8-azaprostaglandine derivatives, pharmaceutical composition and agent for prophylaxis of diseases

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: Described are derivatives of general formula I (all symbols are as described in specification), pharmaceutically acceptable salts thereof or cyclodextrin clathrates. Such compounds hardly bind of EP2 subtype of PGE receptor and are useful in prophylaxis of immune diseases, allergy, death of neuronal cells, liver or kidney insufficiency, etc.

EFFECT: new agent for prophylaxis of various diseases.

18 cl, 388 ex, 68 tbl, 3 dwg

 

The technical field

This invention relates to 8-isoprostaglandin. More specifically, this invention relates to:

(1) derived 8-isoprostaglandin represented by the formula (I):

(where all the symbols have the meanings described below), its pharmaceutically acceptable salt or cyclodextrines the clathrate,

(2) a method for obtaining and

(3) a pharmaceutical composition containing it as active ingredient.

The level of technology

Prostaglandin E2(abbreviation PGE2also known as a metabolite in the cascade arachidonate. It is known that PGE2has cytotoxity action, action that reduce the uterus, the action causing the pain, the promoting effect on the digestive peristalsis, an awakening effect, overwhelming effect on the secretion of gastric acid, antihypertensive effect and diuretic action, and so forth.

Recent research has confirmed the existence of different subtypes of PGE receptors, which play different from each physiological role. Currently, there are four subtypes of receptors, called EP1, EP2, EP3and EP4(Negishi M., et al.,J. Lipid Mediators Cell Signaling,12, 379-391 (1995)).

Consider that the receptor subtype EP2refers to inhibition of the images is of TNF-α and strengthen the education of IL-10. Therefore, compounds that can bind to the receptor subtype EP2may be useful for prevention and/or treatment of immune diseases (e.g. autoimmune diseases, such as amyotrophic lateral sclerosis (als), multiple sclerosis, Sjogren syndrome, rheumatoid arthritis and systemic lupus erythematosus and so on, and the rejection of organs after transplantation), allergic diseases (such as asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, food Allergy), the death of neural cells, menstrual cramps, premature births, miscarriages, alopecia, retinal neuropathy such as glaucoma, erectile dysfunction, arthritis, lung injury, pneumosclerosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, liver damage, acute hepatitis, liver cirrhosis, shock, nephritis (acute nephritis, chronic nephritis, renal failure, diseases of the circulatory system (e.g., hypertension, myocardial ischemia, chronic clogged arteries, diseases caused by vibration), systemic inflammatory response syndrome, sepsis syndrome hemophagocytosis syndrome activation of macrophage, of still's disease, Kawasaki disease, burn, systemic granuloma, ulcerative colitis, Crohn's disease, hypercytokinemia in dialysis, multiple organ failure and bone disease (e.g., cracks, re-fracture, undetectable cracks, necromania, pseudoarthrosis, osteomalacia, bone Paget's disease, ankylosing spondylitis, bone metastases, osteoarthritis and fracture bone/cartilage due to similar diseases), etc. Also believe that the compounds are useful as an agent for enhancing osteogenesis/cure after surgery to bone (e.g., fractures, bone grafts, artificial astrogenesis, corporatese, operations in multiple myeloma, lung cancer, breast cancer, etc. and other recovery operations on the bones), or rollover treatment for bone grafts. Also consider that the compounds are useful agents to enhance regeneration of the periodontium in periodontal diseases, etc.

Described derived 8-isoprostaglandin, for example, the compound represented by formula (A):

(where QAselected from the group comprising-COOR3Atetrazol-5-yl and-CONHR4A;

AndAndis a single or CIS double bond;

InAndis a single or TRANS double bond;

UAis

R2Achoose from a group that includes α-thienyl, phenyl, phenoxy, monosubstituted phenyl and mono is alseny phenoxy, where these substituents are selected from the group comprising chlorine, fluorine, phenyl, methoxy, trifluoromethyl and alkyl having from 1 to 3 carbon atoms;

R3Aselected from the group comprising hydrogen, alkyl having from 1 to 5 carbon atoms, phenyl, p-biphenyl;

R4Aselected from the group comprising-COR5Aand-SO2R5A; where the specified R5Aselected from the group comprising phenyl and alkyl having from 1 to 5 carbon atoms, its C5 epimer or alkaline salt, alkaline earth metal or ammonium salt compounds having carboxylate or tetrazol-5-ilen group (published patent application of Japan No. 53-21159 (US 4177346)).

In addition, the above compound represented by the formula (A'):

(where WAselected from the group comprising-COOR3Atetrazol-5-yl, N-(acyloxymethyl)tetrazol-5-yl (having from 2 to 5 carbon atoms in alloctype), N-(phthalidyl)tetrazol-5-yl and N-(tetrahydropyran-2-yl)tetrazol-5-yl, and other symbols have the above values), its C5 epimer or alkaline salt, alkaline earth metal or ammonium salt compounds having carboxylate or tetrazol-5-ilen group.

Also described pyrrolidone represented by the formula (I):

(where R1Brepresents a saturated or unsaturated aliphatic coal is a hydrogen radical with a straight or branched chain, having up to 10 carbon atoms, or a cycloaliphatic hydrocarbon radical having from 3 to 7 carbon atoms, where the radicals can be unsubstituted or substituted by one or more of the following:

a) alkoxy, alkylthio, alkenylacyl or alkenylsilanes straight or branched chain having up to 5 carbon atoms,

b) phenoxypropane, which may have one or two substituent selected from optionally halogenated alkyl groups having from 1 to 3 carbon atoms, halogen atoms, optionally halogenated fenoxaprop and alkoxygroup having from 1 to 4 carbon atoms,

(C) forelocks, titilate or benzyloxypropionic, which may be in the ring one or two substituent selected from optionally halogenated alkyl groups having from 1 to 3 carbon atoms, halogen atoms and alkoxygroup having from 1 to 4 carbon atoms,

d) triptorelin or panafcortelone group,

e) cycloalkyl group having from 3 to 7 carbon atoms,

f) phenyl, thienyl or shriley group which may have one or two substituent selected from optionally halogenated alkyl groups having from 1 to 3 carbon atoms, halogen atoms and alkoxygroup having from 1 to 4 carbon atoms,

R2Bis a saturated or unsaturated aliphatic the sky or cycloaliphatic hydrocarbon radical with a straight or branched chain, having up to 6 carbon atoms, or alifaticheskimi hydrocarbon radical having 7 or 8 carbon atoms, and

nBis the number two, three, or four), its corresponding free acid or its physiologically acceptable salt of the metal or amine (published patent application of Japan No. 52-5764 (DT 2528664)).

In the description of another application described pyrrolidone same species (published patent application of Japan No. 52-73865 (VE 849346) and published patent application of Japan No. 52-133975 (VE 854268)).

Also described compound represented by formula (C):

(C)

(where X1Cand X2Care, independently, CH2or, X3Sis a nitrogen atom or CH, RCis a hydrogen atom or hydroxyl, R1Cand R2Care, independently, CH2or, R3Cis CH2, NH or an oxygen atom, R4Cis NH, CH2or, R5Cis CH2or NH, R6Cis CH2or, mCis 0-4, nCis 0-5) and its pharmaceutically acceptable salt (EP 572365).

Also described compound represented by formula (D):

(if R1Dis a hydrogen atom or ethyl, R2Dis a hydrogen atom or stands and R3Dis hydrogen. If R1Done is camping stands, R2Dis a hydrogen atom and R3Dis stands.) or its pharmaceutically acceptable salt. In the description of another application disclosed 8-isoprostane acid of the same type (published patent application of Japan No. 51-127068 published patent application of Japan No. 51-128961 and published patent application of Japan No. 52-100467 (GB 1523178)).

Also described compounds represented by formulas (E), (E') and (E):

(where REis a complex ester residue, a dashed line indicates a double bond or its absence and the wavy line means α-configuration or β-configuration) (published patent application of Japan No. 51-1461).

Also described is derived prostaglandin represented by the formula (F):

(where R1Frepresents hydrogen, methyl or ethyl, R2F, R3Fand R4Fthe same or different, each represents hydrogen or methyl and RFchoose from a group including:

(where R5Frepresents hydrogen, methyl or ethyl, R6Frepresents methyl, ethyl or acetyl, and R7Fand R8Feach represents a hydrogen or alkyl group with a straight chain having from 1 to 3 carbon atoms). When the condition is and, if R7Fand R8Frepresent hydrogen, R5Fis stands or stands, or if R5Frepresents methyl and R2F, R3F, R4F, R7Fand R8Fall represent hydrogen, R1Frepresents ethyl.) (Published patent application of Japan No. 52-142060 (VE 852941)). Also described is derived prostaglandin of the same type (published patent application of Japan No. 51-138671 (VE 839761)).

The following describes the racemic compound selected from the groups represented by formulas (G) and (G'):

(where RGis a hydrogen atom, a lower alkyl group having from 1 to 4 carbon atoms, when RGis a hydrogen atom, the compounds can form pharmaceutically acceptable non-toxic salts; Z is a TRANS double bond or a saturated bond; the wavy line means α-configuration β-configuration or a mixture.) (published patent application of Japan No. 51-143663 (VE 841165)).

Description of the invention

The authors of this invention have conducted studies with the aim to detect compounds that can specific contact receptor subtype EP2and who have strong agonistic action. Finally, it was discovered the compound of formula (I), which allows to achieve this goal, so was created the invention. Moreover, the authors of this invention have also found a connection that links the receptor subtype EP2and EP4. The connection that binds to both receptors subtypes EP2and EP4expected additive or synergistic effect in the treatment of diseases associated with receptors of both subtypes.

This invention relates to a

(1) derived 8-isoprostaglandin represented by the formula (I):

where T is (1) an oxygen atom, or (2) a sulfur atom;

X is (1) -CH2-, (2) or (3) -S-;

And is And1or And2;

And1is (1) C2-8 alkylene straight-chain, optionally substituted by 1-2 C1-4 alkilani, (2) C2-8 Alcanena straight-chain, optionally substituted by 1-2 C1-4 alkilani, or (3) C2-8 akinlana straight-chain, optionally substituted by 1-2 C1-4 alkilani;

And2is-G1-G2-G3-;

G1is (1) C1-4 alkylene straight-chain, optionally substituted by 1-2 C1-4 alkilani, (2) C2-4 Alcanena straight-chain, optionally substituted by 1-2 C1-4 alkilani, or (3) C2-4 akinlana straight-chain, optionally substituted by 1-2 C1-4 alkilani;

G2represents (1) -Y, (2) -kolco-, (3) -Y-kolco-, (4) -kolco-Y - or (5) -Y-C1-4 alkylene-kolco-;

Y is (1) -S-, (2) -SO-, (3) -SO2-, (4) to the or (5) -NR 1-;

R1is (1) hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl;

G3is (1) communication, (2) C1-4 alkylene straight-chain, optionally substituted by 1-2 C1-4 alkilani, (3) C2-4 Alcanena straight-chain, optionally substituted by 1-2 C1-4 alkilani, or (4) C2-4 akinlana straight-chain, optionally substituted by 1-2 C1-4 alkilani;

D is D1or D2;

D1is (1) -COOH, (2) -COOR2(3) tetrazol-5-yl or (4) -CONR3SO2R4;

R2is (1) C1-10 alkyl, (2) phenyl, (3) C1-10 alkyl substituted by phenyl, or (4) biphenyl;

R3is (1) hydrogen atom or (2) C1-10 alkyl;

R4is (1) C1-10 alkyl or (2) phenyl;

D2represents (1) -CH2HE (2) -CH2OR5, (3) hydroxy, (4) -OR5(5) formyl, (6) -CONR6R7, (7) -CONR6SO2R8, (8) -CO-(NH-amino acid residue-CO)m-OH, (9) -O-(CO-amino acid residue-NH)m-H, (10) -COOR9, (11) -OCO-R10, (12) -COO-Z1-Z2-Z3or

R5is C1-10 alkyl;

R6and R7are each independently (1) hydrogen atom or (2) C1-10 alkyl;

R8is C1-10 alkyl substituted by phenyl;

R9is (1) C1-10 alkyl, substituted biphenyl, optionally substituted by 1-3 substituents selected from C1-10 is Lila, C1-10 alkoxy and halogen, or (2) biphenyl substituted by 1-3 substituents selected from C1-10 alkyl, C1-10 alkoxy or halogen atom;

R10is (1) phenyl, or (2) C1-10 alkyl;

m is 1 or 2;

Z1is (1) C1-15 alkylene, (2) C2-15 Alcanena or (3) C2-15 akinlana;

Z2is (1)-CO-, (2) -OCO-, (3) -COO-, (4) -CONRZ1-, (5) -NRZ2CO-, (6) -O-, (7) -S-, (8) -SO2-, (9) -SO2-NRZ2-, (10) -NRZ2SO2-, (11) -NRZ3-, (12) -NRZ4CONRZ5-, (13) -NRZ6COO-, (14) -OCONRZ7or (15) -OCOO-;

Z3represents (1) hydrogen atom, (2) C1-15 alkyl, (3) C2-15 alkenyl, (4) C2-15 quinil, (5) Z or (6) C1-10 alkyl, substituted C1-10 alkoxy, C1-10 alkylthio, C1-10 alkyl-NRZ8or Z;

Z is (1) C3-15 mono-, bi - or tricarbocyanine-aryl which may be partially or fully saturated or (2) 3-15 membered mono-, bi - or trigeneration-aryl which may be partially or fully saturated and contains 1-4 heteroatoms selected from atoms of oxygen, nitrogen and sulfur;

RZ1, RZ2, RZ3, RZ4, RZ5, RZ6, RZ7and RZ8are, each independently, a hydrogen atom or C1-15 alkyl;

RZ1and Z3together with the nitrogen atom to which they are attached, may form a 5-7-membered saturated managerialism ring, and the heterocyclic ring may soda in order to avoid another heteroatom, selected from atoms of oxygen, nitrogen and sulfur;

Z and rich managerialism the ring formed by RZ1, Z3and the nitrogen atom to which they are attached may be substituted by 1-3 groups selected from the following(1)-(4):

(1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15 quinil, (4) C1-10 alkyl, substituted C1-10 alkoxy, C1-10 alkylthio or C1-10 alkyl-NRZ9-;

RZ9is a hydrogen atom or C1-10 alkyl;

E is E1or E2;

E1is

R11is (1) C1-10 alkyl, (2) C1-10 alkylthio, (3) C1-10 alkyl, substituted C3-8 cycloalkyl, (4) C1-10 alkyl, substituted colcom, or (5) C1-10 alkyl, substituted-W1-W2-ring2;

W1is (1), (2) -S-, (3) -SO-, (4) -SO2-, (5) -NR11-1-, (6) carbonyl, (7) -NR11-1SO2-, (8) carbylamine or (9) aminocarbonyl;

R11-1is (1) hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl;

W2is (1) a bond or (2) C1-8 alkyl, optionally substituted C1-4 alkyl, halogen or hydroxy;

E2is (1) U1-U2-U3or (2) colcom;

U1represents (1) C1-4 alkylene, (2) C2-4 albaniles, (3) C2-4 akinyan, (4)-kolco-, (5) C1-4 alkylene-kolco-, (6) C2-4 albaniles-calico or (7) C2-4 akinyan-kolco-;

U2represents (1) communication, (2) -CH2-, (3) -the NON-, (4), (5) -S-, (6) -SO-, (7) -SO2-, (8) -NR12-, (9) carbonyl, (10) -NR12SO2-, (11) carbylamine or (12) aminocarbonyl;

R12is (1) hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl;

U3represents (1) C1-8 alkyl, optionally substituted by 1-3 substituents selected from C1-10 alkyl, halogen, hydroxy, alkoxy, alkylthio and NR13R14, (2) C2-8 alkenyl, optionally substituted by 1-3 substituents selected from C1-10 alkyl, halogen, hydroxyl, alkoxy, alkylthio and-NR13R14, (3) C2-8 quinil, optionally substituted by 1-3 substituents selected from C1-10 alkyl, halogen, hydroxyl, alkoxy, alkylthio and-NR13R14, (4) C1-8 alkyl, substituted colcom, or (5) calico;

R13and R14are each independently (1) hydrogen atom or (2) C1-10 alkyl;

calico, ring2, colza or colza can be substituted by 1-5 R;

R represents (1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C2-10 quinil, (4) C1-10 alkoxy, (5) C1-10 alkylthio, (6) halogen, (7) hydroxy, (8) nitro, (9) -NR15R16, (10) C1-10 alkyl, substituted C1-10 alkoxy, (11) C1-10 alkyl substituted by 1 to 3 halogen atoms, (12) C1-10 alkyl, substituted C1-10 alkoxy substituted by 1 to 3 halogen atoms, (13) C1-10 alkyl, substituted-NR15R16, (14) Colico, (15) -O-Colico, (16) C1-10 alkyl, substituted colcom, (17) C2-10 alkenyl, substituted colcom, (18) C2-10 quinil, substituted to lcom, (19) C1-10 alkoxy, substituted colcom, (20) C1-10 alkyl, substituted-O-Colico, (21) COOR17, (22) C1-10 alkoxy, substituted by 1-4 halogen atoms, (23) formyl, (24) C1-10 alkyl, substituted hydroxy, or (25) C2-10 acyl;

R15, R16and R17are each independently (1) hydrogen atom or (2) C1-10 alkyl;

calico may be substituted by 1-3 substituents selected from the following(1)-(9):

(1) C2-10 alkyl, (2) C2-10 alkenyl, (3) C2-10 quinil, (4) C1-10 alkoxy, (5) C1-10 alkyl, substituted C1-10 alkoxy, (6) halogen atom, (7) hydroxy, (8) C1-10 alkyl substituted by 1 to 3 halogen atoms, (9) C1-10 alkyl, substituted C1-10 alkoxy substituted by 1 to 3 halogen atoms;

calico, ring2, calico, calico and calico are, each independently,

(1) C3-15 mono-, bi - or tricarbocyanine-aryl which may be partially or fully saturated or (2) 3-15 membered mono-, bi-or trigeneration-aryl which may be partially or fully saturated and contains heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms; and

where

1) if E is E2E2is U1-U2-U3and U1is C2 alkylene or C2 Alcanena, U2is not-SNON-,

2) if U3is C1-8 alkyl, substituted by at least one hydroxy, U1-U2is not C2 alkylene or C2 of alkenyl the room,

3) if a is A1and D is the D1then E is not E1,

4) if T is an oxygen atom, X is-CH2-, D is D1D1is COOH, And a is the1And1is C2-8 alkylene straight chain, E is E2E2is U1-U2-U3U1is C1-4 alkylene and U3is C1-8 alkyl, then U2is not a bond, -CH2-, -NR12or carbonyl,

5) if T is an oxygen atom, X is-CH2-, D is D1D1is COOH, And a is the2, G1is C1-4 alkylene, G2is-O - or-NR1-, G3is a bond or C1-4 alkylene, E is E2E2is U1-U2-U3U1is C1-4 alkylene and U3is C1-8 alkyl, U2is not a bond, -CH2-, -NR12or carbonyl,

6) if T is an oxygen atom, X is-CH2-, D is D1E is E2E2is U1-U2-U3U1is C2 alkylene or C2 Alcanena and U2is-CO-, then a is not And1,

7) 4-[(2-{(2R)-2-[(1E,3S)-3-hydroxycut-1-enyl]-5-oxopyrrolidin-1-yl}ethyl)thio]butane acid and 4-{2-[(2R)-2-((E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]ethyl}benzoic acid excl is obtained,

its pharmaceutically acceptable salt or cyclodextrines the clathrate,

(2) how to obtain it, and

(3) a pharmaceutical composition containing it as active ingredient.

In this invention, C1-4 alkyl includes methyl, ethyl, propyl, butyl and their isomers.

In this invention, C1-8 alkyl includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and their isomers.

In this invention, the C1-10 alkyl includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers.

In this invention, C1-15 alkyl includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and their isomers.

In this invention, C2-8 alkenyl includes ethynyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and their isomers.

In this invention, C2-10 alkenyl includes ethynyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonanal, decanal and their isomers.

In this invention, C2-15 alkenyl includes ethynyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonanal, decanal, undecanal, dodecanal, tridecanal, tetradecanol, pentadecanol and their isomers.

In this invention, C2-8 quinil includes ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl, heptenyl, octenyl and their isomers.

In this invention, C2-alkynyl includes ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl, heptenyl, octenyl, nonini, decenyl and their isomers.

In this invention, C2-15 quinil includes ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl, heptenyl, octenyl, nonini, decenyl, undecenyl, dodecenyl, tridecanol, tetradecanol, pentadecanol and their isomers.

In this invention, C1-4 alkylene with direct chain includes methylene, ethylene, trimethylene and tetramethylene.

In this invention, C2-8 alkylene with direct chain include ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethine and octamethylene.

In this invention, C1-4 alkylene includes methylene, ethylene, trimethylene and tetramethylene and their isomers.

In this invention, C1-15 alkylene includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptameron, octamethylene, nonmotile, decamethrin, undeletion, dodecamethyl, tridecapeptide, tetradecanamide, pentadecapeptide and their isomers.

In this invention, C2-4 albaniles with direct chain includes ethenylene, propylen, bouteillan and their isomers.

In this invention, C2-8 albaniles with direct chain includes C2-8 albaniles, which has a 1-2 double bonds. It includes ethenylene, propylen, butylen, butadienyl, penttinen, pentadienyl, hexarelin, hexadienyl, heptenyl, heptadienyl, hoktanyan and octadiene.

In Dan is the first invention of the C2-4 albaniles includes ethenylene, propylen, bouteillan and their isomers.

In this invention, C2-15 albaniles includes ethenylene, propylen, butylen, penttinen, hexarelin, heptenyl, hoktanyan, nonpenile, decoiler, undecenyl, dodecenyl, tridecene, tetradecene, pentadecane and their isomers.

In this invention, C2-4 akinyan with direct chain includes ethynylene, propylen and boutinere.

In this invention, C2-8 akinyan with direct chain includes C2-8 akinyan that has 1-2 triple bond. It includes ethynylene, propylen, Butyrin, butadienyl, pentikinen, pentadienyl, geksanalem, hexadienyl, Eptingen, heptadienyl, actinidin and octadiene.

In this invention, C2-4 akinyan includes ethynylene, propylen, Butyrin and their isomers.

In this invention, C2-15 akinyan includes ethynylene, propylen, Butyrin, pentikinen, geksanalem, Eptingen, actinidin, noninert, decisoin, undecenyl, dodecenyl, tridecene, tetradecene, pentadecane and their isomers.

In this invention, the C1-10 alkoxy includes methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and their isomers.

In this invention, the C1-10 alkylthio includes methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, Reptilia, octylthio, nonillion, decillia and their isomers.

In Dan is the first invention of the C3-8 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In this invention, the C2-10 acyl includes ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol and their isomers.

In this invention the biphenyl includes 2-phenylphenyl, 3-phenylphenyl or 4-phenylphenyl.

In this invention, the halogen atom includes fluorine atom, chlorine, bromine or iodine.

In this invention the amino acid residue-CO-(NH-amino acid residue-CO)m-OH and-O-(CO-amino acid residue-NH)m-H includes the residue of a natural amino acid or an abnormal amino acids. Natural amino acids or abnormal amino acids include, for example, glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, Proline, asparagine, glutamine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, lysine, arginine, histidine, β-alanine, cystathionine, cystine, homoserine, isoleucine, lanthionine, norleucine, Norvaline, ornithine, sarcosine, teronen etc.

In amino acid residues in a-CO-(NH-amino acid residue-CO)m-OH and-O-(CO-amino acid residue-NH)m-H enabled amino protective group.

In this invention, C3-15 mono-, bi - or tricarbocyanine aryl which may be partially or fully saturated, represented as calico, ring2, calico, calico, ring or Z, includes, for example, cyclopropane, CYCLOBUTANE, cyclopentane cyclohexane, Cycloheptane, cyclooctane, cyclonona, cyclodecane, cyclodecane, cyclododecane, cycletrader, collaterality, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydroanthracene, azulene, pergerson, inden, palikonda, indan, naphthalene, dihydronaphthalene, tetrahydronaphthalene, peridontal, geptalen, perheravintolan, biphenylene, AU-indocin, indocin, acenaphthylene, acenaphthene, fluorene, finale, phenanthrene, anthracene, Spiro[4.4]nonan, Spiro[4.5]decane, Spiro[5.5]undecane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]hept-2-ene, bicyclo[3.1.1]heptane, bicyclo[3.1.1]hept-2-ene, bicyclo[2.2.2]octane, bicyclo[2.2.2]Oct-2-ene, adamantane, noradsanta etc.

In this invention, among 3-15 membered mono-, bi - or trigeneration of arrow, which may be partially or fully saturated and contains heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms, represented as calico, ring2, calico, calico, calico or Z, 3-15 membered mono-, bi - or trigeneration arily containing heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms include a ring such as pyrrole, imidazole, triazole, tetrazole, pyrazole, feast of the Dean, piratin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran, oxepin, thiophene, thiopyran, tiepin, oxazol, isoxazol, thiazole, isothiazol, furazan, oxadiazole, oxazin, oxadiazon, oxazepine, oxadiazon, thiadiazole, teasin, thiadiazin, diazepin, thiadiazin, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzofuran, ditionally, indazole, quinoline, isoquinoline, hemolysin, purine, phthalazine, pteridine, naphthiridine, cinoxacin, hinzelin, cinnolin, benzoxazole, benzothiazole, benzimidazole, chrome, benzocain, benzoxazepin, benzodiazepin, benzothiophen, benzodiazepin, benzodiazepin, benzazepin, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, beta carboline, acridine, fenesin, dibenzofuran, Xanten, dibenzothiophen, phenothiazines, phenoxazin, phenoxathiin, tianren, phenanthridine, phenanthroline, pyrimidin etc.

3-15 Membered mono-, bi - or trigeneration arily that partially or fully saturated and contains heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms include a ring, such as aziridine, azetidine, asokan, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetrazolium, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, di is hydropyridine, tetrahydropyrimidin, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, oxiran, oxetan, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dehydroacetic, tetrahydroazepine, perhydroxyl, thiran, tieton, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyran, dihydrothiophene, tetrahydrothiophene, pengertian, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahydrooxazolo (oxadiazolidine), dihydrooxazolo, tetrahydrooxazolo, Dihydrocodeine, tetrahydroimidazo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydroxyvitamin, tetrahydroazepine, peligrosamente, dihydroeugenol, tetrahydrocortisol (thiadiazolidin), dihydrotriazine, tetrahydrothiophene, dihydrokavain, tetrahydrolipstatin, dihydrothiazine, tetrahydroazepine, targetrotation, dihydrokavain, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, Ossetian, indolin, isoindoline, digitalen furan, perhydroanthracene, dihydroisobenzofuran, peligrosamente, dihydrobenzofuran, targetobjecttype, dihydroisobenzofuran, peligrosamente, dihydroindol, peritoneal, dihydroquinoline, tetrahydroquinoline, perhydroxyl, dihydroisoquinoline, tetrahydroisoquinoline, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalene, perhydroanthracene, dihydroquinoxaline, tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, dihydroindole, tetrahydroindole, permitiendoles, benzocain, dihydroisoxazole, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, digitalisation, tetrahydrobenzene, dihydrobenzofuran, tetrahydrolipstatin, benzodioxepin, dihydroisoxazole, tetrahydrobenzaldehyde, dihydrocarvone, tetrahydrocarbazol, perhydrogenized, dihydrouridine, tetrahydrouridine, perhydrosqualene, dihydrobenzofuran, dihydroisobenzofuran, tetrahydroxybenzophenone, tetrahydrolipstatin, perhydrophenanthrene, perhydrophenanthrene, dioxolane, dioxane, ditiolan, Titian, dioksiinien, benzodioxan, chroman, benzodithiol is, benzodithiol etc.

In this invention, C3-10 mono - or bikebicycle aryl which may be partially or fully saturated, includes, for example, cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclonona, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydroanthracene, azulene, pergerson, inden, palikonda, indan, naphthalene, dihydronaphthalene, tetrahydronaphthalene, peridontal, Spiro[4.4]nonan, Spiro[4.5]decane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]hept-2-ene, bicyclo[3.1.1]heptane, bicyclo[3.1.1]hept-2-ene, bicyclo[2.2.2]octane, bicyclo[2.2.2]Oct-2-ene, adamantane, noradsanta etc.

In this invention, among 3-10-membered mono - or biheterocyclic arrow, which may be partially or fully saturated and contains heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms, 3-10-membered mono - or biheterocyclic arily containing heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms include a ring such as pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran, oxepin, thiophene, thiopyran, tiepin, oxazol, isoxazol, thiazole, isothiazol, furazan, oxadiazole, oxazin oxadiazon, oxazepine, oxadiazon, thiadiazole, teasin, thiadiazin, diazepin, thiadiazin, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzofuran, ditionally, indazole, quinoline, isoquinoline, hemolysin, purine, phthalazine, pteridine, naphthiridine, cinoxacin, hinzelin, cinnolin, benzoxazole, benzothiazole, benzimidazole, chrome, benzofurazan, benzothiadiazole, benzotriazole etc.

3-10-Membered mono - or biheterocyclic arily that partially or fully saturated and contains heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms include a ring, such as aziridine, azetidine, asokan, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetrazolium, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, pengertian oxiran, oxetan, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dehydroacetic, tetrahydroazepine, perhydroxyl, thiran, tieton, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyran, dihydrothiophene, tet is agitation, pengertian, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahydrooxazolo (oxadiazolidine), dihydrooxazolo, tetrahydrooxazolo, Dihydrocodeine, tetrahydroimidazo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydroxyvitamin, tetrahydroazepine, perhydroanthracene, dihydroeugenol, tetrahydrocortisol (thiadiazolidin), dihydrotriazine, tetrahydrothiophene, dihydrokavain, tetrahydrolipstatin, dihydrothiazine, tetrahydroazepine, targetrotation, dihydrokavain, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, Ossetian, indolin, isoindoline, dihydrobenzofuran, perhydroanthracene, dihydroisobenzofuran, peligrosamente, dihydrobenzofuran, targetobjecttype, dihydroisobenzofuran, peligrosamente, dihydroindol, peritoneal, dihydroquinoline, tetrahydroquinoline, perhydroxyl, dihydroisoquinoline, tetrahydroisoquinoline, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalene, perhydroanthracene, dihydroquinoxaline, tetr hydrogenation, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, dihydroindole, tetrahydroindole, permitiendoles, benzocain, dihydroisoxazole, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, dioxolane, dioxane, ditiolan, Titian, dioksiinien, benzodioxan, chroman, benzodithiol, benzodithiol etc.

In this invention, C3-7 monocarbocyclic aryl which may be partially or fully saturated, includes, for example, cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene, benzene, etc.

In this invention, among 3-7-membered managerialistic of arrow, which may be partially or fully saturated and contains heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms, a 3-7-membered monoheterocycles arily containing heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms include a ring such as pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran, oxepin, thiophene, thiopyran, tiepin oxazol, isoxazol, thiazole, isothiazol, the truck is EN, oxidiazol, oxazin, oxadiazon, oxazepine, oxadiazon, thiadiazole, teasin, thiadiazin, diazepin, thiadiazin etc.

3-7-Membered monoheterocycles arily that partially or fully saturated and contains heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms include a ring, such as aziridine, azetidine, asokan, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetrazolium, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, oxiran, oxetan, dihydrofuran, tetrahydrofuran, dehydroacetic, tetrahydroazepine, perhydroxyl, thiran, tieton, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyran, dihydrothiophene, tetrahydrothiophene, pengertian, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahedrons diazol (oxadiazolidine), dihydrooxazolo, tetrahydrooxazolo, Dihydrocodeine, tetrahydroimidazo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydroxyvitamin, tetrahydroazepine, perhydroanthracene, dihydroeugenol, tetrahydrocortisol (thiadiazolidin), dihydrotriazine, tetrahydrothiophene, dihydrokavain, tetrahydrolipstatin, dihydrothiazine, tetrahydroazepine, targetrotation, dihydrokavain, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, Ossetian, dioxolane, dioxane, ditiolan, Titian etc.

In this invention C5-6 monocarbocyclic aryl which may be partially or fully saturated, includes, for example, cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene, benzene, etc.

In this invention, among 5-6-membered managerialistic of arrow, which may be partially or fully saturated and contains heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms, 5-6-membered monoheterocycles arily containing heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms include a ring such as pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, furan, Piran, TIF is h, oxazol, isoxazol, thiazole, isothiazol, furazan, oxadiazole, oxazin, oxadiazon, thiadiazole, teasin, thiadiazin etc.

5-6-Membered monoheterocycles arily that partially or fully saturated and contains heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms include a ring, such as pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetrazolium, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, Ossetian, dioxolane, dioxane, ditiolan, Titian etc.

In this invention, among 3-15 membered mono-, bi - or trigeneration of arrow, which may be partially or fully saturated and contains at least one nitrogen atom, optionally 1-2 oxygen atoms and/or 1-2 sulfur atom, 3-15 membered mono-, bi - or trigeneration arily containing at least one nitrogen atom and optionally 1-2 oxygen atoms and/or 1-2 sulfur atom include, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, indazole, purine, benzimidazole, benzazepin, benzotriazol, carbazole, beta carboline, phenothiazines, phenoxazin, pyrimidin etc.

3-15 Membered mono-, bi - or trigeneration arily that partially or fully saturated and contains at least one nitrogen atom, optionally 1-2 oxygen atoms and/or 1-2 sulfur atom, R is t aziridine, azetidin, asokan, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetrazolium, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahydrooxazolo (oxadiazolidine), dihydrooxazolo tetrahydrooxazolo, Dihydrocodeine, tetrahydroimidazo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydroxyvitamin, tetrahydroazepine, perhydroanthracene, dihydroeugenol, tetrahydrocortisol (thiadiazolidin), dihydrotriazine, tetrahydrothiophene, dihydrokavain, tetrahydrolipstatin, dihydrothiazine, tetrahydroazepine, targetrotation, dihydrokavain, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, indolin, isoindoline, dihydroindol, peritoneal, digit chinolin, tetrahydroquinolin, perhydroxyl, dihydroisoquinoline, tetrahydroisoquinoline, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalene, perhydroanthracene, dihydroquinoxaline, tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, dihydroindole, tetrahydroindole, permitiendoles, dihydroisoxazole, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, digitalisation, tetrahydrobenzene, dihydrobenzofuran, tetrahydrolipstatin, dihydroisoxazole, tetrahydrobenzaldehyde, dihydrocarvone, tetrahydrocarbazol, perhydrogenized, dihydrouridine, tetrahydrouridine, PermitRootLogin etc.

In this invention, among 5-7-membered managerialistic of arrow, which may be partially or fully saturated and contains at least one nitrogen atom, optionally 1-2 oxygen atoms and/or 1-2 sulfur atom, a 5-7 membered monoheterocycles arily containing at least one nitrogen atom and optionally 1-2 oxygen atoms and/or 1-2 sulfur atom include, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, etc.

5-7-Membered monoheterocycles is the cue arily, partially or fully saturated and contains at least one nitrogen atom, optionally 1-2 oxygen atoms and/or 1-2 sulfur atom, include pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetrazolium, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahydrooxazolo (oxadiazolidine), dihydrooxazolo, tetrahydrooxazolo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydroxyvitamin, tetrahydroazepine, perhydroanthracene, dihydroeugenol, tetrahydrocortisol (thiadiazolidin), dihydrotriazine, tetrahydrothiophene, dihydrokavain, tetrahydrolipstatin, dihydrothiazine, tetrahydroazepine, targetrotation, dihydrokavain, tetrahydroazepine, peridotites is in, morpholine, thiomorpholine etc.

Unless otherwise noted, all isomers are included in this invention. For example, alkyl, alkenyl, quinil, alkoxy, alkylthio, alkylene, albaniles, akinyan include normal and branched groups. In addition, this invention also includes isomers on double bond, ring, fused ring (E-, Z -, CIS-, TRANS-isomer), isomers on asymmetric carbon atoms (R-, S-, α-, β-isomer, enantiomer, diastereoisomer), optically active isomers (D-, L-, d-, l-isomer), polar compounds obtained by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, rotamer, mixtures thereof in any ratio, and a racemic mixture.

In accordance with this invention, unless otherwise indicated, and as is obvious to experts in the art, the symbolmeans that the connection on the opposite side of the plane (namely, α-configuration), symbolmeans that the connection on the front side of the plane (namely, β-configuration), symbolmeans that it αconfiguration β-configuration or a mixture thereof, and the symbolmeans that it is a mixture of αconfiguration β-configuration.

Connection, predstavlennogo (I), can be converted into a pharmaceutically acceptable salt known methods.

Pharmaceutically acceptable salt includes a salt of an alkaline metal salt, alkaline earth metal, ammonium salt, amine salt or an acid additive salt, etc.

The salt is preferably soluble in water. Suitable salt means, for example, salt of an alkali metal (potassium, sodium, lithium, etc.), salt, alkaline earth metal (calcium, magnesium etc), ammonium salt, pharmaceutically acceptable salt of organic amine (Tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D-glucamine etc)

An acid additive salt is preferably soluble in water. Suitable acid additive salt includes, for example, salt of inorganic acid (hydrochloride, Hydrobromic, hydroiodic, sulfate, phosphate, nitrate, etc. or salts of organic acids (acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, aconsultant, bansilalpet, toluensulfonate, isetionate, glucuronate, gluconate, etc. and so on

The compound represented by formula (I)and its salt can be converted into MES.

MES preferably is non-toxic and soluble in water. Suitable solvate what is for example, the MES with water or alcohol (e.g. ethanol).

The compounds of this invention represented by formula (I)can be converted into the corresponding cyclodextrine clathrates by the method described in the description of JP-B-50-3362, 52-31404 or 61-52146 using α, β, or γ-cyclodextrin or mixtures thereof. The transformation into the corresponding cyclodextrine clathrates carried out to improve the stability and solubility of compounds in water, and therefore they can be used in medicines.

Among the compounds of formula (I) And preferably is A1or And2and particularly preferably And2.

Calico preferably is C3-10 mono - or beerbottles-aryl which may be partially or fully saturated, or 3-10-membered mono - or biheterocyclic-aryl which may be partially or fully saturated and contains heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms, especially preferred is C3-7 monocarbocyclic aryl which may be partially or completely saturated, or a 3-7-membered managerialistic aryl which may be partially or fully saturated and contains heteroatoms selected from 1-4 nitrogen atoms, 1-2 atoms oxygen and/or 1-2 sulfur atoms.

Most preferably, calico is C5 Il is 6 monocarbocyclic-aryl, which may be partially or fully saturated, or 5-6-membered managerialism-aryl which may be partially or fully saturated and contains heteroatoms selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms, where the most preferred are furan, thiophene, oxazole or benzene.

Among the compounds of formula (I) D is preferably D1or D2and particularly preferably D1.

D1preferably a is-COOH or-COOR2.

D2preferably a is-COO-Z1-Z2-Z3.

Z1preferred is a C1-15 alkylene, more preferably, C1-8 alkylene and especially preferably C1-4 alkylene.

Z2preferably is-CO-, -OCO-, -COO-, -CONRZ1, -OCONRZ7or-OCOO-, particularly preferably, -OCO-, -OCONRZ7or-OCOO-.

Z3preferred is a C1-15 alkyl or C1-10 alkyl, substituted C1-10 alkoxy, C1-10 alkylthio, C1-10 alkyl-NRZ8or Z, particularly preferably C4-12 alkyl.

Among the compounds of formula (I), T is preferably an oxygen atom or a sulfur atom, particularly preferably an oxygen atom.

Among the compounds of formula (I), X is preferably-CH2-, -O - or-S-, particularly preferably-CH2-.

Among the compounds of formula (I) th preference is sustained fashion is F 2.

Among the compounds of formula (I) compound preferably is a compound represented by formula (I-A):

(where all the symbols have the meanings specified above), formula (I-B):

(where all the symbols have the meanings specified above), formula (I-C):

(where all the symbols have the meanings specified above), formula (I-D):

(where all the symbols have the meanings specified above), formula (I-E):

(where all the symbols have the meanings specified above), formula (I-F):

(where all the symbols have the meanings specified above).

Among the compounds of formula (I-a) compound preferably is a compound represented by formula (I-A1):

(where G2A-1is-Ya-Colico, Yais-S-, -SO2-, -O - or-NR1and other symbols have the meanings described above).

Among the compounds of formula (I-a) compound preferably is a compound represented by formula (I-A1-a):

(where calico is C5 or 6 monocarbocyclic-aryl, or 5-6-membered managerialism-aryl which may be partially or is fully saturated and contains heteroatoms, selected from 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms, R100is a hydrogen atom or C1-4 alkyl and the other symbols have the meanings described above).

Calico especially preferably is a furan, thiophene, oxazole, thiazole or benzene and, specifically,

Among the compounds of formula (I-a) compound is most preferable is a compound represented by formula (I-A1-A1):

(where U1a-1is C1-4 alkyl, C2-4 alkenyl or C2-4 quinil, -U2A-1is-O-, -S-, -SO-, -SO2- or-NR12and other symbols have the meanings described above). Among them, the most preferable is a compound represented by formula (I-A1-1):

(where U3a-1is C1-8 alkyl or colcom and other symbols have the meanings described above, or the compound represented by formula (I-A1-2):

(where all the symbols have the meanings described above).

Also preferably the compound represented by formula (I-A1-A2):

(where calico is 3-15 membered mono-, bi - or trigeneration-aryl which may be partially or fully saturated and contains at least one nitrogen atom and optionally a 12 oxygen atoms and/or 1-2 sulfur atom, n is an integer from 1 to 3. Other symbols have the meanings described above)

the compound represented by formula (I-A1-A3):

(where all the symbols have the meanings described above), or

the compound represented by formula (I-A1-A4):

(where all the symbols have the meanings described above).

Among the compounds of formula (I-A-A4) are especially preferred is the compound represented by the formula:

(where all the symbols have the meanings described above).

Particularly preferably, calico is a 5-7-membered managerialism-aryl which may be partially or fully saturated and contains at least one nitrogen atom and optionally 1-2 oxygen atoms and/or 1-2 sulfur atom.

Among the compounds of formula (I-E) is preferably a compound represented by formula (I-E1):

(where all the symbols have the meanings described above, or the compound represented by formula (I-E2):

(where all the symbols have the meanings described above).

Also preferably the compound represented by formula (I-F):

(where all the symbols have the meanings described above)

the compound represented by formula (I-G):

(where all the symbols have the meanings described above), or

the compound represented by formula (I-N):

(where all the symbols have the meanings described above).

Among the compounds represented by formula (I), particularly preferred compounds represented by formula (Ia-1):

formula (Ia-2):

formula (Ia-3):

formula (Ia-4):

formula (Ia-5):

formula (Ia-6):

formula (Ia-7):

formula (Ia-8):

formula (Ia-9):

formula (Ia-10):

formula (Ia-11):

formula (Ia-12):

formula (Ia-13):

formula (Ia-14):

(where all the symbols have the meanings described above).

Most preferably the compound represented by formula (Ia-15):

formula (Ia-16):

formula (Ia-17):

formula (Ia-18):

formula (Ia-19):

(where all the symbols have the meanings described above).

As specific examples of the compounds described in the following table 1-68, compounds described in the examples and their pharmaceutically acceptable salts and cyclodextrine clathrates.

Methods for obtaining compounds of this invention

The compound represented by formula (I), can the t to be obtained in the following manner or way, described in the example.

1. Among the compounds represented by formula (I), the compound in which T represents an oxygen atom and X represents-CH2-, i.e. the compound represented by formula (IA):

(where all the symbols have the meanings described above), can be obtained in the following way.

The compound represented by formula (IA)can be obtained by reductive amination of compounds of formula (II):

(where R18is C1-10 alkyl, and E' has the same meaning as that is, provided that the hydroxyl, amino, carboxy or formyl group represented by E', can be protected, if necessary) with the compound represented by formula (III):

(where A' and D' have the same values as a and D, respectively. Provided that the hydroxyl, amino, carboxy or formyl groups, presents A' and D'may be protected, if necessary)if necessary, followed by removal of the protective group from the resulting product.

Reductive amination is well known. For example, it may be carried out in an organic solvent (e.g. methanol, ethanol, dichloromethane, tetrahydrofuran, dimethoxyethane, diethyl ether) in the presence of a reducing agent (for example, tzianabos is idrica sodium, sodium borohydride, triacetoxyborohydride sodium, pyridinoline) at a temperature of from 0 to 100°C.

The removal of the protective group can be conducted in the following manner.

The reaction of removing the protective group for carboxy, hydroxy, amino or formyl well known and include, for example, the following:

(1) alkaline hydrolysis,

(2) removal of protection in an acidic environment,

(3) removal of protection by hydrogenolysis,

(4) removing the silyl protection

(5) removing the protecting metal

(6) removing the protecting organic compound of the metal.

These methods are described in more detail below.

(1) removal of the protecting alkaline hydrolysis can be carried out, for example, in an organic solvent (e.g. methanol, tetrahydrofuran, dioxane) using a hydroxide of an alkali metal (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide), a hydroxide of alkaline earth metal (such as barium hydroxide, calcium hydroxide) or a carbonate (e.g. sodium carbonate, potassium carbonate), or an aqueous solution, or a mixture thereof, at temperatures from 0 to 40°C.

(2) Removal of protection in acidic medium can be conducted, for example, in an organic solvent (e.g. dichloromethane, chloroform, dioxane, ethyl acetate, anisole) organic acid (e.g. acetic acid, triperoxonane acid, methanesulfonic acid, p-toluolsulfonic acid) or inorganic acid (for example, hydrochloric acid, sulfuric acid), or mixtures thereof (hydrogen bromide/acetic acid)at a temperature of from 0 to 100°C.

(3) removing the protection of the hydrogenolysis can be carried out, for example, in a solvent (e.g. ether type (for example, tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether), an alcohol type (for example, methanol, ethanol), a benzene type (for example, benzene, toluene), a ketone type (for example, acetone, methyl ethyl ketone), a nitrile type (e.g., acetonitrile), an amide type (e.g., dimethylformamide), water, ethyl acetate, acetic acid or a mixed solvent of two or more of these), in the presence of a catalyst (e.g., palladium on charcoal, palladium mobiles, palladium hydroxide, platinum oxide, Raney Nickel)in a hydrogen atmosphere at normal pressure or elevated pressure, or in the presence of ammonium formate at a temperature of from 0 to 200°C.

(4) removing the silyl protection can be carried out, for example, mixed with water, an organic solvent (e.g. tetrahydrofuran, acetonitrile) using tetrabutylammonium fluoride at a temperature from 0 to 40°C.

(5) removing the protecting metal can be carried out, for example, in an acidic solvent (acetic acid buffer with pH 4.2 to 7.2, or a mixture of their fluids with organic solvent, the same is as tetrahydrofuran) in the presence of powdered zinc with or without the application of ultrasonic waves, at a temperature of from 0 to 40°C.

(6) removing the protecting complex metal can be carried out in an organic solvent (for example dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol), water or mixtures thereof, in the presence of an exciting reagent (for example, anti-hydride, triethylsilane, dimedone, research, diethylamine, pyrrolidine), organic acids (e.g. acetic acid, formic acid, 2-ethylhexanoic acid and/or salts of organic acids (for example, 2-ethylhexanoate sodium, 2-ethylhexanoate potassium), in the presence or in the absence of the reagent phosphine type (e.g., triphenylphosphine), using complex metal (tetranitroaniline(0), dichlorobis(triphenylphosphine)palladium(II)acetate, palladium(II), chlorotris(triphenylphosphine)rhodium(I)), at a temperature from 0 to 40°C.

In addition to the above, the removal of protection can also be carried out, for example, the methods described in T.W. Green,Protective Groups in Organic Synthesis, Wiley, New York, 1999.

The compounds of this invention can be easily obtained by selective application of the reaction remove the protection that is understandable to the expert in this field.

Carboxylate groups include, for example, methyl, ethyl, allyl, tert-butyl, trichloroethyl, benzyl (Bn) and phenacyl etc.

Hydroxylamine group including the indicate, for example, methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc) and 2,2,2-trichlorocyanuric (Troc), etc.

Aminosidine groups include, for example, benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)etoxycarbonyl (Bpoc), TRIFLUOROACETYL, 9-fluorenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl, benzoyloxymethyl (BOM) and 2-(trimethylsilyl)ethoxymethyl (SEM), etc.

Formylamino groups include, for example, acetal (for example, dimethylacetal) etc.

Carboxy-, hydroxy-, amino - or formylamino group may be different than listed above must be easily and selectively removed and is not specifically defined. For example, can be used by groups described in T.W. Green,Protective Groups in Organic Synthesis, 3rdEd., Wiley, New York, 1999.

2. Compounds represented by formula (IA)can be obtained by reductive amination of compounds of formula (IV):

(where all the symbols have the meanings described above) with compounds of the formula (V):

(where Aais And1Aor And2AAnd1Ais 1) C1-17 what kilena with a straight chain, optionally substituted by 1-2 C1-4 alkilani, 2) C2-7 Alcanena straight-chain, optionally substituted by 1-2 C1-4 alkilani or 3) C2-7 akinlana straight-chain, optionally substituted by 1-2 C1-4 alkilani, And2Ais-G1a-G2a-G3-, G1ais 1) C1-3 alkylene, optionally substituted by 1-2 C1-4 alkilani, 2) C2-3 Alcanena, optionally substituted by 1-2 C1-4 alkilani or 3) C2-3 akinlana, optionally substituted by 1-2 C1-4 alkilani, G2ahas the same meaning as G2. Provided that the hydroxyl, amino, carboxy or formyl group represented by G2amay be protected if necessary. Other symbols have the meanings described above), if necessary, followed by removal of the protective group from the resulting product.

Reductive amination and the removal of the protective group may be carried out as described above.

3. Among the compounds represented by formula (I), the compound in which T represents an oxygen atom and X represents-O-, i.e. the compound represented by formula (IB):

(where all the symbols have the meanings described above), can be obtained in the following way.

Compounds represented by formula (IB)can be obtained by cyclization of compounds of formula (VI):

(where all the characters who have values, described above), if necessary, followed by removal of the protective group from the resulting product.

Cyclization is well known. For example, it can be carried out in an organic solvent (e.g. tetrahydrofuran, dichloromethane, dimethoxyethane, diethyl ether, dimethylformamide) in the presence of a base (e.g. triethylamine, pyridine, potassium carbonate, sodium bicarbonate) with a carbonylation agent (for example, triphosgene, 1,1'-carbonyl diimidazol (CDI), phosgene) at a temperature of from 0 to 50°C.

The removal of the protective group may be carried out as described above.

4. Among the compounds represented by formula (I), the compound in which T represents an oxygen atom and X represents-S-, i.e. the compound represented by formula (IC):

(where all the symbols have the meanings described above), can be obtained in the following way.

Compounds represented by formula (IC)can be obtained by cyclization of compounds of formula (VII):

(where all the symbols have the meanings described above), if necessary, followed by removal of the protective group from the resulting product.

Cyclization and removal of the protective group may be carried out as described above.

5. Among the compounds represented by formula (I), a connection to what op T represents a sulfur atom, i.e. the compound represented by formula (ID):

(where all the symbols have the meanings described above), can be obtained in the following way.

Compounds represented by formula (ID)can be obtained by teameditorial compounds of the formula (VIII):

(where all the symbols have the meanings described above), if necessary, followed by removal of the protective group from the resulting product.

Miamidian well known. For example, it may be carried out in an organic solvent (e.g. toluene, diethyl ether, methylene chloride, chloroform, dioxane, tetrahydrofuran) in the presence of the agent tonirovania (for example, the reagent of Lesson (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide), phosphorus pentoxide) at a temperature of from 0 to 150°C.

The removal of the protective group can be performed as described above.

6. Among the compounds represented by formula (I), a compound in which D represents-CH2HE, i.e. the compound represented by formula (IE):

(where all the symbols have the meanings described above), can be obtained in the following way.

Compounds represented by formula (IE)can be obtained by reduction of compounds of formula (IX):

(where all the symbols have the meanings described above), if necessary, followed by removal of the protective group from the resulting product.

The recovery is well known. For example, it may be carried out in an organic solvent (e.g. tetrahydrofuran, dimethoxyethane, diethyl ether, dimethylformamide, dioxane, methanol, ethanol, isopropanol) or an aqueous solution in the presence of a reducing agent (e.g. sodium borohydride, lithium borohydride) at a temperature from 0 to 70°C.

The removal of the protective group can be performed as described above.

7. Among the compounds represented by formula (I), a compound in which D represents-CONR3SO2R4, -CONR6R7, -CONR6SO2R8or-CO-(NH-amino acid residue-CO)mHE, i.e. the compound represented by formula (IF):

(where Dais-CONR3SO2R4, -CONR6R7, -CONR6SO2R8or-CO-(NH-amino acid residue-CO)mHE and the other symbols have the meanings described above), can be obtained in the following way.

Compounds represented by formula (IF)can be obtained by amidation of the compounds of formula (X):

(where all the symbols have the meanings described above, with soedineniya (XI-1):

H-NR3SO2R4(XI-1)

(where all the symbols have the meanings described above, the compounds of formula (XI-2):

H-NR6R7(XI-2)

(where all the symbols have the meanings described above, the compounds of formula (XI-3):

H-NR6SO2R8(XI-3)

(where all the symbols have the meanings described above) or compounds of formula (XI-4):

H-(NH-amino acid residue-CO)mHE (XI-4)

(where all the symbols have the meanings described above. Provided that the amino, hydroxy or carboxy in the compounds represented by formula (XI-4)may be protected if necessary), if necessary, followed by removal of the protective group from the resulting product.

Methods of amidation is known. For example, they include the method

(1) through allalone,

(2) via a mixed acid anhydride,

(3) using a condensing agent,

These methods are described in detail below.

(1) Method through allalone can be done, for example, the interaction of carboxylic acids with allelochemical (for example, oxalylamino or thionyl chloride) in an organic solvent (e.g. chloroform, dichloromethane, diethyl ether or tetrahydrofuran) or without a solvent at temperatures from -20°C to the boiling temperature under reflux. Then the scientists derived acylhomoserine may be subject to interaction with alcohol in an inert organic solvent (for example, chloroform, dichloromethane, diethyl ether or tetrahydrofuran) in the presence of a base (e.g. pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or diisopropylethylamine and so on) at a temperature of from 0 to 40°C. alternatively, the received derived acylhomoserine may be subject to interaction in an organic solvent (e.g. dioxane, tetrahydrofuran) using an alkaline aqueous solution (for example, sodium bicarbonate, sodium hydroxide) at a temperature of from 0 to 40°C.

(2) the Method via a mixed acid anhydride can be performed, for example, the interaction of carboxylic acids with allelochemical (for example, revalorisation, mozillateam or methylchloride) or acid derivative (for example, etelcharge.com or isobutylparaben) in an organic solvent (e.g. chloroform, dichloromethane, diethyl ether, tetrahydrofuran) or without a solvent, in the presence of a base (e.g. pyridine, triethylamine, dimethylamine, dimethylaminopyridine or diisopropylethylamine) at a temperature of from 0 to 40°C. Then derived the mixed acid anhydride can be subjected to interaction with amine in an organic solvent (for example, chloroform, methylene chloride, diethyl ether or tetrahydrofuran)at a temperature of from 0 to 0° C.

(3) Method using condensing agent can be accomplished, for example, the interaction of carboxylic acids with alcohol in an organic solvent (e.g. chloroform, dichloromethane, dimethylformamide, diethyl ether or tetrahydrofuran) or without a solvent, in the presence or in the absence of a base (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine), using a condensing agent (for example, 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbodiimide (CDI), iodide 2-chloro-1-methylpyridine or cyclic anhydride 1-papapostolou acid (PPA)), in the presence or in the absence of 1-hydroxybenzotriazole (HOBt), at temperatures from 0 to 40°C.

The reaction described in (1), (2) and (3)can be conducted in an atmosphere of inert gas (e.g. argon, nitrogen) to prevent penetration of water for optimal results.

The removal of the protective group can be performed as described above.

8. Among the compounds represented by formula (I), a compound in which D represents-O-(CO-amino acid residue-NH)m-N or-OCO-R10, i.e. the compound represented by formula (IG):

(where Dbrepresents-O-(CO-amino acid residue-NH)m-N or-OCO-R10and other symbols have the mn of the treatment, described above), can be obtained in the following way.

Compounds represented by formula (IG)can be obtained by esterification of compounds of formula (XII):

(where Dwithis-OH or-CH2HE and the other symbols have the meanings described above, with compounds of the formula (XIII-1):

HO-(CO-amino acid residue-NH)m-N (XIII-1)

(where all the symbols have the meanings described above. Provided that the amino, hydroxy or carboxy in the compounds represented by formula (XIII-1), can be protected if necessary), or compounds of formula (XIII-2):

HO2C-R10(XIII-2)

(where R10matter described above) if necessary, followed by removal of the protective group from the resulting product.

Methods of esterification is known. For example, they include the method

(1) through allalone,

(2) via a mixed acid anhydride,

(3) using a condensing agent,

These methods are described in detail below.

(1) Method through allalone can be done, for example, by the interaction of the carboxylic acid with an agent forming gelegenheid acid (for example, oxalylamino or thionyl chloride etc. in an organic solvent (e.g. chloroform, dichloromethane, diethyl ether or tetrahydrofuran) or without a will dissolve the La at a temperature of from -20° C to the boiling temperature under reflux. Then the derived acylhomoserine may be subject to interaction with alcohol in an inert organic solvent (e.g. chloroform, dichloromethane, diethyl ether or tetrahydrofuran) in the presence of a base (e.g. pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or diisopropylethylamine and so on) at a temperature of from 0 to 40°C. alternatively, the received derived acylhomoserine may be subject to interaction in an organic solvent (e.g. dioxane, tetrahydrofuran) using an alkaline aqueous solution (for example, sodium bicarbonate, sodium hydroxide) at a temperature of from 0 to 40°C.

(2) the Method via a mixed acid anhydride can be performed, for example, the interaction of carboxylic acids with allelochemical (for example, revalorisation, mozillateam or methylchloride) or acid derivative (for example, etelcharge.com or isobutylparaben) in an organic solvent (e.g. chloroform, dichloromethane, diethyl ether, tetrahydrofuran) or without a solvent, in the presence of a base (e.g. pyridine, triethylamine, dimethylamine, dimethylaminopyridine or diisopropylethylamine) at a temperature of from 0 to 40°C. Then derived compound is about anhydride acid can be subjected to interaction with alcohol in an organic solvent (for example, chloroform, methylene chloride, diethyl ether or tetrahydrofuran) at a temperature of from 0 to 40°C.

(3) the Method using a condensing agent can be accomplished, for example, the interaction of carboxylic acids with alcohol in an organic solvent (e.g. chloroform, dichloromethane, dimethylformamide, diethyl ether or tetrahydrofuran) or without a solvent, in the presence or in the absence of a base (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine), using a condensing agent (for example, 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbodiimide (CDI), iodide 2-chloro-1-methylpyridine or cyclic anhydride 1-papapostolou acid (PPA)), in the presence or in the absence of 1-hydroxybenzotriazole (HOBt), at temperatures from 0 to 40°C.

The reaction described in (1), (2) and (3)can be conducted in an atmosphere of inert gas (e.g. argon, nitrogen) to prevent penetration of water for optimal results.

The removal of the protective group can be performed as described above.

9. Among the compounds represented by formula (I), a compound in which D represents formyl, i.e. the compound represented by the formula (IH):

(where all the symbols have the meanings described above), can the t to be obtained in the following way.

Compounds represented by formula (IH)can be obtained by oxidation of compounds of formula (XIV):

(where all the symbols have the meanings described above), if necessary, followed by removal of the protective group.

Methods of oxidation are known. For example, they include the method

(1) oxidation by Turn

(2) oxidation with a reagent dessa-Martin

(3) oxidation with TEMPO reagent.

These methods are described in detail below.

(1) Method of oxidation in Turn includes, for example, the interaction of oxalicacid with dimethylsulfoxide in an organic solvent (e.g. chloroform, dichloromethane) at a temperature of -78°C, and then the interaction of the obtained solution with the combination of alcohol, and then with a tertiary amine (e.g. triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-ethylpiperidine, diazabicyclo[5.4.0]undec-7-Yong) at a temperature of from -78°C to 20°C.

(2) Method with the reagent dessa-Martin includes, for example, the treating compound in an organic solvent (e.g. chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, tert-butyl alcohol) in the presence of reagent dessa-Martin (1,1,1-triacetoxy-1,1-dihydro-1,2-benzoyloxy-3-(1H)-she) in the presence or in the absence of a base (e.g. pyridine) at a temperature of from 0 to 40°C.

(3) Method with what eaction TEMPO includes, for example, the treating compound in an organic solvent (e.g. chloroform, dichloromethane, tetrahydrofuran, toluene, acetonitrile, ethyl acetate, water) or in the mixed solvent in the presence of the reagent of TEMRO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) and the agent, regenerating the oxidizing agent (for example, aqueous hydrogen peroxide, sodium hypochlorite, 3-chloroperbenzoic acid, identiteta, peroxymonosulfate potassium (Oxon, trade mark)), in the presence or in the absence of a Quaternary ammonium salt (for example, tetrabutylammonium chloride, tetrabutylammonium bromide)in the presence or in the absence of inorganic salt (for example, sodium bromide, potassium bromide)in the presence or in the absence of inorganic bases (e.g. sodium hydrogen carbonate, sodium acetate)at a temperature of from 20 to 60°C.

Oxidation is not limited to the above methods, you can apply any method of oxidation, easily and selectively oxidizing the alcohol to the ketone. For example, apply any oxidation Jones, PCC oxidation (chlorbromuron pyridinium), oxidation complex of sulfur trioxide-pyridine or the methods described inComprehensive Organic Transformations(Richard C. Larock, VCH Publishers, Inc., (1989), pp. 604-614).

10. Among the compounds represented by formula (I), a compound in which D represents-COOR2, -COOR9or-COO-Z1 -Z2-Z3, i.e. the compound represented by the formula (IJ):

(where Ddis-COOR2, -COOR9or-COO-Z1-Z2-Z3and other symbols have the meanings described above), can be obtained in the following way.

Compounds represented by formula (IJ)can be obtained by esterification of compounds of formula (X):

(where all the symbols have the meanings described above, with the compound of formula (XV-1):

R19-R2(XV-1)

(where R19is hydroxy or a halogen atom and other symbols have the meanings described above), a compound of formula (XV-2):

R19-R9(XV-2)

(where all the symbols have the meanings described above), or a compound of formula (XV-3):

R19-Z1A-Z2A-Z3A(XV-3)

(where Z1a, Z2aand Z3Aare the Z1, Z2and Z3, respectively. Provided that the hydroxy, amino, carboxy or formyl in the compounds represented by Z1A-Z2A-Z3Amay be protected if necessary), if necessary, followed by removal of the protective group.

Etherification with a compound of formula (XI-1), (XI-2 and XI-3), in which R17is hydroxyl, can be carried out as described above.

These who eficacia with the compound of formula (XI-1), (XI-2 and XI-3), in which R17is halogen, can be carried out, for example, in an organic solvent (for example, dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethylacetamide)in the presence of a base (e.g. potassium carbonate, cesium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide)at a temperature of from 0 to 150°C.

The removal of the protective group can be performed as described above.

Compounds represented by formulas (II), (III), (IV), (V), (VI), (VII), (XI-1), (XI-2), (XI-3), (XI-4), (XIII-1), (XIII-2), (XV-1), (XV-2) and (XV-3) are known compounds or can be obtained by known methods.

For example, the compounds of formulas (VI) and (VII) can be obtained by the method shown in the reaction scheme 1.

The reaction scheme 1

In the reaction scheme 1, R20is a protective group for hydroxy, AC is an acetyl group and the other symbols have the meanings described above.

In the reaction scheme 1, the compound of formula (XVI)is used as the source, is a known compound or can be easily obtained by known methods.

11. Among the compounds represented by formula (I), the compound in which T is an oxygen atom, E is E2E2is U1-U2-U3 U1is methylene and U2is-NH-, i.e. the compound represented by formula (IK):

(where all the symbols have the meanings described above), can be obtained in the following way.

Compounds represented by formula (IK)can be obtained by reductive amination of compounds of formula (XIX):

(where all the symbols have the meanings described above, with compounds of the formula (XX):

N2N-U3'(XX)

(where U3'has the same value as U3. Provided that the hydroxy, amino, carboxy or formyl in the compounds represented U3'may be protected if necessary. Other symbols have the meanings described above), if necessary, followed by removal of the protective group.

Reductive amination and the removal of the protective group may be carried out as described above.

12. Among the compounds represented by formula (I), the compound in which T represents an oxygen atom, And represents And2And2is G1-G2-G3, G1represents C1-4 alkylene, G2is-Y-, -Y-kolco - or-Y-C1-4 alkylene-kolco-, Y represents-S-, E is E2E2is U1-U2-U3U1is methylene and U 2represents-O-, i.e. the compound represented by formula (IL):

(where abis G1A-G2A-G3A, G1Arepresents C1-4 alkylene straight chain, G2Ais-S-, -S-kolco - or-S-C1-4 alkylene-colcom and other symbols have the meanings described above), can be obtained in the following way.

Compounds represented by formula (IL)can be obtained by the coupling of compounds of formula (XXI):

(where R21is C1-3 alkylene and other symbols have the meanings described above) with compounds of the formula (XXII):

R22-R23-G3-D'(XXII)

(where R22represents a halogen atom, R23represents a bond, -kolco - or C1-4 alkylene-kolco-. Provided that the hydroxy, amino, carboxy or formyl in the compounds represented by R23may be protected if necessary. Other symbols have the meanings described above), if necessary, followed by removal of the protective group.

The reaction is known. For example, it can be carried out in an organic solvent (e.g. ethanol, methanol, tetrahydrofuran, dichloromethane, dimethylformamide) using a base (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, methylalanine, diethylamine) at a temperature of from 0 to 40°C.

The removal of the protective group can be performed as described above.

Compounds represented by formulae (XX) and (XXII)are known or can be easily obtained by known methods.

Compounds represented by the formulae (XIX) and (XXI)can be obtained by the method shown in reaction schemes 2, 3 and 4.

The reaction scheme 2

The reaction scheme 3

The reaction scheme 4

In the reaction schemes 2, 3 and 4 R24represents a hydrogen atom or

R25is a protective group for hydroxy. Et is ethyl, Boc is tert-butoxycarbonyl and other symbols have the meanings described above.

In the reaction schemes 2, 3 and 4 compound of formula (XXIII) are used as initial substances, and compounds of formula (XXX), (XXXIV) and (XXXVIII) are known compounds or can be easily obtained by known methods.

Each is described here, the reaction of the reaction product can be purified General purification methods such as distillation under normal or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silicagel is or magnesium silicate, washing and recrystallization. Cleaning can be carried out in each reaction or after completion of several reactions.

The pharmacological activity of the compounds in accordance with this invention:

For example, the pharmacological activity of the compounds of this invention was confirmed by experiments conducted in the laboratory using cells that Express the receptor subtypes prostanoid.

(i) the Experiment for binding with the receptor using cells that Express the receptor subtypes prostanoid

According to the method described by Sugimoto et al. (J. Biol. Chem.,267, 6463-6466 (1992)), the cells of Cho, which Express the receptor subtypes prostanoid (mouse EP1, EP2, EPand EP4, respectively), receive, and use as authentic samples of membranes.

The reaction solution (200 μl)containing fraction obtained membranes (0.5 mg/ml) and3N-PGE2, incubated at room temperature for 1 hour. The reaction is stopped by adding ice-cold buffer (3 ml) and the reaction mixture is subjected to vacuum filtration through a glass filter (GF/B), which is captured associated3N-PGE2and radioactivity binding was measured in liquid scintillation counter.

The Kd value obtained from the graph of Scatchard [Ann. N. Y. Acad. Sci ., 51, 660 (1949)]. Nonspecific binding is defined as binding in the presence of excess (2.5 μm) unlabeled PGE2. Measurement of inhibition of binding3N-PGE2the compounds of the present invention is carried out with the addition of3N-PGE2(2.5 nm) and several concentrations of the compounds of this invention. In this reaction in all cases, use the next buffer.

Buffer: 10 mm potassium phosphate (pH 6.0), 1 mm EDTA, 1 mm MgCl2and 0,1M NaCl.

The dissociation constant Ki (μm) of each compound calculated by the following equation.

Ki = IC50/(1+([C]/Kd))

IC50: concentration of the compounds of this invention, in which it inhibits half the specific binding of [3N]PGE2

C: concentration of [3N]PGE2

Kd: dissociation constant of [3N]PGE2

The binding activity (Ki) of the compound obtained in example 4(1), mouse receptor EP2is 14 nm.

Toxicity:

The toxicity of the compounds of this invention represented by formula (I)is very low, and therefore the connection can be considered safe for pharmaceutical use.

Industrial applicability

Application in pharmaceutical compositions

Compounds in accordance with this invention are specific and strongly associated with subtype EP2/sub> the PGE receptor, and it is believed that they are related to the inhibition of the formation of TNFα and to improve education for IL-10. Therefore, it is believed that compounds that bind to the receptor EP2useful for prevention and/or treatment of immune diseases (e.g. autoimmune diseases, such as amyotrophic lateral sclerosis (als), multiple sclerosis, Sjogren syndrome, rheumatoid arthritis and systemic lupus erythematosus and so on, and the rejection of organs after transplantation), allergic diseases (such as asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, food Allergy), the death of neural cells, menstrual cramps, premature births, miscarriages, alopecia, retinal neuropathy such as glaucoma, erectile dysfunction, arthritis, lung injury, pneumosclerosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, liver damage, acute hepatitis, liver cirrhosis, shock, nephritis (acute nephritis, chronic nephritis, renal failure, diseases of the circulatory system (e.g., hypertension, myocardial ischemia, chronic clogged arteries, diseases caused by vibration), systemic inflammatory response syndrome, sepsis syndrome hemophagocytosis, syndrome, macrophage activation, disease Steele, Bo is esni Kawasaki, burn, systemic granuloma, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure and bone disease (e.g., cracks, re-fracture, undetectable cracks, necromania, pseudoarthrosis, osteomalacia, bone Paget's disease, ankylosing spondylitis, bone metastases, osteoarthritis and fracture bone/cartilage due to similar diseases), etc. Also believe that the compounds are useful as an agent for enhancing osteogenesis/cure after surgery to bone (e.g., fractures, bone grafts, artificial astrogenesis, corporatese, operations in multiple myeloma, lung cancer, breast cancer and so, other reconstructive operations on the bones), or rollover treatment for bone grafts. Also consider that the compounds are useful agents to enhance regeneration of the periodontium in periodontal diseases, etc.

Among the compounds represented by formula (I), distinguish those that are associated with receptor EP4and receptor EP2. It is believed that compounds that bind to the receptor EP4useful for prevention and/or treatment of immune diseases (e.g. autoimmune diseases, such as amyotrophic lateral sclerosis (als), multiple sclerosis, Sjogren syndrome, repmat idny arthritis and systemic lupus erythematosus and so on, and the rejection of organs after transplantation), asthma, loss of neural cells, arthritis, lung injury, pneumosclerosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, liver damage, acute hepatitis, nephritis (acute nephritis, chronic nephritis, renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory response syndrome, sepsis syndrome hemophagocytosis syndrome activation of macrophage, of still's disease, Kawasaki disease, burn, systemic granuloma, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure and shock, etc. Receptor EP4also plays a role in the protective effect of the mucous membrane, and, thus, the connection is considered to be useful for prevention and/or treatment of ulcers of the digestive tract, such as stomach ulcers and duodenal ulcers and stomatitis. Receptor EP4also plays a role in trichogram action and hair growth, and therefore the connection is considered to be useful for prevention and/or treatment of alopecia and alopecia, etc. moreover, the receptor EP4plays a role in the maturation of the cervical canal, and therefore the compound is useful as an agent for the maturation of the cervical canal.

Moreover, the connection that communicates with the receptor EP4has Wuxi is ivyshim osteogenesis action thus, it is considered useful not only for the prevention and/or treatment of diseases of the bones, which decreases the amount of bone, for example, 1) primary osteoporosis due to, for example, aging, menopause, ovariectomy, 2) secondary osteoporosis (e.g., caused by glucocorticoid osteoporosis, giperglikemicescoa osteoporosis, osteoporosis caused real condition caused by immunosuppressants osteoporosis, osteoporosis caused by renal failure, inflammatory osteoporosis, osteoporosis caused by Cushing's syndrome, rheumatic osteoporosis), 3) bone disease, such as cancer of the bone, hypercalcemia, Behcet's disease, bone failure (for example, alveolar bone deficiency, maxillary deficiency, infantile idiopathic bone deficiency) and osteonecrosis, but is also used as an agent to enhance osteogenesis/treatment after surgery to bone (e.g., fractures, bone grafts, artificial atrogenes, corporates, other transactions recovery of the bones), or replacement of the transfer of the bones.

Moreover, EP4may cause physiological sleep and to inhibit platelet aggregation, and the connection that communicates with the receptor EP4, it is considered useful to prevent sleep disturbances and tro the Bose.

The connection that communicates with receptors EP2and EP4may exhibit additive or synergistic effect in diseases associated with both receptors.

The compound represented by formula (I)or its pharmaceutically acceptable salt can be introduced in combination with other pharmaceutical preparations to achieve the following objectives:

1) to Supplement and/or enhance the preventive and/or therapeutic action of the compounds included in the composition;

2) to improve the kinetics of/absorption of the compounds included in the composition, and the dose of the compound; and/or

3) to eliminate the side effects of the compounds included in the composition.

The compound represented by formula (I), and other pharmaceutical compositions can be introduced in the form of compositions containing these components are introduced in one preparative form, or you can type in a separate formulation. If such pharmaceutical composition is administered in a separate formulation, they can be introduced simultaneously or at different times. In the latter case, the compound represented by formula (I)may be introduced to other pharmaceutical compositions. Alternatively, other pharmaceutical compositions can be introduced before the compound represented by formula (I). The method of introduction of such farm is sitechecker compositions may be the same or different.

Diseases in which occur prophylactic and/or therapeutic effect of the above combined preparative forms, not limited in a certain way, but may include those for which the preventive and/or therapeutic effect of the compound represented by formula (I), supplemented and/or enhanced.

Examples of other pharmaceutical compositions to complement and/or enhance the preventive and/or therapeutic activity of a compound represented by the formula (I), diseases of the bones include, for example, the inhibitor of phosphodiesterase-4, the drug biphosphonate, vitamin D, calcium adjuvant, drug estrogen, the drug calcitonin drug-based isoflavon, anabolic steroid drug, a drug of vitamin K, an inhibitor of cathepsin K, prostaglandins, statin, parathyroid hormone and growth factors, etc.

Examples of other pharmaceutical compositions to complement and/or enhance the preventive and/or therapeutic activity of a compound represented by the formula (I), and chronic obstructive pulmonary disease and/or asthma include, for example, the inhibitor of phosphodiesterase-4, steroids, stimulants β-adrenergic receptors antagonist of leukotriene receptor, enzyme inhibitor of the synthesis of thromboxane, receptor antagonist And thromboxane a2the inhibitor of the release of mediate the RA, antihistamines, xanthine derivatives, anticholinergic drugs, inhibitors of cytokines, prostaglandins, drug Forskolin, an elastase inhibitor, an inhibitor of Metaprocess, expectorant and antibiotic, and so on

Examples of other pharmaceutical compositions to complement and/or enhance the preventive and/or therapeutic activity of a compound represented by the formula (I), menstrual pain include, for example, analgesics (nonsteroidal anti-inflammatory drugs (NSAID), an inhibitor of cyclooxygenase (SOH), and so on), oral contraceptives, hormone, antispasmodic, stimulant β-adrenergic receptors antagonist of the vasopressin V1a, the inhibitor prostaglandines, local anesthetic, a calcium channel blocker, a potassium channel blocker, an antagonist of leukotriene receptor, a relaxant of smooth muscle vasodilator, etc.

Examples of other pharmaceutical compositions to complement and/or enhance the preventive and/or therapeutic activity of a compound represented by the formula (I), arthritis or rheumatoid arthritis include, for example, the inhibitor Metaprocess, immunosuppressant, steroidal anti-inflammatory drug (NSAID), steroids, inhibitors of phosphodiesterase-4 and so on

Examples of other pharmaceutical compositions to complement and/or improve prevention is the definition and/or therapeutic activity of a compound, represented by formula (I), for erectile dysfunction include, for example, the inhibitor of phosphodiesterase-5, etc.

Examples of other pharmaceutical compositions to complement and/or enhance the preventive and/or therapeutic activity of a compound represented by the formula (I), when the shock include, for example, an elastase inhibitor, etc.

Examples of other pharmaceutical compositions to complement and/or enhance the preventive and/or therapeutic activity of a compound represented by the formula (I), colitis include, for example, the inhibitor synthase nitric oxide, poly(ADP-ribose)polymerase, an inhibitor of phosphodiesterase-4, an elastase inhibitor, an antagonist of interleukin-8 and so on

Examples of other pharmaceutical compositions to complement and/or enhance the preventive and/or therapeutic activity of a compound represented by the formula (I), acute nephritis, chronic nephritis include, for example, steroids, inhibitors of phosphodiesterase-4, non-steroidal anti-inflammatory drugs, receptor antagonist And thromboxane a2the antagonist of the leukotriene receptor, antagonist of angiotensin II, angiotensin converting enzyme, diuretic, etc.

Examples of other pharmaceutical compositions to complement and/or enhance the preventive and/or therapeutic activity of a compound represented by the formula (I), PR is hypertension include for example, the blocker calcium channel antagonist of angiotensin II, angiotensin converting enzyme inhibitor of phosphodiesterase-4, diuretic, etc.

Examples of the inhibitor of phosphodiesterase-4 include, for example, rolipram, cilomilast (trade name Ariflo), Bay 19-8004, NIK-616, cilomilast BY-317), cipamfylline (BGL-61063), atizoram (CP-80633), SCH-351591, YM-976, V-A, PD-168787, D-4386 and IC-485, etc.

Examples of the inhibitor of phosphodiesterase-5 include, for example, sildenafil, etc.

Examples of the preparation of biphosphonate include, for example, alendronate sodium, clodronate disodium, pamidronate disodium, etidronate disodium, ibandronate, encadrant disodium, minodronate, olpadronate, risedronate sodium, Mildronat and zoledronate etc.

Examples of the preparation of calcitonin include, for example, calcitonin and elcatonin etc.

Examples of prostaglandins (hereinafter designated as "PG") include agonist receptor PG and receptor antagonist PG.

Examples of PG receptor include the PG receptors (EP1, EP2, EP3, EP4), PGD receptors (DP), the PGF receptors (FP) and the PGI receptor (IP), etc.

Examples of steroids for topical use include, for example, clobetasol, propionate, diflorasone acetate, fluocinonide, mometasone furoate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, budesonide, valerate, AMC is none, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, depradine propionate, prednisolone valerate acetate, fluoqinolona acetonide, beclomethasone dipropionate, triamcinolone acetonide, flumetazon pivalate, alklometazon dipropionate, clobetasone butyrate, beclomethasone propionate and fludroxycortide etc.

Examples of drugs steroids for internal use or injection include, for example, cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, prednisolone butyl acetate, prednisolone sodium phosphate, haloperidol acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone acetate and betamethasone etc.

Examples of drugs steroids for inhalation include beclomethasone propionate, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-R, ciclesonide, dexamethasone palmitate, mometasone furoate, prasterone sulfate, deflazacort, methylpredn is the zolona stratanet and methylprednisolone sodium succinate, etc.

Examples of stimulants β-adrenergic receptors include, for example, fenoterola hydrogen bromide, salbutamol sulfate, terbutalina sulfate, formoterol fumarate, salmeterol xinafoate, isoproterenol sulfate, ortsiprenalina sulfate, clorprenaline sulfate, epinephrine, trimetoquinol hydrochloride, geksoprenalina sulfate, procaterol hydrochloride, tulobuterol hydrochloride, tulobuterol, pirbuterol hydrochloride, clenbuterol hydrochloride, mabuterol hydrochloride, ritodrine hydrochloride, bambuterol, dopexamine hydrochloride, meleagrina tartrate, AR-S, levosalbutamol, R,R-formoterol, isoxsuprine, metaproterenol, KUR-1246, KUL-7211, AR-S and S-1319, etc.

Examples of antagonist of leukotriene receptor include, for example, pranlukast hydrate, montelukast, zafirlukast, seratrodast, MCC-847, KCA-757, CD-615, YM-158, L-740515, CP-195494, LM-1484, RS-635, A-93178, S-36496, BIIL-284 and ONO-4057, etc.

Examples of the inhibitor of the enzyme for the synthesis of thromboxane include, for example, ozagrel hydrochloride and microdust sodium, etc.

Examples receptor antagonist And2include, for example, seratrodast, ramatroban, dumitrean the dihydrate of calcium and KT-2-962 etc.

Examples of the inhibitor selection of the mediator includes, for example, tranilast, sodium cromoglycate, amlexanox, reprint, ibudilast, casinolist and pemirolast potassium.

Examples of antihistamines include ketotifen fumarate, MEK is itzin, azelastine hydrochloride, oxatomide, terfenadine, emedastine difumarat of epinastine hydrochloride, astemizole, Bastin, cetirizine hydrochloride, bepotastine, Fexofenadine, loratadine, desloratadine, olopatadine hydrochloride, 427, ZCR-2060, NIP-530, mometasone furoate, mizolastine, BP-294, andolast, auranofin and acrivastine etc.

Examples of xanthine derivatives include, for example, aminophylline, theophylline, doxofylline, cipamfylline, diprophylline etc.

Examples of anticholinergic drugs include, for example, ipratropium bromide, oxytrope bromide, plutopia bromide, tiotropia bromide, temiverine, Tiotropium bromide and reatreat (UK-112166) etc.

Examples of the inhibitor of cytokines include, for example, suplatast tosilate (trade name IPD), etc.

Examples of the salt include, for example, ponikarovsky ammonia spirit, sodium bicarbonate, Bromhexine hydrochloride, carbocisteine, Ambroxol hydrochloride, capsules Ambroxol hydrochloride sustained-selection, methylcysteine hydrochloride, acetyl cysteine ethyl L-cysteine hydrochloride and tyloxapol etc.

Examples of growth factors include, for example, the growth factor of the fibroblast (FGF), growth factor vascular endothelial (VEGF), a growth factor, hepatocyte (HGF) and insulin-like growth factor, etc.

Examples of NSAIDs include, for example, Szasz is IRIN, the sodium salicylate, aspirin, composition of dealuminated aspirin, diflunisal, indomethacin, suprofen, openmath, dimethyl, isopropylethylene, bufexamac, felbinac, diclofenac, tolmetin sodium, clinoril, fenbufen, napleton, proglumetacin, indomethacin, farnesyl, acemetacin, proglumetacin maleate, amfenac sodium, movetalk, etodolac, ibuprofen, ibuprofen of Picanol, naproxen, flurbiprofen aksetil, Ketoprofen, fenoprofen calcium, cuprofen, oxaprozin, pranoprofen, loxoprofen sodium, alminoprofen, zaltoprofen, mefenamico acid, mefenamic aluminum, tolfenamic acid, floctafenine, ketovinylation, oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam, ointment Napalm, epirizole, tiaramide hydrochloride, tinoridine hydrochloride, emorfazone, calponin, Amigrenin, saridon, Sedes G, amipro N, bisolvon, antipyretics pianoboy system, acetaminophen, phenacetin, dimethocaine mesilate, the composition of symetrica, antipyretics system of antipyrine, bromfenac, fenamad, sulindac, nabumetone and Ketorolac etc.

Examples of inhibitors " include, for example, celecoxib, rofecoksib, etoricoxib etc.

Examples of spasmolytic include, for example, scopolamine, etc.

Examples antagonist of the vasopressin V1a include, for example, relcovaptan etc.

Examples of the inhibitor prostaglandines include, for example, salats lapiredi, mesalazin, salasin, 4-aminosalicylic acid, JTE-522, auranofin, carprofen, divinename, flunoxaprofen, flurbiprofen, indomethacin, Ketoprofen, lornoxicam, loxoprofen, meloxicam, oxaprozin, parceled, piperoxan, piroxicam, piroxicam-β-cyclodextrin, piroxicam cinnamate, tropine indometacina, zaltoprofen, pranoprofen,touki-syakuyaku-sanandsyakuyaku-kanzou-touetc.

Examples of local anesthetics include, for example, cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine, etidocaine, bupivacaine and 2-chlorotoluene hydrochloride etc.

Examples of calcium channel blockers include, for example, nifedipine, benidipine hydrochloride, diltiazem hydrochloride, verapamil hydrochloride, nisoldipine, nitrendipin, bepridil hydrochloride, amlodipine, besylate, lomerizine hydrochloride, isradipine, nimodipine, felodipine and nicardipine, etc.

Examples of blockers of potassium channels include, for example, dofetilide, E-4031, elocuent, sematilide, emailid, azimilide, tedisamil, RP5886, sotalol, piroxicam and ibutilide etc.

Examples of vasodilators include, for example, nitroglycerine, the isosorbide dinitrate treatment and isosorbide Mononitrate etc.

Examples of diuretics include, for example, lures, furosemide, acetazolamide, diclofenamide, methazolamide, trichlormethiazide, mefruside, Speer is nolactone and aminophylline, etc.

The weight ratio of the compound represented by formula (I), and other pharmaceutical compositions is not limited.

Arbitrary two or more pharmaceutical compositions may be introduced in combination.

Examples of other pharmaceutical compositions to complement and/or enhance the preventive and/or therapeutic activity of a compound represented by the formula (I)include not only those that are currently known, but also those which will be detected on the basis of the above mechanism.

To apply the compounds in accordance with this invention, represented by formula (I)or compounds represented by formula (I), in combination with other pharmaceutical compositions, these compounds are usually administered in the entire human organism or part of an oral or parenteral.

Input dose is determined depending on, for example, age, body weight, symptom, the desired therapeutic effect, the route of administration and duration of treatment. For an adult dose to the patient is from 1 ng to 100 mg, by oral administration, up to several times a day, and from 0.1 ng to 10 mg by parenteral administration up to several times a day, or by continuous introduction of veins from 1 to 24 hours a day.

As noted above, the applied doses depend on different States. So have IU the cases, which can be applied dose is less than the above intervals.

The compound represented by formula (I) in accordance with this invention or a concomitant drug, combining a compound represented by the formula (I), with other medicines, you can enter in the form of compositions, such as solid or liquid compositions for oral administration or injection, in compositions for external use, suppositories, eye drops or inhalers for parenteral administration.

Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders and granules. Capsules include hard capsules and soft capsules.

In such solid forms one or more active compounds can be mixed with carriers such as lactose, lures, glucose, microcrystalline cellulose, starch), binding agents (such as hydroxypropylcellulose, polyvinylpyrrolidone or alumosilicate magnesium), leavening agents (such as Cellulosics calcium), lubricating agents (such as magnesium stearate), stabilizing agents and adjuvants for a solution (such as glutamic acid or aspartic acid), and it is obtained by methods well known in normal pharmaceutical practice. Solid forms may Ave is desired, to have the shell of the enrobing agent (such as sugar, gelatin, hydroxypropylcellulose or phthalate of hydroxypropylmethylcellulose) or have a coating of one or more films. The coating may include a protective capsule or absorbable materials such as gelatin.

Liquid forms for oral administration include pharmaceutically acceptable solutions, suspensions and emulsions, syrups and elixirs. In such forms one or more active ingredients can be dissolved, suspended or emulsified in a solvent, widely used in this field (such as purified water, ethanol or their mixture). In addition to these, the liquid form can also include some additives, such as wetting agents, suspendresume agents, emulsifying agents, sweeteners, colorants, flavorings, preservatives or binders.

Parenteral compositions for external use include, for example, ointment, gel, cream, lotion, patch, liniment, sprayed agent, inhaler, spray, aerosol, eye drops and nose drops, etc. They include one or more active ingredients and get them known methods or conventional methods.

Ointment get known method or conventional method. For example, it is produced by grinding into powder or melting one or more active with the of dinani and substrate. The substrate for ointments selected from known or standard. For example, higher fatty acids or esters of higher fatty acids (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, esters of adipic acid, an ester of myristic acid, an ester of palmitic acid, ester of stearic acid, ester of oleic acid, etc.), wax (yellow beeswax, spermaceti, ceresin, etc), surfactants (polyoxyethyleneglycol ether, ester phosphoric acid, etc.), higher alcohols (cetanol, stearyl alcohol, cetosteatil alcohol etc), silicone oil (dimethylpolysiloxane etc), hydrocarbons (hydrophilic petrolatum, medical petrolatum, purified lanolin, light liquid paraffin, etc.), a glycol (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol etc), vegetable oil (castor oil, olive oil, hemp oil, turpentine oil etc), butter (milk, oil, egg-yolk oil, squalane, squalene etc), water, power absorption inhibitor that is compatible with the skin, etc. are applied as separate substances selected from the above or a mixture containing two or more kinds selected from the above. Moreover, the composition can be on the obtained preservatives, stabilizers, antioxidants, flavorings, etc.

Gel get known or standard methods. For example, it is obtained by melting one or more active compounds and substrate. The substrate for a gel selected from known or standard. For example, a lower alcohol (ethanol, isopropyl alcohol, etc.), gelling agent (carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose etc), neutralizing agent (triethanolamine, diisopropanolamine etc), surfactants (polyethylene-glycol monostearate etc), resin, water, power absorption inhibitor that is compatible with the skin, etc. are used as individual substances selected from the above or mixtures containing two or more kinds selected from the above. Moreover, the composition can include preservatives, stabilizers, antioxidants, flavorings, etc.

Cream get known methods or standard methods. For example, it is obtained by melting or emulsifying one or more active ingredients and the substrate. The substrate for the cream to choose from known or standard. For example, ester of higher fatty acid, a lower alcohol, a hydrocarbon, polisport (propylene glycol, 1,3-butyleneglycol etc), higher alcohol (2-hexyldecanol, cetanol etc), emulsifying agent (Paul is oksietilenovym ether, ester of fatty acid and so on), water, power absorption inhibitor that is compatible with the skin, etc. are used as individual substances selected from the above or mixtures containing two or more kinds selected from the above. Moreover, the composition can include preservatives, stabilizers, antioxidants, flavorings, etc.

Gadgets get a known method or the standard method. For example, they are obtained by melting one or more active compounds and substrate and then plasticized mixture is placed on the substrate. The substrate for lotions selected from known or standard. For example, thickening agent (polyacrylic acid, polyvinylpyrrolidone, Arabian gum, starch, gelatin, methylcellulose, etc.), filler (kaolin, zinc oxide, talc, calcium, magnesium etc), water, solubilizers agent, thickening agent, inhibitor, compatible with the skin, etc. are applied as separate substances selected from the above or mixtures containing two or more kinds selected from the above. Moreover, the composition can include preservatives, stabilizers, antioxidants, flavorings, etc.

The patch get known method or standard method. For example, it is obtained by melting one or more active compounds and substrate and then decrease in the t to the substrate. The substrate for the patch selected from known or standard. For example, a polymer substrate, a fat, higher fatty acid, a thickener, an inhibitor that is compatible with the skin, etc. are applied as separate substances selected from the above or mixtures containing two or more kinds selected from the above. Moreover, the composition can include preservatives, stabilizers, antioxidants, flavorings, etc.

Liniment get known method or standard method. For example, one or more active compounds may be dissolved, suspended or emulsified in water, alcohol (ethanol, polyethylene glycol, etc.), higher fatty acid, glycerine, soap emulsifying agent, suspendium agent, etc. in the form of a substance selected from the above or mixtures containing two or more kinds selected from the above. Moreover, the composition can include preservatives, stabilizers, antioxidants, flavorings, etc.

Sprayed agent, inhaler and spray in addition to diluent may contain a stabilizer such as sodium bisulfite, and an isotonic buffer such as sodium chloride, sodium citrate or citric acid. The method of producing spray is described, for example, in U.S. patent No. 2868691 and 3095355.

Injections for parenteral administration include article is realnye aqueous suspension, emulsion and solid form, which is dissolved or suspended in solvents for injection immediately before use. Injection of one or more active compounds may be dissolved, suspended or emulsified in a solvent(s). Solvents may include distilled water for injection, physiological salt solution, vegetable oil, propylene glycol, polyethylene glycol, alcohol, for example ethanol, or a mixture. Injections may include some additives, such as stabilizers, adjuvants for solutions (such as glutamic acid, aspartic acid or Polysolvate 80 (registered trademark)), suspendresume agents, emulsifying agents, softening agents, buffer agents, preservatives. They can be sterilized at the last stage or can be obtained by aseptic processing. They can also be in the form of sterile solid dosage forms, such as products obtained by lyophilization, which can be dissolved in sterile water or some other sterile diluent for injection immediately before use.

Eye drops for parenteral administration can be in the form of a liquid, suspension, emulsion, or ointment, or may be dissolved in solvents in the application.

Such eye drops get any known sposobnie, one or more active substances are dissolved, suspended or emuleret in the solvent. As a solvent for eye drops can be applied sterilized purified water, saline and other aqueous or not aqueous solutions (e.g., vegetable oil), in pure form or in combination. Eye drops may include isotonic agent (e.g., sodium chloride, concentrated glycerin), a buffering agent (such as sodium phosphate, sodium acetate), surfactants (for example, Polysolvate 80 (trade mark), polyxystra 40, polyoxyethylene-utverjdenie castor oil), stabilizer (sodium citrate, edetate sodium), preservatives (e.g. benzalkonium chloride, paraben), etc. with the appropriate selectivity if necessary. Eye drops are sterilized in the final stage or receive aseptic processing. Alternatively, aseptic solid agent, for example, prior to the product obtained by lyophilization, can be restored in an aseptic form or may be dissolved in aseptic distilled water for injection or other solvent before use.

Metered inhalations for parenteral administration include aerosols, powders for inhalation or liquid for inhalation. Liquid for inhalation can be dissolved or suspend is arranged in water or other appropriate solvent if necessary.

Such inhalation get known methods.

For example, a liquid for inhalation receive a selection of suitable additives of antiseptics (such as benzalkonium chloride or p-aminobenzoic acid), coloring agent, a buffering agent (such as sodium phosphate or sodium acetate), isotonic agent (such as sodium chloride or concentrated glycerin), thickener (such as carboxyvinyl polymer), or amplifier, absorption, etc. if necessary.

Powder for inhalation receive a selection of suitable additives of lubricating agents (such as stearic acid and its salt), a coupling agent (such as starch, dextrin), a diluent such as lactose, cellulose), coloring agent, an antiseptic (such as benzalkonium chloride or p-aminobenzoic acid), amplifier, absorption, etc.

With the introduction of liquid for inhalation is usually applied by spray (spray sprinklers), with the introduction of powder for inhalation is usually used apparatus for the introduction of inhalation agents for powder.

Other compositions for parenteral administration include suppositories for rectal administration and pessaries for vaginal administration, which contain one or more active substances and can be obtained by methods known as such.

Local application:

The local application in accordance with the data of the invention the compound of the present invention can locally apply to diseases (especially diseases of the bones, which lowers the amount of bone). The form of connection in accordance with this invention is not limited to the method of its introduction. Connection in accordance with this invention may be in the form of injections, solid agent such as an agent for attachments, granule and powder, and ointment, injected intramuscularly, subcutaneously or on the joint.

Compositions with delayed release is not limited by form, so that the connection in accordance with this invention can be continuously put in place diseases (especially diseases of the bones, which decreases the amount of bone). Composition with delayed release may be in the form of injections delayed release (e.g., microencapsulated composition, the resulting composition nanoferrites composition, sealing compositions (e.g., compositions in the form of a film) or the like.

Microencapsulated composition, the resulting composition and nanohelices composition in accordance with this invention are powdered pharmaceutical composition of the polymer, degradable in vivo, containing as active ingredients compounds represented by formula (I), optionally in combination with other pharmaceutical compositions.

Examples of polymers that are degradable in vivo, matched with the accordance with this invention include polymers of esters of aliphatic acids and their copolymers, esters of polyacrylic acid, polyhydroxyalkane acid, polyalkylacrylate, complex poliorcetes, polycarbonates and polyaminoamide. These compounds can be used alone or in mixture of two or more. Examples of polymers of ester of aliphatic acid and their copolymers include polylactic acid, polyglycolic acid, polylimonene acid, polyblock acid and a copolymer of lactic acid-glycolic acid. These compounds can be used alone or in mixture of two or more. In addition to these compounds, esters of poly-α-cyanoacrylate acid, poly-β-hydroxybutiric acid, polytrimethylene, complex poliorcetes, polycholorinated, polietilensorbit, poly-γ-benzyl-L-glutamic acid can be used alone or in mixture of two or more. Among these compounds, preferred are lactic acid, polyglycolic acid and copolymers of lactic acid-glycolic acid, more preferably, copolymers of lactic acid-glycolic acid.

The average molecular weight of such polymers, degradable in vivo, used in accordance with this invention, is preferably from about 2000 up to 800,000, more preferably from about 5,000 to 200,000. For example, polylactic acid preferably has a mass-average m is molecular weight of from about 5,000 to 100,000, more preferably from about 6000 to 50000. Polylactic acid can be synthesized by any method known per se. In the copolymer of lactic acid-glycolic acid ratio of lactic acid to glycolic acid is preferably from about 100/0 to 50/50 (wt./wt.), especially from about 90/10 to 50/50. The mass-average molecular weight of the copolymer of lactic acid-glycolic acid is preferably from about 5000 to 10000, more preferably from about 10000 to 80000. The copolymer of lactic acid-glycolic acid can be synthesized by any means known as such.

The term "mass-average molecular weight" in this description means the molecular weight in polystyrene equivalent, some gel chromatography (GPC).

The amount of the above polymer, degradable in vivo, can be changed depending on the intensity of the pharmacological action of the compounds represented by formula (I), and the desired dosage of funds in accordance with the purposes of the present invention. For example, a polymer that is degradable in vivo, can be used in an amount of from about 0.2 to 10,000 times, preferably from about 1 to 1000 times, more preferably, from about 1 to 100 times (wt.) relative to the physiologically active compound.

Examples of ways of receiving the Oia microspheric, microencapsulated and nanohelices compositions include a method of drying immersion (for example, the method of water/oil", method, "water/oil/water), method, phase separation method, spray drying, granulation method through ultracritical liquid and similar methods.

Method of drying immersion (water/oil) and a method of spray drying is described in more detail below.

(1) In the method of drying immersion (method, "water/oil) first get the solution of polymer, degradable in vivo, in an organic solvent. The organic solvent used to obtain the resulting microencapsulated and nanohelices compositions preferably has a boiling point of 120°C or less. Examples of organic solvents used in this description, include halogenated hydrocarbons (e.g. dichloromethane, chloroform), aliphatic esters (e.g. ethyl acetate), ethers, aromatic hydrocarbons and ketones (e.g. acetone). These compounds can be used as a mixture of two or more in the appropriate ratio. Among the preferred organic solvents are dichloromethane and acetonitrile, especially dichloromethane. The concentration of polymer is degradable in vivo, in organic solution depends on the molecular weight of the polymer, degradable in vivo, type organic is one solvent, etc., but it usually ranges from about 0.01 to 80% (vol./wt.), preferably from about 0.1 to 70% (vol./wt.), more preferably from about 1 to 60% (vol./wt.).

The compound represented by formula (I), then add and dissolve in the polymer solution, degradable in vivo, in an organic solvent, optionally in combination with other pharmaceutical compositions. The amount of compounds represented by formula (I)added optionally in combination with other pharmaceutical compositions depends on the type of the added pharmaceutical composition, the actions of the pharmaceutical composition in osteogenesis, duration, etc. but usually it is from about 0,001% to 90% (wt./wt.), preferably from about 0.01% to 80% (wt./wt.), more preferably from about 0.3% to 30% (wt./wt.), calculated in units of concentration in the polymer solution, degradable in vivo, in an organic solvent.

Next, the thus obtained organic solution is added to the aqueous phase which is then treated in the mixer, the emulsifier or the like to obtain an emulsion of oil-in-water". The volume of the aqueous phase during this process predestinated from about 1 to 10,000 times, preferably from about 2 to 5000, especially from about 5 to 2000 times relative to the oil phase. The emulsifier may be added to the aqueous phase, which is th a homogeneous phase. As the emulsifier may be used any substance capable of forming a stable emulsion of oil-in-water. Examples of the emulsifier include anionic surfactants, nonionic surfactants, derivatives polyoxyethylenesorbitan oil, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, and gelatin. These compounds can be used in appropriate combinations. The concentration of emulsifier in homogeneous aqueous phase is preferably from 0.001% to 20% (wt./wt.), more preferably from about 0.01% to 10% (wt./wt.), especially from about 0.05% to 5% (wt./wt.).

Evaporation of the solvent, which is an oil phase, carried out by any known method. In more detail, the evaporation of the solvent can be carried out at normal pressure or a gradually decreasing pressure under stirring with a stirrer, a magnetic stirrer or the like, or can be conducted at a regulated pressure using a rotary evaporator. Thus obtained resulting composition then fractionary by centrifugation or filtration. Resulting composition is washed with a solution of surface-active substances, alcohol or similar several times to remove free connection, presents four who Ulai (I), optionally in combination with another pharmaceutical composition, and the emulsifier with its surface again dispersed in distilled water or dispersing agent containing media (e.g., mannitol, sorbitol, lactose) and then dried by freezing. In the above method of "water/oil" resulting composition can be obtained by a method comprising dispersing the compound represented by formula (I), the solution of polymer, degradable in vivo, in an organic solvent, optionally in combination with other pharmaceutical compositions, for example, by the method of "water/oil/water.

(2) To obtain the resulting composition by the method of drying by spraying an organic solvent or emulsion containing the dissolved polymer, degradable in vivo, and the compound represented by formula (I), optionally in combination with another pharmaceutical composition that is sprayed into the drying chamber of the spray dryer through a nozzle so that an organic solvent or water in the spray droplets were evaporated in a very short period of time with obtaining the resulting composition. Examples used include two nozzles nozzles for liquids, a nozzle under pressure and the rotary disk. They are used for spraying an organic solvent or aqueous solution inhibito is and aggregation (for example, mannitol, lactose, gelatin) simultaneously with the spraying of the emulsion oil-in-water, which is necessary for inhibition of aggregation of the microspheres. Microspheric composition, thus obtained, is then treated under reduced pressure, optionally by heating, to remove the water and solvent.

Examples of film compositions include a film material obtained by dissolving the above polymer, degradable in vivo, and compounds represented by formula (I), optionally in combination with another pharmaceutical composition in an organic solvent, and then evaporating the resulting solution to dryness, and gelatinizing material obtained by dissolving the above polymer, degradable in vivo, and compounds represented by formula (I), optionally in combination with another pharmaceutical composition in an organic solvent, and then adding a granulating agent (for example, cellulose, polycarbonate) to the solution.

Microspheres, microcapsules and nanospheres in accordance with this invention can be used as such. Alternatively, spherical, rod-like, acicular, granular, blankaartia or creamy pharmaceutical compositions can be processed as raw materials to obtain compositions in various forms is Ah.

Further, these compositions can be used as parenteral compositions for local application (e.g., injection, solid agents such as the submersible agents, granules and powders, liquid agents, such as suspensions, ointments, etc. for injection intramuscularly, subcutaneously, organs or joints). For example, for injection of the resulting composition, the resulting composition is suspended with the baking powder, preservative, an isotonic agent, a buffer, a pH regulator, etc. with obtaining water suspension as composition, ready for injection. Alternatively, the resulting composition can be dispersed with vegetable oil optional mixed with a phospholipid, such as lecithin, or triglyceride aliphatic acids with medium chain length (for example, Mygliol-812) obtaining a suspension in oil for injection, which can be applied in practice.

The diameter of the microspherical particles of the composition may be arbitrary so that it provided the desired dispersibility and passing through the syringe when the use of a composition in the form of a suspension for injection. For example, the average diameter of the particles resulting composition is from about 0.1 to 300 μm, preferably from about 1 to 150 μm, more preferably from about 2 to 100 microns. Pharmaceutical compositions in accordance with this invention preferably have the form of a suspension, as specified above. Pharmaceutical compositions in accordance with this invention also preferably have the form of particles. Thanks pharmaceutical composition causes less pain to the patient during introduction through the syringe when the conventional hypodermic or intramuscular injection. Particularly preferably, the pharmaceutical composition in accordance with this invention have the form of injections. Examples of the method of aseptic processing resulting composition include a method that provides asepsis at all stages, the method comprising sterilization with gamma rays, and the method comprising adding a preservative. However, this invention is not limited to these methods.

Pharmaceutical compositions in accordance with this invention can be used to treat bone disease in which the amount of bone tissue is reduced, as the compound represented by formula (I), optionally in combination with other pharmaceutical compositions, can gradually be released within 1 week to 3 months depending on the type and amount of polymer that is degradable in vivo. In the treatment of diseases of the bones, treatment of fracture often requires fixing the damaged body part and cover with a plaster bandage, and the introduction of the pharmaceutical composition can be carried is about only once, but not often. Therefore, the pharmaceutical composition introduced, therefore, must continue to provide treatment. Thus, pharmaceutical compositions in accordance with this invention is particularly useful in such treatment.

The dose of the pharmaceutical composition in accordance with this invention depends on the type, content and form of the compounds represented by formula (I), optionally in combination with other pharmaceutical compositions, the duration of release of the pharmaceutical composition, treat the animal, etc. but is usually effective amount of the compound represented by formula (I), optionally in combination with other pharmaceutical compositions. With the introduction of the lesion in the form of microspherical composition, for example, a one-time dose for an adult patient (weight 50 kg) is from about 0.001 mg to 500 mg, preferably from about 0.01 to 50 mg, in the calculation of the effective component. The pharmaceutical composition in accordance with this invention can be introduced only once during the period from 1 week to 3 months above-stated amount.

The optimal way of carrying out this invention

Below is a more detailed description of this invention in the form of reference examples and examples, which, however, dannheisser is not limited.

The solvents in parentheses are manifesting or an eluting solvent, and the ratio of the used solvents are given in volume in the chromatographic separations or TLC.

The solvents in parentheses for NMR is a spectroscopic solvents.

HPLC is carried out in conditions of measurement F.

THP is tetrahydropyran-2-yl and BOC represents tert-butoxycarbonyl.

If the connection includes two diastereoisomer, the term "more polar" refers to the compound having a lower Rf value, and the term "less polar" refers to the compound having a larger Rf value.

The names of the compounds in examples 1-10 are given in accordance with the IUPAC nomenclature or trivial item. The names of the compounds in the examples 11-22 are using ACD/Name Pro, version 6.0 or in accordance with the IUPAC nomenclature or trivial item.

Reference example 1

S-(2,2-diatexite)attentioin

In the atmosphere of argon diethylacetal 2-bromoacetaldehyde (7,29 g) and thioacetic potassium (to 4.23 g) are mixed in dimethylformamide (20 ml) and the mixture is stirred at a temperature of 50°C for 5 hours. After cooling, to the reaction solution was added water, then extracted with a mixed solvent of ethyl acetate-hexane. The organic layer is washed with water and saturated of rest the rum salt, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the connection header (7,10 g)having the following physical data.

TLC: Rf 0.56 to (n-hexane:ethyl acetate=9:1);

1H-NMR (CDCl3): δ 4,43 (t, J = 5.4 Hz, 1H), 3,67-of 3.43 (m, 4H), 3.04 from (d, J=5.4 Hz, 2H), 2,28 (s, 3H), 1.14 in (t, J=7.2 Hz, 3H).

Reference example 2

Ethyl ester of 2-(2,2-detoxication)thiazole-4-carboxylic acid

To a solution of the compound obtained in reference example 1 (1,76 g), ethyl ester 2-bromothiazole-4-carboxylic acid (1.80 g) and tributylphosphine (0,19 ml) in ethanol (10 ml) is added potassium carbonate (1,57 g) in an ice bath and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the solution extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the connection header. The compound obtained is used in the next reaction without purification.

TLC: Rf of 0.40 (toluene:ethyl acetate=9:1);

1H-NMR (CDCl3): δ 8,02 (s, 1H), 4,77 (t, J=5.4 Hz, 1H), 4,39 (kV, J=7.2 Hz, 2H), 3,79-of 3.54 (m, 4H), 3,47 (d, J=5.4 Hz, 2H), 1,39 (t, J=7.2 Hz, 3H), 1,22 (t, J=7.2 Hz, 6H).

Reference example 3

Ethyl ester of 2-(formylmethylene)thiazole-4-carboxylic acid

The compound obtained in reference example 2 was dissolved in ethanol (15 ml) and add the keys 2N hydrochloric acid (5.7 ml). The mixture is stirred at a temperature of 60°C for 3 hours. After cooling, to the reaction solution was added water and extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to obtain the specified title compound (714 mg)having the following physical data:

TLC: Rf 0,20 (n-hexane:ethyl acetate=4:1);

1H-NMR (CDCl3): δ 9,72 (t, J=2.1 Hz, 1H), with 8.05 (s, 1H), 4,39 (kV, J=6,9 Hz, 2H), 4.09 to (d, J=2.1 Hz, 2H), 1,39 (t, J=6.9 Hz, 3H).

Reference example 4

(1S)-1-(1-Ethylcyclohexyl)-3-(1-phenyl-1H-tetrazol-5-ylthio)propan-1-ol

To a solution of (1S)-1-(1-ethylcyclohexyl)propane-1,3-diol (8.90 g) in toluene (110 ml) is added tetrabutylammonium chloride (1.56 g) and 2N aqueous sodium hydroxide solution (170 ml). When the temperature of the reaction mass to about 25°C to the reaction solution add taillored (11.3 g), then the solution is stirred at a temperature of 25°C for 1 hour. To the reaction solution was added 1-phenyl-1H-tetrazol-5-thiol (11,0 g), then the solution is stirred at a temperature of 60°C for 1 hour. After cooling, to the reaction solution was added water and the solution is separated. The aqueous layer was extracted with tert-butylmethylamine ether. Mixed by organicheskikh washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the title compound (17.9 g)having the following physical data:

TLC: Rf of 0.67 (n-hexane:ethyl acetate=1:1).

Reference example 5

(1S)-1-(1-Ethylcyclohexyl)-3-(1-phenyl-1H-tetrazol-5-ylsulphonyl)propan-1-ol

To a solution of the compound obtained in reference example 4 (17.9 g)in methanol (225 ml) add a solution of peroxymonosulfate potassium (trade name OXONE) (52,0 g) in water (225 ml) at room temperature and the mixture is stirred at a temperature of 60°C for 8 hours. After cooling, to the reaction solution was added water and the solution extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the title compound (19.7 g)having the following physical data: TLC: Rf 0,78 (n-hexane:ethyl acetate=1:1).

Reference example 6

(1S)-1-(1-Ethylcyclohexyl)-3-(1-phenyl-1H-tetrazol-5-ylsulphonyl)-1-(tetrahydropyran-2-yloxy)propane

In an argon atmosphere to a solution of the compound obtained in reference example 5 (19.7 g)and 2,3-dihydro-2H-Piran (of 5.68 g) in methylene chloride (100 ml) add monohydrate p-toluenesulfonic acid (54 mg) in an ice bath and the mixture is stirred at a temperature of from 0°C to 10°C for 2 hours. To the reaction is Astaro add triethylamine (1 ml), then the solution is concentrated. The resulting residue is purified column chromatography on silica gel (n-hexane:ethyl acetate=9:1→4:1) to obtain the specified title compound (15.3 g)having the following physical data:

TLC: Rf 0.50 to 0.45 (n-hexane:ethyl acetate=4:1);

1H-NMR (CDCl3): δ 7,80 is 7.50 (m, 5H)and 4.65 (m, 0,3H), of 4.44 (m, 0,7H), 4,05 is 3.40 (m, 5H), 2,30-of 1.35 (m, 16H), 1,00-of 0.85 (m, 3H).

Reference example 7

Ethyl ester (4R)-4-formyl-4-tert-butoxycarbonylamino acid

In an argon atmosphere to a stirred solution of ethyl ester (4R)-4-tert-butoxycarbonylamino-5-hydroxypentanal acid (1,62 g) and diisopropylethylamine (6.5 ml) in a mixture of dimethyl sulphoxide, ethyl acetate (1:1, 40 ml) is added a complex of a sulfur trioxide-pyridine (2,96 g) in an ice bath and the mixture is stirred in an ice bath for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 0,5N hydrochloric acid, water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the title compound (1.65 g)having the following physical data:

TLC: Rf of 0.25 (n-hexane:ethyl acetate=4:1);

1H-NMR (CDCl3): δ a 9.60 (s, 1H), 5,20 (width, 1H), 4,27 (width, 1H), 4,14 (kV, J=7.2 Hz, 2H), 2,60-of 2.20 (m, 3H), 1.91 a (m, 1H), 1,45 (s, 9H), of 1.26 (t, J=7.2 Hz, 3H).

Reference example 8

E. the silt ether (4R,5E,8S)-4-tert-butoxycarbonylamino-8-(1-ethylcyclohexyl)-8-(tetrahydropyran-2-yloxy)Oct-5-ene acid

In an argon atmosphere a solution of 0.5 m bis(trimethylsilyl)amide potassium in toluene (18.6 ml) is added dropwise to a solution of the compound obtained in reference example 6 (or 4.31 g)in anhydrous 1,2-dimethoxyethane (30 ml) at a temperature of -78°C and the mixture is stirred for 1 hour at the same temperature. To the reaction mixture is added dropwise a solution of the compound obtained in reference example 7, (1.65 g) in 1,2-dimethoxyethane (10 ml), the mixture is heated to a temperature of 0°C for 2 hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution and the reaction mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (n-hexane:ethyl acetate=9:1→4:1) to obtain the specified title compound (1.20 g)having the following physical data:

TLC: Rf of 0.50 (n-hexane:ethyl acetate=4:1);

1H-NMR (CDCl3): δ 5,85-of 5.55 (m, 1H), the 5.45 and 5.30 (m, 1H), 4,65-4,55 (m, 1H), 4,20-of 3.85 (m, 5H), 3,65 is 3.40 (m, 2H), 2,45-of 1.40 (m, 20H), USD 1.43 (s, 9H), 1.30 and of 1.20 (m, 3H), 1.00 m-0,85 (m, 3H).

Reference example 9

Hydrochloride ethyl ester (4R,5E,8S)-4-amino-8-(1-ethylcyclohexyl)-8-hydroxycut-5-ene acid

To a solution of the compound obtained in reference example 8 (172 mg)in ethanol (2 ml) is added 4N solution is aristovo hydrogen in dioxane (0.5 ml) and the mixture is stirred at room temperature for 8 hours. The reaction solution is concentrated to obtain specified in the title compound (120 mg).

TLC: Rf of 0.20 (chloroform:methanol=9:1)

Example 1

(13TH,16α )-17,17-Propane-16-hydroxy-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

In an argon atmosphere a solution of the compound obtained in reference example 9 (120 mg)and the compound obtained in reference example 3 (102 mg)in tetrahydrofuran (2 ml) was stirred at room temperature for 30 minutes. To the solution add triacetoxyborohydride sodium (116 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the solution extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (ethyl acetate) to give the compounds of this invention (93 mg)having the following physical data:

TLC: Rf of 0.29 (ethyl acetate);

1H-NMR (CDCl3): δ 8,02 (s, 1H), of 5.82 (dt, J=is 15.3 and 6.9 Hz, 1H), 5,39 (DD, J=15,3, and 8.7 Hz, 1H), 4,39 (kV, J=7.2 Hz, 2H), 4,19 (m, 1H), 3,82 (m, 1H), 3,56-to 3.35 (m, 4H), 2,50-of 1.55 (m, 13H), of 1.40 (m, 1H), 1,39 (t, J=7.2 Hz, 3H), 1.26 in (m, 1H), from 0.90 (t, J=7.5 Hz, 3H).

Examples 1(1)-1(16)

According to the method of example 1 using the compound obtained in reference example 3, or the corresponding derived alder is Yes and the connection obtained in reference example 9, or a corresponding amine derivative are given the following compounds of this invention.

Example 1(1)

Butyl ether (13TH)-20-methyl-15-hydroxy-9-oxo-5,17-dithia-8-isapros-13-ene acid

more polar

TLC: Rf of 0.40 (ethyl acetate);

1H-NMR (CDCl3): δ 5,73 (DD, J=15,3, 5,1 Hz, 1H), 5,61 (DD, J=15,3, 8,1 Hz, 1H), 4,24 (m, 1H), 4,15 (m, 1H), 4,08 (t, J=7.2 Hz, 2H), 3,68 (m, 1H), 3,11 (m, 1H), 2,80-of 2.20 (m, 13H), 1,97 is 1.70 (m, 3H), 1,67-of 1.32 (m, 8H), were 0.94 (t, J=7.5 Hz, 3H), of 0.93 (t, J=7.5 Hz, 3H).

Connection is the only isomer, although the configuration in position 15 not defined.

Example 1(2)

(13TH,15thα)-15-Hydroxy-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.51 (ethyl acetate);

1H-NMR (CDCl3): δ 8,02 (s, 1H), 5,78 (DD, J=15,3, 5.7 Hz, 1H), 5,54 (DD, J=15,3, 9.0 Hz, 1H), 4,39 (kV, J=6,9 Hz, 2H), 4,21 (m, 1H), 4,10 (m, 1H), 3,79 (m, 1H), 3,50-to 3.38 (m, 3H), 2,50 is 2.10 (m, 3H), 1,95 (Sirs, 1H), 1.77 in (m, 1H), 1,66-of 1.20 (m, 11H), of 0.87 (t, J =6.9 Hz, 3H).

Example 1(3)

Butyl ether (13TH,15thα)-20,20-ethano-15-hydroxy-9-oxo-5-thia-8-isapros-13-ene acid

TLC: Rf is 0.49 (ethyl acetate);

1H-NMR (CDCl3): δ 5,74 (DD, J=15,9, 6.0 Hz, 1H), 5,52 (DD, J=15,9, and 8.4 Hz, 1H), 4,21-a 4.03 (m, 4H), 3,63 (m, 1H), 3,10 (m, 1H), 2,73-of 2.20 (m, 9H), 1,98-of 1.18 (m, 16H), of 0.93 (t, J=7.5 Hz, 3H), of 0.65 (m, 1H), and 0.40 (m, 2H)that 0,00 (m, 2H).

Example 1(4)

Ethyl ether (13TH,16&x003B1; )-17,17-propane-16-hydroxy-9-oxo-20-nor-8-isapros-13-ene acid

TLC: Rf is 0.42 (ethyl acetate);

1H-NMR (CDCl3): δ 5,77 (dt, J=15,3, 7.2 Hz, 1H), 5,38 (DD, J=15,3, 9.0 Hz, 1H), 4,12 (kV, J=7.2 Hz, 2H), a 4.03 (m, 1H), 3,62-3,44 (m, 2H), 2,88 (m, 1H), 2,50-1,20 (m, 23H), 2,28 (t, J=7.5 Hz, 2H), 1,25 (t, J=7.2 Hz, 3H), of 0.93 (t, J=7.2 Hz, 3H).

Example 1(5)

Methyl ether (13TH,16α)-17,17-propane-16-hydroxy-9-oxo-2,7-(1,3-interphenylene)-3,4,5,6,20-pentanol-8-isapros-13-ene acid

TLC: Rf of 0.54 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 7,30-7,22 (m, 1H), 7,20-7,10 (m, 3H), 5,70 (dt, J=15,0, 7.2 Hz, 1H), of 5.34 (DD, J=to 15.0, 9.0 Hz, 1H), 4,91 (d, J=to 15.0 Hz, 1H), 3,92 (d, J=to 15.0 Hz, 1H), a 3.87 (m, 1H), 3,70 (s, 3H), 3,61 (s, 2H), 3,52 (DD, J=9,9, 2.1 Hz, 1H), 2,55-of 1.35 (m, 14H), of 0.93 (t, J=7.2 Hz, 3H).

Example 1(6)

Ethyl ether (13TH,16α)-17,17-propane-16-hydroxy-9-oxo-1,5-(1,3-interphenylene)-2,3,4,20-tetranor-8-isapros-13-ene acid

TLC: Rf of 0.38 (ethyl acetate);

1H-NMR (CDCl3): δ 7,86 (m, 2H), was 7.36 (m, 2H), 5,72 (m, 1H), 5,35 (DD, J=15,3, and 8.7 Hz, 1H), 4,37 (kV, J=6,9 Hz, 2H), 4.00 points (m, 1H), 3,63 is-3.45 (m, 2H), 2,98 (m, 1H), 2,65 (m, 2H), 2,50-2,07 (m, 4H), 2.05 is is 1.23 (m, 16H), of 0.91 (t, J=7.5 Hz, 3H).

Example 1(7)

Methyl ether (13TH,16α)-17,17-propane-16-hydroxy-9-oxo-1,5-(2,5-intertitle)-2,3,4,20-tetranor-8-isapros-13-ene acid

TLC: Rf of 0.32 (ethyl acetate);

1H-NMR (CDCl3): δ to 7.61 (d, J=3.6 Hz, 1H), 6,80 (d, J=3.6 Hz, 1H), of 5.75 (m, 1H), are 5.36 (DD, J=15,0, and 8.7 Hz, 1H), 4,01 (m, 1H), 3,86 (s, 3H), 3,66 (m, 2H), 3,03 (m, 1H), 2,82 (m, 2H) 2,50-of 2.15 (m, 4H), 2,10-to 1.37 (m, 13H), of 0.90 (t, J=7.5 Hz, 3H).

Example 1(8)

Methyl ether (13TH,16α)-17,17-propane-16-hydroxy-9-oxo-1,6-(1,4-interphenylene)-2,3,4,5,20-pentanol-8-isapros-13-ene acid

TLC: Rf of 0.27 (ethyl acetate).

Example 1(9)

(13TH)-17,17-Propane-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-isapros-13-EN

TLC: Rf of 0.29 (n-hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,02 (s, 1H), of 5.68 (dt, J=15,3, and 6.6 Hz, 1H), 5,22 (DD, J=15,3, 9.0 Hz, 1H), 4,39 (kV, J=7.2 Hz, 2H), 4,13 (m, 1H), 3,83 (m, 1H), 3,49-to 3.41 (m, 2H), 3,32 (m, 1H), 2,44-to 2.29 (m, 2H), 2,19 (m, 1H), 2,04 is 1.48 (m, 8H), 1,43 to 1.31 (m, 6H), of 1.05 (s, 3H).

Example 1(10)

(16α)-17,17-Propane-16-hydroxy-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isoprostane

TLC: Rf of 0.25 (ethyl acetate);

1H-NMR (CDCl3): δ 8,01 (s, 1H), to 4.38 (q, J=7.2 Hz, 2H), with 3.89 (m, 1H), and 3.72 (m, 1H), 3,56-3,30 (m, 4H), 2,46-of 2.09 (m, 3H), 2,02-of 1.20 (m, 16H), of 1.39 (t, J=7.2 Hz, 3H), of 0.91 (t, J=7.5 Hz, 3H).

Example 1(11)

Methyl ether (13TH,16α)-17,17-propane-16-hydroxy-9-oxo-1,5-(1,4-interphenylene)-2,3,4,20-tetranor-8-isapros-13-ene acid

TLC: Rf of 0.29 (ethyl acetate);

1H-NMR (CDCl3): δ to 7.95 (d, J=8.1 Hz, 2H), 7,25 (d, J=8.1 Hz, 2H), 5,69 (dt, J=is 15.3 and 6.9 Hz, 1H), of 5.34 (DD, J=15,3, and 8.7 Hz, 1H), 3,97 (m, 1H), 3,90 (s, 3H), 3.72 points is-3.45 (m, 2H), 2,97 (m, 1H), 2,66 (t, J=7.8 Hz, 2H), 2,50-of 1.55 (m, 15H), of 1.50 and 1.35 (m, 2H), of 0.91 (t, J=7.5 Hz, 3H).

Example 1(12)

(13TH,16α)-17,17-Propane-16-hydroxy-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-8-isapros-13-EN

TLC: Rf 0.14 (ethyl acetate);

1H-NMR (CDCl3): δ of 8.04 (s, 1H), 5,78 (dt, J=15,3, and 6.6 Hz, 1H), 5,38 (DD, J=15,3, and 8.7 Hz, 1H), 4,42 (kV, J=7.2 Hz, 2H), 4,06 (m, 1H), 3,65-to 3.50 (m, 2H), 3,10-3,00 (m, 2H), 2,50-of 1.55 (m, 17H), USD 1.43 (m, 1H), 1,40 (t, J=7.2 Hz, 3H), of 0.92 (t, J=7.2 Hz, 3H).

Example 1(13)

(13TH,16α)-17,17-Propane-16-hydroxy-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-5,8-dianapost-13-EN

TLC: Rf 0,49 (ethylacetat:methanol=9:1);

1H-NMR (CDCl3): δ 7,37 (s, 1H), 6,07 (width, 1H), of 5.81 (dt, J=15,3, and 6.6 Hz, 1H), 5,41 (DD, J=15,3, 9.0 Hz, 1H), 4,34 (kV, J=6,9 Hz, 2H), 4,07 (m, 1H), 3,66 is 3.40 (m, 5H), 2,50-to 1.60 (m, 14H), of 1.44 (m, 1H), 1,36 (t, J=6.9 Hz, 3H), of 0.92 (t, J=7.5 Hz, 3H).

Example 1(14)

(13TH)-5-(4-Ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.30 (hexane:ethyl acetate=1:2);

1H-NMR: δ 8,02 (s, 1H), to 5.66 (dt, J=is 15.3 and 6.9 Hz, 1H), total of 5.21 (DD, J=15,3, and 8.7 Hz, 1H), 4,39 (kV, J=6,9 Hz, 2H), 4,14 (m, 1H), 3,83 (dt, J=13,5, 6,9 Hz, 1H), 3,48 is 3.40 (m, 2H), 3,30 (dt, J=13,5, 6,9 Hz, 1H), 2,48 is 2.10 (m, 4H), 2,08-of 1.93 (m, 2H), 1,71 (m, 1H), 1,39 (t, J=6.9 Hz, 3H), 1,35-of 1.16 (m, 5H), 0,86 (t, J=7.2 Hz, 3H).

Example 1(15)

(13TH)-17,17-Propane-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.32 (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,02 (s, 1H), 5,69 (dt, J=15,3, and 6.6 Hz, 1H), total of 5.21 (DD, J=15,3, 9.0 Hz, 1H), 4,39 (kV, J=7.2 Hz, 2H), 4,12 (m, 1H), 3,84 (dt, J=13,5, 6,9 Hz, 1H), 3,50-3,39 (m, 2H), and 3.31 (dt, J=13,5, 6,9 Hz, 1H), 2,48-2,12 (m, 3H), 1,96-of 1.52 (m, 8H), 1,47-of 1.32 (m, 8H), to 0.74 (t, J=7.2 Hz, 3H).

Example 1(16)

(13TH)-14-(3,5-Dichlorophenyl)-5-(4-ataxia bonisteel-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.27 (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ to 7.95 (s, 1H), 7.23 percent (t, J=1.8 Hz, 1H), 7,18 (d, J=1.8 Hz, 2H), 6,50 (d, J=15,9, 1H), 6,04 (DD, J=15,9, 9.0 Hz, 1H), 4,47-4,34 (m, 3H), with 3.89 (m, 1H), 3,56 of 3.28 (m, 3H), 2,55 with 2.14 (m, 3H), of 1.86 (m, 1H), 1,38 (t, J=7.2 Hz, 3H).

Example 2

(13TH,16α)-17,17-Propane-16-hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

To a solution of the compound obtained in example 1 (93 mg)in ethanol (2 ml) is added 2N aqueous sodium hydroxide solution (0.5 ml) and the mixture is stirred at room temperature for 2 hours. The reaction solution is neutralized with hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (chloroform:methanol:acetic acid=90:10:1) to give the compounds of this invention (78 mg)having the following physical data:

TLC: Rf of 0.25 (chloroform:methanol=4:1);

1H-NMR (CDCl3): δ 8,08 (Sirs, 1H), of 5.84 (m, 1H), 5.40 to (m, 1H), 4,10 (m, 1H), 4,00-2,50 (width, 2H), 3,78 (m, 1H)and 3.59 (m, 1H), 3,49 (m, 1H), 3,32 (m, 2H), 2,50 is 1.58 (m, 12H), of 1.44 (m, 1H), 1.26 in (m, 1H), to 0.92 (t, J=7.5 Hz, 3H).

Examples 2(1)-2(16)

According to the method of example 2 using the compound obtained in examples 1(1)-1(16)instead of the compound obtained in example 1, produces the t following compounds of the present invention.

Example 2(1)

(13TH)-20-Methyl-15-hydroxy-9-oxo-5,17-dithia-8-isapros-13-ANOVA acid

more polar

TLC: Rf of 0.37 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ of 5.75 (DD, J=15,6, 4.8 Hz, 1H), 5,63 (DD, J=15,6, 8,1 Hz, 1H), 4,25 (m, 1H), 4,17 (m, 1H), 3,66 (m, 1H), 3,23-of 2.20 (m, 16H), 1,99 is 1.70 (m, 3H), 1,58 (m, 2H), 1,40 (m, 2H), of 0.93 (t, J=7.2 Hz, 3H).

Connection is the only isomer, although the configuration in position 15 not defined.

Example 2(2)

(15α,13TH)-15-Hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.30 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 8,10 (s, 1H), 5,80 (DD, J=15,6, 6.0 Hz, 1H), 5,55 (DD, J=15,6, and 8.7 Hz, 1H), 4,30-of 3.77 (m, 5H), 3,60 be 3.29 (m, 3H), 2,58-of 2.20 (m, 3H), of 1.80 (m, 1H), 1,62-to 1.21 (m, 8H), to 0.88 (t, J=7.5 Hz, 3H).

Example 2(3)

(15α,13TH)-20,20-Ethano-15-hydroxy-9-oxo-5-thia-8-isapros-13-ANOVA acid

TLC: Rf of 0.37 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 5,73 (DD, J=15,3, 5.7 Hz, 1H), of 5.53 (DDD, J=15,3 and 8.1, 1.0 Hz, 1H), 4,18 (m, 2H), 3,63 (m, 1H), 3,30-2,78 (m, 2H), 2,75-of 2.20 (m, 10H), 1,98-to 1.67 (m, 3H), 1,62-1,10 (m, 8H), and 0.62 (m, 1H), and 0.40 (m, 2H), -0,02 (m, 2H).

Example 2(4)

(13TH,16α)-17,17-Propane-16-hydroxy-9-oxo-20-nor-8-isapros-13-ANOVA acid

TLC: Rf of 0.38 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 5,79 (dt, J=is 15.3 and 6.9 Hz, 1H), 5,38 (DD, J=15,3, and 8.7 Hz, 1H), of 4.05 (m, 1H), 4,00 3.00 for (width, 2H), to 3.58 (DD, J=a 9.9, 2.4 Hz, 1H), 3,52 (m, 1H), 2,87 (m, 1H), 2,50-of 1.20 (m, 24H), of 0.93 (t, J=7.2 Hz, 3H)./p>

Example 2(5)

(13TH,16α)-17,17-Propane-16-hydroxy-9-oxo-2,7-(1,3-interphenylene)-3,4,5,6,20-pentanol-8-isapros-13-ANOVA acid

TLC: Rf of 0.32 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 7,25 (m, 1H), 7,20-7,10 (m, 3H), 5,71 (dt, J=15,3, 7.2 Hz, 1H), 5,32 (DD, J=15,3, 9.0 Hz, 1H), 4,96 (d, J=14.4 Hz, 1H), 4,50-3,00 (width, 2H), 3,86 (d, J=14.4 Hz, 1H), 3,81 (m, 1H), 3,65 (d, J=15.3 Hz, 1H)and 3.59 (d, J=15.3 Hz, 1H), of 3.56 (DD, J=9,9, 2.1 Hz, 1H), 2,55 of 1.50 (m, 13H), of 1.44 (m, 1H), 0,93 (t, J=7.2 Hz, 3H).

Example 2(6)

(13TH,16α)-17,17-Propane-16-hydroxy-9-oxo-1,5-(1,3-interphenylene)-2,3,4,20-tetranor-8-isapros-13-ANOVA acid

TLC: Rf of 0.48 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ to 7.93 (m, 2H), 7,45-7,38 (m, 2H), 5,74 (m, 1H), are 5.36 (DD, J=15,3, 9.0 Hz, 1H), 4,01 (m, 1H), 3,63-3,51 (m, 2H), 3,00 (m, 1H), to 2.67 (t, J=7,0 Hz, 2H), 2,55-2,12 (m, 4H), 2,08 is 1.58 (m, 12H), of 1.41 (m, 1H), of 0.91 (t, J=7.8 Hz, 3H).

Example 2(7)

(13TH,16a)-17,17-Propane-16-hydroxy-9-oxo-1,5-(2,5-intertitle)-2,3,4,20-tetranor-8-isapros-13-ANOVA acid

TLC: Rf to 0.19 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ to 7.68 (d, J=3,9 Hz, 1H), 6,83 (d, J=3,9 Hz, 1H), 5,77 (m, 1H), 5,65 (Sirs, 1H), are 5.36 (DD, J=15,3, and 8.7 Hz, 1H), of 4.05 (m, 1H), 3,62-to 3.50 (m, 2H), 3,03 (m, 1H), 2,86 (t, J= 7,0 Hz, 2H), 2,55-to 2.18 (m, 4H), 2,11-1,58 (m, 12H), of 1.41 (m, 1H), to 0.92 (t, J=7.2 Hz, 3H).

Example 2(8)

(13TH,16a)-17,17-Propane-16-hydroxy-9-oxo-1,6-(1,4-interphenylene)-2,3,4,5,20-pentanol-8-isapros-13-ANOVA acid

TLC: Rf 0.28 in (ethyl acetate:acetic acid=100:1);

1H-NMR (CDCl3): δ 8,01 (d, J=8.1 Hz, 2H), 7,29 (d, J=8.1 Hz, 2H), 567 (DDD, J=15,3, 8,1, 6,6 Hz, 1H), 5,27 (DD, J=15,3, 9.0 Hz, 1H), 3,88-and 3.72 (m, 2H), only 3.57 (DD, J=a 9.6, 2.7 Hz, 1H), 3,20 (m, 1H), 3.00 and is 2.80 (m, 2H), 2,50 is 1.58 (m, 13H), a 1.45 (m, 1H), 0,93 (t, J=7.5 Hz, 3H).

Example 2(9)

(13TH)-17,17-Propane-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-isapros-13-EN

TLC: Rf of 0.35 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 5,74 (dt, J=15,0, 6,9 Hz, 1H), 5,27 (DD, J=15,0, and 8.4 Hz, 1H), 4,06 (m, 1H), 3,82 (m, 1H), 3,49 (m, 1H), 3,40-3,20 (m, 2H), 2,53-of 2.15 (m, 3H), 2,09-of 1.53 (m, 9H), 1,50-of 1.40 (m, 2H), 1,08 (s, 3H).

Example 2(10)

(16a)-17,17-Propane-16-hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isoprostane

TLC: Rf 0.28 in (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 8,07 (s, 1H), 5,00-4,00 (width, 2H), 3,88 (m, 1H), 3.75 to 3,20 (m, 5H), 2,50-of 1.20 (m, 18H), of 0.91 (t, J=7.2 Hz, 3H).

Example 2(11)

(13TH,16a)-17,17-Propane-16-hydroxy-9-oxo-1,5-(1,4-interphenylene)-2,3,4,20-tetranor-8-isapros-13-ANOVA acid

TLC: Rf is 0.24 (ethyl acetate:acetic acid=100:1);

1H-NMR (CDCl3): δ 8,00 (d, J=8.1 Hz, 2H), 7,27 (d, J=8.1 Hz, 2H), 7,00-4,00 (width, 2H), 5,71 (dt, J=the 15.6, 6.9 Hz, 1H), are 5.36 (DD, J=15,6, and 8.7 Hz, 1H), 4.00 points (m, 1H), to 3.58 (m, 1H), 3,53 (DD, J=a 9.9, 2.4 Hz, 1H), 2,98 (m, 1H), to 2.67 (t, J=7.5 Hz, 2H), 2,50-of 1.55 (m, 15H), USD 1.43 (m, 1H), of 0.91 (t, J=7.2 Hz, 3H).

Example 2(12)

(13TH,16a)-17,17-Propane-16-hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-8-isapros-13-EN

TLC: Rf of 0.47 (chloroform:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ 8,13 (s, 1H), 5,81 (the t, J=15,0, 7.2 Hz, 1H), 5,41 (DD, J=15,0, and 8.7 Hz, 1H), 5,50-4,00 (width, 2H), 4,07 (m, 1H), 3,61 (DD, J=a 9.6, 2.7 Hz, 1H), of 3.56 (m, 1H), 3,14 (m, 1H), 3.04 from (t, J=7.5 Hz, 2H), 2,50-to 1.60 (m, 15H), a 1.45 (m, 1H), to 0.92 (t, J=7.5 Hz, 3H).

Example 2(13)

(13TH,16a)-17,17-Propane-16-hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5,8-dianapost-13-EN

TLC: Rf is 0.49 (chloroform:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ 11,78 (width, 1H), 7,31 (s, 1H), 6,03 (dt, J=15,0, 7.2 Hz, 1H), from 5.29 (DD, J=15,0, and 8.7 Hz, 1H), 4,07 (m, 1H), 3,65-3,30 (m, 5H), 2,50-of 1.55 (m, 15H), of 1.42 (m, 1H), from 0.90 (t, J=7.5 Hz, 3H).

Example 2(14)

(13TH)-5-(4-Carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.37 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 5,72 (dt, J=15,3, and 6.6 Hz, 1H), 5,27 (DD, J=15,3, 9.0 Hz, 1H), of 4.05 (m, 1H), 3,80 (m, 1H), 3,51 (m, 1H), 3,40-is 3.21 (m, 2H), 2,54-of 2.15 (m, 3H), 2.13 and is 2.00 (m, 2H), of 1.75 (m, 1H), 1,45-1,17 (m, 6H), to 0.89 (t, J=6.6 Hz, 3H).

Example 2(15)

(13TH)-17,17-Propane-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.37 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 8.09 (s, 1H), 5,74 (dt, J=15,3, and 6.6 Hz, 1H), 5,28 (DD, J=15,3, and 8.7 Hz, 1H), 4,06 (m, 1H), 3,82 (m, 1H), 3,49 (m, 1H), 3,41 is 3.23 (m, 2H), 2,54-of 2.16 (m, 3H), 2,04-1,89 (m, 2H), 1,88-to 1.63 (m, 7H), 1,52-of 1.40 (m, 4H), of 0.77 (t, J=7.2 Hz, 3H).

Example 2(16)

(13TH)-14-(3,5-Dichlorophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.33 (chloroform:methanol:acetic acid=9:1:0,1);

1The NMR (CDCl 3): δ 8,08 (s, 1H), 7,27 (t, J=1.8 Hz, 1H), 7,24 (d, J=1.8 Hz, 2H), of 6.49 (d, J=15,6, 1H), 6,07 (DD, J=15,6, and 8.7 Hz, 1H), 4,30 (m, 1H), 3,90 (m, 1H), 3,49 (m, 1H), 3,41-3,30 (m, 2H), 2,62 is 2.43 (m, 2H), to 2.35 (m, 1H), 1,89 (m, 1H).

Reference example 10

The hydrochloride of the ethyl ester of 2-(2-aminoacetic)thiazole-4-carboxylic acid

To a solution of ethyl ester of 2-bromothiazole-4-carboxylic acid (3.00 g) in ethanol (15 ml) add tributylphosphine (25 mg) and the group probably facilitates (1.2 g) and the mixture is stirred at room temperature for 16 hours. Next, the group probably facilitates (1.0 g) is added to the mixture and it is stirred at a temperature of 50°C for 5 hours. After cooling to room temperature the reaction solution is neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The residue is diluted with ethyl acetate (30 ml) and to it add 4N solution of hydrogen chloride in ethyl acetate. The precipitated solid is filtered off with obtaining specified in the title compound (2.28 g)having the following physical data:

TLC: Rf of 0.20 (chloroform:methanol=9:1);

1H-NMR (CD3OD): δ with 8.33 (s, 1H), 4,37 (kV, J=7.2 Hz, 2H), 3,55 (t, J=6.6 Hz, 2H), 3,37 (t, J=6.6 Hz, 2H), 1,38 (t, J=7.2 Hz, 3H).

Reference example 11

Ethyl ester of 3-(4-tert-butylbenzoyl)propanoic acid

To a solution of tert-bout is Ventola (2.00 g) in 1,2-dichloroethane (30 ml) is added aluminum chloride (2.2 g) in an ice bath. To the mixture are added dropwise ethylsuccinate (2.3 ml), the mixture is then stirred at room temperature for 23 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (n-hexane:ethyl acetate=9:1→5:1) to obtain the specified title compound (629 mg)having the following physical data:

TLC: Rf of 0.65 (n-hexane:ethyl acetate=3:1);

1H-NMR (CDCl3): δ a 7.92 (d, J=8.7 Hz, 2H), of 7.48 (d, J=8.7 Hz, 2H), 4,16 (kV, J=7.2 Hz, 2H), 3,29 (t, J=6.6 Hz, 2H), 2,75 (t, J=6.6 Hz, 2H), of 1.34 (s, 9H), of 1.26 (t, J=7.2 Hz, 3H).

Example 3

Ethyl ester of 2-(2-(2-(4-tert-butylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

In an argon atmosphere to a solution of the compound obtained in referential example 10 (270 mg)in ethanol (5 ml) is added sodium bicarbonate (84 mg) and the mixture is stirred for 10 minutes. Then there was added acetic acid (0,12 ml) and the compound obtained in reference example 11 (262 mg), and the mixture is stirred at room temperature for 15 minutes. To the reaction solution add cyanoborohydride sodium (125 mg) and the solution stirred at a temperature of 70�B0; C during the night. To the reaction solution was added water and the solution extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (n-hexane:ethyl acetate=1:1→2:3) to give the compounds of this invention (170 mg)having the following physical data:

TLC: Rf 0.28 in (hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ to 7.99 (s, 1H), 7,34 (d, J=8,4 Hz, 2H), 7,12 (d, J=8,4 Hz, 2H), 4,79 (DD, J=7,8, a 5.4 Hz, 1H), and 4.40 (q, J=7.2 Hz, 2H), 3,93 (dt, J=14,4, 7.2 Hz, 1H), 3.45 points of 3.28 (m, 2H), 3,01 (dt, J=14,4, 6,9 Hz, 1H), 2,64 is 2.33 (m, 3H), 1,90 (m, 1H), 1,40 (t, J =7.2 Hz, 3H), of 1.30 (s, 9H).

Examples 3(1)-3(13)

According to the method of example 3 using the corresponding derivative instead of the compound obtained in reference example 11, the following compounds of this invention.

Example 3(1)

Ethyl ester of 2-(2-(2-(4-n-butylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.64 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 7,14 (d, J=8,4 Hz, 2H), 7,10 (d, J=8,4 Hz, 2H), 4,79 (DD, J=7,5, a 5.4 Hz, 1H), to 4.41 (q, J=7.2 Hz, 2H), 3,93 (dt, J=14,1, 7.2 Hz, 1H), 3,37 (m, 2H), 3,01 (dt, J=14,1, 6.3 Hz, 1H), 2,64-to 2.35 (m, 5H), 1,90 (m, 1H), 1.55V (m, 2H), 1,40 (t, J=7.2 Hz, 3H), of 1.35 (m, 2H), of 0.93 (t, J=7.2 Hz, 3H).

Example 3(2)

Ethyl ester of 2-(2-(2-(4-(1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazo the-4-carboxylic acid

TLC: Rf to 0.80 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ to 7.99 (s, 1H), 7,31 (d, J=8.1 Hz, 2H), 7,18 (d, J=8.1 Hz, 2H), 4,82 (m, 1H)and 4.65 (m, 1H), and 4.40 (q, J=7.2 Hz, 2H), 3,91 (m, 1H), 3,36 (m, 2H), to 3.02 (m, 1H), 2,65 to 2.35 (m, 3H), 2,10-of 1.55 (m, 6H), of 1.40 (t, J=7.2 Hz, 3H), 1,40-of 1.15 (m, 4H), of 0.87 (t, J=6.6 Hz, 3H).

Example 3(3)

Ethyl ester of 2-(2-(2-(4-propoxyphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.15 (n-hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 7,11 (d, J=9.0 Hz, 2H), at 6.84 (d, J=9.0 Hz, 2H), amounts to 4.76 (DD, J=7,8, a 5.4 Hz, 1H), and 4.40 (q, J=7.2 Hz, 2H), 3,94-3,81 (m, 3H), 3,44 of 3.28 (m, 2H), 3,01 (dt, J=14,4, 6,9 Hz, 1H), 2,60 to 2.35 (m, 3H), of 1.88 (m, 1H), 1,80 (kV, J=7.2 Hz, 2H), 1,40 (t, J=7.2 Hz, 3H), of 1.03 (t, J=7.2 Hz, 3H).

Example 3(4)

Methyl ester 2-(2-(2-(1,1'-biphenyl-4-yl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.23 (hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ 7,98 (s, 1H), 7,62-7,52 (m, 4H), 7,49-to 7.32 (m, 3H), 7,31-7,24 (m, 2H), 4,89 (t, J=6.3 Hz, 1H), to 4.38 (q, J=7.2 Hz, 2H), 3,98 (dt, J=14,4, 7.2 Hz, 1H), 3.46 in-3,37 (m, 2H), 3,06 (dt, J =14,4, 6,9 Hz, 1H), 2,64-is 2.37 (m, 3H), of 1.95 (m, 1H), 1,38 (t, J=7.2 Hz, 3H).

Example 3(5)

Ethyl ester of 2-(2-(2-(4-n-hexylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.34 (ethyl acetate:n-hexane=1:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 7,21-7,26 (m, 4H), 4,82-of 4.75 (m, 1H), to 4.41 (q, J=6.9 Hz, 2H), 3,98-a 3.87 (m, 1H), 3,44 be 3.29 (m, 2H), 3,07-2,95 (m, 1H), 2,63 is 2.33 (m, 5H), 1,97-of 1.84 (m, 1H), 1,65-is 1.51 (m, 2H), 1,46-1,21 (m, 9H), 0,93-of 0.82 (m, 3H).

Example 3(6)

p> Ethyl ester of 2-(2-(2-(4-n-propylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf 0.21 in (ethyl acetate:n-hexane=1:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 7,15-to 7.09 (m, 4H), 4,79 (DD, J=7,5, 5.7 Hz, 1H), to 4.41 (q, J=7.2 Hz, 2H), 3,93 (dt, J=14,1, 7.2 Hz, 1H), 3,42-3,39 (m, 2H), 3.00 and (dt, J=a 14.1, 6.6 Hz, 1H), 2,60 to 2.35 (m, 5H), 1,96 of-1.83 (m, 1H), 1,68-of 1.55 (m, 2H), 1,40 (t, J=7.2 Hz, 3H), of 0.93 (t, J=7.2 Hz, 3H).

Example 3(7)

Ethyl ester of 2-(2-(2-phenyl-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.15 (ethyl acetate:n-hexane=1:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), was 7.36-7,27 (m, 3H), 7.24 to 7,16 (m, 2H), a 4.83 (t, J=6,9 Hz, 1H), and 4.40 (q, J=6.9 Hz, 2H), 3,95 (dt, J=14,1, 7.2 Hz, 1H), 3.46 in-3,30 (m, 2H), 3,01 (dt, J=14,1, 6.3 Hz, 1H), 2,64 to 2.35 (m, 3H), 1,99 of-1.83 (m, 1H), 1,40 (t, J=6.9 Hz, 3H).

Example 3(8)

Ethyl ester of 2-(2-(2-(4-ethylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf to 0.17 (ethyl acetate:n-hexane=1:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 7,20-7,07 (m, 4H), 4,79 (DD, J=7,5, a 5.4 Hz, 1H), and 4.40 (q, J=7.2 Hz, 2H), 3,93 (dt, J=14,1, 6,9 Hz, 1H), 3,37 (dt, J=6,6, 1.8 Hz, 2H), 3,01 (dt, J=14,1, 6.3 Hz, 1H), 2,66-is 2.37 (m, 5H), 1,96-of 1.84 (m, 1H), 1,40 (t, J=6.9 Hz, 3H), of 1.23 (t, J=7.2 Hz, 3H).

Example 3(9)

Ethyl ester of 2-(2-(2-(4-n-pentylphenol)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf 0.31 in (ethyl acetate:n-hexane=1:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 7,15-was 7.08 (m, 4H), 4,78 (DD, J=8,1, 5.7 Hz, 1H), to 4.41 (q, J=7.2 Hz, 2H), 3,98-3,86 (m, 1H), 3,37 (dt, J=6,6, 2.4 Hz, 2H), 3,06-2,95 (m, 1H), 2,63 to 2.35 (m, 5H), 1,9-to 1.86 (m, 1H), 1,40 (t, J=7.2 Hz, 3H), 1,37-of 1.26 (m, 4H), 0,91-of 0.85 (m, 3H).

Example 3(10)

Ethyl ester of 2-(2-(2-(4-were)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.33 (ethyl acetate:n-hexane=1:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 7,20-7,05 (m, 4H), 4,82-of 4.75 (m, 1H), and 4.40 (q, J=6.9 Hz, 2H), 3,98-3,86 (m, 1H), 3,37 (dt, J=6,3, 2,1 Hz, 2H), 3,06-2,96 (m, 1H), 2,62 of-2.32 (m, 6H), 1,96 of-1.83 (m, 1H), 1,40 (t, J=6,9 Hz, 3H).

Example 3(11)

Ethyl ester of 2-(2-(2-(4-n-octylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.25 (ethyl acetate:n-hexane=1:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 7,20-to 7.09 (m, 4H), 4,82 was 4.76 (m, 1H), to 4.41 (q, J=7.2 Hz, 2H), 3,98-a 3.87 (m, 1H), 3,37 (dt, J=6.3, in the 2.4 Hz, 2H), 3,06-2,96 (m, 1H), 2,63 to 2.35 (m, 5H), 1,97-of 1.84 (m, 1H), 1,65-of 1.52 (m, 2H,), of 1.40 (t, J=7.2 Hz, 3H), 1,35 is 1.23 (m, 10H), 0,92-of 0.85 (m, 3H).

Example 3(12)

Ethyl ester of 2-(2-(2-(4-n-heptylphenol)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.32 (ethyl acetate:n-hexane=1:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 7,19-7,05 (m, 4H), 4,82 was 4.76 (m, 1H), and 4.40 (q, J=7.2 Hz, 2H), 3,98-a 3.87 (m, 1H), 3,37 (dt, J=6,6, and 2.1 Hz, 2H), 3,06-2,95 (m, 1H), 2,63-of 2.34 (m, 5H), 1,98-of 1.85 (m, 1H), 1,66-of 1.52 (m, 2H,), of 1.40 (t, J=7.2 Hz, 3H), 1,37-to 1.21 (m, 8H), 0,95-of 0.82 (m, 3H).

Example 3(13)

Ethyl ester of 2-(2-(2-(4-n-hexylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.32 (ethyl acetate:n-hexane=1:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 7,24 (t, J=7.8 Hz, 1H), 7,13-was 7.08 (m, 1H), 7.03 is-6,97 (m, 2H), 4,82 was 4.76 (m, 1H), and 4.40 (q, J=7.2 Hz, 2), 3,99-to 3.89 (m, 1H), 3,38 (dt, J=6,6, 1.2 Hz, 2H), 3,07-of 2.97 (m, 1H), 2,62-of 2.36 (m, 5H), 1,97-of 1.85 (m, 1H), 1,63-is 1.51 (m, 2H), 1,40 (t, J=7.2 Hz, 3H), 1,37-1,22 (m, 6H), 0,92-of 0.83 (m, 3H).

Examples 4-4(13)

According to the method of example 2 using the compound obtained in example 3-3(13)instead of the compound obtained in example 1 given the following compounds of this invention.

Example 4

2-(2-(2-(4-tert-Butylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.29 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,07 (s, 1H), 7,39 (d, J=8,4 Hz, 2H), 7,14 (d, J=8,4 Hz, 2H), and 4.68 (DD, J=7,5, 6.0 Hz, 1H), 3,97 (m, 1H), 3,30-3,10 (m, 3H), 2,69-2,39 (m, 3H), of 1.95 (m, 1H), 1,32 (s, 9H).

Example 4(1)

2-(2-(2-(4-n-Butylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.25 (chloroform:methanol:acetic acid=200:20:1);

1H-NMR (CDCl3): δ 8,07 (s, 1H), 7,19 (d, J=8,4 Hz, 2H), 7,12 (d, J=8,4 Hz, 2H), 4,67 (DD, J=7,8, 6.0 Hz, 1H), 3,94 (m, 1H), 3,30 was 3.05 (m, 3H), 2,70-to 2.40 (m, 5H), of 1.95 (m, 1H), 1,60 (m, 2H), 1,36 (m, 2H), 0,93 (t, J=7.5 Hz, 3H).

Example 4(2)

2-(2-(2-(4-(1-Hydroxyhexyl)phenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.51 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 8,07 (s, 1H), 7,37 (d, J=8.1 Hz, 2H), 7,20 (d, J=8.1 Hz, 2H), 4,77-4,63 (m, 2H), 3.96 points (m, 1H), 3,35-of 3.07 (m, 3H), 2.71 to 2,40 (m, 3H), 2,02 is 1.58 (m, 3H), 1,55-1,17 (m, 6H), of 0.87 (t, J=6.6 Hz, 3H).

Example 4(3)

2-(2-(2-(4-shall propoxyphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.35 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 7,14 (d, J=8.7 Hz, 2H), 6.89 in (d, J=8.7 Hz, 2H)and 4.65 (DD, J=7,5, and 6.6 Hz, 1H), 3,92 (t, J=6.6 Hz, 2H), with 3.89 (m, 1H), 3,32 was 3.05 (m, 3H), 2,69-of 2.38 (m, 3H), of 1.95 (m, 1H), is 1.81 (m, 2H,), was 1.04 (t, J=7.5 Hz, 3H).

Example 4(4)

2-(2-(2-(1,1'-Biphenyl-4-yl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf 0.31 in (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,07 (s, 1H), 7,65-of 7.55 (m, 4H), 7,49-7,41 (m, 2H), 7,40-7,27 (m, 3H), amounts to 4.76 (DD, J=7,8, 5.7 Hz, 1H), 4,01 (m, 1H), 3,38-3,11 (m, 3H), was 2.76 is 2.43 (m, 3H), 2,00 (m, 1H).

Example 4(5)

2-(2-(2-(4-n-Hexylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf 0.26 (methylene chloride:methanol=5:1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 7,22-7,10 (m, 4H), 4.72 in with 4.65 (m, 1H), 4,00-of 3.85 (m, 1H), 3,31-is 3.08 (m, 3H), 2.71 to 2,40 (m, 5H), 2,02-1,89 (m, 1H), 1,67-and 1.54 (m, 2H), 1,43-of 1.24 (m, 6H), 0.95 to-0,83 (m, 3H).

Example 4(6)

2-(2-(2-(4-n-Propylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf 0,24 (methylene chloride:methanol=5:1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 7,22-7,11 (m, 4H), 4.72 in with 4.65 (m, 1H), 4,00-3,86 (m, 1H), 3,44-to 3.09 (m, 3H), 2,70-to 2.40 (m, 5H), 2,01-1,89 (m, 1H), 1.70 to of 1.57 (m, 2H), were 0.94 (t, J=7.2 Hz, 3H).

Example 4(7)

2-(2-(2-Phenyl-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf 0.21 in (methylene chloride:methanol=5:1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 7,42-7,31 (m, 3H), 7,28-7,20 (m, 2H), 4,76-4,70 (m, 1H), was 4.02-to 3.89 (m, 1H), 3,34-3,10(m, 3H), 2.71 to to 2.42 (m, 3H), 2,02-1,90 (m, 1H).

Example 4(8)

2-(2-(2-(4-Ethylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf 0,17 (methylene chloride:methanol=5:1);

1H-NMR (CDCl3): δ 8,07 (s, 1H), 7,22-7,10 (m, 4H), 4,70 with 4.64 (m, 1H), 4,01-3,88 (m, 1H), 3,29-of 3.12 (m, 3H), 2.71 to to 2.41 (m, 5H), 2,01-1,89 (m, 1H), 1,25 (t, J=7.5 Hz, 3H).

Example 4(9)

2-(2-(2-(4-n-Pentylphenol)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.23 (methylene chloride:methanol=5:1);

1H-NMR (CDCl3): δ 8,84 (Sirs, 1H), 8,08 (s, 1H), 7,22-to 7.09 (m, 4H), 4,74-of 4.67 (m, 1H), 3,98-a 3.87 (m, 1H), 3,35-of 3.12 (m, 3H), 2,69-to 2.40 (m, 5H), 2,03-of 1.88 (m, 1H), 1,66-of 1.55 (m, 2H), 1,42-1,25 (m, 4H), 0,93-of 0.85 (m, 3H).

Example 4(10)

2-(2-(2-(4-Were)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf 0,17 (dichloromethane:methanol=5:1);

1H-NMR (CDCl3): δ 8,07 (s, 1H), 7,22-to 7.09 (m, 4H), 4,70-4,63 (m, 1H), 3,98-of 3.85 (m, 1H), 3,30-3,03 (m, 3H), 2,69-to 2.41 (m, 3H), of 2.36 (s, 3H), 2,01-of 1.88 (m, 1H).

Example 4(11)

2-(2-(2-(4-n-Octylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.32 (dichloromethane:methanol=5:1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 7,22-to 7.09 (m, 4H), 4,70-4,63 (m, 1H), 4,00-to 3.89 (m, 1H), 3,31-is 3.08 (m, 3H), 2,67-to 2.40 (m, 5H), 2,01-1,90 (m, 1H), 1,68-and 1.54 (m, 2H), 1,39 is 1.16 (m, 10H), 0,96-of 0.82 (m, 3H).

Example 4(12)

2-(2-(2-(4-n-Heptylphenol)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.16 (dichloromethane:methanol=5:1);

1H-NMR (CDCl3): δ which 9.22(Sirs, 1H), of 8.09 (s, 1H), 7.23 percent-to 7.09 (m, 4H), 4.75 V-and 4.68 (m, 1H), 4,01-3,86 (m, 1H), 3,36-of 3.12 (m, 3H), 2,69-2,39 (m, 5H), 2,02-1,89 (m, 1H), 1,67-of 1.53 (m, 2H), 1,39 is 1.20 (m, 8H), 0,92-of 0.83 (m, 3H).

Example 4(13)

2-(2-(2-(3-n-Hexylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.32 (dichloromethane:methanol=5:1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 7,29 (t, J=8,1 Hz, 1H), 7.18 in-7,13 (m, 1H), 7,06-7,00 (m, 2H), 4,71 with 4.65 (m, 1H), 4,01-3,90 (m, 1H), 3,30-of 3.07 (m, 3H), 2,69-to 2.41 (m, 5H), 2,02-1,89 (m, 1H), 1,64-of 1.52 (m, 2H), 1,37-1,22 (m, 6H), 0,91-of 0.82 (m, 3H).

Examples 5(1)-5(45)

According to the method of example 1 using the compound obtained in reference example 3, or the corresponding derivative of the aldehyde and the compound obtained in reference example 9, or a corresponding amine derivative are given the following compounds of this invention.

Example 5(1)

(13TH,16α)-17,17-Propane-16-hydroxy-5-(4-methoxycarbonylamino-2-yl)-9-oxo-1,2,3,4,20-pentanol-8-isapros-13-EN

TLC: Rf 0,07 (ethyl acetate);

1H-NMR (CDCl3): δ to 8.14 (s, 1H), 5,78 (dt, J=to 15.0, 7.5 Hz, 1H), lower than the 5.37 (DD, J=to 15.0, 9.0 Hz, 1H), of 4.05 (m, 1H), 3,90 (s, 3H), 3,62-to 3.49 (m, 2H), 3,05 (m, 1H), 2,80 (t, J=7.5 Hz, 2H), 2.49 USD with 2.14 (m, 4H), 2,10-of 1.52 (m, 11H), the 1.44 (m, 1H), of 0.91 (t, J=7.5 Hz, 3H).

Example 5(2)

5-(4-Ethoxycarbonylmethyl-2-yl)-9-oxo-14,15-(1,4-interphenylene)-1,2,3,4-tetranor-5-thia-8-isoprostane

TLC: Rf to 0.19 (ethyl acetate:n-hexane=1:1);

1H-NMR (CDCl3): δ to 7.99 (s, 1H), 7,10-7,01 (m, 4H), 4,43-4,34 (m, 3H), 3,44 of 3.28 (m, 3H), is 3.08 vs. 2.94 (m, 1H), 2,89-to 2.41 (m, 8H), 1,84 is 1.48 (m, 4H), 1.41 to to 1.19 (m, 9H), 0,92 is 0.81 (m, 3H).

Example 5(3)

(13TH)-5-(4-Ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,18,19,20-heptanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.29 (n-hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,03 (s, 1H), 5,65 (dt, J=15,3, and 6.6 Hz, 1H), 5,22 (DD, J=15,3, and 8.7 Hz, 1H), and 4.40 (q, J=7.2 Hz, 2H), 4,14 (m, 1H), 3,83 (dt, J=13,5, 6,9 Hz, 1H), 3,50 is 3.40 (m, 2H), 3,30 (dt, J=13,5, 6,9 Hz, 1H), 2,46-2,10 (m, 3H), 2,02-1,90 (m, 2H), 1,72 (m, 1H), 1,39 (t, J=7.2 Hz, 3H), 1,38 of 1.28 (m, 2H), of 0.85 (t, J=7.2 Hz, 3H).

Example 5(4)

(13TH)-5-(4-Ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-isapros-13-EN

TLC: Rf of 0.30 (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,02 (s, 1H), 5,65 (dt, J=15,3, and 6.6 Hz, 1H), total of 5.21 (DD, J=15,3, and 8.7 Hz, 1H), and 4.40 (q, J=7.2 Hz, 2H), 4,14 (m, 1H), 3,83 (dt, J=13,5, 6,9 Hz, 1H), 3,50-3,39 (m, 2H), 3,29 (dt, J=13,5, 6,9 Hz, 1H), 2,46-2,10 (m, 3H), 2,04-of 1.93 (m, 2H), 1,72 (m, 1H), 1,39 (t, J=7.2 Hz, 3H), 1,36-1,17 (m, 4H), 0,86 (t, J=7.2 Hz, 3H).

Example 5(5)

Ethyl ester of (2E,13TH,16thα)-17,17-propane-16-hydroxy-3,6-(1,4-interphenylene)-9-oxo-4,5,20-trinor-8-isapros-2,13-diene acid

TLC: Rf of 0.30 (ethyl acetate);

1H-NMR (CDCl3): δ the 7.65 (d, J=16.0 Hz, 1H), 7,45 (d, J=9.0 Hz, 2H), 7,20 (d, J=9.0 Hz, 2H), 6,40 (d, J=16.0 Hz, 1H), 5,67 (dt, J=15,4, 7.2 Hz, 1H), 5,28 (DD, J=15,4, to 8.7 Hz, 1H), 4,25 (kV, J=7.2 Hz, 2H), 3,88-3,70 (m, 2H), only 3.57 (m, 1H), 3.15 in (m, 1H), 2.95 and-2,70 (m, 2H), 2,50-of 1.40 (m, 15H), of 1.35 (t, J=7.2 Hz, 3H), of 0.92 (t, J=7.2 Hz, 3H).

Example 5(6)

Methyl ether (13TH,16α)-17,17-propane-16-hydroxy-1,7-(2,5-intertitle)-9-oxo-2,3,4,5,6,20-hexanor-8-isapros-13-ene is sloty

TLC: Rf of 0.58 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ of 0.93 (t, J= 7.2 Hz, 3H), at 1.73 (m, 11N), to 2.35 (m, 4H), 3,55 (m, 1H), 3,86 (s, 3H), 4,01 (m, 1H), 4,20 (d, J=to 15.4 Hz, 1H), 4.92 in (d, J=to 15.4 Hz, 1H), lower than the 5.37 (DD, J=to 15.0, 9.0 Hz, 1H), 5,78 (dt, J=15,0, 7,2 Hz, 1H), 6,93 (m, 1H), to 7.64 (m, 1H).

Example 5(7)

(13TH)-5-(4-Ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf 0.36 and (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,02 (s, 1H), to 5.66 (dt, J=15,3, and 6.6 Hz, 1H), total of 5.21 (DD, J=15,3, and 8.7 Hz, 1H), and 4.40 (q, J=7.2 Hz, 2H), 4,14 (m, 1H), 3,83 (dt, J=13,5, 6,9 Hz, 1H), 3,50 is 3.40 (m, 2H), 3,29 (dt, J=13,5, 6,9 Hz, 1H), 2,46-2,12 (m, 3H), 2,03 is 1.91 (m, 2H), 1,72 (m, 1H), 1,39 (t, J=7.2 Hz, 3H), 1,38-1,17 (m, 8H), of 0.87 (t, J=7.2 Hz, 3H).

Example 5(8)

(13TH)-5-(4-Ethoxycarbonylmethyl-2-yl)-9-oxo-20-methyl-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.37 (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,02 (s, 1H), to 5.66 (dt, J=15,0, and 6.6 Hz, 1H), total of 5.21 (DD, J=to 15.0, 9.0 Hz, 1H), and 4.40 (q, J=7.2 Hz, 2H), 4,14 (m, 1H), 3,83 (dt, J=a 13.8, 6.9 Hz, 1H), 3,50 is 3.40 (m, 2H), 3,29 (dt, J=a 13.8, 6.9 Hz, 1H), 2,46-2,12 (m, 3H), 2,03-of 1.93 (m, 2H), 1,72 (m, 1H), 1,39 (t, J=7.2 Hz, 3H), 1,38 is 1.16 (m, 10H)to 0.88 (t, J=7.2 Hz, 3H).

Example 5(9)

Methyl ether (13TH,15thα)-15-hydroxy-1,6-(1,4-interphenylene)-9-oxo-2,3,4,5-tetranor-8-isapros-13-ene acid

TLC: Rf of 0.18 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.89 (m, 3H), 1,49 (m, N), 2,12 (m, 1H), 2,35 (m, 2H), 2,87 (m, 2H), 3,12 (m, 1H), 3,79 (m, 2H), 3,91 (s, 3H), 4,11 (m, 1H), 5,38 (DD, J=15,38, charged 8.52 Hz, 1H), 5,58 (DD, J=15,38, 6,32 Hz, 1H), 7,25 (d, J=of 7.69 Hz, 2H), of 7.96 (d, J=7,97 Hz, 2H).

Example 5(10

Methyl ether (13TH,15thα)-15-hydroxy-1,5-(2,5-intertitle)-9-oxo-2,3,4-trinor-8-isapros-13-ene acid

TLC: Rf 0.26 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.89 (t, J=6,59 Hz, 3H), of 1.40 (m, N), of 1.80 (m, 3H), 2,31 (m, 2H), and 2.83 (t, J=of 7.69 Hz, 2H), 2,98 (m, 1H), to 3.58 (m, 1H), 3,86 (s, 3H), 4,08 (m, 3H), of 5.48 (DD, J=15,38, 8,79 Hz, 1H), of 5.68 (DD, J=15,38, 6,32 Hz, 1H), for 6.81 (d, J=3,85 Hz, 1H), 7.62mm (d, J=3,85 Hz, 1H).

Example 5(11)

Ethyl ether (13TH,15thα)-15-hydroxy-9-oxo-5-thia-8-isapros-13-ene acid

TLC: Rf of 0.30 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.89 (m, 3H), of 1.41 (m, 8H), is 1.81 (m, 4H), 2,32 (m, 5H), 2.63 in (m, 4H), 3,11 (m, 1H), to 3.67 (m, 1H), 4,13 (m, 4H), of 5.53 (DD, J=15,38, 8,24 Hz, 1H), 5,74 (DD, J=15,38, 5,77 Hz, 1H).

Example 5(12)

(13TH)-5-(4-Ethoxycarbonylmethyl-2-yl)-9,15-dioxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.38 (ethyl acetate);

1H-NMR (CDCl3): δ 8,02 (s, 1H), return of 6.58 (DD, J=the 15.6, and 7.8 Hz, 1H), 6,24 (d, J=15.6 Hz, 1H), to 4.52 is 4.35 (m, 3H), 3,99-3,88 (m, 1H), 3,53-3,37 (m, 2H), 3,29-3,19 (m, 1H), of 2.51 (t, J=7.5 Hz, 2H), 2,47-2,22 (m, 3H), 1,89-1,78 (m, 1H), 1,61 of 1.50 (m, 2H), 1,42 is 1.23 (m, 5H), of 0.90 (t, J=7.5 Hz, 3H).

Example 5(13)

5-(4-Ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isoprostane

TLC: Rf of 0.35 (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,02 (s, 1H), 4,39 (kV, J=7.2 Hz, 2H), with 3.89 (m, 1H), 3,71 (m, 1H), 3,54-of 3.31 (m, 3H), 2,46-2,22 (m, 2H), 2,12 (m, 1H), 1,78 is 1.60 (m, 2H), 1,39 (t, J=7.2 Hz, 3H), 1,38 is 1.16 (m, 11H), of 0.87 (t, J=7.2 Hz, 3H).

Example 5(14)

(13TH,15thα)-20-Ethyl-15-hydroxy-5-(4-butoxycarbonylmethyl--yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.40 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.88 (m, 3H), of 0.97 (t, J=7,42 Hz, 3H), of 1.27 (m, 10H), of 1.45 (m, 4H), to 1.76 (m, 3H), 1,95 (d, J=4,40 Hz, 1H), 2,30 (m, 3H), 3,41 (m, 3H), 3,76 (m, 1H), 4,08 (m, 1H), 4,22 (m, 1H), 4,33 (m, 2H), of 5.55 (m, 1H), 5,79 (m, 1H), to 7.99 (d, J=3,02 Hz, 1H).

Example 5(15)

(13TH,15thα)-20-Methyl-15-hydroxy-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.32 (ethyl acetate);

1H-NMR (CDCl3): δ to 7.99 (s, 1H), 5,79 (DD, J=15,3, 5.7 Hz, 1H), 5,54 (DDD, J=15,3, and 8.4, 1.2 Hz, 1H), 4,33 (t, J=6.9 Hz, 2H), 4.26 deaths-of 4.16 (m, 1H), 4,14-Android 4.04 (m, 1H), 3,80-3,70 (m, 1H), 3,50-3,30 (m, 4H), 2,45-of 2.15 (m, 3H), 1,95-1,90 (m, 1H), 1,80-of 1.65 (m, 3H), 1,50-of 1.40 (m, 3H), 1,35-of 1.20 (m, 8H), of 0.97 (t, J=7.2 Hz, 3H), 0,90-0,80 (m, 3H).

Example 5(16)

(13TH,15thα)-20-n-Propyl-15-hydroxy-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.32 (ethyl acetate);

1H-NMR (CDCl3): δ to 7.99 (s, 1H), 5,78 (DD, J=15,6, 5.7 Hz, 1H), 5,54 (DDD, J=15,6, and 8.4, 1.2 Hz, 1H), 4,33 (t, J=6.9 Hz, 2H), 4.26 deaths-of 4.16 (m, 1H), 4,14-Android 4.04 (m, 1H), 3,80-3,70 (m, 1H), 3,50-3,30 (m, 4H), 2,45-of 2.15 (m, 3H), 1,95-1,90 (m, 1H), 1,80-of 1.65 (m, 3H), 1,50-of 1.40 (m, 3H), 1,35-of 1.20 (m, 12H), of 0.97 (t, J=7.2 Hz, 3H), 0,90-0,80 (m, 3H).

Example 5(17)

(13Z)-5-(4-Ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf 0.28 in (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,02 (s, 1H), 5,59 (dt, J=10.5V, and 7.8 Hz, 1H), 5,22 (DD, J=10,5, 9.9 Hz, 1H), 4.53-in (dt, J=9,9, 6,9 Hz, 1H), 4,39 (kV, J=7.2 Hz, 2H), of 3.77 (dt, J=14,1, 6.3 Hz, 1H), 3.45 points (t, J=6.3 Hz, 2H), 3.33 and (dt, J=14.1 to, 6.3 Hz, 1H), 2,45-of 1.93 (m, 5H), to 1.67 (m, 1H), 1,39 (t, J=7.2 Hz, 3H), 1,38 is 1.16 (m, 6H), of 0.87 (t, J=7.2 Hz, 3H).

Example 5(18)

(13Z)-16-oxa-17,17-dimethyl-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-isapros-13-EN

TLC: Rf of 0.20 (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,02 (s, 1H), USD 5.76 (dt, J=11,1, 6.3 Hz, 1H), lower than the 5.37 (DD, J=11,1, 9.9 Hz, 1H), with 4.64 (dt, J=9,9, and 6.6 Hz, 1H), 4,39 (kV, J=7.2 Hz, 2H), 4.04 the-3,90 (m, 2H), 3,82 (dt, J=13,5, 6.3 Hz, 1H), 3,54-to 3.41 (m, 2H), 3,35 (dt, J=13,5, 6.3 Hz, 1H), 2,48 and 2.13 (m, 3H), 1,71 (m, 1H), 1,39 (t, J=7.2 Hz, 3H), 1,19 (s, 9H).

Example 5(19)

(13TH)-16-oxa-17,17-dimethyl-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-isapros-13-EN

TLC: Rf of 0.20 (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,02 (s, 1H), 5,77 (dt, J=15,3, 5,1 Hz, 1H), 5,50 (DD, J=15,3, 9.0 Hz, 1H), and 4.40 (q, J=7.2 Hz, 2H), 4,20 (dt, J=5,1, 8,1 Hz, 1H), 3,90-of 3.78 (m, 3H), 3,44 (t, J=6.3 Hz, 2H), and 3.31 (dt, J=13,2, 6.3 Hz, 1H), 2,48-2,12 (m, 3H), 1.77 in (m, 1H), 1,39 (t, J=7.2 Hz, 3H), of 1.18 (s, 9H).

Example 5(20)

(13TH,15thα)-19-Phenyl-15-hydroxy-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.27 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.96 (t, J=7,14 Hz, 3H)and 1.51 (m, 11N), 2,00 (d, J=4,67 Hz, 1H), to 2.29 (m, 3H), 2,58 (t, J=of 7.69 Hz, 2H), 3,37 (m, 3H), 3,76 (m, 1H), 4,14 (m, 2H), or 4.31 (t, J=6,59 Hz, 2H), 5,54 (DDD, J=15,38, charged 8.52, 1,10 Hz, 1H), 5,78 (DD, J=15,66, 5,77 Hz, 1H), 7,21 (m, 5H), 7,98 (s, 1H).

Example 5(21)

(13TH,15thα)-20-Phenyl-15-hydroxy-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.29 (ethyl acetate);

1H-NMR (CDCl3): 4 to 0.97 (t, J=7,42 Hz, 3H), of 1.52 (m, 13H), of 1.97 (d, J=4,67 Hz, 1H), 2,31 (m, 3H), at 2.59 (t, J=7,14 Hz, 2H), 3,40 (m, 3H), of 3.77 (m, 1H), 4,14 (m, 2H), 4,32 (t, J=6.87 in Hz, 2H), 5,54 (DDD, J=15,38, charged 8.52, 1,10 Hz, 1H), 5,79 (DD, J=15,38, 5,49 Hz, 1H), 7,22 (m, 5H), 7,95 (s, 1H).

Example 5(22)

(13TH,15thα)-20-Benzyl-15-hydroxy-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.29 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.97 (t, J=7,42 Hz, 2H), of 1.52 (m, 15 NM), a 1.96 (d, J=4,67 Hz, 1H), 2,31 (m, 3H), at 2.59 (t, J=7,42 Hz, 2H), 3,39 (m, 3H), of 3.77 (m, 1H), 4,14 (m, 2H), 4,32 (t, J=6.87 in Hz, 2H), 5,55 (DDD, J=15,66, 8,79, 1,10 Hz, 1H), 5,78 (DD, J=15,66, 5,77 Hz, 1H), 7.23 percent (m, 5H), of 7.97 (s, 1H).

Example 5(23)

Methyl ether (13TH,16α)-17,17-propane-16-hydroxy-1,6-(1,3-interphenylene)-9-oxo-2,3,4,5,20-pentanol-8-isapros-13-ene acid

TLC: Rf of 0.29 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.92 (t, J=7.4 Hz, 3H), USD 1.43 (m, 1H), 2,00 (m, 14N), 2,80 (m, 1H), 2,92 (m, 1H), 3.15 in (m, 1H), only 3.57 (DD, J=9,7, 2.3 Hz, 1H), 3,76 (m, 1H), 3,88 (m, 1H), 3,91 (m, 3H), of 5.26 (DD, J=15,2, a 8.9 Hz, 1H), 5,79 (dt, J=15,2, 7.2 Hz, 1H), 7,39 (m, 2H), 7,89 (m, 2H).

Example 5(24)

(15α)-15-Hydroxy-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isoprostane

TLC: Rf of 0.20 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.89 (t, J=6,59 Hz, 3H), of 1.48 (m, 15 NM), of 1.97 (m, 1H), and 2.14 (m, 1H), a 2.36 (m, 2H), 2,53 (d, J=5,22 Hz, 1H), 3,60 (m, 6N), to 4.38 (q, J=7,14 Hz, 2H), to 7.99 (s, 1H).

Example 5(25)

Methyl ether (15α)-15-hydroxy-1,6-(1,4-interphenylene)-9-oxo-2,3,4,5-tetranor-5-thia-8-isoprostanes acid

p> TLC: Rf of 0.20 (ethyl acetate);

1H-NMR (CDCl3): δ of 0.90 (t, J=6,59 Hz, 3H), 1,47 (m, 13H), 2,04 (m, 1H), 2,32 (m, 2H), 2,87 (m, 2H), 3,06 (m, 1H), 3,40 (m, 1H), only 3.57 (m, 1H), 3,86 (m, 4H), 7,30 (d, J=charged 8.52 Hz, 2H), of 7.97 (d, J=charged 8.52 Hz, 2H).

Example 5(26)

(13TH)-17,17-Dimethyl-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-isapros-13-EN

TLC: Rf of 0.20 (hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ 8,02 (s, 1H), 5,67 (dt, J=15,0, 6,9 Hz, 1H), total of 5.21 (DD, J=15,0, and 8.7 Hz, 1H), 4,39 (kV, J=7.2 Hz, 2H), 4,14 (m, 1H), 3,83 (dt, J=13,5, 6,9 Hz, 1H), 3,50-3,37 (m, 2H), 3,30 (dt, J=13,5, 6,9 Hz, 1H), 2,46-2,11 (m, 3H), 2.00 in 1,89 (m, 3H), 1,71 (m, 1H), 1,39 (t, J=7.2 Hz, 3H), 1,22-1,12 (m, 2H), 0,86 (s, 9H).

Example 5(27)

(13TH)-17,17-Dimethyl-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.20 (hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ 8,02 (s, 1H), 5,67 (dt, J=15,0, 6,9 Hz, 1H), total of 5.21 (DD, J=15,0, and 8.7 Hz, 1H), 4,39 (kV, J=7.2 Hz, 2H), 4,14 (m, 1H), 3,83 (dt, J=13,5, and 6.6 Hz, 1H), 3,50-to 3.38 (m, 2H), 3,30 (dt, J=13,5, and 6.6 Hz, 1H), 2,47-2,08 (m, 3H), 1,96-of 1.84 (m, 3H), 1,72 (m, 1H), 1,39 (t, J=7.2 Hz, 3H), 1,24-of 1.18 (m, 2H), 0,86-of 0.71 (m, 9H).

Example 5(28)

Butyl ether (13TH,15thα)-19-phenyl-15-hydroxy-9-oxo-20-nor-5-thia-8-isapros-13-ene acid

TLC: Rf of 0.33 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ 7,32-7,24 (m, 2H), 7,21-7,14 (m, 3H), 5,72 (DD, J=15,3, 6.0 Hz, 1H), 5,50 (DDD, J=15,3, 9,0, 0.6 Hz, 1H), 4,20-4,00 (m, 4H), 3,70-of 3.60 (m, 1H), 3,10-3,00 (m, 1H), 2,70-of 2.50 (m, 6H), 2,45-of 2.15 (m, 5H), 1,95-of 1.30 (m, 14H), of 0.93 (t, J=7.2 Hz, 3H).

Example 5(29)

Butyl ether (13TH,15thα)-20-FeNi is-15-hydroxy-9-oxo-5-thia-8-isapros-13-ene acid

TLC: Rf of 0.33 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ 7,30-of 7.23 (m, 2H), 7,20-7,13 (m, 3H), 5,73 (DD, J=15,3, 5.7 Hz, 1H), 5,51 (DDD, J=15,3, to 8.7, 1.2 Hz, 1H), 4,20-of 4.05 (m, 4H), 3.75 to of 3.60 (m, 1H), 3.15 and was 3.05 (m, 1H), 2,70-of 2.50 (m, 6H), 2,45-of 2.15 (m, 5H), 1,95-of 1.30 (m, 16H), of 0.93 (t, J=7.5 Hz, 3H).

Example 5(30)

Butyl ether (13TH,15thα)-20-benzyl-15-hydroxy-9-oxo-5-thia-8-isapros-13-ene acid

TLC: Rf of 0.33 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ 7,30-7,22 (m, 2H), 7,20-to 7.15 (m, 3H), 5,73 (DD, J=15,3, 5.7 Hz, 1H), 5,52 (DDD, J=15,3, and 8.4, 1.2 Hz, 1H), 4,20-of 4.05 (m, 4H), 3.72 points-of 3.60 (m, 1H), 3.15 and was 3.05 (m, 1H), 2,70-of 2.20 (m, 11H), 1,95-of 1.20 (m, 18H), 0,93 (t, J=7.5 Hz, 3H).

Example 5(31)

14-oxa-14-phenyl-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.45 (ethyl acetate);

1H-NMR (CDCl3): δ of 7.97 (s, 1H), 7,25 (DD, J=8,7, 7.5 Hz, 2H), 6,94 (t, J=7.5 Hz, 1H), to 6.88 (d, J=8.7 Hz, 2H), 4,37 (DD, J=9,9, 3.6 Hz, 1H), 4,35-4,27 (m, 2H), 4,14 (m, 1H), 4,00 (DD, J=9,9, 3.6 Hz, 1H), 3,64-of 3.32 (m, 3H), 2,58 (m, 1H), 2,37 (m, 1H), 2,22 (m, 1H), 2,03 (m, 1H), 1,80 by 1.68 (m, 2H), 1,52 to 1.37 (m, 2H), 0,97 (t, J=7.2 Hz, 3H).

Example 5(32)

14-oxa-14-(3,5-dichlorophenyl)-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.53 (ethyl acetate);

1H-NMR (CDCl3): δ of 7.97 (s, 1H), 6,93 (t, J=1.8 Hz, 1H), 6.87 in (d, J=1.8 Hz, 2H), 4,69 (DD, J=10,2, 3.0 Hz, 1H), to 4.38-4,30 (m, 2H), 4,12 (m, 1H), 4,00 (DD, J=10,2, 3.0 Hz, 1H), 3,84 (m, 1H), 3,61 (m, 1H), 3,47 (m, 1H), 3,26 (m, 1H), 2.57 m (m, 1H), 2,39 (m, 1H), 2,23 (m, 1H), 2.06 to (m, 1H), 1,80 was 1.69 (m, 2H), 1,52-to 1.38 (m, 2H), 0,97 (t, J=7.2 Hz, 3H).

P is the iMER 5(33)

(13TH,16α)-17,17-Propane-16-hydroxy-6-(4-ethoxycarbonylmethyl-2-ylsulphonyl)-9-oxo-1,2,3,4,5,20-hexanor-8-isapros-13-EN

TLC: Rf of 0.33 (ethyl acetate);

1H-NMR (CDCl3): δ of 0.93 (t, J=7.5 Hz, 3H), of 1.42 (m, 1H), 1,42 (t, J=7.2 Hz, 3H), of 1.84 (m, 10H), to 2.29 (m, 4H), of 3.75 (m, 5H), 4,22 (m, 1H), 4,45 (kV, J=7.2 Hz, 2H), 5,39 (DD, J=15,1, 9.0 Hz, 1H), to 5.93 (dt, J=15,1, 7,2 Hz, 1H), of 8.47 (s, 1H).

Example 5(34)

14-oxa-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-isoprostane

TLC: Rf of 0.47 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.88 (t, J=7.2 Hz, 3H), of 0.97 (t, J=7.2 Hz, 3H), 1,23-1,58 (m, 7H), 1,69-1,89 (m, 3H), of 2.09 (m, 1H), 2,28 (m, 1H), 2,44 (m, 1H), 3,37-of 3.60 (m, 6H), 3,63 (DD, J=10,2, 3.6 Hz, 1H), 3,84-of 3.97 (m, 2H), to 4.33 (t, J=6.6 Hz, 2H), 8,00 (s, 1H).

Example 5(35)

17,17-Propane-5-(4-ethoxycarbonylmethyl-2-yl)-9,16-dioxo-1,2,3,4,20-pentanol-5-thia-8-isoprostane

TLC: Rf 0,41 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.74 (t, J=7.5 Hz, 3H), of 1.39 (t, J=7,1 Hz, 3H), and 1.56 (m, 1H), 1,65-2,00 (m, N), 2,10-to 2.55 (m, 8H), 3,35-3,55 (m, 3H), and 3.72 (m, 1H), 3,88 (m, 1H), to 4.38 (q, J=7,1 Hz, 2H), 8,01 (s, 1H).

Example 5(36)

(13TH)-17-oxa-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.16 (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,02 (s, 1H), 5,70 (dt, J=15,3, and 6.6 Hz, 1H), 5,33 (DD, J=15,3, and 8.7 Hz, 1H), and 4.40 (q, J=7.2 Hz, 2H), 4,15 (m, 1H), 3,82 (m, 1H), 3,50-of 3.27 (m, 7H), 2,47-2,12 (m, 5H), at 1.73 (m, 1H), 1,39 (t, J=7.2 Hz, 3H), of 1.17 (t, J=7.2 Hz, 3H).

Example 5(37)

(13TH)-16-oxa-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,420-pentanol-5-thia-8-isapros-13-EN

TLC: Rf to 0.17 (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,02 (s, 1H), 5,79 (dt, J=15,3, 5,1 Hz, 1H), of 5.53 (DDT, J=15,3, and 8.4, 1.8 Hz, 1H), 4,39 (kV, J=7.2 Hz, 2H), 4,24 (m, 1H), 3,92 (DD, J=5,1, 1.8 Hz, 2H), 3,85 (m, 1H), 3,50-to 3.41 (m, 2H), 3,40-3,24 (m, 3H), 2,49 with 2.14 (m, 3H), 1.77 in (m, 1H), 1,65-is 1.51 (m, 2H), 1,39 (t, J=7.2 Hz, 3H), of 0.90 (t, J=7.2 Hz, 3H).

Example 5(38)

13-(N-(Benzylmethyl)amino)-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,14,15,16,17,18,19,20-undecane-5-thia-8-isoprostane

TLC: Rf of 0.32 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.97 (t, J=7,20 Hz, 3H), of 1.45 (m, 2H), 1,73 (m, 2H), 1,90 (m, 1H), 2,10 (m, 1H), 2,33 (m, 2H), to 3.02 (m, 1H), and 3.16 (m, 1H), 3,29 (m, 1H), 3,50 (m, 2H), 3,82 (m, 2H), 4,28 (m, 4H), 5,67 (t, J=6,50 Hz, 1H), 7,30 (m, 3H), 7,42 (m, 2H), 8,01 (s, 1H).

Example 5(39)

(13TH)-19-Phenyl-5-(4-ethoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf 0,41 (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,01 (s, 1H), 5,64 (dt, J=the 15.6, 6.6 Hz, 1H), 5,20 (DD, J=15,6, and 8.7 Hz, 1H), to 4.38 (q, J=7.2 Hz, 2H), 4,13 (m, 1H), 3,81 (m, 1H), 3,48-to 3.38 (m, 2H), 3.27 to (m, 1H), 2,58 (t, J=7.5 Hz, 2H), 2,46-2,11 (m, 3H), 2,04-of 1.93 (m, 2H), 1.69 in (m, 1H), 1,64-of 1.52 (m, 2H), 1,38 (t, J=7.2 Hz, 3H), 1,40-1,22 (m, 4H).

Example 5(40)

5-(4-Ethoxycarbonylmethyl-2-yl)-9,13-dioxo-1,2,3,4,20-pentanol-5-thia-8,14-dianapost

TLC: Rf to 0.19 (ethyl acetate);

1H-NMR (CDCl3): δ 8,02 (s, 1H), 7,32 (m, 1H), 4,45-4,34 (m, 3H), 3,88 (m, 1H), 3,48-3,30 (m, 3H), 3,29-3,11 (m, 2H), 2,74 (dt, J=16,2, and 7.8 Hz, 1H), 2,39 is 2.10 (m, 3H), 1,48 is 1.34 (m, 5H), 1,31-1,10 (m, 4H), 0,81 (t, J=6,9 Hz, 3H).

Example 5(41)

(13TH)-16-Hydroxy-5-(4-taxicab diltiazem-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf 0.28 in (ethyl acetate);

1H-NMR (CDCl3): δ of 0.91 (m, 3H), of 1.36 (m, 7H), of 1.74 (m, 1H), 2,25 (m, 5H), to 3.58 (m, 6N), 4,18 (m, 1H), 4,39 (kV, J=7,1 Hz, 2H), lower than the 5.37 (m, 1H), 5,80 (m, 1H), 8,01 (m, 1H).

Example 5(42)

13-(N-Methyl-N-(benzylmethyl)amino)-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,14,15,16,17,18,19,20-undecane-5-thia-8-isoprostane

TLC: Rf of 0.55 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.96 (t, J=7,28 Hz, 3H), of 1.44 (m, 2H), 1,73 (m, 2H), 2,03 (m, 2H), 2,25 (m, 1H), 2,42 (m, 1H), 2,86 (s, 3H), 2,95 (DD, J=13,87, 8,10 Hz, 1H), 3,20 (DD, J=14,01, 4,12 Hz, 1H), 3,29 (m, 1H), 3,42 (m, 2H), 3,82 (m, 2H), 4,30 (m, 4H), 7,38 (m, 5H), 8,01 (s, 1H).

Example 5(43)

14-oxa-14-(pyridin-3-yl)-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.47 (ethyl acetate:methanol=9:1);

1H-NMR (CDCl3): δ to 0.97 (t, J=7,40 Hz, 3H), of 1.46 (m, 2H), 1,74 (m, 2H), 2,07 (m, 1H), 2,32 (m, 2H), 2,60 (m, 1H), 3,34 (m, 1H), 3,49 (m, 1H), 3,61 (m, 1H), with 3.89 (m, 1H), 4,13 (m, 2H), 4,32 (m, 2H), 4,59 (DD, J=10,16, 3,30 Hz, 1H), 7,18 (DDD, J=8,40, 4,40, 0,60 Hz, 1H), 7,26 (DDD, J=8,40, 2,90, 1,40 Hz, 1H), of 7.97 (s, 1H), they were 8.22 (DD, J=4,40, 1,40 Hz, 1H), 8,32 (m, 1H).

Example 5(44)

(13TH,15thα)-19-Phenoxy-15-hydroxy-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

1H-NMR (CDCl3): δ 7,98 (s, 1H), 7,25 (m, 2H), 6.90 to (m, 3H), of 5.81 (DD, J=15,0, 5.7 Hz, 1H), 5,58 (DD, J=15,0, and 8.4 Hz, 1H), 4,32 (t, J=7.2 Hz, 2H), 4,18 (m, 2H), 3,93 (t, J=7.2 Hz, 2H), to 3.67 (m, 1H), 3,42 (m, 3H), 2,31 (m, 3H), 2,12 (d, J=5,1 Hz, 1H), 1,78 (m, 5H), 1,50 (m, 6H), is 0.96 (t, J=7.2 Hz, 3H).

Example 5(45)

(13TH,15THB1; )-20-Phenoxy-15-hydroxy-5-(4-butoxycarbonylmethyl-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

1H-NMR (CDCl3): δ to 7.99 (s, 1H), 7,25 (m, 2H), 6.90 to (m, 3H), of 5.82 (DD, J=15,0, 5.7 Hz, 1H), 5,58 (DD, J=15,0, and 8.4 Hz, 1H), 4,32 (t, J=7.2 Hz, 2H), 4,18 (m, 2H), 3,95 (t, J=7.2 Hz, 2H), to 3.67 (m, 1H), 3,42 (m, 3H), 2,31 (m, 3H), 2,04 (d, J=5,1 Hz, 1H), 1,78 (m, 5H), 1,50 (m, 8H), is 0.96 (t, J=7.2 Hz, 3H).

Examples 6(1)-6(92)

According to the method of example 2 using the compound obtained in examples 5(1)-5(45), or the corresponding ester instead of the compound obtained in example 1 given the following compounds of this invention.

Example 6(1)

(13TH,16α)-17,17-Propane-16-hydroxy-5-(4-carboxykinase-2-yl)-9-oxo-1,2,3,4,20-pentanol-8-isapros-13-EN

TLC: Rf of 0.10 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,21 (s, 1H), of 5.82 (dt, J=15,3, 7.2 Hz, 1H), 5,42 (DD, J=15,3, 9.0 Hz, 1H), 4,06 (m, 1H), 3,64 (DD, J=a 9.6, 2.1 Hz, 1H), 3,49 (dt, J=14,1, 7.2 Hz, 1H), and 3.16 (DDD, J=14,1, 8,1, 6.0 Hz, 1H), and 2.83 (t, J=7.5 Hz,, 2H), 2,52-of 2.16 (m, 4H), 2,15-1,90 (m, 5H), 1,90-of 1.56 (m, 6H), of 1.44 (m, 1H), to 0.92 (t, J=7.5 Hz, 3H).

Example 6(2)

5-(4-Carboxymethy-2-yl)-9-oxo-14,15-(1,4-interphenylene)-1,2,3,4-tetranor-5-thia-8-isoprostane

TLC: Rf of 0.55 (methylene chloride:methanol=5:1);

1H-NMR (CDCl3): δ 8,07 (s, 1H), 7,16-7,01 (m, 4H), 3,98-a 3.83 (m, 1H), of 3.73-3,62 (m, 1H), 3,50-3,19 (m, 4H), 2.71 to a 2.01 (m, 8H), 1,82-is 1.51 (m, 4H), 1,39-of 1.18 (m, 6H), 0,93-0,78 (m, 3H).

Example 6(3)

(13TH)-5-(4-Carboxymethy-2-yl)-9-oxo-1,2,3,4,18,19,20-Athanor-5-thia-8-isapros-13-EN

TLC: Rf is 0.42 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 8.09 (s, 1H), 5,71 (dt, J=is 15.3 and 6.9 Hz, 1H), 5,27 (DD, J=15,3, and 8.7 Hz, 1H), 4,07 (m, 1H), 3,82 (DDD, J=15,3, 9,0, 5.7 Hz, 1H), 3,50 (DDD, J=15,3, 9,6, 5.7 Hz, 1H), 3,41-up 3.22 (m, 2H), 2,55-2,17 (m, 3H), 2,17-to 1.98 (m, 2H), of 1.75 (m, 1H), 1,41 (kV, J=7.5 Hz, 2H), of 0.90 (t, J=7.5 Hz, 3H).

Example 6(4)

(13TH)-5-(4-Carboxymethy-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-isapros-13-EN

TLC: Rf to 0.39 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 8.09 (s, 1H), 5,72 (dt, J=15,3, and 6.6 Hz, 1H), 5,27 (DD, J=15,3, 9.0 Hz, 1H), 4,06 (m, 1H), 3,81 (DDD, J=15,3 and 9.6, 6.3 Hz, 1H), 3,50 (DDD, J=15,3, 9,6, 5.7 Hz, 1H), 3,42-up 3.22 (m, 2H), 2,44 was 2.25 (m, 3H), 2,25-a 2.01 (m, 2H), of 1.75 (m, 1H), 1,44-of 1.32 (m, 4H), of 0.90 (t, J=6.9 Hz, 3H).

Example 6(5)

(13TH,16α)-17,17-Propane-16-hydroxy-3,6-(1,4-interphenylene)-9-oxo-4,5,20-trinor-3-oxa-8-isapros-13-ANOVA acid

TLC: Rf of 0.30 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ to 0.92 (t, J=7.5 Hz, 3H), USD 1.43 (m, 1H), 1,55-of 2.50 (m, 13H), 2,65-to 2.85 (m, 2H), 3,10 (m, 1H), only 3.57 (DD, J=a 9.6, 2.7 Hz, 1H), 3,65-of 3.80 (m, 2H), 4,00-5,00 (width, 2H), 4,63 (s, 2H), 5,20 (DD, J=to 15.0, 9.0 Hz, 1H), ceiling of 5.60 (dt, J=15,0, 7.2 Hz, 1H), 6,85 (d, J=8,2 Hz, 2H), to 7.09 (d, J=8,2 Hz, 2H).

Example 6(6)

(2ND,13TH,16thα)-17,17-Propane-16-hydroxy-3,6-(1,4-interphenylene)-9-oxo-4,5,20-trinor-8-isapros-2,13-diene acid

TLC: Rf of 0.48 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 0.93 (t, J=7.5 Hz, 3H), of 1.44 (m, 1H), 1,55-of 2.50 (m, 13H), of 2,75 2,95 (m, 2H), 3,18 (m, 1H), only 3.57 (DD, J=a 9.6, 2.4 Hz, 1H), 3,70-3,90 (m,2H), of 5.29 (DD, J=15,3, and 8.7 Hz, 1H), of 5.68 (dt, J=15,3, 7.5 Hz, 1H), 6,41 (d, J=15,9 Hz, 1H), 7.23 percent (d, J=8,2 Hz, 2H), 7,47 (d, J=8,2 Hz, 2H), 7,73 (d, J=15,9 Hz, 1H).

Example 6(7)

(13TH,16α)-17,17-Propane-16-hydroxy-1,7-(2,5-intertitle)-9-oxo-2,3,4,5,6,20-hexanor-8-isapros-13-ANOVA acid

TLC: Rf is 0.42 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 0.93 (t, J=7.5 Hz, 3H), of 1.44 (m, 1H), 1,55-2,60 (m, 13H), 3,00-4,50 (width, 2H), only 3.57 (DD, J=9,9, 2.1 Hz, 1H), was 4.02 (m, 1H), 4,20 (d, J=to 15.0 Hz, 1H), 4,94 (d, J=to 15.0 Hz, 1H), lower than the 5.37 (DD, J=15,3, and 9.3 Hz, 1H), 5,80 (dt, J=15,3, 7.5 Hz, 1H), 6,95 (d, J=3.0 Hz, 1H), 7,68 (d, J=3.0 Hz, 1H).

Example 6(8)

(13TH)-5-(4-Carboxymethy-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.30 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 5,72 (dt, J=15,0, 6,9 Hz, 1H), 5,26 (DD, J=15,0, and 8.7 Hz, 1H), 4,06 (m, 1H), 3,81 (DDD, J=13,5, 9,6, 6.0 Hz, 1H), 3,50 (DDD, J=13,5, 9,6, 5,1 Hz, 1H), 3,40-is 3.21 (m, 2H), 2,55 with 2.14 (m, 3H), 2,12-to 1.99 (m, 2H), of 1.75 (m, 1H), 1,45-of 1.20 (m, 8H), to 0.88 (t, J=6.9 Hz, 3H).

Example 6(9)

(13TH)-5-(4-Carboxymethy-2-yl)-9-oxo-20-methyl-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.30 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 8.09 (s, 1H), 5,71 (dt, J=15,3, and 6.6 Hz, 1H), 5,26 (DD, J=15,3, and 8.7 Hz, 1H), 4,06 (m, 1H), 3,81 (DDD, J=13,5, 9,6, 5.7 Hz, 1H), 3,49 (DDD, J=13,5, 9,6, 5.7 Hz, 1H), 3,42-3,20 (m, 2H), 2,54-of 2.15 (m, 3H), 2,14-to 1.99 (m, 2H), of 1.75 (m, 1H), 1,45-1,17 (m, 10H)to 0.88 (t, J=6.9 Hz, 3H).

Example 6(10)

(13TH,15thα)-15-Hydroxy-1,6-(1,4-interphenylene)-9-oxo-2,3,4,5-tetranor-8-isapros-13-enova to the slot

TLC: Rf of 0.51 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (d6-DMSO): δ to 7.84 (d, J=8,4 Hz, 2H), 7,28 (d, J=8,4 Hz, 2H), 5,62 (DD, J=15,6, 6.3 Hz, 1H), 5,33 (DD, J=15,6, and 8.7 Hz, 1H), 4,71 (d, J=4,8 Hz, 1H), 4,00-a-3.84 (m, 2H), 3,60 (m, 1H), 2,99 (m, 1H), 2,89-of 2.66 (m, 2H), 2,30-2,00 (m, 3H), 1,60 (m, 1H), 1,50-of 1.15 (m, 8H), 0,81 (t, J=6.3 Hz, 3H).

Example 6(11)

(13TH,15thα)-15-Hydroxy-1,5-(2,5-intertitle)-9-oxo-2,3,4-trinor-8-isapros-13-ANOVA acid

TLC: Rf of 0.44 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 7.69 (d, J=3,9 Hz, 1H), 6,83 (d, J=3,9 Hz, 1H), 5,69 (DD, J=15,3, 6.0 Hz, 1H), 5,49 (DDD, J=15,3, and 8.4, 1.0 Hz, 1H), 4,20-to 3.99 (m, 2H), 3,60 (m, 1H), 3,00 (m, 1H), 2,85 (t, J=7.8 Hz, 2H), 2,52-2,17 (m, 3H), 2.00 in to 1.70 (m, 3H), 1,61 is 1.20 (m, 8H), to 0.89 (t, J=6.3 Hz, 3H).

Example 6(12)

(13TH,15thα)-15-Hydroxy-9-oxo-5-thia-8-isapros-13-ANOVA acid

TLC: Rf is 0.49 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 5,73 (DD, J=15,3, 5.7 Hz, 1H), of 5.53 (DDD, J=15,3, and 8.4, 1.2 Hz, 1H), 4,18 (m, 2H), 3,63 (m, 1H), 3,11 (m, 1H), 2,78-of 2.20 (m, 9H), 2.00 in to 1.70 (m, 3H), 1,62-to 1.21 (m, 8H), of 0.90 (t, J=6.6 Hz, 3H).

Example 6(13)

5-(4-Carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isoprostane

TLC: Rf of 0.37 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 8.09 (s, 1H), 3,94 (DDD, J=13,2, 9,3, 5,1 Hz, 1H), 3,65 (m, 1H), 3,54 is 3.25 (m, 3H), 2,52-of 2.28 (m, 2H), 2,16 (m, 1H), 1,82-of 1.62 (m, 2H), 1,46-1,02 (m, 11H), to 0.88 (t, J=6.9 Hz, 3H).

Example 6(14)

(13TH,15thα)-20-Ethyl-15-hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-in

TLC: Rf of 0.10 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 8,10 (s, 1H), 5,79 (DD, J=15,3, 5.7 Hz, 1H), 5,55 (DD, J=15,3, and 8.7 Hz, 1H), 4,21-4,11 (m, 2H), 4,0-3,1 (W), 3,90 of 3.75 (m, 1H), 3,55-3,30 (m, 3H), 2,56-of 2.20 (m, 3H), 1,86-1,72 (m, 1H), 1,62-of 1.42 (m, 2H), 1,42 is 1.20 (m, 10H), of 0.90 (t, J=7.2 Hz, 3H).

Example 6(15)

(13TH,15thα)-20-Methyl-15-hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf 0,20 (methylene chloride:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 8.09 (s, 1H), 5,79 (DD, J=15,6, 6.0 Hz, 1H), of 5.53 (DD, J=15,6, 9.0 Hz, 1H), 4,20-4,10 (m, 2H), 3,90-3,70 (m, 1H), 3,50-3,30 (m, 3H), 2,50-of 2.20 (m, 3H), 1.85 to to 1.70 (m, 1H), 1.60-to of 1.40 (m, 2H), 1,40-1,15 (m, 8H), 0.95 to-0,80 (m, 3H).

Example 6(16)

(13TH,15thα)-20-n-Propyl-15-hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.23 (methylene chloride:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 8.09 (s, 1H), 5,79 (DD, J=15,3, 6.0 Hz, 1H), of 5.53 (DD, J=15,3, and 8.4 Hz, 1H), 4,20-4,10 (m, 2H), 3,90-3,70 (m, 1H), 3,50-3,30 (m, 3H), 2,50-of 2.20 (m, 3H), 1.85 to to 1.70 (m, 1H), 1.60-to of 1.40 (m, 2H), 1,40-1,15 (m, 12H), 0,90-0,80 (m, 3H).

Example 6(17)

(13Z)-5-(4-Carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.34 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 5,67 (dt, J=10,8, and 7.8 Hz, 1H), 5.25-inch (DD, J=10,8, 9.6 Hz, 1H), 4,49 (dt, J=9,6, 7.2 Hz, 1H), 3,76 (m, 1H), 3,51 (m, 1H), 3,42 is 3.23 (m, 2H), 2,54 of-2.32 (m, 2H), 2,22 (m, 1H), 2,17 is 2.01 (m, 2H), 1,71 (m, 1H), 1,45-of 1.20 (m, 6H), of 0.90 (t, J=6.6 Hz, 3H).

Example 6(18)

(13Z)-16-oxa-17,17-dimethyl-5-4-carboxymethy-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-isapros-13-EN

TLC: Rf of 0.30 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), of 5.84 (dt, J=10,8, 7.2 Hz, 1H), 5,41 (DDT, J=10,8, 9,9, 1.5 Hz, 1H), to 4.62 (dt, J=9,9, 7.2 Hz, 1H), 4,07 (DDD, J=11,7, to 7.2, 1.5 Hz, 1H), 3,94 (DDD, J=11,7, to 7.2, 1.5 Hz, 1H), 3,82 (m, 1H), 3,60-3,38 (m, 2H), 3,24 (m, 1H), 2,56-to 2.18 (m, 3H), of 1.74 (m, 1H), 1,23 (s, 9H).

Example 6(19)

(13TH)-16-oxa-17,17-dimethyl-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-isapros-13-EN

TLC: Rf 0.28 in (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), of 5.83 (dt, J=15,3, 5,1 Hz, 1H), 5,55 (DDT, J=15,3, 9,0, 1.5 Hz, 1H), 4,14 (m, 1H), 3,93 (DD, J=5,1, 1.5 Hz, 2H), 3,83 (dt, J=13,8, and 7.8 Hz, 1H), 3,50 (dt, J=13,8, and 7.8 Hz, 1H), 3,32 (t, J=7,8 Hz, 2H), 2,55-2,17 (m, 3H), 1,79 (m, 1H), 1,21 (s, 9H).

Example 6(20)

(13TH,15thα)-19-Phenyl-15-hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.34 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 8.09 (s, 1H), was 7.36-7,10 (m, 5H), 5,79 (DD, J=15,0, 5.7 Hz, 1H), ceiling of 5.60-of 5.15 (m, 1H), 4,22-4,10 (m, 2H), 3,80 (m, 1H), 3,47 of 3.28 (m, 3H), 2,64-to 2.18 (m, 5H), 1,82 is 1.23 (m, 7H).

Example 6(21)

(13TH,15thα)-20-Phenyl-15-hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.34 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 8.09 (s, 1H), of 7.36 for 7.12 (m, 5H), 5,78 (DD, J=15,3, 5.7 Hz, 1H), 5,54 (DD, J=15,3, and 8.7 Hz, 1H), 4,20-4,10 (m, 2H), 3,81 (m, 1H), 3,55-of 3.27 (m, 3H), 2,65-of 2.20 (m, 5H), 1.85 to to 1.23 (m, 9H).

Example 6(22)

(13TH,15thα)-20-Benzyl-15-hydrox the-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf of 0.35 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 8.09 (s, 1H), 7,37 for 7.12 (m, 5H), 5,78 (DD, J=15,3, 6.0 Hz, 1H), 5,55 (DDD, J=15,3, to 8.7, 1.2 Hz, 1H), 4,20-4,08 (m, 2H), 3,81 (m, 1H), 3,55-of 3.27 (m, 3H), 2,64-of 2.20 (m, 5H), 1,86-to 1.21 (m, 11H).

Example 6(23)

(13TH,16α)-17,17-Propane-16-hydroxy-1,6-(1,3-interphenylene)-9-oxo-2,3,4,5,20-pentanol-8-isapros-13-ANOVA acid

TLC: Rf 0,41 (ethyl acetate:acetic acid=100:1);

1H-NMR (CDCl3): δ to 0.92 (t, J=7.5 Hz, 2H), 1,44 (m, 1H), 1,55-of 2.50 (m, 13H), 2,75-3,00 (m, 2H), 3,20 (m, 1H)and 3.59 (DD, J=a 9.9, 2.4 Hz, 1H), 3,70-3,90 (m, 2H), 5,28 (DD, J=to 15.0, 9.0 Hz, 1H), 5,79 (dt, J=15,0, 7.2 Hz, 1H), 7,39 (t, J=7.5 Hz, 1H), 7,46 (m, 1H), 7,92-of 8.00 (m, 2H).

Example 6(24)

(15α)-15-Hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isoprostane

TLC: Rf is 0.49 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 3,95 is 3.23 (m, 6H), 2,55 e 2.06 (m, 3H), of 1.94 (m, 1H), 1,78 is 1.60 (m, 2H), 1.59 CI of 1.00 (m, 10H)to 0.89 (t, J=6.6 Hz, 3H).

Example 6(25)

(15α)-15-Hydroxy-1,6-(1,4-interphenylene)-9-oxo-2,3,4,5-tetranor-5-thia-8-isoprostane acid

TLC: Rf 0.21 in (chloroform:methanol=9:1;

1H-NMR (CDCl3CD3OD): δ of 7.97 (d, J=8.1 Hz, 2H), 7,30 (d, J=8.1 Hz, 2H), 3,82 (m, 1H), 3,60-3,30 (m, 3H), 3,20 (m, 1H), 3,01 is 2.80 (m, 2H), 2,45-of 2.21 (m, 2H), 2,08 (m, 1H), 1,80-of 1.20 (m, 13H), to 0.89 (t, J=6.6 Hz, 3H).

Example 6(26)

(13TH)-17,17-Dimethyl-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-isapros-13-EN

TLC: Rf of 0.34 (chloroform:methanol:acetic sour is a=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 5,73 (dt, J=15,3, and 6.6 Hz, 1H), 5,27 (DD, J=15,3, 9.0 Hz, 1H), of 4.05 (m, 1H), 3,83 (DDD, J=13,5, 9,0, 6.3 Hz, 1H), 3,49 (DDD, J=13,5, 9,6, 6.0 Hz, 1H), 3,39-is 3.21 (m, 2H), 2,54-of 2.15 (m, 3H), 2,09-of 1.97 (m, 2H), of 1.75 (m, 1H), 1.30 and of 1.20 (m, 2H), 0,89 (s, 9H).

Example 6(27)

(13TH)-17,17-Dimethyl-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.35 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 8.09 (s, 1H), 5,72 (dt, J=15,0, 6,9 Hz, 1H), 5,26 (DD, J=15,0, and 8.7 Hz, 1H), of 4.05 (m, 1H), 3,82 (DDD, J=13,5, 9,0, 6,9 Hz, 1H), 3,49 (DDD, J=13,5, 9,9, 6.0 Hz, 1H), 3,40-3,24 (m, 2H), 2,54-of 2.15 (m, 3H), 2,10-of 1.93 (m, 2H), of 1.75 (m, 1H), 1,29 is 1.16 (m, 4H), and 0.98 and 0.75 (m, 9H).

Example 6(28)

(13TH,15thα)-19-Phenyl-15-hydroxy-9-oxo-20-nor-5-thia-8-isapros-13-ANOVA acid

TLC: Rf 0,24 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ 7,30-of 7.23 (m, 2H), 7,21-7,14 (m, 3H), 5,71 (DD, J=15,3, 5.7 Hz, 1H), 5,50 (DD, J=15,3, and 8.4 Hz, 1H), 4,20-4,06 (m, 2H), 3.72 points-to 3.58 (m, 1H), 3,14-3,00 (m, 1H), 2,70-of 2.16 (m, 11H), 1,96-to 1.82 (m, 2H), 1,80-1,20 (m, 7H).

Example 6(29)

(13TH,15thα)-20-Phenyl-15-hydroxy-9-oxo-5-thia-8-isapros-13-ANOVA acid

TLC: Rf 0,24 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ 7,30-of 7.23 (m, 2H), 7,21-7,14 (m, 3H), 5,72 (DD, J=15,3, 5.7 Hz, 1H), 5,51 (DD, J=15,3, 8,1 Hz, 1H), 4,20-4,06 (m, 2H), 3.72 points-to 3.58 (m, 1H), 3,16 totaling 3.04 (m, 1H), 2,72-of 2.16 (m, 11H), 1,96-to 1.82 (m, 2H), 1,80-1,24 (m, 9H).

Example 6(30)

(13TH,15thα)-20-Benzyl-15-hydroxy-9-oxo-5-thia-8-isapros-13-ANOVA acid

TLC: Rf 0,24 (methylene chloride:methanol=9:1);

1Mr. YAM is (CDCl 3): δ 7,30-of 7.23 (m, 2H), 7,21-7,14 (m, 3H), 5,73 (DD, J=15,3, a 5.4 Hz, 1H), 5,51 (DDD, J=15,3 and 8.1, 0.9 Hz, 1H), 4,20-4,06 (m, 2H), 3.72 points-of 3.60 (m, 1H), 3,16 totaling 3.04 (m, 1H), 2,72-of 2.16 (m, 11H), 1,96-of 1.84 (m, 2H), 1,80 is 1.20 (m, 11H).

Example 6(31)

14-oxa-14-phenyl-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.35 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 7,29 (DD, J=8,4, 7.5 Hz, 2H), 6,98 (t, J=7.5 Hz, 1H), to 6.88 (d, J=8,4 Hz, 2H), 4,20 (DD, J=9,9, 3.6 Hz, 1H), 4.09 to (m, 1H), 3,99 (DD, J=9,9, a 5.4 Hz, 1H), 3,91 (m, 1H, in), 3.75 (m, 1H), 3,51 (m, 1H), 3,29 (m, 1H), 2,60 (m, 1H), 2,43 (m, 1H, in), 2.25 (m, 1H), 1,96 (m, 1H).

Example 6(32)

14-oxa-14-(3,5-dichlorophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.41 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,11 (s, 1H), 6,98 (t, J=1.8 Hz, 1H), PC 6.82 (d, J=1.8 Hz, 2H), or 4.31 (DD, J=9,9, 3.0 Hz, 1H), 4,08 (m, 1H), 3,98 (DD, J=9,9, 3.0 Hz, 1H), 3,90 (m, 1H), 3,68 (m, 1H), 3,48 (m, 1H), or 3.28 (m, 1H ), at 2.59 (m, 1H), 2,43 (m, 1H, in), 2.25 (m, 1H), 1,97 (m, 1H).

Example 6(33)

(13TH,16α)-17,17-Propane-16-hydroxy-6-(4-carboxymethy-2-ylsulphonyl)-9-oxo-1,2,3,4,5,20-hexanor-8-isapros-13-EN

TLC: Rf 0.14 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 0.93 (t, J=7.5 Hz, 3H), of 1.44 (m, 1H), 1,55-of 2.20 (m, 10H), 2,20-to 2.55 (m, 4H), 3,60-4,00 (m, 5H), 4,00-and 4.40 (m, 2H), 5,41 (DD, J=15,3, 9.0 Hz, 1H), 5,96 (dt, J=15,3, 7.2 Hz, 1H), 8,54 (s, 1H).

Example 6(34)

14-oxa-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-isoprostane/p>

TLC: Rf of 0.25 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 3.96 points at 3.69 (m, 3H), to 3.58-to 3.38 (m, 5H), 3,29 (m, 1H), 2,56-to 2.29 (m, 2H), 2,12 (m, 1H), 1,75 (m, 1H), 1,60 is 1.48 (m, 2H), 1,42-1,24 (m, 2H), of 0.91 (t, J=7.2 Hz, 3H).

Example 6(35)

17,17-Propane-5-(4-carboxymethy-2-yl)-9,16-dioxo-1,2,3,4,20-pentanol-5-thia-8-isoprostane

TLC: Rf of 0.43 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 0.75 (t, J=7.5 Hz, 3H), 1.30 and 2.00 in (m, 11N), 2,10-to 2.55 (m, 7H), 3.25 to 3,55 (m, 3H), to 3.67 (m, 1H), 3,95 (m, 1H), of 8.09 (s, 1H).

Example 6(36)

(13TH)-17-oxa-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.34 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 5,77 (dt, J=is 15.3 and 6.9 Hz, 1H), lower than the 5.37 (DD, J=15,3, and 8.7 Hz, 1H), 4,07 (m, 1H), 3,76 (m, 1H), 3,63-of 3.42 (m, 5H), 3,38 of 3.28 (m, 2H), 2,55-2,17 (m, 5H), to 1.76 (m, 1H), 1,20 (t, J=7.2 Hz, 3H).

Example 6(37)

(13TH)-16-oxa-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.36 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 8.09 (s, 1H), of 5.83 (dt, J=15,3, a 5.4 Hz, 1H), 5,57 (DDT, J=15,3, to 8.7, 1.2 Hz, 1H), 4,15 (m, 1H), 3,98 (DD, J=5,4, 1.2 Hz, 2H), 3,85 (m, 1H), 3,55-3,26 (m, 5H), 2,55-2,17 (m, 3H), 1,79 (m, 1H), 1,68-1,53 (m, 2H), to 0.92 (t, J=7.2 Hz, 3H).

Example 6(38)

13-(N-(Phenylsulfonyl)amino)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,14,15,16,17,18,19,20-undecane-5-thia-8-isoprostane

TLC: Rf is 0.22 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 2,00-2,5 (m, 2N), of 2.38 (m, 1H), 2,60 (m, 1H), 3.00 and-of 3.42 (m, 5H), 3,90-was 4.02 (m, 2H), to 6.19 (t, J=6,6 Hz, 1H), 7,45-of 7.60 (m, 3H), 7,86 (m, 2H), of 8.09 (s, 1H).

Example 6(39)

13-(N-(Benzylmethyl)amino)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,14,15,16,17,18,19,20-undecane-5-thia-8-isoprostane

TLC: Rf of 0.27 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 1,90-to 2.18 (m, 2H), 2,31 (m, 1H), of 2.51 (m, 1H), 2.95 and is 3.40 (m, 5H), 3,76 (m, 1H), 3,91 (m, 1H), or 4.31 (s, 2H), 5,72 (t, J=6,6 Hz, 1H), 7,30-7,40 (m, 3H), 7,40 was 7.45 (m, 2H), 8,12 (s, 1H).

Example 6(40)

(13TH)-19-Phenyl-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.43 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), was 7.36-7.23 percent (m, 2H), 7,22-7,14 (m, 3H), 5,69 (dt, J=15,0, and 6.6 Hz, 1H), 5.25-inch (DD, J=15,0, and 8.7 Hz, 1H), Android 4.04 (m, 1H), 3,80 (m, 1H), 3,48 (m, 1H), 3,38-3,18 (m, 2H), 2,61 (t, J=7.5 Hz, 2H), 2,53-to 2.29 (m, 2H), of 2.21 (m, 1H), 2,13-to 1.98 (m, 2H), 1,73 (m, 1H), 1,68-and 1.54 (m, 2H), 1,48 is 1.34 (m, 4H).

Example 6(41)

5-(4-Carboxymethy-2-yl)-9,13-dioxo-1,2,3,4,20-pentanol-5-thia-8,14-dianapost

TLC: Rf to 0.17 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,11 (s, 1H), 7,16 (t, J=5.4 Hz, 1H), to 4.41 (DD, J=8,4, 3.6 Hz, 1H), 3,90 (m, 1H), 3,53 is 3.23 (m, 5H), of 2.72 (m, 1H), 2,47-2,03 (m, 3H), 1,52-of 1.35 (m, 2H), 1,34-1,10 (m, 4H), of 0.82 (t, J=6.9 Hz, 3H).

Example 6(42)

(13TH)-16-Hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf 0.28 in (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ to 0.92 (t, J=6,30 Hz, 3H), of 1.41 (m, 4H), of 1.74 (m, 1H), 2,3 (m, 5H), 3,52 (m, 5H), 4,10 (m, 1H), to 4.52 (Shir. s, 2H), lower than the 5.37 (m, 1H), of 5.82 (m, 1H), 8,07 (s, 1H).

Example 6(43)

13-(N-Methyl-N-(benzylmethyl)amino)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,14,15,16,17,18,19,20-undecane-5-thia-8-isoprostane

TLC: Rf of 0.33 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 1,89 (m, 1H), 2.06 to (m, 1H), to 2.29 (m, 1H), 2,44 (m, 1H), was 2.76 (DD, J=14,30, 7,80 Hz, 1H), 2,85 (s, 3H), to 3.02 (DD, J=14,30, and 4.40 Hz, 1H), 3,20 (m, 1H), 3,34 (m, 2H), and 3.72 (m, 1H), 3,90 (m, 1H), 4,30 (, 2H), 7,39 (s, 5H), 8,10 (s, 1H).

Example 6(44)

14-oxa-14-(pyridin-3-yl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.32 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 2.09 (m, 1H), and 2.26 (m, 1H), 2,43 (DDD, J=Ls 16.80, 9,90, 5,70 Hz, 1H), 2,62 (DDD, J=Ls 16.80, 10,00, of 6.90 Hz, 1H), 3,23 (m, 1H), 3,47 (m, 1H), 3,68 (m, 1H), 3,84 (m, 1H), 4,17 (m, 2H), 4,88 (m, 1H), 6,64 (Shir. s, 1H), 7,31 (m, 2H), 8,03 (s, 1H), they were 8.22 (m, 1H), 8,58 (m, 1H).

Example 6(45)

14-oxa-14-(2,5-dichlorophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.44 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), to 2.29 (m, 1H), 2,45 (m, 1H), 2,68 (m, 1H), or 3.28 (m, 1H), 3,55 (m, 1H), 3,81 (m, 1H), 3,99 (m, 2H), 4,15 (m, 1H), 4,30 (DD, J=9,89, 2,47 Hz, 1H), 6,93 (m, 2H), 7,29 (d, J=a 9.60 Hz, 1H), 8,08 (s, 1H).

Example 6(46)

14-oxa-14-(2,4,5-trichlorophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.44 (chloroform:methanol:xyna acid=90:10:1);

1H-NMR (CDCl3): δ a 1.96 (m, 1H), 2,37 (m, 2H), 2,69 (m, 1H), 3.27 to (m, 1H), 3,53 (m, 1H), of 3.77 (m, 1H), 3,97 (m, 2H), 4,13 (m, 1H), 4,37 (DD, J=9,89, 2,47 Hz, 1H), 7,07 (s, 1H), 7,46 (s, 1H), of 8.09 (s, 1H).

Example 6(47)

14-oxa-14-(3,4-dichlorophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.40 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.97 (m, 1H), and 2.26 (m, 1H), 2,43 (m, 1H), 2,59 (m, 1H), or 3.28 (m, 1H), 3,48 (m, 1H), 3,70 (m, 1H), 3,94 (m, 2H), 4,08 (m, 1H), 4,25 (m, 1H), 6,76 (DD, J=8,80, 2,70 Hz, 1H), 7,02 (d, J=2,70 Hz, 1H), 7,33 (d, J=8,80 Hz, 1H), 8,10 (s, 1H).

Example 6(48)

14-oxa-14-(2,3,4,5,6-pentafluorophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.38 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ a 2.01 (m, 1H), 2,28 (m, 1H), 2,43 (m, 1H), 2,59 (m, 1H), 3,39 (m, 1H), 3,52 (m, 1H), 3,70 (m, 1H), 4,10 (m, 3H), of 4.38 (DD, J=9,90, 3,00 Hz, 1H), 8,10 (s, 1H).

Example 6(49)

14-oxa-14-(3,4-differenl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.36 (chloroform:methanol:acetic acid=90:10:1;

1H-NMR (CDCl3): δ of 1.97 (m, 1H), and 2.26 (m, 1H), 2,43 (m, 1H), 2,59 (m, 1H), 3,29 (m, 1H), 3,48 (m, 1H), 3,71 (m, 1H), 3,94 (m, 2H), 4,07 (m, 1H), 4,18 (m, 1H), 6,59 (m, 1H), 6.73 x (m, 1H), 7,07 (m, 1H), 8,10 (, 1H).

Example 6(50)

14-oxa-14-(2-nitro-3-were)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.33 (chlorofo the m:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.84 (m, 1H), 2,32 (m, 1H), 2,32 (s, 3H), 2,48 (m, 2H), 3.27 to (m, 1H), of 3.45 (m, 1H), 3,69 (m, 1H), 3.96 points (m, 1H), 4,10 (m, 2H), 4,23 (m, 1H), 6.87 in (d, J=8,10 Hz, 1H), 6,92 (d, J=8,10 Hz, 1H), to 7.32 (t, J=8,10 Hz, 1H), 8,07 (s, 1H).

Example 6(51)

14-oxa-14-(3-chloro-4-formylphenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.56 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 2,00 (m, 1H), to 2.29 (m, 1H), 2,45 (m, 1H), 2,61 (m, 1H), 3,29 (m, 1H), 3,48 (m, 1H), 3,69 (m, 1H), 3,94 (m, 1H), 4,12 (m, 2H), and 4.40 (m, 1H), 6,91 (m, 1H), 6,98 (d, J=2.20 Hz, 1H), of 7.90 (d, J=8,79 Hz, 1H), 8,10 (s, 1H), 10,32 (s, 1H).

Example 6(52)

14-oxa-14-(4-nitro-3-were)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.51 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 2,00 (m, 1H), to 2.29 (m, 1H), 2,45 (m, 1H), 2,62 (m, 1H), 2,62 (s, 3H), 3,29 (m, 1H), 3,48 (m, 1H), 3,70 (m, 1H), 3,94 (m, 1H), 4,11 (m, 2H), 4,36 (m, 1H), for 6.81 (m, 2H), 8,07 (m, 1H), 8,10 (, 1H).

Example 6(53)

14-oxa-14-(3-nitro-2-were)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.47 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 2,02 (m, 1H), 2,33 (m, 1H), 2,33 (s, 3H), 2,47 (m, 1H), 2,62 (m, 1H), 3,29 (m, 1H), 3,50 (m, 1H), and 3.72 (m, 1H), 3.96 points (m, 1H), 4,14 (m, 2H), 4,29 (DD, J=9,60, 3,00 Hz, 1H), 7,07 (d, J=8,20 Hz, 1H), 7,27 (t, J=to 8.20 Hz, 1H), 7,44 (m, 1H), of 8.09 (s, 1H).

Example 6(54)

14-oxa-14-(4-chloro-3-were)-5-(carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.51 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.95 (m, 1H), 2,33 (m, 2H), 2,33 (s, 3H), at 2.59 (m, 1H), 3.27 to (m, 1H), 3,49 (m, 1H), 3,74 (m, 1H), 3,92 (m, 2H), 4,06 (m, 1H), 4,16 (DD, J=9,60, 3,00 Hz, 1H), 6,66 (DD, J=8,80, 2,70 Hz, 1H), 6,76 (d, J=2,70 Hz, 1H), 7.23 percent (d, J=8,80 Hz, 1H), of 8.09 (s, 1H).

Example 6(55)

14-oxa-14-(3-nitro-4-were)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.56 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 2,02 (m, 1H), 2,35 (m, 2H), of 2.51 (s, 3H), 2.63 in (m, 1H), 3,29 (m, 1H), 3,49 (m, 1H), 3,70 (m, 1H), 3,93 (m, 1H), 4,10 (m, 2H), to 4.41 (DD, J=there is a 10.03, 2,88 Hz, 1H), 5,66 (Shir. s, 1H), 7,06 (DD, J=scored 8.38, 2,61 Hz, 1H), 7,24 (d, J=charged 8.52 Hz, 1H), 7,54 (d, J=2,75 Hz, 1H), 8,10 (s, 1H).

Example 6(56)

14-oxa-14-(3-bromophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf and 0.46 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ a 1.96 (m, 1H), 2,25 (m, 1H), 2,43 (m, 1H), 2,60 (m, 1H), or 3.28 (DDD, J=13,40, 10,16, are 5.36 Hz, 1H), 3,49 (DDD, J=13,40, 10,16, with 5.22 Hz, 1H), and 3.72 (m, 1H), 4,01 (m, 3H), 4,22 (DD, J=9,89, to 3.02 Hz, 1H), PC 6.82 (TD, J=4,60, of 2.34 Hz, 1H), 7,10 (m, 3H), of 8.09 (s, 1H).

Example 6(57)

14-oxa-14-(2,3-dimetilfenil)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.48 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.97 (m, 1H), 2,11 (s, 3H), and 2.27 (s, 3H), and 2.27 (m, 1H), 2,45 (m, 1H), 2.63 in (m, 1H), 3,26 (DDD, J=13,40, 10,16, 5,49 Hz, 1H), 3,52 (DDD, J=1,40, 10,16, with 5.22 Hz, 1H), 3,88 (m, 3H), 4,17 (m, 2H), of 6.68 (d, J=charged 8.52 Hz, 1H), for 6.81 (d, J=of 7.69 Hz, 1H), 7,05 (t, J=7,97 Hz, 1H), 8,08 (s, 1H).

Example 6(58)

14-oxa-14-(4-chloro-2,6-dimetilfenil)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.47 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), 2,34 (m, 2H), 2,34 (C, 6N), at 2.59 (m, 1H), 3.27 to (DDD, J=13,32, there is a 10.03, with 5.22 Hz, 1H), 3,49 (m, 1H), 3,74 (m, 1H), 3,91 (m, 2H), 4,12 (m, 2H), 6,62 (s, 2H), 8,08 (s, 1H).

Example 6(59)

14-oxa-14-(naphthalene-2-yl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.44 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ a 2.01 (m, 1H), 2,28 (m, 1H), 2,45 (m, 1H), 2,64 (m, 1H), 3,29 (m, 1H), 3,52 (m, 1H), 3,80 (m, 1H), 3,94 (m, 1H), 4,12 (m, 2H), 4,32 (m, 1H), 7,12 (m, 2H), was 7.36 (TD, J=7,49, 1,24 Hz, 1H), 7,46 (TD, J=7,55, to 1.37 Hz, 1H), to 7.75 (m, 3H), of 8.06 (s, 1 H)

Example 6(60)

14-oxa-14-(2-fluoro-3-cryptomailer)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.35 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.95 (m, 1H), 2,28 (m, 1H), 2,44 (m, 1H), 2,61 (m, 1H), 3,35 (DDD, J=13,40, 10,10, of 5.40 Hz, 1H), 3,52 (DDD, J=13,40, 10,10, of 5.40 Hz, 1H), and 3.72 (m, 1H), 4.09 to (m, 3H), 4,33 (DD, J=9,48, 2,88 Hz, 1H), 7,17 (m, 3H), of 8.09 (s, 1H).

Example 6(61)

14-oxa-14-(3, 5dimethylphenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.45 (chloroform:methanol:acetic who islot=90:10:1);

1H-NMR (CDCl3): δ of 1.93 (m, 1H), 2,23 (m, 1H), 2,28 (C, 6N), 2,42 (m, 1H), 2,59 (m, 1H), 3.27 to (m, 1H), 3,51 (m, 1H), 3,95 (m, 5H), 6,50 (s, 2H), only 6.64 (s, 1H), 8,08 (s, 1H).

Example 6(62)

14-oxa-14-(3,4,5-trimetilfenil)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.43 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.92 (m, 1H), 2,10 (s, 3H), of 2.20 (m, 1H), 2,25 (C, 6N), 2,42 (m, 1H), 2,58 (m, 1H), 3,26 (m, 1H), 3,51 (m, 1H), 3.96 points (m, 5H), 6,55 (s, 2H), 8,07 (s, 1H).

Example 6(63)

14-oxa-14-(5,6,7,8-tetrahydronaphthalen-1-yl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf is 0.42 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ to 1.76 (m, 4H), of 1.97 (m, 1H), and 2.27 (m, 1H), 2,58 (m, 6N), 3,23 (m, 1H), 3,51 (m, 1H), 3.96 points (m, 5H), is 6.61 (d, J=8,24 Hz, 1H), 6,74 (d, J=7,42 Hz, 1H), 7,06 (t, J=7,97 Hz, 1H), 8,07 (s, 1H).

Example 6(64)

14-oxa-14-(4-acetyl-3-were)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf is 0.42 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.97 (m, 1H), 2,45 (m, 3H), by 2.55 (s, 6N), with 3.27 (m, 1H), 3,49 (m, 1H), 3,74 (m, 1H), 3,93 (m, 1H), 4,08 (m, 2H), 4,24 (m, 1H), 6,74 (m, 2H), 7,74 (d, J=9,34 Hz, 1H), 8,08 (s, 1H).

Example 6(65)

14-oxa-14-(naphthalene-1-yl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.43 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDC 3): δ 2,07 (m, 1H), 2,35 (m, 1H), of 2.51 (m, 1H), 2,70 (m, 1H), 3,26 (m, 1H), 3,55 (m, 1H), 3,92 (m, 2H), 4,23 (m, 2H), 4,36 (m, 1H), PC 6.82 (m, 1H), 7,37 (m, 1H), 7,50 (m, 3H), 7,82 (m, 1H), 8,03 (, 1H), 8,09 (m, 1H).

Example 6(66)

14-oxa-14-(2-chloro-3-triptoreline)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf is 0.42 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ a 1.96 (m, 1H), of 2.38 (m, 2H), 2,69 (m, 1H), and 3.31 (m, 1H), 3,55 (m, 1H), 3,81 (m, 1H), 4,11 (m, 3H), 4,33 (m, 1H), 7,14 (m, 1H), 7,34 (m, 2H), 8,08 (s, 1H).

Example 6(67)

14-oxa-14-(3-were)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf is 0.49 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.95 (m, 1H), 2,25 (s, 1H), 2,33 (s, 3H), 2,43 (m, 1H), 2,60 (m, 1H), 3.15 in (Shir. s, 1H), or 3.28 (m, 1H), 3,51 (m, 1H), 3,76 (m, 1H), 3,94 (m, 2H), 4,12 (m, 2H), of 6.68 (m, 2H), for 6.81 (m, 1H), 7,17 (t, J=of 7.69 Hz, 1H), 8,08 (s, 1H).

Example 6(68)

14-oxa-14-(4-were)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.47 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), 2,23 (m, 1H), to 2.29 (s, 3H), 2,42 (DDD, J=Ls 16.80, 10,00, 6,00 Hz, 1H), 2,59 (DDD, J=Ls 16.80, 10,00, of 6.90 Hz, 1H), or 3.28 (DDD, J=13,20, 10,20, of 5.40 Hz, 1H), 3,50 (DDD, J=13,20, 10,20, of 5.40 Hz, 1H), of 3.77 (DDD, J=13,20, 10,20, of 5.40 Hz, 1H), 3,93 (m, 2H), 4,10 (m, 2H), 6,77 (d, J=8,80 Hz, 2H), to 7.09 (d, J=8,80 Hz, 2H), 8,08 (s, 1H).

Example 6(69)

14-oxa-14-(2,3,5-trichlorophenyl)-5-(4-carboxymethy-2-yl)9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.55 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.95 (m, 1H), 2,30 (m, 1H), 2,45 (m, 1H), 2,68 (m, 1H), 3,26 (m, 1H), 3,54 (m, 1H), 3,78 (m, 1H), 3,99 (m, 2H), 4,15 (m, 1H), 4,32 (m, 1H), to 6.88 (d, J=2.20 Hz, 1H), 7,14 (DD, J=2,20, of 0.55 Hz, 1H), 8,08 (s, 1H).

Example 6(70)

14-oxa-14-(3-chloro-4-forfinal)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf value of 0.52 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ a 1.96 (m, 1H), 2,25 (m, 1H), 2,43 (m, 1H), 2,59 (m, 1H), or 3.28 (m, 1H), 3,48 (m, 1H), 3,70 (m, 1H), 3,93 (m, 2H), 4,07 (m, 1H), 4,21 (m, 1H), 6.75 in (dt, J=9,00, 3,00 Hz, 1H), 6,94 (DD, J=5,70, 3,00 Hz, 1H), 7,05 (t, J=9,00 Hz, 1H), of 8.09 (s, 1H).

Example 6(71)

14-oxa-14-(2,3-dichlorophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.41 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.93 (m, 1H), to 2.29 (m, 1H), 2,45 (m, 1H), to 2.67 (m, 1H), 3,29 (m, 1H), of 3.56 (m, 1H), 3,81 (m, 1H), 4,12 (m, 4H), at 6.84 (DD, J=7,42, with 1.92 Hz, 1H), 7,14 (m, 2H), 8,07 (s, 1H).

Example 6(72)

14-oxa-14-(3-nitrophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.45 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 2,04 (m, 1H), to 2.29 (m, 1H), 2,45 (m, 1H), 2.63 in (m, 1H), 3,30 (m, 1H), 3,49 (m, 1H), 3,69 (m, 1H), 3,95 (m, 1H), 4,13 (m, 2H), of 4.45 (m, 1H), 7.23 percent (m, 1H), 7,44 (t, J=8,24 Hz, 1H), 7,76 (t, J=2,34 Hz, 1H), a 7.85 (m, 1H), of 8.09 (s, 1H).

Example 6(73)

14-oxa-14-(3-triptime ylphenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.43 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ to 1.98 (m, 1H), and 2.27 (m, 1H), 2,44 (m, 1H), 2,61 (m, 1H), 3,29 (m, 1H), 3,49 (m, 1H), 3,71 (m, 1H), was 4.02 (m, 3H), 4,30 (DD, J=9,75, 2,88 Hz, 1H), 7,07 (m, 1H), 7,13 (Shir. s, 1H), 7,25 (m, 1H), 7,41 (t, J=7,97 Hz, 1H), of 8.09 (s, 1H).

Example 6(74)

14-oxa-14-(3-trifloromethyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.43 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ to 1.98 (m, 1H), and 2.26 (m, 1H), 2,43 (m, 1H), 2,60 (m, 1H), 3,29 (m, 1H), 3,49 (m, 1H), 3,71 (m, 1H), was 4.02 (m, 3H), 4,24 (DD, J=9,89, to 3.02 Hz, 1H), 6.75 in (lat. s, 1H), 6,84 (m, 2H), 7,30 (t, J=8,24 Hz, 1H), of 8.09 (s, 1H).

Example 6(75)

14-oxa-14-(2-chloro-4-methoxyphenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.43 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.92 (m, 1H), and 2.26 (m, 1H), 2,43 (m, 1H), 2,65 (m, 1H), and 3.31 (m, 1H), of 3.56 (m, 1H), 3,76 (s, 3H), 3,80 (m, 2H), 4,06 (m, 3H), 6.75 in (DD, J=9,00, 2,70 Hz, 1H), 6,85 (d, J=9,00 Hz, 1H), of 6.96 (d, J=2,70 Hz, 1H), 8,07 (s, 1H).

Example 6(76)

14-oxa-14-(4-chloro-3-ethylphenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.50 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ to 1.21 (t, J=7,50 Hz, 3H), of 1.95 (m, 1H), 2,25 (m, 1H), 2,43 (m, 1H), 2,59 (m, 1H), 2,70 (kV, J=7,50 Hz, 2H), 3.27 to (m, 1H), 3,49 (m, 1H), to 3.73 (m, 1H), a 4.03 (m, 4H), of 6.66 (DD, J=8,70, 3,00 Hz, 1H), 6,76 (d, J=3,00 Hz, 1H), 7.23 percent (d, J=8.7 Hz, 1H), 8,08 (s, 1H).

Example 6(77)

14-oxa-14-(4-methylindol-7-yl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf value of 0.52 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ at 1.91 (m, 1H), 2,10 (m, 2H), measuring 2.20 (s, 3H), 2,24 (m, 1H), 2,42 (m, 1H), 2,60 (m, 1H), 2,84 (m, 4H), of 3.25 (m, 1H), 3,52 (m, 1H), 3.96 points (m, 5H), 6,55 (d, J=to 8.20 Hz, 1H), 6,92 (d, J=to 8.20 Hz, 1H), 8,07 (s, 1H).

Example 6(78)

14-oxa-14-(4-fluoro-3-were)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.50 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), 2,24 (d, J=1.90 Hz, 3H), of 2.25 (m, J=1,92 Hz, 1H), 2,42 (m, 1H), 2,59 (m, 1H), 3.27 to (m, 1H), 3,49 (m, 1H), 3,75 (m, 1H), 4,01 (m, 4H), of 6.66 (m, 2H), 6,91 (t, J=9,00 Hz, 1H), 8,08 (s, 1H).

Example 6(79)

14-oxa-14-(2,3,4-trichlorophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.41 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), a 2.36 (m, 2H), to 2.67 (m, 1H), or 3.28 (DDD, J=13,20, the 10.40, with 5.22 Hz, 1H), 3,54 (DDD, J=13,20, the 10.40, 4,94 Hz, 1H), 3,80 (m, 1H), 4,06 (m, 3H), 4,28 (DD, J=9,75, 2,61 Hz, 1H), 6,83 (d, J=9,07 Hz, 1H), 7,34 (d, J=9,07 Hz, 1H), 8,08 (s, 1H).

Example 6(80)

14-oxa-14-(2-chloro-4-forfinal)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.33 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), 2,28 (m, 1H), 2,45 (m, 1H), 2,66 (m,1H), of 3.31 (DDD, J=13,20, the 10.40, with 5.22 Hz, 1H), 3,55 (DDD, J=13,20, the 10.40, 4,94 Hz, 1H), 3,80 (m, 1H), 4,01 (m, 2H), 4,13 (m, 1H), 4,23 (DD, J=9,60, 1.80 Hz, 1H), 6,91 (m, 2H), 7,15 (DD, J=7,97, to 3.02 Hz, 1H), 8,08 (s, 1H).

Example 6(81)

14-oxa-14-(4-chloro-3-nitrophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.37 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 2,03 (m, 1H), to 2.29 (m, 1H), 2,45 (m, 1H), 2,62 (m, 1H), 3.27 to (DDD, J=13,50, 10,10, are 5.36 Hz, 1H), 3,47 (DDD, J=13,50, 10,10, 5,49 Hz, 1H), 3,68 (m, 1H), with 3.89 (m, 1H), 4,10 (m, 2H), 4,51 (DD, J=9,89, a 2.75 Hz, 1H), to 7.09 (DD, J=9,00, 2,90 Hz, 1H), 7,43 (d, J=9,00 Hz, 1H), 7,49 (d, J=2,90 Hz, 1H), 8,11 (s, 1H).

Example 6(82)

14-oxa-14-(2,4-dichlorophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.34 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.93 (m, 1H), to 2.29 (m, 1H), 2,45 (m, 1H), 2,66 (m, 1H), 3,29 (DDD, J=13,32, the 10.40, with 5.22 Hz, 1H), 3,55 (DDD, J=13,32, the 10.40, with 5.22 Hz, 1H), 3,80 (m, 1H), 4.00 points (m, 2H), 4,14 (m, 1H), 4,25 (DD, J=9,60, 1.80 Hz, 1H), 6,86 (d, J=8,79 Hz, 1H), 7,20 (DD, J=8,79, 2,47 Hz, 1H), 7,38 (d, J=2,47 Hz, 1H), 8,08 (s, 1H).

Example 6(83)

14-oxa-14-(4-chloro-3-triptoreline)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.34 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 2,00 (m, 1H), and 2.27 (m, 1H), 2,44 (m, 1H), 2,62 (m, 1H), 3,29 (m, 1H), 3,48 (m, 1H), 3,69 (m, 1H), 4,01 (m, 3H), 4,33 (DD, J=9,75, 2,88 Hz, 1H), 7,01 (DD, J=8,80, 2,90 Hz, 1H), 7,21 (d, J=2,90 Hz, 1H), 7,40 (d, J=8,80 Hz, 1H), 8,10 (s, 1H).

Example 6(84)

14-oxa-14-(2,4-dimetilfenil)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.34 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.95 (m, 1H), 2,16 (s, 3H), and 2.26 (s, 3H), and 2.26 (m, 1H), 2,43 (m, 1H), 2,61 (m, 1H), 3,25 (DDD, J=13,30, 10.30 a.m., with 5.22 Hz, 1H), 3,51 (DDD, J=13,30, 10.30 a.m., with 5.22 Hz, 1H), 3,79 (m, 1H), 3,95 (m, 2H), 4,12 (m, 2H), of 6.68 (d, J=8,24 Hz, 1H), 6,95 (m,2N),8,07 (s, 1H).

Example 6(85)

14-oxa-14-(3-ethylphenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.34 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.23 (t, J=of 7.69 Hz, 3H), of 1.94 (m, 1H), 2,24 (m, 1H), 2,42 (m, 1H), 2,61 (m, 3H), of 3.27 (DDD, J=13,30, the 10.40, 5,49 Hz, 1H), 3,51 (DDD, J=13,30, the 10.40, with 5.22 Hz, 1H), 3,78 (m, 1H), 3,94 (m, 2H), 4,07 (m, 1H), 4.16 the (DD, J=9,60, 3,00 Hz, 1H), 6,70 (m, 2H), at 6.84 (d, J=7,97 Hz, 1H), 7,21 (t, J=of 7.69 Hz, 1H), 8,08 (s, 1H).

Example 6(86)

14-oxa-14-(3-methyl-4-methylthiophenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.36 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.93 (m, 1H), 2,38 (m, J=of 14.28 Hz, 2H), a 2.36 (s, 3H), 2.40 a (s, 3H), 2,60 (m, 1H), 3,26 (DDD, J=13,30, the 10.40, with 5.22 Hz, 1H), 3,50 (DDD, J=13,30, the 10.40, are 5.36 Hz, 1H), 3,75 (m, 1H), Android 4.04 (m, 4H), 6,72 (m, 2H), 7,17 (d, J=7,97 Hz, 1H), 8,08 (s, 1H).

Example 6(87)

14-oxa-14-(4-chloro-3, 5dimethylphenyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.36(chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.93 (m, 1H), 2,34 (m, 2H), 2,34 (C, 6N), at 2.59 (m, 1H), 3,25 (DDD, J=13,30, 10,50, 5,49 Hz, 1H), 3,49 (DDD, J=13,30, 10,50, with 5.22 Hz, 1H), 3,76 (m, 1H), 3,91 (m, 2H), 4.09 to (m, 2H), is 6.61 (s, 2H), 8,08 (s, 1H).

Example 6(88)

14-oxa-14-(2,3,5-tryptophanyl)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.32 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.95 (m, 1H), 2,28 (m, 1H), 2,44 (m, 1H), 2,62 (m, 1H), and 3.31 (m, 1H), 3,51 (m, 1H), and 3.72 (m, 1H), 4,05 (m, 3H), 4,32 (DD, J=9,75, 2,88 Hz, 1H), 6,55 (m, 2H), of 8.09 (s, 1H).

Example 6(89)

14-oxa-14-(4-fluoro-3-triptoreline)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.36 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ to 1.98 (m, 1H), and 2.27 (m, 1H), 2,44 (m, 1H), 2,60 (m, 1H), 3,29 (DDD, J=13,30, 10,20, to 5.08 Hz, 1H), 3,48 (DDD, J=13,30, 10,20, 4,94 Hz, 1H), 3,70 (m, 1H), 4,01 (m, 3H), 4,27 (DD, J=being 9.61, to 3.02 Hz, 1H), was 7.08 (m, 3H), of 8.09 (s, 1H).

Example 6(90)

14-oxa-14-(4-chloro-3-forfinal)-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

TLC: Rf of 0.41 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ a 1.96 (m, 1H), and 2.26 (m, 1H), 2,43 (m, 1H), 2,59 (m, 1H), 3.27 to (DDD, J=13,32, 10.30 a.m., with 5.22 Hz, 1H), 3,48 (DDD, J=13,32, 10,30, of 5.40 Hz, 1H), 3,71 (m, 1H), 3,93 (m, 2H), 4,08 (m, 1H), 4,21 (DD, J=9,75 at 3.16 Hz, 1H), only 6.64 (m, 1H), 6,72 (DD, J=10,44, a 2.75 Hz, 1H), 7,28 (t, J=8,65 Hz, 1H), of 8.09 (s, 1H).

Example 6(91)

(13TH,15thα)-19-Phenoxy-15-hydroxy--(4-carboxymethy-2-yl)-9-oxo-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf is 0.22 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ and 1.63 (m, 7H), to 2.35 (m, 3H), 3,39 (m, 3H), of 3.78 (m, 1H), 3,94 (t, J=6,18 Hz, 2H), 4,18 (m, 2H), 5,09 (m, 2H), 5.56mm (DD, J=15,38, charged 8.52 Hz, 2H), of 5.81 (DD, J=15,38, 5,77 Hz, 1H), 6.89 in (m, 3H), 7,26 (m, 2H), 8,07 (s, 1H).

Example 6(92)

(13TH,15thα)-20-Phenoxy-15-hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

TLC: Rf is 0.22 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ to 1.47 (m, 6N), to 1.76 (m, 3H), 2,35 (m, 3H), 3,38 (m, 3H), 3,79 (m, 1H), 3,94 (t, J=6,32 Hz, 2H), 4.16 the (m, 2H), amounts to 4.76 (m, 2H), 5,55 (DDD, J=15,31, 8,58, of 0.82 Hz, 1H), 5,80 (DD, J=15,38, 5,77 Hz, 1H), 6,91 (m, 3H), 7,27 (m, 2H), 8,08 (s, 1H).

Example 7(1) and 7(2)

According to the method of example 3 using the corresponding derivative instead of the compound obtained in reference example 11, the following compounds of this invention.

Example 7(1)

Ethyl ester of 2-(2-(2-(4-(2-hydroxymethylene)phenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf 0,11 (ethyl acetate:n-hexane=3:1);

1H-NMR (CDCl3): δ 8,02 (s, 1H), to 7.59-of 7.55 (m, 1H), 7,44-to 7.32 (m, 4H), 7,30-of 7.23 (m, 3H), 4,93-a 4.86 (m, 1H), 4,58 (d, J=5.4 Hz, 2H), to 4.38 (q, J=7.2 Hz, 2H), 3,99-a 3.87 (m, 1H), 3,51-3,30 (m, 2H), 3,16 was 3.05 (m, 1H), 2,68 at 2.45 (m, 3H), 2,03-1,89 (m, 1H), 1,81 (t, J=5.4 Hz, 1H), 1,38 (t, J=7.2 Hz, 3H).

Example 7(2)

Ethyl ester of 2-(2-(2-(4-(2-propoxyethyl)phenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.13 (hexane:etelaat is=1:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 7,19 (d, J=8,4 Hz, 2H), 7,12 (d, J=8,4 Hz, 2H), 4,79 (m, 1H), and 4.40 (q, J=7.2 Hz, 2H), 3,93 (m, 1H), 3,61 (t, J=7.2 Hz, 2H), 3,44-of 3.32 (m, 4H), 3,01 (m, 1H), 2,87 (t, J=7.2 Hz, 2H), 2,64-of 2.34 (m, 3H), of 1.88 (m, 1H), 1,68 is 1.48 (m, 2H), 1,40 (t, J=7.2 Hz, 3H), of 0.89 (t, J=7.2 Hz, 3H).

Examples 8(1) and 8(2)

According to the method of example 2 using the compound obtained in example 7(1) or 7(2), instead of the compound obtained in example 1 given the following compounds of this invention.

Example 8(1)

2-(2-(2-(4-(2-Hydroxymethylene)phenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.16 (methylene chloride:methanol=5:1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 7,58-7,53 (m, 1H), 7,45-to 7.32 (m, 4H), 7,29-7,22 (m, 3H), of 4.83 was 4.76 (m, 1H), br4.61 (s, 2H), 4,05-of 3.96 (m, 1H), 3,37-is 3.21 (m, 3H), 2,70 is 2.44 (m, 3H), 2,07-of 1.94 (m, 1H).

Example 8(2)

2-(2-(2-(4-(2-Propoxyethyl)phenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf of 0.27 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 8.06 (s, 1H), 7,25 (d, J=8.1 Hz, 2H), 7,13 (d, J=8.1 Hz, 2H), 4,67 (m, 1H), 3,94 (m, 1H), to 3.67 (t, J=6.9 Hz, 2H), 3.43 points (t, J=6.9 Hz, 2H), 3,35 totaling 3.04 (m, 3H), 2,90 (t, J=6.9 Hz, 2H), 2,70-2,36 (m, 3H), of 1.94 (m, 1H), 1,69 of 1.50 (m, 2H), of 0.90 (t, J=7.2 Hz, 3H).

Example 9

(13TH,15thα)-15-Hydroxy-5-(4-(2-(2-ethyl-2-methylbutanoate)etoxycarbonyl)thiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isapros-13-EN

Connection polucen the e in example 2(2) (312 mg), 2-(2-ethyl-2-methylbutanoate)ethanol (700 mg) and triethylamine (0.33 ml) dissolved in ethyl acetate (8 ml) and the mixture is then stirred for 5 minutes. To the reaction solution was added 1-methanesulfonylaminoethyl (341 mg) and then the solution was stirred at room temperature for 3 hours. To the reaction solution was added water, then extracted with ethyl acetate. The extract is successively washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=1:3→ethyl acetate) to give the compounds of this invention (316 mg)having the following physical data.

TLC: Rf of 0.30 (ethyl acetate);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 5,79 (d, J=15,6, 5.7 Hz, 1H), 5,54 (DDD, J=15,6, and 8.4, 1.0 Hz, 1H), 4,55 (m, 2H), and 4.40 (m, 2H), 4,20 (m, 1H), 4,10 (m, 1H), 3,79 (m, 1H), 3,53-of 3.31 (m, 3H), 2,50-2,19 (m, 3H), 2,09 (d, J=4,7 Hz, 1H), 1,83-to 1.61 (m, 3H), 1,58 is 1.20 (m, 10H), 1,10 (s, 3H), 0.95 to-0,78 (m, 9H).

Example 9(1)Example 9(4)

According to the method of example 9 using the appropriate carboxylic acid derivative instead of the compound obtained in example 2(2), obtain the following compounds of the present invention.

Example 9(1)

2-(2-Ethyl-2-methylbutanoate)ethyl ester (13TH,15thα)-15-hydroxy-1,6-(1,4-interphenylene)-9-oxo-2,3,4,5-tetranor-8-isapros-13-ENES is th acid

TLC: Rf 0.28 in (ethyl acetate);

1H-NMR (CDCl3): δ a 7.92 (d, J=8.1 Hz, 2H), 7,25 (d, J=8.1 Hz, 2H), 5,59 (DD, J=15,6, 6.3 Hz, 1H), 5,39 (DD, J=15,6, and 8.7 Hz, 1H), 4,55 (m, 2H), to 4.41 (m, 2H), 4,12 (m, 1H), 3,80 (m, 2H), 3,11 (m, 1H), 3.00 and is 2.80 (m, 2H,), 2,44 was 2.25 (m, 2H), 2,16 (m, 1H), 1,79 is 1.23 (m, 14H), 1,10 (s, 3H), 0.95 to-0,78 (m, 9H).

Example 9(2)

2-(2-Ethyl-2-methylbutanoate)ethyl ester (13TH,15thα)-15-hydroxy-1,5-(2,5-intertitle)-9-oxo-2,3,4-trinor-8-isapros-13-ene acid

TLC: Rf 0.26 (ethyl acetate);

1H-NMR (CDCl3): δ a 7.62 (d, J=3.3 Hz, 1H), for 6.81 (d, J=3.3 Hz, 1H), of 5.68 (DD, J=15,6, 6.3 Hz, 1H), 5,48 (DD, J=15,6, and 8.7 Hz, 1H), 4,47 (m, 2H), to 4.38 (m, 2H), 4,18-4,00 (m, 2H), 3,60 (m, 1H), 2,99 (m, 1H), and 2.83 (t, J=7.8 Hz, 2H), 2,50-of 2.16 (m, 3H), 1,97 is 1.23 (m, 16H), 1,10 (s, 3H), 0,98 is 0.80 (m, 9H).

Example 9(3)

2-(2-Ethyl-2-methylbutanoate)ethyl ester (13TH,15thα)-15-hydroxy-9-oxo-5-thia-8-isapros-13-ene acid

TLC: Rf 0.26 (ethyl acetate);

1H-NMR (CDCl3): δ 5,73 (DD, J=15,3, 5.7 Hz, 1H), 5,52 (DD, J=15,3, 9.0 Hz, 1H), 4,28 (s, 4H), to 4.15 (m, 2H), 3,66 (m, 1H), 3,09 (m, 1H), 2.77-to of 2.50 (m, 4H), 2,49-of 2.20 (m, 5H), 1,96-to 1.82 (m, 2H), 1,80-1,22 (m, 14H), 1,10 (s, 3H), 0,94 is 0.80 (m, 9H).

Example 9(4)

(15α)-15-Hydroxy-5-(4-(2-(2-ethyl-2-methylbutanoate)etoxycarbonyl)thiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-isoprostane

TLC: Rf of 0.45 (ethyl acetate);

1H-NMR (CDCl3): δ of 0.85 (m, N), 1,10 (s, 3H)and 1.51 (m, N), to 1.98 (m, 1H), 2,13 (m, 1H), 2,39 (m, 3H)and 3.59 (m, 6N), 4,39 (m, 2H), to 4.52 (m, 2H), of 7.97 (s, 1H).

Example 10

14-oxa-14-(3,5-dichloro enyl)-5-(4-hydroxymethylimidazole-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanol-5-thia-8-isoprostane

To a solution of the compound obtained in example 5(32) (125 mg)in tetrahydrofuran (3 ml) is added sodium borohydride (40 mg) and the mixture is stirred at room temperature for 1 day. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (n-hexane:ethyl acetate=1:4) to give the compounds of this invention (68,9 mg)having the following physical data.

TLC: Rf of 0.34 (ethyl acetate);

1H-NMR (CDCl3): δ of 1.93 (m, 1H), 2,22 (m, 1H), of 2.38 (m, 1H), 2,53 (m, 2H), 3,34 (m, 1H), 3,51 (m, 2H), 3,93 (m, 2H), 4,11 (m, 2H), 4,68 (Shir. s, 2H), 6,77 (d, J=1.70 Hz, 2H), 6,99 (t, J=1.70 Hz, 1H), 7,05 (s, 1H).

Example 11

(2R)-2-(3,5-Dichlorphenoxy)-1-(2-(4-methoxymethyl-1,3-thiazol-2-ylthio)ethyl)pyrrolidin-5-he

In an argon atmosphere to a solution of the compound obtained in example 10 (112 mg)in tetrahydrofuran (1 ml) is added sodium hydride (13 mg) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution add methyliodide (0.1 ml) and the solution stirred for 1 hour. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer is washed with water and saturated dissolve the Ohm salt, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (n-hexane:ethyl acetate=1:4→ethyl acetate) to give the compounds of this invention (of 98.2 mg)having the following physical data.

TLC: Rf of 0.44 (ethyl acetate);

1H-NMR (CDCl3): δ a 1.96 (m, 1H), 2,22 (m, 1H), of 2.38 (DDD, J=16,90, 9,80, 5,13 Hz, 1H), 2,54 (DDD, J=16,90, 9,80, 7,30 Hz, 1H), 3,42 (s, 3H), 3,42 (m, 3H), a 3.87 (DDD, J=13,55, 7,78, 6,04 Hz, 1H), 3,97 (DD, J=9,60, 4,00 Hz, 1H), 4,10 (DDD, J=11,63, 7,78, 3,30 Hz, 1H), 4,18 (DD, J=9,60, 3,90 Hz, 1H), 4,48 (m, 2H), 6,78 (d, J=1.65 Hz, 2H), 6,98 (t, J=1.65 Hz, 1H), to 7.09 (s, 1H).

Example 12

2-(2-((2R)-2-(3,5-Dichlorphenoxy)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxamide

To a solution of the compound obtained in example 6(32) (300 mg)in toluene (4.0 ml) add oxalicacid (0,07 ml) and dimethylformamide (one drop) and the mixture is stirred at room temperature for 40 minutes. The reaction mixture was concentrated and dissolved in anhydrous tetrahydrofuran (2.0 ml). By ammonia water (1.0 ml) is added the above solution in tetrahydrofuran at a temperature of 0°C and the mixture is stirred for 30 minutes. The reaction mixture was concentrated and extracted with dichloromethane. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (this is acetat) to obtain the compounds of this invention (280 mg), having the following physical data.

TLC: Rf of 0.55 (ethyl acetate);

1H-NMR (CDCl3): δ 8,02 (s, 1H), to 7.99 (s, 1H), 7,01 (t, J=1.5 Hz, 1H), 6,78 (d, J=1.5 Hz, 2H), 5,65 (s, 1H), 4,17-3,91 (m, 4H), 3,63 (m, 1H), 3,50 (m, 1H), and 3.31 (m, 1H), 2,53 (m, 1H), 2.40 a (m, 1H), 2,22 (m, 1H), with 1.92 (m, 1H).

Examples 12(1)-12(4)

According to the method of example 12, using the appropriate amine derivative, amide derivative or a derivative sulfonamida instead of ammonia water, get the following compounds of the present invention.

Example 12(1)

2-(2-((2R)-2-(3,5-Dichlorphenoxy)-5-oxopyrrolidin-1-yl)ethylthio)-N,N-dimethyl-1,3-thiazole-4-carboxamide

TLC: Rf of 0.23 (ethyl acetate);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), 2,23 (m, 1H), of 2.38 (DDD, J=16,93, 9,80, 5,00 Hz, 1H), 2,53 (DDD, J=16,93, 9,70, of 7.23 Hz, 1H), 3,10 (s, 3H), up 3.22 (s, 3H), 3,47 (m, 3H), 3,92 (m, 2H), 4,06 (m, 1H), 4,14 (DD, J=9,60, 3,90 Hz, 1H), 6,77 (d, J=1,74 Hz, 2H), 6,99 (t, J=1,74 Hz, 1H), 7,68 (s, 1H).

Example 12(2)

(2R)-2-(3,5-Dichlorphenoxy)-1-(2-(4-(4-methylpiperazin-1-ylcarbonyl)-1,3-thiazol-2-ylthio)ethyl)pyrrolidin-5-he

TLC: Rf of 0.55 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ of 1.93 (m, 1H), 2,23 (m, 1H), 2,31 (s, 3H), 2,46 (m, 6N), 3,47 (m, 3H), 3,80 (m, 4H), 3,95 (m, 2H), 4,08 (m, 2H), 6,76 (d, J=1,74 Hz, 2H), 6,99 (t, J=1,74 Hz, 1H), 7,71 (s, 1H).

Example 12(3)

2-(2-((2R)-2-(3,5-Dichlorphenoxy)-5-oxopyrrolidin-1-yl)ethylthio)-N-methylsulphonyl-1,3-thiazole-4-carboxamide

TLC: Rf of 0.47 (methylene chloride:methane is l=9:1);

1H-NMR (DMSO-D6): δ 8,00 (s, 1H), 7,15 (d, J=1.8 Hz, 2H), 7,11 (t, J=1.8 Hz, 1H), 4,59 (m, 1H), 4,16-4,00 (m, 2H), 3,70 (m, 1H), 3,50-3,20 (m, 2H), 2,97 (s, 3H), 2,60 was 2.25 (m, 2H), 2,25-2,00 (m, 2H), of 1.85 (m, 1H).

Example 12(4)

N-Benzoyl-2-(2-((2R)-2-(3,5-dichlorphenoxy)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxamide

TLC: Rf of 0.20 (hexane:ethyl acetate=1:2);

1H-NMR (CDCl3): δ 8,21 (s, 1H), 8,00-a 7.92 (m, 2H), to 7.61 (m, 1H), 7,55-7,46 (m, 2H), 6,99 (t, J=1.5 Hz, 1H), of 6.71 (d, J=1.5 Hz, 2H), 4,10-3,88 (m, 4H), 3.72 points-of 3.54 (m, 2H), 3,42 (m, 1H), 2,44 (m, 1H), 2,35-to 2.06 (m, 2H), to 1.86 (m, 1H).

Examples 13(1)-13(8)

According to the method of example 1 using the compound obtained in reference example 3, or the corresponding derivative of the aldehyde and the compound obtained in reference example 9, or a corresponding amine derivative are given the following compounds of this invention.

Example 13(1)

Butyl ether 2-(2-((2R)-2-(2-naphthylacetyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf is 0.22 (hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ to 0.96 (t, J=7,30 Hz, 3H), of 1.44 (m, 2H), 1,74 (m, 2H), 2,10 (m, 1H), and 2.26 (m, 1H), 2,41 (m, 1H), 2.63 in (m, 1H), 3,39 (m, 1H), 3,51 (m, 1H), to 3.64 (m, 1H), 3,94 (m, 1H), 4,13 (DD, J=9,60, of 3.60 Hz, 1H), is 4.21 (m, 1H), 4,33 (m, 2H), 4,57 (DD, J=9,60, 3,00 Hz, 1H), 7,10 (m, 1H), 7,19 (m, 1H), 7,33 (m, 1H), 7,42 (m, 1H), 7,71 (m, 3H), 7,94 (s, 1H).

Example 13(2)

Butyl ether 2-(2-((2R)-2-(3-ethylenoxide)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-to benovoy acid

TLC: Rf 0.28 in (hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ to 0.97 (t, J=7,30 Hz, 3H), of 1.20 (t, J=7,70 Hz, 3H), of 1.45 (m, 2H), 1,73 (m, 2H), 2,03 (m, 1H), of 2.21 (m, 1H), 2,37 (m, 1H), 2,59 (m, 3H), of 3.48 (m, 3H), 3,95 (m, 2H), 4,14 (m, 1H), 4,35 (m, 3H), of 6.73 (m, 3H), 7,15 (m, 1H), 7,98 (s, 1H).

Example 13(3)

Butyl ether 2-(2-((2R)-5-oxo-2-(3-triftormetilfullerenov)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf to 0.63 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.97 (t, J=to 7.32 Hz, 3H), of 1.45 (m, 2H), 1,74 (m, 2H), 2,10 (m, 1H), 2,25 (m, 1H), 2.40 a (DDD, J=of 16.84, 9,98, with 5.22 Hz, 1H), 2,61 (DDD, J=of 16.84, 9,98, 7,14 Hz, 1H), 3,32 (DDD, J=13,46, 9,25, of 5.68 Hz, 1H), 3,48 (DDD, J=13,46, 9,25, 5,18 Hz, 1H), 3,62 (DDD, J=13,90, 9,00, 5.50 Hz, 1H), 3,88 (DDD, J=13,90, 9,00, 5.50 Hz, 1H), 4,06 (DD, J=10,34, to 3.02 Hz, 1H), 4,17 (m, 1H), 4,32 (t, J=6,68 Hz, 2H), and 4.68 (DD, J=10,34, to 3.02 Hz, 1H), to 7.09 (m, 1H), 7,20 (m, 2H), 7,35 (m, 1H), of 7.96 (s, 1H).

Example 13(4)

Butyl ether 2-(2-((2R)-5-oxo-2-(3-cryptomaterial)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.64 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.97 (t, J=to 7.32 Hz, 3H), of 1.45 (m, 2H), 1,74 (m, 2H), 2,07 (m, 1H), 2,24 (m, 1H), 2,39 (DDD, J=16,90, 10,00, 5,20 Hz, 1H), 2,59 (DDD, J=16,90, 10,20, to 7.15 Hz, 1H), 3.33 and (DDD, J=13,40, 9,00, 5,80 Hz, 1H), 3,49 (DDD, J=13,40, 9,20, 5,20 Hz, 1H), 3,60 (DDD, J=13,70, 9,00, 5,20 Hz, 1H), with 3.89 (DDD, J=13,70, 9,20, 5,80 Hz, 1H), was 4.02 (DD, J=of 10.25, 3,48 Hz, 1H), 4,15 (m, 1H), 4,32 (t, J=6,68 Hz, 2H), 4,57 (DD, J=of 10.25, 3,11 Hz, 1H), PC 6.82 (m, 3H), 7,24 (m, 1H), of 7.97 (s, 1H).

Example 13(5)

Ethyl ester of (3-((2R)-2-(3,5-dichlorphenoxy)-5-oxopyrrolidin-1-ilma is Il)phenoxy)acetic acid

TLC: Rf 0.25 in (hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ of 1.30 (t, J=7,14 Hz, 3H), 1,96 (m, 1H), of 2.21 (m, 1H), 2,46 (m, 1H), 2.63 in (m, 1H), a 3.87 (m, 3H), 4,21 (d, J=15,11 Hz, 1H), 4,27 (kV, J=7,14 Hz, 2H), 4,56 (s, 2H), a 4.83 (d, J=15,11 Hz, 1H), of 6.68 (d, J=1.65 Hz, 2H), 6,76 (m, 1H), for 6.81 (m, 1H), to 6.88 (m, 1H), 6,97 (t, J=1.65 Hz, 1H), 7,20 (t, J=7,80 Hz, 1H).

Example 13(6)

Methyl ester of (2E)-3-(3-((2R)-2-(3,5-dichlorphenoxy)-5-oxopyrrolidin-1-ylmethyl)phenyl)-2-propanolol acid

TLC: Rf 0.25 in (hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ of 1.97 (m, 1H), 2,23 (m, 1H), 2,48 (m, 1H), 2,66 (m, 1H), 3,81 (s, 3H), 3,88 (m, 3H), and 4.40 (d, J=15,11 Hz, 1H), 4,74 (d, J=15,11 Hz, 1H), 6,38 (d, J=16,21 Hz, 1H), 6,62 (d, J=1,79 Hz, 2H), 6,95 (t, J=1,79 Hz, 1H), 7,30 (m, 2H), 7,38 (m, 2H), to 7.59 (d, J=16,21 Hz, 1H).

Example 13(7)

Methyl ester 3-(3-((2R)-2-(3,5-dichlorphenoxy)-5-oxopyrrolidin-1-ylmethyl)phenyl)propanoic acid

TLC: Rf is 0.22 (hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ a 1.96 (m, 1H), of 2.21 (m, 1H), has 2.56 (m, 4H), 2,88 (t, J=of 7.69 Hz, 2H), 3,66 (s, 3H), 3,86 (m, 3H), 4,25 (d, J=15,11 Hz, 1H), 4,80 (d, J=15,11 Hz, 1H), 6,66 (d, J=1.65 Hz, 2H), 6,97 (t, J=1.65 Hz, 1H)that was 7.08 (m, 3H), 7,20 (t, J=7,83 Hz, 1H).

Example 13(8)

Ethyl ester of 2-(2-((2R)-5-oxo-2-(pyridine-2-intoximeter)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.50 (ethyl acetate);

1H-NMR (CDCl3): δ to 1.38 (t, J=7,00 Hz, 3H), of 1.98 (m, 1H), of 2.21 (m, 1H), 2,34 (m, 1H), 2,52 (m, 1H), 3,50 (m, 3H), of 3.97 (m, 1H), 4,16 (m, 1H), to 4.38 (m, 3H), 4.53-in (DD, J=12,00, 4,00 Hz, 1H), 6,69 (m, 1H), to 6.88 (m, 1H), 7,56 (m, 1H), 8,01 (s, 1 is), 8,10 (m, 1H).

Examples 14(1)-14(52)

According to the method of example 2 using the compound obtained in examples 13(1)-13(8), or the corresponding ester instead of the compound obtained in example 1 given the following compounds of this invention.

Example 14(1)

(15α,13TH)-15-Hydroxy-9-oxo-17-phenyl-18,19,20-trinor-5-thia-8-isapros-13-ANOVA acid

TLC: Rf of 0.44 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 7,37-to 7.15 (m, 5H), 5,78 (DD, J=15,3, a 5.4 Hz, 1H), ceiling of 5.60 (DDD, J=15,3, and 8.4, 1.2 Hz, 1H), 4,25-4,10 (m, 2H), to 3.64 (m, 1H), 3,12 (m, 1H), 2,82 is 2.10 (m, 12H), 2.00 in to 1.70 (m, 5H).

Example 14(2)

(15α,13TH)-15-Hydroxy-9-oxo-18-phenyl-19,20-dinor-5-thia-8-isapros-13-ANOVA acid

TLC: Rf of 0.43 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 7,37-to 7.15 (m, 5H), 5,72 (DD, J=15,3, 5.7 Hz, 1H), 5,50 (DD, J=15,3, and 8.4 Hz, 1H), 4,65-4,08 (m, 4H), 3,63 (m, 1H), 3,10 (m, 1H), 2,72-2,19 (m, 11H), 1,99 of 1.50 (m, 7H).

Example 14(3)

2-(2-((2R)-5-Oxo-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-1-intoximeter)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf is 0.59 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 2,07 (m, 3H), 2,31 (m, 1H), 2,47 (m, 1H), 2,64 (m, 3H), and 2.83 (m, 2H), or 3.28 (m, 1H), 3,51 (m, 1H), to 3.73 (m, 1H), Android 4.04 (m, 3H), 4.26 deaths (DD, J=10,00, 3,00 Hz, 1H), 7,02 (m, 1H), 7,27 (m, 1H), 7,70 (m, 1H), of 8.09 (s, 1H).

Example 14(4)

2-(2-((2R)-2-(3,5-Diferenciate)-5-oxopyrrolidin-1-yl)is tilty)-1,3-thiazole-4-carboxylic acid

TLC: Rf value of 0.52 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.95 (m, 1H), 2,23 (m, 1H), 2,41 (DDD, J=17,10, 9,90, 5.50 Hz, 1H), 2,58 (DDD, J=17,10, 10,10, 7,10 Hz, 1H), 3,26 (DDD, J=13,50, 10,00, of 5.40 Hz, 1H), 3,48 (DDD, J=13,50, 10,00, of 5.40 Hz, 1H), 3,65 (DDD, J=13,50, 10,00, of 5.40 Hz, 1H), 3,90 (m, 1H), 3,95 (DD, J=9,90, 4,70 Hz, 1H), 4,08 (m, 1H), 4,23 (DD, J=9,90, 3,00 Hz, 1H), gold 6.43 (m, 3H), 8,08 (s, 1H).

Example 14(5)

2-(2-((2R)-2-(4-Methoxy-2-nitrophenoxy)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.43 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ at 1.91 (m, 1H), 2,28 (m, 1H), 2,43 (DDD, J=17,00, 10,20, 6,60 Hz, 1H), 2,60 (DDD, J=17,00, 10,20, 6,60 Hz, 1H), 3,34 (DDD, J=13,20, 10,20, 5,20 Hz, 1H), 3,51 (DDD, J=13,20, 10,20, 5,20 Hz, 1H), 3,76 (m, 1H), 3,82 (s, 3H), 4.09 to (m, 3H), 4,25 (m, 1H),? 7.04 baby mortality (d, J=9,00 Hz, 1H), 7,11 (DD, J=9,00, 3,00 Hz, 1H), 7,41 (d, J=3,00 Hz, 1H), 8,07 (s, 1H).

Example 14(6)

2-(2-((2R)-2-(4-Acetyl-3-forfinancial)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.50 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 1,99 (m, 1H), 2,28 (m, 1H), 2,44 (m, 1H), 2,59 (d, J=4,90 Hz, 3H), at 2.59 (m, 1H), or 3.28 (DDD, J=13,50, the 10.40, of 5.40 Hz, 1H), 3,48 (DDD, J=13,50, the 10.40, of 5.40 Hz, 1H), 3,70 (m, 1H), 3,94 (DDD, J=13,50, the 10.40, of 5.40 Hz, 1H), 4,10 (m, 2H), 4,33 (DD, J=9,60, 3,00 Hz, 1H), 6,65 (DD, J=12,50, 2,50 Hz, 1H), 6,76 (DD, J=8,65, 2,50 Hz, 1H), 7,89 (t, J=8,65 Hz, 1H), 8,10 (s, 1H).

Example 14(7)

2-(2-((2R)-2-(3-Ethynylbenzene)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

The SH: Rf of 0.48 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.95 (m, 1H), 2,25 (m, 1H), 2,42 (m, 1H), 2,59 (m, 1H), is 3.08 (s, 1H), 3.27 to (DDD, J=13,50, 10,20, 5,00 Hz, 1H), 3,49 (DDD, J=13,50, 10,20, 5,00 Hz, 1H), 3,74 (m, 1H), 4,18 (DD, J=10,00, 3,00 Hz, 1H), to 6.88 (m, 1H), 7,00 (m, 1H), 7,13 (m, 1H), 7,24 (m, 1H), 8,08 (s, 1H).

Example 14(8)

2-(2-((2R)-2-(4-Formyl-3-methoxyphenoxy)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.48 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 2,02 (m, 1H), to 2.29 (m, 1H), 2,45 (DDD, J=17,00, 10,00, 7,00 Hz, 1H), 2.63 in (DDD, J=17,00, 10,00, 7,00 Hz, 1H), 3,29 (DDD, J=13,40, 10,20, 5,20 Hz, 1H), 3,49 (DDD, J=13,40, 10,20, 5,20 Hz, 1H), 3,71 (m, 1H), 3,90 (s, 3H), 3,94 (m, 1H), 4,11 (m, 2H), to 4.38 (m, 1H), 6,44 (d, J=2.20 Hz, 1H), 6,56 (m, 1H), 7,81 (d, J=8,50 Hz, 1H), 8,10 (s, 1H), 10,29 (s, 1H).

Example 14(9)

2-(2-((2R)-2-(2-Chloro-3,5-diferenciate)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.54 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ a 1.96 (m, 1H), of 2.38 (m, 2H), 2,69 (m, 1H), 3,29 (m, 1H), 3,55 (m, 1H), 3,78 (m, 1H), 4.00 points (m, 2H), 4,17 (m, 1H), 4,33 (DD, J=10,20, 2,80 Hz, 1H), return of 6.58 (m, 2H), of 8.09 (s, 1H).

Example 14(10)

(15α,13TH)-15-Hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-18-phenoxy-1,2,3,4,19,20-hexanor-5-thia-8-isapros-13-EN

TLC: Rf is 0.59 (chloroform:methanol=4:1);

1H-NMR (CDCl3): δ 8,07 (s, 1H), 7,31-7,25 (m, 2H), 6,97-6,87 (m, 3H), of 5.82 (DD, J=15,0, 5,1 Hz, 1H), 5,59 (DD, J=15,0, and 8.4 Hz, 1H), 4,30-4,24 (m, 1H), 4,18-4,12 (m, 1H), 4.00 points (t, J=5.7 Hz, 2H), 3,86-3,74 (m, 1H), 3,56-of 3.27 (m, 5H), 2,53-to 2.18 (m, 3H), 2,10 to 1.76 (m, 5H)

Example 14(11)

(15α,13TH)-15-Hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-17-phenoxy-1,2,3,4,18,19,20-heptanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.38 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 7,31-7,26 (m, 2H), 6,98-to 6.88 (m, 3H), 5,86 (DD, J=15,3, 5.7 Hz, 1H), 5,64 (DD, J=15,3, and 8.4 Hz, 1H), 4.53-in-4,48 (m, 1H), 4,19-4,07 (m, 3H), 3,81-3,74 (m, 1H), 3,50-3,30 (m, 3H), 2,46-2,19 (m, 3H), 2,04 of 1.99 (m, 1H), 1,79-of 1.73 (m, 1H), 1.30 and 1,24 (m, 1H), 0,93-0,83 (m, 1H).

Example 14(12)

2-(2-((2R)-2-(3,5-Dichlorophenylthio)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.56 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), 2,32 (m, 2H), 2,54 (DDD, J=18,30, 10,50, 6,00 Hz, 1H), 3,17 (DD, J=12,90, of 6.90 Hz, 1H), 3,40 (m, 4H), of 3.96 (m, 2H), 7,18 (t, J=1.80 Hz, 1H), 7,21 (d, J=1.80 Hz, 2H), 8,11 (s, 1H).

Example 14(13)

(15α,13TH)-15-Hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-18-(naphthalene-2-yl)-1,2,3,4,19,20-hexanor-5-thia-8-isapros-13-EN

TLC: Rf 0.26 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ 8,03 (s, 1H), 7,81-7,74 (m, 4H), 7,58 (s, 1H), 7,47-7,39 (m, 2H), 7,31-7,28 (m, 1H), USD 5.76 (DD, J=15,3, a 5.4 Hz, 1H), 5,52 (DD, J=15,3, 8,1 Hz, 1H), 4,22-4,07 (m, 4H), 3,79-and 3.72 (m, 1H), 3.45 points-of 3.25 (m, 3H), and 2.79 (t, J=7.2 Hz, 2H), 2,44-to 2.18 (m, 3H), 1,84-of 1.55 (m, 5H).

Example 14(14)

(15α,13TH)-15-Hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-19-(naphthalene-2-yl)-1,2,3,4,20-pentanol-5-thia-8-isapros-13-EN

TLC: Rf is 0.22 (chloroform:methanol:acetic acid=91:0,1);

1H-NMR (CDCl3): δ 8,07 (s, 1H), 7,81-7,74 (m, 3H), to 7.59 (s, 1H), 7,47-7,39 (m, 2H), 7,33-7,28 (m, 1H), 5,74 (DD, J=15,3, 6.0 Hz, 1H), 5,49 (DD, J=15,9, 9.0 Hz, 1H), 4,16-4,07 (m, 4H), 3,79-and 3.72 (m, 1H), 3.45 points-of 3.25 (m, 5H), 2,79-to 2.74 (m, 2H), 2,44-to 2.18 (m, 3H), 1,84-of 1.55 (m, 5H).

Example 14(15)

(15α,13TH,18E)-15-Hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-19-naphthalene-2-yl-1,2,3,4,19,20-hexanor-5-thia-8-isapros-of 13.18-Dien

TLC: Rf is 0.22 (chloroform:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 8.06 (s, 1H), 7,78-7,74 (m, 3H), of 7.65 (s, 1H), 7,55 (DD, J=8,7, 2.8 Hz, 1H), 7,46-7,39 (m, 2H), 6,55 (d, J=15.3 Hz, 1H), 6,36-6,27 (m, 1H), of 5.84 (DD, J=15,3, a 5.4 Hz, 1H), 5,59 (DD, J=15,0, 9.6 Hz, 1H), 4,30-4,12 (m, 2H), 3,86-3,71 (m, 4H), 3,47-of 3.32 (m, 3H), 2,47-to 2.18 (m, 4H), 1,79 was 1.69 (m, 3H).

Example 14(16)

2-(2-((2R)-2-Benzoyloxymethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0.36 and (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ of 8.06 (s, 1H), 7,40-of 7.24 (m, 5H), a 4.53 (s, 2H), 3,85-3,82 (m, 2H), 3.75 to to 3.56 (m, 2H), 3,52-to 3.34 (m, 2H), 3,24 (m, 1H), 2.57 m) was 2.25 (m, 2H), 2,12 (m, 1H), 1,78 (m, 1H).

Example 14(17)

2-(2-((2R)-2-(3-Dimethylaminobenzoyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.44 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.95 (m, 1H), 2,24 (m, 1H), 2,42 (DDD, J=17,00, 10,20, 5,70 Hz, 1H), 2,60 (DDD, J=17,00, 10,20, 6,60 Hz, 1H), 2,94 (C, 6N), or 3.28 (DDD, J=13,20, the 10.40, 5,20 Hz, 1H), 3,52 (DDD, J=13,20, the 10.40, 5,20 Hz, 1H), 3,92 (m, 4H), 4,18 (DD, J=9,90, 3,00 Hz, 1H), 4,79 (Shir. s, 1H), 6,26 (m, 2H), 6,41 (m, 1H), 7,14 (t, J=8,40 Hz, 1H), 8,07 (s, 1H).

the example 14(18)

3-((2R)-2-(3,5-Dichlorphenoxy)-5-oxopyrrolidin-1-ylmethyl)venexiana acid

TLC: Rf 0.31 in (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.97 (m, 1H), 2,23 (m, 1H), 2,52 (m, 1H), 2,68 (m, 1H), 3,88 (m, 3H), 4.26 deaths (d, J=15,11 Hz, 1H), 4,59 (s, 2H), 4,78 (d, J=15,11 Hz, 1H), to 6.67 (d, J=1.65 Hz, 2H), PC 6.82 (m, 3H), of 6.96 (t, J=1.65 Hz, 1H), 7,19 (t, J=7,83 Hz, 1H).

Example 14(19)

(2E)-3-(3-((2R)-2-(3,5-Dichlorphenoxy)-5-oxopyrrolidin-1-ylmethyl)phenyl)-2-Papanova acid

TLC: Rf and 0.46 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ to 1.98 (m, 1H), 2,25 (m, 1H), 2,52 (m, 1H), 2,69 (m, 1H), 3,86 (m, 3H), to 4.41 (d, J=15,38 Hz, 1H), amounts to 4.76 (d, J=15,38 Hz, 1H), 6.42 per (d, J=16,21 Hz, 1H), 6,63 (d, J=1,79 Hz, 2H), of 6.96 (t, J=1,79 Hz, 1H), 7,31 (m, 2H), 7,42 (m, 2H), 7,69 (d, J=16,21 Hz, 1H).

Example 14(20)

3-(3-((2R)-2-(3,5-Dichlorphenoxy)-5-oxopyrrolidin-1-ylmethyl)phenyl)propanoic acid

TLC: Rf of 0.64 (ethyl acetate:methanol=9:1);

1H-NMR (CDCl3): δ of 1.97 (m, 1H), 2,22 (m, 1H), 2,48 (m, 1H), 2,65 (m, 3H), 2,89 (t, J=7,51 Hz, 2H), a 3.87 (m, 3H), 4.26 deaths (d, J=15,01 Hz, 1H), 4,79 (d, J=15,01 Hz, 1H), 6,66 (d, J=1,83 Hz, 2H), 6,97 (t, J=1,83 Hz, 1H), to 7.09 (m, 3H), 7,20 (m, 1H).

Example 14(21)

5-(3-((2R)-2-(3,5-Dichlorphenoxy)-5-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic acid

TLC: Rf of 0.23 (methylene chloride:methanol=15:1);

1H-NMR (CDCl3): δ of 7.69 (d, J=3.6 Hz, 1H), 7,00 (t, J=1.8 Hz, 1H), PC 6.82 (d, J=3.6 Hz, 1H), 6.75 in (d, J=1.8 Hz, 2H), 4,06-3,86 (m, 2H), 3,69 (m, 1H), 3,17 (m, 1H), 2,88 (t, J=7.5 Hz, 2H), 2,54 (m, 1H, to 2.41 (m, 1H), of 2.21 (m, 1H), 2,10-of 1.78 (m, 4H).

Example 14(22)

4-(2-((2R)-2-(3,5-Dichlorphenoxy)-5-oxopyrrolidin-1-yl)ethyl)benzoic acid

TLC: Rf 0.34 in (methylene chloride:methanol=15:1);

1H-NMR (CDCl3): δ 8,02 (d, J=8,4 Hz, 2H), 7,30 (d, J=8,4 Hz, 2H), 7,00 (t, J=2.1 Hz, 1H), 6,74 (d, J=2.1 Hz, 2H), 3,98-and 3.72 (m, 4H), 3,37 (m, 1H), to 3.02 (m, 1H), 2,92 (m, 1H), 2,52 (m, 1H), 2,39 (m, 1H), 2,16 (m, 1H), to 1.86 (m, 1H).

Example 14(23)

2-(2-((2R)-5-Oxo-2-(pyridine-2-intoximeter)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf is 0.24 (chloroform:methanol:acetic acid=90:10:0,3);

1H-NMR (CDCl3): δ 2,03 (m, 1H), 2,24 (m, 1H), 2,41 (m, 1H), 2,58 (m, 1H), or 3.28 (m, 1H), 3,41 (m, 1H), 3,75 (m, 2H), of 4.05 (m, 1H), 4,28 (DD, J=11,50, and 4.40 Hz, 1H), and 4.75 (m, 1H), 6.75 in (d, J=to 8.20 Hz, 1H), 6,92 (m, 1H), to 7.61 (m, 1H), 8,08 (s, 1H), 8,10 (m, 1H).

Example 14(24)

2-(2-((2R)-5-Oxo-2-(quinoline-5-intoximeter)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.16 (chloroform:methanol=9:1);

1H-NMR (DMSO-D6): δ 8,68 (DD, J=4.2, and 1.2 Hz, 1H), 8,35 (d, J=8,4 Hz, 1H), 7,79 (s, 1H), 7,69-7,53 (m, 2H), 7,50 (DD, J=8,4, 4,2 Hz, 1H), 7,17 (d, J=6,9 Hz, 1H), 4,51 (m, 1H), 4,30-4,12 (m, 2H), 3,80 (m, 1H), 3,50-3,10 (m, 3H), 2,55-of 2.38 (m, 1H), 2,35-2,05 (m, 2H), up to 1.98 (m, 1H).

Example 14(25)

2-(2-((2R)-5-Oxo-2-(quinoline-6-intoximeter)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.16 (chloroform:methanol=9:1);

1H-NMR (DMSO-D6): δ 8,71 (DD, J=4,5, 1.5 Hz, 1H), 8,24 (d, J=8,4 Hz, 1H), 7,88 (d, J=9.0 Hz, 1H), 7,79 (s, 1H), 7,55 (m, 1H), 7,43 (DD, J=8,4, and 4.5 Hz, 1H), 7,37 (DD, J9,0, 3.0 Hz, 1H), 4,54 (Sirs, 1H), 4,18-4,06 (m, 2H, in), 3.75 (m, 1H), 3,50-3,10 (m, 3H), 2,60-of 2.30 (m, 1H), 2,30-2,02 (m, 2H), 1.93 and (m, 1H).

Example 14(26)

2-(2-((2R)-5-Oxo-2-(quinoline-8-intoximeter)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,08 (chloroform:methanol=9:1);

1H-NMR (DMSO-D6): δ 8,84 (DD, J=4,5, and 2.1 Hz, 1H), 8,31 (s, 1H), 8,27 (d, J=6,9 Hz, 1H), 7,56-7,44 (m, 3H), 7.23 percent (DD, J=6,6, and 2.1 Hz, 1H), 4,49 (d, J=8,1 Hz, 1H), 4,27-4,13 (m, 2H), 3,86 (m, 1H), 3,65-3,20 (m, 3H), 2,62 (m, 1H), 2,30-2,05 (m, 2H), 1,95 (m, 1H).

Example 14(27)

2-(2-((2R)-5-Oxo-2-(2-venlafaxine)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.23 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 7,33-7,24 (m, 2H), 7.23 percent-7,14 (m, 3H), 3,86-3,51 (m, 4H), of 3.69 (t, J=6.6 Hz, 2H), 3,44 (DD, J=9,9, 5.7 Hz, 1H), 3,29 (m, 1H), and 3.16 (m, 1H), 2,86 (t, J=6.6 Hz, 2H), 2,52-of 2.24 (m, 2H), 2,11 (m, 1H), 1,71 (m, 1H).

Example 14(28)

2-(2-((2R)-5-Oxo-2-(2-phenylpropionyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.23 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 8,08 (s, 1H), 7,33-7,24 (m, 2H), 7.23 percent-7,13 (m, 3H), 3,91-with 3.79 (m, 2H), and 3.72 (m, 1H), 3,59-to 3.38 (m, 5H), and 3.31 (m, 1H), 2,70-2,61 (m, 2H), 2,56-of 2.28 (m, 2H), 2.13 in (m, 1H), 1,96 is 1.70 (m, 3H).

Example 14(29)

(15α,13TH)-15-Hydroxy-9-oxo-3,7-(1,3-interphenylene)-3-thia-20-ethyl-4,5,6-trinor-8-isapros-13-ANOVA acid

TLC: Rf 0.28 in (chloroform:methanol=6:1):

1H-NMR (CDCl3): δ to 0.88 (m, 3H), 1.26 in (m, 10H), of 1.53 (m, 2H), 1,76 (m, 1H), measuring 2.20 (m, 1H), 2,44 (m, 2H)and 3.59 (s, 2H), 3,90 (m, 1H), 3,97 (d, J=14,65 Hz, 1H), 4,1 (m, 1H), 4,78 (d, J=14,65 Hz, 1H), 5,43 (DDD, J=15,60, 8,56, 1,19 Hz, 1H), 5,65 (DD, J=15,60, of 5.40 Hz, 1H), 7,07 (d, J=of 8.06 Hz, 1H), 7.23 percent (m, 2H), 7,32 (m, 1H).

Example 14(30)

2-(2-((2R)-5-Oxo-2-(pyridine-4-intoximeter)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.32 (methylene chloride:methanol:water=80:20:1);

1H-NMR (DMSO-D6): δ to 1.86 (m, 1H), 2,30 (m, 3H), 3,36 (m, 3H), of 3.77 (m, 1H), 4,11 (m, 2H), 4,37 (m, 1H), of 6.96 (d, J=6,00 Hz, 2H), at 8.36 (m, 3H), to 13.09 (Shir. s, 1H).

Example 14(31)

(15α,13TH)-15-Hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-17-phenyl-1,2,3,4,18,19,20-heptanol-8-isapros-13-EN

TLC: Rf of 0.47 (methylene chloride:methanol=5:1);

1H-NMR (CDCl3): δ to 1.83 (m, 3H), of 2.34 (m, 4H), to 2.67 (m, 2H), 3.33 and (m, 2H), 3.46 in (m, 1H), 3,83 (m, 1H), 4,15 (m, 2H), 5,58 (DDD, J=15,33, 8,65, of 1.28 Hz, 1H), of 5.81 (DD, J=15,30, of 5.40 Hz, 1H), 7,25 (m, 5H), 8,07 (s, 1H).

Example 14(32)

2-(2-((2R)-5-Oxo-2-(2-cryptomaterial)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.38 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), 2,28 (m, 1H), 2,44 (m, 1H), 2,61 (m, 1H), 3,32 (m, 1H), 3,50 (m, 1H), 3,75 (m, 1H), 4,01 (m, 2H), 4,14 (m, 1H), 4,25 (DD, J=9,90, 3,00 Hz, 1H), 7,00 (m, 2H), 7,26 (m, 2H), 8,08 (, 1H).

Example 14(33)

2-(2-((2R)-5-Oxo-2-(4-cryptomaterial)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.43 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.97 (m, 1H), and 2.27 (m, 1H), 2,44 (m, 1H), 2,60 (m, 1H), 3,29 (m, 1H), 349 (m, 1H), to 3.73 (m, 1H), 3.96 points (m, 2H), 4.09 to (m, 1H), 4,18 (DD, J=9,90, 3,30 Hz, 1H), to 6.88 (d, J=9,10 Hz, 2H), 7,16 (d, J=9,10 Hz, 2H), of 8.09 (s, 1H).

Example 14(34)

2-(2-((2R)-2-(3-(tert-Butyl)phenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.48 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 1,31 (s, N), of 1.97 (m, 1H), 2,25 (m, 1H), 2,43 (m, 1H), 2,61 (m, 1H), 3,29 (m, 1H), 3,52 (m, 1H), 3,78 (m, 1H), 3.96 points (m, 2H), 4,08 (m, 1H), 4,18 (DD, J=of 9.30, 3,00 Hz, 1H), 6,69 (DD, J=7,70, 2,40 Hz, 1H), 6.90 to (m, 1H),? 7.04 baby mortality (m, 1H), 7,22 (d, J=of 7.70 Hz, 1H), 8,08 (s, 1H).

Example 14(35)

2-(2-((2R)-2-(4-Chlorphenoxy)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.43 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.97 (m, 1H), 2,25 (m, 1H), 2,43 (m, 1H), 2,60 (m, 1H), 3,29 (m, 1H), 3,49 (m, 1H), 3,71 (m, 1H), 3,94 (m, 2H), 4,08 (m, 1H), 4,20 (DD, J=9,90, 3,00 Hz, 1H), PC 6.82 (d, J=9,10 Hz, 2H), 7,24 (d, J=9,10 Hz, 2H), of 8.09 (s, 1H).

Example 14(36)

2-(2-((2R)-2-(2-Chloro-5-methylphenoxyacetic)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.40 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ at 1.91 (m, 1H), to 2.29 (m, 1H), 2,33 (s, 3H), of 2.45 (m, 1H), 2,66 (m, 1H), 3,30 (m, 1H), to 3.58 (m, 1H), 3,86 (m, 1H), was 4.02 (m, 2H), 4,18 (m, 2H), 6,74 (m, 2H), 7,24 (d, J=8,10 Hz, 1H), 8,07 (s, 1H).

Example 14(37)

2-(2-((2R)-2-(3-Chloro-5-methoxyphenoxy)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.43 (chloroform:mutanolysin acid=90:10:1);

1H-NMR (CDCl3): δ of 1.95 (m, 1H), 2,25 (m, 1H), 2,43 (m, 1H), 2,59 (m, 1H), 3.27 to (m, 1H), 3,49 (m, 1H), and 3.72 (m, 1H), of 3.77 (s, 3H), 3,92 (m, 2H), 4,06 (m, 1H), 4,18 (DD, J=9,90, 3,00 Hz, 1H), 6,32 (t, J=2.00 Hz, 1H), 6,50 (t, J=2.00 Hz, 1H), 6,54 (t, J=2.00 Hz, 1H), of 8.09 (s, 1H).

Example 14(38)

2-(2-((2R)-2-(2-Acetyl-4-chloro-5-methylphenoxyacetic)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.48 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 2,02 (m, 1H), of 2.38 (s, 3H), 2,43 (m, 3H), of 2.54 (s, 3H), of 3.32 (m, 1H), 3,48 (m, 1H), 3,69 (m, 1H), 3,99 (m, 1H), 4,15 (m, 2H), 4,27 (m, 1H), 6,86 (s, 1H), 7,68 (s, 1H), 8,08 (s, 1H).

Example 14(39)

2-(2-((2R)-2-(3-Methoxyphenoxy)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0.14 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ of 1.93 (m, 1H), 2,22 (m, 1H), 2,42 (m, 1H), 2,58 (m, 1H), 3.27 to (m, 1H), 3,48 (m, 1H), 3,75 (m, 4H), of 3.96 (m, 2H), 4,13 (m, 2H), 6.48 in (m, 3H), 7,17 (t, J=8,24 Hz, 1H), of 8.06 (s, 1H).

Example 14(40)

2-(2-((2R)-2-(3-Ethoxyphenoxy)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,13 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ of 1.34 (t, J=7,14 Hz, 3H), of 1.88 (m, 1H), 2,19 (d, J=of 6.96 Hz, 1H), a 2.36 (m, 1H), 2,50 (DD, J=10,07, 6,77 Hz, 1H), 3,21 (m, 1H), 3,44 (m, 1H), 3,92 (m, 7H), 6,38 (m, 2H), 6,47 (DD, J=8,06, 2.20 Hz, 1H), 7,11 (t, J=8,24 Hz, 1H), 8,02 (s, 1H).

Example 14(41)

2-(2-((2R)-2-(3-Diplomaticheskii)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,08 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ 2,03 (m, 1H), 2,24 (m, 1H), 2,42 (s, 1H), 2,58 (s, 1H), 3,26 (m, 1H), 3,48 (m, 1H), 3,71 (m, 1H), 4,07 (m, 4H), 6,60 (m, 4H), 7,25 (m, 1H), 8,07 (s, 1H).

Example 14(42)

2-(2-((2R)-5-Oxo-2-(3-(1,1,2,2-tetrafluoroethoxy)phenoxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,11 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ 2,00 (m, 1H), 2,42 (m, 3H), of 3.28 (m, 1H), 3,48 (m, 1H), 3,71 (s, 1H), 4.00 points (m, 3H), 4,22 (DD, J=9,79, to 3.02 Hz, 1H), of 5.89 (m, 1H), for 6.81 (m, 3H), 7,27 (m, 1H), 8,08 (s, 1H).

Example 14(43)

(15α,13TH)-15-Hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-17-(3,4-dichlorophenyl)-1,2,3,4,18,19,20-heptanol-5-thia-8-isapros-13-EN

TLC: Rf of 0.38 (chloroform:methanol:acetic acid=50:10:1);

1H-NMR (CD3OD): δ of 1.74 (m, 3H), to 2.29 (m, 3H), of 2.64 (m, 2H), 3,36 (m, 3H), of 3.78 (m, 1H), a 4.03 (m, 1H), 4,28 (m, 1H), 5,52 (m, 1H), 5,80 (m, 1H), 7,10 (DD, J=8,06, 2.20 Hz, 1H), 7,34 (d, J=2.20 Hz, 1H), 7,39 (d, J=of 8.06 Hz, 1H), of 8.06 (s, 1H).

Example 14(44)

2-(2-((2R)-2-(3-Aminophenoxy)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.16 (methylene chloride:methanol:acetic acid=18:2:1);

1H-NMR (CDCl3): δ 1,90 (m, 1H), 2,16 (m, 1H), 2,35 (m, 1H), of 2.51 (m, 1H), 3,20 (m, 1H), 3,44 (m, 1H), 3,89 (m, 7H), 6,23 (m, 3H), of 6.99 (t, J=of 8.06 Hz, 1H), to 7.99 (s, 1H).

Example 14(45)

2-(2-((2R)-2-(3-Methylaminopropyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,09 (methylene chloride:methanol:MC is Usna acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.93 (m, 1H), 2,23 (m, 1H), 2,41 (m, 1H), 2.57 m (m, 1H), 2,82 (s, 3H), of 3.25 (m, 1H), 3,50 (m, 1H), 3.96 points (m, 6N), 6,14 (t, J=to 2.29 Hz, 1H), and 6.25 (m, 2H), was 7.08 (t, J=of 8.06 Hz, 1H), of 8.06 (s, 1H).

Example 14(46)

2-(2-((2R)-2-(3-Amino-2-methylphenoxyacetic)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.15 (methylene chloride:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ to 1.98 (m, 4H), and 2.27 (m, 1H), 2,44 (m, 1H), 2,60 (m, 1H), 3,23 (m, 1H), 3,51 (m, 1H), 4.00 points (m, 7H), 6,28 (d, J=of 8.06 Hz, 1H), 6,38 (d, J=of 8.06 Hz, 1H), of 6.96 (t, J=7.87 in Hz, 1H), of 8.06 (s, 1H).

Example 14(47)

2-(2-((2R)-2-(3-Amino-4-methylphenylethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,20 (methylene chloride:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ of 1.92 (m, 1H), 2,09 (s, 3H), 2,22 (m, 1H), 2.40 a (m, 1H), to 2.55 (m, 1H), 3,24 (m, 1H), 3,49 (m, 1H), 3,97 (m, 7H), to 6.22 (m, 2H), 6,93 (d, J=7.87 in Hz, 1H), of 8.06 (s, 1H).

Example 14(48)

(15α,13TH)-15-Hydroxy-5-(4-carboxymethy-2-yl)-9-oxo-17-(naphthalene-2-yl)-1,2,3,4,18,19,20-heptanol-5-thia-8-isapros-13-EN

TLC: Rf to 0.39 (chloroform:methanol:acetic acid=50:10:1);

1H-NMR (CD3OD): δ 2,02 (m, 7H), 2,82 (m, 2H), 3,21 (m, 2H), and 3.72 (m, 1H), 4,13 (m, 2H), vs. 5.47 (m, 1H), 5,78 (m, 1H), was 7.36 (m, 4H), 7,60 (m, 1H), 7,78 (m, 3H).

Example 14(49)

2-(2-((2R)-2-(3-Aminoethylthiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,02 (methylene chloride:methanol=9:1);

1H-NMR (DMSO-D6): ; of 1.93 (m, 1H), 2,36 (m, 3H), 3,34 (m, 7H), of 3.97 (s, 2H), 4,13 (d, J=2,93 Hz, 1H), 4,60 (DD, J=10,44, 3,48 Hz, 1H), at 6.84 (DD, J=8,24, 2.38 Hz, 1H), 6,92 (d, J=7,32 Hz, 1H), 7,21 (m, 1H), 7,60 (s, 1H), 7,72 (s, 1H).

Example 14(50)

2-(2-((2R)-2-(3-Dimethylaminomethylphenol)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,17 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ 2,04 (m, 1H), 2,33 (m, 3H), to 2.67 (s, 6N), of 3.07 (m, 1H), 3,68 (m, 5H), 4.09 to (m, 1H), 4,29 (m, 2H), 6.75 in (d, J=7,32 Hz, 1H), to 6.88 (DD, J=7,87, a 2.01 Hz, 1H), 7,18 (m, 1H), 7,53 (s, 1H), 7,81 (s, 1H).

Example 14(51)

2-(2-((2R)-2-(3,5-Dichlorosalicylic)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,09 (methylene chloride:methanol=9:1);

1H-NMR (DMSO-D6): δ of 1.74 (m, 1H), 1,97 (m, 1H), measuring 2.20 (m, 2H), 3.43 points (m, 4H), of 3.75 (m, 3H), 4.53-in (s, 2H), 7,34 (s, 2H), 7,50 (s, 1H), 7,88 (s, 1H).

Example 14(52)

2-(2-((2S)-2-(2-(3,5-Dichlorophenyl)ethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.44 (methylene chloride:methanol:acetic acid=9:1:0,1);

1H-NMR (CDCl3): δ by 1.68 (m, 2H), to 2.29 (m, 6N), 3,32 (m, 3H), 3,63 (m, 1H), 3,90 (m, 1H), 7,01 (d, J=2.20 Hz, 2H), 7,16 (t, J=2,01 Hz, 1H), 8,03 (s, 1H).

Reference example 12

(5R)-5-(tert-Butoxycarbonyloxyimino)pyrrolidin-2-he

In an argon atmosphere to a solution of (5R)-5-hydroxyethylpyrrolidine-2-it (15.0 g) in dimethylformamide (130 ml) was added imidazole (10.6 g) and tert-butyldimethylsilyl (20.5 g) and the mixture stirred the ri room temperature for 3 hours. The reaction solution was poured into ice and extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the connection header (33,0 g)having the following physical data.

TLC: Rf 0,71 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ 0,06 (C, 6N), 0,89 (s, N), at 1.73 (m, 1H), 2,17 (m, 1H), 2,35 (m, 2H), 3,44 (DD, J=10,20, 7,80 Hz, 1H), 3,63 (DD, J=10,20, 3,90 Hz, 1H), 3,76 (m, 1H), 5,76 (Shir. s, 1H).

Reference example 13

Ethyl ester of ((2R)-2-(tert-butoxycarbonylmethyl)-5-oxopyrrolidin-1-yl)acetic acid

In an argon atmosphere to a solution of the compound obtained in reference example 12 (33,0 g)in anhydrous tetrahydrofuran (300 ml) is added tert-piperonyl potassium (16.0 g) in an ice bath and the mixture is stirred for 10 minutes. To the reaction solution are added dropwise Bromeliaceae (15,9 ml) and the solution stirred at room temperature overnight. To the reaction solution was added saturated aqueous solution of ammonium chloride and the solution extracted with ethyl acetate. The obtained organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the connection header (41,0 g)having the following physical data.

TLC: Rf 0,73 (ethyl acetate).

Reference p is the iMER 14

(5R)-1-(2-Hydroxyethyl)-5-(tert-butoxycarbonyloxyimino)pyrrolidin-2-he

In an argon atmosphere to a solution of the compound obtained in reference example 13 (41,0 g)in a mixture of tetrahydrofuran-ethanol (9:1, 300 ml) is added sodium borohydride (14,7 g) and the mixture is stirred at room temperature for 6 hours. The reaction solution was poured into a mixture of ice-water saturated solution of ammonium chloride and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the connection header (36,7 g)having the following physical data.

TLC: Rf of 0.29 (ethyl acetate)

Reference example 15

((2R)-2-(tert-Butoxycarbonylmethyl)-5-oxopyrrolidin-1-yl)ethylmethanesulfonate

In the atmosphere of argon methanesulfonanilide (11,1 ml) added dropwise into a solution of the compound obtained in reference example 14 (36,7 g), and triethylamine (27,1 ml) in methylene chloride (250 ml) in an ice bath and the mixture is stirred for 1 hour. To the reaction solution was added water and the solution extracted with methylene chloride. The obtained organic layer was washed with hydrochloric acid, water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the header is connected to the I (45.6 g), having the following physical data.

TLC: Rf of 0.53 (ethyl acetate).

Reference example 16

S-((2R)-2-(tert-Butoxycarbonylmethyl)-5-oxopyrrolidin-1-yl)utilitythat

In an argon atmosphere to a solution of the compound obtained in reference example 15 (45.6 g), in dimethylformamide (130 ml) add potassium thiosulfate (14.8 g) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the connection header (39.9 g)having the following physical data.

TLC: Rf 0.26 (n-hexane:ethyl acetate=1:1).

Reference example 17

Ethyl ester of 2-(2-((2R)-2-(tert-butoxycarbonylmethyl)-5-oxopyrrolidin-1-yl)ethylthio-1,3-thiazole-4-carboxylic acid

In an argon atmosphere to a solution of the compound obtained in reference example 16 (39.9 g), ethyl ester of 2-bromo-1,3-thiazole-4-carboxylic acid (30,7 g) and tributylphosphine (2,63 g) in ethanol (260 ml) is added potassium carbonate (26,9 g) in an ice bath and the mixture is stirred at room temperature overnight. To the reaction solution was added water, the solution extracted with ethyl acetate. The obtained organic layer was washed with water and saturated of rest the rum salt, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the connection header (57,0 g).

TLC: Rf 0.26 (n-hexane:ethyl acetate=1:1).

Reference example 18

Butyl ether 2-(2-((2R)-2-(tert-butoxycarbonylmethyl)-5-oxopyrrolidin-1-yl)ethylthio-1,3-thiazole-4-carboxylic acid

To a solution of the compound obtained in reference example 17 (57,0 g), butanol (260 ml) is added potassium carbonate (17.9 g) and the mixture is stirred at a temperature of 80°C for 4 hours. After cooling, the reaction solution is filtered and concentrated. The resulting residue is dissolved in ethyl acetate. The solution is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the connection header (64,1 g)having the following physical data.

TLC: Rf 0.39 to (n-hexane:ethyl acetate=1:1).

Reference example 19

Butyl ether 2-(2-((2R)-2-hydroxymethyl-5-oxopyrrolidin-1-yl)ethylthio-1,3-thiazole-4-carboxylic acid

To a solution of the compound obtained in reference example 18 (64,1 g)in tetrahydrofuran (130 ml) add a solution of tetrabutylammonium fluoride (1.0 mol/l) in tetrahydrofuran (130 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and extracted with ethyl acetate. The organic layer is washed with water and nasy the military solution of salt, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (ethyl acetate-hexane) to obtain specified in the connection header (24,0 g)having the following physical data.

TLC: Rf to 0.19 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.97 (t, J=7,30 Hz, 3H), of 1.45 (m, 2H), 1,74 (m, 2H), 1,90 (m, 1H), 2,13 (m, 1H), 2.40 a (m, 2H), 3,32 (t, J=5.50 Hz, 1H), 3.43 points (m, 1H), of 3.56 (m, 1H), 3,80 (m, 5H), to 4.33 (t, J=6,70 Hz, 2H), 7,99 (s, 1H).

Reference example 20

Butyl ether 2-(2-((2R)-2-formyl-5-oxopyrrolidin-1-yl)ethylthio-1,3-thiazole-4-carboxylic acid

In an argon atmosphere to a solution of the compound obtained in reference example 19 (205 mg), and triethylamine (of 0.48 ml) in ethyl acetate (4 ml) is added dimethyl sulfoxide (2 ml) and a complex of a sulfur trioxide-pyridine (273 mg) at a temperature of 10°C and the mixture is stirred at a temperature of from 10 to 20°C for 2 hours. To the reaction solution was added water and extracted with ethyl acetate. The obtained organic layer was washed with hydrochloric acid, water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the title compound (219 mg)having the following physical data.

TLC: Rf 0.26 (ethyl acetate);

1H-NMR (CDCl3): δ and 0.98 (t, J=7,60 Hz, 3H), 1,58 (m, 5H), of 2.25 (m, 3H), 3.43 points (m, 2H), a 4.03 (m, 2H), 4,32 (t, J=6,70 Hz, 2H), with 4.64 (m, 1H), 8,00 (s, 1H, RS 9.69 (d, J=1,10 Hz, 1H).

Example 15

Butyl ether 2-(2-((2R)-2-heptylamine-5-oxopyrrolidin-1-yl)ethylthio-1,3-thiazole-4-carboxylic acid

In an argon atmosphere to a solution of the compound obtained in reference example 20 (120 mg)in methylene chloride (3 ml) is added n-heptylamine (98 μl) and the mixture is stirred at room temperature for 1 hour. To the reaction solution add triacetoxyborohydride sodium (140 ml) and the solution stirred at room temperature for 2 hours. To the reaction mixture is added aqueous saturated solution of sodium bicarbonate and the mixture extracted with methylene chloride. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (ethyl acetate→ethyl acetate:methanol=9:1) to give the compounds of this invention (119 mg)having the following physical data.

TLC: Rf 0.14 (ethyl acetate:methanol=9:1);

1H-NMR (CDCl3): δ to 0.88 (t, J=6,90 Hz, 3H), of 0.97 (t, J=7,40 Hz, 3H), 1.26 in (m, 8H), USD 1.43 (m, 4H), of 1.74 (m, 2H), 1,89 (m, 1H), 2,12 (m, 1H), 2,30 (DDD, J=16,90, 9,90, the ceiling of 5.60 Hz, 1H), 2,45 (DDD, J=17,20, 10,00, 7,20 Hz, 1H), 2.57 m (m, 2H), 2,78 (m, 2H), 3,47 (m, 3H), a 3.87 (m, 2H), 4,33 (t, J=6,77 Hz, 2H), 8,00 (s, 1H).

Examples 15(1)-15(10)

According to the method of example 15 using the appropriate derived amine instead of n-heptylamine is, get the following compounds of the present invention.

Example 15(1)

Butyl ether 2-(2-((2R)-2-(3,5-dichlorophenylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf to 0.63 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.96 (t, J=7,28 Hz, 3H), USD 1.43 (m, 2H), 1,72 (m, 2H), of 1.88 (m, 1H), 2,36 (m, 3H), 3,32 (m, 3H), 3,55 (m, 2H), 3,94 (m, 1H), 4,10 (m, 1H), or 4.31 (t, J=6,46 Hz, 2H), 4,73 (m, 1H), 6,45 (d, J=1,79 Hz, 2H), only 6.64 (t, J=1,79 Hz, 1H), 8,01 (s, 1H).

Example 15(2)

Butyl ether 2-(2-((2R)-5-oxo-2-(piperidine-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.29 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ to 0.97 (t, J=7,50 Hz, 2H), of 1.44 (m, 8H), 1,72 (m, 3H), 2,07 (m, 1H), and 2.26 (m, 4H), to 2.41 (m, 4H), 3,50 (t, J=6,59 Hz, 2H), to 3.67 (m, 1H), 3,92 (m, 2H), 4,33 (t, J= 6,77 Hz, 2H), 8,01 (s, 1H).

Example 15(3)

Butyl ether 2-(2-((2R)-2-(morpholine-4-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.51 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ to 0.97 (t, J=7,41 Hz, 3H), of 1.45 (m, 2H), 1,74 (m, 3H), 2,10 (m, 1H), 2,32 (m, 5H), of 2.51 (m, 3H), 3,51 (t, J=7,05 Hz, 2H), 3,65 (m, 5H), of 3.96 (m, 2H), 4,33 (t, J= 6,77 Hz, 2H), 8,00 (s, 1H).

Example 15(4)

Butyl ether 2-(2-((2R)-2-(4-methylpiperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.27 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ to 0.97 (t, J=7,41 Hz, 3H), of 1.45 (m, 2H), 1,73 (m, 3H), of 2.08 (m, 1H), of 2.25 (s, 3H), of 2.45 (m, N), 3,51 (t, J=6,68 Hz, 2H), 3,66 (m, 1H), 3,93 (m, 2H), 4,33 (t, J =6,77 Hz, 2H), 8,01 (s, 1H).

Example 15(5)

Butyl ether 2-(2-((2R)-2-(4-(tert-butoxycarbonyl)piperazine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.37 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.97 (t, J=7,50 Hz, 3H), of 1.45 (m, 2H), 1,45 (s, N), of 1.74 (m, 3H), 2,11 (m, 1H), 2.40 a (m, 8H), to 3.35 (t, J=4,94 Hz, 4H), 3,50 (t, J=6.87 in Hz, 2H), 3,63 (m, 1H), 3,95 (m, 2H), 4,33 (t, J=6,77 Hz, 2H), 8,01 (s, 1H).

Example 15(6)

Butyl ether 2-(2-((2R)-2-(4-benzylpiperazine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,08 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.96 (t, J=7,41 Hz, 3H), of 1.44 (m, 2H), 1,71 (m, 3H), of 2.09 (m, 1H), 2.40 a (m, N), of 3.45 (s, 2H), 3,50 (t, J=6,77 Hz, 2H), to 3.67 (m, 1H), 3,91 (m, 2H), 4,30 (t, J =6,77 Hz, 2H), 7,28 (m, 5H), 8,00 (s, 1H).

Example 15(7)

Butyl ether 2-(2-((2R)-2-(cyclohexylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.44 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 0,99 (m, 5H), to 1.21 (m, 4H), for 1.49 (m, 4H), of 1.81 (m, 5H), to 2.13 (m, 1H), of 2.38 (m, 3H), and 2.79 (d, J=5,13 Hz, 2H), 3,47 (m, 3H), a 3.87 (m, 2H), 4,33 (t, J=6,59 Hz, 2 H ) 8,00 (s, 1H).

Example 15(8)

Butyl ether 2-(2-((2R)-2-benzylamino-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0.36 and (ethyl) - Rev. Etat:methanol=9:1);

1H-NMR (CDCl3): δ to 0.96 (t, J=7,30 Hz, 3H), of 1.44 (m, 2H), 1,72 (m, 2H), 1,96 (m, 1H), 2,22 (m, 2H), 2,46 (m, 1H), 2,90 (m, 2H), 3.43 points (m, 3H), 3,90 (m, 4H), 4,29 (t, J=6,70 Hz, 2H), 7,29 (m, 5H), of 7.97 (s, 1H).

Example 15(9)

Butyl ether 2-(2-((2R)-2-(N-cyclohexyl-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,59 (ethyl acetate:methanol=4:1);

1H-NMR (CDCl3): δ to 0.97 (t, J=7,51 Hz, 3H)and 1.15 (m, 5H), of 1.45 (m, 2H), 1,72 (m, 8H), to 2.06 (m, 1H), measuring 2.20 (s, 3H), 2,28 (m, 2H), 2,41 (m, 2H), 2,53 (DD, J=12,90, 6,30 Hz, 1H), 3,49 (t, J=6,68 Hz, 2H), 3,63 (dt, J=13,73, of 6.68 Hz, 1H), 3,80 (m, 1H), 3,95 (dt, J=13,73, of 6.68 Hz, 1H), 4,33 (t, J=6,77 Hz, 2H), 8,01 (s, 1H).

Example 15(10)

Butyl ether 2-(2-((2R)-2-(N-benzyl-N-cyclohexylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,76 (ethyl acetate);

1H-NMR (CDCl3): δ to 0.97 (t, J=to 7.32 Hz, 3H), 1,17 (m, 5H), of 1.45 (m, 2H), 1,78 (m, 8H), to 1.96 (m, 1H), of 2.21 (m, 2H), 2.40 a (m, 2H), 2,69 (DD, J=of 13.18, 5,13 Hz, 1H), 3.45 points (m, 5H), to 3.64 (d, J=13,80 Hz, 1H), 3,85 (m, 1H), or 4.31 (t, J=6,68 Hz, 2H), from 7.24 (m, 5H), of 7.97 (s, 1H).

Example 16(1)-16(61)

According to the method of example 2 using the compound obtained in example 15, 15(1)-15(10), or the corresponding ester instead of the compound obtained in example 1 given the following compounds of this invention.

Example 16(1)

2-(2-((2R)-2-Heptylamine-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC:Rf of 0.33 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ of 0.85 (t, J=6,90 Hz, 3H), 1,25 (m, 8H), to 1.79 (m, 3H), 2,32 (m, 3H), 2,52 (m, 1H), only 2.91 (DD, J=11,81, 9,34 Hz, 1H), 3,09 (DD, J=9,34, to 7.32 Hz, 2H), 3,32 (m, 2H), to 3.58 (m, 1H), 3,74 (m, 2H), 4,39 (m, 1H), 7,88 (s, 1H).

Example 16(2)

2-(2-((2R)-2-(3,5-Dichlorophenylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.40 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 1.88 (m, 1H), of 2.21 (m, 1H), 2,45 (m, 2H), 3,42 (m, 5H), 3,61 (Shir. s, 2H), 4.00 points (m, 2H), 6,47 (d, J=1.80 Hz, 2H), 6,67 (t, J=1.80 Hz, 1H), 8,10 (s, 1H).

Example 16(3)

2-(2-((2R)-2-(N-Acetyl-N-(3,5-dichlorophenyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0.31 in (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 1,71 (m, 1H), 1,96 (s, 3H), of 2.15 (m, 1H), 2,39 (m, 2H), 3,44 (m, 4H), 3,95 (m, 2H), 4,28 (m, 1H), 7,13 (d, J=1.65 Hz, 2H), 7,40 (t, J=1.65 Hz, 1H), 8,10 (s, 1H).

Example 16(4)

2-(2-((2R)-5-Oxo-2-(piperidine-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.20 (chloroform:methanol:water=40:10:1);

1H-NMR (CDCl3): δ is 1.51 (m, 2H), equal to 1.82 (m, 5H), was 2.34 (m, 3H), 2,65 (DD, J=of 13.18, 6,77 Hz, 1H), 2,84 (m, 3H), is 3.08 (DD, J=of 13.18, a 4.03 Hz, 1H), 3,47 (m, 4H), 3,90 (m, 1H), 4,27 (m, 1H), 7,98 (s, 1H).

Example 16(5)

2-(2-((2R)-2-(Morpholine-4-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0.28 in (chloroform:methanol:water=40:10:1);

1H-NMR (CDCl3): δ of 1.78 (m, 1H) of 2.16 (m, 1H), of 2.51 (m, 8H), 3,44 (m, 2H), 3,70 (m, 5H), 3,95 (m, 2H), 8,08 (s, 1H).

Example 16(6)

2-(2-((2R)-2-(4-Methylpiperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,07 (chloroform:methanol:water=40:10:1);

1H-NMR (CDCl3): δ to 1.59 (m, 1H), 2.05 is (m, 1H), 2,23 (m, 1H), 2,39 (m, 2H), 2,68 (s, 3H), 2,68 (m, 2H), 3,06 (m, 7H), of 3.46 (m, 1H), 3,62 (m, 2H), 3,97 (m, 2H), 7,89 (s, 1H).

Example 16(7)

2-(2-((2R)-2-(4-(tert-Butoxycarbonyl)piperazine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf is 0.42 (chloroform:methanol:water=40:10:1);

1H-NMR (CDCl3): δ 1,47 (s, N)and 1.83 (m, 1H), 2,18 (m, 1H), 2,53 (m, 8H), 3.43 points (m, 6N), 3,70 (m, 1H), 3,95 (m, 2H), 8,08 (s, 1H).

Example 16(8)

2-(2-((2R)-2-(4-Benzylpiperazine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.35 (chloroform:methanol:water=40:10:1);

1H-NMR (CDCl3): δ was 1.69 (m, 1H), 2,09 (m, 1H), 2,35 (m, 3H), 2.91 in (m, N), of 3.48 (m, 3H), 3,83 (m, 2H), 4.00 points (d, J=of 13.18 Hz, 1H), 4,13 (d, J=of 13.18 Hz, 1H), 7,40 (m, 5H), 8,07 (s, 1H).

Example 16(9)

2-(2-((2R)-2-Cyclohexylamino-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.36 (chloroform:methanol:water=40:10:1);

1H-NMR (CDCl3): δ to 1.21 (m, 3H), of 1.59 (m, 3H)and 1.83 (m, 2H), 2,37 (m, 6N), of 2.81 (m, 1H), 3,26 (m, 3H), of 3.57 (m, 1H), of 3.77 (m, 2H), of 4.44 (m, 1H), 7,88 (s, 1H).

Example 16(10)

2-(2-((2R)-2-Benzylamino-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-Urbanova acid

TLC: Rf 0,70 (methylene chloride:methanol:water=80:20:1);

1H-NMR (DMSO-D6): δ is 1.81 (m, 1H), 2,07 (m, 2H), 2,28 (m, 1H), was 2.76 (m, 1H), 2,88 (m, 1H), 3,34 (m, 3H), 3,51 (Shir. s, 2H), 3,81 (m, 4H), 7,32 (m, 5H), compared to 8.26 (s, 1H).

Example 16(11)

2-(2-((2R)-2-(N-Cyclohexyl-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,13 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ 1,09 (m, 1H), 1,30 (m, 4H), by 1.68 (m, 1H), 1,92 (m, 5H), a 2.36 (m, 3H), 2.63 in (s, 3H), 2,77 (DD, J=12,90, of 8.33 Hz, 1H), 2,93 (m, 1H), 3,03 (DD, J=12,90, 3,00 Hz, 1H), 3,42 (m, 3H), 3,95 (m, 1H), 4,37 (m, 1H), of 7.96 (s, 1H).

Example 16(12)

2-(2-((2R)-2-(N-Benzyl-N-cyclohexylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.29 (ethyl acetate:methanol=4:1);

1H-NMR (CDCl3): δ 1,19 (m, 5H), and 1.63 (m, 1H), 1,80 (m, 5H), 1,99 (m, 1H), and 2.26 (m, 2H), 2.49 USD (m, J=of 13.27, of 7.23 Hz, 2H), 2,72 (DD, J=made 13.36, 5,49 Hz, 1H), and 3.16 (m, 2H), 3,47 (m, 2H), 3,61 (d, J=13,20 Hz, 1H), 3,69 (d, J=13,20 Hz, 1H), 3,94 (m, 1H), 7,28 (m, 5H), with 8.05 (s, 1H).

Example 16(13)

2-(2-((2R)-2-Hexylamino-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.32 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ 0,84 (t, J=6,90 Hz, 3H), of 1.29 (m, 6N), to 1.79 (m, 3H), 2,32 (m, 3H), of 2.51 (m, 1H), 2,93 (DD, J=11,90, 8,88 Hz, 1H), 3,09 (DD, J=8,88, 7,60 Hz, 2H), 3,32 (m, 2H), to 3.58 (m, 1H), 3,74 (m, 2H), 4,39 (m, 1H), 7,89 (s, 1H).

Example 16(14)

2-(2-((2R)-5-Oxo-2-(4-phenylpiperidine-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carb is a new acid

TLC: Rf of 0.30 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ of 1.94 (m, 5H), of 2.25 (m, 2H), by 2.55 (m, 5H), 3,01 (m, 1H), 3,36 (m, 4H), 3,63 (m, 1H), 3,92 (m, 1H), 4,19 (m, 1H), 7,19 (m, 3H), 7,28 (m, 2H), 8,01 (s, 1H).

Example 16(15)

2-(2-((2R)-2-(4-Benzylpiperidine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.32 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ of 1.64 (m, 5H), 1,90 (m, 1H), 2,32 (m, 5H), 2,53 (d, J=4,94 Hz, 2H), 2,66 (DD, J=to 13.09, 7,14 Hz, 1H), 3,11 (DD, J=to 13.09, of 4.67 Hz, 1H), 3,44 (m, 5H), to 3.89 (dt, J= 14,01, to 7.09 Hz, 1H), 4,25 (m, 1H), 7,10 (m, 2H), from 7.24 (m, 3H), of 8.00 (s, 1H).

Example 16(16)

2-(2-((2R)-5-Oxo-2-(3-phenylpropylamine)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0.35 in (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ of 2.16 (m, 6N), a 2.45 (m, 1H), has 2.56 (t, J=of 7.69 Hz, 2H), 2,93 (DD, J=12,36, of 8.33 Hz, 1H), 3.04 from (DD, J=9,06, 7,05 Hz, 2H), up 3.22 (m, 1H), 3,34 (m, 1H), to 3.58 (m, 3H), 4,28 (m, 1H),? 7.04 baby mortality (m, 2H), 7,19 (m, 3H), 7,89 (s, 1H).

Example 16(17)

2-(2-((2R)-2-(Naphthalene-2-ylmethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0.28 in (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ 7,98 (s, 1H), to 7.77-7,63 (m, 4H), 7,52 (DD, J=8,7, 1.8 Hz, 1H), 7,8-7,37 (m, 2H), 4,34 (d, J=13,2 Hz, 1H), 4.26 deaths (m, 1H), 4,10 (d, J=13,2 Hz, 1H), 3,66-of 3.32 (m, 3H), of 3.13 (m, 2H), 2,80 (m, 1H), 2,42-to 1.98 (m, 4H).

Example 16(18)

2-(2-((2R)-2-(3,5-Dimethylpiperidin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

The SH: Rf 0,19 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ to 7.99 (s, 1H), 4.26 deaths (m, 1H), 3,88 (m, 1H), only 3.57 (m, 1H), 3,85-the 3.65 (m, 2H), 3,55-to 3.02 (m, 3H), 2,84 (m, 2H), 2,58 (DD, J=12.9 Hz, 6.9 Hz, 1H), 2,50-of 2.15 (m, 3H), 2,10-to 1.70 (m, 4H), of 0.90 (d, J=6.3 Hz, 3H), from 0.88 (d, J=7.5 Hz, 3H), and 0.61 (q, J=11,9 Hz, 1H).

Example 16(19)

2-(2-((2R)-5-Oxo-2-(2-phenylethylamine)methyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0.25 in (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ to $ 7.91 (s, 1H), 7,21-7,13 (m, 3H), 7,09-7,01 (m, 2H), 4,35 (m, 1H), 3,76-3,47 (m, 3H), 3,44 totaling 3.04 (m, 6H), to 2.94 (DD, J=12,0, to 8.7 Hz, 1H), 2,50 (m, 1H), 2,39-to 2.18 (m, 3H).

Example 16(20)

2-(2-((2R)-5-Oxo-2-(1,2,3,4-tetrahydronaphthalen-1-illuminometer)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.37 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ of 7.96 and 7.69 (each m, 1H), to $ 7.91 and 7,87 (each s, 1H), was 7.36-7,21 (m, 1H), 7,19-7,00 (m, 1H), 7,19-7.00 and 6,89 (each m, 1H), of 5.05 and 4,43 (each m, 1H), 4.72 in-4,55 (m, 1H), 3,86-3,66 (m, 1H), 3,64-of 3.43 (m, 1H), 3,38-3,10 (m, 3H), 2,90-2,62 (m, 3H), 2,58-of 1.85 (m, 8H).

Example 16(21)

2-(2-((2R)-2-(1,2,3,4-Tetrahydroisoquinoline-2-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,24 (methylene chloride:methanol=9:1);

1H-NMR (CDCl3): δ 8,00 (s, 1H), 7.24 to 7,07 (m, 3H), 7,03 (m, 1H), 4,15 (m, 1H), 3,94 (m, 1H), 3,91 (d, J=12.0 Hz, 1H), 3,83 (d, J=12.0 Hz, 1H), 3,65 (m, 1H), 3.45 points-to 3.34 (m, 2H), 3,20-to 2.85 (m, 5H), 2,70 (DD, J=12,9, 6,0 Hz, 1H), 2,54 is 2.10 (m, 3H), of 1.88 (m, 1H).

Example 16(22)

2-(2-((2R)-2-(2-(3,5-Dichlorophenoxy)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-,3-thiazole-4-carboxylic acid (salt triperoxonane acid)

TLC: Rf is 0.22 (chloroform:methanol:acetic acid=40:10:1);

1H-NMR (CD3OD): δ 2,02 (m, 1H), 2,39 (m, 3H), 3,30 (m, 1H), to 3.58 (m, 6N), a-3.84 (m, 1H), 4,25 (m, 1H), 4,37 (m, 2H), 6,93 (d, J=1,74 Hz, 2H),? 7.04 baby mortality (t, J=1,74 Hz, 1H), 8,23 (s, 1H).

Example 16(23)

2-(2-((2R)-5-Oxo-2-(3-triphtalocyaninine)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.33 (methylene chloride:methanol:acetic acid=9:1:0,3);

1H-NMR (CDCl3): δ to 1.86 (m, 1H), and 2.14 (m, 1H), 2.40 a (m, 2H), 3,37 (m, 5H), of 3.96 (m, 2H), 6,37 (s, 1H), 6,47 (m, 2H), was 7.08 (m, 1H), 8,04 (s, 1H).

Example 16(24)

2-(2-((2R)-2-(((1S,2R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf value of 0.52 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ of 0.90 (m, 1H), 0,97 (s, 3H), of 1.17 (s, 3H), USD 1.43 (m, 1H), 1,97 (m, 6N), 2,32 (m, 4H), 2,52 (m, 2H), 2,96 (m, 2H), 3,29 (m, 3H), 3,53 (m, 2H), 3,80 (m, 1H), 4,49 (m, 1H), 7,83 (s, 1H).

Example 16(25)

2-(2-((2R)-2-(3-Methylcyclohexylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

more polar

TLC: Rf of 0.43 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ and 0.98 (m, 3H), of 1.65 (m, 7H), 2,11 (m, 2H), 2,30 (m, 3H), 2,48 (m, 1H), 2,84 (m, 1H), 3,54 (m, 6N), 4,39 (m, 1H), 7,83 (m, 1H).

Example 16(26)

2-(2-((2R)-2-(3-Methylcyclohexylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

less polar

TLC: Rf of 0.45 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ 0,89 (m, 4H), of 1.34 (m, 4H), by 1.68 (m, 1H), of 1.84 (m, 1H), 2,22 (m, 5H), 2,48 (m, 1H), 2,81 (m, 1H), 3,25 (m, 3H), to 3.58 (m, 1H), 3,74 (m, 2H), to 4.41 (m, 1H), 7,83 (m, 1H).

Example 16(27)

2-(2-((2R)-2-(4-Methylcyclohexylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

more polar

TLC: Rf of 0.45 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ of 0.93 (d, J=of 6.96 Hz, 3H), of 1.55 (m, 4H), to 1.87 (m, 5H), 2,31 (m, 3H), 2,48 (m, 1H), 2,88 (m, 1H), 3,18 (m, 1H), and 3.31 (m, 2H), only 3.57 (m, 1H), 3,74 (m, 2H), of 4.44 (m, 1H), 7,86 (s, 1H).

Example 16(28)

2-(2-((2R)-2-(4-Methylcyclohexylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

less polar

TLC: Rf 0,46 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ of 0.90 (d, J=6,60 Hz, 3H), 1.00 m (m, 2H), 1,37 (m, 1H), 1,60 (m, 2H), 1,80 (m, 2H), 2,24 (m, 5H), 2.49 USD (m, 1H), 2,80 (m, 1H), 3,19 (m, 1H), 3,30 (m, 2H), only 3.57 (m, 1H), 3,74 (m, 2H), to 4.41 (m, 1H), of 7.82 (s, 1H).

Example 16(29)

2-(2-((2R)-2-Cyclohexylethylamine-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,41 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ of 1.07 (m, 5H), to 1.76 (m, 6N), is 2.41 (m, 4H), 2.95 and (m, 3H), 3,29 (m, 2H), 3,52 (m, 1H), to 3.64 (m, 1H), 3,81 (m, 1H), 4,50 (m, 1H), a 7.85 (s, 1H).

Example 16(30)

2-(2-((2R)-2-(Indan-1-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic sour is and

TLC: Rf of 0.47 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CD3OD): δ 1,90 (m, 1H), 2.40 a (m, 5H), to 3.33 (m, 8H), a 3.87 (m, 1H), 4,48 (m, 1H), 7,27 (m, 3H), 7,54 (d, J=7,2 Hz, 0,4H), to 7.67 (d, J=7,2 Hz, 0,6N), 7,89 (s, 0,6N), of 7.97 (s, 0,4N).

Example 16(31)

2-(2-((2R)-5-Oxo-2-((tetrahydrofuran-2-ylmethyl)aminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,19 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ 1,50 (m, 1H), 1,87 (m, 2H), 2.06 to (m, 1H), of 2.38 (m, 4H), of 2.97 (m, 2H), 3,36 (m, 4H), of 3.57 (m, 1H), 3,81 (m, 3H), 4,35 (m, 2H), to 7.84 (m, 1H).

Example 16(32)

2-(2-((2R)-2-(2-Methylbenzylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.43 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ of 2.08 (m, 1H), 2,31 (m, 3H), of 2.35 (s, 3H), was 2.76 (m, 1H), 3,21 (m, 2H), 3,50 (m, 2H), 3,70 (m, 1H), 4.00 points (d, J=13,60 Hz, 1H), 4,21 (d, J=13,60 Hz, 1H), to 4.38 (m, 1H), 7,14 (m, 3H), 7,47 (d, J=7,30 Hz, 1H), to $ 7.91 (s, 1H).

Example 16(33)

2-(2-((2R)-2-(2-(1-Cyclohexen-1-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,49 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ of 1.53 (m, 4H), of 1.88 (m, 4H), to 2.41 (m, 6N), with 2.93 (m, 1H), 3,19 (m, 2H), 3,34 (m, 2H), to 3.58 (m, 1H), to 3.73 (m, 2H), to 4.38 (m, 1H), 5,41 (m, 1H), 7,86 (s, 1H).

Example 16(34)

2-(2-((2R)-5-Oxo-2-((2R)-2-phenylpropylamine)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.43 (methylene chloride:methanol:water=40:101);

1H-NMR (CDCl3): δ of 1.34 (d, J=7,00 Hz, 3H), 2,24 (m, 4H), at 2.59 (m, 1H), 3,18 (m, 6N), of 3.60 (m, 2H), 4,30 (m, 1H), 7,13 (m, 2H), 7,22 (m, 3H), of 7.90 (s, 1H).

Example 16(35)

2-(2-((2R)-2-(2-(Ethylthio)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.32 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ of 1.18 (t, J=7,40 Hz, 3H), 2,30 (m, 3H), 2,50 (kV, J=7,40 Hz, 2H), 2,52 (m, 1H), 2.91 in (m, 2H), of 3.07 (DD, J=12,30, of 7.70 Hz, 1H), or 3.28 (m, 3H), 3,41 (m, 1H), 3,68 (m, 3H), 4,28 (m, 1H), 7,92 (s, 1H).

Example 16(36)

2-(2-((2R)-2-(2-(2-Forfinal)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.43 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ 2,31 (m, 3H), 2,53 (m, 1H), 2,99 (m, 1H), 3.15 in (m, 2H), 3,26 (m, 1H), 3,38 (m, 3H), 3,66 (m, 3H), 4,33 (m, 1H), 6,94 (m, 2H), 7,06 (m, 1H), 7,16 (m, 1H), 7,89 (s, 1H).

Example 16(37)

2-(2-((2R)-2-Cyclooctylamino-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,49 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ is 1.51 (m, 8H), to 1.79 (m, 4H), and 2.14 (m, 2H), 2,31 (m, 2H), 2,48 (m, 1H), 2,78 (m, 1H), 3,30 (m, 2H), 3,52 (m, 3H), 3,74 (m, 2H), to 4.41 (m, 1H), 7,82 (s, 1H).

Example 16(38)

2-(2-((2R)-2-(2,3-Dimethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,59 (methylene chloride:methanol:acetic acid=9:1:0,2);

1H-NMR (CDCl3): δ of 1.97 (m, 4H), 2,19 (m, 4H), 2,44 (m, 2H), 3,35 (m, 4H, of 3.57 (m, 1H), 3,98 (m, 2H), 6,47 (d, J=8,42 Hz, 1H), is 6.61 (d, J=7,32 Hz, 1H), 6,99 (t, J=7.87 in Hz, 1H), 8,04 (s, 1H).

Example 16(39)

2-(2-((2R)-2-(3,4-Dimethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,54 (methylene chloride:methanol:acetic acid=9:1:0,2);

1H-NMR (CDCl3): δ to 1.87 (m, 1H), 2,12 (m, 7H), of 2.38 (m, 2H), 3,37 (m, 5H), 3,93 (m, 2H), 6,34 (m, 2H), to 6.88 (d, J=of 8.06 Hz, 1H), 8,02 (s, 1H).

Example 16(40)

2-(2-((2R)-5-Oxo-2-(5,6,7,8-tetrahydronaphthalen-1-illuminometer)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.57 (chloroform:methanol:acetic acid=9:1:0,2);

1H-NMR (CDCl3): δ of 1.88 (m, 3H), 2,35 (m, 5H), by 2.73 (t, J=6,04 Hz, 2H), 3,38 (m, 4H)and 3.59 (m, 1H), was 4.02 (DD, J=8,42, was 4.76 Hz, 2H), was 4.02 (m, 2H), 6,44 (d, J=of 8.06 Hz, 1H), 6,56 (d, J=of 6.96 Hz, 1H), 7,02 (d, J=7,69 Hz, 1H), 8,07 (s, 1H).

Example 16(41)

2-(2-((2R)-2-(3-Chloro-4-tortenelmietlen)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.47 (chloroform:methanol:acetic acid=9:1:0,2);

1H-NMR (CDCl3): δ to 1.86 (m, 1H), 2,15 (m, 1H), 2,39 (m, 2H), 3,34 (m, 5H), 3,95 (m, 2H), 6,38 (m, 1H), 6,55 (DD, J=5,86, with 2.93 Hz, 1H), to 6.88 (t, J=8,79 Hz, 1H), 8,04 (s, 1H).

Example 16(42)

2-(2-((2R)-2-(3-Chloro-4-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.53 (chloroform:methanol:acetic acid=9:1:0,2);

1H-NMR (CDCl3): δ of 1.85 (m, 1H), 2,13 (m, 4H), of 2.38 (m, 2H), 3,36 (m, 5H), of 3.94 (m, 2H), 6,36 (DD, J=8,24, 2.38 Hz, 1H), 6,55 (d, J=2,56 Hz, 1H), 6,93 (d, J=8,42 Hz, 1H), 8,03 (s, 1H).

Example 16(43)

2-(2-((2R)-2-(3,5-Dimethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.54 (chloroform:methanol:acetic acid=9:1:0,2);

1H-NMR (CDCl3): δ 1,89 (m, 1H), 2,11 (m, 7H), is 2.37 (m, 2H), 3,30 (m, 4H), 3,50 (m, 1H), 3,93 (m, 2H), to 6.19 (s, 2H), 6.35mm (s, 1H), 8,02 (s, 1H).

Example 16(44)

2-(2-((2R)-2-(3-Brompheniramine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.57 (methylene chloride:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ of 1.92 (m, 1H), of 2.21 (m, 1H), 2,46 (m, 2H), 3.43 points (m, 5H), to 4.01 (m, 2H), 6,54 (m, 1H), 6,77 (t, J=2.00 Hz, 1H), 6,86 (m, 1H), 7,02 (t, J=8,10 Hz, 1H), 8,11 (s, 1H).

Example 16(45)

2-(2-((2R)-2-(3,4-Dichlorophenylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,59 (methylene chloride:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ at 1.91 (m, 1H), of 2.21 (m, 1H), 2,46 (m, 2H), 3.43 points (m, 5H), was 4.02 (m, 2H), 6,47 (DD, J=8,80, 2,80 Hz, 1H), 6,70 (d, J=2,80 Hz, 1H), 7,19 (d, J=8,80 Hz, 1H), 8,12 (s, 1H).

Example 16(46)

2-(2-((2R)-5-Oxo-2-(3-cryptomaterial)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,59 (methylene chloride:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), measuring 2.20 (m, 1H), 2,48 (m, 2H), 3.46 in (m, 5H), of 4.05 (m, 2H), 6,79 (m, 2H), 6,97 (m, 1H), 7,26 (m, 1H), 8,11 (s, 1H).

Example 16(47)

2-(2-(2R)-2-(4-Fluoro-3-cryptomaterial)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.57 (methylene chloride:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), 2,24 (m, 1H), 2,48 (m, 2H), 3.45 points (m, 5H), Android 4.04 (m, 2H), 6,76 (m, 2H), 7,01 (t, J=of 9.30 Hz, 1H), 8,11 (s, 1H).

Example 16(48)

2-(2-((2R)-2-(4-Chloro-3-cryptomaterial)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.57 (methylene chloride:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ of 1.92 (m, 1H), 2,24 (m, 1H), 2,47 (m, 2H), 3.45 points (m, 5H), is 4.03 (m, 2H), 6,69 (DD, J=8,60, 2,60 Hz, 1H), 6.89 in (d, J=2,60 Hz, 1H), 7,25 (m, 1H), 8,11 (s, 1H).

Example 16(49)

2-(2-((2R)-5-Oxo-2-(3,4,5-trichlorophenylacetic)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.57 (methylene chloride:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ 1,90 (m, 1H), 2,23 (m, 1H), 2,47 (m, 2H), 3.45 points (m, 5H), to 4.01 (m, 2H), only 6.64 (m, 2H), 8,12 (m, 1H).

Example 16(50)

2-(2-((2R)-2-(3-Bromo-4-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.57 (methylene chloride:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ of 1.93 (m, 1H), 2,19 (m, 1H), and 2.27 (s, 3H), 2,46 (m, 2H), 3.43 points (m, 5H), to 4.01 (m, 2H), 6,50 (DD, J=8,40, is 2.40 Hz, 1H), at 6.84 (d, J=2,40 Hz, 1H), 7,01 (d, J=8,40 Hz, 1H), 8,10 (s, 1H).

Example 16(51)

2-(2-((2R)-2-(1-Methylhexanamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.50 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3):δ of 0.85 (m, 3H), 1,31 (m, N), and 1.56 (m, 1H), 1,92 (m, 1H), 2,32 (m, 3H), 2.49 USD (m, 1H), was 2.76 (m, 1H), and 3.31 (m, 3H), of 3.56 (m, 3H), 3,80 (m, 1H), 4,46 (m, 1H), 7,81 (m, 1H).

Example 16(52)

2-(2-((2R)-2-(2-Ethylhexyloxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,51 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ 0,80 (m, 6N), 1.27mm (m, N), to 1.76 (m, 1H), 2,34 (m, 3H), of 2.51 (m, 1H), 2,99 (m, 3H), of 3.28 (m, 2H), only 3.57 (m, 2H), 3,80 (m, 1H), 4,54 (m, 1H), 7,89 (s, 1H).

Example 16(53)

2-(2-((2R)-2-Octylamine-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf value of 0.52 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ of 0.85 (t, J=6,90 Hz, 3H), of 1.27 (m, 10H), to 1.79 (m, 2H), 2,33 (m, 3H), of 2.51 (m, 1H), 2,88 (m, 1H), 3,09 (m, 2H), and 3.31 (m, 2H), 3,68 (m, 3H), to 4.41 (m, 1H), 7,82 (s, 1H).

Example 16(54)

2-(2-((2R)-2-Nonlaminated-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf value of 0.52 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ 0,86 (t, J=6,90 Hz, 3H), 1,25 (m, N), to 1.79 (m, 2H), 2,32 (m, 3H), of 2.51 (m, 1H), 2,90 (m, 1H), is 3.08 (m, 2H), and 3.31 (m, 2H), 3,66 (m, 3H), and 4.40 (m, 1H), a 7.85 (s,1H).

Example 16(55)

2-(2-((2R)-2-((1S)-1-Cyclohexylethylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,46 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ 1,08 (m, 5H), of 1.35 (d, J=to 6.80 Hz, 3H), 1,72 (m, 6N), 2,31 (m, 3H), 2,48 (m, 1H), 2,80 (m, 1H), 3,29 (m, 3H), 3,52 (m, 1H), 3,65 (m, 1H), 3,82 (m, 1H), 4.53-in (m, 1H), 7,83 (s, 1H).

Example 16(56)

2-(2-((2R)-2-(Adamantane-1-ylmethyl)amino)methyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,49 (methylene chloride:methanol:water=40:10:1);

1H-NMR (CDCl3): δ was 1.58 (m, N), to 1.86 (m, 3H), 2,35 (m, 3H), 2,53 (m, 1H), 2,72 (s, 2H), 3,23 (m, 3H), to 3.58 (m, 2H), 3,83 (m, 1H), of 4.66 (m, 1H), 7,94 (s, 1H).

Example 16(57)

2-(2-((2R)-2-(3-Chloro-2-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.64 (methylene chloride:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ of 1.97 (m, 1H), 2,18 (s, 3H), of 2.21 (m, 1H), 2,48 (m, 2H), 3,39 (m, 4H)and 3.59 (m, 1H), Android 4.04 (m, 2H), 6,51 (d, J=8,00 Hz, 1H), PC 6.82 (d, J=8,00 Hz, 1H), 7,03 (t, J =8,00 Hz, 1H), of 8.09 (s, 1H).

Example 16(58)

2-(2-((2R)-2-(2,4-Dichlorophenylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,66 (methylene chloride:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), 2,25 (m, 1H), 2.49 USD (m, 2H), 3,40 (m, 4H), to 3.58 (m, 1H), 4,01 (m, 2H), 6,59 (d, J=at 8.60 Hz, 1H), 7,11 (DD, J=8,60, is 2.40 Hz, 1H), 7,27 (m, 1H), 8,10 (s, 1H).

Example 16(59)

2-(2-((2R)-2-(5-Chloro-2-methoxyphenylacetyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,68 (methylene chloride:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), 2,23 (m, 1H), 2,48 (m, 2H), 3,37 (m, 4H), of 3.57 (m, 1H), 3,81 (s, 3H), 4,01 (m, 2H), 6,54 (m, 1H), 6,65 (m, 2H), 8,08 (s, 1H).

Example 16(60)

2-(2-(2R)-2-(4-Bromo-3-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.64 (methylene chloride:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ of 1.92 (m, 1H), 2,22 (m, 1H), 2,30 (s, 3H), 2,46 (m, 2H), 3,42 (m, 5H), to 4.01 (m, 2H), 6,33 (DD, J=8,40, 2,50 Hz, 1H), 6,50 (d, J=2,50 Hz, 1H), 7,28 (m, 1H), 8,10 (s, 1H).

Example 16(61)

2-(2-((2R)-5-Oxo-2-(3-triftormetilfullerenov)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.64 (methylene chloride:methanol:acetic acid=80:20:1);

1H-NMR (CDCl3): δ of 1.94 (m, 1H), 2,23 (m, 1H), 2,48 (m, 2H), 3.45 points (m, 5H), is 4.03 (m, 2H), of 6.71 (m, 1H), 6.87 in (m, 1H), 7,00 (m, 1H), 7,20 (t, J=7,80 Hz, 1H), 8,11 (s, 1H).

Examples 17(1)-17(345)

According to the method of example 15→example 16 using the appropriate derived amine instead of n-heptylamine receive the following compounds of the present invention, provided that the following compounds are extracted by the method of backward extraction or ion exchange resins.

Example 17(1)

2-(2-((2R)-2-(Naphthalene-1-ylmethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: is 3.08 minutes;

MS data (ESI, I promise. 20V): 442 (M+N)+.

Example 17(2)

2-(2-((2R)-2-(2-(Morpholine-4-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,70 minutes;

MS data (ESI, I promise. 20V): 415 (M+N)+.

Example 17(3)

2-(2-((2R)-2-(N,N-bis(3-Methylbutyl)aminomethyl)-5-ocsober is lidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,18 minutes;

MS data (ESI, I promise. 20V): 442 (M+N)+.

Example 17(4)

2-(2-((2R)-2-(Asokan-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,90 minutes;

MS data (ESI, I promise. 20V): 398 (M+N)+.

Example 17(5)

2-(2-((2R)-2-(N-(2-Diethylaminoethyl)-N-ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,78 minutes;

MS data (ESI, I promise. 20V): 429 (M+N)+.

Example 17(6)

2-(2-((2R)-5-Oxo-2-(piperidine-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,79 minutes;

MS data (ESI, I promise. 20V): 370 (M+N)+.

Example 17(7)

2-(2-((2R)-2-(Cyclobutylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,80 minutes;

MS data (ESI, I promise. 20V): 356 (M+N)+.

Example 17(8)

2-(2-((2R)-2-((1S,2R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-ylmethylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,18 minutes;

MS data (ESI, I promise. 20V): 438 (M+N)+.

Example 17(9)

2-(2-((2R)-2-Cyclopentylmethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,85 minutes;

MS data (ESI, OIT. 20V): 370 (M+N)+.

Example 17(10)

2-(2-((2R)-2-(2-Methylcyclohexylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,96 minutes;

MS data (ESI, I promise. 20V): 398 (M+N)+.

Example 17(11)

2-(2-((2R)-2-(3-Methylcyclohexylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,00 minutes;

MS data (ESI, I promise. 20V): 398 (M+N)+.

Example 17(12)

2-(2-((2R)-2-(4-Methylcyclohexylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,00 minutes;

MS data (ESI, I promise. 20V): 398 (M+N)+.

Example 17(13)

2-(2-((2R)-2-Cyclohexylethylamine-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,03 minutes;

MS data (ESI, I promise. 20V): 398 (M+N)+.

Example 17(14)

2-(2-((2R)-2-(2-(1-Methylpyrrolidine-2-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,69 minutes;

MS data (ESI, I promise. 20V): 413 (M+N)+.

Example 17(15)

2-(2-((2R)-2-(1-Ethylpyrrolidin-2-ylmethylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,70 minutes;

MS data (ESI, I promise. 20V): 413 (M+N)+.

Primer(16)

2-(2-((2R)-2-(Furan-2-ylmethylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,85 minutes;

MS data (ESI, I promise. 20V): 382 (M+N)+.

Example 17(17)

2-(2-((2R)-2-(Indan-1-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,98 minutes;

MS data (ESI, I promise. 20V): 418 (M+N)+.

Example 17(18)

2-(2-((2R)-2-(N-(2-Propenyl)-N-cyclohexylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.97 min;

MS data (ESI, I promise. 20V): 424 (M+N)+.

Example 17(19)

2-(2-((2R)-2-Cycloheptylmethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,98 minutes;

MS data (ESI, I promise. 20V): 398 (M+N)+.

Example 17(20)

2-(2-((2R)-5-Oxo-2-(1,2,3,4-tetrahydro-β-carbolin-2-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.04 from minutes;

MS data (ESI, I promise. 20V): 457 (M+N)+.

Example 17(21)

2-(2-((2R)-5-Oxo-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,74 minutes;

MS data (ESI, I promise. 20V): 356 (M+N)+.

Example 17(22)

2-(2-((2R)-5-Oxo-2-(tetrahydrofuran-2-ylmethylamino)p is Raiden-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,81 minutes;

MS data (ESI, I promise. 20V): 386 (M+N)+.

Example 17(23)

2-(2-((2R)-2-(2-(Indol-3-yl)-1-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,06 minutes;

MS data (ESI, I promise. 20V): 459 (M+N)+.

Example 17(24)

2-(2-((2R)-2-(N-(2-(Indol-3-yl)ethyl)-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,05 minutes;

MS data (ESI, I promise. 20V): 459 (M+N)+.

Example 17(25)

2-(2-((2R)-5-Oxo-2-(4-phenylpiperazin-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,02 minutes;

MS data (ESI, I promise. 20V): 447 (M+N)+.

Example 17(26)

2-(2-((2R)-2-(4-Hydroxy-4-phenylpiperidine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,95 minutes;

MS data (ESI, I promise. 20V): 462 (M+N)+.

Example 17(27)

2-(2-((2R)-5-Oxo-2-(pyridine-2-ylmethylamino)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,83 minutes;

MS data (ESI, I promise. 20V): 393 (M+N)+.

Example 17(28)

2-(2-((2R)-5-Oxo-2-(2-(pyridin-2-yl)ethylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,71 mi is by Uta;

MS data (ESI, I promise. 20V): 407 (M+N)+.

Example 17(29)

2-(2-((2R)-5-Oxo-2-(pyridine-3-ylmethylamino)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,66 minutes;

MS data (ESI, I promise. 20V): 393 (M+N)+.

Example 17(30)

2-(2-((2R)-5-Oxo-2-(pyridine-4-ylmethylamino)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,65 minutes;

MS data (ESI, I promise. 20V): 393 (M+N)+.

Example 17(31)

2-(2-((2R)-2-(1-Ethoxycarbonylpyrimidine-4-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,93 minutes;

MS data (ESI, I promise. 20V): 457 (M+N)+.

Example 17(32)

2-(2-((2R)-5-Oxo-2-(2-(piperidine-1-yl)ethylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,73 minutes;

MS data (ESI, I promise. 20V): 413 (M+N)+.

Example 17(33)

2-(2-((2R)-2-(Perhydroxyl-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.97 min;

MS data (ESI, I promise. 20V): 424 (M+N)+.

Example 17(34)

2-(2-((2R)-2-(tert-Butylaminoethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,80 minutes;

MS data (ESI, I promise. 20V): 358 (M+N)+.

<> Example 17(35)

2-(2-((2R)-5-Oxo-2-(1-phenylethylamine)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,98 minutes;

MS data (ESI, I promise. 20V): 406 (M+N)+.

Example 17(36)

2-(2-((2R)-2-(1,2-Dimethylpropylene)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.88 min;

MS data (ESI, I promise. 20V): 372 (M+N)+.

Example 17(37)

2-(2-((2R)-2-(2-Methoxy-1-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,80 minutes;

MS data (ESI, I promise. 20V): 374 (M+N)+.

Example 17(38)

2-(2-((2R)-2-(1,3-Dimethylbutylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,98 minutes;

MS data (ESI, I promise. 20V): 386 (M+N)+.

Example 17(39)

2-(2-((2R)-2-(1-Methylpropylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,83 minutes;

MS data (ESI, I promise. 20V): 358 (M+N)+.

Example 17(40)

2-(2-((2R)-2-(1-Ethylpropylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.88 min;

MS data (ESI, I promise. 20V): 372 (M+N)+.

Example 17(41)

2-(2-((2R)-2-(1-Methylbutylamine)-5-oxopyrrolidin the-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,93 minutes;

MS data (ESI, I promise. 20V): 372 (M+N)+.

Example 17(42)

2-(2-((2R)-2-(2-Methoxybenzylidene)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.97 min;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(43)

2-(2-((2R)-2-(2-Methylbenzylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,99 minutes;

MS data (ESI, I promise. 20V): 406 (M+N)+.

Example 17(44)

2-(2-((2R)-2-(3-Methoxybenzylidene)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.97 min;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(45)

2-(2-((2R)-2-(4-Chlorobenzylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.04 from minutes;

MS data (ESI, I promise. 20V): 426 (M+N)+.

Example 17(46)

2-(2-((2R)-2-(4-Methoxybenzylidene)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,96 minutes;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(47)

2-(2-((2R)-2-(4-Methylbenzylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,00 minutes;

MS data (ESI, I promise. 20V): 406 (MH) +.

Example 17(48)

2-(2-((2R)-2-(2,2-Dimethylpropanoyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.91 in minutes.

MS data (ESI, I promise. 20V): 372 (M+N)+.

Example 17(49)

2-(2-((2R)-2-(2-Methylpropylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,83 minutes;

MS data (ESI, I promise. 20V): 358 (M+N)+.

Example 17(50)

2-(2-((2R)-2-(2-Veretrainer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,70 minutes;

MS data (ESI, I promise. 20V): 348 (M+N)+.

Example 17(51)

2-(2-((2R)-2-(2-Phenylenediamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,01 minutes;

MS data (ESI, I promise. 20V): 421 (M+N)+.

Example 17(52)

2-(2-((2R)-2-(N-(2-Diethylaminoethyl)-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,73 minutes;

MS data (ESI, I promise. 20V): 415 (M+N)+.

Example 17(53)

2-(2-((2R)-2-(2-Methoxyethylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,77 minutes;

MS data (ESI, I promise. 20V): 360 (M+N)+.

Example 17(54)

2-(2-((2R)-2-(2-(4-Were)atrami the said;")-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,09 minutes;

MS data (ESI, I promise. 20V): 420 (M+N)+.

Example 17(55)

2-(2-((2R)-2-(4-Phenylbutanoate)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,16 minutes;

MS data (ESI, I promise. 20V): 434 (M+N)+.

Example 17(56)

2-(2-((2R)-2-(Pentylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.97 min;

MS data (ESI, I promise. 20V): 372 (M+N)+.

Example 17(57)

2-(2-((2R)-2-(N-Benzyl-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,94 minutes;

MS data (ESI, I promise. 20V): 406 (M+N)+.

Example 17(58)

2-(2-((2R)-2-(N-Methyl-N-(2-phenylethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,02 minutes;

MS data (ESI, I promise. 20V): 420 (M+N)+.

Example 17(59)

2-(2-((2R)-2-(N-Benzyl-N-isopropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,96 minutes;

MS data (ESI, I promise. 20V): 434 (M+N)+.

Example 17(60)

2-(2-((2R)-2-(N,N-bis(2-methylpropyl " aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.97 min;

MS data (ESI, polozhitb): 414 (M+N) +.

Example 17(61)

2-(2-((2R)-2-(N-Benzyl-N-ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,96 minutes;

MS data (ESI, I promise. 20V): 420 (M+N)+.

Example 17(62)

2-(2-((2R)-2-(N,N-Diethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: was 2.76 min;

MS data (ESI, I promise. 20V): 358 (M+N)+.

Example 17(63)

2-(2-((2R)-2-(N-Methyl-N-propylaminoethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,81 minutes;

MS data (ESI, I promise. 20V): 358 (M+N)+.

Example 17(64)

2-(2-((2R)-2-(N,N-Dipropylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.88 min;

MS data (ESI, I promise. 20V): 386 (M+N)+.

Example 17(65)

2-(2-((2R)-2-(N-Benzyl-N-butylaminoethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: is 3.08 minutes;

MS data (ESI, I promise. 20V): 448 (M+N)+.

Example 17(66)

2-(2-((2R)-2-Butylaminoethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.88 min;

MS data (ESI, I promise. 20V): 358 (M+N)+.

Example 17(67)

2-(2-((2R)-2-(2-(1-Cyclohexen-1-yl)ethylaminomethyl)-5-oxopyrrolidin the n-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,09 minutes;

MS data (ESI, I promise. 20V): 410 (M+N)+.

Example 17(68)

2-(2-((2R)-2-(Cyclopropanemethylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,82 minutes;

MS data (ESI, I promise. 20V): 356 (M+N)+.

Example 17(69)

2-(2-((2R)-2-(4-tert-Butylcyclohexylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,23 minutes;

MS data (ESI, I promise. 20V): 440 (M+N)+.

Example 17(70)

2-(2-((2R)-2-(1-Propylethylene)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,06 minutes;

MS data (ESI, I promise. 20V): 400 (M+N)+.

Example 17(71)

2-(2-((2R)-2-(N-Methyl-N-(2-methylpropyl " aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,85 minutes;

MS data (ESI, I promise. 20V): 372 (M+N)+.

Example 17(72)

2-(2-((2R)-2-(N-Ethyl-N-propylaminoethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,81 minutes;

MS data (ESI, I promise. 20V): 372 (M+N)+.

Example 17(73)

2-(2-((2R)-2-(N-Ethyl-N-(pyridine-4-ylmethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,78 minutes;

<> MS data (ESI, I promise. 20V): 421 (M+N)+.

Example 17(74)

2-(2-((2R)-2-(2-(N-Ethyl-N-(3-were))ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,09 minutes;

MS data (ESI, I promise. 20V): 463 (M+N)+.

Example 17(75)

2-(2-((2R)-2-(2-(Pyridin-4-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,66 minutes;

MS data (ESI, I promise. 20V): 407 (M+N)+.

Example 17(76)

2-(2-((2R)-2-(4-tert-Butylbenzylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,21 minutes;

MS data (ESI, I promise. 20V): 448 (M+N)+.

Example 17(77)

2-(2-((2R)-2-(3-Methylthiopropionate)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.88 min;

MS data (ESI, I promise. 20V): 390 (M+N)+.

Example 17(78)

2-(2-((2R)-2-(N-Methyl-N-isopropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: was 2.76 min;

MS data (ESI, I promise. 20V): 358 (M+N)+.

Example 17(79)

2-(2-((2R)-2-Isopropylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: was 2.76 min;

MS data (ESI, I promise. 20V): 344 (M+N)+.

Note the p 17(80)

2-(2-((2R)-2-(2-(Thiophene-2-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,96 minutes;

MS data (ESI, I promise. 20V): 412 (M+N)+.

Example 17(81)

2-(2-((2R)-2-(2-tert-Butyldimethylsilyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,02 minutes;

MS data (ESI, I promise. 20V): 418 (M+N)+.

Example 17(82)

2-(2-((2R)-2-(1-Benzylpyrrolidine-3-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.86 min;

MS data (ESI, I promise. 20V): 461 (M+N)+.

Example 17(83)

2-(2-((2R)-2-(N-(2-Propenyl)-N-cyclopentylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,89 minutes;

MS data (ESI, I promise. 20V): 410 (M+N)+.

Example 17(84)

2-(2-((2R)-2-(5-Methylfuran-2-ylmethylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,93 minutes;

MS data (ESI, I promise. 20V): 396 (M+N)+.

Example 17(85)

2-(2-((2R)-2-(2-(Pyridin-3-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,67 minutes;

MS data (ESI, I promise. 20V): 407 (M+N)+.

Example 17(86)

2-(2-((2R)-2-((2R)-2-Phenylpropylamine the said;")-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,02 minutes;

MS data (ESI, I promise. 20V): 420 (M+N)+.

Example 17(87)

2-(2-((2R)-2-(Pyrazole-3-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,81 minutes;

MS data (ESI, I promise. 20V): 368 (M+N)+.

Example 17(88)

2-(2-((2R)-2-(1,2,3,6-Tetrahydropyridine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: was 2.76 min;

MS data (ESI, I promise. 20V): 368 (M+N)+.

Example 17(89)

2-(2-((2R)-2-(2-Verbentrainer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,93 minutes;

MS data (ESI, I promise. 20V): 410 (M+N)+.

Example 17(90)

2-(2-((2R)-2-(3-Verbentrainer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,96 minutes;

MS data (ESI, I promise. 20V): 410 (M+N)+.

Example 17(91)

2-(2-((2R)-2-(2-Phenylpropylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,03 minutes;

MS data (ESI, I promise. 20V): 420 (M+N)+.

Example 17(92)

2-(2-((2R)-2-(2,5-Differentiability)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,96 minutes;

MS data (ESI, I promise. 20V): 428 (IS+M) +.

Example 17(93)

2-(2-((2R)-2-(1-Aripirazole-5-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,80 minutes;

MS data (ESI, I promise. 20V): 396 (M+N)+.

Example 17(94)

2-(2-((2R)-2-(2-Ethyldiethanolamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,90 minutes;

MS data (ESI, I promise. 20V): 390 (M+N)+.

Example 17(95)

2-(2-((2R)-2-(N-(3-Dimethylaminopropyl)-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,63 minutes;

MS data (ESI, I promise. 20V): 401 (M+N)+.

Example 17(96)

2-(2-((2R)-2-(2-(2-Forfinal)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,02 minutes;

MS data (ESI, I promise. 20V): 424 (M+N)+.

Example 17(97)

2-(2-((2R)-2-Cyclooctylamino-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,06 minutes;

MS data (ESI, I promise. 20V): 412 (M+N)+.

Example 17(98)

2-(2-((2R)-2-(3-Pyrrolin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,73 minutes;

MS data (ESI, I promise. 20V): 354 (M+N)+.

Example 17(99)

2-(2-((2R)-2-(2-Methylpiperidin-1-ILM is Teal)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,79 minutes;

MS data (ESI, I promise. 20V): 384 (M+N)+.

Example 17(100)

2-(2-((2R)-2-(3-Methylpiperidin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.86 min;

MS data (ESI, I promise. 20V): 384 (M+N)+.

Example 17(101)

2-(2-((2R)-2-(4-Methylpiperidin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.86 min;

MS data (ESI, I promise. 20V): 384 (M+N)+.

Example 17(102)

2-(2-((2R)-2-(3-(Morpholine-4-yl)propylaminoethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,67 minutes;

MS data (ESI, I promise. 20V): 429 (M+N)+.

Example 17(103)

2-(2-((2R)-2-(Azepin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,84 minutes;

MS data (ESI, I promise. 20V): 384 (M+N)+.

Example 17(104)

2-(2-((2R)-2-(1,1,3,3-Tetramethylbutylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,06 minutes;

MS data (ESI, I promise. 20V): 414 (M+N)+.

Example 17(105)

2-(2-((2R)-2-(1,1-Dimethylpropylene)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,85 minutes;

MS data (ESI, Polo is it. 20V): 372 (M+N)+.

Example 17(106)

2-(2-((2R)-2-(1-Methyl-3-phenylpropylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,10 minutes;

MS data (ESI, I promise. 20V): 434 (M+N)+.

Example 17(107)

2-(2-((2R)-2-(1,5-Dimethylhexylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,18 minutes;

MS data (ESI, I promise. 20V): 414 (M+N)+.

Example 17(108)

2-(2-((2R)-2-(1-Methylhexanamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,09 minutes;

MS data (ESI, I promise. 20V): 400 (M+N)+.

Example 17(109)

2-(2-((2R)-2-(1-Methylheptadecyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,20 minutes;

MS data (ESI, I promise. 20V): 414 (M+N)+.

Example 17(110)

2-(2-((2R)-2-(2-Chlorobenzylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,96 minutes;

MS data (ESI, I promise. 20V): 426 (M+N)+.

Example 17(111)

2-(2-((2R)-2-(4-Verbentrainer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,98 minutes;

MS data (ESI, I promise. 20V): 410 (M+N)+.

Example 17(112)

2-(2-((2R)-2-(2-Ethylhexyl Enomatic)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,18 minutes;

MS data (ESI, I promise. 20V): 414 (M+N)+.

Example 17(113)

2-(2-((2R)-2-(2-Diethylaminoethylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,65 minutes;

MS data (ESI, I promise. 20V): 373 (M+N)+.

Example 17(114)

2-(2-((2R)-2-(2-Propylaminoethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,74 minutes;

MS data (ESI, I promise. 20V): 340 (M+N)+.

Example 17(115)

2-(2-((2R)-2-(2-Propylaminoethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: was 2.76 min;

MS data (ESI, I promise. 20V): 342 (M+N)+.

Example 17(116)

2-(2-((2R)-2-(3-Methylbutanoyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,95 minutes;

MS data (ESI, I promise. 20V): 372 (M+N)+.

Example 17(117)

2-(2-((2R)-2-(3-Dimethylaminopropylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,64 minutes;

MS data (ESI, I promise. 20V): 387 (M+N)+.

Example 17(118)

2-(2-((2R)-2-(3-Ethoxypropylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.86 min;

MS data (ESI, I promise. 20V):388 (M+N) +.

Example 17(119)

2-(2-((2R)-2-Octylamine-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.25 min;

MS data (ESI, I promise. 20V): 414 (M+N)+.

Example 17(120)

2-(2-((2R)-2-Nonlaminated-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,34 minutes;

MS data (ESI, I promise. 20V): 428 (M+N)+.

Example 17(121)

2-(2-((2R)-2-(2,6-Differentiability)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,93 minutes;

MS data (ESI, I promise. 20V): 428 (M+N)+.

Example 17(122)

2-(2-((2R)-2-(3-Methoxypropylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,81 minutes;

MS data (ESI, I promise. 20V): 374 (M+N)+.

Example 17(123)

2-(2-((2R)-2-(3-Butoxyphenyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,05 minutes;

MS data (ESI, I promise. 20V): 416 (M+N)+.

Example 17(124)

2-(2-((2R)-2-(N,N-bis(2-Methoxyethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,83 minutes;

MS data (ESI, I promise. 20V): 418 (M+N)+.

Example 17(125)

2-(2-((2R)-2-(3-Chlorobenzylamino)-5-oxopyrrolidin the-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,03 minutes;

MS data (ESI, I promise. 20V): 426 (M+N)+.

Example 17(126)

2-(2-((2R)-2-(3-Dimethylamino-2,2-dimethylpropanoyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,69 minutes;

MS data (ESI, I promise. 20V): 415 (M+N)+.

Example 17(127)

2-(2-((2R)-2-(4-Methyl-1,4-diazepan-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,66 minutes;

MS data (ESI, I promise. 20V): 399 (M+N)+.

Example 17(128)

2-(2-((2R)-2-(4-Ethylpiperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,75 minutes;

MS data (ESI, I promise. 20V): 399 (M+N)+.

Example 17(129)

2-(2-((2R)-2-((1S)-1-Cyclohexylethylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,06 minutes;

MS data (ESI, I promise. 20V): 412 (M+N)+.

Example 17(130)

2-(2-((2R)-2-(5-Methylpyrazole-3-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,85 minutes;

MS data (ESI, I promise. 20V): 382 (M+N)+.

Example 17(131)

2-(2-((2R)-2-((1R)-1-(4-Were)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.04 from m the chickpeas;

MS data (ESI, I promise. 20V): 420 (M+N)+.

Example 17(132)

2-(2-((2R)-2-(1-Ethynylcyclohexanol)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,96 minutes;

MS data (ESI, I promise. 20V): 408 (M+N)+.

Example 17(133)

2-(2-((2R)-2-(2,6-Dimethylmorpholine-4-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,81 minutes;

MS data (ESI, I promise. 20V): 400 (M+N)+.

Example 17(134)

2-(2-((2R)-2-(N-Methyl-N-(2-(pyridin-2-yl)ethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,73 minutes;

MS data (ESI, I promise. 20V): 421 (M+N)+.

Example 17(135)

2-(2-((2R)-2-(N-Methyl-N-(1-methylpiperidin-4-yl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,61 minutes;

MS data (ESI, I promise. 20V): 413 (M+N)+.

Example 17(136)

2-(2-((2R)-2-(1,1-Diethyl-2-propylaminoethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.91 in minutes.

MS data (ESI, I promise. 20V): 396 (M+N)+.

Example 17(137)

2-(2-((2R)-2-(N-Ethyl-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,71 minutes;

MS data (ESI, I promise. 20V: 344 (M+N) +.

Example 17(138)

2-(2-((2R)-2-(N-Ethyl-N-(2-methyl-2-propenyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,78 minutes;

MS data (ESI, I promise. 20V): 384 (M+N)+.

Example 17(139)

2-(2-((2R)-2-(1-(4-Forfinal)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,01 minutes;

MS data (ESI, I promise. 20V): 424 (M+N)+.

Example 17(140)

2-(2-((2R)-2-((1R,2R,4S)-Bicyclo[2.2.1]hept-2-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,95 minutes;

MS data (ESI, I promise. 20V): 396 (M+N)+.

Example 17(141)

2-(2-((2R)-2-((2S)-2-Methoxypiperidine-1-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,83 minutes;

MS data (ESI, I promise. 20V): 400 (M+N)+.

Example 17(142)

2-(2-((2R)-2-(1,2,4-Triazole-4-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,79 minutes;

MS data (ESI, I promise. 20V): 369 (M+N)+.

Example 17(143)

2-(2-((2R)-2-(1-Methylbenzimidazole-2-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,93 minutes;

MS data (ESI, I promise. 20V): 432 (M+N)+.

When is EP 17(144)

2-(2-((2R)-5-Oxo-2-(5-phenylpyrazol-3-illuminometer)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,03 minutes;

MS data (ESI, I promise. 20V): 444 (M+N)+.

Example 17(145)

2-(2-((2R)-5-Oxo-2-(thiophene-2-ylmethylamino)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,89 minutes;

MS data (ESI, I promise. 20V): 398 (M+N)+.

Example 17(146)

2-(2-((2R)-2-(2-(4-Aminosulphonylphenyl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,85 minutes;

MS data (ESI, I promise. 20V): 485 (M+N)+.

Example 17(147)

2-(2-((2R)-2-(Adamantane-1-ylmethyl)amino)methyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,18 minutes;

MS data (ESI, I promise. 20V): 450 (M+N)+.

Example 17(148)

2-(2-((2R)-2-(4-Aminosulphonylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,83 minutes;

MS data (ESI, I promise. 20V): 471 (M+N)+.

Example 17(149)

2-(2-((2R)-2-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,93 minutes;

MS data (ESI, I promise. 20V): 478 (M+N)+.

Example 17(150)

2-(2-((2's)-2-(6,7-Hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,81 minutes;

MS data (ESI, I promise. 20V): 464 (M+N)+.

Example 17(151)

2-(2-((2R)-2-(2-(3,4-Dihydroxyphenyl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,83 minutes;

MS data (ESI, I promise. 20V): 438 (M+N)+.

Example 17(152)

2-(2-((2R)-5-Oxo-2-(2,2,2-triptoreline)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,89 minutes;

MS data (ESI, I promise. 20V): 384 (M+N)+.

Example 17(153)

2-(2-((2R)-2-(3-Methylbenzylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,01 minutes;

MS data (ESI, I promise. 20V): 406 (M+N)+.

Example 17(154)

2-(2-((2R)-2-(1,4'-Bipiperidine-1'-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,73 minutes;

MS data (ESI, I promise. 20V): 453 (M+N)+.

Example 17(155)

2-(2-((2R)-2-(4-(1,3-Benzodioxol-5-ylmethyl)piperazine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,96 minutes;

MS data (ESI, I promise. 20V): 505 (M+N)+.

Example 17(156)

2-(2-((2R)-5-Oxo-2-(4-(3-triptoreline)piperazine-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Time derivan the HPLC: 3,22 minutes;

MS data (ESI, I promise. 20V): 515 (M+N)+.

Example 17(157)

2-(2-((2R)-2-(4-(4-Methoxyphenyl)piperazine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,01 minutes;

MS data (ESI, I promise. 20V): 477 (M+N)+.

Example 17(158)

2-(2-((2R)-5-Oxo-2-(4-(4-triptoreline)piperazine-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,23 minutes;

MS data (ESI, I promise. 20V): 515 (M+N)+.

Example 17(159)

2-(2-((2R)-2-(N-Methyl-N-(4-(pyridin-3-yl)butyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,75 minutes;

MS data (ESI, I promise. 20V): 449 (M+N)+.

Example 17(160)

2-(2-((2R)-2-(N-Methyl-N-(2-(pyridin-4-yl)ethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.68 min;

MS data (ESI, I promise. 20V): 421 (M+N)+.

Example 17(161)

2-(2-((2R)-2-(N-Methyl-N-(pyridine-3-ylmethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,73 minutes;

MS data (ESI, I promise. 20V): 407 (M+N)+.

Example 17(162)

2-(2-((2R)-2-(N-Methyl-N-(6-methylpyridin-2-ylmethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Time derivarives: 2.91 in minutes;

MS data (ESI, I promise. 20V): 421 (M+N)+.

Example 17(163)

2-(2-((2R)-2-(4-Cyclohexylpiperazine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.91 in minutes.

MS data (ESI, I promise. 20V): 453 (M+N)+.

Example 17(164)

2-(2-((2R)-2-(4-(3-Methoxyphenyl)piperazine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,05 minutes;

MS data (ESI, I promise. 20V): 477 (M+N)+.

Example 17(165)

2-(2-((2R)-2-(4-(2-Methoxyphenyl)piperazine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,02 minutes;

MS data (ESI, I promise. 20V): 477 (M+N)+.

Example 17(166)

2-(2-((2R)-2-(4-(2,4-Acid))piperazine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.04 from minutes;

MS data (ESI, I promise. 20V): 507 (M+N)+.

Example 17(167)

2-(2-((2R)-2-(4-(2,4-Dimetilfenil))piperazine-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,21 minutes;

MS data (ESI, I promise. 20V): 475 (M+N)+.

Example 17(168)

2-(2-((2R)-5-Oxo-2-(4-((2E)-3-phenyl-2-propenyl)piperazine-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,07 mine is s;

MS data (ESI, I promise. 20V): 487 (M+N)+.

Example 17(169)

2-(2-((2R)-5-Oxo-2-(4-(2-oxo-2-pyrrolidin-1-retil)piperazine-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,84 minutes;

MS data (ESI, I promise. 20V): 482 (M+N)+.

Example 17(170)

2-(2-((2R)-2-(4-Ethoxycarbonylmethyl-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,89 minutes;

MS data (ESI, I promise. 20V): 443 (M+N)+.

Example 17(171)

2-(2-((2R)-5-Oxo-2-(4-(4-oxo-1-phenyl-1,3,8-diazaspiro[4.5]decane-8-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,01 minutes;

MS data (ESI, I promise. 20V): 516 (M+N)+.

Example 17(172)

2-(2-((2R)-5-Oxo-2-(4-(5-triptorelin-2-yl)-1,4-diazepan-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,15 minutes;

MS data (ESI, I promise. 20V): 530 (M+N)+.

Example 17(173)

2-(2-((2R)-2-(N-(2-(3,4-Acid)ethyl)-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,98 minutes;

MS data (ESI, I promise. 20V): 480 (M+N)+.

Example 17(174)

2-(2-((2R)-2-(N-Benzyl-N-(2-cyanoethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

p> Retention time HPLC: 3,18 minutes;

MS data (ESI, I promise. 20V): 445 (M+N)+.

Example 17(175)

2-(2-((2R)-2-(N-Benzyl-N-(2-dimethylaminoethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,03 minutes;

MS data (ESI, I promise. 20V): 463 (M+N)+.

Example 17(176)

2-(2-((2R)-2-(N-(Furan-2-ylmethyl)-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.88 min;

MS data (ESI, I promise. 20V): 396 (M+N)+.

Example 17(177)

2-(2-((2R)-2-(N-Ethyl-N-(4-hydroxybutyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,77 minutes;

MS data (ESI, I promise. 20V): 402 (M+N)+.

Example 17(178)

2-(2-((2R)-2-(N,N-bis(2-Ethoxyethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,00 minutes;

MS data (ESI, I promise. 20V): 446 (M+N)+.

Example 17(179)

2-(2-((2R)-2-(N-(2-Cyanoethyl)-N-ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,79 minutes;

MS data (ESI, I promise. 20V): 383 (M+N)+.

Example 17(180)

2-(2-((2R)-2-(N-(2-Methoxyethyl)-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Time derivan the HPLC: 2,80 minutes;

MS data (ESI, I promise. 20V): 374 (M+N)+.

Example 17(181)

2-(2-((2R)-2-(6-Methoxy-1,2,3,4-tetrahydro-β-carbolin-2-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,03 minutes;

MS data (ESI, I promise. 20V): 487 (M+N)+.

Example 17(182)

2-(2-((2R)-2-(3,4-Dihydropyrido[4,3-b]-1,6-naphthiridine-2-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,74 minutes;

MS data (ESI, I promise. 20V): 470 (M+N)+.

Example 17(183)

2-(2-((2R)-2-Phenyliminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,20 minutes;

MS data (ESI, I promise. 20V): 378 (M+N)+.

Example 17(184)

2-(2-((2R)-2-(2-Methoxyphenylacetyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,18 minutes;

MS data (ESI, I promise. 20V): 408 (M+N)+.

Example 17(185)

2-(2-((2R)-2-(2-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,35 minutes;

MS data (ESI, I promise. 20V): 392 (M+N)+.

Example 17(186)

2-(2-((2R)-2-(2,3-Dimethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,34 minutes;

MS data (ESI, I promise. 20V): 406 (M+N) +.

Example 17(187)

2-(2-((2R)-2-(2,4-Dimethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.33 min;

MS data (ESI, I promise. 20V): 406 (M+N)+.

Example 17(188)

2-(2-((2R)-2-(2,5-Dimethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,43 minutes;

MS data (ESI, I promise. 20V): 406 (M+N)+.

Example 17(189)

2-(2-((2R)-2-(2,6-Dimethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.13 min;

MS data (ESI, I promise. 20V): 406 (M+N)+.

Example 17(190)

2-(2-((2R)-2-(3-Methoxyphenylacetyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,26 minutes;

MS data (ESI, I promise. 20V): 408 (M+N)+.

Example 17(191)

2-(2-((2R)-2-(3-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,26 minutes;

MS data (ESI, I promise. 20V): 392 (M+N)+.

Example 17(192)

2-(2-((2R)-2-(3,4-Dimethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,19 minutes;

MS data (ESI, I promise. 20V): 406 (M+N)+.

Example 17(193)

2-(2-((2R)-2-(4-Chlorpheniramine)-5-OK who pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.46 in minutes.

MS data (ESI, I promise. 20V): 412 (M+N)+.

Example 17(194)

2-(2-((2R)-2-(4-Diethylaminobenzylidene)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,93 minutes;

MS data (ESI, I promise. 20V): 449 (M+N)+.

Example 17(195)

2-(2-((2R)-2-(4-Methyldiphenylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,38 minutes;

MS data (ESI, I promise. 20V): 424 (M+N)+.

Example 17(196)

2-(2-((2R)-2-(4-tert-Butylphenylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,51 minutes;

MS data (ESI, I promise. 20V): 434 (M+N)+.

Example 17(197)

2-(2-((2R)-2-(4-Isopropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,40 minutes;

MS data (ESI, I promise. 20V): 420 (M+N)+.

Example 17(198)

2-(2-((2R)-2-(4-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,16 minutes;

MS data (ESI, I promise. 20V): 392 (M+N)+.

Example 17(199)

2-(2-((2R)-2-(2,4-Dimethoxyphenylacetic)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,98 minutes;

MS data (ESI, ologit. 20V): 438 (M+N)+.

Example 17(200)

2-(2-((2R)-2-(3,4-Dimethoxyphenylacetic)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,98 minutes;

MS data (ESI, I promise. 20V): 438 (M+N)+.

Example 17(201)

2-(2-((2R)-2-(4-Isopropoxyphenyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,16 minutes;

MS data (ESI, I promise. 20V): 436 (M+N)+.

Example 17(202)

2-(2-((2R)-2-(2-tert-Butylphenylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,71 minutes;

MS data (ESI, I promise. 20V): 434 (M+N)+.

Example 17(203)

2-(2-((2R)-2-(2-Fluoro-5-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.46 in minutes.

MS data (ESI, I promise. 20V): 410 (M+N)+.

Example 17(204)

2-(2-((2R)-2-(2-Chloro-6-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,48 minutes;

MS data (ESI, I promise. 20V): 426 (M+N)+.

Example 17(205)

2-(2-((2R)-2-(4-Methoxy-2-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,09 minutes;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(206)

u> 2-(2-((2R)-2-(3,5-Differentiability)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.46 in minutes.

MS data (ESI, I promise. 20V): 414 (M+N)+.

Example 17(207)

2-(2-((2R)-2-(3-Ethoxyphenylacetic)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,36 minutes;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(208)

2-(2-((2R)-2-(3-(1-Hydroxyethyl)phenyliminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,05 minutes;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(209)

2-(2-((2R)-2-(3-Hydroxyethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,00 minutes;

MS data (ESI, I promise. 20V): 408 (M+N)+.

Example 17(210)

2-(2-((2R)-2-(4-fluoro-2-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,41 minutes;

MS data (ESI, I promise. 20V): 410 (M+N)+.

Example 17(211)

2-(2-((2R)-2-(4-Cyanomethylene)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,21 minutes;

MS data (ESI, I promise. 20V): 417 (M+N)+.

Example 17(212)

2-(2-((2R)-2-(3-Hydroxymethyl-2-Methylpheniltiomethyl)-5-cooperrider-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,05 minutes;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(213)

2-(2-((2R)-2-(5-Methoxy-2-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,37 minutes;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(214)

2-(2-((2R)-2-(2-methoxy-6-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,00 minutes;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(215)

2-(2-((2R)-2-(2-Cyanomethylene)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.33 min;

MS data (ESI, I promise. 20V): 417 (M+N)+.

Example 17(216)

2-(2-((2R)-5-oxo-2-(5,6,7,8-Tetrahydronaphthalen-1-illuminometer)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: to 3.58 minutes;

MS data (ESI, I promise. 20V): 432 (M+N)+.

Example 17(217)

2-(2-((2R)-2-(Indan-5-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,23 minutes;

MS data (ESI, I promise. 20V): 418 (M+N)+.

Example 17(218)

2-(2-((2R)-2-(1,3-Benzodioxol-5-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.07 minutes is;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(219)

2-(2-((2R)-5-Oxo-2-(quinoline-5-illuminometer)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.91 in minutes.

MS data (ESI, I promise. 20V): 429 (M+N)+.

Example 17(220)

2-(2-((2R)-5-Oxo-2-(quinoline-6-illuminometer)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,89 minutes;

MS data (ESI, I promise. 20V): 429 (M+N)+.

Example 17(221)

2-(2-((2R)-5-Oxo-2-(quinoline-8-illuminometer)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: is 3.08 minutes;

MS data (ESI, I promise. 20V): 429 (M+N)+.

Example 17(222)

2-(2-((2R)-2-(2-Cyanovinylene)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,31 minutes;

MS data (ESI, I promise. 20V): 403 (M+N)+.

Example 17(223)

2-(2-((2R)-2-(2-Tortenelmietlen)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,37 minutes;

MS data (ESI, I promise. 20V): 396 (M+N)+.

Example 17(224)

2-(2-((2R)-2-(2,4-Differentiability)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,41 minutes;

MS data (ESI, I promise. 20V): 414 (M+N)+.

Example 17(225)

2-(2-((2R)-5-OK, what about the-2-(2,4,5-cryptorhynchinae)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,44 minutes;

MS data (ESI, I promise. 20V): 432 (M+N)+.

Example 17(226)

2-(2-((2R)-5-Oxo-2-(2,4,6-cryptorhynchinae)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,43 minutes;

MS data (ESI, I promise. 20V): 432 (M+N)+.

Example 17(227)

2-(2-((2R)-2-(2,5-Differentiability)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,41 minutes;

MS data (ESI, I promise. 20V): 414 (M+N)+.

Example 17(228)

2-(2-((2R)-2-(2,6-Differentiability)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,38 minutes;

MS data (ESI, I promise. 20V): 414 (M+N)+.

Example 17(229)

2-(2-((2R)-2-(2-Chlorpheniramine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.46 in minutes.

MS data (ESI, I promise. 20V): 412 (M+N)+.

Example 17(230)

2-(2-((2R)-2-(2-Ethoxyphenylacetic)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,28 minutes;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(231)

2-(2-((2R)-2-(2-Methyldiphenylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,50 minutes;

MS data (ESI, I promise. 20V): 44 (M+N) +.

Example 17(232)

2-(2-((2R)-2-(2-Isopropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,55 minutes;

MS data (ESI, I promise. 20V): 420 (M+N)+.

Example 17(233)

2-(2-((2R)-2-(2,4,6-Trimethylaminoethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,15 minutes;

MS data (ESI, I promise. 20V): 420 (M+N)+.

Example 17(234)

2-(2-((2R)-2-(2-Isopropyl-6-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,35 minutes;

MS data (ESI, I promise. 20V): 434 (M+N)+.

Example 17(235)

2-(2-((2R)-2-(2-Ethylenediaminetetra)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,48 minutes;

MS data (ESI, I promise. 20V): 406 (M+N)+.

Example 17(236)

2-(2-((2R)-2-(2-Ethyl-6-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,27 minutes;

MS data (ESI, I promise. 20V): 420 (M+N)+.

Example 17(237)

2-(2-((2R)-2-(2,6-Diethylaniline)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,40 minutes;

MS data (ESI, I promise. 20V): 434 (M+N)+.

Example 17(238)

2-(2-((2R)-2-(3-Cyanophenyl Enomatic)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,31 minutes;

MS data (ESI, I promise. 20V): 403 (M+N)+.

Example 17(239)

2-(2-((2R)-2-(3-Tortenelmietlen)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,38 minutes;

MS data (ESI, I promise. 20V): 396 (M+N)+.

Example 17(240)

2-(2-((2R)-2-(3,4-Differentiability)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,43 minutes;

MS data (ESI, I promise. 20V): 414 (M+N)+.

Example 17(241)

2-(2-((2R)-2-(5-fluoro-2-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,48 minutes;

MS data (ESI, I promise. 20V): 410 (M+N)+.

Example 17(242)

2-(2-((2R)-2-(3-Chlorpheniramine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,48 minutes;

MS data (ESI, I promise. 20V): 412 (M+N)+.

Example 17(243)

2-(2-((2R)-2-(3-Chloro-2-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,57 minutes;

MS data (ESI, I promise. 20V): 426 (M+N)+.

Example 17(244)

2-(2-((2R)-2-(3-Chloro-4-tortenelmietlen)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,50 minutes;

MS data (ESI, polozhitb): 430 (M+N) +.

Example 17(245)

2-(2-((2R)-2-(3-Chloro-4-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,56 minutes;

MS data (ESI, I promise. 20V): 426 (M+N)+.

Example 17(246)

2-(2-((2R)-2-(3,5-Dimethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.32 minutes;

MS data (ESI, I promise. 20V): 406 (M+N)+.

Example 17(247)

2-(2-((2R)-2-(2-Methoxy-5-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.25 min;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(248)

2-(2-((2R)-2-(3-Ethylenediaminetetra)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,38 minutes;

MS data (ESI, I promise. 20V): 406 (M+N)+.

Example 17(249)

2-(2-((2R)-2-(4-Tortenelmietlen)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,26 minutes;

MS data (ESI, I promise. 20V): 396 (M+N)+.

Example 17(250)

2-(2-((2R)-2-(4-Chloro-2-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,57 minutes;

MS data (ESI, I promise. 20V): 426 (M+N)+.

Example 17(251)

2-(2-((2R)-2-(4-Nitrophenylamino the Teal)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,29 minutes;

MS data (ESI, I promise. 20V): 423 (M+N)+.

Example 17(252)

2-(2-((2R)-2-(4-Ethoxyphenylacetic)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,09 minutes;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(253)

2-(2-((2R)-2-(4-Ethylenediaminetetra)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,31 minutes;

MS data (ESI, I promise. 20V): 406 (M+N)+.

Example 17(254)

2-(2-((2R)-2-(4-(2-Hydroxyethyl)phenyliminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,95 minutes;

MS data (ESI, I promise. 20V): 422 (M+N)+.

Example 17(255)

2-(2-((2R)-5-Oxo-2-(4-propylpentanoate)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,44 minutes;

MS data (ESI, I promise. 20V): 420 (M+N)+.

Example 17(256)

2-(2-((2R)-2-(4-Butylphenylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,56 minutes;

MS data (ESI, I promise. 20V): 434 (M+N)+.

Example 17(257)

2-(2-((2R)-5-Oxo-2-(2-propylpentanoate)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,61 minutes;

MS data (ESI, I promise. 20V): 40 (M+N) +.

Example 17(258)

2-(2-((2R)-2-(4-(1-methylpropyl " phenyliminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,53 minutes;

MS data (ESI, I promise. 20V): 434 (M+N)+.

Example 17(259)

2-(2-((2R)-2-(4-Chloro-2-tortenelmietlen)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,52 minutes;

MS data (ESI, I promise. 20V): 430 (M+N)+.

Example 17(260)

2-(2-((2R)-5-Oxo-2-(2,3,4-cryptorhynchinae)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,48 minutes;

MS data (ESI, I promise. 20V): 432 (M+N)+.

Example 17(261)

2-(2-((2R)-2-(2-Butylphenylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,72 minutes;

MS data (ESI, I promise. 20V): 434 (M+N)+.

Example 17(262)

2-(2-((2R)-2-(2-Chloro-4-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,57 minutes;

MS data (ESI, I promise. 20V): 426 (M+N)+.

Example 17(263)

2-(2-((2R)-2-(2-Isopropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,56 minutes;

MS data (ESI, I promise. 20V): 418 (M+N)+.

Example 17(264)

2-(2-((2R)-2-(3-Fluoro-4-methyl shall anilinomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.46 in minutes.

MS data (ESI, I promise. 20V): 410 (M+N)+.

Example 17(265)

2-(2-((2R)-2-(3-Methyldiphenylamine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,43 minutes;

MS data (ESI, I promise. 20V): 424 (M+N)+.

Example 17(266)

2-(2-((2R)-2-(2-(1-methylpropyl " phenyliminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,66 minutes;

MS data (ESI, I promise. 20V): 434 (M+N)+.

Example 17(267)

2-(2-((2R)-2-(3-fluoro-2-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,47 minutes;

MS data (ESI, I promise. 20V): 410 (M+N)+.

Example 17(268)

2-(2-((2R)-2-(2-Fluoro-4-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,47 minutes;

MS data (ESI, I promise. 20V): 410 (M+N)+.

Example 17(269)

2-(2-((2R)-2-(1H-Indazol-6-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,96 minutes;

MS data (ESI, I promise. 20V): 418 (M+N)+.

Example 17(270)

2-(2-((2R)-2-(1,4-Benzodioxan-6-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,05 minutes;

MS Yes the data (ESI, will believe. 20V): 436 (M+N)+.

Example 17(271)

2-(2-((2R)-2-(4-Methyl-2-oxo-2H-chromen-7-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,22 minutes;

MS data (ESI, I promise. 20V): 460 (M+N)+.

Example 17(272)

2-(2-((2R)-2-(2-Brompheniramine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,49 minutes;

MS data (ESI, I promise. 20V): 458 (M+N)+.

Example 17(273)

2-(2-((2R)-2-(2-Bromo-4-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,56 minutes;

MS data (ESI, I promise. 20V): 472 (M+N)+.

Example 17(274)

2-(2-((2R)-2-(2,3-Dichlorophenylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,54 minutes;

MS data (ESI, I promise. 20V): 446 (M+N)+.

Example 17(275)

2-(2-((2R)-2-(2,4-Dichlorophenylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,59 minutes;

MS data (ESI, I promise. 20V): 446 (M+N)+.

Example 17(276)

2-(2-((2R)-2-(2,5-Dichlorophenylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,56 minutes;

MS data (ESI, I promise. 20V): 446 (M+N)+.

Example 17(277)

2-(2((2R)-2-(2-Chloro-5-cryptomaterial)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,63 minutes;

MS data (ESI, I promise. 20V): 480 (M+N)+.

Example 17(278)

2-(2-((2R)-5-Oxo-2-(2-cryptomaterial)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,51 minutes;

MS data (ESI, I promise. 20V): 446 (M+N)+.

Example 17(279)

2-(2-((2R)-2-(3-Brompheniramine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,47 minutes;

MS data (ESI, I promise. 20V): 458 (M+N)+.

Example 17(280)

2-(2-((2R)-2-(3,4-Dichlorophenylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: to 3.58 minutes;

MS data (ESI, I promise. 20V): 446 (M+N)+.

Example 17(281)

2-(2-((2R)-2-(3,5-Dichlorophenylamino)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,63 minutes;

MS data (ESI, I promise. 20V): 446 (M+N)+.

Example 17(282)

2-(2-((2R)-2-(5-Chloro-2-methoxyphenylacetyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,47 minutes;

MS data (ESI, I promise. 20V): 442 (M+N)+.

Example 17(283)

2-(2-((2R)-5-Oxo-2-(3-cryptomaterial)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,54 minutes;

MS data (ES, will believe. 20V): 446 (M+N)+.

Example 17(284)

2-(2-((2R)-2-(4-Cyanophenylacetic)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,23 minutes;

MS data (ESI, I promise. 20V): 403 (M+N)+.

Example 17(285)

2-(2-((2R)-2-(4-Brompheniramine)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,48 minutes;

MS data (ESI, I promise. 20V): 458 (M+N)+.

Example 17(286)

2-(2-((2R)-2-(4-Bromo-2-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: to 3.58 minutes;

MS data (ESI, I promise. 20V): 472 (M+N)+.

Example 17(287)

2-(2-((2R)-2-(4-Bromo-3-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,56 minutes;

MS data (ESI, I promise. 20V): 472 (M+N)+.

Example 17(288)

2-(2-((2R)-2-(4-fluoro-2-cryptomaterial)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,56 minutes;

MS data (ESI, I promise. 20V): 464 (M+N)+.

Example 17(289)

2-(2-((2R)-2-(4-Chloro-3-cryptomaterial)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.64 min;

MS data (ESI, I promise. 20V): 480 (M+N)+.

Example 17(29)

2-(2-((2R)-2-(4-Methoxyphenylacetyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,96 minutes;

MS data (ESI, I promise. 20V): 408 (M+N)+.

Example 17(291)

2-(2-((2R)-2-(4-Butoxyaniline)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,29 minutes;

MS data (ESI, I promise. 20V): 450 (M+N)+.

Example 17(292)

2-(2-((2R)-5-Oxo-2-(4-interferometer)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,66 minutes;

MS data (ESI, I promise. 20V): 448 (M+N)+.

Example 17(293)

2-(2-((2R)-2-(4-Hexylaniline)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,79 minutes;

MS data (ESI, I promise. 20V): 462 (M+N)+.

Example 17(294)

2-(2-((2R)-2-(4-Heptylaniline)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,92 minutes;

MS data (ESI, I promise. 20V): 476 (M+N)+.

Example 17(295)

2-(2-((2R)-2-(3-aminocarbonylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,98 minutes;

MS data (ESI, I promise. 20V): 421 (M+N)+.

Example 17(296)

2-(2-((2R)-2-(2,5-Dimethoxyaniline)-5-oxopyrrolidin-1-yl)is tilty)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.25 min;

MS data (ESI, I promise. 20V): 438 (M+N)+.

Example 17(297)

2-(2-((2R)-5-Oxo-2-(3,4,5-trimethoxybenzylamine)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.11 min;

MS data (ESI, I promise. 20V): 468 (M+N)+.

Example 17(298)

2-(2-((2R)-2-(2,6-Diisopropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,55 minutes;

MS data (ESI, I promise. 20V): 462 (M+N)+.

Example 17(299)

2-(2-((2R)-2-(4-Bromo-2-tortenelmietlen)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,52 minutes;

MS data (ESI, I promise. 20V): 476 (M+N)+.

Example 17(300)

2-(2-((2R)-2-(2-Chloro-5-methoxyphenylacetyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,44 minutes;

MS data (ESI, I promise. 20V): 442 (M+N)+.

Example 17(301)

2-(2-((2R)-2-(2,5-Diethoxyaniline)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.46 in minutes.

MS data (ESI, I promise. 20V): 466 (M+N)+.

Example 17(302)

2-(2-((2R)-2-(2-Methylinosine-8-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,98 minutes;

MS data (ESI, will believe. 20V): 443 (M+N)+.

Example 17(303)

2-(2-((2R)-2-(2-(1-Methylpropyl)-6-ethylenediaminetetra)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,59 minutes;

MS data (ESI, I promise. 20V): 462 (M+N)+.

Example 17(304)

2-(2-((2R)-2-(5-Chloro-2,4-dimethoxyaniline)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,26 minutes;

MS data (ESI, I promise. 20V): 472 (M+N)+.

Example 17(305)

2-(2-((2R)-2-(5-Chloro-2-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,54 minutes;

MS data (ESI, I promise. 20V): 426 (M+N)+.

Example 17(306)

2-(2-((2R)-2-(1H-Indazol-5-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2,85 minutes;

MS data (ESI, I promise. 20V): 418 (M+N)+.

Example 17(307)

2-(2-((2R)-5-Oxo-2-(4-triphtalocyaninine)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,59 minutes;

MS data (ESI, I promise. 20V): 462 (M+N)+.

Example 17(308)

2-(2-((2R)-2-(4-Cyano-3-cryptomaterial)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,42 minutes;

MS data (ESI, I promise. 20V): 471 (M+N)+ .

Example 17(309)

2-(2-((2R)-2-(2-Bromo-4-tortenelmietlen)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,51 minutes;

MS data (ESI, I promise. 20V): 476 (M+N)+.

Example 17(310)

2-(2-((2R)-2-(2-Chloro-4-tortenelmietlen)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,47 minutes;

MS data (ESI, I promise. 20V): 430 (M+N)+.

Example 17(311)

2-(2-((2R)-5-Oxo-2-(2,3,4-trichlorophenylacetic)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,68 minutes;

MS data (ESI, I promise. 20V): 482 (M+N)+.

Example 17(312)

2-(2-((2R)-2-(5-Isopropyl-2-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,62 minutes;

MS data (ESI, I promise. 20V): 434 (M+N)+.

Example 17(313)

2-(2-((2R)-2-(2-Methylinosine-6-illuminometer)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 2.91 in minutes.

MS data (ESI, I promise. 20V): 443 (M+N)+.

Example 17(314)

2-(2-((2R)-2-(3-Isopropoxyaniline)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,41 minutes;

MS data (ESI, I promise. 20V): 436 (M+N)+.

Example 17(315)

2-(2-((2R)-5-Oxo-2-(4-shall triftormetilfullerenov)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,55 minutes;

MS data (ESI, I promise. 20V): 446 (M+N)+.

Example 17(316)

2-(2-((2R)-2-(3-Methylaminoanthraquinone)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,01 minutes;

MS data (ESI, I promise. 20V): 435 (M+N)+.

Example 17(317)

2-(2-((2R)-2-(3-Chloro-2,6-diethylaniline)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,81 minutes;

MS data (ESI, I promise. 20V): 468 (M+N)+.

Example 17(318)

2-(2-((2R)-2-(3-Isopropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3.46 in minutes.

MS data (ESI, I promise. 20V): 420 (M+N)+.

Example 17(319)

2-(2-((2R)-2-(2,3-Dimethoxyaniline)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,26 minutes;

MS data (ESI, I promise. 20V): 438 (M+N)+.

Example 17(320)

2-(2-((2R)-2-(3-Methoxy-5-cryptomaterial)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,56 minutes;

MS data (ESI, I promise. 20V): 476 (M+N)+.

Example 17(321)

2-(2-((2R)-2-(4-(Morpholine-4-yl)phenyliminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time In the LC: 2,87 minutes;

MS data (ESI, I promise. 20V): 463 (M+N)+.

Example 17(322)

2-(2-((2R)-2-(2-fluoro-5-cryptomaterial)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,56 minutes;

MS data (ESI, I promise. 20V): 464 (M+N)+.

Example 17(323)

2-(2-((2R)-2-(2-Chloro-5-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,54 minutes;

MS data (ESI, I promise. 20V): 426 (M+N)+.

Example 17(324)

2-(2-((2R)-5-Oxo-2-(3,4,5-trichlorophenylacetic)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,71 minutes;

MS data (ESI, I promise. 20V): 482 (M+N)+.

Example 17(325)

2-(2-((2R)-2-(3-Chloro-4-methoxyphenylacetyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,30 minutes;

MS data (ESI, I promise. 20V): 442 (M+N)+.

Example 17(326)

2-(2-((2R)-2-(4-Chloro-2-methoxy-5-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,55 minutes;

MS data (ESI, I promise. 20V): 456 (M+N)+.

Example 17(327)

2-(2-((2R)-5-Oxo-2-(4-Interoceanmetal)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,40 minutes;

MS data (ESI, I promise. 20V: 464 (M+N) +.

Example 17(328)

2-(2-((2R)-2-(4-Hexyloxyphenyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,52 minutes;

MS data (ESI, I promise. 20V): 478 (M+N)+.

Example 17(329)

2-(2-((2R)-2-(2,3-Differentiability)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,40 minutes;

MS data (ESI, I promise. 20V): 414 (M+N)+.

Example 17(330)

2-(2-((2R)-5-Oxo-2-(2,3,4,5-tetracosapentaenoic)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,50 minutes;

MS data (ESI, I promise. 20V): 450 (M+N)+.

Example 17(331)

2-(2-((2R)-2-(5-tert-Butyl-2-methoxyphenylacetyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,49 minutes;

MS data (ESI, I promise. 20V): 464 (M+N)+.

Example 17(332)

2-(2-((2R)-2-(3-Chloro-4-cyanoaniline)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,35 minutes;

MS data (ESI, I promise. 20V): 437 (M+N)+.

Example 17(333)

2-(2-((2R)-5-Oxo-2-(2-triphtalocyaninine)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,57 minutes;

MS data (ESI, I promise. 20V): 462 (M+N)+.

Example 17(334)

2-(2-((R)-5-Oxo-2-(4-triftormetilfullerenov)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,70 minutes;

MS data (ESI, I promise. 20V): 478 (M+N)+.

Example 17(335)

2-(2-((2R)-5-Oxo-2-(3-triphtalocyaninine)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,59 minutes;

MS data (ESI, I promise. 20V): 462 (M+N)+.

Example 17(336)

2-(2-((2R)-2-(2-Methoxy-5-cryptomaterial)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,56 minutes;

MS data (ESI, I promise. 20V): 476 (M+N)+.

Example 17(337)

2-(2-((2R)-2-(2-Chloro-4,6-dimethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,56 minutes;

MS data (ESI, I promise. 20V): 440 (M+N)+.

Example 17(338)

2-(2-((2R)-2-(2-Chloro-4-fluoro-5-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: to 3.58 minutes;

MS data (ESI, I promise. 20V): 444 (M+N)+.

Example 17(339)

2-(2-((2R)-2-(2-Cyano-4,5-dimethoxyaniline)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,20 minutes;

MS data (ESI, I promise. 20V): 463 (M+N)+.

Example 17(340)

2-(2-((2R)-2-(2-Fluoro-3-cryptomaterial)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

BP is me holding HPLC: 3,57 minutes;

MS data (ESI, I promise. 20V): 464 (M+N)+.

Example 17(341)

2-(2-((2R)-2-(3-Fluoro-4-methoxyphenylacetyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,23 minutes;

MS data (ESI, I promise. 20V): 426 (M+N)+.

Example 17(342)

2-(2-((2R)-2-(4-Diftormetilirovaniya)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,39 minutes;

MS data (ESI, I promise. 20V): 444 (M+N)+.

Example 17(343)

2-(2-((2R)-2-(3-Bromo-4-Methylpheniltiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,56 minutes;

MS data (ESI, I promise. 20V): 472 (M+N)+.

Example 17(344)

2-(2-((2R)-2-(2-Diftormetilirovaniya)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,44 minutes;

MS data (ESI, I promise. 20V): 444 (M+N)+.

Example 17(345)

2-(2-((2R)-5-Oxo-2-(3-triftormetilfullerenov)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

Retention time HPLC: 3,66 minutes;

MS data (ESI, I promise. 20V): 478 (M+N)+.

Reference example 21

tert-Butyl (1R)-2-benzyloxy-1-hydroxyethylacrylate

In an argon atmosphere to a solution of 2,5-dioxopiperidin-1-yl O-benzyl-N-tert-butoxycarbonyl-L-serinate (to 4.41 g) is tetrahydrofuran (30 ml) is added sodium borohydride (644 mg) in an ice bath and the mixture is stirred at room temperature overnight. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with aqueous saturated solution of ammonium chloride and a saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the connection header (3,30 g)having the following physical data.

TLC: Rf 0,42 (n-hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ 1,45 (s, N), 2,61 (Shir. s, 1H), and 3.72 (m, 5H), a 4.53 (s, 2H), 5,17 (Shir. s, 1H), 7,34 (m, 5H).

Reference example 22

Hydrochloride (2R)-2-amino-3-benzyloxyphenol

To a solution of the compound obtained in reference example 21 (3,30 g)in toluene (20 ml) is added 4N solution of hydrogen chloride in dioxane (4 ml) and the mixture is stirred at room temperature for 2 hours and at a temperature of 60°C for 1 hour. After cooling, to the reaction mixture was added hexane and the mixture is filtered. The resulting residue is dried to obtain specified in the connection header (2,18 g)having the following physical data.

TLC: Rf 0.21 in (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 2,31 (Shir. s, 4H), of 3.69 (m, 5H), 4,55 (s, 2H), 7,31 (m, 5H).

Reference example 23

(4R)-4-Benzoyloxymethyl-2-oxo-1,3-oxazolidin

In an argon atmosphere to a solution of the compound obtained in reference example 22 (2.15 g)in tetrahydrofuran (20 ml) is added 1,1'-carbonyldiimidazole (1,77g) and triethylamine (2,75 ml) in an ice bath and the mixture is stirred at room temperature overnight. To the reaction solution was added 1,1'-carbonyldiimidazole (1.77 g) and the mixture is stirred at a temperature of 60°C for 3 hours. After cooling, to the reaction solution was added hydrochloric acid. The reaction mixture was extracted with ethyl acetate. The obtained organic layer is washed with water, saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the header of the compound (2.00 g)having the following physical data.

TLC: Rf 0,68 (ethyl acetate);

1H-NMR (CDCl3): δ 3,47 (d, J=6,20 Hz, 2H), a 4.03 (m, 1H), 4,11 (DD, J=8,40, 5,10 Hz, 1H), 4,45 (t, J=8,40 Hz, 1H), of 4.54 (s, 2H), 5,62 (Shir. s, 1H), 7,32 (m, 5H).

Reference example 24

Ethyl ester (4R)-4-benzoyloxymethyl-2-oxo-1,3-oxazolidin-1-luxusni acid

In an argon atmosphere to a solution of the compound obtained in reference example 23 (2.00 g), and Bromeliaceae (2,42 g) in tetrahydrofuran (20 ml) is added tert-piperonyl potassium (1.29 g) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and extracted with ethyl acetate. The organic layer is washed with water, saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to obtain the specified title compound (1.18 g), it is found the following physical data.

TLC: Rf 0,42 (n-hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ to 1.24 (t, J=7,10 Hz, 3H), 3,52 (DD, J=9,60, 4,00 Hz, 1H), 3,60 (DD, J=9,60, 6,60 Hz, 1H), 3,97 (d, J=18,00 Hz, 1H), 4,01 (DD, J=8,70, 6,30 Hz, 1H), 4,15 (m, 3H), 4,22 (d, J=18,00 Hz, 1H), of 4.44 (t, J=8,70 Hz, 1H), 4,47 (d, J=12,00 Hz, 1H), 4,53 (d, J=12,00 Hz, 1H), 7,33 (m, 5H).

Reference example 25

Ethyl ester (4R)-4-hydroxymethyl-2-oxo-1,3-oxazolidin-1-luxusni acid

In an argon atmosphere to a solution of the compound obtained in reference example 24 (1,17 g), in ethanol (20 ml) is added palladium hydroxide on coal (200 mg). In an atmosphere of hydrogen the mixture is stirred over night. The reaction mixture was filtered and concentrated to obtain specified in the title compound (810 mg)having the following physical data.

TLC: Rf is 0.42 (ethyl acetate);

1H-NMR (CDCl3): δ to 1.32 (t, J=7,10 Hz, 3H), 3,63 (m, 3H), 3,74 (d, J=18,00 Hz, 1H), 3,86 (m, 1H), 4.26 deaths (m, 2H), 4,39 (d, J=18,00 Hz, 1H), 4,42 (d, J=8,00 Hz, 1H).

Reference example 26

Ethyl ester (4R)-4-(3,5-dichlorphenoxy)-2-oxo-1,3-oxazolidin-1-luxusni acid

In argon atmosphere, diethylazodicarboxylate (40% solution in toluene) (90,54 ml) was added dropwise to a solution of the compound obtained in reference example 25 (203 mg), 3,5-dichlorphenol (196 mg) and triphenylphosphine (314 mg) in tetrahydrofuran (5 ml) and the mixture is stirred at room temperature for 4 hours. To the reaction solution add triphen fastin (157 mg) and diethylazodicarboxylate (40% solution in toluene) (0,27 ml) and the solution stirred at room temperature for 4 hours. The reaction solution is concentrated and the resulting residue is purified column chromatography on silica gel (methylene chloride:ethyl acetate=100:3) to obtain the specified title compound (271 mg)having the following physical data.

TLC: Rf of 0.45 (methylene chloride:ethyl acetate=4:1);

1H-NMR (CDCl3): δ of 1.26 (t, J=7,14 Hz, 3H), 4,14 (m, 7H), 4,37 (m, 1H), 4,57 (t, J=8,93 Hz, 1H), 6,78 (d, J=1.65 Hz, 2H), 7,02 (t, J=1.65 Hz, 1H).

Example 18

(4R)-4-(3,5-Dichlorphenoxy)-1-(2-hydroxyethyl)-2-oxo-1,3-oxazolidin

In an argon atmosphere to a solution of the compound obtained in reference example 26 (270 mg)in tetrahydrofuran (5 ml) is added sodium borohydride (88 mg) and the mixture is stirred at room temperature overnight. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer is washed with water, saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (ethyl acetate) to obtain the specified title compound (138 mg)having the following physical data.

TLC: Rf 0.21 in (methylene chloride:ethyl acetate=1:1);

1H-NMR (CDCl3): δ to 3.41 (m, 1H)and 3.59 (m, 1H), 3,86 (m, 2H), 4,10 (m, 2H), 4,28 (m, 2H), 4,51 (t, J=8,10 Hz, 1H), PC 6.82 (d, J=1.80 Hz, 2H), 7,02 (t, J=1.80 Hz, 1H).

Reference example 27

(2-((4R)-4-(3,5-Dichlorophenoxy ethyl)-2-oxo-1,3-oxazolidin-1-yl)ethylmethanesulfonate

Methanesulfonanilide (0,051 ml) was added dropwise to the compound obtained in example 18 (135 mg), and triethylamine (0,12 ml) in methylene chloride (2 ml) in an ice bath and the mixture is stirred for 1 hour. To the reaction solution was added hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water, saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the title compound (193 mg)having the following physical data.

TLC: Rf of 0.53 (methylene chloride:ethyl acetate=1:1);

1H-NMR (CDCl3): δ 3,03 (s, 3H), to 3.58 (m, 1H), 3,81 (m, 1H), 4.09 to (m, 2H), 4,23 (DD, J=8,50, 4,80 Hz, 1H), to 4.38 (m, 3H), 4,53 (t, J=8,50 Hz, 1H), 6,83 (d, J=1.80 Hz, 2H), 7,03 (t, J=1.80 Hz, 1H).

Reference example 28

S-((4R)-4-(3,5-Dichlorphenoxy)-2-oxo-1,3-oxazolidin-1-yl)utilitythat

In an argon atmosphere a solution of the compound obtained in reference example 27 (193 mg), and thioacetate potassium (75 mg) in dimethylformamide (2 ml) is stirred at a temperature of 60°C for 2 hours. The organic layer is washed with water, saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the title compound (165 mg)having the following physical data.

TLC: Rf of 0.65 (methylene chloride:ethyl acetate=1:2);

1H-NMR (CDCl3): δ of 2.34 (s, 3H), of 3.07 (m, 2H), 3,37 (m, 1H), 3,60 (m, 1H), 4,17 (who, 4H), to 4.46 (m, 1H), 6,85 (d, J=1.80 Hz, 2H), 7,02 (t, J=1.80 Hz, 1H).

Example 19

Ethyl ester of 2-(2-((4S)-4-(3,5-dichlorphenoxy)-2-oxo-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

In an argon atmosphere from a solution of the compound obtained in reference example 28 (165 mg), and ethyl 2-bromothiazole-4-carboxylate (114 mg) in ethanol dearyou and it is added potassium carbonate (91 mg). The mixture is stirred at room temperature overnight. To the reaction solution was added water and extracted with ethyl acetate. The organic layer is washed with water, saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the compounds of this invention (144 mg)having the following physical data.

TLC: Rf of 0.43 (toluene:ethyl acetate=1:1);

1H-NMR (CDCl3): δ of 1.39 (t, J=7,10 Hz, 3H), of 3.33 (DDD, J=13,80, of 9.30, 6,00 Hz, 1H), 3,49 (DDD, J=13,80, of 9.30, 5,10 Hz, 1H), 3,65 (DDD, J=14,30, of 9.30, 5,10 Hz, 1H), 3,81 (DDD, J=14,30, of 9.30, 6,00 Hz, 1H), 4,07 (DD, J=10,50, 3,00 Hz, 1H), and 4.40 (m, 5H), 4,69 (DD, J=10,50, 3,00 Hz, 1H), make 6.90 (d, J=1.80 Hz, 2H), of 6.96 (t, J=1.80 Hz, 1H), 8,00 (s, 1H).

Example 20(1) and 20(2)

According to the method of example 2 using the compound obtained in example 19, or the corresponding ester instead of the compound obtained in example 1 given the following soybeans is inane of the present invention.

Example 20(1)

2-(2-((4S)-4-(3,5-Dichlorphenoxy)-2-oxo-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.58 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 3,37 (DDD, J=13,50, of 9.30, 6,00 Hz, 1H), 3,53 (DDD, J=13,50, of 9.30, 6,00 Hz, 1H), 3,69 (DDD, J=14,10, of 9.30, 5,20 Hz, 1H), 3,83 (DDD, J=14,10, of 9.30, 6,00 Hz, 1H), 4,06 (m, 1H), 4,36 (m, 4H), at 6.84 (d, J=1.80 Hz, 2H), 6,98 (t, J=1.80 Hz, 1H), 8,14 (s, 1H).

Example 20(2)

2-(2-((4S)-2-Oxo-4-((3-(triptoreline)phenoxy)methyl)-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0.26 (chloroform:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ 3,39 (m, J=14,20, 9,00, 5,90 Hz, 1H), 3,54 (DDD, J=14,20, 9,00, and 5.30 Hz, 1H), 3,71 (DDD, J=14,20, 9,00, and 5.30 Hz, 1H), 3,85 (DDD, J=14,20, 9,00, 5,90 Hz, 1H), 4,08 (m, 1H), or 4.31 (m, 3H), 4,47 (t, J=of 7.90 Hz, 1H), 6,78 (s, 1H), 6,86 (m, 2H), 7,31 (d, J=8,10 Hz, 1H), 8,13 (s, 1H).

Example 21

Ethyl ester of 2-(2-((2R)-2-(3,5-dichlorphenoxy)-5-dioxopyrimidine-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

To a solution of the compound obtained in example 5(32) (190 mg)in toluene (3 ml) is added a reagent of Lesson (97 mg) and the mixture is stirred at a temperature of 50°C for 1 hour. After cooling to room temperature the reaction solution is purified column chromatography on silica gel (hexane:ethyl acetate=4:1) to give the compounds of this from the retene, having the following physical data.

TLC: Rf of 0.35 (hexane:ethyl acetate=4:1);

1H-NMR (CDCl3): δ of 1.34 (t, J=7,14 Hz, 3H), 2,17 (m, 2H), 2,97 (m, 1H), 3,21 (m, 2H), to 3.64 (m, 1H), a 4.03 (m, 2H), 4,19 (m, 1H), 4,36 (m, 3H), 4.92 in (DD, J=10,71, a 2.75 Hz, 1H), 6,86 (m, 3H), 7,94 (s, 1H).

Example 21(1) and 21(2)

According to the method of example 21, using the appropriate ester instead of the compound obtained in example 5(32), given the following compounds of this invention.

Example 21(1)

Methyl ester 2-(2-((4S)-4-(3,5-dichlorphenoxy)-2-thioxo-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.47 (hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ to 3.36 (DDD, J=13,50, 9,90, 5,10 Hz, 1H), 3,65 (DDD, J=13,50, 10,20, 5,10 Hz, 1H), 3,93 (s, 3H), of 3.97 (m, 1H), 4,14 (m, 2H), 4,63 (m, 3H), 4.92 in (m, 1H), 6,93 (d, J=1.80 Hz, 2H), 6,97 (t, J=1.80 Hz, 1H), 8,02 (, 1H).

Example 21(2)

Methyl ester 2-(2-((4S)-2-thioxo-4-(3-cryptomaterial)-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.43 (hexane:ethyl acetate=1:1);

1H-NMR (CDCl3): δ to 3.41 (DDD, J=13,70, 9,70, and 5.30 Hz, 1H), 3,65 (DDD, J=13,70, 9,80, of 5.40 Hz, 1H), with 3.89 (s, 3H), of 3.96 (DDD, J=13,80, 9,60, 5.50 Hz, 1H), 4,17 (m, 2H), with 4.64 (m, 3H), 4,82 (m, 1H), 6,86 (m, 3H), 7,26 (m, 1H), 8,01 (s, 1H).

Example 22(1)-22(3)

According to the method of example 2 using the compound obtained in 21, 21(1) or 21(2), instead of the compound obtained in example 1 given the following is soedineniya of the present invention.

Example 22(1)

2-(2-((2R)-2-(3,5-Dichlorphenoxy)-5-dioxopyrimidine-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0.26 (chloroform:methanol=9:1);

1H-NMR (CDCl3): δ 8,17 (s, 1H), of 6.96 (t, J=2.1 Hz, 1H), 6,86 (d, J=2.1 Hz, 2H), of 4.66 (DD, J=10,2, 3.0 Hz, 1H), of 4.44-4,24 (m, 2H), 4,16-3,95 (m, 2H), to 3.73 (m, 1H), 3,39 (m, 1H), 3,17 (m, 1H), 3.04 from (m, 1H), and 2.26 (m,, 1H), 2.06 to (m, 1H).

Example 22(2)

2-(2-((4S)-4-(3,5-Dichlorphenoxy)-2-thioxo-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf of 0.57 (methylene chloride:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 3.43 (m, 1H), 3,70 (m, 1H), 3.96 points (m, 1H), 4,08 (m, 1H), 4,19 (m, 1H), 4,57 (m, 4H), 6.87 in (d, J=1.80 Hz, 2H), 6,98 (t, J=1.80 Hz, 1H), 8,16 (s, 1H).

Example 22(3)

2-(2-((4S)-2-Thioxo-4-(3-cryptomaterial)-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazole-4-carboxylic acid

TLC: Rf 0,54 (methylene chloride:methanol:acetic acid=90:10:1);

1H-NMR (CDCl3): δ of 3.46 (m, 1H), 3,70 (m, 1H), 3,97 (m, 1H), 4,10 (m, 1H), 4,22 (m, 1H), 4,58 (m, 4H), at 6.84 (m, 3H), 7,28 (t, J=to 8.20 Hz, 1H), 8,16 (s, 1H).

Example compositions 1

The following components are mixed in the usual way and pressed to obtain 100 tablets each containing 0.5 mg of active ingredient.

- α-Cyclodextrin 2-(2-(2-(4-n-butylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid 250 mg (containing 50 mg)
- calcixerollic200 mg
- stearate100 mg
- microcrystalline cellulose9.2 grams

Example composition 2

After mixing the following components in the usual way the resulting solution is sterilized in the usual way and portions of 1 ml poured into ampoules, respectively, and dried by freezing in a conventional way to obtain 100 ampoules for injection, each containing 0.2 mg of the active ingredient.

- α-Cyclodextrin 2-(2-(2-(4-n-butylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid100 mg (containing 20 mg)
- mannitol5 g
- distilled water100 ml

1. Derived 8-isoprostaglandin represented by the formula

where T is (1) an oxygen atom, or (2) a sulfur atom;

X is (1) -CH2or (2) -O-;

And is-G1-G2-G3-;

G1is C1-4 alkylene straight-chain, optionally substituted by 1-2 C1-4 alkilani;

G2represents (1) -Y, (2)-ring 1 - or (3)-Y-kolco-; calico the C is (1) C5 or 6 monocarbocyclic-aryl, which may be fully saturated, or 5-6-membered managerialism-aryl, which contains heteroatoms selected from 1 atom of nitrogen, 1 oxygen atom and/or 1 sulfur atom, and may be partially or fully saturated;

Y is (1) -S -, or (2) -SO2-;

G3is (1) communication, (2) C1-4 alkylene straight-chain, optionally substituted by 1-2 C1-4 alkilani or (3) C2-4 Alcanena straight-chain, optionally substituted by 1-2 C1-4 alkilani;

D is D1or D2;

D1is (1) -COOH, or (2) -COOR2;

R is C1-10 alkyl;

D2represents (1) -CH2HE or (2) -CONR6R7(4) -COO-Z1-Z2-Z3R6and R7are each independently (1) hydrogen atom or (2) C1-10 alkyl;

E is E1or E2;

E1is

;

R11is (1) C1-10 alkyl, (2) C1-10 alkylthio, (3) C1-10 alkyl, substituted C3-5 cycloalkyl, (4) With 1 to 10 alkyl, substituted naphthalene ring, or phenyl which may be substituted by 1 or 2 halogen atoms or (5) C1-10 alkyl, substituted Deputy-0-phenyl;

E2is U1-U2-U3;

U1represents (1) 1-4 alkylene, (2) C2-4 albaniles, (3) -calico or (4) C1-4 alkylene-kolco-;

U2is (1) communication, (2) -CH2-, (3) NON-, (4), (5) -S-, (6) -NR12or (7) carbonyl;

R is (1) hydrogen atom, (2) C1-10 alkyl, (3) C2-10 acyl or (4) C3-8 cycloalkyl;

U3is (1) C1-8 alkyl, optionally substituted by 1-3 substituents selected from C1-10 alkyl, halogen, hydroxy, alkoxy, alkylthio and NR13R14, (2) C2-8 alkenyl, optionally substituted by 1-3 substituents selected from C1-10 alkyl, halogen, hydroxyl, alkoxy, (3) C1-8 alkyl, substituted colcom or (5) colcom;

R13and R14are each independently (1) hydrogen atom or (2) C1-10 alkyl;

calico may be substituted by 1-3 R;

R represents (1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C1-10 alkoxy, (4) halogen, (5) hydroxy, (6) nitro, (7) -NR15R16, (8) C1-10 alkyl, substituted C1-10 alkoxy, (9) C1-10 alkyl substituted by 1 to 3 halogen atoms, (10) C1-10 alkyl, substituted C1-10 alkoxy substituted by 1 to 3 halogen atoms, (11) C1-10 alkyl, substituted-NR15R16, (12) C1-10 alkoxy, substituted by 1-4 halogen atoms, (13) C1-10 alkyl, substituted hydroxy, (14) C2-10 acyl, (15) cyano, (16) NH2SO2-, (17) C1-10 alkyl, substituted cyano, (18) C1-10 alkylthio substituted by 1-3 halogen atoms, or (19) -C(O)-NR15R16;

R15, R16and R17are each independently (1) hydrogen atom or (2) C1-10 alkyl;

< num="3652"> calico is (1) C3-15 mono - or beerbottles-aryl which may be partially or fully saturated or (2) a 5-10 membered mono - or biheterocyclic-aryl which may be partially or fully saturated and contains a heteroatom selected from 1 atom of nitrogen, 1 oxygen atom and/or 1 sulfur atom; and

where

1) if E is E2E2is U1-U2-U3and U1is C2 alkylene or C2 Alcanena, U is not-SNON-,

2) if U3is C1-8 alkyl, substituted by at least one hydroxy, U1-U2is not C2 alkylene or C2 Alcanena,

3) if T is an oxygen atom, X is-CH2-, D1is the D1D1is COOH, And a is the2, G1is C1-4 alkylene, G2is-O - or-NR1-, G3is a bond or C1-4 alkylene, E is E2E2is U1-U2-U3U1is C1-4 alkylene and U3is C1-8 alkyl, U2is not a bond, -CH2-, -NR12or carbonyl,

4) 4-[(2-{(2R)-2-[(1E,3S)-3-hydroxycut-1-enyl]-5-oxopyrrolidin-1-yl}ethyl)thio]butane acid and 4-{2-[(2R)-2-((E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]ethyl}benzoic acid excluded

its pharmaceutically acceptable salt or cycle the dekstrinovym the clathrate.

2. Derived 8-isoprostaglandin according to claim 1, represented by formula (I-A)

where all symbols have the values given in claim 1, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

3. Derived 8-isoprostaglandin according to claim 1 or 2, represented by formula (I-A1)

where G2A-1is-Ya-Colico, Yais-S-, -SO2- or-O-and the other symbols have the values given in claim 1, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

4. Derived 8-isoprostaglandin according to claim 1 or 2, represented by formula (I-A1-a)

where calico is C5 or 6 monocarbocyclic-aryl, or 5-6-membered managerialism-aryl which may be partially or fully saturated and contains a heteroatom selected from 1 atom of nitrogen, 1 of oxygen atoms and/or 1-2 sulfur atom, R100is a hydrogen atom or C1-4 alkyl and the other symbols have the meanings provided in section 3, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

5. Derived 8-isoprostaglandin according to claim 1 or 2, represented by formula (I-Al-al)

where U1a-1is C1-4 alkylene is or C2-4 Alcanena, U2a-1is-O-, -S - or-NR12and other symbols have the meanings provided in paragraph 4, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

6. Derived 8-isoprostaglandin according to claim 1 or 2, represented by formula (I-A1-1)

where U3a-1is C1-8 alkyl or colcom and other symbols have the meanings provided in paragraph 4, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

7. Derived 8-isoprostaglandin according to claim 1 or 2, represented by formula (I-al-2)

where all the symbols have the meanings provided in paragraph 4, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

8. Derived 8-isoprostaglandin according to claim 1 or 2, represented by formula (1-A1-A2)

where calico is a 5-10 membered mono-, bi - or trigeneration-aryl which may be partially or fully saturated and contains at least one nitrogen atom and optionally 1 oxygen atom and/or 1 sulfur atom, n is an integer from 1 to 3, the other symbols have the meanings provided in paragraph 4, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

9. Derived 8-isoprostaglandin according to any one of claims 1 to 4, presents fo what moloi (1-A1-A4)

where all the symbols have the meanings provided in paragraph 4, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

10. Derived 8-isoprostaglandin according to claim 9 represented by formula (1-A1-A4)

where all the symbols have the meanings provided in paragraph 4, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

11. Derived 8-isoprostaglandin according to claim 1, represented by formula (I-E1)

where all the symbols have the meanings provided in paragraph 4, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

12. Derived 8-isoprostaglandin according to claim 1, represented by formula (I-E2)

where all the symbols have the meanings provided in paragraph 4, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

13. Derived 8-isoprostaglandin according to claim 1, represented by formula (I-F)

where all symbols have the values given in claim 1, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

14. Derived 8-isoprostaglandin according to claim 1, represented by formula (I-G)

g is e, all the symbols have the meanings presents in claim 1, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

15. Derived 8-isoprostaglandin according to claim 1, represented by formula (I-H)

where all symbols have the values given in claim 1, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

16. Derived 8-isoprostaglandin according to claim 1, which is the compound described in any of examples 1-22, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

17. Pharmaceutical composition having activity of agonist receptors EP2and/or EP4containing as an active ingredient derived 8-isoprostaglandin according to any one of claims 1 to 16, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

18. Agent for prevention and/or treatment of immune diseases, allergic diseases, the death of neural cells, menstrual cramps, premature births, miscarriages, alopecia, retinal neuropathy, erectile dysfunction, arthritis, lung injury, pneumosclerosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, liver damage, acute hepatitis, liver cirrhosis, shock, nephritis, renal failure, diseases of the circulatory system syndrome is and inflammatory responses sepsis syndrome hemophagocytosis syndrome activation of macrophage, of still's disease, Kawasaki disease, burn, systemic granuloma, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure and bone disease, which comprises as an active ingredient derived 8-isoprostaglandin according to any one of claims 1 to 16, its pharmaceutically acceptable salt or cyclodextrines the clathrate.

Priority points and features:

05.03.2002 according to claim 2 to 12, article 16, in examples 1-10 22.01.2003 on P16 of examples 11-22 from 05.03.2002 on PP, 18 with the exception.



 

Same patents:

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I):

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound of the formula (I): or its pharmaceutically acceptable salt wherein X is chosen from the group consisting of carbon (C), oxygen (O), nitrogen (N) and sulfur (S) atoms; Z represents nitrogen atom (N); Y is chosen from the group consisting of =O, =S or their tautomers; SPU means a spacer element providing distance d between Z and N atom wherein -SPU- represents bi-radical -(CR6R7)n- wherein n means 1, 2, 3, 4 or 5; N atom in common with R1 and R2 forms heterocyclic ring wherein indicated heterocyclic ring is chosen from the group consisting of piperidine and 8-azabicyclo[3.2.1]octane and wherein heterocyclic ring is substituted with one or more substitutes R4 chosen from the group consisting of hydrogen atom, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkylidene, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkyloxyimino-group each of them is substituted optionally with a substitute R5 and wherein at least with one of indicated substitutes R4 is represented by R4' chosen from the group consisting of (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkylidene wherein each of them is substituted optionally with a substitute R5 wherein R5 is chosen from the group consisting of hydrogen, halogen atom, hydroxy-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, (C2-C8)-alkenyl and (C2-C8)-alkynyl; RX can absent or can be chosen from the group consisting of hydrogen atom and optionally substituted (C1-C8)-alkyl; R3 can be represented in 0-4-fold range and chosen from the group consisting of halogen atom, optionally substituted (C1-C8)-alkyl and (C1-C8)-alkoxy-group; each R6 and R7 is chosen optionally and independently among the group consisting of hydrogen atom, hydroxy-group and optionally substituted (C-C8)-alkyl. Also, invention relates to a pharmaceutical composition possessing the selective activity with respect to M and/or M4-subtypes of muscarinic receptors and antagonism with respect to D2-dopamine receptors and comprising compound of the formula (I) by claim 1 in common with pharmaceutically acceptable carriers or excipients. Also, invention relates to a method for enhancing activity of cholinergic receptor comprising interaction of cholinergic receptor and system comprising cholinergic receptor with the effective amount of at least one compound of the formula (I) by claim 1. Also, invention relates to using the compound according to any claim among 1-11 or its pharmaceutically acceptable salt, or pharmaceutical composition containing any base for preparing a medicinal preparation used in prophylaxis aim or treatment of psychosis or for attenuation of symptoms associated with psychosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, chemical technology, pesticides.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (I): wherein Q means nitrogen atom (N); Y means nitro-group (-NO2); Z means -NR3; R1 and R2 mean in common alkylene bridge that comprises two or three carbon atoms and, optionally, a heteroatom chosen from the group comprising -NR5 and oxygen atom (O); R3 means unsubstituted (C1-C12)-alkyl; R5 means hydrogen atom (H) or (C1-C12)-alkyl. Method involves the following steps: (a) interaction of compound of the formula (II): wherein X means a leaving group with a halogenated agent to yield compound of the formula (III): wherein W means halogen atom and wherein treatment of compound of the formula (III) involves extraction of compound of the formula (III) with hydrochloric acid taken in the concentration 10-50 wt.-%, and (b) interaction of the synthesized compound of the formula (III) with compound of the formula (IV): wherein R1, R2, Y, Z and Q have above given values. In the process for synthesis of compound of the formula (III) the stage (a) involves purification stage wherein formed crude product is treated with water at acid range of pH values.

EFFECT: improved method of synthesis.

3 cl, 6 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

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

22 cl, 8 tbl, 453 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): in free form or as a salt wherein Ar1 means phenyl substituted with one or some halogen atoms; Ar2 means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C1-C8)-alkyl, (C1-C8)-halogenalkyl, (C1-C8)-alkoxy-group or (C1-C8)-alkoxycarbonyl; R1 means hydrogen atom or (C1-C8)-alkyl optionally substituted with hydroxy-,(C1-C8)-alkoxy-, acyloxy-group, -N(R2)R3, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl, -CON(R4)R5 or monovalence cyclic organic group; each among R2 and R3 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R2 means hydrogen atom and R3 means acyl or -SO2R6, or R and R3 in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R4 and R5 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R4 and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R6 means (C1-C8)-alkyl, (C1-C8)-halogenalkyl or phenyl optionally substituted with (C1-C8)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar1 means para-chlorophenyl and R1 means hydrogen atom then Ar2 doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

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

7 cl, 47 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new pyrasole derivatives of formula I wherein R5 represents phenyl or heteroaryl ring of formulae IIIa-IIIh meanings of the rest substituents are as defined in specification. Also disclosed are pharmaceutical composition based on said derivatives of formula I and uses thereof.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same for HIV inhibition.

13 cl, 54 ex, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 1-[1-(hetero)aryl-1-perhydroxyalkylmethyl]piperazine compounds of the general formula (I): wherein A means naphthyl, phenyl optionally substituted with methoxy-group, heteroaryl chosen from group comprising thienyl, furyl, indolyl or (C3-C6)-alkenyl optionally substituted with phenyl; Z means subgroup of the general formula: wherein k, l, m and n mean 0 or 1; R6 and R7 mean halogen atom, and to their physiologically acceptable acid-additive salt. Compounds possess antagonistic activity with respect to tachykinin receptors and can be used in treatment of digestive tract functional and inflammatory disorders. Also, invention describes a method for synthesis of proposed compounds and intermediate substances used in realization of this method, and medicinal agents containing indicated compounds.

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

9 cl, 3 tbl, 40 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to a new biologically active compound of 4-oxoquinoline that is useful as an anti-HIV agent and to its pharmaceutically acceptable salt. Invention describes an anti-HIV agent comprising compound of 4-oxoquinoline represented by the following formula [I] or its pharmaceutically acceptable salt as an active component wherein ring Cy represents phenyl group, naphthyl group or pyridyl group and each this group is substituted optionally with 1-5 substituted chosen from the following group A wherein A represents the group consisting of cyano-group, phenyl group, nitro-group, halogen atom, (C1-C4)-alkyl group, halogen-(C1-C4)-alkyl group, halogen-(C1-C4)-alkoxy-group, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3 and -COORa1 wherein Ra1 and Ra2 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or benzyl group, and Ra3 represents (C1-C4)-alkyl group; R1 represent a substitute chosen from the following group B, or (C1-C10)-alkyl group optionally substituted with 1-3 substitutes chosen from halogen atom and the following group B wherein the group B represents the group consisting of phenyl group optionally substituted with phenyl group or 1-5 halogen atoms; (C3-C6)-cycloalkyl group, imidazolyl group, benzothiophenyl group, thiazolyl group optionally substituted with 1-3 (C1-C6)-alkyl groups, morpholinyl group, pyridyl group, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4 and -NRa5COORa6 wherein Ra4 and Ra5 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or phenyl group; Ra6 represents (C1-C4)-alkyl group; R2 represents hydrogen atom or (C1-C4)-alkyl group; R31 represents hydrogen atom, cyano-group, hydroxy-group, halogen atom or (C1-C4)-alkoxy-group; X represents -C-R32, and Y represents -C-R33 or nitrogen atom wherein R32 and R33 are similar or different and each represents hydrogen atom, cyano-group, halogen atom, pyrrolidinyl group, (C1-C10)-alkyl group optionally substituted with 1-3 halogen atoms, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10 or -N=CH-NRa10Ra11 wherein Ra7 and Ra8 are similar or different and each represents hydrogen atom, phenyl group or (C1-C10)-alkyl group optionally substituted with (C3-C6)-cycloalkyl group or hydroxy-group; Ra9 represents (C1-C4)-alkyl group and Ra10 and Ra11 are similar or different and each represents hydrogen atom or (C1-C4)-alkyl group. Also, invention describes compound of the formula (III) given in the invention description, integrase inhibitor, antiviral agent, ant-HIV composition, anti-HIV agent, using compound of 4-oxoqionoline, method for inhibition of integrase activity, method for prophylaxis or treatment of viral infectious disease, pharmaceutical composition used for inhibition of integrase activity, antiviral composition and commercial package (variants). Invention provides the development of a pharmaceutical agent possessing inhibitory effect on activity of integrase.

EFFECT: valuable medicinal properties of compound, agent and composition.

40 cl, 7 tbl, 250 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

Muscarinic agonists // 2269523

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein Z1 represents -CR1 or nitrogen atom (N); Z2 represents -CR2; Z3 represents -CR3 or N; Z4 represents -CR4; W1 represents oxygen (O), sulfur (S) atom or -NR5; one of W2 and W3 represents N or -CR6 and another among W2 and W3 represents CG; W1 represents NG; W2 represents -CR5 or N; W3 represents -CR6 or N; or W1 and W3 represent N and W2 represents NG; G represents compound of the formula (II): wherein Y represents oxygen atom (O), -C(O)- or absent; p = 1, 2, 3, 4 or 5; Z is absent; each t = 2. Also, invention describes a method for enhancing activity of the muscarinic cholinergic receptor and a method for treatment of morbid states when modification of cholinergic and, especially, muscarinic receptors m1, m4 or both m1 and m4 offers the favorable effect.

EFFECT: valuable medicinal properties of agonists.

14 cl, 2 tbl, 101 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: method relates to piperazinedione compounds of formula I wherein and are independently direct bond or double bond; F represents H or CH(RaRb), when is single bong, or C(RaRb), when is double bond; Z represents R3O-(Ar)-B, wherein B represents CH(Rc), when is single bond or C(Rc), when is double bond; Ar represents piridyl; and R3 represents alkyl, aryl, C(O)Rd, C(O)NRdRe or SO2Rd ; R1 and R2 are independently H, C(O)Rd. Compounds of formula I have antitumor activity. Methods for treatment of tumors and angiogenesis inhibition also are disclosed.

EFFECT: new compounds useful in treatment of tumors and angiogenesis inhibition.

42 cl, 23 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to new compounds of formula wherein R1 represents linear or branched C1-C9-alkyl optionally substituted with C3-C8-cycloalkyl, C6-cycloalkyl, 2-furil; 3-furil, 2-thiazolyl, 2-thenyl, 3-thienyl, phenyl; X represents oxygen, NR4, wherein R4 is H, C1-C4-alkyl; Z represents H with the proviso, that when X and Y are oxygen, R1 is not methyl, ethyl, isopropyl, isobutyl or phenyl; and when X is oxygen, and Y is NR2, wherein R2 is hydrogen, methyl, isopropyl or tert-butyl R1 is not methyl. Compounds of present invention are useful as synthetic intermediates for bioactive substances.

EFFECT: new synthetic intermediates for bioactive substances.

8 cl, 28 dwg, 3 tbl, 38 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

Chalcone coumarins // 2266291

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): or their pharmaceutically acceptable salts or solvates wherein Ar represents a substituted or unsubstituted (preferably aromatic one) carbocyclic or heterocyclic group wherein abovementioned carbocyclic or heterocyclic group comprises 5 or 6 atoms in cyclic structure wherein a heteroatom is taken among the group consisting of nitrogen (N) and sulfur (S) atom and any substitutes at Ar group are taken independently of one another of the group consisting of Cl, Br, F atoms and OR10 wherein R10 represents saturated or unsaturated lower hydrocarbon (C1-C6)-radical of normal or branched structure; R represents OR10 wherein R10 corresponds to above given value; R1 represents lower hydrocarbon (C1-C6)-radical of normal or branched structure under condition that if R1 represents -CH3 and R means -OCH3 or -OH then Ar group can't represent 4-methoxyphenyl or 3,4-dimethoxyphenyl. Also, invention proposes a component of medicinal agent used in treatment or prophylaxis of neoplasms. Also, invention proposes a pharmaceutical composition possessing with an anti-proliferative activity and comprising the effective amount of one or some compounds of the formula (I) in combination with one or some pharmaceutically acceptable additives. Invention provides the development of chalcone coumarins possessing with the enhanced anti-proliferative effect with respect to sensitive tumor cells, cells with resistance to conventional chemotherapeutic agents, among them, to anti-tumor medicinal agents of the last generation represented by paclitaxel and docetaxel.

EFFECT: valuable medicinal properties of compounds and compositions.

1 tbl, 21 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-pyrrolidone of the formula (I): wherein Q means -CH2-, -O-; B means -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -CH2-CH=CH-CH2 under condition that if B means -CH=CH-, -CH=CH-CH2- then Q means -CH2-; X means -O-, -S-, -SO- or -SO2- or a simple bond under condition that if X meana simple bond then Q means oxygen atom; J means -(CRbRc)n- wherein n means a whole number from 1 to 4; both Rb and Rc mean hydrogen atom, or both Rb and Rc mean (C1-C4)-alkyl and one of them means hydrogen atom (H), or Rb and Rc in common with carbon atom to which they are bound form (C2-C5)-polymethylene group or -CH2-CH=CH-; A means -CH2-CH2-, -CH=CH- or -C≡C-; Z means -C(O)OR' wherein R' means H, (C1-C6)-alkyl; n means 1, 2, 3 or 4; R1 means -(CH2)pR7 wherein R7 means (C1-C)-alkyl, (C3-C8)-cycloalkyl, furanyl substituted with trifluoromethyl, phenyl or phenyl-Y-phenyl wherein Y means oxygen atom (O), a simple chemical bond and phenyl is optionally substituted with 1, 2 or three substitutes chosen independently from group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen atom, halogen-(C1-C6)-alkyl; p means 0, 1, 2, 3, 4, 5; R2 means H, (C1-C6)-alkyl; R3, R4, R5 and R6 mean H, or their pharmaceutically acceptable salts or solvates, individual isomers or racemic or nonracemic mixture of isomers. Compounds of the formula (I) elicit competitive affinity in binding EP2, EP3 and EP4 that allows their using as components of pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

11 cl, 11 ex

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