Diaryl-5,6-condensed heterocyclic acids, pharmaceutical composition and method of protection from the effects of leukotrienes

 

(57) Abstract:

Describes the new diaryl-5,6-condensed heterocyclic acids of General formula (I) where the values of the NET, Y, R1; R3-R7X2X3, Z1, Z2, R22, p, m, Q1, Q2specified in paragraph 1 of the claims, which are antagonists of the actions of leukotrienes. Compounds useful as protivoastmaticheskih, anti-allergic, anti-inflammatory and cytotoxity agents. They are also useful in the treatment of sore throat, spasms, brain, nephritis renal glomeruli, hepatitis, endotoxemia, uveitis and allograft rejection. Also described pharmaceutical composition and method of protection from the effects of leukotrienes. 3 S. and 8 C.p. f-crystals, 2 PL.

Leukotrienes are a group methodistic of the hormones produced by living organisms from arachidonic acid. The major leukotrienes are leukotriene B4(indicated by the abbreviation is fully4), LTS4, D4and LA4. The biosynthesis of these leukotrienes begins with the action of the enzyme 5-lipoxygenase on arachidonic acid to produce the epoxide known as leukotriene A4(LTA4), kneza, and metabolism of leukotrienes described in the book Leukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam (1989). The action of leukotrienes on living organisms and their contribution in various States of disease are also discussed in the book Rokach.

In U.S. patent N 4957932, Young et al., describes compounds of formula I as leukotriene antagonists and inhibitors of leukotriene biosynthesis. These compounds differ from the previously described Young that have a different heterocyclic ring in the left part of the structure. Fujikawa describes thieno [2,3-b] pyridine 2 EP N 367235, but a place of connection and the nature of the principal Deputy differ from those of the present compounds. Musser et al. describe the connection 3 in the US patent N 4794188, as being an inhibitor of lipoxygenase and have anti-inflammatory and anti-allergic activities. However, the connection 3 is different from these compounds is mainly due to the fact that Ar1different from our HETA group. Thus, the compounds of the present invention are new.

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The present invention relates to 5,6-condensed heterocyclic acids having activity as leukotriene antagonists, to methods for their preparation and to methods and pharmaceuticalindustry as leukotriene antagonists, compounds of the present invention are useful as anti-asthmatic, anti-allergic, anti-inflammatory and cytotoxity agents. They are also useful in the treatment of sore throat, spasms, brain, nephritis renal glomeruli, hepatitis, endotoxemia, uveitis and allograft rejection.

Detailed description of the invention

Compounds according to the invention is best represented by formula I

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where R1denotes H or R2;

R2denotes lower alkyl, lower alkenyl, lower quinil, -CF3, -CH2F, -CHF2Ph(R26)2CH2Ph(R26)2or CH2CH2Ph(R26)2or two R2groups attached to the same atom, may form a ring containing up to 8 carbon atoms and up to 2 heteroatoms selected from O, S and N;

R3denotes H or R2;

R4means R3, halogen, -NO2, -CN, -OR3, -SR2N(R3)2, NR3COR7, S(O)R2or S(O)2R2;

CR3R22may be a remnant of a common amino acid;

R5denotes H, halogen, -NO2, -N3, -CN, -SR2, -S(O)R2, S(O)2)2-(CH2)5-R8or-CH2CON(R20)2;

R7denotes H or lower alkyl;

R8means: (A) A monocyclic or bicyclic heterocyclic radical containing from 3 to 12 carbon atoms nucleus and 1 or 2 heteroatoms nucleus selected from N, S and O, and each ring in the heterocyclic radical is formed of 5 or 6 atoms, or B) the radical W-R9;

R9contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;

R10means-SR11, -OR15or-N(R12)2;

R11denotes lower alkyl, -COR14Ph(R26)2CH2Ph(R26)2or CH2CH2Ph(R26)2;

R12denotes H, R11or two groups R12attached to the same N may form a saturated ring of 5 or 6 members comprising carbon atoms and up to two heteroatoms selected from O, S and N;

R13denotes lower alkyl, lower alkenyl, lower quinil-CF3Ph(R26)2CH2Ph(Ph26)2or CH2CH2Ph(P>16represents H, lower alkyl or OH;

R17denotes lower alkyl, lower alkenyl, lower quinil, Ph(R26)2CH2Ph(R26)2or CH2CH2Ph(R26)2;

R18means R13;

R19represents H, lower alkyl, lower alkenyl, lower quinil, -CF3, Ph, CH2Ph or CH2CH2Ph;

R20represents H, lower alkyl, Ph(R26)2CH2Ph(R26)2or CH2CH2Ph(R26)2or two groups R20attached to the same N may form a saturated ring of 5 or 6 members comprising carbon atoms and up to two heteroatoms selected from O, S and N;

R21denotes H or R17;

R22means R4, CHR7OR3or CHR7SR2;

R23, R24and R25denote each independently H, lower alkyl, -CN, -CF3, COR3, CO2R7, CON(R20)2, OR3, SR2, S(O)R2, S(O)2R2N(R12)2, halogen or electron pair;

R26represents H, lower alkyl, -SR27, -OR28, -N(R28), -CO2R7, CON(R28)2, -COR7, -CN, CF3, NO2SCF3or halogen;<, or two groups R28attached to the same N may form a saturated ring of 5 or 6 members, including the carbon atoms and up to two heteroatoms selected from O, S and N;

m and m' denote independently 0-8;

p and p' represent independently 0-8;

m + p is 1-10, where X2denotes O, S, S(O) or S(O)2and Z1is the link;

m + p = 0-10, where Z1is HET(R23R24R25);

m + p = 0-10, where X2is CR3R16;

m' + p' = 1-10, where X3denotes O, S, S(O) or S(O)2and Z2is the link;

m' + p' = 0-10, where Z2denotes HET(R23R24R25);

m' + p'= 0-10, where X3denotes CR3R16;

S = 0-3;

Q1denotes tetrazol-5-yl, -CO2R3, -CO2R6, -CONHS(O)2R13, -CN, -CON(R20)2, NR21S(O)2R13, -NR21CON(R20)2, -NR21COR14, OCON(R20)2, -COR19, -S(O)R18, -S(O)2R18, -S(O)2R18, -S(O)2N(R20)2,

-NO2, NR21CO2R17, -C(N(R12)2)=NR21, -C(R19)=NOH, or C(R3)2OH; or, if Q1denotes CO2H and R22represents-OH, -SH, CHR7OH or-other3then Qso take water;

Q2denotes H, OR15, lower alkyl, halogen, or Q1;

W represents O, S or NR3;

X1denotes O, S, -S(O)-, -S(O)2, =NR3, -C(R3)2or communication;

X2and X3independently denote O, S, S(O), S(O)2, CR3R16or communication;

Y represents-CR3= CR3-, -C(R3)2-X1-, -X1-C(R3)2-, -C(R3)2-X1-C(R3)2-, -CC-, -CO-, -NR3CO-, -CONR3Is O, S or NR3;

Z1and Z2are independently HET(R23R24R25or communication;

HET denotes diradical benzene, pyridine, furan, thiophene or 1,2,5-thiadiazole;

HETA means HE1or HE2;

HE1does

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HE2does

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A and A1represent N or CR5;

B denotes O, S ILA S(O);

D represents N or CR4;

E denotes CR4when D denotes CR4;

E denotes CR3when D is N;

or their pharmaceutically acceptable salts.

Preferred compounds of formula I are the compounds of formula

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where B is S or O;

R4denotes H, halogen, CN, CF3or S(O)2R2oznachaet CO2R3, CO2R6, -CONHS(O)3R13tetrazol-5-yl or C(R3)2OH;

Q2denotes C(R3)2OR3, halogen or lower alkyl;

X2represents S or O;

Y represents-CH=CH-, -CH2-O-, -CH2-CH2-, -CC -, or-CH(CH2)CH-;

Z2denotes HET(R23R24);

HET denotes diradical benzene or thiophene;

and the other substituents such as defined for formula I.

The group of most preferred compounds of the formula I is described by the formula Ib:

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where R3denotes lower alkyl, or two groups R3attached to the same carbon atom, may form a ring with 3 to 6 members, optionally containing one oxygen atom or one sulfur atom;

R4denotes H, halogen, -CN, CF3or-S(O)2R2;

R23and R24represent independently H, halogen or lower alkyl;

m and m' is independently 1-5;

p' = 0 or 1;

Q1denotes-CO2R3tetrazol-5-yl or -- CONHS(O)2R and

Q2denotes H, C(R3)2OH or or15.

Definition

The following abbreviations have the following meanings:

Ac = acetimidoyl

DIPHOS = 1,2-bis(diphenylphosphino)ethane

DMAP = 4-(dimethylamino)pyridine

DMF = N,N-dimethylformamide = DMF)

DMSO = dimethylsulfoxide

Et3N = triethylamine

Fur = purandar

KHMDS = potassium hexamethyldisilazane

LDA = lithium diisopropylamide

MCPBA = meta-chlormadinone acid

MS = methanesulfonyl = mesyl

MSO = methanesulfonate = mesilate

NBS = N-bromosuccinimide

NCS = N-chlorosuccinimide

NSAID = nonsteroidal anti-inflammatory drug

PCC = pyridine chlorproma

PDC = pyridine dichromate

Ph = phenyl

Phe = bersoldier

PPTS = pyridine p-toluensulfonate

pTSA = p-toluensulfonate acid

Pye = pyridinyl

r.t. = room temperature

the rac. = racemic

Tdz = 1,2,5-thiadiazole-3,4-diyl

Tf = trifloromethyl = trityl

TfO = triftorbyenzola = triplet

Tn= 2 - or 3-thienyl

THF = tetrahydrofuran = THF

Thi = theoffender

THP = tetrahydropyran-2-yl

TLC = thin layer chromatography = TLC

Ts = p-toluensulfonyl = tosyl

TsO = p-toluenesulfonate = toilet

Tz = IH (or 2H)-tetrazol-5-yl

C3H5= allyl

Abbreviation alkyl groups

Me = methyl

Et = ethyl

n-Pr = normal propyl

C - Pr = cyclopropyl

s - Bu = cyclobutyl

s - Pen = cyclopentyl

C-Hex = cyclohexyl

The term alkyl, alkenyl and quinil implies a linear, branched and cyclic structures and combinations thereof.

The term "alkyl" includes "cycloalkyl" and "lower alkyl" and covers carbon fragments having up to 20 carbon atoms. Examples of alkyl groups include octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylene and the like.

"Lower alkyl" includes "lower cycloalkyl" and implies alkyl groups consisting of 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec - and tert-butyl, pentyl, hexyl, heptyl and the like.

"Cycloalkyl" includes "lower cycloalkyl" and implies a hydrocarbon containing one or more rings comprising from 3 to 12 carbon atoms, and the hydrocarbon contains up to 20 carbon atoms. Examples cycloalkyl groups are cyclopropyl, cyclopentyl, cycloheptyl, substituted, cyclobutylmethyl, 2-ethyl-1-bicyclo[4,4,0]decyl and the like.

"Lower cycloalkyl" means a hydrocarbon containing one or bol the Rami of the lower cycloalkyl groups are cyclopropyl, cyclopropylmethyl, cyclobutyl, 2-cyclopentylmethyl, cycloheptyl, bicyclo 2,2,1-hept-2-yl and the like.

The term "alkenyl" includes "cycloalkenyl" and "lower alkenyl" and implies alkeneamine group consisting of from 2 to 20 carbon atoms. Examples alkenyl groups include allyl, 5-mission-1-yl, 2-dodecen-1-yl and the like.

"Lower alkenyl" includes "lower cycloalkenyl" and implies alkeneamine group consisting of from 2 to 7 carbon atoms. Examples of the lower alkenyl groups include vinyl, allyl, Isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl and the like.

"Cycloalkenyl" includes "lower cycloalkenyl" and implies alkeneamine group consisting of from 3 to 20 carbon atoms, which contain a ring consisting of from 3 to 12 carbon atoms, and in which the double bond may be located anywhere in the structure. Examples cycloalkenyl groups are cyclopropene-1-yl, cyclohexen-3-yl, 2-vinylacetat-1-yl, 5-methylindole-1-yl and the like.

"Lower cycloalkenyl" implies alkeneamine group consisting of from 3 to 7 carbon atoms, and which contain a ring containing 3 to 7 carbon atoms, and in which the double bond may be Capenter-1-yl and the like.

The term "quinil" includes "cycloalkenyl" and "lower quinil" and implies alkyline group consisting of from 2 to 20 carbon atoms. Examples etkinlik groups are ethinyl, 2-pentadecyl-1-yl, 1-aksin-1-yl and the like.

"Lower quinil" includes "lower cycloalkenyl" and implies alkyline group consisting of from 2 to 7 carbon atoms. Examples of the lower etkinlik groups include ethinyl, propargyl, 3-methyl-1-pentenyl, 2-heptenyl and the like.

"Cycloalkenyl" includes "lower cycloalkenyl" and implies alkyline group consisting of from 5 to 20 carbon atoms, which include a ring consisting of from 3 to 20 carbon atoms. Alchemilla triple bond can be anywhere in the group, provided that, if she is in the ring, this ring shall consist of 10 members or more. Examples of cycloalkenyl are cyclododecyl-3-yl, 3-cyclohexyl-1-propyne-1-yl and the like.

"Lower cycloalkenyl" implies alkyline group consisting of 5 to 7 carbon atoms, which include a ring consisting of from 3 to 5 carbon atoms. Examples of the lower cycloalkenyl groups are cyclopropylethyl, 3-(cyclobutyl)-1-PROPYNYL and the like.

"Lower and the coy configuration. Examples of the lower alkoxygroup include methoxy, ethoxy, propoxy, isopropoxy, cyclopropylamine, cyclohexyloxy and the like.

"Lower alkylthio" means ancilliary consisting of from 1 to 7 carbon atoms, straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthiopropionate, isopropylthio, cycloheptyl and so on, For illustration, PropertyGroup means-SCH2CH2CH3.

"Lower alkylsulfonyl" means alkylsulfonyl group consisting of from 1 to 7 carbon atoms, straight, branched or cyclic configuration. Examples of the lower alkylsulfonyl groups include methylsulphonyl, 2-butylsulfonyl, cyclohexanesulfonyl and so on, For illustration, 2-butylsulfonyl group means - S(O)2CH(CH3)CH2CH3.

The term "alkylaryl" includes "lower alkylsulphonyl" and implies acylcarnitine group consisting of from 1 to 20 carbon atoms, straight, branched or cyclic configuration. Examples alkylcarboxylic groups are formyl, 2-methyl-butanol, octadecenoyl, 11-cyclohexylphenol and the like. Thus, 11-cyclohexylaniline group javljaetsja from 1 to 8 carbon atoms, straight, branched or cyclic configuration. Examples of the lower alkylcarboxylic are formyl, 2-methylbutanoyl, cyclohexylethyl, etc. To illustrate 2-metilbutanoilny group mean-COCH(CH3)CH2CH3.

The term Ph(R26)2denotes a phenyl group substituted with two R26substituents.

Halogen includes F, Cl, Br and I.

It should be borne in mind that the meaning of any substituent (e.g., R7, R12, R26and so on ) in a particular molecule does not depend on its value anywhere elsewhere in the molecule. Thus, -N(R12)2is-NHH, -NHCH3, -NHC6H5and so on

The ring formed when connecting two groups of R2will include cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, pyrrolidine, piperidine, morpholine, thiomorpholine and piperazine.

The heterocycles formed when two groups R12, R20or R27connect through N include pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine and N-methylpiperazine.

When Q1and R22and the carbon atoms to Cohocton.

Proletarienne live on Q (i.e., when Q=COOR6) intended for inclusion in ethers, such as described by Saari et al., J. Med. Chem. 21, N 8, 746-753 (1978), Sakamoto et al., Chem. Pharm. Bull. 32, N 6, 2241-48 (1984) and Bundgaard et al., J. Med. Chem. 30, N 3, 451-454 (1987). For values of R8some representative monocyclic and bicyclic radicals are 2.5 dioxo-1-pyrrolidinyl, (3-pyridylcarbonyl)amino, 1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl, 1,3-dihydro-2H-isoindole-2-yl, 2,4-imidazolidin-1-yl, 2,6-piperidinedione-1-yl, 2-imidazolyl, 2-oxo-1,3-dioxolan-4-yl, piperidine-1-yl, morpholine-1-yl piperazine-1-yl.

The term "common amino acid" means the following amino acids: alanine, asparagine, aspartic acid, arginine, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, Proline, serine, threonine, tryptophan, tyrosine and valine. (See F. H. C . Crick, Simposium of the Society of Experimental Biology, 1958 (12), p. 140).

Optical isomers, the Diastereomers and Geometric isomers

Some compounds described herein have one or more asymmetric centers and can, therefore, form the diastereomers and optical isomers. The present invention covers such possible diastereomers as well as Some of the compounds, described herein contain olefinic double bonds, and, unless otherwise indicated, include both E and Z geometric isomers.

Salt

The pharmaceutical compositions of the present invention contain a compound of formula I as the active ingredient or its pharmaceutically acceptable salt and can also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc and the like. Especially preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, Bmin, the Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, geranamine, Isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polianinova resins, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine and the like.

When the connection according to the invention is a base, the salt can be derived from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzosulfimide, benzoin, camphorsulfonate, lemon, econsultancy, fumaric, gluconic, glutamic, Hydrobromic, chloride-hydrogen, isetionate, lactic, maleic, malic, almond, methansulfonate, mucus, nitrogen, Paveway, Pantothenic, phosphoric, succinic, sulfuric, grape, p-toluensulfonate and the like. Particularly preferred are citric, Hydrobromic, chloride-hydrogen, maleic, phosphoric, sulfuric and grape acid.

Be aware that when discussing treatment methods, which are presented hereinafter, references to compounds of formula I include pharmaceutically acceptable salts.

Application

Checks symptoms called leukotrienes in humans. These suppress the action of leukotriene suggests that their compounds and pharmaceutical compositions useful in the treatment, prevention or improvement of conditions mammals and especially humans:

1) lung diseases, including diseases such as asthma, chronic bronchitis, and related obstructive airway diseases,

2) allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis and the like,

3) inflammation, such as arthritis or intestinal inflammatory diseases,

4) pain,

5) skin disorders such as atopic eczema, and the like,

6) cardiovascular disorders such as angina, myocardial ischemia, hypertension, platelet aggregation and the like,

7) renal failure due to ischemia caused by immunological or chemical (cyclosporin) etiology,

8) migraine or cluster headache

9) eye diseases such as uveitis,

10) hepatitis resulting from chemical, immunological or infectious stimuli,

11) trauma or shock States such as birth injuries, endotoxic repitions purpose of cytokines, such as interleukin II and tumor necrosis factor,

14) chronic lung diseases such as cystic fibrosis, bronchitis and other diseases of small and large Airways, and

15) cholecystitis.

Thus, the compounds of the present invention can also be used for treatment or prevention of diseases of mammals (especially humans), such as erosive gastritis; erosive inflammation of the esophagus; diarrhea; spasm of cerebral vessels; premature birth; miscarriage; dysmenorrhea; ischemia; damage caused by harmful agents, or necrosis of tissues of liver, pancreas, kidney or attack; damage to the underlying tissue of the liver caused hepatoxicity agents such as CCl4and D-galactosamine; ischemic renal failure; liver damage caused by disease; caused by salts of bile acids damage the pancreas or stomach; cellular abnormalities caused by injury or stress; and renal failure caused by glycerin.

Cytotoxity activity of the compounds can occur in animals and humans by fixing the lowered resistance of the gastric mucosa to prednazone. In addition to the weakening of the action of nonsteroidal anti-inflammatory drugs on the gastrointestinal tract, animal studies show that chitosamine connections will be protected from damage of the stomach caused by oral introduction of strong acids, strong bases, ethanol, hypertonic saline solutions and the like.

To measure chitosamine ability can be applied two tests. These tests are: (A) investigation of damage caused by ethanol, and (B) the study of ulcers induced by indomethacin, and they are described in EP N 140684.

The dose levels

The intensity of prophylactic or therapeutic dose of the compounds of formula I will, of course, vary depending on the nature and severity of the condition, which is subjected to treatment and the specific compounds of formula I and the way of its introduction. It will also vary depending on age, weight and individual susceptibility of the patient. Typically, the level of the daily dose ranges for anti-asthmatic, anti-allergic or anti-inflammatory use and typical use of not to cytotoxity lies in the range from about 0.001 mg to about 100 mg per 1 kg of body weight technol or fractional doses. On the other hand, in some cases, it may be necessary doses above these limits.

For applications that use composition for intravenous administration, suitable level doses for anti-asthmatic, anti-inflammatory or protivoallergicheskogo of application is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of the compounds of formula I per 1 kg of body weight per day and for chitosamine application of from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of the compounds of formula I per 1 kg of body weight per day.

In the case for applications that use the composition for oral administration, a suitable level of doses for anti-asthmatic, anti-inflammatory or anti-allergic use is, e.g. from about 0.01 mg to about 100 mg of the compounds of formula I per 1 kg of body weight per day, preferably from about 0.1 mg to about 10 mg per 1 kg of body weight per day, and for chitosamine application of from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 10 mg to about 100 mg) the compounds of formula I per 1 kg of body weight per day.

For the treatment of Zabol the Directors or suspensions of the compounds of formula I in a suitable ophthalmic compositions.

The exact amount of the compounds of formula I, intended for use as chitosamine agent will depend, inter alia, from where it will be assigned: for the treatment of diseased cells or to prevent future losses, from the nature of the affected cells (e.g., gastrointestinal ulcers compared with neurotic necrosis) and on the nature of the calling of the disease agent. An example of using the compounds of formula I to prevent further wounding a game could be together with the compound of the formula I and NSAID that would otherwise cause such lesions (eg, indomethacin). In this application, the compound of formula I is from 30 minutes before to 30 minutes after administration of NSAID. Preferably it is administered prior to or concurrent with NSAlD (for example, in combined dosage forms).

Pharmaceutical compositions

Can be used any suitable route of administration to a mammal, especially a human, an effective dosage of the compounds of the present invention. For example, you can use oral, rectal, outdoor, parenteral, ocular, pulmonary, nasal, and the like. Dosage forms on the Sabbath.">

The pharmaceutical compositions of the present invention contain a compound of formula I as the active ingredient or its pharmaceutically acceptable salt and can also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (inhaled through the nose or mouth) or nasal administration, although the most suitable way in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. The easy way they can be presented in unit dosage form and received by any of the methods well known to specialists.

For administration by inhalation the compounds according to the present invention is conveniently used in the form of an aerosol spray cans of powley in the form of compositions, and the powder composition may be inhaled with the aid of the device for inhalation of the powder. The preferred system for inhalation is an aerosol for inhalation from a metered supply (MDI - metered dose inhalation), which may consist of a suspension or solution of the compounds of formula I in a suitable gas-plungers, such as fluorocarbons or hydrocarbons.

Appropriate external structures of the compounds of formula I include transdermal devices, aerosols, creams, ointments, lotions, antiseptic powders for powder of wounds and the like.

In the practical use of the compounds of formula I can be combined as the active ingredient in a homogeneous mixture with a pharmaceutical carrier according to conventional pharmaceutical methods of preparing mixtures. The carrier may take a wide variety of forms, depending on the desired for the introduction of a form of administration, for example oral, or parenteral (including intravenous). When preparing the compositions for oral dosage forms in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions, you can use any of the usual pharmaceutical environment, such as, for example, water, glycols, oils, cuts, sugar, microcrystalline cellulose, diluents, granulating agents, lubricating agents, binders, loosening agents and the like, in the case of oral solid preparations such as powders, capsules and tablets, with a preference for solid oral preparations compared to liquid preparations. Because of the ease of introduction of tablets and capsules represent the most convenient oral dosage form units, in which case, obviously, apply solid pharmaceutical carriers. If desired, tablets may be coated using standard aqueous or nonaqueous techniques.

In addition to conventional dosage forms listed above, the compounds of formula I can also be entered by using the tools and/or emitting device controlled release, such as described in U.S. patents NN 3845770, 3916899, 3536809, 3598123, 3630200 and 4008719, descriptions of which are incorporated herein as references.

The pharmaceutical compositions of the present invention suitable for oral administration may be presented as fractional units, such as capsules, pills or tablets, each containing a predetermined amount of the active ingredient in powder form is in a liquid emulsion of the type water-in-oil. Such compositions can be obtained by any of the methods used in pharmacy, but all methods include the stage of binding to the Association the active ingredient with the carrier that contains one or more necessary ingredients. Typically, the compositions are obtained by uniform and thorough mixing of the active ingredient with liquid carriers or well razmelchenija solid carriers or both and then, if necessary, shaping the product that is desired. For example, a tablet may be obtained by extrusion or by molding optionally with one or more auxiliary ingredients. Molded tablets can be obtained by pressing in the appropriate machine the active ingredient in Svobodnaya form, such as powder or granules, optionally mixed with a binder agent, a lubricating agent, an inert diluent, surface-active agent or dispersing agent. Molded tablets can be obtained by molding in a suitable machine a mixture of the powdered compound moistened inert liquid diluent. Preferably, each tablet contains from about 1 mg to about 500 mg of the active ingredient and each wafer or capsule with rmaceuticals dosage forms of the compounds of formula I.

Suspension for injection (intramuscularly), mg/ml:

The compound of formula I - 10

Methylcellulose - 5,0

Tween 80 and 0.5

Benzyl alcohol - 9,0

Benzalconi chloride - 1,0

Water for injection To a total volume of 1 ml

Tablet mg/tablet:

The compound of formula I - 25

Microcrystalline cellulose 415

Povidone - 14,0

Pre gelatinising starch - 43,5

Magnesium stearate - 2,5 - 500

The capsule mg/capsule:

The compound of formula I - 25

Powder lactose - 573,5

Magnesium stearate - 1,5 - 600

Aerosol, spray:

The compound of formula I, mg - 24

Lecithin, NF liquid concentrate, mg - 1,2

Trichlorofluoromethane, NF, g - 4,025

DICHLORODIFLUOROMETHANE, NF, g - 12,15

Combination with other drugs

In addition to the compounds of formula I, pharmaceutical compositions of the present invention may also contain other active ingredients, such as cyclo-oxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac diflunisal and the like. The mass ratio of the compounds of formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. ID, the mass ratio of the compounds of formula I to the NSAID will generally range in area from about 1000:1 to about 1:1000, preferably from about 200:1 to about 1:200. Combinations of the compounds of formula I and other active compounds are usually in this area, but in each case will be used effective dose of each active ingredient.

NSAID can be described in five groups:

(1) derivatives of propionic acid,

(2) derivatives of acetic acid,

(3) the derivative Funambol acid,

(4) okinami, and

(5) derivative biphenylcarbonic acid,

or its pharmaceutically acceptable salt.

Derivatives of propionic acid, which can be used include: alminoprofen, benoxaprofen, Burlakova acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, Ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, prana-proven, suprofen, tiaprofenic acid and tioxaprofen. Similar in structure to the derivatives of propionic acid having similar analgesic and anti-inflammatory properties are also intended for inclusion in this group.

Thus, the "derivative prospaltella drugs, space group-CH(CH3)COOH or-CH2CH2COOH (which may not necessarily be in the form of a pharmaceutically acceptable salt group, e.g.- CH(CH3)COO-Na+or-CH2CH2COO-Na+), typically attached directly or via a carbonyl group to a ring system, preferably to an aromatic ring system.

Derivatives of acetic acid, which can be used include: indomethacin, which is a preferred NSAID, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, enclosing acid, fentiazac, furofenac, ibufenac, isoxepac, sulindac, tiopinac, tolmetin, zidometacin, zomepirac. Similar in structure to the derivatives of acetic acid having similar analgesic and anti-inflammatory properties are also intended for inclusion in this group.

Thus, derivatives of acetic acid," as defined herein are non-narcotic analgesic/nonsteroidal antiinflammatory drugs having a free group-CH2COOH (which may not necessarily be in the form of a pharmaceutically acceptable salt group, e.g.,- CH

Derivatives Funambol acid, which can be used include: flufenamic acid, meclofenamic acid, niflumova acid and tolfenamic acid. Similar in structure to the derivatives of Funambol acid having similar analgesic and anti-inflammatory properties are also intended to

included in this group.

Thus, the derivative Funambol acid" as defined herein are non-narcotic analgesic/non-steroidal anti-inflammatory drugs which contain the basic structure

< / BR>
which may contain a variety of substituents and in which the free group-COOH may be in the form of a pharmaceutically acceptable salt group, e.g.- COO-Na+.

Derivatives biphenylcarbonic acid, which can be used include: diflunisal and flufenisal. Similar in structure to the derivatives biphenylcarbonic acid having similar analgesic and anti-inflammatory properties are also intended for inclusion in this group.

Thus, the "derivative biphenylcarbonic acid" as defined herein are non-narcotic anal is the structure

< / BR>
which may contain a variety of substituents and in which the free group-COOH may be in the form of a pharmaceutically acceptable salt group, e.g.- COO-Na+.

Oxicam that can be used in the present invention include: isoxicam, piroxicam, sudoxicam and tenoxicam. Similar in structure to oxicam having similar analgesic and anti-inflammatory properties are also intended for inclusion in this group.

Thus, oxicam" as defined herein are non-narcotic analgesic/non-steroidal anti-inflammatory drugs which contain the basic structure

< / BR>
where R is an aryl or heteroaryl ring system.

Can also be used following NSAID: amfenac sodium, alminoprofen, nitrazepan, entretenir, auranofin, bendazac, lisinac, benzydamine, beneprotein, properly, buttala, cinmetacin, coprokazan, classimat, dasadmin, debacle, deleteln, detomidine, dexindoprofen, diacerein, di-filamin, divinename, emorfazone, antenova acid, analika, epirizole, Etisalat, etodolac, etofenamate, fanatical mesilate, fenclova, perclorate, glucometry, gametal, ibuproxam, isophtalic, sonicrim, ibuprofen, isoxicam lefetamine HCl, Leflunomide, levamisol, lonazolac calcium, latifat, loxoprofen, lysine clonixinate, meclofenamate sodium, Meselson, nabumeton, Nintendo, nimesulid, Arbanassi, oximation, hexapedal, personsal citrate, timeproven, peltatin, piperoxan, pyrazole, pirfenidone, proglumetacin maleate, proquazone, pyridoxin proven, sudoxicam, tolmetin, talniflumate, tenoxicam, thiazolin button, talvin B, tiaramide HCl, diflunisal, timelady, solpadol, tryptamide and openmath.

Can also be used following NSAID indicated by a numeric code (see , for example, Pharmaprojects): 480156, AA861, AD1590, AFP802, AFP860, AI77B, AP504, AU800, BPPC, BW540C, CHIN01N127, CN100, EB382, EL508, F1044, GV3658, ITF182, KCNTEI6090, KME4, LA2851, MR714, MR897, MY309, ON03144, PR823, PV102, PV108, R830, RS2131, SCR152 SH440, SIR133, SPAS510, SQ27239, ST281, SY6001, TA60, TAI-901(4-benzoyl-1-indocaribbean acid), TVX2706, U60257, UR2301 and WY41770.

Finally, NSAID, which can be used include salicylates, especially acetylsalicylic acid and phenylbutazone and their pharmaceutically acceptable salts.

In addition indometacin other preferred NSAID is acetylsalicylic acid, diclofenac, fenbufen, fenoprofen, rmaceuticals composition, including the compounds of formula I may also contain inhibitors of the biosynthesis of leukotrienes, such as described in European patent N 138481 (24 April 1985), European patent N 115394 (August 8, 1984), European patent N 136893 (April 10, 1985) and the European patent N 140709 (may 8, 1985), which is incorporated herein by reference.

The compounds of formula I can also be used in combination with leukotriene antagonists such as described in European patent N 106565 (24 April 1985) and the European patent N 104885 (April 4, 1984), which is incorporated herein by reference, and others known in the field, which are described in European patent applications NN 56172 (July 21, 1982) and 61800 (10 June 1982); and in the description of the patent in the UK N 2058785 (April 15, 1981), which is incorporated herein by reference.

Pharmaceutical compositions comprising the compounds of formula I may also contain a second active ingredient, antagonists of prostaglandin, such as described in European patent 11067 (28 may 1980), or antagonists of thromboxane, such as described in U.S. patent N 4237160. They may also contain inhibitors of histidine decarboxylase, such as formutilities described in U.S. patent N 4325961. Compounds of formula Yamasa, aminothiadiazole described in the European patent N 40696 (December 2, 1981), Benadryl, cimetidine, famotidine, framarin, histadyl, phenergan, rantidine, terfenadine and similar compounds such as described in U.S. patent NN 4283408, 4362736 and 4394508. Pharmaceutical compositions may also contain an inhibitor of K+/H+ATPase, such as omeprazole, are described in U.S. patent N 4255431, and the like. The compounds of formula I can also be conveniently combined with most roll cages agents, such as 1,3-bis(2-carboxylato-5-yloxy)-2-hydroxypropan and related structure compounds disclosed in the description of the patent in the UK NN 1144905 and 1144906. Other useful pharmaceutical composition containing the compounds of formula I in combination with serotonin antagonists, such as methysergide, serotonin antagonists, described in Nature, 316, 126-131 (1985), and the like. Each of the references cited in this paragraph is incorporated herein by reference.

Other successful pharmaceutical compositions containing the compounds of formula I in combination with anticholinergic agents such as ipratropium bromide, bronchodilatory, such as beta agonist salbutamol, metaproterenol, terbutaline, fenoterol and the like, is passed antagonists nifedipine, diltiazem, nitrendipine, verapamil, nimodipine, felodipina and so on, and corticosteroids, hydrocortisone, methylprednisolone, betamethasone, dexamethasone, beclomethasone, and the like.

Methods of synthesis of

Compounds of the present invention can be obtained according to the following methods (see methods A-L listed at the end of the description). Temperatures are indicated in degrees Celsius.

How A

Methyl ester II is treated with an excess of a reducing agent, such as sociallyengaged, in a solvent such as THF, at 0oC with obtaining alcohol, which is oxidized with a reagent such as manganese dioxide, to obtain the aldehyde III. Compound III is subjected to condensation with acetone in a basic environment with the formation of thienopyridine IV, which is converted into 2,3-disubstituted thienopyridine V in accordance with the techniques described in the methods B, C and D. Processing thienopyridine V halogenation agent such as NBS, followed by interaction with triphenylphosphine gives fosfonovoi salt VI. The interaction of VI with an aldehyde VII in the presence of a strong base such as tert-piperonyl potassium bis(trimethylsilyl)amide or potassium, utility, followed hydrolases patent N 480717 (method H), as well as in these examples.

Method B

Processing thienopyridine IV obtained by the method A, glorieuses agent such as Trichloroisocyanuric acid or sulfurylchloride gives 2,3-dichlorothiophene Ve. Interaction IV with chlorine in concentrated sulfuric acid in the presence of silver sulfate leads to 3-chloranilide Vf. Processing IV strong base, such as alkylate or LDA gives the anion thienopyridine-2-yl, which interacts with various electrophiles, giving various Deputy in the second position IV; for example, anion 1) interacts with NCS or chlorine obtaining 2-hardenability Va; 2) interacts with N-fluoro-bis(benzazolyl)amidon (PhS(O)2)2NF or fluorine perchlorate (FClO4) to obtain 2-portionability Vb; 3) reacts with bromine cyan (Enrichment) to obtain 2-canadianamerican Vc; and 4) communicates with the anhydride triftormetilfullerenov acid to obtain 2-triftormetilfullerenov Vd.

The method C

2-Chloro - or 2-portionability (Va, b) transform in a variety of 2,3-disubstituted thienopyridine by the following sequence:

1) the deprotonation of 2-chloro - or 2-portionability (Va, b) with a strong onion with various electrophiles to form a 2,3-disubstituted thienopyridines: for example, interaction with N-fluoro-bis(benzazolyl)amidon or fluorine perchlorate with obtaining Vh; interaction with anhydride triftormetilfullerenov acid to obtain Vi; the interaction with N-bromosuccinimide or bromine to obtain Vj; and the interaction with N-chlorosuccinimide or chlorine to obtain Vk.

2-Chloro-3-portionability (Vh, X= Cl) is converted into 3-portionability (Vg) by the following sequence:

1) interaction with tert-butyllithium in THF;

2) protonation with water.

Method D

3-Chloro - or 3-portionability (Vf, g) obtained by the method B or method C, deprotonated with strong bases, such as alkylate or LDA to obtain 3-chloro - or 3-portionerade-2-yl anion which reacts with various electrophiles to obtain 2,3-disubstituted thienopyridines; for example, interaction with bromine cyan gives VI; interaction with anhydride triftormetilfullerenov acid gives the Vm; the interaction with the acid chloride methanesulfonic acid gives Vn; interaction with N-fluoro-bis(benzazolyl)amidon or fluorine perchlorate gives Vo; and the interaction with N-chlorosuccinimide or chlorine gives Vp.

Method E

The double bond in loadentitiesbyid by hydrolysis of the methyl ester gives the acid IX.

Method F

Yodelin XI interacts with trimethylsilylacetamide (X) in the presence of Iodide complex of copper (I) chloride (triphenylphosphorane (II) obtaining pornopedia XII, which is converted to 2,3-dichloropyridine XIVa by chlorination using Trichloroisocyanuric acid or sulfurylchloride or converted in the XIII by removal of the silyl group with hydrogen fluoride in the presence of pyridine. Both XIVa and XIII is converted in a variety of 2,3-disubstituted pornopedia XIV by interactions described in the methods B, C, D, and J. In conclusion XIV is converted into the acid XV using the techniques described in method A.

Method G

The aldehyde III, obtained by the method A, is subjected to condensation with sodium salt of pyruvic acid, followed by esterification with methanol in the presence of concentrated hydrochloric acid to obtain methyl ester XVI. Chlorination XVI or using sulfurylchloride, or by using Trichloroisocyanuric acid gives 2,3-dichlorothiophene XVII. XVII is converted into fosfonovoi salt XVIII by the following sequence:

1) restore with DIBAL in THF;

2) substitution of the hydroxy-group chlorine interaction with glorious is, such as toluene or acetonitrile. XVIII is converted into the final product VIII by the method described in method A.

Method H

Compound XIX is treated with acid chloride acid in the presence of a base and subsequent interaction with pentasulfide phosphorus in THF in the presence of a base such as Na2CO3obtaining thiazolidine XX. Oxidation XX using MCPBA gives N-oxide, which interacts with trimethylsilylcyanation and dialkylammonium with the formation of nitrile XXI. Nitrile XXI is converted into fosfonovoi salt by the following sequence:

1) restore nitrile XXI using DIBAL in THF to obtain aldehyde;

2) recovery of the aldehyde using NaBH4in THF-CH3OH;

3) receiving nelfinavir alcohol interaction with methylchloride in the presence of triethylamine; and

4) interaction between nelfinavir with triphenylphosphine.

Fosfonovoi salt is converted into the final acid by the methods described in method A.

The way I

Ether thiophene XXIV, obtained according to literature method (K. H. Weber and H. Daniel; Annalen (1979) 328; H. K. Gakhar, A. Khanna P. Baveja, Indian J. Chem. 16B (1928) 305) transform in thienopyridine XXV by the following sequence:

1) restoration of l the following reasons, such as sodium hydroxide.

XXV XXVI is converted into by the methods described in method J. In conclusion, XXVI is converted into the acid XXVII, using the techniques described in method A.

Method J

Thienopyridine XXV subjected to chlorination or sulfurylchloride or trichlorocyanuric acid to obtain 2,3-dichlorothiophene XXVIa.

The deprotonation XXV using strong bases such as alkylate or LDA in THF leads to the formation of thienopyridine-2-yl anion which reacts with N-chlorosuccinimide or chlorine obtaining 2-hardenability XXVIb; or he interacts with N-fluoro-bis(benzazolyl)amidon or fluorine perchlorate with obtaining 2-portionability XXVIc.

The deprotonation XXVIc or using alkylate or LDA followed by interaction with N-fluoro-bis(benzazolyl)amidon or fluorine perchlorate gives dipertanyakan XXVIi.

The deprotonation XXVIb or using alkylate or with LDA and subsequent interaction with an electrophilic agent gives 2,3-disubstituted thienopyridine; for example, interaction with bromine cyan gives XXVIe; interaction with N-fluoro-bis(benzazolyl)amidon or fluorine perchlorate gives XXXIf; interaction with angii damping aqueous ammonium chloride gives XXVIh or XXVIg respectively.

Method K

Ketone XXVIII is converted into chiral allylic alcohol XXIX the following sequence:

1) chiral restoration by the method of Corey (complex BH3/oxazaborolidine) (J. Am. Chem. Soc., 1987, 109, 5551 and 7925);

2) interaction-Bromeliaceae ether in the presence of a base;

3)restore using DIBAL.

Processing XXIX the diazomethane/Pd (OAc)2then methylchloride and triethylamin the amine, followed by substitution with sodium cyanide and then hydrolysis with potassium hydroxide gives the acid XXX. Acid XXX is converted into a tertiary alcohol XXXI by formation of a lithium derivative with n-BuLi followed by addition of acetone. Both XXX and XXXI, is converted into aldehydes XXXII and XXXIII through the following interactions:

1) esterification with diazomethane;

2) removing TNR-protective group using PPTS, and

3) oxidation with manganese oxide.

Aldehydes XXXII and XXXIII is converted into the final acid XXXIIIa by methods described in method A.

Method L

3-Aminothiophene XXXIV transform in aminoketone XXXV interaction with bromoethanol XL (obtained from known compounds-dihydroxyacetone in two stages:

1) montaditos using TBDMSCl;

2) bromer the form in thienopyridine by the following sequence:

1) bromirovanii the position of the thiophene ring with one equivalent of bromine;

2) treatment of bromo derivatives with liquid ammonia at -80oC; and

3) oxidation by oxygen.

XXXVI transform into fortianalyzer XXXVII using the techniques described in method B.

Fosfonovoi salt XXXVIII get from XXXVII by the following sequence:

1) removal of the TBDMS ether using PPTS;

2) bromination using tetrabromide carbon and DIPHOS; and

3) interaction with triphenylphosphine.

The final product XXXIX obtained from postnasal salt XXXVIII using the techniques described in method A.

Representative compounds

Table. 1 and 2 illustrate compounds that are representative compounds of the present invention. In the tables

Y1means-X2(C(R3)2)mZ1(CR3R22)pQ1and

W1means-X3(C(R3)2)m'Z2(CR3R4)p'Q2in formula I.

Connection table. 1 are compounds of formula Ic

< / BR>
Connection table. 2 are compounds of the formula I

< / BR>
Studies to determine Bayaut, using the following studies:

1. The study of binding receptors [3H]D4in DMSO-differentiated cells U 937 (human monocytic cell line).

2. Binding receptors [3H]D4on the membranes of the lung of Guinea pigs.

3. Binding receptors [3H]D4on the membranes of the human lung.

4. In vitro Guinea-pig trachea.

5. In vivo studies on shot Guinea pigs.

The above tests are described T. R. Jcnes et al., Can. J. Physiol. Pharmacol. 1991, 69, 1847-1854.

Studies in asthmatic rats

Rats received out of line with congenital asthma. Used as females (190-250 g) and males (260-400 g).

Egg albumin (J.A.), the degree of purity V, crystallized and lyophilized, received from the company Sigma Chemical Cj., St. Louis. The aluminum hydroxide obtained from the company Regis Chemical Company, Chicago. Bimaleate of methylsergide set by the company Sandoz Ltd., Basel.

Control infection and subsequent registration of respiration is carried out in a clean plastic box with internal dimensions HH inches. The top box is removed; when using it firmly fix the four clamps and sealing support with Pomos De Vilbiss (N 40) and each end of the box also has an output hole. Pneumotachograph Fleisch N 0000 inserted in one end of the box and is connected with a sensor for measuring the pressure (RT-A), which is then attached to the pre-amplifier, Buxco Electronics (Buxco Electronics Inc., Sharon., Conn). A preamplifier connected to denegrate Beckman Tyre R Dynograph and the computer Buxco containing the analyzer hesitation, Data Acquisition Logger with special software. If aerosolization antigen weekend vents and pneumotachograph isolated from the camera. The holes are closed and pneumotachograph and Luggage connected with the registration of respiratory models. For the control of infection, 2 ml of 3% solution of antigen in saline solution are placed in each nebulizer and the aerosol is supplied with air from a small diaphragm pump Potter at 10 psi and a flow rate of 8 liters/minute.

Rats activated by injection (subcutaneously) 1 ml suspension containing 1 ml J.A. and 200 mg hydroxide albumin in saline. They are used in the period from 12 to 24 days after activation. To eliminate the serotonin component of the response of rats pre-treated to 3.0 µg/kg methylsergide intravenously 5 minutes prior to aerosol infection control. Rats are then treated with an aerosol of 3% ON in finasa 30 minutes. The duration of continuous dyspnea was measured using the computer Buxco.

The compounds are usually administered either orally 2-4 hours prior to infection control, either intravenously over 2 minutes to control infection. They are either dissolved in saline or 1% of methocel or suspended in 1% methocel. Injected volume is 1 ml/kg (intravenous) or 10 ml/kg (orally). Before oral treatment of rats starve during the night. The activity of compounds is determined by the degree of their ability to reduce the duration of dyspnea caused by antigen, compared with the control group, treated indifferent solvent. Usually the connection is evaluated in a series of doses and determine the ED50. This value is set as the dose (mg/kg), which could inhibit the duration of symptoms by 50%.

Pulmonary mechanics trained in sensitive squirrel monkeys

Research methodology includes sitting trained squirrel monkeys on the chairs in the camera, processed by aerosol. In order to control register pulmonary-mechanical measurement of respiration during a period of about 30 minutes to establish each monkey normal control values on this d 400 SP) and given in a volume of 1 ml/kg body weight. For aerosol introduction connections using ultrasonic spray De Vilbiss. The pre-treatment period varies from 5 minutes to 4 hours before monkeys subjected to control contamination of the aerosol doses or leukotriene D4 (LTD4or antigen Ascaris suum; dilution 1:25.

After control of infection data every minute is calculated using the computer as percentage changes relative to control values for each parameter of respiration, including the resistance of the Airways to the effects of (RL) and dynamic compliance (Cdyn). The results for each tested compound are essentially obtained for a minimum period of 60 minutes after control of infection, which is then compared to the previously obtained natural baseline control values for this monkey. In addition, the full value within 60 minutes after control of infection for each monkey (natural base reference value and data research) separately averaged and used to calculate the total inhibition percentage of the studied compound reactions LTD4or Ascaris antigen. For statistical anal the ptx2">

The warning is caused by a narrowing of the lumen of the bronchi in sheep with allergies

A. Rationale.

Some allergic sheep with known sensitivity to the specific antigen (Ascaris suum) respond to inhalation control the acute infection and slower bronchial reactions. Course during both acute and delayed bronchial reactions corresponds to the passing of time, observed in asthma and pharmacological modification of both reactions such detected in humans. The effect of antigen on these sheep to a large extent is observed on a wide airway and conveniently be recorded in the form of changes in the light resistance or specific resistance of the lung rendered effect.

B. Methods.

Preparation of animals: use adult sheep with a weight of 35 kg (oscillation from 18 to 50 kg). All the animals meet two criteria: a) they have a natural skin reaction at the dilution of 1:1000 or 1:10000 extract of Ascaris suum (Greer Diagnostics, Lenois, NC); and b) they are pre-reacted to the inhalation control infection with Ascaris suum both acute and delayed narrowing of the bronchi (W. M. Abraham et al., Am. Rev. Resp. Dis., 28, 839-844 (1983)).

Lthe maximum end nasotracheal tube attached to pneumotachograph (Fleusch, Dyna Sciects, Blue Bell, PA). The signals of flow and repair the pressure registered on the oscilloscope (Model DR-12, Electronics for Medicine, White Plains NY), which is connected to the computer PDP-II Digital (Digital Equipment Corp. , Maynard, MA) for liseinoprel RLusing analysis of 10-15 breaths. Volume thoracic gas (Vtgmeasure body plethysmograph to obtain specific lung resistance (SRL = RLVtg).

Aerosol release systems: aerosols extract of Ascaris suum (1: 20) obtained using capable of spraying medication dispensers (Raindrop R, Puritan Bennett), which provide an aerosol with a mass medium aerodynamic diameter of 6.2 μm (geometric standard deviation of 2.1), as determined by the analyzer electrical size of the Model. 3030; Thermal Systems, St. Paul, MN). The end of the spray is directed into a plastic t-fragment, one end of which is connected to nasotracheal tube, the other end of which is attached to the respiratory Harvard respirator. The aerosol is released when inhaled volume of 500 ml at a rate of 20 times per minute. Thus, each sheep receives an equivalent dose of antigen as in the placebo and drug test.

Experimental Protocol: prior to infection control antigen carry out basic measurements of SRLthe introduction of the compounds begin 1 hour prior to infection control, measurement of SRLrepeat and then sheep subjected inhalational 1, 2, 3, 4, 5, 6, 6,5, 7, 7,5 and 8 hours after infection control antigen. Placebo and test drugs are separated by at least an interval of 14 days. Upon further study of the sheep give the dose in the form of food to lump the compounds with subsequent introduction of the compounds for 0.5-1 hour to control infection with Ascaris and 8 hours after Ascaris, as described above.

Statistical analysis: to compare acute immediate reactions to the antigen and the peak of the slow reaction of the control and treated animal medicine use study Well-Wallis one way ANOVA.

The invention is further illustrated by the following non-limiting examples in which, unless otherwise stated:

(i) all transactions carried out at room or normal temperature, i.e. at a temperature in the region of 18o-25oC;

(ii) evaporation of solvent is carried out using a rotary evaporator under reduced pressure (600-4000 Pascal: 4.5 to 30 mm RT.CT.) with a bath temperature of up to 60oC;

(iii) the course of the reaction is monitored by thin-layer chromatography (TLC) and reaction times are given for illustration only;

(iv) point melting temperatures are inaccurate and "decomp." indicates decomposition; before dimorphism can occur when simultaneous selection of substances with different melting temperatures;

(v) the structure and purity of all final products confirm at least one of the following techniques: TLC, mass spectrometry, spectroscopy, nuclear magnetic resonance (NMR), or microanalytical data;

(vi) the outputs are presented for illustration only;

(vii) in the case when they are given, NMR data are presented as values () for the main defined protons presented in ppm (M. D.) relative to trimethylsilane (TMS) as internal standard, determined at 300 MHz or 400 MHz using the indicated solvent; conventional abbreviations used for signal shape are: s - singlet; d - doublet; t - triplet; m - multiplet; br broadened; and so on; in addition, the Ar signal aromatics;

(viii) chemical symbols have their usual meanings; also use the following abbreviations: about. (volume), mass (mass), so Kip. (boiling point), l (liter(s)), ml (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (mmol), EQ. (equivalent(s)).

Example 1. 1-(((1(R)-(3-(2-(3-Chlorothieno[3,2-b] pyridine-5-yl) ethynyl)phenyl-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)- -cyclopropaneacetic sodium.

Stage 1: 3-Amino-2-formylthiophene.

Krzemi methyl-3-amino-2-thiophenecarboxylate (30 g, 190 mmol) over 30 minutes. The resulting mixture is stirred 1 hour at 0oC. Very slowly, drop by drop, add water (15 ml) followed by slow addition of aqueous NaOH (15 ml, 3.5 M). Then add more water (43 ml) and THF (300 ml). The mixture was well stirred for 30 minutes and then filtered through celite. Celite was washed with additional THF. The filtrate is concentrated to an oil, which was dissolved in 2 l of EtOAc. Solution in EtOAc dried over anhydrous MgSO4and filtered. The resulting solution of crude 3-amino-2-hydroxythiophene then treated MnO2(100 g). The mixture is stirred at room temperature for 20 hours and then filtered through celite. The filtrate is evaporated to obtain 23.3 g (65%) specified in the connection header.

1H NMR (CDCl3) 6.10 (2H, br s), 6.54 (1H, d, J = 5 Hz), 7.48 (1H, d, J = 5 Hz), 9.57 (1H, s).

Stage 2: Thieno[3,2-b]pyridine-5-carboxylic acid.

To a solution of 3-amino-2-formylthiophene (10 g, 78 mmol) in EtOH (50 ml) was added a mixture of NaOH (50 ml, 5%) and sodium salt of pyruvic acid (17,16 g, 156 mmol). The mixture is heated to 60oC for 2 hours. The mixture is cooled and washed with Et2O:EtOAc 1:1 and then acidified with 1 N. HCl to pH 3 at 0oC. the Mixture is filtered and the solid product is dried in air is 5 Hz), 8.00 (1H, d, J = 8.4 Hz), 8.28 (1H, d, J = 5.5 Hz), 8.65 (1H, d, J = 8.4 Hz).

Stage 3: 3-Chlorothieno[3,2-b]pyridine-5-carboxylic acid.

To a solution of Ag2SO4(of 6.96 g of 22.3 mmol) in conc. H2SO4(60 ml) at 100oC add thieno[3,2-b]pyridine-5-carboxylic acid (4 g, of 22.3 mmol). Through quickly stir the mixture bubbled Cl2over a period of 2 hours. The mixture is cooled and then poured onto ice (250 ml). AgCl precipitates and is filtered. The filtrate is diluted with water (500 ml) and allowed to crystallize at 0oC during the night. The product is filtered and dried in air to obtain 3.04 from g (64%) specified in the connection header.

1H NMR (CD3SOCD3) 8.10 (1H, d, J = 8.4 Hz), 8.39 (1H, s), 8.72 (H, d, J = 8.4 Hz).

Stage 4: 3-Chloro-5-(chloromethyl)thieno[3,2-b]pyridine.

The acid from step 3 atrificial excess diazomethane. To a solution of the corresponding ester (1.2 g, 5.6 mmol) in THF (10 ml) at -78oC was added DIBAL (9,36 g, 1.5 M). The resulting mixture was stirred at 0oC for 1 hour. Add methanol (0.5 ml) followed by addition of HCl (10 ml, 0.5 M). The mixture is extracted with EtOAc. The organic extract is dried over anhydrous MgSO4and concentrated in vacuo. Chromatography of the crude product on silica gel refrigerator in S(O)Cl2(5 ml) for 5 minutes. The excess reagent is removed in vacuo. Then add NaHCO3. The mixture is extracted with EtOAc. Concentration of the dried (anhydrous MgSO4) organic extract gives 1.2 g (98%) specified in the connection header.

Stage 5: ((3-Chlorothieno[3,2-b]pyridine-5-yl)triphenylphosphonium chloride.

To a solution of 3-chloro-5-(chloromethyl)thieno 3,3-pyridine (1.2 g, 5.5 mmol) in CH3CN (20 ml) was added P(Ph)3(2,88 g, 11 mmol). The mixture is refluxed for 20 hours and then evaporated to dryness. Add Et2O (8 ml). The mixture is vigorously stirred and the crystalline salt is filtered and washed with additional Et2O obtaining 2.1 g (81%) specified in the connection header.

1H NMR (CD3SOCD3) 5.75 (2H, d, J = 18.75 Hz), 7.48 (1H, d, J = 7.5 Hz), 7.65-8.00 (15H, m), 8.25 (1H, s), 8.55 (1H, d, J = 7.5 Hz).

Stage 6: 1,1-Cyclopropanemethanol cyclic sulfite.

To a solution of complex BH3THF (1 M in THF, 262 ml) was added diethyl 1,1-cyclopropanedicarboxylic (25 g, 134 mmol) at 25oC in an atmosphere of N2. The solution is refluxed for 6 hours, cooled to room temperature and carefully added MeOH (300 ml). The solution is stirred for 1 cha is 2
(15.9 g, 134 mmol) over a period of time of 15 minutes at 25oC. After stirring for 15 minutes, the mixture was washed with aqueous NaHCO3. The organic extract is dried over Na2SO4filter and concentrate with quantitative obtaining specified in the title compound as a white solid product.

Stage 7: 1-(Hydroxymethyl)cyclopropanecarbonitrile.

To a solution of the derived cyclic sulfite with stage 6 (14,7 g, 99 mmol) in DMF (83 ml) was added NaCN (9,74 g, 199 mmol). The mixture is heated at 90oC for 20 hours. After cooling, add EtOAc (400 ml) and the solution washed with saturated solution of NaHCO3(55 ml), saturated NaCl and dried over Na2SO4. The solution is concentrated with the receipt of 7.1 g (65%) specified in the connection header.

Stage 8: 1-(Acetyltributyl)cyclopropanecarbonitrile.

To a solution of alcohol from step 7 (42 g, 378 mmol) in dry CH2Cl2(450 ml) at -30oC was added Et3N (103,7 ml, 741 mmol) followed by dropwise addition of CH3S(O)2Cl (43,3 ml, 562 mmol). The mixture is heated to 25oC, washed with NaHCO3, dried over Na2SO4and concentrated in vacuo to obtain the corresponding nelfinavir. M is stirred at 25oC for 18 hours. Add EtOAc (1.5 l) and the solution washed with NaHCO3, dried over Na2SO4and concentrated in vacuo to obtain 45 g (70%) specified in the connection header.

Step 9: Methyl 1-(mercaptomethyl)cyclopropaneacetic.

To a solution of the nitrile from step 8 (45 g, 266 mmol) in MeOH (1,36 l) add H2O (84 ml) and conc. H2SO4(168 ml). The mixture is refluxed for 20 hours, cooled to 25oC, add H2O (1 l) and the product extracted with CH2Cl2(2x 1.5 liters). The organic extract was washed with H2O and dried over Na2SO4. Concentration of the organic solution give 36 g (93%) specified in the connection header.

Step 10: 3-(((2-Tetrahydropyranyl)oxy)methyl)benzaldehyde.

Isopropylalcohol (150 g, 1.1 mol) is dissolved in THF (1 l) and EtOH (1 l) at 0oC. Portions added NaBH4(11,0 g, 291 mol) and the mixture is stirred for 1 hour at 0oC. the Addition of 25% aqueous NH4OAc and extracted with EtOAc (2x), followed by purification by flash chromatography (20% ---> 40% EtOAc in hexane) to give 60 g of 3-(hydroxymethyl)benzaldehyde.

Alcohol (0.44 mmol) dissolved in CH2Cl2, (500 ml). Added DHP (50 g, 0.59 mol) and PTSA (1 g, 5 OK purified using flash chromatography (50 -> 15% EtOAc in hexane) to give 85 g specified in the connection header.

Stage 11: 1-(3-(((2-Tetrahydropyranyl)oxy)methyl)phenyl)-2 - propen-1-ol.

The aldehyde from step 10 (85 g, 386 mmol) in toluene (1 l) at 0oC is slowly added magnesium bromide in Et2O (450 ml, 1 M, 450 mmol) over a period of more than 30 minutes. After stirring for 1 hour at 0oC, the reaction mixture was quenched with 25% aqueous NH4OAc and extracted with EtOAc (3x). Evaporation and purification by flash chromatography (15% -> 25% EtOAc in hexane) to give 82 g (86%) specified in the connection header.

Stage 12: Ethyl 2-(3-(3-(((2-tetrahydropyranyl)oxy)methyl)- phenyl)-3-oksipropil)benzoate.

Allyl alcohol with stage 11 (24.8 g, 100 mmol) and ethyl 2-bromobenzoate of 25.2 g, 110 mmol) dissolved in DMF (200 ml). Added LiCl (4,2 g, 100 mmol), LiOAc 2H2O (25,5 g, 250 mmol) and n-Bu4N+Cl-(55 g, 200 mmol) and the resulting mixture three times Tegaserod. Then add Pd(OAc)2(1 g) and the mixture Tegaserod three more times before heating it at 100oC under stirring for 1 hour. After cooling to room temperature the reaction mixture was poured into H2O (600 ml), 10% aqueous NaHCO3(200 ml) and Et2O. the Crude product is extracted with Et2O (2), washing is STCA on a short column of silica gel (20% EtOAc in hexane) to give 34 g (86%) specified in the connection header.

1H NMR (CD3COCD3): 8.02 (1H, bs), 7.92 (1H, d), 7.88 (1H, d), 7.65 (1H, d), 7.50 (3H, m), 7.32 (1H, bt), 4.8 (1H, d), 4.70 (1H, bs), 4.54 (1H, d), 4.3 (2H, q), 3.82 (1H, m), 3.50 (1H, m), 3.35 (2H, m), 1.9-1.45 (8H, m), 1.32 (3H, t).

Stage 13: Ethyl 2-(3(S)-hydroxy-3-(3-(((2-(2-tetrahydropyranyl) oxy)methyl)phenyl)propyl)benzoate.

Ketoester from the stage 12 (24.8 g, 62.5 mmol) dissolved in THF (230 ml) and cooled to -45oC. is added dropwise a solution in THF (15 ml) adduct tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo- [1,2-c][1,3,2]oxazolone of borane (J. Org. Chem. 56, 751 (1991), 4,55 g, 15.6 mol) and the resulting mixture is stirred for 20 minutes at -45oC. To this solution are added dropwise 1.0 M borane in THF (62.5 ml, 62.5 mmol) over 30 minutes. The reaction mixture is stirred for 1 hour at -45oC and then another 2 hours with slow warming to -20oC. After cooling the solution to -40oC it is then poured into 25% aqueous NH4OAc (425 ml) and 1.0 M diethanolamine (40 ml) at 0oC and vigorously stirred for 20 minutes. Specified in the title compound is extracted with EtOAc (3x), dried over MgSO4and concentrate under reduced pressure. The crude oil purified by flash chromatography (25% -> 50% EtOAc in hexane) to obtain and 22.6 g (91%) of product as oil. []2D5= -32,6o(c = 3, CHCl3

Anhydrous CeCl3(17,25 g, 70 mmol) is boiled for 2.5 hours in THF (200 ml), using a nozzle Dean-stark filled with molecular sieves to remove the H2O. the Suspension is cooled to -5oC and added dropwise MeMgCl (114 ml, 3 M in THF, 340 mmol) keeping the internal temperature between -10oC and 0oC. the Suspension of gray is stirred for 2 hours before slowly adding to it the hydroxyether with stage 13 (27,1 g, 68 mmol) in solution in THF (200 ml) via cannula. The resulting mixture was stirred for 1.5 hours and at 0oC or below, and then slowly poured into ice HOAc (1 l) and EtOAc (500 ml) and stirred for 30 minutes. After establishing a pH of 6-7, the crude compound extracted with EtOAc (2x) and the combined organic phases are washed with saturated aqueous NaHCO3and then a saturated solution of salt. Purification on a short column of silica gel (30% to 50% EtOAc in hexane) to give 24.5 g (95%) specified in the connection header.

Stage 15: Methyl 1-(((1(R)-(3-(((2-tetrahydropyranyl)oxy)- methyl)phenyl)-3-(2-(1- hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)- cyclopropaneacetic.

Diol from step 14 (17.9 g, with 46.6 mmol) dissolved in CH3CN (40 ml) and DMF (10 ml) and cooled to -42oC in nitrogen atmosphere. Primeamerica 1.5 hours with a mechanical stirrer, maintaining the temperature between -42oC and -35oC; then it is cooled to -45oC. Add the thiol from step 9 (7,84 g, for 48.9 mmol) and then added dropwise DMF (15 ml). To the reaction mixture was added tert-piperonyl potassium in THF (56 ml, 1.75 M, is 97.9 mmol) over 20 minutes with a syringe. Stirring is continued for 5 hours under slow heating from -35oC to -22oC, getting very thick translucent gel. The reaction is quenched with saturated aqueous NH4Cl (250 ml) and EtOAc (300 ml). The product is extracted with EtOAc, washed with H2O and saturated salt solution and dried over MgSO4. Purification by flash chromatography (20% to 30% EtOAc in hexane) gives 16,8 g (68%) specified in the connection header.

Stage 16: Methyl 1-(((1(R)-(3-(hydroxymethyl)phenyl)-3-(2- -(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)zikrayat.

To hydroxyether from the stage 15 (9,02 g, 17,1 mol) in anhydrous MeOH (60 ml) under nitrogen atmosphere was added pyridine (50 μl) and then PPTS (1.1 g, 4.3 mmol). The reaction mixture is stirred for 3.5 hours at 55oC, then at room temperature over night before was evaporated in vacuum. The residue was diluted with EtOAc (500 ml) and washed with H2O, saturated aqueous NaHCO3, buffer NaH2PO4(pH = 4.5) eat flash chromatography (40% to 60% EtOAc in hexane) to give 6.85 g (91%) specified in the connection header.

1H NMR (CD3COCD3): 7.41 (2H, m), 7.27 (3H, m), 7.09 (3H, m), 4.63 (2H, d), 4.19 (1H, t), 3.95 (1H, t), 3.88 (1H, s), 3.57 (3H, s), 3.1 (1H, ddd), 2.8 (1H, ddd), 2.5 (2H, s), 2.4 (2H, d), 2.17 (2H, m), 1.52 (6H, s), 0.52-0.35 (4H, m).

Stage 17: Methyl 1-(((1(R)-(3-(formylphenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic.

To dihydroxyethyl from the stage 16 (6.8 g, to 15.4 mmol) in EtOAc (150 ml) at 50oC add MnO2(6.7 g, with 76.8 mmol). After stirring for 30 minutes at 50oC add another MnO2(6.7 g) and after 30 minutes add the third portion MnO2(6.7 g). An hour later the warm reaction mixture was filtered through celite and the cake washed with additional EtOAc. Evaporation of the solvent gives the desired aldehyde 5,62 g (83%).

1H NMR (CD3COCD3): 10.4 (1H, s), 7.9 (1H, bs), 7.8 (2H, m), 7.58 (1H, t), 7.38 (1H, bd), 7.1 (3H, m), 4.1 (1H, t), 3.54 (3H, s), 3.13 (1H, ddd), 2.85 (1H, ddd), 2.51 (2H, s), 2.49 (2H, d), 2.2 (2H, m), 1.51 (6H, s), 0.52-0.32 (4H, m).

Stage 18: Methyl 1-(((1(R)-(3-(2-(3-chlorothieno[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)- methyl)cyclopropaneacetic.

To a suspension of postnasal salt with stage 5 (409 mg, 0.85 mmol) in dry THF (5 ml) at -78oC was added a solution of tert-butoxide potassium (0,716 ml, 1 M solution in THF). The mixture is heated to room those who mol). The mixture was stirred at -78oC for 30 minutes, warmed up to 0oC for 15 minutes. Add water NH4OAc and the mixture extracted with EtOAc. The organic extract was washed with saturated salt solution, dried over MgSO4and concentrated to oil. Chromatography of the crude oil on silica gel (elution with 20% EtOAc in hexane) gives 420 ml (98%) specified in the connection header.

1H NMR (CD3COCD3): 0.35-0.55 (4H, m), 1.55 (6H, s), 2.1-2.3 (2H, m), 2.45 (2H, d, J = 7.5 Hz), 2.55 (2H, s), 2.8-2.95 (1H, m), 3.1-3.25 (1H, m), 3.55 (3H, s), 4.05 (1H, t, J = 7.5 Hz), 7.05-7.15 (4H, m), 7.4 (2H, d, J = 3.75 Hz), 7.5 (1H, d, J = 15 Hz), 7.6 (1H, m), 7.75 (1H, d, J = 7.5 Hz), 7.8 (1H, s), 7.85-7.95 (1H, d, J = 15 Hz), 8.05 (1H, s), 8.45 (1H, d, J = 8 Hz).

Stage 19: Sodium 1-(((1(R)-(3-(2-(3-chlorothieno[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxymethylation)phenyl)propyl)thio)- methyl)cyclopropaneacetic

To a solution of ester from step 18 in THF (1 ml) and MeOH (1 ml) was added aqueous NaOH (1 N., of 1.4 ml). The mixture is stirred at 25oC for 20 hours. Add NH4Cl and the mixture extracted with EtOAc. The organic extract was washed with saturated salt solution, dried over MgSO4and concentrated to oil. Chromatography of the crude oil on silica gel (elution with 20% EtOAc/5% HOAc in hexane) to give 330 mg (79%) of the appropriate acid. To this acid in 3 ml of EtOH priba is inane.

The exact mass of C33H33ClNO3S2Na (M+1): calculated 614,1566

found 614,1566.

1H NMR (CD3COCD3): 0.2-0.43 (4H, m), 1.53 (6H, 2s), 2.26 (2H, m), 2.28 (2H, s), 2.6 (2H, s), 2.75-2.85 (1H, m), 2.95-3.3 (1H, m), 4.04 (1H, dd, J = 7.5 Hz, J' = 11.25 Hz), 7.01-7.08 (3H, m), 7.33-7.8 (3H, m), 7.42-7.47 (1H, d, J = 16.5 Hz), 7.53 (1H, d, J = 7 Hz), 7.65 (1H, s), 7.66 (1H, d, J = 8.5 Hz), 7.82-7.88 (1H, d, J = 17 Hz), 8.0 (1H, s), 8.34-8.37 (1H, d, J = 8.5 Hz).

Example 2. 1-(((1(R-(3-(2-(Thieno[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3- (2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio) methyl)cyclopropaneacetic sodium.

Stage 1: ((Thieno[3,2-b]pyridine-5-yl)methyl)triphenylphosphonium chloride.

Using the methods described in stages 4-5 example 1, thieno-[3,2-b]pyridine-5-carboxylic acid is converted into the specified header connection.

1H NMR (CDCl3): 7.2 (2H, dd), 7.5-8.0 (17H, m), 8.2 (2H, m).

Stage 2: 1-(((1(R)-(3-(2-(Thieno[3,2-b]pyridine-5-yl) ethynyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)-thio)methyl) cyclopropaneacetic sodium.

Using the methods described in stages 18-19 example 1, fosfonovoi salt from step 1 is converted into the specified header connection.

1H (CDCl3): 0.5 (4H, m), 1.6 (6H, 2s), 2.1 (2H, m), 2.4 (2H, m), 2.6 (2H, m), 2.9 (1H, m), 3.2 (1H, m), 4.0 (1H, t), 7.1 (3H, m), 7.2-7.5 (6H, m), 7.6 (2H, t), 7.8 (2H, t), 8.2 (1H, d, J = 8 Hz).

Analysis.P> Example 3. 1-(((1(R)-(3-(2-(3-Bratiano[3,2-b]pyridine-5-yl)ethynyl)phenyl)-3- (2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio) methyl)cyclopropaneacetic sodium.

Stage 1: Methyl 3-bratiano[3,2-b]pyridine-5-carboxylate.

To a solution of HCl (10%) in MeOH (10 ml) was added thieno[3,2-b]pyridine-5-carboxylic acid (1.0 g, 5.6 mmol, from step 2 of example 1) and the mixture refluxed for 2 hours. After cooling to room temperature the solvent is removed by evaporation and the residue partitioned between EtOAc and H2O. Solid Na2CO3add up until the system will not become mainstream. Separation, drying and evaporation of the organic layer yield 0.75 g (70%) of methyl thieno[3,2-b]pyridine-5-carboxylate.

To a solution of methyl thieno[3,2-b]pyridine-5-carboxylate (0.400 g, 2,07 mmol) in 2 ml of CHCl3at 0oC bubbled HCl for 2 minutes. The solvent is evaporated under reduced pressure and the solid residue in a mixture of bromine (2 ml) and CHCl3(2 ml) is heated in a sealed tube for 12 hours at 70oC. After cooling, add 10% solution of NaHCO3and the reaction mixture was extracted with CH2Cl2(3x50 ml). The organic phase was washed with NaHCO3and dried over Na2SO4. Organic solvents upar is of 0,343 g (61%).

1H NMR (CDCl3): 4.06 (3H, m), 7.89 (1H, s), 8.19 (1H, d). 8.33 (1H, d).

MS, m/e 272 (m++ 1).

Stage 2: 3-Bratiano[3,2-b]pyridine-5-methanol.

To a solution of methyl ester (0,388 g of 1.42 mmol) from step 1 in 5 ml of THF at -78oC was added DIBAL (3,55 mmol) over 5 minutes. The reaction mixture is left for 30 minutes, after which the solution is cooled to 0oC and quenched with MeOH. Add a solution of potassium tartrate and the mixture extracted with EtOAc. The organic phase is dried over Na2SO4and the solvent evaporated. The crude oil purified by flash chromatography on silica gel with EtOAc:hexane 2:3 with obtaining 0,338 g (98%) specified in the header of alcohol.

1H NMR (CDCl3): 3.97 (1H, t), 4.94 (2H, d), 7.29 (1H, d), 7.79 (1H, S), 8.16 (1H, d).

Stage 3: 3-Bromo-5-(chloromethyl)thieno [3,2-b]pyridine.

A mixture of thionyl chloride (5 ml) and ethanol (0,331 g, 1.35 mmol) from stage 2 is heated at 70oC for 30 minutes, after which the solvent is evaporated. The residue is treated with bicarbonate and extracted with dichloromethane. The organic phase is dried over Na2SO4and the solvent is removed. The crude product is purified by flash chromatography on silica gel with EtOAc:hexane 5:95 with getting 0,170 g (48%) specified in the header chloride.

1

A mixture of the chloride (0,165 g of 0.62 mmol) from step 3 and triphenylphosphine (0,325 g of 1.24 mmol) in 4 ml of acetonitrile is refluxed for 12 hours. After that, the resulting suspension is cooled and the solvent evaporated. The crude solid product is treated with acetone: ether 1:1 with obtaining 0,296 g (91%) specified in the header of postnasal salt.

1H NMR (CDCl3): 6.04 (2H, d), 7.58-7.71 (10H, m), 7.94-7.99 (6H, m), 8.08 (1H, d), 8.26 (1H, d).

Stage 5: Methyl 1-(((1(R)-(3-(2-(3-bratiano[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)-phenyl)propyl) thio)methyl)cyclopropaneacetic.

To a 1 molar solution of tert-butoxide potassium (or 0.57 ml, or 0.57 mmol) was added at -78oC suspension of postnasal salt (0,290 g, 0.55 mmol) from step 4 in 3 ml of THF. The temperature is brought to 0oC for 20 minutes, then lowered to -78oC, followed by addition of 0.5 molar solution of methyl 1-(((1(R)-(3-(formylphenyl) -3-(2-(1-hydroxy-1-methylethyl)phenyl) propyl)thio)methyl) cyclopropaneacetic (1,47 ml, 0.44 mol) from step 17 of example 1. Bath maintained at 0oC for 1 hour and the reaction mixture was quenched with 25% aqueous NH4The OAc. The organic solvent is evaporated and specified in the header of the product was then purified flash chromatography on silica gel with n is 2H, m), 2.42 (2H, AB), 2.55 (2H, s), 2.89 (1H, m), 3.14 (1H, m), 3.57 (3H, s), 3.90 (1H, s), 4.0 (1H, t), 7.04-7.25 (3H, m), 7.40 (3H, m), 7.50 (1H, d), 7.5 (1H, m), 7.70 (1H, d), 7.76 (1H, s), 7.90 (1H, s), 8.13 (1H, s), 8.39 (1H, d).

Stage 6: 1-(((1(R)-(3-(2-(3-Bratiano[3,2-b]pyridine-5- -yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)- phenyl)propyl)thio)methyl)cyclopropaneacetic sodium.

2 n NaOH solution (of 0.41 ml, 0.82 mmol) was added to methyl ether (0,279 g, 0.41 mmol) from step 5 in 2 ml of methanol/THF (0.5 ml/1.5 ml) and stirred for 12 hours. The solution was poured into 25% aqueous NH4Cl and extracted with EtOAc. The organic solvent is evaporated and the crude oil purified flash chromatography on silica gel with EtOAc/hexane 40:60 with 2% acetic acid with getting 0,224 g (86%) of the corresponding carboxylic acid. This acid is dissolved in ethanol and added 1 EQ of sodium hydroxide (1 BC). The solvent is removed and the oil lyophilized obtaining 0,231 g (99%) specified in the connection header.

Exact mass for C33H33BrNaNO3S2+H+: calculated 658,1060

found 658,1061.

Example 4. 1-(((1(R)-(3-(2-(2,3-Dichlorethene[3,2-b]pyridin-5-yl)ethynyl)phenyl) -3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium.

Stage 1: Methyl 2,3-dichlorethene[3,2-b]pyridine-5-carboxylate.

patat under reflux in CH3CN for 16 hours. The solvent is removed by evaporation and the crude solid product chromatographic on silica gel with 5% EtOAc in toluene as eluent to obtain 0,189 g (70%) specified in the connection header.

1H NMR (C6D6): 3.55 (3H, s), 6.75 (1H, d, J=6.5 Hz), 7.75 (1H, d, J = 6.5 Hz).

Stage 2: 2,3-Dichloro-5-(chloromethyl)thieno[3,2-b]pyridine.

Using the methods described in stage 2 of example 3, methyl 2,3-dichlorethene[3,2-b] pyridine-5-carboxylate (0,100 g, 0.38 mmol) is converted into 99% specified in the connection header.

1H NMR (CDCl3): 4.75 (2H, s), 7.50 (1H, d), 8.00 (1H, d).

Stage 3: ((2,3-Dichlorethene [3,2-b]pyridine-5-yl)methyl) triphenylphosphonium chloride.

Using the methods described in stage 4 of example 3 2,3-dichloro-5-(chloromethyl)thieno[3,2-b]pyridine (0,078 g, 0.30 mmol) transform in 81% specified in the connection header.

1H NMR (CDCl3): 6.05 (1H, d), 7.50-8.00 (16H, m), 8.42 (1H, d).

Stage 4: Methyl 1-(((1(R)-(3-(2-(2,3-dichlorethene[3,2-b] pyridine-5-yl) ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl) thio)methyl)cyclopropaneacetic.

Using the methods described in stage 18 of example 1, ((2,3-dichlorethene[3,2-b] pyridine-5-yl)methyl)triphenylphosphonium chloride (0,280 g, 0.54 mmol) transform in 77% of the decree (2H, s), 2.88 (1H, m), 3.15 (1H, m), 3.58 (3H, s), 4.06 (1H, t), 7.13 (3H, m), 7.40-7.50 (4H, m), 7.59 (1H, m), 7.71 (1H, d), 7.76 (1H, s), 7.92 (1H, d), 8.31 (1H, d).

Stage 5: 1-(((1(R)-(3-(2-(2,-Dichlorethene[3,2-b]pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)- phenyl)propyl)thio)methyl)cyclopropaneacetic sodium.

Using the methods described in stage 19 of example 1, the above methyl ether (0,176 g, 0.27 mmol) is converted into 86% specified in the connection header.

Analysis. Calculated for C33H32Cl2NNaO3S21,5 H2O:

C 58,66; H 5,22; N 2,07; Cl 10,49.

Found: C 58,78; H 5,15; N 2,27; Cl 11,06.

Example 5. 1-(((1(R)-(3-(2-(3-Chlorothieno[3,2-b]pyridine-5-yl)ethyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio) methyl)cyclopropaneacetic sodium.

Stage 1: Methyl 1-(((1(R)-(3-(2-(3-chlorothieno[3,2-b] pyridine-5-yl)ethyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)-phenyl)propyl)thio)methyl) cyclopropaneacetic.

To a solution of the olefin from step 18 of example 1 (270 g, 0,456 mmol) in THF at 0oC add BH3in THF (1 M) (1,36 ml, 1.37 mmol). The mixture is stirred for 5 hours at room temperature. The addition of 25% aqueous NH4OAc and extraction with EtOAc, followed by purification flash chromatography (15% EtOAc in toluene) to give 110 mg (41%) saturated compounds.

Stall)cyclopropaneacetic.

Following the methods described for stage 19 of example 1, the ester from step 1 hydrolyzing to acid with a yield of 90%.

1H NMR (300 MHz, CD3COCD3): 0.30-0.55 (4H, m), 1.50 (6H, 2s), 2.10-2.20 (2H, m), 2.40 (2H, m), 2.50 (2H, s), 2.80 (2H, m), 3.10 (1H, m), 3.15 (2H, m), 3.30 (2H, m), 3.45 (1H, m), 7.15-7.45 (8H, m), 8.00 (1H, s), 8.30 (1H, d).

Then get sodium salt specified in the connection header.

Analysis. Calculated for C33H35ClNS2O3Na 3H2O:

C 59,19; H 6,18; N 2,09.

Found: C 59,16; H Of 5.92; N 2,08.

Example 6. 1-(((1(R)-(3-(2-(2-Chlorothieno[3,2-b]pyridine-5-yl)ethynyl)phenyl)-3- (2-(1-hydroxy-1-methylethyl) phenyl)propyl)thio) methyl)cyclopropaneacetic sodium.

Stage 1: 2-Chloro-5-methylthieno[3,2-b]pyridine.

To a solution of 5-methylthieno[3,2-b] pyridine (of 3.60 g, 24 mmol) and N,N-Diisopropylamine (100 μl) in THF (80 ml) at -78oC added dropwise 16 ml of n-BuLi (1.6 M, 25.6 mmol). The mixture was stirred at -78oC for 20 minutes and then is directed through the cannula into a solution of N-chlorosuccinimide (4.5 g, 34 mmol) in THF (300 ml) at -10oC. the Mixture was stirred at -10oC for 30 minutes. Then add a saturated solution of NH4Cl and the product extracted with EtOAc, dried over MgSO4and concentrated to oil. Chromatography of the crude oil on silica gel (is (CDCl3): 2.65 (3H, s), 7.12 (1H, d, J = 7.5 Hz), 7.34 (1H, s). 7.90 (1H, d, J=7.5 Hz).

Stage 2: 5-(methyl bromide)-2-chlorothieno[3,2-b]pyridine.

A mixture of the product from step 1 (0,371 g, 2.0 mmol), N-bromosuccinimide (0,396 g, 2.2 mmol) and benzoyl peroxide in 10 ml of carbon tetrachloride is boiled under irradiation of solar light for 1 hour. After cooling to room temperature the solvent is removed and listed in the title bromide purified flash chromatography on silica gel (elution with 5% EtOAc in hexane) to give the 0,284 g (46%).

1H NMR (CDCl3): 4.63 (2H, s), 7.38 (1H, s), 7.40 (1H, d), 8.04 (1H, d).

Stage 3: ((2-Chlorothieno [3,2-b]pyridine-5-yl)methyl)triphenylphosphonium bromide.

Bromide solution (0,304 g of 1.16 mmol) from stage 2 and triphenyl of phosphine (0,455 g of 1.73 mmol) in 6 ml of acetonitrile is stirred at room temperature for 12 hours. Add ether and the solid product washed with ether to obtain 0,550 g (91%) specified in the header of postnasal salt.

1H NMR (CD3COCD3CD3SOCD3): 5.68 2H, d), 7.37 (1H, s), 7.42 (1H, d), 7.75 (6H, m), 7.80-7.95 (9H, m), 8.38 (1H, d).

Stage 4: 1-(((1(R)-(3-(2-(2-Chlorothieno[3,2-b]pyridine-5- -yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)- phenyl)propyl)thio)methyl)cyclopropaneacetic sodium.

Using me in the connection header.

1H NMR (CDCl3) of the acid 0.38-0.61 (4H, m), 1.61 (3H, s), 1.64 (3H, s), 2.20 (2H, m), 2.31-2.45 (2H, m), 25 (1H, d, J = 14 Hz), 2.62 (1H, d, J = 13 Hz), 2.90 (1H, m), 3.19 (1H, m), 4.00 (1H, t), 7.08-7.19 (2H, m), 7.21-7.48 (8H, m), 7.57 (1H, d, J = 16 Hz), 7.69 (1H, s ), 7.96 (1H, d, J= 8.2 Hz).

Example 7. 1-(((1(R)-(3-(2-(2-Fortiana[3,2-b]pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio) methyl)cyclopropaneacetic sodium.

Stage 1: 2-Fluoro-5-methylthieno 3,2-b]pyridine.

To a solution of 2.23 g (15 mmol) of 5-methylthieno[3,2-b]pyridine in 35 ml of THF was added 80 μl (0.6 mmol) of Diisopropylamine and then added 10.3 ml n-utility (1.4 M in hexane) at -78oC. After stirring at -78oC for 15 minutes, add a solution of 6.9 g (22 mmol) of N-fluoro bis(benzazolyl)amide in 30 ml of THF. The reaction mixture was stirred at -78oC for 1 hour, warmed to 0oC and stirred at 0oC for 2 hours. Water treatment with ammonium chloride and ethyl acetate, followed by chromatographic purification toluene/ethyl acetate = 6:1 give 1.18 g (47%) specified in the connection header.

1H NMR (CDCl3): 7.87 (1H, d, J = 8 Hz), 7.11 (1H, d, J = 8 Hz), 6.88 (1H, d, J = 2.5 Hz), 2.64 (3H, s).

Another product identified as 2-(phenylsulfonyl)-5-methylthieno [3,2-b]pyridine, was also highlighted.

Using the methods described in stages 2-4 in example 6, receive specified in the header of the connection.

1H NMR 0.24-0.45 (4H, m), 1.5-1.53 (6H, 2s), 1.13-2.35 (2H, m), 2.35 (2H, s), 2.6 (2H, d, J = 5 Hz), 2.77-2.85 (1H, m), 3.1-3.25 (1H, m), 4.03 (1H, t, J = 7.5 Hz), 7.0-7.07 (4H, m), 7.3-7.37 (4H, m), 7.46 (1H, s), 7.49 (1H, d, J = 8 Hz), 7.68-7.71 (1H, d, J = 9 Hz), 7.76 (1H, s), 8.17 (1H, d, J = 8 Hz).

Example 8. 1-(((1(R)-(3-(2-(2,3-Divertito[3,2-b]pyridine-5-yl)ethynyl)phenyl)-3- (2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl) cyclopropaneacetic sodium.

Step 1: 2,3-Debtor-5-methylthieno[3,2-b]Eridan.

To a solution of 2-fluoro-5-methylthieno[3,2-b]pyridine (example 7, step 1) (1,00 g, 6,00 mmol) in 30 ml THF at -78oC was added n-utility (6.6 mmol). After 5 minutes, the temperature was raised to -20oC for 0.5 minutes bubbled PERCHLORYL fluoride. The reaction mixture is heated to 0oC, poured into 10% solution of NaHCO3and extracted with EtOAc. The solvent is evaporated and is listed in the title compound purified flash chromatography on silica gel with EtOAc/hexane 3:1 to receive 0,376 g (34%).

1H NMR (CDCl3): 2.67 (3H, s), 7.81 (1H, d), 7.84 (1H, d).

Stage 2: 5-methyl bromide-2,3-divertito[3,2-b]pyridine.

The product from step 1 (0.518 g, 2.8 mmol), N-bromosuccinimide (0,548 g is 3.08 mmol) and benzoyl peroxide (0,034 g, 0.14 to whom to room temperature the solvent is removed and listed in the title bromide purified flash chromatography on silica gel with toluene to obtain 0,341 g (46%).

1H NMR (CDCl3): 4.67 (2H, s), 7.49 (1H, d), 7.98 (1H, dd).

Stage 3: ((2,3-Divertito[3,2-b]pyridine-5-yl)methyl) triphenylphosphonium bromide.

Bromide solution (0,335 g of 1.27 mmol) from stage 2 and triphenylphosphine (0,366 g of 1.40 mmol) in 4 ml of acetonitrile was stirred at room temperature for 20 hours. The solvent is removed and the crude solid product is treated with acetone/ether 1:1 with obtaining 0,493 g (74%) specified in the header of postnasal salt.

1H NMR (CDCl3): 5.96 (2H, d), 7.63-8.04 (16H, m), 8.21 (1H, d).

Stage 4: Methyl 1-(((1(R)-(3-(2-(2,3-divertito[3,2-b]pyridine-5-yl) ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl) thio)methyl)cyclopropaneacetic.

Using the methods described in stage 18 of example 1, the phosphonium bromide (0,484 g of 0.91 mmol) from step 3 convert 86% specified in the connection header.

1H (CD3COCD3): 0.45 (4H, m), 1.55 (6H, s), 2.20 (2H, m), 2.40 (2H, AB system), 2.55 (2H, s), 2.89 (1H, m), 3.18 (1H, dt), 3.57 (3H, s), 3.90 (1H, s), 4.05 (1H, t), 7.10-7.25 (3H, m), 7.35-7.45 (4H, m), 7.56 (1H, m), 7.62 (1H, d), 7.75 (1H, s), 7.85 (1H, d), 8.23 (1H, d).

Stage 5: 1-(((1(R)-(3-(2-(2,3-Divertito[3,2-b]pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl) thio)methyl)cyclopropaneacetic sodium.

To a solution of methyl ester (0,200 g, 0.33 mmol) with a hundred who liveout a 10% solution of NH4OAc and extracted with EtOAc. Organic solvents were evaporated and the crude oil purified flash chromatography on silica gel with EtOAc:hexane 4:6 with 2% acetic acid with getting 0,183 g (94%) of the corresponding carboxylic acid. This acid is dissolved in ethanol and added 1 equivalent of sodium hydroxide. The solvents were removed and the resulting oil is treated with water and lyophilized obtaining 0,183 g (96%) specified in the connection header.

Analysis. Calculated for C33H32F2NNaO3S22H2O:

C 60,80; H 5,58; N 2,5.

Found C 60,85; H 5,11; N 2,14.

Example 9. 1-(((1(R)-(3-(2-(2-Chloro-3-fortiana[3,2-b] pyridine - 5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl) cyclopropaneacetic sodium.

Stage 1: 2-Chloro-3-fluoro-5-methylthieno[3,2-b]pyridine.

To a solution of 550 mg (3 mmol) of 2-chloro-5-methylthieno[3,2-b]pyridine (example 6, step 1) and 14 μl (0.1 mmol) of Diisopropylamine in 12 ml of THF at -78oC is added to 2.3 ml of n-utility (1.4 M in hexane). After stirring for 10 minutes at -78oC FClO4(gas) is bubbled into the reaction mixture for 15 seconds. Dark red color turns into yellow. The reaction mixture was stirred at -78oC for 15 managerour with ethyl acetate. Chromatographic purification on silica gel with toluene/ethyl acetate = 10:1 give 340 mg (57%) specified in the header of the product.

1H NMR (CDCl3): 7.88 (1H, dd, J = 8 Hz, J' = 0.5 Hz), 7.20 (1H, d, J = 8 Hz), 2.70 (3H, s).

Stage 2: 5-(methyl bromide)-2-chloro-3-fortiana[3,2-b]pyridine.

Using the methods described in stage 2 of example 8, get listed at the beginning of the connection.

1H NMR (CDCl3): 8.0 (1H, dd, J = 8 Hz, J'= 0.5 Hz), 7.52 (1H, d, J = 8 Hz), 4.69 (2H, s).

Stage 3: ((2-Chloro-3-fortiana[3,2-b]pyridine-5-yl)methyl)- triphenylphosphonium bromide.

Using the methods described in stage 3 of example 8, get listed at the beginning of the connection.

1H NMR (DMSO-d6): 8.46 (1H, d, J=8 Hz), 7.88-7.68 (15H, m), 7.42 (1H, d, J=8 Hz), 5.67 (2H, d, J = 14 Hz).

Stage 4: Methyl 1-(((1(R)-(3-(2-(2-chloro-3-fortiana[3,2-b]pyridine-5-yl)ethynyl)phenyl) -3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl) cyclopropaneacetic.

Using the methods described in stage 18 of example 1, from postnasal salt with stage 3 receive specified in the header of the connection.

1H NMR (CDCl3): 7.95 (d, J = 8 Hz, 1H), 7.70 (d, J = 14 Hz, 1H), 7.60 (s, 1H), 7.49 (m, 2H), 7.38-7.08 (m, 7H), 3.92 (t, J = 7 Hz, 1H), 3.60 (s, 3H), 3.12 (m, 1H), 2.85 (m, 1H), 2.49 (s, 2H), 2.38 (s, 2H), 2.20 (m, 2H), 1.60 (s, 3H), 1.58 (s, 3H), 0.50 (m, 4H).

Using the methods described in stage 19 of example 1, methyl ester from step 4 is converted into the specified header connection.

1H (CDCl3): 7.90 (d, J=8 Hz, 1H), 7.66 (d, J = 5, 1H), 7.62 (d, J = 9 Hz, 1H), 7.50 (d, J = 9 Hz, 1H), 7.42 (m, 1H), 7.35-7.05 (m, 7H), 3.97 (t, J = 7 Hz, 1H), 3.16 (m, 1H), 2.88 (m, 1H), 2.58-2.34 (m, 4H) 2.18 (m, 2H), 1.60 (s, 3H), 1.59 (s, 3H), 0,47 (m, 4H).

Example 10. 1-(((1(R)-(3-(2-(3-Chloro-2-fortiana[3,2-b] -pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl) propyl)thio)methyl)cyclopropaneacetic sodium.

Stage 1: 3-Chloro-2-fluoro-5-methylthieno[3,2-b]pyridine.

To a solution of 461 mg (2,74 mmol) 2-fluoro-5-methylthieno[3,2-b] pyridine (example 7, step 1) and 14 μl (0.1 mmol) of Diisopropylamine in 12 ml of THF at -78oC gain of 2.15 ml of n-utility (1.4 M hexane). After stirring for 10 minutes at -78oC was added a solution of 585 mg (4.4 mmol) of N-chlorosuccinimide in 10 ml of THF. The mixture was stirred at -78oC for 20 minutes, warmed to 0oC, stirred at 0oC for 30 minutes and then partitioned between aqueous ammonium chloride and ethyl acetate. Chromatographic purification on silica gel using hexane/ethyl acetate = 8:1 yield 350 mg (63%) specified in the header of the product.

1H NMR (CDCl3): 7.88 (d, J = 8 Hz, 1H), 7.18 (d, J = 8 Hz, 1H), 2.70 (s, 3H).

Using the methods described in stages 2-5 of example 8, receive specified in the header of the connection from the product from step 1.

1H NMR (CD3COCD3): 0.2-0.55 (4H, m), 1.5 (3H, s), 1.55 (3H, s), 2.1 (2H, m), 2.25 (2H, s), 2.65 (2H, s), 2.70-2.85 (1H, m), 3.15-3.25 (1H, m), 4.05 (1H, t, J = 7.5 Hz), 6.95-7.1 (3H, m), 7.3-7.4 (4H, m), 7.5 (1H, d, J = 7.5 Hz), 7.65 (1H, d, J = 7.5 Hz), 7.7 (1H, s), 7.85 (1H, d, J = 15 Hz), 8.28 (1H, d, J = 7.5 Hz).

Example 11. 1-(((1(R)-(3-(2-(2-(Phenylsulfonyl)thieno[3,2-b]pyridine-5-yl) ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)- methyl)cyclopropaneacetic sodium.

Using the methods described in stages 2-4 of example 6, get mentioned in the title compound 2-(phenylsulfonyl)-5- -methylthieno[3,2-b]pyridine allocated in stage 1 of example 7.

1H NMR of the acid (CDCl3): 0.36-0.53 (3H, m), 0.58 (1H, m), 1.61 (3H, s), 1.63 (3H, s), 2.05 (1H, s), 2.19 (2H, m), 2.34-2.52 (3H, m), 2.60 (1H, d), 2.90 (1H, m), 3,19 (1H, m), 4.0 (1H, t), 7.07-7.20 (3H, m), 7.23-7.38 (4H, m), 7.43 (1H, m), 7.50-7.70 (6H, m), 8.03-8.13 (4H, m).

Analysis. Calculated for C39H38NNaO5S33,6 H2O:

C 59,69; H OF 5.81; N 1,78.

Found: C 59,68; H 5,70; N Of 1.52.

Example 12. 1-(((1(R)-(3-(2-(2,3-Dichlorprop[3,2-b]pyridine-5-yl)ethynyl)phenyl)-3-(2- (1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium.

Stage 1: 2-(Trimethylsilyl)-6-methylfuran[3,2-b]PY mmol) and bis(triphenylphosphine)palladium (II) chloride (lower than the 5.37 g, the 7.65 mmol) in Et3N (380 ml) is refluxed for 20 hours. The mixture is cooled and diluted with ether filtered through celite, the filtrate was concentrated in vacuo and the residue chromatographic on silica gel (elution with 10% EtOAc in hexane) to give 15 g (86%) specified in the connection header.

1H NMR (CD3COCD3): 0.40 (9H, s), 2.54 (3H, s), 7.12 (1H, d, J = 8 Hz), 7.14 (1H, s), 7.75 (1H, d, J = 8 Hz).

Stage 2: 2,3-Dichloro-5-methylfuran[3,2-b]pyridine.

To a solution of 2-trimethylsilyl-5-methylfuran[3,2-b] pyridine (1,05 g of 5.15 mmol) in CH2Cl2(16 ml) at 0oC add trichloroisocyanurate acid (1.2 g, 5,15 mmol). The mixture was stirred at 0oC for 30 minutes and then at room temperature for 20 hours. Add 30% solution of EtOAc in hexane. The resulting mixture was filtered through a short layer of silica gel and elute with 30% EtOAc in hexane. Evaporation of the filtrate gives 1 g (96%) specified in the connection header.

1H NMR (CD3COCD3): 2.61 (3H, s), 7.33 (1H, d, J = 8 Hz), 7.84 (1H, d, J = 8 Hz).

Stage 3: ((2,3-Dichlorprop[3,2-b]pyridine-5-yl)triphenylphosphonium bromide.

To a solution of 2,3-dichloro-5-methylfuran[3,2-b]pyridine (0.5 g, 2,47 mmol) in CCl4(15 ml) was added N-bralani lamp for 1 hour.

The resulting mixture was cooled and filtered through celite. Evaporation of the filtrate gives an oil which is dissolved in CH3CN (10 ml). To the mixture was added triphenylphosphine (1.29 g, 4,94 mmol) and the mixture is stirred at room temperature for 20 hours. The solvent is removed and the residue triturated in ether to obtain, after filtration of 1 g (77%) specified in the connection header.

1H NMR (CDCl3): 5.9 (2H, d, J = 15 Hz), 7.55-8.0 (16H, m), 8.2 (1H, d, J = 9 Hz).

Stage 4: Methyl 1-(((1(R-(3-(2-(2,3-dichlorprop[3,2-b] pyridine-5 - yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl propyl) thio)methyl)cyclopropaneacetic.

Using the methods described in stage 18 of example 1, fosfonovoi salt from the stage 3 is converted into the specified header connection with 92% yield.

1H NMR (CD3COCD3): 0.40-0.50 (4H, m), 1.53 (6H, s ), 2.20 (2H, m), 2.40 (2H, AB system), 2.57 (2H, s), 2.90 (1H, m), 3.15 (1H, s), 3.59 (3H, s), 3.9 (1H, s), 4.05 (1H, t), 7.10 (3H, m), 7.40 (1H, m), 7.55 (1H, m), 7.62 (1H, d), 7.74-7.80 (2H, m), 7.91 (1H, d).

Stage 5: 1-(((1(R)-(3-(2-(2,3-Dichlorprop[3,2-b] pyridine-5-yl) ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)-phenyl)propyl) thio)methyl)cyclopropaneacetic sodium.

Using the methods described in stage 19 of example 1, methyl ester from step 4 (0,176 g, 0.27 mmol) convert from 86% yield specified in the

C 60,08; H Are 5.36; N 2,12; Cl 10,75.

Found: C 60,04; H 5,01; N To 2.06; Cl 11,07.

Example 13. 1-(((1(R)-(3-(2-(3-Chlorpro[3,2-b]pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio) methyl)cyclopropaneacetic sodium.

Stage 1: 3-Chloro-5-methylfuran[3,2-b]pyridine.

To a solution of 2,3-dichloro-5-methylfuran[3,2-b]pyridine (0,661 g of 3.27 mmol) (example 12, step 2) in 16 ml of THF was added a 1.7 M solution of tert-utility (Android 4.04 ml, 6,87 mmol). After 30 minutes the solution is quenched at -78oC methanol and a solution of NH4Cl. The reaction mixture is brought to room temperature and extracted with EtOAc. The solvent is evaporated and is listed in the title compound purified flash chromatography on silica gel with EtOAc:hexane 1:4 and obtaining 0,444 g (81%).

1H NMR (CDCl3): 2.71 (3H, s), 7.16 (1H, d), 7.65 (1H, d), 7.84 (1H, s).

Stage 2: 5-methyl bromide-3-chlorpro[3,2-b]pyridine.

Using the methods described in stage 2 of example 8, 3-chloro-5-methylfuran[3,2-b]pyridine (0,245 g of 1.46 mmol) convert from 46% yield specified in the header connection.

1H NMR (CDCl3): 4.70 (2H, s), 7.50 (1H, d), 7.78 (1H, d), 7.90 (1H, s).

Stage 3: ((3-Chlorpro[3,2-b]pyridine-5-yl)methyl)triphenylphosphonium bromide.

Using the methods described in stage 3 of example 8, 5-br is CLASS="ptx2">

1H NMR (CDCl3): 5.90 (2H, m), 7.55-8.00 (17H, m), 8.25 (1H, d).

Stage 4: Methyl 1-(((1(R)-(3-(2-(3-chlorpro[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2- (1-hydroxy-1-methylethyl)- phenyl)propyl)thio)methyl) cyclopropaneacetic.

Using the methods described in stage 18 of example 1, ((3-chlorpro[3,2-b] pyridine-5-yl)methyl)triphenyl phosphonium bromide (0,273 g of 0.53 mmol) convert the 75% output in the specified header connection.

1H NMR (CD3COCD3): 0.40-0.55 (4H, m), 1.55 (6H, s), 2.23 (2H, m), 2.40 (2H, AB system), 2.58 (2H, s), 2.90 (1H, m), 3.20 (1H, m), 3.60 (3H, s), 3.90 (1H, s), 4.05 (1H, t), 7.13 (2H, m), 7.40-7.60 (6H, m), 7.65 (1H, d), 7.70-7.85 (2H, m), 7.95 (1H, d), 8.30 (1H, s).

Stage 5: 1-(((1(R)-(3-(2-(3-Chlorpro[3,2-b]pyridine-5-yl)ethynyl)phenyl-3- (2-(1-hydroxy-1-methylethyl)-phenyl)propyl)thio)methyl)cyclopropaneacetic sodium.

Using the methods described in stage 5 of example 8, the methyl ester from step 4 (0,160 g, 0.28 mmol) convert the output 83% specified in the header of the connection.

Analysis. Calculated for C33H33ClNNaOS42H2O:

C 62,49; H Of 5.89; N 2,21; C1 5,59.

Found: C 62,23; H 5,33; N 2,20; Cl 5,34.

Example 14. (R) 1-((3-(2-Bromophenyl)-1-(3-(2-(2,3- dichlorethene[3,2-b]pyridine-5-yl)ethynyl)-phenyl)propoxy)methyl) cyclopropaneacetic sodium.

Stage 1: 3-(2-Bromophenyl)-1-(3-(((2-then it is carbonated is l), 1,2-dibromobenzene with (16 ml), Pd(OAc)2(830 mg), LiCl (5,38 g), LiOAc 2H2O (31.6) and n-Bu4NCl (67,96 g) in 240 ml Tegaserod and heated at 85oC in an atmosphere of N2for 30 minutes and at 90oC for 45 minutes. The mixture was added to ice and 25% of NH4OAc (2 l). Specified in the header of the ketone is extracted with EtOAc, dried over Na2SO4and purified flash chromatography on silica gel with EtOAc:hexane 10:90; output 29,53 g (60%).

1H NMR (CDCl3): 7.97 (1H, s), 7.90 (1H, d), 7.57 (2H, t), 7.45 (1H, dd), 7.32 (1H, dd), 7.24 (1H, dd), 7.09 (1H, m), 4.83 (1H, d), 4.47 (1H, t), 4.55 (1H, d), 3.92 (1H, m), 3.58 (1H, m), 3,32 (2H, m), 3.20 (2H, m), 1,95-1.45 (6H, m).

Stage 2: 3-(2-Bromophenyl)-1-(3-(((2-tetrahydropyranyl)oxy)- methyl)phenyl)-1-propanol.

A solution of the ketone from step 1 (29,00 g, 72 mmol) in 260 ml of anhydrous THF at -55oC (the temperature of the reaction mixture) are added dropwise to a solution of (S)-tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo[1,2-c][1,3,2] oxazolone (4,07 g, 0.2 equiv.; J.Org. Chem. 56, 751 (1991)) in 70 ml of THF and then added 1.0 M of borane in THF (75 ml). Mixture is allowed to warm to -20oC for more than 3 hours. Then it is cooled to -45oC, quenched with 10% aqueous diethanolamine and warmed to room temperature. Then add 25% aqueous NH4OAc and chiral alcohol is extracted with EtOAc, dried over Na2S is R (CDCl3): 7.53 (1H, d), 7.40-7.16 (6H, m), 7.05 (1H, m), 4.80 (1H, d), 4.72 (2H, m), 4.50 (1H, d), 3.93 (1H, m), 3.55 (1H, m), 2.90 (1H, m), 2.80 (1H, m), 2.0 (2H, m), 1.95 (1H, d, OH), 1.90-1.48 (6H, m).

Stage 3: Methyl 2-((3-(2-bromophenyl) -1(R)-(3-(((2-tetrahydropyranyl) oxy)methyl)phenyl) propoxy)methyl)propanoate.

At 0oC 95% NaH (2.4 g, 100 mmol) in portions added to a stirred solution of the alcohol from step 2 (29.5 g, 73 mmol) in 400 ml DMF and the mixture was stirred at 0oC for 1 hour. Then added methyl 2-(methyl bromide)acrylate (10 ml, 88 mmol) and the mixture was stirred at 0oC for 8 hours and at room temperature over night. Quenched with saturated aqueous NH4Cl and the product is extracted with ether, washed with saturated salt solution, dried over Na2SO4and purified flash chromatography with EtOAc:hexane 1:5; output of 20.00 g (82%).

1H NMR (CDCl3): 7.50 (1H, d, J = 7.5 Hz), 7.37-7.17 (6H, m), 7.04 (1H, m), 6.33 (1H, br, s), 5.97 (1H, br, s), 4.79 (1H, d, J = 11 Hz), 4.70 (1H, m), 4.50 (1H, d, J = 11 Hz), 4.35 (1H, dd), 4.12 (1H, d), 4.02 (1H, d), 3.92 (1H, m), 3.73 (3H, s), 3.55 (1H, m), 2.90 (1H, m), 2.78 (1H, m), 2.12 (1H, m), 2.00 (1H, m), 1.90-1.50 (6H, m).

Stage 4: 2-((3-(2-Bromophenyl)-1(R)-(3-(((2-tetrahydropyranyl)- oxy)methyl)phenyl) propoxy)methyl)-2-propen-1-ol.

To a solution of ester from step 3 (29,69 g, 59 mmol) in 300 ml of CH2Cl2at -78oC is slowly added 1.5 M RAS is Then added 2 M grape acid and the solution is neutralized 10 N. NaOH. The product is extracted with EtOAc, dried over Na2SO4and concentrate to obtain 26,90 g, 96% indicated in the header of alcohol.

1H NMR (CDCl3): 7.52 (1H, d), 7.38-7.13 (6H, m), 7.03 (1H, m), 5.14 (2H, AB system), 4.80 (1H, d), 4.74 (1H, t), 4.53 (1H, d), 4.33 (1H, dd), 4.30 (2H, AB system), 3.97 (1H, d), 3.88 (1H, m), 3.55 (1H, m), 2.90 (1H, m), 2.75 (1H, m), 2.19-1.50 (9H, m).

Stage 5: 1-((3-(2-Bromophenyl) -1(R)-(3-(((2-tetrahydropyranyl)- oxy)methyl)phenyl)propoxy) methyl)cyclopropanemethanol.

At 0oC Pd(OAc)2(500 mg) and 0.4 M CH2N2in the air (1,84) at the same time portions are added to a solution of allyl alcohol from step 4 (20,45 g, 43,0 mmol) in 80 ml of THF. When the reaction completed, the mixture is filtered through a small pellet of silica gel and concentrated. The residue is purified flash chromatography on silica gel with EtOAc:toluene 15:85 to obtaining 12,40 g (59%) specified in the header of the product.

1H NMR (CDCl3): 7.51 (1H, d), 7.38-7.14 (6H, m), 7.05 (1H, m), 4.79 (1H, 2d), 4.72 (1H, br s), 4.50 (1H, 2d), 4.25 (1H, dd), 3.92 (1H, m), 3.65 (1H, m), 3.54 (2H, m), 3.28 (2H, AB system), 2.90 (1H, m), 2.78 (1H, m), 2.65 (1H, m), 2.18-1.50 (8H, m), 0.55 (2H, m), 0.43 (2H, m).

Stage 6: 1-((3-(2-Bromophenyl) -1(R)-(3-(((2-tetrahydropyranyl)- oxy)methyl)phenyl)propoxy) methyl)cyclopropanecarbonitrile.

To a solution of alcohol from step 5 (15,30 g, 31,3 mmol) in 200 ml of CH2Cl2at -40oUP>o
C for 30 minutes and at 0oC for 1 hour. Then add aqueous saturated NaHCO3and mesilate extracted with CH2Cl2, dried over Na2SO4and washed twice with toluene. To this solution nelfinavir in 240 ml of anhydrous dimethyl sulfoxide was added NaCN (of 7.69 g, 157 mmol) and the mixture is stirred at room temperature overnight. Then add water (1 l), 250 ml of saturated NaHCO3and the product is extracted with ether, washed with saturated salt solution, dried over Na2SO4and purified flash chromatography with EtOAc:toluene 5:95; output: 13,43 g (86%).

1H NMR (CDCl3): 7.54 (1H, d), 7.38-7.15 (6H, m), 7.06 (1H, m), 4.80 (1H, d), 4.72 (1H, m), 4.50 (1H, d), 4.26 (1H, dd), 3.94 (1H, m), 3.57 (1H, m), 3.32 (1H, d), 3.09 (1H, d), 2.93 (1H, m), 2.81 (1H, m), 2.75 (1H, d), 2.45 (1H, d), 2.18-1.50 (8H, m), of 0.68-0.49 (4H, m).

Stage 7: 1-((3-(2-Bromophenyl) -1(R)-(3-(((2-tetrahydropyranyl)- oxy)methyl)phenyl)propoxy) methyl)cyclopropane acid.

A mixture of the nitrile from step 6 (13,22 g of 26.5 mmol), 8 N. KOH (330 ml) and EtOH (130 ml) is heated under reflux for 17 hours. Then at room temperature was added 25% aqueous NH4OAc (500 ml) and Asón (190 ml) (giving pH 6) and the product extracted with EtOAc and dried over Na3SO4. Flash chromatography of the residue with EtOAc:toluene:AcOH 10:90:1 D4.79 (1H, d), 4.74 (1H, m), 4.54 (1H, d), 4.38 (1H, m), 3.94 (1H, m), 3.60 (1H, m), 3.39 (1/2H, d), 3.28 (1/2H, d), 3.20 (1/2H, d), 3.03 (1/2H, d), 2.89 (1H, m), 2.78 (1H, m), 2.78 (1/2H, d), 2.63 (1/2H, d), 2.45 (1/2H, d), 2.28 (1/2H, d), 2.18 (1H, m), 2.05 (1H, m), 1.95-1.50 (6H, m), 0.62-0.43 (4H, m).

Step 8: Methyl 1-((3-(2-bromophenyl) -1(R)-(3-hydroxymethyl) phenyl)propoxy) methyl)cyclopropaneacetic.

The acid from step 7 (1,816 g, 3,51 mmol) atrificial CH2N2at 0oC in the ether: THF. An excess of CH2N2quenched with AcOH and the product is concentrated and washed twice with toluene. This ester was dissolved in 20 ml of MeOH and then added pyridine (7 ml) and p-toluensulfonate pyridine (220 g, 0.88 mmol). After 6 days of stirring, the solvent is evaporated, then add 25% aqueous NH4OAc and the product extracted with EtOAc, dried over Na2SO4and purified using flash chromatography on silica gel EtOAc:hexane 30:70; output of 1.53 g (97%).

1H NMR (CDCl3): 7.50 (1H, d), 7.35-7.18 (6H, m), 7.04 (1H, m), 4.70 (2H, d), 4.21 (1H, dd), 3.63 (3H, s), 3.18 (1H, a of AB system), 2.93 (1H, m), 2.78 (1H, m), 2.45 (2H, s), 2.08 (1H, m), 1.98 (1H, m), 1.95 (1H, t, OH), 0.58-0.40 (4H, m).

Stage 9: (R)1-((3-(2-Bromophenyl)-1-(3-(2-(2,3-dichlorethene- [3,2-b]pyridine-5-yl)ethynyl)phenyl)propoxy)methyl)cyclopropaneacetic sodium

Using the methods of example 1, stage 17-19, but applying on stage 18 ((2,3-dichlorethene[3,2-b] pyridine-5-yl)methyl)triphenylphosphine (free acid CDCl3): 8.02 (1H, d), 7.68 (1H, d), 7.60-7.48 (4H, m), 7.43-7.34 (2H, m), 7.28-7.19 (3H, m), 7.07 (1H, m), 4.34 (1H, dd), 3.38 (1H, d), 3.19 (1H, d), 2.93 (1H, m), 2.80 (1H, m), 2.70 (1H, d), 2.49 (1H, d), 2.18 (1H, m), 2.08 (1H, m), 0.64-0.47 (4H, m).

Example 15. 1-((1(R)-(3-(2-(2,3-Dichlorethene[3,2-b] pyridine-5-yl)- ethynyl)phenyl)-3-(2-(1-hydroxy-1 - methylethyl)phenyl) propoxy)methyl)- cyclopropaneacetic sodium.

Stage 1: Methyl 1-((3-(2-(1-hydroxy-1-methylethyl)phenyl)- 1(R)-(3-(((2-tetrahydropyranyl) oxy)methyl)phenyl) propoxy)methyl) cyclopropaneacetic.

To a chilled solution of example 14, stage 7 (2,216 g, to 4.28 mmol) in 30 ml THF at -100oC was added 1.6 M BuLi in hexane (5,9 ml) and the mixture was stirred at -78oC for 30 minutes. Then add acetone (630 μl, 8.6 mmol) and the mixture was stirred at -78oC for 1 hour and then allowed to warm to -20oC. Then add saturated aqueous NH4Cl and the products were extracted with EtOAc. At 0oC add diazomethane 0.5 M When the esterification is complete, the excess CH2N2quenched with AcOH. The solution is dried over Na2SO4concentrated and washed with toluene. Flash chromatography of the residue with EtOAc:hexane 15: 85 to 35: 65 gives, first, the remaining starting material (dibromononane), secondly, the product-addition of acetone and, thirdly, specified in the header of 3.57 (IH, m), 3.30 (1H, d), 3.20 (1H, m), 3.14 (1H, d), 2.96 (1H, m), 2.58 (1H, d), 2.33 (1H, d), 2.17-1.48 (8H, m), 1.65 (6H, 2s), 1.27 (1H, s, OH), 0.51 (4H, m).

Stage 2: 1-((1(R)-(3-(2-(2,3- Dichlorethene[3,2-b]pyridine-5-yl)ethynyl)phenyl)-3- (2-(1-hydroxy-1-methylethyl)phenyl)propoxy) methyl)cyclopropaneacetic sodium.

Using the methods of example 1, stage 16-19, but applying on stage 18 ((2,3-dichlorethene[3,2-b] pyridine-5-yl)methyl) triphenylphosphonium bromide (example 4, step 3), of the ester from step 1 are specified in the header of the sodium salt.

11H NMR (free acid CDCl3): 8.00 (1H, d), 7.70 (1H, d), 7.60-7.50 (3H, m), 7.42-7.30 (3H, m), 7.26 (2H, m), 7.20-7.08 (2H, m), 4.45 (1H, dd), 3.30 (1H, m), 3.31 (1H, d), 3.20 (1H, d), 2.95 (1H, m), 2.58 (1H, d), 2.38 (1H, d), 2.18 (1H, m), 2.07 (1H, m), 1.70 (6H, 2s), 0.64-0.47 (4H, m).

Example 16. 1-(((3-(4-Cyclopropylmethyl)-1(R)-(3-(2- (2,3-dichlorethene[3,2-b] pyridine-5-yl) ethynyl)phenyl)propyl)thio) methyl)cyclopropaneacetic sodium.

Stage 1: 3-(1-Hydroxy-2-propen-1-yl)benzonitrile.

To 3-cyanobenzaldehyde (25 g, 0,190 mmol) in THF (576 ml) are added dropwise at -10oC vinylmania in THF (202 ml, 0,201 mmol). After 15 minutes the reaction mixture was poured into a cold solution of 25% aqueous ammonium acetate and extracted with EtOac. The resulting mixture was purified using flash chromatography to obtain 17.5 g (60%) specified in the connection header.

oC was added dropwise a solution of DIBAL (157 ml, 0,235 mmol). The resulting mixture was slowly cooled to 0oC. After completion of the reaction, the reaction mixture was poured into 10% solution of grape acid (1 liter). After stirring for 1 hour specified in the header of the product is extracted with EtOAc and purified by flash chromatography (40% to 50% EtOAc in hexane) to give 15 g (88%) of aldehyde.

Stage 3: 1-(3-(2-(2,3-Dichlorethene [3,2-b]pyridine-5-yl)- ethynyl)phenyl)-2-propen-1-ol.

To a suspension of postnasal salt according to example 4, stage 3 (10 g, and 19.4 mmol) in THF (110 ml) at -78oC add 1 M tert-butoxide potassium in THF (of 17.8 ml, 17.8 mmol). After 10 minutes at 0oC mixture of yellow bring to room temperature over a period of 10 minutes and then cooled to -78oC. Then add the aldehyde from step 2 (2,63 g, 16,23 mmol) in THF (40 ml) and the reaction mixture is stirred 1 hour at 0oC and 1 hour at room temperature. The reaction mixture is neutralized by adding a solution of 25% aqueous ammonium acetate, extracted with EtOAc and purified using flash chromatography to obtain 4.0 g (70%) of olefin product.

Stage 4: 3-(4-Cyclopropylmethyl)-1-(3- (2-(2,3-dichlorethene [3,2-b]pyridine-5-yl) ethynyl)phenyl)propan-1-it.

C mg), of lithium acetate (749 mg) and palladium acetate (50 mg) in DMF (6,98 ml) was bubbled nitrogen. The mixture is heated in a nitrogen atmosphere at 70oC for 10 minutes. After treatment with 25% aqueous solution of ammonium acetate EtOAc and the organic phase is evaporated to dryness. The obtained solid product is treated with acetone to obtain 650 mg of the ketone in the form of a white solid product. The filtrate is purified on silica gel with more than 200 mg of ketone.

Stage 5: 3-(4-Cyclopropylmethyl)-1(S)(3-(2- (2,3-dichlorethene [3,2-b]pyridine-5-yl) ethynyl)phenyl)propan-1-ol.

To a solution of CH2Cl2(4,0 ml) (1)-B-chlorodiisopinocampheylborane (904 mg, 2.82 mmol) at -30oC was added a solution of the ketone from step 4 (45 mg, 0,934 mmol) in CH2Cl2(4.6 ml). The temperature is slowly brought up to 0oC for more than 3 hours. Then add saturated solution of NH4Cl and the mixture is stirred over night at room temperature. After the elimination of the 25% aqueous solution of NH4OAc product extracted with EtOAc. After evaporation the residue was added ether and then 1 HCl solution. Cleaners containing hydrochloride salt was filtered and washed three times with ether. To a suspension of the salt in water and EtOAc was added 1 n NaOH solution and diethanolamine (10%). After evaporation obtain 270 mg (60%) of the desired hir is 3-dichlorethene[3,2-b]pyridine.

To a solution of alcohol (stage 5) (230 mg, 0.47 mmol) in CH2Cl (2.5 ml) at -40oC was added Et3N (100 μl, 0,717 mmol) and MsCl (45,0 μl, 0,547 mmol). The resulting mixture was then heated to 0oC. After a period of 10 minutes was added a saturated solution of NaHCO3. Mesilate extracted with CH2Cl2, dried over Na2SO4evaporated and double-distilled with toluene and used in the next stage.

Stage 7: 1-(((3-(4-Cyclopropylmethyl)-1(R)-(3- (2-(2,3-dichlorethene [3,2-b] pyridine-5-yl)ethynyl)phenyl)propyl)thio)methyl)- cyclopropaneacetic sodium.

In a solution of thiol acids obtained by hydrolysis of the ester from step 9 of example 1 (63,0 mg, 0,431 mmol) in THF (1.7 ml) bubbled N2. Then for more than 15 minutes at -15oC added dropwise n-utillity. After a period of 15 minutes at -15oC the temperature is slowly brought up to -5oC. To the resulting suspension at -20oC was added a solution of nelfinavir (stage 6) (230 mg, 0,411 mmol) in THF (1.7 ml). The temperature is slowly raised to -5oC, then 0oC and up to room temperature. After 2 hours, a clear solution quenched by addition of 25% aqueous solution of NH4OAc, extracted with EtOAc and dried over Na2SO4. Specified in the header of the product Oh">

1H NMR (300 MHz, CD3COCD3: of 0.30-0.50 (4H, m), 0.60-0.85 (4H, m), 1.85 (1H, m), 2.15 (2H, m), 2.48 (2H, s), 2.55 (2H, AB system), 2.60 (2H, m), 3.95 (1H, t), 7.00 (4H, AA, BB system), 7.30-7.45 (3H, m), 7.60 (1H, m), 7.68 (1H, s), 7.75 (1H, d), 7.89 (1H, d), 8.49 (1H, d).

Example 123. (R)1-(((3-(2-(1-Hydroxy-1-methylethyl)phenyl)-1- -(3-(2-(2-methylthiazole[5,4-b]pyridine-5-yl)ethynyl)phenyl)propyl)- thio)methyl)cyclopropaneacetic sodium.

Stage 1: N-Acetyl-2-chloro-3-pyridylamine.

To a solution of 2-chloro-3-pyridylamine (14.9 g, 116 mmol) in 300 ml THF was added K2CO3(32 g, 232 mmol) and acetylchloride (12 ml, 169 mmol) and the mixture is stirred at room temperature overnight. Add saturated NH4Cl and the product extracted with EtOAc, dried over Na2SO4and filtered through silica gel with getting 20,81 g is specified in the header of the product.

1H NMR (CDCl3): 8.73 (1H, d), 8.13 (1H, d), 7.65 (1H, br s, NH), 7.28 (1H, dd), 2.27 (3H, s).

Stage 2: 2-Methylthiazole[5,4-b]pyridine.

Pentasulfide phosphorus (56,5 g), Na2CO3(13,7 g) is stirred together in 400 ml of THF for 30 minutes. To this solution was added a solution of product from step 1 (17,32 g) in 100 ml THF and the mixture is stirred at room temperature overnight. Added 2 M NaOH (500 ml) and the mixture is stirred at room temperature for the try flash chromatography on silica gel with EtOAc:toluene 20:80; output: 12,07 g (83%).

1H NMR (CDCl3): 8.54 (1H, d), 8.18 (1H, d), 7.40 (1H, dd), 2.88 (3H, s).

Stage 3: 2-Methylthiazole[5,4-b]pyridine N-oxide.

To a solution of product from step 2 (8.00 g) in 400 ml of CH2Cl2add m-chlormadinone acid (26,0 g) and the mixture is stirred at room temperature overnight. Add 0.5 M NaOH and purified flash chromatography on silica gel with acetone:toluene:methanol 40:40:20.

1H NMR (CDCl3): 8.29 (1H, d), 7.86 (1H, d), 7.38 (1H, dd), 2.88 (3H, s).

Stage 4: 5-Cyano-2-methylthiazole[5,4-b]pyridine.

To a solution of product from step 3 (4,706 g, 28.3 mmol) in 60 ml of CH2Cl2add trimethylsilylacetamide (7,6 ml, 57 mmol) and the mixture is stirred at room temperature for 30 minutes. Then add dimethylcarbamoyl (5,2 ml, 56 mmol) and the mixture refluxed overnight. At 0oC add 2 N. NaOH (60 ml) and the mixture is stirred at this temperature for one hour. The product is extracted with EtOAc, dried over Na2SO4and purified flash chromatography on silica gel with EtOAc:toluene 10:90; output: 4,50 g (91%).

1H NMR (CDCl3): 8.26 (1H, d), 7.80 (1H, d), 2.93 (2H, s).

Stage 5: 5-Formyl-2-methylthiazole[5,4-b]pyridine.

To sustainablymanaged in toluene (40 ml) and the mixture was stirred at -78oC for 2 hours. Then add 10% solution of grape acid and the mixture is stirred at room temperature for 2 hours, neutralized 10 N. NaOH and extracted with EtOAc. Specified in the header of the product dried over Na2SO4and purified flash chromatography on silica gel with EtOAc:hexane 20:80 to obtain 3,733 g (83%) as a white solid product.

1H NMR (CDCl3): 10.13 (1H, s), 8.33 (1H, d), 8.12 (1H, d), 2.95 (3H, s).

Stage 6: 5-(Hydroxymethyl)-2-methylthiazole[5,4-b]pyridine.

To a suspension of product from step 5 (3,733 g, 21 mmol) in 200 ml of EtOH at 0oC added NaBH4(800 mg, 21 mmol) and the mixture was stirred at 0oC for 5 minutes. Then slowly added saturated aqueous NH4Cl and the mixture extracted with EtOAc: THF 1:1, dried over Na2SO4and purified flash chromatography on silica gel with acetone:toluene 30:70; output: 3,49 g (92%).

1H NMR (CDCl3): 8.15 (1H, d), 7.37 (1H, d), 4.89 (2H, d), 3.45 (1H, t, OH), 2.87 (3H, s).

Stage 7: 5-(((Methanesulfonyl)oxy)methyl)-2-methylthiazole- [5,4-b]pyridine.

To a solution of alcohol from step 6 (303 mg, 1,68 mmol) in 17 ml of CH2Cl2at -40oC added triethylamine (350 μl, 2.5 mmol) and methanesulfonamide (170 μl, 2.2 mmol) and the solution peremeshivaemogo extracted with CH2Cl2, dried over Na2SO4concentrate and remote water twice, washed with toluene.

1H NMR (CDCl3): 8.23 (1H, d), 7.48 (1H, d), 5.43 (2H, s), 3.10 (3H, s), 2.88 (3H, s).

Stage 8: ((2-Methylthiazole[5,4-b] pyridine-5-yl)methyl - triphenylphosphonium methanesulfonate.

The solution nelfinavir with stage 7 (1,68 mmol) and triphenylphosphine (660 mg, 2,52 mmol) in 8 ml anhydrous CH3CN heated under reflux for 2 hours. The solvent is evaporated and the oil treatment twice with ether and the ether double-decanted. Again treated with 25 ml of ether over 2.5 days. The solvent is decanted from the obtaining very hygroscopic solid product, which is dried in vacuum; yield: 732 mg (84%).

1H NMR (DMSO): 8.20 (1H, d), 7.65-7.90 (15H, m), 7.41 (1H, d), 5.58 (2H, d), 2.77 (3H, s), 2.29 (3H, s).

Stage 9: (R) 1-(((3-(2-(1-Hydroxy-1-methylethyl)-1-(3-(2-(2- methylthiazole[5,4-b] pyridine-5-yl)-ethynyl)phenyl)propyl)thio)methyl)- cyclopropaneacetic sodium.

Using the methods described in stages 18-19 example 1, from postnasal salt from step 8 receive specified in the header of the connection.

Analysis. Calculated for C33H35N2O3S2Na 3,6 H2O:

C 60,09; H 6,45; N 4,25.

Found: C 60,04; H 6,41; N 4,28.

< / BR>
In - S or O;

D is N or CR4;

R1, R5and R7each, N.;

R3- H, lower alkyl, or two R3groups attached to the same carbon atom, may form a 3-6-membered hydrocarbon ring;

R4- H, lower alkyl, halogen or S(O)2R2where R2is phenyl;

m and m1each independently is 1 to 6;

R and R1each independently 0 or 1;

Q1- CO2R3;

Q2is hydrogen, C(R3)2OR SIG3, OR SIG15or cycloalkyl3-C7;

X2Is S or O;

X3- connection;

Y IS-CH=CH-;

Z1- connection;

Z2- NO(R23R24), where NO denotes diradical benzene;

R15, R22, R23and R24each is hydrogen,

or their pharmaceutically acceptable salts.

2. Connection on p. 1 of formula Ia

< / BR>
where Is S or O;

R3- H, lower alkyl, or two R3groups attached to the same carbon atom, form a 3-6-membered hydrocarbon ring;

R4Is h, halogen or S(O)2R2where R2is phenyl;

R5- N.;

m and m1each independently is 1 to 6;

R1= 0 or 1;

Q1
Z2- NO(R23R24), where NO diradical benzene;

R23and R24- hydrogen.

3. Connection on p. 1 of formula Ib

< / BR>
where R3- H, lower alkyl, or two R3groups attached to the same carbon atom, form a 3-6-membered hydrocarbon ring;

R4Is h, halogen or S(O)2R2where R2is phenyl;

R23and R24- N.;

m and m' each independently is 1 to 5;

R1= 0 or 1;

Q1- CO2R3;

Q2- H, C(R3)2HE or SIG or15where R15- hydrogen.

4. Connection on p. 1, selected from the group including

1-(((1(R)-(3-(2-(3-chlorothieno[3,2-b] pyridine-5-yl-)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium;

1-(((1(R)-(3-(2-(thieno[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1 - methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium;

1-(((1(R)-(3-(2-(3-bratiano[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium;

1-(((1(R)-(3-(2-(2,3-dichlorethene[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1 - methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium;

1-(((1(R)-(3-(2-(3-chlorothieno[3,2-b] pyridine-5-yl)those who 3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1 - methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium;

1-(((1(R)-(3-(2-(2-fortiana[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1 - methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium;

1-(((1(R)-(3-(2-(2,3-divertito[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1 - methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium;

1-(((1(R)-(3-(2-(2-chloro-3-fortiana[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1 - methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium;

1-(((1(R)-(3-(2-(3-chloro-2-fortiana[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1 - methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium;

1-(((1(R)-(3-(2-(2-phenylsulfonyl)thieno[3,2-b]pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1 - methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium;

1-(((1(R)-(3-(2-(2,3-dichlorprop[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1 - methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium;

1-(((1(R)-(3-(2-(3-chlorpro[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1 - methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic sodium;

(R) 1-((3-(2-bromophenyl)-1-(3-(2-(2,3-dichlorethene[3,2-b] pyridine-5-yl)ethynyl)phenyl)propoxy)methyl)cyclopropaneacetic sodium;

1-((1(R)-(3-(2-(2,3- dichlorethene[3,2-b] pyridine-5-yl)ethynyl)phenyl)-3-(2-(1-hydroxy-1 - methylethyl)phenyl)propoxy)methyl)cyclopropaneacetic sodium;

1-sodium;

(R) 1-(((3-(2-(1-hydroxy-1-methylethyl)phenyl)-1-(3-(2-(2-methylthiazole[5,4-b] pyridine-5-yl)ethynyl)phenyl) propyl)thio)methyl)cyclopropaneacetic sodium.

5. Pharmaceutical composition having the activity of a leukotriene antagonist, characterized in that it contains an effective amount of the compounds of formula I on PP.1 to 4, or its pharmaceutically acceptable salt in combination with a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to p. 5, characterized in that it further contains an effective amount of a second active ingredient selected from the group comprising non-steroidal anti-inflammatory drugs; peripheral analgesic agents, inhibitors of collagenase, leukotriene antagonists, inhibitors of leukotriene biosynthesis, antagonists of N1- or H2receptors, antihistamines tools, antagonists and prostaglandin antagonists ACE.

7. The pharmaceutical composition according to p. 6, wherein the second active ingredient is a nonsteroidal anti-inflammatory drug.

8. The pharmaceutical composition according to p. 7, characterized in that the mass ratio of the compounds of formula I or e is of Otieno on mammals, characterized in that the mammal is administered an effective amount of the compounds of formula I under item 1.

10. The method according to p. 9, characterized in that the mammal is man.

11. Compounds of General formula I on PP.1 to 4, having the activity of a leukotriene antagonist.

 

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The invention relates to compounds of the following formula 1, which inhibit the enzyme glycinamide ribonucleotide the formyl transferase (GARFT)

The invention relates to new N-substituted azabicycloalkanes

The invention relates to new heterocyclic compounds of the formula I where ring a and ring To represent optionally substituted benzene or cycloalkane ring or optionally substituted 5 - or 6-membered aromatic heterocyclic ring containing one to two heteroatoms selected from nitrogen, sulfur and oxygen

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I

The invention relates to tricyclic derivatives of pyrrole General formula (I), where R1-R4denote hydrogen, halogen, lower alkyl, phenyl, cycloalkyl or lower alkoxy, a R2indicates additional lower alkoxycarbonyl, acyloxy or mesilate; R5denotes lower alkyl; R6, R7represent hydrogen or lower alkyl; X represents-CH2CH(C6H5), -CH= C(C6H5)-, -YCH2-, -CH=CH - (CR11R12)n; R11and R12denote hydrogen, phenyl, lower alkyl; h denotes 1-3 and Y denotes O or S, and pharmaceutically acceptable acid additive salts

The invention relates to disubstituted polycyclic compounds, their derivatives, pharmaceutical preparations and methods of use in treating mammals disorders mental and/or neurological dysfunction and/or depressions such as diseases associated with degeneration of the nervous system, and not only their

The invention relates to medicine, for new thienopyrimidine derivatives of the formula

where the radicals R1, R2, R3, R4, W and n are specified in paragraph 1 of the claims

The invention relates to new N-substituted azabicycloalkanes

The invention relates to new heterocyclic compounds of the formula I where ring a and ring To represent optionally substituted benzene or cycloalkane ring or optionally substituted 5 - or 6-membered aromatic heterocyclic ring containing one to two heteroatoms selected from nitrogen, sulfur and oxygen

The invention relates to new derivatives of dihydropyridines, possessing valuable pharmacological properties, in particular derived analyoung of dihydropyridines and means of selective blocking the reabsorption of cations

The invention relates to compounds which inhibit the protease encoded by human immunodeficiency virus, or their pharmaceutically acceptable salts, and such compounds are used for the prevention of infection by HIV, treating infection by HIV and the treatment of acquired as a result immunodeficiency syndrome (AIDS)
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