Triheterocylic compounds, pharmaceutical compositions thereof and methods for cancer treatment

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the triheterocylic compounds of formula (Ia) and their pharmaceutically acceptable salts used as growth inhibitors of the cancer or tumor cells, to the preparation method and pharmaceutical compositions thereof, to the treatment method used aforesaid compounds as well as to the intermediates of formula (II) the to the method of its preparation. In general formulas (Ia) and

, Q1 is -N(R1)-; Q2 is -C(R3)-; Q3 is -C(R5)-; Q4 is -C(R9)-; R1 is -Ym(Ra), where -Ra is -H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-; R2 is -H; R3, R4 and R5 independently are -Ym(Rb), where Rb is -H, halogen, -C1-C8 alkyl, -O-(C1-C8 alkyl) or -OR14, -at condition that if value m of radical Ym(Rb) is equal 0, then R5 is not H; R6 is -H; R7 is -Ym-(RC), where -RC is -O-(C1-C8 alkyl) or -NH(phenyl), R8 is -Ym(Rd), where - Rd is -H, -OH, R9, R10, R11, R12 and R13 independently are -Ym(Re), where Re is -H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14, or -O-C(O)OR14; every R14 independently is -H, -C1-C8 alkyl, -phenyl, 5-6-membered heterocycle containing one heteroatom being S; every Y independently is -C1-C8 alkylene-; every m independently is equal 0 or 1.

EFFECT: claimed compounds can find application for treatment of different cancer species.

41 cl, 4 tbl, 4 dwg, 8 ex

 

1. The technical field to which the invention relates.

The present invention relates to trigeneration compounds, compositions containing trilateralism connection, and methods useful in the treatment or prevention of cancer or tumors involving the introduction of an effective amount of trilateralism connection. Compounds, compositions and methods according to the invention are also useful in the treatment or prevention of cancer or neoplasm or to inhibit the growth of cancer cells or tumor cells, treatment or prevention of a viral infection, or for inhibiting the replication or infectivity of a virus.

2. Background of the invention

2.1 Cancer and tumors

Cancer-stricken in the world, 20 million adults and children, and this year revealed more than 9 million new cases (international Agency for research on cancer; www.irac.fr). According to the American society for the fight against cancer it is estimated that about 563100 Americans could die from cancer this year, more than 1,500 people a day. Since 1990 only in the United States died from cancer almost five million, and identified approximately 12 million new cases.

Currently, cancer therapy includes surgery, chemotherapy and/or radiation therapy to destroy cancer cells in the patient's body (see, for example, Stockdal, 1998, "Principles of Cancer Patient Management", in Scientific American: Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV). All these methods have certain difficulties for the patient. Operation, for example, may be contraindicated due to patient or may be unacceptable to the patient. In addition, surgical intervention may lead to incomplete removal of tumor tissue. Radiation therapy is effective only when irradiated tumor tissue has a higher sensitivity to radiation than normal tissue, and, in addition, radiation therapy can often cause serious side effects (Id.) With regard to chemotherapy, there are many chemotherapeutic agents suitable for the treatment of tumors. However, despite the availability of a number of chemotherapy drugs chemotherapy has many drawbacks (see, for example, Stockdale, 1998, "Principles Of Cancer Patient Management," in Scientific American Medicine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10). Almost all chemotherapeutic agents are toxic, and chemotherapy leads to significant, and often dangerous, side effects, including severe nausea, depression of activity of the bone marrow, immunosuppression, etc. in Addition, many tumor cells are resistant or develop resistance to chemotherapeutic assets via multiple drug resistance.

Tamura t al., JP 93086374, reveal metalloproteinases and/or prodigiosin-25C as useful in the treatment of leukemia, but give data only for activity prodigiosin-25C in the cells L-5178Y in vitro. Hirata et al., JP 10120562, describe the use of cyclopropylidene as an inhibitor vacuole-type ATPase proton pump and believe that cyclopropylidene can have enhancing antitumor activity ability. Hirata et al., JP 10120563, describe the use of cyclopropylidene as a therapeutic agent against leukemia, as immunosuppressant and as inducing apoptosis factor. In JP 61034403, from Kirin Brewery Co. Ltd, describes the ability of prodigiosin to increase the survival time of mice with leukemia. Boger, 1988, J. Org. Chem. 53:1405-1415 describes the cytotoxic activity of prodigiosin, prodigiosin and 2-methyl-3-interpretivist in vitro against leukemia P388 cells of mice. The national cancer Institute (see web-site Developmental Therapeutics Program of the NCI/NIH), describes the data obtained from the results of the screening of tumor cell lines, including the screening for butylcyclohexyl-prodiginine-HCl; however, the study does not show that used to screen compounds are selective against cancer cells (for example, in comparison with normal cells).

Thus, in this region there is an urgent n is a need for new compounds, compositions and methods useful in the treatment of cancer and tumors, characterized by reduced side effects or no side effects. In addition, there is a need for methods of treatment of cancer, providing specific treatment against cancer cells with high specificity and reduced toxicity.

2.2 Viruses and diseases

In addition to cancer of the large number of diseases of humans and animals caused by virulent and opportunistic viral infections (see, Belshe (Ed.) 1984Textbook of Hurnan Virology, PSG Publishing, Littleton, MA). Viral diseases of a wide variety of tissues, including the respiratory tract, CNS, skin, urinary system, eyes, ears, immune system, gastrointestinal tract and musculoskeletal system, affect large numbers of people of all ages (see Table 328-2 In: Wyngaarden and Smith, 1988,Cecil Textbook of Medicine,18th Ed., W.B. Saunders Co., Philadelphia, pp.1750-1753).

Although considerable efforts to develop effective antiviral therapy, viral infections continue to threaten the lives of millions of people around the world. Basically attempts to create antiviral drugs is focused on certain stages of the life cycle of the virus (see, for example, Mitsuya, H., et al., 1991, FASEB J. 5:2369-2381, discussing HIV). However, a common disadvantage associated with the use of many modern antiviral drug medium is in, are harmful side effects, such as toxicity in the body of the “owner” or resistance of some viral strains.

Thus, in this area there is a need for anti-viral compounds, compositions and methods that allow safe and reliable to treat viral disease and do not have the above disadvantages.

Citation and identification of any reference in sections 2 of this application is not an admission that the reference determines the prior art for the present invention.

3. The invention

The present invention relates to compounds having the formula (Ia):

and their pharmaceutically acceptable salts, where:

Q1means-O-, -S - or-N(R1)-;

Q2means-C(R3)- or-N-;

Q3means-C(R5)- or-N-;

Q4means-C(R9)- or-N-;

R1means-Ym(Ra), where-Rameans-H, -OH, -C1-C8alkyl, -C2-C8alkenyl, -C2-C8quinil, -C3-C12-cycloalkyl, -phenyl, -naphthyl,

-3-9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, --R 14, -SOR14,

-S(Oh)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -OS(O)2O-,

-O-C(S)R14, -O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14,

-C(S)other14, -C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14,

-NHC(S)N(R14)2, -NR14C(S)other14or-NR14C(S)N(R14)2;

R2means-H, -C1-C8alkyl or-OH;

R3, R4and R5independent mean-Ym(Rb), where Rbmeans-H, halogen, -NH2, -CN, -NO2, -SH, -N3, -C1-C8alkyl, -O-(C1-C8alkyl),

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl, -phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(O)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -O-C(S)R14,

-O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14,

-C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2, -NR14C(S)other14, -NR14C(S)N(R14)23and R4or R4and R5together with the carbon atom to which they are attached, form a 5 to 9 membered ring, provided that if Q3means-C(R5)- and m=0, R5is not H;

R6means-H, halogen, -OH, -NH2, -C1-C8alkyl or-O-(C1-C8alkyl);

R7means-Ym-(Rc), where-Rcmeans-C1-C8alkyl,

-O-(C1-C8alkyl), -O-benzyl, -OH, -NH2, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2, -NH(naphthyl),

-N(naphthyl)2, -CN, -NO2, -N3, -C2-C8quinil, -OR14, -O(CH2)nOR14,

-C(O)R14, -O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(O)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14,

- (CH2)nC(O)O(CH2)nCH3, -O-C(S)R14, -O-C(S)OR14, -O-C(S)other14,

-O-C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2, -NHC(S)R14,

-NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2, -NR14C(S)other14,

-NR14C(S)N(R14)2;

R8means-Ym(Rd), where-Rdmeans-H, -H, halogen, amino, -NH(C1-C5alkyl), -N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2,

-NH(naphthyl), -N(naphthyl)2, -CN, -NO2N3, -C1-C8alkyl,

-O-(C1-C8alkyl), -(C1-C8alkyl)-OH, -C2-C8alkenyl,

-C2-C8quinil, -C3-C12cycloalkyl, -phenyl, -naphthyl,

-3-9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)otherl4, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -O-C(S)R14, -O-C(S)OR14,

-O-C(S)other14,- C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2;

R9, R10, R11, R12and R13independent mean-Ym(Re), where Remeans-H, halogen, -NH2C1-C8alkyl, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2, -NH(naphthyl),

-N(naphthyl)2, -C(O)NH(C1-C5alkyl), -C(O)N(C1-C5alkyl)2,

-NHC(O)(C1-C5Alki is), -NHC(=NH2+)NH2, -CN, -NO2N3,

3-9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14,- C(S)R14, -O-C(S)OR14,

-O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2or R11and R12together with the carbon atom to which they are attached, form a 5 to 9 membered heterocycle;

each R14independently denotes-H, -C1-C8alkyl, -C3-C12cycloalkyl, -phenyl, -naphthyl, -3 to 9-membered heterocycle, -C2-C8alkenyl or-C2-C8quinil;

each Y independently denotes-C1-C8alkylene-, -C2-C8albaniles - or-C2-C8akinyan-;

each m is independently 0 or 1; and

each n independently denotes an integer that varies from 0 to 6.

In some specific embodiments, the implementation of the-O-benzyl is unsubstituted.

In some particular option is the implementation of R 7means 3 methoxybenzyloxy.

In some specific embodiments, the implementation-phenyl is unsubstituted.

In some specific embodiments, the implementation of R14means pendimethalin. According to even more specific options for the implementation of R1means-C(O)other14and R14means pendimethalin.

In some specific embodiments, the implementation of R7means-och2C(O)OC2H5.

In some specific embodiments, the implementation of R14means benzyloxyphenyl. According to even more specific options for the implementation of R1means-C(O)other14and R14means benzyloxyphenyl.

In some specific embodiments, the implementation of R14means paraprotein. According to even more specific options for the implementation of R1means-C(O)R14and R14means paraprotein.

In some specific embodiments, the implementation of Rameans parahydroxybenzoic. According to even more specific variants of realization of Ymmeans-CH2and R14means parahydroxybenzoic.

In some specific embodiments, the implementation of R7means-NH(phenyl)OCH3.

In some specific embodiments, the implementation of R1means -(CH2)2OS(O)2O-.

In some specific embodiments, Khujand who conduct R 11and R12not combined together with the carbon atom that is attached to each of the groups.

Further, the invention relates to compositions containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound having the formula (Ia):

and their pharmaceutically acceptable salts, where:

Q1means-O-, -S - or-N(R1)-;

Q2means-C(R3)- or-N-;

Q3means-C(R5)- or-N-;

Q4means-C(R9)- or-N-;

R1means-Ym(Ra), where-Rameans-H, -OH, -C1-C8alkyl,

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl, -phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(Oh)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -OS(O)2O-,

-O-C(S)R14, -O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14,

-C(S)other14, -C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14,

-NHC(S)N(R14)2, -NR14C(S)other14or-NR14C(S)N(R14) 2;

R2means-H, -C1-C8alkyl or-OH;

R3, R4and R5independent mean-Ym(Rb), where Rbmeans-H, halogen, -NH2, -CN, -NO2, -SH, -N3, -C1-C8alkyl, -O-(C1-C8alkyl),

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl, -phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(O)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -O-C(S)R14,

-O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14,

-C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

NR14C(S)other14, -NR14C(S)N(R14)2or R3and R4or R4and R5together with the carbon atom to which they are attached, form a 5 to 9 membered ring, provided that if Q3means-C(R5)- and m=0, R5is not H;

R6means-H, halogen, -OH, -NH2, -C1-C8alkyl or-O-(C1-C8alkyl);

R7means-Ym-(Rc), where-Rc- C 1-C8alkyl,

-O-(C1-C8alkyl), -O-benzyl, -OH, -NH2, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2, -NH(naphthyl),

-N(naphthyl)2, -CN, -NO2, -N3, -C2-C8quinil, -OR14, -O(CH2)nOR14,

-C(O)R14, -O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(O)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14,

- (CH2)nC(O)O(CH2)nCH3, -O-C(S)R14, -O-C(S)OR14, -O-C(S)other14,

-O-C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2, -NHC(S)R14,

-NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2, -NR14C(S)other14,

-NR14C(S)N(R14)2;

R8means-Ym(Rd), where-Rdmeans-H, -OH, halogen, amino, -NH(C1-C5alkyl), -N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2,

-NH(naphthyl), -N(naphthyl)2, -CN, -NO2N3, -C1-C8alkyl,

-O-(C1-C8alkyl), -(C1-C8alkyl)-OH, -C2-C8alkenyl,

-C2-C8quinil, -C3-C12cycloalkyl, -phenyl, -naphthyl,

-3-9-membered heterocycle, -OR142)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)otherl4, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -O-C(S)R14, -O-C(S)OR14,

-O-C(S)other14,- C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2;

R9, R10, R11, R12and R13independent mean-Ym(Re), where Remeans-H, halogen, -NH2C1-C8alkyl, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2, -NH(naphthyl),

-N(naphthyl)2, -C(O)NH(C1-C5alkyl), -C(O)N(C1-C5alkyl)2,

-NHC(O)(C1-C5alkyl), -NHC(=NH2+)NH2, -CN, -NO2N3,

3-9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS() 2R14,- C(S)R14, -O-C(S)OR14,

-O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2or R11and R12together with the carbon atom to which they are attached, form a 5 to 9 membered heterocycle;

each R14independently denotes-H, -C1-C8alkyl, -C3-C12cycloalkyl, -phenyl, -naphthyl, -3 to 9-membered heterocycle, -C2-C8alkenyl or-C2-C8quinil;

each Y independently denotes-C1-C8alkylene-, -C2-C8albaniles - or-C2-C8akinyan-;

each m is independently 0 or 1; and

each n independently denotes an integer that varies from 0 to 6.

In some specific embodiments, the implementation

-O-benzyl is unsubstituted.

In some specific embodiments, the implementation of R7means 3 methoxybenzyloxy.

In some specific embodiments, the implementation-phenyl is unsubstituted.

In some specific embodiments, the implementation of R14means pendimethalin. According to even more specific options for the implementation of R1means-C(O)other14and R14means pendimethalin.

In some Conques is to maintain options for implementation of R 7means-och2C(O)OC2H5.

In some specific embodiments, the implementation of R14means benzyloxyphenyl. According to even more specific options for the implementation of R1means-C(O)other14and R14means benzyloxyphenyl.

In some specific embodiments, the implementation of R14means paraprotein. According to even more specific options for the implementation of R1means-C(O)R14and R14means paraprotein.

In some specific embodiments, the implementation of Rameans parahydroxybenzoic. According to even more specific variants of realization of Ymmeans-CH2and R14means parahydroxybenzoic.

In some specific embodiments, the implementation of R7means-NH(phenyl)OCH3.

In some specific embodiments, the implementation of R1means -(CH2)2OS(O)2O-.

In some specific embodiments, the implementation of R11and R12not combined together with the carbon atom that is attached to each of the groups.

According to another aspect of the invention relates to methods of treating cancer in a patient, including the introduction in need of such treatment to the patient an effective amount of the compounds or pharmaceutically acceptable salts of the compounds having the above formula (Ia), is de Q 1-Q4, R2, R4, R6-R8and R10-R13defined above for compounds of formula (Ia).

According to another aspect of the invention concerns methods of treatment directed against the virus and viral infection in a patient, including the introduction in need of such treatment to the patient an effective amount of the compounds or pharmaceutically acceptable salts of the compounds having the above formula (Ia), where Q1-Q4, R2, R4, R6-R8and R10-R13defined above for compounds of formula (Ia).

A further aspect of the present invention relates to methods useful for obtaining trilateration compounds having the formula (Ia).

One of the ways of carrying out the invention concerns a method of obtaining compounds having the formula (Ia):

including contacting the compounds of formula (II)

with the compound of the formula (iv)

in the presence of an organic solvent and a proton acid over a period of time and at a temperature sufficient to obtain the compounds of formula (Ia),

where

Q1means-O-, -S - or-N(R1)-;

Q2means-C(R3)- or-N-;

Q3means-C(R5)- or-N-;

Q4oznacza is t-C(R 9)- or-N-;

R1means-Ym(Ra), where-Rameans-H, -OH, -C1-C8alkyl,

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl, -phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(Oh)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -OS(O)2O-,

-O-C(S)R14, -O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14,

-C(S)other14, -C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14,

-NHC(S)N(R14)2, -NR14C(S)other14or-NR14C(S)N(R14)2;

R2means-H, -C1-C8alkyl or-OH;

R3, R4and R5independent mean-Ym(Rb), where Rbmeans-H, halogen, -NH2, -CN, -NO2, -SH, -N3, -C1-C8alkyl, -O-(C1-C8alkyl),

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl, -phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14,-O-C(O)other 14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(O)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -O-C(S)R14,

-O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14,

-C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2or R3and R4or R4and R5together with the carbon atom to which they are attached, form a 5 to 9 membered ring, provided that if Q3means-C(R5)- and m=0, R5is not H;

R6means-H, halogen, -OH, -NH2, -C1-C8alkyl or-O-(C1-C8alkyl);

R7means-Ym-(Rc), where-Rcmeans-C1-C8alkyl,

-O-(C1-C8alkyl), -O-benzyl, -OH, -NH2, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2, -NH(naphthyl),

-N(naphthyl)2, -CN, -NO2, -N3, -C2-C8quinil, -OR14, -O(CH2)nOR14,

-C(O)R14, -O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(O)2R , -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14,

- (CH2)nC(O)O(CH2)nCH3, -O-C(S)R14, -O-C(S)OR14, -O-C(S)other14,

-O-C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2, -NHC(S)R14,

-NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2, -NR14C(S)other14,

-NR14C(S)N(R14)2;

R8means-Ym(Rd), where-Rdmeans-H, -OH, halogen, amino, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2,

-NH(naphthyl), -N(naphthyl)2, -CN, -NO2N3, -C1-C8alkyl,

-O-(C1-C8alkyl), -(C1-C8alkyl)-OH, -C2-C8alkenyl,

-C2-C8quinil, -C3-C12cycloalkyl, -phenyl, -naphthyl,

-3-9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)otherl4, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -O-C(S)R14, -O-C(S)OR14,

-O-C(S)other14,- C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14 2,

-NR14C(S)other14, -NR14C(S)N(R14)2;

R9, R10, R11, R12and R13independent mean-Ym(Re), where Remeans-H, halogen, -NH2C1-C8alkyl, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2, -NH(naphthyl),

-N(naphthyl)2, -C(O)NH(C1-C5alkyl), -C(O)N(C1-C5alkyl)2,

-NHC(O)(C1-C5alkyl), -NHC(=NH2+)NH2, -CN, -NO2N3,

3-9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14,- C(S)R14, -O-C(S)OR14,

-O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2or R11and R12together with the carbon atom to which they are attached, form a 5 to 9 membered heterocycle;

each R14independently denotes-H, -C1-C8alkyl, -C3-C12cycloalkyl, -phenyl, -NAF is Il, -3-9-membered heterocycle, -C2-C8alkenyl or-C2-C8quinil;

each Y independently denotes-C1-C8alkylene-, -C2-C8albaniles - or-C2-C8akinyan-;

each m is independently 0 or 1; and

each n independently denotes an integer that varies from 0 to 6.

In some specific embodiments, the implementation of the-O-benzyl is unsubstituted.

In some specific embodiments, the implementation of R7means 3 methoxybenzyloxy.

In some specific embodiments, the implementation-phenyl is unsubstituted.

In some specific embodiments, the implementation of R14means pendimethalin. According to even more specific options for the implementation of R1means-C(O)other14and R14means pendimethalin.

In some specific embodiments, the implementation of R7means-och2C(O)OC2H5.

In some specific embodiments, the implementation of R14means benzyloxyphenyl. According to even more specific options for the implementation of R1means-C(O)other14and R14means benzyloxyphenyl.

In some specific embodiments, the implementation of R14means paraprotein. According to even more specific options for the implementation of R1means-C(O)R14and R14means parab ompany.

In some specific embodiments, the implementation of Rameans parahydroxybenzoic. According to even more specific variants of realization of Ymmeans-CH2and R14means parahydroxybenzoic.

In some specific embodiments, the implementation of R7means-NH(phenyl)OCH3.

In some specific embodiments, the implementation of R1means -(CH2)2OS(O)2O-.

In some specific embodiments, the implementation of R11and R12not combined together with the carbon atom that is attached to each of the groups.

According to another variant implementation of the invention concerns a method of obtaining compounds having the formula (Ia):

this method involves the following stages:

(a) contacting the compounds of formula (II)

with the compound of the formula (v)

where M denotes Li, Na, K, Rb or Cs,

in the presence of an essentially anhydrous aprotic organic solvent for a period of time and at a temperature sufficient to obtain the compounds of formula (vi)

where M takes values above, and

(b) protonation of the compounds of formula (vi) using donor H+ over a period of time and at a temperature sufficient to obtain a connection Faure the uly (Ia),

where

Q1means-O-, -S - or-N(R1)-;

Q2means-C(R3)- or-N-;

Q3means-C(R5)- or-N-;

Q4means-C(R9)- or-N-;

R1means-Ym(Ra), where-Rameans-H, -OH, -C1-C8alkyl,

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl, -phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(Oh)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -OS(O)2O-,

-O-C(S)R14, -O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14,

-C(S)other14, -C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14,

-NHC(S)N(R14)2, -NR14C(S)other14or-NR14C(S)N(R14)2;

R2means-H, -C1-C8alkyl or-OH;

R3, R4and R5independent mean-Ym(Rb), where Rbmeans-H, halogen, -NH2, -CN, -NO2, -SH, -N3, -C1-C8alkyl, -O-(C1-C8alkyl),

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl-phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(O)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -O-C(S)R14,

-O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14,

-C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2or R3and R4or R4and R5together with the carbon atom to which they are attached, form a 5 to 9 membered ring, provided that if Q3means-C(R5)- and m=0, R5is not H;

R6means-H, halogen, -OH, -NH2, -C1-C8alkyl or-O-(C1-C8alkyl);

R7means-Ym-(Rc), where-Rcmeans-C1-C8alkyl,

-O-(C1-C8alkyl), -O-benzyl, -OH, -NH2, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2,

-NH(phenyl), -N(phenyl)2, -NH(naphthyl), -N(naphthyl)2, -CN, -NO2, -N3, -C2-C8quinil, -OR14, -O(CH2)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n -R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -O(CH2)nC(O)O(CH2)nCH3,

-O-C(S)R14, -O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14,

-C(S)other14, -C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14,

-NHC(S)N(R14)2, -NR14C(S)other14, -NR14C(S)N(R14)2;

R8means-Ym(Rd), where-Rdmeans-H, -OH, halogen, amino, -NH(C1-C5alkyl), -N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2,

-NH(naphthyl), -N(naphthyl)2, -CN, -NO2N3, -C1-C8alkyl,

-O-(C1-C8alkyl), -(C1-C8alkyl)-OH, -C2-C8alkenyl,

-C2-C8quinil, -C3-C12cycloalkyl, -phenyl, -naphthyl,

-3-9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)otherl4, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -O-C(S)R14, -O-C(S)OR14,

-O-(S)other 14,- C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2;

R9, R10, R11, R12and R13independent mean-Ym(Re), where Remeans-H, halogen, -NH2C1-C8alkyl, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2, -NH(naphthyl),

-N(naphthyl)2, -C(O)NH(C1-C5alkyl), -C(O)N(C1-C5alkyl)2,

-NHC(O)(C1-C5alkyl), -NHC(=NH2+)NH2, -CN, -NO2N3,

3-9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14,- C(S)R14, -O-C(S)OR14,

O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2or R11and R12together with the carbon atom to which they are also dinani, form a 5-9-membered heterocycle;

each R14independently denotes-H, -C1-C8alkyl, -C3-C12cycloalkyl, -phenyl, -naphthyl, -3 to 9-membered heterocycle, -C2-C8alkenyl or-C2-C8quinil;

each Y independently denotes-C1-C8alkylene-, -C2-C8albaniles - or-C2-C8akinyan-;

each m is independently 0 or 1; and

each n independently denotes an integer that varies from 0 to 6.

In some specific embodiments, the implementation of the-O-benzyl is unsubstituted.

In some specific embodiments, the implementation of R7means 3 methoxybenzyloxy.

In some specific embodiments, the implementation-phenyl is unsubstituted.

In some specific embodiments, the implementation of R14means pendimethalin. According to even more specific options for the implementation of R1means-C(O)other14and R14means pendimethalin.

In some specific embodiments, the implementation of R7means-och2C(O)OC2H5.

In some specific embodiments, the implementation of R14means benzyloxyphenyl. According to even more specific options for the implementation of R1means-C(O)other14and R14means benzyloxyphenyl.

In some specific embodiments, the implementation of R 14means paraprotein. According to even more specific options for the implementation of R1means-C(O)R14and R14means paraprotein.

In some specific embodiments, the implementation of Rameans parahydroxybenzoic. According to even more specific variants of realization of Ymmeans-CH2and R14means parahydroxybenzoic.

In some specific embodiments, the implementation of R7means-NH(phenyl)OCH3.

In some specific embodiments, the implementation of R1means -(CH2)2OS(O)2O-.

In some specific embodiments, the implementation of R11and R12not combined together with the carbon atom that is attached to each of the groups.

Further, the invention relates to compositions containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound having the formula (Ib):

or its pharmaceutically acceptable salt,

where:

Q1means-O-, -S - or-N(R1)-;

Q2means-C(R3)- or-N-;

Q3means-C(R5)- or-N-;

Q4means-C(R9)- or-N-;

R1means-Ym(Ra), where-Rameans-H, -OH, -C1-C8alkyl,

-C2-C8alkenyl, -C2-C8quinil, -C3-C12recloak is l, -phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(Oh)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -OS(O)2O-,

-O-C(S)R14, -O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14,

-C(S)other14, -C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14,

-NHC(S)N(R14)2, -NR14C(S)other14or-NR14C(S)N(R14)2;

R2means-H, -C1-C8alkyl or-OH;

R3, R4and R5independent mean-Ym(Rb), where Rbmeans-H, halogen, -NH2, -CN, -NO2, -SH, -N3, -C1-C8alkyl, -O-(C1-C8alkyl),

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl, -phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(O)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R4 , -O-C(S)R14,

-O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14,

-C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2or R3and R4or R4and R5together with the carbon atom to which they are attached, form a 5 to 9 membered ring, provided that if Q3means-C(R5)- and m=0, R5is not H;

R6means-H, halogen, -OH, -NH2, -C1-C8alkyl or-O-(C1-C8alkyl);

R7and R8independent mean-Ym-(Rd), where-Rdmeans-H

-OH, halogen, amino, -NH(C1-C5alkyl), -N(C1-C5alkyl)2,

-NH(phenyl), -N(phenyl)2, -NH(naphthyl), -N(naphthyl)2, -CN, -NO2, -N3,

-C1-C8alkyl, -O-(C1-C8alkyl), -(C1-C8alkyl)-OH, -O-benzyl,

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl, -phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -CH2O(CH2)nOR14,

-O-C(O)R14, -C(O)(CH2)n-R14, -C(O)R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)otherl4, -S-R14, -SOR14,

-S(O)2R14, -NHC(O)R1414, -NHSOR14, -NHS(O)2R14, -O-C(S)R14,

-O-C(S)OR14, -O-C(S)other14,- C(S)N(R14)2, -C(S)OR14, -C(S)other14,

-C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2;

R9, R10, R11, R12and R13independent mean-Ym(Re), where Remeans-H, halogen, -NH2C1-C8alkyl, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2, -NH(naphthyl),

-N(naphthyl)2, -C(O)NH(C1-C5alkyl), -C(O)N(C1-C5alkyl)2,

-NHC(O)(C1-C5alkyl), -NHC(=NH2+)NH2, -CN, -NO2N3,

3-9-membered heterocycle, -OR14, -CH2O(CH2)nOR14, -O-C(O)R14,

-C(O)(CH2)n-R14, -C(O)R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14,- C(S)R14, -O-C(S)OR14,

-O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14/sub> C(S)N(R14)2or R11and R12together with the carbon atom to which they are attached, form a 5 to 9 membered heterocycle;

each R14independently denotes-H, -C1-C8alkyl, -C3-C12cycloalkyl, -phenyl, -naphthyl, -3 to 9-membered heterocycle, -C2-C8alkenyl or-C2-C8quinil;

each Y independently denotes-C1-C8alkylene-, -C2-C8albaniles - or-C2-C8akinyan-;

each m is independently 0 or 1; and

each n independently denotes an integer that varies from 0 to 6.

In some specific embodiments, the implementation of the-O-benzyl is unsubstituted.

In some specific embodiments, the implementation of R7means 3 methoxybenzyloxy.

In some specific embodiments, the implementation-phenyl is unsubstituted.

In some specific embodiments, the implementation of R14means pendimethalin. According to even more specific options for the implementation of R1means-C(O)other14and R14means pendimethalin.

In some specific embodiments, the implementation of R7means-och2C(O)OC2H5.

In some specific embodiments, the implementation of R14means benzyloxyphenyl. According to even more specific options for the implementation of R1means-C(O)other 14and R14means benzyloxyphenyl.

In some specific embodiments, the implementation of R14means paraprotein. According to even more specific options for the implementation of R1means-C(O)R14and R14means paraprotein.

In some specific embodiments, the implementation of Rameans parahydroxybenzoic. According to even more specific variants of realization of Ymmeans-CH2and R14means parahydroxybenzoic.

In some specific embodiments, the implementation of R7means-NH(phenyl)OCH3.

In some specific embodiments, the implementation of R1means -(CH2)2OS(O)2O-.

In some specific embodiments, the implementation of R11and R12not combined together with the carbon atom that is attached to each of the groups.

According to another aspect of the invention relates to methods of treating cancer in a patient, including the introduction in need of such treatment to the patient an effective amount of the compounds or pharmaceutically acceptable salts of the compounds having the above formula (Ib)where Q1-Q4, R2, R4, R6-R8and R10-R13defined above for compounds of formula (Ib).

According to another aspect of the invention concerns methods of treatment directed against the virus and viral infection in a patient, including the introduction in need of such treatment to the patient an effective amount of the compounds or pharmaceutically acceptable salts of the compounds having the above formula (Ib)where Q1-Q4, R2, R4, R6-R8and R10-R13defined above for compounds of formula (Ib).

The present invention also encompasses compounds having the formula (II):

and their pharmaceutically acceptable salts, where:

Q1means-O-, -S - or-N(R1)-;

Q4means-C(R9)- or-N-;

R1means-Ym(Ra), where-Rameans-H, -OH, -C1-C8alkyl,

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl, -phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(Oh)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -OS(O)2O-,

-O-C(S)R14, -O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14,

-C(S)other14, -C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14,

-NHC(S)N(R14)2, -NR14 C(S)other14or-NR14C(S)N(R14)2;

R6means-H, halogen, -OH, -NH2, -C1-C8alkyl or-O-(C1-C8alkyl);

R7and R8independent mean-Ym-(Rd), where-Rdmeans-H

-OH, halogen, amino, -NH(C1-C5alkyl), -N(C1-C5alkyl)2,

-NH(phenyl), -N(phenyl)2, -NH(naphthyl), -N(naphthyl)2, -CN, -NO2, -N3,

-C1-C8alkyl, -O-(C1-C8alkyl), -(C1-C8alkyl)-OH, -O-benzyl,

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl, -phenyl,

-naphthyl, -C7-C12(phenyl)alkyl, -C7-C12(naphthyl)alkyl,

-C7-C12(phenyl)alkenyl, -C7-C12(naphthyl)alkenyl,

-C7-C12(phenyl)quinil, -C7-C12(naphthyl)quinil,

-3-9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)otherl4, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -O-C(S)R14, -O-C(S)OR14,

-O-C(S)other14,- C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NH(S)other 14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2;

R9, R10, R11, R12and R13independent mean-Ym(Re), where Remeans-H, halogen,

-NH2C1-C8alkyl, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2, -NH(naphthyl),

-N(naphthyl)2, -C(O)NH(C1-C5alkyl), -C(O)N(C1-C5alkyl)2,

-NHC(O)(C1-C5alkyl), -NHC(=NH2+)NH2, -CN, -NO2N3,

3-9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14,- C(S)R14, -O-C(S)OR14,

-O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2or R11and R12together with the carbon atom to which they are attached, form a 5 to 9 membered heterocycle;

each R14independently denotes-H, -C1-C8alkyl, -C3-C12/sub> cycloalkyl, -phenyl, -naphthyl, -3 to 9-membered heterocycle, -C2-C8alkenyl or-C2-C8quinil;

each Y independently denotes-C1-C8alkylene-, -C2-C8albaniles - or-C2-C8akinyan-;

each m is independently 0 or 1; and

each n independently denotes an integer that varies from 0 to 6.

The compound of formula (Ia), (Ib) or (II) or its pharmaceutically acceptable salt ("trilateralism compound") is useful in the treatment or prevention of cancer or tumors in need of such treatment or prophylaxis of a patient having an inhibitory effect on the growth of a cancer cell or tumor cells, for the treatment or prevention of a viral infection in need of such treatment or prophylaxis of a patient, or for inhibiting the replication or infectivity of a virus.

Further, the invention relates to methods of treatment or prevention of cancer or tumors, including the introduction in need of such treatment or prevention to the patient an effective amount of trilateralism connection.

The invention also relates to methods of inhibiting the growth of cancer or tumor cells, comprising contacting a cancer or neoplastic cell with an effective amount of trilateralism connection.

In addition, the invention is concerned with osobov treatment or prophylaxis of viral infections, including the introduction in need of such treatment or prevention to the patient an effective amount of trilateralism connection.

The invention also relates to methods of inhibiting the replication or infectivity of a virus comprising contacting a virus or virusinfection cells with an effective amount of trilateralism connection.

According to a further aspect of the invention relates to methods useful for obtaining trilateration compounds having the formula (Ib).

One of the ways of carrying out the invention concerns a method of obtaining compounds having the formula (Ib):

including contacting the compounds of formula (II)

with the compound of the formula (iv)

in the presence of an organic solvent and a proton acid over a period of time and at a temperature sufficient to obtain the compounds of formula (Ib),

where Q1-Q4, R2, R4, R6-R8and R10-R13defined above for trigeneration compounds of formula (Ib).

According to another variant implementation of the invention concerns methods for producing compounds having the formula (Ib):

incorporating the following stages:

(a) contacting connection is of formula (II)

with the compound of the formula (v)

where M denotes Li, Na, K, Rb or Cs,

in the presence of an essentially anhydrous aprotic organic solvent, for a period of time and at a temperature sufficient to obtain the compounds of formula (vi)

where M takes values above; and

(b) protonation of the compounds of formula (vi) using donor H+over a period of time and at a temperature sufficient to obtain the compounds of formula (Ib),

where Q1-Q4, R2, R4, R6-R8and R10-R13defined above for compounds of formula (Ib).

According to another aspect of the invention concerns methods for producing compounds having the formula (II):

including contacting the compounds of formula (iii)

with the compound of the formula (ii) or a compound of formula (iia)

in the presence of an organic solvent, a base and Ni - or Pd-catalyst for a period of time and at a temperature sufficient to obtain the compounds of formula (II)

where Q1-Q4, R6-R8and R10-R13defined above for trigeneration compounds of the formula (II) and where R15 independently mean C1-C8alkyl, cycloalkyl or phenyl.

According to a particular variant implementation trilateralism connection represents a connection 1:

Connection 1,

or its pharmaceutically acceptable salt.

In another variant implementation trilateralism connection is a tartrate saltconnections 1.

According to another variant implementation trilateralism connection is mesilate saltconnections 1.

According to another variant implementation trilateralism compound is a prodrugconnections 1. According to a more specific options prodrugconnections 1iscompound 66orconnection 67or their pharmaceutically acceptable salts.

Compound 66
mono[2-(3-{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indol-1-yl}-1,1-dimethyl-3-oxopropyl)-3-were]new ether phosphoric acid
Connection 67
mono(2-{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indole-1-carbonyl}benzyl)new EPE is phosphoric acid

The present invention encompasses compounds having formula (Ic):

and its pharmaceutically acceptable salts, where:

Q1means-O-, -S - or-N(R1)-;

Q2means-C(R3)- or-N-;

Q3means-C(R5)- or-N-;

Q4means-C(R9)- or-N-;

R1means-Ym(Ra), where-Rameans-H, -OH, -C1-C8alkyl,

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl, -phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(Oh)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -OS(O)2O-,

-O-C(S)R14, -O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14,

-C(S)other14, -C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14,

-NHC(S)N(R14)2, -NR14C(S)other14or-NR14C(S)N(R14)2;

R2means-H, -C1-C8alkyl or-OH;

R3, R4and R5independent mean-Ym(Rb), where Rbmeans-H, halogen, -NH2, -CN, -NO , -SH, -N3, -C1-C8alkyl, -O-(C1-C8alkyl),

-C2-C8alkenyl, -C2-C8quinil, -C3-C12cycloalkyl, -phenyl,

-naphthyl, -3 to 9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14,

-O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(O)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14, -O-C(S)R14,

-O-C(S)OR14, -O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14,

-C(S)N(R14)2, -NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2or R3and R4or R4and R5together with the carbon atom to which they are attached, form a 5 to 9 membered ring;

R6means-H, halogen, -OH, -NH2, -C1-C8alkyl or-O-(C1-C8alkyl);

R7means-Ym-(Rc), where-Rcmeans-C1-C8alkyl,

-O-(C1-C8alkyl), -O-benzyl, -OH, -NH2, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2, -NH(naphthyl),

-N(naphthyl)2, -CN, -NO2, -N3, -C2-C8quinil, -OR14, -O(CH2)nOR14,

-C(O)R14, -O-C(O)R14, -C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14,

-O-C(O)N(R14)2, -C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14,

-S(O)2R14, -NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14,

- (CH2)nC(O)O(CH2)nCH3, -O-C(S)R14, -O-C(S)OR14, -O-C(S)other14,

-O-C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2, -NHC(S)R14,

-NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2, -NR14C(S)other14,

-NR14C(S)N(R14)2;

R8means-Ym(Rd), where-Rdmeans-H, -OH, halogen, amino, -NH(C1-C5alkyl), -N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2,

-NH(naphthyl), -N(naphthyl)2, -CN, -NO2N3, -C1-C8alkyl,

-O-(C1-C8alkyl), -(C1-C8alkyl)-OH, -C2-C8alkenyl,

-C2-C8quinil, -C3-C12cycloalkyl, -phenyl, -naphthyl,

-3-9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)otherl4, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14 , -NHSR14, -NHSOR14, -NHS(O)2R14, -O-C(S)R14, -O-C(S)OR14,

-O-C(S)other14,- C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(R14)2;

R9, R10, R11, R12and R13independent mean-Ym(Re), where Remeans-H, halogen, -NH2C1-C8alkyl, -NH(C1-C5alkyl),

-N(C1-C5alkyl)2, -NH(phenyl), -N(phenyl)2, -NH(naphthyl),

-N(naphthyl)2, -C(O)NH(C1-C5alkyl), -C(O)N(C1-C5alkyl)2,

-NHC(O)(C1-C5alkyl), -NHC(=NH2+)NH2, -CN, -NO2N3,

3-9-membered heterocycle, -OR14, -O(CH2)nOR14, -C(O)R14, -O-C(O)R14,

-C(O)(CH2)n-R14, -O-C(O)OR14, -O-C(O)other14, -O-C(O)N(R14)2,

-C(O)N(R14)2, -C(O)OR14, -C(O)other14, -S-R14, -SOR14, -S(O)2R14,

-NHC(O)R14, -NHSR14, -NHSOR14, -NHS(O)2R14,- C(S)R14, -O-C(S)OR14,

-O-C(S)other14, -O-C(S)N(R14)2, -C(S)OR14, -C(S)other14, -C(S)N(R14)2,

-NHC(S)R14, -NR14C(S)R14, -NHC(S)other14, -NHC(S)N(R14)2,

-NR14C(S)other14, -NR14C(S)N(Rsub> 14)2or R11and R12together with the carbon atom to which they are attached, form a 5 to 9 membered heterocycle;

each R14independently denotes-H, -C1-C8alkyl, -C3-C12cycloalkyl, -phenyl, -naphthyl, -3 to 9-membered heterocycle, -C2-C8alkenyl or-C2-C8quinil;

each Y independently denotes-C1-C8alkylene-, -C2-C8albaniles - or-C2-C8akinyan-;

each m is independently 0 or 1; and

each n independently denotes an integer that varies from 0 to 6.

In some specific embodiments, the implementation of the-O-benzyl is unsubstituted.

In some specific embodiments, the implementation of R7means 3 methoxybenzyloxy.

In some specific embodiments, the implementation-phenyl is unsubstituted.

In some specific embodiments, the implementation of R14means pendimethalin. According to even more specific options for the implementation of R1means With(About)other14and R14means pendimethalin.

In some specific embodiments, the implementation of R7means-och2C(O)OC2H5.

In some specific embodiments, the implementation of R14means benzyloxyphenyl. According to even more specific options for the implementation of R1means With(About)other14the

R14means benzyloxyphenyl.

In some specific embodiments, the implementation of R14means paraprotein. According to even more specific options for the implementation of R1means-C(O)R14and R14means paraprotein.

In some specific embodiments, the implementation of Rameans parahydroxybenzoic. According to even more specific variants of realization of Ymmeans-CH2and R14means parahydroxybenzoic.

In some specific embodiments, the implementation of R7means-NH(phenyl)OCH3.

In some specific embodiments, the implementation of R1means -(CH2)2OS(O)2O-.

In some specific embodiments, the implementation of R11and R12not combined together with the carbon atom that is attached to each of the groups.

According to another aspect of the invention concerns pharmaceutical compositions containing the compound of the above formula (Ic), where Q2and Q3, R1-R8and R10-R13defined above for compounds of formula (Ic).

According to another aspect of the invention relates to methods of treating cancer in a patient, including the introduction in need of such treatment to the patient an effective amount of the compounds or pharmaceutically acceptable salts of the compounds having videocasino the formula (Ic), where Q2and Q3, R1-R8and R10-R13defined above for compounds of formula (Ic).

According to another aspect of the invention concerns methods of treatment directed against virus and viral infection in a patient, including the introduction in need of such treatment to the patient an effective amount of the compounds or pharmaceutically acceptable salts of the compounds having the above formula (Ic), where Q2-Q3, R1-R8and R10-R13defined above for compounds of formula (Ic).

3.1 Definitions and abbreviations

As used herein, "halogen" means-F, -Cl, -Br or-I.

As used herein, "C1-C8alkyl" means a linear or branched saturated hydrocarbon group with 1-8 carbon atoms which may be unsubstituted or optionally substituted by one or more groups selected from the group comprising halogen, -NH2, -OH, -O-(C1-C8alkyl), phenyl or naphthyl. Examples of C1-C8- linear or branched alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl,

2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-p is ntil, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, 1-heptyl and 1-octyl.

As used herein, "C1-C5alkyl" means a linear or branched saturated hydrocarbon group with 1-5 carbon atoms. Examples of C1-C5linear or branched alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl and 1-pentyl.

As used herein, "C2-C8alkenyl" means unsaturated linear or branched hydrocarbon group containing 2-8 carbon atoms and at least one double bond, which may be unsubstituted or optionally substituted phenyl or naftilos group.

As used herein, "C2-C8quinil" means unsaturated linear or branched hydrocarbon group containing 2-8 carbon atoms and at least one triple bond, which may be unsubstituted or optionally substituted phenyl or naftilos group.

As used herein, "C1-C8alkylene" means C1-C8alkyl group in which one of atomo is hydrogen, C 1-C8the alkyl group is replaced by a link.

As used herein, "C2-C8albaniles" means C2-C8alkenylphenol group, in which one atom of hydrogen, C2-C8alkenylphenol group is replaced by a link.

As used herein, "C2-C8akinyan" means C2-C8alkylamino group, in which one atom of hydrogen, C2-C8alkenylphenol group is replaced by a link.

As used herein, "C3-C12cycloalkyl" means a non-aromatic saturated monocyclic, bicyclic or tricyclic system hydrocarbon ring containing 3-12 carbon atoms. Examples of C3-C12cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, substituted, bicyclo[2.2.2]Oct-2-enyl and bicyclo[2.2.2]octyl.

As used in this description, "-3-9-membered heterocycle" means a 3-9-membered aromatic or nonaromatic monocyclic or bicyclic ring of carbon atoms and 1-4 heteroatoms selected from oxygen, nitrogen and sulfur. Examples 3-9-membered heterocycles include, but are not limited to, aziridinyl, oxiranyl, thiiranes, azirines, diaziridines, diazirines, oxazolidinyl, azetidine, azetidinone, oxet the Nile, titanyl, piperidinyl, piperazinil, morpholinyl, pyrrolyl, oxazinyl, triazinyl, diazines, triazines, tetrazines, imidazolyl, benzimidazolyl, tetrazolyl, indolyl, ethenolysis, chinoline, hintline, pyrrolidinyl, purinol, isoxazolyl, benzisoxazole, furanyl, furutani, pyridinyl, oxazolyl, benzoxazolyl, thiazolyl, benzothiazolyl, thiophenyl, pyrazolyl, triazolyl, benzodiazepin, benzotriazolyl, pyrimidinyl, isoindolyl and indazoles.

"5-9-membered ring" means a 5 to 9 membered aromatic or nonaromatic monocyclic or bicyclic ring consisting only of carbon atoms or carbon atoms and 1-4 heteroatoms selected from oxygen, nitrogen and sulfur. Examples 5-9-membered rings include, but are not limited to, cyclopentyl, cyclohexyl or cycloheptyl, which can be saturated or unsaturated, piperidinyl, piperazinil, morpholinyl, pyrrolyl, oxazinyl, triazinyl, diazines, triazines, tetrazines, imidazolyl, benzimidazolyl, tetrazolyl, indolyl, ethenolysis, chinoline, hintline, pyrrolidinyl, purinol, isoxazolyl, benzisoxazole, furanyl, furutani, pyridinyl, oxazolyl, benzoxazolyl, thiazolyl, benzothiazolyl, thiophenyl, pyrazolyl, triazolyl, benzodiazepin, benzotriazolyl, pyrimidinyl, isoindolyl and indazoles.

As used in this description, -O-benzyl group can b shall be substituted or unsubstituted.

As used in this description, -phenyl group can be substituted or unsubstituted.

When specified, which is described in this description of the group is "substituted or unsubstituted", in the case of the substituted groups of these groups can be substituted by any appropriate Deputy or deputies, do not have a negative impact on the desired activity of the compound. Examples of preferred substituents can be found in the following illustrative examples of connections and options for implementation, and include halogen (chlorine, iodine, bromine or fluorine); C1-6alkyl; C2-6alkenyl; C2-6quinil; hydroxyl; C1-6alkoxyl; amino; nitro; thiol; a simple thioether; Imin; cyano; amido; phosphonate; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (=O), halogenated (e.g., trifluoromethyl); a carbocyclic cycloalkyl, which may be monocyclic or condensed or unfused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heteroseksualci, which may be monocyclic or condensed or unfused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinil, morpholinyl or triazinyl); carbocyclic or heterocyclic, Monaci the symbolic or condensed or unfused polycyclic aryl (for example, phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, chinoline, ethenolysis, acridines, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophene or benzofuran); benzyloxy; amino (primary, secondary, or tertiary); -N(CH3)2; O-lower alkyl; -O-aryl, aryl; aryl-lower alkyl; CO2CH3; -OCH2CH3; methoxy; CONH2; OCH2CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3; and such groups may also be substituted condensed ring structure or bridge, for example-OCH2Oh.

These substituents may optionally be substituted by the Deputy selected from specified groups.

"Effective amount" means the amount trilateralism compounds effective for treatment or prevention of cancer or tumors; inhibition of cancer cell growth or tumor cells; treatment or prevention of viral infection or inhibiting the replication or infectivity of a virus.

The phrase "essentially anhydrous"as used in this description with reference to the reaction mixture or organic solvent, means that the reaction mixture or the organic solvent contain approximately less than 1 mass percent of the odes; one of the embodiments less than 0.5 weight percent water; in another variant implementation of less than 0.25 percent of water by weight of the reaction mixture, or an organic solvent.

One of the embodiments when administered to a patient such as a mammal in veterinary use or to a human for clinical purposes trilateration compound is administered in isolated form. As used herein, "isolated" means that trilateration connection is separated from other components of either (a) a natural source, such as a plant or cell, mainly bacterial culture, or (b) a synthetic organic chemical reaction mixture. According to another variant implementation trilateration connection purified by conventional methods. As used herein, "purified" means that, as highlighted, the isolate contains at least 95%, preferably at least 98%, private trilateralism connection by weight of the isolate.

As used herein, the term "T/C value" means the value obtained by: (a) dividing the magnitude of the changes compared to the initial average tumor volume treated mice on the magnitude of the changes compared to the initial average volume Apokalipsa, corresponding negative control; and (b) the numerical value obtained at stage (a), multiplied by 100.

It should be noted that trilateration compounds according to the invention can have one or more chiral centers and/or one or more double bonds and, therefore, exist as stereoisomers, such as isomers relative to the double bond (i.e., geometric isomers), enantiomers or diastereomers. According to the invention described in this description of chemical structures and, therefore, the compounds according to the invention cover all the corresponding enantiomers and stereoisomers, that is, as stereochemical pure form (e.g., geometrically pure, enantiomerically pure or diastereomers pure)and enantiomeric and stereometria mixtures, e.g. racemates.

As used in this specification and unless otherwise stated, the term "stereochemical pure" means a composition containing a single stereoisomer of the compounds and essentially free of other stereoisomers of the compound. For example, stereochemical pure compound having one chiral center must be essentially free of the opposite enantiomer of the compound. Stereochemical pure compounds with two chiral center must be essentially free of other diastereomers with the organisations. Typical stereomono pure compound contains approximately more than 80 wt.% stereoisomer of the compound and approximately less than 20 wt.% other stereoisomers of the compound, more preferably more than 90 wt.% one stereoisomer of the compound and less than 10 wt.% other stereoisomers of the compound, more preferably more than 95 wt.% one stereoisomer of the compound and less than 5 wt.% other stereoisomers of the compound, and most preferably more than 97 wt.% one stereoisomer of the compound and less than 3 wt.% other stereoisomers of the compound.

Enantiomeric and stereoisomeric mixtures of compounds according to the invention can be separated into its constituent enantiomers and stereoisomers are well-known methods such as gas chromatography with chiral phase high-performance liquid chromatography with chiral phase, crystallization of the compounds as chiral salt complex or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can be obtained from stereomono or enantiomerically pure intermediates, reagents, and catalysts by well-known methods of asymmetric synthesis.

It should be noted that if there is a discrepancy between the depicted structure and name, shows the structure shall prevail. In addition, if you erased Kimia structure or part of a structure is not specified, for example, using bold or dashed lines, the structure or part of a structure should be interpreted as covering all possible stereoisomers.

In this description, unless otherwise noted, used the following abbreviations and definitions:

ReductionDefinition
BOC-C(O)OC(CH3)3
DEFN,N-diethylformamide
dppf1,1-bis(diphenylphosphino)ferrocene
DMFN,N-dimethylformamide
DMSOthe sulfoxide
THFtetrahydrofuran
EtOActhe ethyl acetate
EtOHethanol
MeOHmethanol
Tf-SO2CF3
dbadibenzylideneacetone
Phphenyl
TBDMSCltert-butyldimethylsilyloxy
DBU1,8-diazabicyclo[5.4.0]undec-7-EN
LC/MSliquid chromatography/mass spectrometry

4. Brief description of drawings

Figure 1 shows a comparison of the actions of tartrate of compound 1 on the viability of cancer cell lines H1299 and C33A and normal cell lines HMEC and MRC5, measured 72 hours after treatment with 0.5 μm tartrate connection1.

Figure 2 illustrates the change in body mass SCID mice over a period of time after treatment with cisplatin at a dose of 4 mg/kg or tartrate connection1at the dose of 4.5 mg/kg Line -□- indicates the control group, the line -∆- means the group treated with cisplatin, and the linemeans the group treated tartrate connection1.

Figure 3 illustrates the change in tumor volume SCID mice, which are implanted cervical cancer cells C33A human treated with cisplatin at a dose of 4 mg/kg or tartrate connection1at the dose of 4.5 mg/kg Line -□- indicates the control group, the line -∆- means the group treated with cisplatin, and the linemeans group, the processing is subjected to the tartrate connection 1.

Figure 4: conversion of compound66(prodrug) in connection1(medicine) over time in the presence of purified placental alkaline phosphatase person.

Figure 5: conversion of compound66(prodrug) in connection1(medicine) over time in the presence of purified intestinal phosphatase calf.

Fig.6: effect mesilate salt compounds1and the connection66(prodrug) on the growth of prostate tumors in mice.

5. Detailed description of the invention

5.1 Trilateration the compounds of formula (Ia)

As indicated above, the present invention encompasses compounds having the formula (Ia)

and their pharmaceutically acceptable salts, where:

Q1-Q4, R2, R4, R6-R8and R10-R13defined above for formula (Ia).

The first subclass trilateration compounds of formula (Ia) is a subclass, where:

Q1means-NH-;

Q2means-C(R3)-;

Q3means-C(R5- and

Q4means-C(R9)-.

The second subclass trilateration compounds of formula (Ia) is a subclass, where:

Q1means-O-;

Q2means-C(R3)-;

Q3means-C(R5- and

Q4means-C(R9)-.

A third subclass of trilateration the compounds of formula (Ia) is the subclass where:

Q1means-S-;

Q2means-C(R3)-;

Q3means-C(R5- and

Q4means-C(R9)-.

The fourth subclass trilateration compounds of formula (Ia) is a subclass, where:

Q1means-NH-;

Q2means-N-;

Q3means-C(R5- and

Q4means-C(R9)-.

The fifth subclass trilateration compounds of formula (Ia) is a subclass, where:

Q1means-NH-;

Q2means-C(R3)-;

Q3means-N -

Q4means-C(R9)-.

A sixth subclass trilateration compounds of formula (Ia) is a subclass, where:

Q1means-NH-;

Q2means-C(R3)-;

Q3means-C(R5)-;

Q4means-CH - and

R2and R6mean-H.

Seventh subclass trilateration compounds of formula (Ia) is a subclass, where:

Q1means-NH-;

Q2means-C(R3)-;

Q3means-C(R5)-;

Q4means-CH - and

R2, R4, R6, R8and R10-R13mean-H.

Eighth subclass trilateration compounds of formula (Ia) is a subclass, where:

Q1means-NH-;

Q2means-C(C1-C8alkyl)-;

Q3means-C(C1-C8alkyl)-;

p> Q4means-CH-;

R2, R4, R6, R8and R10-R13mean-H and

R7means-O-(C1-C8alkyl).

Illustrative trilateralism compound of formula (Ia) is:

Connection 1

or its pharmaceutically acceptable salt.

One of the options for the implementation of the pharmaceutically acceptable salt of the compound1is the tartrate salt (tartrate). In another variant implementation of the pharmaceutically acceptable salt of the compound1is mutilata salt.

Other illustrative trilateration the compounds of formula (Ia) below:

connection2
2-[5-(4-iodine-3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indole;
connection3
2-[4-methoxy-5-(3-methoxy-1H-pyrrol-2-ylmethylene)-5H-pyrrol-2-yl]-1H-indole;
connection4
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-5,6-dimethoxy-1H-indole;
connect the s 7
5-bromo-2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indole;
connection5
tert-butyl ester 2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-5,6-dimethoxyindole-1 carboxylic acid;
connection8
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-3-(4-phenylpiperazin-1-ylmethyl)-1H-indole;
connection6
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-3-morpholine-4-ylmethyl-1H-indole;
connection9
2-({2-5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-3-hydroxymethyl-4-methoxy-5H-pyrrol-2-yl]-1H-indol-3-ylmethyl}amino)ethanol;
connection10
[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-2-(3-methylaminomethyl-1H-indol-2-yl)-5H-pyrrol-3-yl]methanol;
connection13
[2-(3-allelomimetic-1H-indol-2-yl)-5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-3-yl]-methanol;
connection11
{5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-2-[3-isopropylaminomethyl)-1H-indol-2-yl]-4-methoxy-5H-pyrrol-3-yl}methanol;
connection1
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indole;
connection12
{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indol-3-yl}thiophene-3-ylmethanone;
connection14
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-ethoxy-5H-pyrrol-2-yl]-3-(2-morpholine-4-retil)-1H-indole;
connection15
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-5-methoxy-1H-indole;
connection18
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-isopropoxy-5H-pyrrol-2-yl]-3-(2-pyrrolidin-2-retil)-1H-indole;
connection16
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-m is toxi-5H-pyrrol-2-yl]-1H-indole-3-carboxylic acid;
connection19
methyl ester 5-{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indol-3-yl}-5-oxopentanoic acid;
connection17
3-iodine-2-[5-(4-iodine-3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indole;
connection20
ethyl ether {2-[5-(4-amoxicill-3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indol-3-yl}Okrokana acid;
connection21
tert-butyl ester 5-bromo-2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indole-1-carboxylic acid;
connection24
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-ethoxy-5H-pyrrol-2-yl]-3-(2-pyrrolidin-2-retil)-1H-indole;
connection22
{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indol-3-yl}-(5-pyridin-2-althofen-2-yl)methanon;
connection25
1-{2-[5-(3,5-dimethyl-1H-Pierre is l-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indol-3-yl}Etalon;
connection23
{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indol-3-yl}isoxazol-3-ylmethanone;
connection26
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indole-3-carbaldehyde;
connection27
{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indol-3-yl}furan-3-ylmethanone;
connection30
tert-butyl ester 2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-5-methoxyindol-1-carboxylic acid;
connection28
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-ethoxy-5H-pyrrol-2-yl]-1H-indole;
connection31
(2-{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-ethoxy-5H-pyrrol-2-yl]-1H-indol-3-yl}ethyl)dimethylamine;
connect the s 29
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-isopropoxy-5H-pyrrol-2-yl]-1H-indole;
connection32
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-isopropoxy-5H - pyrrol-2-yl]-3-(2-morpholine-4-retil)-1H-indole and
connection33
(2-{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-isopropoxy-5H-pyrrol-2-yl]-1H-indol-3-yl}ethyl)dimethylamine
connection34
2-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-5-(1H-indol-2-yl)-2H-pyrrol-3-ol
connection37
{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indol-3-yl}methanol
connection35
1-{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indol-1-yl}-2-methylpropan-1-he
connection38
tert-butyl ester 2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-isopropoxy-5H-pyrrol-2-yl]-1H-indol-4-silt ether carboxylic acids
connection36
tert-butyl ester 2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indol-4-silt ether carboxylic acids
connection39
dimethylamide 2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indole-1-carboxylic acid
connection40
2-{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indol-1-yl}ethanol
connection43
{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indol-1-yl}phenylmethanone
connection41
3-{5-[5-(1H-indol-2-yl)-3-methoxyfuran-2-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}propan-1-ol
connection44
2,3-dihydroxypropyl ester 2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indole-1-carboxylic acid
connection42
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene-4-isopropoxy-5H-pyrrol-2-yl]-5-fluoro-1H-indol
connection45
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-isopropoxy-5H-pyrrol-2-yl]-6-fluoro-1H-indol
connection46
6-chloro-2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-isopropoxy-5H-pyrrol-2-yl]-1H-indole
connection48
(3-hydroxypropyl)amide 2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-1H-indole-3-carboxylic acid
connection47
2-{5-[1-(3,5-dimethyl-1H-pyrrol-2-yl)ethylidene]-4-methoxy-5H-pyrrol-2-yl}-1H-indole
connection49
tert-butyl ester 2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indole-1-carboxylic acid
connection50
2-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-5-(1H-indol-2-yl)-2H-pyrrol-3-ol
connection53
ethyl ester of [2-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-5-(1H-indol-2-yl)-2H-pyrrol-3-yloxy]acetic acid
connection51
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-methoxybenzyloxy)-5H-pyrrol-2-yl]-1H-indole
connection54
(4-benzyloxyphenyl)amide 2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indole-1-carboxylic acid
connection52
(4-dimethylaminophenyl)amide 2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indole-1-carboxylic acid
connection55
(4-bromophenyl)-(2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indol-1-yl}metano
connection58
4-{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indole-1-ylmethyl}phenol
connection56
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-isopropoxy-5H-pyrrol-2-yl]-1H-indol-6-ol
connection59
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)--methoxy-5H-pyrrol-2-yl]-1H-indol-4-ol
connection57
2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-isopropoxy-5H-pyrrol-2-yl]-1H-indol-4-ol
connection60
6-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]-5H-[1,3]dioxol[4,5-f]indol
connection61
[2-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-5-(1H-indol-2-yl)-2H-pyrrol-3-yl]-(4-methoxyphenyl)amine
connection64
2-[5-(3,5-dimethyl)-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indole-1-ymetray ether of 2,2-dimethylpropionic acid
connection62
{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indol-1-yl}acetic acid
connection65
sodium salt of mono-(2-{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indol-1-yl}ethyl)new ether sulfuric acid
link is 63
methyl ester of 3-{5-[5-(1H-indol-2-yl)-3-methoxyfuran-2-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}propionic acid

and their pharmaceutically acceptable salts.

5.2 Trilateration the compounds of formula (Ib)

As indicated above, the present invention encompasses compounds having the formula(Ib)

and their pharmaceutically acceptable salts, where:

Q1-Q4, R2, R4, R6-R8and R10-R13defined above for formula (Ib).

The present invention also concerns compositions containing a pharmaceutically acceptable carrier and an effective amount trilateralism the compounds of formula (Ib) or its pharmaceutically acceptable salt.

The present invention also relates to methods of treatment or prevention of cancer or tumors, including the introduction in need of such treatment or prevention to the patient an effective amount of trilateralism the compounds of formula (Ia) or (Ib).

In addition, the invention relates to methods of inhibiting growth of a cancer or neoplastic cell comprising contacting a cancer or neoplastic cell with an effective amount of trilateralism the compounds of formula (Ia) or (Ib).

Further, the invention relates to methods of treatment or prevention in RosNOU infection, including the introduction in need of such treatment or prevention to the patient an effective amount of trilateralism the compounds of formula (Ia) or (Ib).

In addition, the invention relates to methods of inhibiting the replication or infectivity of a virus comprising contacting a virus or virusinfection cells with an effective amount of trilateralism the compounds of formula (Ia) or (Ib).

The first subclass trilateration compounds of formula (Ib) is a subclass, where:

Q1means-NH-;

Q2means-C(R3)-;

Q3means-C(R5- and

Q4means-C(R9)-.

The second subclass trilateration compounds of formula (Ib) is a subclass, where:

Q1means-O-;

Q2means-C(R3)-;

Q3means-C(R5- and

Q4means-C(R9)-.

The third subclass trilateration compounds of formula (Ib) is a subclass, where:

Q1means-S-;

Q2means-C(R3)-;

Q3means-C(R5- and

Q4means-C(R9)-.

The fourth subclass trilateration compounds of formula (Ib) is a subclass, where:

Q1means-NH-;

Q2means-N-;

Q3means-C(R5- and

Q4means-C(R9)-.

The fifth subclass triguero Ilichevsky compounds of formula (Ib) is a subclass where:

Q1means-NH-;

Q2means-C(R3)-;

Q3means-N -

Q4means-C(R9)-.

A sixth subclass trilateration compounds of formula (Ib) is a subclass, where:

Q1means-NH-;

Q2means-C(R3)-;

Q3means-C(R5)-;

Q4means-CH - and

R2and R6mean-H.

Seventh subclass trilateration compounds of formula (Ib) is a subclass, where:

Q1means-NH-;

Q2means-C(R3)-;

Q3means-C(R5)-;

Q4means-CH - and

R2, R4, R6, R8and R10-R13mean-H.

Eighth subclass trilateration compounds of formula (Ib) is a subclass, where:

Q1means-NH-;

Q2means-C(C1-C8alkyl)-;

Q3means-C(C1-C8alkyl)-;

Q4means-CH-;

R2, R4, R6, R8and R10-R13mean-H and

R7means-O-(C1-C8alkyl)-.

One of the ways of carrying out the invention relates to compositions containing a pharmaceutically acceptable carrier and a compound1or its pharmaceutically acceptable salt. In another variant implementation of the pharmaceutically acceptable salt is a tartrate salt. According to the about another variant implementation of the pharmaceutically acceptable salt is mutilata salt.

According to other variants of the implementation of the connection used in these ways, is the connection1or its pharmaceutically acceptable salt. According to another variant implementation of the pharmaceutically acceptable salt is a tartrate salt. According to another variant implementation of the pharmaceutically acceptable salt is mesilate salt.

5.3 Trilateration the compounds of formula II

As indicated above, the present invention encompasses compounds having the formula (II)

and their pharmaceutically acceptable salts, where:

Q1-Q4, R6-R8and R10-R13defined above for formula (II).

The first subclass trilateration compounds of the formula (II) is a subclass, where:

Q1means-NH - and

Q4means-C(R9)-.

The second subclass trilateration compounds of the formula (II) is a subclass, where:

Q1means-O - and

Q4means-C(R9)-.

The third subclass trilateration compounds of the formula (II) is a subclass, where:

Q1mean-S and

Q4means-C(R9)-.

The fourth subclass trilateration compounds of the formula (II) is a subclass, where:

Q1means-NH-;

Q4means-CH - and

R6Osnach the et-H.

The fifth subclass trilateration compounds of the formula (II) is a subclass, where:

Q1means-NH-;

Q4means-CH-;

R6means H and

R10-R13mean-H.

A sixth subclass trilateration compounds of the formula (II) is a subclass, where:

Q1means-NH-;

Q4means-CH-;

R6means-H;

R8and R10-R13mean-H and

R7means-O-(C1-C8alkyl).

The present invention also relates to compositions containing a pharmaceutically acceptable carrier and an effective amount of the compounds of formula (II) or its pharmaceutically acceptable salt.

In addition, the invention relates to methods of treatment or prevention of cancer or tumors, including the introduction in need of such treatment or prevention to the patient an effective amount of trilateralism the compounds of formula (II).

The invention also relates to methods of inhibiting growth of a cancer or neoplastic cell comprising contacting a cancer or neoplastic cell with an effective amount of trilateralism the compounds of formula (II).

Further, the invention relates to methods of treatment or prophylaxis of viral infections, including the introduction in need of such treatment or prevention to the patient an effective amount is STV trilateralism the compounds of formula (II).

In addition, the invention relates to methods of inhibiting the replication or infectivity of a virus comprising contacting a virus or virusinfection cells with an effective amount of trilateralism the compounds of formula (II).

5.4 Methods of obtaining trilateration connections

Further, the invention relates to methods useful for obtaining trilateration connections.

Compounds according to the invention can be obtained via standard, well-known synthetic methodology,see,for example,March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4thed., 1992. Illustrative methods are described below. Source materials suitable for producing compounds according to the invention and the corresponding intermediate compounds are commercially available or can be obtained from commercially available materials using known synthetic methods and reagents.

Example of synthesis methods, useful for obtaining trilateration compounds below and summarized in figure 1.

Trilateration compounds can be obtained according to the conventional organic syntheses, for example, as described below. Scheme 1 provides a General methodology, which can be obtained trilateration connection, where Q1-Q4, R2, R4, R6-R8and R10R 13defined above for trigeneration compounds of formulas (Ia), (Ib) and (II).

Scheme 1

For example, commercially available or obtained synthetically, pyrrolidine formula (i) are formirovanie on Vilsmeier in the presence of phosphorylated and alifornia getting octabromodiphenyl parralelled formula (iior octabromodiphenyl pyrrolidinone (iia). The compound of formula (iioriia) were then catalyzed by palladium or Nickel reaction cross combinations with Bronevoy acid of the formula (iii), which gives digitalizable compound of formula (II). The compound of formula (II) then subjected to the reaction mix in acidic conditions with a pyrrole of the formula (iv), which leads to the formation of compounds of formula (IaorIb). According to alternative implementation, the compound of formula (II) is subjected to condensation with the compound of the formula (v) (the anion of the compounds of formula (iv)), obtaining the compound of formula (IaorIb).

5.4.1 Obtaining compounds of formula (Ia) compounds of the formula (II) mediated by acid combination

One of the specific embodiments the invention relates to methods of obtaining trilateration compounds of formula (Ia)

including contacting the compounds of formula (II)

with the compound of the formula (iv)

in the presence of an organic solvent and a proton acid over a period of time and at a temperature sufficient to obtain the compounds of formula (Ia),

where Q1-Q4, R2, R4, R6-R8and R10-R13defined above for trigeneration compounds of formula (Ia).

Possible monitoring education trilateralism the compounds of formula (Ia) using conventional analytical techniques, including, but not limited to, thin layer chromatography ("TLC"), high performance liquid chromatography ("HPLC"), gas chromatography ("GC") and spectroscopy nuclear magnetic resonance ("NMR"), such as1H or13C NMR.

Concentration trilateralism the compounds of formula (II) in the reaction mixture will typically range from about 0.01 mol to 3 mol per liter of reaction mixture. One of the options for the implementation of the concentration trilateralism the compounds of formula (II) in the reaction mixture ranges from about 0.05 mol to 1 mol per liter of reaction mixture. In another variant implementation of the concentration trilateralism the compounds of formula (II) in reactionnaire varies approximately from 0.1 mol to 0.5 mol per liter of reaction mixture.

The amount of the compounds of formula (iv) in the reaction mixture is typically at least about 1.5-fold molar excess relative to the number trilateralism the compounds of formula (II). One of the options for the implementation of a number of compounds of formula (iv) in the reaction mixture is at least about 2-fold molar excess of up to 10-fold molar excess relative to the number trilateralism the compounds of formula (II). According to another variant of implementation, the amount of the compounds of formula (iv) in the reaction mixture is at least about 3-fold molar excess of up to 10-fold molar excess relative to the number trilateralism the compounds of formula (II).

The number of proton acid in the reaction mixture is typically from about 0.0001 to 5 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation, the number of proton acid in the reaction mixture ranges from about 0.001 to 3 molar equivalents per equivalent trilateralism the compounds of formula (II). According to another variant of implementation, the number of proton acid in the reaction mixture ranges from about 0.01 to 1 molar equivalent of n is equivalent trilateralism the compounds of formula (II).

Suitable protonic acids for use in the method according to the invention include, but are not limited to, such acids as hydrochloric acid, Hydrobromic acid, itestosterone acid, hydrofluoric acid, sulfuric acid, Perlina acid, nitric acid, methanesulfonate acid, econsultancy acid, triftormetilfullerenov acid, benzolsulfonat acid, p-toluensulfonate acid, p-bromobenzophenone acid, p-nitrobenzenesulfonic acid, p-triftormetilfullerenov acid, mixtures of these acids and water mixtures of these acids. One of the embodiments of the proton acid is an aqueous hydrochloric acid or aqueous Hydrobromic acid.

The reaction mixture additionally contains an organic solvent. Suitable organic solvents include, but are not limited to, alcohols, such as methanol, ethanol, isopropanol and tert-butanol; ethers, such as diethyl ether, diisopropyl ether, THF and dioxane. One of the embodiments the solvent is methanol or ethanol.

One of the embodiments, the reaction mixture is substantially anhydrous.

The amount of organic solvent in the reaction mixture is usually on ENISA least about 10 molar equivalents per equivalent trilateralism the compounds of formula (II). One of the options for the implementation of the organic solvent present in the reaction mixture in amounts of at least about 20 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation of the organic solvent present in the reaction mixture in amounts of at least about 30 molar equivalents per equivalent trilateralism the compounds of formula (II). According to another variant implementation of the organic solvent present in the reaction mixture in amounts of at least about 40 molar equivalents per equivalent trilateralism the compounds of formula (II). One of the options for the implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 10 molar equivalents to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 20 molar equivalents of up to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II). According to another variant, the wasp is estline organic solvent present in the reaction mixture in a quantity changing in the range from about 30 molar equivalents to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 40 molar equivalents of up to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II).

Typically, the interaction occurs over a period of time in the range from about 5 minutes to 20 hours. One of the options for implementing the interaction occurs over a period of time in the range from about 10 minutes to 10 hours. In another variant implementation, the interaction occurs over a period of time in the range from about 30 minutes to 2 hours.

Usually the reaction temperature varies from about 25ºC to 100ºC. One of the ways of carrying out the reaction temperature varies from about 25ºC to 40ºC. In another variant implementation, the reaction temperature is approximately equal to room temperature.

Usually the total yield of isolated and purified trilateralism the compounds of formula (Ia) is approximately more than 70 percent in relation to the number trilateralism the compounds of formula (II) or the number of compounds of formula (iv). One of the options for implementing the overall yield isolated and purified trilateralism the compounds of formula (Ia) is approximately more than 75 percent based on the number trilateralism the compounds of formula (II) or the compounds of the formula (iv). In another variant implementation, the total yield of isolated and purified trilateralism the compounds of formula (Ia) is approximately more than 80 percent in relation to the number trilateralism the compounds of formula (II) or trilateralism the compounds of formula (iv).

5.4.2 Method of obtaining compounds of formula (Ia) compounds of the formula (II) by the condensation reaction

In another variant implementation of the invention concerns methods for obtaining the compounds of formula (Ia), which includes stages:

(a) contacting the compounds of formula (II)

with the compound of the formula (v)

where M denotes Li, Na, K, Rb or Cs,

in the presence of an essentially anhydrous aprotic organic solvent for a period of time and at a temperature sufficient to obtain the compounds of formula (vi)

where M takes values above, and

(b) protonation of the compounds of formula (vi) using donor H+over a period of time and so is the temperature value, sufficient to obtain the compounds of formula (Ia),

where Q1-Q4, R2, R4, R6-R8and R10-R13defined above for compounds of formula (Ia).

Possible monitoring education trilateralism the compounds of formula (Ia) using conventional analytical techniques, including, but not limited to, TLC, HPLC, GC and NMR, such as1H or13C NMR.

Concentration trilateralism the compounds of formula (II) in the reaction mixture will typically range from about 0.01 mol to 3 mol per liter of reaction mixture. One of the options for the implementation of the concentration trilateralism the compounds of formula (II) in the reaction mixture ranges from about 0.05 mol to 1 mol per liter of reaction mixture. In another variant implementation of the concentration trilateralism the compounds of formula (II) in the reaction mixture ranges from about 0.1 mol to 0.5 mol per liter of reaction mixture.

The amount of the compounds of formula (v) in the reaction mixture is typically from about equimolar quantity to 2 times molar excess relative to an equivalent number trilateralism the compounds of formula (II). One of the options for the implementation of a number of compounds of formula (v) in the reaction socialable approximately equimolar relative to the amount of trilateralism the compounds of formula (II).

One of the embodiments, the reaction mixture is substantially anhydrous.

The compound of formula (v) can be obtained by deprotonation of compounds of formula (iv) using a base such as n-utility, using techniques well known to the specialist in the field of organic synthesis. As examples of methods suitable for obtaining compounds of formula (v) from compounds of formula (iv) using the base, see Martinez et al.,J. Org. Chem.,46, 3760 (1981) and Minato et al.,Tetrahedron Lett.,22:5319 (1981).

The reaction mixture may also contain essentially anhydrous aprotic organic solvent. Suitable aprotic solvents include, but are not limited to, THF, DMF, DMSO,N-methylpyrrolidinone and diethyl ether. Such aprotic solvents can be obtained essentially anhydrous when stored over a desiccant, when stored over molecular sieves or by distillation.

One of the options for the implementation of the aprotic solvent is an essentially anhydrous THF, is separated by distillation from nitrobenzophenone.

The amount of organic solvent in the reaction mixture is typically at least about 10 molar equivalents per equivalent trilateralism the compounds of formula (II). One of the options for the implementation of organic the ski solvent present in the reaction mixture in a quantity at least about 20 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation of the organic solvent present in the reaction mixture in amounts of at least about 30 molar equivalents per equivalent trilateralism the compounds of formula (II). According to another variant implementation of the organic solvent present in the reaction mixture in amounts of at least about 40 molar equivalents per equivalent trilateralism the compounds of formula (II). One of the options for the implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 10 molar equivalents to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 20 molar equivalents of up to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II). According to another variant implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 30 molar equivalents to 1000 molar equivalents per equivalent target aziklicescoe the compounds of formula (II). In another variant implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 40 molar equivalents of up to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II).

Usually stage (a) is conducted at a temperature of from about-78ºC to 100ºC. One of the options for the implementation of stage (a) is conducted at a temperature of from about-25ºC to 75ºC. In another variant implementation stage (a) is conducted at a temperature of approximately-10ºC to 30ºC. Usually stage (a) is carried out over a period of time sufficient to obtain a reaction mixture in which the number trilateralism the compounds of formula (II) is reduced, at least 85 percent of the original quantity. One of the options exercise period of time is sufficient to obtain a reaction mixture in which the number trilateralism the compounds of formula (II) is reduced at least 90 percent of the original quantity. In another variant implementation, the period of time is sufficient to obtain a reaction mixture in which the number trilateralism the compounds of formula (II) is reduced, at least 93 percent of the original quantity. Possible monitoring of the flow interaction with the use of the conventional analytical methods, including, but not limited to, any of the above.

Usually stage (a) is carried out over a period of time in the range from about 0.5 hour to 48 hours. One of the options for the implementation of stage (a) is carried out over a period of time in the range from about 2 hours to 24 hours. In another variant implementation stage (a) is carried out over a period of time in the range from about 4 hours to 12 hours.

The method also includes a step of protonation of the compounds of formula (vi) using donor H+.

Suitable donors H+include, but are not limited to, water and proton acid, such as hydrochloric acid, Hydrobromic acid, itestosterone acid, hydrofluoric acid, sulfuric acid, Perlina acid, nitric acid, methanesulfonate acid, econsultancy acid, triftormetilfullerenov acid, benzolsulfonat acid, p-toluensulfonate acid, p-bromobenzophenone acid, p-nitrobenzenesulfonic acid, p-triftormetilfullerenov acid and mixtures of these acids. One of the embodiments, the acid is a hydrochloric acid or Hydrobromic acid. In another variant implementation, the acid is an aqueous hydrochloric acid or aqueous brimstowad the native acid.

Usually stage (b) is carried out over a period of time in the range from about 10 seconds to 1 hour. One of the options for the implementation of stage (b) is carried out over a period of time in the range from about 30 seconds to 0.5 hours. In another variant implementation stage (b) is carried out over a period of time in the range from about 1 minute to 10 minutes.

The compound of formula (Ia) can be isolated and purified as described above.

5.4.3 Obtaining compounds of formula (Ib) from compounds of formula (II) mediated by acid combination

One of the specific embodiments the invention relates to methods of obtaining trilateration compounds of formula (Ib)

including contacting the compounds of formula (II)

with the compound of the formula (iv)

in the presence of an organic solvent and a proton acid over a period of time and at a temperature sufficient to obtain the compounds of formula (Ib),

where Q1-Q4, R2, R4, R6-R8and R10-R13defined above for trigeneration compounds of formula (Ib).

Possible monitoring education trilateralism the compounds of formula (Ib) using conventional analytical techniques, including, but is s limited to, thin-layer chromatography ("TLC"), high performance liquid chromatography ("HPLC"), gas chromatography ("GC") and spectroscopy nuclear magnetic resonance ("NMR"), such as1H or13C NMR.

Concentration trilateralism the compounds of formula (II) in the reaction mixture will typically range from about 0.01 mol to 3 mol per liter of reaction mixture. One of the options for the implementation of the concentration trilateralism the compounds of formula (II) in the reaction mixture ranges from about 0.05 mol to 1 mol per liter of reaction mixture. In another variant implementation of the concentration trilateralism the compounds of formula (II) in the reaction mixture ranges from about 0.1 mol to 0.5 mol per liter of reaction mixture.

The amount of the compounds of formula (iv) in the reaction mixture is typically at least about 1.5-fold molar excess of up to 10-fold molar excess relative to the number trilateralism the compounds of formula (II). One of the options for the implementation of a number of compounds of formula (iv) in the reaction mixture is at least about 2-fold molar excess of up to 10-fold molar excess relative to the number trilateralism the compounds of formula (II). Another is arianto the implementation of a number of compounds of formula (iv) in the reaction mixture is at least about 3-fold molar excess of up to 10-fold molar excess relative to the number trilateralism the compounds of formula (II).

The number of proton acid in the reaction mixture is typically from about 0.0001 to 5 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation, the number of proton acid in the reaction mixture ranges from about 0.001 to 3 molar equivalents per equivalent trilateralism the compounds of formula (II). According to another variant of implementation, the number of proton acid in the reaction mixture ranges from about 0.01 to 1 molar equivalent per equivalent trilateralism the compounds of formula (II).

Suitable protonic acids for use in the methods of the invention include, but are not limited to, such acids as hydrochloric acid, Hydrobromic acid, itestosterone acid, hydrofluoric acid, sulfuric acid, Perlina acid, nitric acid, methanesulfonate acid, econsultancy acid, triftormetilfullerenov acid, benzolsulfonat acid, p-toluensulfonate acid, p-bromobenzophenone acid, p-nitrobenzenesulfonic acid, p-triform telesolutions acid, mixtures of these acids and water mixtures of these acids. One of the embodiments of the proton acid is an aqueous hydrochloric acid or aqueous Hydrobromic acid.

The reaction mixture additionally contains an organic solvent. Suitable organic solvents include, but are not limited to, alcohols, such as methanol, ethanol, isopropanol and tert-butanol; ethers, such as diethyl ether, diisopropyl ether, THF and dioxane. One of the embodiments the solvent is methanol or ethanol.

One of the embodiments, the reaction mixture is substantially anhydrous.

The amount of organic solvent in the reaction mixture is typically at least about 10 molar equivalents per equivalent trilateralism the compounds of formula (II). One of the options for the implementation of the organic solvent present in the reaction mixture in amounts of at least about 20 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation of the organic solvent present in the reaction mixture in amounts of at least about 30 molar equivalents per equivalent trilateralism the compounds of formula (II). On another is the variant of implementation of the organic solvent present in the reaction mixture in a quantity at least about 40 molar equivalents per equivalent trilateralism the compounds of formula (II). One of the options for the implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 10 molar equivalents to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 20 molar equivalents of up to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II). According to another variant implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 30 molar equivalents to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 40 molar equivalents of up to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II).

Typically, the interaction occurs over a period of time in the range from about 5 minutes to 20 hours. One of the options Khujand the exercise of the interaction occurs over a period of time in the range from about 10 minutes to 10 hours. In another variant implementation, the interaction occurs over a period of time in the range from about 30 minutes to 2 hours.

Usually the reaction temperature varies from about 25ºC to 100ºC. One of the ways of carrying out the reaction temperature varies from about 25ºC to 40ºC. In another variant implementation, the reaction temperature is approximately equal to room temperature.

Usually the total yield of isolated and purified trilateralism the compounds of formula (Ib) is approximately more than 70 percent in relation to the number trilateralism the compounds of formula (II) or the compounds of the formula (iv). One of the options for implementing the overall yield isolated and purified trilateralism the compounds of formula (Ib) is approximately more than 75 percent based on the number trilateralism the compounds of formula (II) or the compounds of the formula (iv). In another variant implementation, the total yield of isolated and purified trilateralism the compounds of formula (Ib) is approximately more than 80 percent in relation to the number trilateralism the compounds of formula (II) or trilateralism the compounds of formula (iv).

5.4.4 Method of obtaining compounds of formula (Ib), the compounds of the formula (II) by the condensation reaction

In another variant implementation of the invention concerns methods for obtaining the compounds of formula (Ib), which includes stages:

(a) contacting the compounds of formula (II)

with the compound of the formula (v)

where M denotes Li, Na, K, Rb or Cs,

in the presence of an essentially anhydrous aprotic organic solvent for a period of time and at a temperature sufficient to obtain the compounds of formula (vi)

where M takes values above, and

(b) protonation of the compounds of formula (vi) using donor H+over a period of time and at a temperature sufficient to obtain the compounds of formula (Ib),

where Q1-Q4, R2, R4, R6-R8and R10-R13defined above for compounds of formula (Ib).

Possible monitoring education trilateralism the compounds of formula (Ib) using conventional analytical techniques, including, but not limited to, TLC, HPLC, GC and NMR, such as1H or13C NMR.

Concentration trilateralism the compounds of formula (II) in the reaction mixture will typically range from about 0.01 mol to 3 mol per liter of reaction mixture. One of the options for the implementation of the concentration trilateralism soedineniya (II) in the reaction mixture ranges from about 0.05 mol to 1 mol per liter of reaction mixture. In another variant implementation of the concentration trilateralism the compounds of formula (II) in the reaction mixture ranges from about 0.1 mol to 0.5 mol per liter of reaction mixture.

The amount of the compounds of formula (v) in the reaction mixture is typically from about equimolar quantity to 2 times molar excess relative to an equivalent number trilateralism the compounds of formula (II). One of the options for the implementation of a number of compounds of formula (v) in the reaction mixture of approximately equimolar relative to the amount of trilateralism the compounds of formula (II).

One of the embodiments, the reaction mixture is substantially anhydrous.

The compound of formula (v) can be obtained by deprotonation of compounds of formula (iv) using a base such as n-utility, using techniques well known to the specialist in the field of organic synthesis. As examples of methods suitable for obtaining compounds of formula (v) from compounds of formula (iv) using the base, see Martinez et al.,J. Org. Chem.,46, 3760 (1981) and Minato et al.,Tetrahedron Lett.,22:5319 (1981).

The reaction mixture may also contain essentially anhydrous aprotic organic solvent. Suitable aprotic solvents including the Ute, but not limited to, THF, DMF, DMSO,N-methylpyrrolidinone and diethyl ether. Such aprotic solvents can be obtained essentially anhydrous when stored over a desiccant, when stored over molecular sieves or by distillation.

One of the options for the implementation of the aprotic solvent is an essentially anhydrous THF, is separated by distillation from nitrobenzophenone.

The amount of organic solvent in the reaction mixture is typically at least about 10 molar equivalents per equivalent trilateralism the compounds of formula (II). One of the options for the implementation of the organic solvent present in the reaction mixture in amounts of at least about 20 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation of the organic solvent present in the reaction mixture in amounts of at least about 30 molar equivalents per equivalent trilateralism the compounds of formula (II). According to another variant implementation of the organic solvent present in the reaction mixture in amounts of at least about 40 molar equivalents per equivalent trilateralism the compounds of formula (II). One of the options for the implementation of organic Rast is oritel is present in the reaction mixture in a quantity changing in the range from about 10 molar equivalents to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 20 molar equivalents of up to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II). According to another variant implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 30 molar equivalents to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II). In another variant implementation of the organic solvent present in the reaction mixture in a quantity which varies from about 40 molar equivalents of up to 1000 molar equivalents per equivalent trilateralism the compounds of formula (II).

Usually stage (a) is conducted at a temperature of from about-78ºC to 100ºC. One of the options for the implementation of stage (a) is conducted at a temperature of from about-25ºC to 75ºC. In another variant implementation stage (a) is conducted at a temperature of approximately-10ºC to 30ºC. Usually stage (a) is carried out over a period of time sufficient to obtain actionnow mixture, in which the number trilateralism the compounds of formula (II) is reduced, at least 85 percent of the original quantity. One of the options exercise period of time is sufficient to obtain a reaction mixture in which the number trilateralism the compounds of formula (II) is reduced at least 90 percent of the original quantity. In another variant implementation, the period of time is sufficient to obtain a reaction mixture in which the number trilateralism the compounds of formula (II) is reduced, at least 93 percent of the original quantity. Possible monitoring of the flow of interaction using conventional analytical techniques, including, but not limited to, any of the above.

Usually stage (a) is carried out over a period of time in the range from about 0.5 hour to 48 hours. One of the options for the implementation of stage (a) is carried out over a period of time in the range from about 2 hours to 24 hours. In another variant implementation stage (a) is carried out over a period of time in the range from about 4 hours to 12 hours.

The method also includes a step of protonation of the compounds of formula (vi) using donor H+.

Suitable donors H+include, but are not limited to, water and proton KIS the GTC, such as hydrochloric acid, Hydrobromic acid, itestosterone acid, hydrofluoric acid, sulfuric acid, Perlina acid, nitric acid, methanesulfonate acid, econsultancy acid, triftormetilfullerenov acid, benzolsulfonat acid, p-toluensulfonate acid, p-bromobenzophenone acid, p-nitrobenzenesulfonic acid, p-triftormetilfullerenov acid and mixtures of these acids. One of the embodiments, the acid is a hydrochloric acid or Hydrobromic acid. In another variant implementation, the acid is an aqueous hydrochloric acid or aqueous Hydrobromic acid.

Usually stage (b) is carried out over a period of time in the range from about 10 seconds to 1 hour. One of the options for the implementation of stage (b) is carried out over a period of time in the range from about 30 seconds to 0.5 hours. In another variant implementation stage (b) is carried out over a period of time in the range from about 1 minute to 10 minutes.

The compound of formula (I b) can be isolated and purified as described above.

5.4.5 Method of obtaining compounds of formula (II) using Bronevoy acid

In another variant implementation of the invention concerns methods floor the treatment of compounds of formula (II)

including contacting the compounds of formula (ii) or the compounds of formula (iia)

with the compound of the formula (iii)

in the presence of an organic solvent, a base and Ni - or Pd-catalyst for a period of time and at a temperature sufficient to obtain the compounds of formula (II)

where Q1, Q4, R6-R8and R10-R13defined above for compounds of formula (II) and where R15means independently C1-C8alkyl, cycloalkyl or phenyl.

Possible monitoring education trilateralism the compounds of formula (II) using conventional analytical techniques, including, but not limited to, TLC, HPLC, GC and NMR, such as1H or13C NMR.

The concentration of the compounds of formula (ii) or (iia) will typically range from about 0.01 mol to 3 mol per liter of solvent. One of the options for the implementation of the concentration of the compounds of formula (ii) or (iia) varies approximately from 0.05 mol to 1 mol per liter of solvent. In another variant implementation, the concentration of the compounds of formula (ii) or (iia) ranges from about 0.1 mol to 0.5 mol per liter of reaction mixture.

The amount of the compounds of formula iii are typically varies from about one molar equivalent of up to 3-fold molar excess of the equivalent of the compounds of formula (ii) or (iia). One of the options for the implementation of a number of compounds of formula (iii) typically varies from about one molar equivalent of up to 2-fold molar excess of the equivalent of the compounds of formula (ii) or (iia). According to another variant of implementation, the amount of the compounds of formula (iii) is about 1.5-fold molar excess of the equivalent of the compounds of formula (ii) or (iia).

Suitable for use in the method of grounds include, but are not limited to, carbonates of alkali metals such as Na2CO3and K2CO3; hydroxides of alkali metals and alkaline earth metals, such as LiOH, NaOH, KOH, RbOH, CsOH, FrOH, Be(OH)2, Mg(OH)2Ca(OH)2, Sr(OH)2,

Ba(OH)2and Ra(OH)2; and alkoxides of alkali metals and alkaline earth metals, such as LiOR, NaOR, KOR, RbOR, CsOR, FrOR, Be(OR)2, Mg(OR)2, Ca(OR)2, Sr(OR)2, Ba(OR)2and Ra(OR)2where R is an alkyl group, such as, but not limited to, methyl, ethyl, n-butyl, tert-butyl or isopropyl. Additional grounds, suitable for use according to the method include sodium acetate, potassium acetate, K3PO4, TlOH and steric employed amines, such as triethylamine and diisopropylethylamine. One of the embodiments is based on the Ba(OH)2.

The number of grounds on which commonly ranges from about one molar equivalent of up to 3-fold Molar excess of the equivalent of the compounds of formula (ii) or (iia). One of the embodiments the amount of the base is approximately one molar equivalent of up to 2-fold molar excess of the equivalent of the compounds of formula (ii) or (iia). According to another variant of implementation, the amount of base is about 1.5-fold molar excess of the equivalent of the compounds of formula (ii) or (iia). In alternative implementation, the number of bases and number of the compounds of formula (iii) are equimolar.

Suitable for use according to the invention Ni - and Pd-catalysts include, but are not limited to, Pd(dppf)2Cl2Pd(PPh3)4Pd(dba)2(PPh3)2Pd(PPh3)2Cl2Pd(dba)2Pd2(dba)3/P(OMe)3Pd2(dba)3/P(tert-butyl)3, NiCl2[P(OMe)3]2, Ni(dppf)2Cl2, Ni(NEt2)2Cl2and Ni(PPh3)4. One of the embodiments the catalyst is Pd(dppf)2Cl2.

The number of Ni - and Pd-catalyst generally ranges approximately from 0.001 molar equivalent to the equimolar amount to the equivalent of the compounds of formula (ii) or (iia). One of the embodiments, the amount of catalyst varies approximately from 0.01 molar equivalent to 0.5 molar equivalent per equivalent of soy is inane formula (ii) or (iia). According to another variant of implementation, the amount of catalyst varies approximately from 0.05 molar equivalent to 0.2 molar equivalent per equivalent of the compound of formula (ii) or (iia).

The amount of organic solvent is usually at least about 10 molar equivalents per equivalent of compound of formula (ii) or (iia). One of the options for the implementation of the organic solvent is present in amount of at least about 20 molar equivalents per equivalent of compound of formula (ii) or (iia). In another variant implementation of the organic solvent is present in amount of at least about 30 molar equivalents per equivalent of compound of formula (ii) or (iia). According to another variant implementation of the organic solvent is present in amount of at least about 40 molar equivalents per equivalent of compound of formula (ii) or (iia). One of the options for the implementation of the organic solvent is present in a quantity which varies from about 10 molar equivalents to 1000 molar equivalents per equivalent of compound of formula (ii) or (iia). In another variant implementation of the organic solvent is present in a quantity which varies from about 20 molar equivalents of up to 1000 molar equivalent is allentow on the equivalent of the compounds of formula (ii) or (iia). According to another variant implementation of the organic solvent is present in a quantity which varies from about 30 molar equivalents to 1000 molar equivalents per equivalent of compound of formula (ii) or (iia). In another variant implementation of the organic solvent is present in a quantity which varies from about 40 molar equivalents of up to 1000 molar equivalents per equivalent of compound of formula (ii) or (iia).

Usually the time period is changed in the range from about 1 hour to 20 hours. One of the options exercise period of time varies in the range from about 1 hour to 10 hours. According to another variant of implementation, the time period is changed in the range from about 2 hours to 6 hours.

Typically, the temperature ranges from about 25 ° C to 150 ° C. In another variant implementation, the temperature varies from approximately 40ºC to 120ºC. According to another variant implementation, the temperature varies from approximately 50ºC to 100ºC.

Suitable solvents include, but are not limited to, ethers such as diethyl ether and diisopropyl ether; THF, dioxane, DMF, a mixture of DMF/water, DMSO, benzene and toluene.

One of the embodiments the solvent is a mixture of DMF/water

In a specific embodiment, the solvent is a mixture of DMF/water 4:1.

The compound of formula (II) can be isolated and purified as described above for trilateralism the compounds of formula (Ib).

5.5 Therapeutic/prophylactic administration and composition

Thanks to show activity trilateration compounds suitable for use in veterinary medicine and medicine for humans. For example, trilateration compounds useful in the treatment or prevention of cancer or neoplasm or to inhibit the growth of cancer or tumor cells. Trilateration compounds are also useful in the treatment or prevention of a viral infection, or for inhibiting the replication or infectivity of a virus.

The invention relates to methods of treatment and prevention by introducing the patient an effective amount of trilateralism connection. The patient is an animal, including, but not limited to, human, mammal or animal other than man, such as cow, horse, sheep, pig, chicken, Turkey, quail, cat, dog, mouse, rat, rabbit, or Guinea pig, and more preferably the patient is a mammal, more preferably human.

Consider the composition containing effective if estvo trilateralism connection can be entered in any conventional manner, for example by infusion or bolus injection, by absorption through epithelial or skin-mucous lining (e.g., mucosa of the oral, rectal and intestinal membrane, etc. and can be put together with another biologically active agent. The administration can be systemic or local. There are various delivery systems, such as encapsulation in liposomes, microparticles, microcapsules and capsules, etc. that can be used to introduce trilateralism connection. According to some variants of the implementation of the patient is given more than one trilateralism connection. Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectally, by inhalation, or local introduction in the ears, nose, eyes, or skin. The preferred route of administration is left to the discretion of the practitioner and depends partly on the area of localization of the disease (such as region localization carcinoma or viral infection).

According to a specific implementation options may be desirable local application of one or more trigate acyclicity compounds require surface treatment. This can be achieved, for example, but without limitation, by local infusion during surgery, by local application, for example in combination with a bandage on the wound after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, with the specified implant has a porous, non-porous or glutinously material, including membranes, such as elastique membranes, or fibers. One of the options for the implementation of the introduction can be performed by direct injection at the site of localization (or primary site) carcinoma, tumors or tumors or precancerous tissue. In another variant implementation of the introduction can be performed by direct injection at the site of localization (or primary site), viral infection, tissue or organ transplant, or autoimmune reactions.

In some embodiments, the implementation may be desirable introduction of one or more trilateration connections in the Central nervous system by any convenient method, including intraventricular and intrathecal injection. Intraventricular injection can facilitate intraventricularly catheter, for example, connected to the reservoir, such as an Ommaya reservoir.

Can also be used pulmonary introduction, for example, by IP is the use of an inhaler or nebulizer, and formulation in the composition with aerosolised means or by perfusion using fluorocarbon or synthetic pulmonary surfactant. In some embodiments, the implementation trilateration compounds can be formulated into a composition in the form of a suppository, with traditional binders or carriers such as triglycerides.

In another variant implementation trilateration compounds can be delivered in vesicule, in particular in the liposome (see, Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; more broadly, see ibid).

According to another variant implementation trilateration compounds can be delivered in systems with controlled release. Another option may not be used in the pump (see, Langer, above; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); (Saudek et al., N. Engl. J. Med. 321:574 (1989)). Alternatively, the implementation can be used polymeric materials (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105(1989)). According to another variant implementation of the system with controlled release can be placed adjacent to the target for trigeneration compounds, for example the brain, whereas the om is only required part of the systemic dose ( seefor example, Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Can be used in other systems with controlled release, please review Langer (Science 249:1527-1533 (1990)).

Consider the compositions contain an effective amount trilateralism compounds and pharmaceutically acceptable carrier.

For any of the embodiments, the term "pharmaceutically acceptable" means approved by the Federal regulatory Agency or by a state government or listed in the U.S. Pharmacopeia or other generally recognized Pharmacopoeia for use in animals and more preferably to humans. The term "carrier" means a diluent, excipient, excipient or solvent, which is injected trilateralism connection. Such pharmaceutical carriers can be liquids, such as water and oils, including oils, petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Pharmaceutical carriers may serve as a physiological solution, Arabian gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, can be used AIDS, stabilizers, zapustit the Lee, lubricants and dyes. With the introduction of the patient trilateration compounds and pharmaceutically acceptable carriers must be sterile. One of the options for the implementation of the water is the carrier of intravenous trilateralism connection. Saline solutions and aqueous dextrose and glycerol can also be used as liquid carriers, particularly in solutions for injection. Suitable pharmaceutical carriers include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice flour, chalk, silica gel, sodium stearate, glycerylmonostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, Polysorbate 20, and the like. Consider the composition, if desired, can also contain minor amounts of wetting or emulsifying medium or buffer substances for pH control.

Consider the composition can be in the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, slow release formulations, suppositories, aerosols, sprays or any other suitable for use form. One of the options for the implementation of the pharmaceutically acceptable carrier is a capsule (see, for example, U.S. patent No. 5698155). Other examples of suitable pharmaceutical carriers are described in "Remington''s Pharmaceutical Sciences" by E.W. Martin.

The phrase "pharmaceutically acceptable salt (salt)", as used herein, includes, but is not limited to, salts of acidic or basic groups that may be present in compounds used in the present compositions. Trilateration compounds included in the present composition, which is the basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to obtain a pharmaceutically acceptable acid additive salts of such basic compounds are those acids which form non-toxic acid additive salts, i.e. salts containing pharmacologically acceptable anions, including but not limited to, sulfate, citrate, molinological, acetic acid, oxalic salt, hydrochloride, hydrobromide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannat, Pantothenate, bitartrate, ascorbate, succinate, maleate, getitemat, fumarate, gluconate, glucuronate, saharat, formate, benzoate, glutamate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate, who Eilat, hydroxyethylsulphonic, pamoate (i.e. 1,1'-Methylenebis-(2-hydroxy-3-aftout)). Included in these compositions trilateration compounds containing the amino group, in addition to the above acids can form pharmaceutically acceptable salts with various amino acids. Included in these compositions are compounds having an acid nature, able to form basic salts with various pharmaceutically and cosmetically acceptable cations. Examples of such salts include salts of alkali metals or alkaline earth metals and, in particular, salts of calcium, magnesium, sodium, lithium, zinc, potassium and iron.

According to another variant implementation trilateration compounds comprise the composition according to standard techniques in the form of pharmaceutical compositions intended for humans. Usually trilateration compounds for intravenous administration are solutions in sterile isotonic aqueous buffer. If necessary, the composition may also include solubilizers tool. Compositions for intravenous administration, optionally, may include a local anesthetic agent, such as lignocaine, for pain at the injection site. Typically, the ingredients are supplied either separately or mixed together in unit dosage forms is, for example, in the form of dry liofilizirovannogo powder or not containing water concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active funds. When trilateralism compound is administered by infusion, these connections can be distributed, for example, bottles for infusion containing sterile pharmaceutical grade water or saline. When trilateralism compound is administered by injection, can be supplied in vials with sterile water for injection or saline solution, so that the ingredients can be mixed prior to introduction.

Compositions for oral delivery can be, for example, in the form of tablets, pellets, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. Oral input compositions can contain one or more optional tools, such as sweeteners, such as fructose, aspartame or saccharin; corrigentov, such as peppermint, wintergrove oil or cherry oil; colorants and preservatives, providing a pharmaceutically acceptable preparation. In addition, in the case of tablets or pills of the composition can be coated to slow disintegration and absorption in the gastrointestinal tract, which provides for the constant action over a long period of time. Selectively permeable membranes surrounding osmotically active conductive connections, are also useful for oral administration trilateration compounds. In these latter platforms fluid from the environment surrounding the capsule is absorbed by a conductive compound, which swells, displacing the active ingredient or a composition of components through the hole. Such delivering platform can provide, essentially, a zero order profile delivery as opposed to a pointed profile of the formulations of immediate release. Can also be used to provide time delay substance, such as glycerylmonostearate or glitzenstein. Oral compositions can include standard carriers such as mannitol, lactose, starch, magnesium stearate, Nachrichten, cellulose, or magnesium carbonate. Such media must have pharmaceutical purity.

The number trilateralism compound that will be effective in the treatment of specific disorders or conditions, depends on the nature of the violation or condition and can be installed using standard clinical techniques. In addition, tests in vitro or in vivo can be optionally used to facilitate establishing the optimal dose range. The exact dose used in the compositions, also depends on the method of administration and the severity of the disease or impairment and is chosen at the discretion of the physician based on the status of a particular patient. However, a suitable effective dose range for intravenous administration is usually about from 0.1 to 5 mg, preferably from 0.5 to 3 mg trilateralism compound per kilogram of body weight. In specific embodiments, the implementation of centuries dose of approximately from 0.1 to 0.5 mg/kg, 0.3 to 0.8 mg/kg, from 0.8 to 1.2 mg/kg, from 1.2 to 2.0 mg/kg, or from 2.0 to 3.0 mg/kg (or equivalent dose, presents per square meter of body surface). Alternative appropriate range of doses for centuries, the introduction can be obtained with doses of approximately from 8 to 500 mg without amendments on the patient's body mass or surface area of the body. A suitable dose range for intranasal is usually about 0.01 PG/kg body weight to 1 mg/kg of body weight. Suppositories generally contain from 0.5 wt.% up to 10 wt.% one or more trilateration compounds alone or in combination with another therapeutic agent. Oral compositions can contain from about 10 wt.% to 95 wt.% one or more trilateration compounds alone or in combination with another therapeutic agent. In particular the x carrying out the invention a suitable dose range for oral administration is usually from 0.1 to 20 mg, preferably from 0.5 to 10 mg and more preferably from 1 to 5 mg trilateralism compound per kg of body weight or an equivalent dose presented per square meter of body surface. In specific embodiments, the implementation of the oral dose is from about 1 to 7.5 mg/kg, from 7.5 to 10 mg/kg, from 10 to 12.5 mg/kg, from 12.5 to 15 mg/kg or 15 to 20 mg/kg (or equivalent dose, presents per square meter of body surface). In another variant implementation of a suitable dose range for oral administration is from about 20 to 2000 mg, without amendments on the patient's body mass or surface area of the body. Other effective doses can be extrapolated from the curves dose-effect, in vitro, or test systems experimental animal models. Such animal models and systems are well known in this field.

The invention also relates to pharmaceutical packs or kits comprising one or more containers containing one or more trilateration compounds. Optional, together with such container (containers) can be a statement in the form prescribed by the Agency regulating the manufacture, use or sale of pharmaceuticals or biological products, this statement reflects the resolution is AGENTSTVO production, use or sale for the introduction of man. In some embodiments, implementation, such as introduction for the treatment or prevention of cancer, the kit may also contain one or more chemotherapeutic agents, useful for the treatment of cancer or tumors, intended for injection in combination with trilateralism connection.

Trilateration connection preferably examined in vitro and then in vivo for the desired therapeutic or prophylactic activity prior to use in humans. For example, in vitro tests can be used to determine whether it is preferable to the introduction of a certain trilateralism connection or combination trilateration connections.

One of the options for the implementation of the patient's tissue grown in culture and lead in contact with trilateralism connection or otherwise treated trilateralism connection, see the effect of such trilateralism connections on the tissue sample and compare with contactually cloth. In other variants of the implementation using the model cell culture, in which cells of the cell culture is brought into contact with trilateralism connection or otherwise treated trilateralism connection, see the three who heterotsiklicheskikh connection to culture cells and compared with contactually culture cells. Usually lower level of proliferation or survival of exposed cells compared to contactibility cells indicates that trilateralism connection is an effective treatment for the patient. The efficacy and safety of such trilateration compounds can also be demonstrated by the application of experimental animal models.

Other well-known qualified methods are also included in the scope of the invention.

5.6 Inhibition of cancer and tumors

Demonstrate the ability trilateration compounds to inhibit the proliferation of tumor cells, transformation of cells and the formation of tumors in vitro and in vivo by using a series of tests, known or described in this specification. In such tests can be used in cells of a cancer cell line or cells of an organism of the patient. Many tests are well known in this field can be used to assess such survival and/or growth; for example, cell proliferation can be monitored by determining inclusions (3H)-thymidine, by direct counting of cells by introducing changes in transcription, translation or activity of known genes such as proto-oncogene (for example,fos/i> ,myc), or markers of the cell cycle (Rb, cdc2, cyclin A, Dl, D2, D3, E and so on). The levels of this protein and mRNA and activity can be determined using any well-known in this field by the way. For example, the protein can be quantified known immunodiagnostics ways, such as Western blotting or immunoassay using commercially available antibodies (for example, many antibodies to the markers of the cell cycle from Santa Cruz Inc.). mRNA can be quantified by methods that are well known and standard in this area, for example by Northern analysis, protection using RNase polymerase chain reaction in combination with reverse transcription, etc. Viability of cells can be studied with the use of staining Trifanova blue or other markers for cell death or viability known in this field. Differentiation can be assessed visually based on changes in morphology, etc.

The present invention relates to analysis of cell cycle and cell proliferation in various well-known in this field of ways, including, but not limited to, the following:

As one example of the inclusion of bromodeoxyuridine (BRDU) can be used as tests to identify proliferating cells. BRDU-test your identify is the duty to regulate cell population, undergoing DNA synthesis through the incorporation of BRDU into newly synthesized DNA. Newly synthesized DNA can then be detected using antibodies against BRDU (see, Hoshino et al., 1986, Int. J. Cancer 38, 369; Campana et al., 1988, J. Immunol. Meth. 107, 79).

Cell proliferation can also be studied by applying on (3H)-thymidine (see,for example,, Chen, J., 1996, Oncogene 13:1395-403; Jeoung, J., 1995, J. Biol. Chem. 270:18367-73). This test allows us to quantitatively characterize the DNA synthesis in S-phase. In this test, cells synthesizing DNA, include (3H)-thymidine into newly synthesized DNA. Inclusion can then be measured is the default for the field of methods, such as a radioisotope counting in a scintillation counter (e.g., liquid scintillation counter Beckman LS 3800).

To measure cell proliferation can also be used for detection of the nuclear antigen of proliferating cells (PCNA). PCNA is a protein in 36 kilodaltons, the expression of which is increased in proliferating cells, in particular in the early phases G1 and S, and therefore, PCNA may serve as a marker for proliferating cells. Labeled cells identified by immune staining using antibody against PCNA (see, Li et al., 1996, Curr. Biol. 6:189-199; Vassilev et al., 1995, J. Cell Sci. 108:1205-15).

Cell proliferation can also be is valued by sampling for counting the cell population for a certain period of time (for example, daily determination of the number of cells). Counting cells can be produced using hemacytometer and light microscopy (for example, hemacytometer HyLite, Hausser Scientific). Plotting the number of cells from time receive a growth curve for the population. In a specific embodiment, cells are counted in this way, initially mixed with dye Trifanova blue (Sigma), while the living cells do not let the dye and counted as viable members of the population.

The DNA content and/or the index of the frequency of mitoses cells can be assessed, for example, on the basis of an index of DNA ploidy cells. For example, cells in the G1 phase of the cell cycle typically have an index of DNA ploidy 2N. Cells in which DNA is replicated, but has not progressed through mitosis (for example, cells in S-phase) have an index higher ploidy than 2N and up to 4N content of DNA. Index of ploidy and cell cycle kinetics can be measured using tests probibition (see, for example, Turner, T., et al., 1998, Prostate 34:175-81). Alternatively, the DNA ploidy can be measured quantitatively by staining DNA in Felgen (binds DNA stoichiometric) using a computerized microdensitometric paint systems (see, for example, Bacus, S., 1989, Am. J. Pathol. 135:783-92)According to another variant implementation of the possible analysis of DNA content by obtaining chromosome preparation (Zabalou, S., 1994, Hereditas. 120:127-40; Pardue, 1994, Meth. Cell Biol. 44:333-351).

Protein expression of the cell cycle (for example, CycA, CycB, CycE, CycD, cdc2, Cdk4/6, Rb, p21, p27, etc.) provides basic information regarding the proliferative state of a cell or population of cells. For example, identification in antiproliferative signaling pathway can be performed by

the induction of p21cip1. Elevated levels of expression of p21 in cells lead to weak entry in Gl cell cycle (Harper et al., 1993, Cell 75:805-816; Li et al., 1996, Curr. Biol. 6:189-199). Induction of p21 can be identified by immune staining using commercially available antibodies against p21 (for example, Santa Cruz). Likewise, the proteins of the cell cycle can be investigated by Western blot analysis using commercially available antibodies. According to another variant implementation of the cell population synchronize before detection of the protein of the cell cycle. Proteins of the cell cycle can be detected by FACS (cell sorters-activated fluorescence) analysis using antibodies against the studied protein. Determination of changes in the length of the cell cycle or speed of cell cycle may also be used to assess the inhibition of cell proliferation trilateralism compounds according to the invention. One of the options domestic is the length of the cell cycle is determined by the doubling time of a population of cells (e.g., using cells exposed or not exposed to one or more trilateralism connections). In another variant implementation of the FACS analysis is used to analyze the development phase of the cell cycle or cleaning up Gl, S and G2/M fractions (see, for example, Delia, D. et al., 1997, Oncogene 14:2137-47).

Violation of the control action (control) run the cell cycle and/or induction control (control) run the cell cycle can be investigated as described in this description means or methods known in this field. Without limitation, the startup control of the cell cycle is a mechanism that ensures that some cellular phenomena occur in a certain sequence. Genes control run are characterized by mutations, allowing subsequent events to occur without the completion of the previous event (Weinert, T., and Hartwell, L., 1993, Genetics, 134:63-80). Induction or inhibition of genes startup control of the cell cycle can be investigated, for example, Western blot analysis or immunological staining, etc. Infringement action control (control) run the cell cycle can be optionally installed on the development of cells with the passage of control without the prior display of a specific event (for example, the progression in mitosis without completing the replication of genomic DNA.

In addition to the effects of expression of a particular protein in the cell cycle activity and post-translational modification of proteins involved in the cell cycle, can play a significant role in the regulation and the proliferative state of the cell. The invention relates to studies involving the detection of post-translational modifications (e.g. phosphorylation) is known in this field by the way. For example, antibodies that detect phosphorylated tyrosine residues, are commercially available and can be used in Western blot analysis for the detection of proteins with these modifications. According to another example of modification, such as miesterioasa can be detected by thin-layer chromatography or HPLC with reversed phase (see, for example, Glover, C., 1988, Biochem. J. 250:485-91; Paige, L., 1988, Biochem J.; 250:485-91).

The activity of protein pathways and cell cycle and/or protein complexes are often mediated by kinase activity. The present invention relates to the research activity of the kinase by methods such as test histone H1 (see, for example, Delia, D. et al., 1997, Oncogene 14:2137-47).

Using techniques well known in this field can also be demonstrated that trilateration compounds can alter cell proliferation in cultured cells in vitro. To ncrete examples of models of cell cultures include, but not limited to, lung cancer, primary tumor cells of the lung of rats (Swafford et al., 1997, Mol. Cell. Biol., 17:1366-1374) and cell lines both undifferentiated cancer (Mabry et al., 1991, Cancer Cells, 3:53-58); colorectal cell lines for colon cancer (Park and Gazdar, 1996, J. Cell Biochem. Suppl. 24:131-141); multiple stable cell lines for breast cancer (Hambly et al., 1997, Breast Cancer Res. Treat. 43:247-258; Gierthy et al., 1997, Chemosphere 34:1495-1505; Prasad and Church, 1997, Biochem. Biophys. Res. Commun. 232:14-19); the number of well-characterized cellular models of prostate cancer (Webber et al., 1996, Prostate, Part 1, 29:386-394; Part 2, 30:58-64; and Part 3, 30:136-142; Boulikas, 1997, Anticancer Res. 17:1471-1505); for cancer of the genitourinary system, stable cell line bladder cancer man (Ribeiro et al., 1997, Int. J. Radiat. Biol. 72:11-20); organ culture transitional cell carcinomas (Booth et al., 1997, Lab Invest. 76:843-857) and model progression in rats (Vet et al., 1997, Biochim. Biophys Acta 1360:39-44) and stable cell lines for leukemias and lymphomas (Drexler, 1994, Leuk. Res. 18:919-927, Tohyama, 1997, Int. J. Hematol. 65:309-317).

Can also be demonstrated that trilateration compounds inhibit the transformation of cells (or evolution to malignant phenotype) in vitro. In this embodiment, cells with a transformed cell phenotype is brought into contact with one or more trilateralism compounds and study the change in the Hara is the characteristics, associated with a transformed phenotype (a set of characteristics in vitro, associated with the ability to form tumors in vivo), such as, for example, but not limited to, kolonialapologie on soft agar, a more rounded cell morphology, less dense connection with the substrate, loss of contact inhibition, loss of anchor dependence, release of proteases such as plasminogen activator, increased migration sugar, decreased serum requirement, or the expression of fetal antigens, and so on (see, Luria et al., 1978, General Virology, 3d Ed., John Wiley & Sons, New York, pp. 436-446).

One of the embodiments trilateration compounds are cytotoxic.

In another variant implementation trilateration compounds demonstrate a greater level of cytotoxicity in cancer cells than in non-cancer cells.

Loss of invasiveness or reduced adhesion may also be used to demonstrate the anticancer effects trilateration compounds. For example, a crucial aspect of education metastatic carcinoma is the ability of precancerous or cancerous cells to separate from the primary site of the disease and establish a new colony growth at the secondary site. The ability of cells to spread to peripheral areas reflects the potential in moznosti malignant condition. Loss of invasiveness can be measured by various known in the field of ways, including, for example, induction of intercellular adhesion mediated by E-cadherine. Such mediated E-cadherine adhesion can lead to phenotypic reversion and loss of invasiveness (Hordijk et al., 1997, Science 278:1464-66).

Loss of invasiveness can be further investigated by inhibiting cell migration. Commercially available a number of 2-dimensional and 3-dimensional cell matrix (Calbiochem-Novabiochem Corp. San Diego, CA). Cell migration through or into the matrix can be examined by microscopy method zentralverlag shooting or videography or any known in this area as a way to quantify the migration of cells. In a similar embodiment, the loss of invasiveness study in response to hepatorenal growth factor (HGF). HGF-induced scattering of cells is in accordance with the invasiveness of cells, such as renal cell dogs Madin-Darby (MDCK). This analysis identifies a cell population that has lost activity on the dispersion of cells under the action of HGF (Hordijk et al., 1997, Science 278:1464-66).

Alternative loss of invasiveness can be measured by the movement of cells in the chamber chemotaxis (Neuroprobe/Precision Biochemicals Inc. Vancouver, BC). In this test, the chemoattractant incubated on one side of the camera (e.g. the R, at the bottom of the camera) and the cells plated on the filter, separating the opposite direction (for example, the top of the camera). So that the cells pass from the upper chamber to the bottom chamber, the cells must actively move through the pores in the filter. Analysis method “checkerboard” of the number of migrated cells can then be correlated with invasiveness (see, for example, Ohnishi, T., 1993, Biochem. Biophys. Res. Commun. 193:518-25).

Can also be demonstrated that trilateration compounds inhibit the formation of tumors in vivo. A large number of models of hyperproliferative disorders, including tumors and lesions metastases in animals it is known in this area (see table 317-1, Chapter 317, "Principals of Neoplasia," in Harrison''s Principals of Internal Medicine, 13th Edition, Isselbacher et al., eds., McGraw-Hill, New York, p. 1814 and Lovejoy et al., 1997, J. Pathol. 181:130-135). Specific examples include lung cancer transplantation nodules tumors in rats (Wang et al., 1997, Ann. Thorac. Surg. 64:216-219) or the introduction of metastases of lung cancer in SCID mice lacking NK cells (Yono and Sone, 1997, Gan To Depending Ryoho 24:489-494); for colon cancer, transplantation carcinoma of the colon by introducing cancer cells human colon Nude mouse (Gutman and Fidler, 1995, World J. Surg. 19:226-234), the model of ulcerative colitis person on the Oedipus Tamarine (Warren, 1996, aliment oil displayed pure. Pharmacol. Ther. 10 Supp 12:45-47) and the model in mice with mutations of tumor suppressor adenomas is tonyh polyps (Polakis, 1997, Biochim. Biophys. Acta 1332:F127-F147); for breast cancer, transgenic models of breast cancer (Dankort and Muller, 1996, Cancer Treat. Res. 83:71-88; Amundadittir et al., 1996, Breast Cancer Res. Treat. 39:119-135) and chemical induction of tumors in rats (Russo and Russo, 1996, Breast Cancer Res. Treat. 39:7-20); for prostate cancer, chemically induced and transgenic models in rodents, and xenograft models of human (Royai et al., 1996, Semin. Oncol. 23:35-40); for cancer of the genitourinary system, induced neoplasm of the urinary bladder in rats and mice (Oyasu, 1995, Food Chem. Toxicol 33:747-755) and xenografts transitional cell carcinoma of the man in Nude mice (Jarrett et al., 1995, J. Endourol. 9:1-7) and hematopoietic cancers, transplantirovannam allogeneic bone marrow in animals (Appelbaum, 1997, Leukemia 11 (Suppl. 4):S15-S17). It also describes common patterns in animals, applicable for many types of cancer, including, but not limited to, a mouse model with the absence of p53 (Donehower, 1996, Semin. Cancer Biol. 7:269-278), Min mice (Shoemaker et al., 1997, Biochem. Biophys. Acta, 1332:F25-F48) and immune response to tumors in rats (Frey, 1997, Methods, 12:173-188).

For example, trilateralism the connection can be introduced to a subject animal, preferably trained animal Prednisolonum to the development of some type of tumor, and after this test, the animal is examined for reduced incidence of tumor formation in comparison with controlee, why not enter trilateralism connection. Alternatively, trilateralism connection can be entered in the test animals with tumors (e.g., animals in which tumors have been induced by introduction of malignant, neoplastic, or transformed cells, or by the introduction of a carcinogen) and subsequent study of tumors in the test animals for tumor regression in comparison to the controls, which do not enter trilateralism connection.

5.7 Treatment or prevention of cancer or tumors, optionally including the use of chemotherapy or radiation therapy

Cancer or tumor, including, but not limited to, neoplasma, tumors, metastases, or any disease or disorder characterized by uncontrolled cell growth, can be treated or prevented by introducing an effective amount of trilateralism connection.

According to some variants of the implementation of these methods of treatment or prevention of cancer or tumors include the introduction of anticancer chemotherapeutic drugs, including, but not limited to, methotrexate, Taxol, mercaptopurine, tioguanin, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosamine, cisplatin, carboplatin, mitomycin, duck is basin, procarbazine, etoposide, campatelli, bleomycin, doxorubicin, idarubitsin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel and docetaxel. In another variant implementation of the anticancer means are one or more of the funds listed below in table 1.

TABLE 1
Exposure:γ-irradiation
Alkylating funds
Nitrogen mustard derivatives:cyclophosphamide
ifosfamide
trofosfamide
chlorambucil
Nitrosoanatabine:carmustin (BCNU)
lomustin (CCNU)
The alkyl sulphonatesthe busulfan
treosulfan
Triazine: the dacarbazine
Containing platinum compounds:cisplatin
carboplatin
Vegetable alkaloids
Vinca alkaloids:vincristine
vinblastine
vindesine
vinorelbine
Taxaide:paclitaxel
docetaxel
Inhibitors of DNA topoisomerase
Apoptolidin:etoposide
teniposide
topotecan
9-aminocamptothecin
containinaton
Kristol
mitomicina:
mitomycin Cmitomycin C
Antimetabolites
Antifolates:
Inhibitors of DHFR:methotrexate
trimetrexate
Inhibitors of IMP dehydrogenase:mycofenolate acid
teatterin
ribavirin
EICAR
Inhibitors ribonucleotides:hydroxyurea
deferoxamine
Pyrimidine analogs:
Wratislavia analogs5-fluorouracil
floxuridine
doxifluridine
redirected
Casinowe analogscytarabine (Ara C)
citizenoriented
fludarabine
Purine analogues:mercaptopurine
tioguanin
Hormone therapy:
Receptor antagonists:
Antiestrogenstamoxifen
raloxifene
megestrol
LHRH agonists:goserelin
leuprolide
Antiandrogens:flutamide
bikalutamid
Retinoids/Deltoids
Analogues of vitamin D3:EB 1089
CB 1093
KH 1060
Photodynamic therapy:verteporfin (BPD-MA)
phthalocyanine
the photosensitizer Pc4
dimethoxyphenethyl A
(2BA-2-DMHA)
Cytokines:α-interferon
γ-interferon
the tumor necrosis factor
Other:
Inhibitors isoprenaline:lovastatin
Dofaminergicheskie neurotoxins:ion 1-methyl-4-phenylpyridine
The kinase inhibitors:staurosporin
machinemessiah
The aktinomitinov:D
dactinomycin
Bleomycin:bleomycin A2
bleomycin B2
peplomycin
The anthracyclines:daunorubicin
doxorubicin (adriamycin)
idarubitsin
epirubicin
pirarubicin
zorubicin
mitoxantrone
The MDR inhibitorsverapamil
Inhibitors of Ca2+ATPase:thapsigargin

In other variants of the implementation of the methods of treatment or prevention of cancer or tumors include radiation therapy and/or one or more chemotherapeutic agents in case of option exercise, where the cancer has not recognized not capable of being what I treatment. Trilateralism compound can be administered to the patient who also underwent surgery as a cancer treatment.

According to another particular variant implementation of the invention concerns a method for the treatment or prevention of cancer, which is recognized as not treatable by the method of chemotherapy and/or radiation therapy.

According to a particular variant of the implementation of an effective amount trilateralism connection, use in conjunction with chemotherapy and/or radiation therapy. According to another particular variant of the implementation of chemotherapy and/or radiation therapy is used before or after introduction introduction trilateralism connection for a period at least equal an hour, five o'clock or 12 o'clock, day, or week, following or before the introduction trilateralism connection.

If trilateralism compound is administered before the use of chemotherapy or radiation therapy, chemotherapy and/or radiation therapy is used, even if trilateralism compound exerts its therapeutic or prophylactic effect. If chemotherapy and/or radiation therapy is used before the introduction of trilateralism connection trilateralism connection enter, even if chemotherapy and/or radiation therapy have its therapeutic effect.

Chimioth rapitinka tools can be introduced over a number of sessions, can be used either one or a combination of these chemotherapeutic agents. With regard to radiation therapy may be used in any Protocol radiation therapy depending on the type being treated for cancer. For example, but without limitation, may be applied to x-ray irradiation; in particular, high-energy megavoltage (radiation with energy above 1 MeV) can be used for deep tumors and x-ray irradiation in the form of an electronic beam or a constant voltage for skin cancer. When irradiated tissue can be used for gamma-ray emitting radioisotopes, such as radioactive isotopes of radium, cobalt and other elements.

In addition, the invention relates to methods of treating cancer or tumors using trilateralism connections as an alternative to chemotherapy or radiation therapy, when chemotherapy or radiation therapy has proven or may prove too toxic, such as lead to unacceptable or intolerable to the patient being treated, side effects. The patient considered curable compositions may, optionally, to receive another treatment of cancer, such as surgery, radiation therapy or chemotherapy, depending on what the treatment is considered acceptable or p is renosky.

5.8 Cancers or tumors amenable to treatment or prevention

Cancers or neoplasms and related disorders that may respond to the treatment or prevention by introducing trilateralism compounds include, but are not limited to, diseases or neoplasms listed in table 2 (the review of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia:

TABLE 2
CANCERS AND TUMORS
Leukemia
acute leukemia
acute T-cell leukemia
acute lymphocytic leukemia
acute military leukemia
myeloblastic
promyelocytic
myelomonocytic
monocytic erythroleucus
chronic leukemia
chronic miliitary (granulocytic) leukemia
chronic lymphocytic leukemia
Polycythemia Vera
Lymphoma
Hodgkin's disease
non-Hodgkin's lymphoma
Multiple myeloma
Macroglobulinemia waldenstrom
The disease is heavy chains
Solid tumor
sarcoma and carcinoma
fibrosarcoma
myxosarcoma
liposarcoma
chondrosarcoma
osteoplastica sarcoma
chordoma
angiosarcoma
ehotelier.com
lymphangiosarcoma
lymphangiosarcoma
sinovioma
mesothelioma
Ewing's sarcoma
leiomyosarcoma
rhabdomyosarcoma
colon cancer
pancreatic cancer
breast cancer
ovarian cancer
prostate cancer
ploscockletocny is cancer
basal cell carcinoma
adenocarcinoma
cancer of the sweat glands
cancer of the sebaceous glands
papillary cancer
papillary adenocarcinoma
cystadenocarcinoma
medullary carcinoma
bronchogenic cancer
renal cell carcinoma
hepatoma
cancer of the bile ducts
horiokartsinoma
seminoma
embryonal cancer
Wilms tumor
cervical cancer
cancer of the uterus
testicular tumor
lung cancer
small cell lung cancer
bladder cancer
epithelial cancer
glioma
astrocytoma
medulloblastoma
craniopharyngioma
ependymoma
pinealoma
hemangioblastoma
acoustic neuroma
oligodendroglioma
meningioma
melanoma
neuroblastoma
retinoblastoma

According to a specific implementation options to treat or prevent cancer, malignant or deproliferation changes (such as metaplasia and dysplasia), or hyperproliferative disorders, ovarian, brain, breast, colon, lung, skin, pancreas, prostate gland, bladder or uterus. Other specific options exercise treat or prevent sarcoma, melanoma or leukemia.

In another variant implementation trilateration compounds used for the treatment or prevention of cancer, including prostate cancer (more preferably insensitive to hormonal factor), neuroblastoma, lymphoma (predominantly follicular or diffuse B-both), breast cancer (predominantly estrogen-receptor, cancer), colon cancer and rectal cancer, endometrial cancer, ovarian cancer, lymphoma (mainly non-Hodgkin's), lung cancer (predominantly small cell), or testicular cancer (mainly reproductive cells).

In another variant implementation trilateration connect the deposits are useful for inhibiting cell growth, originating from cancer or tumors, such as prostate cancer (more preferably insensitive to hormonal factor), neuroblastoma, lymphoma (predominantly follicular or diffuse B-both), breast cancer (predominantly estrogen-receptor, cancer), colon cancer and rectal cancer, endometrial cancer, ovarian cancer, lymphoma (mainly non-Hodgkin's), lung cancer (predominantly small cell), or testicular cancer (mainly reproductive cells).

According to specific variants of the invention trilateration compounds are useful for inhibiting the growth of cells, where the specified cell is from a cancer or neoplasm, specified in table 2 or in this specification.

5.10 Demonstrate inhibition of viruses and viral infections

Using various tests known in the field or described herein, can be demonstrated that trilateration compounds inhibit the replication or infectivity of a virus or virusinfection cells in vitro or in vivo. According to some variants of the implementation of such tests can be used cells cell lines or cells taken from the patient. In specific embodiments, the implementation of the test cells m which may be infected with a virus before the test or during the test. Cells can be brought into contact with the virus. Some other options for the implementation of the test can be used for culture of virus-free cells.

One embodiment of the invention demonstrates that trilateralism compound has activity in treating or preventing viral disease by contacting cultured cells that serve as an indicator of viral responses (e.g., education of viral inclusions) in vitro with trilateralism compound, and comparing the level of the indicator in the cells contacted trilateralism connection, level indicator in cells not had such contact, where a lower level in exposed cells indicates that trilateralism compound has activity in treating or preventing viral disease. Model cells that can be used for such tests include, but are not limited to, a viral infection of T-lymphocytes (Selin et al., 1996, J. Exp. Med. 183:2489-2499); infection of hepatitis B cells dedifferentiates hepatoma (Raney et al., 1997, J. Virol. 71:1058-1071); viral infection of cultured epithelial cells of the salivary gland (Clark et al., 1994, Autoimmunity 18:7-14); synchronous infection of HIV-1 lymphocytic cell lines and CD4+(Wainberg et al., 1997, Virology 233:364-373); in the originate infection of respiratory epithelial cells (Stark et al., 1996, Human Gene Ther. 7:1669-1681) and amphitropous retroviral infection of cells NIH-3T3 (Morgan et al., 1995, J. Virol. 69:6994-7000).

Alternatively, the implementation can be demonstrated that trilateralism compound has activity in treating or preventing viral disease by introducing trilateralism connection to the trained animal with symptoms of viral infection, such as a characteristic respiratory symptoms in experimental models on the animal, or the specified test animal does not show viral reaction, and subsequently this animal infected by a means that causes viral response, and the measured change in viral reaction after the introduction trilateralism connection, where a reduction in viral response or prevention of viral response indicates that trilateralism compound has activity in treating or preventing viral disease. Animal models that can be used for such tests include, but are not limited to, Guinea pigs for respiratory viral infections (Kudlacz and Knippenberg, 1995, Inflamm. Res. 44:105-110); of mice to influenza (Dobbs et al., 1996, J. Immunol. 157:1870-1877); sheep for respiratory viral infection syncytium (masot on et al., 1996, Zentralbl. Veterinarmed. 43:233-243); mice for neurotrophic viral infection (Barna et al., 1996, Virology 223:31-343); hamsters for measles (Fukuda et al., 1994, Acta Otolaryngol. Suppl (Stockh.) 514:111-116); of mice to infection encephalomyocarditis (Hirasawa et al., 1997, J. Virol. 71:4024-4031) and mice for cytomegalovirus infection (Orange and Biron, 1996, J. Immunol. 156:1138-1142). According to some variants of the invention, more than one trilateralism connection is used to test the animal, virus or virusinfection the cell.

5.11 Viruses and viral infections

Viruses and viral infections that can be treated or prevented by the introduction of trilateralism compounds include, but are not limited to, viruses and viral infections listed in table 3, including, but not limited to, DNA viruses, such as hepatitis B and hepatitis type C; parvoviruses, such as adeno-associated virus and cytomegalovirus; papovaviruses, such as the human papilloma virus, the virus polyoma and SV40; adenoviruses; herpesviruses, such as herpes virus type I (HSV-I), herpes simplex virus type II (HSV-II) and Epstein-Barr; poxviruses, such as variola virus man (smallpox) and vaccinia virus; and RNA viruses such as human immunodeficiency virus type I (HIV-I), human immunodeficiency virus type II (HIV-II), lymphotropic T-cell virus human type I (HTLV-I), lymphotropic T-cell virus human type II (HTLV-II), influenza virus, measles virus, rabies virus, the virus Sand is th, the picornaviruses, such as poliovirus, Coxsackievirus, rhinovirus, reovirus, togavirus, such as rubella virus (rubella measles and fever virus Semliki forest, arbovirus and hepatitis type A.

One of the embodiments of the invention trilateration compounds useful in the treatment or prevention of a viral infection caused by a virus, is given in table 3. In another variant implementation trilateration compounds are useful for inhibiting the replication or infectivity of a virus, is given in table 3. According to another variant implementation trilateration compounds are useful for inhibiting the growth of cells infected by virus, is given in table 3.

TABLE 3
The herpes viruses:EBV
HHV-(KSHV)
herpesvirus of saimiri
Adenoviruses:All strains
Retroviruses:HIV-1 and 2
HTLV-1
papillomavirus person :HPV all strains
Birnavirus:the virus infectious pankreaticheskogo necrosis
Other:the virus of African swine fever (all strains)

5.12 PRODRUGS

The present invention also encompasses prodrugs trilateration compounds according to the invention is:

Connection66
mono[2-(3-{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indol-1-yl}-1,1-dimethyl-3-oxopropyl)-3-were]new ether phosphoric acid
Connection67
mono(2-{2-[5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-4-methoxy-5H-pyrrol-2-yl]indole-1-carbonyl}benzyl)new ether phosphoric acid

In some embodiments implementing the invention relates to methods of treating cancer in a patient, comprising the administration to a patient an effective amount of a compound66or connection67. In some embodiments implementing the invention relates to methods of treating viral infection in a patient, comprising the administration to the patient effective amounts of the connections 66or connection67. Illustrative methods of synthesis of compounds66or connection67accordingly described in example 4.

The invention also relates to prodrugs trilateration compounds according to the invention. Prodrugs include derivatives trilateration compounds which can be subjected to hydrolysis, oxidation, or otherwise interact in biological conditions (in vitro or in vivo), giving active trilateration compounds according to the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds according to the invention, containing biohydrology groups, such as biokerosene amides, biohydrology esters, biohydrology carbamates, biohydrology carbonates and biokerosene phosphate analogues. According to some variants of the implementation of prodrugs trilateration compounds with functional carboxyl groups are lower alkalemia esters of carboxylic acids. Complex carboxylate esters usually formed by esterification of any of those present in the molecule groups of carboxylic acids. Prodrugs can typically be obtained using well known methods such as methods describedBurgerinMedicinal Chemistry and Drug Discovery 6th ed.(Donald J. Abrahamed., ed., 2001, Wiley) andDesign and Application of Prodrugs(H. Bndgaarded., 1985, Harwood Academic Publishers Gmfh). Biohydrology group trilateration connections 1) does not inhibit the biological activity of the compound but can confer this connection improved performance in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted into a biologically active compound in vivo. Examples biohydrology esters include, but are not limited to, lower alkalemia esters, alkoxysilane esters, alchilcicloalchilsulfai esters and complex kalinovye esters. Examples biohydrology amides include, but are not limited to, lower alkylamide, amides of α-amino acids, alkoxysilane and alkylaminocarbonyl. Examples biohydrology carbamates include, but are not limited to, lower alkylamines followed, substituted Ethylenediamine, amino acids, hydroxyethylamine, heterocyclic and heteroaromatic amines and simple polyetheramines.

6. EXAMPLES

6.1 EXAMPLE 1

Hydrochloride connection1receive as shown in figure 2a below.

Scheme 2a

Getting 5-bromo-3-methoxyphenol-2-carboxaldehydeB

To a solution of phosphorylated (220 mol.%, to 5.58 g) in dry dichloromethane (20 ml) is added DMF (220 mol.%, 1,4 ml), dropwise, over 2 is displaced. The resulting reaction mixture was stirred at room temperature for 30 min and concentrated in vacuo, obtaining the complex Vilsmeier in the form of a white solid. After drying in vacuum for 1 h, the white solid is suspended in dry dichloromethane (20 ml) and cooled to 0ºC. Add dropwise a solution of 4-methoxy-3-pyrrolin-2-it (A) (1 g, 8,84 mmol) in dichloromethane (10 ml) and the resulting reaction mixture was stirred at 0ºC for 30 min, then at room temperature for 20 hours the Mixture was poured on ice (75 ml), treated with 4n. aqueous NaOH (50 ml), diluted with EtOAc (100 ml) and stirred for 15 minutes, the Layers separated and the aqueous layer was extracted with EtOAc (3×60 ml). The combined organic layers washed with saturated salt solution (3×200 ml), dried over Na2SO4, filtered and concentrated in vacuo, obtaining the crude residue, which was purified flash chromatography on a column of silica gel, using gradient elution with a mixture of 0-20% EtOAC/hexane, giving the connectionBin the form of a white solid.

NMR1H (300 MHz, CDCl3): δ (ppm) of 3.95 (s, 3H); 5,90 (s, 1H); of 9.30 (s, 1H), 9,92-10,34 (users, 1H), m/z: 205,1 [M+1].

Getting 5-indolyl-3-methoxyfuran-2-carboxaldehydeC

To a mixture of compoundB(120 mg, of 0.60 mmol), N-Boc-indovinelli acid (150 mol.%, 230 mg), octahydrate of barium hydroxide (150 mol.%, Mg) and dichloro(diphenylphosphinomethyl)palladium(II) (10 mol.%, 48 mg) is added degassed mixture of 4:1 DMF/water (15 ml, 0,04M). The mixture is stirred for 3 h at 80°C, then diluted with EtOAc (20 ml) and water. The resulting solution was filtered through a layer of celite and the layers separated. The organic layer was washed with saturated salt solution (3×50 ml), dried over Na2SO4, filtered and concentrated in vacuo, obtaining the crude residue, which was purified using flash chromatography on a column of silica gel with a gradient elution with a mixture of 0-75% EtOAC/hexane, giving the connectionWithin the form of a green solid.

1H NMR (300 MHz, CD3OD): δ (ppm) of 3.95 (s, 3H); 6,40 (s, 1H); to 6.95 (s, 1H); 7,00 (t, 1H); to 7.15 (t, 1H); to 7.35 (d, 1H); rate of 7.54 (d, 1H); was 9.33 (s, 1H). m/z: 241,17 [M+1].

Getting hydrochloride connection1

To a solution of compoundC(2 mg, 8 mmol) and 2,4-dimethylpyrrole (100 mol.%, 0.8 mg) in methanol (0.4 ml) was added 1 drop of a saturated methanolic HCl. The obtained dark red solution is stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue is dried in vacuum, obtaining hydrochloride connection1.

NMR1H (300 MHz, CDCl3): δ (ppm) of 2.33 (s, 3H); 2.63 in (s, 3H); Android 4.04 (s, 3H); 6,10 (s, 1H); 6.30-in (s, 1H); 7,07-7,16 (m, 3H); 7,30 (m, 1H); of 7.60 (d, 2H); 12,22-12,38 (users, 1H); 12,90-13,10 (users, 1H). m/z: 319,17 [M+1].

Getting tartrate connection1

About one gram of the hydrochloride compounds the Oia 1dissolved in 100 ml ethyl acetate and washed with 5% NaOH solution (2×20 ml) (until the aqueous layer will not have a pH in the range of 9 to 10). The resulting organic layer is then separated, dried and evaporated, receiving the connection1(free base).

About five grams of compound1transferred into the flask for freeze drying and add 100 ml of acetonitrile. The resulting orange suspension is shaken for one minute. Then add 50 ml of distilled water and of 2.36 g of L-tartaric acid. The resulting red-purple mixture was shaken for 5 minutes. Add 50 ml of distilled water and thick brown suspension is shaken for 5 minutes. Flask for freeze-drying, containing suspension, immediately cooled to the temperature range from -53 to-78ºC for freezing the suspension. Then the flask is placed in a freeze dryer and apply vacuum. The flask is maintained at a pressure less than 50 mtorr (0.07 mbar) before drying substances, getting tartrate connection1as a red-brown amorphous powder.

Hydrochloride connection1also receive, as shown in figure 2b below.

Scheme 2b

Synthesis of 5-bromo-3-methoxypsoralen (B')

To the mixture diethylformamide (3 EQ, 5,8 ml) and chloroform (5 ml) at 0°C is added dropwise a solution oxib omega phosphorus (2.5 EQ, of 12.6 g) in chloroform (15 ml). The resulting suspension is stirred at 0ºC for 30 min and the solvent is removed on a rotary evaporator, receiving complex Vilsmeier in the form of a white solid. After drying in vacuum for 20 min, the solid product is treated with chloroform (10 ml) and cooled to 0ºC. Add dropwise a solution of 4-methoxy-3-pyrrolin-2-it (A, 2 g of 17.7 mmol) in chloroform (20 ml) and the mixture is heated to room temperature, then heated at 60ºC for 5 hours the Mixture was poured on ice (75 ml) and the pH of the aqueous solution is brought to pH 7-8, processing 2H. NaOH. To the resulting precipitate add EtOAc (40 ml) and the mixture filtered through Celite®to remove the black solid substance containing a salt of phosphorus.

Two layers are separated and the aqueous layer was extracted with EtOAc (3×100 ml). The organic layers are combined, washed with saturated salt solution (3×200 ml), dried over Na2SO4, filtered and the solvent is removed by evaporation on a rotary evaporator, giving the crude intermediate enamineB'.

The residue is filtered through a layer of silica gel (50 ml)using a mixture of 10% EtOAC/hexane as eluent, which gives the enamine in the form of oil, which on drying in vacuum leads to solid substance beige color.

Output: 3,20 g, 70%.

M/Z: 260,1 [M+1]

NMR1H (300 MHz, CDCl3): δ (ppm) of 1.24 to 1.37 (m, 6H); and 3.31-3.46 in (square, 2H); 3,76 (s, 3H), 4,03-4,18 square, 2H); 5,58 (s, 3H); 6,98 (s, 3H).

Synthesis of 5-indolyl-3-methoxyfuran-2-carboxaldehyde (C)

To a degassed solution of toluene (1.5 ml) is added Pd(OAc)2(0.1 EQ, 86 mg) and PPh3(of 0.45 EQ, 456 mg). The mixture immediately becomes yellow-brown, stirred at 70ºC for 20 min in an atmosphere of N2.

A solution of 5-bromo-3-methoxypropane (B', 1,17 g, 4,51 mmol) andN-Boc-indovinelli acid (B", 10,1 EQ, 1.29 g) in a mixture of 10% water/dioxane (15 ml) Tegaserod and blow N2. The solution is transferred to a suspension of Pd(PPh3)4in toluene, followed by addition of Na2CO3(3.0 EQ, of 1.23 g). The mixture is stirred for 3 h at 100ºC, then treated with NaOMe (1.0 EQ, 244 mg). The mixture is stirred for 15 min at 100ºC, then treated with another portion of NaOMe (1.0 EQ, 244 mg) and stirred at 100ºC for 10 minutes

The mixture was poured into water (100 ml), the pH of the solution was lowered to pH 7 with 2n. HCl and the mixture is stirred for 10 minutes Brown precipitate was separated by filtration through a funnel with a porous filter and washed with water (2×50 ml). The residue is dissolved in acetone and the solvent is removed by evaporation on a rotary evaporator. The obtained solid product is treated with 5 ml of CHCl3and Et2O (10 ml), and the solution is allowed to settle for 5 min before the formation of a yellow solid, which was separated by filtration through a funnel with a porous what iltram. The yellow solid product is washed with 10 ml of CHCl3then 2×10 ml Et2O.

Thus, the required 5-indolyl-3-methoxyfuran-2-carboxaldehyde (C) receives a yellow solid and used without further purification.

Output: 807 mg, 75%.

M/Z: 241,17 [M+H+1]

NMR1H (300 MHz, CD3OD): δ (ppm) of 3.95 (s, 3H); 6,40 (s, 1H); to 6.95 (s, 1H); 7,00 (t, 1H); to 7.15 (t, 1H); to 7.35 (d, 1H); rate of 7.54 (d, 1H); was 9.33 (s, 1H).

The condensation of 5-indolyl-3-methoxyfuran-2-carboxaldehyde (C) with 2,4-dimethylpyrrole

To a suspension of 5-indolyl-3-methoxyfuran-2-carboxaldehyde (C, 200 mg, 0.83 mmol) and 2,4-dimethylpyrrole (1.1 EQ, 94 μl) in methanol (8,3 ml) add a solution of HCl in methanol (200 μl). The solution immediately becomes dark pink, stirred for 2 h at room temperature. The solvent is removed on a rotary evaporator and the solid product was dissolved in EtOAc (30 ml). The organic phase is washed with aqueous NaHCO3(feast upon., 2×60 ml), saturated salt solution (2×60 ml), dried over anhydrous Na2CO3, filtered and evaporated.

The product was then purified by chromatography on a column of silica gel using a mixture of EtOAc/hexane in a gradient of 0-30% as eluent.

Output: 237 mg, 90%.

M/Z: 319,17 [M+1]

NMR1H (300 MHz, acetone-d6): δ (ppm) to 2.13 (s, 3H); of 2.21 (s, 3H); 4,00 (s, 3H); of 5.81 (s, 1H); 6,44 (s, 1H); 6,88-7,22 (m, 5H); 8,02 (d, 1H).

6.2 EXAMPLE 2

The effects of tartrate of compound1n the viability of cancer cells in vitro

To demonstrate the effect of tartrate of compound1cell viability was measured cellular ATP levels before and after processing the selected cell lines tartrate connection1. Selected cell lines include cells, C33A cervical carcinoma, normal lung fibroblasts Mrc-5 cell line carcinoma of the prostate human PC-3 cell line carcinoma human ovarian OVCAR-3 cell line non-small cell lung cancer H460 cell line of human lung carcinoma A549 cells, non-small cell human lung cancer H1299 cell line carcinoma cancer human breast MCF-7 cell line of human adenocarcinoma SW-480 cell line of mouse melanoma B16-F1 (American Type Culture Collection, Manassas, VA USA), normal epithelial cells of the mammary gland HMEC (Clonetics, San Diego, CA, USA) and cell line carcinoma breast cancer human ADR-RES (NCI, MD, USA), cells were cultured in the medium recommended by the American type culture collection. Cell lines were seeded on 96-well titration microplates (PerkinElmer Life Sciences Inc, Boston, MA, USA) at confluentes, allowing to reach confluence after 4 days of growth. The day after the cultivation, the cells treated with tartrate connection1at various concentrations. The original solutions tartrate connection1get in dimetilan is oxide (Sigma-Aldrich Inc., St. Louis, Missouri, USA), bred recommended medium and then added to the cells. The total amount of DMSO on the cells is 1%. After 3 days of incubation, the levels of ATP in the cells counted using fluorescent detection system ViaLight (Bio-Whittaker, MD, USA). The results are graphically compared to untreated control cells, the value of which is taken for 100.

As illustrated by the histogram in figure 1, tartrate connection1has a much greater effect on ATP levels in cancer cells than in normal cells. Measurement of ATP levels after 72 hours after treatment 0,5M-tartrate connection1shows that the tartrate connection1it becomes much more effective at lower levels of ATP in cancer cell lines H1299 and C33A compared with the levels of ATP in normal cell lines HMEC and MRC-5. These results show that the tartrate connection1selectively cytotoxic against cancer cells and are useful for the treatment or prevention of cancer, in particular lung cancer or cervical cancer.

To further demonstrate the effectiveness of tartrate of compound1as anticancer tools that evaluate the effects of different concentrations of tartrate of compound1at the cellular levels of ATP in ten different cancer cell lines. As pok is shown in table 1, tartrate connection1shows great efficacy in reducing cellular levels of ATP in cancer cell lines than in normal lines of epithelial breast cells HMEC. These results indicate that the tartrate connection1is a selective anticancer agent.

Table 1
Antioncogene actions tartrate connection1
Cell lineFabricIC50tartrate compounds1 (μm)
C-33ACervix0,2
PC-3Prostate0,2
OVCAR-3Ovarian0,2
H460NSCLC0,3
A549NSCLC0,4
H1299NSCLC0,5
NCI/ADR-RESBreast cancer (many who develop drug resistance) 0,4
MCF-7Breast cancer0,6
SW-480Colon and rectum0,2
B16-F1Melanoma mice0,06
HMECNormal mammary gland4,00
*Inhibitory concentration 50(IC50based on the measurement of ATP levels during sampling after 72 h after treatment, compared to untreated cells.

6.3 EXAMPLE 3

The effects of tartrate of compound 1 on the growth of tumor cells of the cervix in vivo

To demonstrate the antitumor activity of tartrate of compound1in vivo experiments conducted on mice SCID/SCID CB17 (Charles River, MA, USA), which is injected cancer cells human cervical C33A. Received the mouse is used as a model of cervical cancer man.

Cancer cells human cervical C33A support in RPMI (Hyclone, UT, USA), supplemented with 10% inactivated fetal calf serum (Bio-Whittaker, MD, USA) and 1% of a mixture of penicillin-streptomycin-1-glutamine (Gibco, NY, USA), in an atmosphere of 5% CO2at 37 degrees C, and passedout on the times per week. Cells are grown to confluence below 70% and then harvested using trypsin (Bio-Whittaker, MD, USA). The cells are then centrifuged and washed twice using phosphate buffered saline (PBS), and resuspended in PBS at 2×106cells in 100 µl. Viability study by colouring Trifanova blue (Gibco, NY, USA) and used for in vivo studies only bottles, characterized by a cell viability of more than 95%.

C33A cells injected subcutaneously into the lateral surface of the abdomen of female mice SCID/SCID CB17. Perform each mouse inoculation suspension of 2×106tumor cells in 150 μl on day zero. Use three experimental groups of ten mice each: (a) group negative control, (b) the positive control group and (c) the group treated tartrate connection1.

Processing begins on the fourteenth day after the transplantation of C33A cells. Tartrate connection1enter CC once a day for five consecutive days at a dose of 4.5 mg/kg Daily to get fresh tartrate connection1the solvent solution containing 5% dextrose (Abbot Laboratories, QC, Canada) and 2% of Polysorbate 20 (Sigma, St. Louis, Missouri, USA). The negative control group treated only with solvent. The injection volume for both groups processed by tartrate connection1and for a group of tricatel the aqueous control is 150 μl. The positive control group treated every 3 days to five times of cisplatin (Sigma, St. Louis, Missouri, USA) at a dose of 4 mg/kg Cisplatin receive in the form of a composition in PBS for each day of injection and injected I.P. with injectable volume of 80 ál.

Mice are weighed and the tumor was measured on day 13 and every 2 days after the start of treatment. Observation continued for 40 days after the initial implantation of the tumor. Changes in body weight and estimated tumor volume represent graphically.

As shown in figure 2, mice treated tartrate connection1characterized by a slight loss of mass, whereas treated with cisplatin group positive control has a weight loss of 28% on day 29. Two mice died in the treated cisplatin group on days 29 and 32 after the loss of 2.2 g and 7 g of body weight, respectively.

As shown in figure 3, treatment tartrate connection1at the dose of 4.5 mg/kg once a day for five days, resulting in a statistically significant (p<0,0001) reduction in tumor growth compared to mice treated only with solvent. On days 36 and 39 animals treated with 4.5 mg/kg tartrate connection1,have on average significantly (p<0.001) and smaller tumors than animals treated only with solvent. The value of T/C on days 36 and 39 are 14% and 22%, respectively. On average marked messestand the e changes in body weight.

As shown in figure 3, tartrate connection1significantly reduces tumor human cervical implanted SCID-mice, a model of artificially implanted cancer human cervical.

Therefore, tartrate connection1useful for suppression of cervical cancer and treatment or prevention of cervical cancer in a patient, in particular in humans.

6.4. EXAMPLE 4

Synthesis of compound 66 and connection 67

Scheme 3

With respect to the pattern3the intermediate connectionHsynthesized according to the method described in Nicolaou, M.G.et al. J. Org. Chem.1996,61, 8636-8641.

According to scheme 3, the intermediate connectionH(1 g of 1.76 mmol) dissolved in acetonitrile (18 ml), cooled to 0 and treated with a solution of hydrogen fluoride-pyridine (1,76 ml) for 5 min to remove the silyl group. Free primary alcohol oxidized to carboxylic acids using Jones reagent (6 ml) is added over a period of 30 min) and the reaction mixture was kept at 0ºC, vigorously stirring for 1 hour Add 2-propanol (4 ml)to quench the residual Jones reagent, and the mixture is stirred for another 10 minutes Add saturated aqueous solution of NH4Cl (40 ml) and EtOAc (30 ml) and separate the layers. The organic phase is washed with saturated aqueous NH4Cl (2×40 ml), dried over besod the nd Na 2SO4and filtered through a funnel with a porous glass filter. The solvent is removed on a rotary evaporator, receiving a yellow-green oil, which is purified by chromatography on a column of silica gel, using as eluent a mixture of EtOAc/hexane in a gradient of 0-50%. Carboxylic acidIisolated in the form of a colourless oil.

Yield: 570 mg, 70%.

NMR1H (300 MHz, CDCl3): δ (ppm) of 1.45 (s, 6H); 2,19 (s, 3 H); 2,78 (s, 1H); 5,07-5,16 (m, 4 H); 6.87 in (m, 1H); 7,09-7,22 (m, 2H); 7,31 (s, 9H).

Carboxylic acidI(570 mg, 1,22 mmol) dissolved in CH2Cl2(12 ml) and cooled to 0ºC. The solution is treated with oxalylamino (138 μl, was 1.58 mmol), DMF (50 μl) and stirred for 1 h at room temperature. The solvent is removed by evaporation on a rotary evaporator and the residual acid chlorideJdriedin the vacuumwithin 2 hours, getting a white solid.

A solution of compound1(309 mg, 0.98 mmol) in THF (5 ml) is cooled to 0 and treated with solid potassium hydride (155 mg, to 2.94 mmol, 70% oil dispersion). The reaction mixture was stirred at 0ºC for 30 minutes Intermediate productJdissolved in THF (5 ml) and added dropwise to the anion of compound1. The mixture is stirred at 0°C for another 30 min, then quenched with saturated

aqueous NaHCO3(30 ml). Add EtOAc (15 ml) and separate the layers. The organic phase is washed with saturated RA is tworoom salt (3×30 ml), dried over anhydrous Na2SO4, filtered through a funnel with a porous glass filter and the solvent is removed on a rotary evaporator. The residue is purified by chromatography on a column of silica gel, using as eluent a mixture of EtOAc/hexane in a gradient of 0-20%, which gives dibenzyltoluene the prodrugKas an orange oil.

Yield: 320 mg, 42%.

M/Z: 768,35 [M+1].

1H NMR (300 MHz, CDCl3): δ (ppm) to 1.38 (s, 6H); of 2.09 (s, 3H); 2,17 (s, 3H); 2,39 (s, 3H); of 5.84 (s, 2H); of 3.80 (s, 3H); 4,87-4,99 (m, 4H); of 5.84 (s, 1H); 6,01 (s, 1H); 6,46-6,56 (1, 2H); 6,79 (s, 1H); 6,83-6,94 (m, 3H); 7,05-7,13 (m, 2H); 7,15-of 7.23 (m, 4H); 7,27-to 7.35 (m, 5H); of 7.36 was 7.45 (m, 2H); to 9.93-10,31 (users, 1H).

Dibenzyltoluene the prodrugK(130 mg, 0,17 mmol) dissolved in CH2Cl2(4 ml), treated with TMSBr (132 μl, 1 mmol) and stirred under heating at the boiling point under reflux for 45 minutes the Solvent is removed by evaporation on a rotary evaporator and the residue is driedin the vacuumthroughout the night. The residue is dissolved in CH2Cl2(20 ml) and washed with saturated salt solution (3×40 ml). The organic layer is dried over anhydrous Na2SO4, filtered through a funnel with a porous glass filter and the solvent is removed on a rotary evaporator, receiving phosphate prodrug66with the removed protecting group in the form of a reddish-orange solid.

Yield: 100 mg, 100%.

M/Z: 588,28 [M+1].

1H NMR (300 MHz, DMSO-d6): δ (ppm) was 1.43 (s, 6H); of 1.84 (s, 3H); of 2.38 (s, 3H); 2.71 to (s, 3H); 3,55-3,71 (users, 2H); of 4.05 (s, 3H); 6,34-6,55 (m, 3H); 6,92-7,06 (m, 2H); 7,17 (s, 1H); 7.23 percent (s, 1H); 7,26-7,47 (m, 2H); 7,58-7,73 (d, 1H); 7,75-of 7.90 (d, 1H).

Scheme 4

According to the pattern41,2-benzodithiol (L, 3 g, and 21.7 mmol) and TBDMSCl (2,94 g of 19.5 mmol) dissolved in CH2Cl2(28 ml), cooled to 0ºC and then treated with a solution of triethylamine (12.1 ml, and 86.8 mmol) in CH2Cl2(11 ml). The mixture is stirred at room temperature for 1 h and the solvent is removed on a rotary evaporator. The residue is dissolved in EtOAC (30 ml) and washed with saturated salt solution (3×60 ml). The organic layer is dried over anhydrous Na2SO4and filtered through a funnel with a porous glass filter. The solvent is removed on a rotary evaporator, getting sililirovany benzyl alcoholMin the form of a colorless oil.

Yield: 4.5 g, 91%.

1H NMR (300 MHz, CDCl3): δ (ppm) to 0.06 (s, 6H); to 0.80 (s, 9H); 2,99-3,19 (users, 1H); 4,56 (s, 2H); 4,70 (s, 2H); 7,14-to 7.32 (m, 4H).

The solution dibenzylamine (3,76 g, 13.5 mmol) in CH2Cl2(10 ml) is treated with oxalylamino (1,17, 13.5 mmol) and DMF (0.5 ml). The mixture is stirred at room temperature for 1 h, the solvent is removed on a rotary evaporator and the residue is dried in vacuum for 2 h, getting dibenzylammonium in the form of a yellowish solid. the STATCOM is suspended in CH 2Cl2(5 ml), cooled to 0ºC, treated with a solution of benzyl alcoholM(1.7 g, 6.7 mmol) in CH2Cl2(5 ml), and then DBU (2,02 ml, 13.5 mmol, added dropwise). The mixture is stirred at room temperature for 1 h 30 min and the solvent is removed on a rotary evaporator. The residue is purified by chromatography on a column of silica gel, using as eluent a mixture of EtOAc/hexane in a gradient of 0-10%.

Yield: 1.3 g, 40%.

1H NMR (300 MHz, CDCl3): δ (ppm) of 0.01 (s, 6H); or 0.83 (s, 9H); the 4.65 (s, 2H); 4,87-4,96 (d, 4H); 4,96-of 5.06 (d, 2H); 7,07-7,41 (m, 14H).

DimensionfulN(1.3 g, 2,53 mmol) dissolved in acetonitrile (25 ml), cooled to 0°C and treated with a solution of hydrogen fluoride-pyridine (2.5 ml) for 5 min to remove the silyl group. Free primary alcohol oxidized to carboxylic acids using Jones reagent (5 ml, is added over a period of 30 min) and the reaction mixture was kept at 0ºC, vigorously stirring for 1 hour Add 2-propanol (6 ml)to quench the residual Jones reagent, and the mixture is stirred for another 10 minutes Add saturated aqueous solution of NH4Cl (40 ml) and EtOAc (30 ml) and separate the layers. The organic phase is washed with saturated aqueous NH4Cl (2×40 ml), dried over anhydrous Na2SO4and filtered through a funnel with a porous glass filter. The solvent is removed on a rotary evaporator, the floor is yellow tea oil, which is used in the next stage without purification.

Yield: 1.0 g, 98%.

1H NMR (300 MHz, CDCl3): δ (ppm) 5,04-5,17 (d, 4H); 5,56-5,5,67 (d, 2H); 7,27-7,41 (m, 11N); of 7.48-7,58 (m, 2H); 7,80-to 8.12 (m, 1H).

Benzoic acidO(1.0 g, 2,42 mmol) dissolved in CH2Cl2(24 ml) and cooled to 0ºC. The solution is treated with oxalylamino (420 μl, 4,84 mmol), DMF (50 μl) and stirred for 1 h at room temperature. The solvent is removed by evaporation on a rotary evaporator and the residual benzoyl chloridePdriedin the vacuumwithin 2 hours, getting a white solid.

A solution of compound1(384 mg, to 1.21 mmol) in THF (12 ml) is cooled to 0 and treated with solid potassium hydride (192 mg, of 3.64 mmol, 70% oil dispersion). The reaction mixture was stirred at 0ºC for 30 minutes Intermediate productPdissolved in THF (5 ml) and added dropwise to the anion of compound1. The mixture was stirred at 0ºC for 30 min, then quenched with saturated

aqueous NaHCO3(30 ml). Add EtOAc (15 ml) and separate the layers. The organic phase is washed with saturated salt solution (3×30 ml), dried over anhydrous Na2SO4, filtered through a funnel with a porous glass filter and the solvent is removed on a rotary evaporator. The residue is purified by chromatography on a column of silica gel, using as eluent a mixture of EtOAc/hexane in a gradient of 0-20%, h is about giving dibenzyltoluene the prodrug Qas an orange oil.

Output: 422 mg, 50%.

M/Z: 712,24 [M+1].

1H NMR (300 MHz, CDCl3): δ (ppm) at 1.91 (s, 3H); 2,12 (s, 3H); of 3.77 (s, 3H); 4,85-4,96 (d, 4H); 5,33-5,44 (d, 2H); 5,71 (s, 1H); 5,79 (s, 1H); 6,79 (s, 1H); 7,06 (s, 1H); 7,11-7,35 (m, 15H); 7,41-to 7.68 (m, 4H).

Dibenzyltoluene the prodrugQ(100 mg, 0.14 mmol) was dissolved in wet CH2Cl2(2 ml), treated with TFA (2 ml). The mixture is stirred while heating at the boiling point under reflux for 3 h and the solvent is removed by evaporation on a rotary evaporator. Phosphate prodrug67cleanse RP-HPLC on a C18-column using a gradient

a mixture of H2O/CH3CN as the mobile phase (pH 9).

M/Z: 532,17 [M+1].

1H NMR (300 MHz, DMSO-d6): δ (ppm) of 2.30 (s, 3H); 2.40 a (s, 3H); 3,98 (s, 3H); 4,65-to 4.81 (d, 2H); 6,24 (s, 1H); to 6.43 (s, 1H); 6.48 in-6,60 (d, 2H); 7,05-to 7.18 (m, 2H); 7,19 of 7.3 (m, 1H); 7,33 (s, 1H); 7,39-7,46 (d, 2H); 7,46-rate of 7.54 (m, 1H); 7,54-to 7.64 (m, 1H); to 7.64 to 7.75 (m, 1H).

6.5 EXAMPLE 5

The solubility of tartrate of compound 1, mesilate salt of compound 1 and compound 66

To determine whether the compound is soluble in the solution, the solution is filtered over a PTFE 0.2 μm filters (Whatman Inc. Clifton, New Jersey, USA)to measure the concentration in the filtrate by LC/MS and compared with the expected concentration. If the concentration of the compound in the filtrate equal to ±15% of expected concentration, the connection is considered soluble to dissolve the E.

Detection of tartrate of compound1, mesilate salt compounds1or connection66method LC/MS carried out using a HPLC system consisting of a Quaternary gradient HPLC pump Waters Alliance (Waters, Milford, MA, USA), and mass spectrometer with a single quadrupole lens ZQ2000 (Waters, Milord, MA, USA). Used column C18MS XTerra: column 50×2.1 mm, 3.5 mm, at 20ºC. Sample inject and share the following conditions: the mobile phase "A" consists of 5 mm ammonium formate, 0.1% of formic acid in water and mobile phase "B" consists of 5 mm ammonium formate, 0.1% of formic acid in methanol. Use the following linear gradient: 0 to 1 min, 94% of "A" and 6% "B"; 1-4 min, 6%-100% "B"; 4-8 min, 100% B"; 8-9 min, 100% B"-6% "B"; 9-12 min, 94% of "A" and 6% "B". System of a mass spectrometer consists of a mass spectrometer with a single quadrupole lens Waters ZQ2000 (Waters, Milord, MA, USA)equipped with an ionization source method elektrorazpredelenie (ES). Mass detector operates in the positive ion mode (ES+) and selective ion recording mode (SIR). Compounds detected at m/z equal to the corresponding molecular weight plus 1.

Connection1poorly soluble in water. The solubility of the tartrate salt of the compound1equal to 0.1 mg/ml Mutilata salt compounds1is the preferred salt, because the solubility of the specified salt four times higher (0.4 mg/ml). This increase is ikenie solubility has a positive effect on the storage stability of the connection 1in the composition. The composition containing 0.6 mg/ml of tartrate salt of compound1, 9.6% of polyethylene glycol 300, 0.4% Polysorbate 20 and 5% dextrose tends to be precipitated in an hour after receiving as 40%-50% tartrate connection1is retained by the filter of 0.2 μm. On the contrary, the composition containing 0.6 mg/ml mesilate salt compounds1, 9.6% of polyethylene glycol 300, 0.4% Polysorbate 20 and 5% dextrose, shows no signs of precipitation after 72 hours after receipt. Thus, mutilata salt compounds1much better, because it significantly increases the stability of the composition, making the composition suitable for clinical application.

The introduction of phosphate increases the solubility of poorly soluble compounds. Phosphate prevents the penetration of compounds into cells, but can be gradually removed under the action of alkaline phosphatase in the plasma. Therefore, the connection, which entered phosphate is a prodrug. For example, the connection66is a phosphate prodrug of the compound1and solubility connection66in the water is 10 mg/ml - 100 times higher than tartrate connection1. In vivo, because phosphate is not removed immediately under the action of alkaline phosphatase, the prodrug has the time to dispergirujutsja in the total blood volume. As the phosphate group is removed, freed of Lech is STV manages to be distributed in the tissue. Therefore, the less soluble the drug is not deposited in the blood. The advantage of prodrugs is that the prodrug can be entered on a smaller scale, because it can be dissolved at higher concentrations in aqueous solution.

6.6 EXAMPLE 6

Conversion of phosphate procarcinogen connection 66 to the corresponding biologically active equivalent under the action of alkaline phosphatase in vitro

Conversion to the biologically active drug phosphate prodrugs under the action of intestinal alkaline phosphatase calf and placental alkaline phosphatase person measured in vitro using purified enzymes. Purified putting intestinal phosphatase (calf Roche Diagnostic Inc. Laval, Quebec, Canada) or placental alkaline phosphatase person (Sigma-Aldrich Canada Ltd. Oakville, Ontario, Canada) is added at a concentration of 0.02 Units/100 μl of the solution containing 15 μm compound66, 20 mm Tris-HCl, pH 7.4 and 0.9% NaCl. The solutions are incubated for 30, 60 or 120 minutes. A solution containing 15 μm compound66, 20 mm Tris-HCl, pH 7.4 and 0.9% NaCl, used as a control (time = 0 minutes). To each solution add an equal volume (100 μl) cooled with ice acetonitrile and the mixture is then shaken and transferred to glass tubes. The standard curve concentrations for prodrugs and drugs get in a mixture of 10 mm Tris-HCl, pH 7,4, of 0.45% NaCl and 50% of clonicel. All samples immediately analyze LC/MS.

As shown in figure 4 and 5, as intestinal alkaline phosphatase calf, and placental alkaline phosphatase person can turn a fraction procarcinogen connection66,present in the solution in the drug connection1within two hours.

6.7 EXAMPLE 7

Influence mesilate salt of compound 1 and compound 66, respectively, on the growth of tumor cells of the prostate gland in vitro

Use cancer cells PC3 adenocarcinoma of the prostate of a man from the American type culture collection (ATCC). These cells are guaranteed not to contain Mycoplasma infection. Cell support in Roswell Park Memorial Institute (RPMI)supplemented with 10% inactivated fetal calf serum and a mixture of 1% penicillin-streptomycin-1-glutamine, in an environment of 5% carbon dioxide (CO2) at 37 degrees C. For indicating the growth of prostate carcinoma cells are grown to confluence less than 70% in complete medium and then harvested using trypsin (Bio Whittaker, MD, USA). The cells are then centrifuged and washed 2 times with phosphate buffered saline (PBS) and resuspended in PBS with 1.5×106cells/ml. of 0.1 PC3 Cells transplanted subcutaneously into the lateral surface of the abdomen SCID mice (Charles River Laboratories, Wilmington, MA, USA) in the form of a suspension of tumor cells (1.5 x 106cells in 100 μl PBS) in l is minirnum Cabinet with air supply. Eleven (11) days measure the size of each tumor. Ten days after transplantation, the mice are randomly divided into groups of 10 mice for tumor size so that the average tumor size in each group was comparable. The relative size and tumor volume calculated as follows: length (cm) × [width (cm)]2/2. Then perform 5 consecutive intravenous (tail vein) injection to mice or 200 ál 9.6% of polyethylene glycol 300, 0.4% Polysorbate 20 and 5% dextrose (diluent), 4,84 µmol/kg mesilate salt compounds1together with 9.6% of polyethylene glycol 300, 0.4% Polysorbate 20 and 5% dextrose; 4,84 µmol/kg connection66(prodrug), together with 5% dextrose or 14,51 µmol/kg connection66(prodrug) in the composition with 5% dextrose. As shown in Fig.6, and mutilata salt compounds1and the connection66(prodrug) substantially reduce the growth of prostate tumors in mice.

6.8 EXAMPLE 8

The influence of compounds on the viability of cancer cells in vitro

To further demonstrate antioncogenes actions trilateration compounds according to the invention were synthesized some compounds and demonstrated the influence of these compounds on the viability of cancer cells by measuring cellular ATP levels in the cancer cell line is H1299 and C33A, as described in example 2 of this application. As indicated in table 4, these compounds are effective in reducing the cellular levels of ATP in cancer cell lines H1299 and C33A. However, it is believed that these compounds applicable for methods in vivo according to the invention, i.e. for the treatment and prevention of cancer and viral infections, respectively. It should be noted that while this test is based on cells indicates antioncogenic activity in vivo, this test is useful not only for assessing antioncogenic activity trilateration compounds according to the invention. In addition, antiviral and other biological activity of the compounds according to the invention can be installed and evaluated in trials in other experimental systems, well-known experts in this field.

It should also be noted that for medical use in vivo efficacy is not the only factor in assessing the suitability of the compounds as pharmaceutical agents. Other factors such as toxicity and bioavailability also determine the suitability of the compounds as pharmaceutical agents. Toxicity and bioavailability can also be studied in an experimental system known qualified.

The present invention is not limited in scope to the specific implementation options described in the examples, which are considered to illustrate the novel aspects of the invention, and any functionally equivalent variant of implementation covered by the scope of the present invention and the attached claims. Indeed, various modifications of the invention, complementary options shown and described herein, become obvious to the person skilled in the art and fall under the scope of the invention and the attached claims.

In the description of a number of literary sources, the disclosure of which is fully incorporated into it by reference.

1. The compound having the formula

and its pharmaceutically acceptable salt,
where Q1means-N(R1)-;
Q2means- (R3)-;
Q3means-C(R5)-;
Q4means-C(R9)-;
R1means-Ym(Ra), where-Rameans-H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-;
R2means-N;
R3, R4and R5independent mean-Ym(Rb), where Rbmeans-H, halogen, -C1-C8alkyl, -O-(C1-sub> 8alkyl) or-OR14, provided that if the value of m radical Ym(Rb) 0, R5is not H;
R6means-N;
R7means-Ym-(RC), where-Rcmeans-O-(C1-C8alkyl), or-NH(phenyl),
R8means-Ym(Rd), where-Rdmeans-H-HE,
R9, R10, R11, R12and R13independent mean-Ym(Re), where Remeans-H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14or-O-C(O)OR14,;
each R14independently denotes-H, -C1-C8alkyl, -phenyl, 5-6-membered heterocycle containing 1 heteroatom, which is a S;
each Y independently denotes-C1-C8alkylene-;
each m independently is 0 or 1.

2. The compound according to claim 1, where Q1means-NH-, Q2means-C(R3)-, Q3means-C(R5)and Q4means-C(R9)-.

3. The compound according to claim 1, where Q1means-NH-, Q2means-C(R3)-, Q3means-C(R5)-, Q4means-CH - and R2and R6mean-N.

4. The compound according to claim 1, where Q1means-NH-, Q2means-C(R3)-, Q3means-C(R5)-, Q4means-CH - and R2, R4, R6, R8and R10-R13mean-N.

5. The compound according to claim 1, where Q1OZNA the AET-NH-, Q2means-C(C1-C8alkyl)-, Q3means-C(C1-C8alkyl)-, Q4means-CH-, R7means-O-(C1-C8alkyl) -, and R2, R4, R6, R8and R10-R13mean-N.

6. The compound according to claim 5 having the formula

or its pharmaceutically acceptable salt.

7. The compound of formula (II)

or its pharmaceutically acceptable salt,
where Q1means-NH-;
Q4means-C(R9)-;
R6means-N;
R7and R8independent mean-Ym-(Rd), where-Rdmeans-H, -OH, -NH(phenyl) or-O-(C1-C8alkyl);
R9, R10, R11, R12and R13independent mean-Ym(Re), where Remeans-H, halogen, 5-6-membered heterocycle with two heteroatoms, selected from N or O, -OR14, -O-C(O)OR14;
each R14independently mean H, -C1-C8alkyl, -phenyl, -naphthyl, -5-6-membered heterocycle containing one heteroatom represents S;
each Y independently denotes-C1-C8alkylene-; and
each m independently is 0 or 1.

8. The compound of formula (II):

or its pharmaceutically acceptable salt,
where Q1means-NH-;
Q4means-CH-;
R6means-N;
R and R8independent mean-Ym-(Rd), where-Rdmeans-H, -OH, -NH(phenyl) or-O-(C1-C8alkyl);
R10, R11, R12and R13independent mean-Ym(Re), where Remeans-H, halogen, 5-6-membered heterocycle with two heteroatoms, selected from N or O, -OR14or-O-C(O)OR14;
each R14independently mean H, -C1-C8alkyl, -phenyl, -naphthyl or 5 to 6 membered heterocycle containing one heteroatom, representing S,
each Y independently denotes-C1-C8alkylene-; and
each m independently is 0 or 1.

9. The compound of formula (II):

or its pharmaceutically acceptable salt,
where Q1means-NH-;
Q4means-CH-;
R6means-H;
R7and R8independent mean-Ym-(Rd), where-Rdmeans-N, -NH(phenyl) or-O-(C1-C8alkyl),
R10, R11, R12and R13mean N;
each Y independently denotes-C1-C8alkylene-; and
each m independently is 0 or 1.

10. The compound of formula (II):

or its pharmaceutically acceptable salt,
where Q1means-NH-;
Q4means-CH-;
R6means-H;
R7means-O-(C1-C8alkyl);
R8independent means-Ym-(Rd/sub> ), where-Rdmeans-H, -OH, -NH(phenyl), -N(phenyl)2, -0-(C1-C8alkyl),
R10, R11, R12and R13denote H;
each Y independently denotes-C1-C8alkylene -; each m independently is 0 or 1.

11. Pharmaceutical composition having the property of inhibiting cancer or tumor cells containing an effective amount of the compounds of formula (Ia) according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent.

12. Pharmaceutical composition having the property of inhibiting cancer or tumor cells containing an effective amount of the compound or its pharmaceutically acceptable salt of the compound according to claim 6 and a pharmaceutically acceptable carrier or diluent.

13. A method of treating cancer in a patient, including the introduction in need of such treatment to the patient an effective amount of the compounds of formula (Ia) according to claim 1 or its pharmaceutically acceptable salt, where the cancer is a prostate cancer, colon cancer, cervical cancer, breast cancer, nahodkinskuju lymphoma, chronic lymphocytic leukemia, acute miliitary leukemia, acute lymphocytic leukemia, non-small cell lung cancer, beta-cell lymphoma, T-cell leukemia, adenocarcinoma, lung carcinoma, cancer of the bile about the shackles, melanoma or multiple myeloma.

14. The method according to item 13, where the compounds of formula Ia or pharmaceutically acceptable salts of Q1means-NH-, Q2means-C(R3)-, Q3means-C(R5)and Q4means-C(R9)-.

15. The method according to item 21, where the compounds of formula Ia or pharmaceutically acceptable salts of Q1means-NH-, Q2means- (R3)-, Q3means-C(R5)-, Q4means-CH-, and R2and R6mean-N.

16. The method according to item 13, where the compounds of formula Ia or pharmaceutically acceptable salts of Q1means-NH-, Q2means- (R3)-, Q3means-C(R5)-, Q4means-CH - and R2, R4, R6, R8and R10-R13mean-N.

17. The method according to item 13, where the compounds of formula Ia or pharmaceutically acceptable salts of Q1means-NH-, Q2means-C(C1-C8alkyl)-, Q3means-C(C1-C8alkyl)-, Q4means-CH-, R7means-O-(C1-C8alkyl) -, and R2, R4, R6, R8and R10-R13mean-N.

18. The method according to item 13, additionally including the introduction of another chemotherapeutic where the other chemotherapeutic agent is a nitrogen mustard gas containing platinum compound, taxoid, analogue of cytosine, apipath Illin, the kinase inhibitor, anthracyclin, cytokine or a Vinca alkaloid.

19. A method of treating cancer in a patient, including the introduction in need of such treatment to the patient an effective amount of a compound according to claim 6 or its pharmaceutically acceptable salt, where the cancer is a prostate cancer, colon cancer, cervical cancer, breast cancer, nahodkinskuju lymphoma, chronic lymphocytic leukemia, acute miliitary leukemia, acute lymphocytic leukemia, non-small cell lung cancer, beta-cell lymphoma, T-cell leukemia, adenocarcinoma, lung carcinoma, cancer of the bile ducts, melanoma or multiple myeloma.

20. The method according to claim 19, further including the introduction of another therapeutic agent, where the other chemotherapeutic agent is a nitrogen mustard gas containing platinum compound, taxoid, analogue of cytosine, apoptolidin, a kinase inhibitor, anthracyclin, cytokine, or a Vinca alkaloid.

21. The method of obtaining the compounds of formula (Ia)

including contacting the compounds of formula (II)

with the compound of the formula (iv)

in the presence of an organic solvent and a proton acid, for a period of time and at a temperature sufficient to obtain the value of the formula (Ia),
where Q1means-N(R1)-;
Q2means-C(R3)-;
Q3means-C(R5)-;
Q4means-C(R9)-;
R1means-Ym(Ra), where-Rameans-H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-;
R2means-N;
R3, R4and R5independent mean-Ym(Rb), where Rbmeans-H, halogen, -C1-C8alkyl, -O-(C1-C8alkyl) or-OR14, provided that if the value m of the radical Ym(Rb) 0, R5is not H;
R6means-N;
R7means-Ym-(Rc), where-Rcmeans-O-(C1-C8alkyl), or-NH(phenyl),
R8means-Ym(Rd), where-Rdmeans H or HE,
R9, R10, R11, R12and R13independent mean-Ym(Re), where Remeans-H, halogen, 5-6-membered heterocycle with 2 heteroatoms selected from N or O, -OR14or-O-C(O)OR14,;
each R14independently denotes-H, -C1-C8alkyl, -phenyl, or 5-6-membered heterocycle with one heteroatom, which is a S;
each Y independently denotes-C1-C8alkylene-; and
each m independently is 0 or 1.

22. The method according to item 21, where the organic solvent is alcohol.

23. The method according to item 22,where the alcohol is a methanol or ethanol.

24. The method according to item 21, where the acid is an aqueous chloride-hydrogen acid or aqueous Hydrobromic acid.

25. The method of obtaining the compounds of formula (II)

including the interaction of the compounds of formula (iii)

with the compound of the formula (ii)

or a compound of formula (iia)

in the presence of an organic solvent, a base and a Pd-catalyst, for a period of time and at a temperature sufficient to obtain the compounds of formula (II), where R15independent means1-C8alkyl, and where
Q1means-N(R1)-;
Q4means-C(R9)-;
R1means-Ym(Ra), where-Rameans-H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-;
R2means-N;
R7and R8independent mean-Ym(Rd), where-Rdmeans-H, -OH or-O-(C1-C8alkyl),
R9, R10, R11, R12and R13independent mean-Ym(Re), where Remeans-H, halogen, 5-6-membered heterocycle with 2 heteroatoms selected from N or O, -OR14or-O-C(O)OR14,;
each R14independently denotes-H, -C1-C8alkyl, -phenyl, -naphthyl, or 5-6-membered heterocycle with one of the m a heteroatom, which is a S;
each Y independently denotes-C1-C8alkylene-; and
each m independently is 0 or 1.

26. The method according A.25, where the organic solvent is dioxane, toluene or a mixture of dimethylformamide/water.

27. The method according A.25, where the base is alkali metal hydroxide or carbonate of an alkali metal.

28. The method according A.25, where the base is barium hydroxide or potassium carbonate.

29. The method according A.25, where the Pd catalyst is a PdCl2(dppf).

30. The compound having the formula

or its pharmaceutically acceptable salt.

31. The compound having the formula

or

or its pharmaceutically acceptable salt.

32. Pharmaceutical composition having the property of inhibiting cancer or tumor cells containing an effective amount of a compound according p or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent.

33. A method of treating cancer in a patient, including the introduction in need of such treatment to the patient an effective amount of a compound according p where the cancer is a prostate cancer, colon cancer, cervical cancer, breast cancer, nahodkinskuju lymphoma, chronic lymphocytic LEU is the Accademia, acute miliitary leukemia, acute lymphocytic leukemia, non-small cell lung cancer, beta-cell lymphoma, T-cell leukemia, adenocarcinoma, lung carcinoma, cancer of the bile ducts, melanoma or multiple myeloma.

34. The compound having the structure

35. The connection according to claim 6, where the pharmaceutically acceptable salt is a tartaric acid salt or mesilate salt.

36. The method according to claim 19, where the pharmaceutically acceptable salt is a tartaric acid salt or mesilate salt.

37. The method according to item 13, where the cancer is a prostate cancer, colon cancer, cervical cancer, breast cancer, chronic lymphocytic leukemia, acute miliitary leukemia or acute lymphocytic leukemia.

38. The method according to p where the other chemotherapeutic agent is cisplatin, paclitaxel, doxorubicin, etoposide, citizenoriented or vincristine.

39. The method according to claim 20, where the other chemotherapeutic agent is a nitrogen mustard, platinum source connection, taxoid, analogue of cytosine, apoptolidin, a kinase inhibitor, anthracycline, or a Vinca alkaloid.

40. The method according to claim 20, where the other chemotherapeutic agent is cisplatin, paclitaxel, doxorubicin, etoposide, citizenoriented or in Kristin.

41. The method according to p where the cancer is a prostate cancer, colon cancer, cervical cancer, breast cancer, chronic lymphocytic leukemia, acute miliitary leukemia or acute lymphocytic leukemia.



 

Same patents:

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to novel 2,4-pyridindiamine compounds of formula (1). In structural formula (I) L1 is direct bond; L2 is direct bond; R2 is phenyl group, three times substituted with three groups R8; R4 is X represents N; Y is selected from group consisting of O, NH, S, SO and SO2; Z is selected from group consisting of O, NH; on condition that if Y is selected from group consisting of NH, S, SO and SO2, Z is not the same as Y; R5 is selected from group consisting from R6, halogen; each R6 is independently selected from group consisting of hydrogen, halogen; R8 is selected from group consisting from Ra, Rb, Ra substituted with one or several similar or different groups Ra or Rb, -ORa, -O-CHRaRb; each R35 independently on others is selected from group consisting of hydrogen and R35, or in alternative case, two groups R35, bound to one and the same carbon atom are taken together with formation of oxogroup (=O), and the remaining two groups R35 each independently on each other are selected from group consisting from hydrogen and R8; each Ra is independently selected from group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl; each Rb is suitable group which is independently selected from group consisting of -ORd, halogen, -CF3, -C(O)NRcRc, and -OC(O)ORd; each Rc is independently protective group or Ra; each Rd is independently protective group or Ra; each index m is independently integer number from 1 to 3.

EFFECT: novel compounds can be used for treatment or prevention of autoimmune diseases, for instance such as rheumatoid arthritis and/or related to it symptoms, systemic lupus erythematosus and/or related to it symptoms, as well as and/or related to it symptoms.

41 cl, 14 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. Claimed compounds have antibacterial effect. In formula (I) , X is ; R1 is i) hydrogen, ii) (CH2)nNR5R6, iv) NRCO2R, v) (C1-6alkyl)CN, CN, (CH2)pOH; Y is NR*, O or S(O)p; is phenyl or 5-6-member heteroaryl with N or S as heteroatoms; R3 is NR(C=X2)R12, NR*R12, or -(O)n-5-6-member heteroaryl with 1-3 heteroatoms selected out of N, O, which can be linked over either carbon atom or heteroatom; the indicated 5-6-member heteroaryl can be optionally substituted by 1-3 groups of R7; R4, R4a, R4b and R4c are independently i) hydrogen, ii) halogen; other radicals are defined in the claim.

EFFECT: pharmaceutical composition containing effective volume of the claimed compound.

13 cl, 1 dwg, 194 ex

FIELD: chemistry.

SUBSTANCE: in compound of formula I , R1 is hydrogen; R2 is phenyl substituted by trifluoromethyl and optionally by other substitute selected out of a group including lower hydroxyl alkyl, lower alkylamino, lower hydroxyl alkylamino, dilower alkylamino, 1H-imidazolyl, lower alkyl-1H-imidazolyl, carbamoyl, lower alkylcarbamoyl, pyrrolidino, piperazino, lower alkylpiperazino, morpholino, lower alkoxy, trilfuoro-lower alkoxy, phenyl, pyridyl and halogenyl; R4 is methyl; where 'lower' prefix denotes radical with up to 7 carbon atoms. Also invention concerns pharmaceutical composition and method of treatment, as well as application of the claimed compounds in obtaining pharmaceutical composition.

EFFECT: improved proteinkinase inhibition properties.

9 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the new substituted dihydroquinazolines of formula (I) and to their pharmaceutically acceptable salts having antiviral properties. In general formula (I) , Ar is phenyl group which can be mono-, di- or trisubstituted. The substituting group are independently selected from the group including C1-6 alkyl-, C1-6 alkoxy-, trifluoromethyl groups and halogen atoms or two substituting groups together with linked carbon atoms form 1,3-dioxolane; R1 is hydrogen atom, amine group, C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthiol group, cyanic group, halogen atoms, nitro group or trifluoromethyl group; R2 is hydrogen atom, C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthiol group, cyanic group, halogen atoms, nitro group or trifluoromethyl group; R3 is C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthiol group, cyanic group, halogen atoms, nitro group or trifluoromethyl group; or one of the radicals R1, R2 and R3 is hydrogen atom and two others together with linked carbon atoms form cyclopentane or cyclohexane ring, R4 is hydrogen atom or C1-6 alkyl group, R5 is hydrogen atom or alkyl group, R6 is carboxyl, aminocarbonyl, alkoxycarbonyl groups, halogen atoms, cyanic or hydroxyl groups, R7 is hydrogen atom or halogen atoms and R8 is hydrogen atom or halogen atoms, its pharmaceutically acceptable salts.

EFFECT: claimed compounds can find application for treatment and prevention of diseases and as antiviral agents.

21 cl, 3 tbl, 201 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new nitroxide compounds with formula I: where one of A, B and D represents N-O and others represent CR6; R1 represents alkyl, containing 1 to 4 carbon atoms, which is branched or straight and which is unsubstituted or substituted once or several times with a halogen; R2 represents alkyl, containing 1 to 12 carbon atoms, which is branched or straight and which is unsubstituted or substituted once or several times with a halogen; cycloalkylalkylk, containing 3 to 10 carbon atoms, which is unsubstituted or substituted once or several times with oxo, aryl, containing 6 to 14 carbon atoms, which is unsubstituted or substituted once or several times with OCF3; or a heterocyclic group, which is saturated, partially saturated or unsaturated, with 5 to 10 atoms in the ring, where at least 1 atom in the ring is an atom of N, O, or S; R3 represents cycloalkyl, containing 3 to 10 carbon atoms, which is unsubstituted once or several times with oxo, aryl, containing from 6 to 14 carbon atoms or which is unsubstituted or substituted once or several times with OCF3; or heteroaryl, with 5 to 10 atoms in the ring, in which at least 1 atom in the ring is a heteroatom; R represents H or alkyl, containing 1 to 4 carbon atoms. The invention also relates to pharmaceutically used salts of these compounds, pharmaceutical compositions containing these compounds, method of inhibiting PDE4 enzyme and to methods treatment using these compounds.

EFFECT: new compounds with useful biological properties.

62 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula 1: where R1 stands for cycloalkyl containing 3 to 10 carbon atoms, R2 stands for alkyl containing 1 to 4 carbon atoms, R3 stands for pyridylmethyl, R4 stands for phenyl unsubstituted or substituted with carboxy-, cyanogroup or alkoxycarbonyl; or to its pharmaceutically acceptable salts provided the specified compounds is not 4-(2-chlor-4-methoxyphenyl)-5-methyl-2-[N-(1-propylindazole-6-yl)-N-propylamino]thiazole where optically active compound can be in the form of one of its separated enantiomers or their mixtures, including racemic mixtures, or to compounds of formula II: where R3 stands for hydrogen or pyridylmethyl, R4 stands for hydrogen or phenyl unsubstituted or substituted with carboxy-, cyanogroup, alkoxycarbonyl, tetrazole-5-yl or phenylsulphonyl aminocarbonyl; R7 stands for alkoxygroup containing 1 to 4 carbon atoms being branched or nonbranched; R8 stands for -CO-C1-4- alkyl or dioxanyl, and at least one of R3 and R4 is different from hydrogen, or to its pharmaceutically acceptable salts where optically active compound can be in the form of one of its separated enantiomers or their mixtures, including racemic mixtures. Additionally, the invention refers to pharmaceutical enzyme PDE4, based on compounds of formula I and II and to their application for producing medical products for enzyme PDE4 inhibition in treatment of various diseases.

EFFECT: compound improvement.

35 cl, 11 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I or its pharmaceutically acceptable salts: , where R1 is phenyl group optionally substituted by substitutes selected out of halogen atom, -O-C1-6-alkyl; or R1 is phenyl condensed with aromatic or non-aromatic 5-7-member ring where the ring can optionally include up to three heteroatoms selected independently out of N, O and S; R2 is hydrogen, -O-C1-6-alkyl, -C1-6-alkyl or halogen atom; R3 is C1-6-alkyl, -(CH2)P-NO2, -(CH2)p-NR4R5, -(CH2)P-CONHOH, -(CH2)p-CN, -(CH2)P-CO2H, -(CH2)p-CO2R4, -(CH2)P-CONR4R5, -(CH2)p-OR4, -(CH2)p-NHCOR4 or -(CH2)p-NHSO2R4; R4 and R5 are independently hydrogen or C1-6-alkyl; p is 0, 1, 2, 3 or 4; X is C1-10-alkylene group; one of A1 and A2 is nitrogen atom, while the other is NR7; and R7 is hydrogen atom or OH-group. Also invention concerns pharmaceutical composition, method of TGF-β and/or activine signal transit route inhibition, method of reduction of excessive exocellular matrix accumulation for mammals, method of tumour cell metastasis inhibition for mammals, method of treatment of cancer neoplasm caused by TGF-β superexpression by TGF-β signal transit route inhibition for mammals, method of disease treatment, and method of thrombosis inhibition for mammals.

EFFECT: new compounds with useful biological properties.

16 cl, 19 ex, 2 tbl, 8 dwg

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: description is given of a piperidine derivative with general formula (I) , where L represents CH or N; M represents CH or N; under the condition that, L and M both do not represent CH; R1 represents phenyl (possibly substituted with a halogen or C1-4alkyl), S(O)2(C1-4alkyl), S(O)2(C1-4fluroalkyl), S(O)2phenyl (possibly substituted with CF3 or OCF3), benzyl, benzoyl (possibly substituted with a halogen) or C(O)NHphenyl (possibly substituted with a halogen); R2 represents phenyl, possibly substituted with a halogen; R3 represents hydrogen or C1-4alkyl; R4 represents methyl or ethyl; R5 represents phenyl-NH, phenyl (C1-2alkyl), phenyl(C1-C2)alkyl-NH or pyridyl(C1-2alkyl). The phenyl can be substituted with a halogen, cyano, C1-4alkyl, C1-4alkoxy, S(O)k(C1-4alkyl) or S(O)2NR8R9; k is equal to 2; R8 and R9 represent hydrogen or its pharmaceutical salts. The compound is a modulator of the activity of the CCR5 receptor. Description is given of the method of obtaining the compound, where L represents N, and the pharmaceutical composition based on a compound with formula (I).

EFFECT: design of a method of obtaining a compound, where L represents N, and a pharmaceutical composition based a compound with formula (I).

7 cl, 7 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns to new diamides of pyrimidine-4,6-dicarboxylic acid of I formula, selective inhibitors of collagenases possessing properties which concern to the metalloproteinase superfamily and the matrix metalloproteinases. The bonds render influence on hyperactivity of the matrix metalloproteinase-13 (MMP-13) and thus do not render influence on MMP-3 and MMP-8. In the formula I R1 means an atom of hydrogen, R2 means - (C1-C6)-alkyl where alkyl is unitary replaced by phenyl where phenyl is replaced 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 identical or different and independently from each other mean i) atom of hydrogen or ii) - (C1-C6)-alkyl or R9 and R10 together with atom of nitrogen to which they are bound, form 5, 6-links the sated cycle, and instead of one or two other atoms of carbon there can be also a heteroatom from an oxygen row, sulphur and nitrogen, and in case of nitrogen atoms of nitrogen independently from each other can be unsubstituted or substituted with (C1-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-SN, 3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10) where R9 and R10 have the specified above value, 4) -(C0-C6)-alkyl-C(O)-N (R8)-(C0-C6)-alkyl-N(R9)-(R10) where R8 means hydrogen, R9 and R10 have the specified above value, 5) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the specified above value, and Het means the sated or nonsaturated monocyclic heterocyclic system with number of links from 3 to 6 which contains in a cycle of 1 or 2 identical or different heteroatoms from a number nitrogen, oxygen and sulphur and unsubstituted or one-, two- or triple independently from each other is replaced by halogen, b) hydroxy,) -(C1-C6)-alkyl, and alkyl is unsubstituted or one-, two- or triple is substituted by halogen, d)=0,e)-Het, R4 and R5 or R5 and R6 together with atom of Carboneum to which they are bound, independently from each other form 5 or 6-unit cycle which is sated and contains one or two heteroatoms from an oxygen row.

EFFECT: obtaining of bonds which can find application for treatment of degenerate diseases of joints, such as osteoarthritis, rheumatic disease.

7 cl, 3 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

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