Benzimidazole derivatives in treating disorders associated with vanilloid receptor trpv1

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzimidazole derivatives of general formula I wherein: R1 = CN, halogen or C(=O)CH3; R2 means methyl or H; R3=H or halogen; R4 and R5 independently mean methyl or ethyl, or R4 and R5 together with a carbon atom whereto attached form C3-6cycloalkyl or 5-6-member heterocycloalkyl; R6 and R7 independently mean H, halogen, methyl or ethyl; or their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and their application in therapy.

EFFECT: compounds may be used in treating osteoarthritis, chronic tendinitis, pelvic pain and peripheral neuropathy, gastroesophageal reflux disease, irritable bowel syndrome and overactive bladder.

39 cl, 34 ex

 

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 these compounds and to novel intermediate compounds used to produce it.

PRIOR art

The feeling of pain in mammals is due to activation of peripheral terminala specialized populations of sensory neurons, known as pain receptors. Capsaicin, the active ingredient in hot peppers that causes prolonged activation of pain receptors and also causes a dose-dependent pain in humans. Cloning vanilloideae receptor 1 (VR1 or TRPV1) showed 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 indicate that it is activated also harmful increase body temperature, acidification of the tissues and other inflammatory mediators (Tominaga, M., Caterina, M.J. et al. Neuron (1998), v.21, p.531-543). The expression of VR1 is also regulated after peripheral nerve injury type, which leads to neuropathic pain. These properties VR1 make it extremely suitable target for the Oli and diseases involving inflammation. Despite the fact that agonists of the receptor VR1 can act as analgesics through the destruction of pain receptors, the use of agonists such as capsaicin and its analogues, are limited because of their pungency, neurotoxicity and induction of hypothermia. Instead, agents that block the activity of VR1 should be more useful. Antagonists could save analgesic properties, but to avoid side effects from the painfulness and neurotoxicity.

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

Another potential application relates to treatment resistance activators VR1.

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

In WO 2004/100865 disclosed compounds showing inhibitory activity against vanilloideae receptor 1 (VR1).

DEFINITIONS:

Used in this application, the following terms have the following meanings:

The term "(+, -)" will mean the racemic mixture of such compounds.

The term "alkyl", used alone or as suffix or prefix, refers to hydrocarbonyl radicals with a straight or branched chain, containing from 1 to about 12 carbon atoms.

The term "alkylene", ispolzuemyi alone or as suffix or prefix, refers to divalent hydrocarbon radicals with a straight or branched chain, containing from 1 to about 12 carbon atoms, which serve to connect the two structures together.

The term "alkenyl", used alone or as suffix or prefix, refers to monovalent hydrocarbon radicals with a straight or branched chain, having at least one carbon-carbon double bond and containing at least 2 and up to about 12 carbon atoms.

The term "quinil", used alone or as suffix or prefix, refers to monovalent hydrocarbon radicals with a straight or branched chain, having at least one carbon-carbon triple bond and containing at least 2 and up to about 12 carbon atoms.

The term "amine" or "amino" refers to radicals of the General formula-NRR', where R and R' are independently selected from hydrogen or alkyl radical.

The term "aromatic" refers to hydrocarbonyl radicals having one or more polyunsaturated carbon rings having aromatic character (e.g., 4n+2 delocalized electrons) and containing from 6 up to about 14 carbon atoms.

The term "aryl"used alone or as suffix or prefix, refers to a hydrocarbon radical having one or more Pauline is saturated carbon rings having aromatic character (e.g., 4n+2 delocalized electrons) and containing from 5 up to about 14 carbon atoms, where the radical is located on the carbon atom of the aromatic ring.

The term "cycloalkyl", used alone or as suffix or prefix, refers to a monovalent containing ring hydrocarbon radical containing at least 3 up to about 12 carbon atoms.

The term "heteroseksualci" refers to saturated or unsaturated cycloalkyl, in which at least one ring carbon atom (and any associated hydrogen atoms) are independently replaced with at least one heteroatom selected from O and N. Such cycloalkyl include, but are not limited to, groups such as morpholinyl, piperidinyl, piperazinil and pyrrolidinyl.

The term "halogen" or "halogen" refers to radicals of fluorine, chlorine, bromine and iodine.

The term "heterocycle" or "heterocyclic" or "heterocyclic group" refers to containing ring monovalent and divalent radicals having one or more heteroatoms, independently selected from N, O, P and S, as part of a ring structure, and containing at least 3 and up to about 20 atoms in the ring, preferably 5 - and 6-membered rings. Heterocyclic groups can be nassen the mi or unsaturated, containing one or more double bonds, and heterocyclic groups may contain more than one ring.

The term "heteroaryl" refers to heterocyclic monovalent and divalent radicals having aromatic character.

Heterocyclic groups include, for example, a monocyclic group, such as: aziridine, oxirane, thiran, azetidin, oxetan, Titan, pyrrolidin, pyrrolin, imidazolidin, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2.5-dihydrofuran, tetrahydrofuran, teofan, thiophene, piperidine, 1,2,3,6-tetrahydropyridine, piperazine, morpholine, thiomorpholine, Piran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridines, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperazin, 2,3,4,7-tetrahydro-1H-azepin homopiperazin, 1,3-doxepin, 4,7-dihydro-1,3-doxepin and hexamethylene. In addition, the heterocyclic groups include heteroaryl ring, such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolin, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl. In addition, heterocyclic groups cover a polycyclic group such as indole, and the valleys, the quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, 1,2-benzisoxazol, benzothiophen, benzoxazol, benzthiazole, benzimidazole, benzotriazole, thioxanthen, carbazole, carboline, acridine, pyrrolizidine and finalisation.

In addition to the polycyclic heterocycles described above, the heterocyclic group include polycyclic heterocyclic group, in which the ring condensation between two or more rings includes more than one relationship, common to both rings, and more than two atoms common to two rings. Examples of such bridged heterocycles include Hinkley, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.

The term "hydrocarbonyl" refers to any structure containing only carbon atoms and hydrogen, up to 14 carbon atoms.

The term "mammal" includes any of a variety of warm-blooded vertebrate animals of the class Mammalia, including, but not limited to, people, usually characterized by hair on the skin.

The term "patient" refers to a person who receives medical attention care or treatment.

DETAILED DESCRIPTION of the INVENTION

One embodiment of the invention is a compound of the formula I:

the de

R1selected from CN, halogen, C(=O)CH3;

R2selected from methyl or H;

R3selected from H or halogen;

each of R4and R5independently selected from methyl or ethyl, or R4and R5together with the carbon atom to which they are attached, form a 3-6-membered cycloalkyl or 5 - or 6-membered geterotsyklicescoe group;

each of R6and R7independently selected from H, halogen, methyl or ethyl;

or its pharmaceutically acceptable salt;

where the compound of formula I is as follows:

N-[4-(1-cyano-1-methylethyl)benzyl]-2-(6,7-debtor-1H-benzimidazole-1-yl)-ndimethylacetamide;

2-(7-chloro-1H-benzimidazole-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-terbisil]ndimethylacetamide;

(+)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}ndimethylacetamide;

(+)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(+,-)-2-(6-chloro-7-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}ndimethylacetamide;

(+)-2-(7-acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;

(+)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(+)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;

(+)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(+)-N-{1-[4-(1-cyano shall kilobytes)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(R)(+)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(R)(+)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;

(+)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;

(+)-2-(7-acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;

(R)(+)-N-{1-[4-(1-cyano-1-ethylpropyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R1independently selected from chlorine or fluorine.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R3selected from chlorine or fluorine.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R1independently selected from chlorine or fluorine, and R3selected from chlorine or fluorine.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R4and R5independently selected from methyl or ethyl.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R1independently selected from chlorine or fluorine, and R4and R5independently selected from methyl or ethyl.

3selected from chlorine or fluorine, and R4and R5independently selected from methyl or ethyl.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R1independently selected from chlorine or fluorine, R3selected from chlorine or fluorine, and R4and R5independently selected from methyl or ethyl.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R4and R5together with the carbon atom to which they are attached, form a 3-, 4 - or 6-membered cycloalkyl or 5 - or 6-membered geterotsyklicescoe group.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R1independently selected from chlorine or fluorine, and R4and R5together with the carbon atom to which they are attached, form a 3-, 4 - or 6-membered cycloalkyl or 5 - or 6-membered geterotsyklicescoe group.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R3selected from chlorine or fluorine, and R4and R5together with the carbon atom to which they are attached, form a 3-, 4 - or 6-membered cycloalkyl or 5 - or 6-membered geterotsyklicescoe group.

One embodiment of the invention is the soybean is inania formula I or its pharmaceutically acceptable salt, where R1independently selected from chlorine or fluorine, R3selected from chlorine or fluorine, and R4and R5together with the carbon atom to which they are attached, form a 3-, 4 - or 6-membered cycloalkyl or 5 - or 6-membered geterotsyklicescoe group.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where each of R6and R7independently selected from fluorine or chlorine.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where each of R6and R7independently selected from N.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R1independently selected from chlorine or fluorine, and each of R6and R7independently selected from N.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R3selected from chlorine or fluorine, and each of R6and R7independently selected from N.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R1independently selected from chlorine or fluorine, R3selected from chlorine or fluorine, and each of R6and R7independently selected from N.

One embodiment of the invention is the connection forms of the crystals I or its pharmaceutically acceptable salt, where R4and R5independently selected from methyl or ethyl, and each of R6and R7independently selected from N.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R1independently selected from chlorine or fluorine, R4and R5independently selected from methyl or ethyl, and each of R6and R7independently selected from N.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R3selected from chlorine or fluorine, R4and R5independently selected from methyl or ethyl, and each of R6and R7represents N.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R1independently selected from chlorine or fluorine, R3selected from chlorine or fluorine, R4and R5independently selected from methyl or ethyl, and each of R6and R7represents N.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R4and R5together with the carbon atom to which they are attached, form a 3-, 4 - or 6-membered cycloalkyl or 5 - or 6-membered geterotsyklicescoe group, and each of R6and R7represents N.

One embodiment of the invention I which is a compound of formula I or its pharmaceutically acceptable salt, where R1independently selected from chlorine or fluorine, R4and R5together with the carbon atom to which they are attached, form a 3-, 4 - or 6-membered cycloalkyl or 5 - or 6-membered geterotsyklicescoe group, and each of R6and R7represents N.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R3selected from chlorine or fluorine, R4and R5together with the carbon atom to which they are attached, form a 3-, 4 - or 6-membered cycloalkyl or 5 - or 6-membered geterotsyklicescoe group, and each of R6and R7represents N.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt, where R1independently selected from chlorine or fluorine, R3selected from chlorine or fluorine, R4and R5together with the carbon atom to which they are attached, form a 3-, 4 - or 6-membered cycloalkyl or 5 - or 6-membered geterotsyklicescoe group, and each of R6and R7represents N.

One embodiment of the invention is a compound selected from:

(S) - (-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;

(S) - (-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(7-fluoro-1H-benzimidazole-1-yl)ndimethylacetamide;

(S) - (-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]e is Il}-2-(7-chloro-1H-benzimidazole-1-yl)ndimethylacetamide;

(S) - (-)-N-{1-[4-(1-cyano-1-ethylpropyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(-)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(-)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}ndimethylacetamide;

(-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}ndimethylacetamide;

(-)-2-(7-acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;

(S) - (-)-2-(7-acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;

(-)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(-)-2-(7-chloro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;

(-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-terbisil]ndimethylacetamide;

(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;

(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide;

(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide;

(-)-N-{1-[4-(4-cyanoacrylate-2H-thiopyran-4-yl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)acetone is a;

(-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(7-fluoro-1H-benzimidazole-1-yl)ndimethylacetamide;

(-)-N-{1-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(-)-N-{1-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(7-cyano-1H-benzimidazole-1-yl)ndimethylacetamide;

(-)-2-(6,7-debtor-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide;

(-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide;

(S) - (-)-2-(6-chloro-7-fluoro-1H-benzimidazole-1-yl)-N-{[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;

and its pharmaceutically acceptable salt.

One embodiment of the invention is a compound selected from:

(+,-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;

(+,-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(+,-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(7-fluoro-1H-benzimidazole-1-yl)ndimethylacetamide;

(+,-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(7-chloro-1H-benzimidazole-1-yl)ndimethylacetamide;

(+,-)-N-{1-[4-(1-cyano-1-ethylpropyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(+,-)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(+,-)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide is;

(+,-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}ndimethylacetamide;

(+,-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}ndimethylacetamide;

(+,-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}ndimethylacetamide;

(+,-)-2-(7-acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;

(+,-)-2-(7-acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;

(+,-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;

(+,-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;

(+,-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;

(+,-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide;

(+,-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide;

(+,-)-N-{1-[4-(4-cyanoacrylate-2H-thiopyran-4-yl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

N-[4-(1-cyano-1-methylethyl)-2-methylbenzyl]-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

2-(7-cyano-1H-benzimidazole-1-yl)-N-[4-(1-cyano-1-methylethyl)-2-methylbenzyl]ndimethylacetamide;

(+,-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(+,-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(7-fluoro-1H-benzimidazole-1-ylacetamide;

(+,-)-N-{1-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;

(+,-)-N-{1-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(7-cyano-1H-benzimidazole-1-yl)ndimethylacetamide;

(+,-)-2-(7,6-debtor-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide;

(+,-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide;

2-(6-chloro-7-fluoro-1H-benzimidazole-1-yl)-N-{[4-(1-cyano-1-methylethyl)-2-methylbenzyl]ndimethylacetamide;

and its pharmaceutically acceptable salts.

One embodiment of the invention is the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide and its pharmaceutically acceptable salt.

One embodiment of the invention is the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide and its pharmaceutically acceptable salt.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt for use in the treatment of chronic nociceptive pain disorders in mammals.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt for use in the treatment of osteoarthritis.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt for use in cured and chronic tendonitis.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt for use in the treatment of pelvic pain.

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt for use in the treatment of peripheral neuropathy (mainly PHN (post herpetic neuralgia)).

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt for use in the treatment of gastroesophageal reflux disease (GERD).

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt for use in the treatment of irritable bowel syndrome (IBS).

One embodiment of the invention is a compound of formula I or its pharmaceutically acceptable salt for use in the treatment of overactive bladder.

One embodiment of the invention is a method of treating nociceptive pain disorders, including the introduction of an effective amount of the compounds of formula I or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating nociceptive pain disorders, including the introduction of an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-mutilat the l)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient, who needs this.

One embodiment of the invention is a method of treating nociceptive pain disorders, including the introduction of an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating chronic nociceptive pain disorders, including the introduction of an effective amount of the compounds of formula I or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating chronic nociceptive pain disorders, including the introduction of an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating chronic nociceptive pain disorders, including the introduction of an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treatment of osteoarthritis, including the introduction of effective the sector number of the compounds of formula I or its pharmaceutically acceptable salt to a patient, who needs this.

One embodiment of the invention is a method of treating osteoarthritis comprising introducing an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating osteoarthritis comprising introducing an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating chronic tendonitis, including the introduction of an effective amount of the compounds of formula 1 or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating chronic tendonitis, including the introduction of an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating chronic tendonitis, including the introduction of an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzoni the azole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient, who needs this.

One embodiment of the invention is a method of treating chronic tendonitis, including the introduction of an effective amount of the compounds of formula I or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating chronic tendonitis, including the introduction of an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating chronic tendonitis, including the introduction of an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method for the treatment of pelvic pain, including the introduction of an effective amount of the compounds of formula I or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method for the treatment of pelvic pain, including the introduction of an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient, n is gaudemus.

One embodiment of the invention is a method for the treatment of pelvic pain, including the introduction of an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methyl ethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating peripheral neuropathy (mainly PHN), including the introduction of an effective amount of the compounds of formula I or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating peripheral neuropathy (mainly PHN), including the introduction of an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating peripheral neuropathy (mainly PHN), including the introduction of an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating gastroesophageal reflux disease (GERD), comprising introducing an effective amount is and the compounds of formula 1 or its pharmaceutically acceptable salt to a patient, who needs this.

One embodiment of the invention is a method of treating gastroesophageal reflux disease (GERD), comprising introducing an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating gastroesophageal reflux disease (GERD), comprising introducing an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating irritable bowel syndrome (IBS), comprising introducing an effective amount of the compounds of formula 1 or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating irritable bowel syndrome (IBS), comprising introducing an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating irritable bowel syndrome (IBS), including the rst is giving an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient, who needs this.

One embodiment of the invention is a method of treating overactive bladder, comprising introducing an effective amount of the compounds of formula 1 or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating overactive bladder, comprising introducing an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a method of treating overactive bladder, comprising introducing an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

One embodiment of the invention is a pharmaceutical composition comprising a compound of formula 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

One embodiment of the invention is a pharmaceutical composition containing the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

the ne embodiment of the invention is a pharmaceutical composition, containing the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

The characteristics and advantages of the invention may be more easily understood by the average specialists in the art when reading the following detailed description. You should take into account that some features of the invention, which, for clarity, described above and below in the context of separate embodiments, can also be merged to form a single embodiment. Conversely, various features of the invention, which, for brevity, described in the context of a single embodiment, may be combined with the education of their podnominatsii.

Some compounds according to the invention have a chiral center. Such forms can be fractionated by chiral chromatography, and programada fractionated compounds have greater antagonistic activity than levogyrate. Not wishing to be bound by any theory, currently believe that (+)-isomers are (R)-enantiomers, (- )- isomers are (S)-enantiomers. Thus, although programada, (D) or (+) or (R), and levogyrate, (L) or (-) or (S)-compounds are compounds according to the invention, specific compounds invented by the Yu represent levogyrate, (S) or (-)connection.

Sign declared rotation observed for the wavelength of sodium measured at 22°C in the standard way in solvents and concentrations, which are believed to intermolecular Association does not occur.

Recently confirmed that the chiral (-)-2-[4-(1-amino-ethyl)phenyl]-2-methylpropionitrile obtained by the fractionation of the corresponding racemic mixture has an (S)-configuration. Also confirmed that (-)-amine is chiral original substance, resulting in (-)-active final compounds claimed in this application. Since no inversion amine chiral stereogenic centre, as it was observed, did not occur in response combinations, assume that the configuration of (-)-active final compounds (obtained with this specific chiral amine) is also an (S)-configuration.

For chiral end (-)-active compounds, obtained using different but similar benzyl amines described above, largely suggest that the chiral center has the same (S)-configuration, but there may be exceptions to this General statement.

To confirm the chiral structure of 2-[4-(1-amino-ethyl)phenyl]-2-methylpropionitrile tested. The results of infrared vibrational circular dichroism (VCD), the joint is haunted with the molecular-mechanical calculations and the calculation method of the density functional theory predicted VCD spectra, consistent with the proposed configurations.

Specific compounds described in this application, illustrate but do not limit the invention, other compounds within the scope of the invention will be obvious to experts in the art upon consideration of the processes, methods and compounds described in this application.

Compounds proposed in this application are useful in the free base form, but can also be offered in the form of a pharmaceutically acceptable salt and/or in the form of a pharmaceutically acceptable hydrate. For example, the pharmaceutically acceptable salt of compounds of formula I include salts derived from mineral acids, such as, for example: methansulfonate, econsultation, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, Hydrobromic acid, uudistoodetena acid, nitric acid and phosphoric acid. Pharmaceutically acceptable salt can also be obtained with organic acids including aliphatic mono - and dicarboxylate and aromatic acids.

Other pharmaceutically acceptable salts of the compounds of the present invention include, for example, sulfate, persulfate, bisulfate, bisulfite, nitrate and phosphate.

The compounds of formula I can be obtained by methods known in the chemical industry to obtain tructure similar compounds. Accordingly, the compounds of this invention can be obtained using procedures known in the literature, starting from known compounds or readily derived intermediates.

In this application the proposed synthetic methods for obtaining compounds, the precursors or application in the practical aspects of the present invention.

Specialists in the art will understand that some compounds of the present invention contain, for example, asymmetrically substituted carbon and, therefore, may exist and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism, thus, it should be understood that the present invention encompasses the racemic, optically active, polymorphic or stereoisomeric form, or mixtures thereof, and these forms have properties that are useful in the treatment of the disorders described below. Obtaining optically active forms well known in the art (for example, by separation of the racemic form by the methods of recrystallization, synthesis from optically active starting compounds, chiral synthesis or by chromatographic separation using a chiral stationary phase).

The compounds of formula I are antagonists of VR-1. Connection is ormula I and their pharmaceutically acceptable salts can also be used in the treatment of pain, acute pain, chronic pain, nociceptive pain, acute nociceptive pain, chronic nociceptive pain, neuropathic pain, acute neuropathic pain, chronic neuropathic pain, inflammatory pain, acute inflammatory pain, chronic inflammatory pain. The treatment of such disorders includes the introduction of a warm-blooded animal, preferably a mammal, more preferably a human in need of such treatment, an effective amount of the compounds of formula I or pharmaceutically acceptable salts of the compounds.

In addition, the proposed use of the compounds of formula I in the treatment of osteoarthritis, chronic tendonitis, pelvic pain and peripheral neuropathy (mainly PHN), gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS) and overactive bladder.

In addition, the proposed use of the compounds of formula I in obtaining drugs for the treatment of disorders such as pain in warm-blooded animal, preferably a mammal, more preferably a person suffering from this disorder.

In addition, in the proposed invention the pharmaceutical composition is suitable for treatment of the above disorders involving the introduction of a warm-blooded animal having a disorder, EF the objective amount of the pharmaceutical compositions of the compounds of formula I or pharmaceutically acceptable salt.

The invention also proposed a pharmaceutical composition comprising a compound of formula I, as defined in this application, or a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable carrier.

At least one connection described in this application demonstrates antagonistic activity against VR-1 in the analysis described in this application better than about 1 μm. Found that the selected compounds of the present invention are active antagonists with activity less than about 100 nm.

Compounds described in this application may be offered or delivered in a form suitable for oral administration, for example, in the form of a tablet, pellet, hard and soft capsules, aqueous or oil solution, emulsion and suspension. The connection can also be offered to local injection, for example, in the form of a cream, ointment, gel, spray or aqueous solutions, oily solutions, emulsions or suspensions. Compounds described in this application can also be offered in a form suitable for nasal administration, for example, as a nasal spray, nose drops or as a dry powder. The composition can also be inserted into the vagina or rectum in the form of a suppository. Compounds described in this application, you can also enter parenteral, such as the er, by intravenous, intravascular, subcutaneous or intramuscular injection or infusion. The compounds can be administered by insufflation (for example, in the form of fine powder). Connections can also enter transdermally or sublingually.

Compounds according to the invention, respectively, can be obtained by conventional methods using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and/or preservatives.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will need to vary depending on the patient being treated and the particular route of administration. The size of the dose of the compounds of formula I for therapeutic or prophylactic purposes, of course, will vary in accordance with the nature and severity of the condition, age and sex of the animal or patient and the route of administration, according to well known principles of medicine. There are various tests and in vivo tests to determine the usefulness of the compounds of the disorders listed above, and particularly as antagonists of the receptor VR-1.

Connect the exclusion of the General formula I or its pharmaceutically acceptable salt, MES or hydrolisis in vivo ester, or pharmaceutical composition or drug containing the compound of formula I, is administered concurrently, simultaneously, sequentially or separately from each other(their) compound or compounds selected from the following:

(1) treatments for neuropathic pain, including, for example, gabapentin, LIDODERM, pregablin and equivalents, including, but not limited to, their pharmaceutically acceptable salt and pharmaceutically active(e) isomer(s) and metabolite(s);

(2) treatment of nociceptive pain, including, for example, celecoxib, etoricoxib, lumiracoxib, rofecoksib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol and equivalents, including, but not limited to, their pharmaceutically acceptable salt and pharmaceutically active(e) isomer(s) and metabolite(s);

(3) treatment of urinary incontinence, including, for example, darifenacin, flavoxate, oxybutynin, propiverine, robalzotan, solifenacin, tipi, tolterodine and equivalents, including, but not limited to, their pharmaceutically acceptable salt and pharmaceutically active(e) isomer(s) and metabolite(s).

In such combination products employ the compounds of this invention in the dose range described in this application, and the other pharmaceutically active agent in an approved on the exposure ranges and/or dosage, described in the published reference.

Ways to get

In another aspect of the present invention the methods of obtaining compounds of the formula I or their salts, solvate or solvated salts.

In the following description of such methods should be understood that, if necessary, suitable protective groups will be added and subsequently removed from the various reactants and intermediates in a manner that will be easily understood by a person skilled in the field of organic synthesis. Customary 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-Interscience, New York, (1999). The references and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, in "Advanced Organic Chemistry", March, 4thed. McGraw Hill (1992) or in "Organic Synthesis", Smith, McGraw Hill, (1994). For typical examples of heterocyclic chemistry, see, for example, "Heterocyclic Chemistry", J.A.Joule, K.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 term "room temperature" and "ambient temperature" shall mean, unless otherwise specified, the temperature from 16 to 25°C.

Reduction

DCEdichlo is Ethan
DCMdichloromethane
DMAPN,N-dimethylaminopyridine
EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HATUO(7-asobancaria-1-yl)-N,N,N,N'-tetramethylurea hexaphosphate
HPLCliquid chromatography high-resolution
KHMDShexamethyldisilazane potassium
LCliquid chromatography
BP. level.retention time
TFAtriperoxonane acid
THFtetrahydrofuran
DMFdimethylformamide
TMEDAtetramethylethylenediamine
EtOActhe ethyl acetate
DEAdiethylamin
DMSOthe sulfoxide
minminute
TEMPO2,2,6,6-tetramethyl-1-piperidinyloxy
MPLCliquid chromatography medium pressure
MTBEmethyl tert-butyl ether
TLCthin-layer chromatography
MeCNacetonitrile
CDCround-bottom flask
MSmass spectroscopy low-resolution
HRMSmass spectroscopy, high-resolution
[M+H]molecular ion + proton
DIPEAdiisopropylethylamine
NMRnuclear magnetic resonance
Pd-Cpalladium on carbon
EtOHethanol
MeOHmethanol
t-BuOKtert-butyl potassium
STPstandard temperature and pressure
CCDthe device charge-coupled

Experimental methods:

All source materials are commercially available or described in the literature. Spectra1H-NMR recorded in Variant at 400 MHz. Mass spectra were recorded on (LC-MS; LC: Agilent 1100, Waters ESI-MS, column Phenomenex Synergi Polar (4 μm) 30×2 mm, the flow rate of 1.75 ml/min, mobile phase: a = water (0.05% of TFA) and B = MECN (0.05% of TFA), gradient: 5-95%, the time gradient: 2,25 min). The final connection will be analyzed by LCMS Agilent 1100 (MS: Agilent APPI-MSD, flow rate: 3.5 ml/min, column: SB Bond (1,8 µm) of 4.6×30 mm; column temperature: 70°C, mobile phase: a = water (0.05% of TFA) and B = MECN (0.05% of TFA), gradient: 5-95%,the time gradient: 4.5 min). The enantiomers of each product can be separated using column Chiralcel OD or AD from Chiral Technologies Inc.

The final products are named by converting racemic image molecules in the name IUPAC using laboratory software ACD. Enantiomeric characteristics at the beginning of each title[(+), (-), (+,-), R, S] add depending on what is known about the connection at this time.

Scheme 1: Synthesis of (7-chloro-1H-benzimidazole-1-yl)acetic acid

Stage a) of intermediate compound 1

Synthesis of 2-[(2-chloro-6-nitrophenyl)amino]ethanol

2,3-Dichloronitrobenzene (300 g, 1.56 mol) is mixed with ethanol (600 ml) and ethanolamine (282 ml, and 4.68 mol). The mixture is heated at the temperature of reflux distilled for 20 h, then cooled and concentrated in vacuo. Removal cleaners containing hydrochloride salt ethanolamine crude product is dissolved in 3.5 l of AcOEt and 1 l of water. The aqueous phase is removed and the organic phase is twice washed with 700 ml of water and brine. After drying over anhydrous magnesium sulfate, the solution is filtered and evaporated in vacuo to give the desired product (336 g, 99%) as an orange oil.

Stage b) of the intermediate compound 2

Synthesis of 2-[(2-chloro-6-AMINOPHENYL)amino]ethanol

To a solution of 2-[(2-chloro-6-nitrophenyl)amino]ethanol (120 g, 0,554 mol) in methanol (1.5 l) at 60°C add dissolve the Na 2S2O4(85%, 318 g, 1.55 mol) in water (1,12 l) for 20 minutes, the resulting suspension is stirred at 60°C for an additional 20 minutes Discolored mixture is allowed to cool and concentrated in vacuo. To an ice bath, add 800 ml of 1.5 M NaOH solution and the mixture is extracted three times with 500 ml of AcOEt. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is evaporated to give the desired product (72.4 g, 70%).

Stage b) of the intermediate compound 3

Synthesis of 2-(7-chloro-1H-benzimidazole-1-yl)ethanol

2-[(2-Chloro-6-AMINOPHENYL)amino]ethanol (72.4 g, 0,388 mol) is dissolved in formic acid (350 ml) and stirred at the temperature of reflux distilled for 1 hour. The reaction mixture is concentrated to dryness under reduced pressure to obtain a dark solids, and then to the residue is added 500 ml of 2 N. HCl and the mixture is heated at the temperature of reflux distilled for 30 minutes the Solution is cooled on ice and add 50%NaOH solution to alkaline values, and the resulting suspension is filtered under vacuum and the resulting solid dried to give the desired product (70,8 g, 93%).

Stage g) of intermediate compound 4

Synthesis of 2-(7-chloro-1H-benzimidazole-1-yl)acetic acid

2-(7-Chloro-1H-benzimidazole-1-yl)ethanol (50 g, 0,254 mol) is dissolved in 1 ml of acetonitrile and sodium phosphate buffer (750 ml, pH of 6.7) and the mixture is heated to 0°C, within 3 hours add TEMPO (2.9 g 18.5 mmol), then solid NaClO2(119 g, 85%, 1.06 mol). At the same time add a solution of NaOCl (1.65 M, 40 ml) up until the reaction mixture becomes dark brown. The mixture is left to mix for 16 hours at 45°C. the Excess oxidant quenched (ice bath) solid Na2SO3(100 g), which add up to the total discoloration of the reaction mixture. At this stage, a precipitate may form. It's a hard substance, which contains 2-(7-chloro-1H-benzimidazole-1-yl)acetic acid and mineral product is filtered and dissolved in 500 ml of water. The resulting solution was then acidified to pH 2 using 6 N. HCl. The precipitate is filtered and washed with water to obtain 3,76 g of the desired product. The aqueous phase from the reaction mixture acidified with 6 N. HCl to pH 2 and the solid that formed was filtered and washed with water to obtain 41,83 g of the desired product. A solution of acetonitrile, obtained from the organic phase, concentrate with obtaining a suspension of the crude product in water, which is purified by dissolving in 50%NaOH solution. The aqueous solution is then washed with AcOEt and precipitated with 6 N. HCl to pH 6 with receipt of 1.76 g of the desired product with a total yield 47,35 g (88%) of the desired product.

Scheme 2: Synthesis of (6,7-Debtor-1H-benzimidazole-1-yl)acetic acid

Scheme 2: C the MES (6,7-debtor-1H-benzimidazole-1-yl)acetic acid.

Stage a) of the intermediate compound 5

Synthesis of 2-[(2,3-debtor-6-nitrophenyl)amino]ethanol

A solution of 1,2,3-Cryptor-4-nitrobenzene (5.0 g, of 28.2 mmol) and ethanolamine (1,72 g of 28.2 mmol) in 100 ml of ethanol is stirred over night at room temperature, then at 70°C for 5 hours. The reaction mixture is concentrated to dryness and purified using flash chromatography on silica gel using a gradient from 80/20 to 20/80 heptane/ethyl acetate, to obtain an orange solid. Output (3.8 g, 62%).1H-NMR (400 MHz, CDCl3) δ million-11.67 (t, J=5.08 Hz, 1H), 3.77-3.83 (m, 2H), 3.88-3.94 (m, 2H), 6.51 (ddd, J=9.77, 8.59, 7.03 Hz, 1H), 8.02 (ddd, J=9.77, 5.66, 2.34 Hz, 1H), 8.21 (s, 1H).

Stage b) of the intermediate compound 6

Synthesis of 2-[(6-amino-2,3-differenl)amino]ethanol

To a solution of 2-[(2,3-debtor-6-nitrophenyl)amino]ethanol (3.8 g, to 17.4 mmol) in 70 ml of ethyl acetate and 30 ml of ethanol is added 10% Pd/C (380 mg). The reaction mixture was shaken under hydrogen pressure of 50 psi (344,75 kPa) for 3 hours. Pressure periodically adjusted to 50 psi (344,75 kPa). The reaction mixture was filtered through celite, washed with ethanol and concentrated. The resulting material is used without further purification in the next stage.1H-NMR (400 MHz, CDCl3) δ million-13.17-3.27 (m, 2H), 3.68-3.78 (m, 2H), 6.38 (ddd, J=8.89, 4.69, 2.05 Hz, 1H), 6.61-6.70 (m, 1H).

Stage b) of the intermediate compound 7

Synthesis of 2-(6,7-debtor-1H-b is Intimidator-1-yl)ethanol

A solution of 2-[(6-amino-2,3-differenl)amino]ethanol in 100 ml of formic acid is heated to 100°C for 2 hours. The reaction mixture is concentrated to dryness, poured into 100 ml of 2 N. NH3in ethanol and stirred for 2.5 hours, the Reaction mixture was concentrated and poured into ethyl acetate. The precipitate is collected by filtration and washed with cold ethyl acetate. The mother liquid is concentrated and purified using flash chromatography on silica gel using ethyl acetate/heptane. Total yield 3.2 g or 93% for two steps on the basis of 3.8 g of 2-[(2,3-debtor-6-nitrophenyl)amino]ethanol.

Stage b) of the intermediate compound 8

Synthesis of (6,7-debtor-1H-benzimidazole-1-yl)acetic acid.

2-(6,7-Debtor-1H-benzimidazole-1-yl)ethanol (2,96 g, 15 mmol) poured into 75 ml of MeCN and sodium phosphate buffer (56 ml, 0.67 M, pH 6.8) and the mixture is heated to 42°C. Add TEMPO (165 mg, 1.05 mol), followed by simultaneously adding dropwise the solution of NaClO2(3,38 g, 80% purity, 30 mmol in 15 ml of water and bleach solution (350 μl of 6% NaOCl in 7.5 ml of water) for 1.5 hours. After 48 h add the same amount of NaClO2and bleach. After an additional 24 hours add TEMPO (165 mg, 1.05 mol) and the reaction mixture stirred for 72 hours Darkened the reaction mixture is allowed to cool to room temperature, followed by adding dropwise 30 ml of a saturated solution of the Na 2SO3(exothermic). The reaction mixture becomes almost colorless. Using 2 N. NaOH, pH increase to 9.2 and the reaction mixture is extracted 4 times with ethyl acetate. the pH is then reduced to 3.8 with 2 N. HCl and the solution left to stand for 48 hours. Allocate 1.98 g of white crystalline substance. The mother liquid is reduced to half volume and allowed to stand. Bring more of 260 mg (Total yield of 2.23 g, 70%).

1H-NMR (400 MHz, DMSO-D6) δ million-15.19 (s, 2H), 7.25 (ddd, J=1.62, 8.89, 7.62 Hz, 1H), 7.49 (ddd, J=8.94, 3.86, 1.07 Hz, 1H), 8.13-8.28 (m, 1H), 13.38 (s, 1H).

Scheme 3: Synthesis of (7-cyano-1H-benzimidazole-1-yl)acetic acid

Stage a) of intermediate compound 9

Synthesis of 2-chloro-3-nitrobenzamide

2-Chloro-3-nitrobenzoic acid (100 g, 0,496 g) is heated to the temperature of reflux distilled in pure thionyl chloride for 2.5 hours with stirring (out gas). After cooling, thionyl chloride evaporated to dryness. The obtained solid substance was dissolved in 150 ml of dichloromethane, cooled in an ice bath and add 400 ml of 28%aqueous ammonium hydroxide for 1 hour (reaction is exothermic). Then add 100 ml of water to facilitate precipitation. The formed precipitate is filtered, washed with water and dried for 16 hours over R2About5in vacuum to give the desired product (83,2 g, 83%) as pale yellow is iplogo solids.

1H-NMR (300 MHz, DMSO-d6) δ million17.61 (t, J=7.93 Hz, 1H), 7.72 (dd, J=7.63, 1.47 Hz, 1H), 8.04 (dd, J=7.94, 1.47 Hz, 1H).

Stage b) of the intermediate compound 10

Synthesis of 2-chloro-3-nitrobenzonitrile

2-Chloro-3-nitrobenzamide (83 g, 0,413 mol of well-dried) is added to the boiling solution of a dehydrating agent, and this mixture is then left at this temperature for 4 hours and at room temperature for 16 hours. The mixture is quenched with ice, add 400 ml of water to facilitate separation of the phases and the aqueous phase discarded. The organic phase is washed with water and brine and then dried over anhydrous Na2SO4. The solution is filtered and concentrated to give the desired product (74,4 g, 99%).

1H-NMR (300 MHz, DMSO-d6) δ million17.76 (t, J=7.93 Hz, 1H), 8.27 (dd, J=7.93 1.47 Hz, 1H), 8.36 (dd, J=8.22 1.47 Hz, 1H).

* Obtaining trimethylsilyltriflate (dehydrating agent):

P2About5(254 g; 1,79 mol) in 1 l of anhydrous dichloromethane is stirred at the temperature of reflux distilled and add 330 ml hexamethyldisiloxane (1.54 mol) for 1 hour using a dropping funnel (reaction is exothermic). The reaction mixture was then allowed to mix at this temperature for 1 hour.

Stage b) of the intermediate compound 11

Synthesis of 2-[(2-hydroxyethyl)amino]-3-nitrobenzonitrile

2-Chloro-3-nitrobenzonitrile (74 g, 0,408 mol) is mixed with ethanol (370 ml) ethanolamine (57 ml). The mixture is stirred for 16 h at room temperature. To complete the reaction, the reaction mixture was refluxed for 2 hours. After cooling, the mixture was concentrated in vacuo; the product precipitates as a red solid. Removal cleaners containing hydrochloride salt ethanolamine, the suspension is triturated with 500 ml of water and filtered under vacuum. The solid is washed with ethanol and ether, then dried obtain the desired product (75 g, 89%).

1H-NMR (300 MHz, DMSO-d6) δ million-13.55-3.60 (m, 2H), 3.69-3,74 (m, 2H), 6.75 (dd, J=7.63, 8.52 Hz, 2H), 7.90 (dd, J=7.63, 1.76 Hz, 2H), 8.27 (dd, J=8.52, 1.76 Hz, 1H), 3.35 m, 1H).

Stage g) of intermediate compound 12

Synthesis of 3-amino-2-[(2-hydroxyethyl)amino]benzonitrile

Methanol (500 ml) and 5% Pd/activated carbon (wet, of 3.45 g) are added to 2-[(2-hydroxyethyl)amino]-3-nitrobenzonitrile (69 g of 0.333 mol). The suspension is shaken in a Parr apparatus under hydrogen pressure of 20 psig (137,9 kPa) for 1 hour. The mixture was then filtered on celite and evaporated to dryness to give the desired substance (62,7 g). This product is used in the next stage without additional purification.

1H-NMR (300 MHz, MeOD) δ million-13.41 (t, J=5.43 Hz, 2H), 3.70 (t, J=5.43 Hz, 2H), 6.75 (t, J=7.71 Hz, 1H), 6.87 (dd, J=7.71, 1.61 Hz, 1H), 6.92 (dd, J=7.71, 1.61 Hz, 1H).

Stage e) of intermediate compound 13

Synthesis of 1-(2-hydroxyethyl)-1H-benzimidazole-7-carbonitrile

3-Amino-2[(2-hydroxyethyl)amino]benzonitrile (38 g, crude) was dissolved in formic acid (150 ml) and stirred at the temperature of reflux distilled for 1 hour. The reaction mixture is concentrated to dryness under reduced pressure to obtain a dark solid. This solid is dissolved in 200 ml of methanol with heating and, while it is still hot, add 60 ml of triethylamine and heated under reflux for 1 hour. The mixture was concentrated in vacuo and the precipitate filtered and washed with water, then dried obtain the desired compound (27 g, 70% from intermediate compound (11).

1H-NMR (300 MHz, DMSO-d6) δ million13.79 (dt, J=5.14 Hz, 2H), 4.51 (t, J=5.14 Hz, 2H), 5.04 (t, J=5.14 Hz, 1H), 7.34 (dd, J=7.63, 0.77 Hz, 1H), 7.74 (dd, J=7.63, 0.77 Hz), 8.02 (dd, J=7.73, 0.77 Hz), 8.36 (s, 1H).

Stage e) of the intermediate compound 14

Synthesis of (7-cyano-1H-benzimidazole-1-yl)acetic acid

1-(2-Hydroxyethyl)-1H-benzimidazole-7-carbonitrile (61,4 g 0,328 mol) is dissolved in acetonitrile (1.2 l) and sodium phosphate buffer (930 ml, pH 6.8) and the mixture is heated to 40°C. Add TEMPO (3.6 g 22.7 mol), then solid NaClO2(148,3 g, 85%, 1,31 mol) for 3 hours. At the same time add a solution of NaOCl (1.65 M, 50 ml) up until the reaction mixture becomes dark brown. The mixture is left to mix for 16 hours at 45°C. the Excess oxidant quenched (ice bath) solid Na2SO3that adds up to a full obespechiva the Oia reaction mixture.

At this stage, a precipitate may form. This solid contains the desired products and products in the form of mineral salts, it is filtered and dissolved in 500 ml of water. The resulting solution was then acidified to pH 2 using 6 N. HCl. The precipitate is filtered and washed with water to give the desired product (12.7 g, 19%). The aqueous phase obtained from the reaction mixture, acidified with 6 N. HCl to pH 2, and the solid which formed was filtered and washed with water and dried to give the desired product (43,0 g, 65%) of the final product. The acetonitrile from the organic phase evaporated to obtain a suspension of the crude product in water, which is purified by dissolving in 50%solution of NaOH, washing AcOEt and deposition using 6 N. HCl to pH 6 to give the desired product (4,2 g, 6%), (59,9 g, United outputs 90%).

1H-NMR (300 MHz, DMSO-d6) δ million-15.31 (s, 2H), 7.36 (t, J=7.78 Hz, 1H), 7.74 (dd, J=1.03, 7.78 Hz, 1H), 8.03 (dd, J=1.03, 7.78 Hz, 1H), 8.37 (s, 1H).

Scheme 4: Synthesis of (7-acetyl-1H-benzimidazole-1-yl)acetic acid

Stage a) of intermediate compound 15

Synthesis of 1-[1-(2-hydroxyethyl)-1H-benzimidazole-7-yl]ethanone.

A solution of 1-(2-hydroxyethyl)-1H-benzimidazole-7-carbonitrile (to 0.29 g, 1.5 mmol) in dry THF (6.2 ml) is cooled to -78°C. and slowly added MeLi (5.8 ml, 9.3 mmol). After the addition the reaction mixture was allowed to warm to temperatureincrease environment and leave in this state for 30 minutes The temperature is lowered again to -78°C. and slowly add water (4 ml). After heating, the reaction mixture is acidified to pH 4 and heated at 50°C for 30 minutes the Solvent is removed under reduced pressure and the residue is divided between ethyl acetate and aq. NaHCO3. The organic extract is then washed with water and brine, dried over Na2SO4and concentrate. Purification is carried out on a flash column of silica gel using a mixture of ethyl acetate-methanol as eluent to give the desired product (0.25 g, 80%).

1H-NMR (400 MHz, DMSO-D6) δ million-12.67 (s, 3H), 3.51 (q, J=5.1 Hz, 2H), 4.41 (t, J=5.3 Hz, 2H), 4.77 (t, J=5.1 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.78 (dd, J=7.6, 1.0 Hz, 1H), 7.88 (dd, J=8.1, 1.0 Hz, 1H), 8.20 (s, 1H).

Stage b) of the intermediate compound 16

Synthesis of (7-acetyl-1H-benzimidazole-1-yl)acetic acid.

1-[1-(2-Hydroxyethyl)-1H-benzimidazole-7-yl]alanon (0,30 g of 1.47 mmol) are oxidized to the desired acid in accordance with the method described for the synthesis of (7-cyano-1H-benzimidazole-1-yl)acetic acid (stage e, the intermediate compound 14), to give the desired product (0.24 g, 75%).

1H-NMR (400 MHz, METHANOL-D4) δ million-12.64 (s, 3H), 5.34 (s, 2H), 7.46 (t, J=7.81 Hz, 1H), 7.90-7.99 (m, J=6.84, 6.84 Hz, 2H), 8.56 (s, 1H).

Scheme 5: Synthesis of (7-fluoro-1H-benzimidazole-1-yl)acetic acid

Stage a) of the intermediate compound 17

Synthesis of 2-[(2-fluoro-6-n is trienyl)amino]ethanol

2,3-Diplomarbeit (15 g, was 94.3 mmol) was dissolved in 200 ml of ethanol. Add ethanolamine (11,4 ml, amounts to 188.7 mmol, 2 EQ.) and the mixture is stirred at room temperature overnight (the reaction is completed according to TLC). The ethanol is evaporated and the resulting residue is dissolved in ethyl acetate, washed with water (to remove excess ethanolamine), dried over magnesium sulfate, filtered and evaporated to dryness to give the desired product as a dark orange oil (18.3 g, 97%). This crude substance use in the next stage without additional purification.

1H-NMR (400 MHz, CD3OD) δ 3.61-3.68 (m, 2H), 3.69-3.76 (m, 2H), 4.88 (s, 2H), 6.61-6.67 (m, 1H), 7.27 (ddd, J=14,16, 7.91, 1.56 Hz, 1H), 7.91 (dt, J=8.69, 1.51 Hz, 1H). MS [M+H]calculated: 201, found: 201.

Stage b) of the intermediate compound 18

Synthesis of 2-(7-fluoro-1H-benzimidazole-1-yl)ethanol

2-[(2-Fluoro-6-nitrophenyl)amino]ethanol (18,3 g of 91.5 mmol) was dissolved in 90 ml of formic acid, is added to a suspension of 10% Pd-C (300 mg) in 10 ml of formic acid. The mixture shaken in a Parr apparatus at atmospheric pressure H2throughout the night. The reaction mixture was filtered through celite, the solvent evaporated in vacuum and the resulting residue is dissolved in 2 M NH3in ethanol. This solution was stirred at room temperature for 1 h (for hydrolysis of the adduct of formic acid). A precipitate. This mixture is evaporated to dryness and purify the via column chromatography (SiO 2, DCM/MeOH, 10:1 to 5:1) to give the desired product as a white solid (10.5 g, 64%) TLC: DCM/MeOH, 5:1, Rf=0,23.

1H-NMR (400 MHz, CD3OD) δ 3.86-3.95 (m, 2H), 4.46 (t, J=5.27 Hz, 2H), 7.03 (dd, J=11.72, 8.01 Hz, 1H), 7.21 (td, J=8.11, 4.88 Hz, 1H), 7.47 (d, J=7.81 Hz, 1H), 8.13 (s, 1H). MS [M+H]calculated: 181, found: 181.

Stage b) of the intermediate compound 19

Synthesis of (7-fluoro-1H-benzimidazole-1-yl)acetic acid

2-(7-Fluoro-1H-benzimidazole-1-yl)ethanol (706 mg, to 3.92 mmol) are suspended in 20 ml of acetonitrile and 15 ml of 1 M sodium phosphate buffer (pH 6.5). The mixture is heated to 35°C. Add TEMPO (43 mg, 0.27 mmol), then NaClO2(80%, 887 mg, to 7.84 mmol)dissolved in 4 ml of water and diluted bleach (2 ml of a 0.4%aqueous solution). After adding the bleach reaction mixture becomes red-brown. To complete the reaction, if necessary, add more TEMPO (22 mg), NaClO2(440 mg in 2 ml water and diluted bleach (1 ml) and the mixture is stirred for 6 hours at 35°C. After cooling at room temperature the reaction mixture was quenched by adding saturated aqueous Na2SO3(5 ml). Red-brown color disappears. the pH was adjusted to 8-9 by adding 2 M NaOH and the mixture is washed with ethyl acetate (2x). The organic layer removed and the aqueous phase is acidified with 1 M HCl (to pH 3). The desired product crystallizes in the aqueous phase in the form of a white solid ve is esta (537 mg, 70%). TLC: dichloromethane/methanol, 10:1+5% triethylamine, Rf=0,33 (s.m.: Rf=0,56).

1H-NMR (400 MHz, CD3OD) δ 5.19 (s, 2H); 7.05 (dd, J=11.52, 8.20 Hz, 1H); 7.24 (td, J=8.15, 4.98 Hz, 1H); 7.49 (d, J=8.20 Hz, 1H); 8.19 (s, 1H). MS [M+H]calculated: 196, found: 195.

Scheme 6: Synthesis of 2-[4-(1-amino-ethyl)phenyl]-2-methylpropionitrile

Stage a) of the intermediate compound 20

Synthesis of 2-(4-bromophenyl)-2-methylpropionitrile.

Obtaining 2-(4-bromophenyl)-2-methylpropionitrile carried out as described in J. Med. Chem. (1995), no 38, page 1608-1628. Sodium hydride (60%suspension in oil, of 6.66 g, 166,3 mmol) is added in several portions over 1 hour to 2-(4-bromophenyl)acetonitrile (10 g, 51,0 mmol)dissolved in anhydrous DMF and methyliodide (14,838 g, 102,0 mmol) at 0°C. the solution becomes viscous and brown-orange paste. Leave it to mix with slow warming to room temperature (18 h). The organic solution was partitioned between water and ethyl acetate, separated, dried over anhydrous sodium sulfate and filtered. The solution is concentrated under reduced pressure and the crude product was then purified on silica gel using a gradient of 0-20% ethyl acetate in hexane, to give the desired compound (4.9 g, 42%) as a colourless oil.

1H-NMR (400 MHz, CHLOROFORM-D) δ million-11.71 (s, 6N), 7.35 (d, J=8.79 Hz, 2H), 7.52 (d, J=8.79 Hz, 2H).

Stage b) of the intermediate is giving 21

Synthesis of 2-(4-acetylphenyl)-2-methylpropionitrile.

2-(4-Bromophenyl)-2-methylpropionitrile (1 g, of 4.46 mmol) dissolved in anhydrous THF (75 ml), the solution is cooled to -100°C in a bath with diethyl ether and liquid nitrogen, add 2 M n-utility in hexane (4.0 ml, 8.0 mmol)and this reaction mixture was stirred for 10 minutes, then add N-methoxy-N-methylacetamide (1.6 g, 15.6 mmol)and the reaction mixture is then left to slowly warm to room temperature. After processing (washing with acidic brine) and concentration the crude mixture was purified on silica gel using a gradient of 0-50% ethyl acetate in hexane, to give the desired compound (660 mg, 78%) as a colourless oil.

1H-NMR (400 MHz, CHLOROFORM-D) δ million-11.76 (s, 6N), 2.62 (s, 3H), 7.59 (d, J=8.79 Hz, 2H), 7.99 (d, J=8.79 Hz, 2H).

Stage b) of the intermediate compound 22

Synthesis of 2-[4-(1-amino-ethyl)phenyl]-2-methylpropionitrile.

Getting 2-[4-(1-amino-ethyl)phenyl]-2-methylpropionitrile carried out in accordance with the General method described in Tetrahedron (2004), 60, page 1463-1471. The acetophenone, 2-(4-acetylphenyl)-2-methylpropionitrile (600 mg, is 3.21 mmol) was dissolved in 28%solution of ammonia in ethanol (20,0 ml). Add isopropyl titanium (1,82 g, 6.42 per mmol) and this reaction mixture is then left to mix for 18 h at room temperature. Sodium borohydride added in two portions, the eat allowed to mix for 3 hours Colourless solution slowly turns gray, then white, add water and the titanium oxide is removed by filtration. The organic solution was partitioned between water and ethyl acetate, separated, dried over anhydrous sodium sulfate and filtered. The solution is concentrated under reduced pressure. The resulting residue is dissolved in diethyl ether, filtered and added HCl in ether, the precipitate is filtered, then dried to give the desired product as HCl salt (500 mg, 69%) as a yellow solid.

1H-NMR (400 MHz, METHANOL-D4) δ million-11.61 (d, J=6.90 Hz, 3H), 1.70 (s, 6N), 4.46 (q, J=6.90 Hz, 1H), 7.49 (dt, J=8.64, 2.34, 2.10 Hz, 2H), 7.60 (dt, J=8.64, 2.10 Hz, 2H). MS [M+H] calculated: 189,1, found: 189,3.

Scheme 7: Synthesis of 2-(4-(1-amino-ethyl)-2-forfinal)-2-methylpropionitrile

Stage a) of the intermediate compound 23

Synthesis of 2-(4-bromo-2-forfinal)-2-methylpropionitrile

2-(4-Bromo-2-forfinal)-2-methylpropionitrile obtained from (4-bromo-2-forfinal)acetonitrile (10 g, 51,0 mmol) using the method described above for intermediate connection 20, to give the desired product (11 g, 89%) as a crude pale yellow oil, which does not require additional purification.

1H-NMR (400 MHz, CHLOROFORM-D) δ million-11.77 (d, J=0.78 Hz, 6N), 7.24-7.40 (m, 3H).

Stage b) of the intermediate compound 24

Synthesis of 2-(4-acetyl-2-forfinal)-2-IU is ispropanol

2-(4-Acetyl-2-forfinal)-2-methylpropionitrile obtained from (4-bromo-2-forfinal)acetonitrile (5.0 g, 21,0 mmol) using the method described for intermediate 21, to give the desired product (4.15 g, 99%) as a crude yellow oil, which is not clear later after processing.

1H-NMR (400 MHz, CHLOROFORM-D) δ million-11.79-1.81 (m, 6N), 2.58 (s, 3H), 7.60 (t, J=7.91 Hz, 1H), 7.65 (dd, J=12.40, 1.46 Hz, 1H), 7.72 (dd, J=8.11, 1.86 Hz, 1H).

Stage b) of the intermediate compound 25

Synthesis of 2-(4-(1-amino-ethyl)-2-forfinal)-2-methylpropionitrile

2-(4-(1-amino-ethyl)-2-forfinal)-2-methylpropionitrile obtained from the crude (4-acetyl-2-forfinal)acetonitrile (2.4 g, 11.7 mmol) using the method described for intermediate 22, to give the desired product as HCl salt (2.1 g, 67%) as a crude pale yellow oil, which does not require additional purification after processing.

1H-NMR (400 MHz, DMSO-D6) δ million-11.19 (d, J=6.44 Hz, 3H), 1.67 (s, 6N), 1.95 (s, 3H) 3.95 (q, J=6.44 Hz, 1H), 7.19 (dd, J=8.11, 1.66 Hz, 1H), 7.26 (dd, J=13.48, 1.56 Hz, 1H), 7.34 (t, J=8.30 Hz, 1H). MS [M+H] calculated: 207,13 found: 207,15.

Scheme 8: Synthesis of 2-{4-(aminomethyl)-2-forfinal)-2-methylpropionitrile

Stage a) of the intermediate compound 26

Synthesis of 2-(4-formyl-2-forfinal)-2-methylpropionitrile

2-(4-Formyl-2-forfinal)-2-methylpropionitrile and get the (4-bromo-2-forfinal)acetonitrile (5,2 g, 21.5 mmol) and N-methoxy-N-methylformamide (3.8 g, 43,0 mmol) using method similar to the method described for intermediate 21, to give the desired product which is used directly in the next stage.

1H-NMR (400 MHz, CHLOROFORM-D) δ million11.82 (s, 3H), 1.81 (s, 3H), 7.59 (dd, J=11.62, 1.07 Hz, 1H), 7.65-7.74 (m, 2H), 9.97 (d, J=1.95 Hz, 1H).

Stage b) of the intermediate compound 27

Synthesis of 2-(4-(aminomethyl)-2-forfinal)-2-methylpropionitrile

2-(4-(1-amino-ethyl)-2-forfinal)-2-methylpropionitrile obtained from the crude (4-acetyl-2-forfinal)acetonitrile (untreated 26) using the General method described for intermediate 22, to give the desired product as HCl salt (1.2 g, 16% for stages a and b) as a crude pale yellow oil, which does not require additional purification after processing.

1H-NMR (400 MHz, CHLOROFORM-D) δ 1.77 (s, 6N), 4.13 (s, 2H), 7.31 (d, J=10.55 Hz, 2H), 7.58 (t, J=8.11 Hz, 1H). MS [M+H] calculated: 193,1, found: 193.3 M..

Scheme 9: Synthesis of 1-[4-(1-amino-ethyl)phenyl]cyclobutanecarbonitrile

Stage a) of the intermediate compound 28

Synthesis of 4-(1-cyanocyclohexyl)benzonitrile

Solid KHMDS (3,48 g, 17.5 mmol) dissolved in THF (20,0 ml) and cooled to 0°C. Add cyclobutanecarbonitrile (1.42 g, 17.5 mmol) and the resulting solution was stirred for 40 minutes. Add a solution of perbenzoate (2,12 g, 17.5 mmol) in THF (10.0 ml) and the mixture is stirred for 2 hours at 0°C. To the reaction mixture add 1 N. HCl (50,0 ml) and the aqueous phase extracted with EtOAc (4×40,0 ml). The combined organic phases are dried over MgSO4, filtered and concentrated on a rotary evaporator. The product was then purified using flash chromatography (CombiFlash), elwira mixture of heptanol and EtOAc (from 0% EtOAc to 40% EtOAc), to give the desired product (1,76 g, 9,67 mmol, 55%).1H-NMR (400 MHz, DMSO-D6) δ million-11.92-2.12 (m, 1H), 2.19-2.37 (m, 1H), 2.57-2.69 (m, 2H), 2.71-2.82 (m, 2H), 7.67 (d, J=8.59 Hz, 2H), 7.91 (d, J=8.79 Hz, 2H).

Stage b) of the intermediate compound 29

Synthesis of 1-[4-(1-amino-ethyl)phenyl]cyclobutanecarbonitrile

4-(Cyanocinnamate)benzonitrile (335 mg, of 1.84 mmol) is mixed with THF (10.0 ml) and cooled to -78°C in gaseous N2. Added MeLi (1,15 ml of 1.84 mmol, 1.60 M in Et2O) and the mixture was stirred at -78°C for 15 minutes. Add the mixture NaBH4(70.0 mg, of 1.84 mmol) in Meon (10.0 ml) and the solution heated to 0°C for 1 hour. Add 1 N. HCl (40,0 ml) and the solution concentrated to dryness on a rotary evaporator. The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Synergi Gemini (5 μm) of 21.2×50 mm (high pH), mobile phase: a = water (10 mm NH4CO3) B = MECN, (95,0 mg, 0.475 mmol, 26%).1H-NMR (400 MHz, DMSO-D6) δ million-11.23 (d, J=6.64 Hz, 3H), 1.90-2.06 (m, 1H), 2.16-2.35 (m, 1H), 2.52-2.64 (m, 2H), 2.64-2.78 (m, 2H), 4.00 (q, J=6.64 Hz, 1H),7.36 (d, J=8.59 Hz, 2H), 7.42 (d, J=8.20 Hz, 2H).

Scheme 10: Synthesis of 1-[4-(1-amino-ethyl)phenyl]-cyclopropanecarbonitrile

Stage a) of the intermediate compound 30

Synthesis of 4-(1-cyanocyclohexyl)benzonitrile

Solid KHMDS (6,82 g, to 34.3 mmol) dissolved in THF (60,0 ml) and cooled to -40°C. Add cyclopropanecarbonitrile (2.30 g, to 34.3 mmol) and the resulting solution was stirred for 30 minutes. Add a solution of 4-perbenzoate (4.15 g, to 34.3 mmol) in THF (20,0 ml) and the mixture is stirred for 20 minutes at -40°C, then for 2 hours at room temperature. Add a saturated solution of NaHCO3(50,0 ml) and the aqueous phase extracted with EtOAc (4×40,0 ml). The combined organic phases are dried over MgSO4, filtered and concentrated on a rotary evaporator. The product was then purified using flash chromatography (CombiFlash), elwira mixture of heptanol and EtOAc (from 0% EtOAc to 70% EtOAc) (743 mg, was 4.42 mmol, 13%).1H-NMR (400 MHz, DMSO-D6) δ million-11.60-1.67 (m, 2H), 1.84-1.90 (m, 2H), 7.49 (d, J=8.59 Hz, 2H), 7.85 (d, J=8.79 Hz, 2H).

Stage b) of the intermediate compound 31

Synthesis of 1-[4-(1-amino-ethyl)phenyl]cyclopropanecarbonitrile

4-(Cyanocobalamin)benzonitrile (132 mg, 0.786 mmol) is mixed with THF (10.0 ml) and cooled to -78°C in gaseous N2. Added MeLi (0,639 ml of 1.02 mmol, 1.60 M in Et2O) and the mixture was stirred at -78°C for 60 minutes. Add the mixture NaBH4(39,0 mg of 1.02 mmol) in Meon (10 ml) and the solution heated to 0°C for 1 hour. Add 1 N. HCl (40,0 ml) and the solution concentrated to dryness on a rotary evaporator. The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Synergi Gemini (5 μm) of 21.2×50 mm (high pH), mobile phase: a = water (10 mm NH4CO3) B = MECN, (23,0 mg, 0,0623 mmol, 14%).1H-NMR (400 MHz, DMSO-D6) δ million-11.32 (d, J=6.64 Hz, 3H), 1.42-1.51 (m, 2H), 1.66-1.77 (m, 2H), 4.09-4.20 (m, J=6.84 Hz, D), 7.30 (d, J=8.59 Hz, 2H), 7.42 (d, J=8.20 Hz, 1H).

Scheme 11: Synthesis of 1-[4-(1-amino-ethyl)phenyl]-cyclohexanecarbonitrile

Stage a) of the intermediate compound 32

Synthesis of 4-(1-cyanocyclohexyl)benzonitrile

Solid KHMDS (4,36 g of 22.0 mmol) dissolved in THF (80,0 ml) and cooled to 0°C. Add cyclohexanecarbonitrile (2.38 g, 22,0 mmol) and the resulting solution was stirred for 40 minutes. Add a solution of 4-perbenzoate (1,33 g, 10,95 mmol) in THF (10.0 ml) and the mixture is stirred for 2 hours at 0°C and 10 hours at room temperature. Add 1 N. HCl (50,0 ml) and the aqueous phase extracted with EtOAc (4×50,0 ml). The combined organic phases are dried over MgSO4, filtered and concentrated on a rotary evaporator. The product was then purified using flash chromatography (CombiFlash), elwira mixture of heptanol and EtOAc (from 0% EtOAc to 30% EtOAc) (1.55 g, 7,38 mmol, 67%).1H-NMR (400 MHz, DMSO-D6) δ million-11.23-1.38 (m, 1H), 1.52-1.68 (m, 2H), 1.68-1.78 (m, 1H), 1.78-1.93 (m, 4H), 2.00-2.11 (m, 2H), 7.75 (d, J=8.79 Hz, 2H),7.91 (d, J=8.79 Hz, 2H).

Stage b) of the intermediate compound 33

Synthesis of 1-[4-(1-amino-ethyl)phenyl]cyclohexanecarbonitrile

4-(Cyanocyclohexyl)benzonitrile (1.55 g, 7,38 mmol) is mixed with THF (40,0 ml) and cooled to -78°C in gaseous N2. Added MeLi (9,23 ml of 14.8 mmol, 1.60 M in Et2O) and the mixture was stirred at -78°C for 60 minutes. Add the mixture NaBH4(558 mg, of 14.8 mmol) in Meon (40,0 ml) and the solution heated to 0°C for 2 hours. Add 1 N. HCl (50,0 ml) and the solution concentrated to dryness on a rotary evaporator. The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Synergi Gemini (5 μm) of 21.2×50 mm (high pH), mobile phase: a = water (10 mm NH4CO3) B = MECN, (510 mg, 2,24 mmol, 30%).1H-NMR (400 MHz, DMSO-D6) δ million-11.22 (d, J=6.64 Hz, 3H), 1.25-1.34 (m, 1H), 1.52-1.68 (m, 2H), 1.69-1.76 (m, 1H), 1.76-1.88 (m, 4H), 1.99-2.07 (m, 2H), 3.96 (q, J=6.51 Hz, 1H), 7.37-7.45 (m, 4H).

Scheme 12: Synthesis of (7-chloro-6-fluoro-1H-benzimidazole-1-yl)acetic acid.

Stage a) of the intermediate compound 34

2-[(2-Chloro-3-fluoro-6-nitrophenyl)amino]ethanol.

2-Chloro-1,3-debtor-4-nitrobenzene (lower than the 5.37 g, 27.7 mmol), ethanolamine (1,69 g, 27.7 mmol) and Et3N (2,80 g, 27.7 mmol) was stirred in EtOH (40,0 ml) at room temperature for 2 hours. The solvent is then evaporated and the resulting residue suspended in EtOAc (50,0 ml) and washed with 0.5 N. NaOH (50,0 ml). The aqueous phase extragear the Ute 4 times EtOAc (4×50,0 ml). The combined organic phases are dried with MgSO4filter and concentrate. The product was then purified using flash chromatography on silica gel, elwira mixtures of heptane and EtOAc (5.53 g, 85%).1H-NMR (400 MHz, DMSO-D6) δ million-13.39 (dd, J=10.55, 5.27 Hz, 2H), 3.53 (t, J=5.47 Hz, 2H), 4.89 (s, 1H), 6.89 (dd, J=9.37, 8.01 Hz, 1H), 7.19 (t, J=4.69 Hz, 1H), 8.01 (dd, J=9.47, 5.96 Hz, 1H).

Stage b) of the intermediate compound 35

2-[(6-Amino-2-chloro-3-forfinal)amino]ethanol.

2-[(2-Chloro-3-fluoro-6-nitrophenyl)amino]ethanol (5,52 g, 22.7 mmol) was dissolved in Meon (40,0 ml). The first solution is added a pre-mixed solution of Na2S2O4(13.8 g, 79.5 mmol) in water (40,0 ml). The resulting solution was stirred for 5 minutes at 60°C., then for 2 hours at room temperature. The solvent is evaporated and the resulting residue is suspended in a saturated solution of NaHCO3(40,0 ml). The aqueous phase is extracted 4 times with EtOAc (4×40,0 ml). The combined organic phases are dried with MgSO4filter and concentrate. The product is pure enough according to the1H-NMR (2,07 g, 45%).1H-NMR (400 MHz, DMSO-D6) δ million-12.99 (m, 2H), 3.32 (s, 1H), 3.48 (t, J=5.57 Hz, 2H), 4.09 (s, 1H), 4.73-4.95 (m, 2H), 6.55 (dd, J=8.79, 5.66 Hz, 1H), 6.71 (t, J=8.89 Hz, 1H).

Stage b) of the intermediate compound 36

2-(7-Chloro-6-fluoro-1H-benzimidazole-1-yl)ethanol.

2-[(6-Amino-2-chloro-3-forfinal)amino]ethanol (2,07 g, 10.2 mmol) was dissolved in formic acid (50,0 ml) the resulting solution was heated to 100°C for 1 hour. The solution is cooled to room temperature and then evaporated to dryness. The residue is suspended in NH3(50,0 ml, 2 N. in EtOH) and stirred for 1 hour. The solution is concentrated to dryness and the residue suspended in EtOAc (50,0 ml). The organic phase is washed with 2 N. NaOH (50,0 ml) and the resulting aqueous phase is extracted 4 times with EtOAc (4×50,0 ml). The combined organic phases are dried with MgSO4filter and concentrate. The product is dissolved in EtOAc, filtered and recrystallized from EtOAc (895 mg, 41%).1H-NMR (400 MHz, DMSO-D6) δ million-13.74 (t, J=5.27 Hz, 2H), 4.52 (t, J=5.47 Hz, 2H), 4.99 (s, 1H), 7.25 (dd, J=10.16, 8.79 Hz, 1H), 7.64 (dd, J=8.79, 4.49 Hz, 1H), 8.21 (s, 1H).

Stage g) of the intermediate compound 37

(7-Chloro-6-fluoro-1H-benzimidazole-1-yl)acetic acid.

2-(7-Chloro-6-fluoro-1H-benzimidazole-1-yl)ethanol (550 mg, 2.57 mmol) was dissolved in Asón (20,0 ml). Added dropwise Jones reagentand(3,31 ml, 3.00 mmol, 0,907 M) and the solution stirred for 1 hour at room temperature. The solution was diluted with iPrOH (50,0 ml) and the solvents evaporated. To the solution add 6 N. NaOH to pH 11. The aqueous phase washed with EtOAc (50,0 ml) and the organic phase is extracted 3 times with water (3×50,0 ml). The combined aqueous phases are acidified with 12 N. HCl to pH 3. The aqueous phase is then extracted 4 times with EtOAc (4×50,0 ml). The combined organic phases are dried with MgSO4filter and concentrate. The product is pure enough according to1 H-NMR (236 mg, 40%).1H-NMR (400 MHz, DMSO-D6) δ million-15.18 (s, 2H), 7.24 (dd, J=10.16, 8.79 Hz, 1H), 7.64 (dd, J=8.79, 4.49 Hz, 1H), 8.13-8.30 (m, 1H).

andThe Jones reagent is prepared by mixing 997 mg CrO31.00 ml of H2SO4and 10.0 ml of water.

Alternative obtain (7-chloro-6-fluoro-1H-benzimidazo-1-yl)acetic acid

Stage 1. Synthesis of N-(2-chloro-3-fluoro-6-nitrophenyl)licensedialog ether

In a three-neck round-bottom flask equipped with nitrogen bubbler and a thermometer, download K2CO3(40,0 g, 289,3 mmol), licensedialog ester hydrochloride (17,4 g, 138,8 mmol) and 2-propanol (200 ml). The resulting mixture was stirred at room temperature for one hour. 3-Chloro-2,4-diplomarbeit (22,4 g, by 115.7 mmol, 1 EQ.) loaded into the reaction mixture, which becomes yellow suspension. This suspension is stirred at room temperature for 18 hours the reaction is controlled using the1H-NMR spectroscopy.

After confirming completion of the reaction the mixture is diluted with iPrOAc (560 ml) and to the above mixture are added dropwise 1 M HCl (225 ml) (control allocation of CO2) with vigorous stirring. Dark yellow suspension becomes transparent and colorless two-phase solution. The organic layer is separated and washed with 1 M HCl (3×100 ml) and then dried over MgSO4. The desiccant filter, the comfort and the filtrate is evaporated to dryness on a rotary evaporator to obtain the crude product as a yellow solid (29,1 g), which according to the1H-NMR is very clean.

1H-NMR (400 MHz, CDCl3) δ: 8.08 (ddd, 1H), 6.7 (m, 1H), 4.35 (s, 2H), 3.8 (s, 3H).

The reaction mixture is subjected to monitoring by taking aliquots of the reaction mixture in iPrOAc, clearing her 1 N. HCl and then separation and evaporation of the organic layer to dryness and analysis of the obtained yellow solid with1H-NMR.

Stage 2. The conversion of N-(2-chloro-3-fluoro-6-nitrophenyl)licensedialog ether (7-chloro-6-fluoro-1H-benzimidazo-1-yl)acetic acid hydrochloride

A.

Into the flask Parra for hydrogenation download N-(2-chloro-3-fluoro-6-nitrophenyl)glycemically ester (15 g, of 60.8 mmol) of formic acid (150 ml). The resulting mixture is heated to about 50°C with the formation of a clear solution which is cooled to room temperature. To this solution was added 5% Pd-C (0.6 g, 4 wt.%) and the reaction mixture hydronaut at 40 pounds per square inch (275,8 kPa) for 3 hours Completion of the reaction is confirmed with1H-NMR.

Also carry out the same reaction using 12.3 g (49,8 mmol) of N-(2-chloro-3-fluoro-6-nitrophenyl)licensedialog ether, 125 ml of formic acid and 0.5 g catalyst.

After confirming completion of the reaction, the reaction mixture after the above two experiments was filtered through a funnel of porous glass over a layer is TA. The filter cake is washed with hot formic acid (60°C) up until the filtrate becomes colorless. The filtrate is evaporated to dryness under reduced pressure and the resulting brown precipitate is dried in a vacuum oven at 60°C for 3 hours to obtain a brown solid (24.2 g). Hydrogenation leads to the formation of a mixture of products, which transform in the benzimidazole as follows.

This is the crude substance was dissolved in formic acid (242 ml) and conc. HCl (242 ml). The resulting mixture is heated to the temperature of reflux distilled and incubated for 2 hours After confirming completion of the reaction1H-NMR, the reaction mixture was evaporated to dryness on a rotary evaporator. The obtained solid residue is dissolved in 300 ml of MeCN with formation of a suspension, which is again concentrated to dryness. The obtained brown solid residue triturated with 300 ml of MeCN at room temperature for one hour. The solid is collected by filtration and dried in a vacuum oven at 60°C for 18 h to give the desired product (23,2 g, 79%) as cleaners containing hydrochloride salt.1H-NMR (400 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.83 (dd, 1H), 7.52 (t, 1H), 5.5 (s, 2H).

Stage 3. The selection of the desired (7-chloro-6-fluoro-1H-benzimidazole-1-yl)acetic acid.

Cleaners containing hydrochloride salt of the desired acid (5 g) is suspended in the e (25 ml). Under moderate stirring to this suspension is added dropwise 2 M NaOH until then, until all has dissolved, to obtain a transparent brown solution. This aqueous solution was washed with EtOAc (2×25 ml). The aqueous layer was separated and acidified by adding dropwise 1 M HCl up until the pH of the reaction mixture reaches about 4.2. Formed suspension which is cooled to 0-5°C., immersing in a bath of ice and water and soaking for one hour under moderate stirring. The solid is collected by filtration and the filter cake dried in the air during the weekend to give the desired product 37 as a pale brown solid (2.5 g, 60%).

Scheme 13: Synthesis of (6-chloro-7-fluoro-1H-benzimidazole-1-yl)acetic acid.

Stage a) of the intermediate compound 38

2-(6-Chloro-7-fluoro-1H-benzimidazole-1-yl)ethylformate

1,3-Dichloro-2-fluoro-4-nitrobenzene (9,70 g, 46.2 mmol), ethanolamine (7,05 g, 231,0 mmol) was stirred in EtOH (25,0 ml) at 60°C for 24 hours. The solvent is then evaporated and the resulting residue is dissolved in Meon (150,0 ml). The first solution is added a pre-mixed solution of Na2S2O4(23.7 g, to 136.4 mmol) in water (100 ml). The resulting solution was stirred for 30 minutes at 60°C. the Solvent is evaporated and the resulting residue is suspended in a saturated solution NaHCOsub> 3(40,0 ml). The aqueous phase is extracted 4 times with EtOAc (4×100,0 ml). The combined organic phase was filtered and concentrated. The crude substance is heated at 100°C in formic acid (60,0 ml) for 3 hours, then stirred at room temperature for 18 hours, the Reaction mixture was concentrated under reduced pressure, to the obtained residue, add conc. the sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (3×100 ml). The combined organic phases are dried with MgSO4filter and concentrate. The obtained solid is triturated with methanol to obtain the expected product 2-(6-chloro-7-fluoro-1H-benzimidazole-1-yl)ethylformate (2.2 g, 19%).1H-NMR (400 MHz, CHLOROFORM-D) δ million-14.49-4.62 (m, 2H), 4.64-4.77 (m, 2H), 7.31 (dd, J=8.59, 7.03 Hz, 1H), 7.46 (d, J=8.59 Hz, 1H), 8.02 (s, 1H), 8.23 (s, 1H).

Stage b) of the intermediate compound 39

2-(6-Chloro-7-fluoro-1H-benzimidazole-1-yl)ethanol.

2-(6-Chloro-7-fluoro-1H-benzimidazole-1-yl)ethylformate (1.1 g, a 4.53 mmol) was dissolved in Meon (50,0 ml) with triethylamine (5.0 ml) and stirred at room temperature for 18 hours. The reaction mixture was then concentrated to obtain the expected product 2-(6-chloro-7-fluoro-1H-benzimidazole-1-yl)ethanol (0.95 g, 98%) as a white powder.1H-NMR (400 MHz, METHANOL-D4) δ million-13.90 (t, J=4.69 Hz, 2H), 4.47 (t, J=5.08 Hz, 2H), 7.30 (dd, J=8.79, 6.84 Hz, 1H, 7.45 (dd, J=8.59, 0.78 Hz, 1H), 8.16-8.19 (m, 1H).

The study is in) intermediate connection 40

(6-Chloro-7-fluoro-1H-benzimidazole-1-yl)acetic acid.

2-(6-Chloro-7-fluoro-1H-benzimidazole-1-yl)ethanol (800 mg, 3,74 mmol) poured into 40 ml of MeCN and sodium phosphate buffer (30 ml, 0.67 M, pH 6.8) and the mixture is heated to 36°C. Add TEMPO (174 mg, 1.12 mol), followed by simultaneously adding dropwise the solution of NaClO2(201 mg, 80% purity, of 2.23 mmol in 15 ml of water and bleach solution (500 μl of a 6%aqueous solution of NaOCl) for 2 hours. After 24 hours the reaction mixture is allowed to cool to room temperature, then added dropwise a saturated solution of Na2SO3. Using conc. HCl, the pH was lowered to 1 and the precipitated white powder, which is filtered and washed with a few drops of distilled water. The obtained solid is dried in vacuum to obtain the expected product (7-chloro-6-fluoro-1H-benzimidazole-1-yl)acetic acid (540 mg, 63%) as a white powder.1H-NMR (400 MHz, METHANOL-D4) δ million-14.08 (s, 2H), 6.50 (dd, J=8.59, 7.03 Hz, 1H), 6.66 (d, J=8.59 Hz, 1H), 7.37 (s, 1H).

Scheme 14: Synthesis of 4-[4-(1-amino-ethyl)-3-were]tetrahydro-2H-thiopyran-4-carbonitrile

Stage a) of the intermediate connection 41

Tetrahydro-2H-thiopyran-4-carbonitrile

A mixture of tetrahydro-4H-thiopyran-4-it (8.0 g, 68,9 mmol), toiletriesthe (of 14.76 g of 75.6 mmol) and 1,2-dimethoxyethane (400 ml) is stirred under nitrogen atmosphere at 0°C in an ice bath, if e is ω slowly adding a solution of t-BuOK in THF (1.0 M, 15.1 mmol) via syringe. Mixture was allowed to warm to room temperature with stirring for 5 hours. The content is again cooled to 0°C in an ice bath and add water (10.0 ml) to extinguish the reaction. The solvent is removed on a rotary evaporator and in a vessel add EtOAc (100 ml) and saturated aqueous NaHCO3(100 ml). The phases are separated and the organic phase is washed with brine, dried with Na2SO4and concentrate to a residue, which was purified by column chromatography on silica gel (EtOAc/hexane) to give the product (3.5 g, 27.6 mmol, 41%).1H-NMR (400 MHz, DMSO-D6) δ million-11.79-1.94 (m, 2H), 1.97-2.14 (m, 2H), 2.51-2.73 (m, 4H), 2.96-3.10 (m, 1H).

Stage b) of the intermediate compound 42

4-(4-Cyano-3-were)tetrahydro-2H-thiopyran-4-carbonitrile

A solution of tetrahydro-2H-thiopyran-4-carbonitrile (197 mg, 1.55 mmol) and THF (2.0 ml) is added slowly via syringe to a mixture of KHMDS (324 mg, and 1.63 mmol) in THF (3.0 ml), stirring at -78°C under nitrogen atmosphere. The temperature of the support at -78°C for 30 min, then the vessel slowly add a mixture of 4-fluoro-2-methylbenzonitrile (222 mg, of 1.64 mmol) in THF (1.0 ml). Mixture was allowed to warm to room temperature and stirred for 3 hours, then quenched with saturated aqueous NH4Cl. The solvent is removed on a rotary evaporator and add EtOAc (10.0 ml) and water (10.0 ml). The phases are separated and the organic phase is washed with RA is Saul, dried with Na2SO4and concentrate to obtain the product (252 mg, 1.04 mmol, 67%).1H-NMR (400 MHz, DMSO-D6) δ million-11.84-1.95 (m, 2H), 2.03-2.14 (m, 2H), 2.51 (s, 3H), 2.57-2.72 (m, 4H), 7.23-7.31 (m, 1H), 7.41 (dd, J=9.96, 1.76 Hz, 1H), 7.89 (dd, J=8.59, 5.86 Hz, 1H).

Stage b) of the intermediate compound 43

4-[4-(1-amino-ethyl)-3-were]tetrahydro-2H-thiopyran-4-carbonitrile

4-(4-Cyano-3-were)tetrahydro-2H-thiopyran-4-carbonitrile (983 mg, 4,06 mmol) stirred in THF (40,0 ml) at -78°C. in a nitrogen atmosphere as in the vessel via syringe slowly added 1.6 M solution metallice in Et2O. the Contents stirred for 3 hours at -20°C, then quenched Meon (40,0 ml) and warmed to room temperature. Slowly add NaBH4(460 mg, 12.2 mmol) at 0°C in an ice bath and the mixture is heated to room temperature and stirred for 16 hours. Add to 1.0 N. aqueous HCl to pH 3.0, and the solvent is removed on a rotary evaporator. To the residue add concentrated aqueous HCl (3.0 ml) and the mixture is stirred for 16 hours. Content neutralized with 1.0 M aqueous NaOH and add EtOAc (40,0 ml). The layers are separated and the organic layer is dried with Na2SO4and concentrate to a residue, which was purified column chromatography on silica gel (10% Meon in DCM) (253 mg, 1.05 mmol, 26%).

Scheme 15: Synthesis of 2-[4-(1-amino-ethyl)-3-were]-2-methylpropionitrile

Stage a) of the intermediate compound 44

(4-Bromo-3-were)methanol

Methyl-4-bromo-3-methylbenzoate (17.0 g, 74,2 mmol) dissolved in anhydrous THF (100 ml). The solution is cooled to 0°C. and to the mixture is added 2 M solution of lithium aluminum hydride in THF (40 ml). The solution is allowed to mix for 30 min at this temperature. Then the reaction mixture is added dropwise a cold solution of HCl to dissolve the complex of aluminum. The desired product is extracted with ethyl acetate, the organic phase is washed with brine (200 ml), dried with MgSO4and concentrated in vacuo to obtain the expected product (4-bromo-3-were)methanol (14.4 g, 97%) as a clear yellow oil, pure according to proton NMR, and used in this form in the next stage.1H-NMR (400 MHz, CHLOROFORM-D) δ million-1is 2.40 (s, 3H), 4.61 (s, 2H), 6.89-7.10 (m, J=8.20, 1.56, 0.59 Hz, 1H), 7.23 (d, J=2.34 Hz, 1H), 7.50 (d, J=8.20 Hz, 1H).

Stage b) of the intermediate compound 45

1-Bromo-4-(methyl bromide)-2-methylbenzo

(4-Bromo-3-were)methanol (14.4 g, 71,6 mmol) dissolved in anhydrous CH2Cl2(150 ml) and add CBr4(26,1 g, 79,0 mmol). The reaction mixture was cooled to 0°C and small portions add PPh3(20.7 g, 79,0 mmol). The reaction mixture was stirred for 2 h and the resulting triphenylphosphine oxide is filtered, and the solvent is removed in vacuum. The obtained semi-solid, vases is all filtered through a layer of silica gel and washed with hexane/EtOAc (9:1) to obtain the expected product 1-bromo-4-(methyl bromide)-2-methylbenzoyl in the form of a clear oil, contaminated bromoform, which are used directly in the next stage.1H-NMR (400 MHz, CHLOROFORM-D) δ million-14.39-4.44 (m, 3H), 7.07 (dd, J=8.20, 2.34 Hz, 1H), 7.26 (t, J=1.17 Hz, 1H), 7.49 (d, J=8.20 Hz, 1H).

Stage b) of the intermediate compound 46

2-(4-Bromo-3-were)acetonitrile

1-Bromo-4-(methyl bromide)-2-methylbenzo (45 with untreated stage b, 68.2 mmol)dissolved in CH2Cl2(500 ml), mixed and stirred with potassium cyanide (24 g, 364 mmol) and N-Tetra(n-butyl)ammonium bromide (1.2 g, of 3.64 mmol) in distilled water (500 ml). This reaction mixture was vigorously stirred for 6 hours the Organic phase is separated, dried over MgSO4filter and concentrate. The obtained residue is purified on silica gel using a gradient from 0 to 30% ethyl acetate in heptane, to obtain the expected product 2-(4-bromo-3-were)acetonitrile (12.4 g, 87% after two steps) as a clear yellow oil.1H-NMR (400 MHz, CHLOROFORM-D) δ million-12.41 (s, 3H), 3.68 (s, 2H), 7.01 (dd, J=8.50, 2.05 Hz, 1H), 7.21 (d, J=1.37 Hz, 1H), 7.53 (d, J=8.20 Hz, 1H).

Stage g) of the intermediate compound 47

2-(4-Bromo-3-were)-2-methylpropionitrile

To a stirred solution of 2-(4-bromo-3-were)acetonitrile (11.2 g, 53,3 mmol) in anhydrous DMF (125 ml) add methyliodide (13,2 ml, 213 mmol). The solution is cooled to 0°C and small portions add sodium hydride (60%suspension in oil, of 3.84 g, 160 the mol) over 20 minutes The reaction mixture is then left to mix and slowly warmed to room temperature for 18 hours and Then at 0°C. slowly add water (500 ml), then extracted with ethyl acetate containing 10% of hexanol. The organic layer is separated, dried with MgSO4filter and concentrate under reduced pressure to obtain the expected product 2-(4-bromo-3-were)-2-methylpropionitrile (12,6 g, 99%) as a clear yellow oil, which was used in the next stage without additional purification.1H-NMR (400 MHz, CHLOROFORM-D) δ million-11.71 (s, 6N), 2.43 (s, 3H), 7.14 (dd, J=8.40, 2.34 Hz, 1H), 7.34 (d, J=2.54 Hz, 1H) 7.53, (d, J=8.40 Hz, 1H).

Stage d) intermediate connection 48

2-(4-Acetyl-3-were)-2-methylpropionitrile

To a stirred solution of 2-(4-bromo-3-were)-2-methylpropionitrile (5.0 g, 21,0 mmol) in anhydrous THF (75 ml) at -100°C. add n-utility (2 M in hexane) (21 ml, 42 mmol). This reaction mixture is stirred at this temperature for 5 minutes, then add N-methoxy-N-methylacetamide (4,33 g, 42 mmol). Then the solution is warmed to room temperature over 1 h and Then slowly add the acid brine (30 ml brine, 15 ml of 3%aq. HCl) and the solution extracted with EtOAc (3×100 ml). The organic layer is dried over MgSO4filter and concentrate under reduced pressure. The crude product is purified on silica gel using gradie the t from 0 to 30% EtOAc in heptane, to obtain the expected product 2-(4-acetyl-2-were)-2-methylpropionitrile (1.0 g, 24%).1H-NMR (400 MHz, CHLOROFORM-D) δ million-11.71 (s, 6N) 2.53 (s, 3H), 2.56 (s, 3H), 7.30-7.38 (m, 2H), 7.70 (d, J=8.01 Hz, 1H).

Stage e) of the intermediate compound 49

2-[4-(1-amino-ethyl)-3-were]-2-methylpropionitrile

To a stirred solution of 2-(4-acetyl-3-were)-2-methylpropionitrile (1.0 g, equal to 4.97 mmol) in 7 M ammonia in the Meon (40 ml) add isopropyl titanium (IV) (3.0 g, 9,95 mmol). The reaction mixture was allowed to mix for 24 h at room temperature. After cooling to 0°C. add sodium borohydride (1.0 g, to 19.9 mmol) and the reaction mixture was stirred and allowed to warm to room temperature 1 hour Then add conc. ammonium hydroxide (15 ml) and the titanium oxide is removed by filtration and washed with ethyl acetate. The filtrate is extracted with EtOAc (2×100 ml) and the combined organic layers dried over MgSO4filter and concentrate under reduced pressure to obtain the expected product 2-[4-(1-amino-ethyl)-3-were]-2-methylpropionitrile (1.0 g, 99%) as a clear yellow oil.1H-NMR (400 MHz, CHLOROFORM-D) δ million11.33 (d, J=6.64 Hz, 3H), 1.44 (s, 2H) 1.70 (s, 6N) 2.36 (s, 3H), 4.34 (q, J=6.44 Hz, 1H) 7.22 (d, J=1.95 Hz, 1H), 7.28 (dd, J=8.20, 2.15 Hz, 1H), 7.48 (d, J=8.20 Hz, 1H).

Scheme 16: Synthesis of 2-[4-(1-amino-ethyl)-2-were]-2-methylpropionitrile

Stage a)of the intermediate compound 50

(4-Bromo-2-were)methanol

4-Bromo-2-methylbenzoic acid (11.1 g, 51.6 mmol) dissolved in anhydrous THF (11.2 ml). The solution is cooled to 0-5°C and the mixture was added 1 M solution NR3in THF (103 ml). The mixed solution is kept for 3 h at room temperature. Then add cold water (20 ml) and the reaction mixture is washed with a saturated solution of NaHCO3(120 ml). The aqueous phase is extracted with diethyl ether (3×300 ml) and the combined organic phases are washed with brine (200 ml), dried with MgSO4and concentrated in vacuo. The resulting oil purified flash chromatography, elwira a mixture of hexane/EtOAc from 95:5 to 70:30, to obtain the expected product (4-bromo-2-were)methanol (10.4 g, 100%) as a clear oil.

1H-NMR (300 MHz, CHLOROFORM-D): δ 7.36-7.30 (2H, m), 7.25-7.21 (1H, m), 4.65 (2H, s), 2.32 (3H, s).

Stage b) of the intermediate compound 51

1-Bromo-4-(methyl bromide)-3-methylbenzo

(4-Bromo-2-were)methanol (10.4 g, 51.6 mmol) was dissolved in anhydrous CH2Cl2(150 ml) and add GVS4(18,8 g of 56.8 mmol). The reaction mixture is cooled to 0-5°C and add PPh3(14.9 g, with 56.8 mmol). The reaction mixture was stirred over night, then add hexane/EtOAc (9:1) (250 ml) under vigorous stirring. The triphenylphosphine oxide, which is formed during the reaction is filtered and the filtrate concentrated in vacuo. Received mA is lo purify through a layer of silica gel with hexane/EtOAc (8:2). The solvent is removed on a rotary evaporator, and bromoform removed by vacuum distillation (15 mm Hg, because: 40-50°C) to obtain the expected product 1-bromo-4-(methyl bromide)-3-methylbenzene (13,23 g, 97%) as a yellow oil.1H-NMR (300 MHz, CHLOROFORM-D): δ 7.37-7.27 (2H, m), 7.17 (1H, d, J=8.1 Hz), 4.45 (2H, s), 2.39 (3H, s).

Stage b) of the intermediate compound 52

2-(4-Bromo-2-were)acetonitrile

1-Bromo-4-(methyl bromide)-3-methylbenzo (13,2 g, 50,1 mmol) dissolved in DMF (65 ml). The reaction mixture is cooled to 0-5°C. and added NaCN (3,66 g, 74,6 mmol), then water (8 ml). The reaction mixture was stirred over night at room temperature and add water (170 ml), and then feast upon. NaHCO3(130 ml) and hexane/Et2O (2:1) (150 ml). The organic phase is separated and the aqueous phase is extracted with a mixture of hexane/Et2O (2:1) (3×150 ml). The combined organic phases are washed with water (170 ml), dried over MgSO4filter and concentrate under reduced pressure to obtain the expected product 2-(4-bromo-2-were)acetonitrile (9,76 g, 93%) as an orange oil.1H-NMR (300 MHz, CHLOROFORM-D): δ 7.40-7.32 (2H, m), 7.23 (2H, d, J=8,2 Hz), 3.61 (2H, s), 2.32 (3H, s).

Stage g) of the intermediate compound 53

2-(4-Bromo-2-were)-2-methylpropionitrile

To a stirred solution of 2-(4-bromo-2-were)acetonitrile (3,93 g of 18.8 mmol) in anhydrous DMF (35 ml) add methyliodide (at 2.45 ml, to 39.4 mmol). The solution ohlajdauche 0°C and add sodium hydride (60%suspension in oil, 1.47 g, with 61.1 mmol) in 3 equal portions over 20 minutes, the Reaction mixture is then left to mix and slowly warmed to room temperature for 18 hours the Solution turns into a thick brown-orange paste. Then at 0°C. slowly add water (50 ml) and the solution extracted with a solution of hexane/Et2O, 2:1 (3×50 ml). The organic layer was washed with brine, dried with MgSO4filter and concentrate under reduced pressure. The crude product was then purified using flash chromatography elwira a mixture of hexane/EtOAc (9:1), to obtain the expected product 2-(4-bromo-2-were)-2-methylpropionitrile (3.1 g, 66%) as a clear yellowish oil.1H-NMR (300 MHz, CHLOROFORM-D): δ 7.40-7.30 (2H, m), 7.16 (2H, d, J=8.5 Hz), 2.63 (3H, s), 1.77 (6N, s).

Stage d) intermediate connection 54

2-(4-Acetyl-2-were)-2-methylpropionitrile

To a stirred solution of 2-(4-bromo-2-were)-2-methylpropionitrile (3.1 g, 13,0 mmol) in anhydrous THF (75 ml) at -78°C. add n-utility (2 M in hexane) (7,16 ml of 14.3 mmol). This reaction mixture is stirred at this temperature for 10 minutes, then add N-methoxy-N-methylacetamide (2,77 ml, 26.0 mmol) and then the solution is warmed to room temperature over 1 h and Then slowly add the acid brine (30 ml brine, 15 ml of 3%aq. HCl) and the solution extracted with EtOAc (3×100 ml). The organic layer is dried with MgSOsub> 4filter and concentrate under reduced pressure. The crude product was then purified using flash chromatography using a gradient from 5 to 20% EtOAc in hexane to obtain the expected product 2-(4-acetyl-2-were)-2-methylpropionitrile (1.77 g, 68%) as a yellowish oil.1H-NMR (300 MHz, CHLOROFORM-D): δ 7.84-7.74 (2H, m), 7.43-7.40 (1H, m), 2.70 (3H, s), 2.60 (3H, s), 1.81 (6N, s).

Stage e) of the intermediate compound 55

2-[4-(1-amino-ethyl)-2-were]-2-methylpropionitrile

To a stirred solution of 2-(4-acetyl-2-were)-2-methylpropionitrile (1,77 g 8,80 mmol) in 7 M ammonia in the Meon (45 ml) is added freshly distilled isopropyl titanium (IV) (5,20 ml, 17.6 mmol). The reaction mixture was left to mix for 18 h at room temperature. After cooling to 0°C. add sodium borohydride (500 mg, 13,2 mmol) and the reaction mixture stirred at 0°C until gas no longer stand out, and then at room temperature for 3 hours Then add water (25 ml) and the titanium oxide is removed by filtration on a Buechner funnel. The filtrate is extracted with EtOAc (3×100 ml) (add brine (10 ml) to facilitate separation between the two layers) and the combined organic layers are concentrated under reduced pressure. The crude product (which contains water) dissolved in Et2O (75 ml), washed with brine, dried over MgSO4 and filtered. To mix well the filtrate is added slowly 5-6 N. HCl in 2-propanol (2.2 ml). The obtained white precipitate was filtered on a Buechner funnel and dried in vacuum to obtain the expected product 2-[4-(1-amino-ethyl)-2-were]-2-methylpropionitrile (1,58 g, 75%) as a white solid.1H-NMR (300 MHz, CD3OD): δ 7.55 (1H, d, J=8.0 Hz), 7.44-7.37 (2H, m), 4.97 (3H, s), 4.52 (1H, q, J=6.9 Hz), 2.75 (3H, s), 1.86 (6N, s), 1.69 (3H, d, J=6.9 Hz).

Scheme 17: Synthesis of 2-[4-(1-amino-ethyl)-2-chlorophenyl]-2-methylpropionitrile

Stage a) of the intermediate compound 56

(4-Bromo-2-chlorophenyl)methanol

To a stirred solution of 4-bromo-2-chlorbenzoyl acid (4,27 g of 18.1 mmol) in tetrahydrofuran (39 ml) at 0°C. add borane-tertrahydrofuran ring complex (1 M in THF) (36,3 ml of 36.3 mmol). The reaction mixture was stirred for 16 h at room temperature. At 0°C. slowly add water, then slowly add aq. the feast upon. NaHCO3. The resulting solution was extracted with EtOAc (3×50 ml). The combined organic layer was washed with brine, dried over anhydrous MgSO4filter and concentrate under reduced pressure. The crude product was then purified using flash chromatography (eluent: hexane/EtOAc 85:15 to 70:30) to obtain the expected product (4-bromo-2-chlorophenyl)methanol (4,34 g, 108%).1H-NMR (300 MHz, CHLOROFORM-D): δ 7.53 (1H, d, J=1.8 Hz), 7.43 (1H, d, J=8.2, 1.8 Hz), 7.38 (1H, d, J=8.2 Hz), 4.74 (2H, d, J=6.2 Hz), 1,90 (1H, t, J=6.3 Hz).

Stage b) of the intermediate compound 57

4-Bromo-1-(methyl bromide)-2-chlorobenzene

To a stirred solution of (4-bromo-2-chlorophenyl)methanol (4,34 g and 19.6 mmol) in dichloromethane (98 ml) at 0°C. add tetrabromide carbon (6.5 g, a 19.6 mmol) and triphenylphosphine (5,14 g and 19.6 mmol). The reaction mixture was stirred for 16 h at room temperature. Then the solvent is removed and the crude solid is suspended in a mixture of hexane/EtOAc, 9:1 (100 ml), and filtered through a layer of silica gel. Layer was washed with a mixture of hexane/EtOAc, 9:1 (100 ml)and the filtrate was concentrated in vacuo to obtain the expected product 4-bromo-1-(methyl bromide)-2-chlorobenzene (7,19 g, 129%), contaminated bromoform.1H-NMR (300 MHz, CHLOROFORM-D): δ 7.57 (1H, d, J=2.0 Hz), 7.39 (1H, dd, J=8.2, 2.0 Hz), 7.30 (1H, d, J=8.2 Hz), 4.53 (2H, s).

Stage b) of the intermediate compound 58

2-(4-Bromo-2-chlorophenyl)acetonitrile

To a stirred solution of 4-bromo-1-(methyl bromide)-2-chlorobenzene (7,19 g, to 25.3 mmol) in dichloromethane (60 ml) and water (60 ml) is added tetrabutylammonium bromide (0,82 g of 2.53 mmol). Then add potassium cyanide (4.94 g, to 75.8 mmol) in water (60 ml). The resulting solution was stirred for 4 h at room temperature, and it quickly becomes orange. Then add saturated aq. the solution of NaHCO3and the mixture is extracted with CH2Cl2(3×100 ml). Obyedinenny the organic layer washed with brine, dried over anhydrous MgSO4and filtered through a layer of silica gel. Layer was washed with CH2Cl2and the filtrate concentrated under reduced pressure to obtain the expected product 2-(4-bromo-2-chlorophenyl)acetonitrile (5,38 g, 92%), contaminated bromoform.1H-NMR (300 MHz, CHLOROFORM-D): δ 7.60 (1H, d, J=1.9 Hz), 7.47 (1H, dd, J=8.3, 1.9 Hz), 7.39 (1H, d, J=8.3 Hz), 3.79 (2H, s).

Stage g) of the intermediate compound 59

2-(4-Bromo-2-chlorophenyl)-2-methylpropionitrile

To a stirred solution of 2-(4-bromo-2-chlorophenyl)acetonitrile (1,11 g, 4,82 mmol) in anhydrous DMF (7,6 ml) add methyliodide (0.63 ml, 10.1 mmol). The solution is cooled to 0°C and add sodium hydride (60%suspension in oil, 0,63 g, 15.7 mmol) in 5 portions over 1 h, the Reaction mixture is then left to mix with slow warming to room temperature for 18 hours the Solution turns into a thick brown-orange paste. Then slowly add water (20 ml) and the solution extracted with a solution of hexane/Et2O, 3:1 (3×25 ml). The organic layer was washed with brine, dried over MgSO4filter and concentrate under reduced pressure. The crude product was then purified using flash chromatography (eluent: hexane/EtOAc from 9:1 to 8:2) to obtain the expected product 2-(4-bromo-2-chlorophenyl)-2-methylpropionitrile (0,79 g, 63%).1H-NMR (300 MHz, CHLOROFORM-D): δ 7.61 (1H, d, J=2.1 Hz), 7.43 (1H, dd, J=8.5, 2.1 Hz), 7.34 (1H, d, J=8.6 G is), 1.85 (6N, s).

Stage d) intermediate connection 60

2-(4-Acetyl-2-chlorophenyl)-2-methylpropionitrile

To a stirred solution of 2-(4-bromo-2-chlorophenyl)-2-methylpropionitrile (2.85 g, 11.0 mmol) in anhydrous THF (60 ml) at -78°C add m-utility (2 M in hexane) (6,1 ml, 12.1 mmol). The reaction mixture is stirred at this temperature for 10 minutes, then add undiluted N-methoxy-N-methylacetamide (2,34 ml of 22.0 mmol) and the solution stirred for 10 min at -78°C and then warmed to room temperature for another one hour. Then slowly add the acid brine (60 ml) and the solution extracted with EtOAc (3×60 ml). The organic layer is dried over MgSO4filter and concentrate under reduced pressure. The crude product was then purified using flash chromatography (eluent: hexane/EtOAc from 1:0 to 7:3) to obtain the expected product 2-(4-acetyl-2-chlorophenyl)-2-methylpropionitrile (1,57 g, 64%) as a yellow oil.1H-NMR (300 MHz, CHLOROFORM-D): δ 7.96 (1H, d, J=1.9 Hz), 7.81 (1H, dd, J=8.3, 1.9 Hz), 7.55 (1H, d, J=8.3 Hz), 2.56 (3H, s), 1.85 (6N, s).

Stage e), the intermediate connection 61

2-(4-(1-amino-ethyl)-2-chlorophenyl)-2-methylpropionitrile hydrochloride

To a stirred solution of 2-(4-acetyl-2-chlorophenyl)-2-methylpropionitrile (1,57 g, was 7.08 mmol) in 7 M ammonia in a solution of methanol (35 ml) is added freshly distilled isopropyl titanium (IV) (4,2 ml of 14.2 mmol). Reactionuses leave mixed for 18 h at room temperature. After cooling to 0°C. add sodium borohydride (0.40 g, 10.6 mmol) and the reaction mixture was stirred at 0°C as long as you do not stop the gas, and then at room temperature for 4 hours Then add water (40 ml) and the titanium oxide is removed by filtration on a Buechner funnel. The filtrate is extracted with EtOAc (3×50 ml) and the combined organic layers are concentrated under reduced pressure. The obtained residue was dissolved in Et2O (200 ml), washed with brine, dried over anhydrous MgSO4and filtered. To this solution add 5 N. HCl in 2-propanol (1.8 ml, cent to 8.85 mmol). The precipitate is filtered on a Buechner funnel and dried to give the desired 2-(4-(1-amino-ethyl)-2-chlorophenyl)-2-methylpropionitrile hydrochloride (1,17 g, 64%) as a white solid.1H-NMR (300 MHz, CD3OD): δ 7.69 (1H, d, J=10.7 Hz), 7.68 (1H, s), 7.52 (1H, dd, J=8.3, 2.0 Hz), 4.53 (1H, q, J=6.8 Hz), 1.90 (6N, s), 1.66 (3H, d, J=6.9 Hz).13C-NMR (75 MHz, CD3OD): δ 142.5, 140.2, 136.0, 132.0, 130.1, 127.9, 52.0, 37.8, 28.4, 21.3.

Scheme 18: Synthesis of 2-[4-(aminomethyl)phenyl]-2-methylpropionitrile

Stage a) of the intermediate compound 62

4-(1-Cyano-1-methylethyl)benzonitrile

2-Methyl-2-(4-were)propanenitrile (3.51 g, 15.7 mmol) dissolved in dry DMF (10 ml). Added Zn(CN)2(2,02 g, and 17.2 mmol) and Pd(PPh3)4(906 mg, 5 mol.%) and the mixture is heated at 100°C for 3 hours. Reactio the ing mixture is diluted with water and the solid removed by filtration. The solid residue is dissolved in methanol, filtered to remove insoluble impurities, concentrated in vacuo and purified by using MPLC with direct phase (SiO2from hexane to EtOAc) to give 4-(1-cyano-1-methylethyl)benzonitrile (2.28 g, a 13.4 mmol, 85%) as a white solid.1H-NMR (400 MHz, DMSO-D6) δ million-11.70 (s, 6N), 7.73 (dt, J=8.64, 2.03 Hz, 2H), 7.92 (dt, J=8.69, 2.00 Hz, 2H).

Stage b) of the intermediate compound 63

2-[4-(Aminomethyl)phenyl]-2-methylpropionitrile

4-(1-Cyano-1-methylethyl)benzonitrile (2.28 g, 13,41 mmol) dissolved in dry THF and the solution cooled to 0°C. Added Red-Al (85%solution in toluene, 2,62 ml, 13,41 mmol hydride) and the reaction mixture was stirred at 0°C for 4 hours. The mixture is quenched with methanol and concentrated in vacuo. The residue is dissolved in CH2Cl2and washed with 2 portions of water, dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was then purified using MPLC with direct phase (SiO2from DCM to DCM/MeOH, 3:1) to give 2-[4-(aminomethyl)phenyl]-2-methylpropionitrile (900 mg, 5.17 mmol, 39%) as a colourless oil.1H-NMR (400 MHz, DMSO-D6) δ million-11.68 (s, 6N), 4.00-4.05 (m, 2H), 7.55 (q, J=8.59 Hz, 4H), 8.35 (broadened s, 2H).

Scheme 19: Synthesis of 2-[4-(aminomethyl)-3-were]-2-methylpropionitrile

Stage a) of the intermediate compound 64

2-(4-Formyl-3-were)-2-methylpropionitrile

2-(4-Bromo-3-were)-2-methylpropionitrile (of 3.31 g of 13.9 mmol) dissolved in dry THF (80 ml). The mixture is cooled to -78°C and added tert-BuLi (1.7 M in pentane, 18 ml of 30.6 mmol). After 30 minutes the reaction mixture was quenched with DMF (10 ml), the volatiles evaporated and the residue purified by using MPLC with direct phase (SiO2from heptane to heptane/EtOAc, 3:1) to give 2-(4-formyl-3-were)-2-methylpropionitrile (1.89 g, 10.2 mmol, 73%) as a colourless liquid.1H-NMR (400 MHz, DMSO-D6) δ million-11.70 (s, 6N), 2.64 (s, 3H), 7.49 (s, 1H), 7.55 (dd, J=8.01, 2.15 Hz, 1H), 7.86 (d, J=7.81 Hz, 1H), 10.22 (s, 1H).

Stage b) of the intermediate compound 65

2-[4-(Aminomethyl)-3-were]-2-methylpropionitrile

2-(4-Formyl-3-were)-2-methylpropionitrile (1.89 g, 10.2 mmol) dissolved in 50 ml of 7 M NH3in the Meon. Added Ti(OiPr)4(6 mmol, 20 mmol) and the mixture is stirred for 3 hours at room temperature. Added NaBH4(0.6 g, 15 mmol) and the reaction mixture is left at room temperature over night. The mixture was quenched by adding 25 ml of 2 M NH4OH. The precipitate is filtered off and washed with EtOAc. The phases are separated, the organic phase is dried over magnesium sulfate, filtered and evaporated to dryness to obtain 2-[4-(aminomethyl)-3-were]-2-methylpropionitrile (1,325 g, to 7.09 mmol, 87%). The crude product is used without further purification.1H-NMR (400 MHz, DMSO-D6) δ 1.64 (s, 6N, the first p is tamer), 1.65 (s, 6N, second rotamer), 2.28 (s, 3H, first of rotamer), 2.29 (s, 3H, second rotamer), 3.32 (broad s, 2H), 3.67 (s, 2H, first of rotamer), 3.68 (s, 2H, second rotamer), 7.24-7.27 (m, 1H) 7.28 (s, 1H), 7.36-7.40 (m, 1H).

Scheme 20: Compartment (S)-(-)-2-[4-(aminomethyl)-3-were]-2-methylpropionitrile from (R)-(+)-2-[4-(aminomethyl)-3-were]-2-methylpropionitrile

Stage a) of the intermediate compound 66, 67 and 68.

tert-Butyl N-[1-[4-(2-cyanoprop-2-yl)phenyl]ethyl]carbamate

To a stirred solution of racemic 2-[4-(1-amino-ethyl)phenyl]-2-methylpropanamide hydrochloride (1 g, of 3.97 mmol) in THF (12 ml) was added Et3N (2,22 ml, 15.9 mmol). Added dropwise di-tert-BUTYLCARBAMATE (0.87 g, of 3.97 mmol) in THF (2 ml) and the reaction mixture was stirred at room temperature for 18 hours the mixture is filtered through a layer of silica gel and washed with a solution of EtOAc and hexane, 1:1. The filtrate is concentrated under reduced pressure and the crude product is left to stand until such time as will not harden. Its clear by recrystallization in 30 ml of hexane to give the desired compound tert-butyl-N-[1-[4-(2-cyanoprop-2-yl)phenyl]ethyl]-carbamate (0.87 g, 68%) as a white solid vashista.

1H-NMR (300 MHz, CHLOROFORM-D): δ 7.44-7.41 (2H, m), 7.33-7.30 (2H, m), 4.80 (2H, s), 1.71 (6N, s), 1.44 (3H, s), 1.42 (S, s).

Two enantiomers of 67 and 68 separated on a chiral column CHIRALPAK ® AY ® using a mixture alue is that hexane:IPA (isopropanol) (9:1) at 25°C with UV detector, set at 220 nm. Two enantiomers were measurements of optical rotation [α]D=-76,2° (1,36, Meon) for isomer 67 and [α]D=+78,7° (C=1,20, Meon) for isomer 68.

Stage b) of the intermediate compound 69 (the same process is carried out to obtain 70 68).

S(-)2-[4-(1-amino-ethyl)phenyl]-2-methylpropionitrile

4 M hydrogen chloride (34,7 ml, 138,70 mmol) in dioxane are added to a solution of (-)tert-butyl N-[1-[4-(2-cyanoprop-2-yl)phenyl]ethyl]carbamate 67 (8.00 g, 27,74 mmol) in tetrahydrofuran (45 ml) at room temperature. The reaction mixture is stirred for 2 hours and the solvent concentrated to dryness. The residue is suspended in EtOAc (45 ml) and stirred for 1 hour. The solid is collected and air-dried to obtain the HCl salt of (S)-2-(4-(1-amino-ethyl)phenyl)-2-methylpropionitrile (between 6.08 g, 97%) as a white solid. Substance suspended in MTBE (80 ml) and added 2 M NaOH (40 ml). The mixture is gently stirred for 1 hour and the organic phase is separated. The aqueous phase is extracted with MTBE (40 ml). The combined organic layers dried over anhydrous MgSO4and the solvent concentrated to obtain the expected product of S(-)-2-[4-(1-amino-ethyl)phenyl]-2-methylpropionitrile (4,88 g, 93%) as a colourless oil.

1H-NMR (400 MHz, CHLOROFORM-D) δ million-11.39 (d, J=6.64 Hz, 3H), 1.53-1.63 (m, 2H), 1.68-1.76 (m, 6N), 4.14 (q, J=6.64 Hz, 1H), 7.34-7.40 (m, 2H), 7.41-7.46 (m, 2H). M (ESI, ionizaciya elektrorazpredelenie) (M+N)+188,9. [α]D=-21,0° (1.44, EtOH).

For the other isomer 70, obtained by the method described above, [α]D=+19,0° (C=0,39, EtOH)

Confirmation of the absolute configuration of intermediate compounds 69 and 70 using Vibrational Circular Dichroism (VCD).

A brief description.

This method involves the calculation of VCD spectra of the pure enantiomers, which can be determined the absolute configuration. These calculated spectra are then compared with the experimental VCD spectra obtained from chiral substances. Comparing specific spectral characteristics, constitute confirmation of the absolute configuration of the enantiomers.

Computer spectral model.

Search by molecular mechanics Monte Carlo simulation of low-energy conformers for 69 was performed using MacroModel in the graphical user interface Maestro (Schrödinger Inc.). 12 identified conformers with the lowest energy use as starting points and minimize using density functional theory (DFT) in Gaussian03.

For each of the conformers was determined optimized structure, frequency/intensity of harmonic oscillations, the rotational force VCD and free energies at STP (standard temperature and pressure (including zero energy fluctuations). In these races each used the generalized gradient approximation (GGA) B3LYP exchange-correlation density functionals. In particular, GGA is a combination of metabolic functionality Becke (3-parametric HF/DFT hybrid exchange functional [B3]) {Becke, A.D.J. Chem. Phys. 93, 98, 5648} with dynamic correlation functional of Lee-Yang-Parr (LYP) {Lee, C; Yang, W.; Parr, R.G. Phys. Rev. In 1988, 37, 785}. Used basis set 6-31G* {Hariharan, P.C.; Pople, J.A. Theor. Chim. Acta, 1973, 28, 213}.

IR and VCD spectra for each conformer receive outgoing files Gaussian 03 using one of the many programs to fit lorentzweg forms of spectral lines (the line width of 5 cm-1) to the calculated spectra. Thus, it can be made direct comparisons between the simulated and experimental spectra.

Experiment

30 mg 69 and 70, respectively, was dissolved in of 0.28 ml of d6-DMSO. The solutions were separately loaded in 0.1 mm BaF2infrared cell for analysis 4 cm-1resolution using 5-hour dehistoricised scan Protocol VCD. All analyses were conducted using the device ChiralR™ Bio Tools, Inc. The device consisted of one set of a photoelastic modulator for polarization modulation at 37,024 kHz with a λ/4 delay (optimized for the spectral region centered around 1400 cm-1). Used the increased synchronization with a time constant of 30 MS and a high-pass filter 20 kHz and the low pass filter 4 kHz.

Raza is Italy

Comparison of the infrared spectra of vibrational circular dichroism (VCD) with predicted VCD spectra (obtained as a result of calculations by the method of molecular mechanics and density functional theory) shows that the structure is consistent with the proposed S-configuration for intermediate compounds 69 and R-configuration for intermediate connection 70.

Scheme 21: Enantioselective synthesis of S(-)2-[4-(aminomethyl)-3-were]-2-methylpropionitrile

Stage a) of the intermediate compound 71

N-{(S,S)-1-[4-(1-Cyano-1-methylethyl)phenyl]ethyl}-2-methylpropan-2-sulfinamide.

In a 500 ml 3-necked round bottom flask equipped with a thermometer, inlet for nitrogen, a rubber gasket and a magnetic stirrer, download 8,13 g (36,93 mmol, presumably containing 85% only ketone) arylmethylidene and (S)-(-)-tert-butylsulfonyl (4,47 g, 1 EQ.). Installing blown off with nitrogen. Add anhydrous THF (82 ml, 10 wt. parts of the crude weight) and the resulting solution was moderately stirred in nitrogen atmosphere. To this solution through the syringe added Ti(OEt)4(15,32 ml, 2 EQ.). The obtained dark yellow solution is heated in a nitrogen atmosphere to a gentle reflux distilled under moderate stirring and incubated for approximately 24 hours (there is a slight foaming of the reaction mixture). Analysis with the aid of the d 1H-NMR shows that the reaction was completed.

First, the reaction mixture was cooled to ambient temperature and then to 0-5°C by immersion in a water bath with ice. To this mixture is added sodium borohydride (2.1 g, 1.5 EQ.) (note: there is a moderate foaming and esotericist from 3 to 10°C). The resulting reaction mixture was stirred at 0-5°C. for another 5 hours and then allowed to warm to ambient temperature and stirred overnight (approximately 14 hours). A sample is taken for IPC1H-NMR, which shows that all ketamin spent.

The mixture is cooled to 0-5°Spostare add acetone (16,3 ml, about 6 EQ.) within 15-20 minutes of consumption of the remaining hydride (note: there is esotericist from about 3 to 15°C). After the addition completed, the reaction mixture is stirred for 15 minutes. Download Meon (2 ml) to verify the presence of residual hydride hydrogen gas is not observed. The mixture is left to warm to room temperature and transferred into a 500-ml Erlenmeyer flask. A round bottom flask was washed with 160 ml of MTBE. The resulting mixture was vigorously stirred for 5 minutes. In parts download brine (10 ml) for 2-3 minutes to induce deposition of the titanium reagent. The resulting suspension is vigorously stirred during the course the e 30 minutes and then filtered through a thick layer of sand. The sand layer was washed with 3×30 ml MTBE. The combined filtrate is stirred with 150 ml of brine within the next 1 hour getting muddy two-phase mixture, which is transferred into a separating funnel. The lower aqueous layer is removed and the upper organic layer is filtered through a layer of celite. The filtrate is evaporated to dryness to obtain the desired product N-{(S,S)-1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-methylpropan-2-sulfinamide (11.1 g) as a yellow syrup. It is assumed that this stuff is 100% pure and used directly in the next stage without additional purification.

As reported by Almana (Ellman et al. Tetrahedron, 40 (1999) 6709-6712), the crude product consists of a mixture of 2 diastereomers with a predominance of one. The ratio of these two isomers indicates the degree of asymmetry caused by the chiral sulfanilic group. Usually the ratio observed for this decrease varies from 92:8 to 95:5, as shown HPLC and1H-NMR analysis of the crude mixture of products.

1H-NMR 400 MHz (CHLOROFORM-D) δ 1.26 (s, N), 1.53 (d, 3H, J=8 Hz), 1.75 (s, 6N), 4.52-4.62 (m, 1H), 7.40 (d, 2H, J=8 Hz), 7.48 (d, 2H, J=8 Hz).

Stage b) of the intermediate compound 72

In a 250 ml round bottom flask, equipped with magnetic stirrer containing substituted sulfonamide (11.1 g, 1 EQ., it is assumed that is 100% pure)obtained at the previous step, add dioxane (283 ml). The resulting solution was cooled to 0-5°C in a water bath with ice, vigorously stirring. In this solution through a syringe loaded HCl in dioxane (28,3 ml, 3 EQ.) one portion. White solid immediately starts to precipitate from solution. The resulting suspension is stirred at 0-5°C. (bath temperature) in the next 10 minutes to obtain a thick white suspension. At this stage, the cooling bath removed. A small sample of the reaction mixture are taken and analyzed by thin-layer chromatography. All original sulfinamide spent.

The mixture is diluted with EtOAc (28,3 ml) and stirred for 5 minutes at room temperature. The white solid is then collected by vacuum filtration. The flask was washed with 2×10 ml of EtOAc. The filter cake was washed with a further 2×10 ml of EtOAc and then dried in a stream of nitrogen. The filter cake is then dried at 40-45°C in a vacuum oven overnight to obtain 4,28 g white crystalline solid. Analysis of this substance with1H-NMR spectroscopy showed the presence of only the desired amine hydrochloride.

According to the observation of the authors of the invention the optical purity of this chiral amine, which directly correlates with the ratio of the two diastereomeric sulfinamide predecessors, ranging from 84 to 90% E.E. (enantiomeric excess). These quantities shall confirm, the final stage of HCl treatment does not affect the optical purity of the amine.

1H-NMR 400 MHz (CHLOROFORM-D) δ 1.20 (d, 3H, J=8 Hz), 1.70 (s, 3H), 1.71 (s, 3H), 3.73 (AB q, 1H, J=14.6 Hz), 4.50 (br. s, 1H), 7.17 (d, 2H, J=8 Hz), 7.21-7.31 (m, 5H), 7.41 (d, 2H, J=8 Hz).

HCl amine salt (3.12 g, 13,89 mmol, 1 EQ.) dissolved in 26 ml of water in 100-ml round bottom flask with gentle stirring with a magnetic stirrer. To this solution was added 2 M aqueous sodium hydroxide (7,6 ml, 1.1 EQ.) for bringing the resulting pH to 13-14, which leads to the formation of a light emulsion. In this emulsion load MTBE (26 ml) and the resulting mixture is vigorously stirred. The upper organic layer is collected and the aqueous layer was diluted with brine (15 ml), then extracted with 26 ml of MTBE. The organic layers are combined, washed with brine (15 ml) and then dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and evaporation of the filtrate to dryness received amine in the form of pale yellow light of the oil.

The oil obtained above, dissolved in acetone (26 ml) and stirred in a nitrogen atmosphere. To download Amin solution of (+)-almond acid (2 g, 0.95 to EQ. the HCl salt of amine) in acetone (15 ml), obtained in a separate vessel. This vessel is then washed with acetone (5 ml). The precipitation of crystalline solids (salts) was quickly getting hard white suspension. E is the suspension is stirred for 15 minutes and then cooled to 0-5°C and stirred for another 30 minutes. White solid is collected by vacuum filtration and washed with acetone (2×10 ml). The filter cake is dried in a vacuum oven at 40-45°C. overnight (approximately 16 hours) receipt to 3.67 g (77%) salt (+)-almond acid in the form of a crystalline white solid.

1H-NMR spectroscopic analysis outlined above product in deuterated chloroform showed that there is only one enantiomer Amin.

A 2-l round bottom flask equipped with overhead stirrer, download salt almond acid (50,8 g, 149,3 mmol, 1 EQ.) and MTBE (1 l, 6.5 parts) to obtain a suspension. To this suspension under moderate stirring, a solution of NaOH (1 M, 672 ml, 672 mmol, 4.5 EQ.). The obtained two-phase mixture was vigorously stirred at room temperature for 30 minutes and then transferred into a separating funnel. The layers are separated. The aqueous layer was diluted with 500 ml of brine and extracted with MTBE (2×250 ml). The combined organic phases are dried over MgSO4. After removal of the drying agent followed evaporating the filtrate to dryness received the free amine as a pale yellow oil (27.7 g, 99%).

1H-NMR 400 MHz (CHLOROFORM-D) δ 1.20 (d, 3H, J=8 Hz), 1.70 (s, 3H), 1.71 (s, 3H), 3.73 (AB Quartet, 1H, J=14, 6 Hz), 4.50 (br. s, 1H), 7.17 (d, 2H, J=8 Hz), 7.21-7.31 (m, 5H), 7.41 (d, 2H, J=8 Hz).

Scheme 22: Enantioselective synthesis of (-)1-[4-[1-amino-ethyl]phenyl]-cyclo is utan-1-carbonitrile

Stage a) of the intermediate compound 73

1-(4-Bromophenyl)cyclobutanecarbonitrile

To a stirred suspension of sodium hydride (60%suspension in oil, 12,24 g, 255 mmol) in anhydrous DMSO (240 ml) is added dropwise 2-(4-bromophenyl)acetonitrile (20,0 g, 102 mmol)dissolved in anhydrous DMSO (40 ml). After 45 min the reaction mixture was cooled to 0°C and slowly added 1,3-dibromopropane (30,9 g of 15.5 ml, 153 mmol)dissolved in anhydrous DMSO (40 ml), to maintain the temperature below 45°C. the Reaction mixture was stirred over night at room temperature, and poured into cold water (1.2 l). The product is extracted with CH2Cl2(6×100 ml), dried over MgSO4filter and concentrate under reduced pressure. The product was then purified using flash chromatography elwira a mixture of hexane: EtOAc (from 100% to 95:5), to obtain the expected product 1-(4-bromophenyl)cyclobutanecarbonitrile (9,9 g, 41%) as a yellowish oil.1H-NMR (300 MHz, CHLOROFORM-D): δ 7.57-7.49 (2H, m), 7.33-7.24 (2H, m), 2.89-2.77 (2H, m), 2.66-2.34 (3H, m), 2.15-1.99 (1H, m).

Stage b) of the intermediate compound 74

1-(4-Acetylphenyl)cyclobutanecarbonitrile

To a stirred solution of 1-(4-bromophenyl)cyclobutanecarbonitrile (2.8 g, to 11.9 mmol) in anhydrous THF (70 ml) at -78°C. add n-utility (2 M in hexane) (7,44 ml, 14.9 mmol). The reaction mixture is stirred at this temperature T. the value of 10 min, then add N-methoxy-N-methylacetamide (2,50 ml of 23.8 mmol) and the solution is then left to warm to room temperature over 1 h and Then slowly add a mixture of brine (30 ml) and 1 N. HCl (15 ml) and the solution extracted with EtOAc (3×100 ml). The organic layer is dried over MgSO4filter and concentrate under reduced pressure. The crude product was then purified using flash chromatography with a gradient from 0 to 20% EtOAc in hexane to obtain 1-(4-acetylphenyl)cyclobutanecarbonitrile (1.35 g, 57%) as a yellowish oil.1H-NMR (300 MHz, CHLOROFORM-D) δ 8.03- (2H, m), 7.56-7.50 (2H, m), 2.94-2.81 (2H, m), 2.71-2.57 (2H, m), 2.62 (3H, s), 2.57-2.40 (1H, m), 2.18-2.05 (1H, m).

Stage b) of the intermediate compound 75

(-)-1-[4-[1-amino-ethyl]phenyl]CYCLOBUTANE-1-carbonitrile

1-(4-acetylphenyl)cyclobutanecarbonitrile (8.6 g, 43.2 mmol) and anhydrous THF (85 ml) and (S)-(-)-tert-butylsulfide (5.7 g, 1.1 EQ.) add tetraethyl titanium (18 ml, 2 EQ.). The resulting mixture is heated to the temperature of reflux distilled in a nitrogen atmosphere and maintained at a temperature of reflux distilled within 18 hours. An aliquot is taken and analyzed in relation to the completion of the reaction.

The mixture is cooled to room temperature and then to 0-5°C. To the reaction mixture in small portions over 10 minutes, add sodium borohydride (2.4 g, 1.5 equivalents). The resulting mixture was left to warm to room temperature is 1 hour 3 hours.

The reaction mixture was quenched by adding acetone (19 ml, 6 EQ.) and the resulting mixture was diluted with brine (25 ml). Under moderate stirring add MTBE (80 ml) and stirring is continued for about 15 minutes. The obtained two-phase mixture is filtered through ceramic funnel Packed by alicom. The organic layer is collected and dried over anhydrous magnesium sulfate. The result of this evaporation of the organic solution to dryness under reduced pressure to obtained the desired substituted chiral sulfinamide in the form of a viscous syrup (13.3 g). This crude substance use without additional purification.

The crude chiral sulfinamide (13.3 g), obtained above, was dissolved in dioxane (130 ml) with moderate stirring in a round bottom flask. In the mix download 4 M HCl in dioxane (32,8 ml, 3 EQ.) and stirring is continued at room temperature overnight (approximately 16 hours). The reaction mixture is evaporated to dryness on a rotary evaporator and the resulting residue triturated with EtOAc (100 ml) for 1 hour. The white solid is filtered and washed. In the drying of the precipitate on the filter in a vacuum oven over night received the expected chiral amine (-)-1-[4-[1-amino-ethyl]phenyl]CYCLOBUTANE-1-carbonitrile (5.0 g) in its cleaners containing hydrochloride in the form of a white solid. Data1H-NMR (400 MHz, DMSO-d6 ) δ 1.52 (3H, d, J=8 Hz), 1.94-2.07 (1H, m), 2.20-2.35 (1H, m), 2.55-2.67 (2H, m), 2.70-2.80 (2H, m), 4.44 (1H, q, J=6.8 Hz), 7.52 (2H, J=8.4 Hz), 7.61 (2H, d, J=8.4 Hz), 8.40-8.90 (3H, m).

Before the reaction mix to obtain the final chiral examples receive free base of intermediate 75 using the method described in stage b, described under intermediate compound 72.

Scheme 23: Enantioselective synthesis of (-)2-[4-[1-amino-ethyl]-3-were]-2-methylpropionitrile

To 2-(4-acetyl-3-were)-2-methylpropionitrile (1.47 g, approximate analysis 80% => 5.8 mmol) and anhydrous THF (12 ml, 10 parts) with (S)-(-)-tert-butylsulfide (0.7 g, 1 EQ.) add tetraethyl titanium (2.4 ml, 2 EQ.). The resulting mixture is heated to the temperature of reflux distilled in an atmosphere of nitrogen and incubated for 22 hours (during the night), followed by stirring at room temperature over a weekend. Analysis of the reaction mixture showed that the reaction was completed.

Under moderate stirring, the reaction mixture was cooled to 0-5°C. (water bath with ice). In the reaction mixture in small portions over 10 minutes, add sodium borohydride (0.35 g, 1.5 equivalents). The resulting mixture is stirred for 3 hours at 0-5°C and then allow it to slowly warm to room temperature. Stirring at room temperature cont Laut for another 1 hour.

After cooling the mixture to 0-5°C. the reaction mixture was quenched by adding acetone (2 ml, 6 EQ.) and the resulting mixture was diluted with brine (4 ml). Under moderate stirring add MTBE (20 ml) and stirring is continued for 10 minutes. This water-organic mixture is filtered through a layer of celite. The organic phase is collected and dried over anhydrous magnesium sulfate. The result of this evaporation of the organic solution to dryness under reduced pressure to obtained the desired substituted chiral sulfinamide in the form of a yellow viscous syrup (1.88 g). Range1H-NMR spectrum of this substance indicates the presence of the desired substituted sulfonamide as the main product together with other impurities. This is the crude substance is believed to be 100% pure and used without further purification.

The result of the above crude chiral sulfinamide (0.28 g, 0.4 mmol) dissolved in dioxane (3 ml) with moderate stirring in a round bottom flask. In the resulting solution download 4 M HCl in dioxane (0.7 ml, 3 EQ.) and the resulting mixture was stirred at room temperature for 30 minutes to obtain a heavy white suspension. This suspension is evaporated to dryness on a rotary evaporator and the resulting residue triturated with EtOAc (10 ml) for 10 minutes. White solid is collected by filtration and then washed EtOAc. a result of the natural drying of the precipitate on the filter at room temperature to obtain hydrochloride of the desired chiral amine (-)2-[4-[1-amino-ethyl]-3-were]-2-methylpropionitrile in the form of a white powder (95 mg).

1H-NMR (400 MHz, DMSO-d6) δ 1.48 (3H, d, J=8 Hz), 1.68 (6N, s), 2.39 (3H, s), 4.53 (1H, ABq, J=16,8 Hz), 7.39 (1H, d, J=2 Hz), 7.44 (1H, dd, J=8,2 Hz), to 7.64 (1H, d, J=8 Hz), 6.8-9 (unresolved m, exchange for D2O).

Scheme 24: Synthesis of 2-[4-(1-amino-ethyl)phenyl]-2-ethylbutanal

Stage a) of the intermediate compound 77

4-(1-Cyano-1-ethylpropyl)benzonitrile.

4-Cyanomethylphosphonate (1,02 g, 7,18 mmol) and ethyliodide (2.25 g, 14.4 mmol) are added to DMF (20,0 ml) and the resulting solution was cooled to 0°C. Portions add NaH (576 mg, 14.4 mmol). The mixture is heated to room temperature and then stirred for 3 hours. Add water (100 ml) and the aqueous phase extracted with EtOAc (4 x 50,0 ml). The combined organic phases are dried with MgSO4, filtered and concentrated on a rotary evaporator. The product was then purified using the Combi-Flash chromatography on silica gel, elwira mixtures of heptane and EtOAc (100/0 to 70/30), (936 mg, 5.51 mmol, 77%).1H-NMR (400 MHz, DMSO-D6) δ million-10.77 (t, J=7.42 Hz, 6N), 1.89-2.14 (m, 4H), 7.64 (d, J=8.40 Hz, 2H), 7.92 (d, J=8.59 Hz, 2H).

Stage b) of the intermediate compound 78

2-[4-(1-amino-ethyl)phenyl]-2-ethylbutanal.

4-(1-Cyano-1-ethylpropyl)benzonitrile (936 mg, 5.51 mmol) are added to THF (20,0 ml) and the resulting solution was cooled to -78°C. Add MeLi (3,44 ml, 5.51 mmol) and the solution stirred for 20 minutes. NaBH4(208 mg, 5.51 mmol) is mixed with the Meon (20,0 ml) and added to eromu solution. The resulting solution was warmed to room temperature and stirred for 1 hour. Add 1 N. HCl (50,0 ml), then 1 N. NaOH (60,0 ml). The aqueous phase is extracted with EtOAc (4 x 50,0 ml) and the combined organic phases are dried with MgSO4, filtered and concentrated on a rotary evaporator. The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Gemini (5 μm) of 21.2×50 mm, mobile phase: a = water (10 mm NH4CO3), B = MeCN (528 mg, 2,44 mmol, 44%).1H-NMR (400 MHz, DMSO-D6) δ million-10.77 (t, J=7.32 Hz, 6N), 1.22 (d, J=6.45 Hz, 3H), 1.82-2.07 (m, 4H), 3.97 (q, J=6.64 Hz, 1H), 7.32 (d, J=8.40 Hz, 2H), 7.40 (d, J=8.20 Hz, 2H).

Example 1:

(R)(+) and (S) - (-)-2-(7-Cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide.

2-[4-(1-amino-ethyl)phenyl]-2-methylpropanamide hydrochloride obtained according to scheme 6 (557 mg, 2.49 mmol), (7-cyano-1H-benzimidazole-1-yl)acetic acid (500 mg, 2.49 mmol), obtained according to scheme 3, and DMAP (601 mg, equal to 4.97 mmol) are mixed in DMF (10.0 ml). Added HATU (945 mg, 2.49 mmol) and the mixture is stirred for 18 hours. The reaction mixture was filtered and then purified by HPLCMS: Waters prep LCMS, flow rate: 27 ml/min, column: SynerSi (4 µm) Polar RP and 21.2×50 mm, mobile phase: a = water (0.05% of TFA) and B = MeCN, used a gradient from 40% to 70% In And within 10 minutes Factions unite, add 1 N. NaOH and the desired compound is extracted with etelaat the om. The combined organic fractions concentrated under reduced pressure to obtain the product (610 mg, of 1.64 mmol, 66%).1H-NMR (400 MHz, METHANOL-D4) δ million-11.50 (d, J=7.03 Hz, 3H), 1.68 (s, 6N) 4.98-5.09 (m, 1H), 5.33 (s, 2H) 7.37-7.43 (m, 3H), 7.46 (d, J=8.20 Hz, 2H), 7.68 (d, J=7.62 Hz, 1H), 7.97 (dd, J=8.20, 0.98 Hz, 1H), 8.28 (s, 1H), 8.89 (d, J=7.62 Hz, 1H). MS [M+H]calculated: 372,2 found: 372,3.

The enantiomers separated using chiral HPLC: preparative pumps Gilson, Inc., flow rate: 18 ml/min, column®: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 80% A: 20% of isocratic [α]D=-156 (=8,2, Meon) and [α]D=+136 (=13,4, Meon).

Example 2:

(R)(+) and (S) - (-)-N-{1-[4-(1-Cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide.

N-{1-[4-(1-Cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide synthesized according to example 1 by mixing (6,7-debtor-1H-benzimidazole-1-yl)acetic acid (500 mg, 2.36 mmol), obtained according to scheme 2, 2-[4-(1-amino-ethyl)phenyl]-2-methylpropanamide hydrochloride (525 mg, 2.36 mmol), obtained according to the scheme 6, DMAP (570 mg, 4,71 mmol) and HATU (896 mg, 2.36 mmol) in DMF (10.0 ml). The product was then purified by HPLCMS: Waters prep LCMS, 27 ml/min, column: SynerSi (4 µm) Polar RP and 21.2×50 mm, mobile phase: a = water (0.05% of TFA) and B = MeCN, used a gradient from 40% to 60% In in And within 10 minutes Factions unite, add 1 N. NaOH, and the desired connection extrag the shape with ethyl acetate. The combined organic fractions concentrated under reduced pressure to obtain the product (450 mg, 2.36 mmol, 50%).1H-NMR (400 MHz, METHANOL-D4) δ million-11.49 (d, J=7.03 Hz, 3H), 1.68 (s, 6N), 5.03 (m, 1H), 5.20 (m, 2H), 7.30 (dt, J=11.23, 8.98, 7.32 Hz, 1H), 7.35-7.42 (m, 2H), 7.44-7.54 (m, 3H), 8.56 (s, 1H). MS [M+H]calculated: 383,2 found: 383,3.

HRMS(ESI+) calculated for C21H21F2N4O 383,16779 [M+H]+, found 383,16782.

The enantiomers separated using chiral HPLC: preparative pumps Gilson, Inc., flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = i-D (with 0.1% DEA), isocratic 80% And 30% C. [α]D=-160 (C=5,4, Meon) and [α]D=+164 (C=6,0, Meon).

Example 3

(R)(+) and (S) - (-)-N-{1-[4-(1-Cyano-1-methylethyl)phenyl]ethyl}-2-(7-fluoro-1H-benzimidazole-1-yl)ndimethylacetamide.

N-{1-[4-(1-Cyano-1-methylethyl)phenyl]ethyl}-2-(7-fluoro-1H-benzimidazole-1-yl)ndimethylacetamide synthesized according to example 1 by mixing (7-fluoro-1H-benzimidazole-1-yl)acetic acid (200 mg, of 1.03 mmol)obtained according to scheme 5, 2-[4-(1-amino-ethyl)phenyl]-2-methylpropanamide hydrochloride (231 mg, of 1.03 mmol)obtained according to the scheme 6, DMAP (249 mg, of 2.06 mmol) and HATU (391 mg, of 1.03 mmol) in DMF (4.0 ml). The product was then purified by HPLCMS: Waters prep LCMS, 27 ml/min, column: SynerSi (4 µm) Polar RP and 21.2×50 mm, mobile phase: a = water (0.05% of TFA) and B = MeCN, used a gradient from 30% to 50% In And within 10 minutes Factions unite, add 1 .NaOH, and the desired compound is extracted with ethyl acetate. The combined organic fractions concentrated under reduced pressure to obtain the product (226 mg, 0,621 mmol, 60%).1H-NMR (400 MHz, METHANOL-D4) δ million-11.48 (d, J=7.03 Hz, 3H), 1.69 (s, 6N), 5.03 (q, J=6.90 Hz, 4H), 5.09 (d, J=16.99 Hz, 1H), 5.14 (d, J=16.99 Hz, 1H), 7.00 (dd, J=11.43, 8.11 Hz, 1H), 7.20 (td, J=8.11, 4.88 Hz, 1H), 7.37 (d, J=8.20 Hz, 2H), 7.43-7.50 (m, 3H), 8.10 (s, 1H); MS [M+H]calculated: 365,2 found: 365,3.

I believe that the enantiomers can be separated using chiral HPLC: preparative pumps Gilson, Inc., flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 80% A: 20% of socratica.

Example 4:

(R) (+) and (S) - (-)-N-{1-[4-(1-Cyano-1-methylethyl)phenyl]ethyl}-2-(7-chloro-1H-benzimidazole-1-yl)ndimethylacetamide.

N-{1-[4-(1-Cyano-1-methylethyl)phenyl]ethyl}-2-(7-chloro-1H-benzimidazole-1-yl)ndimethylacetamide synthesized according to example 1 by mixing (7-chloro-1H-benzimidazole-1-yl)acetic acid (100 mg, 0.48 mmol), obtained according to scheme 1, 2-[4-(1-amino-ethyl)phenyl]-2-methylpropanamide hydrochloride (107 mg, 0.48 mmol), obtained according to the scheme 6, DMAP (115 mg, 0.95 mmol) and HATU (181 mg, 0.48 mmol) in DMF (2.0 ml). The product was then purified by HPLCMS: Waters prep LCMS, 27 ml/min, column: SynerSi (4 µm) Polar RP and 21.2×50 mm, mobile phase: a = water (0.05% of TFA) and B = MeCN, used a gradient from 40% to 70% In And within 10 minutes Fractions are combined and dried by sublimation with p is the receiving of the desired product as TFA salt (50 mg, 0,100 mmol, 21%).1H-NMR (400 MHz, METHANOL-D4) δ million-11.48 (d, J=7.03 Hz, 3H), 1.69 (s, 6N) 5.03 (q, J=6.71 Hz, 1H), 5.21-5.34 (m, 2H) 7.16-7.28 (m, 2H), 7.38 (d, 2H) 7.46 (d, 2H), 7.59 (dd, J=7.52, 1.27 Hz, 1H), 8.13 (s, 1H); MS [M+H]calculated: 381,1, found: 381,3.

I believe that the enantiomers can be separated using chiral HPLC: preparative pumps Gilson, Inc., flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 80% A: 20% of socratica.

Example 5:

(+) and (-)-N-{1-[4-(1-Cyano-1-ethylpropyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide.

2-[4-(1-amino-ethyl)phenyl]-2-ethylbutanal (520 mg, 2,41 mmol), obtained according to scheme 24, (6,7-debtor-1H-benzimidazole-1-yl)acetic acid (510 mg, 2,41 mmol), obtained according to scheme 2, and Et3N (731 mg, 7.22 mmol, 1,00 ml) are mixed in MeCN (15.0 ml). Added HATU (915 mg, is 2.41 mmol) and the mixture is stirred for 2 hours. Add 1 N. NaOH (40,0 ml) and the aqueous phase extracted with EtOAc (4 times 40,0 ml). The combined organic phases are dried with MgSO4, filtered and concentrated on a rotary evaporator. The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Gemini (5 μm) of 21.2×50 mm, mobile phase: a = water (10 mm NH4CO3) B = MeCN, (804 mg, a 1.96 mmol, 81%).1H-NMR (400 MHz, DMSO-D6) δ million-10.77 (t, J=7.32 Hz, 6N), 1.40 (d, J=7.03 Hz, 3H), 1.83-2.13 (m, 4H)4.96 (ddd, J=14.65, 7.23, 7.03 Hz, 1H) 5.08 (s, 2 is), 7.21 (ddd, J=11.57, 8.93, 7.62 Hz, 1H), 7.35-7.41 (m, 4H), 7.45 (ddd, J=8.84, 3.86, 0.78 Hz, 1H), 8.19-8.22 (m, 1H), 8.83 (d, J=8.01 Hz, 1H); MS [M+H]calculated: 411,0 found: 411,3.

The enantiomers separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel AD 21×250 mm (20 μm), mobile phase: A = hexane with 0.1% DEA) B = i-D (with 0.1% DEA), αD=-149 (C=3.2, and Meon) and αD=+178 (=3,4, Meon).

Example 6

(+) and (-)-N-{1-[4-(1-Cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide.

N-{1-[4-(1-Cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide synthesized according to example 5 by mixing (6,7-debtor-1H-benzimidazole-1-yl)acetic acid (212 mg, 1.00 mmol)obtained according to scheme 2, 1-[4-(1-amino-ethyl)phenyl]cyclobutanecarbonitrile (200 mg, 1.00 mmol)obtained according to scheme 9, Et3N (304 mg, 3.00 mmol, 0,418 ml) and HATU (280 mg, 1.00 mmol) in MeCN (10.0 ml). The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Gemini (5 μm) of 21.2×50 mm, mobile phase: a = water (10 mm NH4CO3) B = MeCN, (220 mg, 0,558 mmol, 56%).1H-NMR (400 MHz, DMSO-D6) δ million-11.39 (d, J=7.03 Hz, 3H), 1.91-2.05 (m, 1H), 2.16-2.34 (m, 1H), 2.53-2.64 (m, 2H), 2.66-2.78 (m, 2H), 4.87-5.01 (m, 1H), 5.07 (s, 2H), 7.11-7.31 (m, 1H), 7.33-7.49 (m, 5H), 8.19 (s, 1H), 8.84 (d, J=7.81 Hz, 1H); MS [M+H]calculated: 395,0 found: 395,2.

The enantiomers separated using chiral HPLC: preparative pumps Gilson, speed on the eye: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), αD=-135 (C=0,57, Meon) and αD=+199 (C=4,1, Meon).

Example 7

(+) and (-)-N-{1-[4-(1-Cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide.

N-{1-[4-(1-Cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide synthesized according to example 5 by mixing (6,7-debtor-1H-benzimidazole-1-yl)acetic acid (233 mg, 1.10 mmol), obtained according to scheme 2, 1-[4-(1-amino-ethyl)phenyl]cyclohexanecarbonitrile (250 mg, 1.10 mmol), obtained according to scheme 11, Et3N (111 mg, 1.10 mmol, 0,153 ml) and HATU (418 mg, 1.10 mmol) in MeCN (10.0 ml). The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Gemini (5 μm) of 21.2×50 mm, mobile phase: a = water (10 mm NH4CO3) B = MeCN, (336 mg, coefficient was 0.796 mmol, 72%).1H-NMR (400 MHz, DMSO-D6) δ million-11.38 (d, J=7.03 Hz, 3H), 1.23-1.35 (m, 1H), 1.51-1.69 (m, 2H), 1.69-1.78 (m, 1H), 1.77-1.89 (m, 4H), 1.99-2.09 (m, 2H), 4.87-5.00 (m, 1H), 5.07 (s, 2H), 7.14-7.28 (m, 1H), 7.37 (d, J=8.40 Hz, 2H), 7.42-7.53 (m, 3H), 8,19 (s, 1H), 8,83 (d, J=7,81 Hz, 1H); MS [M+H]calculated: 424,0 found: 423,3.

The enantiomers separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), αD=151 polyurthane (=5,6, Meon) and αD=+194 (=2,8, Meon).

Example 8

(+) and (-)-2-(cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)-phenyl]ethyl}ndimethylacetamide.

2-(7-Cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]-ethyl}ndimethylacetamide synthesized according to example 5 by mixing (7-cyano-1H-benzimidazole-1-yl)acetic acid (216 mg, of 1.08 mmol)obtained according to scheme 3, 1-[4-(1-amino-ethyl)phenyl]cyclohexanecarbonitrile (246 mg, of 1.08 mmol)obtained according to scheme 11, Et3N (328 mg, 3,24 mmol, 0,452 ml) and HATU (411 mg, of 1.08 mmol) in MeCN (10.0 ml). The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Gemini (5 μm) of 21.2×50 mm, mobile phase: a = water (10 mm NH4CO3) B = MeCN, (443 mg, of 1.08 mmol, quantitative).1H-NMR (400 MHz, DMSO-D6) δ million11.22-1.36 (m, 1H), 1.39 (d, J=6.84 Hz, 3H) 1.53-1.68 (m, 2H), 1.68-1.77 (m, 1H), 1.77-1.89 (m, 4H), 1.98-2.08 (m, 2H), 4.88-5.02 (m, 1H), 5.24 (dd, J=24.61, 17.77 Hz, 2H), 7.35 (t, J=7.91 Hz, 1H), 7.40 (d, J=8.40 Hz, 2H), 7.46 (d, J=8.40 Hz, 2H), 7.72 (d, J=7.62 Hz, 1H), 8.01 (dd, J=8.20, 0.78 Hz, 1H), 8.35 (s, 1H), 8.85 (d, J=7.81 Hz, 1H); MS [M+H]calculated: 412,0, found: 412,3.

The enantiomers separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), αD=-208 (=2,2, Meon) and αD=+190 (=2,4, Meon).

Example 9

(+) and (-)-2-(7-Cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)-phenyl]ethyl}ndimethylacetamide.

2-(7-Cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]-ethyl}ndimethylacetamide synthesized according to example 5 by the shift of the air traffic management (7-cyano-1H-benzimidazole-1-yl)acetic acid (86,5 mg, 0,430 mmol), obtained according to scheme 3, 1-[4-(1-amino-ethyl)phenyl]cyclopropanecarbonitrile (80.0 mg, 0,430 mmol), obtained according to scheme 10, Et3N (131 mg, 1,29 mmol, 0,180 ml) and HATU (163 mg, 0,430 mmol) in MeCN (10.0 ml). The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Synergi Polar (5 μm) of 21.2×50 mm, mobile phase: a = water (0.05% of TFA) and B = MeCN, (23,0 mg, 0,0623 mmol, 14%).1H-NMR (400 MHz, CHLOROFORM-D) δ million-11.35 (dd, J=7.81, 5.47 Hz, 2H), 1.49 (d, J=7.03 Hz, 3H), 1.68 (dd, J=7.42, 5.08 Hz, 2H), 5.00-5.13 (m, 3H), 6.65 (d, J=7.42 Hz, 1H), 7.22 (d, J=8.59 Hz, 2H), 7.29 (d, J=8.20 Hz, 2H), 7.33 (d, J=7.81 Hz, 1H), 7.59 (d,, J=7.62 Hz, 1H), 7.96-8.06 (m, 2H); MS [M+H]calculated: 370,0 found: 370,0.

I believe that the enantiomers can be separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 80% A: 20% of socratica.

Example 10

(+) and (-)-2-(7-Cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)-phenyl]ethyl}ndimethylacetamide.

2-(7-Cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}-ndimethylacetamide synthesized according to example 5 by mixing (7-cyano-1H-benzimidazole-1-yl)acetic acid (95,0 mg, 0.475 mmol), obtained according to scheme 3, 1-[4-(1-amino-ethyl)phenyl]cyclobutanecarbonitrile (95 mg, 0.475 mmol), obtained according to scheme 9, Et3N (144 mg, 1,43 mmol, 0,199 ml) and HATU (181 mg, 0.475 mmol) in MeCN (10,0 m is). The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Gemini (5 μm) of 21.2×50 mm, mobile phase: a = water (10 mm NH4CO3) B = MeCN, (34,0 mg, 0,0888 mmol, 19%).1H-NMR (400 MHz, DMSO-D6) δ million-11.40 (d, J=7.03 Hz, 3H), 1.89-2.05 (m, 1H), 2.15-2.34 (m, 1H), 2.52-2.66 (m, 2H), 2.66-2.80 (m, 2H), 4.88-5.01 (m, 1H), 5.25 (dd, J=22.66, 17.58 Hz, 2H), 7.31-7.46 (m, 5H), 7.71 (dd, J=7.62, 0.78 Hz, 1H), 8.01 (dd, J=8.01, 0.78 Hz, 1H), 8.36 (s, 1H), 8.87 (d, J=7.62 Hz, 1H); MS [M+H]calculated: 384,0 found: 384,2.

I believe that the enantiomers can be separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 80% A: 20% of socratica.

Example 11

(R) (+) (3)(-)-2-(7-Acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide.

2-(7-Acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]-ethyl}ndimethylacetamide synthesized according to example 5 by mixing 7-acetyl-1H-benzimidazole-1-luxusni acid (90,0 mg, 0,413 mmol), obtained according to scheme 4, 2-[4-(1-amino-ethyl)phenyl]-2-methylpropionitrile (77,6 mg, 0,413 mmol), obtained according to scheme 6, and Et3N (125 mg, 1,24 mmol, 0,173 ml) and HATU (157 mg, 0,413 mmol) in dry MeCN (10.0 ml). The product was then purified using reversed-phase HPLC: preparative Gilson pumps; flow rate: 30 ml/min; column: Synergi Polar (4 μm) of 21.2×50 mm; mobile phase: a = water (0.05% of TFA) In MeCN (49.5 mg, 0,128 mmol, 31,0%).1H-NMR (400 MHz, DMSO-D6) δ million-11.35 (d, J=7.03 Hz, 3H), 1.66 (s, 6N), 2.38 (s, 3H), 4.74-4.87 (m, J=7.23, 7.23 Hz, 1H), 5.14 (s, 2H), 7.26 (t, J=7.81 Hz, 1H), 7.35 (d, J=8.40 Hz, 2H), 7.45 (d, J=8.40 Hz, 2H), 7.71 (d, J=7.62 Hz, 1H), 7.85 (d,, J=8.01 Hz, 1H), 8.21 (s, 1H), 8.65 (d, J=7.81 Hz, 1H); MS [M+H] calculated: 389,19 found: 389,09.

The enantiomers separated using chiral HPLC: preparative Gilson pumps; flow rate: 18 ml/min; column: Chiralcel AD 21×250 mm (20 μm); mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA); αD=+171 (C=2, Meon) and αD=-162 (C=2, Meon).

Example 12

(+) and (-)-2-(7-Acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide.

2-(7-Acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide synthesized according to example 5 by mixing HATU (179 mg, 0,472 mmol), 7-acetyl-1H-benzimidazole-1-luxusni acid (103 mg, 0,472 mmol), obtained according to scheme 4, 2-[4-(1-amino-ethyl)-2-forfinal]-2-methylpropionitrile (97,0 mg, 0,472 mmol), obtained according to scheme 7, and Et3N (143 mg, of 1.42 mmol, 0,200 ml) in dry MeCN (10.0 ml). The product was then purified using reversed-phase HPLC: preparative Gilson pumps; flow rate: 30 ml/min; column: Gemini (5 μm) of 21.2×50 mm; mobile phase: A=10.0 mm NH4HCO3in H2O=MeCN (52,4 mg, 0,129 mmol, 27,0%).1H-NMR (400 MHz, DMSO-D6) δ million-11.36 (d, J=7.03 Hz, 3H), 1.70 (s, 6N), 2.40 (s, 3H), 4.72-4.90 (m, 1H), 5.17 (dd, J=21.48, 17.19 Hz, 2H), 7.18 (d, J=7.81 Hz,1H), 7.21-7.32 (m, 2H), 7.40 (t, J=8.30 Hz, 1H), 7.72 (d, J=7.62 Hz, 1H), 7.86 (d, J=7.81 Hz, 1H), 8.22 (s, 1H), 8.72 (d, J=7.42 Hz, 1H); MS [M+H] calculated: 407,18 found: 407,17.

The enantiomers separated using chiral HPLC: preparative Gilson pumps; flow rate: 18 ml/min; column: Chiralcel AD 21×250 mm (20 μm); mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA); αD=+166 (C=2, Meon) and αD=-159 (=1,60, Meon).

Example 13:

(+) and (-)-2-(7-Cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide.

2-(7-Cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide synthesized according to example 1 by mixing 2-[4-(1-amino-ethyl)-2-forfinal]-2-methylpropanamide hydrochloride (260 mg, of 0.94 mmol), obtained according to scheme 7, (7-cyano-1H-benzimidazole-1-yl)acetic acid (200 mg, 0,94 mmol), obtained according to scheme 3, and DMAP (228 mg, 1,89 mmol, 1,00 ml) and HATU (358 mg, 2.49 mmol) in DMF (5.0 ml). The product was then purified using HPLC: Waters prep LCMS, flow rate: 27 ml/min, column: SynerSi (4 µm) Polar RP and 21.2×50 mm, mobile phase: a = water (0.05% of TFA) and B = MeCN, used a gradient from 40% to 60% In in And within 10 minutes Factions unite, add 1 N. NaOH, and the desired compound is extracted with ethyl acetate. The combined organic fractions concentrated under reduced pressure to obtain the product (69 mg, 1.77 mmol, 19%).1H-NMR (400 MHz, METHANOL-D4) δ million-11.50 (d, J=7.03 Hz, 3H), 1.72-1.7 (m, 6N), 5.02 (q, J=6.97 Hz, 1H), 5.31 (d, J=17.58 Hz, 1H), 5.36 (d, J=17.58 Hz, 1H), 7.17-7.25 (m, 2H), 7.39 (dd, J=8.20, 7.62 Hz, 1H), 7.43 (t, J=8.40 Hz, 1H), 7.67 (dd, J=7.62, 0.78 Hz, 1H), 7.97 (dd, J=8.20, 0.98 Hz, 1H), 8.26 (s, 1H); MS [M+H]calculated: 390,2, found: 390,3.

The enantiomers separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel®AD 21×250 mm (20 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 70% And 30% of isocratic αD=-173 (=5,5, Meon) and αD=+180 (=5,7, Meon).

Example 14

N-{1-[4-(1-Cyano-1-methylethyl)-3-forfinal]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide

Amide synthesized in accordance with modified example 1 by mixing (6,7-debtor-1H-benzimidazole-1-yl)acetic acid (781 mg, 3,68 mmol), obtained according to scheme 2, 2-[4-(1-amino-ethyl)-2-forfinal]-2-methylpropanamide hydrochloride (1.07 mg, to 4.41 mmol), obtained according to scheme 7, Et3N (1.23 ml, 8,82 mmol) and HATU (1.68 g, to 4.41 mmol) in DMF (15.0 ml). The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Gemini (5 μm) of 21.2×50 mm, mobile phase: a = water (0,075% TFA) and B = MeCN (0,075% TFA), (565 mg as TFA salt, 1.10 mmol, 30%);1H-NMR (400 MHz, DMSO-D6) δ million-11.38 (d, J=6.84 Hz, 3H), 1.71 (s, 6N), 4.87-5.00 (m, J=7.23, 7.23 Hz, 1H), 5.09 (s, 2H), 7.16-7.29 (m, 3H), 7.36-7.51 (m, 2H), 8.19 (s, 1H), 8.86 (d, J=7.62 Hz, 1H). MS [M+H]calculated: 401,4 found: 401.3.

The enantiomers separated using chiral HPLC: preparation of the active pumps Gilson, flow rate: 18 ml/min, column: Chiralpak OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = iPrOH (with 0.1% DEA).

Example 15

2-(7-Chloro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide

Amide synthesized according to example 1 by mixing (7-chloro-1H-benzimidazole-1-yl)acetic acid (521 mg, 2.48 mmol), obtained according to scheme 1, 2-[4-(1-amino-ethyl)-2-forfinal]-2-methylpropanamide hydrochloride 721 mg, of 2.97 mmol), obtained according to scheme 7, Et3N (824 μl, 5,95 mmol) and HATU (1.13 g, of 2.97 mmol) in DMF (10.0 ml). The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Gemini (5 μm) of 21.2×50 mm, mobile phase: a = water (0,075% TFA) and B = MeCN (0,075% TFA), (421 mg as TFA salt, 0.82 mmol, 33%);1H-NMR (400 MHz, DMSO-D6) δ million-11.38 (d, J=7.03 Hz, 3H), 1.64-1.76 (m, 6N), 4.88-4.98 (m, 1H), 5.27 (s, 2H), 7.18-7.28 (m, 3H), 7.28-7.33 (m, 1H), 7.41 (t, J=8.30 Hz, 1H), 7.65 (d, J=7.81 Hz, 1H), 8.47 (s, 1H), 8.85 (d, J=7.62 Hz, 1H). MS [M+H]calculated: 399,9 found: 399,3.

The enantiomers separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralpak OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = iPrOH (with 0.1% DEA).

Example 16:

2-(7-Chloro-1H-benzimidazole-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-terbisil]ndimethylacetamide.

2-(7-Chloro-1H-benzimidazole-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-terbisil]ndimethylacetamide synthesized according to the of example 14 (7-chloro-1H-benzimidazole-1-yl)acetic acid (150 mg, 0,712 mmol), obtained according to scheme 1, and 2-[4-(aminomethyl)-2-forfinal]-2-methylpropanamide hydrochloride (196 mg, 0,855 mmol), obtained according to scheme 8, Et3N (238 μl, 1,71 mmol) and HATU (325 mg, 0,855 mmol) in DMF (3.0 ml). The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Gemini (5 μm) of 21.2×50 mm, mobile phase: a = water (0,075% TFA) and B = MeCN (0,075% TFA). Output = 14 mg as TFA salt (0.035 mmol, 5%).1H-NMR (400 MHz, DMSO-D6) δ million-11.67 (s, 6N), 4.30 (d, J=5.86 Hz, 2H), 5.24 (s, 2H), 7.10-7.22 (m, 3H), 7.23-7.28 (m, 1H), 7.38 (t, J=8.40 Hz, 1H), 7.62 (d, J=7.81 Hz, 1H), 8.31 (s, 1H), 8.81 (s, 1H). MS [M+H]calculated: 385,1, found: 385,0.

Example 17:

2-(7-Cyano-1H-benzimidazole-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-terbisil]ndimethylacetamide.

2-(7-Cyano-1H-benzimidazole-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-terbisil]ndimethylacetamide synthesized according to example 14 from (7-cyano-1H-benzimidazole-1-yl)acetic acid (150 mg, 0,746 mmol), obtained according to scheme 3, 2-[4-(aminomethyl)-2-forfinal]-2-methylpropanamide hydrochloride (205 mg, 0,896 mmol), obtained according to scheme 8, Et3N (250 μl, to 1.79 mmol) and HATU (341 mg, 0,896 mmol) in DMF (3.0 ml). The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Gemini (5 μm) of 21.2×50 mm, mobile phase: a = water (0,075% TFA) and B = MeCN (0,075% TFA). Output = 21 mg as TFA salt (0,043 mmol, 6%).1H-NMR (400 MHz, DMSO-D6) δ million-11.62-1.71 (m, 6N), 4.32 (d, J=5.86 is C, 2H), 5.26 (s, 2H), 7.13-7.25 (m, 2H), 7.29-7.41 (m, 2H), 7.71 (d, J=7.42 Hz, 1H), 8.00 (d, J=8.01 Hz, 1H), 8.36 (s, 1H), 8.84-8.93 (m, 1H). MS [M+H]calculated: 376,2 found: 376,0.

Example 18:

N-[4-(1-Cyano-1-methylethyl)-3-terbisil]-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide.

N-[4-(1-Cyano-1-methylethyl)-3-terbisil]-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide synthesized according to example 14 with (6,7-debtor-1H-benzimidazole-1-yl)acetic acid (150 mg, 0,707 mmol), obtained according to scheme 2, 2-[4-(aminomethyl)-2-forfinal]-2-methylpropanamide hydrochloride (194 mg, 0,848 mmol), obtained according to scheme 8, Et3N (237 μl, 1.70 mmol) and HATU (323 mg, 0,848 mmol) in DMF (3.0 ml). The product was then purified using HPLC: preparative Gilson pumps, flow rate: 30 ml/min, column: Gemini (5 μm) of 21.2×50 mm, mobile phase: a = water (0,075% TFA) and B = MeCN (0,075% TFA). Output = 25 mg as TFA salt, 0.05 mmol, 7%).1H-NMR (400 MHz, DMSO-D6) δ million-11.74-1.87 (m, 6N), 4.43 (d, J=5.66 Hz, 2H), 5.22 (s, 2H), 7.19-7.40 (m, 2H), 7.45-7.61 (m, 2H), 8.34 (s, 1H), 8.91-9.04 (m, 1H). MS [M+H]calculated: 387,1, found: 387,0.

Example 19:

(S) - (-)-2-(7-Chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide.

A mixture of (7-chloro-6-fluoro-1H-benzimidazole-1-yl)acetic acid (1,00 g, 4,39 mmol), obtained according to scheme 12, (S) - (-)-2-{4-[1-amino-ethyl]phenyl}-2-methylpropionitrile (825 mg 4,39 mmol), obtained according to scheme 20 or 21, and Et3N (1,33 g, 13,2 IMO the e l e C of 1.84 ml) is stirred in MeCN (50,0 ml). Added HATU (1,67 g, 4,39 mmol) and after 2 hours of stirring, the mixture is diluted with 1 N. NaOH (100 ml) and then extracted 4 times with EtOAc (4×75,0 ml). The combined organic phases dried over Na2SO4. The mixture is filtered and concentrated. The product was then purified using prep. pump Gilson, flow rate: 30 ml/min, column: Gemini™ (5 μm) of 21.2×50 mm, mobile phase: A=10 mm ammonium bicarbonate, B=MeCN (1.01 g, 58%).1H-NMR (400 MHz, DMSO-D6) δ million-11.39 (d, J=7.03 Hz, 3H), 1.66 (s, 6N), 4.92 (Quint., J=7.23 Hz, 1H), 5.19 (s, 2H), 7.23 (dd, J=10.16, 8.98 Hz, 1H), 7.37 (d, J=8.20 Hz, 2H), 7.47 (d, J=8.59 Hz, 2H), 7.63 (dd, J=8.79, 4.49 Hz, 1H), 8.21 (s, 1H), 8.81 (d, J=7.81 Hz, 1H). MS [M+H]calculated: 399,1, found: 399,2. [α]D=-165 (=1,02 METHANOL).

HRMS(ESI+) calculated for C21H21ClFN4O 399,13824 [M+H]+, found 399,13832.

Example 20:

(+) and (-) 2-(7-Chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-metalsteel)-3-forfinal]ethyl}ndimethylacetamide.

A mixture of (7-chloro-6-fluoro-1H-benzimidazole-1-yl)acetic acid (210 mg, 0,921 mmol), obtained according to scheme 12, 2-{4-[1-amino-ethyl]-2-forfinal}-2-methylpropionitrile (190 mg 0,921 mmol), obtained according to scheme 7, and Et3N (280 mg, was 2.76 mmol, 0,39 ml) is stirred in MeCN (10.0 ml). Added HATU (350 mg, 0,921 mmol) and after 2 hours of stirring, the mixture is diluted with 1 N. NaOH (40,0 ml) and then extracted 4 times with EtOAc (4×40,0 ml). The combined organic phases dried over MgSO4. CME is ü filtered and concentrated. The product was then purified using prep. pump Gilson, flow rate: 30 ml/min, column: Synergi Polar (4 μm) of 21.2×50 mm, mobile phase: a = water with 0.1% TFA), B = MeCN (206 mg, 54%).1H-NMR (400 MHz, DMSO-D6) δ million-11.38 (d, J=6.84 Hz, 3H), 1.71 (s, 6N), 4.85-5.00 (m, J=7.13, 7.13 Hz, 1H), 5.21 (s, 2H), 7.15-7.31 (m, 3H), 7.42 (t, J=8.30 Hz, 1H), 7.63 (dd, J=8.89, 4.39 Hz, 1H), 8.21 (s, 1H), 8.84 (d, J=7.81 Hz, 1H). The enantiomers separated on a chiral column AD, elwira 30% EtOH (0.1% of DIEA) and 70% hexane (0,1% DIEA). MS [M+H]calculated: 417,1, found: 417,3, [α]D=+154 (with a=13, Meon) and [α]D=-155 (C=15, Meon).

I believe that the enantiomers can be separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 80% A: 20% of socratica.

Example 21:

(+) and (-)-2-(7-Chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide.

To a solution of (7-chloro-6-fluoro-1H-benzimidazole-1-yl)acetic acid (100 mg, 0.44 mmol), obtained according to scheme 12, 2-{4-[1-amino-ethyl]-2-were}-2-methylpropionitrile (88,5 mg, 0.44 mmol), obtained according to scheme 16, and DMAP (106 mg, 0.88 mmol), stirred in anhydrous DMF (2.0 ml), added HATU (166 mg, 0.44 mmol). After 18 hours of stirring the mixture was diluted with methanol (200 μl). The solution is purified directly on the preparative LCMS system equipped with a column Synergi Polar (4 μm) of 21.2×50 mm, mobile-FA is a: A = water with 0.1% TFA), B = MeCN using short from 40 to 60% In 10 min gradient method. Pure fractions are combined to neutralize TFA 4 N. NaOH solution and then extracted with ethyl acetate, separated, dried over anhydrous Na2SO4filter and concentrate under reduced pressure to obtain the expected product (+) and (-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}-ndimethylacetamide (290 mg, 53%) as a white solid.1H-NMR (400 MHz, METHANOL-D4) δ million-11.48 (d, J=7.03 Hz, 3H), 1.76 (s, 6N), 2.61 (s, 3H), 4.99 (q, J=7.03 Hz, 1H) 5.19-5.36 (m, 2H), 7.13-7.25 (m, 3H), 7.33 (d, J=8.20 Hz, 1H), 7.59 (dd, J=8.98, 4.30 Hz, 1H), 8.14 (s, 1H). MS [M+H]calculated: 413,2 found: 413,3.

I believe that the enantiomers can be separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 80% A: 20% of socratica.

Example 22:

(+) and ( - ) - N-{1-[4-(4-Cyanoacrylate-2H-thiopyran-4-yl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide

Amide synthesized according to example 1 by mixing (6,7-debtor-1H-benzimidazole-1-yl)acetic acid (96 mg, 0.45 mmol), obtained according to scheme 2, 4-[4-(1-amino-ethyl)-3-were]tetrahydro-2H-thiopyran-4-carbonitrile (129 mg, 0.50 mmol), obtained according to scheme 14, Et3N (0,69 ál, 0.50 mmol) and HATU (189 mg, 0,mol) in MECN (3.0 ml). The connection is cleaned by column chromatography on silica gel (10% Meon in DCM) (121 mg, 59%).1H-NMR (400 MHz, DMSO-D6) δ million-11.35 (d, J=7.03 Hz, 3H), 2.05-2.16 (m, 2H), 2.26-2.35 (m, 5H), 2.72-2.81 (m, J=14.06 Hz, 2H), 2.88-2.99 (m, J=12.50, 12.50 Hz, 2H), 5.01-5.11 (m, 3H), 7.16-7.26 (m, 1H), 7.30 (s, 1H), 7.33-7.38 (m, 1H), 7.39-7.48 (m, 2H), 8.18 (s, 1H), 8.84 (d, J=7.42 Hz, 1H). MS [M+H]calculated: 455,5 found: 455,3.

I believe that the enantiomers can be separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 80% A: 20% of socratica.

Example 23:

N-[4-(1-Cyano-1-methylethyl)benzyl]-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide

(6,7-Debtor-1H-benzimidazole-1-yl)acetic acid (42 mg, 0.2 mmol), obtained according to scheme 2, was dissolved in CH2Cl2(2 ml). Add triethylamine (83 μl, 0.6 mmol), then pivaloate (25 μl, 0.2 mmol). After 30 minutes, add 2-[4-(aminomethyl)phenyl]-2-methylpropionitrile (35 mg, 0.2 mmol), obtained according to scheme 18, dissolved in 1 ml of CH2Cl2. The mixture is stirred over night at room temperature, concentrated in vacuo and purified by HPLCMS: Waters prep LCMS, 27 ml/min, column: X-Bridge Prep C18 OBD, 30×50 mm, particle size 5 μm, mobile phase: a = water (10 mm NH4CO3) B = MeCN, used a gradient from 40% to 60% In in And within 10 minutes Faction unite is dried by sublimation to give the desired product (17 mg, 0.05 mmol, 25%). MS (ESI) (M+1) 383,3.1H-NMR (400 MHz, DMSO-D6) δ million-11.65 (s, 6N), 2.30 (s, 3H) 4.29 (d, J=5.47 Hz, 2H), 5.09 (s, 2H), 7.19-7.31 (m, 3H), 7.32-7.35 (m, 1H), 7.47 (dd, J=8.98, 3.91 Hz, 1H), 8.22 (8, 1H), 8.66-8.74 (m, 1H).

Example 24:

N-[4-(1-Cyano-1-methylethyl)-2-methylbenzyl]-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide

(6,7-Debtor-1H-benzimidazole-1-yl)acetic acid (91 mg, 0.43 mmol), obtained according to scheme 2, is dissolved in DCM (3 ml). Add DIPEA (0.1 ml), then pivaloate (53 μl, 0.43 mmol). After 1 hour, add 2-[4-(aminomethyl)-3-were]-2-methylpropionitrile (80 mg, 0.43 mmol), obtained according to scheme 19. The mixture is stirred over night at room temperature, concentrated in vacuo and purified by HPLCMS: Waters prep LCMS, 27 ml/min, column: X-Bridge Prep C18 OBD, 30×50 mm, particle size 5 μm, mobile phase: a = water (10 mm NH4CO3) B = MeCN, used a gradient from 30% to 50% In And within 10 minutes Fractions are combined and dried by sublimation to give the desired product (59 mg, 0.15 mmol, 35%). MS (ESI) (M+1) 369,2.1H-NMR (400 MHz, DMSO-D6) δ million-11.67 (s, 6N), 4.33 (d, J=5.86 Hz, 2H), 5.10 (s, 2H), 7.23 (ddd, J=11.62, 8.89, 7.62 Hz, 1H), 7.32 (d, J=8.59 Hz, 2H), 7.44-7.51 (m, 3H), 8.21 (s, 1H), 8.80 (t, J=5.86 Hz, 1H).

Example 25:

2-(7-Cyano-1H-benzimidazole-1-yl)-N-[4-(1-cyano-1-methylethyl)-2-methylbenzyl]ndimethylacetamide

(7-Cyano-1H-benzimidazole-1-yl)acetic acid (86 mg, 0.43 mmol), obtained according to the but the scheme 3, dissolved in DCM (3 ml). Add DIPEA (0.1 ml), then pivaloate (53 μl, 0.43 mmol). After 1 hour, add 2-[4-(aminomethyl)-3-were]-2-methylpropionitrile (80 mg, 0.43 mmol), obtained according to scheme 19. The mixture is stirred over night at room temperature, concentrated in vacuo and purified by HPLCMS: Waters prep LCMS, 27 ml/min, X-Bridge Prep C18 OBD, 30×50 mm, particle size 5 μm, mobile phase: a = water (10 mm NH4CO3) B = MeCN, used a gradient from 30% to 50% In And within 10 minutes Fractions are combined and dried by sublimation give the desired product (47 mg, 0.13 mmol, 30%). MS (ESI) (M+1) 372,3.1H-NMR (400 MHz, DMSO-D6) δ million-11.65 (s, 6N), 2.31 (s, 3H), 4.29 (d, J=5.08 Hz, 2H), 5.26 (s, 2H), 7.25-7.29 (m, 1H), 7.30-7.40 (m, 3H), 7.73 (dd, J=7.62, 0.98 Hz, 1H), 8.03 (dd, J=8.20, 0.78 Hz, 1H), 8.38 (s, 1H), 8.74 (t, J=5.27 Hz, 1H).

Example 26:

(+) and (-)-N-{1-[4-(1-Cyano-1-methylethyl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide

To a solution of (6,7-debtor-1H-benzimidazole-1-yl)acetic acid (250 mg, 1.18 mmol)obtained according to scheme 2, 2-[4-(1-amino-ethyl)-3-were]-2-methylpropionitrile (202 mg, 1.18 mmol)obtained according to scheme 15, and DMAP (285 mg, 2,35 mmol), stirred in anhydrous DMF (4.0 ml), added HATU (448 mg, 1.18 mmol). After 18 hours stirring, the mixture is diluted with 1 N. NaOH (40,0 ml) and then extracted 4 times with EtOAc (4×40,0 ml). The combined organic phases dried over MgSO4. The mixture f is trout and concentrate. The product was then purified on the preparative LCMS system equipped with a column Synergi Polar (4 μm) of 21.2×50 mm, mobile phase: a = water (0.01 M ammonium carbonate buffer), B = MeCN using short from 40 to 60% In 10 min gradient method at high pH. Pure fractions are combined and then extracted with ethyl acetate, separated, dried over anhydrous Na2SO4filter and concentrate under reduced pressure to obtain the desired product N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide (350 mg, 75%) as a white solid.1H-NMR (400 MHz, METHANOL-D4) δ million-11.44 (d, J=6.84 Hz, 3H), 1.66 (s, 6N), 2.36 (s, 3H), 5.06 (d, J=16.99 Hz, 1H), 5.11 (d, J=16.99 Hz, 1H), 5.20 (q, J=7.03 Hz, 1H), 7.14 (ddd, J=11.38, 8.84, 7.52 Hz, 1H), 7.26 (d, J=2.15 Hz, 1H), 7.32 (dd, J=6.05, 2.15 Hz, 1H), 7.37-7.43 (m, 2H), 8.09 (s, 1H). MS [M+H]calculated: 397,2 found: 397,3. The enantiomers separated on chiral OD column using methanol and CO2as the mobile phase.

Alternatively, chiral (-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide can be obtained directly using chiral intermediate (-)2-[4-[1-amino-ethyl]-3-were]-2-methylpropionitrile, obtained as described in scheme 23, and the appropriate acid above.

Example 27:

(+) and (-)-2-(7-Cyano-1H-benzoni the azole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}ndimethylacetamide

To a solution of (7-cyano-1H-benzimidazole-1-yl)acetic acid (250 mg, 1,24 mmol), obtained according to scheme 3, 2-[4-(1-amino-ethyl)-3-were]-2-methylpropionitrile (251 mg of 1.24 mmol)obtained according to scheme 15, and DMAP (150 mg, 1,24 mmol), stirred in anhydrous DMF (4.0 ml), added HATU (473 mg, 1,24 mmol). After 18 hours of stirring the mixture was diluted with methanol (200 μl). The solution is purified directly on the preparative LCMS system equipped with a column Synergi Polar (4 μm) of 21.2×50 mm, mobile phase: a = water with 0.1% TFA), B = MeCN using short from 40 to 60% In 10 min gradient method. Pure fractions are combined to neutralize TFA 4 N. NaOH solution and then extracted with ethyl acetate, separated, dried over anhydrous Na2SO4filter and concentrate under reduced pressure to obtain the expected product (+) and (-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}ndimethylacetamide (206 mg, 43%) as a white solid.1H-NMR (400 MHz, METHANOL-D4) δ million-11.45 (d, J=6.84 Hz, 3H), 1.66 (s, 6H), 2.37 (s, 3H), 5.20 (q, J=6.84 Hz, 1H), 5.30 (s, 2H), 7.25 (d, J=1.95 Hz, 1H), 7.32 (dd, J=8.20, 2.15 Hz, 1H), 7.38 (dd, J=8.11, 7.71 Hz, 1H), 7.44 (d, J=8.20 Hz, 1H), 7.67 (dd, J=7.42, 0.78 Hz, 1H), 7.96 (dd, J=8.20, 0.98 Hz, 1H), 8,24 (s, 1H). MS [M+H]calculated: 386,2 found: 386,2.

Alternatively, chiral (-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}ndimethylacetamide can be obtained directly the public using chiral intermediate (-)2-[4-[1-amino-ethyl]-3-were]-2-methylpropionitrile, obtained as described in scheme 23, and the appropriate acid above.

Example 28:

(+) and (-)-N-{1-[4-(1-Cyano-1-methylethyl)-2-were]ethyl}-2-(7-fluoro-1H-benzimidazole-1-yl)ndimethylacetamide

To a solution of (7-fluoro-1H-benzimidazole-1-yl)acetic acid (250 mg, 1,29 mmol), obtained according to scheme 5, 2-[4-(1-amino-ethyl)-3-were]-2-methylpropionitrile (260 mg 1,29 mmol), obtained according to scheme 15, and DMAP (156 mg, 1,29 mmol), stirred in anhydrous DMF (4.0 ml), added HATU (490 mg, 1,29 mmol). After 18 hours of stirring the mixture was diluted with methanol (200 μl). The solution is purified directly on the preparative LCMS system equipped with a column Synergi Polar (4 μm) of 21.2×50 mm, mobile phase: a = water with 0.1% TFA), B = MeCN using short from 40 to 60% In 10 min gradient method. Pure fractions are combined to neutralize TFA 4 N. NaOH solution and then extracted with ethyl acetate, separated, dried over anhydrous Na2SO4filter and concentrate under reduced pressure to obtain the expected product (+) and (-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(7-fluoro-1H-benzimidazole-1-yl)ndimethylacetamide (306 mg, 63%) as a white solid.1H-NMR (400 MHz, METHANOL-D4) δ million-11.44 (d, J=6.84 Hz, 3H), 1.66 (s, 6N) 2.35 (s, 3H), 5.02-5.14 (m, 2H), 5.19 (q, J=7.03 Hz, 1H), 6.99 (dd, J=11.52, 7.42 Hz, 1H), 7.19 (dt, J=8.15, 4.98 Hz, 1H), 7.26 (d, J=2.15 Hz, 1H), 7.32 (dd, J=8.01, 2.34 Hz, 3H), 7.39 (d, J=8.2 Hz, 1H), 7.45 (d, J=7.62 Hz, 1H), 8.09 (s, 1H). MS [M+H]calculated: to 379.2 found: to 379.2.

Alternatively, chiral (-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(7-fluoro-1H-benzimidazole-1-yl)ndimethylacetamide can be obtained directly using chiral intermediate (-)2-[4-[1-amino-ethyl]-3-were]-2-methylpropionitrile, obtained as described in scheme 23, and the appropriate acid above.

Example 29:

(+) and (-)-N-{1-[3-Chloro-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide

To a solution of (6,7-debtor-1H-benzimidazole-1-yl)acetic acid (285 mg, 1.35 mmol), obtained according to scheme 2, 2-[4-(1-amino-ethyl)-2-chlorophenyl]-2-methylpropionitrile (300 mg, 1.35 mmol), obtained according to scheme 17, and DMAP (325 mg, 2,69 mmol), stirred in anhydrous DMF (3.0 ml), added HATU (511 mg, 1.35 mmol). After 18 hours of stirring the mixture was diluted with methanol (200 μl). The solution is purified directly on the preparative LCMS system equipped with a column Synergi Polar (4 μm) of 21.2×50 mm, mobile phase: a = water with 0.1% TFA), B = MeCN using short from 40 to 60% In 10 min gradient method. Pure fractions are combined to neutralize TFA 4 N. NaOH solution and then extracted with ethyl acetate, separated, dried over anhydrous Na2SO4filter and concentrate under reduced pressure to obtain expected the CSO product (+) and (-)-N-{1-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide (300 mg, 55%) as a white solid.1H-NMR (400 MHz, METHANOL-D4) δ million-11.50 (d, J=7.03 Hz, 3H), 1.83 (s, 6N) 5.02 (q, J=7.03 Hz, 1H), 5.14 (s, 2H), 7.17 (ddd, J=11.33, 8.98, 7.42 Hz, 1H), 7.33 (dd, J=8.20, 1.95 Hz, 1H), 7.43 (ddd, J=8.89, 3.81, 1.37 Hz, 1H), 7.47 (d, J=2.34 Hz, 1H), 7.51 (d, J=8.20 Hz, 1H), 8.13 (s, 1H). MS [M+H]calculated: 379,1, found: 379,3.

I believe that the enantiomers can be separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 80% A: 20% of socratica.

Example 30:

(+) and (-)-N-{1-[3-Chloro-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(7-cyano-1H-benzimidazole-1-yl)ndimethylacetamide

To a solution of (7-cyano-1H-benzimidazole-1-yl)acetic acid (271 mg, 1.35 mmol), obtained according to scheme 3, 2-[4-(1-amino-ethyl)-2-chlorophenyl]-2-methylpropionitrile (300 mg, 1.35 mmol), obtained according to scheme 17, and DMAP (325 mg, 2,69 mmol), stirred in anhydrous DMF (3.0 ml), added HATU (511 mg, 1.35 mmol). After 18 hours of stirring the mixture was diluted with methanol (200 μl). The solution is purified directly on the preparative LCMS system equipped with a column Synergi Polar (4 μm) of 21.2×50 mm, mobile phase: a = water with 0.1% TFA), B = MeCN using short from 40 to 60% In 10 min gradient method. Pure fractions are combined to neutralize TFA 4 N. NaOH solution and then extracted with ethyl acetate, separated, dried over betw denim Na 2SO4filter and concentrate under reduced pressure to obtain the expected product (+) and (-)-N-{1-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(7-cyano-1H-benzimidazole-1-yl)ndimethylacetamide (290 mg, 53%) as a white solid.1H-NMR (400 MHz, METHANOL-D4) δ million-11.50 (d, J=7.03 Hz, 3H), 1.83 (s, 6N) 5.02 (q, J=7.03 Hz, 1H), 5.14 (s, 2H) 7.17 (ddd, J=11.33, 8.98, 7.42 Hz, 1H), 7.33 (dd, J=8.20, 1.95 Hz, 1H), 7.43 (ddd, J=8.89, 3.81, 1.37 Hz, 1H), 7.47 (d, J=2.34 Hz, 1H), 7.51 (d, J=8.20 Hz, 1H), 8.13 (s, 1H). MS [M+H]calculated: 417,1, found: 417,3.

I believe that the enantiomers can be separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 80% A: 20% of socratica.

Example 31:

(+) and (-)-2-(6,7-Debtor-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide.

To a solution of (6,7-debtor-1H-benzimidazole-1-yl)acetic acid (500 mg, 2.36 mmol), obtained according to scheme 2, 2-{4-[1-amino-ethyl]-2-were}-2-methylpropionitrile (477 mg, 2.36 mmol), obtained according to scheme 16, and DMAP (570 mg, 4,71 mmol), stirred in anhydrous DMF (4.0 ml), added HATU (896 mg, 2.36 mmol). After 18 hours of stirring the mixture was diluted with EtOAc (100 ml). The organic phase is washed in distilled water, dried over anhydrous MgSO4. The mixture is filtered and concentrated. The product was then purified on preparative what the LCMS system, equipped with a column Synergi Polar (4 μm) of 21.2×50 mm, mobile phase: a = water with 0.1% TFA), B = MeCN using short from 40 to 60% In 10 min gradient method. Pure fractions are combined to neutralize TFA 4 N. NaOH solution and then extracted with ethyl acetate, separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the expected product (+) and (-)-2-(6,7-debtor-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide (627 mg, 67%) as a white solid.1H-NMR (400 MHz, METHANOL-D4) δ million-11.48 (d, J=7.03 Hz, 3H), 1.75 (s, 6N), 2.61 (s, 3H), 4.99 (q, J=7.03 Hz, 1H), 5.12 (s, 2H), 7.12-7.25 (m, 3H), 7.33 (d, J=8.20 Hz, 1H), 7.42 (ddd, J=8.89, 3.61, 1.17 Hz, 1H), 8.13 (s, 1H). MS [M+H]calculated: 397,2 found: 397,2.

I believe that the enantiomers can be separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 80% A: 20% of socratica.

Example 32:

(+) and (-)-2-(7-Cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide.

To a solution of (7-cyano-1H-benzimidazole-1-yl)acetic acid (100 mg, 0.50 mmol), obtained according to scheme 3, 2-{4-[1-amino-ethyl]-2-were}-2-methylpropionitrile (101 mg, 0.50 mmol), obtained according to scheme 16, and DMAP (120 mg, 1.00 mmol), stirred in anhydrous DMF (0 ml), added HATU (189 mg, 0.50 mmol). After 18 hours of stirring the mixture was diluted with methanol (200 μl). The solution is purified directly on the preparative LCMS system equipped with a column Synergi Polar (4 μm) of 21.2×50 mm, mobile phase: a = water with 0.1% TFA), B = MeCN using short from 40 to 60% In 10 min gradient method. Pure fractions are combined to neutralize TFA 4 N. NaOH solution and then extracted with ethyl acetate, separated, dried over anhydrous Na2SO4filter and concentrate under reduced pressure to obtain the expected product (+) and (-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide (143 mg, 75%) as a white solid.1H-NMR (400 MHz, METHANOL-D4) δ million-11.49 (d, J=7.03 Hz, 3H), 1.75 (s, 6N), 2.61 (s, 3H), 4.99 (q, J=7.03 Hz, 1H), 5.28-5.40 (m, 2H), 7.21-7.29 (m, 2H), 7.33 (d, J=8.20 Hz, 1H), 7.37-7.44 (m, 1H), 7.69 (dd, J=7.42, 0.78 Hz, 1H), 7.98 (dd, J=8.20, 1.17 Hz, 1H), 8.27 (s, 1H). MS [M+H]calculated: 386,2 found: 386,2.

I believe that the enantiomers can be separated using chiral HPLC: preparative Gilson pumps, flow rate: 18 ml/min, column: Chiralcel OD 21×250 mm (5 μm), mobile phase: A = hexane with 0.1% DEA) B = EtOH with 0.1% DEA), 80% A: 20% of socratica.

Example 33:

(S)-(-)2-(6-Chloro-7-fluoro-1H-benzimidazole-1-yl)-N-{[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide.

To a solution of (6-chloro-7-fluoro-1H-benzimidazole-1-yl)acetic acid (100 is g, 0.44 mmol), obtained according to scheme 13, (S) - (- )- 2-{4-[1-amino-ethyl]phenyl}-2-methylpropionitrile (88,5 mg, 0.44 mmol), obtained according to scheme 20 or 21, and DMAP (106 mg, 0.88 mmol), stirred in anhydrous DMF (2.0 ml), added HATU (166 mg, 0.44 mmol). After 18 hours of stirring the mixture was diluted with methanol (200 μl). The solution is purified directly on the preparative LCMS system equipped with a column Synergi Polar (4 μm) of 21.2×50 mm, mobile phase: a = water with 0.1% TFA), B = MeCN using short from 40 to 60% In 10 min gradient method. Pure fractions are combined to neutralize TFA 4 N. NaOH solution and then extracted with ethyl acetate, separated, dried over anhydrous Na2SO4filter and concentrate under reduced pressure to obtain the expected product (S)-(-)-2-(6-chloro-7-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide (290 mg, 53%) as a transparent solid substance.1H-NMR (400 MHz, METHANOL-D4) δ million-11.50 (d, J=7.03 Hz, 3H), 1.69 (s, 6N), 5.03 (q, J=7.01 Hz, 1H), 5.07-5.18 (m, 2H), 7.29 (dd, J=9.37, 6.64 Hz, 3H), 7.39 (d, J=8.59 Hz, 2H), 7.44 (d, J=9.37 Hz, 1H), 7.48 (d, J=8.59 Hz, 2H), 8.14 (s, 1H). MS [M+H]calculated: 399,1, found: 399,2, [α]D=-138° (C=0.5 IN METHANOL).

Example 34:

2-(6-Chloro-7-fluoro-1H-benzimidazole-1-yl)-N-{[4-(1-cyano-1-methylethyl)-2-methylbenzyl]ndimethylacetamide.

To a solution of (6-chloro-7-fluoro-1H-benzimidazole-1-yl)acetic acid (85 mg, 0.37 to IMO is b) obtained according to scheme 13, 2-[4-(aminomethyl)-3-were]-2-methylpropionitrile (70 mg of 0.37 mmol), obtained according to scheme 19, and DMAP (90 mg, of 0.74 mmol), stirred in anhydrous DMF (2.0 ml), added HATU (142 mg, and 0.37 mmol). After 18 hours of stirring the mixture was diluted with methanol (200 μl). The solution is purified directly on the preparative LCMS system equipped with a column Synergi Polar (4 μm) of 21.2×50 mm, mobile phase: a = water with 0.1% TFA), B = MeCN using short-term from 30% to 60% In 10 min gradient method. Pure fractions are combined to neutralize TFA 4 N. NaOH solution and then extracted with ethyl acetate, separated, dried over anhydrous Na2SO4filter and concentrate under reduced pressure to obtain the expected product 2-(6-chloro-7-fluoro-1H-benzimidazole-1-yl)-N-{[4-(1-cyano-1-methylethyl)-2-methylbenzyl]ndimethylacetamide (18 mg, 12%) as a transparent solid substance.1H-NMR (400 MHz, METHANOL-D4) δ million-11.46 (d, J=7.03 Hz, 3H), 1.68 (s, 6H), 2.38 (s, 3H), 5.05-5.16 (m, 2H), 5.21 (q, J=6.90 Hz, 1H), 7.25-7.31 (m, 2H), 7.35 (dd, J=8.98, 1.95 Hz, 1H), 7.41 (d, J=8.20 Hz, 1H), 7.44 (d, J=8.98 Hz, 1H), 8.14 (s, 1H). MS [M+H]calculated: 413,2 found: 413,3.

Pharmacology:

Biological assessment of TRPV1 person, FLIPR™ analysis of the mobilization of calcium.

The activity of the compounds of the present invention (IC50measure analysis visualization using 384-tablet, which controls induzirovanny drug level of intracellular CA 2in intact cells. Activation hTRPV1 (human receptor V1 for short-term capacity (human Transient Receptor Potential V1)corresponds to the inventory number: AM with the following modification: instead of phenylalanine at position 589 present leucine)receptors expressed in cells, SOME T-Rex (embryonic human kidney, tetracycline-regulated cells)were quantitatively determined in the device Molecular Devices FLIPR II™ to increase the fluorescent signal. Inhibition of hTRPV1 compounds determined by the decrease in fluorescent signal in response to the activation of 20 nm capsaicin. hVR1-inducible HEK cells T-Rex is grown in 1X medium Needle in the modification of Dulbecco with additives (DMEM, Wisent, 319-005-CL) with 10% fetal bovine serum (Wisent, 090850), 2 mm L-glutamine (Wisent, 609-065-EL), 5 μg/ml of blasticidin S HCL (Invitrogen R-210-01) and 350 μl/ml zeocin (Invitrogen R-250-05). The cells are sown in 384-well black tablet, coated polylysine (falcon, BD) at a concentration of 10,000 cells/well/50 μl for 16 hours or 5500 cells/well/50 μl for 48 hours in a humid incubator (5% CO2and 37°C) DMEM without selective agent. Cells HEK T-Rex hVR1 induced with 0.1 µg/ml tetracycline (Invitrogen, 550205) for 16 hours before the experiment. On the day of the experiment environment is removed from the tablets with the cells by inverting. To each well is added to the boot solution, 30 μl of a balanced salt solution is Hanks, 1 mm CaCl2and 5 mm glucose, pH 7.4 (Wisent, 311-520-VL) with indicator dye calcium FLUO-4 AM 4 μm (Molecular Probes F14202) and Pluronic F-127 0,004% (Invitrogen P3000MP)using recapital Labsystems multidrop. Tablets incubated at 37°C for 30-40 minutes before the start of the experiment. The complete incubation by washing the cells 4 times in buffer for analysis using a Skatron Embla (Moleculare Devices corp), leaving a residual volume of 25 μl buffer/well. Tablets with cells and then transferred to a FLIPR-ready additions connection.

On the day of the experiment capsaicin and connection was diluted three-fold concentration range (10-point serial dilution) to add using FLIPR. For all analyses, calcium undertake background reading for 10 seconds, then added to 12.5 μl of compounds give the total volume of the wells of 37.5 μl. Data are collected every second for 60 images and then every 10 seconds for 23 images before adding the agonist during the overall time period of 300 seconds. Before adding the agonist take a second background reading for 10 seconds, then added to 12.5 μl of agonist or buffer, receiving the final volume of 50 µl. After stimulation with agonist FLIPR continues to collect data every second for 60 images and then every 10 seconds for 21 images during the overall period of time of 280 seconds. Emission fluorescence reading is the use of filter 1 (radiation 520-545 nm) using a CCD camera on FLIPR.

Compounds with antagonistic properties against hVR1, will inhibit the increase in intracellular calcium in response to the addition of capsaicin, which leads thus to a decrease in fluorescent signal. Data export using FLIPR as the sum of fluorescence, calculated under the curve after the addition of capsaicin. Data analyzed using a sigmoidal matches nonlinear program tracing the curves from the points (XLfit version 5.0.6 ID Business Solutions Limited, Guildford, UK). For each connection receive data in respect of maximum inhibition, extremum-tilt and IC50.

The following results were obtained.

# exampleTRPV1 Hu HEKcl2+ CapAnt CR, the mean IC50 (nm)
1158,5
289,85
6180,3
821,43
9483,3
1065,45
12429
13 110,6
161162
18476,4
20237,9
2185,16
2254,88
231055
24514,5
25788
2665,97
2756.78 has
28570,9
29110
3091,59
3153,99
3249,42
34683,5

List of abbreviations:

VR1vanilloideae receptor 1
IBSirritable bowel syndrome
IBDinflammatory bowel disease
FLIPRtablet reader to visualize fluorescence
GERDgastroesophageal reflux disease
DRGthe ganglion of the rear spine
BSAbovine serum albumin
HEPES4-(2-hydroxyethyl)piperazine-1-econsultancy acid
EGTAethylene glycol-bis(2-aminoethylamino)-N,N,N',N'-tetraoxane acid
DMEMWednesday Needle, modified, Dulbecco

Examples of pharmaceutical compositions

1. Tablet
mg tablet
The connection according to the invention50,0
Polysorbate 803,0
Lactose178,0
Corn starchPre gelatinizing corn starch22,5
Magnesium stearate1,5
Purified waterAs needed

The connection according to the invention is sieved and mixed with the lactose, corn starch and pre-gelatinization corn starch. In purified water dissolve Polysorbate 80. To the mixture add the appropriate volume of Polysorbate 80 and the mixture granularit. After drying, the granules are sieved and mixed with magnesium stearate. Then the granules are pressed into tablets.

2. Capsule
Ingredientsmg/capsule
Caetanina according to the invention2,0
2. Lactose190,0
3. Corn starch21,0
4. Talc15,0
5. Magnesium stearate2,0
230,0

The source components are weighed and then sieved. Active ingredient (1) is mixed with the original components (2) and (3) for 30 minutes and then crushed. The resulting mixture is mixed with components (4) and (5) within 15 minutes. Then the mixture is filled hard gelatin capsules of a suitable size, which are then packaged properly.

1. The compound of the formula

where R1selected from CN, halogen, or C(=O)CH3;
R2selected from methyl or H;
R3selected from H or halogen;
each of R4and R5independently selected from methyl or ethyl, or R4and R5together with the carbon atom to which they are attached, form a 3-6-membered cycloalkyl or 5-or 6-membered geterotsyklicescoe group;
each of R6and R7independently selected from H, halogen, methyl or ethyl;
or its pharmaceutically acceptable salt;
where the compound of formula I is the following:
N-[4-(1-cyano-1-methylethyl)benzyl]-2-(6,7-debtor-1H-benzimidazole-1-yl)-ndimethylacetamide;
2-(7-chloro-1H-benzimidazole-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-terbisil]ndimethylacetamide;
(+)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}ndimethylacetamide;
(+)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(+,-)-2-(6-chloro-7-fluoro-1H-benzimidazole-1-yl)-N-{1-[-(1-cyano-1-methylethyl)-2-were]ethyl}ndimethylacetamide;
(+)-2-(7-acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;
(+)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(+)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;
(+)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(+)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(R)(+)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(R)(+)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;
(+)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;
(+)-2-(7-acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;
(R)(+)-N-{1-[4-(1-cyano-1-ethylpropyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide.

2. A compound selected from:
(S) - (-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;
(S) - (-)-N-{1-[4-(1-cyano-1-ethylpropyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(-)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(-)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)-phenyl]ethyl}ndimethylacetamide;
(-)-2-(7-acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-is iano-1-methylethyl)-phenyl]ethyl}ndimethylacetamide;
(S) - (-)-2-(7-acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;
(-)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(-)-2-(7-chloro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;
(-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-terbisil]ndimethylacetamide;
(-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(7-fluoro-1H-benzimidazole-1-yl)ndimethylacetamide;
(S) - (-)-2-(6-chloro-7-fluoro-1H-benzimidazole-1-yl)-N-{[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;
or its pharmaceutically acceptable salt.

3. A compound selected from:
(+,-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-phenyl]ethyl}ndimethylacetamide;
(+,-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(+,-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(7-fluoro-1H-benzimidazole-1-yl)ndimethylacetamide;
(+,-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(7-chloro-1H-benzimidazole-1-yl)ndimethylacetamide;
(+,-)-N-{1-[4-(1-cyano-1-ethylpropyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(+,-)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(+,-)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}-2-(6,7-debtor-1H-Benson Gasol-1-yl)ndimethylacetamide;
(+,-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)-phenyl]ethyl}ndimethylacetamide;
(+,-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)-phenyl]ethyl}ndimethylacetamide;
(+,-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyanocyclohexyl)-phenyl]ethyl}ndimethylacetamide;
(+,-)-2-(7-acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-phenyl]ethyl}ndimethylacetamide;
(+,-)-2-(7-acetyl-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;
(+,-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;
(+,-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide;
(+,-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-forfinal]ethyl}ndimethylacetamide;
(+,-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide;
(+,-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide;
(+,-)-N-{1-[4-(4-cyanoacrylate-2H-thiopyran-4-yl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
N-[4-(1-cyano-1-methylethyl)-2-methylbenzyl]-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
2-(7-cyano-1H-benzimidazole-1-yl)-N-[4-(1-cyano-1-methylethyl)-2-methylbenzyl]ndimethylacetamide;
(+,-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(+,-)-N-{1-[4-(1-cyano-1-methylethyl)-2-were]ethyl}-2-(7-fluoro-1H-benzimidazole-1-yl)ndimethylacetamide;
(+,-)-N-{1-[3-the ENT-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide;
(+,-)-N-{1-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(7-cyano-1H-benzimidazole-1-yl)ndimethylacetamide;
(+,-)-2-(7,6-debtor-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide;
(+,-)-2-(7-cyano-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-were]ethyl}ndimethylacetamide;
2-(6-chloro-7-fluoro-1H-benzimidazole-1-yl)-N-[4-(1-cyano-1-methylethyl)-2-methylbenzyl] ndimethylacetamide;
or its pharmaceutically acceptable salt.

4. Connection (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt.

5. Connection (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt.

6. The compound according to claim 1 for use in the treatment of nociceptive pain disorders in a mammal.

7. The compound according to claim 1 for use in the treatment of chronic nociceptive pain disorders in a mammal.

8. The compound according to claim 1 or its pharmaceutically acceptable salt for use in the treatment of osteoarthritis.

9. The compound according to claim 1 or its pharmaceutically acceptable salt for use in the treatment of tendinitis.

10. The compound according to claim 1 or its pharmaceutically acceptable salt for use in the treatment of chronic tendonitis.

11. The compound according to claim 1 or its pharmaceutically acceptable salt for use in the treatment of pelvic pain.

2. The compound according to claim 1 or its pharmaceutically acceptable salt for use in the treatment of peripheral neuropathy (mainly PHN (post herpetic neuralgia)).

13. The compound according to claim 1 or its pharmaceutically acceptable salt for use in the treatment of gastroesophageal reflux disease (GERD).

14. The compound according to claim 1 or its pharmaceutically acceptable salt for use in the treatment of irritable bowel syndrome (IBS).

15. The compound according to claim 1 or its pharmaceutically acceptable salt for use in the treatment of overactive bladder.

16. A method for the treatment of nociceptive pain disorders, including the introduction of an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt to a patient in need of it.

17. A method for the treatment of nociceptive pain disorders, including the introduction of an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

18. A method for the treatment of nociceptive pain disorders, including the introduction of an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

19. A method of treating chronic but eceptive pain disorders including the introduction of an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt to a patient in need of it.

20. A method of treating chronic nociceptive pain disorders, including the introduction of an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1 methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

21. A method of treating chronic nociceptive pain disorders, including the introduction of an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

22. A method of treating osteoarthritis comprising introducing an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt to a patient in need of it.

23. A method of treating osteoarthritis comprising introducing an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

24. A method of treating osteoarthritis comprising introducing an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically who priemlemoj salt to the patient, who needs this.

25. Treatment of tendinitis, including the introduction of an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt to a patient in need of it.

26. Treatment of tendinitis, including the introduction of an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

27. Treatment of tendinitis, including the introduction of an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

28. A method for the treatment of chronic tendinitis, including the introduction of an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt to a patient in need of it.

29. A method for the treatment of chronic tendinitis, including the introduction of an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

30. A method for the treatment of chronic tendinitis, including the introduction of an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its farmaci is almost acceptable salt to a patient, who needs this.

31. A method for the treatment of pelvic pain, including the introduction of an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt to a patient in need of it.

32. A method for the treatment of pelvic pain, including the introduction of an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

33. A method for the treatment of pelvic pain, including the introduction of an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

34. A method of treating peripheral neuropathy (mainly PHN), including the introduction of an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt to a patient in need of it.

35. A method of treating peripheral neuropathy (mainly PHN), including the introduction of an effective amount of the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-ndimethylacetamide or its pharmaceutically acceptable salt to a patient in need of it.

36. A method of treating peripheral neuropathy (mainly PHN), including the introduction of an effective amount of the compound (S)(-)-N-{1-[4-(1-cyano-1-eilati)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt to a patient, who needs this.

37. Pharmaceutical composition having inhibitory action against vanilloideae receptor 1 (VR1), which contains the compound according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

38. Pharmaceutical composition having inhibitory action against vanilloideae receptor 1 (VR1)containing the compound (S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazole-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-ndimethylacetamide or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

39. Pharmaceutical composition having inhibitory action against vanilloideae receptor 1 (VR1)containing the compound (S)(-)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-debtor-1H-benzimidazole-1-yl)ndimethylacetamide or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I, as well as to their physiologically acceptable salts wherein: X means NH; R1 means (C1-C6)-alkyl; R2 means OH; R2' means H; R5' means (C1-C6)-alkylene-O-S(O)2-R6; R3, R3', R4, R4' and R5 independently mean H, OH, (C1-C6)-alkylene-O-S(O)p-R6, O-(CH2)m-phenyl; at least one of the radicals R3, R3', R4, R4' and R5 has the value -O-(CH2)m-phenyl; R6 means OH; m=1; p=2.

EFFECT: compounds can find application in medicine, eg as lipid-lowering agents.

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula

wherein: m, n, R0, R1, R2, R3 and R4 have the values presented in clause 1 of the patent claim provided the compound of formula (I) cannot represent N-methyl-1-(phenylsulphonyl)-1H-indole-4-methanamine.

EFFECT: compounds show 5-NT6 receptor antagonist activity that that allows them being used in the pharmaceutical composition.

19 cl, 3 tbl, 192 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.

EFFECT: obtaining novel biologically active compounds possessing properties of γ-secretase inhibitor.

127 cl, 447 ex, 94 tbl

FIELD: chemistry.

SUBSTANCE: described are novel 7-member heterocyclic compounds of general formula (values of radicals are given in the claim) or salts thereof or solvates thereof having chymase inhibiting activity and suitable for preventing or treating different diseases in which chymase is involved, a method of producing said compounds, intermediate compounds and a pharmaceutical composition for preventing or treating diseases in which chymase is involved, including compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.

EFFECT: improved properties of the compound.

23 cl, 12 tbl, 308 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where each radical R-R5 and Y assume values given in the description, or salts thereof, which have GPR40 receptor modulating action.

EFFECT: intensification of secretion of insulin or an agent for preventing or treating diabetes, and a pharmaceutical composition based on said compounds.

17 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of organic chemistry, notably to derivatives of dihydroimidazole with the general formula (I) and to its pharmaceutically acceptable salts where X1 and X2 denote halogen; R1 and R2 are chosen from the group including -H, -CH3, -CH2CH3 on the condition that both R1 and R2 do not denote hydrogen; R3 denotes -H or -C(=O)-R7; and if R6 denotes hydrogen, then R4 denotes -OCH3, -OCH2CH3 or -OCH(CH3)2; R5 denotes -H, - halogen, -CF3, -OCH3, -C(CH3)2, - cyclopropyl, - cyano group, -C(CH3)3, -C(CH3)2OR (where R denotes -H), -C(CH3)2CH-OR (where R denotes -CH3), -C(CH3)2CN, -C(CH3)2COR (where R denotes -CH3), -SR (where R denotes -CH2CH3) or -SO2R (where R denotes -CH3, -CH2CH3, 1-pyrrolidine, -NH-tert-butyl); and if R6 does not denote hydrogen, then R4 denotes -OCH2CH3; R5 denotes hydrogen, -Cl, -OCH3, tert butyl; R6 denotes -Cl, cyclopropyl, -SO2R (where R denotes -CH3, 1-pyrrolidine, -NH-tert-butyl or -N(CH3)2); and R7 is chosen from the group including i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted with chlorine, -OCH3 or cyano group, ii) 1-piperidinyl, iii) -NRc2 (where Rc denotes -CH2CH2OH, -CH2CH2OCH3 or -CH2CH(OH)CH2OH, iv) substituted piperazidine with the formula where R is chosen from the group including a) hydrogen, c) -CH(CH3)2, k) -CH2CH2Rd (where Rd denotes -OH, -OCH3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morfolinil, 2-izotiazolidinil-1, 1-dioxide), l) -CH2CH2CH2Re (where Re denotes -OCH3, -SO2CH3, -SO2CH2CH3, -CN), m) -CH2-CO-Rh (where Rh denotes -NH2, 1-pyrrolidinyl, 4-morfolinil), n) -SO2Ri (where Ri denotes -CH3, -CH2CH3), o) -CORj (where Rj denotes -CH3, 2-tetrahydrofuranyl, -NH2, -N(CH3)2), p) 4-tetrahydro-2H-thiopiranyl-1,1-dioxide, q) 4-piperidinyl-1-acetyl, r) 4-piperidinyl-1-dimethylcarboxamide, and s) 3-tetrahydrothiophenyl-1,1-dioxide; v) substituted oxopiperazine with the formula where R denotes -H; and vi) substituted piperidine with the formula where R denotes -CONH2, -OH, -CH2OH, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazinyl) or 4-morfolinil. Moreover, the invention refers to the pharmaceutical composition based on the compound with the formula (I), to application of the formula (I) compound for production of a drug, to the production process of the formula (I) compound.

EFFECT: new derivatives of dihydroimidazole that may be used as anticancer drugs.

40 cl, 204 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the compounds of formula I in which R1 is chosen from the group including: H; alkyl; alkylenearyl and pyridin; R2 is chosen from the group including: cycloalkyl; aryl; CO-NH-cycloalkyl; CO-NH-aryl either unsubstituted or substituted with the help of halogen, CF3; SO2-aryl either unsubstituted or substituted with the help of alkyl; or in which R1 and R2 together form a 5- or 6-membered ring that does not need to contain 1 additional nitrogen heteroatom and that may also be substituted with the help of aryl; and that may also contain a carbonyl group; and that may also be condensed with aryl; R3 and R4 denote H; and acid additions to their physiologically acceptable salts. Invention also refers to a pharmaceutical composition, to the way of production of the formula I compound, to application of the formula I compound, and to the way of treatment or prevention of fatty degeneration, type II diabetes, metabolic syndrome and associated and/or secondary diseases or pathologic conditions endured by mammals.

EFFECT: production of new bioactive compounds that inhibit the isoenzyme of hydroxy citric acid II (hCA II).

11 cl, 11 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel azoles of general formula 1A and 1B and pharmaceutically acceptable salts thereof, having activity on hepatitis C and hepatitis GBV-C virus. Said compounds have NS5A viral protein ligand properties and can be used as active components for a pharmaceutical composition and a medicinal agent for treating diseases caused by said viruses. In general formula 1A and 1B, the solid lines accompanied by dotted lines denote a single or double bond, wherein if one of them is a single bond, the other is a double bond; X and Y optionally assume different values and denote a nitrogen, oxygen or sulphur atom or a NH group; R1 and R2 optionally denote identical radicals 2.1-2.20, in which the asterisk (*) indicates site of the bond to azole fragments. Said fragments and values of A and B are given in the claim.

EFFECT: more value of the compounds.

10 cl, 1 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzimidazole derivatives of formula

and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, C3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2; R4 denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)2, oxo group, NH2, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH2, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R3 denotes cycloalkyl and R1 denotes cycloalkyl, then R4 can also denote phenyl; R5, R6, R7 and R8 independently denote H, halogen, lower alkoxy group or lower alkyl, or R6 and R7, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compound of formula (I) is not selected from a group comprising butylamide 2-[2-(2-chlorophenyl)benzoimidazol-1-yl]-4-methylpentanoic acid and 2-(2-benzo[1,3]dioxol-5-ylbenzoimidazol-1-yl)-N-benzyl-butyric acid amide. The invention also relates to a pharmaceutical composition based on the formula I compound.

EFFECT: novel benzimidazole derivatives which are useful as farnesoid X receptor antagonists are obtained.

30 cl, 379 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic electroluminescent devices based on compounds of formula

where Y, Z is selected from N, P, P=O, C=O, O, S, S=O and SO2; Ar1, Ar2, Ar3 are selected from benzene, naphthaline, anthracene, phenanthrene, pyridine, pyrene or thiophene, optionally substituted with R1; Ar4, Ar5, Ar6, Ar7 are selected from benzene, naphthaline, anthracene, phenanthrene, pyridine, pyrene, thiophene, triphenylamine, diphenyl-1-naphthylamine, diphenyl-2-naphthylamine, phenyldi(1-naphthyl)amine, phenyldi(2-naphthyl)amine or spirobifluorene, optionally substituted with R1; E is a single bond, N(R1), O, S or C(R1)2; R1 denotes H, F, CN, alkyl, where the CH2 can be substituted with -R2C=CR2 -, -C=C-, -O- or -S-, and H can be substituted with F, optionally substituted aryl or heteroaryl, where R1 can form a ring with each other; R2 denotes H, aliphatic or aromatic hydrocarbon; X1, X4, X2, X3 are selected from C(R1)2, C=O, C=NR1, O, S, S=O, SO2, N(R1), P(R1), P(=O)R1, C(R1)2-C(R1)2, C(R1)2-C(R1)2-C(R1)2, C(R1)2-O and C(R1)2-O-C(R1)2; n, o, p, q, r and t are equal to 0 or 1; s = 1.

EFFECT: obtaining novel compounds - emission layer dopants, and novel electroluminescent devices based on said compounds which emit a blue colour.

18 cl, 91 ex, 6 tbl

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to cocrystalline form of (1S)-1,5-anhydro-1-[3-(1-benzothiene-2-ylmethyl)-4-fluorophenyl]-D-glucitol (compound A) with L-proline. Proposed cocrystalline form is a promising anti-diabetes medicine.

EFFECT: cocrystalline form of compound is characterised with constant composition, improved stability in storage, and also low hygroscopicity, and is suitable for use as crystalline medicinal substance to produce pharmaceutical preparations.

11 cl, 1 ex, 2 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of hydroperoxides of alkylaromatic hydrocarbons which can serve as a source of oxygen-containing organic compounds (phenol, methylphenols, acetone, cyclohexanone etc) and as an initiator of emulsion polymerisation of unsaturated hydrocarbons. The invention discloses a method for synthesis of hydroperoxides of alkylaromatic hydrocarbons through liquid-phase oxidation of these hydrocarbons with atmospheric oxygen at atmospheric pressure, process temperature of 110-130°C, for 1-3 hours in the presence of a 4-methyl-N-hydroxyphthalimide catalyst in amount of 1.0-2.0 wt %.

EFFECT: catalyst prevents use of an initiator and alkaline additives, which considerably simplifies the process, higher conversion of initial alkylaromatic hydrocarbons while preserving high selectivity of the process.

2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns a new glucitol derivative of formula (I): wherein m represents an integer chosen from 1-3; each R1, R2, R3 and R4 are independently choose from hydrogen atom and benzyl groups; Ar1 represents a naphthyl group which can be substituted by one or more substitutes chosen from the group, consisting of C1-C6alkyl group or halogen atom; A represents 5-7-members aromatic heterocyclic group containing one or more heteroatoms independently chosen from oxygen atom and sulphur atom which can form a condensed cycle with an aromatic carbocycle or an aromatic heterocycle where A can be substituted by one or more Rb provided when A is a benzocondensed cycle containing two or more rings, the group -(CH2)m- is connected with a heterocycle in A; Each Rb is independently chosen from C1-C6alkyl group, halogen atom and C1-C6-alkoxy group; or to their pharmaceutically acceptable salts. These compounds are used as a Na+ cotransport inhibitor and exhibits ability to reduce blood sugar level.

EFFECT: invention covers a pharmaceutical composition based on these compounds and to the method for treatment and prevention of such diseases associated with hyperglycemia, as diabetes, diabetes complications and obesity.

12 cl, 4 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel benzimidazole derivatives of formula any isomers thereof or any mixture of isomers thereof or a pharmaceutically acceptable salt, where R is -(CR'R")n-Rc, where Rc is C1-6-alkyl, R' is hydrogen or C1-6-alkyl, and R" is hydroxy; n equals 1; X is N; and Y, Z and W is CRd, where each Rd is hydrogen; Ro is halogen. The invention also relates to a pharmaceutical composition containing a compound of formula I, use of the compound of formula I and a GABAA-receptor complex modulating method.

EFFECT: obtaining novel benzimidazole derivatives which are sensitive to GABAA-receptor complex modulation.

8 cl, 1 tbl, 9 ex

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