Novel spiro[imidazolidine-4,3'-indole]-2,2',5(1'h)-triones for treating conditions associated with vanilloid receptor 1

FIELD: chemistry.

SUBSTANCE: invention relates to a compound (4R)-1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-en-1-yl]-2H,5H-spiro[imidazolidine-4,3'-indole]-2,2',5(1'H)-trione or pharmaceutically acceptable salt thereof. The invention also relates to use of the said compound to prepare a medicinal agent for use in therapy of conditions associated with vanilloid receptor 1 (VR1).

EFFECT: novel optical isomer which can be used to treat acute or chronic disorders.

6 cl, 2 tbl

 

The SCOPE of the INVENTION

The present invention relates to new compounds, to pharmaceutical compositions containing these compounds and to the use of such compounds in therapy. The present invention also relates to methods of producing such compounds and intermediate compounds for their preparation.

PRIOR art

The sensation of pain in mammals is the result of activation of peripheral endings of specialized populations of sensory neurons known as nociceptors. Capsaicin, the active ingredient in hot peppers, produces prolonged activation of nociceptors, but also produces a dose-dependent pain in humans. Cloning vanilloideae receptor 1 (VR1 or TRPV1) demonstrated that VR1 is a molecular target for capsaicin and its analogues (Caterina, M.J., Schumacher, M.A., et.al., Nature (1997), v.389, p.816-824). Functional studies using VR1 show that it is activated also detrimental high temperature, the influence of acids on tissue and other inflammatory mediators (Tominaga, M., Caterina, M.J. et.al., Neuron (1998), v.21, p.531-543). The expression of VR1 is regulated after peripheral nerve injuries of a certain type, which leads to neuropathic pain. These properties VR1 make it a very suitable target for pain and Zab is the diseases, are involved in inflammation. Although agonists of the receptor VR1 can act as analgesics by destruction of nociceptors, the use of agonists such as capsaicin and its analogues, are limited because of their pungency, neurotoxicity and inducing hypothermia. Instead, more useful can be agents that block the activity of VR1. Antagonists could maintain analgesic properties, but to exclude the pungency and neurotoxic side effects.

It is believed that compounds with the activity of inhibitors VR1, potentially useful for the treatment and/or prevention of disorders such as pain, especially the pain of inflammatory or traumatic origin, arthritis, ischemia, cancer, fibromyalgia, pain in the lumbar region and postoperative pain (Walker et al., J. Pharmacol. Exp.Ther. (2003) Jan; 304(1):56-62). In addition to these visceral pain, such as chronic pain in the pelvic region, cystitis, irritable bowel syndrome (IBS), pancreatitis and the like, as well as neuropathic pain, such as sciatica, neuropathy in HIV, multiple sclerosis, etc. (Walker et al., ibid, Rashid et al., J. Pharmacol. Exp. Ther. (2003) Mar; 304(3):940-8), are potential pain conditions that can be treated by inhibiting VR1. It is also believed that these compounds are potentially useful in inflammatory disorders such as asthma, cough, inflammatory disease the bowel (IBD) (Hwang and Oh Curr Opin Pharmacol (2002) Jun; 2(3):235-42). Compounds with activity of VR1 blockers, useful as itching and skin diseases such as psoriasis, and at the gastroesophageal reflux (GERD), vomiting, cancer, incontinence and overactive bladder (Yiangou et af., BJU Int (2001) Jun; 87(9):774-9; Szallasi, Am. J. Clin. Pathol. (2002) 118: 110-21). Inhibitors VR1 is also potentially useful for the treatment and/or prevention of the effects of activators VR1, such as capsaicin or tear gas, acid or high temperature (Szallasi, ibid).

Another potential application relates to the treatment of tolerance to the activators VR1.

Inhibitors VR1 can also be useful in the treatment of interstitial cystitis and pain associated with interstitial cystitis.

Inhibitors VR1 can also be useful in the treatment of obesity and migraine. The use of VR1 antagonists for the treatment of obesity are disclosed in WO 2006/007851.

In EP 66378 and EP 2890604 disclosed derivatives of Spiro-as for use as inhibitors aldozoreduktaza.

In WO 92/07830 disclosed derivatives of Spiro-as and their use as antagonists against gastrin-releasing peptide.

DETAILED description of the INVENTION

The present invention is to provide a connection of this type, which exhibit inhibitory activity against vanilloideae prescriptions the ora 1 (VR1) along with good DMPK-properties (drug metabolism and pharmacokinetics).

The present invention is to provide such compounds which exhibit improved efficiency in vitro, improved selectivity and improved solubility.

According to the present invention proposed the compounds of formula I

where R1and R2independently represent halogeno or C1-3halogenoalkane, X represents an ethynyl or ethinyl,

or their salts,

provided that it is not a 1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-Trion in racemic form.

One of the embodiments of the present invention relates to a compound of formula I, where R1represents halogen, and R2represents a C1-3halogenoalkane.

Another embodiment of the present invention relates to the compound of formula I, where R1represents chloro or fluorescent, and R2represents a C1-3chloroalkyl or C1-3foralkyl.

Another embodiment of the present invention relates to compounds of formula I, where R1represents chloro.

One of the embodiments of the present invention relates to compounds of formula I, where R1and R2represent chloro.

Another embodiment of the present invention relates to connection is of formula I, where X represents a

or

Another embodiment of the present invention relates to the compound of formula I, where X represents ethinyl.

One of the embodiments of the present invention relates to the compound of formula I, selected from the group consisting of

1'-[(2E)-3-(3-chloro-4-tryptophanyl)prop-2-EN-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1'H)-trione and

1'-[3-(3,4-dichlorophenyl)prop-2-in-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-trione.

Another embodiment of the present invention relates to the compound of formula I for use as a medicinal product, provided that the compound is not 1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-Trion in racemic form.

The following embodiment of the present invention relates to the compound of formula I

where R1and R2independently represent halogeno or C1-3halogenoalkane, X represents an ethynyl or ethinyl, or its pharmaceutically acceptable salts for use as pharmaceuticals for the treatment of disorders mediated by VR1.

One of the embodiments of the present invention relates to the use of compounds having the formula I

where 1and R2independently represent halogeno or C1-3halogenoalkane, X represents an ethynyl or ethinyl,

or its salts

in the manufacture of medicines,

provided that the compound is not 1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-Trion in racemic form. In one of the embodiments of this application is intended for the treatment of disorders mediated by VR1.

Another embodiment relates to the use of compounds having the formula I

where R1and R2independently represent halogeno or C1-3halogenoalkane, X represents an ethynyl or ethinyl, or its salt, in the manufacture of a medicinal product for the treatment of disorders mediated by VR1.

The present invention also provides for a pure single enantiomer having the formula II:

where R1and R2independently represent halogeno or C1-3halogenoalkane, X represents an ethynyl or ethinyl, and salt.

One of the embodiments of the present invention relates to the enantiomer of formula II, where R1represents halogen, and R2represents a C1-3halogenoalkane.

Another embodiment of the present invention relates to enantiomer is in formula II, where R1represents chloro or fluorescent, and R2represents a C1-3chloroalkyl or1-3foralkyl.

Another embodiment of the present invention relates to the enantiomer of formula II, where R1represents chloro.

One of the embodiments of the present invention relates to the enantiomer of formula II, where R1and R2represent chloro.

Another embodiment of the present invention relates to the enantiomer of formula II, where X is a

or

Another embodiment of the present invention relates to the enantiomer of formula II, where X represents ethinyl.

One of the embodiments of the present invention relates to the enantiomer of formula II selected from the group consisting of

(4R)-1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1'H)-trione,

(4R)-1'-[(2E)-3-(3-chloro-4-tryptophanyl)prop-2-EN-1-yl]-2H,5H-Spiro [imidazolidine-4,3'-indole]-2,2',5(1'H)-trione and

(4R)-1'-[3-(3,4-dichlorophenyl)prop-2-in-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-trione.

Below are definitions of various terms used in this description and in the claims to the characteristics of the present invention.

For the avoidance of doubt, it should be borne in mind that if in this description, the group determined the expression is "defined above or "defined above, the specified group covers the first and most broad definition, as well as all other definitions for this group.

Unless specifically stated otherwise, used in the description of the item corresponds to the examples and the rules established in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated in this description by reference in part on examples of names of chemical structures and rules for naming chemical structures.

For the avoidance of doubt, it should be borne in mind that in this description, "C1-3" means a carbon group having 1, 2 or 3 carbon atoms.

In this description, unless otherwise specified, the term "alkyl" includes both remotemachine and branched alkyl groups and may represent, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl or tert-hexyl.

Specified in this descriptionis a TRANS-atenolol group, andis a CIS-atenolol group.

In this description, unless otherwise specified, the term "halogen" and "halogen" may be a fluorescent, iodide, chloro or bromo.

The term "halogenated" means alkyl group, a cat heaven substituted with halogen in number from one to a complete replacement, where fully substituted halogenoalkane can be represented by the formula ChL2h+1where L represents a halogen, a "h" indicates the number of carbon atoms. If there is more than one halogen, the halogen may be the same or different and may be selected from the group consisting of F, Cl, Br and I. it is Clear that the terms "alkyl" and "halogen" here we have a definition for them above. In some embodiments halogenated represents a C1-3halogenoalkane", and this group contains 1-3 carbon atoms, in some embodiments it contain 1-2 carbon atoms, and in some embodiments it contains 1 carbon atom. If halogenoalkane completely replaced by halogen atoms, such group here called perhalogenated, an example of which is alkyl fully substituted by fluorine atoms, and it is here called "the perfluoroalkyl." In some embodiments examples of halogenoalkane include, but are not limited to, deformity, vermeil, 2,2,2-triptorelin, 2,2-dottorati, 2-foretel, 1,2,2-triptorelin, 1,2-dottorati, 1,1-dottorati, 1,1,2-triptorelin, 3,3,3-cryptochromes, 2,2-direcror, 3,3-direcror, 3-forproper, 2,3,3-cryptochromes, 2,3-direcror, 2,2,3,3,3-pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3-cryptochromes, 1,2,3,3-tetrafluoropropyl, 1,2,3-cryptochromes, 3,3-direcror, 1,2,2,3-tetrafluoropropyl, 4,deformaty, 3,3-deformaty, 4,4,4-tripcomputer, 3,3-deformaty, etc. In some embodiments examples of the perfluoroalkyl include, but are not limited to, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, 1,2,2,2-titrator-1-trifloromethyl etc. In one of the embodiments, the term "C1-3halogenoalkane" may include, but are not limited to, vermeil, deformity, trifluoromethyl, foradil, defloratin or bromopropyl.

The present invention relates to compounds of formula I and the enantiomers of formula II, as defined above, and their salts. Salts for use in pharmaceutical compositions should be pharmaceutically acceptable salts, but other salts may be useful for producing compounds of the formula I and/or enantiomers of formula II.

A suitable pharmaceutically acceptable salt of the compounds and enantiomers according to the invention is, for example, salt accession acids or bases, for example salts with inorganic(Oh) or organic(Oh) with base and acid. In addition, a suitable pharmaceutically acceptable salt of the compounds and enantiomers according to the invention is a salt of an alkaline metal salt, alkaline-earth metal or salt with an organic base.

Other pharmaceutically acceptable salts and methods of obtaining these salts can be found, for example, in Remington''s Pharmaceutical Sciences (18thEdition, Mack Publishing Co.).

This is the invention also relates to any and all tautomeric forms of the compounds of formula I and enantiomers of formula II.

Ways to get

The present invention provides methods of making compounds of formula I or enantiomers and II or their salts.

Everywhere in the description below, such methods assume that in those cases, where appropriate, suitable protective groups will be attached to various reagents and intermediate compounds and subsequently remove them by methods known to experts in the field of organic synthesis. Conventional methods for use of such protective groups, and examples of suitable protective groups are described, for example, in "Protective Groups in Organic Synthesis", T.W.Green, P.G.M.Wuts, Wiley-lnterscience, New York (1999). Descriptions of other suitable reactions and references are listed in the benefits of organic chemistry, for example in "Advanced Organic Chemistry", March, 4thed. McGraw Hill (1992) or in "Organic Synthesis", Smith, McGraw Hill (1994). Representative examples of heterocyclic chemistry see, for example, "Heterocyclic Chemistry", J.A.Joule, .Mills, G.F.Smith, 3rded. Chapman and Hall (1995), p.189-224, and "Heterocyclic Chemistry", T. L. Gilchrist, 2nded. Longman Scientific and Technical (1992), p.248-282.

The terms "room temperature" and "ambient temperature" means, unless otherwise specified, the temperature from 16 to 25°C.

The term "elevated temperature" means, unless otherwise specified, the temperature from 50 to 150°C.

SCHEMA

Scheme 1

Scheme 2

Scheme 3

One of the embodiments of the invention relates to a method for producing compounds of formula I, where R1, R2and X are as defined above, including the possible interaction of the protected compounds of formula III

1) with KCN and (NH4)2CO3at elevated temperature in a suitable solvent,

and then maybe

2) the conversion of compounds of formula I into another compound of formula I;

and/or

3) remove any protective groups;

and/or

4) formation of pharmaceutically acceptable salts.

One of the embodiments of the present invention relates to a method for obtaining enantiomers of formula II, where R1, R2and X are as defined above, including the possible interaction of the protected compounds of formula III

1) with KCN and (NH4)2CO3at elevated temperature in a suitable solvent,

and after that the selection of the specified enantiomer from the racemic mixture of supercritical fluid chromatography.

Intermediate compounds

Another embodiment of the invention relates to compounds selected from the group consisting of

1-allyl-1H-indole-2,3-dione,

1-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-1H-indole-2,3-dione,

1-{(2E)-3-[4-chloro-3-trifluoromethyl)phenyl]prop-2-EN-1-yl}-1H-indole-2,3-dione,

1-prop-2-in-1-yl-1H-indole-2,3-dione,

1-[3-(3,4-dichlorophenyl)prop-2-in-1-yl]-1H-indole-2,3-dione, which can be used as intermediates for producing compounds for the treatment of disorders mediated by VR1, in particular for use as intermediate compounds of the formula I and/or enantiomers of formula II.

One of the embodiments of the present invention relates to a process for the preparation of intermediate compounds of formula III, where R1, R2and X are such as defined above, including:

the interaction can be protected compounds of formula IV

with

,

where HAL represents a halogen atom, in the presence of a suitable palladium catalyst such as PD(P(t-Bu)3)2or Pd(OAc)2, in a suitable solvent,

and after that can:

2) the conversion of intermediate compounds of formula III in another intermediate compound of formula III;

and/or

3) remove any protective groups.

The pharmaceutical composition

According to one embodiments of the present invention proposed a pharmaceutical composition comprising a therapeutically effective amount of the compounds of formula (I) and/or enantiomers of formula (II)or its salt as an active ingredient together with the ne or more pharmaceutically acceptable diluents, the excipients and/or inert carriers.

The composition may be presented in a form suitable for oral administration, for example in the form of tablets, pills, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) in the form of a sterile solution, suspension or emulsion, for topical administration, for example in the form of ointment, patch, or cream or for rectal administration, for example in the form of a suppository.

In General, the above compositions can be prepared in conventional manner using one or more conventional excipients, pharmaceutically acceptable diluents and/or inert carriers. Suitable daily doses of the compounds of formula (I) and/or enantiomers of formula (II) for the treatment of a mammal, including humans, are from about 0.01 to 250 mg/kg body weight by oral administration and from about 0.001 to 250 mg/kg body weight at parenteral administration.

A typical daily dose of the active ingredient varies widely and depends on various factors, such as relevant indication, the severity of the disease, which is treated, the route of administration, age, weight and sex of the patient and used a particular connection, and can be determined by the treating physician.

Medical n the applicatio

Compounds of the present invention are useful in therapy. Compounds and enantiomers according to the invention or their salts, and their respective active metabolites exhibit high efficiency and selectivity in relation to individual groups vanilloideae receptor 1 (VR1). Therefore, it is expected that the compounds of the present invention will be useful in the treatment of conditions associated with excitatory activation vanilloideae receptor 1 (VR1).

Connections can be used for producing inhibitory effect of VR1 in mammals, including humans.

VR1 is actively expressed in the peripheral nervous system and in other tissues. Therefore, it is expected that the compounds according to the invention is suitable for treatment of disorders mediated by VR1.

It is expected that the compounds according to the invention suitable for the treatment of acute and chronic pain, acute and chronic neuropathic pain and acute and chronic inflammatory pain.

Examples of such disorders may be selected from the group comprising pain in the lumbar region, postoperative pain, visceral pain, such as chronic pain in the pelvis, etc.

It is also expected that the compounds according to the invention suitable for the treatment of acute and chronic nociceptive pain.

In addition, relevant disorder can be selected from the C group, including cystitis, including interstitial cystitis and related pain, ischemia, sciatica, multiple sclerosis, arthritis, osteoarthritis, rheumatoid arthritis, fibromyalgia, pain and other signs and symptoms associated with psoriasis, pain and other signs and symptoms associated with cancer, vomiting, urinary incontinence, overactive bladder and neuropathy in HIV.

Additional relevant disorder may be selected from the group including disease gastro-oesophageal reflux (GERD), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and pancreatitis.

Other relevant disorders associated with respiratory diseases and can be selected from the group comprising asthma, cough, chronic obstructive pulmonary disease, specifically chronic obstructive pulmonary disease (COPD) and emphysema, pulmonary fibrosis and interstitial lung disease.

Other relevant disorders are obesity and associated with obesity diseases or disorders, and migraine.

In one of the embodiments of obesity or associated with obesity disease or disorder is selected from the following: cardiovascular disease, hypertension, cancer and reproductive disorders.

The inhibitor(s) VR1 can be entered either by mouth or by inhalation. aspiratore disease may represent acute and chronic disease and may be associated with infection(s) and/or exposure to environmental pollution and/or irritating agents.

Compounds and enantiomers according to the invention can also be used as an antitoxin for the treatment of (over-) exposure to activators VR1, such as capsaicin, tear gas, acid or high temperature. As for high temperatures, the potential exists for application of VR1 antagonists for pain caused (sun) burn, or inflammatory pain due to burn injuries.

Connections can also be used to treat tolerance activators VR1.

One of the embodiments of the invention relates to compounds and enantiomers according to the invention, as defined here above, for use as pharmaceuticals.

Another embodiment of the invention relates to compounds and enantiomers according to the invention, as defined here above, for use as pharmaceuticals for the treatment of disorders mediated by VR1.

Another embodiment of the invention relates to compounds and enantiomers according to the invention, as defined here above, for use as pharmaceuticals for the treatment of acute and chronic pain disorders.

Another embodiment of the invention relates to compounds and enantiomers according to the invention, as defined here above, for use as pharmaceuticals for the treatment of acute and chronic n is receptive pain.

Another embodiment of the invention relates to compounds and enantiomers according to the invention, as defined here above, for use as pharmaceuticals for the treatment of acute and chronic neuropathic pain.

Another embodiment of the invention relates to compounds and enantiomers according to the invention, as defined here above, for use as pharmaceuticals for the treatment of acute and chronic inflammatory pain.

One embodiment of the invention relates to compounds and enantiomers according to the invention, as defined here above, for use as medicines for the treatment of pain in the lumbar region, postoperative pain, visceral pain, such as chronic pain in the pelvic region.

Another embodiment of the invention relates to compounds and enantiomers according to the invention, as defined here above, for use as pharmaceuticals for the treatment of cystitis, including interstitial cystitis and related pain, ischemia, sciatica, multiple sclerosis, arthritis, osteoarthritis, rheumatoid arthritis, fibromyalgia, pain and other signs and symptoms associated with psoriasis, pain and other signs and symptoms associated with cancer, vomiting, urinary incontinence, overactive bladder and neuropathy in HIV.

Another embodied the E. of the invention relates to compounds and enantiomers according to the invention, as defined here above, for use as pharmaceuticals for the treatment of gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and pancreatitis.

Another alternate embodiment of the invention relates to compounds and enantiomers according to the invention, as defined here above, for use as pharmaceuticals for the treatment of respiratory diseases selected from the group comprising asthma, cough, chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease and emphysema, pulmonary fibrosis and interstitial lung disease.

One of the embodiments of the invention relates to the use of compounds and enantiomers according to the invention, as defined here above, in the manufacture of medicines for the treatment of disorders mediated by VR1, and for the treatment of acute and chronic pain disorders, acute and chronic neuropathic pain and acute and chronic inflammatory pain, and respiratory diseases, and any other disorder mentioned above.

Another embodiment of the invention relates to a method of treatment of disorders mediated by VR1, and acute and chronic pain disorders, acute and chronic neuropathic pain and acute and chronic vospalitelnaya, and respiratory diseases, and any other disorder mentioned above, including the introduction in need of such treatment of a mammal, including human, a therapeutically effective amount of the compounds and/or enantiomer, according to the invention, as defined here above.

The following embodiment of the invention relates to pharmaceutical compositions containing the compound and/or the enantiomer according to the invention, as defined here above, for use in the treatment of disorders mediated by VR1, and for the treatment of acute and chronic pain disorders, acute and chronic neuropathic pain and acute and chronic inflammatory pain, and respiratory diseases, and any other disorder mentioned above.

In the context of the present description, the terms "therapy" and "treatment" cover the warning and prevention, if there are specific indications to the contrary. The terms "treat", "therapeutic" and "therapeutically" should be interpreted accordingly.

In this description, unless otherwise specified, the terms "inhibitor" and "antagonist" means a compound that in any way, partially or completely blocks transducible metabolic chains, leading to the response produced by the ligand.

Unless otherwise indicated, the term "disorder"refers to any condition and disease associated with what aktivnosti vanilloideae receptor.

Non-medical use

In addition to their use in therapeutic medicine, the compounds and enantiomers according to the invention or their salts are also useful as pharmacological tools for the development and standardization vitro and in vivo test systems for the evaluation of the effects of inhibitors associated with VR1 activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

Examples

The invention is illustrated by the following non-limiting examples.

General methods

The invention is illustrated in the following Examples, in which, as a rule:

(1) the operation was carried out at ambient temperature or at room temperature, i.e. in the range 17 to 25°C and in an atmosphere of inert gas, such as argon, unless otherwise noted;

(2) the evaporation was carried out on a vacuum rotary evaporator, and the procedure was carried out after removal of residual solids by filtration;

(3)1H NMR spectra were recorded on Bruker 400 MHz; mass spectra were recorded using electrospray ionization (ERIE) (LC-MS (liquid chromatography-mass spectrometry); LC: Waters 2790, MS-column XTerra C82.5 μm 2.1 x 30 mm, buffer gradient of H2O+0.1%of TFA:CH3CN+0,04%TFA, MS: Micromass ZMD/AMMONIATING buffer)./p>

(4) the outputs if they are not necessarily the maximum achievable;

(5) used the following abbreviations:

allocallyloxycarbonyl
DCEdichloroethane
DCMdichloromethane
DMAPdimethylaminopyridine
EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HATUO-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaphosphate
HPLChigh performance liquid chromatography
LCliquid chromatography
MsClmethanesulfonanilide
MSmass spectrometry
time beats.retention time
TFAtriperoxonane acid
THFtetrahydro the uranium
DMFdimethylformamide
TMEDAtetramethylethylenediamine
EtOActhe ethyl acetate
BuLiutility
TMEDAtetramethylethylenediamine

INTERMEDIATE COMPOUND 1: 1-Allyl-1H-indole-2,3-dione

Isatin (10,102 g of 68.7 mmol) was dissolved in 100 ml of dry DMF and added Cs2CO3(24,609 g, and 75.5 mmol). To the resulting purple-brown suspension was added allylbromide (7.2 ml, 83 mmol)and this reaction mixture was stirred at room temperature for 16 hours Received a murky orange-brown mixture was concentrated in vacuo, and the residue was distributed between EtOAc (160 ml) and water (80 ml). The layers were separated, and the aqueous layer was extracted with additional EtOAc (2×80 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuum. To the residue was added 300 ml of hexanol. The mixture was heated on a water bath to 70°C. and was added EtOAc until then, until the connection is passed into the solution (approximately 80 ml EtOAc). A small amount of insoluble red substance was removed, and the solution was then left to cool. the received red crystals were filtered off, washed with hexane, 3×30 ml) and then dried under vacuum to obtain specified in the connection header (11,740 g, 91%).1H NMR (600 MHz, CHLOROFORM-D) δ million-14.36 (d, J=5.6 Hz, 2H), 5.26-5.34 (m, 2H), 5.78-5.88 (m, 1H), 6.88 (d, J=7.9 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.56 (td, J=7.8, 1.3 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H). MS (ERIE) (M+N)+=188.

INTERMEDIATE COMPOUND 2: 1-[(2E)-3-(3,4-dichlorophenyl)-prop-2-EN-1-yl]-1H-indole-2,3-dione

A mixture of 1-allyl-1H-indole-2,3-dione (1,00 g of 5.34 mmol), Pd(P(t-Bu)3)2(0,0819 g, 0.16 mmol), 1,2-dichloro-4-yogashala (1,458 g of 5.34 mmol), dry toluene (10 ml) and N-cyclohexyl-N-methylcyclohexylamine (1.23 ml, 5,86 mmol) in dried thermostat sealed tube was heated in an atmosphere of N2for 16 h at 80°C. the Reaction mixture was cooled, diluted with CH2Cl2and put on silicagel column, pre-packaged CH2CL2. The column was suirable with a gradient from 100% CH2Cl2to 95:5 CH2CL2:EtOAc. The appropriate fractions were combined to obtain specified in the title compound as an orange solid (1,489 g, 84%).1H NMR (600 MHz, CHLOROFORM-D) δ million-14.52 (d, J=5.9 Hz, 2H), 6.19 (dt, J=15.9, 5.9 Hz, 1H), 6.56 (d, J=15.6 Hz, 1H), 6.91 (d, J=7.9 Hz, 1H), 7.09-7.20 (m, 2H), 7.37 (d, J=8.2 Hz, 1H), 7.42 (s, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.64 (d, J=7.4 Hz, 1H).

INTERMEDIATE COMPOUND 3: 1-{(2E)-3-[4-chloro-3-(trifluoromethyl)phenyl]prop-2-EN-1-yl}-1H-indole-2,3-dione

Six CTD is selected dried in a thermostat sealed tubes in the atmosphere N 2download 1-allyl-1H-indole-2,3-dione (0,100 g, 0,534 mmol), Pd(P(t-Bu)3)2(0,0082 g to 0.016 mmol), 4-bromo-1-chloro-2-(trifluoromethyl)benzene (0,139 g, 0,536 mmol), dry toluene (1 ml) and N-cyclohexyl-N-methylcyclohexylamine (0,12 ml, or 0.57 mmol). The tubes were heated for 16 h at 80°C in an oil bath and then the reaction mixture was cooled and concentrated in vacuum. This crude substance was used in the next stage.

INTERMEDIATE COMPOUND 4:1-prop-2-in-1-yl-1H-indole-2,3-dione

To a solution of isatin (200 mg, of 1.36 mmol) in DMF (5 ml) was added cesium carbonate (487 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 90 minutes. Then add propylbromide (243 μl, and 1.63 mmol). The reaction mixture was stirred over night at room temperature, concentrated in vacuo, dissolved in EtOAc and washed with saturated aqueous Panso3(1x). The layers were separated, and the aqueous layer was extracted with additional EtOAc (2x). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. Additional purification of the residue was not necessary. The connection specified in the header received in the form of an orange solid (255 mg, quantitative yield).1H NMR (400 MHz, CDCl3) δ 2.31 (t, J=2.54 Hz, 1H), 4.55 (d, J=2.54 Hz, 2H), 7.12-7.15 (m, 1H), 7.19 (dt, J=7.52, 0.78 Hz, 1H), 7.63-7.68 (m, 2H).

TEMPORARILY THE SECOND COMPOUND 5: 1-[3-(3,4-dichlorophenyl)prop-2-in-1-yl]-1H-indole-2,3-dione

To a mixture of 1-prop-2-in-1-yl-1H-indole-2,3-dione (190 mg, of 1.03 mmol), 1,2-dichloro-4-yogashala (420 mg, 1.54 mmol), copper iodide(I) (11.0 mg, 0.06 mmol) and triphenylphosphine (40,0 mg, 0.15 mmol) in degassed DMF (24 ml) was added triethylamine (307 μl, of 2.15 mmol). The reaction mixture was stirred for 5 minutes and then was added Pd(OAc)2(13,0 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 2 days, concentrated in vacuo, dissolved in EtOAc and washed with saturated aqueous NaHCO3(1x). The layers were separated, and the aqueous solution was extracted with additional EtOAc (2x). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified column chromatography on silica gel, elwira with a gradient of solvents from 35% EtOAc/hexane up to 75% EtOAc/hexane, obtaining specified in the title compound as an orange solid having a purity of 90% (375 mg, quantitative yield).1H NMR (400 MHz, DMSO-D6) δ 4.82 (s, 2H), 7.18 (dt, J=7.52, 0.78 Hz, 1H), 7.32 (d, J=8.01 Hz, 1H), 7.41 (dd, J=8.40, 1.95 Hz, 1H), 7.60 (dd, J=7.42, 0.78 Hz, 1H), 7.63 (d, J=8.40 Hz, 1H), 7.70-7.75 (m, 2H).

CONNECTION 1: 1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-Trion

Spent four identical reactions. For each reaction in a sealed tube, 1-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-1H-indol-,3-dione (200 mg, 0,602 mmol) was dissolved in 5 ml of N,N-dimethylacetamide (5 ml). Was added ammonium carbonate (0,555 g, 5,78 mmol), then a solution of KCN (0,0470 g, 0,722 mmol) in water (5 ml). The tube was tightly closed and then heated to 100°C in oil bath for 2 hours the Color of the reaction mixtures was changed from red to dark purple to yellow. The reaction mixture was cooled and then concentrated in vacuum. Each reaction mixture was transferred into EtOAc (5 ml) and water (5 ml). All 4 of the reaction mixture was passed through a column Varian ChemElut CE1020, and the column was washed with additional EtOAc (2×20 ml). The organic extracts were concentrated in vacuo, and the residue was purified column chromatography on silica gel (1:2 hexane:EtOAc) to obtain specified in the connection header (0,7075 g, 73%) as a white solid.1H NMR (400 MHz, METHANOL-D4) δ million-14.45-4.53 (m, 1H), 4.57-4.66 (m, 1H), 6.35 (dt, J=16.1, 5.1 Hz, 1H), 6.59 (dt, J=16.2, 1.5 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 7.17 (td, J=7.6, 0.9 Hz, 1H), 7.30 (dd, J=8.4, 2.0 Hz, 1H), 7.37 (dd, J=7.4, 1.0 Hz, 1H), 7.39-7.45 (m, 2H), 7.53 (d, J=2.1 Hz, 1H). MS (FIAD (photoionization at atmospheric pressure)) (M+H)+=402. Analysis: calculated for C19H13CL2N3About3: C, 56,74; N, 3,26; N, 10,45; found: C, 56,64; N, 3,26; N, 10,27.

Individual enantiomers of 1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1'H)-trione was obtained by separation of the racemic mixture (214 mg) is supercritical fluid chromatography (SFH) on chiral solid media using Berger SFC Multigram II system (Mettler Toledo) (conditions SFH: eluent 50% ethanol/CO 2column CHIRALCEL® OD SFC (Chiral Technologies), 21 x 250 mm, 10 micron, flow rate 50 ml/min, UV detector with variable wavelength 254 nm or 280 nm, run 6 minutes). Enantiomeric purity was determined SFH on chiral solid media using Berger SFC Analytix/MS (Mettler Toledo) (conditions SFH: eluent 50% ethanol/CO2column CHIRALCEL® OD SFC (Chiral Technologies), a 4.6×250 mm, 5 micron, flow rate of 2.2 ml/min, UV detector diode matrix, MS detector, run 6 minutes). Output: 80,7 mg (38%) of the first eluruumideta enantiomer, 80.0 mg (37%) of the second eluruumideta enantiomer. The names of the enantiomers in the IUPAC nomenclature assigned using the software ACD/Name (ACD/Labs Release 7.00 Product version: 7.07, dated July 16, 2003).

ENANTIOMER 1A: (4S)-1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1'H)-Trion

First eluruumist enantiomer: retention time=2,46 min, E.E. (enantiomeric excess)>99%, [α]D22=+16,8 (0.959 g/100 ml, CD3OD),1H NMR (400 MHz, METHANOL-D4) δ million-14.44-4.53 (m, 1H), 4.57-4.65 (m, 1H), 6. 35 (dt, J=16.1, 4.9 Hz, 1H), 6.58 (dt, J=16.0, 1.6 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 7.17 (td, J=7.6, 0.9 Hz, 1H), 7.30 (dd, J=8.4, 2.0 Hz, 1H), 7.35-7.39 (m, 1H), 7.38-7.45 (m, 2H), 7.52 (d, J=2.0 Hz, 1H). MS (FIAD) (M+H)+=402.

The absolute configuration of the enantiomers was determined by x-ray crystallographic method.

ENANTIOMER 1B: (4R)-1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-2H,5H-is pyro[imidazolidine-4,3'-indole]-2,2',5(1'H)-Trion

Second eluruumist enantiomer: retention time=4,21 min, E.E.>99%, [α]D22=-15,0 (0,908 g/100 ml, CD3OD),1H NMR (400 MHz, METHANOL-D4) δ million-14.44-4.53 (m, 1H), 4.56-4.65 (m, 1H), 6.35 (dt, J=16.0, 5.1 Hz, 1H), 6.58 (dt, J=16.1, 1.5 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 7.17 (td, J=7.6, 0.9 Hz, 1H), 7.30 (dd, J=8.5, 2.1 Hz, 1H), 7.35-7.39 (m, 1H), 7.39-7.45 (m, 2H), 7.52 (d, J=2.0 Hz, 1H). MS (FIAD) (M+H)+=402.

The absolute configuration of this enantiomer was determined by x-ray crystallographic method.

COMPOUND 2: 1'-{(2E)-3-[4-chloro-3-(trifluoromethyl)phenyl]prop-2-EN-1-yl}-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1'H)-Trion

Six test tubes with crude 1-{(2E)-3-[4-chloro-3-(trifluoromethyl)phenyl]prop-2-EN-1-yl}-1H-indole-2,3-dione was treated identically. The substance in each test tube was dissolved in N,N-dimethylacetamide (4,4 ml). To each tube was added ammonium carbonate (0,493 g, 5,13 mmol), then a solution of KCN (0,0417 g, 0,640 mmol) in water (4.4 ml). The tube was tightly closed and then heated to 100°C in oil bath for 3 hours the Reaction mixture was cooled and then concentrated in vacuum. Each reaction mixture was transferred into EtOAc (8 ml) and water (5 ml) and passed through a column Varian ChemElut CE1020. The column was washed with additional EtOAc (2×8 ml)and the organic extracts were concentrated in vacuum. The residue was purified preparative LC/MS with reversed phases with obtaining specified in the connection header 0,2834 g, 20% over two stages) as a pale orange solid, which was then subjected to lyophilization.1H NMR (400 MHz, DMSO-D6) δ million-14.48-4.59 (m, 2H), 6.52 (dt, J=16.2, 4.8 Hz, 1H), 6.58-6.65 (m, 1H), 7.10-7.18 (m, 2H), 7.38-7.45 (m, 2H), 7.64-7.68 (m, 1H), 7.71-7.81 (m, 2H), 8.68 (d, J=1.0 Hz, 1H), 11.43 (s, 1H). MS (FIAD) (M+H)+=436.

Individual enantiomers of 1'-{(2E)-3-[4-chloro-3-(trifluoromethyl)-FINEP]prop-2-EN-1-yl}-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-trione was obtained by separation of the racemic mixture (19,96 d) supercritical fluid chromatography (SFH) on chiral solid media using the system Novasep SFC SuperSep 50 (Novasep, Inc.) (conditions SFH: eluent 30% methanol/CO2column CHIRALCEL®OD-H SFC (Chiral Technologies, Inc.), 3×25 cm, 5 micron, flow rate 150 ml/min, UV detector with variable wavelength 230 nm, run 5 minutes). Enantiomeric purity was determined SFH on chiral solid media using Berger SFC (Mettler Toledo) (conditions SFH: eluent 30% methanol/CO2column CHIRALCEL®OD-H SFC (Chiral Technologies, Inc), a 4.6×250 mm, 5 micron, flow rate 2 ml/min, UV detector with variable wavelength 220 nm run 9 minutes). Output: 80,7 mg (38%) of the first eluruumideta enantiomer, 80.0 mg (37%) of the second eluruumideta enantiomer. The names of the enantiomers in the IUPAC nomenclature assigned using the software ACD/Name (ACD/Labs Release 7.00 Product version: 7.07, dated July 16, 2003).

ENANTIOMER 2A: (4S)-1'-{(2E)-3-[4-chloro-3-(trifluoromethyl)phenyl]-prop-2-EN-1-yl}-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-Trion

First eluruumist enantiomer: retention time=4,29 min, E.E.>99%, [α]D22=+16,8 (1.03 g/100 ml, CD3OD),1H NMR (400 MHz, DMSO-D6) δ million-14.53 (d, J=4.5 Hz, 2H), 6.52 (dt, J=16.2, 4.8 Hz, 1H), 6.58-6.67 (m, 1H), 7.09-7.19 (m, 2H), 7.37-7.46 (m, 2H), 7.63-7.69 (m, 1H), 7.71-7.76 (m, 1H), 7.79 (d, J=2.0 Hz, 1H), 8.68 (d, J=1.4 Hz, 1H), 11.43 (s, 1H). MS (FIAD) (M+H)+=436.

The absolute configuration of this enantiomer was determined by x-ray crystallographic method.

ENANTIOMER 2B: (4R)-1'-{(2E)-3-[4-chloro-3-(trifluoromethyl)phenyl]-prop-2-EN-1-yl}-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-Trion

Second eluruumist enantiomer: retention time=of 5.92 min, E.E.>98%, [α]D22=-15,6 (1.33 g/100 ml, CD3OD),1H NMR (400 MHz, DMSO-D6) δ million-14.53 (d, J=4.5 Hz, 2H), 6.52 (dt, J=16.2, 4.8 Hz, 1H), 6.58-6.66 (m, 1H), 7.09-7.19 (m, 2H), 7.37-7.46 (m, 2H), 7.63-7.68 (m, 1H), 7.70-7.76 (m, 1H), 7.79 (d, J=2.0 Hz, 1H), 8.68 (d, J=1.4 Hz, 1H), 11.43 (s, 1H). MS (FIAD) (M+H)+=436.

The absolute configuration of this enantiomer was determined by x-ray crystallographic method.

COMPOUND 3: 1'-[3-(3,4-dichlorophenyl)prop-2-in-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1'H)-Trion

A mixture of Intermediate compound 5 (50 mg, 0.15 mmol), potassium cyanide (12 mg, 0.18 mmol) and ammonium carbonate (140 mg, 1,45 mmol) in a mixture 1:1 Meon:N2O (2.5 ml) was heated at 100°C for 6 hours. The reaction mixture was then cooled, concentrated in vacuo to remove the Meon, diluted the EtOAc and washed with H 2O (1x). The layers were separated, and the aqueous layer was extracted with additional EtOAc (3x). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified HPLC with reversed phase gradient of 50-80% CH3SP in N2Oh, containing 0.1% triperoxonane acid) to produce specified in the connection header (output 2 mg, 3%) as its TFA-salt. This substance was subjected to lyophilization of CH3SP/H2About obtaining a pale yellow solid. Purity (HPLC): 95% (215 nm), 94% (254 nm);1H NMR (400 MHz, DMSO (dimethyl sulfoxide)-D6) δ million-14.82-4.93 (m, 2H), 7.17 (dt, J=7.57, 0.88 Hz, 1H), 7.32 (d, J=7.81 Hz, 1H), 7.40 (dd, J=8.30, 2.05 Hz, 1H), 7.44 (dd, J=7.42, 0.78 Hz, 1H), 7.49 (dt, J=7.76, 1.27 Hz, 1H), 7.64 (d, J=8.20 Hz, 1H), 7.70 (d, J=1.95 Hz, 1H), 8.69 (d, J=1.56 Hz, 1H), 11.42 (s, 1H). Found: C, 57,05; N, Of 2.75; N, 10,55. With19H11N3About3CL2has: C, 57,02; N, 2,77; N, 10,50%.

Individual enantiomers of 1'-[3-(3,4-dichlorophenyl)prop-2-in-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1'H)-trione was obtained by separation of the racemic mixture (200 mg) supercritical fluid chromatography (SFH) on chiral solid media using Berger SFC Multigram II system (Mettler Toledo) (conditions SFH: eluent 50% ethanol/CO2column CHIRALCEL®OD SFC (Chiral Technologies), 21×250 mm, 10 micron, flow rate 50 ml/min UV detector with variable wavelength 254 is m or 280 nm, run 6 minutes). Enantiomeric purity was determined SFH on chiral solid media using Berger SFC Analytix/MS (Mettler Toledo) (conditions SFH: eluent 50% ethanol/CO2column ChiralCel OD SFC (Chiral Technologies), a 4.6×250 mm, 5 micron, flow rate of 2.2 ml/min, UV detector diode matrix, MS detector, run 6 minutes). Yield: 83 mg (42%) of the first eluruumideta enantiomer, 82 mg (41%) of the second eluruumideta enantiomer. The names of the enantiomers in the IUPAC nomenclature assigned using the software ACD/Name (ACD/Labs Release 7.00 Product version: 7.07, dated July 16, 2003).

ENANTIOMER 3A: (4S)-1'-[3-(3,4-dichlorophenyl)prop-2-in-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-Trion

First eluruumist enantiomer: retention time=3,19 min, E.E.>99%, [α]D22=+72,8 (from 1.00 g/100 ml, CD3OD),1H NMR (400 MHz, CD3OD) δ million-14.74-4.88 (m, 2H), 7.20 (dt, J=7.57, 0.88 Hz, 1H), 7.26-7.31 (m, 2H), 7.36 (dd, J=7.52, 0.68 Hz, 1H), 7.45-7.51 (m, 2H), 7.55 (d, J=1.76 Hz, 1H). MC (FIAD) (M+N)+=400.

The absolute configuration of this enantiomer was determined by x-ray crystallographic method.

ENANTIOMER 3B: (4R)-1'-[3-(3,4-dichlorophenyl)prop-2-in-1-yl]-2H,5H-Spiro [imidazolidine-4,3'-indole]-2,2',5(1 N)-Trion

Second eluruumist enantiomer: retention time=4,47 min, E.E.>99%, [α]D22=-75,1 (1,03 g/100 ml, CD3OD),1H NMR (400 MHz, CD3OD) δ million-14.74-4.87 (m, 2H), 7.17-7.22 (m, 1H), 7.26-.31 (m, 2H), 7.35-7.38 (m, 1H), 7.44-7.51 (m, 2H), 7.54 (d, J=1.76 Hz, 1H). MC (FIAD) (M+H)+=400.

The absolute configuration of this enantiomer was determined by x-ray crystallographic method.

Pharmacology

A screening study hVR1 using FLIPR (tablet reader with fluorometrically visualization)

Before the experiment transfetsirovannyh cells Cho (cells Chinese hamster ovary), stably expressing the hVR1 (human vanilloid receptor 1), sow (15,000 cells per well) in 50 μl of medium in black 384-well plate with clear bottom (Greiner) and cultured in a humidified incubator (37°C, 2% CO2within 24-30 hours.

Then the medium is removed from the hole by turning the tablet, and using multi-channel pipettor (Labsystems) add 2 μl of Fluo-4. After incubation with the dye for 40 min in the dark at 37°C and 2% CO2present extracellular dye washed using EMBLA (Scatron), leaving the cells in 40 ál analytical buffer (1×HBSS (saline Hanks), 10 mm D-glucose, 1 mm l2, 10 mm HEPES, 10×7,5% NaHCO3and 2.5 mm probenecid).

FLIPR analysis Protocol definitions IC50

To determine the IC50the fluorescence is read using the filter 1 FLIPR (em (emission) 520-545 nm). The cellular source of the reading performed for 30 seconds, followed by adding 20 μl of 10 t is skilled semi-log concentration of test compounds to obtain cell concentrations in the range from 3 μm to 0.1 nm. Data are collected every 2 seconds for another 5 minutes, then using a FLIPR-pipettor add a solution of VR1 agonist: either 50 nm solution of capsaicin or MES buffer (2-[N-morpholino]econsultancy acid) (pH 5,2). FLIPR continues to collect data for another 4 minutes of Compounds with antagonistic properties against hVR1, inhibit the increase in intracellular calcium in response to the addition of capsaicin. This in turn leads to a weakening of the fluorescence signal and gives reduced reading fluorescence compared to controls without connection with the buffer. FLIPR-program exports the data as the sum of fluorescence, calculated under the curve, after the addition of capsaicin. For each connection determines the maximum inhibition, corner hill coefficient and the values of the IC50.

Comparative determination of the activity of aldozoreduktaza was conducted by MDS Pharma Services - Taiwan Ltd. The results of this study are presented below in table 1.

List of abbreviations

GERD
VR1vanilloid receptor 1
IBSirritable bowel syndrome
IBDinflammatory zabolevania bowel
disease gastroesophageal reflux
HEPES4-(2-hydroxyethyl)piperazine-1-econsultancy acid

Results

Typical values IC50measured in the above analyses is 10 μm or less. In one aspect of the present invention is IC50is less than 3000 nm. In another aspect of the present invention is IC50is less than 1000 nm.

Table 1
The results FLIPR analysis of hVR1 and comparative determination of the activity of aldozoreduktaza

Example No.IC50(human VR1, capsaicin) nmIC50(allocatedata) nm
Enantiomer 1A10000 nm25 nm
Enantiomer 1B43 nm758 nm
Enantiomer 2A3850 nm33 nm
enantiomer 2B 241 nm3300 nm
Enantiomer 3A15454 nm72,3 nm
Enantiomer 3B881 nm983 nm

Biological tests

Pharmacological properties in vivo of the compounds of the present invention was determined using two classic sensitive to NSAID (non-steroidal anti-inflammatory drug) models of inflammation, carraginanous model and the model with complete adjuvant's adjuvant (FCA).

In the first model carrageenan lambda (derived from seaweed polysaccharide, type IV, 100 μl, Sigma-Aldrich), dissolved in sterile saline 0,9%solution of a concentration of 1% and in the second model, FCA (25 μl, from Sigma-Aldrich (1 ml FCA contains 1 mg of tubercle bacilli killed by heating and dried to 0.85 ml of mineral oil and 0.15 ml of mannimekalai, see Nagakura et al., Journal of Pharmacology and Experimental Therapeutics, 2003; 306(2):490-497)) is injected into the subcutaneous space under the foot (plantar) surface (intraplantar, IPL) in the left hind paw of the rat. This causes an inflammatory response, accompanied by itching, redness and hyperalgesia. In the case of carrageenan thermal (mechanical) hyperalgesia fully developed which is 3 hours and remains stable for 6 hours, and in the case of FCA she develops completely for 24 h and remains stable for weeks. To assess the degree of hyperalgesia was selected thermal plantar test (based on the method of assessment of nociception Hargreaves, see Pain 1988; 32(1):77-88), as it provides a reliable, wealthy and reproducible results. Rats are placed in individual boxes made of organic glass on the glass surface, the temperature of which is maintained at 30°C, and the heat source (the rate of temperature increase: ~1.1°C/s) that focus on the plantar surface of the affected paw. Record the time from the beginning of thermal treatment until the animal draws back paw. Reducing the time delay between stimulus and response otdergivanija feet (PWL) is relatively exposed to animals is an indicator hyperalgesic state.

The degree of elimination of hyperalgesia measured by the ability of the compound to return PWL to normal levels. (4R)-1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-Trion (i.e., the enantiomer 1B) administered orally during the established phase of inflammation and testing when it is Tmax. PWL of each animal was measured twice and the mean of two measurements taken for the response. Then the response of all animals in this group average, is for each group calculate the standard deviation and standard error (SEM). Data expressed as mean ±SEM. Statistical significance is assessed using criteria Student for comparison have not been exposed to and subjected to treatment groups, and single-factor dispersion analysis One Way ANOVA followed by verification of multiple comparisons with a control (media) group by Holm-Sidak (Holm-Sidak) regarding the effectiveness of medicines. Set the level of statistical significance p<0,05. To calculate the effective dose ED50, effective concentration EC, effective concentration EC and the maximum effect Emax, for nonlinear regression analysis (model sigmoid equation with variable slope) using GraphPad Prism®version 4.

Before any manipulation rats (150-175 g, Charles River, St. Constant, Canada) were groups of 7-9 in a room with controlled temperature (22±1.5°C, humidity 30-80%, the cycle of light/dark 12 h) and adapted in the area for animals during at least one day. All protocols experiments were approved AstraZeneca Animal Care Committee (Committee on bioethics of AstraZeneca). The experiments were conducted during the light phase of the cycle, the room was illuminated with an intensity of 300 Lux. Animals received food and water without restrictions.

The efficiency and effectiveness of test compounds in vivo for nociceptive pain, summi ofany below in table 2. The test compound is a potent and effective in eliminating thermal hyperalgesia caused by carrageenan and FCA.

Table 2
Efficiency and effectiveness in carraginanous and FCA models in vivo
Test the connection: (4R)-1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-2H,5H-Spiro [imidazolidine-4,3'-indole]-2,2',5(1'H)-Trion
Karragenana modelFCA-model
ED50 (µmol/kg)10,652,8
AS (µm)4,824
The observed Emax (%)76100
Extrapolated Emax (%)88>100
AS (µm)10,7100

1. The compound (4R)-1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-Trion or its pharmaceutically acceptable salt.

<> 2. The compound according to claim 1 for use in therapy of conditions associated with vanilloid receptor 1 (VR1).

3. The use of compound (4R)-1'-[(2E)-3-(3,4-dichlorophenyl)prop-2-EN-1-yl]-2H,5H-Spiro[imidazolidine-4,3'-indole]-2,2',5(1 N)-Trion or its pharmaceutically acceptable salts in the manufacture of a medicine for the treatment of acute and/or chronic pain disorders.

4. The use according to claim 3, where the pain disorder is an acute pain disorder.

5. The use according to claim 3, where chronic pain disorder is a chronic neuropathic pain.

6. The use according to any one of claim 2 to 5, where pain disorder is any one of the following: acute and chronic inflammatory pain, acute and chronic nociceptive pain, pain in the lumbar region, postoperative pain, visceral pain, such as chronic pain in the pelvic region, cystitis, including interstitial cystitis and related pain, ischemia, sciatica, multiple sclerosis, arthritis, fibromyalgia, pain caused by burns and/or inflammatory pain due to burn injuries, pain and other signs and symptoms associated with psoriasis, pain and other signs and symptoms associated with cancer, vomiting, urinary incontinence, overactive bladder, neuropathy in HIV disease gastroesophageal reflux (GERD), Shin is rum irritable bowel (IBS), inflammatory bowel disease (IBD) and/or pancreatitis, including signs and/or symptoms associated with these diseases.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to a method of treating one or more drug dependences, nicotine addiction and/or obesity, involving administration of an effective amount of the compound, sufficient for lowering production and/or secretion of dopamine, where the said compound has general formula: and its pharmaceutically acceptable salts, where R1 is hydrogen or methyl when R2 is Cy; R2 is hydrogen or methyl when R1 is Cy; and where Cy is a group which is optionally substituted with -R, -OR, -NR2 or a halogen, where each R is independently optionally substituted with a lower alkyl, aryl or heteroaryl. The invention also relates to methods of treating one or more drug dependences, nicotine addiction or obesity.

EFFECT: novel methods of treating addictions.

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1 tbl, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention describes 6,6-dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-α]isoquinoline-9-spiro-2-(3-aroyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-7H-pyrroles) and 6,6-dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-α]isoquinoline-9-spiro-2-(3-benzoyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrrole) of the formula (I) (a, b, c) wherein Ar means C6H5 (a); p-C6H4OMe (b); p-C6H4Br (c) eliciting analgesic activity and related to substituted 13-aza-analogs of steroids, and to a method for their synthesis. Invention provides the development of a simple method of synthesis of 6,6-dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-α]isoquinoline-9-spiro-2-(3-aroyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrroles) related to 13-azagonanes - heterocyclic analogs of steroid comprising a spiro-heterocyclic substitute at position 16 of tetracyclic system among them compound 6,6-dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-α]isoquinoline-9-spiro-2-(3-benzoyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrrole) elicits analgesic activity and these compounds have not been described. The proposed reaction represents a novel approach to synthesis of heterocyclic analogs of steroids.

EFFECT: improved method of synthesis, valuable medicinal property of compound.

2 tbl, 3 ex

FIELD: organic chemistry, microbiology.

SUBSTANCE: invention relates to novel 5-methyl-2-oxo-1-phenyl-4-ethoxycarbonyl-2,3-dihydro-1H-pyrrole-3-spiro-2-(3-benzoyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydropyrroles) of the formula (IIIa,b): wherein X means -OCH3; Y means -CH3 (IIIa); X means bromine atom (Br); Y means chlorine atom (Cl) (IIIb). Proposed compounds elicit an antimicrobial activity with respect to gram-positive microflora. Also, invention describes a method for their synthesis.

EFFECT: valuable biological property of compounds.

3 cl, 1 sch, 1 tbl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel 11,11-dimethyl-1-oxo-1,2,10,11-tetrahydrobenzo[h]pyrrolo[2,1-a]-isoquinoline-2-spiro-2-(1-aryl-3-aroyl-4-hydroxy-5-oxo-2,5-dihydropyrroles) of the formulae (Ia-d): wherein Ar means Ph (Ia, b), C6H4OEt-4 (Ic), C6H4Cl-4 (Id); Ar' means C6H4Me-4 (Ia, c, d), C6H4Cl-4 (Ib) that elicit antibacterial activity against gram-positive microflora. Compounds of the formula (I) are prepared by interaction of 1-aryl-4-aroyl-5-methoxycarbonyl-2,3-dihydro-2,3-pyrrolidones with 1,3,3-trimethyl-3,4-dihydrobenzo[f]isoquinoline in absolute benzene medium at boiling for 2 min followed by isolation of end products by the known procedures. Synthesized compounds are not toxic practically.

EFFECT: improved preparing method, valuable biological properties of compounds.

1 tbl, 1 sch, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to chemical-pharmaceutical industry and deals with composition of alpha-lipoic (thioctic) acid in form of solution for infusions and to method of treating diseases selected from group, which includes alcoholic and/or diabetic polyneuropathy, coronary atherosclerosis, Botkin's disease (mild and moderate severity), liver cirrhosis, poisoning with heavy metal salts and intoxications of various etiology.

EFFECT: pharmaceutic composition possesses improved technologic properties and bioavailability, it also preserves stability in long storage.

3 cl, 1 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to addictology and deals with correction of pain syndrome in condition of opioid withdrawal. For this purpose in addition to standard therapy on the 1-st, 3-rd and 5-th day of treatment performed are injections of complex medication mixture with composition: lidocaine 80 mg, lidase 32 CU, ketorol 120 mg, dalargin 2 mg, 0.9% sodium chloride solution 2 ml subcutaneously to the depth from 1 to 2 cm into two points in backbone projection at level Th11-Th12 and L4-L5 on the middle of distance between spinous processes of adjacent vertebra in dose 5 ml with 48 hour interval.

EFFECT: method makes it possible to inhibit pain syndrome efficiently and quickly due to multi-level impact on general links of pathological algic system, as well as to reduce medication loading on organism.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: rats' spinal cord is cut completely at the inferior thoracic level Th7. IT is followed with electrical stimulation with electrodes placed on a dorsal surface of the spinal cord on segments L2 and S1, as well as with introduction of quipazine and 8-OHDRAT. Hind limbs of an animal rest against a treadmill. Quipazine is administered intraperitoneally 0.3 mg/kg, 8-OHDRAT is introduced 5 min later subcutaneously 0.1-0.3 mg/kg, and electrical stimulation is started 10 min later. Spinal cord segments L2 and S1 are stimulated simultaneously by rectangular pulses of duration 0.2 ms, frequency 40-50 Hz, intensity 1-4 V. An integrated effect is started from the 7th day following a cutting procedure and carried on daily within a therapeutic course of 7 days.

EFFECT: method allows to induce interrelated step motions.

2 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: method involves the intravenous and/or intramuscular introduction of the drugs used in myelopathy, balneotherapy in the form of baths. Acupressure and manual therapy are applied in addition. The manual therapy requires such techniques, as ischemic compression, release phenomenon, fascial broach, postisometric relaxation of the muscles involved in a pathological process. Discontinuous therapeutic plasmapheresis is applied with using either Baxter, or Bekman, or Haemophoenix apparatuses, and/or extracorporal ultraviolet blood irradiations is ensured by the apparatus Isolda MD 73 M. The apparatus Cryo-Jet is used for cryotherapy with cooled dry air at the level of degenerative dystrophic changed vertebral motor cervical segments and muscle attachment points.

EFFECT: method improves clinical effectiveness due to fast pain management, enlarged range of active and passive motions, normalised muscular tonus, increased muscular strength and corrected vegetovascular disorders.

6 cl, 3 ex

FIELD: medicine.

SUBSTANCE: synthesis of perineural layer continuity is followed by the injective introduction of a suspension of silicon nanocrystals in the nerve injury area. The injection point is exposed to the thermal and/or electric fields then. The thermal exposure is enabled by a frosted lamp through a red filter. The electric field is generated by alternating voltage electric stimulation -100 mV to +100 mV of frequency 1 to 40 Hz. The thermal and/or electric length exposure is 5 minutes 3 times a day for 7 days.

EFFECT: invention allows reducing time of recovery of nerve fibre conductivity and ensuring faster injured nerve repair.

4 cl, 3 ex

FIELD: medicine.

SUBSTANCE: there is claimed application of dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor), vildagliptin or its salt for production of medication for prevention, retardation of progress or treatment of peripheral diseases such as peripheral neuropatia, neurodegenerative disorders, cognitive disorders, as well as for improvement of memory and ability to learn, and pharmaceutical composition for the same purpose. It is demonstrated: vildagliptin increases stage of wakefulness and response to external stimuli, increases REM sleep phase.

EFFECT: combination of vildagliptin with donepezil considerably improves disturbed ability to learn.

23 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to neurology and reflexotherapy and can be used for treating neurological manifestations of vertebral osteochondrosis. The method involves introduction of the medicine mixture in acupuncture points. The mixture contains 0.05% cyanocobalamin, 1% Lidocaine and Diprospan suspension. The relation of the medicines in the mixture is 1:1:1. And the mixture is introduced into the acupuncture points VB 25 (2), V 24 (2), V 52(2), T4 at a depth of 0.4 - 2.0 cm.

EFFECT: method provides prolonged remission.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to experimental medicine and concerns development of the methods for prevention of cicatricial nerve compression, traumatic peripheral paralyses and pareses. It is ensured by introduction of 2 ml of polymer hydrogel of carboxymethyl cellulose sodium salt to an experimental animal into within an operational nerve trauma.

EFFECT: invention allows providing effective prevention, because gel forms a barrier between nerve surfaces and surrounding tissues, that prevents growth of connective tissue and cicatricial compression of nervous fibre that in turn improves regeneration of nervous tissue and restores nerve conductivity.

1 tbl, 1 ex, 9 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, to neurology. Method includes carrying out following procedures during one session: darsonval, laser therapy, vacuum therapy, acupuncture. Starting with the second day, additionally acupressure of compression zone with spasmolytics and chondroprotectors is performed. Staring with the third day, additionally therapeutic exercises are made. Treatment course includes from 8 to 15 procedures.

EFFECT: method reduces treatment terms and increases remission duration.

2 cl, 3 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to neurology, and can be used in treatment of the patients with diskogenic radiculopathy of lumbosacral spine. That is ensured by intravenous drop infusion of the mixed medicinal preparations containing 2.4% aminophylline 5-10 ml, dexamethasone 8-16 mg per 100 ml of 0.9% sodium chloride brine at rate 30-35 drops per minute during 4-5 days. Upon termination of the infusion, lasix 20-40 mg is added to the mixture. Then 30 minutes after introduction of the mixture, manual therapy follows as postisometric relaxation of posterior muscles of thigh. Starting from the 2-3 day of introduction of the mixture, postisometric relaxation is combined with mobilisation and manipulations within lumbosacral spine.

EFFECT: method allows improving clinical effectiveness in such patients owing to integrated effect on various links of pathogenesis.

2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the following compounds: N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trofluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-methyl-1-hydroxy-ethyl)-1-ethyl-1H-imidazole-4-yl}-benzyl}-3-hydroxy-propyl)-3-chloro-4-(,2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidazole-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trifluoro-1-methyl-ethoxy)-benzamide, 3-chloro-N-[2-[(N,N-dimethylglicyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-(1-(2-(dimethylamino)acetamido)-3-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide, 3-chloro-N-(2-[(2-methylalanyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-[(3-hydroxy)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide, as well as to their pharmaceutically acceptable salts.

EFFECT: obtained compounds and salts can be used for treatment cell proliferative diseases and disorders by modulating activity of mitotic kinesin CENP-E.

26 cl, 102 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to drugs and concerns application of 9-dialkylaminoethylsubsituted-2-(4-fluorophenyl)imidazo[1,2]benzimidazole dihydrochloride of general formula I (where NR2 has the values specified in the formula) as a kappa-opioid the agonist.

EFFECT: invention aims at extending the range of products exhibiting kappa-opioid agonistic activity.

2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmacology, and concerns a pharmaceutical composition for treating tuberculosis containing at least one oxazole compound chosen from 2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidine-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole and 2-methyl-6-nitro-2-{4-[4-(4-trifluoromethylphenoxymethyl)piperidine-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole, and at least one cellulose compound chosen from a group consisting of hydroxypropylmethylcellulose phthalate and hydroxypropyl methyl cellulose acetate succinate.

EFFECT: composition exhibits better water-solubility of an oxazole compound.

15 cl, 2 dwg, 1 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I)

or pharmaceutically acceptable salts thereof, in which: R1, R2, R3, R4, A and E are as described in the claim, and to pharmaceutical composition containing said compounds, and a method of treating and application in order to treat conditions mediated by antagonistic activity towards acid pump, such as gastrointestinal diseases, gastrooesophageal diseases, gastrooesophageal reflux disease (GERD), laryngopharyngeal reflux disease, peptic ulcers, gastric ulcers, duodenal ulcers, NSAID- induced ulcers, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, nonerosive reflux disease (NERD), viscerogenic pain, cancer, heartburn, nausea, oesophagitis, dysphagia, hypersalivation, disorders of the respiratory channel or asthma.

EFFECT: possibility of using compounds to treat different diseases.

9 cl, 1 tbl, 16 ex

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