Tetrahydroisoquinolin-1-one derivative or pharmaceutically acceptable salt thereof, useful as bb2 antagonist

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

 

The technical field to which the invention relates

The present invention relates to a pharmaceutical agent, in particular, to a derivative tetrahydroisoquinoline-1, or its salt, which is suitable as a therapeutic agent against irritable bowel syndrome.

Background of invention

The irritable bowel syndrome (IBS) is a syndrome that causes chronic symptoms such as abdominal pain, bloating, etc., disorders of defecation of the gut such as diarrhoea, constipation, etc., painful defecation, straining on defecation, etc. It occurs due to functional abnormalities of the lower part of the gastrointestinal tract, mainly the colon, despite the absence of organic disorders, such as inflammation, tumors and the like, and is classified by the state chair at the time the dominant diarrhea predominant constipation and IBS alternative, which is alternative repeats diarrhea and constipation. IBS is a disease that has a relatively high frequency of occurrence, covering from 20% to 50% of patients with disease of the digestive tract, which advises doctors as outpatients, which is dominant in women with a ratio of male to female 1:2, regardless of the race, and which has a high prevalence among the younger generation. Because emotional stress is strongly linked to disease status, it is viewed as a typical somatic stress-related diseases, and believe that the elimination of stress is important for easing symptoms. In fact, it is known that abnormal motility of the gastrointestinal tract is considerably accelerated and the symptoms are worse when emotional stress patients with IBS. In addition, since the symptoms continue, probably formed a "vicious circle", in which increasing the anxiety of the patient and also increases the symptoms.

As drug therapy, in the case of IBS, anticholinergic use remedy for abdominal pain and a tricyclic antidepressant for improvement in lowering the threshold for pain in the digestive tract and the weakening of abnormal intestinal motility, stagnations (hemostatic) means the drug for regulating intestinal functions, etc. in case of diarrhea, and salt laxative, etc. in case of constipation, but they are only symptomatic treatment and their effects are unclear. Agent, effects which can be expected as diarrhea and constipation, one is camping calcipotriol, to adjust the hardness of faeces by gelatinization in the gut, but he has a very limited impact, because not only bloating in the initial stages of its introduction, but also the time required for the manifestation of impacts. Anxiolytic drug and antidepressant use, when the anxiety and stress increase significantly due to stress, but they are administered in a lower dose than the dose that is valid in the mental health field, so there are cases in which mental symptoms are not alleviated, or cases in which they are attenuated, but they do not show any effects on the violation of bowel movements bowel. As a rule, from among IBS symptoms, anxiolytic drug in some cases, are effective in diarrhea and abdominal pain, but they tend to manifest a minor effect on constipation.

Alosetron, antagonist 5-NT3-receptor, and Tegaserod, agonist 5-NT-receptor, attracted attention in recent years as agents, and they are used when the dominant diarrhea and dominant constipation, respectively. These agents improve the bowel movement bowel by regulating intestinal motility and quickly show the effect. However, despite the fact that alosetron shows a relatively high percentage of Ulu the solution, constituting from 40 to 60% with abdominal symptoms and diarrhea, constipation occur in 30-35% of patients, and it causes ischemic colitis (including fatal outcomes) as a serious side effect, so its use is limited (non-patent document 1). In addition, it cannot be said that the impact of Tegaserod on the dominant constipation is sufficient, and there is the possibility of tahiphylacsii (phenomenon in which resistance occurs when the drug is repeatedly injected within a short period of time).

Incidentally, when a living organism is exposed to stress, it generates the response of the hypothalamic-pituitary-adrenal system (hPa), which is released adrenocorticotropic hormone (ACTH) through the secretion of stress-related substances from the hypothalamus and subsequent effects on the anterior pituitary and ACTH released into the blood, secretes corticosterone from the adrenal cortex and, thus, shows the different responses to stress, such as high blood pressure, etc. as stress-related substances are known corticotropin-releasing hormone (CRH), bombezin (BB)/gastrin-releasing peptide (GRP), vasopressin, neuropeptide Y, substance P, neurotensin, etc. Secretion of these substances from Hipotel the Musa is accelerated, when the animal raises the stress. In particular, in respect of CRH has been reported that it increases the release of ACTH and increases defecation in the case of colon cancer when it is administered to patients with IBS (non-patent document 2).

The bombezin/fiberglass, as one of the stress-related substances, is an intestinal-brain peptide and expresses various physiological effects through receptor bombezin. Receptor bombezin classified into 3 subtypes - BB1, W and W/RS3 (receptor bombezin subtype 3), and as endogenous ligands of mammalian receptors for BB1 and VV identified neuromedin In and fiberglass, respectively. It was reported that the GRP receptor and VW universally present in the brain, gastrointestinal tract, etc. but fiberglass is considerably increased in the amygdala gland and the hypothalamus, when the animal emerges stress (non-patent document 3). In addition, it was also reported that receptor antagonist W inhibits the increase in the number of ACTH when injected into the cerebral ventricle of rats subjected to stress of restricted mobility (non-patent document 4).

Regarding the role of GRP receptor/W in the functions of the digestive tract was reported that it enhances the reduction in samples selected longitudinal muscle of the ileum of a human and rabbit (non-patent documents 5 and 6) uvelichivaet the water segregation in Guinea pigs when coexisting with vasoactive intestinal peptide (VIP) (non-patent document 7). In addition, it was reported that antagonists of the receptor WV, including RC-3095, i.e. peptide BB2 receptor antagonist, is effective in case of abnormal contractility of intestinal model induced stress defecation. It was also reported that, using the response in terms of reduction of the abdominal muscles as an indicator, RC-3095 effective in abdominal symptom of a model of abdominal pain, induced by the expansion of the colon. Therefore, receptor antagonist W has an excellent effect on abdominal symptoms, and abnormal gut motility (patent document 1).

As stated above, suggest that receptor antagonist W is a therapeutic agent in the case of IBS, providing excellent effect on abdominal symptoms, and abnormal gut motility.

In addition, because the bombezin/GRP also has the function of growth factors, cells and expression of GRP receptor/W raised in various cancer cells in lung cancer, prostate cancer and so on, about the effectiveness of RC-3095 reported in a large number of tumor tests (non-patent documents 8 to 10). From this point of view, you can also expect receptor antagonist W effective against various cancers.

Production is the top priority of tetrahydroisoquinoline-1 is described in patent documents 2-4.

In patent document 2 describes that a derived 3,4-dihydroisoquinoline-1-it is represented by the following formula (A), has an activating caspase activity and inducing apoptosis effect, and is effective in the case of cancer, autoimmune diseases, rheumatoid arthritis, inflammatory intestinal syndrome, psoriasis, etc. But not described by its antagonistic effect on the receptor bombezin type 2 or its effectiveness relative to IBS.

(symbols in the formula refer to publication)

In patent document 3 describes that a derivative tetrahydroisoquinoline-1-it is represented by the following formula (V), is the ligand protein HDM2, has activity, inducing apoptosis, and activity, inhibiting proliferation, and is effective against cancer. However, it is not described by its antagonistic activity against receptor bombezin type 2 or its effectiveness relative to IBS.

(symbols in the formula refer to publication)

In patent document 4 describes that a derivative tetrahydroisoquinoline-1-it is represented by the following formula (C), is an antagonist of the neurotensin receptor-2 (NT-2) and is effective against pain. However, in the case of R5corresponding to R1solenostoma the invention, not described group R1according to the present invention. Furthermore, it is not described by its antagonistic activity against receptor bombezin type 2 or its effectiveness relative to IBS.

(where R5means (C1-C8)alkyl, which is optionally substituted by a group selected from trifloromethyl, halogen, saturated or partially unsaturated (C3-C8)cycloalkyl and (C6-C10)aryl. For other characters, see publication).

Compounds described in the following tables below, 1-11, presented in the form of directory connections. However, for these compounds is not described antagonistic activity against receptor bombezin type 2 and efficacy in IBS. Further, in the following tables use the following abbreviations. Me: methyl, Et: ethyl, iPr: isopropyl, nBu: n-butyl, Ph: phenyl. Table 1-11 moved in the graphical part.

Non-patent document 1: “the American Journal of Gastroenterology”, (USA), 2003, vol. 98, p. 750-758.

Non-patent document 2: “Gut”, (England), 1998, vol. 42, p. 845-849.

Non-patent document 3: “The Journal of Neuroscience”, (USA), 1998, vol. 18, p. 4758-4766.

Non-patent document 4: “Life Sciences”, (Holland), 2002, vol. 70, p. 2953-2966.

Non-patent document 5: “Gastroenterology”, (USA), 1991, vol. 100, p. 980-985.

Non-patent document 6: “Neurogastroenterology and Motility”, (England), 1997, vol. 9, p. 265-270.

Repatent the initial document 7: “Annals of the New York Academy of Science”, (USA), 2000, vol. 921, p. 420-424.

Non-patent document 8: “Cancer”, (USA), 1998, vol. 83, p. 1335-1343.

Non-patent document 9: “British Journal of Cancer, 2000, vol. 83, p.906-913.

Non-patent document 10: “Cancer”, (USA), 2000, vol. 88, p. 1384-1392;

Patent document 1: international Bulletin of publications No. 2006/115135.

Patent document 2: international Bulletin of publications No. 2004/04727.

Patent document 3: international Bulletin of publications No. 2006/97323;

Patent document 4: international Bulletin of publications No. 03/29221.

The disclosure of this invention

The solution of this invention

The aim of the present invention to provide a new pharmaceutical agents that have antagonistic activity against receptor WV, in particular new compounds that are suitable as a therapeutic agent in the case of IBS.

Ways of solving the problem

The authors of the present invention conducted extensive research regarding receptor antagonists W and, as a result, it was found that the new derivative tetrahydroisoquinoline-1-she-containing amide group as the substituent in position 4, has an excellent antagonistic activity against receptor W, thus completing the present invention.

That is, the present invention relates to a derivative of tetrahydrothieno the Jn-1-it, represented by the General formula (I)or its pharmaceutically acceptable salt:

[symbols in the formula have the following meanings:

R1: lower alkylen-HE lower alkylene-N(R0)(R6), the lowest alkylene-CO2R0cycloalkyl, cycloalkenyl, aryl, heterocyclic group, -(lower alkylene, substituted-or SIG0)-aryl or lower alkylene-heterocyclic group,

where the lowest alkylen, cycloalkyl, cycloalkenyl, aryl and heterocyclic group in R1each may be substituted,

R0: the same or different from each other, each represent H or lower alkyl,

R6: R0-C(O)-R0, -CO2-lower alkyl or-S(O)2-lower alkyl,

R2: lower alkyl, lower alkylene-or SIG0lowest alkylen-aryl, lower alkylene-heterocyclic group, a lower alkylene-N(R0)CO-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0-C(O)N(R0)2-C(O)N(R0)-aryl, -C(O)N(R0-the lowest alkylen-aryl, aryl or heterocyclic group,

where the aryl and heterocyclic group in R2each may be substituted,

R3: -H or lower alkyl,

or R2and R3can be combined with education2-6alkylene;

R4: -N(R7)(R8), -N(R0)-OH, -N(R10)-OR7, -N(R0)-N(R )(R7), -N(R0)-S(O)2-aryl or-N(R0)-S(O)2-R7,

where aryl in R4may be substituted,

R7: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-or SIG0lowest alkylene-CO2R0lowest alkylen-C(O)N(R0)2lowest alkylen-C(O)N(R0)N(R0)2lowest alkylen-C(=NH)NH2lowest alkylen-C(=NOH)NH2heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group,

where the lowest alkylene, aryl, heteroaryl and heterocyclic group in R7each may be substituted,

X: simple bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-,

where * X is the value from the connection to the lower alkylene,

m: an integer from 0 to 3,

p: an integer from 0 to 2,

R8: -H or lower alkyl,

or R7and R8can be combined with education groups low alkylen-N(R9-the lowest alkylene, lower alkylene-CH(R9-the lowest alkylene, lower alkylene-aralen lowest alkylene or lower alkylene-aralen-C(O)-,

R9: aryl and heteroaryl, each of which may be substituted,

R10: -H, lower alkyl or-C(O)R0,

R5: lower alkyl, halogen-lower alkyl, halogen, nitro, -or SIG0, -O -, halogen-lower alkyl, -N(R0)2, -O-lower alkylene-CO2R0or-O-lower alkylene-ar is l,

where aryl in R5may be substituted,

provided that when R4means-N(R7)(R8excluded:

(1) connection, where R1means the unsubstituted cyclopentyl and R2means unsubstituted 2-thienyl;

(2) connection, where R1meansunsubstituted cyclohexyl and R2means 4-methoxyphenyl;

(3) connection, where R1means 4-methoxyphenyl and R2means 4-methoxyphenyl; and

(4) the compound, where R1means (morpholine-4-yl)ethyl and R2means 4-ethoxyphenyl,

also excluded are:

2,3-bis(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-(4-Chlorobenzyl)-2-(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-furylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

ethyl 3-{3-[3,5-bis(trifluoromethyl)phenyl]-4-{[2-(4-methoxyphenyl)ethyl]carbarnoyl}-1-oxo-3,4-dihydroisoquinoline-2(1H)-yl}propanoate,

N-benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-1-oxo-2-(tetrahydrofuran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methoxyethyl)-2-(2-morpholine-4-retil)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-[3,5-bis(t is iformity)phenyl]-2-(2-furylmethyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-furylmethyl)-2-(2-morpholine-4-retil)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and

(4-chlorophenyl)[3-(4-chlorophenyl)-4-[(2-methoxyethyl)carbarnoyl]-1-oxo-3,4-dihydroisoquinoline-2(1H)-yl]acetic acid].

The characters further in this document have the same meanings].

Further, the present invention relates to a pharmaceutical agent containing the derivative tetrahydroisoquinoline-1-it is represented by the General formula (I)or its salt as an active ingredient, in particular receptor antagonist W, therapeutic agent against irritable bowel syndrome or therapeutic agent against cancer.

In addition, the present invention relates to the use of compounds represented by formula (I)or its pharmaceutically acceptable salt for a receptor antagonist W, a therapeutic agent against irritable bowel syndrome or therapeutic agent against cancer, and to a method of treating irritable bowel syndrome or cancer, comprising the administration to a patient an effective amount of the compound represented by formula (I)or its pharmaceutically acceptable salt.

Namely, the present application relates:

(1) to pharmaceutical compositions containing a compound described by obsahovali (I), or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier,

(2) the pharmaceutical composition described in paragraph(1), which is an antagonist of the receptor VB,

(3) the pharmaceutical composition described in paragraph(1), which is a therapeutic agent against the syndrome level becomes too low, colon cancer,

(4) the pharmaceutical composition described in paragraph(1), which is a therapeutic agent against cancer,

(5) to the use of compounds described by the General formula (I)or its pharmaceutically acceptable salt for a receptor antagonist W, a therapeutic agent against the syndrome level becomes too low the colon or therapeutic agent against cancer, and

(6) the method of treatment of the syndrome level becomes too low, colon cancer, or cancer, comprising the administration to the patient therapeutically effective amounts of compounds described by the General formula (I)or its pharmaceutically acceptable salt.

The effects of the present invention

The connection according to the present invention is suitable as a therapeutic agent for IBS (irritable bowel syndrome), because it has an excellent antagonistic action on the receptor VB.

Best mode for carrying out the present invention

Now is sabreena described in more detail below.

"Lower alkyl" preferably means a linear or branched alkyl containing 1-6 carbon atoms (hereinafter simply referred to as1-6), and specifically, it includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like, More preferably, it means1-4-alkyl, and, more preferably, it includes methyl, ethyl, n-propyl and isopropyl.

"Lower alkylene" preferably means a linear or branched C1-6-alkylen, and specifically, it includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, METROTILE, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene etc. Preferably, it means1-4-alkylen, and, more preferably, it includes methylene, ethylene and trimethylene.

"Halogen" means F, Cl, Br or I.

"Halogen-lower alkyl" refers to C1-6-alkyl, substituted by one or more halogen atoms. Preferably, it represents a lower alkyl substituted by 1-5 halogen atoms, and more preferably trifluoromethyl.

"Halogen-lower alkylene" is a C1-6-alkylene substituted by one or more halogen atoms. Preferably, it represents the lowest alkylene substituted by 1-5 halogen atoms, and more preferably, it includes deformed the flax and defloration.

"Cycloalkyl" refers to a saturated ring With3-10is a hydrocarbon group which may have a bridge connection. Specifically, it includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, substituted and the like, Preferably, it means3-8-cycloalkyl, more preferably, From3-6-cycloalkyl, and, more preferably, it includes cyclopentyl and cyclohexyl.

"Cycloalkenyl" is a C3-15-cycloalkenyl, which may have a bridge connection, and it includes an annular group condensed with a benzene ring in place of the double bond. Specifically, it includes cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, 1-tetrahydronaphthyl, 1-indanyl, 9-fluorenyl etc. Preferably, it means5-10-cycloalkenyl, and, more preferably, it includes cyclopentenyl and cyclohexenyl.

"Aryl" refers to aromatic, monocyclic to tricyclic, With6-14is a hydrocarbon group, and preferably it includes phenyl and naphthyl, more preferably phenyl.

"Allen" refers to a divalent group formed by removing arbitrary hydrogen atom from the aryl, and it means, preferably, phenylene and, more preferably, orthophenylene.

"Heteroaryl" means a ring group consisting of i monocyclic 5-6-membered heteroaryl, containing 1-4 heteroatoms selected from O, S and N, and ii) bicyclic 8-10 membered heterocycle and tricyclic 11 to 14-membered heterocycle, and each contains from 1 to 5 heteroatoms selected from O, S and N, which are obtained by condensation of the monocyclic heteroaryl and one or two rings selected from the group consisting of monocyclic heteroaryl and the benzene ring. Ring atom S or N may be oxidized to form oxide or dioxide.

"Heteroaryl" preferably includes pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, indolyl, indazoles, benzimidazoles, imidazopyridine, hinely, chinadoll, honokalani, naphthylidine, benzofuranyl, benzothiazol, benzoxazolyl, benzothiazolyl and carbazolyl, and, more preferably, pyrrolyl, pyridyl, furyl, thienyl and thiazolyl.

"Heterocyclic group" means a ring group consisting of i) a monocyclic 3 to 8-membered (preferably 5 to 7-membered) heterocycle containing 1-4 heteroatoms selected from O, S and N, and ii) bicyclic 8 to 14-membered (preferably, 9-11-membered) heterocycle and tricyclic 11-20-membered (preferably 12-15-membered) heterocycle, and each contains from 1 to 5 heteroatoms selected from O, S and N, which receive put the m condensation of the monocyclic heterocycle and one or two rings, selected from the group consisting of monocyclic heterocycle, benzene ring, With5-8-cycloalkane and C5-8cycloalkene. Ring atom S or N may be oxidized to form oxide or dioxide, or may have a bridge connection.

"Heterocyclic group" preferably includes aziridinyl, azetidin, pyrrolidinyl, piperidinyl, piperazinil, homopiperazine, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, homomorpholine, tetrahydrothieno, tetrahydrothiopyran, thiomorpholine, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, indolyl, indazoles, benzimidazoles, imidazopyridine, hinely, chinadoll, honokalani, naphthylidine, benzofuranyl, benzothiazol, benzoxazolyl, benzothiazolyl, dihydroindole, dehydrobenzperidol, dihydrobenzofuranyl, tetrahydropyranyl, benzodioxolyl, dihydroergotoxine, dihydroisoxazole, tetrahydronaphthalene, carbazolyl and hinokitiol, and, more preferably, pyrrolidyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolyl, pyridyl, furyl, thienyl and thiazolyl.

The expression "which may be substituted" means "which is unsubstituted or which is substituted by 1-5 substituents which can be odinakovymi excellent to each other". The expression "substituted" refers to the expression "which is substituted by 1-5 substituents, which are the same or different from each other." Further, if there are a lot of substituents, these substituents may be the same or different from each other.

Deputy for "lower alkylene", which may be substituted, R1preferably a is a group selected from group G1and, more preferably, HE or phenyl.

Group G1: halogen, -or SIG0, -N(R0)(R6and aryl.

Provided that the "aryl" group G1may be substituted by a group selected from the group consisting of halogen, lower alkyl, halogen-lower alkyl, -or SIG0and -- O-halogen-lower alkyl.

Deputy for cycloalkyl", "cycloalkenyl" and "heterocyclic group", each of which may be substituted, R1preferably a is a group selected from group G2more preferably, -or SIG0, -CO2R0, -N(R0)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-or SIG0or-N(R0)S(O)2-lower alkyl and, more preferably, -or SIG0, -N(R0)C(O)R0or-N(R0)S(O)2is lower alkyl.

Group G2: halogen, lower alkyl, halogen-lower alkyl, lower alkylene-or SIG0, -Or SIG0, -O -, halogen-lower alkyl, -N(R0 )2, -N(R0-the lowest alkylen-or SIG0, -N(R0-the lowest alkylene-CO2R0, -N(R0)C(O)R0, -N(R0)C(O)or SIG0, -N(R0)C(O)-aryl, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)-lower alkylene-N(R0)2, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-OR0)-S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2lowest alkylene-CO2R0, -N(R0)S(O)2lowest alkylen-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2lowest alkylene-Si(lower alkyl)3-C(O)N(R0)2-C(O)N(R0-the lowest alkylen-or SIG0-C(O)N(R0-the lowest alkylene-N(R0)2-C(O)N(R0-the lowest alkylene-CO2R0-C(O)N(R0)-O-lower alkylene-heterocyclic group, heterocyclic group, -C(O)R0-C(O)-lower alkylene-or SIG0-C(O)-lower alkylene-N(R0)2-C(O)-heterocyclic group and oxo.

Provided that "aryl" and "heterocyclic group" in the group G2each may be substituted by a group selected from the group consisting of halogen, lower alkyl, halogen-lower alkyl, -or SIG0, -O -, halogen-nissah which the alkyl and oxo.

Deputy for the "aryl"which may be substituted, R1preferably a is a group selected from group G3and, more preferably, -or SIG0or lower alkylene-or SIG0.

Group G3: halogen, lower alkyl, halogen-lower alkyl, -or SIG0, -O -, halogen-lower alkyl, lower alkylene-or SIG0and-CO2Or SIG0.

Deputy for "aryl" and "heterocyclic group"which may be substituted, R2preferably a is a group selected from group G4more preferably, halogen, lower alkyl or-or SIG0and, even more preferably, the halogen.

Group G4: halogen, -CN, nitro, lower alkyl, halogen-lower alkyl, -or SIG0, -N(R0)2, -CO2R0-C(O)N(R0)2, -OS(O)2lower alkyl and oxo.

Deputy for "lower alkylene", which may be substituted, R7preferably a is a group selected from group G5more preferably, the halogen.

Group G5: halogen, -or SIG0, -N(R0)2and aryl.

Provided that the "aryl" group G5may be substituted by a group selected from the group consisting of halogen, lower alkyl, halogen-lower alkyl, -or SIG0and -- O-halogen-lower alkyl.

Deputy for "aryl" and "heterocyclic group", each of which can be C is substituted, in R7preferably a is a group selected from group G6and, more preferably, halogen, -or SIG0lowest alkylen-or SIG0, -CO2R0lowest alkylene-CO2R0, -O-lower alkylene-CO2R0or oxo.

Group G6: halogen, lower alkyl which may be substituted by-or SIG0, halogen-lower alkyl which may be substituted by-or SIG0, -Or SIG0, -CN, -N(R0)2, -CO2R0, -CO2lowest alkylen-aryl, -C(O)N(R0)2lowest alkylene-OC(O)R0lowest alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0lowest alkylene-CO2lowest alkylen-aryl, lower alkylene-C(O)N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2lowest alkylen-aryl, -O-lower alkylene-C(O)N(R0)2, -O -, halogen-lower alkylene-CO2R0, -O -, halogen-lower alkylene-C(O)N(R0)2-C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(=NH)NH2, -C(NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, -C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-or SIG0, -N(R0)C(O)or SIG0, -N(R )S(O)2-lower alkyl, -C(aryl)3and oxo.

Provided that "aryl" and "heterocyclic group" in the group G6each may be substituted by a group selected from the group consisting of halogen, lower alkyl, halogen-lower alkyl, -or SIG0, -O -, halogen-lower alkyl, oxo, thioxo (=S).

Deputy for the "aryl"which may be substituted, R4and Deputy for heteroaryl", which may be substituted, R7preferably a is a group selected from the group consisting of halogen, lower alkyl, halogen-lower alkyl, -or SIG0and -- O-halogen-lower alkyl.

Deputy for "aryl" and "heteroaryl", each of which may be substituted, R9preferably a is a group selected from the group consisting of halogen, lower alkyl, halogen-lower alkyl, -or SIG0and -- O-halogen-lower alkyl.

Deputy for the "aryl"which may be substituted, R5preferably a is a group selected from the group consisting of halogen, lower alkyl, halogen-lower alkyl, -or SIG0and -- O-halogen-lower alkyl.

The preferred embodiment of the present invention is described below:

(a) R1preferably means -(lower alkylene, which may be substituted)-HE or cycloalkyl, aryl or heterocyclic group, each of which can b shall be substituted. More preferably, it means the lowest alkylene, which may be substituted)-HE or cyclopentyl, cyclohexyl, phenyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidyl or piperidyl, each of which may be substituted. More preferably, it means the lowest alkylene, which may be substituted by a group selected from the group consisting of phenyl which may be substituted with halogen, lower alkyl or-or SIG0and-HE-HE or cycloalkyl substituted by a group selected from the group consisting of-or SIG0, -N(R0)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-or SIG0, -N(R0)S(O)2-lower alkyl, and heterocyclic groups. Even more preferably, it means the lowest alkylene, which may be substituted by a group selected from the group consisting of phenyl which may be substituted with halogen, lower alkyl or-or SIG0and-HE-HE or cyclopentyl, or cyclohexyl, each of which is substituted by a group selected from the group consisting of-or SIG0, -N(R0)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-or SIG0, -N(R0)S(O)2-lower alkyl, and heterocyclic groups. Especially preferably, it means cyclohexyl, substituted by a group selected from the group consisting of-or SIG0, -N(R0)C(O)R0and-N(R0)S(O)2is lower alkyl.

(b) R2predpochtitelno means aryl, which may be substituted, and more preferably phenyl which may be substituted with halogen, lower alkyl or-or SIG0and, even more preferably, phenyl, substituted by halogen.

(C) R3preferably means is N.

(d) R4preferably means-N(R0-the lowest alkylene-(aryl or heteroaryl, each of which may be substituted) or-N(R0)-O-lower alkylene-(aryl or heteroaryl, each of which may be substituted). More preferably, it means-NH-lower alkylene-(phenyl, pyridyl, N-oxidability, thienyl or thiazolyl, each of which may be substituted) or-NH-O-lower alkylene-(phenyl, pyridyl, N-oxidability, thienyl or thiazolyl, each of which may be substituted). More preferably, it means-NH-lower alkylene-(phenyl, pyridyl, N-oxidability, thienyl or thiazolyl, each of which may be substituted by a group selected from the group consisting of halogen, -or SIG0lowest alkylen-or SIG0, -CO2R0lowest alkylene-CO2R0and-O-lower alkylene - CO2R0or-NH-O-lower alkylene-(phenyl, pyridyl, N-oxidability, thienyl or thiazolyl, each of which may be substituted by a group selected from the group consisting of halogen, -or SIG0lowest alkylen-or SIG0, -CO2R0lowest alkylene-CO2R0and-O-lower alkylene-sub> 2R0). Even more preferably, it means-NH-lower alkylene-(phenyl which may be substituted by a group selected from the group consisting of halogen, -or SIG0lowest alkylen-or SIG0, -CO2R0lowest alkylene-CO2R0and-O-lower alkylene-CO2R0or-NH-O-lower alkylene-(phenyl which may be substituted by a group selected from the group consisting of halogen, -or SIG0lowest alkylen-or SIG0, -CO2R0lowest alkylene-CO2R0and-O-lower alkylene-CO2R0).

(e) R5preferably means halogen or-or SIG0.

(f) m preferably denotes 0 or 1 and, more preferably, 0.

In a further preferred implementation of the invention compounds containing any combination of each of the preferred groups described in (a)-(f) above are preferred.

In addition, other preferred embodiment for compounds according to the present invention represented by the General formula (I)shown below:

(1) a Compound represented by the General formula (I), where R3means N.

(2) the Compound described in (1), where R2means phenyl which may be substituted with halogen, lower alkyl or-or SIG0.

(3) the Compound described in (2), where R4means-N(R0-the lowest alkylene-(aryl or heteroaryl is, each of which may be substituted) or-N(R0)-O-lower alkylene-(aryl or heteroaryl, each of which may be substituted).

(4) the Compound described in (3), where R1means (lower alkylene, which may be substituted by a group selected from the group consisting of phenyl which may be substituted with halogen, lower alkyl or-or SIG0and-HE-HE; or cycloalkyl substituted by a group selected from the group consisting of-or SIG0, -N(R0)2, -N(R0)C(O)R0, -N(R0-the lowest alkylen-or SIG0, -N(R0)S(O)2-lower alkyl, and heterocyclic group.

(5) a Compound represented by the General formula (I)selected from the group consisting of:

(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-(pyridine-2-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-N-[(1-oxidability-2-yl)methoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}benzoic acid,

(4-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}phenyl)acetic acid,

(3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(metals Lionel)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic acid,

{3-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)ethyl]phenyl}(debtor)acetic acid,

(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-N-(2-{3-[(methylsulphonyl)carbarnoyl]phenyl}ethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

{4-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)ethyl]phenyl}acetic acid and

4-(3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}phenoxy)butane acid;

or its pharmaceutically acceptable salt.

In addition, in the present description, the term "irritable bowel syndrome" (which is hereinafter referred to as IBS) IBS includes the type of diarrhea, IBS-type constipation and IBS alternative type. Disease, is applied to therapeutic agent according to the present invention, is preferably IBS type of diarrhea or IBS alternative types and, particularly preferably, IBS type of diarrhea.

Compounds according to the present invention can exist in the form of other tautomers or geometrical isomers, depending on the type of substituents. In the present description, the connection can be described in only one of the four the e isomer, however, the present invention includes isomers, isolated form or mixture of isomers.

In addition, compound (I) may have asymmetric carbon atoms or axial asymmetry and, consequently, it can be in the form of optical isomers such as (R)-form, (S)-form, etc. the Connection according to the present invention includes both the mixture and the selected form of these optical isomers.

In addition, pharmaceutically acceptable proletarienne form of compound (I) is also included in the present invention. Pharmaceutically acceptable proletarienne form refers to a compound containing a group which can be converted into the amino group, HE CO2N, etc. according to the present invention, by solvolysis or under physiological conditions. Examples of the group which forms Palekastro form, include groups described in Prog. Med., 5, 2157-2161 (1985) or “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163-198.

In addition, the connection according to the present invention may form an acid additive salt or a salt with a base depending on the type of substituents, and these salts are included in the present invention, provided that they are pharmaceutically acceptable salts. Specifically, examples include acid additive salts with inorganic acids such the AK hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid, phosphoric acid, etc. and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, aspartic acid, glutamic acid or the like, and salts with inorganic bases, such as hydroxides of sodium, potassium, magnesium, calcium, aluminum and the like, and with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like, ammonium salt.

In addition, the present invention also includes various hydrates and solvate, polymorphism compounds according to the present invention and pharmaceutically acceptable salt polymorphic form. In addition, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

The way to obtain

The connection according to the present invention and its pharmaceutically acceptable salt can be obtained by applying various known synthesis methods using characteristics based on their fundamental is Oh or type of substituents. In this description, depending on the type of functional groups, in some cases is effective, from the point of view of the methods of obtaining, protecting functional group suitable protecting group (a group that can be easily converted into the functional group) during the stages from the original substances to intermediate compounds. Examples of such functional groups include amino group, hydroxyl group, carboxyl group and the like, and examples of the protective group include groups described in “Protective Groups in Organic Synthesis” (3rd, 1999), edited by Greene and Wuts, which may not necessarily be selected and used in connection with the reaction conditions. In this way, the desired compound can be obtained by introducing a protective group and the reaction, and then, if desirable, the removal of the protective group.

In addition, Palekastro form of compound (I) can be obtained by introducing a specific group during the stages from the original substances to intermediate compounds in a manner analogous to the method for the above-mentioned protective groups, or by performing the reaction using the obtained compound (I). The reaction can be carried out using a method known to a qualified specialist in this field, such as a General esterification, amidation and dehydrate the function.

The following describes typical methods for producing compounds according to the present invention. Each method of obtaining can also be carried out in accordance with the reference documents attached to the present description. Hereinafter, methods of production according to the present invention is not limited to the examples below.

The method of obtaining 1

This method of production is the way in which get the compound (I) according to the present invention, subjecting carboxylic acid (1) and the amine (2) amidation.

This interaction can be carried out using an equivalent amount of carboxylic acid (1) and amine (2), or excessive amounts of any of them, and mixing them in a condition from cooling to heating, preferably at a temperature from -20°C to 60°C, usually for 0.1 hour to 5 days, in a solvent which is inert to the reaction, in the presence of a condensing agent. The solvent as used in this description, is not specifically limited, however, his examples include aromatic hydrocarbons such as benzene, toluene, xylene and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and the like, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane and the like, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidine-2-he (NMP), dimethylsulfoxide (DMSO), ethyl acetate, acetonitrile, water and the like, or mixtures thereof. Examples of the condensing agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole (CDI), diphenylphosphoryl, phosphorus oxychloride and the like, but they are not limited. Additive (for example, 1-hydroxybenzotriazole (HOBt), and the like) in some cases it may be preferable to communicate. In some cases it may be advantageous to smooth reaction, to interact in the presence of organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethyl-4-aminopyridine (DMAP) and the like, or in the presence of inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, etc.

In addition, you can also use the method in which carboxylic acid (1) is converted into a reactive derivative, and then subjected to interaction with the amine (2). Examples of the reactive derivative of carboxylic acid, as used in this description, include gelegenheid acid, obtained by the interaction with a halogenation agent such as phosphorus oxychloride, thionyl chloride and the like, a mixed acid anhydride obtained by the interaction with isobutylene what MIAT, or the like, the active ester obtained by condensation with 1-hydroxybenzotriazole or the like, and others. The interaction of the reactive derivative and the amine (2) can be done in conditions from cooling to heating, preferably at a temperature from -20°C to 60°C, in a solvent which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc.

A method of obtaining a 2: other ways to get

In addition, some compounds represented by formula (I)also can be obtained by subjecting the compound according to the present invention obtained above, any combination of methods, which typically uses a qualified expert in this field, such as conventional amidation, hydrolysis, N-oxidation, reductive amination, sulfonylamine, oxidation, recovery, N-alkylation, O-alkylation, etc. for Example, these compounds can be obtained by reactions as described below, according to the methods described in the examples below, a way that is obvious to the person skilled in the art, or modifying this way.

2-1: Amidation

Amide can be obtained by subjecting the carboxylic acid and the amine amidation.

The amidation can be performed in a similar manner as in sposobnostey 1.

2-2: Hydrolysis

The compound containing carboxyl group, can be obtained by hydrolysis of compounds having ester group.

This interaction can be carried out under conditions of from cooling to heating, in a solvent such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, DMA, NMP, DMSO, pyridine, water and the like, in the presence of acids, including inorganic acids such as sulfuric acid, hydrochloric acid, Hydrobromic acid, etc. and organic acids such as formic acid, acetic acid and the like; or in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, carbonate cesium, ammonia, etc.

2-3: N-Oxidation

N-Oxide compounds can be obtained by oxidation of the nitrogen atom of the heterocycle with the nitrogen atom, such as pyridine and the like, using various oxidants.

This interaction can be done in terms of cooling, at room temperature to heating, using an equivalent amount or an excess of m-chloroperbenzoic acid, peracetic acid, aqueous solution of hydrogen peroxide and the like as an oxidant in a solvent such as halogenated hydrocarbons, acetic acid, water, etc.

2-4: Reductive AMI the licensing

Amin can be alkilirovanii by restoring the imine, which is derived from a primary or secondary amine and carbonyl compounds.

This interaction can be carried out using equivalent amounts of amine and carbonyl compounds, or excess of one of them, in the presence of a reducing agent, in a solvent such as halogenated hydrocarbons, alcohols, ethers, and the like as a reducing agent can be used cyanoborohydride sodium, triacetoxyborohydride sodium, sodium borohydride, etc. This interaction, in some cases, can preferably be carried out in the presence of acid, such as acetic acid, hydrochloric acid, complexes of isopropoxide titanium (IV), etc.

2-5: Sulfonylamine

The sulfonamide can be obtained by sulfonylamine Amin.

This interaction can be realized, for example, in terms of cooling, at room temperature to heating, using an equivalent amount of amine and sulphonylchloride, or excess of one of them, in a solvent such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, pyridine, etc. In some cases it may be advantageous to smooth reaction, to carry out this interaction in the presence of organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, etc. or in the presence of inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, etc.

The means of obtaining the source connections

The source materials used to obtain the compounds according to the present invention can be obtained, for example, using the methods described below, the methods described in the examples get below a known manner, a manner that is obvious for a skilled person skilled in the art, or by modifying this method.

Synthesis of 1 of the original substance

Stage 1:

The compound (5) can be obtained by the interaction of the compound (3) with compound (4).

This interaction can be done in conditions from room temperature to heating, using an equivalent amount of compound (3) and compound (4), or an excessive amount of one of them, in a solvent such as ethers, halogenated hydrocarbons, aromatic hydrocarbons, etc.

Stage 2:

When R3means H, the compound (6)in which the substituents in positions 3 and 4 are TRANS, can be obtained by isomerization of the compound (5).

This interaction can be accomplished by treatment of compound (5) with a base such as sodium hydroxide, hydroxy is potassium and the like, in conditions from room temperature to heating, in a solvent such as halogenated hydrocarbons, alcohols, water, etc.

Synthesis of 2 original substance

The compound (3) can be obtained by dehydration-condensation of the compound (7) with compound (8).

This interaction can be done in conditions from room temperature to heating, using an equivalent amount of the compound (7) and compound (8), or an excessive amount of one of them, in a solvent such as halogenated hydrocarbons, aromatic hydrocarbons, etc. In some cases it may be advantageous to smooth reaction, to use a dehydrating agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieves, etc.

Synthesis of 3 of the original substance

Stage 1:

The compound (10) can be obtained by the interaction of the compound (9) with nitrite.

This interaction can be done in terms of cooling, at room temperature to heating, in a solvent such as ethers, halogenated hydrocarbons, alcohols and the like, in the presence of nitrite, such as amylnitrite, butylnitrite, soliditet etc.

In accordance with these compounds, in some cases advantageous, for about what Cania reaction, to interact in the presence of acid, such as acetic acid, hydrochloric acid, etc. or in the presence of a base such as sodium methoxide, ethoxide sodium tert-piperonyl potassium, etc.

Stage 2:

The compound (11) can be obtained by subjecting the compound (10) rearrangement and then hydrolysis.

The rearrangement reaction can be performed by treating the compound (10) with thionyl chloride or the like in the cooling conditions.

The hydrolysis reaction can be performed in conditions from room temperature to heating in a solvent such as alcohols, water and the like, using a base such as sodium hydroxide, potassium hydroxide, etc.

Stage 3:

The compound (4) can be obtained by dehydration of the compound (11).

The dehydration reaction can be performed in conditions from room temperature to heating using acetylchloride or the like as a dehydrating agent.

The connection according to the present invention is isolated and purified as a free compound, its pharmaceutically acceptable salt, hydrate, MES or polymorpha. Pharmaceutically acceptable salt of the compound (I) according to the present invention can be obtained by reaction of the salt formation using traditional technology.

Isolation and purification can be performed by using conventional chemical the ski operations, such as extraction, fractional crystallization, various types of fractional chromatography, etc.

Various isomers can be distinguished by selecting the corresponding parent compound or by using the differences in physicochemical properties between the isomers. For example, an optical isomer can be obtained in the form of pure stereochemical isomer conventional methods of separation of optical isomers (for example, fractional crystallization to obtain the diastereomeric salts with optically active bases or acids, chromatography using a chiral column and so on, and so on). In addition, the isomers can also be obtained from the appropriate optically active starting compound.

The pharmacological activity of the compounds according to the present invention is confirmed by the following test.

Test example 1

Antagonistic activity against receptor WV

Test for receptor binding W was carried out using the sample membrane, derived from PC-3 cells derived from prostate cancer person. PC-3 cells were cultured using the medium RPMI-1640 containing 5% fetal calf serum, and then the sample membrane was obtained using the following methods. To the cells, isolated by treatment with trypsin was added 50 mm buffer Tris-HCl (pH=7,4, the content is of ASI 0.2 mg/ml trypsinogen inhibitor and 0.2 mg/ml of benzamidine) and homogenized on the device transmitter station. Cell suspension was centrifuged at 1500 rpm for 10 minutes and the thus obtained supernatant for 1 hour and subjected to ultracentrifugation at acceleration of 37,000×g. The precipitate suspended in the above buffer to a concentration of 0.4 mg of protein per ml and kept at a temperature of -80°C.

Test for receptor binding W was performed using the following methodology and expected antagonistic activity of the test compound relative to the receptor. The sample membrane (50 μl), 50 μl of buffer for analysis (20 mm HEPES-HBSS containing 0.1% bovine serum albumin and 0.1 mg/ml bacitracin, pH=7,4),125I[Tyr4]bombezin (0,075 nm) and 2 μl of test compound dissolved in dimethyl sulfoxide were placed in a 96-well analytical tablet, and incubated at room temperature for 2 hours. Nonspecific binding was measured using 1 μm of bombezin. After incubation the reaction solution was filtered through a filter Whatman GF/B, which was impregnated with 0.5% solution of polyethylenimine. The radioactivity on the filter was measured using a scintillation counter for microplate (Top Count, Perkin-Elmer Co., Ltd.). Inhibiting the binding of 50% concentration of typical compounds of the examples presented in table 12. Further, Ex denotes the number of connections.

Table 12
No connection exampleIC50(nm)
6112,8
6218,3
2363,0
542the 4.7
5604,8
589the 5.7
6314,5
7006,7
7017,4
7098,9
7126,7
8566,8

Test example 2

Model defecation induced stress limits mobility

The connection, the test presented test used when dissolved in water for injection, containing a solution of 20% propylene glycol + 20% Tween 80 or 0.5% MC (methylcellulose).

Fifteen minutes after oral administration of test compounds to male rats Wista, exposed feeding, the animal was placed in a cell for testing the stress of restricted mobility (KN-468, Natsume Seisakusho Co., Ltd.). Determined the amount of faeces allocated during the period from the start of the restriction to 1 hour after that. The normal group was placed in a separate cage and likewise determined the amount of faeces, isolated within 1 hour.

The degree of inhibition (%) typical compounds of examples, when administered orally at a dose of that component 1 mg/kg are presented in table 13. In the result, it was confirmed that the compound according to the present invention exhibits excellent activity against weakening symptom of bowel movements bowel.

Table 13
No connection exampleThe degree of inhibition (%)
54240,0
56062,1
58973,9
63153,8
70069,8
70141,3
709 41,5
71255,0
85661,4

In the test result, as described above, it was found that the compound according to the present invention has inhibitory activity against receptor VV. From this point of view, it is obvious that the compound is suitable as a therapeutic agent against diseases associated with receptors WV, in particular IBS, cancer, functional dyspepsia, diabetic gastroparesis, reflux esophagitis, peptic ulcers, etc.

Drug containing one or two or more compounds (I)according to the present invention, or their salts as active ingredient, can be obtained in accordance with a commonly used method of using a pharmaceutical carrier, excipient, etc. which are usually used in this field.

The introduction can be performed by any means of oral administration via tablets, pills, capsules, granules, powders, liquid medicines, or the like; or by parenteral administration via injections such as intraarticular, intravenous or intramuscular injections, suppositories, eye drops, eye ointments, transdermal liquid medicines, ointments, transdermal what's patches, transmucosally liquid medicines, transmucosal patches, inhalations and the like

Relatively solid composition for oral administration according to the present invention using tablets, powders, granules or the like In such solid compositions one or two or more active ingredients are mixed with at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and/or alumosilicate magnesium, etc. In accordance with the conventional method, the composition may contain inert additives such as lubricating substance, such as magnesium stearate, disintegrity agent, such as natrocarbonatite, a stabilizing agent and solubilizers agent. If necessary, tablets or pills may be coated with a sugar coating or a film of gastrosoluble or Intercollege material.

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs or the like and contains a generally used inert diluent such as purified water and ethanol. In addition to the inert solvent, this liquid composition may contain an auxiliary agent such as solubilizers agent, wetting and the UNT and suspendisse agent, sweetener, flavoring agent, a flavoring and a preservative.

Injectable solutions for parenteral administration include sterile aqueous or non-aqueous liquid medicines, suspensions and emulsions. As the aqueous solvent include, for example, distilled water for injection and physiological saline. Examples of non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (Japanese Pharmacopeia), etc. Such composition may further contain a toning agent, a preservative, a wetting agent, emulsion, dispersing agent, stabilizing agent or solubilizers agent. They are sterilized, for example, by filtration through a retaining bacteria filter, mixing with bactericide or by irradiation. In addition, they can also be used to obtain sterile solid compositions and dissolving or suspension in sterile water or a sterile solvent for injection before use.

Medicinal product for external use include ointments, plasters, creams, gels, poultices, sprays, lotions, eye drops, eye ointments, etc. medication contains the most commonly used basis for ointments, foundations for lotion, aqueous or nonaqueous solutions, suspen the AI, emulsions and the like, examples of the bases for ointments or lotion include polyethylene glycol, propylene glycol, white petrolatum, white wax, polyoxyethylenesorbitan castor oil, glycerylmonostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, servicesexperience etc.

Relatively transmucosal agent, such as a dosage form for inhalation, transnasal agent, etc., they are used in solid, liquid or semi-solid state, and can be obtained in accordance with the traditionally known manner. For example, if you want, you can add a known excipient and, optionally, an agent for regulating the pH, antiseptic, surfactant (surfactant), a lubricating agent, a stabilizing agent, a thickener, etc. For their introduction you can use a suitable inhalation device or blowing. For example, the connection can be entered separately or in the form of a powder mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using traditionally known device or atomizer, such as a device for inhalation with the introduction of a certain dose, etc. Inhaler dry powder or the like can be used for single or multiple injections and you can use dry powder or capsule containing the powder. Alta is natively, the connection can be in such form, as aerosol spray under high pressure, which uses the appropriate propellant, for example a suitable gas, such as chlorphenesin, hydroforce, carbon dioxide, etc.

In the case of conventional oral administration, the daily dose generally may be about 0.001 to 100 mg/kg, preferably 0.1 to 30 mg/kg and even more preferably 0.1 to 10 mg/kg body weight, and the introduction is carried out in the form of one portion or in the form of 2-4 separate portions. Also, in the case of intravenous administration, a daily dose of approximately of 0.0001-10 mg/kg body weight, once a day, or two or more times per day. In addition, transmucosally agent is administered at a dose of about 0.001-100 mg/kg body weight, once a day, or two or more times per day. Dose respectively determined depending on the individual case, taking into account the symptoms, age, gender or other

The connection according to the present invention can be used in combination with other therapeutic or prophylactic agents against diseases, in which case the connection according to the present invention is effective. Combined drug can be administered simultaneously or separately and continuously or at desired time interval. Drugs,added together, can be a mixture or obtained individually.

EXAMPLES

In more detail below describes how to obtain the compound (I) according to the present invention with reference to examples. The connection according to the present invention is not limited to the compounds described in the examples below. Further, the methods of obtaining the starting compounds are described in the examples received.

In addition, in the examples, the examples of the preparation and the tables described below, using the following abbreviations:

PEX: Sample receipt; Ex: Example; No Connection, no; Data: physicochemical data (EI+: the value of m/z in EI-MS (cation) (unless otherwise stated, (M)+.), FAB+: the value of m/z FAB-MS (cation) (unless otherwise stated, (M+N)+.), FAB-: the value of m/z FAB-MS (anion) (unless otherwise stated, (M-N)-.), ESI+: the value of m/z ESI-MS (cation) (unless otherwise stated, (M+N)+.), ESI-: the value of m/z ESI-MS (anion) (unless otherwise stated, (M-N)-.), CI+: the value of m/z in CI-MS (cation) (unless otherwise stated, (M+N)+.), APCI+: the value of m/z ARS-MS (cation) (unless otherwise stated, (M+N)+.), APCI-: the value of m/z ARS-MS (anion) (unless otherwise stated, (M-N)-.), AMR: δ (ppm) of characteristic peak at δ (ppm)1H-NMR, DMSO-d6, structure: structural formula (if Hcl, HBr, fum (FUM.) or TFOC indicated in the structural formula, it indicates that the connection is what is hydrochloride, the hydrobromide, fumarate or trifurcation, respectively. In the case where the salt component written figure, this figure indicates the molar ratio of the compound to the salt component. For example, if written 2hcl, it means that the connection is a dihydrochloride. Further, if H2About specified in the structural formula, it means that the connection is in each case the hydrate), Syn: method get (the figure indicates that the receive carried out using the appropriate starting material, similar to the case "connection example", having its number as the example No.). If before the specified number R, this number indicates that the connection will be received, using the appropriate starting material, similar to the case "connection example", having its number as the example No.). The case where there are a lot of figures, indicates that the connection is obtained by performing the reaction in order, starting with the first digit, when using the appropriate starting materials. Note: (racemic mixture means the racemic mixture, diastereomer mixture means diastereomer mixture and the chiral coupling means chiral compound in which a part of its stereochemistry is not clear. Hereinafter, the terms "less polar and more polar the initial" means a product with a low polarity and a product with high polarity, accordingly, compared with the corresponding diastereomers, according to thin-layer chromatography. Next, 3,4-TRANS, 1',2'-CIS, etc. mean relative configuration of the substituents or the like, provided that the figure that without the stroke, indicates the position substituted in tetrahydroisoquinoline-1-about the ring, and dial with bar indicates the position substituted by the Deputy located in position 2 in tetrahydroisoquinoline-1-about the ring. For example, 3,4-TRANS indicates that the substituents in positions 3 and 4 in tetrahydroisoquinoline-1-about the ring are TRANS). BOC: tert-butoxycarbonyl group, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.

In addition,indicates that the double bond is CIS or TRANS, or their mixture.

Example obtain 1

10 g of 5-(Benzyloxy)-1H-inden-1,2(3H)-dione-2-oxime is added to 20 ml of thionyl chloride at 0°C, then stirred for 20 minutes under the same conditions. After heating to room temperature thionyl chloride is evaporated under reduced pressure. To the residue is added 20 ml of 40% aqueous potassium hydroxide solution, and then refluxed overnight. After cooling to room temperature and neutralize by adding concentrated hydrochloric acid, the precipitated solid is collected by filtration, getting 9,9 g -(benzyloxy)-2-(carboxymethyl)benzoic acid as a dark brown powder.

Example of getting 2

To the mixture 2,01 g of diethyl [3-(1,3-dioxolane-2-yl)phenyl]malonate, 2,89 g of calcium chloride and 50 ml ethanol add 2,47 g of sodium borohydride under ice cooling, and then stirred at the same temperature for 2 hours and at room temperature for 4 hours. To the reaction solution add 10 ml of water at room temperature, then stirred for 30 minutes. The insoluble matter is separated by filtration using celite, and the filtrate concentrated under reduced pressure to get 0,76 g of 2-[3-(1,3-dioxolane-2-yl)phenyl]propane-1,3-diol as a colorless oily substance.

Example of getting 3

A mixture of 1.83 g of 2-[3-(1,3-dioxolane-2-yl)phenyl]propane-1,3-dialdictate and 60 ml of 83% aqueous solution of acetic acid is stirred at 50°C for 2 hours. The reaction solution is concentrated under reduced pressure, obtaining of 1.59 g of 2-(3-formylphenyl)propane-1,3-dialdictate in the form of a colorless oily substance.

Example 4

To a solution of 958 mg (6-methylpyridin-3-yl)methanol, 1.3 ml of triethylamine and 95 mg of DMAP in 40 ml of dichloromethane are added dropwise at 1.08 ml of benzoyl chloride, and then stirred at room temperature. To the reaction solution was added water, and then carry out the extraction with chloroform. The organic layer was washed with saturated aqueous chlorine is IDA sodium, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate), obtaining 1767 mg (6-methylpyridin-3-yl)methylbenzoate.

Example of getting 5

To a solution of 1767 mg (6-methylpyridin-3-yl)methylbenzoate 26.5 ml of chloroform added 2440 mg of m-chloroperbenzoic acid under ice cooling, and then stirred for 1 hour. Add an aqueous solution of potassium carbonate to effect the separation of the liquid, the organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The residue concentrated under reduced pressure, obtaining 1891 mg (6-methyl-1-oxidability-3-yl)methylbenzoate.

An example of obtaining 6

To a solution of 1891 mg (6-methyl-1-oxidability-3-yl)methylbenzoate in 38 ml of DMF, add 11 ml triperoxonane anhydride, and then stirred at room temperature overnight. After evaporation triperoxonane anhydride under reduced pressure to add saturated aqueous solution of sodium bicarbonate, then extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: polypropylene cotton the dress is St-methanol), getting 3,675 g [6-(hydroxymethyl)pyridine-3-yl]methylbenzoate.

Example of getting 7

To a solution 858 mg pyrazin-2,5-diylbis(methylene)diacetate 8.6 ml of methanol add 600 mg of zeolite, and then refluxed for 4 days. The zeolite is removed by filtration, then the filtrate is concentrated and the residue purified by column chromatography on silica gel (eluent: chloroform-methanol)to give 209 mg of [5-(hydroxymethyl)pyrazin-2-yl]methyl acetate.

Example obtain 8

To a mixture of 313 mg of 6-(hydroxymethyl)nicotinamide, 540 mg of triphenylphosphine, 503 mg N-hydroxyphthalimide and 4.7 ml of THF are added dropwise to 0.53 ml of diisopropylcarbodiimide, then stirred overnight. After concentrating the thus obtained solid matter suspended in water and add ethyl acetate. After stirring for 30 minutes, the solid is collected by filtration, getting 292 mg of 6-{[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)oxy]methyl}nicotinamide.

Example of getting 9

To a suspension of 292 mg of 6-{[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)oxy]methyl}nicotinamide 4.4 ml of methanol, add 0.2 ml of 40% methylamine/methanol, and then stirred at room temperature for 1 hour. The reaction solution is concentrated and add ethyl acetate and the precipitated crystalline substance separated by filtration is, and then concentrated under reduced pressure, getting 146 mg of 6-[(aminooxy)methyl]nicotinamide.

Example 10

To a mixture of 3.0 g of 6-chloronicotinic acid and 111 ml of THF added 6.4 g of tert-butoxide potassium, then refluxed for 1 day. The reaction solution was poured into water, neutralized with citric acid and then extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, getting 2.16 g of 6-tert-butoxyethanol acid.

Example of getting 11

To a mixed solution 2163 mg of 6-tert-butoxyethanol acid and 32 ml of acetone add 2297 mg of potassium carbonate and 0.97 ml of methyliodide, then stirred at 35°C during the night. Add ethyl acetate and water to effect the separation of liquid and the organic layer is dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, getting 1,191 g of methyl 6-tert-butoxysilane.

Example 12

To a mixed solution 1191 mg of methyl 6-tert-butoxysilane and 35.7 ml of ethanol is added slowly 2153 mg of sodium borohydride, and then stirred at 50°C for 18 hours. After addition of methanol there is added water and ethyl acetate to perform the extraction. The organic layer is dried over anhydrous sulfate m is fester and then concentrated under reduced pressure, getting 0,949 g (6-tert-butoxypropan-3-yl)methanol.

Example of getting 13

To a mixed solution of 1020 mg of 5-[(aminooxy)methyl]-2-tert-butoxypropan, which is produced by the interaction of (6-tert-butoxypropan-3-yl)methanol and N-hydroxyphthalimide in accordance with the example of obtaining 8, with the subsequent removal of phthalimide in accordance with the example of getting a 9, and 20 ml of ethyl acetate added 1.3 ml of concentrated hydrochloric acid under ice cooling, and then stirred for 30 minutes. The obtained solid substance was separated by filtration, the filtrate then add concentrated hydrochloric acid and the precipitated solid is collected by filtration, getting 351 mg hydrochloride 5-[(aminooxy)methyl]pyridine-2(1H)it is in the form of a colorless solid.

Example of getting 14

To a mixture of 659 mg of 1-(chloromethyl)-4-(methylsulphonyl)benzene and 10 ml of DMSO added 525 mg N-hydroxyphthalimide and 445 mg of potassium carbonate, and then stirred at 50°C for 2 hours. The reaction solution is cooled, then there is added water and the precipitated crystalline substance is collected by filtration, getting 685 mg of 2-{[4-(methylsulphonyl)benzyl]oxy}-1H-isoindole-1,3(2H)-dione in the form of a solid white color.

Example get 15

The solution to 5.08 g of tert-butyl [4-(hydroxymethyl)phenoxy]acetate and 4.6 ml of triethylamine in 30 the l dichloromethane added to 1.98 ml methanesulfonanilide under ice cooling, then stirred for 1 hour under ice cooling. The reaction solution was poured into water, then extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent then evaporated. To a solution of the obtained residue in 40 ml of DMF add 4.26 deaths g of sodium azide, and then stirred at 60°C for 15 hours. After allowed to cool, the reaction solution was poured into water, then extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent then evaporated. The residue is purified by column chromatography on silica gel (eluent: ethyl acetate-hexane)to give 5,16 g of tert-butyl [3-(azidomethyl)phenoxy]acetate as a pale yellow oily substance.

Example 16

To a mixed solution of 5.00 g of methyl 5-formylthiophene-3-carboxylate and 50 ml of THF added to 0.67 g of sodium borohydride under ice cooling. To the reaction solution are added dropwise 5 ml of methanol, and then stirred for 1 hour under ice cooling. In the reaction solution was added 1 M hydrochloric acid, extracted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer su is at over anhydrous magnesium sulfate and the solvent is then evaporated, receiving a 4.86 g of methyl 5-(hydroxymethyl)thiophene-3-carboxylate as a pale yellow oily substance.

Example of getting 17

To a mixed solution of a 4.86 g of methyl 5-(hydroxymethyl)thiophene-3-carboxylate and 50 ml of dichloromethane add 4,12 ml of thionyl chloride under ice cooling, and then stirred at room temperature for 15 hours. The reaction solution concentrate, add ethyl acetate and then washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate the solvent is then evaporated, receiving of 4.90 g of methyl 5-(chloromethyl)thiophene-3-carboxylate as a pale yellow oily substance.

Example of getting 18

To a solution of 3.69 g of di-tert-butylmethacrylate in 54 ml of DMF add 1,91 g of tert-butoxide potassium at a temperature of 0°C in an argon atmosphere, and then stirred at room temperature for 1 hour. Slowly add a solution of 2.7 g of methyl 5-(chloromethyl)thiophene-3-carboxylate 8.1 ml of DMF, and then stirred at room temperature overnight. To the reaction solution was added water and ethyl acetate, and then perform the extraction and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure is I. The residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate), obtaining 4,394 g of methyl 5-{[bis(tert-butoxycarbonyl)amino]methyl}thiophene-3-carboxylate.

Example of getting 19

To a mixed solution of 400 mg of ethyl debtor(3-were)acetate and 10 ml of carbon tetrachloride is added 349 mg of N-bromosuccinimide and 15 ml of 2,2'-azobis(isobutyronitrile), then refluxed for 2 hours. After cooling the reaction solution, the insoluble matter is separated by filtration and the filtrate concentrated. To the residue add hexane, washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvent the residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate)to give 458 mg of ethyl [3-(methyl bromide)phenyl](debtor)acetate as a colorless oily substance.

Example of getting 20

To a mixed solution 2,89 g of ethyl 2-methyl-2-(3-were)propionate and 90 ml of carbon tetrachloride is added to 4.98 g of N-bromosuccinimide and 115 mg of 2,2'-azobis(isobutyronitrile), then stirred at a temperature of 80°C for 2 hours and then add back to 4.98 g of N-bromosuccinimide and 115 mg of 2,2'-azobis(isobutyronitrile), then stirred at a temperature of 80 the C for 14 hours. After cooling the reaction solution, the insoluble matter is separated by filtration and the solvent is evaporated. To the residue add hexane and then washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and the solvent is then evaporated, obtaining 6.0 g of pale yellow oily substance. The obtained oily substance was dissolved in 30 ml of THF and add back to 21.7 ml diethylphosphate and 29.3 ml diisopropylethylamine under ice cooling, and then stirred at room temperature for 13 hours. The reaction solution was poured into ice water, then extracted with hexane. The organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate the solvent is evaporated and the residue purified by column chromatography on silica gel (eluent: hexane-ethyl acetate), obtaining 2,95 g of ethyl 2-[3-(dibromomethyl)phenyl]-2-methylpropionate in the form of a pale yellow oily substance.

Example of getting 21

To a mixed solution 2,95 g of ethyl 2-[3-(dibromomethyl)phenyl]-2-methylpropionate and 30 ml of acetic acid add 4.77 g of potassium acetate, and then stirred at a temperature of 100°C for 6 hours. After cooling, the reaction restorated add 10 ml of 6 M hydrochloric acid solution, then stirred at room temperature for 2 hours. The reaction solution was poured into water, then extracted with hexane and the organic layer washed with water and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and the solvent is then evaporated, receiving of 1.74 g of ethyl 2-(3-formylphenyl)-2-methylpropionate in the form of a colorless oily substance.

Example of getting 22

To a mixed solution of 1.00 g of tert-butyl piperidine-4-ylcarbamate and 20 ml of pyridine type of 0.77 ml methanesulfonanilide, then stirred at room temperature for 18 hours. After evaporation of the pyridine under reduced pressure there is added ethyl acetate, then washed with 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying the organic layer over anhydrous magnesium sulfate the solvent is evaporated and the resulting solid is washed with diethyl ether, receiving 1.19 g of tert-butyl [1-(methylsulphonyl)piperidine-4-yl]carbamate in the form of a solid white color.

An example of retrieving 23

To a solution of 1 g of tert-butyl [3-(cyanomethyl)phenoxy]acetate in 20 ml of THF and 10 ml of methanol are added dropwise, the suspension of 1.31 g of cobalt chloride and 20 ml of water and then add back portions 459 mg Bo is sodium hydride at room temperature. After stirring at room temperature for 10 minutes, the insoluble matter is separated by filtration through celite, washed with methanol and then concentrated. The resulting residue is extracted with chloroform, dried over anhydrous magnesium sulfate and the solvent then evaporated. The resulting residue is purified by column chromatography on silica gel (eluent: chloroform-methanol-saturated aqueous ammonia)to give 632 mg of tert-butyl [3-(2-amino-ethyl)phenoxy]acetate as a pale yellow oily substance.

Example of getting 24

To a mixed solution 5,16 g of tert-butyl [3-(azidomethyl)phenoxy]acetate and 50 ml of THF type of 6.17 g of triphenylphosphine and 1.04 ml of water, then stirred at room temperature for 4 days. The solvent is evaporated and add diisopropyl ether. The precipitated solid is separated by filtration and the solvent again evaporated. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol-saturated aqueous ammonia), receiving of 4.10 g of tert-butyl [3-(aminomethyl)phenoxy]acetate as a pale yellow oily substance.

Example get 25

To a mixed solution of 2.00 g of (1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarbonyl acid and 40 ml of dichloromethane type of 1.41 ml of 2-(trimethylsilyl)ethanol ,40 g of DMAP and of 2.21 g of WSC, in this order, and then stirred at room temperature for 60 hours. After evaporation of the solvent there is added ethyl acetate, then washed with water, 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, in that order. The organic layer is dried over anhydrous magnesium sulfate and the solvent is then evaporated, getting 2,82 g 2-(trimethylsilyl)ethyl (1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate in the form of a colorless oily substance.

Example of getting 26

To a solution 2,82 g 2-(trimethylsilyl)ethyl (1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate in 10 ml of ethyl acetate are added 20 ml of 4 M solution of hydrogen chloride in ethyl acetate under ice cooling, and then stirred at room temperature for 6 hours. The reaction solution is evaporated, receiving of 2.30 g of 2-(trimethylsilyl)ethyl (1RS,2SR)-2-aminocyclohexanecarboxylic in the form of a colorless amorphous substance.

Example of getting 27

To the mixed solution and 4.40 g of methyl ester of N-[(benzyloxy)carbonyl]-3-[(methylsulphonyl)amino]-D-alanine, 100 ml of THF and 50 ml of ethanol is added 1.13 g of lithium chloride, and then there is added 1.01 g of sodium borohydride under ice cooling. The reaction solution was stirred at room temperature for 14 the aces and the solvent is then evaporated under reduced pressure. After adding 150 ml of water there is added concentrated hydrochloric acid until a pH of 2 to 3. The solution is extracted with ethyl acetate, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting 3,10 g of benzyl [(1R)-2-hydroxy-1-{[(methylsulphonyl)amino]methyl}ethyl]carbamate in the form of a solid white color.

Example of getting 28

To a mixed solution of 3.10 g of benzyl [(1R)-2-hydroxy-1-{[(methylsulphonyl)amino]methyl}ethyl]carbamate and 50 ml of ethanol is added 500 mg of 5% palladium on coal, then stirred at room temperature for 2 hours in hydrogen atmosphere. Palladium on coal is separated by filtration and the solvent is then evaporated, getting 1,72 g of N-[(2R)-2-amino-3-hydroxypropyl]methanesulfonamide in the form of a colorless oily substance.

An example of obtaining 29

To 700 mg of 2-(6-methoxypyridine-2-yl)ethylamine add 10 ml of 47% aqueous HBR, and then stirred at a temperature of 80°C for 60 hours. After evaporation of the solvent the residue was washed with diethyl ether, getting to 1.21 g of the hydrobromide 6-(2-amino-ethyl)pyridine-2(1H)-it is in the form of a solid pale brown color.

Example 30

The mixture 3980 mg of 2-[2-(1H-tetrazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione, of 0.90 g of hydrazine monohydrate and 80 is l of ethanol is stirred at 70°C for 12 hours. The reaction solution is allowed to cool and the insoluble matter is then collected by filtration. The filtered substance is suspended in dioxane and add 3.57 g of di-tert-BUTYLCARBAMATE at room temperature, then stirred for 12 hours. The insoluble matter is separated by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel with hexane/ethyl acetate as eluent, to obtain 2210 mg of tert-butyl [2-(1H-tetrazol-1-yl)ethyl]carbamate as a colourless solid.

An example of retrieving 31

To a solution 2,62 g of tert-butyl 1H-pyrrole-3-carboxylate and of 7.96 g of N-(2-bromacil)phthalimide in DMF (100 ml) is added 10.2 g of cesium carbonate at room temperature, then stirred for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract is washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The organic layer is concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel using hexane/chloroform as eluent, and washed with diethyl ether, receiving 670 mg of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)ethyl]-1H-pyrrole-3-carboxylate as a colourless TV is Gogo substances.

Example of getting 32

A mixture of 660 mg of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)ethyl]-1H-pyrrole-3-carboxylate, 194 mg of hydrazine monohydrate and 19 ml of ethanol is stirred at 70°C for 12 hours. The reaction solution is allowed to cool and the insoluble matter is then separated by filtration. The filtrate is concentrated under reduced pressure, getting 430 mg of tert-butyl 1-(2-amino-ethyl)-1H-pyrrole-3-carboxylate as a yellow oily substance.

An example of obtaining 33

To a solution of 8.75 g of 2,4-dichlorobenzaldehyde in 100 ml of chloroform, add 5,11 g cyclopentylamine and 5 g of molecular sieves 4Å, then stirred at room temperature overnight. After removal of the molecular sieves 4Å filtering there is added 6,48 g homophthalic anhydride, and then stirred at room temperature overnight and then refluxed for 5 hours. After concentration under reduced pressure there is added ethyl acetate and 1 M aqueous sodium hydroxide solution to separate the liquid. The aqueous layer was acidified by adding 1 M hydrochloric acid, then extracted with a mixture of chloroform-isopropyl alcohol (3:1). The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and the solvent is then evaporated at Pont the leaders introduce pressure. To the obtained residue is added diethyl ether and collected by filtration, getting 4,48 g of 3,4-CIS-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (example receive 33-1) in the form of a colorless crystalline substance. The mother liquor is concentrated and receiving 6,46 g of 3,4-TRANS-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (example obtaining 33-2) as a colorless amorphous substance.

An example of retrieving 34

To a mixed solution of 2,4-dichlorobenzaldehyde in a mixture of chloroform-methanol added TRANS-2-aminocyclohexanol, triethylamine and anhydrous sodium sulfate at room temperature, the reaction solution is stirred at 50°C over night and then there is added homophthalic anhydride at room temperature, then stirred at room temperature overnight. After removing sodium sulfate by filtration there is added chloroform and 1 M aqueous sodium hydroxide solution to separate the liquid and the aqueous layer was stirred at room temperature for 2 hours. This layer is acidified by adding 1 M hydrochloric acid and add ethyl acetate to separate the liquid. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then the flash steam is granted under reduced pressure. To the residue is added diethyl ether, then stirred at room temperature overnight. The precipitated crystalline substance is collected by filtration, getting 7655 mg 3RS,4RS-3-(2,4-dichlorophenyl)-2-(1SR,2SR-2-hydroxycyclohexyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (example obtaining 34-1) in the form of a colorless crystalline substance. After concentration of the mother liquor residue purified by column chromatography on silica gel (eluent: chloroform:methanol)to give 6600 mg 3SR,4SR-3-(2,4-dichlorophenyl)-2-(1RS,2RS-2-hydroxycyclohexyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (example obtaining 34-2) in the form of a colorless crystalline substance.

Example of getting 35

To 4,33 g (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexanol]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid, add 50 ml of ethanol and 2 ml of concentrated sulfuric acid and then refluxed overnight. Add ethyl acetate and water to separate the liquid and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer is dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate, receiving 2.3 g of ethyl (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexanol]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a yellow foam.

Example of getting 36

To a solution of 2.25 g of ethyl (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexanol]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 30 ml of acetonitrile, add 0.75 ml of methanesulfonanilide and 1.6 ml of diisopropylethylamine, then stirred at room temperature overnight. There is added ethyl acetate and water to separate the liquid and the organic layer was washed with saturated aqueous sodium chloride. The organic layer is dried over anhydrous sodium sulfate and then evaporated under reduced pressure. To the residue is added diethyl ether for crystallization and the product collected by filtration, getting 2,02 g of ethyl (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a colourless crystalline substance.

An example of retrieving 37

To a solution of 1.4 g of ethyl (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 20 ml of DMF add 229 mg of sodium hydride under ice cooling, and then stirred at the same temperature for 10 minutes and then there is added 0.17 ml of methyliodide, then stirred while cooling l the house within 30 minutes. Add the water, then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give 545 mg of ethyl (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[methyl(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a colorless amorphous substance.

An example of retrieving 38

To a mixture of 2.0 g of ethyl (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate, 10 ml of methanol and 10 ml of THF, add 10 ml of 1 M aqueous sodium hydroxide solution, and then stirred at room temperature for 1 hour. The solution is acidified by adding 1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining of 1.9 g of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid in the form of crystalline substances pale yellow color.

An example of retrieving 39

A mixture of 8 g of 4-(benzyloxy)-2-(carboxymethy is)benzoic acid and 30 ml of acetylchloride refluxed for 3 hours. The reaction solution is concentrated under reduced pressure, add diethyl ether and the product collected by filtration, receiving 7.50 g of 6-(benzyloxy)-1H-isochroman-1,3(4H)-dione in the form of a solid dark brown color.

Example of getting 40

To 612 mg of 6-[(aminooxy)methyl]pyridine-2(1H)-she received, subjecting 2-[(6-oxo-1,6-dihydropyridines-2-yl)methoxy]-1H-isoindole-1,3(2H)-dione removal phthalimide, in accordance with the example of obtaining 9, add 1.6 ml of 4 M solution of hydrogen chloride in ethyl acetate and the precipitated solid is collected by filtration, getting 263 mg of the hydrochloride of 6-[(aminooxy)methyl]pyridine-2(1H)-she in the form of a colorless solid.

An example of retrieving 41

To 2,04 g of hydrochloride (4-methyl-1H-imidazol-5-yl)methanol are added 20 ml of acetonitrile and there added to 2.1 ml of triethylamine, 3,14 g of di-tert-BUTYLCARBAMATE and 0.17 g of DMAP under ice cooling, and then stirred at room temperature. After concentrating the reaction solution under reduced pressure to the residue is added ethyl acetate and water to separate the liquid and the organic layer was washed with saturated aqueous sodium chloride. The organic layer is dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The resulting residue is subjected to interaction with N-hydroxyphthalimide in line the AI sample receiving 14, interaction with methylamine according to example get 9, and then remove the protective BOC-group in accordance with the example of obtaining 26, receiving of 0.53 g of the dihydrochloride of 5-[(aminooxy)methyl]-4-methyl-1H-imidazole as a colourless solid.

An example of retrieving 42

To a solution of 529 mg (5-herperidin-2-yl)methanol and 0.64 ml of triethylamine in 8 ml of dichloromethane added 0.35 ml of methanesulfonanilide under ice cooling, and then stirred for 1 hour under ice cooling. The reaction solution was poured into water, then extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent then evaporated. The resulting residue is subjected to interaction with N-hydroxyphthalimide in accordance with the example of obtaining 14, getting 522 mg of 2-[(5-herperidin-2-yl)methoxy]-1H-isoindole-1,3(2H)-dione in the form of a solid white color.

An example of retrieving 43

To a mixture of 2.97 g of 4-(hydroxymethyl)phenol, of 4.90 g of tert-butylbromide and 25 ml of DMF add 4,96 g of potassium carbonate at room temperature, then stirred for 12 hours. To the reaction solution was added water, then extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent then evaporated. The mod is to purify via column chromatography on silica gel (eluent: ethyl acetate-hexane), receiving a pale yellow oily substance. This oily substance is subjected to methysulfonylmethane in accordance with the example of obtaining 15, and then subjected to interaction with sodium azide, receiving a 4.03 g of tert-butyl [4-(azidomethyl)phenoxy]acetate as a pale yellow oily substance.

An example of retrieving 44

To a solution of 1.63 g of ethyl (3RS,4RS)-2-[(1SR,2SR)-2-{[(3-chlorpropyl)sulfonyl]amino}cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 20 ml of THF added 142 mg of sodium hydride, and then stirred at 50°C during the night. There is added ethyl acetate and water to separate the liquid. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate)to give 466 mg of ethyl (3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(1,1-dioxothiazolidine-2-yl)cyclohexyl]-1-oxitetraciclina-4-carboxylate as a colourless crystalline substance.

An example of retrieving 45

A solution of 5.0 g of 4-bromothiophene-2-carbaldehyde, 11,4 ml vinyltrimethylsilane and 3.6 g tetranitroaniline in 100 ml of toluene is heated at 110°C for 4 hours under sealed tube. Organicheskikh extracted with ethyl acetate and washed with water. In addition, the organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate)to give 3.4 g of 4-venitien-2-carbaldehyde in the form of liquid brown.

An example of retrieving 46

A solution of 5 g of methyl 1-methyl-1H-imidazole-5-carboxylate and 22.5 g of paraformaldehyde in 50 ml of methanol is heated at a temperature of 140°C for 60 hours under sealed tube. The precipitate is removed by filtration and the solution concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give 4 g of methyl 2-(hydroxymethyl)-1-methyl-1H-imidazole-5-carboxylate, in the form of a solid white color.

An example of retrieving 47

The phosphorus oxychloride (7,4 ml) was added dropwise to an 8.1 ml of DMF at 0°C, then warmed to room temperature. To this solution was added ethyl-3-furaat, then heated to a temperature of 126°C and stirred for 1 hour. After cooling to room temperature the reaction solution was poured into ice water. The organic layer is extracted with diethyl ether and washed with saturated aqueous sodium carbonate. In addition, the organic layer is dried over anhydrous sodium sulfate, and concentrate the ri reduced pressure. The residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate)to give 850 mg of ethyl 5-formyl-3-forunate in a solid yellow color.

Example obtain 48

To a mixed solution of 1.51 g of potassium cyanide and 70 ml of acetonitrile add 6,12 g 1,4,7,10,13,16-hexaoxacyclooctadecane, then stirred for 2 hours. After this there is added a solution of 5.00 g of tert-butyl 3-(chloromethyl)benzoate in 30 ml of acetonitrile, and then stirred at room temperature for 18 hours. The reaction solution is concentrated and diluted with a mixture of diethyl ether-hexane (1:1) and then washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate the solvent is evaporated and the residue purified by column chromatography on silica gel (eluent: hexane-ethyl acetate), obtaining 3,86 g of tert-butyl 3-(cyanomethyl)benzoate as a colorless oily substance.

An example of retrieving 49

A solution of 2 g (benzyloxy)acetic acid in 30 ml of DMF is cooled to 0°C and add back of 2.44 g of 1-(4-AMINOPHENYL)ethanone, 294 mg of DMAP and of 3.73 g WSC/hydrochloride, then stirred at room temperature for 3 hours. Separation of liquids carried out using a mixture of ethyl acetate-1 M solution of hydrochloric acid. The organic layer was washed with saturated aqueous Ki is recarbonate sodium and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, getting 3.12 g of N-(4-acetylphenyl)-2-(benzyloxy)ndimethylacetamide.

Example of getting 50

To a solution of 1.64 g of ethyl 2-(hydroxymethyl)isonicotinate of 32.8 ml of dichloromethane added to 1.24 ml dihydropyran and 2,32 g p-toluensulfonate pyridinium, then stirred overnight. Add ethyl acetate, then washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, obtaining 2.4 g of ethyl 2-[(tetrahydro-2H-Piran-2-yloxy)methyl]isonicotinate.

An example of retrieving 51

To a solution of 1.8 g of 1-[6-(hydroxymethyl)pyridine-2-yl]atanasoska in 36 ml of methanol is added 500 mg of 10% palladium on coal (50% wt.) in argon atmosphere, and then stirred for 7 days in an atmosphere of hydrogen. After filtration through celite, the filtrate is evaporated under reduced pressure, obtaining 1.5 g of [6-(1-amino-ethyl)pyridine-2-yl]methanol.

An example of retrieving 52

To a solution of 2.06 g of 3-amino-4-hydroxybenzoic acid of 20.6 ml of THF added to 4.81 g of CDI, then stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a mixed solution of 3.06 g of sodium borohydride in to 20.6 ml of THF and compared to 8.26 ml of water, cooled to 0°C, which is th is prepared separately, then stirred overnight. Add 1 M hydrochloric acid, then extracted with ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, obtaining 1.2 g of 5-(hydroxymethyl)-1,3-benzoxazol-2(3H)-it.

Example of getting 53

To 5 g diethylpyrazine-2,4-in primary forms add 50 ml ethanol and 50 ml of dichloroethane, and then cooled with ice. Add back portions 932 mg of sodium borohydride, and then stirred for 1 hour under ice cooling and then for 15 hours at room temperature. After cooling with ice, the reaction solution there is added 5 ml of 6 M hydrochloric acid, then stirred for 5 minutes and concentrate. Add saturated aqueous solution of sodium bicarbonate, then extracted with a mixture of chloroform-isopropanol (10:1) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure the residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give 0.7 g of ethyl 4-(hydroxymethyl)pyridine-2-carboxylate (example obtaining 53-1) and 1.6 g of ethyl 2-(hydroxymethyl)isonicotinate (example obtaining 53-2), respectively.

An example of retrieving 54

To 1.6 g of 1-(6-methoxypyridine-2-yl)ethanamine add 23,7 ml of 7% aqueous solution of hydrogen bromide, then stirred at a temperature of 80°C for 60 hours. After evaporation of the solvent under reduced pressure the residue was washed with diethyl ether, receiving 2,95 g of the hydrobromide 6-(1-amino-ethyl)pyridine-2(1H)-it is in the form of a solid pale brown color.

Example of getting 55

To a solution 2,31 g of tert-butyl 1H-pyrazole-3-carboxylate and 6,98 g of N-(2-bromacil)phthalimide in DMF (65 ml) type of 8.95 g of cesium carbonate at room temperature, then stirred for 12 hours. The reaction solution was diluted with water then extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: chloroform-hexane)to give 1.51 g of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)ethyl]-1H-pyrazole-3-carboxylate as a colourless solid.

An example of receiving 56

To a mixture of 2.92 g (2-hydroxyphenyl)acetonitrile, 4.71 g of tert-butylbromide and 110 ml of DMF add the 6.06 g of potassium carbonate at room temperature, then stirred for 12 hours. To the reaction solution was added water, then extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is purified by column chromatography on when likehere, using a mixture of hexane/ethyl acetate as eluent, to obtain 5.29 g of tert-butyl [2-(cyanomethyl)phenoxy]acetate as a yellow oily substance.

An example of retrieving 57

A mixture of 1.38 g of 6-(hydroxymethyl)pyridine-2(1H)-she, 2.15 g of tert-butylbromide, of 3.07 g of silver oxide and 33 ml of DMF was stirred at room temperature for 12 hours and then at 60°C for 12 hours. The insoluble matter is separated by filtration and the filtrate concentrated under reduced pressure. The residue is diluted with ethyl acetate, then washed with saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate)to give 1.92 g of tert-butyl {[6-(hydroxymethyl)pyridine-2-yl]oxy}acetate as a yellow oily substance.

An example of retrieving 58

To a mixture of 1.00 g of 3-hydroxybenzaldehyde, of 1.80 g of tert-butyl (R)-lactate, 2.58 g of triphenylphosphine and 40 ml of THF added 1,71 g diethylazodicarboxylate at room temperature, then stirred for 12 hours. The reaction solution was diluted with ethyl acetate, then washed with 5% aqueous sodium hydrogen carbonate solution. The organic layer is dried over anhydrous magnesium sulfate, and then the concentrate is t under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate), obtaining 1,49 g of tert-butyl (2S)-2-(3-formylphenoxy)propanoate in the form of a colorless oily substance.

To a solution of 1.48 g of tert-butyl (2S)-2-(3-formylphenoxy)propanoate in methanol (30 ml) is added to 0.48 g of sodium borohydride under ice cooling, and then stirred for 1 hour. The reaction solution was diluted with ethyl acetate, add water, neutralize 1 M hydrochloric acid and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, getting to 1.38 g of tert-butyl (2S)-2-[3-(hydroxymethyl)phenoxy]propanoate in the form of a colorless oily substance.

Example retrieve 59

The solution 2,90 g of 1,3-phenylendiamine acid, 3.00 g of 4-methoxybenzylamine and to 2.99 g of potassium bicarbonate in 15 ml of DMF was stirred at room temperature for 36 hours. To the reaction solution was added water, then neutralize 1 M solution of hydrochloric acid. The product is extracted with ethyl acetate and the organic layer is dried over anhydrous magnesium sulfate. After concentration under reduced pressure get 4,72 g of a colorless oily substance. A mixture of the obtained colorless oily substance (4.72 in), 2,42 g HOBt, 2,78 g of WSC hydrochloride, 3,99 g of ammonium chloride, of 7.55 g is ritilin and 18 ml of DMF was stirred at room temperature for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate)to give 4-methoxybenzyl [3-(2-amino-2-oxoethyl)phenyl]acetate as a colourless solid.

To a solution of 1.31 g of 4-methoxybenzyl [3-(2-amino-2-oxoethyl)phenyl]acetate in pyridine (20 ml) is added 718 mg methanesulfonanilide under ice cooling, and then stirred for 2 hours. The reaction solution is concentrated under reduced pressure. The residue is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, in that order. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate)to give 1.25 g of 4-methoxybenzyl [3-(cyanomethyl)phenyl]acetate as a yellow oily substance.

Example of getting 60

A mixture of 5.05 g of 5-methyl-2-frankenboob acid, 7,14 g CDI and 40 ml of DMF is stirred at 50°C for 2 hours. To the reaction solution was added of 6.71 g of DBU is 6,53 g 2-methyl-2-propanol at room temperature, then stirred at 50°C for 48 hours. The reaction solution is concentrated under reduced pressure and the obtained residue was diluted with diethyl ether and washed with 5% aqueous solution of ammonium chloride, saturated aqueous bicarbonatesodium and then with a saturated aqueous solution of sodium chloride, in that order. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: hexane-ethyl acetate), obtaining 2,82 g of tert-butyl 5-methyl-2-furancarboxylic in the form of a yellow oily substance.

An example of retrieving 61

To a solution of 1643 mg 1-[6-(hydroxymethyl)pyridine-2-yl]ethanone in 25 ml ethanol add to 0.72 ml of 50% aqueous hydroxylamine, then stirred overnight. The reaction solution is concentrated under reduced pressure, getting 1806 mg 1-[6-(hydroxymethyl)pyridine-2-yl]atanasoska in the form of an amorphous substance.

An example of retrieving 62

To a mixture of 2.06 g of tert-butyl ({6-[(hydroxymethyl)pyridine-2-yl]oxy}acetate, 2,60 g of triphenylphosphine, 2.70 g of phthalimide and 40 ml of THF added 1.73 g of diethylazodicarboxylate at room temperature, then stirred for 36 hours. To the reaction solution was added ethyl acetate, then washed with 5% aqueous solution of the bicarbonate is sodium. The organic layer is dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure and the residue purified by column chromatography on silica gel, receiving of 2.33 g ({6-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]pyridine-2-yl}oxy)acetic acid as colorless solid.

An example of retrieving 63

To the mixture 1266 mg of {2-[(tetrahydro-2H-Piran-2-yloxy)methyl]pyridine-4-yl}methylbenzoate and 25 ml of methanol add 1166 mg p-toluensulfonate pyridinium, then stirred for 2 hours. Add saturated aqueous sodium hydrogen carbonate solution and chloroform extraction, the organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, getting 941 mg of [2-(hydroxymethyl)pyridine-4-yl]methylbenzoate in the form of an amorphous substance.

Connection examples get 64-371 get a similar manner according to the methods of examples obtain 1-63 and methods of the examples described below, using in each case the relevant source materials. The structural formula and the physicochemical data of the compounds of examples of the preparation are given in tables 14-69.

Example 1

To a solution of 808 mg of 3,4-CIS-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid, 0.3 ml of phenethylamine and 405 mg of HOBt in dichloromethane (20 ml) is added 576 mg of WSC hydrochloride Ave is room temperature, then stirred for 2 hours. To the reaction solution was added chloroform and the organic layer washed with water and saturated aqueous sodium chloride, in that order, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: chloroform), receiving 902 mg of 3,4-TRANS-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colourless crystalline substance.

Example 2

To a mixture of 202 mg of 3,4-CIS-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid and 5 ml of dichloromethane added to 0.055 ml oxalicacid and one drop of DMF under ice cooling, and then stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure, the obtained residue is dissolved in 5 ml of THF and there is added with 0.13 ml of phenethylamine and 0.07 ml of triethylamine and then stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, add ethyl acetate and washed with water and saturated aqueous sodium chloride, in that order. The organic layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Received mod is to purify via column chromatography on silica gel (eluent: chloroform) and the crude product is then collected by filtration, using diethyl ether, to obtain 127 mg of 3,4-CIS-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colourless crystalline substance.

Example 3

To a mixture of 254 mg of 3,4-TRANS-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-N-[2-(2-pyridinyl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml dichloromethane added 173 mg of m-chloroperbenzoic acid under ice cooling, and then stirred at room temperature overnight. To the reaction solution was added chloroform, washed with 10% hydrogen sulfite solution sodium and saturated aqueous sodium chloride, in that order, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: chloroform-methanol) and then recrystallized from ethanol, getting 138 mg of 3,4-TRANS-2-cyclopentyl-3-(2,4-dichlorophenyl)-N-[2-(1-oxidability-2-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colourless crystalline substance.

Example 4

To 654 mg of ethyl ester of N-{[(3,4-TRANS-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}-β-alanine add 5 ml of THF, 2 ml of methanol and 5 ml of 1 M aqueous sodium hydroxide solution at room temperature, then stirred PR is 50°C for 3 hours. After neutralization by addition of 1 M hydrochloric acid added ethyl acetate for extraction. The organic layer is washed with water and saturated aqueous sodium chloride, in that order, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The obtained solid white recrystallized from ethyl acetate, getting 294 mg of N-{[(3,4-TRANS-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}-β-alanine in the form of colorless powdery crystalline substance.

Example 5

To 410 mg of tert-butyl {2-[3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbarnoyl]-3,4-dihydroisoquinoline-2(1H)-yl]ethyl}carbamate add 4 ml of 4 M solution of hydrogen chloride in ethyl acetate, and then stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure and then add chloroform and 1 M aqueous sodium hydroxide solution to separate the liquid. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The obtained residue is recrystallized from a mixture of ethyl acetate-hexane, getting 192 mg of 2-(2-amino-ethyl)-3-(2,4-dichlorophenyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colourless powder Krista is symbolic substance.

Example 6

To a solution of 537 mg of 3,4-TRANS-2-(TRANS-4-aminocyclohexane)-3-(2,4-dichlorophenyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 10 ml of dichloromethane added 0.33 ml of an aqueous solution of formalin and 893 mg triacetoxyborohydride sodium, then stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, then extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate and the solvent is evaporated. The resulting residue is purified by column chromatography on silica gel (eluent: chloroform-methanol) and the resulting solid white recrystallized from ethyl acetate, receiving 82 mg of 3,4-TRANS-3-(2,4-dichlorophenyl)-2-[TRANS-4-(dimethylamino)cyclohexyl]-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colourless crystalline substance.

Example 7

To a solution 2,03 g of 3,4-TRANS-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbarnoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in 20 ml of THF, add 810 mg CDI, then stirred by heating at 50°C for 1 hour. After cooling to room temperature, add a mixture of 200 mg of sodium borohydride and 10 ml of water, then stirred at room t is mperature for 4 hours. Add ethyl acetate and water to separate the liquid and the organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate and then evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform) and the resulting solid is recrystallized from ethyl acetate, getting 255 mg of 3,4-TRANS-2-cyclopentyl-3-(hydroxymethyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colourless crystalline substance.

Example 8

To 304 mg (3RS,4RS)-N-(benzyloxy)-3-(4-methyl-3-nitrophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide add 10 ml of acetic acid and 560 mg of recovered iron, then stirred at 50°C during the night. To the reaction solution was added methanol, then filtered through celite and, after concentration of the mother liquor, add ethyl acetate and water to separate the liquid. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform:methanol). The obtained solid substance is not amaut in hydrochloride, using a 4 M solution of hydrogen chloride in ethyl acetate and recrystallized from isopropyl alcohol, receiving 180 mg hydrochloride (3RS,4RS)-3-(3-amino-4-were)-N-(benzyloxy)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a pale yellow powdery crystalline substance.

Example 9

To 393 mg of 3,4-TRANS-2-cyclopentyl-3-(hydroxymethyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide add 10 ml of THF and 44 mg of sodium hydride, and then stirred at room temperature for 30 minutes. To the reaction mixture add 161 mg of 4-chlorobenzylamino, then stirred at room temperature overnight. To the reaction mixture are added ethyl acetate and water to separate the liquid and the organic layer was washed with saturated aqueous sodium chloride. The organic layer is dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform), the obtained solid is crystallized from a mixture of diethyl ether-hexane and the product is collected by filtration, getting 134 mg of 3,4-TRANS-3-{[(4-Chlorobenzyl)oxy]methyl}-2-cyclopentyl-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdery crystal in the society.

Example 10

To a solution of 573 mg (3RS,4RS)-N-(2-chloroethyl)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 10 ml of DMF, add 150 mg of sodium iodide and 340 mg of 1H-pyrazole, and then stirred at a temperature of 100°C for 24 hours. Add ethyl acetate and water to liquid separation, the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give a colorless crystalline substance. This crystalline material is recrystallized from ethanol, getting 176 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-[2-(1H-pyrazole-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of colorless powdery crystalline substance.

Example 11

To a mixture of 270 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexanol]-3-(2,4-dichlorophenyl)-1-oxo-N-(pyridine-2-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of pyridine type of 0.11 ml of acetic anhydride, and then stirred at room temperature for 2 hours. Add ethyl acetate and water to separate the liquid and the organic layer was washed with saturated aqueous solution of hydrocar is onata sodium and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give a colorless crystalline substance. To the resulting crystalline substance, add diethyl ether and the product collected by filtration, receiving 55 mg of (3RS,4RS)-2-[(1SR,2SR)-2-acetamidocinnamate]-3-(2,4-dichlorophenyl)-1-oxo-N-(pyridine-2-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of colorless powdery crystalline substance.

Example 12

To a mixture of 538 mg (3RS,4RS)-2-{(1SR,2SR)-2-aminocyclohexanol}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 2.5 ml of pyridine, add 0.15 ml of methanesulfonanilide, then stirred at room temperature for 6 hours. Add ethyl acetate and water to separate the liquid and the organic layer washed with 1 M aqueous hydrochloric acid solution and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform) and then recrystallized from a mixture of ethyl acetate-hexane, getting 206 mg of (3RS,4RS)-N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydrothieno the Jn-4-carboxamide in the form of colorless powdery crystalline substance.

Example 13

To a mixed solution of 200 mg (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexanol]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 40 ml of dimethoxyethane add 357 mg sulphonamide, then stirred at a temperature of 80°C for 2 days. The reaction solution is concentrated and add chloroform and then washed with water. The organic layer is dried over anhydrous magnesium sulfate and the solvent then evaporated. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol), crystallized from ethyl acetate and the product is collected by filtration, receiving 62 mg of (3RS,4RS)-2-{(1SR,2SR)-2-[(aminosulfonyl)amino]cyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a crystalline substance of white color.

Example 14

To a mixed solution of 269 mg (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexanol]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of chloroform added to 0.21 ml dimethylsulfoxide, then stirred at room temperature for 15 hours and then at 60°C for 24 hours. In addition, add 500 mg of sodium carbonate and then stirred at 60°C for 5 hours. In addition, the add back of 0.21 ml dimethylsulfoxide, then stirred at temperature is round 60°C for 5 hours. After cooling, the reaction solution is then carry out the separation of liquids using water and chloroform. The organic layer was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvent the residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give a colorless amorphous substance. This is obtained amorphous substance is crystallized from ethyl acetate, receiving 99 mg of (3RS,4RS)-N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-{[(dimethylamino)sulfonylamino]amino}cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a crystalline substance of white color.

Example 15

To a mixed solution of 269 mg (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexanol]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 20 ml of ethanol added 53 mg nitrocefin, then refluxed for 1 hour. The reaction solution is cooled, then concentrated and the residue purified by column chromatography on silica gel (eluent: chloroform-methanol), and then crystallized from acetonitrile and the product collected by filtration, getting 155 mg of (3RS,4RS)-N-(benzyloxy)-2-[(1SR,2SR)-2-(carbamoylation)cyclohexyl]-3-(2,4-dichlorophenyl)-1-ACS is -1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a crystalline substance of white color.

Example 16

To a mixed solution of 269 mg (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexanol]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml DMF added 58 mg of sodium carbonate and 119 mg of the hydrochloride of methylethylacetate, then stirred at 60°C for 1 hour. After that, stirring at 60°C, add 233 mg sodium carbonate and 478 mg of the hydrochloride of methylethylacetate, in the form of four individual portions every hour. After cooling the reaction solution there is added water, and then extracted with a mixture of chloroform-isopropyl alcohol (5:1). The organic layer is dried over anhydrous magnesium sulfate and then concentrated. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol-aqueous ammonia) and then crystallized from ethyl acetate, getting 113 mg (3RS,4RS)-N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(econimically)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a crystalline substance of white color.

Example 17

644 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(2-methoxy-6-methylpyridin-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 1.92 g of pyridine hydrochloride are mixed, then heated from room temperature to 200°C for 15 minutes. The molten mixture is left Oh hidatsa and then subjected to the process of separating liquids using water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give 480 mg of product with low polarity and 146 mg of product with high polarity. Product with low polarity crystallized from ethyl acetate, getting 277 mg (3RS,4RS)-2-[(1SR)-cyclohex-2-EN-1-yl]-3-(2,4-dichlorophenyl)-N-[2-(6-methyl-2-oxo-1,2-dihydropyridines-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide (example 17-1) in the form of a crystalline substance of white color. A product with high polarity is recrystallized from a mixture of ethyl acetate-ethanol, receiving 85 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(6-methyl-2-oxo-1,2-dihydropyridines-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide (example 17-2) in the form of a crystalline substance of white color.

Example 18

To a mixed solution of 456 mg (3RS,4RS)-N-[(3-cyanobenzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 15 ml of DMF add 139 mg of sodium azide and then 114 mg of ammonium chloride at room temperature, then heated to a temperature of 100°C and stirred for 12 hours. The reaction solution is cooled to room t is mperature, then add water and extracted with chloroform. After drying over anhydrous magnesium sulfate the solvent is evaporated and the residue purified by column chromatography on silica gel (eluent: chloroform-methanol). Thus obtained crude purified product is recrystallized from a mixture of ethanol-water, getting 171 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-{[3-(2H-tetrazol-5-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a crystalline substance of white color.

Example 19

A mixture of 730 mg of tert-butyl (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetate, 5 ml of dichloromethane and 5 ml triperoxonane acid is stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure and the resulting residue purified by column chromatography on silica gel (eluent: chloroform-methanol). Thus obtained crude purified product is recrystallized from ethyl acetate, getting 184 mg (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic acid as a colourless crystalline substance.

Example 20

To a solution of 330 mg of 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}benzoic acid in 5 ml of DMF added 122 mg CDI, then stirred at room temperature for 30 minutes. To the reaction solution was added 71 mg methanesulfonamide and 0.11 ml of DBU, and then stirred at room temperature for 3 hours. To the reaction solution was added ethyl acetate, then washed with 1 M hydrochloric acid and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and the solvent then evaporated. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give crude purified product. This product is recrystallized from a mixture of acetonitrile-water, getting 273 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-N-({3-[(methylsulphonyl)carbarnoyl]benzyl}oxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a crystalline substance of white color.

Example 21

To a solution of 128 mg (3RS,4RS)-N-(cyanoethoxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 1,92 ml of methanol add 0,018 ml solution of hydroxylamine at room temperature, then heated to a temperature of 40°C and stirred overnight. The reaction solution is cooled to room temperature and the precipitated crystalline substance is then collected by filtration, receiving 26 mg of (3RS,4RS)-N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a crystalline substance of white color.

Example 22

To a mixed solution of 300 mg of (3RS,4RS)-N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 30 ml of acetonitrile added 132 mg of 1,1'-carbonaceous(1H-imidazole) and 0.27 ml of DBU under ice cooling, and then stirred at room temperature for 1 hours. The reaction solution is concentrated and then add 50 ml of water and 1 M hydrochloric acid until pH 4 to 5. After extraction with ethyl acetate, washing with saturated aqueous solution of sodium chloride and drying over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol). To the thus obtained crude purified product add ethyl acetate and the product is collected by filtration, receiving 61 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a solid white color.

Example 23

To a mixed solution of 280 mg (3RS,4RS)-N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 10 ml of DMF add 0.037 ml of pyridine and then 0,084 ml of 2-ethylhexylcarbonate under ice cooling, and then stirred under ice cooling for 30 minutes. To the reaction solution was added ethyl acetate, then washed with water and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and the solvent is then evaporated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give 305 mg of (3RS,4RS)-N-[(3-{amino[({[(2-ethylhexyl)oxy]carbonyl}oxy)imino]methyl}benzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as an amorphous substance of white color. To 290 mg of this compound add 6 ml of NMP, and then stirred at a temperature of 140°C for 3 hours. The reaction solution is cooled, then add 50 ml of water, then mix. The precipitated solid is collected by filtration. This solid is purified by column chromatography on silica gel (eluent: chloroform-methanol), and then crystallized from the mixture is acetonitrile-water and the product collected by filtration, getting 101 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a crystalline substance of white color.

Example 24

To a solution of 500 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-[(1-trityl-1H-1,2,4-triazole-3-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 7.5 ml of methanol are added dropwise 0.25 ml of concentrated hydrochloric acid under ice cooling, and then stirred at room temperature for 4 hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, then extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol) and recrystallized from ethyl acetate, getting 282 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-(1H-1,2,4-triazole-3-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colourless crystalline substance.

Example 25

A solution of 400 mg (3RS,4RS)-6-(benzyloxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-(pyridine-2-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-4-CT is oksamida and 245 mg of pentamethylbenzene in 15 ml triperoxonane acid is stirred at room temperature overnight. Triperoxonane acid is evaporated under reduced pressure and add ethyl acetate and water to separate the liquid. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The remainder utverjdayut using a mixture of ethyl acetate-isopropyl alcohol and the product is collected by filtration, receiving 350 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-6-hydroxy-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-(pyridine-2-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a solid white color.

Example 26

To a solution of 644 mg (3RS,4RS)-N-[(4-tert-butoxybenzoyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide 8.4 ml dichloromethane added to 0.94 ml triperoxonane acid under ice cooling, and then stirred at room temperature for 1 hour. The solution is concentrated under reduced pressure and then recrystallized from ethyl acetate, getting 363 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-N-hydroxy-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colourless crystalline substance.

Example 27

To a mixed solution of 350 mg of ethyl 1,2-CIS-2-[3,4-TRANS-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbarnoyl]-3,4-dihydroisoquinoline-2(1H)-yl]t is celexaanxiety, 25 ml of THF and 25 ml of ethanol was added 1 ml of 1 M aqueous sodium hydroxide solution, and then stirred at room temperature for 60 hours and then at 60°C for 8 hours. After evaporation of the solvent carry out the separation of liquids using a 1 M solution of hydrochloric acid and chloroform. The organic layer is dried over anhydrous magnesium sulfate and the solvent then evaporated. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol). The obtained residue is washed with a mixture of diisopropyl ether-ethyl acetate, getting 144 mg of ethyl 1,2-TRANS-2-[3,4-TRANS-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbarnoyl]-3,4-dihydroisoquinoline-2(1H)-yl]cyclohexanecarboxylate in a solid white color.

Example 28

To a mixed solution of 334 mg of 2-(trimethylsilylmethyl)-1,2-CIS-2-[3,4-TRANS-3-(2,4-dichlorophenyl)-1-oxo-4-[(pyridine-2-ylethoxy)carbarnoyl]-3,4-dihydroisoquinoline-2(1H)-yl]cyclohexanecarboxylate and 5 ml of THF added to 0.60 ml of 1 M solution of tetrabutylammonium in THF and then stirred at room temperature for 4 hours. To the reaction solution was added 20 ml of DMF, and then stirred at room temperature for 2 hours, after which the THF is evaporated under reduced pressure and again stirred at room temperature for 20 hours. The reaction solution n is grebaut to a temperature of 60°C and stirred for 2 hours, then add back of 0.30 ml of 1 M solution of tetrabutylammonium in THF, and then stirred at 60°C for 2 hours. After evaporation of the solvent under reduced pressure was added 1 M hydrochloric acid and add 1 M aqueous sodium hydroxide solution until pH=2. The solution is extracted with ethyl acetate and chloroform, dried over anhydrous magnesium sulfate and the solvent then evaporated. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol) and the resulting residue is then washed with ethyl acetate, getting 156 mg of 1,2-CIS-2-[3,4-TRANS-3-(2,4-dichlorophenyl)-1-oxo-4-[(pyridine-2-ylethoxy)carbarnoyl]-3,4-dihydroisoquinoline-2(1H)-yl]cyclohexanecarboxylic acid in a solid white color.

Example 29

To a solution of 1000 mg (3RS,4RS)-N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 26 ml of dichloroethane are added dropwise 0.4 ml of pyridine and then 0,23 ml meillor(oxo)acetate under ice cooling, and then stirred at 0°C for 10 minutes, at room temperature for 20 minutes and at a temperature of 80°C for 2 hours. The reaction solution is cooled to room temperature, washed with 0.1 M hydrochloric acid and saturated aqueous chlorite is sodium, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give 670 mg of methyl 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-carboxylate in the form of an amorphous substance of white color.

Example 30

To 400 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid add 8 ml of DMF, 243 mg of O-[3-(tetrahydro-2H-Piran-2-yloxy)benzyl]hydroxylamine, 159 mg of HOBt and 243 mg of WSC, then stirred at room temperature for 3 hours. To the reaction solution was added ethyl acetate and water to separate the liquid and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. To the residue are added dropwise methanol and concentrated hydrochloric acid under ice cooling, and then stirred under ice cooling for 1 hour. The precipitated crystalline substance is collected by filtration, getting 275 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(3-hydroxybenzyl)oxy]-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahed ozkinay-4-carboxamide in the form of a crystalline substance of white color.

Example 31

To a solution of 323 mg (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-yl)acetate 6.5 ml of methanol added 66 mg of potassium carbonate, and then stirred at room temperature for 3 hours. To the reaction solution was added ethyl acetate, then washed with saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol) and then recrystallized from ethyl acetate, getting 157 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]methoxy}-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a crystalline substance of white color.

Example 32

By condensation of 4-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)butane acid and ethylamine using WSC and HOBt, in accordance with example 1, get (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[4-(ethylamino)-4-oxobutyl]-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a colorless crystalline substance.

Example 33/p>

By condensation of 3,4-TRANS-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbarnoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and benzylamine using WSC and HOBt, in accordance with example 1, receive 3,4-TRANS-3-benzylcarbamoyl-2-cyclopentyl-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a colorless crystalline substance.

Example 34

By condensation of CIS-4-[3,4-TRANS-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbarnoyl]-3,4-dihydroisoquinoline-2(1H)-yl]cyclohexanecarboxylic acid and 1-methylpiperazine using WSC and HOBt, in accordance with example 1, receive 3,4-TRANS-3-(2,4-dichlorophenyl)-2-{CIS-4-[(4-methylpiperazin-1-yl)carbonyl]cyclohexyl}-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a colorless crystalline substance.

Example 35

By condensation of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexanol]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and hydroxyoctanoic acid using WSC and HOBt, in accordance with example 1, get (3RS,4RS)-N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(glycolamine)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a colorless crystalline substance.

Example 36

By treating 3,4-TRANS-2-cyclopentyl-3-(3-pyridinyl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamide m-chloroperbenzoic what Isletas, in accordance with example 3, receive 3,4-TRANS-2-cyclopentyl-3-(1-oxidability-3-yl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a colorless crystalline substance.

Example 37

By treating 3,4-TRANS-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-2-[2-(3-pyridinyl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide m-chloroperbenzoic acid, in accordance with example 3, receive 3,4-TRANS-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-2-[2-(1-oxidability-3-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of colorless crystal matter.

Example 38

By treating the methyl 4-{3,4-TRANS-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbarnoyl]-1,2,3,4-tetrahydroisoquinoline-3-yl}benzoate 1 M aqueous solution of sodium hydroxide, in accordance with example 4, get 4-{3,4-TRANS-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbarnoyl]-1,2,3,4-tetrahydroisoquinoline-3-yl}benzoic acid as a colourless crystalline substance.

Example 39

By treating ethyl 4-{3,4-TRANS-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbarnoyl]-3,4-dihydroisoquinoline-2(1H)-yl}propanoate 1 M aqueous solution of sodium hydroxide, in accordance with example 4, get 4-{3,4-TRANS-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbarnoyl]-3,4-dihydroisoquinoline-2(1H)-yl}propanoic acid in the form of a colorless crystalline substance.

Example 40

the houtem processing 4-{[({[(3RS,4RS)-TRANS-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-TRANS-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}benzoic acid with CDI and then sodium borohydride, in accordance with example 7, get (3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-1,2-TRANS-2-hydroxycyclohexyl]-N-{[4-(hydroxymethyl)benzyl]oxy}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a colorless crystalline substance.

Example 41

To a mixed solution of 400 mg (3RS,4RS)-N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 40 ml of acetonitrile added 108 mg CDI and 0.4 ml of DBU under ice cooling, and then stirred at room temperature overnight. After concentrating the reaction solution there is added a saturated aqueous solution of ammonium chloride and ethyl acetate, and then extracted. The organic layer was washed with saturated salt solution, then dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol) and recrystallized from ethyl acetate, receiving 40 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colourless crystalline substance.

Example 42

To a mixture of 300 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid and 6 ml of DMF add aout the dihydrochloride {5-[(aminooxy)methyl]pyrazin-2-yl}methyl acetate, 0.16 ml of triethylamine, 119 mg of HOBt and 200 mg of WSC, then stirred at room temperature for 3 hours. Add ethyl acetate and water to separate the liquid. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. To the residue add 4.5 ml of methanol and 2.4 ml of 1 M aqueous sodium hydroxide solution, and then stirred at 0°C for 2 hours and then add 1 M hydrochloric acid solution for neutralization. Add chloroform for extraction, the organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol) and then recrystallized from ethyl acetate, receiving 73 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)pyrazin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colourless crystalline substance.

Example 43

To a solution of 350 mg (3RS,4RS)-N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide 9.2 ml of dichloroethane are added dropwise 0.15 ml of pyridine. To the reaction solution dropwise we use the t 0,095 ml of 2-chloro-2-oxoacetate under ice cooling, then stirred for 10 minutes at 0°C, for 20 minutes at room temperature and then refluxed for 8 hours. The solution is cooled to room temperature and add ethyl acetate, then washed with 0.1 M hydrochloric acid and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give 323 mg of (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-yl)acetate.

Example 44

To a solution of 600 mg of methyl 5-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}thiophene-3-carboxylate in 40 ml of THF added 45 mg of lithium aluminum hydride at -78°C. the resulting solution was heated to 0°C, then stirred for 3 hours. Add back decahydrate sodium sulfate, and then stirred for 1 hour. After removing sodium sulfate by filtration the organic layer is dried by adding anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography is and silica gel (eluent: chloroform-methanol), getting 162 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[4-(hydroxymethyl)-2-thienyl]methoxy}-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a solid white color.

Example 45

To a solution of 500 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-6-nitro-1-oxo-N-(pyridine-2-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 10 ml of methanol-dioxane (1:1) add 500 mg of Raney Nickel, then stirred for 30 minutes in a hydrogen atmosphere. The catalyst was removed by filtration and the solvent concentrated under reduced pressure, receiving 300 mg of (3RS,4RS)-6-amino-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-(pyridine-2-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a solid black color.

Example 46

To a solution of 300 mg of (3RS,4RS)-6-amino-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-(pyridine-2-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 213 mg of formaldehyde and 11 mg of sulfuric acid in 5 ml of THF added 125 mg of sodium borohydride at 0°C, then stirred for 2 hours. The reaction solution was poured into ice water and the organic layer extracted with ethyl acetate. The solution is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by using the number of the night chromatography with reversed phase silica gel (eluent: acetonitrile-water), receiving 10 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-6-(dimethylamino)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-(pyridine-2-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a solid yellow color.

Example 47

A solution of 343 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-N-(2-hydrazino-2-oksidoksi)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]-cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide 6.9 ml of THF cooled to 0°C and add 116 mg of 1,1'-carbonyldiimidazole and 0.12 ml of triethylamine and then stirred at 0°C for 2 hours and at room temperature for night. Add 0.1 M solution of hydrochloric acid, then extracted with ethyl acetate. The solution was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is recrystallized from ethyl acetate, getting 221 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of powdered crystalline substance of white color.

Example 48

To a mixed solution of 420 mg of benzyl ({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)ethyl]pyridine-2-yl}oxy)acetate, 5 ml of DMF and 5 ml of ethanol EXT the keys 84 mg of 5% palladium on charcoal, then stirred at room temperature for 15 minutes in hydrogen atmosphere. After separation of palladium on coal by filtration the solvent is evaporated and the residue purified by column chromatography on silica gel (eluent: chloroform-methanol)to give 78 mg ({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)ethyl]pyridine-2-yl}oxy)acetic acid in a solid white color.

Example 49

A solution of 480 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[6-(hydroxymethyl)pyridine-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 4.8 ml of dichloromethane cooled to 0°C, add 4.5 mg DMAP and 0.13 ml of pyridine and then added dropwise 0.7 ml of acetic anhydride, and then stirred at room the temperature during the night. To the reaction mixture, water is added, then extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give (6-{[(acetyl - {[3-(2,4-dichlorophenyl)-2-{2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}pyridin-2-yl)acetate.

Example 50

RA is creative 714 mg (3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)pyridine-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide of 14.3 ml of chloroform is cooled to 0°C and add to 0.23 ml of triethylamine, 0.16 ml of acetic anhydride and 6.8 mg of DMAP, in this order, and then stirred at room temperature for 5 hours. The reaction solution is concentrated under reduced pressure and add a mixture of ethyl acetate-water separation of the liquid, then washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The solution is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, obtaining {6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)ethyl]pyridine-2-yl}acetate.

Example 51

To 591 mg [({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]acetic acid, add 8 ml of DMF, 200 mg of tert-butylhydroperoxide, 205 mg of HOBt and 388 mg of WSC hydrochloride, then stirred at room temperature for 3 hours. Add ethyl acetate and water to separate the liquid. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. To the residue add to 7.7 ml of dichloromethane and then cooled to 0°C and add 1.2 ml triperoxonane acid, after which it was stirred at room temperature for 5 hours. The residue is purified by column chromatography on silica gel (eluent: chloroform methanol) and recrystallized from ethyl acetate, getting 417 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-N-(2-hydrazino-2-oksidoksi)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of powdered crystalline substance of white color.

Example 52

A solution of 153 mg (6-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}-1-oxidability-3-yl)methylbenzoate in 3 ml of ethanol cooled to 0°C and add 32 mg of sodium hydroxide, and then stirred at 0°C for 2 hours. The solution is neutralized 1 M solution of hydrochloric acid and add saturated aqueous sodium hydrogen carbonate solution and chloroform to separate the liquid. The organic layer is dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give 24 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1-oxidability-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide.

Example 53

To a solution of 700 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tet is hydroisoquinoline-4-carboxylic acid, 351 mg of 1-phenylmethanesulfonyl and 334 mg of DMAP 10.5 ml of DMF add 525 mg WSC/hydrochloride, then stirred at room temperature overnight. Add 0.1 M solution of hydrochloric acid, then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol) and then add back the ethyl acetate and a saturated aqueous solution of sodium bicarbonate for separating liquid. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Add ethyl acetate and diisopropyl ether and the precipitated solid is collected by filtration, receiving 33 mg of (3RS,4RS)-N-(benzylmethyl)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.

Example 54

To a solution of 566 mg (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(2,2-dimethyl-4H-[1,3]like[5,4-b]pyridin-6-yl)methoxy]-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide 11.3 ml of THF added to 3.2 ml of 1 M hydrochloric acid, then stirred at room temperature for 2 hours. Next up is ablaut 1.6 ml of 1 M hydrochloric acid, then stirred for 2 days. The solution is neutralized with a saturated aqueous solution of sodium bicarbonate and then extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol) and recrystallized from ethyl acetate, getting 196 mg of rel-(3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-hydroxy-6-(hydroxymethyl)pyridine-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in the form of a crystalline substance of white color.

Example 55

To a solution of 433 mg of 6-{[(acetyl - {[3-(2,4-dichlorophenyl)-2-{2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}-1-oxidability-2-yl)acetate in 8.7 ml of methanol added 160 mg of potassium carbonate, then mix. To this solution was added 1 M hydrochloric acid solution and then a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform-methanol). Add ethyl acetate, ethanol and diisopropyl ether to curing, getting 164 mg of 3-(2,4-dichlorophenyl)-N-{[6-(hydro shall simetal)-1-oxidability-2-yl]methoxy}-2-{2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.

Example 56

To a solution of 777 mg {6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)ethyl]-1-oxidability-2-yl}acetate in 17 ml of methanol add to 0.21 ml of hydrazine monohydrate, and then stirred for one week. Add ethyl acetate, then all stirred, concentrated and the residue purified by column chromatography on silica gel (eluent: chloroform-methanol). The ethyl acetate and diisopropyl ether is used for powder, thereby obtaining 501 mg (3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)-1-oxidability-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.

Example 57

A mixture of 590 mg of 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}benzoic acid, 217 mg of CDI and 9 ml of DMF is stirred at 50°C for 1 hour and then add 241 mg guanidiniocarbonyl, and then stirred at this temperature for 3 hours. The reaction solution is allowed to cool and the solvent is then evaporated under reduced pressure. The residue is diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and ZAT is m saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: chloroform-methanol) and recrystallized from acetonitrile, getting 348 mg (3RS,4RS)-N-({3-[(diaminomethylene)carbarnoyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.

Example 58

To a mixture of 990 mg of 4-methoxybenzyl (3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl}carbonyl)amino]ethyl}phenyl)acetate and 10 ml of telengard add 10 ml triperoxonane acid at room temperature, then stirred for 4 hours. The reaction solution is concentrated under reduced pressure. The residue is dissolved in 20 ml of methanol and add 20 ml of a saturated aqueous solution of sodium bicarbonate at room temperature, then stirred for 30 minutes. The organic solvent is evaporated under reduced pressure and the residue diluted with ethyl acetate and neutralized 1 M solution of hydrochloric acid. The product is extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The organic layer will contentresult under reduced pressure and the resulting residue purified by column chromatography on silica gel (eluent: chloroform-methanol), getting 339 mg (3-{2-[({(3RS,4RS)- 3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl}carbonyl)amino]ethyl}phenyl)acetic acid as colorless solid.

Example 59

To a mixture of 980 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(3-hydroxyphenyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 1160 mg of triphenylphosphine, 1080 mg of tert-butyl (2R)-2-hydroxypropanoate and 30 ml of THF added 770 mg of diethylazodicarboxylate at room temperature, then stirred for 12 hours. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: chloroform-methanol)to give 1460 mg of tert-butyl (2S)-2-(3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl}carbonyl)amino]ethyl}phenoxy)propagate in a solid yellow color.

Connection examples 60-899 presented in the following tables, get similarly to the methods of examples 1-59, using in each case the relevant source materials. The structure of each compound of the example presented in tables 70-275, and ways to receive the deposits and physico-chemical data of each connection example shown in tables 276-300.

In addition, the structures of other compounds according to the present invention are listed in tables 301-302. They can easily be synthesized using the methods of obtaining, as described above, the methods described in the examples, the methods apparent to the skilled in this field, or modifying these methods.

Table 14-302 moved in the graphical part.

Industrial applicability

The compound (I) according to the present invention, as described above, is suitable as a therapeutic agent in the case of diseases that are associated with receptors WV, in particular, in the case of IBS, as it has an excellent antagonistic activity against receptor W and, in addition, this compound exhibits superior performance in terms of violations of defecation.

1. Derived tetrahydroisoquinoline-1-it is represented by the General formula (I)or its pharmaceutically acceptable salt:

where the symbols in the formula have the following meanings:
R1: lower alkylen-HE lower alkylene-N(R0)(R6), the lowest alkylene-CO2R0With5-6cycloalkyl,6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylene, substituted -(OR0)-aryl or lower alkylenediamine group,
where the lowest alkylen in R1may be for the of Eden 1-2 groups selected from the group G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1can be substituted by 1-2 groups selected from the group G2; aryl may be substituted by 1-2 groups selected from the group G3;
R0: the same or different from each other, each represent H or lower alkyl,
R6: R0or-S(O)2-lower alkyl,
R2: lower alkyl, lower alkylene-OR0lowest alkylen-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0-the lowest alkylen-aryl, aryl or heterocyclic group,
where aryl in R2may be substituted by 1-3 groups selected from the group G4;
R3: -H or lower alkyl,
or R2and R3can be combined with education5-alkylene;
R4: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or-N(R0)-S(O)2-R7,
R7: lower alkyl, halogenized alkyl, lower alkylene-CN, lower alkylene-OR0lowest alkylene-CO2R0lowest alkylen-C(O)N(R0)2lowest alkylen-C(O)N(R0)N(R0)2lowest alkylen-C(=NOH)NH2heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group,
where the lowest alkylen in R7can be substituted 1-gruppami, selected from the group G1; aryl, heteroaryl and heterocyclic group in R7can be substituted by 1-2 groups selected from the group G6;
X: simple bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-,
where * X is the value from the connection to the lower alkylene,
m: an integer from 0 to 1,
p: an integer 2,
R8: -H,
or R7and R8can be combined with education groups low alkylen-N(R9-the lowest alkylen,
R9: aryl,
R10: -H,
R5: lower alkyl, halogen, nitro, -OR0, -N(R0)2or-O-lower alkylene-aryl,
where the group G1: -OR0N(R0)(R6and aryl;
group G2: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0-the lowest alkylen-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2lowest alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0-the lowest alkylen-OR0, -C(O)N(R0-the lowest alkylene-N(R0)2, -C(O)N(R0-the lowest alkylene-CO2R0, -C(O)N(R0)-O-lower al is rangitiratanga group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo;
provided that the "aryl" group G2may be substituted by one lower alkyl;
group G3: -OR0;
group G4: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2, -CO2R0;
group G5: halogen, -OR0, -N(R0)2and aryl;
group G6: halogen, lower alkyl which may be substituted OR0, halogen-lower alkyl, which is substituted OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2lowest alkylene-OC(O)R0lowest alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0lowest alkylen-C(O)N(R0)2, halogenide alkylen-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2lowest alkylen-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, -C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0-C(aryl)3and oxo;
provided that the "heterocyclic group" in the group G6substituted by 1 group selected from the group consisting of-OR 0, oxo, thioxo (=S);
where "cycloalkenyl" is a C5-10cycloalkenyl comprising a ring group fused with a benzene ring in place of a double bond;
"aryl" refers to aromatic monocyclic6is a hydrocarbon group;
"heterocyclic group" means a ring group consisting of i) a monocyclic 5-6-membered heterocycle containing 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-membered heterocycle containing 1-3 heteroatoms selected from O, S and N, which are obtained by condensation of the monocyclic heterocycle and one ring selected from the group consisting of a monocyclic heterocycle, a benzene ring, while the ring N atom may be oxidized to form oxide;
"heteroaryl" means pyridyl or benzimidazolyl;
provided that when R4means-N(R7)(R8excluded
(1) connection, where R1means the unsubstituted cyclopentyl and R2means unsubstituted 2-thienyl;
(2) connection, where R1means unsubstituted cyclohexyl and R2means 4-methoxyphenyl;
(3) connection, where R1means 4-methoxyphenyl and R2means 4-methoxyphenyl; and
(4) the compound, where R1means (morpholine-4-yl)ethyl and R2means 4-ethoxyphenyl,
provided that excluded
23-bis(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-(4-Chlorobenzyl)-2-(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-furylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
Ethyl 3-{3-[3,5-bis(trifluoromethyl)phenyl]-4-{[2-(4-methoxyphenyl)ethyl]carbarnoyl}-1-oxo-3,4-dihydroisoquinoline-2(1H)-yl}propanoate,
N-benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-1-oxo-2-(tetrahydrofuran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methoxyethyl)-2-(2-morpholine-4-retil)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-2-(2-furylmethyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-furylmethyl)-2-(2-morpholine-4-retil)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and
(4-chlorophenyl)[3-(4-chlorophenyl)-4-[(2-methoxyethyl)carbarnoyl]-1-oxo-3,4-dihydroisoquinoline-2(1H)-yl]acetic acid].

2. Connection as described in claim 1, or its pharmaceutically acceptable salt, where R3means N.

3. Connection as described in claim 2, or its pharmaceutically acceptable salt, where R2means phenyl which may be substituted with halogen, lower alkyl or-OR0.

4. Connection as described in claim 3, or a pharmaceutical is acceptable salt, where R1means5-6cycloalkyl.

5. Connection as described in claim 1, selected from the group consisting of
(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-N-(pyridine-2-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-(methylsulphonyl)amino]cyclohexyl}-N-[(1-oxidability-2-yl)methoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino] cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}benzoic acid,
(4-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}phenyl)acetic acid,
(3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic acid,
{3-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)ethyl]phenyl}(debtor)acetic acid,
(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-N-(2-{3-[(methylsulphonyl)carbarnoyl]phenyl}ethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
{4-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)the Teal]phenyl}acetic acid and
4-(3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulphonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-yl]carbonyl}amino)oxy]methyl}phenoxy)butane acid;
or its pharmaceutically acceptable salt.

6. Pharmaceutical composition for the treatment of irritable bowel syndrome containing the compound according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, which is a receptor antagonist W.

8. The pharmaceutical composition according to claim 6, which is a therapeutic agent against irritable bowel syndrome.

9. The pharmaceutical composition according to claim 6, which is a therapeutic agent against cancer.

10. The use of compounds according to claim 1 or its pharmaceutically acceptable salt for a receptor antagonist W, a therapeutic agent against irritable bowel syndrome or therapeutic agent against cancer.

11. A method of treating irritable bowel syndrome or cancer, comprising the administration to a patient a therapeutically effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to complexes of lanthanides and organic ligands which are luminescent in the visible spectrum and are used in electroluminescent devices, means of protecting security paper and documents from falsification etc. Disclosed are novel luminescent coordination compounds of lanthanides of formula: where Ln is Eu3+, Tb3+, Dy3+, Sm3+, Gd3+.

EFFECT: said compounds have high luminescence intensity and considerable thermal tolerance of up to 400°C, which enables use thereof in modern production of light-emitting diodes.

4 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazo[4,5-b]pyrazine derivatives of general formula or to its pharmaceutically acceptable salt wherein: R1 represents either aryl unsubstituted or substituted by one of the groups: halogen, hydoxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkylC1-6alkoxy, C1-6alkylhydroxy, -C(O)NH2, -C(O)OC1-6alkyl, -C(O)NH C1-6alkyl, cyano, carboxy, heteroaryl and heterocycloalkyl; or heteroaryl unsubstituted or substituted by one of the groups: C1-6alkoxy, hydroxy, -C1-6alkyl, NH2 and NHC1-6alkyl; heterocycloalkyl unsubstituted or substituted by one group =O; and R2 represents H; unsubstituted C3-4alkyl; C1-4alkyl substituted by C5-6cycloalkyl unsubstituted or substituted by one group specified in amino, hydroxyl, C1-6alkoxy, or heterocycloalkyl unsubstituted or substituted by 1-2 groups specified in =O, C1-6alkyl; or C5-6cycloalkyl substituted by one group specified in hydroxyl, C1-6alkoxyl, C1-6alkylC1-6alkoxy, C1-6alkylhydroxy, CONH2; or substituted ir unsubstituted heterocycloalkyl; wherein aryl represents an aromatic structure consisting of 6-10 carbon atoms containing one ring or two condensed rings; wherein heteroaryl represents a 5-10-member aryl ring system containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur; wherein heterocycloalkyl represents a 5-9-member nonaromatic cycloalkyl wherein 1-2 heteroatoms specified in nitrogen and oxygen; provided the compound does not represent 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-one. Also, the invention refers to the specific imidazo[4,5-b]pyrazine derivatives, to a based pharmaceutical composition, to a method of treating or preventing cancer, inflammatory conditions, immunological diseases, metabolic conditions, and to a method of kinase inhibition in a cell expressing said kinase.

EFFECT: there are produced new imidazo[4,5-b]pyrazine derivatives showing effective biological properties.

17 cl, 2 tbl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylpyrrolidinyl methylpyrrolidine amides of formula , where R, R1, R2 and R3 are identical or different and independently denote H, (C1-C4)alkyl, CF3; R4 denotes phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepinyl; where said R4 is optionally substituted one to more times with a substitute selected from halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl, N-acetylpiperidinyl, pyrrolyl, imidazolyl, 5-oxo-4,5-dihydropyrazolyl; or pharmaceutically acceptable salt thereof or enantiomer or diastereomer thereof.

EFFECT: compounds have modulating activity on histamine H3 receptor, which enables use thereof to prepare a pharmaceutical composition.

10 cl, 3 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where values of R, R1, R2, R3 and R4 are given in claim 1.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof in pharmaceutical compositions for treating sleep disorder.

10 cl, 1 tbl, 4 dwg, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of imidazo[4,5-c]chinoline of general formula or to its pharmaceutically acceptable salts, where R1 represents straight-chained C1-C6alkyl, possibly substituted with one substituent, selected from C1-C3alkoxy; Z1 represents C2-C6alkylene; X1 represents NR5 or >NCOR5; Y1 represents C1-C6alkylene; R3 represents C1-C6alkyl, possibly substituted with C1-C6alkoxy; R5 represents hydrogen, piperidinyl, possibly substituted by piperidinyl nitrogen with group R10, group C1-C6alkyl, where the last group is possibly substituted with one substituent, independently selected from NR7R8 or R9; or R5 represents C1-C6alkylene, which can be bound with carbon atom in C2-C6alkylene group Z1 with formation of piperidine ring; each of R7 and R8 independently represents tetrahydropyranyl, piperidinyl, possibly substituted by piperidinyl nitrogen atom with group R10a, C1-C6alkyl, where the last group is possibly substituted with one group, independently selected from OR12; or R7 and R8 together with nitrogen atom, to which they are bound, form 4-7-membered saturated heterocyclic ring, selected from asetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4-oxazepanyl and 1,4-diazepanyl, where heterocyclic ring is possibly substituted with one or two substituents, independently selected from S(O)qR15, OR15, CO2R15, COR15, CONR15R16, NR15CO2R16, pyrimidinyl and C1-C6alkyl, where the last group is possibly substituted with one group, independently selected from OR18 and CO2R18; R9 represents S(O)qR20; R10 and R10a independently represent COR2 or group C1-C6alkyl; each of R12, R15, R16, R18, R20 and R24 independently represents hydrogen or C1-C6alkyl; q equals 2; m and n both equal 0; and A represents phenyl. Invention also relates to method of obtaining formula (I) compound, based on it pharmaceutical composition, and to method of treating said pathological conditions.

EFFECT: obtained are novel derivatives of imidazo[4,5-c]chinoline, useful modulation of TLR7 activity.

17 cl, 18 dwg, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heterocyclic amide compound of formula I: or a pharmaceutically acceptable salt thereof. Described also is a pharmaceutical composition containing said compound, having protein kinase inhibitor, regulator or modulator properties, which is acceptable in treating or preventing a proliferative disease, an anti-proliferative disorder, inflammation, arthritis, neurologic or neurodegenerative disease, cardiovascular disease, hair loss, neural disease, ischemic disorder, viral disease or fungal disease.

EFFECT: high efficiency of using the compounds.

2 cl, 20 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrole nitrogen-containing heterocyclic derivatives of formula (I) or their pharmaceutically acceptable salts:

,

wherein: X means C, N; each R1,R2 means H; R3 means C1-10alkyl; R4 means -[CH2CH(OH)]rCH2NR9R10, -(CH2)nNR9R10; provided X means N, R5 is absent, each R6, R7, R8 means H, halogen; provided X means C, each R5, R6, R7, R8 means H, halogen, hydroxyC1-10alkyl, C1-10alkyl, phenyl, 6-member heteroaryl with one N, -OH, -OR9, -NR9R10, -(CH2)nCONR9R10, -NR9COR10, -SO2R9 and -NHCO2R10, wherein said phenyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, C1-10alkoxyl, halogen; each R9, R10 means H, C1-10alkyl wherein C1-10alkyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, phenyl, halogenophenyl, -OH, C1-10alkoxy, OH- C1-10alkyl; or R9 and R10 together with an attached atom form a 5-6-member heteroring which may contain one O; n is equal to 2- 6; z is equal to 1-2; r is equal to 1-6;.

EFFECT: compounds may be used as protein kinase inhibitors.

14 cl, 2 tbl, 67 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 11-(piperazin-1-yl) dibenzo[b,f[1,4]oxazapine compounds of general formula specified below wherein the radicals are presented in the description, to their pharmaceutically acceptable salts and pharmaceutical compositions. There are also described methods for preparing said compounds.

EFFECT: compounds may be used for treating disorders, such as schizophrenia, resistant schizophrenia, bipolar disorder, psychotic depression, resistant depression, depressive conditions related to schizophrenia, treating resistant OCD, autism, senile dementia, psychotic dementia, L-DOPA-induced psychotic disorder, psychogenic polydipsia, psychotic symptoms of neurological disorders, sleeping disorders.

39 cl, 25 ex, 8 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) wherein R4 represents a group of formula (II) and R1, R2, R3, R5 and X are those as specified in the patent claim.

EFFECT: preparing the pharmaceutical composition applicable in treating chronic obstructive pulmonary disease and containing the compound of formula (I).

8 cl, 3 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: pharmacology.

SUBSTANCE: invention refers to the compound of formula(I) or to is salt where R1 is -H or C1-6 alkyl; R2 is bridged aza-ring chosen out of group including formula and where ring hydrogen atom in bridged aza-ring may be substituted by one or several groups of R22; m, n and p have respective values 1 or 2; r has the value 0 or 1; R21 is C1-6 alkyl, -C1-6 alkyl-O-phenyl or -C1-6 alkyl-phenyl; R22 is C1-6 alkyl-cycloalkyl or -C1-6 alkyl-phenyl; R2 is thienyl, phenyl, pyridyl, pyranzinyl, thiazolyl or pyrazolyl, each of which can be substituted by one or several R31; R31 is the halogen, -OH, -CN, -CF3, C1-6 alkyl or -O-C1-6 alkyl; ring A is the group consisting of thiophene, thiazole, isothiazole, thidiazole, oxazole, isooxazole, cyclohexan, norboran, benzothiophene and 5,6-dihydro-4H-cyclopentathiophene, each of which can be substituted by the group chosen out of the group consisting out of one or several RA1; where RA1 is a halogen, -CN, -NH2, C1-6 alkyl, -O-C1-6 alkyl, CONH2, - HN-C1-6 alkyl, -HN-C1-6 alkyl-O-C1-6 alkyl-phenyl, -HN-C1-6 alkyl-phenyl or -HN-C1-6 alkyl-OH where C1-6 alkyl can be substituted with one or several halogen atoms; V is -NH- or -O-; W is -(CH2)q-; q has the value 0.1 or 2; X is the counteranion and is an ordinary bond; on condition when in case ring A is cyclohexane, R3 is phenyl which can be replaced with one or several R31. The invention also refers to pharmaceutical composition that has antagonistic effect on muscarine receptor M3, on the basis of said compound.

EFFECT: production of new compound and pharmaceutical composition on its basis, which can be applied in the medicine as an active substance for preventive and/or therapeutic drug for treatment of inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma and the like.

14 cl, 60 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide by reacting 1-azabicyclo[2.2.2]oct-3(R)yl ether of 2-hydroxy-2,2-dithien-2-ylacetic acid and 3-phenoxypropyl bromide, where the reaction takes place in a solvent or mixtures of solvents, having boiling point ranging from 50 to 210°C and selected from a group comprising ketones and cyclic ethers, preferably in acetone, dioxane and tetrahydrofuran.

EFFECT: efficient method of obtaining the compounds.

12 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (R)- quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate or salt thereof, involving: 1) converting a compound which is 4-amino-3-methoxypiperidine-1-carboxylate to a salt; 2) converting the ethyl 4-amino-3-methoxypiperidine-1-carboxylate salt into ethyl 4-(diphenylamine)-3-methoxypiperidine-1-carboxylate 3) treating ethyl 4-(diphenylamino)-3-methoxypiperidine-1-carboxylate with hydroxide or hydride of an alkali metal to obtain 3-methoxy-N,N-diphenylpiperidine-4-amine 4) obtainijng a chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine by bringing 3-methoxy-N,N-diphenylpiperidine-4-amine into contact with a chiral splitting agent and extracting the obtained chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine; optional recrystalisation of product 4; converting product 4 or 5 to a base to obtain product 4 or 5 in form of a free base; 7) bringing product 6 into contact with ethyl 6-bromohexanoate to obtain ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 8) esterification of ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate using (R)-quinuclidin-3-ol with a Lewis acid to obtain (R)- quinuclidin-3-yl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 9) removing protection from the 4-amine group of product 8 to obtain (R- quinuclidin-3-yl 6- [(3S,4R)-4-amino-3-methoxypiperidin-1-yl)hexanoate; 10) acylation of product 9 4-amino-5-chloro-2-methoxybenzoic acid to obtain (R)- quinuclidin-3-yl 6-((38,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate; 11) optional conversion of product 10 into a salt.

EFFECT: method increases output of the end product and reduces content of impurities.

7 cl, 3 ex, 6 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I where X1-X4 each independently represent CR1, B represents -C(O)-O- or -C(O)-NH-CH2-, Y represents S or NH, R1 represents H, C1-C4alkoxy, unsubstituted or substituted by once or several times with F, or Het, and Het stands for heterocyclic group, fully saturated, partly saturated or fully unsaturated, containing in cycle 5-10 atoms, of which at least one atom represents N, O or S, unsubstituted or substituted once or several times with C1-C8alkyl, or to its pharmaceutically acceptable salt.

EFFECT: obtaining pharmaceutical composition for selective activation/stimulation of nicotine receptors α7 on the basis of said compound, as well as to their application for treatment of patient, suffering from psychotic disease, neurodegenerative disease, including cholinergic system dysfunction and/or condition of memory failure and/or failure of cognitive abilities.

52 cl, 38 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of general formula:

or its pharmaceutically acceptable salt wherein the ring A represents a phenyl group which can contain 1-3 substitutes specified in a group of substitutes, or a thienyl group which can contain 1-3 substitutes specified in a group of substitutes α; L represents a single bond or a group of formula -NRC CO- (wherein Re represents a hydrogen atom), the ring B represents C6-14 aryl group which can contain 1-3 substitutes specified in a group of substitutes α, or a 5-10-member heterocyclic group which can contain 1-3 substitutes specified in a group of substitutes α; the X, Y, Z , R1 and R2 , R3, R4, R5 and R6 radical values are presented in cl.1 of the patent claim which possess an effect of Aβ protein production inhibition or an effect of BACE1 inhibition.

EFFECT: preparing the compound which is applicable as a preventive or therapeutic agent for neurodegenerative disease caused by Aβ.

13 cl, 35 tbl, 285 ex

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