture was stirred over night at room temperature. The crude product was purified by the method of preparative RP-ΗPLC using H2O with 0.1% TFA) and MeCN (0.1% of TFA) as eluents. Fraction of the product liofilizirovanny that gave specified in the title compound as a white powder.1H-NMR (300 MHz, DMSO-d6) δ: 12,74 (1H, s), 7,47-7,31 (3H, m), 7,2 (1H, C), 5,11-5,09 (1,4H, m), of 4.77-4.75 in (0,7H, m), 4,27-4,18 (2,6H, m), of 3.94 (2H, s), 3,80-3,78 (1,3H, m)2,44 (2H, square, J=7,3 Hz)of 1.11 (3H, t, J=7,3 Hz). MS (ES) for C20H18F4N6O2calculated: 450, found: 451 (M+H)+.

EXAMPLE 6

Triptorelin 4-{5-[(5-ethyl-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s (F8) and triptorelin 4-{5-[(4-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s (F9)

Stage 1: 3,6-Dichloro-4-ethyl-5-methylpyridazin (F1)

To a suspension of 3,6-dichloro-4-ethylpyridine (1 EQ.), AgNO3(0.7 EQ.) and AcOH (2.8 equiv.) in H2O (9.4 ml, 0.6 M) was added a solution of concentrated sulfuric acid (6.6 EQ.) in H2O (9.4 ml, 0.6 M) at 50°C, followed by the addition of a solution of peroxodisulfate ammonium (5.4 EQ.) in H2O (9.4 ml, 0.6 M) at 60°C for 20 minutes the Reaction mixture was heated at 70-75°C for 30 minutes After cooling, the reaction mixture was brought to pH 7 by the action of a 25% ammonium hydroxide solution and was extracted with Et2O. the Extracts were washed H2O, and dried (Na2SO4), the solvent was removed in high vacuum. The residue was purified by chromatography on silica gel, was suirable a mixture of 9:1 petroleum ether:EtOAc, gave the desired product as colourless crystals.1H-NMR (400 MHz, CDCl3) δ: 2,85 (2H, square, J=7,6 Hz), a 2.45 (3H, s)to 1.21 (3H, t, J=7,6 Hz).

Stage 2: 5-[(6-Chloro-5-ethyl-4-metylene Azin-3-yl)(cyano)methyl]-2-perbenzoate (F2) and 5-[(6-chloro-4-ethyl-5-methylpyridazin-3-yl)(cyano)methyl]-2-perbenzoate (F3).

Specified in the title compounds were obtained as described in example 1, Al and A2. The compound was obtained as a mixture of isomers (ratio 1:1), these isomers could not be separated by chromatography on silica gel (eluent petroleum ether:EtOAc, 7:3).1H-NMR (300 MHz, CDCl3) δ: to 7.77-to 7.67 (4H, m), 7,32-7,27 (2H, s), 5,76-5,72 (2H, m), 2,84 (2H, square, J=7.5 Hz), 2.71 to 2,69 (2H, m), is 2.44 (3H, s), 2,31 (3H, s)to 1.21 (3H, t, J=7.5 Hz), of 1.06 (3H, t, J=7.5 Hz). MS (ES) for C16H12ClFN4calculated: 314/316 found: 315/317 (M+H)+.

Stage 3: 5-[(5-Ethyl-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-Formentera acid (F4) and 5-[(4-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-Formentera acid(F5)

Specified in the title compounds were obtained as described in example 1, A3, of a mixture of F2 and F3 and the desired products were obtained as mixtures of isomers F4 and F5. MS (ES) for C15H15FN2O3calculated: 290, found: 291 (M+H)+.

Stage 4: tert-Butyl 4-{5-[(5-ethyl-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-carboxylate (F6) and tert-butyl 4-{5-[(4-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-carboxylate (F7)

To a solution of F4 and F5 (1 EQ.) in DMA was added HBTU (1.2 EQ.), tert-butyl 1-homopiperazines (1.4 EQ.) and DIPEA (3 EQ.). The reaction mixture was stirred for 1 hour at room temperature. The crude product was purified by the method of p is operativnoy RP-HPLC, using H2O with 0.1% TFA) and MeCN (0.1% of TFA) as eluents and combined fractions of the product liofilizirovanny that gave indicated in the title compounds as a mixture of isomers with a ratio of 1.6:1. MS (ES) for C25H33FN4O4calculated: 472, found: 473 (M+H)+.

Stage 5: triptorelin 4-{5-[(5-ethyl-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic]-1,4-diazepan-1-s (F8) and triptorelin 4-{5-[(4-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl-2-perbenzoic]-1,4-diazepan-1-s (F9)

The mixture F6 and F7 was dissolved in a solution of TFA:CH2C12(1:2, and 2.1 ml) and the resulting solution was stirred for 1 hour at room temperature. The solvent was concentrated and the residue was dissolved in MeCN:H2O, froze and then liofilizirovanny. The compounds indicated in the header of the example was obtained as a mixture (ratio F8:F9: 0,42/0,58).1H-NMR (400 MHz, DMSO-d6) δ: 12,70-12,67 (1H, m), 8,86 (2H, s), of 7.36-7,21 (3H, m), of 3.95 (2H, s), 3,90-3,55 (2H, m), 3,54 totaling 3.04 (6H, m), 2,45-to 2.40 (2H, m), 2,02 (3H, s)to 1.99 (2H, s), 1,02-0,92 (1,7H, m, main product), 0,91-081 (1,3H, m, minor product). MS (ES) for C20H26FN4O2calculated: 372, found: 373 (M+H)+.

EXAMPLE 7

Triptorelin 4-{2-fluoro-5-[(5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzoyl}-1,4-diazepan-1-s (G3)

Stage 1: 5-[(6-Chloro-5-isopropylpyridine-3-yl)(cyano)methyl]-2-perbenzoate (G1)

To a cooled with ice to a solution of 5-(cyanomethyl)-2-perbenzoate (1 EQ.) and 3,6-dichloro-4-isopropylpyridine (1.3 EQ.) (Reference: Org. Prep. + Proc. Int. 1988,20, 117 and U.S. patent 4628088, 1986) in THF (38 ml, 0.1 M) was added in portions NaH (1 EQ.). The reaction mixture was stirred at 0°C for 15 min, then warmed to room temperature and was stirred for 2 hours. The reaction was extinguished saturated aqueous NaHCO3and was extracted with EtOAc. The combined organic fractions were washed with saturated salt solution, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, was suirable a mixture of petroleum ether:EtOAc (8:2), which gave specified in the header of the connection.1H-NMR (400 MHz, CDCl3) δ: 7,80-7,79 (2H, m), 7,49 (1H, s), 7,31-7,29 (1H, m), 5,63 (1H, s), 3,34 of 3.28 (1H, m), 1,36-of 1.29 (6H, m). MS (ES) for C16H12ClFN4calculated: 314/316 found: 315/317 (M+H)+.

Stage 2: 2-Fluoro-5-[(5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzoic acid (G2)

Specified in the title compound was obtained as described in example 1, A3. MS (ES) for C15H15FN2O3calculated: 290, found: 291 (M+H)+.

Stage 3: Triptorelin 4-{2-fluoro-5-[(5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzoyl}-1,4-diazepan-1-s (G3)

Specified in the title compound was obtained as described in note the re 6, stage 4+5. Specified in the title compound was obtained as a yellow powder.1H-NMR (400 MHz, DMSO-d6) δ: of 12.76 (1H, s), a total of 8.74 (2H, users), 7,45-7,28 (3H, m), 7,19-7,17 (1H, m), of 3.94 (2H, s), 3,86-to 3.73 (2H, m), 3,55-3,18 (6H, m), 3,02-of 3.00 (1H, m), 2,07-1,90 (2H, m), 1,15-of 1.12 (6H, m). MS (ES) for C20H25FN4O2calculated: 372, found: 373 (M+H)+.

EXAMPLE 8

Triptorelin 4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-ia (H2)

Step 1: tert-Butyl 4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-carboxylate (H1)

To a solution of example 14, N4 (1 EQ.) in DMA (3,7 ml, 0.4 M) was added HBTU (1.2 EQ.), tert-butyl 1-homopiperazines (1.4 EQ.) and DIPEA (3 EQ.). The reaction mixture was stirred for 1 hour at room temperature. The reaction was extinguished saturated aqueous NaHCO3and was extracted with CH2Cl2. The combined organic fractions were washed with saturated salt solution, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by the method of preparative RP-HPLC, using H2O with 0.1% TFA) and MeCN (0.1% of TFA) as eluents and combined fractions of the product liofilizirovanny that gave specified in the header of the connection.1H-NMR (300 MHz, DMSO-d6) δ: 12,69 (1H, s), 7,31-7,07 (3H, m), 4,00-3,98 (2H, m), 3.72 points-of 3.54 (3H, m), 3,39-to 3.35 (4H, m), 3,29-of 3.27 (1H, m), 2,03 (6H, users), 1,79-to 1.77 (1H, m) 1,50 is 1.48 (1H, m), 1,42 (7,7H, s), 1,31 (2,3H, s). MS (ES) for C24H31FN4O4calculated: 458, found: 459 (M+H)+.

Stage 2: Triptorelin 4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-ia (H2)

Specified in the title compound was obtained as described in example 6, stage 5, and was obtained as a yellow powder.1H-NMR (400 MHz, DMSO-d6) δ: of 12.73 (1H, s), 8,11 (2H, users), was 7.36-7,26 (3H, m)4,00 (2H, s), 3,85-of 3.54 (2H, m), 3,37-3,20 (6H, m), 2.05 is-2,03 (7H, m), 1,90-of 1.88 (1H, m). MS (ES) for C19H23FN4O2calculated: 358, found: 359 (M+H)+.

EXAMPLE 9

Triptorelin 1-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-N,2-dimethyl-1-oxopropyl-2-ammonium (I2).

Stage 1: triptorelin 4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-s (I1)

To a solution of intermediate of example 14, N4 (1 EQ.) in DMF (0,97 ml of 0.4 M) was added HBTU (1.2 EQ.) and DIPEA (5 EQ.). After 10 min at room temperature, thereto was added tert-butyl 1-piperidinecarboxylate (1.2 EQ.) and the reaction solution was stirred over night at room temperature. The reaction extinguished saturated aqueous NaHCO3and was extracted with CH2Cl2. The organic phase was washed once with 1 N. hydrochloric acid and saturated saline. The combined organic fractions were washed the feast upon the major salt solution, dried (Na2SO4) and concentrated under reduced pressure. The crude product was dissolved in a solution of TFA:CH2C12(1:2, 3.4 ml) and the resulting solution was stirred for 1 hour at room temperature. The solvent was evaporated to dryness and the crude product was purified by the method of preparative RP-HPLC, using H2O with 0.1% TFA) and MeCN (0.1% of TFA) as eluents (column: Water X-Terra C18). Fraction of the product liofilizirovanny obtaining specified in the title compound as yellow crystals.1H-NMR (400 MHz, DMSO-d6) δ: 12,71 (1H, s)of 8.92 (2H, users), 7,32-7,30 (3H, m)4,00 (2H, s), 3,86-a-3.84 (2H, m), 3.46 in-3,44 (2H, m), 3.25 to of 3.23 (2H, m), 3,11-to 3.09 (2H, m), is 2.05 (3H, s)2,04 (3H, s). MS (ES) for C18H21FN4O2calculated: 344, found: 345 (M+H)+.

Stage 2: triptorelin 1-(4-(5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-N,2-dimethyl-1-oxopropyl-2-ammonium (I2)

N-BOC-N,2-dimethylalanine (3 equiv.) HATU (3 EQ.) and DIPEA (3 EQ.) was dissolved in DMF (40 μl, 0.1 M). After 10 min at room temperature was added a solution of I1 and DIPEA (1.2 EQ.) in DMF (0.1 ml, 0.3m). The reaction solution was stirred over night at room temperature. The crude product was purified by the method of preparative RP-HPLC, using H2O with 0.1% TFA) and MeCN (0.1% of TFA) as eluents (column: Water X-Terra C18). The product fractions liofilizirovanny that gave listed in the connection header in the form of b is the logo of the powder. 1H-NMR (400 MHz, DMSO-d6) δ: 12,72 (1H, s), 8,84-8,82 (2H, m), 7,38-of 7.25 (3H, m)4,00 (2H, s), 3,71 (4H, s)and 3.59 (2H, users), and 3.31 (2H, users), to 2.06 (3H, s)2,04 (3H, s), was 1.58 (6H, s). MS (ES) for C23H30FN5O4calculated: 443, found: 444 (M+H)+.

EXAMPLE 10

Triptorelin 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-8-Aza-1-Sonisphere[4,5]decane (J1)

Specified in the title compound was obtained as described in example 9. The product of example 14, N4, introduced in the interaction with the oxalate salt of tert-butyl l,8-diazaspiro[4,5]decane-1-carboxylate. Specified in the title compound was obtained as a yellow powder.1H-NMR (400 MHz, DMSO-d6) δ: 12,71 (1H, s), 8,73 (2H, users), was 7.36-7,22 (3H, m), 4,15-4,11 (1H, m)4,00 (2H, s), 3,38-of 3.25 (5H, m), 2.05 is to 1.76 (14H, m). MS (ES) for C22H27FN4O2calculated: 398, found: 399 (M+H)+.

EXAMPLE 11

Bis(triptorelin) 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-2-s-3-yl)methyl]-2-perbenzoic}-1 - methyl-8-Aza-1-Sonisphere[4,5]decane (K1)

To a solution of the product of example 11, J1 (1 EQ.) in MeOH (0.5 ml, 0.1 M) was added TEA (2.2 EQ.) to pH 6-7. Then was added formaldehyde (10 EQ., 37% in H2O), NaBH3(CN) (8 EQ.) and NaOAc (2.8 equiv.). The reaction solution was stirred over night at room temperature. The solvent was removed and the crude product was purified by the method of preparative RP-HPLC using H2O (0.1% of TFA) and MeCN (0.1% of TFA) as eluents. Combined fractions of the product liofilizirovanny that gave specified in the header connection. Shows the signals of the main rotamer1H-NMR (400 MHz, DMSO-d6) δ: 12,72 (1H, users), 9,63 (1H, users), was 7.36-7,24 (3H, m), 4.63 to-4,60 (1H, m)4,00 (2H, s), 3,61 (1H, users), 3,49-of 3.42 (1H, m), 3,23-3,17 (2H, m), 2,98-2,84 (1H, m), 2,75-by 2.73 (2H, m), 2,58 (3H, s), 2.40 a-2,31 (1H, m), 2,04 (6H, s), 1,97-to 1.79 (4H, m), 1,63 is 1.60 (1H, m). MS (ES) for C23H29FN4O2calculated: 412, found: 413 (M+H)+.

EXAMPLE 12

Triptorelin 4-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-N,N-dimethyl-2-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}of benzolamide (L3)

Stage 1: 2-(Dimethylamino)-5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzonitrile (L1)

A solution of the product of example 14, N3 (1 EQ.) and dimethylamine (4 EQ., 2 M in MeOH) in dry DMF (2.7 ml, 0.1 M) was sealed in a microwave vial. The reaction solution was heated to 180°C and was stirred for 1.5 hours. Then the solution was cooled to room temperature and the solvent was evaporated in high vacuum. The crude product was purified on SCX cartridge. Specified in the title compound was washed with a solution of 2 M NH3in methanol and concentrated under reduced pressure.1H-NMR (300 MHz, DMSO-d6) δ: 12,67 (1H, users), was 7.45 (1H, s), 7,33 (1H, d, J=8,4 Hz), 7,03 (1H, d, J=8,4 Hz), 3,90 (2H, s), of 2.97 (6H, s), is 2.05 (3H, s)2,03 (3H, s). MS (ES) for C16H18N4 O calculated: 282 found: 283 (M+H)+.

Stage 2: 2-(Dimethylamino)-5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzoic acid (L2)

L1 (1 EQ.) suspended in H2O (0.4 ml of 0.7 M) and the resulting suspension was added an aqueous solution of 15 M NaOH (8 EQ.) and they were heated to the boiling temperature under reflux for 72 hours. The reaction solution was cooled to room temperature and acidified to pH 4 by the action of 2 M HCl. The crude product was purified on SCX cartridge. Specified in the header of the product was washed with a solution of 2 M ammonia in methanol and concentrated under reduced pressure. MS (ES) for C16H19N3O3calculated: 301 found: 302 (M+H)+.

Stage 3: Triptorelin 4-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-N,N-dimethyl-2-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}of benzolamide (L3)

L2 (1 EQ.), TBTU (1.1 EQ.) and DIPEA (1 EQ.) was dissolved in DMF (0.6 ml, and 0.2 M) and the solution was stirred 10 min at room temperature. Then thereto was added a solution of the chloride of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-Iya (PTC Int. Appl., WO 2005020929) (1.1 EQ.) and DIPEA (1.2 EQ.) in DMF (0.3 ml, and 0.2 M). The reaction mixture was stirred over night at room temperature. The crude product was purified by the method of preparative RP-HPLC using H2O with 0.1% TFA) and MeCN (0.1 %of TFA) as eluents (Colo is CA: Water X-Terra C18). Combined fractions of the product liofilizirovanny that gave specified in the title compound as a yellow powder.1H-NMR (400 MHz, DMSO-d6) δ: 12,67 (1H, users), 7.24 to 7,07 (3H, m), 5,07-of 5.05 (1H, m), 4,58 (1H, users), 4.26 deaths is 4.13 (3H, m)to 3.92 (2H, s)of 2.75 (3H, s), 2,5 (3H, overlapped with solvent peak), 2,03 (6H, s). MS (ES) for C22H24F3N7O5calculated: 475, found: 476 (M+H)+.

EXAMPLE 13

Triptorelin 6-(4-isopropoxy-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-FL(M3)

Stage 1: 5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-isopropoxybenzonitrile (M1)

The solution isopropoxide sodium was obtained by reaction of sodium (2.5 EQ.) with a dry 2-propanol (3 ml of 0.03 M), to this solution was added a solution of example 14, N3 (1 EQ.) in a dry 2-propanol (2.4 ml, 0,02 M). The resulting solution was heated to boiling point under reflux and was stirred for 5 hours. The reaction solution was cooled to room temperature and the solvent was evaporated in high vacuum. The crude product was dissolved in EtOAc. The organic phase is washed twice with water, dried (Na2SO4) and the solvent was evaporated to dryness. MS (ES) for C17H19N3O2calculated: 297, found: 298 (M+H)+.

Stage 2: 5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridin-yl)methyl]-2-isopropoxybenzoic acid (M2 )

M1 (1 EQ.) suspended in H2O (0.3 ml of 0.7 M) and the resulting suspension was added 15 M aqueous NaOH solution (8 EQ.) and they were heated to the boiling temperature under reflux for 48 hours. The reaction solution was cooled to room temperature and acidified to pH 4 by the action of 2 M HCl. The crude product was purified on a SAX cartridge. Specified in the header of the product was washed with a solution of 2 M HCl in methanol and the solvent was concentrated under reduced pressure. MS (ES) for C17H20N2O4calculated: 316, found: 317 (M+H)+.

Stage 3: Triptorelin 6-(4-isopropoxy-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s (M3)

Specified in the title compound was obtained as described in example 12, step 3, was obtained as a white powder.1H-NMR (400 MHz, DMSO-d6) δ: 12,70 (1H, s), 7,26-7,24 (1H, m), 7,13-7-05 (2H, m), 5,23-5,19 (0,4H, m), 4,93-4,88 (0,4H, m), the 4.65-4.63 to (1,6H, m), 4,54-4,25 (1,6H, m), 4,16-4,10 (2H, m), 3,93-a 3.87 (3H, m), 2.05 is-2,03 (6H, m), 1.26 in-to 1.21 (3H, m), 1,00 to 0.92 (3H, m). MS (ES) for C23H25F3N6O3calculated: 490, found: 491 (M+H)+.

EXAMPLE 14

6-(4-Fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4,5-dimethylpyridin-3(2H)-he

Stage 1: 5-[(6-Chloro-4,5-dimethylpyridin-3-yl)(cyano)methyl]-2-perbenzoate (N1)

Methods the and repeats the method described in example 1, stage 1, on the basis of 3,6-dichloro-4,5-dimethylpyridine (obtained according to J. Org. Chem. 1955,20, 707-13).1H-NMR (300 MHz, DMSO-d6) δ: 8,05-of 7.96 (1H, m), 7,95-of 7.82 (1H, m), 7,70-to 7.61 (1H, m), 6.48 in (1H, s)to 2.41 (3H, s)to 2.29 (3H, s). MS (ES) for C15H10ClFN4calculated: 300 found: 301 (M+H)+.

Stage 2: 5-[(6-Chloro-4,5-dimethylpyridin-3-yl)methyl]-2-perbenzoate (N2)

The intermediate connection N1 suspended in a mixture of acetic acid, concentrated aqueous HCl, and water (1:1:2, of 0.07 M). The suspension was stirred and heated at the boil under reflux for 75 minutes, the Reaction mixture was cooled to room temperature and the solvents were removed under reduced pressure. To the residue was added saturated aqueous NaHCO3and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by the method of column chromatography on silica gel, was suirable a mixture of petroleum ether-EtOAc (10-80% EtOAc)which gave specified in the title compound as a yellow solid. MS (ES) for C14H11ClFN3calculated: 275, found: 276 (M+H)+.

Stage 3: 5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoate (N3)

To a solution of intermediate compound N2 in acetic acid (0,16 M) was added NaOAc (2 EQ.) and the mixture was stirred and heated up to the singing under reflux for 1 hour. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue is suspended in water and was ground into powder to obtain a fine suspension. The solid was filtered, washed with water, dried in a stream of air and then in a high vacuum. MS (ES) for C14H12FN3O calculated: 257, found: 258 (M+H)+.

Stage 4: 5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-Formentera acid (N4)

To a suspension of intermediate compounds N3 in water (0,35 M) was added NaOH (8 EQ.) and the resulting mixture was stirred and heated to 100°C for 60 minutes the Mixture was cooled in an ice bath and slowly acidified to pH 2-3 step 6 N. HCl. The resulting light yellow precipitate was filtered, dried in a stream of air and then in a high vacuum. MS (ES) for C14H13FN2O3calculated: 276, found: 277 (M+H)+.

Stage 5: 6-(4-Fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl}carbonyl}benzyl)-4,5-dimethylpyridin-3(2H)-he (N5)

The intermediate connection N4 (1 EQ.), TBTU (2 EQ.) and DIPEA (1.1 EQ.) was dissolved in DMF (1.1 ml, and 0.2 M) and the solution was stirred 10 min at room temperature. Then was added a solution of chloride of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-Iya (PTC Int. Appl., WO 2005020929) (2.2 EQ.) and DIPEA (1.2 EQ.) in DMF (1.4 ml of 0.2 M). The reaction mixture was stirred is 5 hours at room temperature. The reaction mixture was diluted with EtOAc and washed twice with saturated saline solution. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by the method of preparative RP-HPLC, using H2O with 0.1% TFA) and MeCN (0.1% of TFA) as eluents. Fraction of the product liofilizirovanny and received triperoxonane salt was distributed between EtOAc and saturated aqueous NaHCO3. The organic phase was dried (Na2SO4) and the solvent was evaporated to dryness. The connection is indicated in the header of the example was obtained as a white powder.1H-NMR (400 MHz, DMSO-d6) δ: 12,70 (1H, s), 7,42-7,31 (3H, m), 5,09 (1H, users), and 4.75 (1H, users), 4,28 (1H, users), to 4.16 (2H, users), to 4.01 (2H, s), 3,78 is 3.76 (1H, m), 2.05 is-2,03 (6H, m). MS (ES) for C20H18F4N6O2calculated: 450, found: 451 (M+H)+.

EXAMPLE 15

6-(4-Fluoro-3-{[4-(2-methylpropyl)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethylpyridin-3(2H)-he

A mixture of 1-(tert-butoxycarbonyl)-2-methylpropene (1 EQ.), TEA (2 EQ.), PyBOP (1 EQ.) and 6-[4-fluoro-3-(piperazine-1-ylcarbonyl)benzyl]-4,5-dimethylpyridin-3(2H)-she (I1) in dry DMF (0.1 M) was heated at 60°C with microwave irradiation for 2 hours. The product was isolated by the method of preparative ΗPLC. After freeze drying of the combined product fractions, the residue was dissolved in 10% TFA/DCM and the solution was warmed to 45°C during the 1 hour. The residue obtained after evaporation of the solvent was further purified on SCX cartridge. Freeze drying from water/MeCN resulted specified in the title compound as a white powder.1H-NMR (400 MHz, DMSO-d6) δ: 12,67 (1H, s), 7,38-7,13 (3H, m), of 3.96 (2H, s), 3,8-3,5 (5H, m), 3,3 (1H under water signal), 3,26-3,13 (2H, m), 2,92-2,78 (1H, m), was 2.76-of 2.58 (1H, m), 2,34-to 2.15 (1H, m), 2,02 (3H, s), from 2.00 (3H, s), 1,75-of 1.46 (3H, m), of 1.26 (3H, s). MS (ES) for C24H30FN5O3calculated: 455, found: 456 (M+H)+.

EXAMPLE 16

Triptorelin 6-[4-fluoro-3-(4-methyl-2,5-dioxoimidazolidin-1-yl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-FL

Step 1: tert-butyl {5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-forfinal}carbamate (O1)

To a mixture of Example 14, N4, tert-BuOH:toluene (1:1, 0,171 M) was added diphenylphosphoryl (2.2 EQ.) and Et3N (2.2 EQ.). The reaction mixture was heated at the boil under reflux until the exhaustion of the original substance, then boiling products were removed under reduced pressure. The obtained residue was distributed between DCM and saturated aqueous NaHCO3; the organic phase was separated, dried (Na2SO4) and filtered. Evaporation of the solvent resulted in a yellow oil (O1), which was used as such in the next stage without purification. MS (ES) for C18H22FN3O3calculated: 347, found: 348 (M+H)+.

The study is 2: triptorelin 6-(3-{[N-(etoxycarbonyl)alanyl]amino}-4-terbisil)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s (O2 )

O1 was dissolved in DCM:TFA (1:1, 0,17 M) and the mixture was stirred at room temperature for 1 hour, then volatile products were removed under high vacuum. The resulting oil and DIPEA (2,35 EQ.) was added to a stirred solution of N-(etoxycarbonyl)alanine (1,35 equiv.) TBTU (1,35 EQ.) and DIPEA (1,35 EQ.) in dry DMF (0.3m). The mixture was stirred at room temperature for 2 days and then diluted with DCM and washed with water. The organic phase was washed with saturated saline solution, dried (Na2SO4) and concentrated under reduced pressure. The product was isolated by the method of preparative HPLC using MeCN/water (with 0.1% TFA) as eluents. Combined fractions of the product liofilizirovanny obtaining specified in the connection header (O2) as a white fluffy powder. MS (ES) for C19H23FN4O4calculated: 390, found: 391 (M+H)+.1H-NMR (300 MHz, DMSO-d6) δ: 12,65 (1H, s), being 9.61 (1H, s), 7,76-the 7.65 (1H, m), 7,45-7,30 (2H, m), 7.23 percent-7,10 (1H, m), 7,01-of 6.90 (1H, m), 4,27 (1H, m), 3,98 (2H, square, J=6.9 Hz), 3,90 (2H, s), 2,03 is 1.96 (6H, m), 1.30 and of 1.23 (3H, m)of 1.16 (3H, t, J=6.6 Hz).

Stage 3: triptorelin 6-[4-fluoro-3-(4-methyl-2,5-dioxoimidazolidin-1-yl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s (O3)

To a solution of O2 in DMF (0.1 M) was added DMAP (3 EQ.) and the mixture was heated in a microwave oven at 180°C for 2 hours. The product was isolated using preparative RP-HPLC, using H2O (+0,1% TFA) and MeCN +0.1% of TFA) as eluents. The desired fractions liofilizirovanny with getting the required connection.1H-NMR (300 MHz, DMSO-d6) δ: 12,67 (1H, s), charged 8.52 (1H, s), 7,35-7,28 (2H, m), 7,25-to 7.18 (1H, m), 4,36-4.26 deaths (1H, m), of 3.97 (2H, s), 2.06 to of 1.97 (6H, m), 1,38 to 1.31 (3H, m). MS (ES) for C17H18FN4O3calculated: 344, found: 345 (M+H)+.

EXAMPLE 17

Triptorelin 6-(3-{[3-[1-(dimethylamino)-1-methylethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}-4-terbisil)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-FL

Stage 1: Methyl N-(tert-butoxycarbonyl)-2-methylalanine (P1)

To a solution of Boc-α-methylalanine in DMF (0,4 M) was added K2CO3(1 EQ.) and MeI (1.2 EQ.). The mixture was stirred at room temperature for 6 hours and then diluted with EtOAc, washed with water and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated in vacuum to obtain specified in the title compound as a yellow solid.1H-NMR (300 MHz, DMSO-d6) δ: 7,20 (1H, users), to 3.58 (3H, s), 1,40-1.27mm (15H, m). MS (ES) for C10H19NO4calculated: 217, found: 240 (M+Na)+.

Step 2: tert-Butyl (2-hydrazino-1,1-dimethyl-2-oxoethyl)carbamate (P2)

To a solution of P1 in 2-propanol (0,56 M) was added hydrazine monohydrate (10 EQ.) and the mixture was stirred overnight at 90°C. the Volatile products were removed under high vacuum and the resulting untreated is this substance was used as such in the next stage. MS (ES) for C9H19N3O3calculated: 217, found: 240 (M+Na)+.

Step 3: Benzyl 5-(2-{2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl}hydrazino)-3,6-dihydropyridin-1(2H)-carboxylate (P3)

Adding Me3O+BF4-(1 EQ.) to a solution of benzyl 3-oxopiperidin-1-carboxylate (1 EQ.) in DCM (0,85 M), the reaction mixture was stirred for 48 hours. Then add P2, suspended in DCM, and the stirring was continued for another 3 days. The mixture was diluted with DCM and washed with 1 N. NaOH solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to obtain specified in the title compound as a clear oil, which was used as such in the next stage. MS (ES) for C21H31N5O5calculated: 433, found: 434 (M+H)+.

Stage 4: triptorelin 7-[(benzyloxy)carbonyl]-3-{1-[(tert-butoxycarbonyl)amino]-1-methylethyl}-5,6,7,8 - tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s (P4)

A solution of P3 in n-BuOH was heated under reflux for 15 minutes the Solvent was removed under reduced pressure and the crude product was purified system Biotage chromatography was carried out with gradient elution 0-15% MeOH/DCM and then was purified preparative RP-HPLC using H2O with 0.1% TFA) and MeCN (0.1% of TFA) as eluents. United fra is the product liofilizirovanny obtaining specified in the title compound as a clear oil. 1H-NMR (300 MHz, DMSO-d6) δ: at 7.55 (1H, users), 7,44-7,29 (5H, m), 5,14 (2H, users), to 4.81 (2H, users), 4,08-of 3.97 (2H, m), 3,90-of 3.77 (2H, m)of 1.55 (6H, users), of 1.30 (9H, m). MS (ES) for C21H29N5O4calculated: 415, found: 416 (M+H)+.

Stage 5: Benzyl 3-[1-(dimethylamino)-1-methylethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-carboxylate (P5)

P4 was dissolved in DCM:TFA (1:1, 0,105 M) and the mixture was stirred at room temperature for 2 hours. Volatile products were removed under high vacuum, the residue was dissolved in MeOH (0.1 M) and then was added TEA (3 EQ.) to pH 7. To the mixture was added formaldehyde (37% aqueous solution, 10 equiv.) NaBH3(CN) (3 EQ.) and AcOH (4 equiv.) and the mixture was stirred at room temperature for 2 hours. Volatile products was evaporated and the crude substance was purified by SCX cartridge, suirable the desired product with a mixture of NH3/MeOH. After evaporation of the solvent a clear oil was used as such in the next stage. MS (ES) for C18H25N5O2calculated: 343, found: 344 (M+H)+.

Stage 6: N,N-Dimethyl-2-(5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-3-yl)propan-2-amine (P6)

The mixture P5 (0.12 mmol) and Pd/C (10%, 22 mg) in MeOH (0,2 M) was stirred in hydrogen atmosphere overnight. The catalyst was filtered and the solvent was removed under reduced pressure to obtain the crude oil used as such in the following is tadie. MS (ES) for C10H19N5calculated: 209, found: 210 (M+H)+.

Stage 7: triptorelin 6-(3-{[3-[1-(dimethylamino)-1-methylethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}-4-terbisil)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s (P7)

To a solution of example 14, N4, and DIPEA (1.3 EQ.) in DMF (0.3m) was added TBTU (1.3 EQ.). The resulting mixture was stirred at room temperature for 40 minutes and then added P6 (1 EQ.). Stirring was continued for 1 hour and the product was isolated by the method of preparative RP-HPLC, using H2O with 0.1% TFA) and MeCN (0.1% of TFA) as eluents. Combined fractions of the product liofilizirovanny obtaining specified in the title compound as a white powder.1H-NMR (400 MHz, DMSO-d6) δ: 12,67 (1H, s), 10,12 (1H, users), 7,43 and 7.36 (1H, m), 7,35-of 7.23 (2H, m), 4,99 (1H, users), of 4.66 (1H, users), the 4.29 (1H, users), 3,98 (2H, s), 4,20-3,63 (3H, partially overlapped with water signal), 2,80-2,69 (6H, m), 2,04-of 1.97 (6H, m), 1,78-of 1.66 (6H, m). MS (ES) for C24H31FN7O2calculated: 467, found: 468 (M+H)+.

EXAMPLE 18

Triptorelin (2R)-2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-methylaziridine (Q2)

Step 1: tert-Butyl (2R)-2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-methylaziridine-1-carboxylate (Q1)

A solution of (2R)1-(tert-butoxycarbonyl)-2-methylaziridine-2-carboxylic acid (1.5 EQ.) and HATU (1.5 EQ.) in dry DMF (0.1 M) was stirred at room temperature for 30 minutes Then was added the product of Example 14, N4 (1.0 EQ.) and DIPEA (1.5 EQ.). The reaction mixture was stirred at 40°C for 48 hours, then diluted with EtOAc, washed sequentially with a saturated aqueous solution of NaHCO3, 1 N. HCl solution and saturated saline solution. The resulting solution was dried (Na2SO4), filtered and concentrated to obtain specified in the title compound, which was used in the next stage without additional purification. MS (ES) for C28H36FN5O5calculated: 541, found: 542 (M+H)+.

Stage 2: triptorelin (2R)-2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-methylaziridine (Q2)

(Q1) was dissolved in a mixture of DCM/TFA (9:1, is 0.06 M) and was stirred for 18 hours at room temperature. The solvent was evaporated under reduced pressure and the crude product was purified preparative RP-HPLC, using H2O with 0.1% TFA) and MeCN (0.1% of TFA) as eluents. The desired fractions liofilizirovanny obtaining specified in the connection header (Q2) as a white solid.1H-NMR (400 MHz, DMSO-d6, 300K) δ: 12,67 (1H, s), 9,16 (1H, users), 8,91 (1H, users), 7,35-7,17 (3H, m), 4,07-3,91 (3H, m), 3.8 to 3.15 in (9H, m), 2,92-by 2.73 (1H, m), 2,60 was 2.25 (1H, m, overlapped with a signal of DMSO), from 2.00 (3H, s)to 1.99 (3H, s), 1.77 in (1,5H, s), 1,72 (1,5H, s). MS (ES) for C25H29F3N5O5calculated: 441, nage is about: 442 (M+H) +.

EXAMPLE 19

Triptorelin 6-{4-fluoro-3-[(4-{[1-(isobutylamino)cyclopentyl]carbonyl}piperazine-1-yl}carbonyl]benzyl}-4,5-dimethylpyridin-3(2H)-he (R2)

Stage 1: 6-[3-({4-[(1-aminocyclopent)carbonyl]piperazine-1-yl}carbonyl)-4-terbisil]-4,5-dimethylpyridin-3(2H)-he (R1)

The desired compound was obtained following the General methodology described in example 18, step 1 and 2, using 1-[(tert-butoxycarbonyl)amino]cyclopentanecarbonyl acid and the product of Example 14, N4, as the starting materials. In addition, in stage 1 was added HOBT (1.3 EQ.). The product was obtained as a yellow solid after purification by SCX cartridge. MS (ES+for C24H30FN5O3calculated: 455, found: 456 (M+H)+.

Stage 2: triptorelin 6-{4-fluoro-3-[(4-{[1-(isobutylamino)cyclopentyl]carbonyl}piperazine-1-yl)carbonyl]benzyl}-4,5-dimethylpyridin-3(2H)-he (R2)

R1 (1.0 EQ.) and 2-methylpropanal (1.0 EQ.) in dry methanol (0.04 M) was stirred at room temperature for 2 hours, NaBH3(CN) (1.0 EQ.) was added and stirred at room temperature for 1 hour. Then added water and the aqueous phase was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and the solvents were removed under reduced pressure. The crude product was purified preparative RP-HPLC, using H2O with 0.1% TFA) and MeCN (0.1% of TA) as eluents. The desired fractions liofilizirovanny obtaining specified in the connection header (CSF2) as a white solid.1H-NMR (400 MHz, DMSO-d6, 300K) δ: 12,66 (1H, s), 8,40 (2H, users), 7,35-7,16 (3H, m), of 3.95 (2H, s), 3.72 points is 3.40 (6H, m), or 3.28 (2H, m), 2,68 (2H, m), 2,52 (1H, m)to 2.13 (4H, m), of 2.08 (3H, s)to 1.98 (3H, s), a 1.88 (4H, m)to 0.96 (6H, d, J=6,4 Hz). MS (ES) for C28H38FN5O3calculated: 511, found: 512 (M+H)+.

The following compounds were obtained according to the procedures described in the examples.

Connection.Chemical nameMolecular ion[M+H]+Obtained by example
20triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-yl)pyrimidine-1-FL4364375
21triptorelin 4-(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)pyridinium4204215
22triptorelin 2-{[(1-{5-[(5-ethyl-6-oxo-1,6-digitop is ridazin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)oxy] methyl}pyridinium 4504515

23triptorelin 2-{[(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-3-yl)oxy]methyl}pyridinium4504515
24triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-5-methoxypyridine4514525
25triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-4-methoxypyridine4514525
26triptorelin 4-(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}pyrrolidin-3-yl)pyridinium4064075
27triptorelin 1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-3-yl)-N,N-dime is ylmethanone 4004015
284-Ethyl-6-[4-fluoro-3-(1'H-Spiro[1-benzofuran-3,4'-piperidine]-1'-ylcarbonyl)benzyl]pyridazin-3(2H)-he4474485
29triptorelin 1-[2-(1-{5-[(5-Ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)ethyl]-1H-pyrazole-2-FL4374385
30triptorelin 5-Chloro-2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)pyridinium455/457456/4585
31triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-6-methoxypyridine4514525
32triptorelin 3-benzyl-7-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-1-FL471 4725
33triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-3,6-dimethylpyrazine-1-FL4504515
34triptorelin 4-ethyl-6-{4-fluoro-3-[(3-phenyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)carbonyl]benzyl}-3-oxo-2,3-dihydropyridin-1-FL4574585
35triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1-(3-methoxybenzyl)piperazine-1-FL4644655

36triptorelin 2-(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)-1,2,3,4-tetrahydroisoquinoline4744755
37triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-FL344 3456
38triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-phenylpiperazin-1-FL4204216
39triptorelin 3-benzyl-4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-FL4344356
40bis(triptorelin) 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-2-(pyridine-3-ylmethyl)piperazine-1-FL4354366
416-(3-{[4-(Cyclopentanecarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-terbisil)-4,5-dimethylpyridin-3(2H)-he4544555
426-(3-{[4-(Cyclopentanecarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-terbisil)-4-ethylpyridine-3(2H)-he4544555
43three is corzett 4-{5-[(4,5-diethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-FL 3863878
44triptorelin 4-{2-fluoro-5-[(5-isopropyl-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzoyl}-1,4-diazepan-1-FL3863876
45triptorelin 4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic]piperazine-1-FL3443459
466-{4-fluoro-3-[(4-propenylbenzene-1-yl)carbonyl]benzyl}-4,5-dimethylpyridin-3(2H)-he4004019
476-(3-{[4-(divercity)piperazine-1-yl]carbonyl}-4-terbisil)-4,5-dimethylpyridin-3(2H)-he4224239
486-(4-fluoro-3-{[4-(3,3,3-tryptophanol)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethylpyridin-3(2H)-he4544559
49 triptorelin 6-{4-fluoro-3-[(4-isobutylpyrazine-1-yl)carbonyl]benzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-FL4144159
50triptorelin 2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]pyridinium4494509

516-(4-fluoro-3-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethylpyridin-3(2H)-he4424439
52triptorelin 1-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-N,N,2-trimethyl-1-oxoprop-2-ammonium4574589
53triptorelin 6-(4-fluoro-3-{[4-(2,2,3,3,3-pentafluoropropanol)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-FL4904913
54triptorelin 6-(4-fluoro-3-{[4-(pyrrolidin-1-ylcarbonyl)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-FL4414423
55triptorelin 6-(4-fluoro-3-{[4-(TRIFLUOROACETYL)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-FL4404413
56triptorelin 1-(1-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)piperidine4264275
57triptorelin 1-(1-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)pyrrolidine4124135
58triptorelin 4-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)hinzelin-1-FL4724735
59 triptorelin 2-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)pyrimidine-1-FL4224235
60bis(triptorelin) 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(3-were)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1,4-die4724735
61triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-FL5265275
62triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-[(4-pertenece)methyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-2-FL5065075

63triptorelin 3-cyano-2-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)pyridinium 4464475
64triptorelin 3-(3,5-differenl)-7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-FL4944955
65bis(triptorelin) 3-[(dimethylammonio)methyl]-7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-2-FL4394405
66triptorelin (7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-N,N-dimethylethanamine43944014
67triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(2-furyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-FL44844914
68triptorelin 7-{5-[(4,5-dimethyl-6-ox is -1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(pentafluoroethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-FL 50050114
69triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-{[4-(trifluoromethyl)phenyl]amino}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-FL54154214
70chloride 2-[(4-{2-fluoro-5-[(6-hydroxy-4,5-dimethylpyridin-3-yl)methyl]benzoyl}piperazine-1-yl)carbonyl]-2-methylpyrrolidine45645715
71triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-FL45845914
72triptorelin 3-(l,3-benzodioxol-5-yl)-7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-FL50250314

73 triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(2-thienyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-FL46446514
74triptorelin 3-cyclopropyl-6-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-2-FL42142214
75triptorelin 6-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-2-FL44945014
76triptorelin 5-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-2-FL44945014
77bis(triptorelin) 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-pyridine-3-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-2-FL459 46014
78triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-7-Aza-1-Sonisphere[3,5]nonane38438510
79triptorelin 1-[(1-{3-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}azetidin-3-yl)methyl]pyrrolidine39839914
80triptorelin 1-(1-{3-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)-3,3-diversative43443514
81triptorelin 5-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1-(2,2,2-triptorelin)-4,5,6,7-tetrahydro-1H-[l,2,3]triazolo[4,5-c]pyridine-3-FL46446514
82triptorelin 1-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic]piperazine-1-yl)carbonyl]-N-methylcyclopentanone 46947018
83triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1-methyl-7-Aza-1-Sonisphere[3,5]nonane39839911

84triptorelin 6-(4-methoxy-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-FL46246313
85triptorelin 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-8-Aza-2-Sonisphere[4,5]decane39839910
86triptorelin 2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-propylpyrrolidine48348418
87triptorelin 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)mate the]-2-perbenzoic}-2-methyl-8-Aza-2-Sonisphere[4,5]decane 41241311
88triptorelin 3-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]piperidine45545618
89triptorelin 3-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-1-methylpiperidine46947018
90triptorelin 1-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-N,N-dimethylcyclopropane45545618
91triptorelin 3-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-N,N-dimethyl-3-oxoprop-1-ammonium44344418
92triptorelin 2-benzyl-2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]--perbenzoic}piperazine-1-yl)carbonyl]pyrrolidine 53153218
93triptorelin 4,5-dimethyl-6-(3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)pyridazin-3(2H)-it43243314
94triptorelin 6-[3-(l,8-diazaspiro[4,5]Dec-8-ylcarbonyl)-4-terbisil]-4-ethyl-3-oxo-2,3-dihydropyridin-1-FL39839910
95triptorelin 3-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]pyrrolidine44144218

96triptorelin 1-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-N-methylcyclopropane44144218
97triptorelin 3-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3 is)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-1-methylpyrrolidine 45545618
98triptorelin 3-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-1,1,1-Cryptor-N,N-dimethyl-3-oxoprop-2-ammonium49749818
99triptorelin 2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-methylpiperidine46947018
100benzyl 2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-methylpiperidin-1-carboxylate60360418
1014-ethyl-6-(4-fluoro-3-{[1-(2,2,2-triptorelin)-1,4,6,7-tetrahydro-5h-[l,2,3]triazolo[4,5-c]pyridine-5-yl]carbonyl}benzyl)pyridazin-3(2H)-he46446514
102triptorelin 4-ethyl-6-{4-fluoro-3-[(1-methyl-1,8-diazaspiro[4,5]Dec-8-yl)carbonyl]benzo is l}-3-oxo-2,3-dihydropyridin-1-FL 41241311
103triptorelin (2S)-2-[2-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-2-oxoethyl]pyrrolidine45545618
104triptorelin 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1-ethyl-8-Aza-1-Sonisphere[4,5]decane42642711
105triptorelin 1-(cyclopropylmethyl)-8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-8-Aza-1-Sonisphere[4,5]decane45245311
1066-[3-({4-[(1-onlinestromectol)carbonyl]-piperazine-1-yl}carbonyl)-4-terbisil]-4,5-dimethylpyridin-3(2H)-he5315325
1076-[3-({4-[(1-aminocyclopent)carbonyl]-piperazine-1-yl}carbonyl)-4-terbisil]-4,5-dimethylpyridin-3(2H)-he 45545619

108triptorelin 6-{3-[(4-{[1-(benzylamino)cyclopentyl]-carbonyl}piperazine-1-yl)carbonyl]-4-terbisil}-4,5-dimethylpyridin-3(2H)-it54545619
109triptorelin 6-(3-{[4-({1-[(cyclopropylmethyl)amino]-cyclopentyl}carbonyl)piperazine-1-yl]carbonyl}-4-terbisil)-4,5-dimethylpyridin-3(2H)-he50951019
110triptorelin 6-[4-fluoro-3-({4-[2-(4-terbisil)prolyl]piperazine-1-yl}carbonyl)benzyl]-4,5-dimethylpyridin-3(2H)-it54955018
111triptorelin 6-[4-fluoro-3-({4-[2-(4-methylbenzyl)prolyl]piperazine-1-yl}carbonyl)benzyl]-4,5-dimethylpyridin-3(2H)-it54554618
112triptorelin 6-[4-fluoro-3-({4-[2-(1-naphthylmethyl)prolyl]piperazine-1-yl}carbonyl)benzyl]-4,5-di is ethylpyridine-3(2H)-it 58158218
113triptorelin 6-(3-{[4-(2-ethylpropyl)piperazine-1-yl]carbonyl}-4-terbisil)-4,5-dimethylpyridin-3(2H)-it46947018

1. The compound of formula IX:

in which the sum of a and j is 1 or 2;
b is 0 or 1;
d is 0 or 1;
X represents N;
R1each independently represents a C1-6-alkyl;
R2each independently represents halogen, C1-6-alkoxy, NH2or N(C1-6-alkyl)2;
With is a 4-membered saturated heterocyclic ring containing one N atom or a 5 - or 6-membered saturated heterocyclic ring containing one or two N atom, or a 7-15 membered monocyclic or condensed or spirolactone polycyclic saturated or partially saturated heterocyclic ring containing 2-4 heteroatoms independently selected from N and O;
And each independently represents a simple bond, O, S=O or NR7;
q each independently 0, 1 or 2;
w is 0, 1, 2 or 3;
R6each independently represents oxo, C1-6-alkyl, halogen-C1-6-alkyl, NRaRb or cycle, which is a3-10-cycloalkyl; C6-10-aryl; C6-10-aryloxy; a 4 membered saturated heterocyclic ring containing one N atom; a 5-or 6-membered saturated heterocyclic ring containing one heteroatom selected from N and O; 5-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from N, O and S, not more than one heteroatom of which represents O or S; a 6 membered heteroaromatic ring containing 1 or 2 nitrogen atom; or 9-10-membered bicyclic unsaturated or partially saturated heterocyclic ring containing 2 heteroatoms selected from N or O;
R7represents hydrogen or C1-6-alkyl;
R8each independently represents cyano, halogen, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, -(C=O)1-6-alkyl, NRaRbWith6-10-aryl-C1-6-alkyl, C6-10-aryl-C1-6-alkoxycarbonyl or6-10-aryl, where aryl ring optionally substituted by a group independently selected from halogen, C1-6-alkyl or halogen-C1-6-alkyl;
each of R9and R10independently represent hydrogen, C1-6-alkyl or halogen-C1-6-alkyl;
each of Raand Rbindependently are selected from hydrogen, C1-6-alkyl; C-10 -cycloalkyl-C1-6-alkyl, phenyl or panels1-6-alkyl;
or its pharmaceutically acceptable salt, or tautomer.

2. The compound according to claim 1, where R2represents fluorine.

3. A compound selected from the group including
triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s;
triptorelin 4-{5-[(4-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s;
6-{3-[(4-acetyl-1,4-diazepan-1-yl)carbonyl]-4-terbisil}-4-ethylpyridine-3(2H)-he;
1-acetyl-4-{5-[(6-chloro-4-ethylpyridine-3-yl)methyl]-2-perbenzoic}-1,4-diazepan;
4-ethyl-6-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)pyridazin-3(2H)-he;
triptorelin 4-{5-[(5-ethyl-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s;
triptorelin 4-{5-[(4-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s;
triptorelin 4-{2-fluoro-5-[(5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzoyl}-1,4-diazepan-1-s;
triptorelin 4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s;
triptorelin 1-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-N,2-dimethyl-1-oxopropyl-2-ammonium;
triptorelin 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-Z-yl)methyl]-2-perbenzoic}-8-Aza-1-asosiasi what about[4,5]decane;
bis(triptorelin)8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-2-s-3-yl)methyl]-2-perbenzoic}-1-methyl-8-Aza-1-Sonisphere[4,5]decane;
triptorelin 4-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-N,N-dimethyl-2-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}of benzolamide;
triptorelin 6-(4-isopropoxy-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;
6-(4-fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4,5-dimethylpyridin-3(2H)-he;
6-(4-fluoro-3-{[4-(2-methylpropyl)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethylpyridin-3(2H)-he;
triptorelin 6-[4-fluoro-3-(4-methyl-2,5-dioxoimidazolidin-1-yl)benzyl]-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;
triptorelin 6-(3-{[3-[1-(dimethylamino)-1-methylethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}-4-terbisil)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;
triptorelin(2R)-2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-methylaziridine;
triptorelin 6-{4-fluoro-3-[(4-{[1-(isobutylamino)cyclopentyl]carbonyl}piperazine-1-yl)carbonyl]benzyl}-4,5-dimethylpyridin-3(2H)-he;
triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-yl)pyrimidine-1-s;
triptorelin 4-(1-{5-[(5-ethyl-6-oxo-1,6-digit pyridazin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)pyridinium;
triptorelin 2-{[(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)oxy]methyl}pyridinium;
triptorelin 2-{[(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-3-yl)oxy]methyl}pyridinium;
triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-5-methoxypyridine;
triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-4-methoxypyridine;
triptorelin 4-(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}pyrrolidin-3-yl)pyridinium;
triptorelin 1-({5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-3-yl)-N,N-dimethylethanamine;
4-ethyl-6-[4-fluoro-3-(1 N-Spiro[1-benzofuran-3,4'-piperidine]-1'-ylcarbonyl)benzyl]pyridazin-3(2H)-he;
triptorelin 1-[2-(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)ethyl]-1H-pyrazole-2-s;
triptorelin 5-chloro-2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)pyridinium;
triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-6-methoxypyridine;
triptorelin 3-benzyl-7-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-1-s;
triptorelin 2-(4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-forb soil}piperazine-1-yl)-3,6-dimethylpyrazine-1-s;
triptorelin 4-ethyl-6-{4-fluoro-3-[(3-phenyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)carbonyl]benzyl}-3-oxo-2,3-dihydropyridin-1-s;
triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1-(3-methoxybenzyl)piperazine-1-s;
triptorelin 2-(1-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)-1,2,3,4-tetrahydroisoquinoline;
triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-s;
triptorelin 4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-phenylpiperazin-1-s;
triptorelin 3-benzyl-4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-s;
bis(triptorelin)4-{5-[(5-ethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-2-(pyridine-3-ylmethyl)piperazine-1-s;
6-(3-{[4-(cyclopentanecarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-terbisil)-4,5-dimethylpyridin-3(2H)-he;
6-(3-{[4-(cyclopentanecarbonyl)-1,4-diazepan-1-yl]carbonyl}-4-terbisil)-4-ethylpyridine-3(2H)-he;
triptorelin 4-{5-[(4,5-diethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1,4-diazepan-1-s;
triptorelin 4-{2-fluoro-5-[(5-isopropyl-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzoyl}-1,4-diazepan-1-s;
triptorelin 4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-s;
6-{4-fluoro-3-[(4-propenylbenzene-1-yl)carbonyl]benzyl}-,5-dimethylpyridin-3(2H)-he;
6-(3-{[4-(divercity)piperazine-1-yl]carbonyl}-4-terbisil)-4,5-dimethylpyridin-3(2H)-he;
6-(4-fluoro-3-{[4-(3,3,3-tryptophanol)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethylpyridin-3(2H)-he;
triptorelin 6-{4-fluoro-3-[(4-isobutylpyrazine-1-yl)carbonyl]benzyl}-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;
triptorelin 2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]pyridinium;
6-(4-fluoro-3-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethylpyridin-3(2H)-he;
triptorelin 1-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-N,N,2-trimethyl-1-oxoprop-2-ammonium;
triptorelin 6-(4-fluoro-3-{[4-(2,2,3,3,3-pentafluoropropanol)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;
triptorelin 6-(4-fluoro-3-{[4-(pyrrolidin-1-ylcarbonyl)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;
triptorelin 6-(4-fluoro-3-{[4-(TRIFLUOROACETYL)piperazine-1-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;
triptorelin 1-(1-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)piperidine;
triptorelin 1-(1-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)pyrrolidine;
triptorelin 4-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-FPO is benzoyl}piperazine-1-yl)hinzelin-1-s;
triptorelin 2-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)pyrimidine-1-s;
bis(triptorelin)7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(3-were)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1,4-die;
triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;
triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-[(4-pertenece)methyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-2-s;
triptorelin 3-cyano-2-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)pyridinium;
triptorelin 3-(3,5-differenl)-7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;
bis(triptorelin) 3-[(dimethylammonio)methyl]-7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-2-s;
triptorelin (7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-N,N-dimethylethanamine;
triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic)-3-(2-furyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;
triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-Digue is dropyridine-3-yl)methyl]-2-perbenzoic}-3-(pentafluoroethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;
triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-{[4-(trifluoromethyl)phenyl]amino}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;
chloride 2-[(4-{2-fluoro-5-[(6-hydroxy-4,5-dimethylpyridin-3-yl)methyl]benzoyl}piperazine-1-yl)carbonyl]-2-methylpyrrolidine;
triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;
triptorelin 3-(1,3-benzodioxol-5-yl)-7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;
triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(2-thienyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-1-s;
triptorelin 3-cyclopropyl-6-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-C]pyridine-2-s;
triptorelin 6-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-C]pyridine-2-s;
triptorelin 5-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine-2-s;
bis(triptorelin) 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-3-pyridine-3-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-2-s;
triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-digit pyridazin-3-yl)methyl]-2-perbenzoic}-7-Aza-1-Sonisphere[3,5]nonane;
triptorelin 1-[(1-{3-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}azetidin-3-yl)methyl]pyrrolidine;
triptorelin 1-(1-{3-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperidine-4-yl)-3,3-diversative;
triptorelin 5-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1-(2,2,2-triptorelin)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-C]pyridine-3-s;
triptorelin 1-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-N-methylcyclopentanone;
triptorelin 7-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1-methyl-7-Aza-1-Sonisphere[3,5]nonane;
triptorelin 6-(4-methoxy-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4,5-dimethyl-3-oxo-2,3-dihydropyridin-1-s;
triptorelin 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-8-Aza-2-Sonisphere[4,5]decane;
triptorelin 2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-propylpyrrolidine;
triptorelin 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-2-methyl-8-Aza-2-Sonisphere[4,5]decane;
triptorelin 3-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]piperidine;
triptorelin 3-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-Digi copyrightin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-1-methylpiperidine;
triptorelin 1-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-N,N-dimethylcyclopropane;
triptorelin 3-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-N,N-dimethyl-3-oxoprop-1-ammonium;
triptorelin 2-benzyl-2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]pyrrolidine;
triptorelin 4,5-dimethyl-6-(3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)pyridazin-3(2H)-he;
triptorelin 6-[3-(1,8-diazaspiro[4,5]Dec-8-ylcarbonyl)-4-terbisil]-4-ethyl-3-oxo-2,3-dihydropyridin-1-s;
triptorelin 3-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]pyrrolidine;
triptorelin 1-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-N-methylcyclopropane;
triptorelin 3-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-1-methylpyrrolidine;
triptorelin 3-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-1,1,1-Cryptor-N,N-dimethyl-3-oxoprop-2-amine;
triptorelin 2-[(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-methylpiperidine;
benzyl 2-[(4-{5-[(4,5-dimethyl-6-the CSR-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)carbonyl]-2-methylpiperidin-1-carboxylate;
4-ethyl-6-(4-fluoro-3-{[1-(2,2,2-triptorelin)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-C]pyridine-5-yl]carbonyl}benzyl)pyridazin-3(2H)-he;
triptorelin 4-ethyl-6-{4-fluoro-3-[(1-methyl-1,8-diazaspiro[4,5]Dec-8-yl)carbonyl]benzyl}-3-oxo-2,3-dihydropyridin-1-s;
triptorelin(2S)-2-[2-(4-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}piperazine-1-yl)-2-oxoethyl]pyrrolidine;
triptorelin 8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-1-ethyl-8-Aza-1-Sonisphere[4,5]decane;
triptorelin 1-(cyclopropylmethyl)-8-{5-[(4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2-perbenzoic}-8-Aza-1-Sonisphere[4,5]decane;
6-[3-({4-[(1-onlinestromectol)carbonyl]piperazine-1-yl}carbonyl)-4-terbisil]-4,5-dimethylpyridin-3(2H)-he;
6-[3-({4-[(1-aminocyclopent)carbonyl]piperazine-1-yl}carbonyl)-4-terbisil]-4,5-dimethylpyridin-3(2H)-he;
triptorelin 6-{3-[(4-{[1-(benzylamino)cyclopentyl]carbonyl}piperazine-1-yl)carbonyl]-4-terbisil}-4,5-dimethylpyridin-3(2H)-he;
triptorelin 6-(3-{[4-({1-[(cyclopropylmethyl)amino]cyclopentyl}carbonyl)piperazine-1-yl]carbonyl}-4-terbisil)-4,5-dimethylpyridin-3(2H)-he;
triptorelin 6-[4-fluoro-3-({4-[2-(4-terbisil)prolyl]piperazine-1-yl}carbonyl)benzyl]-4,5-dimethylpyridin-3(2H)-he;
triptorelin 6-[4-fluoro-3-({4-[2-(4-methylbenzyl)prolyl]piperazine-1-yl}carbonyl)benzyl]-4,5-dimethylpyridin-3(2H)-he;
triptorelin 6-[4-ft is R-3-({4-[2-(1-naphthylmethyl)prolyl]piperazine-1-yl}carbonyl)benzyl]-4,5-dimethylpyridin-3(2H)-he;
triptorelin 6-(3-{[4-(2-ethylpropyl)piperazine-1-yl]carbonyl}-4-terbisil)-4,5-dimethylpyridin-3(2H)-he;
and their pharmaceutically acceptable salts, free bases and tautomers.

4. Pharmaceutical composition having inhibitory activity against poly(D-ribose)polymerase (PARP), comprising the compound according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, or tautomer in combination with a pharmaceutically acceptable carrier.

5. The compound according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, or tautomer for simultaneous, separate or sequential injection with the anti-cancer agent.

6. The compound according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, or tautomer intended for use in therapy as a PARP inhibitor.

7. The use of compounds according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, or tautomer for the preparation of drugs for treatment or prevention of conditions that can be improved by inhibiting PARP.

8. The use of compounds according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, or tautomer for the preparation of drugs for treating or preventing cancer, inflammatory diseases, reperfusion injury, ischemic conditions, strike, p. the targeted failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes, neurodegenerative diseases, retroviral infections, retinal damage, aging or caused by ultraviolet light damage to the skin.

9. The use of compounds according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, or tautomer as chemo - or radiosensibility in the treatment of cancer.

10. A method of treating or preventing cancer, inflammatory diseases, reperfusion injury, ischemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes, neurodegenerative diseases, retroviral infections, retinal damage, aging or caused by ultraviolet light damage to the skin, where the method comprises the administration to a patient in need of such treatment, an effective amount of a compound according to claim 1 or a composition comprising the compound according to claim 1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel spirocyclic cyclohexane derivatives of formula I: , where: R1 and R2 together form a ring and are -CH2CH2CH2-; R3 denotes a saturated, branched or straight, unsubstituted C1-5-alkyl; unsubstituted or monosubstituted with F, Cl, Br, I phenyl; 5-member heteroaryl containing sulphur as a heteroatom; unsubstituted or monosubstituted with F, Cl, Br, I phenyl, attached through a C1-3-alkyl group; R5 denotes H; R6 denotes H, F, Cl; R7, R8, R9 and R10 independently denote H, F, Cl, Br, I; X denotes O, NR17; R17 denotes H, COR12; R12 denotes H, unsaturated, branched or straight, unsubstituted or phenyl-substituted C1-5-alkyl; in form of a racemate; enantiomers, diastereomers, mixtures of enantiomers or diastereomers, or a separate enantiomer or diastereomer; bases and/or salts of physiologically compatible acids or cations.

EFFECT: compounds have binding action on the ORL1 receptor and the µ-opioid receptor, which enables their use to treat various diseases.

12 cl, 11 ex

FIELD: physics.

SUBSTANCE: light-sensitive composition contains 2,2-n-dianisyl-5,6-benzo-[2H]-chromene and 1,3,3-trimethyl-6'-formyl-8'-allyl-spiro-indoline-2,2'-[2H]-chromene in molar ratio 1:0.8-1.6, respectively. Photochromic polymer materials obtained from said composition have optimum optical properties needed to satisfy physiologically based requirements for protective and preventive optical materials: when illuminated with daylight, they "cut" off the spectral region from 400 to 555 nm, while keeping intensity of light incident on eyes with wavelength greater than 555 nm at a level of less than 30%, and in conditions of low-intensity dusk illumination provide full transmission of light with wavelength greater than 400 nm.

EFFECT: protecting eyes and preventing ophthalmic diseases associated with the damaging effect of optical radiation in the visible spectrum.

5 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of 5'-vinyl-6-nitro-spirobenzopyran of formula 1 , where R1=R2=H (SP2); R1=CN, R2=H (SP3); R1=CHO, R2=H(SP4); R1=NC2, R2=H(SP5); R1=CN, R2=CN(SP6); R1=CO2CH3, R2-CN(SP7); R1,R2=-C(O)-O-C(CH3)2-O-(O)C-(SP8), which have photochromic properties, as well as production methods thereof. Disclosed are methods for directed modification on the 5'-position of a photochrome molecule using well-known and simple experimental procedures of organic synthesis (Wittig and Horner-Emmons olefination, nucleophilic bonding on the carbonyl group of reactants containing active methyl or methylene groups: nitromethane, malonodinitrile, cyanoacetic acid and esters thereof, Meldrum acid).

EFFECT: method of producing substituted 5'-vinyl-indoline spirobenzopyrans is characterised by that the starting 5'-formyl derivative in the solution undergoes olefination with different CH-acids in the presence of corresponding bases in an argon atmosphere at high temperature of the reaction mixture.

4 cl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds in the family of azole-substituted spiroheterocyclic compounds, and specifically 5'-(1,3-benzothiazol-2-yl)-substituted spiro[indoline-naphthopyrans] of general formula , where R1=C1-C6 alkyl, R2=H, C1-C6 alkyl, alkoxyl, halogen.

EFFECT: compounds of formula (I) exhibit photoreversible complexing agent properties and can be used, for example, as a sensitive element of photo-controlled chemical sensors of trace amounts of ions of the zinc subgroup of metals with optical response.

2 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of the class spiro[chromen-4,3'-pyrrols], namely to ethyl 1'-R1-3-R2-2-amino-7,7-dimethyl-2', 5-dioxo-5'-phenyl-1',2',5',6,7,8-hexahydrospiro [chromen-4,3'-pyrrol]-4'-carboxylates of formula , where R1=CH2Ph, Ph, C6H11-c, H; R2=CN, COOMe, and to a method for producing them by reaction of 1'-R1-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-carboxylates with malononitrile or methyl cyanoacetate and dimedone in a aprotonic solvent medium.

EFFECT: production of new compounds which can be used as initial products for synthesis of new heterocyclic systems and in pharmacology as those exhibiting analgesic activity.

5 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel cyclic N,N'-diarylthioureas or N,N'-diarylureas of general formula (1), their optic (R)- and (S)-isomers and their pharmaceutically acceptable salts - antagonists of androgenic receptors. In formula (1), where: X represents oxygen or sulfur atom; m=0 or 1, mR1 represents C1-C3alkyl; R2 and R3 represent hydrogen atom; or R2 and R3 together with carbon atom, to which they are bound, form group C=O; or represents group NH; R4 and R5 represent hydrogen atom; or R4 represents hydrogen atom, and R5 represents methyl; or R4 represents hydrogen atom, methyl, and R5 represents group Zn-Y-R6, in which n=1 or 2, Z represents CH2 or C=0 and Y- oxygen atom or N-CH3, or Y represents C=O, and Z represents CH2; R6 represents hydrogen atom, methyl, benzyl, hydroxygroup or R5 and R4 together with atoms, to which they are bound, form five or sic-member heterocycle, including, at least, oxygen or nitrogen atom, which can be substituted by methyl. Invention also relates to method of obtaining compounds.

EFFECT: invention relates to anti-cancer substance, pharmaceutical composition, medication and method of treating prostate cancer with application of invention compounds.

12 cl, 6 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) given below or pharmaceutically acceptable salts thereof:

[where: each of X, Y, Z and W independently denotes a methane group which optionally contains substitutes selected from a group of substitutes α, or a nitrogen atom (except when all elements X, Y, Z and W denote a methane group which optionally contain substitutes selected from the group of substitutes α); A denotes -(C(R3)(R4))m1-; B denotes -O-; D denotes -C(O)-; m1 equals 0; Q denotes a methane group or a nitrogen atom; R denotes a group of formula (II)

, where R6 denotes a lower alkyl group; R7 and R8, together with the nitrogen atom with which they are bonded, form a 5-6-member nitrogen-containing aliphatic heterocyclic group; and where the group of substitutes α includes the following substitutes. Group of substitutes α: halogen atom, hydroxyl group, lower alkyl group, alkoxyl group (said group can be substituted with a cycloalkyl group), amino group, mono- or disubstituted lower alkylamino group, aryl group (said group can be substituted with a halogen atom, a -SO2CH3 group), aryloxy group (said group can be substituted with a halogen atom), heteroaryl group, where 'heteroaryl group' denotes a 5- or 6-member monocyclic saturated or unsaturated group containing 1-2 heteroatoms selected from an oxygen atom or a nitrogen atom (said group can be substituted with an alkoxyl group, alkyl group). The invention also relates to a histamine 3 receptor antagonist, histamine 3 receptor inverse agonist, a prophylactic or medicinal agent, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having histamine H3 receptor antagonist or inverse agonist action.

15 cl, 57 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I) or to its salt or ester in which radicals and symbols have the values presented in claim 1. These compounds are ACC inhibitors.

EFFECT: production of compounds to be applied as a therapeutic agent for various ACC-related disorders such as bacony liver, hyperlipidemia, obesity and diabetes.

13 cl, 48 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds -(Z)-1'-R-6',6'-dimethyl-3-(phenyl(arylamino)methylene)-6',7'-dihydro-3H-spiro[furane-2,3'-indol]-2',4,4',5(1'H,5'H)-tetraons of formula: , where Ar=phenyl, n-methoxyphenyl, n-tollyl; R=allyl, benzyl, phenyl, n-tollyl, n-methoxyphenyl, α-naphtyl, as well as to method of their obtaining, which consists in the following: isopropyl 2-(1-aryl-4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrol-3-yl)-2-oxoacetates are subjected to interaction with N-substituted 3-amino-5,5-dimethylcyclohex-2-enons in medium of inert aprotonic solvent with further separation of target products. Process is carried out at temperature 20-22°C. As solvent, absolute chloroform is used.

EFFECT: obtaining compounds possessing analgesic activity.

4 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 3-aroyl-2-arylhydrazonopyrrolo[1,2-a]quinozaline-1,4(2H,5H)-diones of formula:

Ar=Ph, R=Me, R1=H (a); Ar=4-MeC6H4 R=Me, R1=H (b); Ar=Ph, R=H, R1=COOH (c).

EFFECT: there are produced new compounds possessing analgesic activity that makes them being suggested to be used in medicine as drugs with the analgesic properties.

1 cl, 3 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel, highly crystalline mono(benzenesulphonic acid)besylate salts and polymorphs of the compound of formula (I): , a pharmaceutical composition containing said compounds, methods of producing the salts and use thereof as medicinal agents, particularly for sedative or hypnotic, anxiolytic, muscle relaxation or anticonvulsant purposes.

EFFECT: improved method.

32 cl, 36 dwg, 22 tbl, 10 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel tricyclic derivative of chemical formula 1 or pharmaceutically acceptable salts thereof: formula 1, where Y1, Y2 and Y3 independently denote H, C1-C10 alkyl with a straight or branched chain, hydroxy, C1-C10 alkoxy, -CCOR1, -NR2R3 or -A-B; A denotes -O-, -CH2-, -CH(CH3)-, -CH-N- or -CONH-; B denotes -(CH2)n1-Z, -(CH2)n2-NR2R3 or -(CH2)n3-OR1; Z denotes C5-C20 aryl, unsubstituted or substituted with R5 and selectively R6, C3-C10 cycloalkyl, unsubstituted or substituted with R5 and selectively R6, C1-C20 heterocyclic compound, unsubstituted or substituted with R5 and selectively R6; R1 denotes H or C1-C10 alkyl with a straight or branched chain; R2 and R3 independently denote H, C1-C10 alkyl with a straight or branched chain or -(CH2)n4R7; R5 denotes H, C1-C10 alkyl with a straight or branched chain, C5-C20 aryl or C1-C20 heterocyclic compound; R6 denotes H or C1-C10 alkyl with a straight or branched chain; R7 denotes -NR8R9, -COOR1, -OR1, -CF3, -CN, halogen or Z; R8 and R9 independently denote H or C1-C10 alkyl with a straight or branched chain; n1-n4 respectively denote an integer from 0 to 15; Y denotes H or C1-C10 alkyl with a straight or branched chain. The invention also relates to methods of producing a compound of formula 1, compositions containing the described compound and with effective inhibiting activity on poly(ADP-ribose)polymerase (PARP).

EFFECT: obtaining and describing novel compounds which can be suitable for preventing or treating diseases caused by excess PARP activity, especially neuropathic pain, neurodegenerative diseases, cardiovascular diseases, diabetic neuropathy, inflammatory diseases, osteoporosis and cancer.

23 cl, 123 ex, 7 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula possessing action on a BH4 sensitive condition.

EFFECT: invention refers to a pharmaceutical composition containing said compound to applying the compound for preparing a drug for treating the BH4 sensitive condition, such as a vascular disease, a psychoneurological disease, hyperphenylalaninemia.

12 cl, 31 dwg, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel derivatives of hexahydro pyrazino [2,1-c][1,2,4]triazine of general formula (III) (values of radicals are given in invention formula), their pharmaceutically acceptable salts and application of said compounds for obtaining medication for treatment and prevention of acute myeloid leukemia.

EFFECT: obtaining medication for treatment and prevention of acute myeloid leukemia

3 cl, 3 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted tetrahydropyrrolopyrazines of general formula I, wherein R1, R2 and R3 in each case independently mean hydrogen or groups R1 and R2 or R2 and R3 form a common cycle ; R4 and R5 in each case independently mean H; R6 means branched or unbranched saturated, unsubstituted C1-6-alkyl, or unsubstituted heteroaryl wherein heteroaryl is a 5- or 6-member aromatic residue containing 1 heteroatom specified in a group consisting of N, O and S, or means phenyl wherein phenyl is unsubstituted or single-substituted or double-substituted by 1 or 2 substitutes which in each case are independently specified in a group consisting of F, Cl, Br, I, CF3, C1-6-alkyl, O-C1-6-alkyl, and , or means unsubstituted phenyl attached through C1-3-alkyl chain; R4a, R5a and R6a in each case independently mean H; R7 means (CH2)tC(=O)R8, wherein t is equal to 1, (C=O)(CH2)mNR11R12, wherein m is equal to 1 or 2, C(=O)(CH2)n(C=O)R8, wherein n is equal to 1, 2 or 3, (CH2)sNHC(=O)R8, wherein s is equal to 1 or 2; R8 means NR9R10 or saturated, branched or unbranched, unsubstituted C1-6-alkyl; wherein R9 and R10 in each case independently mean H, saturated, branched or unbranched, unsubstituted C1-6-alkyl, or unsubstituted or saturated C3-8-cycloalkyl, or phenyl, or phenyl attached through C1-3-alkyl wherein the alkyl chain is saturated, branched or unbranched, and wherein phenyl in each case is unsaturated or single or double saturated by 1 or 2 substitutes which independently specified in a group consisting of F, Cl, Br, I, CF3, C1-6-alkyl, O-C1-6-alkyl, pyridyl, and , or unsubstituted heteroaryl attached through C1-3-alkyl wherein heteroaryl is a 5-member aromatic residue 1 heteroatom of which are specified in a group consisting of O and S, wherein the alkyl chain is saturated, branched or unbranched, or heterocyclyl, or heterocyclyl attached through C1-3-alkyl wherein the alkyl chain is saturated, branched or unbranched, and wherein heterocyclyl in each case is saturated, unsubstituted or single substituted by benzyl, and heterocyclyl contains cycloalkyl containing 5 to 6 atoms in a cycle wherein 1 or 2 carbon atoms are substituted by 1 or 2 heteroatoms which are specified in a group consisting of N; or both groups R9 and R10 mean (CH2)3-6, CH2CH2OCH2CH2 or CH2CH2NR14CH2CH2; wherein R14 means phenyl or phenyl attached through C1-3-alkyl wherein phenyl in each case is unsaturated or single substituted by a substitute whih is specified in a group consisting of F, Cl, Br, I, O-C1-6-alkyl, and , or R14 means C(=O)R13; wherein R13 means saturated and unbranched C1-6-alkyl or means phenyl condensed with heteroaryl wherein heteroaryl is a 6-member aromatic residue 1 heteroatom of which is specified in a group consisting of N; R11 and R12 in each case independently mean H, saturated, branched or unbranched C1-6-alkyl, or unsubstituted, saturated C3-8-cycloalkyl, C(=O)R20 or S(=O)2R13; wherein R20 means NR21NR22, or R20 means saturated, branched or unbranched C1-6-alkyl, or means saturated C3-8-cycloalkyl, unsubstituted or single substituted by phenyl, or means unsaturated heteroaryl wherein heteroaryl is a 5-member aromatic residue 1 heteroatom of which is specified in a group consisting of O, or means phenyl wherein phenyl is unsubstituted or single substituted by C1-6-alkyl or means phenyl attached through C1-6-alkyl which is unsubstituted or single substituted by a substitute specified in a group consisting of F, Cl, Br, I and CF3, wherein the alkyl chain is saturated or unsaturated, branched or unbranched; wherein R21 and R22 in each case independently mean H or saturated, branched or unbranched, unsubstituted C1-6-alkyl; in the form of bases and salts of physiologically acceptable acids. The invention also refers to methods for preparing them, to drug preparations for treating disorders or diseases related with at least partially KCNQ2/3 K+ canals containing such compounds.

EFFECT: there are prepared new compounds and based drug preparations which can find application in medicine for managing pain, epilepsy, migraine, panic conditions and urinary incontinence.

17 cl, 2 tbl, 91 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to fluorinated compounds of formula , where: D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more halogen atoms; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: halogen, C1-C10 alkyl; E denotes aryl which can be substituted with one or more fluoro-substitutes or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more fluoro-substitutes, and where Q denotes O; m denotes a number from 1 to 2; under the condition that: R3 is a fluoro-substitute, or group E includes a fluoro-substitute, or group Z includes a fluoro-substitute, with the condition that E does not denote 4-fluorophenyl or a compound of formula , where D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more of the following substitutes: chlorine, bromine, iodine; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: chlorine, bromine, iodine, C1-C10 alkyl; E denotes aryl which can be substituted with one or more chlorine, bromine or iodine atoms, and/or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more substitutes selected from chlorine, bromine, iodine or hydroxy, where Q denotes O, wherein when E denotes phenyl, E does not contain, as a substitute, iodine which is directly bonded to it at position 4; m denotes a number from 1 to 2; wherein at least one of Z, E and R3 includes iodine; under the condition that E does not denote 4-iodophenyl and under the condition that said compound is not a compound of formula (Ia), defined in the following table:

The invention also relates to a pharmaceutical composition based on the compound of formula (I) or (Ia), a diagnosis method, a method of treating said disorders, based on use of the compound of formula (I) or (Ia), and use of the compound of formula (I) or (Ia).

EFFECT: obtaining novel compounds useful in treating disorders in mammals, characterised by anomalous density of peripheral benzodiazepine receptors.

24 cl, 13 dwg, 9 tbl, 23 ex

FIELD: medicine.

SUBSTANCE: invention refers to an agent for activation of lipoprotein lipase containing a benzene derivative of general formula (1) which is used for preventing and treating hyperlipidemia and obesity. The invention also refers to the benzene derivatives of general formula (1a).

EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new bicyclic heterocyclic derivatives of general formula wherein radicals and symbols are specified in the patent claim. Said compounds are FGFR receptor (fibroblast growth factor receptor) inhibitors. The invention also refers to a method for preparing a preferential group of compounds of formula (I), to a pharmaceutical composition containing said compounds, and to the use of said compounds for treating diseases, e.g. cancer.

EFFECT: preparing the new bicyclic heterocyclic derivatives.

22 cl, 16 tbl, 422 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel bicyclic heterocyclic derivatives, which are compounds of formula where values of X1-X5, A, B, R1, R2, q are given in claim 1, as well as pharmaceutical compositions containing said compounds, and use of said compounds to treat cancer.

EFFECT: high efficiency of treatment.

22 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel spirocyclic cyclohexane derivatives of formula I: , where: R1 and R2 together form a ring and are -CH2CH2CH2-; R3 denotes a saturated, branched or straight, unsubstituted C1-5-alkyl; unsubstituted or monosubstituted with F, Cl, Br, I phenyl; 5-member heteroaryl containing sulphur as a heteroatom; unsubstituted or monosubstituted with F, Cl, Br, I phenyl, attached through a C1-3-alkyl group; R5 denotes H; R6 denotes H, F, Cl; R7, R8, R9 and R10 independently denote H, F, Cl, Br, I; X denotes O, NR17; R17 denotes H, COR12; R12 denotes H, unsaturated, branched or straight, unsubstituted or phenyl-substituted C1-5-alkyl; in form of a racemate; enantiomers, diastereomers, mixtures of enantiomers or diastereomers, or a separate enantiomer or diastereomer; bases and/or salts of physiologically compatible acids or cations.

EFFECT: compounds have binding action on the ORL1 receptor and the µ-opioid receptor, which enables their use to treat various diseases.

12 cl, 11 ex

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