Novel substituted indoles

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted indoles or its pharmaceutically acceptable salts of the formula (I): , wherein R1 means hydrogen (H) atom, halogen atom, -CN, nitro-group, -SO2R4, -OH, -OR4, -SO2NR5R6, -CONR5R6, -COOH, -COOCH3, -NR5R6, phenyl, naphthyl or (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atom, -OR8 and -NR5R6 wherein x = 2; R2 means (C1-C7)-alkyl; R3 means phenyl, naphthyl or heteroaryl and each of them is possibly substituted with one or more substitutes chosen independently from H, halogen atom, -CN, -OH, -SO2R4, -OR4, -SO2NR5R6, -CONR5R6, phenyl, naphthyl, (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atoms, -OR8 and -NR5R6, -S(O)xR7 wherein x = 2; R4 means (C1-C6)-alkyl; R5 and R6 mean independently H, (C1-C6)-alkyl, or R5 and R6 in common with nitrogen atom to which they are bound can form 6-membered saturated heterocyclic ring comprising one atom chosen from -NR16; R7 means (C1-C6)-alkyl; R8 means H, (C1-C6)-alkyl; R16 means H, -COY-(C1-C4)-alkyl wherein Y means oxygen atom (O) and wherein alkyl group in the substitute group can be direct, branched or cyclic, and wherein heteroaryl means 5-6-membered heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or means 6,6-condensed bicyclic aromatic ring system comprising one nitrogen atom. Compounds of the formula (I) can be used in production of a medicinal agent used in treatment of asthma and chronic obstructive disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 2 tbl, 59 ex

 

The present invention relates to substituted the indoles, useful as pharmaceutical compounds for treating respiratory disorders, pharmaceutical compositions containing them and to methods for their preparation.

In EPA 1170594 disclosed are methods of identifying compounds useful for treatment of disease conditions mediated by prostaglandin D2, a ligand for a receptor of orthanes CRTh2. In GB 1356834 disclosed a series of compounds, which, as indicated, have anti-inflammatory, analgesic and cough activity. Suddenly discovered that some indeloxazine acids are active at the CRTh2 receptor, and consequently expect that they are potentially useful for the treatment of various respiratory diseases, including asthma and COPD.

Thus, in the first aspect of the invention proposed compound of formula (I) or its pharmaceutically acceptable salt or MES:

in which

R1represents hydrogen, halogen, CN, nitro, SO2R4HE, OR4, S(O)xR4, SO2NR5R6, CONR5R6, NR5R6, aryl (possibly substituted by chlorine or fluorine)2-C6alkenyl,2-C6quinil or1-6alkyl, the latter three groups possibly substituted by one or more than onesemester, independently selected from halogen, OR8and NR5R6, S(O)xR7where x is 0, 1 or 2;

R2represents hydrogen, halogen, CN, SO2R4or CONR5R6CH2HE, CH2OR4or1-7alkyl, the latter group possibly substituted by one or more than one Deputy, independently selected from halogen atoms, OR8and NR5R6, S(O)xR7where x is 0, 1 or 2;

R3represents aryl or heteroaryl, each of which may substituted by one or more than one Deputy, is independently selected from hydrogen, halogen, CN, nitro, HE, SO2R4, OR4, SR4, SOR4, SO2NR5R6, CONR5R6, NR5R6, NHCOR4, NHSO2R4, NHCO2R4, NR7SO2R4, NR7CO2R4With2-C6alkenyl,2-C6the quinil,1-6the alkyl, the latter three groups possibly substituted by one or more than one Deputy, independently selected from halogen atoms, OR8and NR5R6, S(O)xR7where x is 0, 1 or 2;

R4represents aryl, heteroaryl or C1-6alkyl, all of which can be possibly substituted by one or more than one Deputy, is independently selected from the atoms Gal is gene aryl, heteroaryl, OR10HE, NR11R12, S(O)xR13(where x is 0, 1 or 2), CONR14R15, NR14COR15, SO2NR14R15, NR14SO2R15, CN, nitro;

R5and R6independently represent a hydrogen atom, a C1-6alkyl, or aryl or heteroaryl, the latter three of which may be substituted by one or more than one Deputy, independently selected from halogen atoms, aryl, OR8and NR14R15, CONR14R15, NR14COR15, SO2NR14R15, NR14SO2R15, CN, nitro, or

R5and R6together with the nitrogen atom to which they are attached can form a 3-8-membered saturated heterocyclic ring may contain one or more than one atom selected from O, S(O)xwhere x is 0, 1 or 2, NR16and very possibly substituted C1-3by alkyl;

R7and R13independently represent a group With1-C6alkyl, aryl or heteroaryl, all of which can be substituted by halogen atoms;

R8represents a hydrogen atom, C(O)R9C1-C6alkyl (possibly substituted by halogen atoms or by aryl), aryl or heteroaryl group possibly substituted with halogen);

each of R9, R0 , R11, R12, R14, R15independently represents a hydrogen atom, a C1-C6alkyl, aryl, or heteroaryl group (all of which can be substituted by halogen atoms), and

R16represents hydrogen, C1-4alkyl, -SOS1-C4alkyl, COYC1-C4alkyl, where Y is O or NR7.

In the context of the present description, unless otherwise specified, alkyl or Alchemilla group, or alkyl or Alchemilla grouping in the group substituent may be normal, branched or cyclic.

Aryl represents phenyl or naphthyl.

Heteroaryl defined as 5-7-membered aromatic ring or may be 6,6 - or 6,5-condensed bicyclic, where each ring contains one or more than one heteroatom selected from N, S and O. Examples include pyridine, pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan, isoxazol, pyrrole, isothiazol and azulene, naphthyl, inden, quinoline, isoquinoline, indole, indolizine, benzo[b]furan, benzo[b]thiophene, 1H-indazole, benzimidazole, benzthiazole, 1,2-benzisothiazol, benzoxazole, purine, 4H-hemolysin, cinnolin, phthalazine, hinzelin, cinoxacin, 1,8-naphthiridine, pteridine,hinolan.

Heterocyclic ring, as defined for R5and R6mean saturated heterocycles, examples of which included the Ute morpholine, thiomorpholine, azetidin, imidazolidin, pyrrolidine, piperidine and piperazine.

The term "alkyl", alone or as part of another group, includes remotemachine, branched or cyclic alkyl groups.

Preferably R1represents hydrogen, halogen, nitro, NR4R5, nitrile, SO2R4, SO2NR5R6, OMe, aryl, CO2R8or C1-6alkyl which may be substituted by one or more than one Deputy, independently selected from halogen atoms, OR8and NR5R6, S(O)xR7where x is 0, 1 or 2. May contain more than one substituent R1and they may be the same or different. More preferably R1represents aryl, hydrogen, methyl, chloro, fluorescent, nitrile, nitro, bromine, iodine, SO2IU, SO2Et, NR4R5, SO2N-alkyl2, alkyl (possibly substituted by fluorine atoms). Most preferably, R1represents hydrogen, methyl, phenyl, chloro, fluorescent, iodine, nitrile, SO2Me, CF3the nitrile.

The group or groups R1can be in any suitable position of the indole ring, preferably the group(s) R1find(I)4 and / or 5-position. Preferably the number of substituents R1other than hydrogen, is 1 or 2.

Preferably R2/sup> represents a C1-6alkyl, more preferably methyl.

Accordingly, R3represents phenyl or heteroaryl. Suitable heteroaryl groups include 6,6 - or 6,5-condensed bicyclic aromatic ring system may contain one to three heteroatoms selected from nitrogen, oxygen, or sulfur, or a 5-7 membered heterocyclic ring containing one to three heteroatoms selected from nitrogen, oxygen or sulfur.

Examples of suitable heteroaryl groups include pyridine, pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan, isoxazol, pyrrole, isothiazol and azulene, naphthyl, inden, quinoline, isoquinoline, indole, indolizine, benzo[b]furan, benzo[b]thiophene, 1H-indazole, benzimidazole, benzthiazole, benzoxazole, purine, 4H-hemolysin, cinnolin, phthalazine, hinzelin, cinoxacin, 1,8-naphthiridine, pteridine, indole, 1,2-benzisothiazol and hinolan.

Preferably R3represents chenail, phenyl or thiazole, each of which may be substituted, as defined above. More preferably R3represents phenyl or chenail, each of which may be substituted, as defined above.

The group R3may be substituted by one or more than one Deputy from halogen, methoxy, alkyl, CF3, SO2alkyl, aryl or cyano. More predpochtitel what about the substituents on the R 3are fluorine, chlorine, methyl, ethyl, isopropyl, methoxy, SO2Me, trifluoromethyl or aryl. Preferably, the substituents can be in any suitable position of the group R3. Most preferably, when R3represents phenyl, the substituents are in the 4th position.

When R3represents a heterocycle, the heteroatom(s) may be located in any position in the ring.

Preferred compounds according to the invention include:

3-[(4-chlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(2-chloro-4-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(3-chloro-4-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(2-methoxyphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(3-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(4-ethylphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(2-chlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(2,5-dichlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(4-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(4-chloro-2-were)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-4-cyano-2,5-dimethyl-1H-indole-1-acetic acid;

5-chloro-3-[(4-chlorophenyl)thio]-6-cyano-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-1-acetic acid;

3-[(4-CHL is henyl)thio]-4-[(diethylamino)sulfonyl]-7-methoxy-2-methyl-1H-indole-1-acetic acid;

4-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

5-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

6-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

7-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-2-methyl-5-(methylsulphonyl)-1H-indole-1-acetic acid;

2-methyl-3-[(4-were)thio]-6-(methylsulphonyl)-1H-indole-1-acetic acid;

4-bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-4-[4-[(1,1-dimethylmethoxy)carbonyl]-1-piperazinil]-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-2-methyl-4-(1-piperazinil)-1H-indole-1-acetic acid;

5-bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-2-methyl-5-phenyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-5-cyano-2-methyl-1H-indole-1-acetic acid;

3-[(4-cyanophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(3-methoxyphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(4-methoxyphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(3-ethylphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

2,5-dimethyl-3-[(2-were)thio]-1H-indole-1-acetic acid;

3-[(3-chlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(2-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(2,6-dichlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic to the slot;

3-(1H-imidazol-2-ylthio)-2,5-dimethyl-1H-indole-1-acetic acid;

2,5-dimethyl-3-(1H-1,2,4-triazole-3-ylthio)-1H-indole-1-acetic acid;

2,5-dimethyl-3-[(4-methyl-4H-1,2,4-triazole-3-yl)thio]-1H-indole-1-acetic acid;

2,5-dimethyl-3-[(4-methyl-2-oxazolyl)thio]-1H-indole-1-acetic acid;

2,5-dimethyl-3-[(1-methyl-1H-imidazol-2-yl)thio]-1H-indole-1-acetic acid;

2,5-dimethyl-3-[[4-(methylsulphonyl)phenyl]thio]-1H-indole-1-acetic acid;

2,5-dimethyl-3-(8-chinaindia)-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-5-fluoro-2,4-dimethyl-1H-indole-1-acetic acid;

3-[(4-cyanophenyl)thio]-5-fluoro-2,4-dimethyl-1H-indole-1-acetic acid;

3-[(2-chlorophenyl)thio]-5-fluoro-2,4-dimethyl-1H-indole-1-acetic acid;

5-fluoro-3-[(2-methoxyphenyl)thio]-2,4-dimethyl-1H-indole-1-acetic acid;

5-fluoro-3-[(2-ethylphenyl)thio]-2,4-dimethyl-1H-indole-1-acetic acid;

5-fluoro-2,4-dimethyl-3-[[2-(1-methylethyl)phenyl]thio]-1H-indole-1-acetic acid;

5-fluoro-2,4-dimethyl-3-[[2-(trifluoromethyl)phenyl]thio]-1H-indole-1-acetic acid;

2,5-dimethyl-4-(methylsulphonyl)-3-[(4-phenyl-2-thiazolyl)thio]-1H-indole-1-acetic acid;

3-[(3-chlorophenyl)thio]-2,5-dimethyl-4-(methylsulphonyl)-1H-indole-1-acetic acid;

3-[(2-chlorophenyl)thio]-2,5-dimethyl-4-(methylsulphonyl)-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-5-(methoxycarbonyl)-2-methyl-1H-indole-1-acetic acid;

5-carboxy-3-[(4-chlorophenyl)thio]-2-methyl-1H-in the ol-1-acetic acid;

3-[(4-chlorophenyl)thio]-2-methyl-4-nitro-1H-indole-1-acetic acid;

4-amino-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-4-(ethylamino)-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-4-iodine-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-2-methyl-4-phenyl-1H-indole-1-acetic acid

and their pharmaceutically acceptable salts.

Some compounds of formula (I) can exist in different stereoisomeric forms. It should be clear that the invention encompasses all geometric and optical isomers of compounds of formula (I) and mixtures thereof, including racemates. The tautomers and their mixtures also form an aspect of the present invention.

The above compound of formula (I) can be transformed into its pharmaceutically acceptable salt or MES, preferably in salt joining the Foundation, such as a salt of ammonium, sodium, potassium, calcium, aluminum, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or salt accession acids, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or para-toluensulfonate. Preferred salts include the salts of sodium and ammonium.

The above compounds of formula (I) can be converted into their FA is matemticas acceptable salt or MES. Preferred salts include salts of sodium.

In the following aspect, a method for obtaining compounds of formula (I), wherein the compound of formula (II):

in which R1, R2and R3are as defined in formula (I), or their protected derivatives,

subjected to interaction with the compound of the formula (A):

where R17represents a group forming an ester, a L is a leaving group, in the presence of a base, and may thereafter in any order:

- remove any protective group,

is subjected to ester group R17hydrolysis to the corresponding acid,

- form a pharmaceutically acceptable salt.

This interaction can be performed in a suitable solvent, such as THF, using a base such as sodium hydride or the like. Suitable groups R17include groups C1-6alkyl, such as methyl, ethyl or tert-butyl. Suitable L is a leaving group, such as halogen, in particular bromo. Preferably the compound of formula (A) represents ethyl-, methyl - or tert-butylbromide.

Hydrolysis of the ether group, R17can be carried out using conventional techniques, for example by mixing with an aqueous sodium hydroxide or streptococcuses acid.

It should be clear that some functional groups may need to be protected using standard protective group. Protection and removal to protect functional groups, for example, described in "Protective Groups in Organic Chemistry", edited by J.W.F.McOmie, Plenum Press (1973) and in "Protective Groups in Organic Synthesis", 3rdedition, T.W.Greene and P.G.M.Wuts, Wiley-lnterscience (1999).

The compounds of formula (II) can be obtained by reacting the compounds of formula (III) with the compound of the formula (IV):

where R1, R2and R3are as defined in formula (I).

Preferably this interaction is carried out in acetic acid when heated.

Otherwise, the compounds of formula (II) can be obtained by reacting the compounds of formula (V) with the compound of the formula (IV)

where R1, R2and R3are as defined in formula (I).

Preferably this interaction is carried out in a suitable solvent, such as dichloromethane or THF, using gloriouse agent, such as sulphonylchloride or tert-butylhypochlorite.

Compounds of formula (III), (IV) and (V) are commercially available or can be obtained using standard chemical techniques well known in the art.

Otherwise, the compounds of formula (I) can be obtained from compounds of formulas is (VI). This reaction is carried out with the compound of the formula (V) in the presence of a halogenation agent, such as iodine, in a suitable organic solvent, such as DMF,

where R1, R2, R3and R17are as defined for formula (I) and (A), or their protected derivatives. The compound of formula (I) obtained by hydrolysis using standard conditions, as described above.

The compounds of formula (VI) can be obtained from compounds of formula (VII) by reacting with the compound of the formula (A), as described above

Some compounds of formula (VII) are commercially available or can be obtained from compounds of formula (VIII) by reacting with the compound of the formula (In). This interaction is carried out in the presence of thiol, preferably thiosalicylic acid, triperoxonane acid

The compounds of formula (VIII) can be obtained by reacting the compounds of formula (IV) with compound (IX)as described for preparing compounds of the formula (II) above, in which R1, R2and R3are as defined in formula (II), or their protected derivatives. R18represents a C1-C6alkyl (e.g. methyl) or equivalent to R3

Otherwise, the compounds of formula (VII) can be converted into compounds of formula (I) by reacting with the compound of the formula (In). This interaction is carried out in the presence of iodine in a suitable organic solvent, such as DMF. Sometimes this reaction is carried out in the presence of a base such as sodium hydride, after a period of stirring, the reaction mixture is treated with a compound of the formula (A), and then subjected to hydrolysis. Alternative intermediate compound of formula (VIII) can be selected, and then subjected to interaction with the compound of the formula (A) with subsequent hydrolysis.

Otherwise, the compounds of formula (I) can be obtained from compounds of formula (X) by reacting with compounds of the formula (XI)

where R1, R2, R3, R5and R6are as defined in formula (I), a R17is the same as defined in formula (a), or their protected derivatives. Y represents halogen, preferably bromine or iodine. Preferably this reaction is performed using conditions Buchwald reaction using palladium catalysis. A more preferred catalyst is a Pd2(dba)3with BINAP as ligand. This reaction is carried out in toluene in the presence of a base, so the th as tert-piperonyl sodium, at 110°C. the Ether group, R17then subjected to hydrolysis, as described above.

Otherwise, the compounds of formula (I) can be obtained from compounds of formula (X) by reacting with the compound of the formula (XII)

where R1, R2, R3, R5and R6are as defined in formula (I), a R17is the same as defined in formula (a), or their protected derivatives. Y represents halogen, preferably bromine or iodine. Preferably this reaction is carried out using reaction conditions, the combination of Suzuki using palladium catalysis, and the used catalyst is a Pd(PPh3)4. This reaction is performed in ethanol and toluene in the presence of a base such as sodium bicarbonate, while boiling under reflux. Ether group, R17then subjected to hydrolysis, as described above.

The compounds of formula (X) are obtained from compounds of formula (II) by reacting with the compound of the formula (A), as set forth above.

The compounds of formula (XI) and (XII) are commercially available or can be obtained by methods well known in the art.

Some compounds of formula (II), (VI), (VIII) and (X) are new and form a further aspect of the invention.

The following aspect of the invention p is edlozano compound of formula (IA), which is a subclass of formula (I):

where R1and R2independently represent hydrogen, halogen, CN, amino, nitro, C1-6alkyl, C1-6alkoxy, SO2With1-6alkyl or CONR4R5where R4and R5independently represent hydrogen or C1-6alkyl, and

R3represents phenyl or heteroaryl, and each of these groups possibly substituted by one or more than one Deputy, selected from halogen, C1-6of alkyl, C1-6alkoxy, SO2With1-6of alkyl, CN, amino, or CONR4R5where R4and R5independently represent hydrogen or C1-6alkyl,

and its pharmaceutically acceptable salts.

The following aspect of the present invention proposed the use of the compounds of formula (I), its prodrug, pharmaceutically acceptable salt or MES for use in therapy.

The compounds of formula (I) have activity as pharmaceutical agents, in particular as modulators of the activity of the receptor CRTh2, and can be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and animal aggravation or reason which caused intense and unregulated's unstable past also produces what Finance PGD 2and its metabolites. Examples of such conditions/diseases include:

(1) (the respiratory tract) obstructive diseases of the Airways including: asthma (such as bronchial, allergic, hereditary, acquired asthma and pneumoconiosis, particularly chronic or inveterate asthma (for example late asthma or increased airway reactivity)); chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); bronchitis (including eosinophilic bronchitis; acute, allergic, atrophic rhinitis or chronic rhinitis (such as chronic rhinitis with the formation of caseous masses, hypertrophic rhinitis, purulent rhinitis, dry rhinitis), medicamental rhinitis, membranous rhinitis (including croupous, fibrinous and pseudomembranous rhinitis), tuberculosis rhinitis, perennial allergic rhinitis, seasonal rhinitis (including nervous rhinitis (hay fever) and vasomotor rhinitis); nasal polyposis; sarcoidosis; light farmer's and related diseases; pneumosclerosis; idiopathic interstitial pneumonia; cystic fibrosis; antitussive activity; treatment of chronic cough associated with inflammation or iatrogenic induction;

(2) (bone and joints) arthritis, including rheumatic, infectious, autoimmune, seronegative, spondyloarthropathies (such as ankylosing SPO is dieletric, psoriatic arthritis or disease Reiter), Behcet's disease, Sjogren syndrome or systemic sclerosis;

(3) (eye and skin) psoriasis, atopic dermatitis, contact dermatitis, and other eczematous dermatitises, seborrhoeic eczema, lichen planus, bladderwort, the bullous disease, congenital bullous bullosa, urticaria, inflammation of the skin vessels, vasculitis, erythema, dermal eosinophilia, chronic skin ulcers, uveitis, alopecia alopecia, ulcers of the cornea and vernal conjunctivitis;

(4) (gastrointestinal tract) coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, food allergies, which are remote from the intestinal effects (such as migraine, rhinitis and eczema);

(5) (Central and peripheral nervous system neurodegenerative diseases and disorders such as dementia (such as Alzheimer's disease, amyotrophic lateral sclerosis and other diseases motor neuron disease Creutzfeldt-Jakob and other prion diseases, HIV encephalopathy (complex, dementia associated with AIDS), Huntington's disease, fronto-temporal dementia, dementia Taurus Levi's and vascular dementia), polyneuropathy (such as the syndrome of Guillain-Bar, a chronic inflammatory demyelinizing polyadic lanevid, multifocal motor neuropathy), plexopathy, demyelination of the Central nervous system (such as multiple sclerosis, acute disseminated/haemorrhagic encephalomyelitis, and subacute sclerosing panencephalitis), neuromuscular disorders (such as severe myasthenia Syndrome of Lambert-Eaton), spinal disorders (such as tropical spastic prepares syndrome and frozen human), paraneoplastic syndromes (such as spinal cerebellar degeneration and encephalomyelitis), injury to the Central nervous system, migraine, and stroke;

(6) (disorders of other tissues and systems) atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematous, systemic lupus erythematosus, Hashimoto thyroiditis, diabetes type I, nephrotic syndrome, eosinophilic fasciitis, a syndrome of elevated IgE, lepromatous leprosy, idiopathic thrombocytopenic purple; postoperative adhesions, sepsis and ischemic/reperfusion injury in the heart, brain, peripheral limbs, hepatitis (alcoholic, fat and chronic viral), glomerulonephritis, renal insufficiency, chronic kidney failure and other bodies;

(7) (allograft rejection) acute and chronic effects, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic disease graft PR is against the owner;

(8) diseases associated with elevated levels of PGD2or its metabolites.

Thus, in the proposed invention the compound of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, for use in therapy.

Preferred compounds according to the invention are used to treat diseases in which the receptor for chemokines belong to the subfamily of receptor CRTh2.

Specific conditions that can be treated with compounds according to the invention, are asthma, rhinitis and other diseases in which increased levels of PGD2or its metabolites. Preferred compounds according to the invention is used to treat asthma.

The following aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, in the production of drugs for use in therapy.

The following aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, in the production of drugs for use in therapy in combination with drugs used to treat asthma and rhinitis (such as inhaled and oral steroids, inhaled agonists β2-receptor and oral receptor antagonists lacot is Yanov).

The following aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, in the manufacture of medicaments for the treatment of diseases or conditions of the person, which is useful modulation of activity of CRTh2 receptors.

In the context of the present description, the term "therapy" also includes "prevention", if no special contradictory instructions. The term "therapeutic" and "therapeutically" should be understood accordingly.

Further, in the invention, a method for treating diseases mediated PGD2or its metabolites, where the prostanoid binds to its receptor (in particular, with the CRTh2 receptor), wherein the patient is administered a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or prodrug, as defined above.

The invention is also a method of treatment of inflammatory diseases, in particular psoriasis in a patient suffering from the specified disease or having a risk of developing the disease, wherein the patient is administered a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or MES, as defined above.

For the above-mentioned therapeutic applications entered the dosage will be, the end is Oh, vary depending on the compound, the route of administration, the desired treatment of a particular disorder.

The compound of formula (I), prodrugs, and pharmaceutically acceptable salt and solvate can be used by themselves, but usually they will enter in the form of pharmaceutical compositions in which the compound of formula (I)/Sol/MES (active ingredient) is in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration of the pharmaceutical composition will preferably contain from 0.05 to 99% wt./wt. (percent by weight), more preferably from 0.05 to 80% wt./wt., even more preferably from 0.10 to 70% wt./wt. and even more preferably from 0.10 to 50% wt./wt. the active ingredient, all percentages by weight based on the total composition.

The present invention also proposed a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions can be entered locally (for example, in the lung and/or Airways or to the skin) in the form of solutions, suspensions, heptapteridae aerosols and dry powder products or sist the many, for example, by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous injection, or by rectal injection in the form of suppositories, or percutaneous route. Preferably the connection according to the invention is administered orally.

The present invention also proposed a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

Now the invention will be illustrated by the following non-limiting examples in which, unless stated otherwise:

(1) compounds listed in titles and subtitles of the examples and methods were named using the ACD labs/name (version 6.0) from Advanced Chemical Development Inc., Canada;

(2) unless otherwise specified, preparative HPLC with reversed-phase was performed using a column of silica gel, reversed-phase Symmetry, NovaPak or Ex-Terra;

(3) column flash chromatography refers to chromatography on silica gel normal phase;

(4) solvents were dried MgSO4or Na2SO4;

(5) evaporation were carried out by rotary evaporation in vacuo and procedures of processing performed after the UDA is possible residual solids, such as drying agents by filtration;

(6) unless otherwise stated, operations were carried out at ambient temperature, i.e. in the range of 18-25°and in the atmosphere of inert gas such as argon or nitrogen;

(7) the output values are given for illustration only and are not necessarily the maximum attainable;

(8) the structure of the final products of formula I were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; the values of the chemical shift of proton magnetic resonance were measured on the Delta scale and peak sets are listed as follows: s - singlet; d - doublet; t - triplet; m - multiplet; br, broad; q, Quartet; quin quintet;

(9) intermediate compounds, as a rule, are not fully characterised and purity was assessed by thin layer chromatography (TLC), high performance liquid chromatography (HPLC), mass spectrometry (MS), infrared (IR) or NMR analysis;

(10) mass spectra (MS): generally, where they are listed, are given only ions which indicate the original mass; data1H NMR is given in the form of Delta values for major diagnostic protons, given in ppm (m-1regarding tetramethylsilane (TMS) as internal standard;

(11) used the following abbreviations:

EtOAcThe ethyl acetateDMFN-dimethylformamideNMPN-methylpyrrolidineTHFtetrahydrofuranCTroom temperatureTFUtriperoxonane acid

Example 1

3-[(4-Chlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid

1) Ethyl ester of 3-[(4-chlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid

The mixed solution of 3-[(4-chlorophenyl)thio]-2,5-dimethyl-1H-indole (300 mg) in anhydrous N,N-dimethylformamide (15 ml) was treated with sodium hydride (42 mg, 60% dispersion in mineral oil). After 10 min, this reaction mixture was treated with ethylbromoacetate (116 μl) and stirring was continued for 24 hours. This reaction mixture was poured into distilled water (200 ml) and was extracted with diethyl ether (3×100 ml). The extracts were dried (MgSO4), evaporated in vacuo and the residue was purified column flash chromatography, elwira 10% ethyl acetate in isohexane. The connection specified in the subtitle, received in the form of a yellow solid (yield 130 mg).

1H NMR CDCl3: δ (1H, m), 7.17-7.03 (4H, m), 6.94 (2H, m), 4.85 (2H, s), 4.22 (2H, q), 2.46 (3H, s), 2.40 (3H, s), 1.26 (3H, t).

2) 3-[(4-Chlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid

A solution of compound from step (1) (120 m is) in ethanol (5 ml) was treated with water (5 ml) and 2.5 N. a solution of sodium hydroxide (1 ml). The resulting suspension was stirred at 70°C for 1 hour and the ethanol was removed in vacuum. The aqueous residue was acidified using 2 N. hydrochloric acid and the precipitate was filtered and concentrated in vacuum to obtain compound indicated in the title, in the form of a whitish solid (yield 102 mg).

1H NMR d6-DMSO: δ 13.12 (1H, br s), 7.41 (1H, d), 7.27 (1H, m), 7.24 (1H, m), 7.15 (1H, m), 7.01-6.94 (3H, m), 5.08 (2H, s), 2.39 (3H, s), 2.34 (3H, s).

TPL 219-221°C.

Examples 2-10 are examples of compounds of formula (I) were obtained by the General method below.

To a solution of the corresponding arylthiol (1 g) in dichloromethane (15 ml) was added triethylamine (1 molar equivalent), and then 1-chloroacetone (1 molar equivalent). This reaction mixture was stirred for 2 hours. This reaction mixture is washed with water, dried (MgSO4), filtered and evaporated. To the product was added the hydrochloride of 1-(4-were)hydrazine (1 molar equivalent) and acetic acid (15 ml). This reaction mixture was heated at 70°C for 5 hours. In the evaporation of the solvent and purification HPLC with reversed phase gradient system eluents (25% MeCN/NH3(aq.) (0.1%) to 95% MeCN/NH3(aq.) (0,1%)) were below the intermediate table 1.

Table 1
The intermediate connectionNameMS: ES(-ve) (M-H)
(1)3-[(2-chloro-4-forfinal)thio]-2,5-dimethyl-1H-indol304
(2)3-[(3-chloro-4-forfinal)thio]-2,5-dimethyl-1H-indol304
(3)3-[(2-methoxyphenyl)thio]-2,5-dimethyl-1H-indol282
(4)3-[(3-forfinal)thio]-2,5-dimethyl-1H-indol270
(5)3-[(4-ethylphenyl)thio]-2,5-dimethyl-1H-indol280
(6)3-[(2-chlorophenyl)thio]-2,5-dimethyl-1H-indol286
(7)3-[(2,5-dichlorophenyl)thio]-2,5-dimethyl-1H-indol320
(8)3-[(4-forfinal)thio]-2,5-dimethyl-1H-indol270
(9)3-[(4-chloro-2-were)thio]-2,5-dimethyl-1H-indol300

Then these intermediate compounds were subjected to N-alkylation and ester was subjected to hydrolysis as in the example 1. Thus, the received examples 2-10 table 2.

Table 2
ExampleNameMS: ES(-ve) (M-H)
23-[(2-chlorine is-4-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid 362
33-[(3-chloro-4-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid362
43-[(2-methoxyphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid340
53-[(3-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid328
63-[(4-ethylphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid338
73-[(2-chlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid344
83-[(2,5-dichlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid378
93-[(4-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid328
103-[(4-chloro-2-were)thio]-2,5-dimethyl-1H-indole-1-acetic acid358

Example 11

3-[(4-Chlorophenyl)thio]-4-cyano-2,5-dimethyl-1H-indole-1-acetic acid

1) 3-[(4-Chlorophenyl)thio]-2,5-dimethyl-1H-indol-4-carbonitril

The stirred solution of 1-[(4-chlorophenyl)thio]-acetone (6,14 g) in anhydrous dichloromethane (150 ml) at -78°handled sulphonylchloride (2.25 ml). After 30 min was added dropwise freshly prepared solution of N,N,N',N'-tetramethyl-1,8-naphthaleneamine (6,01 g) and 5-amino-2-chloro-benzonitrile (to 3.89 g) in dry dichloro ethane (80 ml) for 30 minutes This mixture was stirred for the next 2 hours, after which was added triethylamine (4.26 deaths ml) and the reaction mixture was allowed to reach room temperature. This reaction mixture was diluted with dichloromethane (200 ml), washed with water, 1 N. HCl and brine. The organic phase was dried (MgSO4), evaporated in vacuo and the residue was purified column flash chromatography, elwira isohexane and ethyl acetate (1:1), with the connection specified in subhead (1 g).

1H NMR CDCl3: δ 12.52 (s, 1H), 7.74 (d, 1H), 7.38 (dd, 1H), 7.29 (m, 2H), 6.97 (m, 2H), 3.29 (s, 3H).

Was also obtained regioisomer 5-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-6-carbonitrile (600 mg).

1H NMR CDCl3: δ 8.68 (1H, s), 7.69 (1H, s), 7.61 (1H, s), 7.15 (2H, dt), 6.91 (2H, dt), 2.57 (3H, s).

2) Methyl ether 3-[(4-chlorophenyl)thio]-4-cyano-2,5-dimethyl-1H-indole-1-acetic acid

To a stirred solution of sodium hydride (96,1 mg of 60% dispersion in mineral oil) in anhydrous tetrahydrofuran (15 ml) was added 3-[(4-chlorophenyl)thio]-2,5-dimethyl-1H-indol-4-carbonitrile (400 mg) in anhydrous tetrahydrofuran (5 ml). After 30 min, this reaction mixture was treated with methylbromide (177 μl) and stirring continued for 4 hours. The solvent was removed in vacuo, the residue was re-dissolved in ethyl acetate, washed with water, brine, dried (MgSO4), evaporated in vacuo and the residue was purified column fluorescence is W-chromatography, elwira mixture 1:1 of ethyl acetate and isohexane. The connection specified in the subtitle, received in the form of a yellow solid (360 mg).

1H NMR CDCl3: δ 7.37 (1H, d), 7.30 (1H, d), 7.18-7.13 (2H, m), 7.00-6.96 (2H, m), 4.92 (2H, s), 3.80 (3H, s), 2.55 (3H, s).

3) 3-[(4-Chlorophenyl)thio]-4-cyano-2,5-dimethyl-1H-indole-1-acetic acid

The product of stage (2) (0.1 g) was dissolved in THF (5 ml) and NaOH (200 μl, a 1.25 M solution). After 3 hours was added an additional amount of NaOH (200 μl, 1.25 M solution) and the reaction mixture was stirred over night at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in water. This solution was acidified with diluted HCl. The resulting precipitate was filtered to obtain the connection specified in the header, in the form of a white solid (86 mg).

1H NMR DMSO: δ 7.99 (1H, d), 7.47 (1H, d), 7.38 (2H, dt), 7.3 (2H, dt), 6.98 (2H, dt), 5.25 (2H, s), 2.49 (3H, s).

MC APCI+[M+H] 390

TPL 237-238°C.

Example 12

5-Chloro-3-[(4-chlorophenyl)thio]-6-cyano-2-methyl-1H-indole-1-acetic acid

1) Methyl ester 5-chloro-3-[(4-chlorophenyl)thio]-6-cyano-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example 11 stage (2), using the product of example 11 stage (1).

2) 5-Chloro-3-[(4-chlorophenyl)thio]-6-cyano-2-methyl-1H-indole-1-acetic acid

The connection specified in the header received by the method of example 1, stage (3), using the product of stage (1).

1H NMR DMSO: δ 8.42 (1H, s), 7.59 (1H, s), 7.3 (2H, dt), 6.99 (2H, dt), 5.24 (2H, s), 2.46 (3H, s).

Example 13

3-[(4-Chlorophenyl)thio]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-1-acetic acid

1) 3-[(4-Chlorophenyl)thio]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indol

The connection specified in the subtitle, received by way of example 11 stage (1) of 3-amino-4-methoxyphenylethylamine.

1H NMR CDCl3: δ 9.00 (1H, s), 7.91 (1H, d), 7.12 (1H, dd), 6.86 (2H, m), 6.73 (1H, d), 4.05 (3H, s), 4.05 (3H, s), 3.46 (2H, q), 2.46 (3H, s), 1.16 (3H, t).

2) Methyl ether 3-[(4-chlorophenyl)thio]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example 11 stage (2) of the product of stage (1).

1H NMR CDCl3: δ 7.92 (1H, d), 7.13 (2H, dt), 6.85 (2H, dt), 6.73 (1H, d), 5.27 (2H, s), 3.98 (3H, s), 3.79 (3H, s), 3.48 (2H, q), 2.38 (3H, s), 1.18 (3H, t).

3) 3-[(4-Chlorophenyl)thio]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example 11 stage (3) of the product of stage (2).

1H NMR DMSO: δ 7.72 (1H, d), 7.24 (2H, m), 6.96 (1H, d), 6.86 (2H, dt), 5.29 (2H, s), 5.27 (2H, s), 3.97 (3H, s), 3.41 (2H, q), 2.34 (3H, s), 1.01 (3H, t).

Example 14

3-[(4-Chlorophenyl)thio]-4-[(diethylamino)sulfonyl]-7-methoxy-2-methyl-1H-indole-1-acetic acid

1) 3-[(4-Chlorophenyl)thio]-N,N-diethyl-7-methoxy-2-methyl-1H-indole-4-sulfonamide

The connection shown is in the subtitle, received by way of example 11 stage (1) of 3-amino-N,N-diethyl-4-methoxy-benzosulfimide.

1H NMR CDCl3: δ 7.80 (1H, d), 7.88 (1H, s), 7.08 (2H, d), 6.85 (2H, d), 6.66 (1H, d), 4.04 (3H, s), 3.25 (4H, q), 3.79 (3H, s), 2.43 (3H, s), 0.98 (6N, t).

2) Methyl ether 3-[(4-chlorophenyl)thio]-4-[(diethylamino)sulfonyl]-7-methoxy-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example 11 stage (2) of the product of stage (1), using it directly without further purification.

3) 3-[(4-Chlorophenyl)thio]-4-[(diethylamino)sulfonyl]-7-methoxy-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example 11 stage (3) of the product of stage (2).

TPL 247-249°C.

1H NMR DMSO: δ 7.56 (1H, d), 7.18 (2H, dt), 6.85-6.79 (3H, m), 5.13 (2H, s), 3.94 (3H, s), 3.14 (4H, q), 2.29 (3H, s) and 0.88 (6N, t).

Example 15

4-Chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

1) 4-Chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indol

To a suspension of the hydrochloride (3-chlorophenyl)-hydrazine (2 g) in acetic acid (30 ml) was added 1-[(4-chlorophenyl)thio]-acetone (2.24 g), acetonitrile (20 ml) and water (10 ml). This mixture was stirred at room temperature overnight. This reaction mixture was concentrated in vacuo and the residue suspended in EtOAc, washed with sodium hydrogen carbonate solution, brine, dried (MgSO4) and concentrated in vacuum. The residue RA is tarali in acetic acid (20 ml) and was heated up to 80° With during the night. This reaction mixture was poured into water, podslushivaet NaOH and the organic matter was extracted in EtOAc. EtOAc was washed with brine, dried (MgSO4) and concentrated in vacuum. In the purification column flash chromatography (10% EtOAc/hexane as eluent) received the connection specified in the subtitle (0,816 g).

1H NMR CDCl3: δ 8.38 (s, 1H), 7.27-7.23 (m, 1H), 7.14-7.07 (m, 4H), 6.96 (dt, 2H), 2.52 (s, 3H).

2) Methyl ether 4-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

To a solution of the product of stage (1) (0.2 g) in THF (5 ml) was added a 1.0 M solution of bis(trimethylsilyl)amide in THF (0,65 ml). This mixture was stirred for 30 min, then was added methylbromide (62 μl), the reaction mixture was stirred at room temperature overnight. Added additional 0.3 ml of 1.0 M solution of bis(trimethylsilyl)amide in THF and 30 μl of methylpropanoate and the mixture was stirred for 3 hours. Then this mixture was purified column flash chromatography (14% ethyl acetate/hexane as eluent) to give the compounds specified in the subtitle (0.21 g).

1H NMR CDCl3: δ 7.17-7.11 (m, 5H), 6.95 (dt, 2H), 4.89 (s, 2H), 3.78 (s, 3H), 2.49 (s, 3H).

3) 4-Chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

To a solution of product from step (2) (0.11 g) in THF (5 ml) was added 1.25 M NaOH solution (water) (0.25 ml). This reaction is mesh was stirred over night at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved/suspended in water. Brought the pH to 2 using dilute HCl (aqueous), and organic matter was extracted in EtOAc, washed with brine, dried over MgSO4and concentrated in vacuum. The residue was purified by solid-phase extraction using NH2the sorbent (2 g), elwira acetonitrile, and then a mixture of 10% triperoxonane acid/acetonitrile, to obtain the compound indicated in heading (0.06 g).

1H NMR CDCl3: δ 7.54 (dd, 1H), 7.27 (dt, 2H), 7.14 (d, 1H), 7.08 (dd, 1H), 6.95 (dt, 2H), 5.16 (s, 2H), 2.43 (s, 3H).

MC APCI-[M-H] 364

TPL 184-187°C.

Example 16

5-Chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

1) 5-Chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indol

The connection specified in the subtitle, received by way of example, stage 15 (1), using hydrochloride (4-chlorophenyl)-hydrazine. The product was purified using flash column chromatography (20% EtOAc/hexane as eluent).

1H NMR CDCl3: δ 8.31 (s, 1H), 7.48 (d, 1H), 7.26 (m, 2H), 7.13 (m, 3H), 6.93 (m, 2H), 2.51 (s, 3H).

2) Methyl ester 5-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example, stage 15 (2)using the product from step (1).

1H NMR CDCl3: δ 7.52 (d, 1H), 7.27 (d, 1H), 7.20-7.10 (m, 3H), 6.97-6.89 (m, 2H), 4.80 (d, 2H), 3.79 (d, 3H), 2.47 (d, 3H).

3) 5-Chloro--[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

To a solution of product from step (2) (0.11 g) in THF (5 ml) was added 1.25 M NaOH solution (water) (0.25 ml). This reaction mixture was stirred over night at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved/suspended in water. Brought the pH to 2 using dilute HCl (aqueous), and a solid substance, which was precipitate was isolated by filtration and dried in vacuum at 40°obtaining the connection specified in the header.

1H NMR CDCl3: δ 7.60 (d, 1H), 7.32-7.26 (m, 3H), 7.19 (dd, 1H), 6.98 (dt, 2H), 5.15 (s, 2H), 2.42 (s, 3H).

MC APCI-[M-H] 364

TPL Decomposes >211°C.

Example 17

6-Chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

1) 6-Chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indol

The connection specified in the subtitle, received by way of example, stage 15 (1).

1H NMR CDCl3: δ 8.27 (s, 2H), 7.39 (d, 1H), 7.34 (d, 1H), 7.10 (m, 3H), 6.92 (m, 2H), 2.50 (s, 3H).

2) Methyl ether 6-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example, stage 15 (2)using the product from step (1).

1H NMR CDCl3: δ 7.43 (d, 1H), 7.27-7.25 (m, 1H), 7.14-7.09 (m, 3H), 6.92 (dd, 2H), 4.85 (s, 2H), 3.80 (d, 3H), 2.46 (d, 3H).

3) 6-Chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

The connection specified in the header received by the method of example 16 stage (3), using the product from step (2).

1H NMR CDCl3: δ 7.71 (d, 1H), 7.33 (d, 1H), 7.26 (dt, 2H), 7.09 (dd, 1H), 6.96 (dt, 2H), 5.08 (s, 2H), 2.40 (s, 3H).

MC APCI-[M-H] 364

TPL Decomposes >189°C.

Example 18

7-Chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

1) 7-Chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indol

The connection specified in the subtitle, received by way of example, stage 15 (1), using hydrochloride (2-chlorophenyl)-hydrazine. The product was purified using flash column chromatography (14% EtOAc/hexane as eluent).

1H NMR CDCl3: δ 8.48 (s, 1H), 7.40 (d, 1H), 7.19 (m, 1H), 7.13-7.11 (m, 2H), 7.06 (t, 1H), 6.96-6.92 (m, 2H), 2.55 (s, 3H).

2) Methyl ester of 7-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example, stage 15 (2)using the product from step (1).

1H NMR CDCl3: δ 7.44 (d, 1H), 7.08-7.19 (m, 3H), 7.03 (td, 1H), 6.92 (dd, 2H), 5.37 (2H, d), 3.81 (3H, d), 2.46 (3H, d).

3) 7-Chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

The connection specified in the header received by the method of example 16 stage (3)using the product from step (2).

1H NMR DMSO: δ 7.35 (dd, 1 H), 7.28 (dt, 2H), 7.20 (dd, 1 H), 7.07 (t, 1 H), 6.98 (dt, 2H), 5.36 (s, 2H), 2.45 (s, 3H).

MC APCI-[M-H] 364

TPL Decomposes >207°C.

Example 19

3-[(4-Chlorophenyl)thio]-2-methyl-5-(methylsulphonyl)-1H-indole-1-acetic acid

1) 3-[(4-Chlorophenyl)thio]-2-methyl-5-(methylsulphonyl)-1H-indole

Connect the s, specified in the subtitle, received by way of example 11 stage (1)of the hydrochloride of 4-methylsulphonyl-aniline.

1H NMR CDCl3: δ 8.78 (1H, s), 8.16 (1H, d), 7.74 (1H, dd), 7.47 (1H, d), 7.13 (2H, dt), 6.92 (2H, dt), 3.06 (3H, s), 2.55 (s, 3H).

2) Methyl ether 3-[(4-chlorophenyl)thio]-2-methyl-5-(methylsulphonyl)-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example 11 stage (2) of the product of stage (1).

1H NMR CDCl3: δ 8.20 (1H, d), 7.79 (1H, dd), 7.38 (1H, d), 7.14 (1H, dd), 6.92 (2H, dd), 4.96 (2H, s), 3.79 (3H, d), 2.52 (3H, s).

3) 3-[(4-Chlorophenyl)thio]-2-methyl-5-(methylsulphonyl)-1H-indole-1-acetic acid

The product of stage (2) (190 mg) was treated with methanol (10 ml), LiOH (18,9 mg) and water (2 ml). This reaction mixture was stirred for 4 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in water, acidified with HCl to obtain the connection specified in the header, in the form of a white solid (44 mg).

1H NMR CDCl3: δ 8.19 (1H, d), 7.79 (1H, dd), 7.39 (1H, d), 7.13 (1H, dd), 6.91 (2H, dd), 4.98 (2H, s), 3.04 (3H, s), 2.53 (3H, s).

TPL 185-187°C.

Example 20

2,5-Dimethyl-3-[[4-(methylsulphonyl)phenyl]thio]-1H-indole-1-acetic acid

1) 3-[(4-Chlorophenyl)thio]-2-methyl-4-(methylsulphonyl)-1H-indole and 3-[(4-chlorophenyl)thio]-2-methyl-6-(methylsulphonyl)-1H-indole

The connection specified in the subtitle, received by way of example 19 stage (1) of the hydrochloride of 3-(methylsulphonyl)aniline with what rucenim a mixture of 3-[(4-chlorophenyl)thio]-2-methyl-6-(methylsulphonyl)-1H-indole and 3-[(4-chlorophenyl)thio]-2-methyl-4-(methylsulphonyl)-1H-indole. This mixture was purified column flash chromatography with a mixture of 50% EtOAc/hexane as eluent. Thus, the product was received:

1H NMR DMSO: δ 7.77 (2H, ddd), 7.33 (2H, t), 7.24 (2H, dt), 6.87 (2H, dt), 3.32 (3H, s), 2.40 (3H, s).

In addition, also provided 3-[(4-chlorophenyl)thio]-2-methyl-6-(methylsulphonyl)-1H-indole. This isomer was used in example 2, stage (1).

1H NMR DMSO: δ 12.30 (1H, s), 7.93 (1H, d), 7.50-7.59 (2H, m), 7.27 (2H, dd), 6.95-7. (2H, m), 3.19 (3H, s), 2.52 (3H, s).

2) 2,5-Dimethyl-3-[[4-(methylsulphonyl)phenyl]thio]-1H-indole-1-acetic acid

To the product of example 21 stage (1) (0.28 g), dissolved in THF (5 ml), was added NaH (63 mg, 60% dispersion in oil) and the reaction mixture was left to mix for 10 minutes was Added ethylbromoacetate (0,13 ml) and the reaction mixture was left to mix for 3 hours. Added EtOH (2 ml) and NaOH (2 ml, 10% water) and the reaction mixture was left to mix for 30 minutes In the evaporation of EtOH followed by the addition of HCl (1 M) obtained white precipitate. This precipitate was filtered and washed with diethyl ether to obtain the connection specified in the header, in the form of solids (0,351 g).

1H NMR DMSO: δ 13.33 (1H, s), 8.02 (1H, dd), 7.81 (1H, dd), 7.40 (1H, t), 7.24 (2H, dt), 6.89 (2H, dt), 5.29 (2H, s), 3.32 (3H, s), 2.39 (3H, s).

MC APCI+[M+DMSO] 488.

Example 21

2-Methyl-3-[(4-were)thio]-6-(methylsulphonyl)-1H-indole-1-acetic acid

1) Ethyl ester of 2-methyl-3-[(4-methylp the Nile)thio]-6-(methylsulphonyl)-1H-indole-1-acetic acid

To a stirred solution of sodium hydride (45 mg, 60% dispersion in mineral oil) in anhydrous tetrahydrofuran (10 ml) was added 3-[(4-chlorophenyl)thio]-2-methyl-6-(methylsulphonyl)-1H-indole (160 mg) (product of example 20 stage (1)). After 30 min, this reaction mixture was treated with ethylbromoacetate (78 μl) and stirring was continued for 1 hour. This reaction mixture was suppressed by ethanol, the solvent was removed in vacuo, the residue was re-dissolved in ethyl acetate, washed with water, dried (MgSO4) and evaporated in vacuo and the residue was purified column flash chromatography, elwira a mixture of 30% ethyl acetate and isohexane. The connection specified in the subtitle, received in the form of a white solid (180 mg).

MS: ES+[M+H] 438.

2) 2-Methyl-3-[(4-were)thio]-6-(methylsulphonyl)-1H-indole-1-acetic acid

The product of stage (1) (180 mg) was dissolved in ethanol (5 ml) was added NaOH (1 ml of 10% solution). After 1 hour the reaction mixture was concentrated in vacuo and the residue was dissolved in water. The solution was acidified aqueous HCl (1 M) and was extracted with ethyl acetate, washed with water, dried (MgSO4) and evaporated in vacuo. The residue was purified using NH2the resin (0.5 g)was loaded in MeCN and released a mixture of 5% acetic acid/MeCN, 30 mg of product as a white solid.

1H NMR DMSO: δ 8.11 (1H, s), 7.50-7.62 (2H, m), 7.24-7.29 (2H, m), 6.98 (2H, dd, 4.96 (2H, s), 3.21 (3H, s), 2.48 (3H, s).

MS: APCI-[M+DMSO] 488.

Example 22

4-Bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

1) 4-Bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indol

The connection specified in the subtitle, received by way of example, stage 15 (1), using hydrochloride (3-bromophenyl)-hydrazine. The product was purified using flash column chromatography (10% EtOAc/hexane as eluent).

1H NMR CDCl3: δ 7.31 (1H, s), 7.30 (2H, d), 7.13 (2H, dt), 7.02 (1H, t), 6.94 (2H, dt), 2.52 (3H, s).

2) 1,1-Dimethylethylene ether 4-bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example 11 stage (2), using the product of stage (1) and tert-butylbromide. The product was purified using flash column chromatography (10% EtOAc/hexane as eluent).

1H NMR CDCl3: δ 7.31 (dd, 1H), 7.21 (dd, 1H), 7.14-7.10 (m, 2H), 7.05 (t, 1H), 6.94-6.91 (m, 2H), 4.77 (s, 2H), 2.49 (s, 3H), 1.43 (s, 9H).

3) 4-Bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

To a solution of product from step (2) (0.09 g) in dichloromethane (2 ml) was added triperoxonane acid (0.1 ml). This reaction mixture was stirred over night at room temperature. Solid, which was precipitate was isolated by filtration, washed with hexane and dried overnight in vacuum at 40°obtaining the connection specified in the header (,025 g).

1H NMR (DMSO): δ 7.59 (dd, 1H), 7.29-7.25 (m, 3H), 7.08 (t, 1H), 6.94 (dt, 2H), 5.16 (s, 2H), 2.43 (s, 3H).

MS: APCI+[M+H] 411

TPL Decomposes >213°C.

Example 23

3-[(4-Chlorophenyl)thio]-4-[4-[(1,1-dimethylmethoxy)carbonyl]-1-piperazinil]-2-methyl-1H-indole-1-acetic acid

In a dry flask was downloaded the product from example 22 stage (2) (1 g), N-tert-butoxycarbonylmethyl (0,48 g), Pd2(dba)3(3 mg), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BINAP (10 mg) and toluene (5 ml). This reaction mixture was heated to 110°C for 1 hour, then allowed to cool. This mixture was diluted with EtOAc, washed with water, dried over MgSO4and concentrated in vacuum. The residue was purified using flash column chromatography (eluent 25% EtOAc/hexane, then 50% EtOAc/hexane/1% acetic acid). As a result of further purification using HPLC with reversed phase (eluent MeCN/NH3(water)), received the connection specified in the header (0,021 g).

1H NMR (DMSO): δ 7.22 (dt, 2H), 7.12 (d, 1H), 7.02 (t, 1H), 6.93 (dt, 2H), 6.66 (d, 1H), 4.57 (s, 2H), 3.33 (s, 4H), 2.79 (s, 4H), 2.36 (s, 3H), 1.39 (s, 9H).

MS: APCI+[M+H] 516

TPL 173°C.

Example 24

3-[(4-Chlorophenyl)thio]-2-methyl-4-(1-piperazinil)-1H-indole-1-acetic acid

1) 1,1-Dimethylethylene ester of 3-[(4-chlorophenyl)thio]-4-[4-[(1,1-dimethylmethoxy)carbonyl]-1-piperazinil]-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example 23. The product was purified is kolonochnoi flash chromatography (eluent 25% EtOAc/hexane).

1H NMR (DMSO) 90°: δ 7.21-7.15 (m, 3H), 7.08 (t, 1H), 6.92 (d, 1H), 4.99 (s, 2H), 3.26 (s, 4H), 2.81 (t, 4H), 2.40 (s, 3H), 1.40 (s, 18H).

2) 3-[(4-Chlorophenyl)thio]-2-methyl-4-(1-piperazinil)-1H-indole-1-acetic acid

To a solution of product from step (1) (0.34 g) in dichloromethane (5 ml) was added 4 M HCl in dioxane (1.3 ml), the mixture was stirred at room temperature overnight. Solid, which was precipitate was isolated by filtration, suspended in dichloromethane (20 ml) and added triperoxonane acid (6 ml) and the reaction mixture was stirred for 18 hours. The mixture was concentrated in vacuo and the residue triturated with ether to obtain a solid substance. This solid was dried over night at 40°With the vacuum connection is specified in the header (0.02 g).

1H NMR (DMSO) 90°: δ 7.28-7.20 (m, 3H), 7.12 (t, 1H), 6.95 (d, 2H), 6.77 (d, 1H), 5.02 (s, 2H), 3.08 (d, 4H), 3.00 (d, 4H), 2.42 (s, 3H).

MS: APCI-[M-H] 414

TPL Decomposes >249°C.

Example 25

5-Bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

1) 5-Bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indol

The connection specified in the subtitle, received by way of example, stage 15 (1), using hydrochloride (4-bromophenyl)-hydrazine. The product was purified flash column-chromatography (eluent 10% EtOAc/hexane).

1H NMR (CDCl3) δ 8.31 (s, 1H), 7.64 (d, 1H), 7.28 (dd, 2H), 7.22 (d, 2H), 7.13 (m, 2H), 6.93 (dt, 2H), 2.51 (s, 3 is).

MS: APCI-[M+H] 352

2) 1,1-Dimethylethylene ester 5-bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example 11 stage (2), using the product of stage (1) and tert-butylbromide. The product was purified using flash column chromatography (10% EtOAc/hexane as eluent).

1H NMR (DMSO): δ 7.54 (d, 1H), 7.45 (d, 1H), 7.34-7.25 (m, 3H), 6.97 (m, 2H), 5.15 (s, 2H), 2.41 (s, 3H), 1.41 (s, 9H).

By adding ethanol to the residue after evaporation was obtained as a by - product ethyl ester 5-bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid, obtained after chromatography.

1H NMR (DMSO): δ 7.56 (d, 1H), 7.46 (d, 1H), 7.34-7.27 (m, 3H), 6.97 (dd, 2H), 5.27 (s, 2H), 4.17 (q, 2H), 2.41 (s, 3H), 1.21 (t, 3H).

3) Sodium salt of 5-bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

To the solution side of the product from step (2) (0.2 g) in ethanol (10 ml) was added 1 M NaOH solution (water) (0.5 ml). This reaction mixture was stirred over night at room temperature. The reaction mixture was concentrated in vacuo and the residue was recrystallized from boiling water. The solid was isolated by filtration, dried overnight at 40°With the vacuum connection is specified in the header (0,13 g).

1H NMR (DMSO): δ 7.39 (d, 1H), 7.37 (d, 1H), 7.26 (d, 2H), 7.21 (dd, 1H), 6.97 (dt, 2H), 4.47 (s, 2H), 2.38 (s, 3H).

Example 26

3-[(4-Chlorophenyl)thio]-2-methyl-5-phenyl-1H-indole-1-acetic acid

1) Ethyl ester of 3-[(4-chlorophenyl)thio]-2-methyl-5-phenyl-1H-indole-1-acetic acid

To a solution of the product of example 25 stage (2) (0.5 g) in ethanol (0.8 ml) and toluene (3 ml) was added 2 M sodium carbonate solution in water (1.4 ml), phenylboronic acid (0,131 g) and tetrakis(triphenylphosphine)palladium (0) (1.2 g). This reaction mixture was heated to education phlegmy for 2 hours, cooled and concentrated in vacuum. The residue was purified column flash chromatography to obtain the connection specified in the subtitle (0.4 g). This compound is used in stage (2) without further specifications.

2) 3-[(4-Chlorophenyl)thio]-2-methyl-5-phenyl-1H-indole-1-acetic acid

The connection specified in the header, received by way of example 26 stage (3). In the purification preparative HPLC with reversed phase received the connection specified in the header.

1H NMR (DMSO): δ 7.61-7.53 (4H, m), 7.46-7.38 (3H, m), 7.31-7.22 (3H, m), 7.01 (2H, dd), 4.91 (2H, s), 2.42 (3H, s).

MS: APCI-[M-H] 406

Example 27

3-[(4-Chlorophenyl)thio]-5-cyano-2-methyl-1H-indole-1-acetic acid

1) 3-[(4-Chlorophenyl)thio]-5-cyano-2-methyl-1H-indol

To a stirred solution of 4-aminobenzonitrile (5 g) in dichloromethane (150 ml), cooled to -70°C, was added tert-butylhypochlorite (4.6 g) dropwise over 5 minutes. This reaction mixture was stirred t the value of 10 minutes, then was added 1-[(4-chlorophenyl)thio]-2-propanone (8,49 g) in solution in dichloromethane (20 ml). After 1 hour, was added triethylamine (5,9 ml) and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with dichloromethane, washed with HCl (aqueous), brine, dried over MgSO4and concentrated in vacuum to obtain a brown solid. As a result of recrystallization from methanol has received the connection specified in the subtitle (7.5 g).

1H NMR (CDCl3) δ 8.61 (s, 1H), 7.84 (s, 1H), 7.44 (dd, 1H), 7.41 (d, 1H), 7.19-7.08 (m, 2H), 6.93 (dd, 2H), 2.56 (s, 3H).

2) Ethyl ester of 3-[(4-chlorophenyl)thio]-5-cyano-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example 11 stage (2)using the product from step (1). Used without further purification in stage (3).

3) 3-[(4-Chlorophenyl)thio]-5-cyano-2-methyl-1H-indole-1-acetic acid

The connection specified in the header, obtained using the method of example 16 stage (3)using the product from step (2).

1H NMR (DMSO): δ 13.34 (s, 1H), 7.82-7.77 (m, 2H), 7.57 (dd, 1H), 7.29 (dt, 2H), 7.02-6.98 (m, 2H), 5.23 (s, 2H), 2.46 (s, 3H).

MS: APCI-[M-H] 355

Example 28

Ammonium salt of 3-[(4-cyanophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid

1) (2,5-Dimethyl-1H-indol-1-yl)acetic acid

60% sodium Hydride/oil (0.64 g) was added to a solution of 2,5-dimethyl-1H-indole (2.0 g) in DMF (1 ml). After 15 min quickly added ethylbromoacetate (2.7 ml) and the reaction mixture was stirred for 20 minutes, the Reaction mixture was extinguished 1% aqueous acetic acid (100 ml), extracted with ethyl acetate (2×100 ml) and washed with water (2×50 ml) and brine (20 ml). The extracts were dried (MgSO4), filtered and evaporated in vacuum to obtain a brown solid. This solid was dissolved in EtOH (20 ml) was added aqueous sodium hydroxide (1 M, 10 ml). After 1 hour the pH of this solution was brought to pH 6 aqueous hydrochloric acid (1 M, ˜10 ml)and then evaporated in vacuum. The residue was purified column flash chromatography (gradient of 1-10% methanol in dichloromethane). The connection specified in the subtitle, obtained as a red solid (1.3 g).

MS: APCI+204 [M+H]+

1H NMR DMSO-d6: δ 7.22-7.17 (2H, m), 6.85 (1H, d), 6.11 (1H, s), 4.87 (2H, s), 2.34 (3H, s), 2.30 (3H, s).

2) Ammonium salt of 3-[(4-cyanophenyl)thio]-2,5-dimethyl-1H-indol-1-yl-acetic acid

Iodine (0.51 g) was added to a solution of 4-cyanobenzoyl (0.27 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with ether to obtain a solid substance. Filtered and dried to obtain the connection specified in the header, in the form of a white solid (025 g).

MS: APCI-[(M-NH4)-N]-334

1H NMR DMSO-d6: δ 7.62 (2H, a), 7.35 (1H, d), 7.10 (1H, s), 7.08 (2H, d), 6.97 (1H, d), 4.80 (2H, s), 2.36 (3H, s), 2.32 (3H, s).

Example 29

3-[(3-Methoxyphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid

Iodine (0.51 g) was added to a solution of 3-methoxybenzamide (0.25 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with ether to obtain a solid substance. Filtered and dried to obtain the connection specified in the header, in the form of a white solid (0,22 g).

MS: APCI-[M-N]-340

1H NMR DMSO-d6: δ 7.40 (1H, d), 7.16 (1H, s), 7.11 (1H, t), 6.98 (1H, d), 6.63 (1H, d), 6.55 (1H, d), 6.45 (1H, s), 5.08 (2H, s), 3.61 (3H, s), 2.39 (3H, s), 2.34 (3H, s).

Example 30

Ammonium salt of 3-[(4-methoxyphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid

Iodine (0.51 g) was added to a solution of 4-methoxybenzamide (0.25 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with ether to obtain a solid substance. Filtered and dried to obtain the connection specified in the header, in the form of a white solid (0.27 g).

MS: APCI-[M-N]-340

1H NMR DMSO-d6: δ 7.24 (1H, d), 7.15 (1H, s), 6.95 (2H, d), 6.90 (1H, d), 6.78 (2H, d), 4.60 (2H, s), 3.66 (3H, s), 2.38 (3H, s), 2.33 (3H, s).

Example 31

Ammonium salt of 3-[(3-ethylphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid

Iodine (0,44 g) was added to a solution of 2-ethylbenzamide (0.32 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with ether to obtain a solid substance. Filtered and dried to obtain the connection specified in the header, in the form of a white solid (0.18 g).

MS: APCI-[(M-NH4)-N]-338

1H NMR DMSO-d6: δ 7.26 (1H), 7.16 (1H, a), 7.08 (1H, s), 7.01-6.85 (3H, m), 6.48 (1H, d), 4.57 (2H, s), 2.83 (2H, q), 2.34 (3H, s), 2.31 (3H, s), 1.31 (3H, t).

Example 32

2,5-Dimethyl-3-[(2-were)thio]-1H-indole-1-acetic acid

Iodine (0.29 grams) was added to a solution of 2-methylbenzamide (0.16 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with ether to obtain a solid substance. Filtered and dried to obtain the connection specified in the header, in the form of a white solid (0.16 g).

MS: APCI-[M-N]-324

1H NMR DMSO-d6: δ 7.24 (1H, d), 7.15 (1H, d), 7.07 (1H, s), 6.97-6.86 (3H, m), 6.47 (1H, d), 4.49 (2H, s), 2.42 (3H, s), 2.33 (3H, s), 2.31 (3H, s).

Example 33

On rieva salt of 3-[(3-chlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid

Iodine (0.29 grams) was added to a solution of 3-chlorobenzamide (0,175 g) and the product from example 28 stage (1) (0.2 g) in EtOH (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum to obtain the product as a colourless oil. Then this oil was dissolved in methanol (10 ml)was treated with aqueous sodium hydroxide (1 M, the value of 0.52 ml) and evaporated in vacuo to obtain sodium salt as a white solid (0,19 g).

MS: APCI-[(M-Na)-H]-344

1H NMR DMSO-d6: δ 7.28-7.15 (2H, m), 7.13-7.06 (2H, m), 6.97-6.88 (3H, m), 4.42 (2H, s), 2.36 (3H, s), 2.33 (3H, s).

Example 34

Sodium salt of 3-[(2-Forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid

Iodine (0.51 g) was added to a solution of 2-fermentative (0.26 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum to obtain the product as a colourless oil. Then this oil was dissolved in Meon (10 ml)was treated with aqueous sodium hydroxide (1 M, the value of 0.52 ml) and evaporated in vacuo to obtain sodium salt as a white solid (0.08 g).

MS: APCI-[(M-Na)-H]-328

1H NMR DMSO-d6: δ 7.24 (1H, d), 7.18 (1H, m), 7.10 (1H, s), 7.09 (1H, m), 6.91 (1H, d), 6.56 (1H, m), 6.56 (1H, m), 4.42 (2H, s), 2.35 (3H, s), 2.33 (3H, s).

Example 35

3-[(2,6-Dichlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid

Iodine (0.51 g) was added to dissolve the near 2,6-dichlorobenzamide (0.36 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with ether to obtain a solid substance. Filtered and dried to obtain the connection specified in the header, in the form of a white solid (0,22 g).

MS: APCI-[M-H]-378

1H NMR DMSO-d6: δ 7.49 (2H, d), 7.29 (1H, m), 7.24 (1H, d), 7.13 (1H, s), 6.88 (1H, d), 4.81 (2H, s), 2.44 (3H, s), 2.29 (3H, s).

Example 36

Ammonium salt of 3-(1H-imidazol-2-ylthio)-2,5-dimethyl-1H-indole-1-acetic acid

Iodine (0.51 g) was added to a solution of 1H-imidazole-2-thiol (0.20 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with ether to obtain a solid substance. Filtered and dried to obtain the connection specified in the header, in the form of a white solid (0,23 g).

MS: APCI-[M-H]-300

1H NMR DMSO-d6: δ 8.15 (1H, s), 7.21 (1H, d), 7.21 (2H, s), 6.90 (1H, d), 4.51 (2H, s), 2.40 (3H, s), 2.35 (3H, s).

Example 37

2,5-Dimethyl-3-(1H-1,2,4-triazole-3-ylthio)-1H-indole-1-acetic acid

Iodine (0.51 g) was added to a solution of 1H-1,2,4-triazole-3-thiol (0.20 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with firom obtaining a solid substance. Filtered and dried to obtain the connection specified in the header, in the form of a white solid (0.24 g).

MS: APCI-[M-N]-301

1H NMR DMSO-d6: δ 8.15 (1H, s), 7.21 (1H, d), 7.20 (1H, s), 6.90 (1H, d), 4.49 (2H, s), 2.40 (3H, s), 2.35 (3H, s).

Example 38

2,5-Dimethyl-3-[(4-methyl-4H-1,2,4-triazole-3-yl)thio]-1H-indole-1-acetic acid

Iodine (0.51 g) was added to a solution of 4-methyl-4H-1,2,4-triazole-3-thiol (0.20 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with ether to obtain a solid substance. Filtered and dried to obtain the connection specified in the header, in the form of a white solid (0.21 g).

MS: APCI-[M-N]-315

1H NMR DMSO-d6: δ 8.44 (1H, s), 7.29 (1H, s), 7.19 (1H, d), 6.90 (1H, d), 4.46 (2H, s), 3.52 (3H, s), 2.46 (3H, s), 2.35 (3H, s).

Example 39

2,5-Dimethyl-3-[(4-methyl-2-oxazolyl)thio]-1H-indole-1-acetic acid

Iodine (0.51 g) was added to a solution of 4-methyl-2-oxazoline (0,23 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with ether to obtain a solid substance. Filtered and dried to obtain the connection specified in the header, in the form of a white solid (0,23 g).

MS: PCI[M-N] -315

1H NMR DMSO-d6: δ 7.69 (1H, s), 7.29 (1H, d), 7.22 (1H, s), 6.95 (1H, d), 4.78 (2H, s), 2.42 (3H, s), 2.36 (3H, s), 1.99 (3H, s).

Example 40

2,5-Dimethyl-3-[(1-methyl-1H-imidazol-2-yl)thio]-1H-indole-1-acetic acid

Iodine (0.51 g) was added to a solution of 1-methyl-1H-imidazole-2-thiol (0,23 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with ether to obtain a solid substance. Filtered and dried to obtain the connection specified in the header, in the form of a white solid (0.21 g).

MS: APCI-[M-N]-314

1H NMR DMSO-d6: δ 7.37 (1H, s), 7.29 (1H, d), 7.15 (1H, s), 6.93 (1H, d), 6.84 (1H, s), 4.97 (2H, s), 3.60 (3H, s), 2.49 (3H, s), 2.36 (3H, s).

Example 41

Ammonium salt of 2,5-dimethyl-3-[[4-(methylsulphonyl)phenyl]thio]-1H-indole-1-acetic acid

1) 4-(Methylsulphonyl)-sensation

1-Fluoro-4-(methylsulphonyl)-benzene (1,74 g) and the hydrate of sodium hydrosulfide (0,67 g) was dissolved in DMF (10 ml) and stirred at room temperature for 24 hours. The reaction mixture was extinguished with water, acidified with 2 M hydrochloric acid (20 ml) and was extracted with ethyl acetate (2×50 ml). Then the combined extracts were washed with water (2×25 ml) and brine (20 ml). The organic solution was dried (MgSO4), filtered and evaporated in vacuum to obtain compounds of the criminal code is mentioned in the subtitle, in the form of a white solid (1.8 g).

MC: ES1+: [M+H] 188

1H NMR CDCl3: δ 7.99 (2H, d), 7.27 (2H, d), 3.05 (3H, s).

2) Ammonium salt of 2,5-dimethyl-3-[[4-(methylsulphonyl)phenyl]thio]-1H-indole-1-acetic acid

Iodine (0.51 g) was added to a solution of the product from example 41 stage (1) (0.565 g) and the product from example 28 stage (1) (0.2 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with ether to obtain solid, which was filtered and dried to obtain the connection specified in the header (0.25 g).

MS: APCI-[M-H] 388

1H NMR DMSO-d6: δ 7.69 (2H, d), 7.31 (1H, d), 7.15 (2H, d), 7.11 (1H, s), 6.95 (1H, d), 4.62 (2H, s), 3.13 (3H, s), 2.36 (3H, s), 2.33 (3H, s).

Example 42

Hemi-ammonium salt of 2,5-dimethyl-3-(8-chinaindia)-1H-indole-1-acetic acid

Iodine (0.25 g) was added to a solution of 8-hyalinella (0.16 g) and the product from example 28 stage (1) (0.1 g) in DMF (5 ml). After 1 hour, the solution was purified HPLC with reversed phase. The solvent is evaporated in vacuum and the oily residue was treated with ether to obtain solid, which was filtered and dried to obtain the connection specified in the header, in the form of a white solid (0.08 g).

MS: APCI-[M-N]-361

1H NMR DMSO-d6: δ 8.97 (1H, s), 8.37 (1H, d), 7.62 (2H, m), 7.32 (1H, d), 7.27 (1H, t), 7.08 (1H, s), 6.94 (1H, d), 6.71 (1H, d), .69 (2H, s), 2.36 (3H, s), 2.30 (3H, s).

Example 43

3-[(4-Chlorophenyl)thio]-5-fluoro-2,4-dimethyl-1H-indole-1-acetic acid

1) 7-Chloro-5-fluoro-2,4-dimethyl-3-methylthio-1H-indol

The stirred solution of 2-chloro-4-fluoro-5-methylaniline (1.65 g) in methylene chloride (100 ml) under nitrogen atmosphere was treated at -65°With a solution of tert-butylhypochlorite (1.13 g) in methylene chloride (5 ml)was stirred at -65°C for 10 min, treated at -65°With a solution of methylthiazole (1,080 g) in methylene chloride (5 ml)was stirred at -65°C for 1 hour, treated at -65°With triethylamine (1,05 g) and allowed to reach ambient temperature. The solution was washed, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel using 25% acetone in isohexane as eluent, to obtain the compound indicated in heading (1.7 g).

MS: APCI-[M-N]-242

1H NMR DMSO-d6: δ 11.67 (1H, s), 7.07 (1H, d), 2.71 (3H, d), 2.48 (3H, s), 2.19 (3H,s).

2) 7-Chloro-5-fluoro-2,4-dimethyl-1H-indol

A solution of the product from stage (1) (1.13 g) and thiosalicylic acid (1,43 g) in triperoxonane acid (50 ml) was stirred at 60°C for 2 hours and evaporated. The residue was dissolved in methylene chloride, washed with 1 N. aqueous sodium hydroxide solution, then with water, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel using 10% ethyl acetate in isoge the San as eluent, obtaining the connection specified in the header (0,82 g).

MC: ES1 197 [M+H]

1H NMR DMSO-d6: δ 11.25 (1H, s), 6.97 (1H, d), 6.28 (1H, q), 2.40 (3H, d), 2.30 (3H, d)

3) 5-fluoro-2,4-dimethyl-1H-indol

Stirred suspension of 10% palladium on carbon (200 mg) in ethanol (50 ml) was treated with a solution of ammonium formate (2.3 g) in water (2 ml)was stirred for 1 min, and treated with a solution of the product from step (2) (721 mg) in ethanol (10 ml)was stirred for 2 hours, and treated with an additional amount of 10% palladium on carbon (500 mg), was stirred at 40°C for 2 hours and filtered. The solids were washed with ethanol and the combined filtrates evaporated. The residue was dissolved in ether, washed, dried (MgSO4) and evaporated to obtain the connection specified in the header.

MS: ES1+[M+H] 163

1H NMR CDCl3: δ 7.82 (1H, s), 7.04-7.01 (1H, m), 6.82 (1H, dd), 6.21-6.21 (1H, m), 2.45 (3H, s), 2.40-2.40 (3H, m).

4) Methyl-5-fluoro-2,4-dimethyl-1H-indol-1-yl-acetate

Stirred suspension of the product from step (3) (2 g) and cesium carbonate (4.8 g) in acetone (100 ml) was treated with methylbromide (4,22 g), was heated under reflux overnight, and treated with an additional quantity of cesium carbonate (2.4 g) and methylpropanoate (1.3 ml), was heated under reflux for 2 hours and evaporated. The residue was dissolved in ethyl acetate, washed with brine (3x) and dried (MgSO 4) and evaporated. The residue was purified by chromatography on silica gel using 20% acetone in isohexane as eluent, to obtain the compounds specified in the header, in the form of a white solid (2.57 m) g).

MS: APCI-[M-H] 253

BP. 176°C.

1H NMR DMSO-d6: δ 6.92-6.83 (2H, m), 6.30 (1H, s), 4.76 (2H, s), 3.74 (3H, s), 2.40-2.39 (6H, m).

5) 5-fluoro-2,4-dimethyl-1H-indol-1-yl-acetic acid

The mixed solution of the product from step (4) (of 2.51 g) in THF (50 ml) was treated with a solution of lithium hydroxide (894 mg) in water (10 ml), was stirred overnight and then concentrated to remove most of THF. The residue was acidified using 1 N. hydrochloric acid and was extracted with methylene chloride, washed and dried (MgSO4) and evaporated extract with getting the connection specified in the header, in the form of a white solid (2,33 g).

1H NMR DMSO-d6: δ 12.98 (1H, s), 7.16 (1H, dd), 6.83 (1H, dd), 6.27 (1H, s), 4.92 (2H, s), 2.32-2.32 (6H, m).

MS: APCI-[M-H] 220

6) 3-[(4-Chlorophenyl)thio]-5-fluoro-2,4-dimethyl-1H-indole-1-acetic acid

The mixed solution of the product from step (5) (221 mg) and iodine (508 mg) in DMF (2 ml) was treated with a solution of 4-chlorothiophenol (288 mg) and was stirred over night. The solution was purified HPLC with reversed phase with obtaining the connection specified in the header (50 mg).

MS: APCI-[M-H] 362

1H NMR DMSO-d6: δ 7.30-7.25 (3H, m), 6.97-6.89 (3H, m), 4.74 (2H, s), 2.44 (3H, d), 236 (3H, s).

Example 44

3-[(4-Cyanophenyl)thio]-5-fluoro-2,4-dimethyl-1H-indole-1-acetic acid

The connection specified in the header received from the product of example 49 stage (5) (221 mg), iodine (508 mg) and 4-dibenzonitrile (270 mg) by the method of example 49 stage (6).

MS: APCI-[M-H] 353

1H NMR DMSO-d6: δ 7.68-7.63 (2H, m), 7.33-7.29 (1H, m), 7.12-7.08 (2H, m), 6.98-6.92 (1H, m), 4.78 (2H, s), 2.40 (3H, d), 2.35 (3H, s).

Example 45

3-[(2-Chlorophenyl)thio]-5-fluoro-2,4-dimethyl-1H-indole-1-acetic acid

The connection specified in the header received from the product of example 49 stage (5) (221 mg), iodine (508 mg) and 2-chlorothiophenol (289 mg) by the method of example 49 stage (6).

MS: APCI-[M-H] 362

1H NMR DMSO-d6: δ 7.45-7.42 (1H, m), 7.25-7.21 (1H, m), 7.13-7.06 (2H, m), 6.94-6.87 (1H, m), 6.53-6.50 (1H, m), 4.53 (2H, s), 2.39 (3H, d), 2.33 (3H, s).

Example 46

5-fluoro-3-[(2-methoxyphenyl)thio]-2,4-dimethyl-1H-indole-1-acetic acid

The connection specified in the header received from the product of example 49 stage (5) (221 mg), iodine (508 mg) and 2-methoxythiophene (280 mg) by the method of example 49 stage (6).

MS: APCI-[M-H] 358

1H NMR DMSO-d6: δ 7.39-7.34 (1H, m), 7.08-6.93 (3H, m), 6.74-6.69 (1H, m), 6.33 (1H, dd), 5.09 (2H, s), 3.89 (3H, s), 2.40 (3H, d), 2.34 (3H, s).

Example 47

5-fluoro-3-[(2-ethylphenyl)thio]-2,4-dimethyl-1H-indole-1-aceticacid

The connection specified in the header received from the product of example 49 stage (5) (221 mg), iodine (508 mg) and 2-ethylthiophene (276 mg) is the procedure of example 49 stage (6).

MS: APCI-[M-H] 356

1H NMR DMSO-d6: δ 7.28-7.23 (1H, m), 7.18 (1 H, dd), 7.03-6.87 (3H, m), 6.47 (1H, dd), 4.71 (2H, s), 2.80 (2H, q), 2.40 (3H, d), 2.35 (3H, s), 1.29.

Example 48

5-fluoro-2,4-dimethyl-3-[[2-(1-methylethyl)phenyl]thio]-1H-indole-1-acetic acid

The connection specified in the header received from the product of example 49 stage (5) (221 mg), iodine (508 mg) and 2-isopropylthiazole (304 mg) by the method of example 49 stage (6).

MS: APCI-[M-N] 370

1H NMR DMSO-d6: δ 7.29-7.25 (2H, m), 7.03 (1H, td), 6.95-6.88 (2H, m), 6.47 (1H, dd), 4.78 (2H, s), 3.44 (1H, quintet), 2.40 (3H, d), 2.35 (3H, s), 1.30 (6H, d).

Example 49

5-fluoro-2,4-dimethyl-3-[[2-(trifluoromethyl)phenyl]thio]-1H-indole-1-acetic acid

The connection specified in the header received from the product of example 49 stage (5) (221 mg), iodine (508 mg) and 2-triptoreline (356 mg) by the method of example 49 stage (6).

MS: APCI-[M-H] 396

1H NMR DMSO-d6: δ 7.70 (1H, d), 7.38 (1H, t), 7.27-7.23 (2H, m), 6.91 (1H, t), 6.76 (1H, d), 4.57 (2H, s), 2.38 (3H, d) and 2.35 (3H, s).

Example 50

2,5-Dimethyl-4-(methylsulphonyl)-3-[(4-phenyl-2-thiazolyl)thio]-1H-indole-1-acetic acid

a) 2,5-Dimethyl-4-(methylsulphonyl)-3-(methylthio)-1H-indole

The connection specified in the header, received by way of example 43 stage (1), using 4-methyl-3-(methylsulphonyl)-benzolamide.

1H NMR DMSO-d6: δ 11.94 (1H, s), 7.49 (1H, d), 7.01 (1H, d), 3.51 (3H, s), 2.69 (3H, s), 2.55 (3H, s), 2.19 (3H, d).

b) 2,5-Dimethyl-4-(methylsulphonyl)-1H-indole

A solution of the product from stage (a) (1,00 who) and thiosalicylic acid (1,15 g) in triperoxonane acid (20 ml) was stirred at 60° C for 2 hours and then concentrated in vacuum. The residue was dissolved in methylene chloride, washed with 1 N. aqueous sodium hydroxide solution and then with water, dried (MgSO4) and evaporated to obtain the connection specified in the header (0,47 g).

1H NMR DMSO-d6: δ 11.36 (1H, s), 7.46 (1H, d), 6.99 (1H, d), 6.64 (1H, d), 3.33 (3H, s), 3.10 (3H, s), 2.66 (3H, s).

C) 2,5-Dimethyl-4-(methylsulphonyl)-3-[(4-phenyl-2-thiazolyl)thio]-1H-indole-1-acetic acid

The mixed solution of the product from step (b) (200 mg) and iodine (210 mg) in DMF (2 ml) was treated with 2-thiazolyl, 4-phenyl - (300 mg) and was stirred for 1 hour. This solution was treated with 60% sodium hydride (about 4.0 molar equivalents) and stirred over night. Added methylbromide (0,30 g) followed by the addition after 30 minutes of stirring water (2 ml), tetrahydrofuran (2 ml) and lithium hydroxide (0.20 g). After stirring for 30 minutes, this reaction mixture was acidified (2 M HCl, 5 ml) and was extracted into ethyl acetate (3×10 ml). The combined organic substance was washed with saturated brine (3×10 ml), dried (MgSO4) and evaporated. The residue was purified preparative HPLC with reversed phase with obtaining the connection specified in the header (172 mg).

MS: APCI-[M-H] 471

1H NMR DMSO-d6: δ 7.94-7.69 (4H, m), 7.49-7.24 (3H, m), 7.19 (1H, d), 5.05 (2H, s), 3.57 (3H, s), 3.34 (3H, s), 2.80 (3H, s).

Prima is 51

3-[(3-Chlorophenyl)thio]-2,5-dimethyl-4-(methylsulphonyl)-1H-indole-1-acetic acid

The connection specified in the header, obtained using the method of example 50 stage (3)using the product from step (2) (200 mg) and 3-chlorobenzoyl (0.3 g).

The compound was purified preparative HPLC with reversed phase with obtaining the connection specified in the header (40 mg).

MS: APCI-[M-H] 422

1H NMR DMSO-d6: δ 7.83-7.69 (1H, m), 7.26-6.97 (MN, m), 6.88-6.73 (2H, m), 5.01 (2H, d), 3.57 (3H, s), 3.32 (3H, s), 2.69 (3H, s).

Example 52

3-[(2-Chlorophenyl)thio]-2,5-dimethyl-4-(methylsulphonyl)-1H-indole-1-acetic acid

The connection specified in the header (55 mg), obtained by the method of example 57 stage (3)using the product from step (2) (200 mg) and 2-chlorbenzoyl (0.3 g).

MS: APCI-[M-H] 422

1H NMR DMSO-d6: δ 7.76 (1H, d), 7.39 (1H, m), 7.21-6.95 (3H, m), 6.34 (1H, m), 4.93 (2H, s), 3.64 (3H, s), 3.29 (3H, s), 2.69 (3H, s).

Example 53

3-[(4-Chlorophenyl)thio]-5-(methoxycarbonyl)-2-methyl-1H-indole-1-acetic acid

(1) 3-[(4-Chlorophenyl)thio]-2-methyl-1H-indole-5-carboxylic acid

To a solution of product from step 27 (1) (2 g) in ethanol (20 ml) was added to 12.5 M sodium hydroxide solution (5 ml). This mixture was heated to education phlegmy within 4 days. After cooling, the mixture was poured into water and brought the pH to 2 using concentrated HCl (aqueous). Solid, which was precipitate was isolated by filtration, and then Perekrest who was litovali from boiling methanol to obtain compound, specified in subhead (2 g).

1H NMR DMSO-d6: δ 12.51 (1H, s), 12.05 (1H, s), 7.96 (1H, d), 7.75 (1H, dd), 7.46 (1H, dd), 7.27 (1H, dd), 6.97 (2H, dd), 2.47 (3H, s).

(2) Methyl ether 3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-5-carboxylic acid

To a solution/suspension of the product from step (1) (1 g) in methanol (50 ml) was added trimethylsilane (12,6 ml). After stirring at room temperature overnight the mixture was concentrated in vacuo to obtain the connection specified in the subtitle, in quantitative yield.

1H NMR DMSO-d6: δ 12.12 (1H, s), 7.97 (1H, d), 7.77 (1H, dd), 7.49 (1H, dd), 7.27 (2H, dt), 6.97 (2H, dt), 3.80 (3H, s), 2.47 (3H, s).

(3) 1,1-Dimethylethylene ester of 3-[(4-chlorophenyl)thio]-5-(methoxycarbonyl)-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example 11 stage (2), using the product of stage (2) and tert-butylbromide. The product was purified using flash column chromatography (14% EtOAc/hexane as eluent).

1H NMR DMSO-d6: δ 8.01 (1H, d), 7.82 (1H, dd), 7.67 (1H, d), 7.28 (2H, m), 6.97 (2H, dt), 5.20 (2H, s), 3.81 (3H, s), 2.44 (3H, s), 1.42 (9H, s).

(4) 3-[(4-Chlorophenyl)thio]-5-(methoxycarbonyl)-2-methyl-1H-indole-1-acetic acid

The connection specified in the header, received by way of example 22 stage (3)using the product from step (3).

1H NMR DMSO-d6: δ 13.28 (1H, s), 8.01 (1H, d), 7.81 (1H, dd), 7.68 (1H, d), 7.28 (2H, d), 6.98 (2H, d), 5.2 (2H, s), 3.82 (3H, s), 2.45 (3H, s).

MS: APCI-[M-H] 388

TPL 221-223°

Example 54

5-Carboxy-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

(1) 5-Carboxy-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

A suspension of the product from example 53 (0.5 g) in 1 M sodium hydroxide (aqueous) (3 ml) was heated in a sealed tube at 100°s using microwave for 10 minutes. This mixture was poured into water and brought the pH to 2 using 2 M HCl (aqueous). Solid, which was precipitate was isolated by filtration, dried overnight in vacuum at 50°obtaining the connection specified in the header (0.1 g).

1H NMR DMSO-d6: δ 7.99 (1H, d), 7.79 (1H, dd), 7.64 (1H, d), 7.28 (2H, dd), 6.99 (2H, dt), 5.19 (2H, s), 2.45 (3H, s).

MS: APCI-[M-H] 374

TPL decomposes >302°

Example 55

3-[(4-Chlorophenyl)thio]-2-methyl-4-nitro-1H-indole-1-acetic acid

1) 3-[(4-Chlorophenyl)thio]-2-methyl-4-nitro-1H-indol

To a stirred solution of 3-nitroaniline (8 g) in THF (700 ml)cooled to -78°C, was added tert-butylhypochlorite (6.3 g) dropwise over 5 minutes. This reaction mixture was allowed to warm up to -65°C for 20 minutes, after which was added 1-[(4-chlorophenyl)thio]-2-propanone (11.6 g) in the form of a solution in tetrahydrofuran (20 ml). After 2 hours, was added triethylamine (8.1 ml) and the reaction mixture was allowed to warm to room temperature. To the reaction mixtures and added 2 M HCl (aqueous), then concentrated in vacuo. The residue is suspended in methanol and the solids which precipitate that was isolated by filtration to obtain the connection specified in the subtitle (5.8 g).

1H NMR DMSO-d6: δ 12.55 (s, 1H), 7.76 (dd, 1H), 7.63 (dd, 1H), 7.31-7.22 (m, 3H), 6.91 (dd, 2H), 2.47 (s, 3H).

2) Ethyl ester of 3-[(4-chlorophenyl)thio]-2-methyl-4-nitro-1H-indole-1-acetic acid

To a stirred suspension of sodium hydride, 60% dispersion in mineral oil (0.85 grams)in THF (100 ml) was added the product from step (1) (5.6 g) in solution in THF (50 ml). After stirring at room temperature for 30 min was added ethylbromoacetate (2,3 ml) dropwise over 10 minutes. After 2 hours, this reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate, washed with water, brine, dried (MgSO4) and concentrated in vacuum. As a result of recrystallization from boiling ethanol has received the connection specified in subhead (5 g).

1H NMR AMCO-d6: δ 7.97 (dd, 1H), 7.65 (dd, 1H), 7.35 (t, 1H), 7.26 (dt, 2H), 6.92 (dt, 2H), 5.40 (s, 2H), 4.19 (q, 2H), 2.45 (s, 3H), 1.22 (t, 3H).

3) 3-[(4-Chlorophenyl)thio]-2-methyl-4-nitro-1H-indole-1-acetic acid

To a solution of the product of stage (2) (0.1 g) in THF (5 ml) was added 1 M NaOH solution (water) (0.25 ml). This reaction mixture was stirred over night at room temperature. The reaction mixture was concentrated in vacuume the residue was dissolved/suspended in water. Brought the pH to 2 using dilute HCl (aqueous), and a solid substance, which was precipitate was isolated by filtration, dried in vacuum at 50°obtaining the connection specified in the header (0.07 g).

1H NMR DMSO-d6: δ 13.37 (s, 1H), 7.97 (d, 1H), 7.64 (d, 1H), 7.34 (t, 1H), 7.25 (dt, 2H), 6.92 (dt, 2H), 5.28 (s, 2H), 2.45 (s, 3H).

MS: APCI-[M-H] 375

TPL decomposes >198°

Example 56

4-Amino-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

1) Ethyl ester of 4-amino-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid

A suspension of the product from example 55 stage (2) (2.25 g) in ethanol (170 ml) was stirred in the presence of 5% Pt/C (0.5 g) under pressure of H22 bar. After stirring overnight, the catalyst was removed by filtration and the filtrate was concentrated in vacuum. In the purification column flash chromatography (14% EtOAc/hexane as eluent) received the connection specified in the subtitle (1.4 g).

1H NMR (DMSO): δ 7.30 (dd, 2H), 7.00 (dt, 2H), 6.85 (t, 1H), 6.68 (dd, 1H), 6.23 (dd, 1H), 5.33 (s, 2H), 5.09 (s, 2H), 4.16 (q, 2H), 2.33 (s, 3H), 1.21 (t, 3H).

Ethyl ester of 3-[(4-chlorophenyl)thio]-4-(ethylamino)-2-methyl-1H-indole-1-acetic acid was also isolated from this reaction mixture as a by-product (0.33 g).

1H NMR DMSO-d6: δ 7.32 (dd, 2H), 7.01 (dd, 2H), 6.95 (t, 1H), 6.73 (d, 1H), 6.16 (d, 1H), 5.70 (t, 1H), 5.11 (s, 2H), 4.16 (q, 2H), 3.05 (dt, 2H), 2.34 (s, 3H), 1.21 (t, 3H), 1.02 (t, 3H).

2) 4-Amino-3-[(4-chlorp the Nile)thio]-2-methyl-1H-indole-1-acetic acid

The connection specified in the header, obtained using the method of example 1, stage (3) (0.03 g).

1H NMR (DMSO): δ 7.29 (dt, 2H), 7.01 (dt, 2H), 6.88 (t, 1H), 6.76 (d, 1H), 6.30 (d, 1H), 4.99 (s, 2H), 2.33 (s, 3H).

MS: APCI-[M-H] 345

TPL decomposes >235°

Example 57

3-[(4-Chlorophenyl)thio]-4-(ethylamino)-2-methyl-1H-indole-1-acetic acid

This compound is obtained using the method of example 55 stage (2), using a byproduct from example 2, stage (1). Purification preparative HPLC with reversed phase.

1H NMR DMSO-d6: δ 7.29 (dt, 2H), 7.02 (m, 2H), 6.88 (t, 1H), 6.64 (d, 1H), 6.11 (d, 1H), 5.66 (t, 1H), 4.51 (s, 2H), 3.04 (dt, 2H), 2.31 (s, 3H), 1.01 (t, 3H).

MS: APCI+[M+H] 375

Example 58

3-[(4-Chlorophenyl)thio]-4-iodine-2-methyl-1H-indole-1-acetic acid

1) 3-[(4-Chlorophenyl)thio]-4-iodine-2-methyl-1H-indol

The connection specified in the subtitle, received by way of example 27 stage (1), using 3-iodoaniline. The product was purified using flash column chromatography (14% EtOAc/hexane as eluent).

1H NMR DMSO-d6: δ 11.99 (1H, s), 7.50 (1H, dd), 7.44 (1H, dd), 7.26 (2H, m), 6.92-6.84 (3H, m), 2.43 (3H, s).

2) 3-[(4-Chlorophenyl)thio]-4-iodine-2-methyl-1H-indole-1-acetic acid

The connection specified in the subtitle, received by way of example 11 stage (2) stage (3)using the product from step (1).

1H NMR AMCO-d6: δ 7.52 (2H, d), 7.25 (2H, dt), 6.93-6.86 (3H, m), 4.86 (2H, s), 2.40 (3H, s).

MS: APCI-[M-H] 456

Example 59

3-[(4-Chlorophenyl)thio-2-methyl-4-phenyl-1H-indole-1-acetic acid

1) 1,1-Dimethylethylene ester of 3-[(4-chlorophenyl)thio]-2-methyl-4-phenyl-1H-indole-1-acetic acid

To a solution of the product of example 22 stage (2) (0.5 g) in ethanol (0.8 ml) and toluene (3 ml) was added 2 M sodium carbonate solution in water (1.4 ml), phenylboronic acid (0,131 g) and tetrakis(triphenylphosphine)palladium (0) (1.2 g). This reaction mixture was heated to education phlegmy for 2 hours, cooled and concentrated in vacuum. The residue was purified column flash chromatography to obtain the connection specified in the subtitle (0.4 g). This compound is used in stage (2) without further specifications.

2) 3-[(4-Chlorophenyl)thio]-2-methyl-4-phenyl-1H-indole-1-acetic acid

To a solution of product from step (1) (0.4 g) in dichloromethane (10 ml) was added triperoxonane acid (2 ml), the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved/suspended in water. Brought the pH to 2 using 2 M HCl (aqueous), and a solid substance, which was precipitate was isolated by filtration. This substance was purified using preparative HPLC with a reversed phase (MeCN/NH3(water as eluent) to obtain a solid substance. This solid is suspended in water and brought the pH to 2 using 2 M HCl (aqueous), the solid was isolated by filtration, triturated with Gex is Mr. and dried over night at 40° With the vacuum connection is specified in the header (0.15 g).

1H NMR DMSO-d6: δ 7.55 (d, 1H), 7.26-7.07 (m, 8H), 6.87 (d, 1H), 6.56 (m, 2H), 5.18 (s, 2H), 2.40 (s, 3H).

MS: APCI+[M+H] 408

Pharmacological data

Analysis of the binding of the ligand

[3H]PGD2bought from Perkin Elmer Life Sciences with a specific activity 100-210 Curie/mmol. All other chemical reagents were of analytical purification.

Cells SOME expressing rhCRTh2/Gα16, routinely maintained in DMEM containing 10% fetal calf serum (HyClone), 1 mg/ml geneticin, 2 mm L-glutamine and 1% non-essential amino acids. For preparation of membrane attached to the substrate transfected cells SOME grew to confluently a two-cultivators for tissue cultures (Fisher, catalog number TCPs-170-E). The maximum levels of expression of the receptor induced by the addition of 500 mm of sodium butyrate in the last 18 hours of cultivation. Attached to the substrate, the cells were washed once with saline, phosphate buffered (FSB, 50 ml cultivator cells) and detached by adding 50 ml of a cultivator cells cooled in ice buffer homogenization membranes [20 mm HEPES (pH 7.4), 0.1 mm dithiothreitol, 1 mm EDTA, 0.1 mm phenylmethylsulfonyl and 100 μg/ml bacitracin]. Cells were besieged by centrifugation p. and 220xg for 10 minutes at 4° With, resuspendable in half the original volume of fresh buffer homogenization membranes and destroyed using a homogenizer transmitter station, within 2×20 second cycles of destruction, keeping the tube all the time in ice. Intact cells were removed by centrifugation at 220xg for 10 minutes at 4°and the membrane fraction was besieged by centrifugation at 90000xg for 30 minutes at 4°C. the resulting sludge resuspendable in 4 ml of homogenization buffer membranes used cultivator cells and protein content was determined. Membranes were stored at -80°in suitable aliquot.

All analyses were performed in white 96 well NBS tablets-bottomed Coming (Fisher). Before analysis of cell membrane SOME containing CRTh2, was applied in the form of a coating on the granules SPA PVT WGA (Amersham). To cover the membranes were incubated with beads at a typical concentration of membrane protein 25 μg per mg of the granules at 4°and With constant shaking overnight (optimal concentration of coating was determined for each batch of membranes). Granules besieged by centrifugation (800xg for 7 minutes at 4°C), washed once analytical buffer (50 mm HEPES pH 7.4, containing 5 mm magnesium chloride) and, finally, resuspendable in analytical buffer at a final concentration of granules 10 mg/ml

Each assay contained 20 ál of 6.25 nm [3H]PGD2, 0 ál saturated membranes granules SPA, both analytical buffer, and 10 μl of a solution of the compound or 13,14-dihydro-15-ketoprostaglandin D2(DK-PGD2to determine nonspecific binding, chemical company Cayman). Connection and DK-PGD2was dissolved in DMSO and diluted in the same solvent up to 100x the required final concentration. Analytical buffer was added to obtain a final concentration of 10% DMSO (now the connection was 10x the required final concentration) and this solution was added to the analytical tablet. Analytical tablet incubated at room temperature for 2 hours and counted on the counter liquid scintillation Wallac Microbeta (1 minute per well).

The compounds of formula (I) have values IC50less than 10 microns.

Specifically, example 23 had pIC50=6,05, example 50 was pIC50=7.2 and example 29 had pIC50=8,35.

1. The compound of formula (I) or its pharmaceutically acceptable salt:

in which

R1represents hydrogen, halogen, CN, nitro, SO2R4HE, OR4, SO2NR5R6, CONR5R6, COOH, COOCH3, NR5R6, phenyl, naphthyl or C1-6alkyl, the latter group possibly substituted by one or more than one Deputy, independently selected from halogen, OR8and NR5R6,S(O) xR7where x is equal to 2;

R2represents a C1-7alkyl;

R3represents phenyl, naphthyl or heteroaryl, each of which may substituted by one or more than one Deputy, is independently selected from hydrogen, halogen, CN, IT, SO2R4, OR4, SO2NR5R6, CONR5R6, NR5R6, phenyl, naphthyl, C1-6the alkyl, the latter group possibly substituted by one or more than one Deputy, independently selected from halogen atoms, OR8and NR5R6, S(O)xR7where x is equal to 2;

R4represents a C1-6alkyl;

R5and R6independently represent a hydrogen atom or a group C1-6alkyl, or

R5and R6together with the nitrogen atom to which they are attached, may form a 6-membered saturated heterocyclic ring containing one atom selected from NR16;

R7is a group of C1-C6alkyl;

R8represents a hydrogen atom or a C1-C6alkyl;

R16represents hydrogen or COYC1-C4alkyl, where Y represents Oh,

and where the alkyl group or the alkyl group in the group substituent may be normal, branched or what ilicakoy,

and where

heteroaryl is a 5-6-membered heteroaromatic ring containing one to three heteroatoms selected from nitrogen, oxygen, or sulfur, or 6,6-condensed bicyclic aromatic ring system containing one nitrogen atom.

2. The compound according to claim 1, in which R1represents phenyl, naphthyl, hydrogen, methyl, chloro, fluorescent, nitrile, nitro, bromine, iodine, SO2Me, SO2Et, NR5R6, SO2N-alkyl2.

3. The compound according to claim 1 or 2, in which R2represents a C1-6alkyl.

4. The compound according to claim 3 in which R3represents chenail, phenyl or thiazole, substituted one or more than one group of fluorine, chlorine, methyl, ethyl, isopropyl, methoxy, SO2Me, trifluoromethyl or phenyl.

5. The compound according to claim 1, chosen from:

3-[(4-chlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(2-chloro-4-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(3-chloro-4-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(2-methoxyphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(3-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(4-ethylphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(2-chlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(2,5-dichlorophenyl)thio]-2,5-dime the Il-1H-indole-1-acetic acid;

3-[(4-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(4-chloro-2-were)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-4-cyano-2,5-dimethyl-1H-indole-1-acetic acid;

5-chloro-3-[(4-chlorophenyl)thio]-6-cyano-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-4-[(diethylamino)sulfonyl]-7-methoxy-2-methyl-1H-indole-1-acetic acid;

4-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

5-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

6-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

7-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-2-methyl-5-(methylsulphonyl)-1H-indole-1-acetic acid;

2-methyl-3-[(4-were)thio]-6-(methylsulphonyl)-1H-indole-1-acetic acid;

4-bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-4-[4-[(1,1-dimethylmethoxy)carbonyl]-1-piperazinil]-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-2-methyl-4-(1-piperazinil)-1H-indole-1-acetic acid;

5-bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-2-methyl-5-phenyl-1H-indole-1-acetic acid;

3-[(4-chlorphen the l)thio]-5-cyano-2-methyl-1H-indole-1-acetic acid;

3-[(4-cyanophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(3-methoxyphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(4-methoxyphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(3-ethylphenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

2,5-dimethyl-3-[(2-were)thio]-1H-indole-1-acetic acid;

3-[(3-chlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(2-forfinal)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-[(2,6-dichlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic acid;

3-(1H-imidazol-2-ylthio)-2,5-dimethyl-1H-indole-1-acetic acid;

2,5-dimethyl-3-(1H-1,2,4-triazole-3-ylthio)-1H-indole-1-acetic acid;

2,5-dimethyl-3-[(4-methyl-4H-1,2,4-triazole-3-yl)thio]-1H-indole-1-acetic acid;

2,5-dimethyl-3-[(4-methyl-2-oxazolyl)thio]-1H-indole-1-acetic acid;

2,5-dimethyl-3-[(1-methyl-1H-imidazol-2-yl)thio]-1H-indole-1-acetic acid;

2,5-dimethyl-3-[[4-(methylsulphonyl)phenyl]thio]-1H-indole-1-acetic acid;

2,5-dimethyl-3-(8-chinaindia)-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-5-fluoro-2,4-dimethyl-1H-indole-1-acetic acid;

3-[(4-cyanophenyl)thio]-5-fluoro-2,4-dimethyl-1H-indole-1-acetic acid;

3-[(2-chlorophenyl)thio]-5-fluoro-2,4-dimethyl-1H-indole-1-acetic acid;

5-fluoro-3-[(2-methoxyphenyl)thio]-2,4-dimethyl-1H-indol-1-UK is usnei acid;

5-fluoro-3-[(2-ethylphenyl)thio]-2,4-dimethyl-1H-indole-1-acetic acid;

5-fluoro-2,4-dimethyl-3-[[2-(1-methylethyl)phenyl]thio]-1H-indole-1-acetic acid;

5-fluoro-2,4-dimethyl-3-[[2-(trifluoromethyl)phenyl]thio]-1H-indole-1-acetic acid;

2,5-dimethyl-4-(methylsulphonyl)-3-[(4-phenyl-2-thiazolyl)thio]-1H-indole-1-acetic acid;

3-[(3-chlorophenyl)thio]-2,5-dimethyl-4-(methylsulphonyl)-1H-indole-1-acetic acid;

3-[(2-chlorophenyl)thio]-2,5-dimethyl-4-(methylsulphonyl)-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-5-(methoxycarbonyl)-2-methyl-1H-indole-1-acetic acid;

5-carboxy-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-2-methyl-4-nitro-1H-indole-1-acetic acid;

4-amino-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-4-(ethylamino)-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-4-iodine-2-methyl-1H-indole-1-acetic acid;

3-[(4-chlorophenyl)thio]-2-methyl-4-phenyl-1H-indole-1-acetic acid

and their pharmaceutically acceptable salts.

6. The compound of formula (I) according to claim 1 for use in the manufacture of drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD).

7. The method of obtaining the compounds of formula (I), wherein the compound of formula (II):

1, R2and R3are as defined in claim 1, or a protected derivative, is subjected to the interaction with the compound of the formula (A):

where R17represents a C1-6alkyl, a L is halogeno,

in the presence of a base, and may thereafter in any order: remove any protective group, is subjected to ester group R17hydrolysis to the corresponding acid to form a pharmaceutically acceptable salt.



 

Same patents:

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new polymorphous crystalline forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)-amino]-ethoxy]-benzyl]-thiazolidine-2,4-dione maleate of formula and stereomers thereof.

EFFECT: polymorphous crystalline forms of high stability.

12 cl, 1 tbl, 13 dwg, 5 ex

FIELD: medicine, organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , or pharmaceutically acceptable salt or solvates thereof, wherein X and Z represent CH or N; Y represents O; R1, R2, and R3 are identical or different and represent hydrogen atom, C1-C6-alkoxy; R5 represents hydrogen atom; R5, R6, R7, and R8 are identical or different and represent hydrogen atom, halogen atom, C1-C4-alkyl, trifluoromethyl; R9 and R10 represent hydrogen atom; R11 represents optionally substituted azolyl. Also disclosed are pharmaceutical composition with inhibiting activity in relates to KDR phosphorylation and method for inhibiting of target blood-vessel angiogenesis.

EFFECT: new pharmaceuticals useful in treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, arteriosclerosis, and Kaposi's sarcoma.

33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

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

22 cl, 8 tbl, 453 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, chemical technology, medicine, endocrinology.

SUBSTANCE: invention relates to a method for preparing an antidiabetic agent pioglitazone of the formula (I): . Method involves condensation of 4-substituted phenol or phenolate of the general formula (II): wherein R represents organic radical comprising amino-group and chosen from group comprising group of the general formula: -NHRa (IIa) wherein Ra means hydrogen atom or protective group that is removed before the following treatment, and group of the general formula: wherein Rb represents carboxyl group as free acid or as salt or ester; M represents hydrogen atom or alkaline metal with pyridine base of the general formula (III): wherein Z means a removing group distinguishing from halogen atom and wherein the following steps are carried out: (a) diazotization reaction of amino-group as a moiety of organic radical R; (b) conversion of diazotized radical R to derivative of 2-halogenpropionate or 2-halogenpropionitrile of the formula: wherein Rb is determined above; X represents halogen atom; (c) cyclization of derivative of 2-halogenpropionate or 2-halogenpropionitrile with thiourea, and (d) hydrolysis of imine prepared. In case when R represents group of the formula (IIa) method involves firstly carrying out the condensation reaction followed by carrying out steps (a)-(d) to obtain agent of the formula (I); or in case when R represents group of the formula (IIb) then method involves firstly carrying out steps (a)-(d) followed by condensation with pyridine base of the general formula (III) to obtain agent of the formula (I). Also, invention describes compounds of the formula (V): wherein Ra represents a protective group chosen from group comprising acyl, n-alkoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-cyanoethoxycarbonyl as an intermediate substance in synthesis of compound of the formula (I).

EFFECT: improved preparing method of agent.

12 cl, 5 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

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

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, cosmetics, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means radical of the following formulae: (a) or (b) wherein R2 and R3 are similar or different and mean hydrogen atom, alkyl with 10-12 carbon atoms, aryl, radical -OR7; X means a binding fragment of the following formula: -(CH2)m-(Z)n-(CO)p-(W)q- wherein a binding fragment can be read from the left to the right or inversely; R4 means alkyl with 1-12 carbon atoms, aryl, aralkyl, heteroaryl or 9-fluorenylmethyl; Y means radical -CH2 or sulfur atom; R5 means hydroxyl, alkoxyl with 1-6 carbon atoms, radical -NH-OH or radical -N(R8)(R9); R6 means alkyl with 1-12 carbon atoms, radical -OR10 or radical -(CH2)r-COR11; R7 means hydrogen tom or aralkyl; Z means oxygen atom or radical -NR12; W means oxygen atom, radical -NR13 or radical -CH2; m, n, p and q are similar or different and can mean 0 or 1 under condition that the sum (m + n + p + q) = 2 or above, and when p = 0 then n or q = 0; R8 means hydrogen atom; R9 means hydrogen atom or aryl; r means 0 or 1; R10 means alkyl with 1-12 carbon atoms; R11 means hydroxyl or radical -OR14; R12 means hydrogen atom or alkyl with 1-12 carbon atoms; R13 means hydrogen atom or alkyl with 1-12 carbon atoms; R14 means alkyl with 1-12 carbon atoms; and optical and geometric isomers of abovementioned compounds of the formula (I), and their salts also. These compounds are useful as activating agents of receptors of type PPAR-γ in pharmaceutical compositions designated for using in medicine, in particular, in dermatology, in treatment of cardiovascular diseases and related to immunity of diseases and/or diseases associated with lipid metabolism, and in cosmetic compositions also.

EFFECT: valuable properties of compounds and compositions.

19 cl, 1 tbl, 2 dwg, 37 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted bicyclic heterocyclic compounds of the formula (I): their tautomeric forms, stereoisomers, polymorphous forms, pharmaceutically acceptable salts and pharmaceutically acceptable solvates wherein groups R1, R2, R3 and R4, and groups R5 and R6 when they are bound with carbon atom they represent hydrogen, halogen atom, hydroxy-group, alkyl, alkoxy-group; R5 and R6 as a single group or both can represent also an oxo-group when they are bound with carbon atom; when R5 and R6 are bound with nitrogen atom then they represent hydrogen atom, hydroxy-group or such unsubstituted groups as alkyl, alkoxy-group, aralkyl. X means oxygen or sulfur atom; Ar means phenylene, naphthylene or benzofuryl. Proposed compounds can be used against obesity and hypercholesterolemia. Also, the invention describes methods for preparing compounds, pharmaceutical compositions, method for treatment and using compounds proposed.

EFFECT: valuable medicinal properties of compounds and compositions.

52 cl, 77 ex

FIELD: chemistry of heterocyclic organic compounds, medicine.

SUBSTANCE: invention relates to a novel heterocyclic derivative of the formula (I'): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents-CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R5 represents (C2-C8)-alkenyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; R20 represents phenyl substituted with unsubstituted (C1-C6)-alkyl, (C1-C6)-alkyl substituted with fluorine atom, (C1-C4)-alkoxy-group, phenyl-(C1-C4)-alkoxy-group, hydroxyl group, halogen atom, nitro-group, unsubstituted amino-group or amino-group substituted with (C1-C4)-alkyl; n means a whole number from 1 to 4, or to its pharmaceutically acceptable salt. Also, invention relates to heterocyclic derivative of the formula (I): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R represents (C4-C8)-alkyl or (C2-C8)-alkenyl or -CO-C≡C-R6 wherein R6 represents (C1-C8)-alkyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; n means a whole number from 1 to 4, or its pharmaceutically acceptable salt. Compounds of the formulas (I') and (I) are effective as a hypoglycemic agent, hypolipidemic agent, agent improving resistance to insulin, therapeutic agent in treatment of diabetes mellitus, therapeutic agent in treatment of diabetes mellitus complications, agents enhancing tolerance to glucose, anti-arteriosclerotic agent, agents against obesity or agent for X syndrome.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 2 tbl, 56 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-phenylaminoimidazoline phenylketone that can be used as IP antagonists. Invention describes 2-phenylaminoimidazoline phenylketone of the general formula (I): wherein R1 mean optionally substituted aryl wherein R1 is optionally substituted with 1, 2 or 3 substitutes chosen independently from series including alkoxy-group, aryl aryloxy-, aralkyloxy-group, halogen atom, ethylenedioxy-group or optionally substituted heterocyclyl that means a monovalent saturated carbocyclic radical comprising from 3 to 7 atoms in cycle and comprising one or two heteroatoms chosen independently from nitrogen and oxygen atoms, and can be optionally substituted with one or more substitutes chosen independently from alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl sulfonyl, furanyloxy-group; R2 means hydrogen atom; A means -C(O)-(CH2)n- or -C(O)-CH2-O-; index n means a whole number from 2 to 6, or its pharmaceutically acceptable salt or solvate. Invention provides preparing novel compounds showing useful biological properties.

EFFECT: valuable properties of compounds.

16 cl, 1 tbl, 23 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

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

32 cl, 1 tbl, 132 ex

FIELD: medicine, organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , or pharmaceutically acceptable salt or solvates thereof, wherein X and Z represent CH or N; Y represents O; R1, R2, and R3 are identical or different and represent hydrogen atom, C1-C6-alkoxy; R5 represents hydrogen atom; R5, R6, R7, and R8 are identical or different and represent hydrogen atom, halogen atom, C1-C4-alkyl, trifluoromethyl; R9 and R10 represent hydrogen atom; R11 represents optionally substituted azolyl. Also disclosed are pharmaceutical composition with inhibiting activity in relates to KDR phosphorylation and method for inhibiting of target blood-vessel angiogenesis.

EFFECT: new pharmaceuticals useful in treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, arteriosclerosis, and Kaposi's sarcoma.

33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of mycophenolate mofetil. Method involves the direct esterification of mycophenolic acid and 2-morpholinoethanol. The esterification reaction is carried out by boiling in ethers medium as a solvent of the general formula R3OR4 wherein R3 and R4 mean independently alkyl. Method involves using from 1.01 to 3.0 mole equivalents of 2-morpholinoethanol. The initial temperature of reaction is in the range 130-138°C and the final temperature of reaction is in the range 140-145°C, and the reaction period is from 5 to 50 h. The ratio of mycophenolic acid to solvent is in the range from 1 g/2 ml to 1 g/5 ml. Invention avoids problems associated with coloring mycophenolate mofetil, low solubility of product in higher ethers.

EFFECT: improved method of synthesis.

8 cl, 3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivative of phenylpiperazine mesylate of the formula: possessing preferable properties as compared with form of a free base of the same compound. Also, invention describes a pharmaceutical composition and a method for inhibition of activity of dopamine D2-receptors and site of serotonin reuptake.

EFFECT: valuable pharmacological properties of derivatives.

3 cl, 1 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

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

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the general formula (I): wherein X means -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO, -SO2; m = 1; A represents a direct bond; R1 means hydrogen atom (H); R2 and R3 are chosen independently from H, (C1-C6)-alkyl, heterocycloalkyl, phenyl, heteroaryl, phenylalkyl, phenylheteroalkyl, heteroarylalkyl, heterocycloalkylalkyl; R4 represents H; R5 represents monocyclic, bicyclic or tricyclic group. Also, invention describes a pharmaceutical composition and using compounds in preparing a medicinal agent for using in treatment of diseases or states mediated by one ore more enzymes representing metalloproteinase. Compounds of the formula (I) are useful as inhibitors of metalloproteinases being especially as inhibitors of MMP12.

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

14 cl, 16 ex

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