Synthesis methods and intermediate compounds during synthesis of stereoisomeric compounds, suitable for treating gastrointestinal disorders and central nervous system disorders

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

 

This application claims the priority stated in the provisional application for U.S. patent No. 60/713149, filed August 31, 2005, and provisional application for U.S. patent No. 60/747762, filed may 19, 2006

The LEVEL of TECHNOLOGY

The cisapride is one of a class of compounds known as benzamide derivatives, the original connection is metoclopramide. U.S. patent No. 4962115 and 5057525 (collectively, "Van Daele, the description of which is fully included in the text of this application as a reference) are provided N-(3-hydroxy-4-piperidinyl)benzamide cisapride. In the patent Van Daele described that these compounds, their pharmaceutically acceptable acid additive salts and stereoisomeric forms stimulate the motility of the gastrointestinal tract.

As a class, these benzamide derivatives have several notable pharmacological effects. Notable pharmacological effects of benzamide derivatives due to their impact on neural systems, which are regulated by the neurotransmitter serotonin. It has long been known that serotonin plays an important role in a number of diseases, which studied the pharmacological properties of benzamide derivatives. Therefore, studies were conducted to determine the location of areas of development and accumulation of serotonin and serotonin cocktail recipes. what s in human body, to establish the link between these areas and various painful conditions.

In this regard, it was found that the main place of manufacture and accumulation of serotonin is enterochromaffin cell of the mucosa of the gastrointestinal tract. It was also found that serotonin is a potent stimulator of the motility of the gastrointestinal tract, enhancing the work of the smooth muscle, accelerating the passage of intestinal contents and reduce the time of suction, as in diarrhea. Specified stimulating effect is also associated with nausea and vomiting.

Due to its effect on serotonin neural system of the gastrointestinal tract many benzamide derivatives are effective antiemetics tools and are widely used to combat vomiting during chemotherapy and radiation therapy of malignant tumors, especially when applied with a strong gag action of compounds such as cisplatin. This effect is almost certainly the result of the ability of these compounds to block the interaction of serotonin (5HT) with specific areas of his actions, called 5HT3receptors, which traditionally are referred to in scientific literature as serotonin M-receptor. Chemotherapy and radiation therapy can cause nausea and vomiting of sredstv the e release of serotonin from the damaged enterochromaffin cells in the gastrointestinal tract. The released neurotransmitter serotonin excites as vagusnye afferent nerve fibers (causing, thus, gag reflex), and serotonin receptors in the chemoreceptor trigger zone of the back field of the brain. Unresolved questions remain about the anatomical region, which is the effect benzamide derivatives, and whether this effect is Central (Central nervous system - CNS), peripheral or combined nature (Barnes et al., J. Pharm. Pharmacol. 40: 586-588, 1988). The cisapride, like other derivatives of benzamide, can be an effective antiemetic agent due to its ability to modulate the interaction of serotonin with 5HT3-receptor.

The second noticeable effect benzamide derivatives is increased contractile activity of smooth muscles of the gastrointestinal tract from the esophagus to the proximal small intestine, thereby accelerating the passage of the contents through the esophagus and intestines, relieves gastric emptying and increases the tone of the lower esophageal sphincter (Decktor et al., Eur. J. Pharmacol. 147: 313-316, 1988). Although benzamide derivatives themselves are not agonists cholinergic receptors, the above effect on smooth muscles can be blocked by antagonists of muscarinic receptors, such as atropine, or inhibitors of neuronastrocyte tetrodotoxin type, acting on sodium channels. Such locking action described in relation to the contractile effect of serotonin in the small intestine. Currently, it is believed that the main effects benzamide derivatives in relation to smooth muscle are the result of their agonistic action on a new class of serotonin receptors, called 5HT4located on neuron inserted intermuscular plexus of the intestinal wall. Activation of these receptors promotes the release of acetylcholine from parasympathetic nerve endings, located approximately smooth muscle fibers, and it is due to the interaction of acetylcholine to its receptors on the membranes of smooth muscle cells, the mechanism is implemented start the contraction of the muscles.

A discussion of the different 5HT receptors, including 5HT4the receptor can be found, for example, in U.S. patent No. 6331401 and 6632827, descriptions of which are fully included in the text of this application by reference.

The cisapride, mainly used to treat gastroesophageal reflux disease (GERD). This disease is characterized by the reflux of gastric contents into the esophagus. One of the most important factors in the pathogenesis of gastroesophageal reflux disease is a weakening of the lower esophageal sphincter due to its failure. nedostatocnosti the lower esophageal sphincter may be due to low basal pressure, relaxation of the sphincter or uncompensated increase in intragastric pressure. Other factors in the pathogenesis of the disease: delayed gastric emptying, low clearance of the esophagus due to violations of peristalsis, as well as the aggressive properties of the reflux material, which can damage the lining of the esophagus. It is assumed that cisapride enhances protivorechii barrier and improves the cleaning of the esophagus by increasing pressure in the lower esophageal sphincter and strengthen the peristaltic contractions.

Since cisapride acts as prokinetics agent, it can also be used to treat dyspepsia, gastroparesis, constipation, postoperative paresis of the intestine and pseudoprobability intestine. Neuralgia is a condition characterized by indigestion, which can be a symptom of a primary dysfunction of the gastrointestinal tract or a complication of other diseases such as appendicitis, dysfunction of the gall bladder or malnutrition. Gastroparesis is a paralysis of the stomach caused by impaired motility of the stomach or a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa or myotonica dystrophy. Constipation is a condition characterized ur the military or difficult defecation as a result of such conditions, as lack of muscle tone or spasticity of the intestine. Postoperative paresis of the intestine is a bowel obstruction due to disorders of muscle tone after surgery. Pseudoprobability bowel is a condition characterized by constipation, colic and vomiting, but without evidence of physical obstruction.

In the treatment of humans and animals is of great importance toxicity of drugs. Toxic side effects (adverse effects)arising from the use of drugs, include a number of conditions from low fever to death. Drug treatment is only justified if the benefits from the application of a treatment regimen exceeds associated with the treatment of the potential risk. Factors that maps the attending physician, include qualitative and quantitative effect of the applied drugs, and also the outcome if the drug is not injected to the patient. Other factors to take into consideration include the physical condition of the patient, stage of disease and the history of its development, as well as all known adverse effects associated with the use of drugs.

Elimination of drugs, as a rule, is the result of metabolite is some activity against drug and its subsequent excretion from the body. Metabolic processes can occur in the bloodstream and/or cellular organelles or organs. The liver is the main organ in which the metabolism of drugs. There are synthetic and non-synthetic reactions metabolic process. During non-synthetic reactions is a chemical transformation of a medicinal product by oxidation, recovery, hydrolysis, or any combination of the above processes. Collectively, these processes are called reactions phase I.

During the reaction phase II, also known as synthetic reactions or reactions of conjugation, the original medicinal product or its intermediate metabolites connect with endogenous substrates with the formation of the product of the merger or conjugation. The metabolites formed during the synthetic reaction, generally more polar and devoid of biological activity. The result of these metabolites easier excreted through the kidneys (urine) or the liver (bile). Synthetic reactions include glucuronidation, conjugation with amino acids, acetylation, sulphonylurea and methylation.

More than 90% of the administered dose of cisapride is metabolized by oxidative N-dealkylation piperidino nitrogen atom or by aromatic hydroxylation at the 4-fervency Il is benzamide rings.

It was found that the introduction of cisapride person causes serious adverse effects, including Central nervous system disorders, increased systolic blood pressure, interaction with other drugs, diarrhea, and cramps in the abdominal cavity. In addition, it is noted that intravenous cisapride is accompanied by additional adverse effects that are not observed after oral administration of cisapride (Stacher et al. [1987] Digestive Diseases and Sciences, 32(11):1223-1230). It is believed that these adverse effects are caused by the metabolites that are formed due to oxidative dealkylation and aromatic hydroxylation of a compound that occurs in the detoxification system of cytochrome P450. There is also a number of undesirable interactions between cisapride and other drugs, which are also caused by the metabolism of the cytochrome P450 system.

In the period from July 1993 to December 1999, registered at least 341 case of developing severe heart arrhythmia associated with taking cisapride (PROPULSID, Janssen Pharmaceutica Products, L.P.). These arrhythmias include ventricular tachycardia, ventricular fibrillation, Torsade de pointes ventricular and prolongation of the QT interval. Marked eighty (80) deaths. In connection with these adverse EF is a known manufacturer voluntarily withdrew the product from sale in the United States; however, the drug can be obtained through a research program with restricted access.

Security agonists 5HT4receptors with prokinetics activity against gastro-intestinal tract (GIT) is limited due to their effect on heart (lengthening of the QTc interval, tachycardia, Torsade de pointes ventricular) and due to adverse drug interactions due to metabolism of the drug by hepatic cytochrome P-450. Prokinetics agent for the digestive tract of this class that do not have these restrictions would be quite valuable for a number of therapeutic areas, including GERD and disorders of gastric emptying. Certain derivatives cisalpina described in U.S. patent No. 6552046 and WO 01/093849 (the descriptions of which are fully included in the text of this application by reference); however, it would be desirable compounds with an even more pronounced beneficial properties.

It is now established that some of the stereoisomers of one such esterified structural and/or functional analog of cisapride have clear and particularly favorable properties.

The INVENTION

The present invention relates to methods and processes for making the compounds and compositions of formula (X), as well as to intermediate compounds suitable DL is producing compounds of the formula (X), for safe and effective treatment of various gastrointestinal disorders, including, without limitation, gastroparesis, gastroesophageal reflux and related conditions. Compounds of the present invention are also suitable for treating a range of conditions affecting the Central nervous system.

Compounds of the present invention include compounds of formula X:

(X)

and their pharmaceutically acceptable salts, where

communication in positions 3 and 4 are in the CIS-position relative to each other;

L represents -(C1-C6alkyl)- (in one embodiment, -(C3-C5alkyl)-), -(C1-C6alkyl)-C(O)- or-C(O)-(C1-C6alkyl)-, where each of the alkyl groups optionally substituted by 1 or 2 groups that are independently represent halogen, C1-C4alkoxy or OH, and where one carbon atom in the alkyl part of the group L may be replaced by-N(R9)-;

R1is a halogen;

R2represents amino, NH(C1-C4alkyl) or N(C1-C4alkyl)(C1-C4alkyl);

R3represents OH or C1-C4alkoxy;

R4represents H or methyl; and

R5represents-O-C3-C8cycloalkyl, -O-heteroseksualci, heterocycla the keel, aryl, -O-aryl, - N(R9)-(C0-C6alkyl)-C(O)-aryl, or-N(R9)-C0-C6alkyl-aryl, -O-heteroaryl, -N(R9)-C1-C6(O)-heteroaryl or-N(R9)-C0-C6alkylglycerol, where each of the cyclic groups may be unsubstituted or substituted in one more delegate provisions of the following substituents: C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6halogenated, C1-C6halogenoalkane, hydroxyl, hydroxy-C1-C4-alkyl, amino, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), -(C0-C6alkyl)-C(O)R11or-O-(C0-C6alkyl)-C(O)R11methylsulfone, C0-C6-sulfonamide or NO2; where

R9in each case independently represents H or C1-C4alkyl;

R11represents a C1-C6alkyl, OH or

R11represents a C1-C6alkoxy, optionally substituted 1 or 2 groups that are independently represents a C1-C4alkoxy, amino, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), -(C0-C6alkyl)-C(O)N(R9-heteroseksualci, -O-heteroseksualci, -C1-C6(O)N(R9-heteroaryl or heteroaryl, where

heterocytolysine group is not necessarily Emesene 1, 2, or 3 groups that are independently represent halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, hydroxy (C1-C6alkyl, C1-C6alkoxycarbonyl, -CO2H, CF3or OCF3,

heteroaryl group optionally substituted by 1, 2, or 3 groups that are independently represent halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, hydroxy (C1-C6alkyl, C1-C6alkoxycarbonyl, -CO2H, CF3or OCF3; or

R11represents-O-heteroseksualci where heteroseksualci optionally substituted by 1, 2, or 3 groups that are independently represent halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, hydroxy (C1-C6alkyl, C1-C6alkoxycarbonyl, -CO2H, CF3or OCF3; and

R20represents a C1-C6alkoxy (preferably C1-C4alkoxy, more preferably methoxy or OH.

The invention relates also to compositions comprising at least one compound of formula (X), obtained using the methods and/or processes of the present invention, and at least one pharmaceutically acceptable excipient, adjuvant, carrier or solvent.

The compounds of formula (X)obtained using the-W methods and/or processes of the present invention, are suitable for the treatment or prevention of gastroesophageal reflux disease and significantly reduce the adverse effects associated with the introduction of cisapride. These adverse effects include, without limitation, diarrhea, cramps in the abdomen and increased blood pressure and heart rate.

In addition, the compounds and compositions produced using the methods and/or processes of the present invention are suitable for the treatment of vomiting and other conditions, including, without limitation, dyspepsia, gastroparesis, constipation, post-operative bowel paresis and pseudoprobability intestine. An additional advantage is that using the above methods of treatment adverse effects associated with the introduction of cisapride, also decrease.

Compounds obtained using the methods and/or processes of the present invention, are ligands 5HT4receptors and, accordingly, can be used for treating conditions mediated by these receptors. These receptors are located in several areas of the Central nervous system, and modulation of these receptors can be used to achieve the desired effects on the Central nervous system.

The advantage of the invention consists in that connection, receiving the data using the methods and/or processes of the present invention to obtain a stereoisomeric compounds, usually contain ester part, which does not reduce the ability of these compounds to provide a therapeutic effect, but which makes them more sensitive to the splitting of the serum and/or by cytosolic esterases, at the same time allowing you to avoid the effects of detoxification of cytochrome P450, which is associated with adverse effects of cisapride, and reducing the incidence of these adverse effects.

The present invention relates also to methods of treatment, including the introduction of compounds of formula (X), obtained using the methods and/or processes of the present invention, therapeutically effective amounts of individuals who need treatment of gastroesophageal reflux disease, dyspepsia, gastroparesis, constipation, postoperative paresis of the intestine and pseudoprobability intestines, and related state.

The advantage of the invention lies in the fact that therapeutic compounds obtained using the methods and/or processes of the present invention are stable during storage and provide a more secure metabolism compared with other drugs; thus, the compounds of the present invention can be used with less frequency poboc what's effects and less toxicity.

In an additional aspect, the present invention relates to the decay products (preferably to the metabolic products of decay), which are formed when the effect of esterases on therapeutic compounds, obtained using the methods and/or processes of the present invention. These decay products can be used as described herein to monitor the excretion of therapeutic compounds from the body of the patient.

BRIEF DESCRIPTION of FIGURES

Figure 1 is a graph showing curves of the effect of concentration with respect to agonistic effects on 5-HT4receptors ATI-7505, serotonin, cisapride and ATI-7500.

Figure 2 is a graph showing the gastric emptying in fed dogs. The presented data refer to the average time of return MMK to the original level for the media, which is the control. Values represent mean+SEM standard error of the mean for 5 dogs. *p<0.05 compared with the carrier, which is the control.

Figure 3 is a graph showing the metabolism of ATI-7505 and ATI-7500 with CYP450-dependent cofactor, NADPH and without it. Shows average values and standard deviation concentrations of ATI-7505 and ATI-7500 in microns. ATI-7505 (2 μm) were incubated with human is Kim microsomal protein (1 mg) in the presence and in the absence of regenerating system NADPH (cofactor).

DETAILED description of the INVENTION

In an additional aspect, the invention relates to methods and/or processes for making compounds of formula (X), as well as to intermediate compounds suitable for preparing compounds of the formula (X), where

R5represents-O-C3-C8cycloalkyl, -O-heteroseksualci, heteroseksualci where heterocytolysine group selected from piperidinyl, piperazinil, pyrrolidinyl, azabicycloalkanes, in some embodiments azabicyclo[2.2.2]Attila, azabicyclo[3.2.1]Attila, azabicycloalkanes, isabellakelly, indolinyl, morpholinyl, thiomorpholine, S,S-dioxothiazolidine and imidazolidinyl, -O-aryl, -N(R9)-C(O)-aryl, or-N(R9)-C0-C6alkylaryl, where each of the cyclic groups is unsubstituted or substituted in one or more delegate positions of the C1-C6the alkyl, C1-C6alkoxy, halogen, C1-C6halogenation, C1-C6halogenoalkane, hydroxyl, hydroxy-C1-C4the alkyl, amino, -NH(C1-C6by alkyl), -N(C1-C6by alkyl)(C1-C6by alkyl), -C(O)R11or NO2; where

R9in each case independently represents H or C1-C4alkyl; and

R11represents a C1-C6alkyl, OH, or

R11represents a C1-C6is laksi, optionally substituted 1 or 2 groups that are independently represents a C1-C4alkoxy, amino, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), -C(O)N(R9-heteroseksualci, heteroseksualci or heteroaryl, where

heterocytolysine group selected from pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, azabicycloalkanes, in some embodiments azabicyclo[2.2.2]Attila, azabicyclo[3.2.1]Attila, azabicycloalkanes and isabellakelly where heterocytolysine group optionally substituted by 1, 2, or 3 groups that are independently represent halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, hydroxy (C1-C6alkyl, C1-C6alkoxycarbonyl, -CO2H, CF3or OCF3,

heteroaryl group selected from pyridyl, pyrimidyl, chinoline, izochinolina and indolyl, where heteroaryl group optionally substituted by 1, 2, or 3 groups that are independently represent halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, hydroxy (C1-C6alkyl, C1-C6alkoxycarbonyl, -CO2H, CF3or OCF3; or

R11represents-O-heteroseksualci where heteroseksualci selected from piperidinyl, pyrrolidinyl, imidazolidinyl, morpholinyl, azabicycloalkanes, is some embodiments azabicyclo[2.2.2]Attila, azabicyclo[3.2.1]Attila, azabicycloalkanes, isabellakelly and tetrahydrofuranyl, and where each heterocytolysine group optionally substituted by 1, 2, or 3 groups that are independently represent halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, hydroxy (C1-C6alkyl, C1-C6alkoxycarbonyl, -CO2H, CF3or OCF3.

In an additional aspect, the present invention relates to methods and/or processes for making compounds of formula (X), as well as to intermediate compounds suitable for preparing compounds of the formula (X), where R1represents chlorine.

In another additional aspect, the present invention relates to methods and/or processes for making compounds of formula (X), as well as to intermediate compounds suitable for preparing compounds of the formula (X), where R2represents amino.

In an additional aspect, the present invention relates to methods and/or processes for making compounds of formula (X), as well as to intermediate compounds suitable for preparing compounds of the formula (X), where R3represents methoxy.

In yet another additional aspect, the present invention relates to methods and/or processes for making compounds of formula (X), as well as to intermediate compounds suitable for the teachings of the compounds of formula (X), where R4represents H or methyl.

In an additional aspect, the present invention relates to methods and/or processes for making compounds of formula (X), as well as to intermediate compounds suitable for preparing compounds of the formula (X), where R1represents chlorine, R2represents amino, R3represents methoxy and R4represents H or methyl.

Another feature of the present invention relates to methods and/or processes for making compounds of formula (X), as well as to intermediate compounds suitable for preparing compounds of the formula (X), where R1represents chlorine, R2represents amino, R3represents methoxy; R4represents H and L represents -(C4-C6alkyl)-C(O)-.

Another feature of the present invention relates to methods and/or processes for making compounds of formula (X), as well as to intermediate compounds suitable for preparing compounds of the formula (X), where two or more previously described features combined.

Another feature of the present invention relates to methods and/or processes of preparing compounds of the formula (XI), which are compounds of formula (X), where L represents -(CH2)5-C(O)-:

XI).

Another feature of the present invention relates to methods and/or processes of preparing compounds of the formula (XI), as well as to intermediate compounds suitable for preparing compounds of the formula (XI), where R1represents chlorine, R2represents amino, R3represents methoxy and R4represents H or methyl.

Another feature of the present invention relates to methods and/or processes of preparing compounds of the formula (XI), as well as to intermediate compounds suitable for preparing compounds of the formula (XI), where R5represents-O-heteroseksualci where heterocytolysine group selected from azabicycloalkanes, in some embodiments, 1-azabicyclo[2.2.2]Oct-3-yl or 8-azabicyclo[3.2.1]Oct-3-yl, azabicycloalkanes, isabellakelly, where the Aza nitrogen optionally substituted by stands or ethyl; and R4represents H or methyl.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XI), as well as to intermediate compounds suitable for preparing compounds of the formula (XI), where R5represents-O-heteroseksualci where heterocytolysine group selected from piperidinyl, piperazinil or pyrrolidinyl, each of which is unsubstituted or substituted in one or two paragraph is great groups, which independently represents a C1-C4alkyl, C1-C4alkoxy, halogen, C1-C4halogenated (in one variant, CF3), C1-C4halogenoalkane (in one embodiment, the OCF3), hydroxyl, hydroxy, C1-C4alkyl, amino, -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkyl), -(C1-C6alkyl)-C(O)R11or NO2; and R4represents H or methyl.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XI), as well as to intermediate compounds suitable for preparing compounds of the formula (XI), where R5represents-O-heteroseksualci where heterocytolysine group selected from indolinyl, morpholinyl, thiomorpholine, S,S-dioxothiazolidine and imidazolyl, each of which is unsubstituted or substituted in one or two positions with groups that are independently represents a C1-C4alkyl, C1-C4alkoxy, halogen, C1-C4halogenated (in one variant, CF3), C1-C4halogenoalkane (in one embodiment, the OCF3), hydroxyl, hydroxy, C1-C4alkyl, amino, -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkyl), -(C0-C6alkyl)-C(O)R11or NO2; 4represents H or methyl.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XI), as well as to intermediate compounds suitable for preparing compounds of the formula (XI), where R5is an O-phenyl, N(R9)-(C0-C6alkyl)-C(O)-phenyl, or-N(R9)-C0-C4alkyl-phenyl, where the phenyl group is substituted by one or two groups that are independently represents a C1-C4alkyl, C1-C4alkoxy, halogen, C1-C4halogenated (in one variant, CF3), C1-C4halogenoalkane (in one embodiment, the OCF3), hydroxyl, hydroxy, C1-C4alkyl, amino, -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkyl), -(C0-C6alkyl)-C(O)R11or NO2; and R4and R9independently represent H or methyl.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XI), as well as to intermediate compounds suitable for preparing compounds of the formula (XI), where R4represents N.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XI), as well as to intermediate compounds suitable for received what I compounds of the formula (X), where R11represents a C1-C6alkoxy, optionally substituted 1 or 2 groups that are independently represents a C1-C4alkoxy, amino, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), -(C0-C6alkyl)-C(O)N(R9-heteroseksualci or heteroseksualci, heterocytolysine group selected from pyrrolidinyl, piperidinyl, piperazinil and morpholinyl where heterocytolysine group optionally substituted by 1, 2, or 3 groups that are independently represent halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, hydroxy (C1-C6alkyl, C1-C6alkoxycarbonyl, -CO2H, CF3or OCF3.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XI), as well as to intermediate compounds suitable for preparing compounds of the formula (X), where two or more previously described features combined.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XII), i.e. compounds of formula (X) the following formula, as well as to intermediate compounds suitable for preparing compounds of the formula (XII):

where R15represents H, C1-C alkyl, C1-C6alkoxy, halogen, C1-C6halogenated (in one embodiment, CF3), C1-C6halogenoalkane (in one embodiment, the OCF3), hydroxyl, hydroxy, C1-C4alkyl, amino, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), methylsulfone, C0-C6the sulfonamide or NO2and R16represents H or-O-(C0-C6alkyl)-C(O)R11. In another embodiment, R15represents H.

In another additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XII), as well as to intermediate compounds suitable for preparing compounds of the formula (XII), where R4and R9independently represent H or methyl, and R11represents OH.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XII), as well as to intermediate compounds suitable for preparing compounds of the formula (XII), where R4and R9independently represent H or methyl, and R11represents a C1-C6alkoxy, optionally substituted 1 or 2 groups that are independently represents a C1-C4alkoxy, amino, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), -(C0-C6/sub> alkyl)-C(O)N(R9-heteroseksualci or heteroseksualci group, where heterocytolysine group selected from azabicycloalkanes, in some embodiments, 1-azabicyclo[2.2.2]Oct-3-yl or 8-azabicyclo[3.2.1]Oct-3-yl, azabicycloalkanes, isabellakelly, where the Aza nitrogen optionally substituted by stands or ethyl, pyrrolidinyl, piperidinyl, piperazinil and morpholinyl where heterocytolysine group optionally substituted by 1, 2, or 3 groups that are independently represent halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, hydroxy (C1-C6alkyl, C1-C6alkoxycarbonyl, -CO2H, CF3or OCF3and R4and R9independently represent H or methyl. In another embodiment, R4, R9and R11defined above, and R15represents H, R1is chlorine; R2represents amino; and R3represents methoxy.

In another additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XII), as well as to intermediate compounds suitable for preparing compounds of the formula (XII), where R4and R9independently represent H or methyl, and R11represents a C1-C6alkoxy, optionally substituted 1 or 2 groups that are independently p is establet a C 1-C4alkoxy, amino, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl) or heteroaryl, where the heteroaryl group is selected from pyridyl, pyrimidyl, chinoline, izochinolina and indolyl, where heteroaryl group optionally substituted by 1, 2, or 3 groups that are independently represent halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, hydroxy (C1-C6alkyl, C1-C6alkoxycarbonyl, -CO2H, CF3or OCF3; and R4and R9independently represent H or methyl. In another embodiment, R4, R9and R11defined above, R15represents H, R1represents chlorine; R2represents amino; and R3represents methoxy.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XII), as well as to intermediate compounds suitable for preparing compounds of the formula (XII), where at least one of R4and R9represents H.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XII), as well as to intermediate compounds suitable for preparing compounds of the formula (XII)where two or more of the previously described features are combined.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XIII), i.e. compounds of formula (X) the following formula, as well as to intermediate compounds suitable for preparing compounds of the formula (XIII):

where R15represents H, C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6halogenated (in one embodiment, CF3), C1-C6halogenoalkane (in one embodiment, the OCF3), hydroxyl, hydroxy, C1-C4alkyl, amino, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl) or methylsulfone, C0-C6-sulfonamide, NO2and R16represents H or-O-(C0-C6alkyl)-C(O)R11. In another embodiment, R15represents H.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XIII), as well as to intermediate compounds suitable for preparing compounds of the formula (XIII), where

R4and R9independently represent H or methyl, and R11represents OH,1-C4alkoxy (in another embodiment With1-C3alkoxy) or (C1-C2alkoxy-C1-C3alkoxy. In another embodiment, R4, R9and R11defined above and R 1represents chlorine; R2represents amino and R3represents methoxy.

In another additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XIII), as well as to intermediate compounds suitable for preparing compounds of the formula (XIII)where R4and R9independently represent H or methyl, and R11represents C1-C4alkoxy, substituted amino, -NH(C1-C6by alkyl), -N(C1-C6alkyl)(C1-C6by alkyl), azabicycloalkanes, in some embodiments, 1-azabicyclo[2.2.2]Oct-3-yl or 8-azabicyclo[3.2.1]Oct-3-yl, azabicycloalkanes, izabellacullen, where the Aza nitrogen optionally substituted by stands or ethyl; and R4represents H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(C0-C6alkyl)-C(O)NH-pyrid-4-yl. In another embodiment, R4, R9and R11defined above, and R1represents chlorine; R2represents amino; and R3represents methoxy.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XIII), as well as to intermediate compounds suitable for preparing compounds of the formula (XIII)where R4and R9independently represent H or methyl, and R11 represents C1-C4alkoxy, substituted amino, -NH(C1-C6by alkyl) or-N(C1-C6alkyl)(C1-C6by alkyl). In another embodiment, R4, R9and R11defined above, and R1represents chlorine; R2represents amino; and R3represents methoxy.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XIII), as well as to intermediate compounds suitable for preparing compounds of the formula (XIII)where R4and R9independently represent H or methyl, and R11represents C1-C4alkoxy, substituted pyrrolidinium, piperidinium, morpholinium, pyridium or -(C0-C6alkyl)-C(O)NH-pyrid-4-yl. In another embodiment, R4, R9and R11defined above, and R1represents chlorine; R2represents amino; R3represents methoxy.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XIII), as well as to intermediate compounds suitable for preparing compounds of the formula (XIII), where at least one of R4and R9represents H.

In an additional aspect, the present invention relates to methods and/or processes for obtaining the compounds is of the formula (XIII), as well as to intermediate compounds suitable for preparing compounds of the formula (XIII)where two or more of the previously described features are combined.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XIV), i.e. compounds of formula (X) the following formula, as well as to intermediate compounds suitable for preparing compounds of the formula (XIV):

(XIV)

where R15represents H, C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6halogenated (in one aspect, CF3), C1-C6halogenoalkane (in one aspect OCF3), hydroxyl, hydroxys1-C4alkyl, amino, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), methylsulfone, C0-C6the sulfonamide or NO2and R16represents H or-O-(C0-C6alkyl)-C(O)R11. In another aspect, R15represents H.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XIV), as well as to intermediate compounds suitable for preparing compounds of the formula (XIV), where R4and R9independently represent H or methyl, and R11represents OH, C1-C4alkoxy (in another embodiment, a C1/sub> -C3alkoxy), or C1-C2alkoxy-C1-C3alkoxy-. In another embodiment, R4, R9and R11defined above, and R1represents chlorine; R2represents amino; and R3represents methoxy. In yet another embodiment, at least one of R4and R9represents H.

In another aspect the present invention relates to methods and/or processes of preparing compounds of the formula (XIV), as well as to intermediate compounds suitable for preparing compounds of the formula (XIV), where R4and R9independently represent H or methyl, and R11represents C1-C4alkoxy, substituted amino, -NH(C1-C6by alkyl), -N(C1-C6alkyl)(C1-C6by alkyl), azabicycloalkanes, in some embodiments, 1-azabicyclo[2.2.2]Oct-3-yl or 8-azabicyclo[3.2.1]Oct-3-yl, azabicycloalkanes, izabellacullen, where the Aza nitrogen optionally substituted by stands or ethyl; and R4represents H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(C0-C6alkyl)-C(O)NH-pyrid-4-yl. In another embodiment, R4, R9and R11defined above, and R1represents chlorine; R2represents amino; and R3represents methoxy.

In another additional aspect, the present invention relates to the means and/or processes of preparing compounds of the formula (XIV), as well as to intermediate compounds suitable for preparing compounds of the formula (XIV), where R4and R9independently represent H or methyl, and R11represents C1-C4alkoxy, substituted amino, -NH(C1-C6by alkyl) or-N(C1-C6alkyl)(C1-C6by alkyl). In another embodiment, R4, R9and R11defined above, and R1represents chlorine; R2represents amino; and R3represents methoxy.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XIV), as well as to intermediate compounds suitable for preparing compounds of the formula (XIV), where R4and R9independently represent H or methyl, and R11represents C1-C4alkoxy, substituted pyrrolidinium, piperidinium, morpholinium, pyridium or -(C0-C6alkyl)-C(O)NH-pyrid-4-yl. In another embodiment, R4, R9and R11defined above, and R1represents chlorine; R2represents amino; and R3represents methoxy.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XIV), as well as to intermediate compounds suitable for preparing compounds of the formula (XIV), where at IU is e one of R 4and R9represents H.

In another aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XIV), as well as to intermediate compounds suitable for preparing compounds of the formula (XIV)where two or more of the previously described features are combined.

Another feature of the present invention relates to methods and/or processes of preparing compounds of the formula (XV), i.e. compounds of formula (X) the following formula, as well as to intermediate compounds suitable for preparing compounds of the formula (XV):

(XV)

where n is 1 or 2.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XV), as well as to intermediate compounds suitable for preparing compounds of the formula (XV), where R4represents H or methyl, and R11represents OH, C1-C4alkoxy (in another embodiment, a C1-C3alkoxy), or C1-C2alkoxy-C1-C3alkoxy-. In another embodiment, R4and R11defined above, and R1represents chlorine; R2represents amino; and R3represents methoxy. In another embodiment of the invention at least one of R4and R9represents H.

In yet an additional aspect of toadie the invention relates to methods and/or processes of preparing compounds of the formula (XV), as well as to intermediate compounds suitable for preparing compounds of the formula (XV), where R4and R9independently represent H or methyl, and R11represents C1-C4alkoxy, substituted amino, -NH(C1-C6by alkyl), -N(C1-C6alkyl)(C1-C6by alkyl), azabicycloalkanes, in some embodiments, 1-azabicyclo[2.2.2]Oct-3-yl or 8-azabicyclo[3.2.1]Oct-3-yl, azabicycloalkanes, izabellacullen,where the Aza nitrogen optionally substituted by stands or ethyl; and R4represents H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or C(O)NH-pyrid-4-yl. In another embodiment, R4, R9and R11defined above, and R1represents chlorine; R2represents amino; and R3represents methoxy.

In an additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XV), as well as to intermediate compounds suitable for preparing compounds of the formula (XV), where R4and R9independently represent H or methyl, and R11represents C1-C4alkoxy, substituted amino, -NH(C1-C6by alkyl) or-N(C1-C6alkyl)(C1-C6by alkyl). In another embodiment, R4, R9and R11defined above, and R1represents chlorine; R2depict is to place a amino; and R3represents methoxy.

In another additional aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XV), as well as to intermediate compounds suitable for preparing compounds of the formula (XV), where R4represents H or methyl, and R11represents C1-C4alkoxy, substituted azabicycloalkanes, in some embodiments, 1-azabicyclo[2.2.2]Oct-3-yl or 8-azabicyclo[3.2.1]Oct-3-yl, azabicycloalkanes, izabellacullen, where the Aza nitrogen optionally substituted by stands or ethyl; and R4represents H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(C0-C6alkyl)-C(O)NH-pyrid-4-yl. In another embodiment, R4, R9and R11defined above, and R1represents chlorine; R2represents amino; and R3represents methoxy.

In another aspect, the present invention relates to methods and/or processes of preparing compounds of the formula (XV), as well as to intermediate compounds suitable for preparing compounds of the formula (XV)where two or more previously described features combined.

In another aspect, the present invention relates to methods and/or processes for making compounds, as well as to intermediate compounds suitable for preparing compounds of any of formula (X), (XI), (XI), (XIII), (XIV) or (XV), where R1R2and R3oriented in the phenyl ring as follows:

.

In another aspect, the present invention relates to methods and/or processes for making compounds, as well as to intermediate compounds suitable for preparing compounds of any of formula (X), (XI), (XII), (XIII), (XIV) or (XV), where the link 3 has S-configuration, and the nexus 4 has the R-configuration.

In another additional aspect, the present invention relates to methods and/or processes for making compounds, as well as to intermediate compounds suitable for preparing compounds of any of formula (X), (XI), (XII), (XIII), (XIV) or (XV), where R1, R2and R3oriented in the phenyl ring as follows:

,

and link 3 has S-configuration, and the nexus 4 has the R-configuration.

In another aspect, the present invention relates to methods and/or processes for making compounds, as well as to intermediate compounds suitable for preparing compounds of any of formula (X), (XI), (XII), (XIII), (XIV) or (XV), where the link 3 has the R-configuration, and the nexus 4 has an "S"-configuration.

In another aspect, the present invention relates to methods and/or processes for making compounds, as well as to intermediate compounds suitable for preparing compounds of any of the forms is l (X), (XI), (XII), (XIII), (XIV) or (XV), where R1, R2and R3oriented in the phenyl ring as follows:

,

and link 3 has the R-configuration, and the nexus 4 has an "S"-configuration.

In still another aspect, the present invention relates to methods and/or processes for making compounds, as well as to intermediate compounds suitable for preparing compounds of the formula (X), where R1represents chlorine; R2represents amino; R3represents methoxy; R4represents H, and R1, R2and R3oriented in the phenyl ring as follows:

,

and

L represents -(C3-C5alkyl)-, where one carbon atom may be replaced by-N(R9)- or -(C2-C6alkyl)-C(O)-. In another aspect, R1, R2and R3defined above, and oriented in the phenyl ring as described above, R4defined above, R5is an O-heteroseksualci where heterocytolysine group selected from azabicycloalkanes, in some embodiments, 1-azabicyclo[2.2.2]Oct-3-yl or 8-azabicyclo[3.2.1]Oct-3-yl, azabicycloalkanes, isabellakelly, where the Aza nitrogen is optionally substituted by stands or ethyl, piperidinyl, piperazinil and pyrrolidinyl where piperidinyl, piperazinil and pyrrolidin the l are unsubstituted or substituted in one or two positions by groups which independently represents a C1-C4alkyl, C1-C4alkoxy, halogen, C1-C4halogenated, C1-C4halogenoalkane, hydroxyl, hydroxy-C1-C4alkyl, amino, -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkyl), -(C0-C6alkyl)-C(O)R11or NO2where

R11represents a C1-C6alkoxy, optionally substituted 1 or 2 groups that are independently represents a C1-C4alkoxy, amino, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), -(C0-C6alkyl)-C(O)N(R9-heteroseksualci or heteroseksualci where heterocytolysine group selected from azabicycloalkanes, in some embodiments, 1-azabicyclo[2.2.2]Oct-3-yl or 8-azabicyclo[3.2.1]Oct-3-yl, azabicycloalkanes, isabellakelly, where the Aza nitrogen optionally substituted by stands or ethyl; and R4represents H or methyl, pyrrolidinyl, piperidinyl, piperazinil and morpholinyl where heterocytolysine group optionally substituted by 1, 2, or 3 groups that are independently represents a C1-C6alkyl, C1-C6alkoxy, hydroxy, hydroxy (C1-C6alkyl, C1-C6alkoxycarbonyl, -CO2H, CF3or OCF3.

In still another aspect of the present image is eenie relates to methods and/or processes for making compounds as well as to intermediate compounds suitable for preparing compounds of the formula (X), where

R1represents chlorine; R2represents amino; R3represents methoxy; R4represents H, and R1, R2and R3oriented in the phenyl ring as follows:

and

L represents -(C3-C5alkyl)-, where one carbon atom may be replaced by-N(R9)- or -(C2-C6alkyl)-C(O)-. In another embodiment, R1, R2and R3defined above, and oriented in the phenyl ring as described above, R4defined above, and R5is heteroseksualci selected from azabicycloalkanes, in some embodiments, 1-azabicyclo[2.2.2]Oct-3-yl or 8-azabicyclo[3.2.1]Oct-3-yl, azabicycloalkanes, isabellakelly, where the Aza nitrogen optionally substituted by stands or ethyl.

Another feature of the present invention relates to methods and/or processes for making compounds of formula (X), as well as to intermediate compounds suitable for preparing compounds of the formula (X), where

R1represents chlorine; R2represents amino; R3represents methoxy; R4represents H, and R1, R2and R3oriented in the phenyl ring as education is Ohm:

and

L is -(C3-C5alkyl)-, where one carbon atom may be replaced by-N(R9)- or -(C2-C6alkyl)-C(O)-. In another embodiment, R1, R2and R3defined above and oriented in the phenyl ring as described above, R4defined above, and R5represents-N(R9)-C0-C4alkyl-aryl, or-N(R9)-(C0-C6alkyl)-C(O)-aryl, where the aryl group is unsubstituted or substituted in one or more delegate positions of the C1-C6the alkyl, C1-C6alkoxy, halogen, C1-C6halogenation, C1-C6halogenoalkane, hydroxyl, hydroxyalkyl, amino, -NH(C1-C6by alkyl), -N(C1-C6alkyl)(C1-C6by alkyl), -(C0-C6alkyl)-C(O)R11or NO2. In another embodiment, the aryl group is a phenyl, substituted -(C0-C6alkyl)-C(O)R11and optionally substituted 1 or 2 groups independently selected from C1-C6of alkyl, C1-C6alkoxy, halogen, CF3, OCF3, hydroxyl, hydroxyalkyl, amino, -NH(C1-C4the alkyl), -N(C1-C4alkyl)(C1-C4the alkyl or NO2where

R11represents a C1-C6alkoxy, optionally substituted 1 or 2 groups, which is s independently represents a C 1-C4alkoxy, amino, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), -(C0-C6alkyl)-C(O)N(R9-heteroseksualci or heteroseksualci where heterocytolysine group selected from pyrrolidinyl, piperidinyl, piperazinil and morpholinyl where heterocytolysine group optionally substituted by 1, 2, or 3 groups that are independently represent halogen, C1-C6alkyl, C1-C6alkoxy, hydroxy, hydroxy (C1-C6alkyl, C1-C6alkoxycarbonyl, -CO2H, CF3or OCF3. In a preferred embodiment, the group -(C0-C6alkyl)-C(O)R1attached to the phenyl ring at position 4.

In another aspect of implementation of the present invention the orientation of the links 3 and 4 connections, obtained using the methods and/or processes of the present invention, is as follows:

.

In a preferred implementation of the present invention the orientation of the links 3 and 4 connections, obtained using the methods and/or processes of the present invention, is as follows:

.

The invention relates also to methods for treating vomiting, dyspepsia, gastroparesis, constipation, pseudoprobability intestine, gastroesophageal of reflux is a or postoperative paresis of the intestine, includes the introduction of a therapeutically effective amount of the compounds or salts of the compounds of formula (X), obtained using the methods and/or processes of the present invention, patients who need specific treatment.

The present invention relates to methods and/or processes for making compounds that are more susceptible to decomposition under the action of serum and/or cytosolic esterases than cisapride, thus avoiding adverse effects associated with metabolism by cytochrome P450.

The advantage of therapeutic compounds, obtained using the methods and/or processes of the present invention is their stability during storage and the relatively short period of existence in physiological environments; thus, the compounds of the present invention can be applied with a lower incidence of side effects and less toxicity.

A preferred feature of the present invention relates to therapeutic stereoisomeric compounds, obtained using the methods and/or processes of the present invention, which are suitable for the treatment of gastroesophageal reflux disease and which contain the ester group, which is susceptible to cleavage by esterases, resulting in Obedinenie destroyed and facilitates its effective removal from the body of the patient. In a preferred embodiment, osushestvleniya of the present invention therapeutic stereoisomeric compounds are metabolized by the detoxification system of the medicinal product phase I.

Another feature of the present invention relates to the decay products (preferably to the metabolic products of disintegration, i.e. metabolites, mainly acids source esters), which are formed when the effect of esterases on therapeutic compounds, obtained using the methods and/or processes of the present invention. The presence of these degradation products in the urine or serum can be used to monitor the rate of excretion of therapeutic compounds from the body of the patient.

The collapse of the compounds, obtained using the methods and/or processes of the present invention, under the influence of esterases is a special advantage in regard to the metabolism of drugs, as these enzymes are ubiquitous in the body, and their activity does not depend on age, sex or conditions to the extent that these factors affect the oxidative metabolism of drugs in the liver.

The present invention relates also to methods for treating disorders such as gastroesophageal the other reflux disease, includes the introduction of a therapeutically effective amount of at least one stereoisomeric structural and/or functional analog of cisapride to the individual that needs specific treatment. A characteristic feature of the present invention relates to a stereoisomeric structural and/or functional analogs of cisapride and to pharmaceutical compositions mentioned esterified compounds.

The present invention also relates to materials and methods for treating vomiting and other conditions, including, without limitation, dyspepsia, gastroparesis, constipation and pseudoprobability intestines, which are characterized by a significant reduction of adverse effects associated with the introduction of cisapride.

The preferred implementation of the present invention relates to methods and/or processes for obtaining therapeutic stereoisomeric compounds, which are suitable for the treatment of gastroesophageal reflux, dyspepsia, gastroparesis, constipation, postoperative paresis of the intestine and pseudoprobability intestine and which contain the ester group, which is affected by esterase, resulting in the compound breaks up and facilitated its effective removal from the body of the patient.

The present invention relates also to methods of synthesis of the useful compounds of the present invention. In particular, the ways of production and purification of these stereoisomeric compounds. How to add the above ester units and the manufacture and purification of stereoisomers are well known in the art and can be easily carried out in accordance with the presented in this guidance document.

The preferred connection

In a preferred embodiment, the present invention relates to methods and/or processes for obtaining isolated stereoisomers of compound I, as well as to intermediate compounds suitable for receiving such stereoisomers, which contains three chiral center.

The connection I

Two of the chiral centers are cisapride and norcisapride and active drugs have a CIS-configuration:


(±)-cisapride

(±)-norcisapride

So, for example, pharmaceutically active norcisapride is a racemic mixture of two CIS-enantiomers:

In one aspect the present invention relates, in particular, to methods and/or processes of preparing compounds with certain confit what oracea third chiral center, in chinuklidinyl parts, as well as to intermediate compounds suitable for obtaining these compounds. This group is eliminated during the transformation in acid metabolite, designated herein as ± compound II:

Compound II

Despite the fact that the stereoisomers of the Compounds I can be obtained by conjugation of R - or S-hinokitiol with (+)- or (-)-norcisapride, resulting in the formation of compound III, IV, V and VI, the preferred methods are described below, in which the core of cisapride is not used.

Compound III: (-)(R)connection I

Compound IV: (+)(R)connection I

compound V: (-)(S)-connection

compound VI: (+)(S)connection I

A preferred feature of the present invention relates to methods and/or processes for obtaining stereoisomers isolated compounds, as well as to intermediate compounds suitable for the production of these compounds, and to compositions comprising these compounds. Isolated stereoisomeric forms of the compounds, obtained using the methods and/or processes of the present invention, contain virtually no other stereoisomer (i.e. stereoisomers the excess). In other words, "R"forms of the compounds contain virtually no "S"-shaped connections and, thus, are in a stereoisomeric excess in relation to the "S"forms. Conversely, the "S"-shaped connections practically do not contain the "R"forms of the compounds and, thus, are in a stereoisomeric excess in relation to the "R"forms. One feature of the present invention relates to isolated stereoisomeric compounds, obtained using the methods and/or processes of the present invention, which are stereoisomeric excess of at least about 80%. A preferred feature of the present invention relates to compounds, obtained using the methods and/or processes of the present invention, which are stereoisomeric excess of at least about 90%. A more preferred feature of the present invention relates to compounds, obtained using the methods and/or processes of the present invention, which are stereoisomeric excess of at least about 95%. Even more preferred feature of the present invention relates to compounds, obtained using the methods and/or processes of the present invention, which are stereoisomeric excess of at least approximately what part of 97.5%. The most preferred feature of the present invention relates to compounds, obtained using the methods and/or processes of the present invention, which are stereoisomeric excess of at least about 99%. Similarly, the "(+)and(-)forms of the compounds were also obtained in stereoisomeric excess.

As described herein, various stereoisomers obtained using methods and/or processes of the present invention, have a special and unexpected properties, which can be advantageously used for the selection of treatment in certain cases. So, for example, compounds containing (3'R)-isomer in hinkleyville ester part, i.e. compounds III and IV, is rapidly metabolized by plasma esterases, whereas the metabolism of compounds containing (3'S)-isomer of hinokitiol, i.e. compounds V and VI, is much slower.

Accordingly, (3'R)-isomers of the compounds I can be used in cases where it is preferable to short duration, for example, for stimulation of gastric motility in the acute episode, such as shock introduction patients with acute gastroparesis or acute gastroesophageal reflux. Another advantage of rapid metabolism by esterases to a much less active is etabolites, the compound (II) is a very small likelihood of drug interactions and toxic effects. Therefore, these (R)-isomers short steps, you can successfully be used as an intravenous composition for the treatment of gastroesophageal reflux in premature infants, in whom, as you know, the metabolism of drugs is less active than adults, due to insufficient development of the CYP450 system. In these infants, the drug is undergoing rapid metabolism without the participation of the CYP450 system, for example, esterases, is a significant advantage. On the other hand, (3'S)-isomers of the compounds I, obtained using the methods and/or processes of the present invention, it is best to use for the treatment of chronic forms of the same disease, e.g., gastroparesis in patients with diabetes or cancer patients receiving opiates and chronic gastroesophageal reflux in patients who require round-the-clock correction.

In addition to differences in metabolism, these individual isomers have different affinity to 5-HT4the receptor, which differ in their effects and, accordingly, the sphere of therapeutic applications. So, in order of decreasing affinity for 5-HT4-receptor isomers can be the size of which is disposed of as follows (values in parentheses of the binding constant Ki); compound IV (1,4 nm), compound VI (3.4 nm), compound III (28 nm) and compound V (72 nm). These experiments to determine the affinity was conducted using a radioisotope method described in the public guidelines, and can be easily reproduced by experts in the field of molecular biology.

On the basis of the above provisions, it is possible to conclude the following: when the link 3 and 4 are in the CIS-position relative to each other, the connection I is a mixture of 4 isomers, consisting of 2 pairs of enantiomers. The first pair of enantiomers is a (+)(R)-compound I and (-)(S)-compound I (compounds IV and V, respectively), the second pair of enantiomers is a (-)(R)-compound I (+)and(S)-compound I (compounds III and VI, respectively). In each of the pairs of properties of the enantiomers differ from each other in regard to how the velocity of hydrolysis by esterases and their affinity for 5-HT4the receptor. Due to these differences, each connection has its own therapeutic benefits that are not interchangeable, i.e. specific to a particular isomer, and not inherent in the racemic mixture. These differences in affinity to the receptor and metabolic rate are not predictable, and these properties cannot be analyzed in the study racemic mixture

Another feature of the present invention relates to a method for obtaining compounds of formula II'

(II')

includes the conversion of the compounds of formula (I')

(I')

or its salts in the compound of formula (II') or its salt, respectively, where X1represents a protective group of nitrogen, and X2selected from the group consisting of hydrogen and protective groups of nitrogen (as such, you can use one of the well-known and widely used N-protective groups, for example, N-benzyl; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzylmethyl) (and preferably X1and X2represent benzyl), and R is a (C1-C8)alkyl, preferably (C1-C4)alkyl, more preferably ethyl. In another embodiment of the present invention and X1and X2are not benzyl.

The invention relates also to compounds of formula II'

(II')

and their salts, where X1represents a protective group of nitrogen, and X2selected from the group consisting of hydrogen and protective groups of nitrogen (as such, you can use one of the well-known and widely used N-protective groups, for example, N-benzyl; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzols hanil) (and preferably X 1and X2represent benzyl), and R is a (C1-C8)alkyl, preferably (C1-C4)alkyl, more preferably ethyl. In another embodiment of the present invention and X1and X2are not benzyl.

Another feature of the present invention relates to a method for obtaining compounds of formula III'

(III');

includes the impact on the compound of the formula (II')

(II')

hydroxide or hydride of an alkali metal (for example, NaOH, KOH, potassium hydride or sodium hydride lithium-aluminum and the like), to obtain the compounds of formula (III'), where X1represents a protective group of nitrogen, and X2selected from the group consisting of hydrogen and protective groups of nitrogen (as such, you can use one of the well-known and widely used N-protective groups, for example, N-benzyl; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzylmethyl) (and preferably X1and X2represent benzyl), and R is a (C1-C8)alkyl, preferably (C1-C4)alkyl, more preferably ethyl. In another embodiment of the present invention and X1and X2are not benzyl.

During the experiments with the connection

unexpectedly, it was found that when using at least 12 equivalents of KOH and 8-fold excess of isopropyl alcohol using a reverse refrigerator hydrolysis reaction yields almost 100% conversion with the almost complete lack of impurities. When using smaller quantities of KOH (such as,5 and 10 EQ.) the transformation occurred approximately 83-98%, with impurities in the range from 1.9% to 7.3%.

The invention relates also to compounds of formula III'

(III');

and their salts, where X1represents a protective group of nitrogen, and X2selected from the group consisting of hydrogen and protective groups of nitrogen (as such, you can use one of the well-known and widely used N-protective groups, for example, N-benzyl; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzylmethyl) (and preferably X1and X2represent benzyl). In another embodiment of the present invention and X1and X2are not benzyl.

Another feature of the present invention relates to a method for obtaining compounds of formula III"

(III");

includes (a) contacting the compounds of formula III'

(III')

with chiral separating agent (for example, tartaric acid, is indolnoe acid, acid Moser, camphorsulfonic acid and the like), with chiral salts III and allocation of chiral salts III";

b) optionally, a recrystallization of the product (a); and

c) contacting (a) or (b) with a base, to obtain the compounds of formula III";

where X1represents a protective group of nitrogen, and X2selected from the group consisting of hydrogen and protective groups of nitrogen (as such, you can use one of the well-known and widely used N-protective groups, for example, N-benzyl; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzylmethyl) (and preferably X1and X2represent benzyl). In another embodiment of the present invention and X1and X2are not benzyl.

Preferably, in this embodiment, the present invention chiral separating agent is (+)-2,3-Dibenzoyl-D-tartaric acid and chiral salt III' is (3S,4R)-enantiomer (+)-2,3-Dibenzoyl-D-tartrate.

It has been unexpectedly found that the use of a chiral salt of (+)-2,3-Dibenzoyl-D-tartaric acid, preferably in the amount of one equivalent of two equivalent of compound III', provides an increased output compared with other chiral separating agents. The interaction of one equivalent of (+)-2,3-Dibenzoyl-D-tartaric acid with two ek is ivalentine III' provides an output, more than three times the output from the interaction of one equivalent of (+)-2,3-Dibenzoyl-D-tartaric acid with two equivalents III'. Thus, in a preferred embodiment, obtaining the compounds of formula III is one equivalent of a chiral separating agent (preferably, (+)-2,3-Dibenzoyl-D-tartaric acid) and two equivalents of the compounds of formula III'.

Another feature of the present invention relates to the compound of formula III"

(III)

and its salts, where X1represents a protective group of nitrogen, and X2selected from the group consisting of hydrogen and protective groups of nitrogen (as such, you can use one of the well-known and widely used N-protective groups, for example, N-benzyl; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzylmethyl) (and preferably X1and X2represent benzyl). In another embodiment of the present invention and X1and X2are not benzyl.

Another feature of the present invention relates to a method for obtaining compounds of formula IV'

(IV');

includes contacting the compounds of formula

(III");

with (C1-C8)alkyl 6-halogenerator (where the halogen is preferably with the Oh bromine), obtaining the compounds of formula (IV')wherein R' represents a (C1-C8)alkyl (preferably ethyl), and X1represents a protective group of nitrogen, and X2selected from the group consisting of hydrogen and protective groups of nitrogen (as such, you can use one of the well-known and widely used N-protective groups, for example, N-benzyl; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzylmethyl) (and preferably X1and X2represent benzyl). In another embodiment of the present invention and X1and X2are not benzyl.

Another feature of the present invention relates to the compound of formula IV'

(IV').

and its salts, where R' represents a (C1-C8)alkyl (preferably ethyl), and X1represents a protective group of nitrogen, and X2selected from the group consisting of hydrogen and protective groups of nitrogen (as such, you can use one of the well-known and widely used N-protective groups, for example, N-benzyl; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzylmethyl) (and preferably X1and X2represent benzyl). In another embodiment of the present invention and X1and X2are not benzyl.

In another aspect of the present image is the buy relates to a method for obtaining compounds of formula V'

(V');

includes contacting the compounds of formula IV'

(IV').

with (R)-Hinkley-3-I and Lewis acid (for example, tetraethoxide titanium (for example, Ti(OiPr)4(tetraisopropoxide titanium) and Ti(OEt)4(tetraethoxide titanium)), TsOH (paratoluenesulfonyl acid), K2CO3and the cat. DMAP (catalytic 4-dimethylaminopyridine)) in an organic solvent (e.g. toluene), where R' represents a (C1-C8)alkyl (preferably ethyl), and X1represents a protective group of nitrogen, and X2selected from the group consisting of hydrogen and protective groups of nitrogen (as such, you can use one of the well-known and widely used N-protective groups, for example, N-benzyl; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzylmethyl) (and preferably X1and X2represent benzyl). In another embodiment of the present invention and X1and X2are not benzyl.

Another feature of the present invention relates to the compound of formula V'

(V');

and its salts, where X1represents a protective group of nitrogen, and X2selected from the group consisting of hydrogen and protective groups of nitrogen (as such, you can use one the of the well-known and widely used N-protective group, for example, N-benzyl; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzylmethyl) (and preferably X1and X2represent benzyl). In another embodiment of the present invention and X1and X2are not benzyl.

Another feature of the present invention relates to a method for obtaining compounds of formula VI'

(VI')

includes deleting groups X1and X2of the compounds of formula V'

(V'),

where X1represents a protective group of nitrogen, and X2selected from the group consisting of hydrogen and protective groups of nitrogen (as such, you can use one of the well-known and widely used N-protective groups, for example, N-benzyl; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzylmethyl) (and preferably X1and X2represent benzyl). In another embodiment of the present invention and X1and X2are not benzyl.

In a preferred embodiment, the specified aspect of the present invention X1and X2are benzyl and deleted impact on V' H2/Pd/C or by ammonium formate /Pd (examples), with (R)-Hinkley-3-yl 6-[(3S,4R)-4-amino-3-methoxypiperidine-1-yl]hexanoate. Applicants unexpectedly discovered, thanks to the gidrirovanie using H 2/Pd/C this method has significant advantages compared to methods dibenzylamine using, for example, ammonium formate. These methods are often dirty and require cleaning on a column of silica gel to remove reagents (for example, ammonium formate), which is impractical in industrial production. Hydrogenation using H2/Pd/C is an extremely clean process and does not require purification on columns.

In another aspect, the present invention relates to a method for producing (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate (VII'), comprising contacting the compounds of formula VI'

(VI')

4-amino-5-chloro-2-methoxybenzoic acid. Preferably, this contacting is performed with the use of EDCI (1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide), HOBt (l-hydroxybenzotriazole), HOSU (N-hydroxysuccinimide), HONB (N-hydroxy-5-narben-endo-2,3-dicarboximide), isobutylacetate, pivaloyloxy or DCC (dicyclohexylcarbodiimide). Most preferably, this contacting is performed with the use of pivaloyloxy (preferably, pivaloyloxy). Unexpectedly, it was found that when using pualeilani received C is acetelyne less impurities, and the product is much easier to clean than when using other alleluya agents. The result is a higher yield of the reaction and significantly higher purity compounds than other alleluya agents.

Compounds of formulas I', II', III', III', IV', V' and VI' are the intermediate compounds suitable for the production of (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate.

In another aspect, the present invention relates to combinations of the above methods. Used in the present invention, the method described as method X-Y, is a process involving the combination of obtaining the compounds of formula X and the method of obtaining the compounds of formula “Y”; and, similarly, the way the X-Y-Z represents the way the X-Y followed by the application of the method of obtaining the compounds of formula Z, etc. Accordingly, the above feature of the invention includes, without limitation, the ways I'-II', II'-III', III'-III, III-IV', IV'-V', V'-VI', VI'-VII', I'-II'-III', II'-III'-III", III'-III ' -IV', III-IV'-V', IV'-V'-VI', V'-VI'AND VII', I'-II'-III'-III", II'-III'-III ' -IV', III'-III"-IV'-V', III-IV'-V'-VI' and IV'-V'-VI'-VII'.

An additional aspect of the present invention relates to a method for producing (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate or its salts, including:

1) obazatelno, the transformation of compounds of formula (I')

(I')

in salt, where R is a (C1-C8)alkyl (preferably (C1-C6)alkyl, (C1-C4)alkyl, or ethyl);

2) the conversion of compounds of formula (I') or its salt in the compound of formula (II')

(II')

or its salt, respectively, where X1represents a protective group of nitrogen, and X2selected from the group consisting of hydrogen and protective groups of nitrogen (as such, you can use one of the well-known and widely used N-protective groups, for example, N-benzyl; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzylmethyl) (and preferably X1and X2represent benzyl).

3) the effect on the compound of the formula (II') hydroxide or hydride of an alkali metal (for example, NaOH, KOH, sodium hydride or potassium hydride lithium - aluminum and the like), to obtain the compounds of formula (III')

(III');

4) obtaining the chiral salt of compound III' exposure to the compound of formula (III') chiral separating agent (for example, tartaric acid, almond acid, acid Moser, camphorsulfonate and the like, or, preferably, (+)-2,3-Dibenzoyl-D-tartaric acid, to obtain the chiral salt (for example, (3S,4R)-enantiomer (+)-2,3-Dibenzoyl the-D-tartrate, if chiral separating agent is (+)-2,3-Dibenzoyl-D-tartaric acid)and the allocation of the CIS isomer thus obtained compound III';

5) optional, recrystallization of the product 4;

6) the transformation of the product 4 or 5 in the base, with the receipt of the product 4 or 5 in free base form;

7) the contacting of the product 6 (C1-C8)alkyl 6-halogenerator (where the halogen preferably represents bromine), with compounds of the formula (IV')

(IV');

where R' represents a (C1-C8)alkyl (preferably ethyl);

8) impact on product 7 (R)-Hinkley-3-I and Lewis acid (for example, tetraethoxide titanium (for example, Ti(OiPr)4(tetraisopropoxide titanium) and Ti(OEt)4(tetraethoxide titanium)), TsOH (paratoluenesulfonyl acid), K2CO3and the cat. DMAP (catalytic 4-dimethylaminopyridine)) in an organic solvent (e.g. toluene), to obtain the compounds of formula (V')

(V');

9) removing protection from a 4-amino group of the product 8 (for example, using H2/Pd/C and ammonium formate /Pd as examples), with (R)-Hinkley-3-yl 6-[(3S,4R)-4-amino-3-methoxypiperidine-1-yl]hexanoate;

10) the acylation product 9 4-amino-5-chloro-2-methoxybenzoic acid (e.g., EDCI (1-ethyl-3-(3'-dimethyln npropyl)carbodiimide), HOBt (l-hydroxybenzotriazole), HOSU (N-hydroxysuccinimide), HONB (N-hydroxy-5-narben-endo-2,3-dicarboximido), isobutylparaben, revalorisation or DCC (dicyclohexylcarbodiimide), with (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate;

11) optional conversion of the product 10 in salt.

An additional aspect of the invention relates to a method for producing (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate or its salts, including:

1) making connections, which is ethyl 4-amino-3-methoxypiperidine-1-carboxylate

in salt;

2) the conversion of salts of ethyl 4-amino-3-methoxypiperidine-1-carboxylate in ethyl 4-(diphenylamine)-3-methoxypiperidine-1-carboxylate

;

3) impact on ethyl 4-(diphenylamino)-3-methoxypiperidine-1-carboxylate hydroxide or hydride of an alkali metal, to obtain 3-methoxy-N,N-diphenylpiperazine-4-amine

;

4) obtaining the chiral salt of 3-methoxy-N,N-diphenylpiperazine-4-amine the influence of 3-methoxy-N,N-diphenylpiperazine-4-amine with chiral separating agent and the selection of the CIS isomer obtained in this way salt of 3-methoxy-N,N-diphenylpiperazine-4-amine;

5) optional, Perekrest is the realisation of the product 4;

6) the transformation of the product 4 or 5 in the base, with the receipt of the product 4 or 5 in free base form;

;

7) alkylation product 6 ethyl 6-bromhexinum, to obtain ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidine-1-yl)hexanoate

;

8) the esterification of ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidine-1-yl)hexanoate using (R)-Hinkley-3-ol, obtaining (R)-Hinkley-3-yl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidine-1-yl)hexanoate

;

9) removing protection from a 4-amino group of the product 8, obtaining (R)-Hinkley-3-yl 6-[(3S,4R)-4-amino-3-methoxypiperidine-1-yl]hexanoate;

10) the acylation product 9 4-amino-5-chloro-2-methoxybenzoic acid to obtain (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate;

11) optional conversion of the product 10 in salt.

Preferably in the specified variant of the invention the salt on the stage 1 is HCl.

Preferably in the specified embodiment of the present invention, the alkali metal hydroxide in stage 3 represents KOH.

Preferably, in this embodiment, a chiral salt in stage 4 represents (+)-2,3-Dibenzoyl-D-tartaric acid, after interaction with A received salt of (3S,4R)-enantiomer (+)-2,3-Dibenzoyl-D-tartrate.

Preferably in the specified embodiment of the present invention for the reactions at the stage 8 is used Ti(OiP)4(isopropoxide titanium (IV)).

Preferably in the specified embodiment of the present invention for the reactions at the stage 9 is used H2/Pd/C.

Preferably in the specified embodiment of the present invention for the reactions at the stage 10 is pualeilani.

Definitions

Used herein the term "alkyl" includes alkyl groups with the specified number of carbon atoms. Alkyl groups can be linear or branched. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, ISO-, sec - and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl etc. If the number of carbon atoms is not specified, the designated "alkyl" portion contains from 1 to 6 carbon atoms.

The term "alkoxy" represents an alkyl group with the specified number of carbon atoms, which is linked with related molecular part through an oxygen bridge. Examples of alkoxygroup include, without limitation, methoxy, ethoxy, propoxy, isopropoxy.

The term "aryl" means an aromatic carbocyclic group having a single ring (e.g. phenyl)which is optionally condensed or otherwise accession what about the other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. The term "aryl" includes condensed polycyclic compounds in which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), where each ring optionally substituted with one, two or three groups, listed below, as well as unfused polycyclic compounds such as, for example, biphenyl or binaphthyl. Preferred aryl groups of the present invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphtho, fluorenyl, tetralinyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. More preferred are phenyl, biphenyl and naphthyl. Most preferred is phenyl. Aryl groups are unsubstituted or, if specified, substituted in one or more delegate positions of different groups. For example, these aryl groups may be optionally substituted, for example, C1-C6the alkyl, C1-C6alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6the quinil, C1-C6halogenation, C1-C6halogenoalkane, amino(C1-C6)alkyl, mono(Ci-C6)alkylamino(CI-C6)alkyl or di(C1-C6)alkylamino(CI- 6)alkyl.

The term "halogenoalkane" refers to alkoxygroup, which is substituted by at least one halogen atom and optionally additionally substituted by at least one additional halogen atom, where each halogen atom independently represent F, Cl, Br or I. Preferred Halogens are F or Cl. Preferred halogenlampe contain 1-6 carbon atoms, more preferably 1-4 carbon atoms, and still more preferably 1-2 carbon atoms. The term "halogenoalkane includes perhalogenated, such as OCF3or OCF2CF3.

The term "heteroaryl" refers to an aromatic cyclic system containing at least one heteroatom selected from nitrogen, oxygen and sulfur. Heteroaryl ring may be condensed or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heteroseksualnymi rings. Examples of heteroaryl groups include, without limitation, pyridyl, pyrimidyl, chinoline, benzothiazyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, ethanolic, hintline, honokalani, phthalazine, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazoles, benzothiazoles, benzimidazoles, benzofuranyl, fu is Anil, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolin, naphthyridine, isopropanol, bromanil, tetrahydroisoquinoline, isoindolines, isobenzofuranyl, isobenzofurandione, isobenzofuranyl, benzoxazolyl, pyridopyrimidines, bettererererer, betterregulation, purinol, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridines, imidazothiazoles, dihydroergotoxine, benzisoxazole, benzoxazine, dihydromethysticin, benzopyranyl, benzothiophene, chromones, chromanones, pyridinyl-N-oxide, tetrahydroquinoline, dihydroquinoline, dihydroquinoline, dihydroisoquinoline, dihydrocoumarin, dihydroisocoumarin, isoindolines, benzodioxane, benzoxazolinone, pyrrolyl N oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, chinoline N-oxide, indolyl N-oxide, indolyl N-oxide, ethanolic N-oxide, hintline N-oxide, honokalani N-oxide, phthalazine N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, triazolyl N-oxide, indolizinyl N-oxide, indazole N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, N oxadiazolyl oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiophene S-oxide, benzothiophene S,S-dioxide. Preferred heteroaryl which group include pyridyl, pyrimidyl, chinoline, indolyl, pyrrolyl, furanyl, thienyl and imidazolyl. More preferred heteroaryl groups include pyridyl, pyrrolyl and indolyl. Heteroaryl groups are unsubstituted or, if specified, substituted in one or more delegate positions of different groups. For example, these heteroaryl groups may be optionally substituted, for example, C1-C6the alkyl, C1-C6alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6the quinil, C1-C6halogenation, C1-C6halogenoalkane, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl or di(C1-C6)alkylamino(C1-C6)alkyl.

The term "heteroseksualci" refers to a ring or ring system containing at least one heteroatom, preferably selected from nitrogen, oxygen and sulfur, where the heteroatom is in a non-aromatic ring. Geteroseksualnoe ring may be fused or otherwise attached to other heteroseksualnymi rings and/or non-aromatic hydrocarbon rings and/or phenyl rings. Preferred heterocytolysine groups have from 3 to 7 members. More preferred heterocytolysine groups have 5 or 6 members. Examples geterotsiklicheskikh groups include, for example, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperazinil, homopiperazine, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothieno, homopiperazine, homomorpholine, homotaurine, homotaurine S,S-dioxide, oxazolidinones, dihydropyrazolo, dihydropyrrole, dihydropyrazine, dihydropyridines, dihydropyrimidines, dihydrofuran, dihydropyran, tetrahydrothieno S-oxide, tetrahydrothieno S,S-dioxide and homotaurine S-oxide. Preferred heterocytolysine groups include azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, piperidinyl, piperazinil, pyrrolidinyl, thiomorpholine, S,S-dioxothiazolidine, morpholinyl and imydasolynidil. More preferred are azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, piperidinyl, piperazinil, pyrrolidinyl, imidazolidinyl and morpholinyl. Heterocyclic groups are unsubstituted or, if specified, substituted in one or more delegate positions of different groups. For example, these heterocyclic groups can be optionally substituted, for example, C1-C61-C6alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6the quinil, C1-C6halogenation, C1-C6halogenoalkane, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl or =O.

The term "pharmaceutically acceptable salts or their pharmaceutically acceptable salts" refers to salts derived from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Because the connection of the present invention is basic, salts may be obtained using pharmaceutically acceptable non-toxic acids. Suitable pharmaceutically acceptable acid additive salts of the compounds of the present invention include salts of acetic acid, benzosulfimide (besylate), benzoic, camphorsulfonic, lemon, ethylenesulphonic, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, isetionate, lactic, maleic, malic, almond, methansulfonate, mucinosa, nitrogen, Paveway, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate and the like acids. The preferred acid additive salts are chlorides and sulfates. In the most preferred embodiment of the present invention of structural and/or functional analogues cisapride is administered in free base form or in the form of mono - or dihydrochloride.

Used in this document, the terms "treating" or "treatment course" refers to the prophylactic introducing the compound or pharmaceutical composition comprising the compound ("prevention"), as well as medical therapy aimed at reducing or eliminating diseases or disorders referred to herein. Prophylactic administration is intended to prevent the occurrence of disorders and can be used to treat patients included in the risk or suffering from one or more of the above disorders. Thus, as used herein, the term "treatment" or its derivative implies partial or complete inhibition of the specified painful conditions through the introduction of the active ingredient of the present invention prophylactically or after the occurrence of the disease condition, treatment types the active ingredient. "Prevention" refers to the introduction of the active ingredient(phrases is tov) to a mammal to protect it from any disorders, described in this document, as well as other disorders.

The term "therapeutically effective amount" refers to the amount needed to achieve a therapeutic effect, such as: 1) sufficient to relieve reflux disease, 2) sufficient to relieve nausea and vomiting, or 3) a quantity sufficient to ease the condition, caused by dysmotility of the gastrointestinal tract. a therapeutically effective amount of structural and/or functional analogues cisapride is determined as described above dosages, frequency of administration.

"Mammal" can be, for example, mouse, rat, pig, horse, rabbit, goat, cow, cat, dog or man. Preferably, the mammal is man.

The term "individual(s)" is defined as a single mammal, which administered the compound of the present invention. Mammal may be, for example, mouse, rat, pig, horse, rabbit, goat, cow, cat, dog or man. Preferably, the mammal is man.

The term "esterified cisapride" refers to therapeutic compounds of the present invention, which are structural and/or functional analogues of cisapride and can contain either hydrolyzed group, ester usually, the cat heaven does not reduce the ability of these compounds to have a beneficial therapeutic effect, but which makes these compounds more susceptible to cleavage by hydrolases, especially whey and/or by cytosolic esterases, and which reduces the interaction of detoxification of drugs cytochrome P450 and derivatives of cisapride. Mediated by esterases metabolism of esterified compounds cisapride reduces system role in detoxification of drugs cytochrome P450 in the metabolism of cisapride and reduces or eliminates the adverse effects caused by cisapride.

The term "structural analogue", as used herein, means that the described connection has the same structural features as the original connection. For example, a structural analogue of cisapride may have one or more structural characteristics similar to the characteristics of the original connection cisapride, such as a substituted aryl ring associated with piperidinium ring through amide linkages, but otherwise structurally different, for example, can include or exclude one or more other chemical parts.

The term "functional analogue", as used herein, means that the described connection has the same functional properties as the parental connection. For example, a functional analogue of cisapride can be characterized by esnecially structural similarity with cisapride or not to show such similarities at all, but perform a similar function, for example, to show agonism against 5-HT4.

The term "adverse effects" includes, without limitation, disorders of the gastrointestinal tract, such as diarrhea, colic and rumbling in the stomach; the fatigue; headache; increased systolic pressure; death; ventricular tachycardia; ventricular fibrillation; Torsade de pointes ventricular; prolonged QT interval; increased heart rate; neurological disorders, and disorders of the Central nervous system; and cisapride interaction with other medicines at simultaneous use, such as digoxin, diazepam, ethanol, acenocoumarol, cimetidine, ranitidine, paracetamol and propranolol.

The term "gastroesophageal reflux disease", as used herein, means the presence and symptoms of such conditions, which cause the reflux of gastric contents into the esophagus.

The terms "providing antiemetic action" and "antiemetic therapy", as used herein, means the relief or prevention of symptoms of nausea and vomiting that occurred spontaneously or due to causes vomiting, chemotherapy or radiation therapy of malignant tumors.

The term "treatment of a condition caused by dysmotility of the gastrointestinal tract"as used in the present who eat the document, means treating the symptoms and conditions associated with the specified disorder, which include, without limitation, gastroesophageal reflux disease, dyspepsia, gastroparesis, constipation, post-operative bowel paresis and pseudoprobability intestine.

The term "prokinetics", as used herein, means increased peristalsis and, therefore, promote the content in the gastrointestinal tract.

The term "dispersion"as used herein means a condition characterized by indigestion, which can be a symptom of a primary dysfunction of the gastrointestinal tract or a complication of other diseases such as appendicitis, dysfunction of the gall bladder or malnutrition.

The term "gastroparesis", as used herein, means paralysis of the stomach caused by impaired motility of the stomach or a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa or myotonica dystrophy.

The term "constipation"as used herein means a condition characterized uragannoj or difficult defecation as a result of such conditions as lack of muscle tone or spasticity of the intestine.

The term "postoperative paresis of the intestine", IP is olshey in this document, mean bowel obstruction due to disorders of muscle tone after surgery.

The term "pseudoprobability intestines", as used herein, means a condition characterized by constipation, colic and vomiting, but without evidence of physical obstruction.

Getting connections

Although the chemical synthesis of various analogues of cisapride may be carried out using the methods described in European patent application No. 0076530 A2, published on 13 April 1983, WO 01/093849, in patent applications U.S. No. 4962115 and 5057525, and Van Daele et al., Drug Development Res. 8: 225-232 (1986), the descriptions of which are fully incorporated herein as references, the compounds of the present invention is preferably obtained in accordance with the description of methods 3-6.

The invention is further illustrated by several examples, which are given after methods. Methods and examples in no way limit the scope or essence of the invention specific given procedures. Specialists will be clear that the starting materials can be varied and the use of additional stages to obtain the compounds of the present invention, as shown in the following examples. Specialists will also be clear that to implement some of the above conversions the requirements may be necessary to use various solvents or reagents. In some cases, to implement the above transformations may be necessary to protect reactive functional groups. In General, the use of protective groups, as well as the conditions necessary to attach or remove the specified groups will be apparent to experts in the field of organic synthesis. When using a protective group may need to stage the removal of protection. Suitable protective groups, and ways to protect and unprotect, such as described in T. Greene, Protecting Groups in Organic Synthesis is well known and accepted by the specialists.

Unless otherwise stated, all chemicals and solvents are of standard commercial quality and used without further purification. Suitable for reaction atmosphere, for example, air, nitrogen, hydrogen, argon, etc. will be obvious to a person.

Method 1.Obtaining (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-2-chloro-6-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate

Step 1. Synthesis of ethyl 4-(dibenzylamino)-3-methoxypiperidine-1-carboxylate (1):

To a solution of racemic ethyl 4-amino-3-methoxypiperidine-1-carboxylate (1 molar part) in DMF was added benzylbromide (approximately 2.2 molar parts), potassium carbonate (approximately 2.4 molar parts) and potassium iodide (approximately 0.2 is olennoi part), respectively. The reaction mixture was heated to approximately 80°C (in the description of the Delta “Δ” is equal to the heat). After about 6 hours the reaction mixture was slowly diluted with water (about 12 parts by volume) and was extracted with, for example, ethyl acetate. The organic layer was washed with saline, and then dried over anhydrous Na2SO4. After filtration and concentration of solvent received 1 in the form of butter yellow-orange (1 molar part).

Step 2. SynthesisN,N-dibenzyl-3-methoxypiperidine-amine 4 (2):

To a solution of 1 was added NaOH (about 10 molar parts) in isopropanol and the mixture was stirred and heated to the boiling temperature under reflux. After 3 to 5 hours, the reaction mixture was cooled to room temperature and the alcohol solvent was removed by rotary evaporation. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saline and dried over anhydrous Na2SO4. After filtration and concentration of the solvent was obtained the crude oil, which was purified via SiO2(CH2Cl2:MeOH:NH4OH; (approximately) 15:1:0,01), with 2.

Step 3. Synthesis of (3S,4R)-N,N-dibenzyl-3-methoxypiperidine-amine 4 (3):

(+)-2,3-Dibenzoyl-D-tartaric acid (approximately 1.2 mass parts) was dissolved in ethanol, before slowly added to a solution of 2 (approximately 1 mass part). The solution is gently heated, and then allowed it to cool to room temperature for crystallization of salt. Salt was filtered and washed using EtOH/H2Oh, before suspendirovanie in the water and convert it to a basis by adding aq.NaOH (7%, wt./wt.), up until the pH reached approximately 12. The suspension was intensively stirred at room temperature and the solid was filtered, washed with water and dried under vacuum, to obtain the CIS isomer 3.

Step 4. Synthesis of ethyl 6-((3S,4R)-4-(dibenzylamino)-3-methoxypiperidine-1-yl)hexanoate (4):

To a solution of 3 (1 molar part) in DMF was added ethyl Bromhexine (approximately 1.2 molar parts), potassium carbonate (about 1.4 molar parts) and potassium iodide (about 0.2 molar part), respectively. Then the reaction mixture was heated to 80°C. after About 8 h, the reaction mixture was slowly diluted with water (about 12 parts by volume) and was extracted with ethyl acetate. The organic layer was washed with saline and then dried over anhydrous Na2SO4. After filtration and concentrated the I solvent received untreated material. After purification via SiO2received alkilirovanny material 4.

Step 5. Synthesis of (R)-Hinkley-3-yl 6-((3S,4R)-4-(dibenzylamino)-3-methoxypiperidine-1-yl)hexanoate (5):

Tetraethoxy titanium was added to a mixture of 4 (1 molar proportion) and (R)-(-)-3-hinokitiol (1 molar part) in toluene. The reaction mixture was supplied with the unit Dean-stark before heating to approximately 90°C and then used a partial vacuum (to maintain the required level of additional solvent was added toluene). The mixture was then cooled to room temperature and the reaction mixture was diluted with ethyl acetate, after which the resulting mixture was added water. The organic layer was separated, washed with saline, dried over anhydrous Na2SO4, filtered and concentrated. As a result of clearing through SiO2received enantiomerically enriched 5.

Step 6. Synthesis of (R)-Hinkley-3-yl 6-((3S,4R)-4-amino-3-methoxypiperidine-1-yl)hexanoate (6):

A solution of 5 (1 molar part) in EtOH was added into the reaction flask containing palladium on coal (about 0.2 molar parts). Then the mixture was pumped air and subjected her to hydrogenolysis using atmospheric H2. After completion of the reaction, the palladium was filtered through zelany filter followed about what Yukai EtOH. The filtrate was concentrated by rotary evaporation, obtaining 6.

Step 7. Synthesis of (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-2-chloro-6-methoxybenzamide)-3-methoxypiperidine-1-yl)hexanoate (7):

To a solution of, for example, ethylchloride (1 molar part) in THF at a temperature about 0°C in parts) was added benzoic acid (1 molar part). The mixture was heated to room temperature for about 1 h, then was cooled to approximately 0°C and one drop of solution was added 6 (1 molar part). Then the reaction mixture was heated to room temperature. After completion of the reaction it was suppressed by addition of a saturated solution of NaHCO3and were extracted using EA. The organic layer was washed with saline, dried over anhydrous Na2SO4was filtered and concentrated, to obtain the desired product 7.

Method 2

Synthesis of (R-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate (or 1-azabicyclo[2.2.2]Oct-3'R-silt ester 6-[4R-(4-amino-5-chloro-2-methoxybenzylamine)-3S-methoxypiperidine-1-yl]hexanoic acid; ATI-7505):

In the acidic environment 1-benzylpiperidine-4-one (1) and Hydrobromic acid were interacted in the presence of acetic acid with the formation of the N-th gasoline is-3-bromopyridin-4-it (2). Action 2 sodium methoxide and solution of methanol gave 1-benzyl-4,4-dimethoxypyridine-3-ol (3). [The presence of beta-amino group reduces to zero the probability of the reaction based on the type of Tabor]. Was carried out by methylation of the hydroxyl group using a hydride base, with subsequent exposure to iodomethane in the presence of DMF as solvent, to obtain compound 4.

As a result, subsequent hydrolysis of the acetal using 1% sulfuric acid when heated received piperidine 5, which is then subjected to reductive aminating using, for example, cyanoborohydride sodium and ammonium acetate in methanol, to obtain 1-benzyl-3-methoxypiperidine-4-amine (6). At this stage 6 can be subjected to chiral separation. This can be used (+)-DBT or other variant of tartaric acid in the presence of a suitable solvent to obtain extremely asymmetrically pure compound 7. To protect the primary amine 7 Boc group can be used Boc-anhydride in the presence of solvent (THF, getting 8. The reaction dibenzylamine by hydrogenolysis using Pd/C in methanol in the presence of atmospheric gaseous hydrogen was provided by the phase alkylation. In R. the result of exposure to 6-bromohexanenitrile in the presence of a weak base and DMF received connection 10. In the result of conversion of nitrile to an ester using (R)-hinokitiol in the presence of dilute acids, received 11. The subsequent removal of the Boc group using TFA received a free amine, which can participate in the reaction combination with the required benzoic acid in the presence of interfacing reagent, such as ethylchloride (and more preferably, isobutylparaben), with ATI-7505 in enantiomerically pure form.

Alternatively, compound 9 can be alkilirovanii using 6-bromhexina in the presence of a weak base. After removal of the Boc protective group received the connection 14. By transesterification 14 through titanium using (R)-hinokitiol and tetraethoxide titanium in the solvent toluene was awarded ATI-7505. The esterase of Karlsburg hydrolyzes esters, which have the S-configuration, therefore, esters R-configuration remain intact. Therefore, ATI-7505 can also be obtained by acting on diastereoisomer mixture 15 of esterase Karlsburg.

Method 3

Alternative synthesis dihydrochloride salt (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate - dihydrochloride salt ATI-7505:

Under intensive stirring of floridacosta in diethyl ether (about 1.4 molar parts) was slowly added to a solution of piperidine carbamate (approximately 1.0 molar part). The mixture was stirred for about 8 hours, then was filtered and washed with diethyl ether. Solid white color additionally washed with dichloromethane and diethyl ether (volume ratio of about 1:1) to remove impurities, and then dried under vacuum, obtaining racemic cleaners containing hydrochloride salt of piperidine carbamate in the form of a solid white color.

To a mixture of piperidine hydrochloride (approximately 1.0 molar part), potassium carbonate (K2CO3, approximately 2.4 molar parts) and potassium iodide (KI approximately 0.1 molar parts) in dimethylformamide at room temperature (C/t) was added benzylbromide (approximately 2.2 molar parts). The reaction mixture was heated to approximately 75°C. after About 18 hours the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (EA). The organic layer was washed with saline, and then dried over betwedn.(anhydrous) sodium sulfate (Na2SO4). Then by filtration under vacuum and the concentrate was obtained the crude oil product. The product precipitated with addition of a mixture of isopropanol and water (volume ratio of about 1:1) and stirring. After filtering condition in the s vacuum received dibenzylpiperazine in a solid white color.

Potassium hydroxide (approximately 10 molar parts) parts) was added to a mixed solution of dibenzyldithiocarbamate (approximately 1.0 molar part) in isopropanol at room temperature and the mixture was stirred and heated to the boiling temperature under reflux. After about 5 hours the reaction mixture was cooled to room temperature and the solvent was removed under vacuum to approximately half volume. The reaction mixture was diluted with water and extracted with ethyl acetate. After washing with saline, the product was dried over anhydrous Na2SO4. Then by filtration under vacuum conditions received piperidine in the form of a semi-solid substance.

Chiral separation of 3,4-disubstituted piperidine derivatives:

(+)-2,3-Dibenzoyl-D-tartaric acid [(+)-DBT; approximately 1.0 molar part] was dissolved in methanol and slowly added to the heated solution (about 70°C) disubstituted piperidine (approximately 1.0 molar part) in methanol and water (volume ratio of about 1:1). The mixture was stirred at the same temperature for about 1 hour, then stopped heating and continued stirring at room temperature for several hours, for example, in one the case for about 16 hours. The obtained salt was collected by vacuum filtration and washed with methanol and water (volume ratio of about 1:1). The wet precipitate was collected and recrystallized two more times using the described procedure.

The wet sediment suspended in water and added 1 N. sodium hydroxide to achieve a pH of about 12). The resulting suspension was stirred for approximately 3 hours at room temperature, then was extracted with ethyl acetate. The organic layer was washed with saline, filtered and concentrated, to obtain enantiomerically enriched 3,4-disubstituted piperidine in the form of a solid white color.

To a mixture of piperidine (approximately 1.0 molar part), K2CO3(approximately 1.2 molar parts) and KI (0.1 molar parts) in the solvent DMF was slowly added ethyl 6-Bromhexine (about 1.1 molar parts). The reaction mixture was heated to approximately 70°C under stirring for about 10 hours, then cooled to room temperature and was diluted with water and extracted with ethyl acetate. The organic layer was separated and then washed with brine and finally dried over anhydrous Na2SO4. Then by filtration and concentration was obtained with untreated is i.i.d. oil. The crude product was purified using flash column-chromatography (for example, with a volume ratio hexane:ethyl acetate 1:1), to obtain the product as a light brownish oil.

To a mixture of the above complex ester piperidine (approximately 1.0 molar part) and (3R)-hinokitiol (approximately 4,0 molar parts) was added tetraethoxy titanium (IV) (approximately 1.0 molar part) at room temperature. The reaction mixture was heated to approximately 85°C under reduced pressure for removal of the formed ethanol. After about 18 hours the reaction mixture was cooled to room temperature and then was diluted with ethyl acetate and extinguished with water. The organic layers were washed with saline and dried over anhydrous Na2SO4. After concentration the crude oil was purified using flash column-chromatography (for example, approximately 100:10:1; CH2Cl2:MeOH:NH4OH), to obtain the product as a clear oil.

Into the reaction flask containing palladium on coal solution was added to the above dibenzylpiperazine ether (approximately 1.0 molar part) in methanol and to this mixture was added ammonium formate (about 4 molar parts). Reacciona the mixture was heated to the boiling temperature under reflux and after about 10 hours the reaction flask was cooled to room temperature and was filtered palladium on coal through zelany filter. The filtrate was concentrated to an oil, which was purified using flash column-chromatography (e.g., SiO2approximately 150:10:1; CH2Cl2:CH3OH:NH4OH), obtaining product aminopiperidine ether in the form of a yellow oil.

To a stirred solution of 4-amino-5-chloro-2-methoxybenzoic acid (approximately 1.2 molar parts) and triethylamine (approximately 2.2 molar parts) in tetrahydrofuran (THF) was slowly added isobutylparaben (approximately 1.2 molar parts) at room temperature. After about 30 minutes the solution piperidino ether (approximately 1.0 molar part) in THF was added to a pre-manufactured, mixed anhydride. The reaction mixture was stirred at room temperature for about 14 hours, then diluted with a saturated solution of sodium bicarbonate. The product was extracted using, for example, ethyl acetate and the separated organic layer is then washed with saline and dried over anhydrous sodium sulfate. After filtration and concentration was obtained the free base of ATI-7505.

The free base of ATI-7505 was dissolved in ethanol and isopropanol (volume ratio of about 1:1) and cooled in an ice ban is. To an ice cold solution was slowly added concentrated hydrochloric acid, and then heated to room temperature. After stirring for about 7 hours at room temperature, the solid was filtered and washed with ethanol and isopropanol (volume ratio of about 1:1), with the wet sludge. The wet sediment resuspendable in ethanol, and then were heated to the boiling temperature under reflux. Stir the solution was heated to room temperature and left for recrystallization. The product was filtered under vacuum, washed with ethanol, and then dried under vacuum, obtaining dihydrochloride salt ATI-7505 in a solid white color.

Method 4:

An alternative method of synthesis dihydrochloride salt (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate dihydrochloride salt - ATI-7505:

To a mixture of (3R)-hinokitiol in dichloromethane drop was added 6-bromohexadecane. The reaction mixture was heated to the boiling temperature under reflux and after about 18 hours, cooled to room temperature. Unreacted (3R)-hinokitiol was filtered and to the filtrate was added diethyl ether to precipitate a need for the constituent of the product. The product was filtered under vacuum and washed with CH2Cl2and diethyl ether (volume ratio of about 1:1), to obtain the product in a solid white color.

Dibenzylpiperazine (approximately 1.0 molar part) was added to a mixture of 6-balkanologie ether (approximately 1.0 molar parts) and potassium carbonate (approximately 2.2 molar parts) in the solvent DMF. The reaction mixture was stirred at a temperature of approximately 70°C for about 11 hours, then cooled to room temperature and was diluted with a saturated solution of sodium bicarbonate. The product was extracted with ethyl acetate. The product is then washed with saline, dried over anhydrous sodium sulfate, filtered and concentrated, to obtain the product as a colourless oil.

Into the reaction flask containing palladium on coal solution was added to the above dibenzylpiperazine ether (approximately 1.0 molar part) in methanol and to this mixture was added ammonium formate (about 4 molar parts). The reaction mixture was heated to the boiling temperature under reflux and after about 10 hours the reaction flask was cooled to room temperature and hoteltravel and palladium on charcoal, for example, through zelany filter. The filtrate was concentrated to an oil, which was purified using flash column-chromatography (e.g., SiO2approximately 150:10:1; CH2Cl2:CH3OH:NH4OH), obtaining product aminopiperidine ether in the form of a yellow oil.

To a stirred solution of 4-amino-5-chloro-2-methoxybenzoic acid (approximately 1.2 molar parts) and triethylamine (approximately 2.2 molar parts) in tetrahydrofuran (THF) was slowly added isobutylparaben (approximately 1.2 molar parts) at room temperature. After about 30 minutes the solution piperidino ether (approximately 1.0 molar part) in THF was added to a pre-manufactured, mixed anhydride. The reaction mixture was stirred at room temperature for about 14 hours, then diluted with a saturated solution of sodium bicarbonate. The product was extracted using, for example, ethyl acetate, and the separated organic layer is then washed with saline and dried over anhydrous sodium sulfate. After filtration and concentration was obtained the free base of ATI-7505.

The free base of ATI-7505 was dissolved in ethanol and isopropanol (volume ratio closer is ina 1:1) and cooled in an ice bath. To an ice cold solution was slowly added concentrated hydrochloric acid, and then heated to room temperature. After stirring for about 7 hours at room temperature, the solid was filtered and washed with ethanol and isopropanol (volume ratio of about 1:1), with the wet sludge. The wet sediment resuspendable in ethanol, and then were heated to the boiling temperature under reflux. Stir the solution was heated to room temperature and left for recrystallization. The product was filtered under vacuum, washed with ethanol, and then dried under vacuum, obtaining dihydrochloride salt ATI-7505 in a solid white color.

Method 5:

An alternative method of synthesis dihydrochloride salt (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate dihydrochloride salt - ATI-7505:

Benzylbromide (approximately 1.2 molar parts) was added to a solution of (3R)-hinokitiol (approximately 1.0 molar part) in dichloromethane. The reaction mixture was stirred at room temperature for about 4 hours, then filtered and washed with dichloromethane, to obtain the product in a solid white color.

6-bromohexadecane (about 1.1 molar parts) was added to a solution of benzylamine (3R)-hinokitiol (approximately 1.0 molar part) and the reaction mixture was heated to approximately 60°C. after about 12 hours the reaction mixture was cooled to room temperature and the product precipitated with addition of diethyl ether. After vacuum filtration, washing with ether and drying the obtained product in the form of an amorphous solid.

A mixture of piperidine (approximately 1.0 molar part), alkanolamide ether (approximately 1.0 molar part) and triethylamine (approximately 2.0 molar parts) In the solvent DMF was heated to approximately 60°C for approximately 6 hours. Then the reaction mixture was cooled to room temperature, diluted with saturated sodium bicarbonate solution and was extracted with ethyl acetate. After washing with salt solution and drying over anhydrous sodium sulfate the organic layer was concentrated, to obtain the product as a colourless oil.

Into the reaction flask containing palladium on coal, was added to the solution dibenzylpiperazine ether (approximately 1.0 molar part) in methanol and to this mixture was added ammonium formate (about 4 molar frequently is). The reaction mixture was heated to the boiling temperature under reflux and after about 10 hours the reaction flask was cooled to room temperature and was filtered palladium on coal, for example, through zelany filter. The filtrate was concentrated to an oil and purified using flash column-chromatography (e.g., SiO2approximately 150:10:1; CH2Cl2:CH3OH:NH4OH), obtaining product aminopiperidine ether in the form of a yellow oil.

To a stirred solution of 4-amino-5-chloro-2-methoxybenzoic acid (approximately 1.2 molar parts) and triethylamine (approximately 2.2 molar parts) in tetrahydrofuran (THF) was slowly added isobutylparaben (approximately 1.2 molar parts) at room temperature. After about 30 minutes the solution piperidino ether (approximately 1.0 molar part) in THF was added to a pre-manufactured, mixed anhydride. The reaction mixture was stirred at room temperature for about 14 hours, then diluted with a saturated solution of sodium bicarbonate. The product was extracted using, for example, ethyl acetate and the separated organic layer is then washed with saline and dried over anhydrous sodium sulfate. After the filter is tion and concentration was obtained the free base of ATI-7505.

The free base of ATI-7505 was dissolved in ethanol and isopropanol (volume ratio of about 1:1) and cooled in an ice bath. To an ice cold solution was slowly added concentrated hydrochloric acid, and then the mixture was heated to room temperature. After stirring for about 7 hours at room temperature, the solid was filtered and washed with ethanol and isopropanol (volume ratio of about 1:1), with the wet sludge. The wet sediment resuspendable in ethanol, and then were heated to the boiling temperature under reflux. Stir the solution was heated to room temperature and left for recrystallization. The product was filtered under vacuum, washed with ethanol, and then dried under vacuum, obtaining dihydrochloride salt ATI-7505 in a solid white color.

Method 6

An alternative method of synthesis dihydrochloride salt (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate dihydrochloride salt - ATI-7505. Although the specific conditions of the reactions, for example of the synthesis method 6, the above conditions shall not be construed as limiting the scope of the method. Specialists will be clear that within the limits specified is th way possible changes in the conditions of the reactions, including, without limitation, the duration, temperature and solvents used for the reactions. The outputs of reactions, where they are also given as an example and, therefore, may vary for each implementation and combination of the conditions of the reactions.

Synthesis of ATI-7505 from CIS-APM tartrate was performed on the basis of the procedures laboratory series using 9.7 g of reagent.

a. Synthesis of C2

Raw materials

CIS-piperidine carbamate, 24 kg

benzylbromide, 37.8 kg

KI, 1,67 kg

K2CO3, 48.7 per kg

N-organic (NMP), 200 kg

EA (ethyl acetate), 360 kg

water, 600 kg

isopropyl alcohol (IPA)/water (1:1 wt./wt.), 250 kg

Procedure

CIS-piperidine carbamate (24 kg, 1 EQ.) and K2CO3(48.7 per kg, 6 EQ.) were loaded into the reactor, then added to the reactor NMP (200 kg). Within 15 minutes, the mixture was stirred at room temperature. Was added to the reactor KI (1,67 kg, 0.1 EQ.), then add benzylbromide (37.8 kg, 2.2 EQ.) and raised the temperature to 75°C for 60 minutes. Selected a sample of the reaction mixture after about 4 hours; the expected duration of response was approximately 7-9 hours.

After the estimated completion of the reaction was added into the reactor water (350 kg) and were extracted using EA (120 kg; 3 times) Collected a layer of EA and washed the EA layer with water (200 kg; 3 times). Concentrated layer EA to solids at 70°C. was Added to the reactor IPA/water (1:1, 200 kg) and the reactor was heated to approximately 75-80°C. was Added IPA/water (1:1) in increments of 25 kg at a temperature of 75-80°C to obtain a clear solution. Slowly cooled the reaction mixture to 5°C. was Collecting the solid by filtration and the wet sediment was dried at a temperature of about 60°C to obtain C2 (31,7 kg; yield 82%). The purity of the obtained party determined using HPLC, was 99.3 percent.

b. Synthesis of C3

Raw materials

KOH, 56,3 kg

IPA, 200 kg

DCM (dichloromethane), 550 kg

Water, 1300 kg

C2, 32 kg

Procedure

Was added to the reactor C2 (32 kg, 1 EQ.), KOH (56,3 kg, 12 EQ.) and IPA (200 kg). Heated the reaction mixture to the boiling temperature under reflux (approximately 82°C). Selected a sample of the reaction mixture after about 4 hours; the expected duration of response was approximately 4-5 hours. After completion of the reaction IPA was removed by distillation at 50°C. was Added to the reactor DCM (230 kg) and water (700 kg) and collected both layers. Was carried out by extraction of the aqueous layer using DCM (160 kg; 2 times) and the combined DCM layers. Washed the DCM layer with water (200 kg; 3 times) and concentrated DCM layer at a temperature of 70°C, obtaining C3 in the form of oil and proceeded to the next step without selecting p is oduct (assuming 100% yield).

c.Synthesis of CIS-AMF tartrate salt

Raw materials

Was added to the reactor, which contained obtained in the previous step connection C3, methanol (260 kg) and water (130 kg). Was added to the reactor (+)-DBT (15,2 kg), dissolved in 130 kg of methanol, at a temperature of 70°C, preferably within 60 minutes. Added one part of methanol (70 kg)to ensure obtaining a clear solution, then cooled the reaction mixture to 50°C. the Product was received at approximately 50°C before being filtered slowly cooled mixture to approximately 10°C. was Collecting the solid by filtration and, preferably, checked the value of the enantiomeric excess (e/e) and solids content.

Put the solid in the reactor. Was added to the reactor MeOH/water (5:1, 600 kg) and the mixture was heated to 70°C. you Can add more MeOH/water (5:1)to obtain a clear solution before cooling the reaction mixture to 50°C. was Slowly cooled the mixture to 10°C, then collected the solid by filtration. Dried the wet sediment at approximately 60°C. In this example, the purity of the obtained CIS- ½ AMP (+)-DBT (12.6 kg, the mass of 31% of theoretical yield 62%)determined using HPLC, was 99.8%, and e/e was 97,9%.

d.The synthesis of the free base of the CISAMP

Raw materials

CIS AMP 1/2 DBT, 10 g, 0,0279 mol

isopropyl ether (IPE), 50 ml

water, 50 ml

45% NaOH, 7.2 g, 0.18 mol

Procedure

Piperidine(+)-dibenzoyltartaric salt (10,00 g; 0,0279 mol) is suspended in 30 ml of water and 50 ml of IPE under vigorous stirring. 45% sodium hydroxide (7.2 g; 0.18 mol) drop by drop) was added to dissolve the solids. Layers IPE washed with water (10 ml, 2 times) and after concentration was obtained a solid white color, representing the crude free base (7.20 g).

e. Synthesis of C5

Raw materials

free base 7.2 g, 0,0232 mol

ethyl 6-bromhexina,4,76 g, 0,0214 mol

potassium carbonate, 5,77 g, 0,0418 mol

potassium iodide, 1.39 g, of 8.37 mmol

DMF (dimethylformamide), 30 ml

isopropyl ether (IPE), 50 ml

water, 50 ml

Procedure

The free base (7.2 g), ethyl 6-bromhexina and 4.75 g; 0,0214 mol), potassium carbonate (5,77 g; 0,0418 mol), potassium iodide (1.39 g; of 8.37 mmol) and DMF (30 ml) were loaded into the reactor. The reaction mixture was heated to 70°C for 1 hour and the completion of the reaction was monitored using HPLC. After 1 hour the reaction mixture was cooled to room temperature and was suppressed by the addition of 30 ml of water and 50 ml of IPE. Layers IPE washed with water (10 ml, 2 times). After concentration was obtained crude compound C5 in the form of a yellow oil (9,10 g).

Raw materials

C5, 9,10 g, 0,0201 mol

(R)-3-hinokitiol, 5.20 g, 0,0409 mol

Ti(OiP)4(isopropoxide titanium (IV)), 1,16 g, 4,08 mmol

toluene, 120 ml

isopropyl ether (60 ml

water, 80 ml

Procedure

C5 (9,10 g; 0,0201 mol), (R)-3-hinokitiol (5.20 g; 0,0409 mol), Ti(OiP)4(1,16 g; 4,08 mmol) and toluene (120 ml) were loaded into the reactor under stirring. The reactor was equipped with a Packed column (24/40; length 15 cm) and short channel (24/40), which was heated for distillation, EtOH, IPA and toluene (oil bath temperature of 160°C). Monitoring completion of the reaction was carried out by HPLC. In this example, synthesis HPLC showed that the starting material was consumed completely. To facilitate the removal of toluene, the pressure is reduced. The reaction mixture was cooled to room temperature and was suppressed by the addition of 40 ml of water and 60 ml of IPE, then washed layers IPE water (20 ml, 2 times) and then concentrated, to obtain the crude C6 in the form of a yellow oil (11,70 g).

g. Synthesis of C7

Raw materials

C6, 11,70 g, 0,0220 mol

5% Pd/C, 1.0 g

IPA, 30 ml

Procedure

C7 (11,70 g), 5% Pd/C (1.0 g) and IPA (30 ml) was loaded into the hydrogenation reactor (N2inert; H2under pressure of 5 atmospheres). The mixture was stirred and heated on a water bath to 70°C for 7 the aces. Monitoring completion of the reaction was carried out using HPLC and TLC showed that the starting materials were used in its entirety. The reaction mixture was cooled to room temperature and filtered through zelany filter with washing IPA. After concentration of the filtrate received 6,66 g C7 in the form of crude oil.

h. The synthesis of the Foundation of ATI-7505

pualeilani

the basis of ATI-7505

Raw materials

4-amino-5-chloro-2-methoxybenzoic acid, 5.0 g, 0,0249 mol

THF, 30 g

the triethylamine, 4.7g, 0,0465 mol

pualeilani, 2.7 g, 0,0225 mol

C7, 66.6 g, 0,0189 mol

diethylketone (DEK), 100 ml

32% HCL

water

45% NaOH

Procedure

Pivaloate (2.7 g; 0,0225 mol) drop by drop) was added to a solution of 4-amino-5-chloro-2-methoxybenzoic acid (5.0 g; 0,0249 mol) and triethylamine (4.7 g; 0,0465 mmol) in THF (20 g) at room temperature. After the addition the reaction mixture became dull and after 60 minutes of this pre-made mixed anhydride solution was added to C7 (6,66 g; 0,0189 mol) in THF (10 g) and left to mix at room temperature. HPLC and TLC showed that the starting material was consumed completely.

The reaction was suppressed by addition of water (40 ml) and DEK (40 ml) was added 32% HCl to pH of 4.0. The combined organic layers were washed with water (10 ml; 2 is Aza) and the aqueous layer was collected. Added DEK (60 ml) to the aqueous layer was added 45% NaOH to pH 12. The aqueous layer was extracted, separated and poured. The combined organic layers were washed with water (10 ml, 2 times) and concentrated, obtaining 12,01 g the Foundation of ATI-7505 in the form of a yellow oil.

i. Synthesis of ATI-7505

the basis of ATI-7505

Raw materials

the basis of ATI-7505, 12,01 g

ethanol (EtOH), 50 ml

IPA, 70 ml

32% HCL

Procedure

12,01 g of the crude base ATI-7505 was dissolved in 50 ml of EtOH. When stirring was slowly added concentrated 32% HCl to a pH of 4.1. After stirring for about 16 hours was added 50 ml of IPA and the reaction mixture was stirred for 2 hours. The solid was filtered and washed with 20 ml IPA. The solid was dried to constant weight, obtaining 9,71 g ATI-7505 in a solid white color. Purity according to HPLC was 98,65 %.

Example 1

Getting dihydrochloride salt 1-azabicyclo[2.2.2]Oct-3'R-silt ester 6-[4R-(4-amino-5-chloro-2-methoxybenzylamine)-3S-methoxypiperidine-1-yl]hexanoic acid

Step 1: Separation of racemic norcisapride

(-)-2,3-Dibenzoyl-L-tartaric acid ((-)-DBT, approximately 1 mass part) was dissolved in ethanol and filtered to remove residual particles. Separately dissolved rat the economic norcisapride (about 0.8 mass parts) in a mixture of ethanol and water, and then was filtered. The filtrate was heated to approximately 75°C, then was added a solution of (-)-DBT. After stirring at the same temperature for about 30 minutes, the mixture was slowly cooled for several hours to approximately 5°C and the resulting salt was collected by vacuum filtration and washed with a mixture of EtOH/H2O. the Wet precipitate was recrystallized from EtOH/H2On heating to approximately 79°C and slow cooling to about 5°C, as before. The product was collected on a vacuum filter and washed with EtOH/H2Oh, by getting wet sediment.

The wet sediment suspended in water and the pH was brought to about 12 using 7% (wt./wt.) aq. NaOH. The resulting suspension was stirred for 3 hours at room temperature, then was filtered under vacuum, washed solid material with water and dried under vacuum. Then, to obtain the salt, the product is re-worked (-)-DBT, using the above General procedure. The selected salt is then neutralized aq. NaOH, as described above. The product was isolated on a filter and dried as described previously, to obtain the base (+)-norcisapride (approximately 0.25 mass part). According to chiral HPLC s/e was approximately 100% (+)-norcisapride. Optical rotation was approximately +5° (IU shall anol; 25°C 589 nm), confirming the presence of positive isomer norcisapride.

Step 2: Linking with ethyl 6-Bromhexine

(+)-Norcisapride (approximately 1 mass part), potassium carbonate (approximately 0,48 mass parts) and potassium iodide (approximately 0,063 mass parts) is suspended in anhydrous ethanol USP. Ethyl 6-Bromhexine (approx 0.76 mass parts) was slowly added to the suspension at room temperature. The mixture was heated to boiling point under reflux to complete the reaction. After cooling to room temperature the reaction mixture was filtered to remove, for example, inorganic solids, and the filtrate was concentrated under reduced pressure to approximately half volume. The product was besieged by slow addition of the crude material in cold water (approximately 13 mass parts) with rapid stirring. The precipitate was filtered under vacuum and washed with water, and then besieged twice by dissolving in anhydrous ethanol and slowly added to cold water, as described above. The obtained wet precipitate was washed with n-heptane and resuspendable in ethyl acetate and n-heptane (1:9;./about.) and was stirred for approximately 1 hour, filtered and dried under vacuum, obtaining 0,73 mass of product binding in Tverdov the substance of white color.

Step 3: Binding of (R)-3-hinokitiol and education dihydrochloride salt

Ester (1 mass part) and (R)-3-hinokitiol (approximately 1,12 mass parts) is suspended in toluene, and then slowly added atoxic titanium (IV) (approximately 0.5 mass part) in the mixed slurry. Under a stream of nitrogen and the mixture was heated to approximately 91°C and the flask was applied partial vacuum through the distiller order azeotropic removal of ethanol. To maintain a minimum amount of solvent in the flask was further added toluene. The reaction was considered complete after about 33 hours.

The mixture was cooled approximately to room temperature and was extracted five times with water. The organic layer was concentrated under reduced pressure and the resulting residue was re-dissolved in EtOH/iD (approximately 1:1 vol./vol.), and then filtered through a filter with pore diameter of the membrane of 0.45 μm to remove all particles. Concentrated hydrochloric acid was slowly added to the stirred filtrate to precipitate the desired product in the form of dihydrochloride salt. The resulting suspension was stirred for several hours at room temperature, was collected using vacuum filtration and washed with EtOH/iD (1:1; vol/vol.), obtaining mass of 0.53 part of neochim is authorized salt.

Untreated dihydrochloride salt resuspendable in ethanol, was heated to the boiling temperature under reflux, then cooled to room temperature for about 1 hour. The product was collected by vacuum filtration and washed with ethanol, and then dried in the air. Solids resuspendable in ethanol and heated to a temperature of approximately 55°C, for obtaining a clear solution, then add warm isopropanol and the product was besieged by slow cooling to room temperature. The resulting suspension was stirred for several hours with a further vacuum filtration and washing, for example, isopropyl. The product was dried under vacuum, first at room temperature for several hours, and then at a temperature of approximately 55°C until reaching constant weight.

Example 2

(+) and (-)-norcisapride can be obtained from its racemic mixture separation of enantiomers using conventional means, such as optical separating acid, in accordance with the method described in U.S. patent No. 6147093 or in "Enantiomers, Racemates and Resolutions", J.Jacques, A.Collet, and S.H.Wilen (Wiley-Interscience, New York, NY) or in S.H. Wilen et al., Tetrahedron (1977) 33:2725.

4 isomer can be obtained in small quantities using preparative column chromatography, with subsequent flash steam is the solvent. This method is suitable for production of small quantities of substances for analytical and research purposes. It is a standard method of separation, commonly used in analytical laboratories for isolation and study of properties of metabolites.

Possible ways of synthesis of compounds IV, VI compounds and (+)-compound II using (+)-norcisapride as the starting material described below. The way of synthesis of compound III, compound V and (-)-compound (II) are identical, except that the starting material is (-)-norcisapride. However, preferably used in the methods and processes described in the methods 2-5, to obtain II-VI compounds and other compounds of the present invention. More preferably used 3-5 ways to produce compounds of the present invention.

Example 3

Obtaining the ethyl ester of (+)-compound II

Equimolar mixture of (+)-norcisapride and ethyl 6-Bromhexine (1 equivalent), a catalytic amount of KI and K2CO3(2 equivalents) in DMF was heated to approximately 60°C for several hours or until TLC analysis showed complete reaction. After cooling to room temperature was added water and the mixture was extracted using EtOAc. The combined organic extracts after avatele washed with water, 10% aqueous solution of LiCl and brine, then dried over Na2SO4. After concentration was obtained ethyl ester (+)-compound II.

Obtain (+)-compound II

A mixture of crude ethyl ester (+)-compound II obtained above (1 EQ.), KOH (2 M, 5 EQ.) in MeOH and THF (sufficient to dissolve the quantity) was stirred at room temperature for about 1-2 hours. MeOH and THF were removed under vacuum and the residue was diluted with water. Washed with an organic solvent such as EtOAc. The aqueous layer was acidified to pH~5 by adding HCl. The precipitate was filtered and dried, to obtain (+)-compound II.

Obtaining compounds IV and VI compounds

A mixture of (+)-compound II (1 EQ.), HCl salt of (R)-(-)-3-hinokitiol (1 EQ.), EDAC (equ.) and DMAP (1 EQ.) in DMF was heated to approximately 50°C during the night. After cooling and dilution with water the mixture was purified using chromatography or crystallization received compound IV. Similarly, using (S)-(+)-hinokitiol received connection VI.

The following compounds were obtained, mainly in accordance with the above described methods and processes, in particular, in accordance with the methods 2-5, and, more preferably, in accordance with the methods 3-5. The title compounds were made using ChemDraw Ultra version 8.03, which can be obtained from Cambidgesoft Corporation, or using the software ACD Namepro version 6.0.

Connection table
(3S)-1-azabicyclo[2.2.2]Oct-3-yl-6-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}hexanoate;
(3S)-1-azabicyclo[2.2.2]Oct-3-yl-6-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}hexanoate;
(3R)-1-azabicyclo[2.2.2]Oct-3-yl-6-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}hexanoate;
8-methyl-8-azabicyclo[3.2.1]Oct-3-yl-6-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}hexanoate;
4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoic acid;
methyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;
methyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;
methyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;
ethyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;

isopropyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;
2-methoxyethyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;
2-pyrrolidin-1-ileti 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;
1 methylpiperidin-4-yl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;
2-pyridine-2-ileti 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;
2-(dimethylamino)ethyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine--yl}acetyl)amino]benzoate;
1 methylpiperidin-3-yl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;
2-morpholine-4-ileti 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;

1,4-dimethylpiperidin-4-yl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;
4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoic acid;
2-oxo-2-(piperidine-4-ylamino)ethyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)amino]benzoate;
1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)piperidine-4-carboxylic acid;
methyl 1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)piperidine-4-carboxylate;
methyl 1-({(3S,R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)piperidine-4-carboxylate;
methyl 1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)piperidine-4-carboxylate;
ethyl 1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)piperidine-4-carboxylate;
2-methoxyethyl 1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}acetyl)piperidine-4-carboxylate;
4-{[2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}ethyl)(methyl)amino]methyl}benzoic acid;

methyl 4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}ethyl)(methyl)amino]methyl}benzoate;
methyl 4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}ethyl)amino]methyl}benzoate;
isopropyl 4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}ethyl)amino]methyl}benzoate;
the dihydrochloride of ethyl 4-{[(2-{(3S,4R)--[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}ethyl)amino]methyl}benzoate;
(3R)-1-azabicyclo[2.2.2]Oct-3-yl 4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl}ethyl)amino]carbonyl}benzoate;
(R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate; or
6-((3S,4R)-4-(4-amino-2-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoic acid.

The manufacture of the compositions, the introduction and enforcement

Dose and route of administration described compounds are similar to those already used and known in the art (see, e.g., Physicians' Desk Reference, 54th ed., Medical Economics Company, Montvale, NJ, 2000).

The magnitude of a prophylactic and/or therapeutic doses of structural and/or functional analog of cisapride for emergency or permanent treatment described in this document disorders will vary depending on the severity of the condition and route of administration. Dosage and possibly frequency injection will also vary depending on age, weight and response of the individual patient. In most cases, the total daily dose of structural and/or functional analogues cisapride for the treatment of the above conditions is CA is approximately 1 mg to 200 mg, single or divided doses. Preferably, the daily dose should be from about 5 mg to 100 mg, in single or divided doses; most preferably, the daily dose should be from about 5 mg to 75 mg, in single or divided doses. Preferably the dose is from 1 to 4 times a day. During treatment the patient's therapy should start with a lower dose, perhaps about 5 mg to 10 mg, and increase to approximately 50 mg and higher depending on the patient's response to treatment. The treatment of children and patients older than 65 years, and patients with impaired renal or hepatic function is recommended to start with small doses, and then the dose should be chitravati in accordance with the individual reaction (reaction) and level (levels) of the drug in the blood. In some cases, professionals will be understood that it may be necessary to use dosages outside these limits. It should be noted that clinical or treating physician will know how and when to terminate, modify or discontinue therapy due to the reaction of the individual patient.

Compounds of the present invention can be produced in various compositions, in accordance with known methods for the production of pharmaceutically useful compositions. The composition is detailed described in many well-known and available specialists sources. For example, in Remington''s Pharmaceutical Science by E.W.Martin described compositions that can be used when implementing the present invention. In General, the compositions of the present invention is made such that an effective amount of biologically active compounds (compounds) combined with a suitable carrier in order to facilitate the efficient introduction of the composition.

The compositions of the present invention include such compositions as suspensions, solutions and elixirs; aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricating agents, binding agents, disintegrating agents and the like, in the case of solid dosage forms for oral administration (such as powders, capsules and tablets); and solid dosage forms for oral administration are preferred over liquid dosage forms for oral administration. Preferred solid dosage form for oral administration are capsules. The most preferred solid dosage form for oral administration are tablets. The preferred amount of the active ingredient (i.e., structural and/or functional analog of cisapride) in solid dosage form comprises about 5 mg, 10 mg and 25 mg

In addition, the pickup is acceptable carriers may be solid or liquid. Solid dosage forms include powders, tablets, pills, capsules, starch capsules, suppositories, and dispersible granules. A solid carrier can be one or more substances, which can act as diluents, corrigentov, soljubilizatory, lubricating agents, suspendresume agents, binding agents, preservatives, leavening agents for tablets or encapsulating materials.

Described pharmaceutical compositions can be divided into standard doses containing appropriate quantities of the active component. Dosage form can be a packaged preparation, such as tablets, capsules and powders, Packed in paper or plastic containers or vials or ampoules. In addition, the dosage form can be a drug in liquid or can be made for inclusion in solid foods, chewing gum or toffee.

In addition to the above main dosage forms, the compounds of the present invention can be administered using the means for controlled release and/or devices for delivery, such as the device described in U.S. patent No. 3845770, 3916899, 3536809, 3598123 and 4008719, descriptions of which are entirely incorporated herein as references.

Any under odasi route of administration can be used for introduction to the patient an effective dose of structural and/or functional analog of cisapride. For example, you can use oral, rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, etc. techniques. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, patches, etc.

One aspect of the present invention relates to methods and/or processes for making compounds and compositions of the present invention.

One aspect of the present invention relates to a method for treatment of gastroesophageal reflux disease in a mammal, which significantly reduced related adverse effects associated with the introduction of cisapride, and which includes an introduction to the person who is in need of such treatment, a therapeutically effective amount of structural and/or functional analog of cisapride or its pharmaceutically acceptable salt. A preferred aspect is the treatment of gastroesophageal reflux disease in humans.

Another aspect of the present invention relates to compositions for the treatment of a person suffering from gastroesophageal reflux disease, which comprises a therapeutically effective amount of structural and/or functional analog of cisapride or its pharmaceutically acceptable salt.

An additional aspect of the present invention refers to is the procedure advances antiemetic effect in a mammal, which significantly reduced the adverse effects associated with the introduction of cisapride, and which includes an introduction to a mammal in need of such antiemetic therapy, therapeutically effective amounts of structural and/or functional analog of cisapride or its pharmaceutically acceptable salt. Preferably, the mammal is man.

In an additional aspect, the present invention relates to antiemetic compositions for the treatment of a mammal, which needs antiemetic therapy, which includes a therapeutically effective amount of structural and/or functional analog of cisapride or its pharmaceutically acceptable salt.

An additional aspect of the present invention relates to a method of treating a condition caused by dysmotility of the gastrointestinal tract in a mammal which comprises the administration to a mammal in need of treatment of motility disorders of the gastrointestinal tract, a therapeutically effective amount of structural and/or functional analog of cisapride or its pharmaceutically acceptable salt. Condition caused by dysmotility of the gastrointestinal tract, include, without limitation, dyspepsia, gastroparesis, constipation, post-operative bowel paresis and pseudoprobability kiseon the ka. Preferably, the mammal is man.

Data that cisapride penetrates into the Central nervous system and binds to receptors 5HT4indicates that cisapride may have Central effects. The cisapride is a powerful ligand 5HT4receptors, which are located in several areas of the Central nervous system. Modulation of serotonergic systems raises a number of behavioral effects. Accordingly, the compounds of the present invention can be used for the treatment of: 1) cognitive disorders, including, without limitation, Alzheimer's disease; 2) behavioral disorders, including, without limitation, schizophrenia, mania, obsessive-compulsive disorder and related disorders the use of psychotropic drugs; 3) mood disorders, including, without limitation, depression and anxiety; and 4) disorders of control of autonomic function, including, without limitation, essential hypertension, and sleep disorders.

Accordingly, the present invention relates also to a method of treatment of cognitive, behavioral disorders, mood disorders, or disorders of control of autonomic function in a mammal, comprising introducing a therapeutically effective amount of structural and/or functional analogue cisap the IDA or its pharmaceutically acceptable salt. Preferably, the mammal is man.

ATI-7505 has a high affinity for 5-HT4receptors

It is known that 5-HT4the receptor is the receptor subtype involved in prokinetics activity of cisapride in the gut. ATI-7505 has high affinity binding to 5-HT4receptor with low nanomolar IC50 values. As shown in table 1, the affinity of ATI-7505 5-HT4the receptor was 18 times greater than that of cisapride, and at least 360 times greater than that of the main metabolite ATI-7505, carboxylic acids.

Table 1
The binding of 5-HT4receptor
5-HT4receptor
Striped body of the Guinea pig
ConnectionIC50(nm)Ki(nm)nH
ATI-75058,31,40,7
ATI-7500>3,000>500 ---
The cisapride15024,90,98
nHthe hill coefficient
Standard prototype antagonist of 5-HT4-receptor [3H]GR113808 (0,70 nm)

ATI-7505 is a potent partial agonist at 5-HT4receptor human

ARYx has carried out research based on stimulation of the adenylate cyclase of cells in which by means of genetic engineering provided a stable expression of the receptor 5-HT4man. It was proved that ATI-7505 is a powerful agonist of 5-HT4-receptor, while its main metabolite, ATI-7500, was relatively weak agonist (figure 1 and table 2). The estimated value EC50for ATI-7505 (4 nm) was approximately 10 times less than for cisapride (49 nm)and about 100 times less than for ATI-7500 (395 nm). On the basis of calculated values of Emaxthe effectiveness of ATI-7505 relative to 5-HT (serotonin) was 85% (table 2); this means that ATI-7505 is a partial agonist of 5-HT4-receptors.

Table 2
Power and efficiency (internal activity) K5-HT 4the receptor of man
ConnectionPowerEfficiency
EC50pEC50% of 5HT (serotonin)
5-HT (serotonin)467not found
ATI-750548,4585
ATI-75003956,4081
The cisapride49777
EC50the concentration causing 50% of maximum increase in adenylate cyclase activity
pEC50- the negative logarithm EC50

ATI-7505 accelerates gastric emptying in fed dogs

In order to evaluate the effects of ATI-7505 on gastric emptying have been set for the experiments in conscious dogs after feeding, using strain gauges placed on the stomach and the small intestine. Price is firm these experiments was to measure time, which is required for returns migrating motor cuts (MMS) to the original level after eating solid food. Reducing the time of return MMK to the original level under the influence of drugs meant an early end of the period of digestion by accelerating gastric emptying. Immediately after the termination of MMK in the middle parts of the small intestine, within 20 minutes of intravenous (IV) infusion was administered different doses of the tested drugs (solvent, ATI-7505 or cisapride). After the end of infusion drugs dogs were given food. Registration contractions of the intestine produced at least 60 minutes prior to infusion of the medicinal product to determine the fasting state and to identify the beginning of MMK in the duodenum, and at least within 30 minutes after the resumption of MMK in the duodenum. Quantitative comparison of the effect of drugs was carried out on the basis of the time of return MMK to the original level as an indicator of gastric emptying after ingestion of solid food. As shown in figure 2, ATI-7505 significantly accelerates the return MMK to the original level, which indicates the acceleration of gastric emptying in healthy fed dogs. The cisapride showed a similar effect.

ATI-7505 in Olivet motility of the stomach and small intestine, slightly affecting the activity of the large intestine

The experiments were carried out to hungry dogs, in consciousness, in order to assess the impact of ATI-7505 on the motility of the stomach, small intestine, colon, compared with cisapride. The specific purpose of the study was to determine the magnitude of the doses of ATI-7505 (/p/) that the nature and strength of the contractile activity in dogs are closest to those under the action of cisapride with conventional therapeutic doses (0.5 mg/kg; 1 mg/kg p/o).

When I/o and p/o introduction as the ATI-7505 and cisapride had prokinetics effect on the intestine of dogs. Onset of action is usually observed within 1-2 minutes and 25-30 min after I/V and p/o injection, respectively. The effects of ATI-7505 on the motility of the stomach and small intestine, consistent with the effects of cisapride. It turned out that like cisapride, ATI-7505 caused a dose-dependent stimulation of contractions of the antrum of the stomach and small intestine, with relatively little influence on the motility of the colon. Prokinetics effects caused by the ATI-7505 in the upper sections of the LCD tract, accompanied by a small but significant (p<0,05) increased frequency of giant migrating contractions (GMC).

The introduction of ATI-7505 not been associated with the development of retrograde giant migrating contractions (RGC). Like ZIS will come, ATI-7505 have minimal impact on the characteristics of the migrating motor complex (MMC) in the antrum of the stomach, and proximal, middle and distal parts of the small intestine. In regard to the frequency of MMK and the duration of Phase III, it was noted only one significant difference: p/o the introduction of ATI-7505 increased frequency of MMK in the proximal small intestine compared to control. The dog was transferred to a/b and p/o doses of ATI-7505 well, and side effects such as diarrhea, anorexia or weight loss, were observed.

In General, the results showed that when calculating doses in mg/kg ATI-7505 is approximately 2 times more powerful than cisapride. In addition, the effects of ATI-7505, like the effects of cisapride, consistent with the mechanism, which is based on facilitating the release of acetylcholine from neurons of the intestine, and not a direct effect on smooth muscle. Thus, ATI-7505 improves the motility of the stomach and small intestine, like cisapride, with minimal impact or no impact on the colon.

Metabolism ATI-7505 is regardless of CYP450

On the basis of data obtained in experiments with pooled human microsomes, ATI-7505 undergoes biotransformation in a single metabolite, ATI-7500, which, as it turns out, does not undergo further metabolism. The transformation of ATI-7505 in ATI-7500 does not depend on prisutstvie is NADPH. Thus, the major route of biotransformation of ATI-7505 is not dependent on CYP450 enzymes.

ATI-7505 did not inhibit CYP450 enzymes

In order to study the ability of ATI-7505 and/or its main metabolite, ATI-7500, to inhibit CYP450 carried out the screening of these two molecules using test Gentest Supersomes™. According to published reports, cisapride has significant inhibitory activity against the isoforms of CYP450 enzymes, CYP3A4, CYP2D6 and, to a lesser extent, 2C9. No connection ATI-7505, nor its major metabolite, ATI-7500, did not show significant inhibitory activity nor in respect of the above three isoforms of CYP450, or to the other isoforms, which are known to be involved in the metabolism of drugs.

ATI-7505 has negligible affinity for channels of cardiomyocytes IKr

Quickly activated potassium (K+) current of detained straightening a person (man IKr) is a K+ channel, which is encoded by the human genome, related ether-a-go-go (hERG). As you know, under the action of cisapride is prolongation of the QT interval by blocking the IKrso the interest was to determine, do AT-7505 and ATI-7500 important inhibitory effect on IKrman. As the test system used HEK-293 mammalian cells expressing K+ Kahn the crystals hERG, in which the potassium current was measured by the method of fixation capacity of intact cells. Values were determined IC50in ascending order: cisapride (9,5 nm)>ATI-7505 (24,521 nm)>ATI-7500 (204,080 nm) (table 3). In General, the data obtained show that ATI-7505 has a much lower proaritmicski potential than cisapride, and suggest that as the ATI-7505 and ATI-7500 has a negligible affinity for the human IKrchannels.

Table 3
The inhibition activity of IKr
ConnectionThe activity of IKrin HEK cells
% of control IKr(10000 nm)IC50
ATI-750578,024521
ATI-750088,9204080
The cisapride09,5
Data are standardized by % control trace IKr(current caused without the compounds or media)

ATI-7505 is not anywayt significant electrophysiological changes in the cardiac muscle of the Guinea pig

Electrophysiological effects of ATI-7505 on the heart muscle was studied on isolated perfuziruemah hearts of Guinea pigs. In the course of the experiments studied ATI-7505, ATI-7500 and cisapride in concentrations up to 10 000 nm. The level at which the effect is not observed (NOEL)was determined as the highest concentration of the test compounds, in which there is a response that is significantly different from baseline (p<0,05). Addressed the following 6 parameters of cardiac muscle: (1) the QT interval; (2) MAPD90(the duration of the monophasic action potential); (3) the interval SA; (4) QRS interval; (5) interval AH and (6) HV. While ATI-7505 was very weak modulator of electrophysiological parameters of the heart muscle, its metabolite, ATI-7500, never had electrophysiological activity (table 4). Level NOEL for ATI-7500 was >10000 nm for the entire series of 6 cardiovascular parameters. Since cisapride had a NOEL of 10 nm in the ratio of the combined number of 6 studied parameters of the cardiac muscle, and ATI-7505 had a joint NOEL 1000 nm, with the conclusion that ATI-7505 has no property of cisapride to modulate the electrophysiological parameters of the heart muscle. In General, the data obtained show that ATI-7505 is significantly more secure than cisapride in regards to the ability to induce electrophysiological from the change in the cardiac muscle.

Table 4
Electrophysiological parameters of isolated perfusing heart
ElectrophysiologicalThe level at which the effect is not observed (NOEL)
The cisaprideATI-7505ATI-7500
The QT interval101000>10000
MAPD90101000>10000
The interval SA100>10000>10000
QRS interval1000>10000>10000
Interval AH1000>10000>10000
The HV interval10001000>10000
United101000>10000
All the molecules studied in the initial concentrations of 10, 100, 1000 and 10 000 nm.
Significant difference (p<0.05) as compared with the initial state was observed when the concentration of molecules in 10 times, except for values specified as >10000 nm.

Metabolism in microsomal preparations person

The metabolism of these compounds was studied on the pool of human microsomes in the presence and in the absence of the cofactor NADPH to the cytochrome P450 system and monitorrole the time of the disappearance of the parental compounds and the appearance of the corresponding acid metabolite, i.e. the corresponding isomer of compound II.

As shown in table 5, compounds III and IV were rapidly hydrolyzed by esterase with formation of the corresponding metabolites (+) and (-) connections II. Metabolism is not dependent on CYP450, because the rate of hydrolysis is not dependent on the presence of NADPH, an essential cofactor for the functioning of CYP450. On the contrary, (±)-S compounds V and VI were quite stable over time under the same conditions. In the given experiment, the number of substrates (compounds III, IV, V, and VI)remaining in the reaction after 5, 60 and 90 minutes, were evaluated by dual method " VE the X-MS. The specified residual quantity correlated with the appearance of a metabolite of compound II. In the aggregate residual substrate and the compound II was unchanged over time the number equal to the number of the source material in the zero moment of time, indicating, thus, that the hydrolysis was the only reaction metabolism, which took place.

Table 5
The compounds were incubated in the United microsomal drug person in the presence of the cofactor NADPH. Determination of the residual amount of the test compounds and the appearance of the metabolite of compound (II) produced in the course of 90 minutes.
Test connectionCompounds III and IVCompounds V and VI
TimeThe remainder of the test compounds (ng/ml)Metabolite (ng/ml)AmountThe remainder of the test compounds (ng/ml)Metabolite (ng/ml)Amount
531,3 233,332,91,534,4
6020,714,535,229,91,5of 31.4
9016,919,436,331,91,5the 33.4

Metabolism in fresh human blood.

Compound was dissolved in DMSO to obtain 12.5 mm stock solution and diluted with water to a final concentration of 2.5 mm (DMSO/H2O=20/80). Fresh blood was obtained from 3 donors-people and placed in heparinized tubes, blood was stored on ice until incubation. Separate aliquots of blood from each donor measured by pipette into 1.5 ml centrifuge tubes and test tubes pre-incubated in a shaker water bath at 37°C for 5 minutes. The reaction was initiated by adding 10 ál of stock solution of the respective test compound in each tube (final concentration 100 μm). Incubation extinguished after 0, 5, 15, 30 and 60 minutes by the addition of acetonitrile (750 ml), after which the tubes of centrif who was garofali at 12000 rpm./min for 2 minutes, and the supernatant was analyzed by using Agilent 1100 for HPLC. The separation was performed on a column of Keystone Intersil ODS2, 250×4.6 mm, 5 m Aqueous mobile phase consisted of 20 mm buffer solution of ammonium acetate (pH of 5.7) and the organic phase acetonitrile. Used gradient: initial condition consisted of 20% acetonitrile for 1 minute. The concentration of acetonitrile linearly decreased to 90% over the next 8 minutes and kept at this level for 1 minute. Then the system is returned to the original conditions within a minute and was left in a specified condition within 4 minutes before the next injection. The peak area corresponding to the parental compound, was determined by absorption at 240, 254 and 290 nm. The results were expressed as the residual amount of the original connection and the data were subjected to kinetic analysis using the software package WinNonLin. The half-periods of the existence of the individual compounds are shown below in table 6.

Table 6
Diastereoisomers configuration
Connection"Half of the" Nord-CIS"Half the of ainulindale The period of existence (min)
III-R
Subject 1a 12.03
Subject 210,37
Subject 39,23
Mean ± CO10,5±1,41
IV+R
Subject 1of 8.47
Subject 28,61
Subject 38,58
Mean ± CO 8,59±0,077
V-S
Subject 1>60 minutes
Subject 2>60 minutes
Subject 3>60 minutes
VI+S
Subject 1>60 minutes
Subject 2>60 minutes
Subject 3>60 minutes

It should be understood that the examples and features described in this application are used only for illustrative purposes and that various modifications or changes in their interpretation can be offered to professionals and should be included in the idea and scope this is the soup of the application and scope of the attached claims. In addition, all patents, patent applications, provisional applications, and publications referenced in or who is opposed to this document is entirely incorporated herein, to the extent that they explicitly do not contradict the ideas of this specification.

The invention, as well as the methods and processes of its implementation and use are described in this document full, clear, concise and exact terms so that any person skilled in the art could make and use the present invention. It should be understood that the above described preferred features of the invention and that it is possible to carry out modifications without departure from the idea or scope of the invention, in the form in which it is indicated in the claims. Specifically to mention make clear the subject matter of the invention as the invention, the following claims sums up the description.

1. The method of obtaining (R)-Hinkley-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate or its salts, including
1) making connections, which is ethyl 4-amino-3-methoxypiperidine-1-carboxylate,

in salt;
2) the conversion of salts of ethyl 4-amino-3-methoxypiperidine-1-carboxylate in ethyl 4-(diphenylamine)-3-methoxypiperidine-1-carboxylate

3) the processing of ethyl 4-(diphenylamino)-3-methoxypiperidine-1-carboxylate hydroxide or hydride of an alkali metal, to obtain 3-methoxy-N,N-diphenylpiperazine-4-amine

4) obtaining the chiral salt of the CIS isomer of 3-methoxy-N,N-diphenylpiperazine-4-amine by contacting 3-methoxy-N,N-diphenylpiperazine-4-amine with chiral separating agent and the allocation obtained by way of chiral salt of the CIS isomer of 3-methoxy-N,N-diphenylpiperazine-4-amine;
5) optional, recrystallization of the product 4;
6) the transformation of the product 4 or 5 in the base, with the receipt of the product 4 or 5 in free base form;

7) the contacting of the product 6 with ethyl 6-bromhexinum, to obtain ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidine-1-yl)hexanoate
;
8) the esterification of ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidine-1-yl)hexanoate using (R)-Hinkley-3-ol and a Lewis acid to obtain (R)-Hinkley-3-yl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidine-1-yl)hexanoate
;
9) removing protection from a 4-amino group of the product 8 with obtaining (R)-Hinkley-3-yl 6-[(3S,4R)-4-amino-3-methoxypiperidine-1-yl]hexanoate;
10) the acylation product 9 4-amino-5-chloro-2-methoxybenzoic acid to obtain (R)-Hinkley-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidine-1-yl)hexanoate;
11) optional conversion of the product 10 in salt.

2. The method according to claim 1, where the salt from the stage 1 is HCl.

3. The method according to claim 1, where the alkali metal hydroxide from the stage 3 is a CON.

4. The method according to claim 1, where the chiral salt with stage 4 represents (+)-2,3-Dibenzoyl-D-tartaric acid.

5. The method according to claim 1, where the Lewis acid is a Ti(OiP)4(isopropoxide titanium (IV)).

6. The method according to claim 1, where removing protection from 4-amino group is used H2/Pd/C.

7. The method according to claim 1, where the acylation product 9 is pualeilani.



 

Same patents:

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: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , in which A denotes hydrogen, B denotes methyl or B is in a trans-position relative oxygen; X denotes CH2; Y denotes a group of formula , , ,

, or ;

, in which the left-hand bond is to an oxygen atom, and the right-hand bond is to the group R; R denotes 5-indolyl; in form of a free base or an acid addition salt. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-7, to a method of preventing and treating psychiatric and neurodegenerative disorders in a person, as well as a method of treating and preventing diseases or pathological condition in which α7 nAChR activation plays a role.

EFFECT: obtaining novel biologically active compounds having α7 nAChR agonist activity.

16 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I

in form of a salt, where R1 and R2 each independently denotes phenyl, where one or both R1 and R2 are substituted in one, two or three positions by the following groups: halogen, C1-C8alkyl or C1-C8alkoxy, and R3 is hydroxy, or R1 and R2 each denotes an unsubstituted phenyl, and R is hydrogen, C1-C8alkyl, C1-C8alkoxy or C1-C8alkylthio, or R1 is C3-C8cycloalkyl and R2 is phenyl or a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes oxygen and sulphur, and R3 is hydroxy, or -CR1R2R3 denotes 9-hydroxy- 9H-fluoren-9-yl or 9-hydroxy-9H-xanthen-9-yl, and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, optionally substituted with phenyl, or R1 and R2 each denotes an unsubstituted phenyl, and R3 is hydroxy and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is 5-methyl-3-isoxazolyl or R1 and R2 each denote unsubstituted phenyl, and R3 is hydroxy and R4 is 1-ethyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen, R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, provided that the formula I compound is not (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrazin-2-ylcarbamoylmethy)-1-azoniumbicyclo[2.2.2]octane, (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide or (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-8, as well as to methods for synthesis of formula I compounds.

EFFECT: obtaining new biologically active compounds which have M3 muscarinic receptor mediated activity.

14 cl, 254 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat diseases mediated by the nicotinic acetylcholine receptor, such as derangement of memory. In general formulae , and A is an indazolyl, benzothiazolyl or isobenzothiazolyl group which corresponds to structural formulae a) to c) respectively or X is O; R1 is H, F, Cl, Br, I, cycloalkyl containing 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; ; R2 is H; R3 is H; R4 is H, F, Cl, Br, I, cycloalkyl which contains 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; R5 is H; Ar is an aryl group containing 6 carbon atoms which is unsubstituted or substituted once or several times with halogen; and Het is a 5- or 6-member heteroaromatic group containing a heteroatom in the ring which is selected from N, O and S, or a 6-member saturated heterocyclic group which contains a heteroatom in the ring which is selected from N and O; and their pharmaceutically acceptable salts, where, if the said compound has formula I, the indazolyl group of group A is bonded through its 3rd, 4th or 7th position, the benzothiazole group of group A is bonded through the 4th or 7th position, the isobenzothiazole group of group A is bonded through the 3rd, 4th or 7th position.

EFFECT: obtaining compounds with properties of nicotinic acetylcholine receptor (nAChR) ligands, and pharmaceutical compositions based on the said compounds.

53 cl, 95 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where B represents a hydrogen atom or a group selected from -R1, -OR1, hydroxy, - O(CO)R1, cyano and non-aromatic heterocycle which is a saturated or unsaturated C3-C10carbocyclic ring in which one or more carbon atoms, preferably 1 or 2 carbon atoms, are substituted with oxygen atoms as heteroatoms, where R1 is selected from a group containing hydrogen atoms, C1-C8alkyl, C2-C8alkenyl and C3-C8cycloalkyl, where the alkyl group is unsubstituted or substituted with one or more substitutes selected from halogen atoms and C1-C4alkyl, and where the alkenyl group is unsubstituted or substituted with one or more substitutes selected from C1-C4alkyl, n equals an integer from 0 to 4, A is selected from a group containing -CH2-, -CH=CR3-, -CR3=CH-, -CR3R4-, -O-, -CO-, -O-(CH2)2-O-, where R3 and R4 each independently represents a hydrogen atom or C1-C8alkyl, m equals an integer from 0 to 8, p equals 2, and the bicyclic azonium ring contains a substitute on position 3, including all possible configurations of asymmetrical centres, D is selected from a group containing: or where R5 is selected from a group containing phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, R6 is selected from a group containing 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, C3-C8cycloalkyl, C1-C8alkyl, C2-C8alkenyl and phenylethyl, R7 represents a hydrogen atom or a group selected from hydroxyl, hydroxymethyl and methyl, Q represents a single bond or a group selected from -CH2-, -CH2CH2-, -O-, -O-CH2-, equals an integer from 0 to 3, X represents a pharmaceutically acceptable anion of mono- or polybasic acid, under the condition that the B-(CH2)n-A-(CH2)m- group does not represent a straight C1-4alkyl and that the following compounds are excluded: 1-allyloxycarbonylmethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-azoniumbicyclo[2.2.2]octane and 1-carboxymethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-azoniumbicyclo [2.2.2]octane. The invention also relates to a method of producing formula (I) compounds, to a pharmaceutical composition, to use of compounds in any of paragraphs 1-14, as well as a combined product.

EFFECT: obtaining novel biologically active compounds with antagonistic activity towards muscarine receptors M3.

21 cl, 64 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of common formula (I) , in which: A, if available, means (C1-C6)-alkyl; R1 means group NR6R7, (C4-C7)-azacycloalkyl, (C5-C9)-azabicycloalkyl, besides, these groups, unnecessarily, are substituted with one or more substituents, selected from (C1-C5)-alkyl or halogen; A-R1 is such that nitrogen of radical R1 and nitrogen in position 1 of pyrazole are necessarily separated at least by two atoms of carbon; R3 means radical H, OH, NH2, ORc, NHC(O)Ra or NHSO2Ra; R4 means phenyl or heteroaryl, unnecessarily, substituted with one or more substituents, selected from halogen, CN, NH2, OH, ORc, C(O)NH2, phenyl, polyfluoroalkyl, linear or ramified (C1-C6)-alkyl, besides these substituents, unnecessarily, are substituted with halogen, and moreover, heteroaryl radicals are 3-10-member, containing one or more heteroatoms, selected from sulphur or nitrogen; R5 means radical H, linear or ramified (C1-C6)-alkyl; Ra means linear or ramified (C1-C6)-alkyl; Rc means linear or ramified (C1-C6)-alkyl, (poly)fluoroalkyl or phenyl; R6 and R7, independently from each other, means hydrogen, (C1-C6)-alkyl; R6 and R7 may create 5-, 6- or 7-member saturated or non-saturated cycle, which includes one heteroatom, such as N, and which, unnecessarily, substituted with one or more atoms of halogen; to its racemates, enantiomers, diastereoisomers and their mixtures, to their tautomers and their pharmaceutically acceptable salts, excluding 3-(3-pyridinyl)-1H-pyrazole-1- butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine. Invention is also related to methods for production of compounds of formula (I) and to pharmaceutical composition intended for treatment of diseases that appear as a result of disfunction of nicotine receptors α7 or favorably responding to their modulation, on the basis of these compounds.

EFFECT: production of new compounds and pharmaceutically acceptable composition on their basis, which may find application in medicine for treatment, prophylaxis, diagnostics and observance over development of psychiatric or neurological disorders or diseases of central nervous system, when cognitive functions deteriorate or quality of sensor information processing drops.

16 cl, 106 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with formula I: , where D is O; E is CH2 or O; n equals 1 or 2, and R1 is chosen from hydrogen, halogen or substituted or unsubstituted 5- or 6-member aromatic or heteroaromatic ring with 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, or is chosen from substituted or unsubstituted 8-, 9- or 10-member condensed heteroaromatic ring system with 0 or 1 nitrogen atom, 0 or 1 oxygen atom, where the said aromatic or heteroaromatic rings or ring systems, when they are substituted, have substitutes which are chosen from -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, halogen, -CF3, -S(O)mR2, where m equals 0, 1 or 2, -NR2R3, -NR2C(O)R3 or -C(O)NR2R3; R2 and R3 are in each case independently chosen from hydrogen, -C1-C4alkyl, -C3-C6cycloalkyl, aryl; or its stereoisomers, enantiomers or pharmaceutically acceptable salts; under the condition that the given compound is not 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydroisoindol-1-one. The invention also relates to compounds with formulae II or III, to a pharmaceutical composition, as well as to use of compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds with activity towards alpha 7 nicotinic acetylcholine receptors (α7 nAChRs).

8 cl, 72 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of formula I in the form of the salt or zwitter-ion, wherein R1 and R3 are independently phenyl, C3-C8 cycloalkyl or thienyl group, R2 is haloid or hydroxyl group; R4 is C1-C8 alkyl substituted with -NR5-CO-R6 or -CO-NR9R10; R5 is hydrogen ; R6 is C1-C8alkyl or C1-C8 alkoxy, each of them is optionally substituted with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R6 is 5-10-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur; R9 is hydrogen or C1-C8alkyl; R10 is C1-C8alkyl, optionally substituted with cyano group, C1-C8 alkoxy group or with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R10 is 5-9-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur. The invention refers also to the pharmaceutic composition, to the application of compound of any of claims 1-5 as well as to the preparation method of compound of formula I of claim 1.

EFFECT: preparation of the new biologically active compounds taking the effect of muscarin receptor M3.

9 cl, 247 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline forms of the tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide of formula (IV)

, where the crystalline form is an at least 80% pure crystalline form of C, the powder X-ray pattern of which includes peaks corresponding to values d in angstrom - approximately 10.7, approximately 4.84, approximately 4.57 and approximately 3.77. The invention also relates to methods of producing crystalline forms in claim 1, a pharmaceutical composition, a method of administering a compound of formula (I) to a recipient, a method of inhibiting monoamine receptor activity, as well as use of compounds in claim 1.

EFFECT: obtaining a novel compound having monoamine receptor inhibiting or inverse agonist activity.

39 cl, 54 ex, 9 tbl, 7 dwg

Novel salt i // 2417220

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which is N-{2-[((2S)-3-{[1-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl}acetamide benzoate or solvate thereof. The invention also relates to a pharmaceutical composition, dry inhalant powder, use of compounds in any of claims 1-6, as well as a method of modulating chemokine receptor 1 (CCR1).

EFFECT: obtaining a novel biologically active compound, having chemokine receptor 1 (CCR1) modulating activity.

13 cl, 6 ex, 2 tbl, 4 dwg

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: chemistry.

SUBSTANCE: compounds have formula (lb) in which R1 denotes (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G; (6) -CONR1HR1J, (7) -NR1K COR1L, or (8) cyano, where m equals 0, 1 or 2;X denote a bond or a spacer which contains 1-3 atoms as the backbone chain; ; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1K and R1L each independently denotes (1) a hydrogen atom, (2) a C1-8alkyl group which can have a substitute (substitutes) selected from a group comprising [1] a hydroxy group, [2] a carboxy group, [3] a C1-6alkoxy group which can be substituted with a halogen and [4] a mono- or disubstituted amino substituted C1-8alkyl group or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl, and where R1C and R1D, or R1H and R1J together with a nitrogen atom to which they are bonded can form piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl; ring A is a benzene ring or a pyridine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl, nitro, C1-6alkoxy and halogen; ring B is a benzene ring, a pyridine ring or a pyrazine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl; R51 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (2) benzene, pyrazole, pyridine, isoxazole, thiophene, benzothiazole, each of which can have a substitute (substitutes) selected from a group comprising C1-4alkokyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl and halogen; R52 denotes a hydrogen atom; R53 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (3) benzene, pyrazole, pyridine, thiophene, benzodioxane, cyclohexan or tetrahydropyran, each of which can have a substitute (substitutes) selected from a group comprising [1] hydroxy group, [2] cyano, [3] carbamoyl, [4] aminocarbonyl, substituted with one or two substitutes selected from (a) hydroxy group, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group, (e) carboxyl and (f) C1-6alkoxycarbonyl, [5] carboxy, [6] halogen, [7] C1-6alkoxy, [8] C1-6alkylsulphonyl, [9] amino, [10] C1-6acylamino, [11] alkyl-sulphonylamino, [12] cyclic aminocarbonyl and [13] C1-8 hydrocarbon group substituted with 1 or 2 substitutes selected from (a) hydroxy, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group and (e) aminocarbonyl, substituted with a C1-8 hydrocarbon group; to salts thereof, N-oxide thereof and solvate thereof. The invention also relates to a pharmaceutical composition based on said compound, having antagonistic activity towards CCR5, to use of formula (1b) compound to produce an agent for preventing or treating CCR5 related diseases. Novel compounds which have anti CCR5 activity are obtained and described. Said compounds are therefore useful in preventing and/or treating CCR5 related diseases, for example various inflammatory diseases, immunological diseases etc.

EFFECT: wider field of use of the compounds.

7 cl, 11 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: novel compounds have general formula (1), or salts thereof:

, where R10 is cyclohexyl optionally substituted with a substitute selected from group A1, or cyclohexenyl optionally substituted with a substitute selected from group A1, R30, R31 and R32 denote hydrogen, R40 denotes C1-10alkyl optionally substituted with a substitute selected from group D1, n equals 0 or 1, X1 denotes nitrogen, and R20, R21, R22 and R23 independently denote hydrogen, except when R20, R21, R22 and R23 all denote hydrogen, C1-6 alkylthio optionally substituted with a substitute selected from group F1, C2-6 alkoxycarbonyl, C1-6 alkyl substituted with a substitute selected from group W1, C1-6 alkyl substituted with a substitute selected from group K1, C1-6 alkoxy substituted with a substitute selected from group W1, a 5-6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from W1, a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from group V1, pyridyl substituted with a substitute selected from group W1, phenyl,optionally substituted with a substitute selected from group W1, C2-7 alkenyl, optionally substituted with a substitute selected from group W1, C2-7 alkynyl optionally substituted with a substitute selected from group W1, a 3-6-member cycloalkyl optionally substituted with a substitute selected from group W1, a 5-6-member cyclalkenyl optionally substituted with a substitute selected from group W1, NR1XR2X, -CO-R1X, -CO-NR1XR2X, -NR1X-CO-R2X, -SO2-R3X or -O-SO2-R3X,where R1X is hydrogen or a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N and O atoms, R2X is a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, and R3X is C1-6 alkyl optionally substituted with a substitute selected from group F1; or R21 and R22 together form a ring selected from group Z1, where group A1 consists of C1-6 alkyl, group D1 consists of cyclopropyl and tetrahydropyranyl, group F1 consists of a halogen, group W consists of hydroxyl, C2-7 alkoxyalkyl, phenoxy, C2-7 alkoxycarbonyl, -NR6XR7X and -CO-NR6XR7X, where R6X and R7X independently denote hydrogen or C1-6 alkyl, group V1 consists of oxo (=O) and ethylenedioxy(-O-CH2CH2-O-), where ethylenedioxy is allowable only if a compound of two rings with one common atom forms together with a substituted 6-member heterocyclic group, group K1 consists of a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, group U1 consists of carboxyl, C1-6 alkoxy, phenyl and CO-NR8XR9X, where R8X and R9X denote hydrogen, and group Z1 consists of

, where R1Z denotes C1-6 alkyl or benzyl. The invention also pertains to a medicinal agent, a cell adhesion or cell infiltration inhibitor, as well as to therapeutic or prophylactic agents.

EFFECT: obtaining novel biologically active compounds having cell adhesion or cell infiltration inhibiting activity.

20 cl, 147 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) , where Z means where R means hydrogen, C4-C6cycloalkyl group attached either through one of ring carbon atoms, or through a lower alkylene group attached to the ring, or a linearly chained or branched lower alkyl group or a lower hydroxyalkyl group, or a lower aminoalkyl group, or a phenyl(lower alkyl) group optionally substituted with 1-2 substitutes chosen from lower alkyl, lower alkoxy, halogen and hydroxy, or heteroaryl(lower alkyl)group where heteroaryl is chosen from the group consisting from thienyl, substituted with lower alkyl group, imidazolyl, and thiazolyl substituted with the lower alkyl group; n means 0 or 1; or Z means a group where R means the lower alkyl group; X1 means methylene or NH group; and X2 means methylene; or X1 means methylene and X2 means methylene or a bond; or X1 means methylene, and X2 means O, S or a bond; Y1 means methylene, and Y2 means methylene, vinylene, ethylene, or a bond; Ar1 means unsubstituted or substituted phenyl; Ar2 means unsubstituted or substituted phenyl, unsubstituted or substituted thienyl, unsubstituted or substituted furyl, unsubstituted or substituted pyridyl; and when Ar1 and Ar2 are substituted, each Ar1 and Ar2 are independently substituted with one or more substituted chosen from lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di- and trihaloalkyl, di- and trihaloalkoxy, mono- and dialkylamino, alkilthio, alkyl ester and nitro; provided that Ar1 and Ar2 do not simultaneously mean unsubstituted phenyl; W means oxygen or sulphur; or to their pharmaceutically acceptable salts; provided those specified in cl. 1 of the patent claim. Besides the invention concerns the compounds chosen from the group, to compounds of formula (I), to pharmaceutical compositions, to a method of inhibition of monoamine receptor activity, to a method of inhibition of monoamine receptor activation, to a method of treating a diseased state associated with serotonin receptor, to a method of treating schizophrenia, to a method of treating migraine, and also to a method of treating psychosis.

EFFECT: preparation of the new biologically active compounds capable to inhibit monoamine receptor activity.

65 cl, 140 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where R1 is selected from group, including: phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, lower alkoxy group, halogen or lower halogenalkyl; naphtyl; tetrahydronaphtyl; C3-7cycloalkyl; -(CHR3)m-phenyl, where m stands for 1, 2, or 3; and phenyl is unsubstituted or mono-, di- or tri-substituted with lower alkoxy group, and where R3 is independently selected from hydrogen and lower alkyl; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur, and heteroaryl is mono-, di- or tri-substituted independently with lower alkoxy group; and R2 is selected from group including: n-butyl; phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, halogen or lower alkoxy group; heteroaryl, where term "heteroaryl" relates to aromatic 5-member ring, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; unsubstituted or mono-, di- or tri-substituted independently with lower alkoxy group; -C(O)-NR4R5; where R4 and R5 stand for lower alkyl or together with nitrogen atom, to which they are bound, form 5-member heterocycle, which can additionally contain heteroatom, selected from N or S, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, able to inhibit DPP-IV.

13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to obtaining physiologically active compounds, particularly to a new water-soluble complex of cis-diaminodichloroplatinum (2+) with isonicotinic acid hydrazide of formula Pt(NH3)2Cl2·2L, where L=INH is isoniaside, isonicotinic acid hydrazide. The method of preparing the complex involves reacting cis-diaminodichloroplatinum (2+) with isonicotinic acid hydrazide with subsequent extraction of the end product.

EFFECT: compound widens the range of water-soluble anti-tumour and anti-metastatic preparations; can be used in medical practice as an analogue of cisplatin on therapeutic effect, but in a more convenient form of administration due to its high solubility and low toxicity.

3 cl, 6 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: described is a compound of formula

or its pharmaceutically acceptable salt, where m, p, q, Ar, R1 and R2 are as given in the description, as well as a pharmaceutical composition with selective affinity to 5-HT receptors which contains a formula (I) compound.

EFFECT: obtained compounds have selective affinity to 5-HT receptors and can be used, as expected, in treating certain central nervous system disorders.

21 cl, 1 tbl, 6 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

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