Pyrimidine compounds of antiproliferative action (ii)

FIELD: medicine; pharmacology.

SUBSTANCE: new discovered pyrimidine compounds of formula where R1-R9 are those as specified are selective inhibitors of group Src of nonreceptor tyrosine kinases. These compounds and their pharmaceutically acceptable salts are antiproliferative agents applied for treatment and fight against solid tumours, specifically breast tumours, rectum tumours, liver and pancreatic tumours.

EFFECT: applicable for cancer treatment.

17 cl, 5 dwg, 16 ex, 1 tbl

 

The present invention relates to new pyrimidine compounds of the formula

,

or its pharmaceutically acceptable salts, in which

R1selected from the group including

H,

C1-C10alkyl,

C1-C10alkyl containing as substituents up to three groups selected from the group comprising aryl, cycloalkyl, heteroaryl, heterocycle, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2where aryl, cycloalkyl, heteroaryl and heterocyclic groups may independently contain as substituents up to three groups selected from the group comprising NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

aryl,

aryl containing as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

heteroaryl,

heteroaryl containing as substituents up to three groups selected from the group comprising (n is ZS.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

a heterocycle,

a heterocycle containing as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

With3-C10cycloalkyl,

With3-C10cycloalkyl containing as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

With2-C10alkenyl,

With2-C10alkenyl containing as substituents up to three groups selected from the group comprising NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2and

With2-C10quinil containing as substituents up to three groups selected from the group comprising NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR 13R14, SO2NR13R14, SOR13, SO2R13CN and NO2;

R2, R3and R4independently selected from the group including

N

NR10R11.

OR12,

SR12,

C1-C10alkyl,

C1-C10alkyl containing as substituents up to three groups selected from the group comprising cycloalkyl, heteroaryl, heterocycle, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2; and where cycloalkyl, heteroaryl and heterocyclic groups may independently contain as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

heteroaryl,

heteroaryl containing as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

a heterocycle containing as substituents up to three groups selected from the group comprising (nissalke, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

With3-C10cycloalkyl,

With3-C10cycloalkyl containing as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

With2-C10alkenyl,

With2-C10alkenyl containing as substituents up to three groups selected from the group comprising NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

With2-C10quinil, and

With2-C10quinil containing as substituents up to three groups selected from the group comprising NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

provided that at least one of R2, R3or R4does not denote H;

R5, R6, R7and R8independently selected from the group including

N,/p>

(ness.)alkyl,

(ness.)alkyl containing as substituents hydroxy - or alkoxygroup,

NR15R16,

HE

OR17,

SR17,

halogen,

COR17,

CO2R17,

CONR17R18,

SO2NR17R18,

SOR17,

SO2R17and

CN;

R9selected from the group comprising N,

and

COR17;

R10and R11independently selected from the group including

N

COR13,

CO2R13,

CONR13R14,

SO2R13,

SO2NR13R14,

(ness.)alkyl,

(ness.)alkyl containing as substituents hydroxy, alkoxygroup or NR15R16,

cycloalkyl,

cycloalkyl containing as substituents hydroxy, alkoxygroup, (ness.)alkyl or NR15R16,

a heterocycle, and

the heterocycle containing the substituents hydroxy, alkoxygroup, (ness.)alkyl or NR15R16,

or, alternatively, NR10R11may form a cycle containing from 3 to 7 atoms, this cycle may optionally contain one or more additional heteroatoms and optionally can contain as substituents of the group comprising one or more groups (ness.)alkyl, OR12, COR 13, CO2R13, CONR13R14, SOR13, SO2R13and SO2NR13R14;

R12selected from the group including

N

(ness.)alkyl,

COR13,

CONR13R14,

With2-C6alkyl containing as substituents hydroxy, alkoxygroup or NR15R16cycloalkyl,

cycloalkyl containing as substituents hydroxy, alkoxygroup, (ness.)alkyl or NR15R16,

a heterocycle, and

the heterocycle containing the substituents hydroxy, alkoxygroup, (ness.)alkyl or NR15R16;

R13and R14independently selected from the group including

N

(ness.)alkyl,

With2-C6alkyl containing as substituents hydroxy, alkoxygroup or NR15R16,

cycloalkyl,

cycloalkyl containing as substituents hydroxy, alkoxygroup, (ness.)alkyl or NR15R16,

a heterocycle, and

the heterocycle containing the substituents hydroxy, alkoxygroup, (ness.)alkyl or NR15R16,

or, alternatively, NR13R14may form a cycle containing from 3 to 7 atoms, this cycle may optionally contain one or more additional heteroatoms and optionally can contain as substituents of the group include the th one or more groups (ness.)alkyl, OR17, COR17, CO2R17, CONR17R18, SO2R17and SO2NR17R18;

R15selected from the group including

N

(ness.)alkyl,

COR17and

CO2R17; and

R16, R17and R18independently selected from the group including

N, and

(ness.)alkyl,

or, alternatively, NR15R16and NR17R18can independently form a cycle containing from 3 to 7 atoms, this cycle may optionally contain one or more additional heteroatoms;

R19and R20independently selected from the group including

H, and

(ness.)alkyl; and

R21selected from the group including

(ness.)alkyl, and

With2-C6alkyl containing as substituents hydroxy, alkoxygroup or NR15R16.

These compounds inhibit the Src group preceptory tyrosinekinase (SFK). These compounds and their pharmaceutically acceptable salts possess antiproliferative activity and are applicable in the treatment and control of cancer, in particular, in the treatment and control solid tumors. In addition, these compounds have a favorable bioavailability profiles. The present invention also relates to pharmaceutical compositions containing such compounds, and to methods of treatment of cancer, the most FAV is preferably - treatment and control tumors of the breast, rectum, liver and pancreas.

Protein kinases are a class of proteins (enzymes)that regulate many cellular functions. This is accomplished by phosphorylation of specific amino acids on protein substrates, which leads to a change in conformation of the protein substrate. The change in conformation of modulating the activity of the substrate or its ability to interact with other binding partners. The enzymatic activity of protein kinase refers to the speed with which the kinase attaches a phosphate group to a substrate. It can be measured, for example, by determining the dependence of the amount of substrate that is converted to product, from time to time. Phosphorylation of the substrate occurs at the active centre of the protein kinase.

Tyrosine kinase is a subset of protein kinases that catalyze the transfer of the terminal phosphate of adenosine triphosphate (ATP) to tyrosinosis residues of protein substrates. These kinases play an important role in spreading the transmitted signal growth factor, which leads to proliferation, differentiation and migration of cells.

For example, it is shown that the Src group preceptory tyrosinekinase specifically involved in the modulation and the growth of cancer cells. Cm. work D..Boschelli and F.Boschelli, "Small molecule inhibitors of Src family kinases," Drugs of th Future 2000, 25(7):717-736. The formation of excessive amounts of Src was detected in the tumors of the rectum, breast, liver and pancreas, as well as some b-cell leukemia and lymphoma. Cm. ibid at str. It was also shown that increased education and increased activity of Src correlates with increased malignancy of the tumor. Cm. ibid at str. Therefore, inhibitors of Src can be used as anticancer drugs.

There are several examples of small molecule inhibitors of the catalytic activity of protein kinases. In particular, small molecule inhibitors typically block the phosphorylation of substrates by the strong interaction and the binding of the protein kinase centre (or "active site") of ATP. Cm. WO 98/24432 and Hennequin L.F. et al., J. Med. Chem. 2002, 45(6), pp 1300. Some of these compounds inhibit multiple targets. For example, in WO 99/61444 (Warner-Lambert) discloses bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidine formula

and argues that they are blocking cyclin-dependent kinases Cdk1, Cdk2 and Cdk4, as well as of tyrosine kinase growth factor receptor HRPT (growth factor receptor derived from platelets) and RPRF. It is alleged that some compounds also inhibit Cdk6.

In US patent No. 6150373 (Hoffmann-La Roche Inc.) disclosed bicyclic nitrogen-containing g is eroticly formula

for which it is established that they inhibit T-cell tyrosinekinase Rlck.

In WO 01/29041 A1 and WO 01/29042 (.Hoffmann-La Roche AG) are disclosed containing alkylamine substituents of bicyclic nitrogen-containing heterocycles of the formula

and

for which it is established that they inhibit mediated R cellular functions and are therefore inhibitors of cell proliferation.

In WO 01/64679 A1 (SmithKline Beecham) discloses 1,5-disubstituted-3,4-dihydro-1H-pyrimido[4,5-D]pyrimidine-2-about the connection formulas

and

for which it is established that they are applicable in the treatment of diseases mediated by kinase CSBP/P38.

There remains a need in an easily synthesized with a small molecule compounds that are effective for the inhibition of catalytic activity of protein kinases, in particular, the group preceptory tyrosinekinase Src ("SFK"), for the treatment of one or more types of cancer, preferably solid tumors. Preferably, such a small molecule inhibitors also had a favorable bioavailability profiles. Therefore, an object of the present invention are such compounds and pharmaceutical compositions containing these compounds.

<> The present invention relates to new pyrimidine compounds may selectively inhibit the activity of SFK. These compounds are applicable for the treatment of cancer, in particular for the treatment and control of solid tumors. In particular, the present invention relates to compounds of the formula

or their pharmaceutically acceptable salts, in which R1, R2, R3, R4, R5, R6, R7, R8and R9are as defined below in the present invention.

The present invention also relates to pharmaceutical compositions containing a therapeutically effective amount of one or more compounds of formula I and the pharmacologically acceptable carrier or excipient.

The present invention also relates to a method of treatment or control of solid tumors, preferably for the treatment and control tumors of the breast, lung, colorectal and prostate cancer, most preferably with tumors of the mammary gland and the rectum, through the introduction of the patient-a person in need of such treatment, an effective amount of the compounds of formula I and/or its pharmaceutically acceptable salt.

The present invention also relates to novel intermediate compounds applicable DL is producing compounds of formula I.

When used in the present invention, the following terms have the following values.

"Alkenyl" means a linear or branched aliphatic hydrocarbon containing at least one carbon-carbon double bond, for example, vinyl, 2-butenyl and 3-methyl-2-butenyl.

"Quinil" means a linear or branched aliphatic hydrocarbon containing at least one carbon-carbon triple bond, for example, ethinyl and 2-butynyl.

"Alkyl" means a linear or branched saturated aliphatic hydrocarbon containing from 1 to 10, preferably from 1 to 6 and more preferably from 1 to 4 carbon atoms. Alkyl groups containing from 1 to 6 carbon atoms, in the present invention are also referred to as "(ness.)alkyl." Typical (ness.)alkali include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl and hexyl. When used in the present invention designation With1-C4alkyl means alkyl containing from 1 to 4 carbon atoms.

"Alkoxygroup" means an alkyl radical that is attached to the rest of the molecule via an oxygen atom (RO-), for example, a methoxy group, ethoxypropan.

"Aryl" means an aromatic hydrocarbon radical, for example, 6-10-membered aromatic or partially aromatic cyclic system. Preferred ar is global groups include, but not limited to, phenyl, naphthyl, tolyl and xylyl.

"Cycloalkyl" means non-aromatic, partially or completely saturated cyclic aliphatic hydrocarbon group containing from 3 to 8 atoms. Examples cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl.

"Effective amount" or "therapeutically effective amount" means an amount of at least one compound of formula I or its pharmaceutically acceptable salt, which significantly inhibits proliferation of tumor cells, including cell line tumors of the person.

"Halogen" means fluorine, chlorine, bromine or iodine, preferably chlorine, fluorine or bromine.

"Heteroatom" means an atom selected from the group comprising N, O and S, preferably n If the heteroatom is N, it may be in the form-NH - or-N-(ness.)alkyl-. If the heteroatom is S, it can be in the form of S, SO or SO2.

"Heteroaryl" means an aromatic heterocyclic ring system containing up to two cycles. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiazolyl, chinoline, pyrimidinyl, imidazole and tetrazole.

"Heterocycle" or "heterocyclyl" means 3-10-membered saturated or partially unsaturated simultaneity is build-cyclic radical, containing from 1 to 3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, and combinations thereof. Examples of preferred heterocyclic compounds are piperidine, piperazine, pyrrolidine and morpholine.

"Hydroxy" means a prefix that indicates the presence of a monovalent group HE.

"IC50" means the concentration of specific compounds proposed in the present invention required to inhibit 50% of specific measured activity. IC50it is possible to measure, in particular, as described below in example 12.

"Pharmaceutically acceptable salt" means ordinary salts obtained by addition of acid, or salts obtained by addition of a base, which retain the biological effectiveness and properties of the compounds of formula I and are obtained from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of salts obtained by addition of an acid include those that are derived from inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those that are derived from organic acids, such as p-toluensulfonate acid, salicylic acid, methanesulfonate acid, oxalic acid,succinic acid, citric acid, malic acid, lactic acid, fumaric acid and the like, Examples of the salts obtained by addition of a base include, which is sourced from the hydroxides of ammonium, potassium, sodium and Quaternary ammonium compounds, such as, for example, Tetramethylammonium. Chemical transformation of pharmaceutical compounds (i.e. drug) in the salt method is well known to chemists pharmacists to provide improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, for example, .Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp.196 and 1456-1457.

"Pharmacologically acceptable", such as a pharmacologically acceptable carrier, excipient and the like, means pharmacologically acceptable and generally non-toxic to the subject, which introduces a particular connection.

"Substituted", as substituted alkyl, means that the substitution can occur at one or more positions and, unless otherwise specified, the substituents in each position of the substitution is independently selected from the specified group.

In one embodiment, the present invention relates to compounds of the formula

or its pharmaceutically acceptable salts, in which

R1selected from the group including

p> N

C1-C10alkyl,

C1-C10alkyl containing as substituents up to three groups selected from the group comprising aryl, cycloalkyl, heteroaryl, heterocycle, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2where aryl, cycloalkyl, heteroaryl and heterocyclic groups may independently contain as substituents up to three groups selected from the group comprising NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

aryl,

aryl containing as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

heteroaryl,

heteroaryl containing as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

a heterocycle,

a heterocycle, sod is Rashi as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

With3-C10cycloalkyl,

With3-C10cycloalkyl containing as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

With2-C10alkenyl,

With2-C10alkenyl containing as substituents up to three groups selected from the group comprising NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2and

With2-C10quinil containing as substituents up to three groups selected from the group comprising NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2;

R2, R3and R4independently selected from the group including

N

NR10R11,

OR12,

SR12,

C1-C10alkyl,

C1-C10alkyl containing as substituents up to three groups selected from the group comprising cycloalkyl, heteroaryl, heterocycle, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2; and where cycloalkyl, heteroaryl and heterocyclic groups may independently contain as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

heteroaryl,

heteroaryl containing as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

a heterocycle containing as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

With3-C10cycloalkyl,

With3-C10cycloalkyl, the content is of ASI as substituents up to three groups selected from the group comprising (ness.)alkyl, NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

With2-C10alkenyl,

With2-C10alkenyl containing as substituents up to three groups selected from the group comprising NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

With2-C10quinil, and

With2-C10quinil containing as substituents up to three groups selected from the group comprising NR10R11, OR12, SR12, halogen, COR13, CO2R13, CONR13R14, SO2NR13R14, SOR13, SO2R13CN and NO2,

provided that at least one of R2, R3or R4does not denote H;

R5, R6, R7and R8independently selected from the group including

N

(ness.)alkyl,

(ness.)alkyl containing as substituents hydroxy - or alkoxygroup,

NR15R16,

OH,

OR17,

SR17,

halogen,

COR17,

CO2R17,

CONR17R18,

SO2NR17R18,

SOR17,

SO 2R17and

CN;

R9selected from the group including

N

and

COR17;

R10and R11independently selected from the group including

N

COR13,

CO2R13,

CONR13R14,

SO2R13,

SO2NR13R14,

(ness.)alkyl,

(ness.)alkyl containing as substituents hydroxy, alkoxygroup or NR15R16,

cycloalkyl,

cycloalkyl containing as substituents hydroxy, alkoxygroup, (ness.)alkyl or NR15R16,

a heterocycle, and

the heterocycle containing the substituents hydroxy, alkoxygroup, (ness.)alkyl or NR15R16,

or, alternatively, NR10R11may form a cycle containing from 3 to 7 atoms, this cycle may optionally contain one or more additional heteroatoms and optionally can contain as substituents of the group comprising one or more groups (ness.)alkyl, OR12, COR13, CO2R13, CONR13R14, SOR13, SO2R13and SO2NR13R14;

R12selected from the group including

N

(ness.)alkyl,

COR13,

CONR13R14,

With2-C6alkyl containing as substituents hydrox the-, alkoxygroup or NR15R16cycloalkyl,

cycloalkyl containing as substituents hydroxy, alkoxygroup, (ness.)alkyl or NR15R16,

a heterocycle, and

the heterocycle containing the substituents hydroxy, alkoxygroup, (ness.)alkyl or NR15R16;

R13and R14independently selected from the group including

N

(ness.)alkyl,

With2-C6alkyl containing as substituents hydroxy, alkoxygroup or NR15R16,

cycloalkyl,

cycloalkyl containing as substituents hydroxy, alkoxygroup, (ness.)alkyl or NR15R16,

a heterocycle, and

the heterocycle containing the substituents hydroxy, alkoxygroup, (ness.)alkyl or NR15R16,

or, alternatively, NR13R14may form a cycle containing from 3 to 7 atoms, this cycle may optionally contain one or more additional heteroatoms and optionally can contain as substituents of the group comprising one or more groups (ness.)alkyl, OR17, COR17, CO2R17, CONR17R18, SO2R17and SO2NR17R18;

R15selected from the group including

N

(ness.)alkyl,

COR17and

CO2R17; and

R16, R1 and R18independently selected from the group including

N, and

(ness.)alkyl,

or, alternatively, NR15R16and NR17R18can independently form a cycle containing from 3 to 7 atoms, this cycle may optionally contain one or more additional heteroatoms;

R19and R20independently selected from the group including

N, and

(ness.)alkyl; and

R21selected from the group including

(ness.)alkyl, and

With2-C6alkyl containing as substituents hydroxy, alkoxygroup or NR15R16.

Compounds disclosed in the present invention and described by the above formula I, can be tautomerism or structural isomerism. It is implied that the present invention encompasses any tautomeric or structural isomeric forms of these compounds and mixtures of such forms (e.g., racemic mixtures) and is not limited to any one tautomeric or structural isomeric form of the above formula I.

If the compounds of formula I possess structural isomerism, the preferred optical isomer represented by the following formula Ia

In a preferred embodiment of the present invention relates to a compound of formula I, in which R1selected from GRU the dust, including aryl and aryl containing as Vice-CN or CON13R14. Especially preferred are such compounds in which the aryl is phenyl.

In another preferred embodiment, the compounds of the formula I R1selected from the group comprising (ness.)alkyl and C2-C6alkyl containing as substituents OR12or CONR13R14. Especially preferred are such compounds in which R1means (ness.)alkyl.

In another preferred embodiment, the compounds of the formula I R2and R3independently selected from the group comprising C1-C10alkyl and C1-C10alkyl containing as substituents OR12or NR10R11.

In another preferred embodiment, the compounds of the formula I R2indicates OR12.

In another preferred embodiment, the compounds of the formula I R3denotes N.

In another preferred embodiment, the compounds of the formula I R3and R4denote N.

In another preferred embodiment, the compounds of the formula I R4represents C1-C10alkyl containing as Vice-NR10R11.

In another preferred embodiment, the compounds of the formula I R5, R6and 8denote N and R7denotes O-(ness.)alkyl, preferably-O-CH3.

In another preferred embodiment, the compounds of the formula I R5denotes halogen, preferably Br.

In another preferred embodiment, the compounds of the formula I R9denotes N.

The following compounds are preferred variant implementation proposed in this invention is:

(±)-3-[7-[3-(2-hydroxyethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile (example 4);

(±)-3-[7-[3-(2-diethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile (example 5b);

(±)-3-[7-[3-(2-dimethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile (example 6);

(±)-3-(3-(4-methoxyphenyl)-4-methyl-7-{3-[2-(4-methylpiperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl)-benzonitrile (example 7);

(±)-3-[7-[3-(2-diethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzamide (example 8);

(±)-3-[7-[3-(2-dimethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzamide (example 9);

(±)-3-(3-(4-methoxyphenyl)-4-methyl-7-{3-[2-(4-metile erasin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl)-benzamide (example 10);

3-(2-bromophenyl)-7-[4-(2-diethylaminoethoxy)-phenylamino]-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-he (enantiomer 1) (example 11f);

3-(2-bromophenyl)-7-[4-(2-diethylaminoethoxy)-phenylamino]-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-he(enantiomer 2) (example 11g) and

(±)-(3-(2-bromophenyl)-7-[4-(2-diethylaminoethoxy)-phenylamino]-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-it.

Connections proposed in the present invention, inhibit Src tyrosine kinase. These compounds are applicable for the treatment of cancer, in particular for the treatment and control of solid tumors, preferably with tumors of the breast, rectum, liver and pancreas. These compounds easily penetrate through the cell membrane and therefore provide good bioavailability profiles, such as improved oral bioavailability.

In an alternative embodiment, the present invention relates to pharmaceutical compositions containing at least one compound of formula I, or its pharmaceutically acceptable salt or complex ether.

These pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, pills, capsules made of hard or soft gelatin, solutions, emulsions or suspensions. You can also enter rectally, for example in the form of suppositories, or pair Teraline, for example, in the form of solutions for injection.

The pharmaceutical composition proposed in the present invention, including the compounds of formula I and/or their salts, can be produced by a method known in the art, for example, using conventional methods of blending, encapsulation, dissolving, granulating, emulsifying, inclusion, making pills or lyophilization. These pharmaceutical preparations can be produced using a therapeutically inert, inorganic or organic carriers. As such carriers for tablets, coated tablets, pills and capsules of hard gelatin to use lactose, corn starch or its derivatives, talc, stearic acid or its salts. Suitable carriers for soft gelatin capsules from include vegetable oils, waxes and fats. Depending on the nature of the active substance in the case of soft gelatin capsules from the media are not usually required. Suitable carriers for the manufacture of solutions and syrups are water, polyols, saccharose, invert sugar and glucose. Suitable carriers for injection are water, alcohols, polyols, glycerine, vegetable oil, phospholipids and surfactants. Suitable carriers for suppositories are natural or hardened oils, waxes, fats and poloid the s polyols.

The pharmaceutical preparations can also contain preserving agents, solubilizing agents, wetting agents, emulsifying agents, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffer substances, substances for the manufacture of coatings and antioxidants. They may also contain therapeutically useful substances, including additional active ingredients that are not described by formula I.

The present invention also relates to the use of compounds of formula I for the treatment of cancer, particularly breast cancer, colon cancer, liver and pancreas by introducing patient-a person in need of such treatment, an effective amount of the compounds of formula I and/or its salts.

As noted above, the compounds proposed in the present invention, including the compounds of formula I, applicable in the treatment and control of cell proliferative disorders, in particular, with oncological disorders. These compounds and compositions containing these compounds particularly useful in the treatment and control of solid tumors, such as tumors of the breast, rectum, liver and pancreas. Thus, the present invention additionally relates to a method of treating solid tumors by in the edenia the patient, in need of such treatment, an effective amount of the compounds of formula I and/or its salts.

A therapeutically effective amount of the compounds in the present invention means the number of connections, which is effective to prevent, reduce or mitigate the symptoms or increase the life expectancy of the subject undergoing treatment. Determination of a therapeutically effective amount refers to the competence of a person skilled in the technical field.

Therapeutically effective amount or dosage of the compounds proposed in the present invention, may vary within wide limits and can be determined by a method known in the art. Such dosages will be adjusted in accordance with the individual requirements in each particular case, including the specific input connection (connection), route of administration, subject to the treatment of a pathological condition, and subjected to treatment of the patient. Usually in the case of oral or parenteral administration to adult humans weighing approximately 70 kg should be suitable daily dose is from about 10 mg to about 10000 mg, preferably from about 200 mg to about 1000 mg, although in the case shown, the upper limit value may be exceeded. The daily dose can the be entered as a single dose or divided doses, or, when administered parenterally, it can be administered by continuous infusion.

In another embodiment, the present invention relates to a method for obtaining compounds of formula I according to claim 1 claims, and this method includes

a) introducing the compound of the formula

in which X denotes Cl or SO2CH3and R1, R5, R6, R7and R8are as defined in claim 1 of the formula of the invention, in the reaction with aniline derivative of the formula

in which R2, R3and R4are as defined in claim 1 of the formula of the invention, to obtain the compounds of formula

in which R9denotes N, and if necessary,

b) introducing the compound of the formula Ib in response to galogenangidridy or anhydride of the acid to obtain the compounds of formula I in which R9doesor COR17and in which R17, R19, R20and R21are as defined in claim 1 claims,

and/or C) if necessary, the conversion of the compounds of formula I in a pharmaceutically acceptable salt.

The present invention also relates to the following new intermediate products which are applicable in the synthesis of compound f is rmula I:

(±)-2-{3-[8-(3-tianfeng)-6-(4-methoxyphenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-phenyl}-ethyl ester acetic acid (example 3C); and

(±)-(2-{3-[8-(3-tianfeng)-6-(4-methoxyphenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-phenyl}-ethyl) ether methanesulfonate acid (example 5A).

Connections proposed in the present invention, can be obtained by any known means. Suitable methods of synthesis of these compounds are given in the examples. Usually the compounds of formula I can be obtained using the following routes of synthesis.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Examples

The following examples illustrate the preferred methods of synthesis of compounds and compositions proposed in the present invention.

Example 1

Example 1A

(±)-1-(2,4-Dichloropyrimidine-5-yl)-ethanol

(±)-1-(2,4-Dichloropyrimidine-5-yl)-ethanol synthesized from 2,4-dichloropyrimidine (Aldrich) as described in the literature, the methodology of work Ple, N.; Turck, A.; Martin, P.; a, S.; Queguiner, G.Tet.Lett, 1993 (34), 1605-1608.

Example 1b

(±)-2,4-Dichloro-5-(1-chloroethyl)-pyrimidine

To a solution of (±)-1-(2,4-dichloropyrimidine-5-yl)-ethanol (1.27 g, 6,60 mmol) (from the above example 1A) in phosphorus oxychloride (5.0 ml, 53,11 mmol) (Aldrich)at 0°C, were added diisopropylethylamine (2,60 ml, 14,78 mmol) (Aldrich). The reaction mixture was stirred at 0°C for 5 min, at ambient temperature for 15 min and then at 115°C for 3 hours the Reaction mixture was cooled to room temperature, diluted with toluene (10 ml) and the mixture is then poured into ice (15 g). After stirring for 10 min the layers were separated and the aqueous re-extract was washed with toluene. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. Purification using flash chromatography (Biotage, 40M, from 10:90 to 15:85 ethyl acetate : hexane in gradient mode) gave (±)-2,4-dichloro-5-(1-chloroethyl)-pyrimidine in the form of oil. (Exit 1,233 g; 88,3%).

Example 1C

(±)-2,4-Dichloro-5-(1-bromacil)-pyrimidine

Solution (±)-1-(2,4-dichloropyrimidine-5-yl)-ethanol (0.50 g; 2,60 mmol) (from the above example 1A) and diisopropylethylamine (1,10 ml of 6.25 mmol) (Aldrich) in dibromomethane (0.35 ml) was cooled to 15°C. One portion was added oxybromide phosphorus (0.73 g; and 2.83 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature. After 20 min the reaction to shift the b was diluted with ethyl acetate and water. The organic phase was washed with brine and then dried over anhydrous sodium sulfate, filtered and concentrated and received untreated (±)-2,4-dichloro-5-(1-bromacil)-pyrimidine (0,61 g; 91,4%). Purification using flash chromatography (Biotage, 40M, 10:90 ethyl acetate : hexane) gave pure (±)-2,4-dichloro-5-(1-bromacil)-pyrimidine in the form of oil, which when stored in the refrigerator to harden.

Alternatively, (±)-2,4-dichloro-5-(1-bromacil)-pyrimidine was prepared as follows.

Ethyl-2-formulalist

The solution Diisopropylamine (120,6 ml, 0.86 mol) (Aldrich) in tetrahydrofuran (370 ml) was cooled to -30°C. was added dropwise n-utility (2,5M in hexano, 344,2 ml, 0.86 mol) (Aldrich) with such speed that the temperature of the reaction mixture was maintained equal to -30 to 0°C. Then the reaction mixture was cooled to -75°in a bath of solid carbon dioxide with acetone. Within 28 min was added dropwise a solution of ethylbutyrate (100 g, 0.86 mol) (Aldrich) in tetrahydrofuran (170 ml) and the temperature of the reaction mixture was maintained equal to from -75 to -70°C. the Mixture was stirred at the same temperature for another 30 minutes Then to this mixture for 25 min was added ethyl formate (125 ml, 1.55 mol) (Aldrich) and the temperature was maintained equal to from -75 to -70°C. the mixture was allowed to warm to room temperature and re is shivali at room temperature for 3 hours When the outer cooling in a bath of cold water for maintaining the temperature of the reaction mixture below 30°With added acetic acid (98,55 ml, 1,72 mol), and then water (430 ml) and dichloromethane (200 ml). After separation of the layers the organic layer was washed with water (300 ml). The combined aqueous layers were extracted with dichloromethane (200 ml).

The combined organic layers were washed with an aqueous solution of sodium bicarbonate (200 ml). The alkaline aqueous solution was extracted with dichloromethane (100 ml). Then all organic layers were combined, dried over sodium sulfate overnight, filtered and distilled to remove the solvent, leaving about 180 ml (Part of the product was converted to tetrahydrofuran.) The residue was distilled at 65-81° (23 mm Hg). Faction peregorevshey when 70-81° (23 mm Hg)gave ethyl-2-formulalist. (Exit 68,35 g, 55.1 per cent).

5-Ethyluracil

Urea (19,39 g, 0.32 mol) (J..Baker) was added over 20 min to fuming sulfuric acid (26-29,5% free SO3, 135 ml, to 2.65 mol) (Aldrich) under cooling in a bath of ice water, keeping the temperature of the reaction mixture is equal to from 8 to 15°C. After stirring for another 30 min was added ethyl-2-formulalist (46,55 g, 0.32 mol) (from the above example 1C) for 18 min, maintaining the same temperature of the reaction mixture. After the lane is masiania for a further 30 min the second portion of urea (15,07 g, 0.25 mol) was added within 10 min at the same temperature. Then the reaction mixture was stirred at room temperature for 65 h at 90-100°C for 2 h (watched the evolution of gas and the reaction was exothermic and the temperature of the reaction mixture increased to 110°). The mixture was cooled to 30°in a bath of ice water. Ice (270 g) was added slowly, maintaining the temperature of the reaction mixture below 35°C. the mixture is Then cooled to 5°and was stirred for 20 minutes the Formed solid substance was collected by filtration, washed with cold water, hexane and diethyl ether and dried by suction and received 5-ethyluracil. (Exit 38,85 g, 85,9%).

2,4-Dichloro-5-ethylpyrimidine

N,N-Diisopropylethylamine (195 ml, 0.86 mol) (Aldrich) was slowly added to a mixture of 5-ethyluracil (52,3 g and 0.37 mol) (from the above example 1C) and phosphorus oxychloride (150 ml, of 1.61 mol) (Aldrich) with external cooling in a bath of cold water. The mixture was boiled under reflux for 3.8 hours and cooled to room temperature. The mixture is then poured into ice (300 g). Were added ethyl acetate (100 ml) and the mixture was stirred at 20°C for 30 min while cooling in a bath of ice water. The resulting mixture was filtered through Celite® and the filtrate was extracted with a mixture of ethyl acetate - hexane (1:1, 3× 300 ml). The combined organic layers were washed with water (250 ml), dried over sodium sulfate, filtered and concentrated to dryness. This residue was dissolved in a mixture of ethyl acetate - hexane (1:1) and filtered through silica gel for TLC (thin layer chromatography) and suirable the same solvent. The filtrate was concentrated to dryness and received 2,4-dichloro-5-ethylpyrimidine. (Exit 56,3 g, to 85.2%).

(±)-2,4-Dichloro-5-(1-bromacil)-pyrimidine

N-Bromosuccinimide (64,2 g, 0.35 mol) (Aldrich) and 2,2'-azo-bis-isobutyronitrile (AIBN, 1.78 g) (Aldrich) was added to a solution of 2,4-dichloro-5-ethylpyrimidine (56,3 g, 0.32 mol) (from the above example 1C) in carbon tetrachloride (400 ml). The mixture was boiled under reflux for 1.5 h and cooled to room temperature. The reaction mixture was filtered through silica gel for TLC (thin layer chromatography) and suirable a mixture of ethyl acetate - hexane (1:8). The filtrate was concentrated to dryness and received (±)-2,4-dichloro-5-(1-bromacil)-pyrimidine. (Yield 81.3 g, 100%).

Example 1d

(±)-[1-(2,4-Dichloropyrimidine-5-yl)-ethyl]-(4-methoxyphenyl)-amine

(±)-2,4-Dichloro-5-(1-bromacil)-pyrimidine (1.97 g; of 7.70 mmol) (from the above example 1) was dissolved in acetonitrile (21 ml). Was added p-anisidine (0.95 g; of 7.70 mmol) (Aldrich), potassium carbonate (1,17 g; 8,48 mmol) and potassium iodide (032 g; of 1.93 mmol) and the mixture was stirred at room temperature. After 16 h the mixture was subjected to distribution between ethyl acetate and water. The organic phase is washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification using flash chromatography (Biotage 40M, from 20:80 to 25:75 ethyl acetate : hexane in gradient mode) gave (±)-[1-(2,4-dichloropyrimidine-5-yl)-ethyl]-(4-methoxyphenyl)-amine. (Exit 1,82 g; 76,3%).

Example 2

(±)-3-[7-Chloro-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile

To a solution of (±)-[1-(2,4-dichloropyrimidine-5-yl)-ethyl]-(4-methoxyphenyl)-amine (0.10 g; 0.34 mmol) (from the above example 1d) in toluene (1 ml) was added 3-cyanobenzylidene (66,6 mg; 0.46 mmol) (Aldrich). The mixture was heated on an oil bath at 110°C for 2 hours After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The residue is triturated with hexane and briefly dried. The solid residue (intermediate urea) was dissolved in freshly tetrahydrofuran (1.5 ml), cooled in a bath of ice water and salt and was treated with tert-piperonyl potassium (1.0m in tetrahydrofuran; 370 μl; and 0.37 mmol) (Aldrich). After 15 min of incubation in the cold according to the analysis by TLC, the reaction was terminated and the reaction mixture was fil is listed through a layer of silica gel (0.5 g) and washed with ethyl acetate. The filtrate was concentrated and the residue was purified using flash chromatography (Biotage 12M, 40:60 ethyl acetate : hexane) and receive (±)-3-[7-chloro-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile in the form of solids. (Yield of 0.13 g; 85,6%).

Example 3A

2-(3-Nitrophenyl)-ethyl ester acetic acid

3-Nitrophenetole alcohol (55 g, 0.33 mol) (Aldrich) was dissolved in pyridine (1.2 l) (Aldrich). Was slowly added acetic anhydride (215 ml, 2.14 mol) (Aldrich) and the mixture was stirred over night at room temperature (TLC: 30% ethyl acetate in hexano indicated full conversion). In the reaction mixture is poured into ice and water (200 ml). The mixture was diluted with ethyl acetate, then sequentially washed with an aqueous solution of 1 N. hydrochloric acid (pH˜1), water and brine. Then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and obtained 2-(3-nitrophenyl)-ethyl ester of acetic acid as a yellow oil. (Exit 58,86 g, 0.28 mol, 85%).

Example 3b

2-(3-AMINOPHENYL)-ethyl ester acetic acid

To a solution of 2-(3-nitrophenyl)-ethyl ester acetic acid (15 g, of 71.7 mmol) (from the above example 3A) in ethyl acetate (150 ml) was added 10% palladium on coal (1.5 g) (Aldrich). This mixture which was Idrizovo at room temperature in a Parr apparatus at a pressure of 50 lbs/inch 2within 1 h the Reaction mixture was filtered through a layer of Celite®and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and obtained 2-(3-AMINOPHENYL)-ethyl ester of acetic acid. (Exit 12,81 g, 71,48 mmol, 99%).

Example 3C

(±)-2-{3-[8-(3-Tianfeng)-6-(4-methoxyphenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-phenyl}-ethyl ester acetic acid

A mixture of (±)-3-[7-chloro-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile (1,00 g; 2,42 mmol) (from the above example 2) and 2-(3-AMINOPHENYL)-ethyl ester acetic acid (2,03 g; 11.3 mmol) (from the above example 3b) was heated on an oil bath at 110°within 1.5 hours After cooling, the mixture was ground with hexane containing a small amount of ethyl acetate. The supernatant liquid was decanted and the residue in two runs was purified using flash chromatography (Biotage 40M; from 50:50 to 70:30 ethyl acetate : hexane in gradient mode). The purified substance was led from a mixture of ethyl acetate : hexane and received (±)-2-{3-[8-(3-tianfeng)-6-(4-methoxyphenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-phenyl}-ethyl ester of acetic acid as a white solid (1,03 g; 77,5%). Melting point: 170-172°C.

Example 4

(±)-3-[7-[3-(2-HYDR shall xitil)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile

(±)-2-{3-[8-(3-Tianfeng)-6-(4-methoxyphenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-phenyl}-ethyl ester acetic acid (10 g; is 1.81 mmol) (from the above example 3C) was dissolved in a mixture of methanol (17 ml) with water (7 ml) and at room temperature for 19 h and treated with potassium carbonate (1,00 g; 7,26 mmol). The reaction mixture was subjected to distribution between ethyl acetate and a mixture of water - brine. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude substance was purified using flash chromatography (Biotage 40M; ethyl acetate) and receive (±)-3-[7-[3-(2-hydroxyethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile. (Yield of 0.67 g; 72,9%). While concentrating a small amount of matter accumulated in the trap solvent. This substance was extracted and was led from ethyl acetate. (Yield 0.09 g; 9.9 per cent). Melting point: 195-200°C. msvr ((mass spectroscopy high-resolution)) (ER+) (elektrorazpredelenie) m/z. Calculated for C29H26N6O3([M+H]+): 507,2139. Found: 507,2145. MCBP(ER+) m/z. Calculated for C29H26H6About3([M+Na]+): 529,9158. Found: 529,1963.

Example 5A

(±)-(2-{3-[8-(3-Tianfeng)-6-(4-methoxyphenyl)-5-methyl-7-the CSR-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-phenyl}-ethyl) ether methanesulfonate acid

(±)-3-[7-[3-(2-Hydroxyethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile (0,67 mg; of 1.27 mmol) (from the above example 4) suspended in dichloromethane (13 ml). The mixture was treated with triethylamine (0,23 ml of 1.65 mmol) and methanesulfonamide (0,13 ml; 1,68 mmol) (Aldrich). As the addition of methanesulfonanilide solid substance was dissolved. After 45 min according to thin-layer chromatography, the reaction was completed. The reaction mixture was diluted with additional dichloromethane and washed with water and then brine. The organic phase was dried over anhydrous sodium sulfate, concentrated and dried in high vacuum and received untreated (±)-(2-{3-[8-(3-tianfeng)-6-(4-methoxyphenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-phenyl}-ethyl)ether methanesulfonate acid in the form of a foamed substance. This substance was used in the next stage without additional purification. (Output: 0,76 g, 95.4 percent).

Example 5b

(±)-3-[7-[3-(2-Diethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile

A mixture of (±)-(2-{3-[8-(3-tianfeng)-6-(4-methoxyphenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-phenyl}-ethyl) ether methane is AlfaNova acid (1.18 g; 2.02 mmol) (from the above example 5A) and diethylamine (1.5 ml, 14.5 mmol) (Aldrich) were placed in a thick-walled flask for carrying out reactions under pressure and heated at 100°C for 100 min After cooling, the mixture was concentrated and the residue was subjected to distribution between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification using flash chromatography (Biotage 40S, from 100:0 to 50:50 ethyl acetate - methanol), and then crystallization from a mixture of ethyl acetate with hexane gave (±)-3-[7-[3-(2-diethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile. (Yield 0.66 g; 57,9%).

Melting point: 128-145°C. MCBP(ER+) m/z. Calculated for C33H35N7O2([M+H]+): 562,2925. Found: 562,2925.

Example 6

(±)-3-[7-[3-(2-Dimethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile

A mixture of (±)-(2-{3-[8-(3-tianfeng)-6-(4-methoxyphenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-phenyl}-ethyl) ester methanesulfonic acid (0,19 g; 0.32 mmol) (from the above example 5A) and dimethylamine (2.0m in tetrahydrofuran; a 2.00 ml, 4.00 mmol) (Aldrich) were placed in a thick-walled flask for holding the reaction is s under pressure and heated at 100° With during the night. After cooling, the mixture was concentrated and the residue was subjected to distribution between ethyl acetate and water. The organic phase is washed with water and brine, dried over anhydrous sodium sulfate and concentrated. Then the crude product was combined with the material obtained in the previous synthesis, and was purified using flash chromatography (Biotage, 12S; from 100:0 to 50:50 ethyl acetate - methanol). This substance was then led from a mixture of ethyl acetate and ether, and was received±)-3-[7-[3-(2-dimethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile in the form of solids. (Yield 0.12 g; 26,8%).

Melting point: 120-135°C. msvr (ER) m/z. Calculated for C31H31N7O2([M+H]+): 534,2612. Found: 534,2619.

Example 7

(±)-3-(3-(4-Methoxyphenyl)-4-methyl-7-{3-[2-(4-methylpiperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl)-benzonitrile

A mixture of (±)-(2-{3-[8-(3-tianfeng)-6-(4-methoxyphenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-phenyl}-ethyl) ester methanesulfonic acid (0.10 g; 0.16 mmol) (from the above example 5A) and 1-methylpiperazine (0.25 ml; of 2.23 mmol) (Aldrich) was heated at 110°C for 1 h After cooling, the mixture was diluted with ethyl acetate and washed with water and R is SOLOM. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude substance was purified using flash chromatography (Biotage 12S; from 100:0 to 40:60 ethyl acetate : methanol in a gradient mode) and then was led from a mixture of ethyl acetate : hexane and received (±)-3-(3-(4-methoxyphenyl)-4-methyl-7-{3-[2-(4-methylpiperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl)-benzonitrile. (Exit to 60.6 mg; 64,1%).

Melting point: 134-155°C. msvr (ER) m/z. Calculated for C34H36N8O2([M+H]+): 589,3034. Found: 589,3041.

Example 8

(±)-3-[7-[3-(2-Diethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzamide

(±)-3-[7-[3-(2-Diethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile (0.35 g; a 0.60 mmol) (from the above example 5b) was dissolved in dimethyl sulfoxide (3.5 ml) and the resulting solution was cooled in a bath of ice water. Was added an aqueous solution of sodium hydroxide (1M; to 1.15 ml, 1.15 mmol), which resulted in the deposition of benzonitrile. Then there was added an aqueous solution of hydrogen peroxide (30%; 195 μl; at 1.91 mmol). Benzonitrile slowly re-dissolved. After 3 h, to the reaction mixture were added water. The first product was separated in the form of a resin,which is then hardened. The solid is collected, washed with water and dried. Recrystallization from a mixture of dichloromethane - ether gave (±)-3-[7-[3-(2-diethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzamide. (Out of 0.30 g; 84,8%). Melting point: 170-175°C. MCBP (ER+) m/z. Calculated for C33H37N7O3([M+H]+): 580,3031. Found: 580,3032. IC500,0045 microns.

Example 9

(±)-3-[7-[3-(2-Dimethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzamide

(±)-3-[7-[3-(2-Dimethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile (of 92.7 mg; 0,17 mmol) (from the above example 6) was dissolved in dimethyl sulfoxide (1.0 ml) and the resulting solution was cooled in a bath of ice water. Was added an aqueous solution of sodium hydroxide (1M; 300 µl; 0.30 mmol), which resulted in the deposition of benzonitrile. Then there was added an aqueous solution of hydrogen peroxide (30%; 53 μl; 0.52 mmol). Benzonitrile was re-dissolved and then the product was precipitated from the solution. After 4 h the reaction mixture was diluted with water. The solid is collected, washed with water and dried. Recrystallization from a mixture of dichloromethane - ether gave (±)-3-[7-[3-(2-dimethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzamide. (Out of 72.9 mg; 76,1%). Melting point: 215-230°C. msvr (ER+) m/z. Calculated for C31H33N7O3([M+H]+): 552,2718. Found: 552,2722.

Example 10

(±)-3-(3-(4-Methoxyphenyl)-4-methyl-7-{3-[2-(4-methylpiperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl)-benzamide

(±)-3-(3-(4-Methoxyphenyl)-4-methyl-7-{3-[2-(4-methylpiperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl)-benzonitrile (0.25 g; 0.41 mmol) (from the above example 7) was dissolved in dimethyl sulfoxide (2.5 ml) and the resulting solution was cooled in a bath of water with ice. Was added an aqueous solution of sodium hydroxide (1M; 750 μl; 0.75 mmol), which resulted in the deposition of benzonitrile. Then there was added an aqueous solution of hydrogen peroxide (30%; 130 μl; of 1.27 mmol). The cooling bath was removed. The solid is dissolved and then deposited a new solid. After 3 h the reaction mixture was diluted with water. The solid is collected, washed with water, dried in air using a laboratory vacuum line. Purification using flash chromatography (Biotage 12S; from 90:10 to 60:40 chloroform - methanol (gradient mode) and subsequent crystallization from methanol - ethyl acetate gave (±)-3-(3-(4-methoxyphenyl)-4-methyl-7-{3-[2-(4-methylpiperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5d]pyrimidine-1-yl)-benzamide in the form of a white solid. (Exit to 35.7 mg; 14,3%). The second portion was collected, adding ether to the stock solution. (Yield of 87.8 mg; 35,1%). Melting point: 243-251°C.

Msvr (ER+) m/z. Calculated for C34H38N8O3([M+H]+): 607,3140. Found: 607,3144.

Example 11

3-(2-Bromophenyl)-7-[4-(2-diethylaminoethoxy)-phenylamino]-1,4-dimethyl-3,4-dihydro-1H-pyrimido [4,5-d]pyrimidine-2-he

Example 11a

1-(4-Methylamino-2-methylsulfonylamino-5-yl)-ethanol

1.5 g of 4-Methylamino-2-methylsulfonylamino-5-carbaldehyde (obtained in accordance with WO 00/24744) was dissolved in 30 ml of THF (tetrahydrofuran). At temperatures below 5°was added dropwise 14 ml of methylacrylamide in the air concentrations of 1,4M. After stirring for 1 h at 0°C for 30 min was added 14 ml of a solution of the Grignard reagent. Stirring was continued for 30 min at 0°and finally at room temperature for 25 hours the Reaction was stopped with saturated solution of ammonium chloride and was extracted with ethyl acetate. Output: of 1.57 g of the crude desired substance.

Example 11b

[5-(1-Chloroethyl)-2-methylsulfonylamino-4-yl]-methylamine

0.25 g of the product of the above example 11a was dissolved in 10 ml of chloroform and was added dropwise to 0.30 g of thionyl chloride. The mixture was boiled under reflux for 2 h, evaporated andreceived 0.31 g of the desired product as hydrochloride.

Example 11S

5-[1-(2-Brompheniramine)-ethyl]-2-methylsulfonylamino-4-yl-methylamine

0.25 g of the product of the above example 11b and 34 mg of sodium iodide in 10 ml of acetonitrile was stirred for 15 min at room temperature. The resulting suspension at room temperature was added dropwise to a mixture of 0.21 g of 2-bromoaniline (Aldrich) and 0.33 g of N-ethyldiethanolamine (Aldrich) in 5 ml of acetonitrile. Stirring was continued for 16 h and the mixture was diluted with 20 ml of water and was extracted with dichloromethane. Chromatography on silica (eluent - CHCl3gave 158 mg of the desired product.

Example 11d

3-(2-Bromophenyl)-1,4-dimethyl-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-he (enantiomers 1+2)

To 1.1 g of the product of the above example 11C in 10 ml of dry DMF (dimethylformamide) under cooling was added 0,236 g of sodium hydride (95%). After stirring for 20 min at room temperature, the mixture was cooled to 5°and was treated with small portions of carbonyldiimidazole (Aldrich) is just 1,01, the Stirring was continued at 5°C for 30 min and at room temperature over night. Then the excess sodium hydride was decomposed by adding a small amount of water when cooled. The mixture was diluted with water, extracted with ethyl acetate and the combined organic phases are evaporated. Untreated chromium which was ographically on chiral phase Chiracel OD-CSP (a commercially available material with a particle size of 20 μm company Daicel, eluent - heptane/isopropanol 1:1) and received 470 mg each separated enantiomer of the desired product as pale yellow powders. First loirevalley enantiomer named "enantiomer 1", and similarly the corresponding enantiomers of chiral compounds derived from it in the following examples of the preparation, called "enantiomer 1". Second loirevalley enantiomer named "enantiomer 2", and similarly the corresponding enantiomers of chiral compounds derived from it in the following examples of the preparation, called "enantiomer 2".

Example 11th

3-(2-Bromophenyl)-7-methanesulfonyl-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-he; enantiomer 1

0,628 g of Meta-chloroperbenzoic acid (MJPBK) (77%) (Aldrich) was dissolved in 50 ml of CH2Cl2and the solution was dried by filtration through sodium sulfate. The dried solution MJPBK dropwise at room temperature was added to the solution 0,437 g of enantiomer 1 of the above example 11d in 20 ml of CH2Cl2and stirring continued over night. The excess of nagkalat was dissolved by washing with dilute solution of sodium bisulfite. The organic phase is washed with aqueous sodium bicarbonate solution, dried and evaporated. Chromatography on silica using a mixture of ethyl acetate/heptane gave 430 mg of the desired product.

Example 11f

3-(2-Bromophenyl)-7-[4-(2-what ethyleneoxy)-phenylamino]-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-he (enantiomer 1)

152 mg of 4-(2-Diethylaminoethoxy)aniline (obtained in accordance with the work Rohamann, Friedrich, Chem.Ber. (1939) 72: R) in 1 ml dry NRM (N-organic processed with the help of 0.43 ml of a 2M solution of HCl in ether and stirred at room temperature for 30 minutes was Added 100 mg of the product from the example above, the 11th and the mixture was heated to 120-130°C for 16 hours the Mixture was diluted with 10 ml of water and podslushivaet by adding NaOH. Extraction with CH2Cl2and concentration of the organic phase gave the crude oil from which the NRM and the excess aniline drove in high vacuum furnace Cuellar. The residue was dissolved in 0.1 ml of methanol and slowly diluted with 0.5 ml water. Formed fine precipitate, which was isolated by centrifugation and then further purified using preparative HPLC (high performance liquid chromatography)-MS (mass spectroscopy). Yield: 20 mg of the desired product.

Example 11g

3-(2-Bromophenyl)-7-[4-(2-diethylaminoethoxy)-phenylamino]-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-he (enantiomer 2)

The desired product was obtained similarly to the compound of the above example, the 11th and example 11f, but on the basis of enantiomer 2 of the product of the above example 11d.

Antiproliferative activity

Antiproliferative activity link is, proposed in the present invention, as demonstrated below in example 12. This activity shows that the compounds proposed in the present invention, applicable in the treatment of cancer, preferably solid tumors, such as tumors of the breast, rectum, liver and pancreas, more preferably tumors of the breast and colon.

Example 12

Analyses kinase

The activity of the compounds proposed in the present invention, as inhibitors of group tyrosinekinase src demonstrated by the following analysis.

Analysis parameters inhibitor SRC:

Reaction mixture:
ATP5 µm
Peptide (Ro + Ja133-Ro)10 µm
Ja133-Ro196 nm
Roof 9.8 microns
RT230 ng/ml
Buffer solution for analysis:4 mm MgCl2
2 mm TCHEPH (trichlorethylene)
50 mm HEPES (N-2-hydroxyethylpiperazine-N-2-
econsultancy KIS the PTA)
0,1% Tween 20
pH of 7.3
Enzyme:2.5 U/ml
Inhibitor:a maximum of 25 microns
minimum of 0.42 nm

Materials:

Labeled Eu phosphotyrosine antibodies: - Lck Cisbio Mab PT66-K,

for Src EG&G Wallac RT Eu-W1024 (all commercially available).

Peptides: NH2-A-E-E-E-I-Y-G-E-F-E-A-K-K-K-K-CONH2and

Ja133-G-Aminocaprylic acid-A-E-E-E-I-Y-G-E-F-E-A-K-K-K-K-CONH2where Ja133 denotes LightCycler-Red 640-N-hydroxysuccinimide ester™;

and both peptides synthesized according to the Protocol optimized solid-phase peptide synthesis (Merrifield (1962) Fed. Proc. Fed. Amer. Soc Exp. Biol. 21, 412) using a peptide synthesizer Zinsser SMP350. Briefly, peptides were collected in 160 mg (scale of 22.8 mmol) modified polystyrene solid phase Rink-Linker by successive conjugation of a 20-fold excess of amino acids, each of which contained a temporary piperidine labile Fmoc group and permanent acid-labile group, tert-Bu-, RE -, and O-tert-Bu - depending on the functional group of the side chain. The sequence of the substrate AEEEIYGEFEAKKKK N-end advanced fixed spacer elements amino acids, amino prelovac acid and glycine. After removal of N-terminal a temporary protective groups in more secured and protected peptide was injected label with a 1.5-fold amount of LightCycler-Red 640-N-hydroxysuccinimide of ester (purchased from the company Roche Diagnostics GmbH) and triethylamine. After 3 h, the resin was washed with dimethylformamide and isopropanol until the eluate blue resin does not become colorless. Fully protected and labeled peptide was extracted from the solid phase and permanent protective group was removed by treatment with a mixture of 80% triperoxonane acid, 10% identicial, 5% thioanisole and 5% water. Finally, the substrate was isolated by purification using preparative HPLC with reversed phase. Purification gave 12,2 mg meet single peak pure blue substance (freeze-dried) by HPLC with reversed phase. Identity confirmed using mass spectroscopy MALDI [2720.0].

Enzymes: Upstate Lck (Rlckactive), Upstate Src (Rc-srcpartially purified) were purchased from company UBI.

Homogeneous fluorescence analysis with a time resolution:

Reader: Perkin Elmer, Wallac Viktor 1420-040 counter for a variety of labels; the System for liquid: Beckman Coulter, Biomek 2000.

ATP, Tween 20, HEPES was purchased from a company Roche Molecular Biochemicals, MgCl2and MnCl2was purchased from Merck Eurolab, THEM acquired the firm Pierce, 384-well tablets small volume of fluorescence PR is obtained from the firm Falcon.

Description of analysis:

First, the enzyme is pre-incubated for 15 min at 15°in aqueous solution with appropriate amounts of inhibitors proposed in the present invention. Then by adding the reaction mixture containing ATP, peptide and RT, and subsequent shaking started the reaction. Over the course of this reaction would be monitored using fluorescence spectroscopy with time resolution using a suitable reader of wells.

The values of the IC50it was possible to obtain the reaction rate using non-linear curve approximation (Excelfit).

The results of the above experiments in vitro, including the values of the IC50shown in the table. According to the above analysis, the compounds proposed in the present invention have values IC50constituting less than 1.0 μm.

IC50(µm) - analyses of the inhibition of the enzyme
ExampleSrc
4<1,0
7<1,0

td align="center"> Src
Example
6<1,0
5b<1,0
8<1,0
9<1,0

ExampleSrc
10<1,0
11f (enantiomer 1)<1,0

Example 13

Composition for tablets

No.Ingredientsmg tablet
1Connection And*525100250500750
2Anhydrous lactose1038335193857
3Sodium salt croscarmellose668163248
4Povidone K 556122436
5Magnesium stearate111369
Full weight120120150300600900
* Connection And connection means proposed in the present invention.

Method of manufacturing:

1. Mix No. 1, 2 and 3 in a suitable mixer for 15 minutes

2. To pelletize powder mixture obtained in stage 1, with a 20% solution of povidone K (No. 4).

3. Dry the granules obtained in stage 2, at 50°C.

4. Skip the granules obtained in stage 3, through a suitable equipment for grinding.

5. Add No. 5 to ground the granules obtained in stage 4, and stir for 3 minutes

6. Compress the granules obtained in stage 5, using a suitable press.

Example 14

Composition for capsules

No.Ingredientsmg/capsule
1Connection And *525100250500
2Anhydrous lactose159123148----
3Corn starch2535403570
4Talc1015101224
5Magnesium stearate12236
The full weight of the contents of the capsules200200300300600
* Connection And connection means proposed in the present invention.

Method of manufacturing:

1. Mix No. 1, 2 and 3 in a suitable mixer for 15 minutes

2. Add 4 and 5 and mix for 3 minutes

3. Place in a suitable capsule.

Example 15

The composition of the solution/emulsion for injection

td align="center"> Soybean oil
No.Ingredientmg/ml
1Connection And*1 mg
2PEG** 40010-50 mg
3Lecithin20-50 mg
41-5 mg
5Glycerin8-12 mg
6Water to1 ml
* Connection And connection means proposed in the present invention.
** Polyethylene glycol

Method of manufacturing:

2. Add No. 3, 4 and 5 to # 6, and stir to disperse, then homogenize.

3. Add the solution obtained in stage 1, to the mixture obtained in stage 2, and homogenize until the dispersion becomes translucent.

4. To perform sterile filtration through the filter hole size 0.2 μm and pour into bottles.

Example 16

The composition of the solution/emulsion for injection

No.Ingredientmg/ml
1Connection And*1 mg
2Glucotrol10-50 mg
3Lecithin20-50 mg
4Soybean oil1-5 mg
5Glycerin8-12 mg
6Waterto 1 ml
* Connection And connection means, before the its in the present invention.

Method of manufacturing:

1. Dissolve No. 1 in No. 2.

2. Add No. 3, 4 and 5 to # 6, and stir to disperse, then homogenize.

3. Add the solution obtained in stage 1, to the mixture obtained in stage 2, and homogenize until the dispersion becomes translucent.

4. To perform sterile filtration through the filter hole size 0.2 μm and pour into bottles.

Although the present invention is illustrated with specific and preferred embodiments, specialists in the art should understand that under normal research and practice of the present invention may be amended and modified. Therefore understood that this invention is not limited by the above description but is defined by the attached claims and their equivalents.

1. The compound of the formula:

,

or its pharmaceutically acceptable salt, in which

R1selected from the group including

With1-C10alkyl,

phenyl containing as substituents up to three groups selected from the group comprising CONR13R14and CN;

R2, R3and R4independently selected from the group including

N

C1- 10alkyl containing as substituents up to three groups selected from the group comprising a heterocycle representing 3-10-membered saturated monovalent cyclic radical containing from 1 to 3 heteroatoms selected from nitrogen, NR10R11, OR12, halogen, SO2R13; and where the heterocyclic group may independently contain as substituents up to three groups selected from (ness.)of alkyl,

provided that at least one of R2, R3or R4does not denote H;

R5, R6, R7and R8independently selected from the group including

N

OR17,

halogen;

R9denotes N;

R10and R11independently selected from the group including

N

(ness.)alkyl;

R12selected from the group including

N

COR13,

With2-C6alkyl containing as Vice-NR15R16;

R13and R14independently selected from the group including

N

(ness.)alkyl;

R15means (ness.)alkyl; and

R16and R17independently represent (ness.)alkyl.

2. The compound of formula I according to claim 1, in which R1selected from the group comprising phenyl, containing as substituents CN and CONR3 R14where the values of R13and R14defined in claim 1.

3. The compound of formula I according to claim 1, in which R1means (ness.)alkyl.

4. The compound of formula I according to claims 1, 2 or 3, in which R2stands With1-C10alkyl containing as substituents OR12or NR10R11.

5. The compound of formula I according to claims 1, 2 or 3, in which R3denotes N.

6. The compound of formula I according to claims 1, 2 or 3, in which R3and R4denote N.

7. The compound of formula I according to claims 1, 2 or 3, in which R4represents C1-C10alkyl containing as Vice-NR10R11.

8. The compound of formula I according to claims 1, 2 or 3, in which R5denotes halogen.

9. The compound of formula I according to claim 1, having the formula

10. The compound of formula I according to claim 1, selected from the group comprising;

(±)-3-[7-[3-(2-hydroxyethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile;

(±)-3-[7-[3-(2-diethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile; and

(±)-3-[7-[3-(2-dimethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzonitrile.

11. The compound of formula I according to claim 1, selected from the group include what it is:

(±)-3-(3-(4-methoxyphenyl)-4-methyl-7-{3-[2-(4-methylpiperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl)-benzonitrile;

(±)-3-[7-[3-(2-diethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzamide;

(±)-3-[7-[3-(2-dimethylaminoethyl)-phenylamino]-3-(4-methoxyphenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl]-benzamide;

(±)-3-(3-(4-methoxyphenyl)-4-methyl-7-{3-[2-(4-methylpiperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine-1-yl)-benzamide; and

(±)-3-(2-bromophenyl)-7-[4-(2-diethylaminoethoxy)-phenylamino]-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-it.

12. The compound of formula I according to claim 1, which is (+)-3-(2-bromophenyl)-7-[4-(2-diethylaminoethoxy)-phenylamino]-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-it.

13. The compound of formula I according to claim 1, which is(-)-3-(2-bromophenyl)-7-[4-(2-diethylaminoethoxy)-phenylamino]-1,4-dimethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-it.

14. Pharmaceutical composition having anti-proliferative activity comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier or excipient.

15. The pharmaceutical composition according to 14, in which the compound suitable for introduction paragraph what they, suffering from cancer.

16. Compounds according to claims 1-3, 9-13, possessing antiproliferative activity.

17. A compound selected from the group including:

(±)-2-{3-[8-(3-tianfeng)-6-(4-methoxyphenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-phenyl}-ethyl ester of acetic acid and

(±)-(2-{3-[8-(3-tianfeng)-6-(4-methoxyphenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-phenyl}-ethyl ester methanesulfonic acid.



 

Same patents:

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new condensed derivatives of azolpyrimidine of formula (I), their tautomeric or stereoisomeric form and their physiologically accepted salts. Compounds of this invention have improved activity of phosphatidyl inositol-3-kinase (P13K) inhibiting, specifically of P13K-γ inhibiting, and can be applied for production of medicinal agents for prevention and treatment of P13K- and P13K-γ activity based diseases. Those diseases are inflammatory and immunoregulatory diseases such as asthma and others. In compounds of formula (I) . X means CR5R6 or NH; Y1 means CR3 or N; chemical bond between means single bond or double bond, as long as means double bond, then Y2 and Y3 mean CH, and as long as mean single bond, then Y2 and Y3 mean regardless CR3R4; Z1, Z2, Z3 and Z4 mean redardless CH , CR2 or N; R1 means phenyl, optionally containing 1 to 3 substitutes selected from group including R11, C3-8cycloalkyl, optionally containing 1 to 3 substitutes selected from group including R11, C1-6alkyl, optionally containing as substitutes one or more halogen atoms, or 3-15-component mono- or bicyclic heterocyclic ring being saturated or non-saturated, optionally containing 1 to 3 substitutes selected from group including R11, and containing 1 to 3 heteroatoms selected from group including N, O and S, where R11 means halogen, nitro-, hydroxyl-, cyano-, carboxy-, amino-, N-(C1-6alkyl)amino-, K-(hydroxyC1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, N(C1-6acyl)amino-, N-(formyl)-N-(C1-6 alkyl) amino-, N-(C1-6alkansulphonyl)amino-, N-(carboxy C1-6 alkyl)-N-(C1-6 alkyl) amino-, N-(C1-6 alkansulphonyl)amino-, N-[N,N-di(C1.6 alkyl)aminomethylene] amino-, N-[N,N-di(C1-6 alkyl)amino(C1-6 alkyl)methylene]amino-, N-[N,N-di(C1-6 alkyl)aminoC1-6alkenyl]amides, aminocarbonyl, N-(C1-6 alkyl)aminocarbonyl, N,N-di(C1-6 alkyl)aminocarbonyl, C3-8 cycloalkyl, C1-6alkylthio, C1-6 alkansulphonyl, sulphamoyl, C1-6alkoxycarbonyl, phenylC1-6alkoxycarbonyl, where specified phenylic fragment optionally contains 1 to 3 substitutes selected from group including R101, C1-6alkyl, optionally containing as substitutes 1, 2 or 3 halogen atoms, C1-6alkoxy, optionally containing as substitutes 1, 2 or 3 halogen atoms, or 5- 7-component saturated or non-saturated ring containing 1 to 3 heteroatoms selected from group containing N, and optionally containing 1 to 3 substitutes selected from group including and R101, where R101 means halogen, carboxy, amino-, N-(C1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, aminocarbonyl, N-(C1-6alkyl)aminocarbonyl, N,N-di(C1-6alkyl)aminocarbonyl, C1-6alkyl, and C1-6alkoxy; R2 mean hydroxy, halogen, nitro-, cyano-, amino-, N-(C1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, N-(hydroxyC1-6alkyl)amino-, N-(hydroxyC1-6alkyl)-N-(C1-6alkyl)amino-, C1-6 acoxy, aminoC1-6 acoxy, C2-6alkenyl, phenyl, 5-7-compound saturated or non-saturated heterocyclic ring containing 1 to 2 heteroatoms selected from group including O and N, and optionally containing as substitutes: hydrohy, d-balkyl, N-(C1-6acyl)amino-, phenyl, phenylC1-6alkyl, C1-6alkyl, optionally containing as substitutes R21, or C1-6alkoxy, optionally containing as substitutes R21, where R21 means cyano group, 1, 2 or3 halogen atoms, hydroxy, amino-, N-(C1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, C1-6alkoxy, hydroxyC1-6alkoxy, -C(O)-R201, -NHC(O)-R201, C3-8 cycloalkyl, phthalymidil, 2-oxo-1,3-oxazolidinyl, phenyl or 5- or 6-compound saturated or non-saturated heterocyclic ring containing 1 to 4 heteroatoms selected from group including O and N, and optionally containing as substitutes hydroxy, C1-6alkyl, N-(C1-6acyl)amides or benzyl, where R201 means hydroxyl, amino-, N-(C1-6alkyl)amino-, N,N-di(C1-6alkyl)amino-, N-(halogenphenylC1-6 alkyl)amides, C1-6alkyl, aminoC1-6alkyl, C1-6alkoxy, 5- or 6-compound saturated or non-saturated heterocyclic ring containing 1 to 2 heteroatoms selected from group including O and N; R3 means hydrogen, halogen, aminocarbonyl or C1-6alkyl, optionally containing as substitutes phenylC1-6alkoxy or 1, 2 or 3 halogen atoms; R4 means hydrogen or C1-6alkyl; R5 means hydrogen or C1-6alkyl; and R means halogen, hydrogen or C1-6alkyl. Invention also refers to medicinal agent, inhibition method and compound application.

EFFECT: compounds under this invention have improved activity.

16 cl, 2 tbl, 18 ex

Asaindoles // 2326880

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to pharmaceutical formulation inhibiting protein kinase, containing inhibiting selective kinase compound amount of general formula (I): , where: R means aryl or indolyl, and the latter is optionally substituted with one or more groups selected from R4, -C(=O)-R, -C(=O)-OR5, -C(=O)-NY1Y2 and -Z2R; R2 means H; R3 means H; R4 means C1-C6 alkyl, optionally substituted with one substitute -C(=O)-NY1Y2; R5 means H; R7 means C1-C6 alkyl; R means C1-C6 alkyl; X1 means C-aryl, C-heteroaryl, such as pyridile or isoxasolyl, and the latter is optionally substituted with one or two C1-C6 alkyls, C-heterocycloalkyl, such as morpholinile or peperidynil, C-halogen, C-CN, C-OH, C-Z2R, C-C(=O)-OR5, C-NYlY2, C-C(=O)-NY1Y2; Y1 and Y2 means redardless H, aryl, C3-C6 cycloaryl, C1-C6 alkyl, optionally substituted with one group selected from phenyl, halogen, heterocyclil, such as morpholinile, phurile, hydroxyl, -C(=O)-OR5, OR7; or group-NY1Y2 can form morpholinile, peperidynil, optionally substituted with one or two substitutes selected from OH, C1-C6 alkyl; Z means O; where aryl as group or part of group means optionally substituted with one or two substitutes monocyclic aromatic C6carbocyclic fragment, where substitute is selected from halogen or C1-C6 alkoxy, C(=O)-OR5; except compounds: 4-chlorine-2-(4-tert-butylphenyl)-1H-pyrrole[2,3-b]pyridine, 2-(5-methoxy-1 -methyl-1 H-indole-3-il)-4-phenyl-1H- pyrrole[2,3-b]pyridine, 2-(5- methoxy-1 -methyl-1 H-indole-3-il)-1H- pyrrole[2,3-b] pyridine-4-carbonitrile, 4-chlorine-2-(5- methoxy-1 -methyl-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine, or 2-(5- methoxy-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine -4- carbonitrile.

EFFECT: application of compound for production of medicinal agent for inflammatory disease.

51 cl, 9 tbl, 148 ex

FIELD: chemistry.

SUBSTANCE: described is the compound of the general formula , where R1, R2, R3, R4, R5, R6, R7, R8 can be identical or different represent independently hydrogen, halogen, percahalogenalkyl, (C1-C3)alkyl or (C1-C3)alkoxy; R9, R10, R11, R12 R13 and R14 can be identical or different and represent independently hydrogen or (C1-C3)alkyl; "n" is equal to 1 or 2, it is preferable that n be equal to 1; not obligatorily R13 and R14 together with nitrogen atom cab form a 6- term heterocyclic ring, where heterocycle can also be substituted by (C1-C3)alkyl that can have "additional heretoatoms", selected from N and O. Described also are intermediate compounds, the method of their production, pharmaceutical composition and the use of pharmaceuticals intended for treatment of the cases when modulation of the 5-HT receptor activity.

EFFECT: compounds as per this invention are applicable in treatment of disturbances of nervous system.

16 cl, 34 ex

FIELD: medicine; pharmacology.

SUBSTANCE: this invention describes new crystal forms of tryazol[4,5-d]pyrimidine formula I , composition methods and based pharmaceutical formulations. Compounds develop high efficiency as antagonist P2T, can be applied for medical prevention and treatment of arterial thrombotic complication, as well as tumour growth and extension.

EFFECT: compounds show high metabolic stability and bioavailability.

22 cl, 5 ex, 6 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to organic substances production and can be applied for production of herbicides and other bioactive compounds. Production of 2-sulphanilamine-1,2,4-triazolo[1,5-a]pyrimidine of general formula , where R1 is metal, phenylic, 4-methyl phenylic, 4-chlorophenylic group, R is phenylic, 4-methyl phenylic, 4-chlorophenylic, methoxyphenylic group, R is metal, phenylic, 4-methyl phenylic, 4-chlorophenylic group is sulphurization of 2-amino-4,7-dihydro-1,2,4-triazolo [1,5-a]pyrimidines (II) by sulphochlorides (III) in pyrimidine and oxidation of produced 2-sulphanilamine-4,7-dihydro-1,2,4-triazolo[1,5-a] pyrimidines (IV) by bromine in acetic acid with sodium acetate occurrence.

EFFECT: method allows to produce compounds using low-price and reasonable raw materials without any complicated processing steps applied.

1 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of heterocyclic compounds, which contain pyrrolo[1,2-а][1,4]diazepine fragment, annelated to aromatic and heteroaromatic ring. Method for preparation of derivatives of pyrrolo[1,2-а][1,4]diazepine of general formula I, where А =

, is described. The said derivatives may be of use as substances with potential CNS activity, or with analgesic, antimicrobial and antifungal effect. Method implies recyclization of furan ring of 5-methyl-furfurylamides of general formula 2, , where А stands for above shown groups, by exposure to temperature of 60-70°С in the mixture of glacial acetic acid and strong hydrochloric acid in volumetric ratio 1:0.15 for 10-15 minutes.

EFFECT: provides for simultaneous formation of pyrrole and diazepine rings and improves yield of end products due to less number of process steps.

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents (C1-C4)-alkyl with branched or linear chain; R2 represents hydrogen atom (H); R3 represents (C1-C4)-alkyl with branched or linear chain; R4 represents (C1-C4)-alkyl with branched or linear chain, (C2-C4)-alkenyl; R5 represents -SO2NR10R11; R8 represents (C1-C4)-alkyl with branched or linear chain; each R10 and R11 represents independently H or (C1-C12)-alkyl with branched or linear chain; or R10 and R11 in common with nitrogen atom to which they are bound form pyrrolinone group, piperidyl, morpholinyl, 4-N(R13)-piperazinyl that are substituted optionally with (C1-C4)-alkyl with branched or linear chain, -NR14R15, phenyl group substituted optionally with -OH or phenyl group bound in common with other substituted phenyl group by carbonyl group; R13 represents (C1-C4)-alkyl with branched or linear chain, (C2-C6)-alkyl with branched or linear chain and substituted with hydroxyl; (C2-C6)-alkyl with branched or linear chain substituted with phenyl; (C2-C6)-hydrocarbon with branched or linear chain substituted with -CO2R8; wherein each radical among R14 and R15 represents independently H; (C1-C4)-alkyl with branched or linear chain, or its pharmaceutically acceptable salt. The claimed compounds possess inhibitory effect on activity of phosphodiesterase-5 and can be used for production of drug for treatment or prophylaxis of diseases associated with phospholipase and its function. Also, invention relates to pharmaceutical composition, medicinal composition for veterinary science, and intermediate compounds IA-IG used for synthesis of compound of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

8 cl, 2 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), -(CH2)3-, -(CH2)4-, -CH2-S-CH2-, -S-CH2-CH2-; R2 is chosen from group consisting of nitrogen (N), sulfur (S) atom; n = 0 or 1; Z is chosen from group consisting of (C2-C10)-alkyl; R3 is chosen from group consisting of H; m = 0-2; R4 is chosen from group consisting of oxygen atom (O), -CH2-; R5 is chosen from group consisting of the following groups:

wherein R6 is chosen from group consisting of H, alkyl-(C1-C5)-alkoxyl; W is chosen from group consisting of -NH wherein each "alkyl" can be linear or branched and can be also cyclic or linear, or branched and comprises such cyclic residues, and each "aryl" comprises monocyclic aromatic group comprising 5-12 carbon atoms bound with one or some heteroatoms chosen from N, O or S atoms, and to their salts and solvates. Also, invention relates to a pharmaceutical composition, to a method for their synthesis and using compounds by claims 1-6. Invention provides synthesis of novel active compounds and pharmaceutical compositions based on thereof that possess affinity to serotonin receptors of subtype 5-HT1A.

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

10 cl, 4 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the general formula (I): wherein R0 represents hydrogen atom; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be similar or different and each represents independently hydrogen atom, halogen atom, perhalogenalkyl, substituted or unsubstituted groups, such as linear or branched (C1-C12)-alkyl, (C3-C7)-cyclaoalkyl, (C1-C12)-alkoxy, cyclo-(C3-C7)-alkoxy group, hydroxyalkyl; R13 and R14 can be similar or different and each represents independently hydrogen atom, substituted or unsubstituted groups, such as linear or branched (C1-C4)-alkyl, (C3-C7)-cycloalkyl, optionally, R13 and R14 in common with nitrogen atom can form 5-6-membered heterocyclic ring wherein heterocycle can be substituted also, and it can comprise one, two or three double bonds or "additional heteroatoms" chosen from nitrogen atom (N); "n" means a whole number in the range 1-6, and pharmaceutical compositions based on its. Indicated compounds are ligands of 5-HT (serotonin) and can be used in treatment in cases if modulation of activity of 5-HT and melatonin is desirable.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

21 cl, 31 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to novel hydrogenated pyrrolo[4,3-b]indoles of the general formula (1): , their racemates, optical isomers, geometric isomers, pharmaceutically acceptable salts and/or hydrates that can be used, for example, in treatment and prophylaxis of different neurodegenerative diseases, such as Alzheimer's syndrome. In the general formula (1): a dotted line with accompanying unbroken line represents ordinary or double bond; R1 and R2 represent independently of one another substitutes of amino group chosen from hydrogen atom, possibly substituted (C1-C6)-alkyl substituted possibly with aryl, possibly substituted phenyl, possibly substituted carbonylamino or thiocarbonylamino group, substituted acyl, possibly substituted aryl sulfonate wherein substituted in indicated R1 and R2 are chosen from (C1-C6)-alkyl, halogen atoms, nitro, carboxy, alkoxy group, aryl; R1n represents one or some similar or different substituted of cyclic system chosen from hydrogen atom, alkyl, aryl, cyano group, halogen atom, 5-6-membered nitrogen-containing heteroaryl. Also, invention relates to methods for synthesis of these compounds, pharmaceutical compositions and their using, and to using compounds in libraries with their using.

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

20 cl, 2 tbl, 12 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to improved synthesis method of pyrlindone hydrochloride having formula (I) 1. Method features intramolecular cyclization of 6-methyl-1-(2-chloroethyl-imino)-1,2,3,4-tetrahydrocarbazole hydrochloride of formula IV 2 at 80°-140°C with alkali agent in presence of phase transfer catalyst to provide 1,2,5,6-tetrahydro-8-methyl-pyrazine[3,2,1-j,k]-4H-carbazole of formula VI 3 followed by reduction at 80°-120°C. Method of present invention makes in possible to produce compound of formula I with yield nearly 70 % and purity more than 99 %.

EFFECT: method of high yield with reduced amount of alkali agent and phase transfer catalyst.

7 cl, 2 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: compounds satisfying the formula I 1 are disclosed, wherein each R1 and R2 independently to one another are H, OH, OA or Hal; or R1 and R2 together are -O-CH2-O- or -O-CH2-CH2-O-; R3 and R4 are A-group; X - group monosubstituted with R8, R5 or R7; R5 is linear or branched C1-C10-alkylene, wherein one or two CH2-groups may be substituted with oxygen atom; R7 is phenyl or phenylmethyl; R8 is COOH, COOA, CONH2, CONHA, CON(A)2 or CN; F is C1-C6-alkyl; and Hal is F, Cl, Br, or I, as well as physiologically acceptable salts or solvates thereof. Methods for production of claimed compounds (I) and pharmaceutical composition containing the same also are disclosed. Said compounds and pharmaceutical composition have activity as phosphodiesterase V inhibitors and are useful in treatment of cardiovascular diseases and potency disorders.

EFFECT: pharmaceutically applicable compounds and compositions.

7 cl, 16 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pyrrolopyridazine derivative of the following formula: wherein R1 represents (C3-C7)-cycloalkyl-(C1-C6)-alkyl group that can be substituted optionally with (C1-C6)-alkyl group; R2 represents (C1-C6)-alkyl group; R3 represents hydroxymethyl group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbonyloxymethyl group, (C1-C6)-alkoxycarbonyloxymethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxycarbonyl group; R4 represents (C6-C10)-aryl group that can be substituted optionally with substitutes taken among the group consisting of (C1-C6)-alkyl groups, halogen-(C1-C6)-alkyl groups, (C1-C6)-alkoxy-groups, halogen-(C1-C6)-alkoxy-groups and halogen atoms; A represents imino-group, oxygen or sulfur atom, or its pharmaceutically acceptable salt. Pyrrolopyridazine derivatives elicit inhibitory activity with respect to gastric juice secretion and protective activity with respect to stomach mucosa and can be useful as a curative agent for prophylaxis or treatment of ulcer disease. Except for, invention relates to a pharmaceutical composition based on compounds of the invention and to a method for prophylaxis and treatment of ulcer disease.

EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

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

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

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

26 cl, 1 tbl, 119 ex

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