Aminonicotinic acid and isonicotinic acid derivatives as dhodg (dihydroorotate dehydrogenase) inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) and its pharmaceutically acceptable salts possessing dihydroorotate dehydrogenase inhibitory ability, to a based pharmaceutical composition, to application thereof in preparing a drug compound and to a combined preparation containing the presented compounds and the other active compound (I) in effective amounts wherein both groups G1 mean CRC, G2 mean a nitrogen atom or group CRd, of the groups G3 and G4 mean a nitrogen atom and the other one means group CH, M means a hydrogen atom or a pharmaceutically acceptable cation, while R1, R2, Ra, Rb, Rc and Rd have the values specified in the patent claim.

EFFECT: preparing pharmaceutically acceptable salts possessing dihydroorotate dehydrogenase inhibitory ability.

25 cl, 115 ex, 2 tbl

 

The present invention relates to new inhibitors of dihydroorotatdehydrogenase (DHODH). These compounds are applicable for the treatment, prevention or suppression of diseases and disorders for which it is known that their flow is improved by inhibition of dihydroorotatdehydrogenase, such as autoimmune diseases, immune and inflammatory diseases, inflammatory bone disorders, malignant neoplastic diseases associated with angiogenesis disorders, viral diseases, and infectious diseases.

Enzyme dihydroorotatdehydrogenase (DHODH) is an enzyme that catalyzes the fourth stage of the pathway of biosynthesis of pyrimidine, namely the transformation of dihydroorotate in the orotate, simultaneously with the electron transfer to ubiquinone (cofactor Q) through intermediate playmonopolyonline (Loffler et al. Mol Cell Biochem, 1997). Unlike parasites (Plasmodium falciparum) (McRobert et al. Mol Biochem Parasitol 2002) and bacteria (E. coli, which from the very beginning, use this path as the source of pyrimidines, in mammalian cells, there is an additional way of recycling.

When homeostatic proliferation of a way of life, which does not depend on DHODH, apparently, sufficient to supply the cells of pyrimidine bases. Only cells with an intensive metabolism, and in particular T and b lymphocytes, forced the I in the new pathways for proliferation. In these cells the inhibition DHODH stops the progression of the cell cycle, inhibiting DNA synthesis and thus cell proliferation (Breedveld FC, et al. Ann Rheum Dis 2000).

Therefore, inhibitors DHODH have a favorable immunodepressive and antiproliferative effects in human diseases characterized by abnormal and uncontrolled cell proliferation leading to chronic inflammation and tissue destruction.

In addition to the suppression of lymphocyte proliferation, inhibitors DHODH (i.e. teriflunomide, maritimus (FK778) and breiner) exert anti-inflammatory effects by inhibiting cytokine production and nuclear factor (NF)-kB-way signal transmission, migration of monocytes and increased production of transforming growth factor beta-1 and induces a shift in the differentiation of a subpopulation of T-helper cells type 1 (Th1) and type 2 (Th2) (Manna et al. J Immunol 2000) (Dimitrova et al. J. Immunol 2002). In addition, the differentiation of osteoclasts, RANKL mediated, is attenuated when the inhibition DHODH (Urushibara et al. Arthrititis Rheum 2004)

In experiments on cocrystallization two inhbitors DHODH that clinical studies are conducted, brachyura (D.L. Dexter et al.; Cancer Res. 1985) and teriflunomide (A-1726), it was found that they both contact the same site, which presumably is also the site of binding is of the cofactor ubiquinone (Liu et al.; Struc. Fold. Des. 2000).

Leflunomide sold under the trade name arava (EP 0780128, WO 97/34600), was the first inhibitor DHODH for sale. Leflunomide is a prodrug of teriflunomide, which is the active metabolite, with moderate activity, inhibiting DHODH man (Fox et al., J. Rheumatol. Suppl. 1998).

Leflunomide is an DMARDs (modifying the disease course Antirheumatic drug), produced by the firm Aventis, which has been approved by the FDA (the Administration for quality supervision, food and drug administration) for the treatment of rheumatoid arthritis in 1998 and EMEA (European Agency for the evaluation of medicinal products) for the treatment of psoriatic arthritis in 2004, is now actively expanding the use of Leflunomide for the treatment of systemic lupus erythematosus, Wegener's granulomatosis (Metzler et al.; Rheumatology 2004; 43(3), 315-320) and infection by HIV (human immunodeficiency virus). In addition, teriflunomide, its active metabolite, effective in multiple sclerosis and is currently undergoing phase III clinical studies (O'connor et al Neurology 2006).

There are more data for other related diseases, such as ankylosing spondylitis (Haibel et al.; Ann. Rheum. Dis. 2005), mnogoslovnoe juvenile idiopathic arthritis (Silverman et al.; Arthritis Rheum. 2005) and sarcoidosis (Baughman et al.; Sarcidosis Vasc. Diffuse Lung Dis. 2004). In addition, it is shown that Leflunomide and FK778 have high antiviral activity against cytomegalovirus. Leflunomide is currently used as a secondary drug to combat cytomegalovirus after transplantation authority (John et al. Transplantation 2004). In addition, Leflunomide reduces HIV replication by approximately 75% at concentrations that can be achieved by the introduction of conventional doses (Schlapfer E et al. AIDS 2003)

Due to the physiological effects mediated by inhibition of dihydroorotatdehydrogenase, recently revealed several inhibitors DHODH intended for the treatment or prevention of autoimmune diseases, immune and inflammatory diseases, destructive bone disorders, malignant neoplastic diseases associated with angiogenesis disorders, viral diseases, and infectious diseases. See, for example, WO 06/044741; WO 06/022442; WO 06/001961, WO 04/056747, WO 04/056746, WO 03/006425, WO 02/080897 and WO 99/45926.

Diseases or disorders in which plays the role of inhibition DHODH include, but are not limited to, autoimmune diseases, immune and inflammatory diseases, inflammatory bone disorders, malignant neoplastic diseases associated with angiogenesis disorders, viral diseases, and infectious ill the deposits.

Autoimmune diseases that can be prevented or treated include, but are not limited to, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondylitis, Wegener's granulomatosis, mnogoslovnoe juvenile idiopathic arthritis, inflammatory bowel disease such as ulcerative colitis and Crohn's disease, Reiter syndrome, fibromyalgia, and diabetes type 1.

Immune and inflammatory diseases that can be prevented or treated include, but are not limited to, asthma, COPD (chronic obstructive pulmonary disease), respiratory distress syndrome, acute or chronic pancreatitis, graft versus host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis, allergic rhinitis, allergic conjunctivitis syndrome behceta, inflammatory condition of the eye such as conjunctivitis and uveitis.

Inflammatory disorders of the bone, which can be prevented or treated include, but are not limited to, osteoporosis, osteoarthritis and associated with multiple myeloma violation of bones.

Malignant neoplastic diseases that can be prevented or treated include, but are not limited to, cancer of the prostate gland is, ovarian and breast cancer.

Associated with angiogenesis disorders that can be prevented or treated include, but are not limited to, hemangioma, neovascularization of the blood vessels of the eye, macular degeneration and diabetic retinopathy.

Viral diseases that can be prevented or treated include, but are not limited to, infection by HIV, hepatitis and cytomegalovirus infection.

Infectious diseases that can be prevented or treated include, but are not limited to, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, shigellosis, and infection with other protozoa, such as malaria.

According to the invention it was found that some amino(ISO)derivatives of nicotinic acid are new active inhibitors DHODH and therefore can be used to treat or prevent these diseases.

Other objects of the present invention is a method of obtaining such compounds; pharmaceutical compositions comprising an effective amount of these compounds; the use of the compounds for the preparation of medicines intended for the treatment of pathological conditions or diseases, the occurrence of which is improved by inhibit the processes DHODH, where a pathological condition or disease is selected from the group comprising rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus, psoriasis and sarcoidosis, and methods of treatment of pathological conditions or diseases, the occurrence of which is improved by inhibition DHODH, where the pathological condition or disease is selected from the group comprising rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus, psoriasis and sarcoidosis, including the introduction of compounds proposed in the present invention, to a subject in need of treatment.

Thus, the present invention relates to new amino(ISO)derivative of nicotinic acid of formula (I)

in which:

- one of the groups G1denotes the nitrogen atom or the group CRcand the other denotes the group of CRc

- G2denotes the nitrogen atom or the group CRd

- R1denotes a group selected from the group comprising hydrogen atoms, halogen atoms, With1-C4is an alkyl group, which optionally may contain 1, 2 or 3 substituent selected from the group comprising halogen atoms and hydroxy-group, and C3-C8-clausilia group, which optionally may contain 1, 2 or 3 substituent selected from the group comprising halogen atoms and hydroxy-group

- R2denotes a group selected from the group comprising hydrogen atoms, halogen atoms, hydroxy-group, With1-C4is an alkyl group, which optionally may contain 1, 2 or 3 substituent selected from the group comprising halogen atoms and hydroxy-group, With1-C4-alkoxygroup, which may not necessarily contain 1, 2 or 3 substituent selected from the group comprising halogen atoms and hydroxy-group, and C3-C8-cycloalkyl group, which optionally may contain 1, 2 or 3 substituent selected from the group comprising halogen atoms and hydroxy-group

- Ra, Rband Rcindependently denote a group selected from the group comprising hydrogen atoms, halogen atoms, With1-C4is an alkyl group, which optionally may contain 1, 2 or 3 substituent selected from the group comprising halogen atoms and hydroxy-group, and C1-C4-alkoxygroup, which may not necessarily contain 1, 2 or 3 substituent selected from the group comprising halogen atoms and hydroxy-group

- Rddenotes a group selected from the group comprising hydrogen atoms, halogen atoms, hydroxy-group, With1 -C4is an alkyl group, which optionally may contain 1, 2 or 3 substituent selected from the group comprising halogen atoms and hydroxy-group, and C1-C4-alkoxygroup, which may not necessarily contain 1, 2 or 3 substituent selected from the group comprising halogen atoms and hydroxy-group, and C3-C8-cycloalkanes, which may not necessarily contain 1, 2 or 3 substituent selected from the group comprising halogen atoms and hydroxy-group

- one of the groups G3and G4denotes a nitrogen atom and the other denotes the group of SN,

M denotes a hydrogen atom or a pharmaceutically acceptable cation, provided that if at least one of the groups Raand Rbdenotes a hydrogen atom and G2refers to a group of CRd, Rddenotes a group selected from the group comprising From1-C4-alkoxygroup, which may not necessarily contain 1, 2 or 3 substituent selected from the group comprising halogen atoms and hydroxy-group, With3-C8-cycloalkanes, which may not necessarily contain 1, 2 or 3 substituent selected from the group comprising halogen atoms and hydroxy-group;

and their pharmaceutically acceptable salts and N-oxides.

When used in the present invention, the term alkyl includes neobyazatelnostyu linear or branched hydrocarbon radicals, containing from 1 to 4 carbon atoms. Preferred substituents of alkyl groups are halogen atoms and hydroxy-group and more preferably halogen atoms.

Examples include methyl, ethyl, n-sawn, ISO-propyl, n-boutigny, second-botilony and tert-botilony radicals.

When used in the present invention, the term alkoxygroup includes optionally substituted linear or branched containing oxygraph radicals containing from 1 to 4 carbon atoms. Preferred substituents of alkoxygroup are halogen atoms and hydroxy-group and more preferably halogen atoms.

Examples include metaxylene, amoxilina, n-propoxyphenyl, isopropoxy, n-butoxyphenyl, second-butoxyphenyl and tert-butoxyl radicals.

When used in the present invention, the term cycloalkyl includes saturated carbocyclic radicals and, unless otherwise stated, cycloalkenyl radical generally contains from 3 to 8 carbon atoms.

Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. If cycloalkenyl radical contains 2 or more substituents, then the substituents may be the same or different. Preferred substituents cycloalkyl groups are halogen atoms and hydroxy-group and more pre is respectfully - the halogen atoms.

When used in the present invention, the term cycloalkanes includes saturated containing oxygraph carbocyclic radicals and, unless otherwise stated, cycloalkenyl radical generally contains from 3 to 8 carbon atoms.

Examples include cyclopropylacetylene, cyclobutylamine, cyclopentylamine, cyclohexylamine and cycloheptylamine radicals. If cycloalkenyl radical contains 2 or more substituents, then the substituents may be the same or different. Preferred substituents of cycloalkyl are halogen atoms and hydroxy-group and more preferably halogen atoms.

When used in the present invention, some of the atoms, radicals, fragments, chains, or cycles, in the structures proposed in the present invention are optionally substituted". This means that these atoms, radicals, fragments, chains or cycles can be unsubstituted or substituted in any position by one or more, e.g. 1, 2, 3 or 4 substituents, so that the hydrogen atoms associated with the unsubstituted atoms, radicals, fragments, chains, or cycles, replaced by a chemically acceptable atoms, radicals, fragments, chains or cycles. If it contains 2 or more C is mustiala, all substituents may be the same or different.

When used in the present invention, the term halogen atom means the atoms of chlorine, fluorine, bromine or iodine, is usually a fluorine atom, chlorine or bromine, most preferably bromine or fluorine. The term halogen when used as a prefix has the same value.

M may denote a hydrogen atom or a pharmaceutically acceptable cation. If M denotes a pharmaceutically acceptable cation, the connection, vpisivaushiesya formula (I), the alternative can be described by the following formula (I*).

When used in the present invention, the term pharmaceutically acceptable cation includes inorganic cations, such as cations of alkali metals (Li+, Na+, K+), cations of alkaline earth metals (CA2+, Mg2+) and other pharmaceutically acceptable inorganic cations known in the art (Zn2+, Al3+), and organic cations, for example, ammonium ion (i.e. NH4+) and substituted ammonium ions such as NH3R1+, NH2(R1)2+, NH(R1)3+and N(R1)4+in which each R1independently selected from the group comprising phenyl group, benzyl group, With1-C4-lkyl and C 3-C8-cycloalkyl.

Examples of some suitable substituted ammonium ions are EtNH3+Et2NH2+Et3NH+, (C6H11)2NH2+CH3CH2CH2CH2NH3+, PhCH2NH3+and (Ph)(PhCH2)NH2+. More typical of the Quaternary ammonium ion is

N(CH3)4+.

Usually M denotes a hydrogen atom or a pharmaceutically acceptable cation selected from the group comprising Li+, Na+, K+Ca2+and Mg2+. Preferably, if M denotes a hydrogen atom or a pharmaceutically acceptable cation selected from the group comprising Li+, Na+and+. More preferably, if M denotes a hydrogen atom or Li+and most preferably, if M denotes a hydrogen atom.

If M in the formula (I) refers to a pharmaceutically acceptable cation having a charge greater than +1, to ensure the electroneutrality of the compounds of additional anions. Protivoiona may be the anion X-, as defined below, or anion, specified above in formula (I*).

When used in the present invention, the term pharmaceutically acceptable salt include salts with pharmaceutically acceptable acid or base Pharmaceutically acceptable acids include both inorganic acids, for example, hydrochloric, sulfuric, phosphoric, diphosphorous, Hydrobromic, yodiewonderdog and nitric acid, and organic acids such as citric, fumaric, maleic, malic, almond, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methansulfonate, econsultancy, benzosulfimide, cyclohexylsulfamate (ciclamino) or p-toluensulfonate acid. Pharmaceutically acceptable bases include hydroxides of an alkali metal (e.g. sodium or potassium) and alkaline earth metal (e.g. calcium or magnesium) and organic bases, for example, alkylamines followed, arylalkylamine and heterocyclic amines.

Other preferred salts in the context of the present invention are Quaternary ammonium compounds, in which the equivalent of the anion (X-) is associated with the positive charge of the atom N. X - may be an anion of various inorganic acids, such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate, or the anion of an organic acid, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, triptorelin, methanesulfonate and p-toluensulfonate. X - is preferably an anion selected from the group comprising chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate and Triforce is at. More preferably, if the X - denotes chloride, bromide, triptorelin or methanesulfonate.

When used in the present invention the N-oxide forms of the basic tertiary amine or imine groups contained in the molecule, using a conventional oxidizing reagent.

In one embodiment of the present invention R1selected from the group comprising hydrogen atoms, bromine and fluorine, methyl, ethyl, cyclopropyl and cyclobutyl.

In another embodiment, the present invention G3denotes the nitrogen atom, and G4denotes a CH group.

In yet another embodiment, the present invention G3refers to a group CH and G4denotes a nitrogen atom.

In yet another embodiment of the present invention, both groups G1denote the group of CRc.

In another embodiment, the present invention each Rcindependently selected from the group comprising hydrogen atoms, fluorine atoms, chlorine atoms, and C1-C3is an alkyl group.

In yet another embodiment of the present invention, the group G2refers to a group of CRd.

In yet another embodiment, the present invention Rdselected from the group comprising hydroxy-group, C1-C3-alkoxygroup, 2,2,2-triptracker and C3-C4-cyclea is maxigrip. Preferably - C1-C3-alkoxygroup, 2,2,2-triptracker and C3-C4-cycloalkanes.

In another embodiment, the present invention Raselected from the group comprising fluorine atoms, methyl groups and cryptometer.

In yet another embodiment, the present invention Rbselected from the group comprising hydrogen atoms, fluorine atoms and chlorine atoms.

In yet another embodiment, the present invention R2selected from the group comprising hydrogen atoms and halogen atoms, preferably hydrogen atoms and fluorine atoms.

In a preferred embodiment of the present invention, both groups G1denote the group C(Rc), G2refers to the group C(Rd), preferably, if G2denotes a group selected from the group comprising C(OH), C(OMe) and C(OEt); Radenotes a fluorine atom, Rbselected from the group comprising hydrogen atoms and fluorine atoms, and R1selected from the group comprising hydrogen atoms, bromine and fluorine, methyl, ethyl and cyclopropyl group. Preferably, if both G1denote the group CH, G2denotes a group selected from the group comprising C(OMe) and C(OEt); Radenotes a fluorine atom, Rbselected from the group comprising hydrogen atoms and fluorine atoms, and R1/sup> selected from the group comprising hydrogen atoms, bromine and fluorine, methyl, ethyl and cyclopropyl group.

In a preferred embodiment of the present invention, Rcdenotes a hydrogen atom, Rddenotes a hydroxy-group or C1-C3-alkoxygroup and R2denotes a hydrogen atom, preferably, if Rcdenotes a hydrogen atom, Rdrepresents C1-C3-alkoxygroup and R2denotes a hydrogen atom.

Especially preferred are compounds in which G3denotes the nitrogen atom, G4refers to a group CH and Rbdenotes a fluorine atom, and compounds in which G3refers to a group of SN, G4denotes a nitrogen atom.

In a preferred embodiment of the present invention, both groups G1denote the group C(Rc), G2refers to the group C(Rd), Radenotes a fluorine atom, Rbselected from the group comprising hydrogen atoms and fluorine atoms, and R1selected from the group comprising hydrogen atoms, bromine and fluorine, methyl, ethyl and cyclopropyl group, Preferably, if Rcdenotes a hydrogen atom, Rdselected from the group comprising C1-C3-alkoxygroup and C3-C4-cycloalkanes, and R2denotes a hydrogen atom. Especially preferred is entrusted are compounds in which G3denotes the nitrogen atom, G4refers to a group CH and Rbdenotes a fluorine atom, and compounds in which G3refers to a group of SN, G4denotes a nitrogen atom.

Preferred individual compounds are proposed in the present invention include the following:

2-(3-Fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid

2-(3'-Ethoxy-3-forbiden-4-ylamino)nicotinic acid

2-(3-Fluoro-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(3'-Ethoxy-3-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(3'-Methoxy-3-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(2,5-Debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

2-(3'-Ethoxy-2,5-diferuloyl-4-ylamino)nicotinic acid

2-(2',3-Debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

2-(2-Methyl-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(3-Chloro-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(3-Chloro-3'-ethoxymethyl-4-ylamino)nicotinic acid

2-(3-Methyl-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(3-Chloro-3'-methoxybiphenyl-4-ylamino)nicotinic acid

2-(3'-(Deformedarse)-3-forbiden-4-ylamino)nicotinic acid

2-(3'-CYCLOBUTANE-3-forbiden-4-ylamino)nicotinic acid

2-(3-Fluoro-3'-(2,2,2-triptoreline)biphenyl-4-and what amino)nicotinic acid

2-(3'-CYCLOBUTANE-3,5-diferuloyl-4-ylamino)nicotinic acid

2-(3,5-Debtor-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(3'-Ethoxy-3,5-diferuloyl-4-ylamino)nicotinic acid

2-(3,5-Debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

3-(3'-Ethoxy-3-forbiden-4-ylamino)isocyanate lithium

3-(3-Fluoro-3'-methoxybiphenyl-4-ylamino)isocyanate lithium

3-(3'-Methoxy-3-(triptoreline)biphenyl-4-ylamino)isocyanate lithium

3-(3-Fluoro-3'-(triptoreline)biphenyl-4-ylamino)isocyanate lithium

2-(3'-Ethoxymethyl-4-ylamino)nicotinic acid

2-(5-fluoro-2-methyl-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(2',3-Debtor-5'-isopropoxyphenyl-4-ylamino)nicotinic acid

2-(3-Fluoro-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid

2-(3,5-Debtor-3'-hydroxybiphenyl-4-ylamino)nicotinic acid

5-Bromo-2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid

5-Bromo-2-(3,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

5-Bromo-2-(3-fluoro-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(3-Fluoro-3'-(triptoreline)biphenyl-4-ylamino)-5-methylnicotinic acid

5-Cyclopropyl-2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid

2-(3,5-Debtor-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid

2-(3'-Ethoxy-5-fluoro-2-methylbiphenyl-4-ylamino)nikodinov the I acid

2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid

2-(3'-Ethoxy-3,5-diferuloyl-4-ylamino)-5-methylnicotinic acid

5-Cyclopropyl-2-(3'-ethoxy-3,5-diferuloyl-4-ylamino)nicotinic acid

2-(3,5-Debtor-3'-methoxybiphenyl-4-ylamino)-5-etilnikotinata acid

5-Bromo-2-(3'-ethoxy-2,5-diferuloyl-4-ylamino)nicotinic acid

5-Cyclopropyl-2-(3'-ethoxy-2,5-diferuloyl-4-ylamino)nicotinic acid

2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)-5-methylnicotinic acid

5-Cyclopropyl-2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid

2-(2',3,5-Cryptor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

2-(2'-Chloro-3,5-diferuloyl-4-ylamino)nicotinic acid

2-(3'-Cyclopropane-3,5-diferuloyl-4-ylamino)nicotinic acid

2-(3,5-Debtor-2-methylbiphenyl-4-ylamino)nicotinic acid

5-Cyclopropyl-2-(2,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

2-(3'-Cyclopropane-3,5-diferuloyl-4-ylamino)-5-cyclopropylamino acid

5-Chloro-2-(3,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

5-Cyclopropyl-2-(3,5-debtor-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(2,3,5-Cryptor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

2-(2'-Chloro-3,5-diferuloyl-4-ylamino)-5-cyclopropylamino acid

2-(3,5-Debtor-3'-methoxy-2-meth is biphenyl-4-ylamino)nicotinic acid

2-(3,5-Debtor-2-methyl-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(2'-Chloro-3,5-debtor-2-methylbiphenyl-4-ylamino)nicotinic acid

5-Chloro-2-(3,5-diferuloyl-4-ylamino)nicotinic acid

5-Chloro-2-(2'-chloro-3,5-diferuloyl-4-ylamino)nicotinic acid

2-(2,3,5,6-Titrator-3'-methoxybiphenyl-4-ylamino)nicotinic acid

2-(3,5-Debtor-2'-methylbiphenyl-4-ylamino)nicotinic acid

3-(3'-Cyclopropane-3-forbiden-4-ylamino)isonicotinate acid

Of particular interest are:

2-(3'-Ethoxy-3-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(3'-Methoxy-3-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(3'-Ethoxy-3,5-diferuloyl-4-ylamino)nicotinic acid

2-(3,5-Debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

3-(3'-Ethoxy-3-forbiden-4-ylamino)isocyanate lithium

3-(3-Fluoro-3'-methoxybiphenyl-4-ylamino)isocyanate lithium

3-(3'-Methoxy-3-(triptoreline)biphenyl-4-ylamino)isocyanate lithium

2-(3-Fluoro-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid

5-Bromo-2-(3,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

5-Cyclopropyl-2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid

2-(3,5-Debtor-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid

2-(3,5-Debtor-3'-methoxybiphenyl-4-ylamino)-5-etilnikotinata acid

2-(2'-Chloro-3,5-ditto is biphenyl-4-ylamino)nicotinic acid

2-(3'-Cyclopropane-3,5-diferuloyl-4-ylamino)nicotinic acid

2-(3,5-Debtor-2-methylbiphenyl-4-ylamino)nicotinic acid

5-Cyclopropyl-2-(2,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

5-Cyclopropyl-2-(3,5-debtor-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

2-(2'-Chloro-3,5-diferuloyl-4-ylamino)-5-cyclopropylamino acid

2-(2,3,5,6-Titrator-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Compounds of General formula (I) can be obtained according to the synthesis scheme shown in figure 1.

1

Compounds of General formula (Ia) (a derivative of nicotinic acid) can be obtained by the reaction of these intermediates (II) with the appropriate chloronicotinic acid (III) in acidic media, such as acetic acid as solvent or acetic acid or p-toluensulfonate acid with a high-boiling solvent, such as water, xylene, ethoxyethanol, DME (dimethyl ether) or DMF (dimethylformamide)at a temperature of from 100 to 160°C. These compounds can also be obtained in alkaline environments, such as DBU (1,8-diazabicylo[5.4.0]undec-7-Yong), DIEA (diisopropylethylamine) or Cs2CO3in high boiling solvent such as xylene, ethoxyethanol, DMF or NMP (N-organic).

Compounds of General formula (Ib), (derivatives of isonicotinic acid which can be obtained by saponification of the corresponding methyl ester (V) base such as lithium hydroxide or sodium hydroxide, solvent, miscible with water, such as ethanol or methanol, at temperatures from 0 to 50°C To produce the corresponding salt.

The compounds of formula (V) can be obtained by the reaction of a combination of ballarino (II) with the appropriate methylchlorosilanes (IV). These reactions can be catalysed palladium catalyst such as Tris(dibenzylideneacetone)-dipalladium(0), with a ligand, such as 9,9-dimethyl-4,5-bis(diphenylphosphino)-N-Xanten, and in the presence of an inorganic base such as cesium carbonate in an inert solvent, such as toluene, dioxane or dimethylformamide, at a temperature from 80°C to the boiling point of the solvent.

Ballarini formula (II) can be obtained according to the synthesis scheme shown in figure 2.

2

Bromo derivatives of formula (VI) is injected into the reaction mix with an appropriate aryl of formula (VII) under the conditions of the Suzuki reaction (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457), where G5means boranova acid or boronate or reaction conditions, the Steele, where G5indicates stannane. These reactions can be catalysed palladium catalyst, such as complex [1,1'-bis(diphenylphosphino)-ferrocene] dichloropalladium(II) with dichloromethane (1:1), tetrakis(triphenylphosphine)-palladium(0), bis(triphenyl spin)palladium(II)chloride or Tris(dibenzylideneacetone)-dipalladium(0) in an aprotic organic solvent, such as dioxane, toluene, DMF or DME, and in the presence of a base such as cesium carbonate, sodium carbonate, potassium carbonate or potassium phosphate at a temperature of from 80 to 140°C.

In the particular case when Raand Rbboth do not represent hydrogen, the compounds of formula (Ia) can be obtained according to the synthesis scheme shown in figure 3.

3

The compounds of formula (Ia) can be obtained from 2-(4-brompheniramine)nicotinic acids of formula (IX) and the appropriate aryl of formula (VII) under the conditions of the Suzuki reaction (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457), where G5means boranova acid or boronate, or when the conditions of the reaction, the Steele, where G5indicates standby.

2-(4-Brompheniramine)nicotinic acid of formula (IX) can be obtained by the reaction of bromoaniline formula (VIII) with a suitable chloronicotinic acid (III) in acidic media, such as acetic acid as a solvent with a high boiling point solvent, such as xylene, ethoxyethanol or DMF, at a temperature of from 100 to 160°C. Alternatively, the reaction can be done in alkaline environments, such as DBU, DIEA or Cs2CO3in the high-boiling solvent such as xylene, ethoxyethanol, DMF or NMP.

In the particular case when G2denotes CRdand Rddenotes a hydroxy-group, the compounds of formula (Ia2) is available on CX is IU synthesis, shown in figure 4.

4

The reaction of nicotinic acid of formula (XII) with meteorous reagent, such as dimethylsulfate, with an inorganic base, such as sodium bicarbonate, in a solvent such as acetone, at a temperature of from 0 the boiling point of the solvent gives methylnicotinate formula (XI).

The reaction methylnicotinate formula (XI) with an alkylating reagent of formula (XIII), in which Rdis the same as defined above, in the present invention, and X denotes useplease group such as chlorine atom or bromine, carried out by standard methods, gives compounds of formula (X).

In addition, the hydrolysis of methylnicotinate formula (X) with a base such as lithium hydroxide or sodium hydroxide, in proton solvent such as methanol or ethanol, at temperatures from 0 to 50°C, gives the desired compounds of formula (Ia2).

In the particular case when R1stands With1-C4is an alkyl group or3-C8-cycloalkyl group, the compounds of formula (Ia3) can be obtained according to the synthesis schemes shown in figure 5 and 6.

5

The reaction bromonicotinic acids of the formula (XV) with the corresponding alkylboronic acid, boronate or stannane formula (XIV) under the conditions of the Suzuki reaction (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457), G 5means boranova acid or boronate, or when the conditions of the reaction, the Steele, where G5indicates stannane, gives the desired compounds of General formula (Ia3).

6

The reaction of metilprednisolone formula (XVII) with the corresponding alkylboronic acid, boronate or stannane formula (XIV) under the conditions of the Suzuki reaction (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457), where G5means boranova acid or boronate, or when the conditions of the reaction, the Steele, where G5indicates stannane, gives compounds of General formula (XVI). Hydrolysis of the obtained nicotinate formula (XVI) with a base such as lithium hydroxide or sodium hydroxide, in proton solvent such as methanol or ethanol, at temperatures from 0 to 50°C, gives derivatives of nicotinic acid of formula (IV). In addition, the compounds of formula (Ia3) can be obtained by the reaction of these nicotinic acid of formula (IV) with the appropriate aniline formula (II) in acidic environments, such as acetic acid as a solvent with high boiling solvent such as xylene, ethoxyethanol or DMF, at a temperature of from 100 to 160°C. Alternatively, the reaction can be done in alkaline environments, such as DBU, DIEA or Cs2CO3in high boiling solvent such as xylene, ethoxyethanol, DMF or NMP.

The syntheses of compounds propose the m invention, and intermediates used for the synthesis illustrated by the following examples (1 to 62), including examples of the synthesis of the intermediate products from 1 to 51), which in no way limit the scope of the present invention.

The spectra of nuclear magnetic resonance1H (1H NMR) was filmed spectrometer Varian Mercury 200. Mass spectra of low-resolution (ICSD) (m/z) shot on the mass spectrometer Micromass ZMD using ionization elektrorazpredelenie (EEC). Chromatographic separation was performed using Waters 2690 equipped with a column Symmetry C18 (2,1×10 mm, 3.5 µm). The mobile phase consisted of formic acid (0.4 ml), ammonia (0.1 ml), methanol (500 ml) and acetonitrile (500 ml) (b) and formic acid (0,46 ml), ammonia (0,115 ml) and water (1000 ml) (A): first, with the 0% phase b for 0.5 min, then 0% to 95% phase b for 6.5 minutes and then for 1 min 95% phase Century. While re-establishing equilibrium between the two injectionem was 1 min. flow Rate was 0.4 ml/min Injection volume was 5 µl. Chromatogram using diode lattice was obtained at 210 nm.

EXAMPLES SYNTHESIS

The INTERMEDIATE PRODUCT 1

3'-Ethoxy-3-forbiden-4-amine

To a solution of 4-bromo-2-foronline (3.2 g, 17,05 mmole), 2M K2CO3(24 ml, 48,00 mmol), Pd(PPh3)4(1.2 g, of 1.02 mmole) in toluene (120 ml) is tmosphere argon was added dropwise a solution of 3-ethoxyphenylacetic acid (4,25 g, 25,61 mmole) in 31 ml of the Meon. The mixture was heated at 80°C overnight and then cooled to room temperature. Added ethyl acetate and the mixture was twice washed with an aqueous solution To a2CO3. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated in vacuum. The obtained residue was purified using flash chromatography elwira with hexane/AcOEt (from 10/1 to 8/1). The obtained solid was recrystallized from hexane and received of 3.78 g of the desired compound as a white solid. Yield = 72%

MCHP: m/z 232 (M+1)+.

Retention time: 6,44 min

1H NMR (250 MHz, CDCl3) δ ppm million: 1,4 (t, J=6.9 Hz, 3H); to 4.1 (q, J=6.9 Hz, 2H); to 6.8 (m, 2H); and 7.1 (m, 2H); 7,2-7,3 (m, 3H).

The INTERMEDIATE PRODUCT 2

3-Fluoro-3'-(triptoreline)biphenyl-4-amine

Received (54%) of 4-bromo-2-foronline and 3-(triptoreline)phenylboronic acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 272 (M+1)+.

Retention time: for 6.81 min

1H NMR (250 MHz, CDCl3) δ ppm million: to 6.8 (m, 1H); to 7.2 (m, 3H); to 7.4 (m, 3H).

The INTERMEDIATE PRODUCT 3

3'-Ethoxy-3-(triptoreline)biphenyl-4-amine

Received (40%) of 4-bromo-2-(triptoreline)aniline and 3-ethoxyphenylacetic acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 98 (M+1) +.

Retention time: min? 7.04 baby mortality

1H NMR (200 MHz, CDCl3) δ ppm million: 1,4 (t, J=7.0 Hz, 3H); 3.9 to (s, 2H); to 4.1 (q, J=7,0 Hz, 2H); to 6.8 (m, 2H); and 7.1 (m, 2H); and 7.3 (m, 3H)

The INTERMEDIATE PRODUCT 4

3-Fluoro-3'-methoxybiphenyl-4-amine

Received (35%) of 4-bromo-2-foronline and 3-methoxyphenylacetic acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 218 (M+1)+.

1H NMR (250 MHz, CDCl3) δ ppm million, a 3.9 (s, 3H); to 6.8 (m, 2H); and 7.1 (m, 2H), and 7.3 (m, 3H)

The INTERMEDIATE PRODUCT 5

3'-Methoxy-3-(triptoreline)biphenyl-4-amine

Received (56%) of 4-bromo-2-(triptoreline)aniline and 3-methoxyphenylacetic acid according to the experimental procedure described for intermediate product 1.

MCHP: m/z 284 (M+1)+.

1H NMR (250 MHz, CDCl3) δ ppm million: of 3.8 (s, 3H); to 6.8 (m, 2H); 7,0 (m, 1H); and 7.1 (m, 1H); 7.3 to 7.4 (m, 3H).

The INTERMEDIATE PRODUCT 6

2.5-Debtor-3'-methoxybiphenyl-4-amine

Was obtained (84%) of 4-bromo-2,5-diptiranjan and 3-methoxyphenylacetic acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 236 (M+1)+.

Retention time: 6,20 min

The INTERMEDIATE PRODUCT 7

3'-Ethoxy-2,5-diferuloyl-4-amine

Received (66%) of 4-bromo-2,5-diptiranjan and 3-ethoxyphenylacetic acid according to the experimental procedure described for intermediate goods is 1.

ICSD: m/z 250 (M+1)+.

Retention time: 6,58 min

The INTERMEDIATE PRODUCT 8

2',3-Debtor-3'-methoxybiphenyl-4-amine

Received (54%) of 4-bromo-2-foronline and 2-fluoro-3-methoxyphenylacetic acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 236 (M+1)+.

Retention time: 5,93 min

1H NMR (200 MHz, CDCl3) δ ppm million: of 3.8 (s, 2H); from 3.9 (s, 3H); to 6.9 (m, 3H); and 7.1 (m, 3H).

The INTERMEDIATE PRODUCT 9

2-Methyl-3'-(triptoreline)biphenyl-4-amine

Received (86%) of 4-bromo-3-methylaniline and 3-(triptoreline)phenylboronic acid according to the experimental procedure described for intermediate product 1.

MCHP: m/z 268 (M+1)+.

Retention time: 6,54 min

1H NMR (200 MHz, CDCl3) δ ppm million: 2,2 (s, 3H); 3,7 (s, 2H); and 6.6 (m, 2H); 7,0 (d, J=8,2 Hz, 1H); to 7.2 (m, 3H); to 7.4 (m, 1H).

The INTERMEDIATE PRODUCT 10

3-Chloro-3'-(triptoreline)biphenyl-4-amine

Received (78%) of 4-bromo-2-Chloroaniline and 3-(triptoreline)phenylboronic acid according to the experimental procedure described for intermediate product 1.

MCHP: m/z 288 (M+1)+.

Retention time: 7,12 min

1H NMR (200 MHz, DMSO (dimethyl sulfoxide)-D6) δ ppm million: 5,6 (s, 2H); 6,9 (d, J=8.6 Hz, 1H); to 7.2 (m, J=8,2 Hz, 1H); 7.5 (a m, 5H).

The INTERMEDIATE PRODUCT 11

3-Chloro-3'-ethoxymethyl-4-amine

Received (79%) of 4-bromo-2-Chloroaniline and 3-e is oxyphenylbutazone acid on experimental methodology, described for intermediate product 1.

MCHP: m/z 248 (M+1)+.

Retention time: 6,75 min

1H NMR (200 MHz, DMSO-D6) δ ppm million: 1,3 (t, J=7.0 Hz, 3H); to 4.1 (q, J=7,0 Hz, 2H), and 5.5 (s, 2H) to 6.8 (m, 2H); and 7.1 (m, 2H); and 7.3 (t, J=7.8 Hz, 1H); 7,4 (dd, J=8,4, and 2.1 Hz, 1H); 7.5 (a, d, J=2.3 Hz, 1H).

The INTERMEDIATE PRODUCT 12

3'-Ethoxymethyl-4-amine

Was obtained (91%) of 4-bromoaniline and 3-ethoxyphenylacetic acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 214 (M+1)+.

Retention time: 5,73 min

1H NMR (200 MHz, CDCl3) δ ppm million: 1,4 (t, J=7.0 Hz, 3H); 3,7 (s, 2H); to 4.1 (q, J=7,0 Hz, 2H); to 6.8 (m, 3H); and 7.1 (m, 2H); to 7.4 (m, 3H).

The INTERMEDIATE PRODUCT 13

3-Methyl-3'-(triptoreline)biphenyl-4-amine

Received (83%) of 4-bromo-2-methylaniline and 3-(triptoreline)phenylboronic acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 268 (M+1)+.

Retention time: 6,82 min

1H NMR (200 MHz, CDCl3) δ ppm million: 2,2 (s, 3H); 3,7 (s, 2H); 6,7 (d, J=9.0 Hz, 1H); and 7.1 (m, J=7.8 Hz, 1H); to 7.4 (m, 5H).

The INTERMEDIATE PRODUCT 14

3-Chloro-3'-methoxybiphenyl-4-amine

Received (87%) of 4-bromo-2-Chloroaniline and 3-methoxyphenylacetic acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 234 (M+1)+.

Retention time: 6,44 min

1H NMR (200 MHz, CDCl3

The INTERMEDIATE PRODUCT 15

3'-(Deformedarse)-3-forbiden-4-amine

Received (76%) of 4-bromo-2-foronline and 2-(3-(deformedarse)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane on the experimental procedure described for intermediate product 1.

ICSD: m/z 254 (M+1)+.

Retention time: 6,24 min

1H NMR (200 MHz, CDCl3) δ ppm million, a 3.9 (s, 2H); 6,5 (t, J=73,8 Hz, 1H); to 6.8 (m, 1H), and 7.1 (m, 1H); and 7.3 (m, 3H); to 7.4 (m, 2H).

The INTERMEDIATE PRODUCT 16

Methyl-2-(3-fluoro-3'-hydroxybiphenyl-4-ylamino)nicotinate

To a mixture of 2-(3-fluoro-3'-hydroxybiphenyl-4-ylamino)nicotinic acid (1 g, is 3.08 mmole) and NaHCO3(0.5 g, 6,17 mmole) in acetone (20 ml) was added dropwise dimethylsulfate (0,47 g, 3,70 mmole). The mixture was heated under reflux overnight and then concentrated. To the crude substance was added ethyl acetate and the mixture washed twice with 4% solution of NaHCO3and brine. Then the organic phase was dried over MgSO4and concentrated in vacuum and received 0.4 g of beige solid, sufficiently pure for use in the next stage of the synthesis. Yield = 36%

MCHP: m/z 339 (M+1)+.

Retention time: 7,02 min

The INTERMEDIATE PRODUCT 17

Methyl-2-(3,5-debtor-3'-hydroxybiphenyl-4-ylamino)nicotinate

Received (52%) of 2-(3,5-debtor-3'-hydroxybiphenyl-4-ylamino)nicotinic sour the s on experimental methodology, described for intermediate product 16.

MCHP: m/z 357 (M+1)+.

Retention time: 6,26 min

The INTERMEDIATE PRODUCT 18

Methyl-2-(3-fluoro-3'-(2,2,2-triptoreline)biphenyl-4-ylamino)nicotinate

A mixture of intermediate 16 (0.36 g, of 1.06 mmole), 2-bromo-1,1,1-triptorelin (0.26 g, 1.6 mmole) and potassium carbonate (0,29 g, 2.13 mmole) in DMF was stirred under nitrogen atmosphere at 120°C during the night. Added water and the mixture was extracted with EtOAc (2×). The combined organic phase was washed with water and brine, dried over MgSO4and concentrated in vacuum. Purification using column chromatography (10% EtOAc in hexano) gave the desired compound as a yellow solid. Yield = 27%

MCHP: m/z 421 (M+1)+.

Retention time: 7,73 min

The INTERMEDIATE PRODUCT 19

Methyl-2-(3'-CYCLOBUTANE-3-forbiden-4-ylamino)nicotinate

Was obtained (48%) of the intermediate product 16 and bromocyclobutane on the experimental procedure described for intermediate product 18.

MCHP: m/z 393 (M+1)+.

Retention time: 8,08 min

The INTERMEDIATE PRODUCT 20

Methyl-2-(3'-CYCLOBUTANE-3,5-diferuloyl-4-ylamino)nicotinate

Received (26%) of the intermediate product 17 and bromocyclobutane on the experimental procedure described for intermediate product 18.

ICSD: m/z 411 (M+1)+.

Time to keep the project: 7,53 min

The INTERMEDIATE PRODUCT 21

2-(4-Bromo-2,6-dipertanyakan)nicotinic acid

A mixture of 2-chloronicotinic acid (1.6 g, 10,15 mmole) and 4-bromo-2,6-diferencia (3,24 g, 15,58 mmole) in acetic acid (40 ml) was heated in an argon atmosphere at 130°C during the night. The mixture was cooled to room temperature and obtained precipitate. The mixture was filtered and the solid was washed with acetic acid and was obtained 2-hydroxynicotinic acid (by-product). The filtrate was partially concentrated and received a second precipitate solids, which corresponded to N-(4-bromo-2,6-differenl)ndimethylacetamide (second by-product). In conclusion, the filtrate was concentrated to dryness and received 3,14 g of the desired compound in the form of a solid substance containing a number of ndimethylacetamide, but the resulting mixture was used in the next stage of the synthesis.

ICSD: m/z 329, 331 (M+1)+.

Retention time: 6,09 min

The INTERMEDIATE PRODUCT 22

Methyl-3-(3'-ethoxy-3-forbiden-4-ylamino)isonicotinate

A mixture of methyl-3-chlorisondamine (1,00 g of 5.83 mmole), intermediate 1 (1.35 g, of 5.83 mmole), Cs2CO3(2.66 g, 8,16 mmole) and Xantphos (0,68 g at 1.17 mmole) in dioxane (20 ml) was stirred in an argon atmosphere for 10 minutes Then added Pd2(dba)3(0,53 g of 0.58 mmole) and the mixture was stirred in argon atmosphere at 120°C during the night. The reaction mixture Phil is trevali through celite and washed with CH 2Cl2. The filtrate was concentrated and was purified by column chromatography, elwira a mixture of EtOAc/hexane/et 3 n (20/79/1), and received the desired connection. Yield = 51%

ICSD: m/z 367 (M+1)+.

1H NMR (250 MHz, CDCl3) δ ppm million: 9,26 (s, 1H); of 8.8 (s, 1H); of 8.25 (d, J=5.3 Hz, 1H); 7,87 (d, J=5.3 Hz, 1H); 7,72 was 7.45 (m, 4H); and 7.3 (d, J=8,2 Hz, 1H); 7,26 (s, 1H); 7,05 (dd, J=8,2, J=1.8 Hz, 1H); 4.25 in (s, J=7 Hz, 2H); 4,12 (s, 3H); to 1.61 (t, J=7 Hz, 3H).

The INTERMEDIATE PRODUCT 23

Methyl-3-(3-fluoro-3'-methoxybiphenyl-4-ylamino)isonicotinate

Received (57%) of methyl-3-chlorisondamine and the intermediate product 4 experimental the procedure described for intermediate product 22.

MCHP: m/z 353 (M+1)+.

1H NMR (250 MHz, CDCl3) δ ppm million: 9,11 (s, 1H); 8,65 (s, 1H); 8,1 (d, J=4.9 Hz, 1H); 7,72 (d, J=5,2 Hz, 1H); 7,58-7,27 (m, 4H); 7,16 (d, J=7,4 Hz, 1H); 7,1 (t, J=1.7 Hz, 1H); 6,9 (dd, J=8,2, J=2.5 Hz, 1H); of 3.96 (s, 3H); a 3.87 (s, 3H).

The INTERMEDIATE PRODUCT 24

Methyl-3-(3'-methoxy-3-(triptoreline)biphenyl-4-ylamino)isonicotinate

Received (76%) of methyl-3-chlorisondamine and intermediate product 5 to the experimental procedure described for intermediate product 22.

MCHP: m/z 419 (M+1)+.

1H NMR (250 MHz, CDCl3) δ ppm million: 9,44 (s, 1H); of 8.95 (s, 1H); 8.3 (the d, J=5,2 Hz, 1H); 7,9 (d, J=4.9 Hz, 1H); 7,72 (m, 3H); 7,53 (m, 1H); to 7.32 (d, J=8,2 Hz, 1H); 7,27 (m, 1H); 7,07 (d, J=9 Hz. 1H); 4,12 (s, 3H); is 4.03 (s, 3H).

The INTERMEDIATE PRODUCT 25

Methyl-3-(3-fluoro-3'-(triptoreline)biphenyl-4-ylamino)is isonicotinate

Received (92%) of methyl-3-chlorisondamine and intermediate 2 experimental the procedure described for intermediate product 22.

ICSD: m/z 407 (M+1)+.

1H NMR (250 MHz, CDCl3) δ ppm million: 8,98 (s, 1H); and 8.5 (s, 1H); to 7.95 (d, J=4.9 Hz, 1H), 7,58 (d, J=4.9 Hz, 1H); 7,46-to 7.15 (m, 6H); 7,06 (m, 1H); 3,81 (s, 3H).

The INTERMEDIATE PRODUCT 26

3'-Ethoxy-5-fluoro-2-methylbiphenyl-4-amine

Received (80%) of 4-bromo-2-fluoro-5-methylaniline and 3-ethoxyphenylacetic acid according to the experimental procedure described for intermediate product 1.

MCHP: m/z 246 (M+1)+.

Retention time: 6,36 min

1H NMR (200 MHz, CDCl3) δ ppm million: 1,4 (t, J=6.8 Hz, 3H); 2,2 (s, 3H); 3,7 (s, 2H); to 4.1 (q, J=7,0 Hz, 2H); 6,7 (d, J=9.0 Hz, 1H); to 6.9 (m, 4H); and 7.3 (m, 1H)

The INTERMEDIATE PRODUCT 27

5-fluoro-2-methyl-3'-(triptoreline)biphenyl-4-amine

Received (92%) of 4-bromo-2-fluoro-5-methylaniline and 3-(triptoreline)phenylboronic acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 286 (M+1)+.

Retention time: of 6.96 min

1H NMR (200 MHz, CDCl3) δ ppm million: 2,2 (s, 3H); 3,7 (s, 2H); 6,7 (d, J=9.0 Hz, 1H), 6,9 (d, J=11.7 Hz, 1H); to 7.2 (m, 3H); to 7.4 (m, 1H).

INTERMEDIATE 28

2',3-Debtor-5'-isopropoxyphenyl-4-amine

Was obtained (95%) of 4-bromo-2-foronline and 2-fluoro-5-isopropoxyaniline acid on experimental the procedure described for p. the receipt of the intermediate product 1.

ICSD: m/z 264 (M+1)+.

Retention time: 6,67 min

1H NMR (200 MHz, CDCl3) δ ppm million: 1,3 (d, J=6.2 Hz, 6N); and 3.8 (s, 2H); 4.5 m (m, 1H); to 6.8 (m, 3H); 7,0 (m, 1H); to 7.2 (m, 2H).

INTERMEDIATE 29

3,5-Debtor-3'-methoxybiphenyl-4-amine

Was obtained (91%) of 4-bromo-2,6-diptiranjan and 3-methoxyphenylacetic acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 236 (M+1)+.

Retention time: 6,34 min

1H NMR (200 MHz, CDCl3) δ ppm million: of 3.8 (s, 2H); from 3.9 (s, 3H); to 6.9 (m, 1H); and 7.1 (m, 4H); and 7.3 (t, J=8.0 Hz, 1H)

The INTERMEDIATE PRODUCT 30

5-fluoro-3'-methoxy-2-methylbiphenyl-4-amine

Received (80%) of 4-bromo-2-fluoro-5-methylaniline and 3-methoxyphenylacetic acid according to the experimental procedure described for intermediate product 1.

MCHP: m/z 232 (M+1)+.

Retention time: min 6,00

1H NMR (200 MHz, DMSO-D6) δ ppm million: 2,1 (s, 3H); 3,7 (s, 3H); to 5.1 (s, 2H); 6,6 (d, J=9.4 Hz, 1H); to 6.8 (m, 4H); and 7.3 (t, J=7.8 Hz, 1H)

The INTERMEDIATE PRODUCT 31

Methyl 2-chloro-5-methylnicotinate

To a solution of methyl 5-bromo-2-chloronicotinate (1,05 g, 4.19 mmole), K3PO4(2,95 g, 13,90 mmole), methylboronic acid (0.32 g, 5,26 mmole) and tricyclohexylphosphine (0.11 g, of 0.39 mmole) in a mixture of toluene/water (16 ml/0.8 ml) in an argon atmosphere was added Pd(OAc)2(0.04 g, of 0.18 mmole). The mixture was heated in an argon atmosphere at 100°C during the night. Then reacciona the mixture was cooled to room temperature and concentrated in vacuum. To the residue was added ethyl acetate and this organic layer was washed with water, brine, dried over MgSO4was filtered and the solvent evaporated in vacuum and obtained the desired product as a yellow oil. Yield = 87%

MCHP: m/z 186 (M+1)+.

Retention time: 4,84 min

The INTERMEDIATE PRODUCT 32

2-Chloro-5-methylnicotinic acid

The intermediate product 31 (0,38 g, is 1.81 mmole) was dissolved in Meon (2 ml) was added 2 n NaOH solution (1,81 ml, 3,62 mmole) and the mixture was stirred at room temperature for 2 hours the Reaction mixture was concentrated to dryness and the residue was re-dissolved in a mixture of EtOAc/water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuum and obtained the desired product as a white solid. Yield = 94%

MCHP: m/z 172 (M+1)+.

Retention time: 3,25 min

1H NMR (200 MHz, DMSO-D6) δ ppm million: 2,2 (s, 3H); 7,6 (d, J=2,53 Hz, 1H); 8.0 a (d, J=2,53 Hz, 1H)

The INTERMEDIATE PRODUCT 33

Methyl-2-(3'-(cyclopropylmethoxy)for 3,5-diferuloyl-4-ylamino)nicotinate

Received (83%) of intermediate 17 and bromocyclobutane on the experimental procedure described for intermediate product 18.

MCHP: m/z 411 (M+1)+.

Retention time: of 7.48 min

The INTERMEDIATE PRODUCT 34

5-Bromo-2-(3'-ethoxy-3,5-diferuloyl-4-ylamino)nicotinic acid

A mixture of 5-bromo-2-giornico inovas acid (1.42 g, 6,01 mmole), intermediate 21 (1.0 g, 4,01 mmole) and p-toluensulfonate acid (0.5 g, 2,42 mmole) in water (10 ml) was heated in an argon atmosphere at 110°C over night. The reaction mixture was cooled to room temperature and obtained precipitate. The precipitate was filtered off, washed with hot water and then cold Meon. In conclusion, the solid is washed with diisopropyl ether and dried in a vacuum Cabinet. Yield = 63%.

ICSD: m/z 449, 451 (M+1)+.

Retention time: 7,52 min

INTERMEDIATE 35

5-Bromo-2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid

Received (73%) of intermediate product 30 and 5-bromo-2-chloronicotinic acid according to the experimental procedure described for intermediate product 34.

ICSD: m/z 431,433 (M+1)+.

Retention time: 7,98 min

The INTERMEDIATE PRODUCT 36

1-Bromo-3-cyclopropanemethanol

A mixture of 3-bromophenol (2.4 g, 13.9 mmole), bromocyclopropane (6,66 ml, 83 mmole) and potassium carbonate (9.6 g, 69,5 mmole) in DMF (16 ml) was heated in a microwave oven at 180°C for 8 h, the Reaction mixture was diluted with a mixture of diethyl ether and water. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and evaporated. Got the oil, 2,87 g with a purity of 81%. This intermediate product used in the next stage.

Time is of derivare: 6,91 minutes

INTERMEDIATE 37

2-(3-Cyclopropanecarbonyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

A mixture of intermediate 36 (2,87 g of 10.9 mmole), bis(pinacolato)Debora (4,16 g, and 16.4 mmole) and potassium acetate (3.2 g, 32.7 mmole) in anhydrous dioxane was stirred in an argon atmosphere and then was added PdCl2dppf.CH2Cl2(0.5 g, 0.55 mmole). The reaction mixture was heated at 100°C for 3 h and Then the crude product was filtered through celite, washed with dioxane and evaporated under reduced pressure. The obtained residue was purified by chromatography with reversed phase, elwira water and a mixture of AcN/MeOH (1/1) in gradient mode (AcN/MeOH(1/1) 0 to 100%). The desired product was obtained as a yellow oil. Yield = 55%.

MCHP: m/z 261 (M+1)+.

Retention time: 7.23 percent min

The INTERMEDIATE PRODUCT 38

3,5-Debtor-2-methylbiphenyl-4-amine

Received (92%) of 4-bromo-2,6-debtor-3-methylaniline and phenylboronic acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 220 (M+1)+.

Retention time: 6.73 x min

INTERMEDIATE 39

5-Bromo-2-(2,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (78%) of intermediate 6 and 5-bromo-2-chloronicotinic acid according to the experimental procedure described for intermediate product 34.

MCHP: m/z 433,435 (M+1)+.

the time of retention: to 7.77 min

The INTERMEDIATE PRODUCT 40

Methyl 2-chloro-5-cyclopropylamino

Received (99%) of methyl 5-bromo-2-chloronicotinate cyclopropylboronic acid according to the experimental procedure described for intermediate product 31.

MCHP: m/z 212 (M+1)+.

Retention time: 5,46 min

INTERMEDIATE 41

2-Chloro-5-cyclopropylamino acid

Received (65%) of intermediate product 40 from the experimental procedure described for intermediate product 32.

MCHP: m/z 198 (M+1)+.

Retention time: 4,29 min

The INTERMEDIATE PRODUCT 42

2-(4-Bromo-2,6-dipertanyakan)-5-cyclopropylamino acid

Received (65%) of intermediate 41 and 4-bromo-2,6-diferencia on the experimental procedure described for intermediate product 34.

MCHP: m/z 369,371 (M+1)+.

Retention time: 7,06 min

INTERMEDIATE 43

2,3,5-Cryptor-3'-methoxybiphenyl-4-amine

Received (60%) of 4-bromo-2,3,6-triptorelin and 3-methoxyphenylacetic acid according to the experimental procedure described for intermediate product 1.

MCHP: m/z 254 (M+1)+.

Retention time: 6,45 min

The INTERMEDIATE PRODUCT 44

4-Bromo-2,6-debtor-3-methylaniline

To a solution of 2,6-debtor-3-methylaniline (5 g, is 34.9 mmole) in acetic acid (50 ml) at 55°C was added dropwise a solution of bromine(1.97 ml, of 38.4 mmole) in acetic acid (10 ml). The reaction mixture was stirred for 1 h and then poured into a mixture of water/ice. The solid was filtered, washed with water and dried in a vacuum Cabinet. Received 6.3 g of a black solid (Yield = 81%).

Retention time: 6,28 min

INTERMEDIATE 45

2-(4-Bromo-2,6-debtor-3-methylphenylamine)nicotinic acid

Received (46%) from intermediate 44 and 2-chloronicotinic acid according to the experimental procedure described for intermediate product 34.

ICSD: m/z 343,345 (M+1)+.

Retention time: 6,50 min

INTERMEDIATE 46

2-(4-Bromo-2,6-dipertanyakan)-5-chloronicotinic acid

Received (36%) of 4-bromo-2,6-diptiranjan and 2.5-dichloronicotinic acid according to the experimental procedure described for intermediate product 34.

ICSD: m/z 363,365 (M+1)+.

Retention time: 7,09 min

INTERMEDIATE 47

2,3,5,6-Titrator-3'-methoxybiphenyl-4-amine

Was obtained (91%) of 4-bromo-2,3,5,6-tetrafluoroaniline and 3-methoxyphenylacetic acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 272 (M+1)+.

Retention time: of 6.49 min

INTERMEDIATE 48

Methyl-3-(2-forgenerating)isonicotinate

Received (34%) of methyl-3-chlorisondamine and 2-foronline EC on the pilot methodology, described for intermediate product 22.

ICSD: m/z 247 (M+1)+.

INTERMEDIATE 49

Methyl-3-(4-bromo-2-forgenerating)isonicotinate

Received (90%) of intermediate 48 experimental the procedure described for intermediate product 44.

ICSD: m/z 323,325 (M+1)+.

1H NMR (250 MHz, CDCl3) δ ppm million, a 3.9 (s, 3H); to 7.3 (m, 3H), and 7.7 (d, J=7.5 Hz, 1H); 8,1 (d, J=7.5 Hz, 1H); and 8.5 (s, 1H); and 9.0 (s, 1H).

The INTERMEDIATE PRODUCT 50

Methyl-3-(2'-chloro-3-forbiden-4-ylamino)isonicotinate

Received (29%) of intermediate 49 and 2-Chlorfenvinphos acid according to the experimental procedure described for intermediate product 1.

ICSD: m/z 357 (M+1)+.

The INTERMEDIATE PRODUCT 51

Methyl-3-(3'-cyclopropane-3-forbiden-4-ylamino)isonicotinate

Received (56%) of the intermediate product 50 and 2-(3-cyclopropanecarbonyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane on the experimental procedure described for intermediate product 1.

ICSD: m/z 379 (M+1)+

Retention time: 7,44 min

EXAMPLES SYNTHESIS

EXAMPLE 1

2-(3-Fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid

A mixture of 2-chloronicotinic acid (a 4.86 g, 30,89 mmole) and intermediate 4 (10,06 g, 46,34 mmole) in acetic acid (160 ml) was heated in an argon atmosphere at 130°C during the night. The reaction mixture which was gladly to room temperature and obtained precipitate. The obtained yellow solid was filtered, washed with acetic acid and diethyl ether and dried in a vacuum Cabinet. Yield = 65%.

1H NMR (200 MHz, CD3OD) δ ppm million, a 3.9 (s, 3H); 7,0 (m, 1H); 7,21 (m, 3H); 7,41 (t, 1H), 7,71 (m, 3H); 8,15 (dd, J=6,05, to 1.76 Hz, 1H); 8,83 (dd, J=to 7.61, to 1.76 Hz, 1H).

ICSD: m/z 339 (M+1)+.

Retention time: 7,09 min

EXAMPLE 2

2-(3'-Ethoxy-3-forbiden-4-ylamino)nicotinic acid

Received (43%) of 2-chloronicotinic acid and intermediate product 1 according to the experimental procedure described for obtaining compounds of example 1.

1H NMR (400 MHz, DMSO-D6) δ ppm million: 1,4 (t, J=6.9 Hz, 3H); to 4.1 (q, J=6.9 Hz, 2H); 6,9 (d, J=8,3 Hz, 1H); 7,0 (m, 1H); 7,2 (d, J=1.7 Hz, 1H); and 7.3 (d, J=7.8 Hz, 1H); 7,4 (t, J=7.8 Hz, 1H); 7.5 (a, d, J=8,3 Hz, 1H), and 7.7 (d, J=12,8 Hz, 1H); to 8.3 (m, 1H); and-8.5 (m, 1H); 8,7 (t, J=8,8 Hz, 1H); to 10.8 (s, 1H)

MCHP: m/z 353 (M+1)+.

Retention time: 7,39 min

EXAMPLE 3

2-(3-Fluoro-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

Received (37%) of intermediate 2 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, DMSO-d6) δ ppm million: 7,0 (dd, J=7,8, a 4.7 Hz, 1H); 7,4 (d, J=8,2 Hz, 1H), and 7.7 (m, 5H); 8,3 (dd, J=7,8, 2.0 Hz, 1H); 8,5 (dd, J=4,7, 2.0 Hz, 1H); 8,8 (t, J=8,8 Hz, 1H); 10,8 (d, J=3.1 Hz, 1H)

MCHP: m/z 393 (M+1)+.

Retention time: 7,63 min

EXAMPLE 4

2-(3'-Ethoxy-3-(triptoreline)biphenyl-4-ylamino)nicotinic sour is and

Received (18%) from intermediate 3 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, DMSO-d6) δ ppm million: 1,4 (t, J=7.0 Hz, 3H); to 4.1 (q, J=7,0 Hz, 2H); 7,0 (m, 2H); and 7.3 (m, 3H), and 7.7 (m, 2H); to 8.3 (m, 1H); and-8.5 (m, 1H); 8,9 (d, J=8.6 Hz, 1H); and 11.2 (s, 1H).

MCHP: m/z 417 (M-1)-.

Retention time: the 7.65 min

EXAMPLE 5

2-(3'-Methoxy-3-(triptoreline)biphenyl-4-ylamino)nicotinic acid

Received (14%) of intermediate 5 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

MCHP: m/z 405 (M-1)+.

Retention time: 7,44 min

EXAMPLE 6

2-(2,5-Debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (12%) of intermediate 6 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, DMSO-D6) δ ppm million: of 3.8 (s, 3H); 7,0 (m, 4H); 7,4 (t, J=8.0 Hz, 1H); 7,6 (dd, J=12,1, 7,4 Hz, 1H); 8.3 (the dd, J=7,8, 2.0 Hz, 1H); 8,5 (dd, J=4,7, 2.0 Hz, 1H); 8,7 (dd, J=13,7, 7,0 Hz, 1H); 11.0 in (s, 1H).

MCHP: m/z 357 (M+1)+.

Retention time: 7,35 min

EXAMPLE 7

2-(3'-Ethoxy-2,5-diferuloyl-4-ylamino)nicotinic acid

Received (36%) of intermediate 7 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz,DMSO-D 6) δ ppm million: 1,4 (t, J=6.9 Hz, 3H); to 4.1 (q, J=6.9 Hz, 2H); 7,0 (m, 4H); 7,4 (t, J=7.8 Hz, 1H); 7,6 (dd, J=12,3, 7.2 Hz, 1H); 8.3 (the dd, J=7,4, 2.0 Hz, 1H); 8,5 (dd, J=5,1, 2.0 Hz, 1H); 8,7 (dd, J=13,7, 7,0 Hz, 1H); 11,0 (s, 1H).

MCHP: m/z 371 (M+1)+.

Retention time: 7,51 min

EXAMPLE 8

2-(2',3-Debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (31%) of the intermediate product 8 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, DMSO-D6): δ ppm million to 3.9 (s, 3H); and 7.1 (m, 4H); to 7.4 (m, 2H); 8,3 (dd, J=7,8, 2.0 Hz, 1H); 8,5 (dd, J=4,9, 1.8 Hz, 1H); 8,7 (t, J=8,8 Hz, 1H); 10,8 (d, J=2.7 Hz, 1H).

MCHP: m/z 357 (M+1)+.

Retention time: min? 7.04 baby mortality

EXAMPLE 9

2-(2-Methyl-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

Was obtained (61%) of intermediate 9 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, CDCl3): δ ppm million to 2.3 (s, 3H); 6.8 cm (dd, J=7,8, a 4.7 Hz, 1H); to 7.2 (m, 4H) 7,5 (m, 3H); and 8.4 (m, 2H); 10,0 (s, 1H)

MCHP: m/z 389 (M+1)+.

Retention time: 7,51 min

EXAMPLE 10

2-(3-Chloro-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

Received (44%) of the intermediate product 10 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, CDCl3): δ ppm million to 6.9 (dd, J=7,8, 5,1 Hz, 1H); and 7.3 (m, 2H); 7,5 (m, 3H), and 7.7 (d =2.0 Hz, 1H); and 8.4 (dd, J=7,8, 2.0 Hz, 1H); 8,5 (dd, J=4,7, 2.0 Hz, 1H); 8,8 (d, J=8.6 Hz, 1H); to 10.6 (s, 1H).

MCHP: m/z 409 (M+1)+.

Retention time: 7,74 min

EXAMPLE 11

2-(3-Chloro-3'-ethoxymethyl-4-ylamino)nicotinic acid

Was obtained (48%) of intermediate 11 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, CDCl3): δ ppm million to 1.5 (t, J=6,9,0 Hz, 3H); to 4.1 (q, J=6.9 Hz, 2H); to 6.9 (m, 2H); and 7.1 (m, 2H); and 7.3 (t, J=7.8 Hz, 1H); 7.5 (a dd, J=8,6, 2.0 Hz, 1H), and 7.7 (d, J=2.3 Hz, 1H); and 8.4 (dd, J=7,8, and 2.3 Hz, 1H); 8,5 (dd, J=4,7, 2,0 Hz, 1H); 8,7 (d, J=9.0 Hz, 1H); to 10.5 (s, 1H)

MCHP: m/z 369 (M+1)+.

Retention time: EUR 7.57 min

EXAMPLE 12

2-(3-Methyl-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

Received (41%) of intermediate 13 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, CDCl3): δ ppm million to 2.4 (s, 3H); to 6.8 (m, J=7,8, a 4.7 Hz, 1H); to 7.2 (m, J=1.6 Hz, 1H); and 7.3 (m, 1H); 7.5 (a m, 4H); 8,2 (d, J=9.4 Hz, 1H); 8.3 (the dd, J=7,8, 2.0 Hz, 1H); and 8.4 (dd, J=4,7, 2.0 Hz, 1H); 10.0 g (s, 1H).

MCHP: m/z 389 (M+1)+.

Retention time: the 7.62 min

EXAMPLE 13

2-(3-Chloro-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (36%) of intermediate product 14 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, CDCl3): δ ppm million to 3.9 (s, 3H); to 6.9 (m, 2H); and 7.1 (m, 2H);to 7.4 (m, 1H); 7.5 (a dd, J=8,6, and 2.3 Hz, 1H), and 7.7 (d, J=2.0 Hz, 1H); and 8.4 (dd, J=7,8, 2.0 Hz, 1H); 8,5 (dd, J=4,9, and 2.1 Hz, 1H); 8,7 (d, J=8.6 Hz, 1H); to 10.5 (s, 1H).

ICSD: m/z 355 (M+1)+.

Retention time: 7,53 min

EXAMPLE 14

2-(3'-(Deformedarse)-3-forbiden-4-ylamino)nicotinic acid

Received (10%) of intermediate 15 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, DMSO-D6): δ ppm million of 7.0 (dd, J=7,6, the 4.7 Hz, 1H); 7,2 (d, J=7.8 Hz, 1H); and 7.3 (t, J=74,1 Hz, 1H); to 7.6 (m, 5H); 8,3 (dd, J=7,8, 2.0 Hz, 1H); 8,5 (dd, J=4,7, 2.0 Hz, 1H); 8,7 (t, J=8,8 Hz, 1H); 10,9 (s, 1H).

ICSD: m/z 375 (M+1)+.

Retention time: 7,43 min

EXAMPLE 15

2-(3'-CYCLOBUTANE-3-forbiden-4-ylamino)nicotinic acid

The intermediate product 19 (0.28 g, to 0.63 mmole) was dissolved in Meon (10 ml) was added 2 n NaOH solution (2 ml). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and was purified by column chromatography with reversed phase and obtained the desired compound as a yellow solid. Yield = 12%

MCHP: m/z 379 (M+1)+.

Retention time: 7.68 per min

1H NMR (200 MHz, CD3OD): δ ppm million to 1.8 (m, 2H); 2,1 (m, 2H); 2,5 (m, 2H); 4.7 in (m, 1H); to 6.8 (m, 2H); to 7.2 (m, 5H); and 8.4 (m, J=7.8 Hz, 2H); 8,6 (t, J=8,4 Hz, 1H)

EXAMPLE 16

2-(3-Fluoro-3'-(2,2,2-triptoreline)biphenyl-4-ylamino)nicotinic acid.

Received (57%) of intermediate product 18 to judge the pilot methodology, described to obtain the compound of example 15.

MCHP: m/z 407 (M+1)+.

Retention time: of 7.36 min

1H NMR (200 MHz, CD3OD): δ ppm million to 4.5 (q, J=8.6 Hz, 2H); to 6.8 (m, 2H); and 7.3 (m, 5H); to 8.3 (m, 2H); 8,6 (t, J=8,8 Hz, 1H).

EXAMPLE 17

2-(3'-CYCLOBUTANE-3,5-diferuloyl-4-ylamino)nicotinic acid

Received (55%) of intermediate product 20 according to the experimental procedure described for obtaining compounds of example 15.

MCHP: m/z 397 (M+1)+.

Retention time: 6,87 min

1H NMR (200 MHz, DMSO-D6): δ ppm million to 1.8 (m, 2H); 2,1 (m, 2H); 2,5 (m, 2H)and 4.9 (m, 1H); 6,9 (t, J=6.4 Hz, 2H); to 7.2 (s, 1H); to 7.4 (m, 2H); 7,6 (d, J=9.4 Hz, 2H); 8,3 (d, J=4.3 Hz, 2H); of 9.7 (s, 1H)

EXAMPLE 18

2-(3,5-Debtor-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

To a mixture of intermediate 21 (0.2 g, and 0.61 mmole), 3-(triptoreline)phenylboronic acid (0,19 g of 0.91 mmole), potassium carbonate (0.17 g, to 1.21 mmole) in 11 ml of a mixture of dioxane/water (10/1) in an argon atmosphere was added Pd(PPh3)4(0.25 g, 0.22 mmole). The mixture was heated under reflux overnight, then filtered through celite and washed with ethyl acetate. The organic phase is twice washed with water, washed with brine, dried over magnesium sulfate, filtered and evaporated in a vacuum and got the oil. This crude substance was purified by means of preparative HPLC (high performance liquid chromatography) and received 60 mg of the desired soybean is inane in the form of a white solid. Yield = 24%

1H NMR (200 MHz, DMSO-D6): δ ppm million to 6.9 (m, 1H); to 7.4 (m, 1H); to 7.6 (m, 3H); 7,8 (m, 2H); or 8.2 (m, 2H)

MCHP: m/z 409 (M-1)-.

Retention time: 7,27 minutes

EXAMPLE 19

2-(3'-Ethoxy-3,5-diferuloyl-4-ylamino)nicotinic acid

Received (28%) of intermediate product 21 and 3-ethoxyphenylacetic acid on experimental the procedure described for obtaining compounds of example 18.

1H NMR (200 MHz, DMSO-D6): δ ppm million to 1.4 (t, J=6.9 Hz, 3H); to 4.1 (q, J=6.9 Hz, 2H); 6,9 (dd, J=7,8, a 4.7 Hz, 1H); 7,0 (m, 1H); to 7.4 (m, 5H); or 8.2 (m, 2H); and 9.5 (s, 1H).

MCHP: m/z 371 (M+1)+.

Retention time: 6,91 min

EXAMPLE 20

2-(3,5-Debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (31%) from intermediate 29 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, DMSO-D6) δ ppm million: of 3.8 (s, 3H); 6,9 (dd, J=7,8, a 4.7 Hz, 1H); 7,0 (m, 1H); to 7.4 (m, 3H); 7,5 (m, 2H); or 8.2 (m, 2H); and 9.5 (s, 1H); to 13.6 (s, 1H)

MCHP: m/z 357 (M+1)+.

Retention time: 6,79 min

EXAMPLE 21

3-(3'-Ethoxy-3-forbiden-4-ylamino)isonicotinate lithium

To a solution of intermediate 22 (0.12 g, of 0.33 mmole) in THF (tetrahydrofuran) (4 ml) at 0°C was added 0,M aqueous LiOH solution (0.02 g, of 0.39 mmole) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was purified by column chromatography, elwira mixture Meon/the HMM (dichloromethane) (from 30 to 50%), and got the desired product as a white solid. Yield = 76%.

1H NMR (250 MHz, DMSO-D6) δ ppm million to 1.2 (t, 3H); to 4.1 (q, 2H); to 6.9 (m, 1H); to 7.2 (m, 2H); to 7.4 (t, 1H); to 7.6 (m, 3H); 7,8 (d, 1H); 8.0 a (d, 1H); and 8.6 (s, 1H); and 11.2 (bs, 1H).

MCHP: m/z 353 (M+1)+.

Retention time: 5,95 min

EXAMPLE 22

3-(3-Fluoro-3'-methoxybiphenyl-4-ylamino)isonicotinate lithium

Received (80%) of intermediate 23 to the experimental procedure described for obtaining the compound of example 21.

1H NMR (250 MHz, DMSO-D6) δ ppm million: 3.8 (s, 3H); to 6.9 (m, 1H); and 7.3 (m, 3H); 7,5 (m, 3H);7,8 (d, J=6,5 Hz, 1H); 8.0 a (d, J=6,5 Hz, 1H) 8,5 (s, 1H); to 11.1 (bs, 1H).

MCHP: m/z 339 (M+1)+.

Retention time: 5,43 min

EXAMPLE 23

3-(3'-Methoxy-3-(triptoreline)biphenyl-4-ylamino)isonicotinate lithium

Received (70%) of intermediate product 24 to the experimental procedure described for obtaining the compound of example 21.

1H NMR (250 MHz, DMSO-D6): δ ppm million to 3.8 (s, 3H); to 6.9 (m, 1H); to 7.2 (m, 2H); to 7.4 (t, 1H), and 7.7 (m, 3H); 7,8 (d, 1H); 8.0 a (d, 1H); and 8.6 (s, 1H); to 11.4 (bs, 1H).

MCHP: m/z 405 (M+1)+.

Retention time: 6,26 min

EXAMPLE 24

3-(3-Fluoro-3'-(triptoreline)biphenyl-4-ylamino)isonicotinate lithium

Received (39%) of intermediate product 25 from the experimental procedure described for obtaining the compound of example 21.

1H NMR (250 MHz, DMSO-D6) δ ppm million: to 7.3 (m, 1H), and 7.7 (m, 7H); 8,0 (m, 1H); and 8.6 (s, 1H); 10,9 (bs, 1H).

ICSD: m/z 393 (M+1)+.

Retention time: 6,53 min

EXAMPLE 25

2-(3'-Ethoxymethyl-4-ylamino)nicotinic acid

Received (25%) of the intermediate product 12 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, CDCl3) δ ppm million: 1,5 (t, J=7.0 Hz, 3H); to 4.1 (q, J=7,0 Hz, 2H); to 6.8 (m, 1H); to 6.9 (m, 1H); to 7.2 (m, 2H); and 7.3 (m, 1H); 7,6 (d, J=8,8 Hz, 2H); 7,8 (d, J=8,8 Hz, 2H); 8,3 (dd, J=7,8, 2.0 Hz, 1H); 8,5 (dd, J=4,7, 2.0 Hz, 1H); from 10.1 (s, 1H).

ICSD: m/z 335 (M+1)+.

Retention time: 6,97 min

EXAMPLE 26

2-(5-fluoro-2-methyl-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

Received (42%) of intermediate product 27 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, DMSO-D6): δ ppm million to 2.3 (s, 3H); 7,0 (dd, J=7,8, a 4.7 Hz, 1H); 7,2 (d, J=12.1 Hz, 1H); to 7.4 (m, J=1.0 Hz, 3H); 7,6 (d, J=9.0 Hz, 1H); 8.3 (the dd, J=7,4, 2.0 Hz, 1H); and-8.5 (m, 2H); 10,7 (d, J=2.7 Hz, 1H).

ICSD: m/z 407 (M+1)+.

Retention time: 7,63 min

EXAMPLE 27

2-(2',3-Debtor-5'-isopropoxyphenyl-4-ylamino)nicotinic acid

Received (57%) of intermediate 28 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

1H NMR (200 MHz, DMSO-D6): δ ppm million to 1.3 (d, J=6.2 Hz, 6H); 4,7 (m, 1H); 7,0 (m, 3H); to 7.2 (m, 1H); 7.5 (a m, 2H); 8,3 (dd, J=7,8, 2.0 Hz, 1H); 8,5 (dd, J=4,7, 2.0 Hz, 1H); 8,7 (t, J=8,8 Hz, 1H); 10,9 (d, J=2.7 Hz, 1H).

+.

Retention time: 7,51 min

EXAMPLE 28

2-(3-Fluoro-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid

Received (13%) from intermediate 4 and intermediate product 32 from the experimental procedure described for obtaining compounds of example 1.

MCHP: m/z 353 (M+1)+.

Retention time: min 7,00

1H NMR (200 MHz, CD3OD): δ ppm million to 2.2 (s, 3H); and 3.8 (s, 3H); to 6.8 (m, J=8,2, 2.3 Hz, 1H); and 7.1 (m, 2H); and 7.3 (m, 3H); 8,1 (m, 2H); 8,5 (t, J=8.6 Hz, 1H).

EXAMPLE 29

2-(3,5-Debtor-3'-hydroxybiphenyl-4-ylamino)nicotinic acid

Received (46%) of intermediate product 21 and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol according to the experimental procedure described for obtaining compounds of example 18.

MCHP: m/z 343 (M+1)+.

Retention time: 5,71 min

1H NMR (200 MHz, DMSO-d6): δ ppm million to 6.8 (dd, J=7,6, a 4.9 Hz, 2H); and 7.1 (m, 2H); and 7.3 (t, J=7.8 Hz, 1H); 7,4 (d, J=9.4 Hz, 2H); or 8.2 (m, 2H); to 10.2 (s, 1H)

EXAMPLE 30

5-Bromo-2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (34%) of intermediate 4 and 5-bromo-2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

ICSD: m/z 417-419 (M+1)+.

Retention time: 7,71 min

EXAMPLE 31

5-Bromo-2-(3,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (13%) from intermediate 29 and 5-bromo-2-chloronicotinic acid poeksperymentujmy method described to obtain the compound of example 1.

ICSD: m/z 435-437 (M+1)+.

Retention time: 6,93 min

1H NMR (200 MHz, DMSO-D6): δ ppm million to 3.8 (s, 3H); 7,0 (m, 1H); to 7.4 (m, 3H) and 7.6 (d, J=9.8 Hz, 2H); 8,3 (d, J=2.7 Hz, 1H); and 8.4 (d, J=2.3 Hz, 1H); from 9.6 (s, 1H).

EXAMPLE 32

5-Bromo-2-(3-fluoro-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

Received (27%) of intermediate 2 and 5-bromo-2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

ICSD: m/z 471-473 (M+1)+.

Retention time: 8,04 min

EXAMPLE 33

2-(3-Fluoro-3'-(triptoreline)biphenyl-4-ylamino)-5-methylnicotinic acid

To a solution of compound of example 32 (0.1 g, of 0.21 mmole), K3PO4(204 mg, 0.96 mmole), methylboronic acid (20 mg, of 0.33 mmole) and tricyclohexylphosphine (14 mg, 0.04 mmole) in a mixture of toluene/water (2 ml/0.1 ml) in an argon atmosphere was added Pd(OAc)2(5 mg, 0.02 mmole). The mixture was heated at 100°C overnight and then cooled to room temperature. The reaction mixture was concentrated and the residue was re-dissolved in ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the solvent evaporated in vacuum. The obtained residue was purified by chromatography with reversed phase, elwira with a mixture of water and AcN/MeOH(1/1) in gradient mode (AcN/MeOH(1/1) from 0 to 70%). Search PR the product was obtained as a yellow solid. Yield = 28%.

ICSD: m/z 407 (M+1)+.

Retention time: 7,80 min

1H NMR (200 MHz, CD3OD): δ ppm million to 2.2 (s, 3H); 7,1 (d, J=7.5 Hz, 1H); 7.5 (a m, 5H); 8,1 (d, J=11,4 Hz, 2H); 8,6 (t, J=8,4 Hz, 1H).

EXAMPLE 34

5-Cyclopropyl-2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (10%) from the compound of example 30 and cyclopropylboronic acid on experimental the procedure described for obtaining the compound of example 33.

MCHP: m/z 379 (M+1)+.

Retention time: to 7.59 min

1H NMR (200 MHz, DMSO-D6): δ ppm million of 0.7 (m, 2H); 1,0 (m, 2H); 2,0 (m, 1H); and 3.8 (s, 3H); to 6.9 (m, 1H); and 7.3 (m, 3H); 7,6 (m, 2H); 8.0 a (d, J=2.5 Hz, 1H); 8.3 (the d, J=2.5 Hz, 1H); 8,7 (t, J=8,8 Hz, 1H); 10,7 (d, J=2.0 Hz, 1H).

EXAMPLE 35

2-(3,5-Debtor-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid

Received (10%) from the compound of example 31 and methylboronic acid on experimental the procedure described for obtaining the compound of example 33.

MCHP: m/z 370 (M+1)+.

Retention time: 6,57 min

1H NMR (400 MHz, DMSO-D6): δ ppm million to 2.2 (s, 3H); and 3.8 (s, 3H; 7,0 (dd, J=7,8, 1.7 Hz, 1H); to 7.4 (m, 3H); 7,5 (d, J=9.4 Hz, 2H); 8,1 (dd, J=20,2, 1.7 Hz, 2H); and 9.3 (s, 1H); to 13.6 (s, 1H).

EXAMPLE 36

2-(3'-Ethoxy-5-fluoro-2-methylbiphenyl-4-ylamino)nicotinic acid

Received (67%) from intermediate 26 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

ICSD: m/z 367

Retention time: 7,08 min

1H NMR (200 MHz, DMSO-D6): δ ppm million: 1,3 (t, J=6.8 Hz, 3H); 2,2 (s, 3H); 4.0 a (q, J=6,8 Hz, 2H); to 6.9 (m, 4H); and 7.1 (d, J=12.1 Hz, 1H); and 7.3 (t, J=7.8 Hz, 1H); 8.3 (the dd, J=7,8, 2.0 Hz, 1H); and 8.4 (m, 2H); 10,6 (d, J=2.3 Hz, 1H).

EXAMPLE 37

2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid

Received (73%) of intermediate product 30 and 2-chloronicotinic acid on experimental the procedure described for obtaining compounds of example 1.

ICSD: m/z 353

Retention time: 6,75 min

1H NMR (200 MHz, DMSO-D6): δ ppm million to 2.2 (s, 3H); and 3.8 (s, 3H); to 6.9 (m, 4H); and 7.1 (d, J=12.1 Hz, 1H); and 7.3 (t, J=7.8 Hz, 1H); and 8.4 (m, 3H); 10,6 (d, J=2.3 Hz, 1H).

EXAMPLE 38

2-(3'-Ethoxy-3,5-diferuloyl-4-ylamino)-5-methylnicotinic acid

Received (6%) of the intermediate product 34 and methylboronic acid on experimental the procedure described for obtaining the compound of example 33.

MCHP: m/z 385 (M+1)+.

Retention time: 7,06 min

1H NMR (200 MHz, DMSO-D6) δ ppm million to 1.4 (t, J=6.8 Hz, 3H) 2,2 (s, 3H) 4,1 (d, J=6,8 Hz, 2H) 7,0 (d, J=1.6 Hz, 1H) to 7.4 (m, 5H) 8,1 (d, J=7,0 Hz, 2H) and 9.4 (s, 1H).

EXAMPLE 39

5-Cyclopropyl-2-(3'-ethoxy-3,5-diferuloyl-4-ylamino)nicotinic acid

Received (14%) of intermediate product 34 and cyclopropylboronic acid on experimental the procedure described for obtaining the compound of example 33.

MCHP: m/z 411 (M+1)+.

Retention time: 7,33 min

1H NMR (200 MHz, DMSO-D6) δ ppm million of 0.6 (m, 2H) 0, (m, 2H) 1,4 (t, J=6.9 Hz, 3H) 1,9 (m, 1H) 4,1 (q, J=6.9 Hz, 2H) 7,0 (m, 1H) to 7.4 (m, 5H) of 7.9 (d, J=2.5 Hz, 1H) 8,1 (d, J=2.5 Hz, 1H) and 9.4 (s, 1H).

EXAMPLE 40

2-(3,5-Debtor-3'-methoxybiphenyl-4-ylamino)-5-etilnikotinata acid

To a solution of compound of example 31 (200 mg, and 0.46 mmole) and tributyl(vinyl)stannane (209 mg, of 0.66 mmole) in DMF (8 ml) in an argon atmosphere was added Pd(PPh3)4(37 mg, 0.07 mmole). The mixture was heated at 100°C overnight and then cooled to room temperature. The reaction mixture was concentrated and the residue was re-dissolved in ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the solvent evaporated in vacuum. The obtained residue was purified using flash chromatography elwira with hexane/AcOEt (from 1/0 to 1/1). The obtained solid was re-dissolved in EtOH (10 ml) was added Pd/C (46 mg, 0.04 mmole) and the reaction mixture was stirred in an atmosphere of hydrogen overnight. The crude substance was filtered through celite and evaporated. The obtained residue was purified by chromatography with reversed phase, elwira with a mixture of water and AcN/MeOH (1/1) in gradient mode (AcN/MeOH (1/1) from 0 to 70%). The desired product was obtained as a yellow solid. Yield = 23%.

MCHP: m/z 385 (M+1)+.

Retention time: 7,01 min

1H NMR (200 MHz, DMSO-D6) δ ppm million to 1.2 (t, J=7.4 Hz, 3H) and 3.8 (m, 3H) 7,0 (m, J=8,2 Hz, 1H) and 7.3 (m, 3H) 7,5 (d, J=9.4 Hz, 2H) 8,1(m, 2H) to 9.6 (s, 1H).

EXAMPLE 41

5-Bromo-2-(3'-ethoxy-2,5-diferuloyl-4-ylamino)nicotinic acid

Received (70%) of intermediate 7 and 5-bromo-2-chloronicotinic acid according to the experimental procedure described for intermediate product 34.

ICSD: m/z 447, 449 (M+1)+.

Retention time: to $ 7.91 min

1H NMR (200 MHz, DMSO-D6) δ ppm million to 1.4 (t, J=6.9 Hz, 3H) 4,1 (d, J=6,9 Hz, 2H) 7,0 (m, 3H) 7,4 (t, J=7,6 Hz, 1H) 7,5 (dd, J=11,9 and 7.6 Hz, 1H) and 8.4 (d, J=2.0 Hz, 1H) and 8.6 (m, 2H) 10,9 (s, 1H).

EXAMPLE 42

5-Cyclopropyl-2-(3'-ethoxy-2,5-diferuloyl-4-ylamino)nicotinic acid

Received (26%) from the compound of example 41 and cyclopropylboronic acid on experimental the procedure described for obtaining the compound of example 33.

ICSD: m/z 411 (M+1)+.

Retention time: of 6.71 min

1H NMR (200 MHz, DMSO-D6) δ ppm million of 0.7 (m, 2H) 1,0 (m, 2H) 1,4 (t, J=7.0 Hz, 3H) 2,0 (m, 1H) 4,1 (q, J=7,0 Hz, 2H) 6,9 (m, 1H) and 7.1 (m, J=10.5 Hz, 2H) and 7.4 (t, J=8.0 Hz, 1H) 7,5 (dd, J=12,1, 7,4 Hz, 1H) 8,0 (d, J=2.3 Hz, 1H) and 8.4 (d, J=2,3 Hz, 1H) 8,7 (dd, J=14,1, 7,0 Hz, 1H) 10,9 (s, 1H).

EXAMPLE 43

2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)-5-methylnicotinic acid

Received (20%) of intermediate 35 and methylboronic acid on experimental the procedure described for obtaining the compound of example 33.

ICSD: m/z 367 (M+1)+.

Retention time: 7,35 min

1H NMR (200 MHz, DMSO-D6) δ ppm million to 2.2 (2s, 6H) and 3.8 (s, 3H) to 6.9 (m, 3H) and 7.1 (d,J=12,5 Hz, 1H) to 7.4 (m, 1H) 8,1 (d, J=2.3 Hz, 1H) 8,3 (d, J=2.3 Hz, 1H) 8,5 (d, J=8.6 Hz, 1H) 10,9 (s, 1H).

EXAMPLE 44

5-Cyclopropyl-2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid

Received (6%) from intermediate 35 and cyclopropylboronic acid on experimental the procedure described for obtaining the compound of example 33.

MCHP: m/z 393 (M+1)+.

Retention time: the 7.62 min

1H NMR (200 MHz, DMSO-D6) δ ppm million of 0.7 (m, 2H) 0,9 (m, 2H) 1,9 (m, 1H) 2,2 (s, 3H) and 3.8 (s, 3H) to 6.9 (m, 3H) and 7.1 (d, J=12,5 Hz, 1H) 7,4 (t, J=7.8 Hz, 1H) and 7.9 (d, J=2.3 Hz, 1H) 8,3 (d, J=2.3 Hz, 1H) 8,5 (d, J=8,2 Hz, 1H) 10,6 (s, 1H).

EXAMPLE 45

2-(2',3,5-Cryptor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (73%) of intermediate 21 (2-fluoro-3-methoxyphenyl)Bronevoy acid on experimental the procedure described for obtaining compounds of example 18.

ICSD: m/z 375 (M+1)+.

Retention time: 6,50 min

1H NMR (200 MHz, DMSO-D6) δ ppm million to 3.9 (s, 3H) 6,9 (dd, J=7,8, a 4.7 Hz, 1H) to 7.2 (m, 3H) 7,4 (d, J=8,2 Hz, 2H) 8,2 (m, 2H) and 9.6 (s, 1H).

EXAMPLE 46

2-(2'-Chloro-3,5-diferuloyl-4-ylamino)nicotinic acid

Received (73%) of intermediate product 21 and 2-Chlorfenvinphos acid on experimental the procedure described for obtaining compounds of example 18.

MCHP: m/z 361 (M+1)+.

Retention time: 6,75 min

1H NMR (200 MHz, DMSO-D6) δ ppm million to 6.9 (dd, J=7,8, a 4.7 Hz, 1H) and 7.3 (d, J=8.6 Hz, 2H) 7,5 (m, 4H) 8,3 (m, 2H) and 9.6 (s, 1H).

EXAMPLE 47

2-(3'-Cyclopropane-3,5-diferuloyl-4-ylamino)nicotinic acid

Received (53%) of intermediate product 21 and the intermediate product 37 experimental the procedure described for obtaining compounds of example 18.

ICSD: m/z 383 (M+1)+.

Retention time: 7,06 min

1H NMR (400 MHz, DMSO-D6) δ ppm million of 0.7 (m, 2H) 0,8 (m, 2H) 4,0 (m, 1H) 6,9 (dd, J=7,4, a 4.7 Hz, 1H) and 7.1 (m, 1H) to 7.4 (m, 3H) 7,5 (d, J=9.4 Hz, 2H) 8,2 (m, 2H) and 9.5 (s, 1H) 13,6 (s, 1H).

EXAMPLE 48

2-(3,5-Debtor-2-methylbiphenyl-4-ylamino)nicotinic acid

Received (33%) of 2-chloronicotinic acid and intermediate product 38 experimental the procedure described for obtaining compounds of example 1.

ICSD: m/z 341 (M+1)+.

Retention time: 7,02 min

1H NMR (200 MHz, DMSO-D6) δ ppm million to 2.1 (s, 3H) 6,9 (dd, J=7,8, a 4.7 Hz, 1H) 7,1 (dd, J=10,5, 2.0 Hz, 1H) to 7.4 (m, 5H) to 8.2 (m, 2H) and 9.5 (s, 1H).

EXAMPLE 49

5-Cyclopropyl-2-(2,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (7%) from intermediate 39 and cyclopropylboronic acid on experimental the procedure described for obtaining the compound of example 33.

ICSD: m/z 397 (M+1)+.

Retention time: to 7.77 min

1H NMR (400 MHz, DMSO-D6) δ ppm million of 0.7 (d, J=5,2 Hz, 2H) 1,0 (d, J=8,3 Hz, 2H) 2,0 (m, 1H) and 3.8 (s, 3H) 7,0 (d, J=7.2 Hz, 1H) and 7.1 (m, 2H) and 7.4 (t, J=7.9 Hz, 1H) 7,5 (dd, J=12,1, 7,4 Hz, 1H) 8,0 (s, 1H) and 8.4 (s, 1H) 8,7 (dd, J=13,7, 7,0 Hz, 1H) to 10.8 (s, 1H) 13,9 (s, 1H).

EXAMPLE 50

p> 2-(3'-Cyclopropane-3,5-diferuloyl-4-ylamino)-5-cyclopropylamino acid

Received (30%) of the intermediate product 42 and intermediate 37 experimental the procedure described for obtaining compounds of example 18.

MCHP: m/z 423 (M+1)+.

Retention time: 7,44 min

1H NMR (200 MHz, DMSO-D6) δ ppm million of 0.8 (m, 8H) to 1.9 (m, 1H) 4,0 (m, 1H) and 7.1 (m, 1H) to 7.4 (m, 5H) of 7.9 (d, J=2.3 Hz, 1H) 8,1 (d, J=2.3 Hz, 1H) and 9.3 (s, 1H) 13,6 (s, 1H).

EXAMPLE 51

5-Chloro-2-(3,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (19%) from intermediate 29 and 2.5-dichloronicotinic acid according to the experimental procedure described for intermediate product 34.

MCHP: m/z 391 (M+1)+.

Retention time: 7,28 min

1H NMR (400 MHz, DMSO-D6) δ ppm million to 3.8 (s, 3H) 7,0 (dd, J=7,8, and 1.6 Hz, 1H) to 7.4 (m, 3H) 7,6 (2s, 2H) 8,2 (d, J=2.5 Hz, 1H) 8,3 (d, J=2.5 Hz, 1H) and 9.5 (s, 1H).

EXAMPLE 52

5-Cyclopropyl-2-(3,5-debtor-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

Was obtained (48%) of intermediate product 42 and 3-(triptoreline)phenylboronic acid on experimental the procedure described for obtaining compounds of example 18.

MCHP: m/z 451 (M+1)+.

Retention time: of 7.48 min

1H NMR (400 MHz, DMSO-D6) δ ppm million of 0.6 (m, 2H) 0,9 (m, 2H) 1,9 (m, 1H) 7,4 (m, 1H) 7,6 (m, 3H) and 7.8 (s, 1H) and 7.8 (dd, J=7,4, 1.2 Hz, 1H) and 7.9 (d, J=2.3 Hz, 1H) 8,1 (d, J=2.7 Hz, 1H) and 9.4 (s, 1H) 13,6 (s, 1H).

EXAMPLE 53

2-(2,3,-Cryptor-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (6%) from intermediate 43 and 2-chloronicotinic acid according to the experimental procedure described for intermediate product 34.

MCHP: m/z 375 (M+1)+.

Retention time: 6,79 min

1H NMR (400 MHz, DMSO-D6) δ ppm million to 3.8 (s, 3H) 6,7 (m, 1H) and 7.1 (m, 3H) 7,4 (m, 2H) and 8.0 (s, 1H) 8,2 (m, 1H) and 11.8 (s, 1H)

EXAMPLE 54

2-(2'-Chloro-3,5-diferuloyl-4-ylamino)-5-cyclopropylamino acid

Received (38%) of intermediate product 42 and 2-Chlorfenvinphos acid on experimental the procedure described for obtaining compounds of example 18.

MCHP: m/z 401 (M+1)+.

Retention time: 7,27 min

1H NMR (400 MHz, DMSO-D6) δ ppm million of 0.7 (m, 2H) 0,9 (m, 2H) 1,9 (m, 1H) 7,3 (2s, 2H) 7,5 (m, 3H) 7,6 (dd, J=5,8, 3.6 Hz, 1H) and 7.9 (d, J=2.6 Hz, 1H) 8,1 (d, J=2.6 Hz, 1H) and 9.4 (s, 1H) 13,6 (s, 1H)

EXAMPLE 55

2-(3,5-Debtor-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid

Received (68%) of intermediate 45 and 3-methoxyphenylacetic acid on experimental the procedure described for obtaining compounds of example 18.

ICSD: m/z 371 (M+1)+.

Retention time: 6,76 min

1H NMR (200 MHz, DMSO-D6) δ ppm million 2,1 (d, J=2.0 Hz, 3H) and 3.8 (s, 3H) 6,8 (dd, J=7,6, a 4.9 Hz, 1H) 7,0 (m, 4H) 7,4 (t, J=8,2 Hz, 1H) 8,2 (m, 2H) 9,7 (s, 1H)

EXAMPLE 56

2-(3,5-Debtor-2-methyl-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid

Received (63%) of intermediate 45 and 3-(triptorelin and)phenylboronic acid on experimental methodology, described to obtain the compound of example 18.

MCHP: m/z 425 (M+1)+.

Retention time: 7,31 min

1H NMR (200 MHz, DMSO-D6) δ ppm million 2,1 (d, J=2.0 Hz, 3H) 6,9 (dd, J=7,8, 5,1 Hz, 1H) 7,1 (dd, J=10,3, 1.8 Hz, 1H) 7,5 (m, 3H) and 7.6 (d, J=7.8 Hz, 1H) 8,2 (m, 2H) and 9.6 (s, 1H)

EXAMPLE 57

2-(2'-Chloro-3,5-debtor-2-methylbiphenyl-4-ylamino)nicotinic acid

Received (63%) of intermediate 45 and 2-Chlorfenvinphos acid on experimental the procedure described for obtaining compounds of example 18.

ICSD: m/z 375 (M+1)+.

Retention time: 6,99 min

1H NMR (200 MHz, DMSO-D6) δ ppm million to 2.0 (s, 3H) 6,9 (dd, J=7,6, a 4.9 Hz, 1H) 7,0 (m, 1H) to 7.4 (m, 3H) 7,6 (dd, J=5,9, 3.1 Hz, 1H) 8,3 (m, 2H) and 9.6 (s, 1H)

EXAMPLE 58

5-Chloro-2-(3,5-diferuloyl-4-ylamino)nicotinic acid

Received (23%) from intermediate 46 and phenylboronic acid on experimental the procedure described for obtaining compounds of example 18.

ICSD: m/z 361 (M+1)+.

Retention time: 7,37 min

1H NMR (400 MHz, DMSO-D6) δ ppm million to 7.4 (t, J=7,4 Hz, 1H) 7,5 (m, 4H) and 7.8 (d, J=7,4 Hz, 2H) 8,2 (d, J=2.7 Hz, 1H) 8,3 (d, J=2.7 Hz, 1H) and 9.5 (s, 1H)

EXAMPLE 59

5-Chloro-2-(2'-chloro-3,5-diferuloyl-4-ylamino)nicotinic acid

Received (15%) from intermediate 46 and 2-chlorophenylalanine acid on experimental the procedure described for obtaining compounds of example 18.

MCHP: m/z 395 (M+1)+.

Retention time:of 7.48 min

1H NMR (400 MHz, DMSO-D6) δ ppm million to 7.3 (d, J=8.7 Hz, 2H) 7,5 (m, 3H) 7,6 (m, 1H) 8,2 (d, J=2.5 Hz, 1H) 8,3 (d, J=2.5 Hz, 1H) and 9.6 (s, 1H) 14,0 (s, 1H)

EXAMPLE 60

2-(2,3,5,6-Titrator-3'-methoxybiphenyl-4-ylamino)nicotinic acid

Received (3%) of intermediate 47 and 2-chloronicotinic acid according to the experimental procedure described for intermediate product 34.

MCHP: m/z 393 (M+1)+.

Retention time: 6,97 min

1H NMR (200 MHz, DMSO-D6) δ ppm million to 3.8 (s, 3H) 6,9 (dd, J=7,6, a 4.9 Hz, 1H) and 7.1 (m, 3H) 7,5 (t, J=8,2 Hz, 1H) 8,3 (m, 2H) 10,2 (s, 1H)

EXAMPLE 61

2-(3,5-Debtor-2'-methylbiphenyl-4-ylamino)nicotinic acid

Received (63%) of intermediate product 21 and tolylboronic acid on experimental the procedure described for obtaining compounds of example 18.

MCHP: m/z 341 (M+1)+.

Retention time: 6,91 min

1H NMR (400 MHz, DMSO-D6) δ ppm million to 2.3 (s, 3H) 6,9 (dd, J=7,6, a 4.9 Hz, 1H) 7,2 (d, J=8.6 Hz, 2H) and 7.3 (m, 4H) 8,2 (dd, J=7,6, 1.9 Hz, 1H) 8,3 (dd, J=4,7, 1.9 Hz, 1H) and 9.5 (s, 1H)

EXAMPLE 62

3-(3'-Cyclopropane-3-forbiden-4-ylamino)isonicotinate acid

To a solution of intermediate 51 (0,13 g 0,34 mmole) in THF (5 ml) at 0°C was added 0,M aqueous LiOH solution (0.02 g, 0,41 mmole) and the mixture was stirred at room temperature overnight. THF is evaporated and the residue was diluted with water. The pH value was brought to 4-5 by addition of 5 n HCl and received asado which was filtered and washed with DHM. The desired product was obtained as a yellow solid. Yield = 62%.

MCHP: m/z 365 (M+1)+.

Retention time: 6.42 per min

1H NMR (400 MHz, DMSO-D6) δ ppm million of 0.7 (s, 2H) 0,8 (m, 2H) 4,0 (m, 1H) and 7.1 (m, 1H) to 7.4 (m, 3H) 7,6 (m, 4H) 8,1 (d, J=5,1 Hz, 1H) 8,5 (s, 1H) and 9.3 (s, 1H).

TABLE 1
ExampleStructure
1
2
3
4
5
6

ExampleStructure
7
8
9
10
11
12
13

ExampleStructure
14
15
16
17
18
19
20

ExampleStructure
21
22
23
24
25
26
27

ExampleStructure
28
29
30
31
32
33

ExampleStructure
34
35
36
37
38
39
40
41

ExampleStructure
42
43
44
45
46
47
48
49
50

ExampleStructure
51
52
53
54
55
56
57
58

Por what measures Structure
59
60
61
62

The PHARMACOLOGICAL ACTIVITY

Research activity in the inhibition DHODH person

Activity DHODH and its inhibition was investigated by the method of recovery Chromogen using DCHIP (2,6-dichlorphenol-indophenol). The oxidation of the substrate (dihydroorotate, L-DHO), as well as restoring cosubstrate (coenzyme Q, CoQ) is associated with the restoration of the Chromogen, therefore, enzymatic activity decreases the absorption of the Chromogen at 600 nm.

Extracts enzymes (8 ál, ~1.5 mcg human protein) were incubated in 96-well plates. Mixture for analysis (200 μl) contained 200 μm CoQD, 100 μm L-DHO, 120 μm DHIF buffer for analysis (100 mm HEPES (N-2-hydroxyethylpiperazine-N-2-econsultancy acid) pH 8.0, 150 mm NaCl, 10% glycerol, 0.05% of Triton X-100) and 2 µl of the tested compound. Compounds were dissolved in DMSO to a concentration of initial solution equal to 1 mm, and for the calculation of the IC50(the concentration of inhibitor, the mu is apparent for inhibition, of 50%) was investigated at various concentrations in the range from 10 μm to 1 PM.

The reaction was initiated by adding enzyme and then incubated for 10 min at room temperature and then reducing the content DHIF was determined by measuring the decrease in absorption at 600 nm using standard equipment (Spectramax).

All reactions were performed twice and the necessary dependencies to determine the values of the IC50, were obtained using the software ABase.

Table 2 shows the activity values obtained in the study of inhibition DHODH person some of the compounds proposed in the present invention, and found that these compounds are active inhibitors DHODH.

TABLE 2
ExampleIC50for DHODH person IC50(nm)
2200
688
13150
1790
1919
20 15
2119
2314
24200
33110
3433
3512
3799
4012
4223
4553
4717

ExampleIC50for DHODH person IC50(nm)
485
506
524
545
566
574
588
603
6111

Functional study: Suppression of lymphocyte proliferation

Mononuclear cells of peripheral blood (MRPC)taken from healthy volunteers, were prepared by centrifugation in a density gradient using the apparatus of Ficoll. Cells were sown on 1×105cells/well in flat-bottomed 96-well plates in RPMI medium 1640 plus 5% fetal bovine serum, 2 mm L-glutamine and a mixture of penicillin/streptomycin. Then MRPC activated with 1 μg/ml of phytohemagglutinin (PHA, Sigma) for 3 days were incubated in a series of breeding at various concentrations of the studied compounds. Then the cells were added tretirovanie thymidine 0.5 µci/well and incubated overnight. Then the culture was collected on filter paper and were counted using a counter beta radiation. The value of the IC50for each compound was calculated by the dose - response.

Connections proposed in the present invention, which have been studied with the help of this study, have values IC50equal to less than 10 μm. Preferred compounds proposed in the present invention have values IC50equal to less than 4 μm, preferably less than 2 μm, most predpochtitel the but - less than 1 micron.

As shown by these results, the compounds proposed in the present invention effectively inhibit DHODH and thereby inhibit cell proliferation, with an intensive metabolism, particularly lymphocytes.

Amino(ISO)derivative of nicotinic acid, proposed in the present invention is applicable for treating or preventing diseases for which it is known that their flow is improved by treatment with the inhibitor dihydroorotatdehydrogenase. Such diseases include, but are not limited to, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus, psoriasis and sarcoidosis.

In accordance with this amino(ISO)derivative of nicotinic acid, proposed in the present invention, and pharmaceutical compositions comprising such compound and/or their salts, can be used in the treatment of disorders of the human or animal, which includes an introduction to the subject in need of such treatment, an effective amount derived amino(ISO)nicotinic acid proposed in the present invention, or its pharmaceutically acceptable salt.

Amino(ISO)derivative of nicotinic acid, proposed in the present invention, it is also possible to combine the other active compounds for the treatment of diseases, for which it is known that their flow is improved by treatment with the inhibitor dihydroorotatdehydrogenase.

The combination proposed in the present invention optionally may include one or more additional active compounds, for which it is known that they are applicable for the treatment of autoimmune diseases, immune and inflammatory diseases, inflammatory bone disorders, malignant neoplastic diseases associated with angiogenesis disorders, viral diseases, and infectious diseases such as (a) anti-TNF-alpha monoclonal antibodies, such as infliximab, certolizumab pegol, golimumab, adalimumab and AME-527, produced by the firm Applied Molecular Evolution, (b) antimetabolites, such as mizoribine, cyclophosphamide and azathioprine, (C) inhibitors ekspressirovali calcineurin (PP-2B)/INS, such as cyclosporine a, tacrolimus and ISA-247, produced by the firm Isotechnika, (d) cyclo-oxygenase inhibitors such as aceclofenac, diclofenac, celecoxib, rofecoksib, etoricoxib, valdecoxib, lumiracoxib, cimicoxib and LAS-34475, produced by the company Almirall Laboratories, S.., (f) antagonists of TNF-alpha, such as etanercept, lenercept, onercept and pegsunercept, (f) inhibitors of the activation of NF-Kappa-b (NFKB), such as sulfasalazin and iguratimod, (g) receptor antagonists, IL-1, such as anakinra and AMG-719, produced f is rmoi Amgen, (h) inhibitors digidrofolatreduktazy (DHFR), such as microtext, aminopterin and CH-1504, produced by the firm Chelsea, (i) inhibitors of inosine-5'-monophosphorylated (IMPDH), such as mizoribine, riboavin, tianfuan, amatuer, mycophenolat modafil, ribamidil and merimepodib, (j) glucocorticoid, such as prednisolone, methylprednisolone, dexamethasone, cortisol, hydrocortisone, triamcinolone acetonide, fluotsinolon acetonide, fluocinonide, clocortolone pivalate, hydrocortisone aceponate, methylprednisolone, sulatan, betamethasone butyrate propionate, Delta-cortisone, Delta dehydrocortisone, prednisone, dexamethasone nutrifaster, triamcinolone, betamethasone valerate, betamethasone, hydrocortisone nutriceutical, prednisolone nutrifaster, hydrocortisone probuct and difluprednate, (k) anti-CD20 monoclonal antibodies such as rituximab, ofatumumab, ocrelizumab and TRU-015, manufactured by the firm Trubion Pharmaceuticals, (1) means acting on b cells, such as BLYSS, BAFF, TACI-Ig and APRIL, (m) inhibitors R, such as AMG-548 (produced by the firm Amgen), ARRY-797 (produced by the firm Array Biopharma), hlormetiazola Etisalat, doramapimod, PS-540446 (produced by the firm BMS), SB-203580, SB-242235, SB-235699, SB-281832, SB-681323, SB-856553 (all produced by the firm GlaxoSmithKline), KC-706 (produced by the firm Kemia), LEO-1606, LEO-15520 (all produced by firm Leo), SC-80036, SD-06 (all produced by the company Pfizer), RWJ-67657 (the issue is contrite firm R.W. Johnson), RO-3201195, RO-4402257 (all produced by firm Roche), AVE-9940 (produced by the firm Aventis), SCIO-323, SCIO-469 (all produced by the company Scios), TA-5493 (produced by the firm Tanabe Seiyaku), and VX-745, VX-702 (all produced by the firm Vertex), and the compounds claimed or described in the patent applications of Spain No. R and R, (n) Jak3 inhibitors, such as SR produced by the company Pfizer, (o) inhibitors Syk, such as R-112, R-406 and R-788, all produced by the company Rigel, (R) MEK inhibitors such as ARRY-142886, ARRY-438162 (all produced by firm Array Biopharma), AZD-6244 (produced by the firm AstraZeneca), PD-098059, PD-0325901 (all produced by the company Pfizer), (q) receptor antagonists RH, such as AZD-9056, produced by the firm AstraZeneca, (r) S1P1 agonists, such as pingomatic, CS-0777, produced by the firm Sankyo and R-3477, produced by the firm Actelion, (s) anti-CD49 monoclonal antibodies such as natalizumab, (t) inhibitors, integrin, such as cilengitide, firegrass, valategrast hydrochloride, SB-273005, SB-683698 (all produced by the firm Glaxo), HMR-1031, produced by the company Sanofi-Aventis, R-1295, produced by the firm Roche, BMS-587101, produced by the firm BMS and CDP-323, produced by the company UCB Celltech, (u) anti-CD88 monoclonal antibodies, such as eculizumab and pexelizumab, (v) receptor antagonist, IL-6, such as CBP-1011, produced by the firm InKine, and C-326, produced by the firm Amgen, (w) anti-IL-6 monoclonal antibodies, such as belimumab, CNTO-328, issue is iesa company Centocor, and VX-30, produced by the firm Vaccinex, (x) anti-CD152 monoclonal antibodies such as ipilimumab is and ticilimumab, (y) fusion proteins containing the extracellular domain associated with cytotoxic T-lymphocyte antigen 4 (CTLA-4), associated with fragments of immunoglobulin G1, such as abatacept, (z) funds used for the treatment of bone disorders, such as bisphosphonates, such as tiludronate disodium, clodronate disodium, distribuiton, etidronate disodium, xidian (K,Na salt), alendronate sodium, meridional, dimethyl-APD, the sodium salt of olpadronate acid, mitronova acid, apamin, hydrate ibandronate sodium and risedronate sodium, (AA) inhibitors VEGF Try kinases, such as akatarawa salt pegaptanib, vatalanib succinate, sorafenib, vandetanib, sunitinib malate, cediranib, pazopanib hydrochloride and AE-941, produced by the company AEterna Zentaris, (bb) other compounds effective in autoimmune diseases, such as gold salts, hydroxyarginine, penicillamine, K-832, SMP114 and AD452, (cc) inhibitors polynucleotides, such as forodesine hydrochloride, R-3421 produced by the firm of Albert Einstein College of Medicine, CI-972 and CI-1000, both produced by the company Pfizer, (dd), anti-RANKL monoclonal antibodies, such as denosumab (her) anti-CD25 monoclonal antibodies, such as enlimomab, daclizumab, basiliximab and LMB-2, produced by the firm th US National Cancer Institute, (ff) inhibitors discontinuties (HDAC), such as divalproex sodium, azetidinone, depsipeptide, sodium butyrate, phenylbutyrate sodium, vorinostat, MS-27-275, produced by the company Mitsui, valproic acid, pyroxene, tributyrin, PX-105684, produced by the company TopoTarget, MG-0103, produced by the firm MethylGene, G2M-777, produced by the company TopoTarget, and CG-781, produced by the firm Celera, and (gg) monoclonal antibodies to anticolonialism factor (GM-CSF), such as the KV-002 produced by the firm KaloBios.

Although amino(ISO)derivative of nicotinic acid, proposed in the present invention, is used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus, psoriasis and sarcoidosis, it may be preferred their use in combination with other active compounds, for which it is known that they are applicable for the treatment of such diseases, such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus, psoriasis and sarcoidosis.

Particularly preferred active compounds to combine with amino(ISO)derivatives of nicotinic acid, proposed in the present invention, for treating or preventing rheumatoi the aqueous arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus, psoriasis or sarcoidosis, are (a) anti-TNF-alpha monoclonal antibodies, such as infliximab, certolizumab pegol, golimumab, adalimumab and AME-527, produced by the firm Applied Molecular Evolution, (b) antagonists of TNF-alpha, such as etanercept, lenercept, onercept and pegsunercept, (C) inhibitors ekspressirovali calcineurin (PP-2B)/INS, such as cyclosporine a, tacrolimus and ISA-247, produced by the firm Isotechnika, (d) receptor antagonists, IL-1, such as anakinra and AMG-719, produced by the firm Amgen, (e) anti-CD20 monoclonal antibodies such as rituximab, ofatumumab, ocrelizumab and TRU-015, manufactured by the firm Trubion Pharmaceuticals, (f) inhibitors R, such as AMG-548 (produced by the firm Amgen), ARRY-797 (produced by the firm Array Biopharma), hlormetiazola Etisalat, doramapimod, PS-540446 (produced by the firm BMS), SB-203580, SB-242235, SB-235699, SB-281832, SB-681323, SB-856553 (all produced by the firm GlaxoSmithKline), KC-706 (produced by the firm Kemia), LEO-1606, LEO-15520 (all produced by firm Leo), SC-80036, SD-06 (all produced by the company Pfizer), RWJ-67657 (produced by the firm R.W.Johnson), RO-3201195, RO-4402257 (all produced by firm Roche), AVE-9940 (produced by the firm Aventis), SCIO-323, SCIO-469 (all produced by the company Scios), TA-5493 (produced by the firm Tanabe Seiyaku), and VX-745, VX-702 (all produced by the firm Vertex) and connect the tion, stated or described in the patent applications of Spain No. R and R, (g) inhibitors of the activation of NF-Kappa-b (NFKB), such as sulfasalazin and iguratimod, and (h) inhibitors digidrofolatreduktazy (DHFR), such as microtext, aminopterin and CH-1504, produced by the firm Chelsea.

The combination proposed in the present invention, can be used to treat disorders, the occurrence of which is improved by inhibition of dihydroorotatdehydrogenase. Thus, the scope of the present invention includes methods of treating these disorders, and the use of combinations proposed in the present invention, for preparing a medicinal product intended for the treatment of these disorders.

Preferred examples of such disorders are rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus, psoriasis and sarcoidosis, more preferably rheumatoid arthritis, psoriatic arthritis and psoriasis, and most preferably rheumatoid arthritis.

The active compounds in the combinations proposed in the present invention, it is possible to enter any suitable way depending on the character undergoing the treatment of disorders, for example, orally (in the form of syrups, tablets, capsules, pellets, drugs re wireimage release bystrorastvorimaya drugs etc); local (in the form of creams, ointments, lotions, nasal sprays or aerosols, and the like); by injection (subcutaneous, intracutaneous, intramuscular, intravenous and the like) or by inhalation (in the form of powder, solution, dispersion, etc.).

The active compounds in the combination, i.e. the inhibitor dihydroorotatdehydrogenase proposed in the present invention, and other optional active compounds can be entered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, joint or sequential introduction of the same or different ways.

One embodiment of the present invention is a set of components, including the inhibitor of dihydroorotatdehydrogenase proposed in the present invention, together with instructions for simultaneous, joint, separate or sequential use in combination with another active compound, applicable for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus, psoriasis and sarcoidosis.

Another embodiment of the present invention is a package comprising the inhibitor dihydroorotatdehydrogenase fo the formula (I) and another active compound, applicable for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus, psoriasis and sarcoidosis.

The pharmaceutical compositions can usually be contained in a single dosage form and may be prepared by any of the methods well known in the pharmaceutical industry.

The composition proposed in the present invention suitable for oral administration may be a separate form, such as capsules, pills or tablets, each of which contains a defined amount of the active ingredient; a powder or granules; solutions or suspensions in aqueous liquids or non-aqueous liquid; or a liquid emulsion of the type oil-in-water, or a liquid emulsion of the type water-in-oil. The active ingredients can also be a bolus, electuary or pasta.

The syrup is typically a suspension or solution of the compound or salt in a liquid carrier, such as ethanol, peanut oil, olive oil, glycerin, or water to which are added flavouring or colouring agents.

If the composition is a tablet, then you can use any pharmaceutical medium customarily used for the preparation of solid products. Examples of such carriers include magnesium stearate, talc, gelatin, gum acacia, stearic acid, starch, lactose and sucrose.

The tablet can be manufactured by extrusion or molding, optionally with the addition of one or more accessory ingredients. Molded tablets can be made by carried out in a suitable pressing machine the active ingredient in granular form, such as powder or granules, optionally mixed with a binder, lubricant agent, inert diluent, surface-active agent or dispersing agent. Molded tablets can be made by carried out in a suitable machine molding a mixture of the powdered compound moistened inert liquid diluent. On the pill may not necessarily be coated or scratches and they can be made so as to provide slow or controlled release of the contained active ingredient.

If the product is a capsule made of hard gelatin, suitable is any standard method of encapsulation using the above media. If the product is a capsule soft gelatin, you can use any pharmaceutical medium customarily used for preparing dispersions or suspensions, for example aqueous gums, cellulose, silicates or oils, and p is meshaut in capsule soft gelatin.

Dry powder composition intended for local injection into the lungs by inhalation, may, for example, be in capsules or cartridges, e.g. made from gelatin, or blister packs, made, for example, of laminated aluminum foil for use in inhalers or the device for insufflation of powders. Usually the products contain a powder mix for inhalation of the compounds proposed in the present invention and a suitable powder base (carrier), such as lactose or starch. Preferred is the use of lactose. Each capsule or cartridge may usually contain from 2 to 150 μg of each therapeutically active ingredient. Alternatively, the active ingredient (the ingredient) may be contained in them without inert fillers.

Composition for inhalation can be placed in a suitable device for inhalation, such as Novolizer SD2FL, which are described in the following applications: WO 97/000703, WO 03/000325 and WO 03/061742.

Typical compositions for nasal injection include those indicated above for inhalation and additionally include not under the pressure of the composition in the form of solutions or suspensions in an inert diluent, such as water, optionally in combination with conventional inert excipients, such as buffers, about isometropia means, agents for the regulation of toychest and agents that modify the viscosity, and they can be administered using a nasal pump.

Typical cutaneous and percutaneous compositions contain conventional aqueous or non-aqueous diluent and represents, for example, cream, ointment, lotion or paste or in the form containing medicinal plaster, bandage or membrane.

Preferably, if the composition is a single dosage form such as tablet, capsule or dispensing aerosol device, so that the patient can enter a single dose.

Of course, the amount of each active compound, which is necessary to ensure therapeutic effect varies depending on the particular active compound, route of administration, treated of the subject, and concrete exposed to the treatment of disorders or diseases.

Effective doses are usually in the range 2-2000 mg of active ingredient per day. The daily dose can be administered one or more doses, preferably 1-4 intake per day. Active ingredients preferably once or twice per day.

If you use a combination of active agents, it is assumed that all active tools are introduced simultaneously or within a very short period of time. Alternatively, one or two AK is active funds can be taken in the morning and other (other) - later in the day. In another embodiment, one or two active funds can be taken twice a day, and other (other) - once a day or at the same time, when once introduced the tool, taken twice a day, or separately. Preferably at least two and more preferably all of these active means to take together at the same time. Preferably at least two and more preferably all active means to introduce into the mixture.

Below preparative forms are given as examples of tracks:

EXAMPLE COMPOSITIONS 1

50,000 Capsules, each of which contained 100 mg of 2-(3,5-debtor-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid (active ingredient), were prepared from the composition of the following composition:

The active ingredient5 kg
The lactose monohydrate10 kg
Colloidal silicon dioxide0.1 kg
Corn starch1 kg
Magnesium stearate0.2 kg

The method

The above ingredients were sifted through sieves the 60 mesh and placed in a suitable mixer and Packed up to 50,000 capsules made of gelatin.

EXAMPLE COMPOSITION 2

50,000 Tablets, each containing 50 mg of 2-(3,5-debtor-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid (active ingredient), were prepared from the composition of the following composition:

The active ingredient2.5 kg
Microcrystalline cellulose1,95 kg
Dried spray lactose9,95 kg
Carboximetilkrahmal0.4 kg
The sodium fumarate0.1 kg
Colloidal silicon dioxide0.1 kg

The method

All the powders were passed through a sieve with openings of 0.6 mm, then mixed in a suitable mixer for 20 minutes and extruded in tablets of 300 mg using a disk with a diameter of 9 mm flat beveled stamps. Disintegration time of the tablets was approximately 3 minutes

1. The compound of formula (I)

in which
- both groups G1denote CRc;
- G2denotes the nitrogen atom or the group CRd;
- R1denotes a group selected from hydrogen atoms, the volume of halogen, With1-C4-alkyl groups and3-C8-cycloalkyl groups;
- R2denotes a group selected from hydrogen atoms, halogen atoms, hydroxy-group, With1-C4-alkyl groups and1-C4-alkoxygroup, which may not necessarily be substituted by 1, 2 or 3 substituents selected from halogen atoms;
- Ra, Rband Rcindependently denote a group selected from hydrogen atoms, halogen atoms, With1-C4-alkyl groups and1-C4-alkoxygroup, which may not necessarily be substituted by 1, 2 or 3 substituents selected from halogen atoms;
- Rddenotes a group selected from hydrogen atoms, halogen atoms, hydroxy-group, With3-C8-cycloalkyl and C1-C4-alkoxygroup, which may not necessarily be substituted by 1, 2 or 3 halogen atoms; and
- one of the groups G3and G4denotes a nitrogen atom and the other denotes the group SN;
M denotes a hydrogen atom or a pharmaceutically acceptable cation;
provided that if at least one of the groups Raand Rbdenotes a hydrogen atom and G2refers to a group of CRd, Rddenotes a group selected from C1-C4-alkoxygroup, which may not necessarily be substituted by 1, 2 or 3 substituents, selected from the at the MOU halogen and C 3-C8-cycloalkyl;
and its pharmaceutically acceptable salts.

2. The compound according to claim 1, in which R1selected from the group comprising hydrogen atoms, bromine and fluorine, methyl, ethyl, cyclopropyl and cyclobutyl.

3. The compound according to claim 1, in which G3denotes the nitrogen atom, and G4denotes the group SN.

4. The compound according to claim 1, in which G3refers to a group CH and G4denotes a nitrogen atom.

5. The compound according to claim 1, in which each Rcindependently selected from the group comprising hydrogen atoms, fluorine atoms, chlorine atoms, and C1-C3is an alkyl group.

6. The compound according to claim 1, in which the group G2refers to a group of CRd.

7. The connection according to claim 6, in which Rdselected from the group comprising hydroxy-group, With1-C3-alkoxygroup, 2,2,2-triptracker and C3-C4-cycloalkanes.

8. The connection according to claim 7, in which Rdselected from the group comprising C1-C3-alkoxygroup, 2,2,2-triptracker and C3-C4-cycloalkanes.

9. The compound according to claim 1, in which Raselected from the group comprising fluorine atoms, a metal of the group and cryptometer.

10. The compound according to claim 1, in which Rbselected from the group comprising hydrogen atoms, fluorine atoms and chlorine atoms.

11. The compound according to claim 1, in which R2selected from the group VK is causa hydrogen atoms and halogen atoms.

12. Connection by claim 11, in which R2selected from the group comprising hydrogen atoms and fluorine atoms.

13. The compound according to claim 1, in which both groups G1denote the group C(Rc), G2refers to the group C(Rd), Radenotes a fluorine atom, Rbselected from the group comprising hydrogen atoms and fluorine atoms, and R1selected from the group comprising hydrogen atoms, bromine and fluorine, metal, ethyl and cyclopropyl group.

14. The connection 13, in which G2denotes a group selected from C(OH), C(OMe) and C(OEt).

15. The connection 13, in which both groups G1denote SN and G2denotes a group selected from C(OMe) and C(OEt).

16. The connection 13, in which Rcdenotes a hydrogen atom, Rdselected from the group comprising C1-C3-alkoxygroup and C3-C4-cycloalkanes, and R2denotes a hydrogen atom.

17. The connection clause 16, in which Rddenotes a hydroxy-group or1-C3-alkoxygroup.

18. The connection 17 in which Rdrepresents C1-C3-alkoxygroup.

19. The compound according to claim 1, in which G3denotes the nitrogen atom, G4refers to a group CH and Rbdenotes a fluorine atom.

20. The compound according to claim 1, in which G3refers to a group of SN, G4denotes a nitrogen atom.

21. Connection p., which is one of the following connections:
2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid,
2-(3'-ethoxy-3-forbiden-4-ylamino)nicotinic acid,
2-(3-fluoro-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid,
2-(3'-ethoxy-3-(triptoreline)biphenyl-4-ylamino)nicotinic acid,
2-(3'-methoxy-3-(triptoreline)biphenyl-4-ylamino)nicotinic acid,
2-(2,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid,
2-(3'-ethoxy-2,5-diferuloyl-4-ylamino)nicotinic acid,
2-(2',3-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid,
2-(2-methyl-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid,
2-(3-chloro-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid,
2-(3-chloro-3'-ethoxymethyl-4-ylamino)nicotinic acid,
2-(3-methyl-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid,
2-(3-chloro-3'-methoxybiphenyl-4-ylamino)nicotinic acid,
2-(3'-(deformedarse)-3-forbiden-4-ylamino)nicotinic acid,
2-(3'-CYCLOBUTANE-3-forbiden-4-ylamino)nicotinic acid,
2-(3-fluoro-3'-(2,2,2-triptoreline)biphenyl-4-ylamino)nicotinic acid,
2-(3'-CYCLOBUTANE-3,5-diferuloyl-4-ylamino)nicotinic acid,
2-(3,5-debtor-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid,
2-(3'-ethoxy-3,5-diferuloyl-4-ylamino)nicotinic acid,
2-(3,5-debtor-3'-methoxybiphenyl-4-ylamine is)nicotinic acid,
3-(3'-ethoxy-3-forbiden-4-ylamino)isocyanate lithium
3-(3-fluoro-3'-methoxybiphenyl-4-ylamino)isocyanate lithium
3-(3'-methoxy-3-(triptoreline)biphenyl-4-ylamino)isocyanate lithium
3-(3-fluoro-3'-(triptoreline)biphenyl-4-ylamino)isocyanate lithium
2-(3'-ethoxymethyl-4-ylamino)nicotinic acid,
2-(5-fluoro-2-methyl-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid,
2-(2',3-debtor-5'-isopropoxyphenyl-4-ylamino)nicotinic acid,
2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid,
2-(3,5-debtor-3'-hydroxybiphenyl-4-ylamino)nicotinic acid,
5-bromo-2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid,
5-bromo-2-(3,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid,
5-bromo-2-(3-fluoro-3'-(triptoreline)biphenyl-4-ylamino)nicotinic acid,
2-(3-fluoro-3'-(triptoreline)biphenyl-4-ylamino)-5-methylnicotinic acid,
5-cyclopropyl-2-(3-fluoro-3'-methoxybiphenyl-4-ylamino)nicotinic acid,
2-(3,5-debtor-3'-methoxybiphenyl-4-ylamino)-5-methylnicotinic acid,
2-(3'-ethoxy-5-fluoro-2-methylbiphenyl-4-ylamino)nicotinic acid,
2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid,
2-(3'-ethoxy-3,5-diferuloyl-4-ylamino)-5-methylnicotinic acid,
5-cyclopropyl-2-(3'-ethoxy-3,5-diferuloyl-4-ylamino)nicotinic acid,
2-(3,5-debtor-3'-methoxybiphenyl-4-ylamino)-5-etilnikotinata acid is the one
5-bromo-2-(3'-ethoxy-2,5-diferuloyl-4-ylamino)nicotinic acid,
5-cyclopropyl-2-(3'-ethoxy-2,5-diferuloyl-4-ylamino)nicotinic acid,
2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)-5-methylnicotinic acid,
5-cyclopropyl-2-(5-fluoro-3'-methoxy-2-methylbiphenyl-4-ylamino)-nicotinic acid,
2-(2',3,5-Cryptor-3'-methoxybiphenyl-4-ylamino)nicotinic acid,
2-(2'-chloro-3,5-diferuloyl-4-ylamino)nicotinic acid,
2-(3'-cyclopropane-3,5-diferuloyl-4-ylamino)nicotinic acid,
2-(3,5-debtor-2-methylbiphenyl-4-ylamino)nicotinic acid,
5-cyclopropyl-2-(2,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid,
2-(3'-cyclopropane-3,5-diferuloyl-4-ylamino)-5-cyclopropyl-nicotinic acid,
5-chloro-2-(3,5-debtor-3'-methoxybiphenyl-4-ylamino)nicotinic acid,
5-cyclopropyl-2-(3,5-debtor-3'-(triptoreline)biphenyl-4-ylamino)-nicotinic acid,
2-(2,3,5-Cryptor-3'-methoxybiphenyl-4-ylamino)nicotinic acid,
2-(2'-chloro-3,5-diferuloyl-4-ylamino)-5-cyclopropylamino acid,
2-(3,5-debtor-3'-methoxy-2-methylbiphenyl-4-ylamino)nicotinic acid,
2-(3,5-debtor-2-methyl-3'-(triptoreline)biphenyl-4-ylamino)-nicotinic acid,
2-(2'-chloro-3,5-debtor-2-methylbiphenyl-4-ylamino)nicotinic acid,
5-chloro-2-(3,5-diferuloyl-4-ylamino)nicotinic acid,
5-chloro-2-(2'-chloro-3,5-diferuloyl-4-ylamino)nikodinov the I acid,
2-(2,3,5,6-titrator-3'-methoxybiphenyl-4-ylamino)nicotinic acid,
2-(3,5-debtor-2'-methylbiphenyl-4-ylamino)nicotinic acid,
3-(3'-cyclopropane-3-forbiden-4-ylamino)isonicotinate acid.

22. The compound according to any one of claims 1 to 21, intended for use for the treatment of pathological conditions or diseases, the occurrence of which is improved by inhibition of dihydroorotatdehydrogenase, where the pathological condition or disease is selected from the group comprising rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus, psoriasis and sarcoidosis.

23. The pharmaceutical composition intended for treating or preventing a pathological condition or disease, the occurrence of which is improved by inhibition of dihydroorotatdehydrogenase comprising the compound according to any one of claims 1 to 21 in an effective amount together with a pharmaceutically acceptable diluent or carrier.

24. The use of compounds according to any one of claims 1 to 21 for the preparation of medicines intended for the treatment of pathological conditions or diseases specified in article 22.

25. Combined preparation for the treatment or prevention of a pathological condition or disease, the course of which improves PR is the inhibition of dihydroorotatdehydrogenase, including
(i) the compound according to any one of claims 1 to 21 in an effective amount and
(ii) another compound in an effective amount selected from the group including:
a) anti-TNF-alpha monoclonal antibodies, such as infliximab, certolizumab pegol, golimumab, adalimumab and AME-527, produced by the firm Applied Molecular Evolution;
b) antagonists of TNF-alpha, such as etanercept, lenercept, onercept and pegsunercept;
c) inhibitors ekspressirovali calcineurin (PP-2B)/INS, such as cyclosporine a, tacrolimus and ISA-247, produced by the firm Isotechnika;
(d) receptor antagonists, IL-1, such as anakinra and AMG-719, produced by the firm Amgen;
e) anti-CD20-monoclonal antibodies such as rituximab, ofatumumab, ocrelizumab and TRU-015, manufactured by the firm Trubion Pharmaceuticals;
f) inhibitors of the activation of NF-Kappa-b (NFKB), such as sulfasalazin and iguratimod;
g) inhibitors digidrofolatreduktazy (DHFR), such as microtext, aminopterin and CH-1504, produced by the firm Chelsea.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medicine, more specifically to a new chemical compound, a 3-(2,2,2-trimethylhydrazinium)propionate derivative - 3-(2,2,2-trimethylhydrazinium)potassium propionate nicotinate, (CH3)3N+NHCH2CH2COOKRCOO--wherein R= , showing endothelioprotective activity.

EFFECT: derivative can find application in medicine in the integrated treatment for endothelial dysfunction correction in cardiovascular diseases.

1 cl, 2 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to acyloxyalkylcarbamate prodrugs (±)4-amino-3-(4-chlorophenyl)butanoic acid, to based pharmaceutical compositions and to their application, for treating spasticity or a spasticity symptom, gastroesophageal reflux disease (GERD), drug addiction, alcohol addiction or alcohol abuse, or cough, or vomiting. Acyloxyalkylcarbamate prodrugs represent a compound of formula (V) or its pharmaceutically acceptable salt where R1 is selected from C1-C6alkyl substituted by C1-C6alkyl, C3-C6cycloalkyl, phenyl, phenyl C1-C6alkyl substituted by phenyl C1-C6alkyl, phenylC2-C6alkenyl, C5-C6heteroaryl containing 1 nitrogen, oxygen or sulphur atom as a heteroatom; R2 and R3 are independently selected from hydrogen, C1-C6alkyl and C3-C6cycloalkyl; R4 is selected from: hydrogen, phenyl, phenyl C1-C6alkyl and C1-C6alkyl and where "substituted" means a group wherein one or two hydrogen atoms are substitute by a substitute which represent C1-C6alkoxy. Also, the invention refers to an intermediate compound of formula (VII) and its pharmaceutically acceptable salt where X represents: fluorine, chlorine, bromine or iodine; R2 and R3 are independently selected from hydrogen and C1-C6alkyl; R4 is selected from: hydrogen, C1-C6alkyl, phenyl and phenyl C1-C6alkyl.

EFFECT: preparation of the acyloxyalkylcarbamate prodrugs (±)4-amino-3-(4-chlorophenyl)butanoic acid which are applicable for the oral introduction and oral introduction with using prolonged release dosage forms.

23 cl, 3 tbl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining optically active amlodipine trough optical separation of (R,S)-amlodipines where (R,S)-amlodipine reacts with optically active O,O'-dibenzoyl- tartaric acid in an isopropanol solvent to obtain optically active salt of amlodipine-hemi-dibenzoyl-L-tartrate or its solvate, and the optically active salt of amlodipine-hemi-dibenzoyl-L-tartrate or its solvate is treated with a base to obtain optically active amlodipine. The invention also relates to (R)-(+)-amlodipine-hemi-dibenzoyl-L-tartrate, (S)-(-)-amlodipine-hemi-dibenzoyl-D-tartrate, (S)-(-)-amlodipine-hemi-dibenzoyl-L-tatrate, (R)-(+)- amlodipine-hemi-dibenzoyl-D-tatrate or solvates thereof.

EFFECT: obtaining enantiomerically pure amlodipine isomers with activity calcium channel blocker properties.

23 cl, 18 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of preparing optically pure amlodipine gentisate involving the following steps: a) preparation of diastereomeric mixture of amlodipine dibenzoyltartrate from racemic (R,S)-amlodipine using isopropanol solvent and optically pure O,O'-dibenzoyltartaric acid with subsequent optical isolation; and b) treatment of the isolated amlodipine dibenzoyltartrate diastereomer with a base and then obtaining optically pure amlodipine gentisate by adding gentisic acid to the resulting free form in a single continuous step.

EFFECT: continuous method is described for preparing optically pure amlodipine gentisate with good yield and high optical purity.

11 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: medicine.

SUBSTANCE: method for production of optically pure solvate dimethyl formamide of L-hemiartrate(S)-amlodipine includes stages of processing of (R,S)-amlodipine base with L-tartaric acid in presence of dimethyl formamide and cosolvent. Invention is also related to solvate DMFA of L-hemiartrate(S)-amlodipine, solvate of DMFA of L-hemiartrate(R)-amlodipine, solvate of dimethyl formamide L-hemiartrate(S)-amplodipine, produced according to clause 1 and characterised with the following spectrum 1H NMR: 1H NMR (CDCl3): 8.01 (s, 1H, CHO); 7.04-7.41 (m, 4H); 5.40 (s, 1H); 4.72 (kk, 2H), 4.36 (s, 1H), 4.02 (m, 2H), 3.77 (m, 2H), 3.57 (s, 3H), 3.28 (m, 2H), 3.0 (s, 3H; DMFA); 2.8 (s, 3H; DMFA); 2.31 (s, 3H), 1.15 (t, 3H), and also to methods for production of salt of hemipentahydrate bezylate(S)-amlopidine, salt of dihydrate of bezylate(S)-amlodipine.

EFFECT: production of specified compound by economic and industrially realisable method with high enantiomer purity.

20 cl, 14 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to vanadium-titanium oxide catalysts, used for producing nicotinic acid through gas phase oxidation of β-picoline with oxygen and methods of producing nicotinic acid using said catalysts. The catalyst contains vanadium oxide, titanium oxide and modifying additives - cerium oxide or one or more metal oxides, chosen from groups IV and V of the periodic table of elements with total content of oxides of modifying elements in the range 1.0 to10.0 wt %, vanadium oxide in amount of 5.0 to 75.0 wt %, and titanium oxide - the rest. A method is described for producing nicotinic acid through oxidation of β-picoline with oxygen in one or more successive layers of catalyst with different grain-size in a tube reactor in the presence of the catalyst described above.

EFFECT: increased activity of catalyst and selectivity on nicotinic acid.

13 cl, 2 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compound represented by formula I, where R1 and R2 are similar or different and each represents: (I) C1-10alkyl group optionally substituted with 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group b C1-6alkoxygroup; (2) C6-14aryl group optionally substituted with 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycabonyl group b carbamoyl group; or (3) C7-13aralkyl group; R3 represents C6-14aryl group optionally substituted with 1-3 substituents selected from C1-6alkyl group, optionally substituted with 1-3 halogen atoms, halogen atom, C1-6alkoxycarbonyl group, carboxyl group, hydroxy group, C1-6alkoxygroup, optionally substituted with 1-3 halogen atoms; R4 represents amino group; L represents C1-10alkylene group; Q represents bond, C1-10alkylene group or C2-10alkenylene group; and X represents: (1) hydrogen atom; (2) cyanogroup; (3) (3a) carboxyl group; (3b) carbamoyl group; and further as presented in invention formula. Invention also describes medication for treating diabetes, peptidase inhibitor, application of formula I compound, method of prevention or treatment of diabetes, method of peptidase inhibiting and method of obtaining formula I compounds.

EFFECT: obtaining novel compounds which have peptidase-inhibiting activity and are useful as medication for prevention and treatment of diabetes.

16 cl, 433 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, more specifically to a new 3-(2,2,2-trimethylhydrazinium)propionate derivative, 3-(2,2,2-trimethylhydrazinium)potassium propionate 5-bromnicotinate (CH3)3N+HCH2CH2COOKRCOO- wherein .

EFFECT: preparing the compound showing high endothelioprotective activity.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, more specifically to a new chemical compound, a 3-(2,2,2-trimethylhydrazinium)propionate derivative, namely 3-(2,2,2-trimethylhydrazinium)potassium propionate 5-nicotinate hydroxide showing endothelioprotective activity.

EFFECT: preparing the compound which can find application in medicine in the integrated treatment for endothelial dysfunction correction in cardiovascular diseases.

1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of 1,3-dicarbonyl compounds and specifically to a method of producing ethyl ether of 3-oxo-3-(2,6-dichloropyridin-3-yl) propanoic acid of formula: . The method involves acylation of potassium 3-oxo-3-ethoxypropanoate with 2,6-dichloronicotinoyl chloride in the presence of anhydrous solvent, ethylamine and magnesium chloride, followed by treatment of the reaction mass with aqueous hydrochloric acid solution and extraction of the end product, characterised by that the solvent used is ethylacetate, where the molar ratio 2,6-dichloronicotinoyl chloride: potassium 3-oxo-3-ethoxypropanoate is equal to 1:1.4-1.6.

EFFECT: high technological effectiveness of synthesis, as well as high output and purity of the disclosed compound.

1 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula used as herbicides, in which Q1 is H or F; Q2 is a halogen provided that when Q1 is H, Q2 is Cl or Br; R1 and R2 independently denote H, C1-C6-acyl; and Ar is a polysubstituted aryl group selected from a group consisting of

a) , b) , c) in which W1 is a halogen; X1 is C1-C4-alkyl, C1-C4-alkoxy, C1-C4-halogenalkyl, -NR3R4; Y1 is C1-C4-alkyl, C1-C4-halogenalkyl, halogen or -CN, or when X1 and Y1 are taken together denotes -O(CH2)nO-, in which n=1; and R3 and R4 independently denote H or C1-C4-alkyl; W2 is F or Cl; X2 is F, CI, -CN, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-alkylthionyl, C1-C4-alkylsulphonyl, C1-C4-halogenalkyl, C1-C4-halogenalkoxy, C1-C4-alkoxy-substituted C1-C4-alkyl, C1-C4-alkoxy-substituted C1-C4-alkoxy, -NR3R4 or fluorinated acetyl; Y2 is a halogen, C1-C4-alkyl, C1-C4-halogenalkyl or -CN, or when W2 is F, Xz and Y2, taken together, denote -O(CH2)nO-, in which n=1; and R3 and R4 independently denote H or C1-C6-alkyl; Y3 is a halogen or -CN; Z3 is F, CI, -NO2, C1-C4-alkoxy, -NR3R4; and R3 and R4 independently denote H; derivatives on the carboxyl group which are suitable for use in agriculture.

EFFECT: compounds are excellent herbicides with a wide range action against weeds and excellent selectivity towards agricultural crops.

19 cl, 7 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compound of general formula (I): , where Ar1 is a phenyl group substituted with 1-3 halogen atoms; Ar2 is a phenyl group which can be substituted with a halogen, alkoxyalkyl, alkoxyhalogenalkyl, or pyridyl group which can be substituted with halogenalkyl; X is -S-, -SO- or -SO2-; Y is a hydrogen atom, -NR1R2 (where R1 is a hydrogen atom, lower alkyl group or hydroxy group; and R2 is a hydrogen atom, lower alkyl group which can be substituted, lower alkanoyl group, alkoxycarbonyl group which can be substituted, lower alkoxy group which can be substituted, amino group which can be substituted; or R1 and R2 together with a nitrogen atom with which they are bonded form a piperidine, morpholine, azetidine or piperazine ring, which can be substituted wiht a hydroxy group) or -OR1', where R1 is a hydrogen atom); Z is an oxygen atom or sulphur atom; and R is a hydrogen atom or a lower alkyl group; or to salts thereof. The invention also relates to a medicinal agent and a pharmaceutical composition which inhibit production/secretion of β- amyloid protein, to use of said compounds to prepare a medicinal agent and to a method of treating diseases caused by abnormal production or secretion of β- amyloid protein.

EFFECT: novel compounds which can inhibit production/secretion of β- amyloid protein and which can be used in treating Alzheimer disease or Down syndrome are obtained and described.

30 cl, 136 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula (I) , in which Ar is furanyl, thiophenyl, thiazolyl, pyridinyl; R1 is independently chosen from a group consisting of hydrogen, lower alkyl, lower alkoxy, halogen and nitro; R2 is independently chosen from a group consisting of hydrogen and halogen; R4 is hydroxyl or residue of pyrrolidine-2-carboxylic acid, piperidine-2-carboxylic acid or 1-aminocyclopentane carboxylic acid, bonded through a nitrogen atom of an amino acid residue; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; p is 0, and s is 0, or to their pharmaceutically acceptable salts, under the condition that, the compound is not S-1- [5-(biphenyl-4-yloxymethyl)furan-2-carbonyl]pyrrolidin-2-carboxylic acid, 5-(biphenyl-4-yloxymethyl)furan-2-carboxylic acid, 3-(biphenyl-4-yloxymethyl)benzoic acid, 2-(biphenyl-3-yloxymethyl)benzoic acid, 4-(biphenyl-3-yloxymethyl)benzoic acid, 4-(biphenyl-4-yloxymethyl)benzoic acid, 5-(biphenyl-4-yloxymethyl)thiophene-2-carboxylic acid. Invention also relates to a pharmaceutical composition based on formula (I) compounds, which stimulates glycogen synthase activity.

EFFECT: wider range of use of the compounds.

27 cl, 34 ex, 8 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to levodop prodrugs, their stereoisomers, enantiomers or pharmaceutically acceptable salts and based on them pharmaceutical composition for ensuring slowed levodop release, as well as to versions of their application and methods of obtaining them, compounds can be applied for treatment or prevention of diseases in which levodop application is indicated. In general formula (I): , Q is selected from X-CO-; X is selected from -O- and -NH-; n equals integer number from 2 to 4; each R1 and R2 is independently selected from hydrogen, -OH, C1-4alkyl and substituted C1-4alkyl, where substituting group is -OH; R3 and R4 represent hydrogen; R5 is selected from hydrogen, C1-4alkyl, phenyl, substituted phenyl, where each substituting group is independently selected from C1-6alcoxy, C1-6alkyl, halogen and -OH; C3-8cycloalkyl, pyridyl, substituted pyridyl, where each substituting group is independently selected from C1-6alkyl and C1-6alcoxy; on condition that formula (I) compound is not a derivative of 1,3-dihexadecanoylpropane-1,2,3-triol.

EFFECT: elaboration of pharmaceutical composition for ensuring slowed levodop release.

48 cl, 4 dwg, 32 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to method of producing diarylamine compound of Formulas , including the stage (1) including formula 21 compound tailing to amine of formula 22 with alkali salt or transition metal catalyst added, and the stage (2) group Y removing from produced compound with acid added: , where radical values are those specified in cl. 1 of formula of invention; as well as to compound of formula (A) or , where X1, X2, X3 and X4 are independently chosen from fluorine and chlorine; and R represents H or methyl.

EFFECT: high-yield production of high purity diaryamines.

49 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , Y represents -CF2(C1-C3 alkyl); W represents -NR1R2, where R1 and R2 independently represent H or C1-C6 alkyl; and acceptable in agriculture carboxyl or 4-aminogroup derivatives. Invention relates to herbicidal composition, containing formula (I) compound and to method of undesirable vegetation control, which includes contacting of vegetation or place of its location with efficient as herbicide amount of compound of formula (I) in item 1, or its application on soil in order to prevent soot emergence.

EFFECT: obtained are novel compounds which can be used as herbicides.

8 cl, 3 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: compound of formula (I) wherein X represents H or F; Y represents C1-C4 alkyl;C1-C4 alkyl substituted C1-C4 by the group alkoxy; C1-C4 alkyl substituted by the group C1-C4 thioalkoxy, or C2-C3 alkenyl; and agriculturally acceptable salts and esters of carboxylic acid group. The compounds have herbicide potency. The herbicide composition and the method of weed control using the compound of formula (I) are also described.

EFFECT: production of the compound characterized with herbicide potency.

4 cl, 5 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and may be used in integrated treatment of stomach cancer. That is ensured by a surgical intervention to place a microirrigator into an abdominal cavity. Then 4 weeks after the surgery, blood 300 ml is taken on the first day to be centrifuged and to recover autoplasma. Autoplasma and chemopreparations are placed into a first flask, autoplasma - into second and third flasks, blood corpuscles and chemopreparations - into a forth force. The 2nd and 3rd flasks are frozen, the 1st and 4th flasks are separately incubated for 40 minutes at 37°C. The incubated blood corpuscles and chemopreparations from the 4th flask are introduced intravenously drop-by-drop. Autoplasma and chemopreparations from the 1st flask are introduced intraperitoneally through the microirrigator. It is followed by 1 session of radiation therapy on the abdominal cavity at single dose 2 Gy. On the 2nd and 4th therapeutic days, only sessions of radiation therapy are applied. On the 3rd and 5th days, the sessions of radiation therapy are preceded by freezing one flask with autoplasma added with chemopreparations, and the flasks are incubated for 40 minutes at 37°C. Then autoplasma and chemopreparations are introduced intraperitoneally through the microirrgator, and the session of radiation therapy is conducted. On the 6th and 7th days, a pause is made. Starting from 8th and 15th days, a five-day therapeutic course is repeated.

EFFECT: method enables reducing rate of metastases in the peritoneum caused by stomach cancer and increasing survival rate of the patients due to combined surgical and chemoradiation therapy in a certain mode.

2 ex

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