Heteroaryl pyrrolidinyl and piperidinyl ketone derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

 

The invention relates to compounds of heteroarylboronic and piperidinylidene formula I

and their pharmaceutically acceptable salt,

where

m is 0-3;

n is 0-2;

Ar represents:

possibly substituted indolyl;

possibly substituted indazoles;

possibly substituted azaindole;

possibly substituted azaindole;

possibly substituted 2,3-dihydro-indolyl;

possibly substituted 1,3-dihydro-indol-2-he-Il;

possibly substituted benzothiophenes;

possibly substituted benzimidazolyl;

possibly substituted benzoxazolyl;

possibly substituted benzisoxazole;

possibly substituted benzothiazolyl;

possibly substituted benzisothiazole;

possibly substituted chinoline;

possibly substituted 1,2,3,4-tetrahydroquinolines;

possibly substituted quinoline-2-he-Il;

possibly substituted ethenolysis;

possibly substituted naphthalenyl;

possibly substituted pyridinyl;

possibly substituted thiophenyl;

possibly substituted pyrrolyl or

possibly substituted phenyl;

R1represents:

With1-6alkyl;

With2-6alkenyl;

With2-6quinil;

hetero-C1-6alkyl;

halo-C1-6alkyl;

halo-C2-6alkenyl;

With3-7cycloalkyl;

With3-7 cycloalkyl-C1-6alkyl;

With1-6alkyl-C3-6cycloalkyl-C1-6alkyl;

With1-6alkoxy;

With1-6alkylsulfonyl;

With1-6alkylsulfanyl;

possibly substituted aryl;

possibly substituted heteroaryl;

heterocyclyl-C1-6alkyl;

aryl-C1-3alkyl, where the aryl part may substituted;

heteroaryl-C1-3alkyl, where the heteroaryl portion may substituted;

aryloxy;

aryl-C1-6alkoxy;

heteroaromatic or

heteroaryl-C1-6alkoxy;

R2represents:

hydrogen or

With1-6alkyl; and

each Raand Rbindependently represents:

hydrogen;

With1-6alkyl;

With1-6alkoxy;

halo;

hydroxy or

oxo;

or Raand Rbtogether form1-2alkylen;

provided that, when m represents 1, n represents 2, and Ar represents a possibly substituted phenyl, then R1is not the stands or ethyl.

Also according to the invention proposed pharmaceutical compositions, methods of use and methods of obtaining the above-mentioned compounds.

In particular, the compounds of the present invention are useful for treating diseases associated with inhibitors of the reuptake of monoamines.

Deficiency of monoamines long time due ivali with depressive anxiolytic and other disorders (see, for example: Charney et al., J. Clin. Psychiatry (1998) 59, 1-14; Delgado et al., J. Clin. Psychiatry (2000) 67, 7-11; Resser et al., Depress. Anxiety (2000) 12 (Suppl 1) 2-19 and Hirschfeld et al., J. Clin. Psychiatry (2000) 61, 4-6). In particular, serotonin (5-hydroxytryptamine and norepinephrine are the major modulatory neurotransmitters, which play an important role in regulating mood. Selective inhibitors of serotonin reuptake (SSRls, selective serotonin reuptake inhibitors)such as fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and ESCITALOPRAM have been proposed for the treatment of depressive disorders (Masand et al., Harv. Rev. Psychiatry (1999) 7, 69-84). Inhibitors of reuptake of norepinephrine or norepinephrine, such as reboxetine, Atomoxetine, desipramine and nortriptyline, have been proposed for effective treatment of depressive disorders and attention deficit disorder and hyperactivity (Scates et al., Ann. Pharmacother. (2000) 34, 1302-1312; Tatsumi et al., Fur. J. Pharmacol. (1997) 340, 249-258).

It is established that increased neurotransmission of serotonin and norepinephrine is synergistic in the pharmacotherapy of depressive and anxiolytic disorders in comparison with gain only neurotransmission of serotonin or norepinephrine (Thase et al., Br. J. Psychiatry (2001) 178, 234, 241; Tran et al., J. Clin. Psychopharmacology (2003) 23, 78-86). Dual reuptake inhibitors and serotonin and norepinephrine, such as DULOXETINE, m is naziran and venlafaxine, currently being developed for the treatment of depressive and anxiolytic disorders (Mallinckrodt et al., J. Clin. Psychiatry (2003) 5(1) 19-28; Bymaster et al., Expert Opin. Investig. Drugs (2003) 12(4) 531-543). Dual reuptake inhibitors of serotonin and norepinephrine also provide possible treatment of schizophrenia and other psychosis, dyskinesia, drug dependence, cognitive disorders, Alzheimer's disease, obsessive-compulsive behavior, syndrome disorders of attention, panic attacks, sociophobia, eating disorders such as obesity, anorexia, bulimia and compulsive overeating, stress, hyperglycemia, hyperlipidemia, ainsliezubaida diabetes, epileptic disorders, such as epilepsy, and treatment of conditions associated with neurological damage resulting from stroke, brain injury, cerebral ischemia, head trauma, and hemorrhage. Dual reuptake inhibitors of serotonin and norepinephrine also provide possible treatment of disorders and painful conditions of the urinary tract, pain and inflammation.

"Triple" reuptake inhibitors (antidepressants broad-spectrum"), which inhibit the reuptake of norepinephrine, serotonin, and dopamine, have recently been recognized as useful in the treatment of depression and other CNS indications (Beer et al., J. Clinicl Pharmacology (2004) 44: 1360-1367; Skohick et al., Eur J Pharmacol. (2003) Feb 14; 461(2-3): 99-104).

Also inhibitors of reuptake of monoamines used in the treatment of pain. It is established that serotonin plays a role in the formation of pain in the peripheral nervous system and is involved in peripheral sensitization and hyperalgesia during inflammation and nerve damage (Sommer et al., Molecular Neurobiology (2004) 30(2), 117-125). It is shown that the inhibitor of the reuptake of serotonin, norepinephrine DULOXETINE is effective in the treatment of pain in model zhivotnykh (Iyengar et al., J. Pharm. .. Therapeutics (2004, 311, 576-584).

Thus, there is a need for compounds that are effective as inhibitors of reuptake of serotonin, reuptake inhibitors of norepinephrine, reuptake inhibitors dopamine, and/or dual reuptake inhibitors of serotonin, norepinephrine and/or dopamine, or triple reuptake inhibitors of norepinephrine, serotonin, and dopamine, as well as in methods of production and use of such compounds in the treatment of depressive, anxiolytic, urinary, pain and other disorders. The present invention satisfies these needs.

Unless otherwise stated, the following terms used in this application, including the description and the claims, have the following definitions. It should be noted that use is used in the description and the attached claims, the singular number include the plural number, unless the context requires otherwise.

"Agonist" refers to a compound that increases the activity of other compounds or site of the receptor.

"Alkyl" means the monovalent linear or branched saturated hydrocarbon group containing only carbon atoms and hydrogen atoms, having from one to twelve carbon atoms.

"Lower alkyl" refers to alkyl group of one to six carbon atoms, i.e. With1-C6the alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, etc. "Branched alkyl" means isopropyl, isobutyl, tert-butyl, etc.

"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropene, butylene, pentile etc.

"Alkoxy" means a group of the formula-OR, where R represents an alkyl group, as defined here. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy etc.

"Alkoxyalkyl" means a group of the formula-R'-R", where R' is made the focus of alkylene and R" is an alkoxy, as defined here. Typical alkoxyalkyl groups include as example 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl and 1-(2-methoxyethyl)-3-methoxypropyl.

"Alkylaryl" means a group of the formula-C(O)-R', where R' is an alkyl, as defined here.

"Alkylsulfonyl" means a group of the formula-SO2-R', where R' is an alkyl, as defined here.

"Alkylsulfanyl" means a group of formula-S-R', where R' is an alkyl, as defined here.

"Alkylsulfonyl" means a group of the formula-Rb-SO2-Rawhere Rarepresents alkyl and Rbis alkylene, as defined here. Typical alkylsulfonyl groups include as example 3-methanesulfonate, 2-methanesulfonate, 2-methanesulfonyl etc.

"Alkylsulfanyl" means a group of the formula-Rb-S-Rawhere Rarepresents alkyl and Rbis alkylene, as defined here.

"Alkylsulfonate" means a grouping of the formula Ra-SO2-O-, where Rarepresents an alkyl, as defined here.

"Amino" means a group of the formula-NRR'where each R and R' independently represents hydrogen or alkyl, as defined by the here. Thus, the "amino" includes "alkylamino" (where one of R and R' is an alkyl and the other represents hydrogen) and dialkylamino" (where both R and R' represent alkyl).

"Alkylcarboxylic" means a group of the formula-NR-C(O)-R', where R represents hydrogen or alkyl, and R' represents an alkyl, as defined here.

"Antagonist" refers to a compound that reduces or prevents the action of another connection or site of the receptor.

"Aryl" means a monovalent cyclic aromatic hydrocarbon group consisting of mono-, bi - or tritsiklicheskogo aromatic ring. The aryl group can be substituted, as defined here. Examples of aryl groups include, but are not limited to, possibly substituted phenyl, naphthyl, tenantry, fluorenyl, indenyl, azulene, acidifier, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfide, diphenylsulfone, diphenylethylene, benzodioxane, benzodioxole, benzoxazines, benzoxazinones, benzoperylene, benzofurazanyl, benzopyranyl, benzomorphans, methylenedioxyphenyl, atlanticcity and the like. Preferred arily may include substituted phenyl, and possibly substituted naphthyl.

"Aryloxy" means a group of the formula-OR, where R represents an aryl group is iroko, as defined here.

"Arylalkyl and aralkyl", which can be used interchangeably, mean a radical RaRbwhere Rarepresents alkylenes group, and Rbrepresents an aryl group, as defined herein; for example, phenylalkyl, such as benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, etc. are examples of arylalkyl.

"Arakaki" means a group of the formula-OR, where R is aracelio group, as defined here.

"Isoindolyl" means a group of the formulawhere one or two of any X1X2X3and X4represent N (Aza) and the others are carbons.

"Azaindole" can be substituted, as defined here for heteroaryl, in position 1, 2 and 3 with any of the provisions of the 4 - up to seventh, which are not nitrogen. Thus, "isoindolyl" includes: "pyrrolopyrimidine" above formula where X2and X4represent N; "pyrrolopyrimidine" above formula where X1and X3represent N; "pyrrolopyrazine" above formula where X1and X4represent N; "pyrrolopyridine" above formula where X1represents N; "pyrrolopyridine" above formula where X2not only is em a N; "pyrrolopyridine" above formula where X3represents N and pyrrolopyridine" above formula, where X4represents N. One preferred isoindolyl is 7-azaindole (X1X2X3=And X4=N) or pyrrolo[2,3-b]pyridinyl. Other preferred azaindole is a 4-isoindolyl or pyrrolo[3,2-b]pyridinyl.

"Azaindole" means a group of the formulawhere one or two of any X1X2X3and X4represent N (Aza) and the others are carbons. "Azaindole" can be substituted, as defined here for heteroaryl, in position 1, 2 and 3 with any of the provisions of the 4 - up to seventh, which are not nitrogen. Thus, "azaindole" includes: "pyrazolopyrimidine" above formula where X2and X4represent N; "pyrazolopyrimidine" above formula where X1and X3represent N; "pyrazolopyrimidine" above formula where X1and X4represent N; "pyrazolopyrimidine" above formula where X1represents N; "pyrazolopyrimidine" above formula where X2represents N; "pyrazolopyrimidine" above formula where X3represents N, and pyrazolopyrimidine" you shall privedennoi formula, where X4represents N.

"Cianelli" means a group of the formula-R'-R", where R' is alkylene, as defined here, and R" is a cyano or nitrile.

"Cycloalkyl" means a monovalent saturated carbocyclic group consisting of a mono - or bicyclic rings. Cycloalkyl may be substituted by one or more substituents, where each Deputy independently from each other represents a hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamines or dialkylamino, unless otherwise specified. Examples cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, including partially unsaturated derivatives.

"Cycloalkane and cycloalkene", which can be used interchangeably, mean a group of the formula-OR, where R is cycloalkyl, as defined here. Typical cycloalkane include temporopolar, cyclobutylamine, cyclopentyloxy, cyclohexyloxy etc.

"Cycloalkenyl" means a group of the formula-R-R", where R' is alkylene and R" represents cycloalkyl, as defined here.

"Alkylcyclohexanes" means a grouping of the formula

where n is 1-4, R isone of alkylene and R' represents alkyl, as defined here. Typical alkylcyclobutanones is 2-(1-methyl-cyclopropyl)-ethyl. Typical alkylcyclohexane include 2-(1-methyl-cyclopropyl)-ethyl and 3-(1-methyl-cyclopropylmethyl).

"Cycloalkylation and cycloalkylcarbonyl", which can be used interchangeably, mean a group of the formula-OR, where R is cycloalkenyl, as defined here. Typical cycloalkylcarbonyl include cyclopropylmethoxy, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethoxy etc.

"Heteroalkyl" means an alkyl radical, as defined here, including branched C4-C7-alkyl, where one, two or three hydrogen atoms are replaced by substituents, independently from each other selected from the group consisting of-ORa, -NRbRcand-S(O)nRd(where n is an integer from 0 to 2), assuming that the accession heteroalkyl radical is through a carbon atom, where Rarepresents hydrogen, acyl, alkyl, cycloalkyl or cycloalkenyl; Rband Rcindependently of one another represent hydrogen, acyl, alkyl, cycloalkyl or cycloalkenyl; and when n represents 0, Rdis hydrogen, alkyl, cycloalkyl or cycloalkylation, and when p represents 1 or 2, Rdrepresents Ala is l, cycloalkyl, cycloalkenyl, amino, acylamino, monoalkylamines or dialkylamino. Typical examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylation, 2,3-dihydroxypropyl, 1-hydroxymethylation, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-amino-ethyl, 3-aminopropyl, 2-methylsulfonylmethyl, aminocarbonylmethyl, aminosulfonyl, aminosulfonyl, methylaminoethanol, methylaminomethyl, methylaminoethanol etc.

"Heteroaryl" means a monocyclic, bicyclic or tricyclic radical with 5-12 ring atoms, having at least one aromatic ring containing one, two or three ring heteroatoms selected from N, O or S, with remaining ring atoms are C, assuming that the attachment point heteroaryl radical will be on an aromatic ring. Heteroaryl ring can be substituted, as defined here. Examples of heteroaryl groups include, but are not limited to, possibly substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, thiophenyl, furanyl, pyranyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidyl, chinoline, ethenolysis, hintline, benzofuranyl, benzothiophene, b is sociopersonal, benzimidazolyl, benzoxazolyl, benzoxadiazole, benzothiazolyl, benzotriazolyl, benzopyranyl, indolyl, isoindolyl, indazoles, triazoles, triazines, honokalani, purinol, hintline, hemolysins, naphthyridine, pteridine, carbazole, azepine, diazepine, acridine etc.

"Heteroaromatic and heteroalkyl", which can be used interchangeably, mean a radical RaRbwhere Rarepresents alkylenes group, and Rbrepresents a heteroaryl group, as defined here.

The terms "halo" and "halogen", which can be used interchangeably, refer to the Deputy fluorine, chlorine, bromine or iodine.

"Haloalkyl" means an alkyl, as defined here, in which one or more hydrogens substituted by the same or different Halogens. Typical haloalkyl include-CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g.,- CF3and so on

"Haloalkoxy" means a group of the formula-OR, where R is haloalkyl group, as defined here. Examples of haloalkoxy groups include, but are not limited to, triptoreline, deformedarse, 2,2,2-triptoreline etc.

"Hydroxyalkyl" refers to a subgroup of heteroalkyl and pertains particularly to an alkyl group, as defined here, which is esena one or more preferably one, two or three hydroxy groups, provided that one and the same carbon atom is not associated with more than one hydroxy group. Typical examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylation, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl.

"Heterocyclimamines" means a saturated cycle, where at least one atom in the cycle is N, NH or N-alkyl and the remaining atoms in the cycle form alkylenes group.

"Heterocyclyl" means a monovalent saturated group consisting of one to three cycles, including one, two, three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). Heterocyclyl ring can be substituted, as defined here. Examples heterocyclyl groups include, but are not limited to, possibly substituted piperidinyl, piperazinil, homopiperazine, azepane, pyrrolidinyl, pyrazolidine, imidazoline, imidazolidine, oxazolidine, isoxazolidine, morpholine, thiazolidine, isothiazolinones, thiadiazolidine, benzothiazolyl, benzoxazolyl, dihydrofurane, tetrahydrofuryl, dihydropyran, tetrahydropyran is, thiomorpholine, themorphological, themorphological, dihydroquinoline, dihydroisoquinoline, tetrahydroquinoline, tetrahydroisoquinoline etc. Preferred heterocyclyl include tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, piperazinil and pyrrolidinyl.

"Maybe substituted", when used in relation to "aryl", phenyl", "heteroaryl (including indolyl, such as indol-1-yl, indol-2-yl and indol-3-yl, 2,3-dihydroindole, such as 2,3-dihydroindol-1-yl, 2,3-dihydroindol-2-yl and 2,3-dihydroindol-3-yl, indazoles, such as indazol-1-yl, indazol-2-yl and indazol-3-yl, benzimidazolyl, such as benzimidazole-1-yl and benzimidazole-2-yl, benzothiophene, such as benzothiophen-2-yl and benzothiophen-3-yl, benzoxazol-2-yl, benzothiazol-2-yl, thienyl, furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, imidazolyl, pyrazolyl and chinoline) or "heterocyclyl", means an aryl, phenyl, heteroaryl or heterocyclyl, which may substituted independently with one to four substituents, preferably one or two substituents selected from alkyl, nikolkina, alkoxy, halo, haloalkyl, haloalkoxy, cyano, nitro, heteroalkyl, amino, acylamino, monoalkylamines, dialkylamines, hydroxyalkyl, alkoxyalkyl, benzyloxy, cycloalkyl, cycloalkene, recloak is alkoxy, alkylsulfonate, possibly substituted thiophenyl, possibly substituted pyrazolyl, possibly substituted pyridinyl, morpholinoethyl, -(CH2)q-S(O)rRf; -(CH2)q-NRgRh; -(CH2)q-C(=O)-NRgRh; -(CH2)q-C(=O)-C(=O)-NRgRh; -(CH2)q-SO2-NRgRh, -(CH2)q-N(Rf)-C(=O)-Ri; -(CH2)q-C(=O)-Rior -(CH2)q-N(Rf)-SO2-Rgwhere q is 0 or 1, r is 0-2, each Rf, Rgand Rhindependently represents hydrogen or alkyl, and each Riindependently represents hydrogen, alkyl, hydroxy or alkoxy. Certain preferred possible substituents for "aryl", phenyl", "heteroaryl", "cycloalkyl" or "heterocyclyl" include alkyl, halo, haloalkyl, alkoxy, cyano, amino, and alkylsulfonyl. More preferred substituents are methyl, fluorine, chlorine, trifluoromethyl, methoxy, amino and methanesulfonyl.

"Leaving group" means a group within the meaning traditionally associated with it in synthetic organic chemistry, an atom or a group substitutable in terms of substitution reactions. Examples of leaving groups include, but are not limited to, halogen, alkane - or arensulfonic, such as methanesulfonate, Athens is Livonians, thiomethyl, benzosulfimide, tosyloxy, titilate, cialisgenericsy, possibly substituted benzyloxy, isopropoxy, acyloxy etc.

"Modulator" means a molecule that interacts with the target. These interactions include, but are not limited to, agonist, antagonist, etc. as defined here.

"Probable" or "possible" means hereinafter described event or circumstance may occur, but is not required, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

"Illness" and "disease state" means any disease, condition, symptom, disorder or reading.

"Inert organic solvent" or "inert solvent" mean a solvent inert under the reaction conditions described in this regard, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, etc. Unless otherwise specified, the solvents used in the reactions of the present invention are inert solvents.

"Pharmaceutically acceptable" means that it is suitable for recip is the research Institute of pharmaceutical compositions that is generally safe, non-toxic and is not undesirable neither biologically nor otherwise improper, and includes that which is acceptable for pharmaceutical use in both veterinary and human.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable, as defined here, and which possess the desired pharmacological activity of the parent compound. Such salts include:

acid additive salts formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzolsulfonat acid, benzoic acid, camphorsulfonic acid, citric acid, econsultancy acid, fumaric acid, glucoheptonate acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonate acid, Mukanova acid, 2-naphthalenesulfonate acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluensulfonate acid, trimethylol Usna acid and the like; or salts formed either by substitution of the acidic proton in the initial connection of a metal ion such as alkali metal ion, alkali earth metal ion or an aluminum ion; or in coordination with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

Preferred pharmaceutically acceptable salts are salts formed from acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium.

It should be understood that all references to pharmaceutically acceptable salts include forms include solvent (solvate) or crystal forms (polymorphs)as defined here, the same acid additive salt.

"Protective group" or "blocking group" means a group which selectively blocks one reaction site in a multifunctional compound, so that a chemical reaction can take place selectively at another unprotected reactive center in the meaning traditionally associated with h is m in synthetic chemistry. Specific methods according to this invention are based on the protective groups to block reactive nitrogen atoms and/or oxygen present in the reacting substances. For example, the terms "amino-protective group" and "nitrogen-protective group" are used herein interchangeably and refer to those organic groups intended to protect nitrogen atom against undesirable reactions during the synthesis process. Typical nitrogen-protective groups include, but are not limited to, TRIFLUOROACETYL, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzoxy, CBZ), p-methoxybenzenesulfonyl, p-nitrobenzenesulfonyl, tert-butoxycarbonyl (VOS) and other Qualified professionals know how to select a group to facilitate the removal and to prevent the following reactions.

"Solvate" refers to forms of inclusion of the solvent, which contain either stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to catch a fixed molar ratio of the solvent molecules in the crystalline solid state, thus forming the MES. If water is the solvent, the resulting MES is a hydrate, when the solvent is alcohol, the resulting MES represents an anion. Hydrates of bresults is the combination of one or more water molecules with one of the compounds, in which water is stored in its molecular state in the form H2O, this combination is capable of forming one or more hydrates.

"Subject" means a mammal, and memleketim. Mammals mean any representative of the class Mammalia, including, but not limited to, humans; non-human primates, such as chimpanzees and other apes and monkeys; farm animals, such as cattle, horses, sheep, goats and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and Guinea pigs, etc. are Examples of memleketim include, but are not limited to, birds, etc. the Term "subject" does not indicate a specific age and gender.

"Morbid condition"associated with neurotransmission serotonin, norepinephrine and/or dopamine, include depressive and anxiolytic disorders, and schizophrenia and other psychosis, dyskinesia, drug dependence, cognitive disorders, Alzheimer's disease, attention deficit disorder, such as ADHD, obsessive-compulsive behaviour, panic attacks, sociophobia, eating disorders such as obesity, anorexia, bulimia and compulsive overeating, stress, hyperglycemia, hyperlipidemia, ainsliezubaida Diab is t, epileptic diseases, such as epilepsy, and treatment of conditions associated with neurological damage resulting from stroke, brain injury, cerebral ischemia, head injury, hemorrhage, and disorders and painful conditions of the urinary tract. "Morbid condition"associated with neurotransmission serotonin, norepinephrine and/or dopamine, also include inflammatory condition in the subject. Compounds according to the invention is probably useful to treat arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic condition.

As used here, "depression" includes, but is not limited to, major depression, prolonged depression, dysthymia, the mental state of depressed mood characterized by feelings of sadness, despair, despondency, depression, melancholy, feelings of low self-esteem, guilt and self-blame, withdrawal from interpersonal contact, and somatic symptoms such as eating disorders and sleep.

As used here, "anxiety" includes, but is not limited to, offensive or unwanted emotional States associated with psychophysiological responses is as unrealistic expectation, imaginary or exaggerated danger or damage, and related physical symptoms such as enhanced heart rate, altered respiration rate, sweating, trembling, weakness and fatigue, feelings of impending danger, powerlessness, fear and tension.

"Disorders of the urinary tract" or "uropathy", used interchangeably with "symptoms of the urinary tract"means pathological changes in the urinary tract. Examples of disorders of the urinary tract include, but are not limited to, stress incontinence, urgency urinary incontinence, benign prostatic hyperplasia (BPH), prostatitis, detrusor hyperreflexia, obstruction of the outlet, frequent urination, nycturia, urgent need to pass urine, overactive bladder, pelvic hypersensitivity, urethritis, prostatodynia, cystitis, idiopathic hypersensitivity of the bladder, etc.

"Painful conditions associated with urinary ways," or "painful conditions of the urinary tract", or "uropathy", used interchangeably with "symptoms of the urinary tract"means pathological changes in the urinary tract, or dysfunction of the smooth muscle of the bladder or its innervation, causing disorder accumulation or excretion of urine. SIM is Toms urinary tract include, but not limited to, overactive bladder (also known as overactive detrusor), obstruction of the outlet, the failure of the outlet and pelvic hypersensitivity.

"Overactive bladder" or "hyperactivity of the detrusor" includes, but is not limited to this, symptomatically manifested changes, such as the urgent urge to urinate, frequent urination, change in bladder capacity, incontinence of urine, the threshold of the bladder, unstable bladder contractions, sphincter spasticity, detrusor hyperreflexia (neurogenic bladder, detrusor instability, etc.

"Obstruction of the outlet" includes, but is not limited to, benign prostatic hyperplasia (BPH), urethral stricture, tumor, low urine flow rate, difficulties in the occurrence of urination, urgent need to pass urine, pain in the suprapubic area, etc.

"The failure of the outlet" includes, but is not limited to this, hypermobility of the urethra, a congenital defect of the sphincter, mixed incontinence, stress incontinence, etc.

"Pelvic hypersensitivity" includes, but is not limited to, pelvic pain, interstitial (cells) cystitis, prostatodynia, Rastatt, vulvodynia, urethritis, orchialgia, overactive bladder, etc.

"Pain" means more or less local discomfort, distress, or agony, resulting from the stimulation of certain nerve endings. There are many kinds of pain, including, but not limited to, shooting pain, phantom pain, jerking pain, acute pain, pain caused by inflammation, neuropathic pain, complex regional pain syndrome, neuralgia, neuropathy, etc. (Dorland''s Illustated Medifical Dictionary, 28-oe edition, W..Saunders Company, Philadelphia, PA). The goal of pain management is to decrease the severity of pain experienced by the subject undergoing treatment.

"Neuropathic pain" means pain, resulting from functional disturbances and/or pathological changes, as well as non-inflammatory lesions in the peripheral nervous system. Examples of neuropathic pain include, but are not limited to, thermal or mechanical hyperalgesia, thermal or mechanical allodynia, diabetic neuropathy pain, pain when pinched, etc.

"Therapeutically effective amount" means an amount of compound that, when you enter a subject for the treatment of painful conditions, is sufficient to carry out similar treatment of painful conditions. "Therapeutically effective quantity is quality" depends on the connection, subjected to the treatment of painful conditions, severity or subjected to treatment for the disease, the age and relative health of the subject, the route and form of administration, the decision of the attending physician-the physician or veterinarian, and other factors.

The terms "above-defined" and "defined here", when related to the parameter, include a reference to the broad definition of the parameter, and also preferred, the most preferred and most preferred definitions if they exist.

"Treated" or "treatment" of the disease condition includes:

(1) preventing the disease condition, i.e. not to cause the onset of clinical symptoms of the disease condition in a subject that may be exposed to or predisposed to the painful condition, but have yet to experience or do not show symptoms of the disease condition;

(2) the suppression of painful conditions, i.e. delay development of the disease condition or its clinical symptoms, or

(3) relief of painful conditions, i.e. induction of temporary or permanent weakening of the painful condition or its clinical symptoms.

The terms "treatment", "interaction" and "expose interaction", when related to a chemical reaction, means adding or mixing two or more reagents under suitable for the operating conditions, to get listed, and/or the desired product. Note that reaction, in which is formed the specified and/or required product, will not necessarily occur immediately when the combination of two reagents that were added at the beginning, i.e. it can be one or more intermediate compounds, which will be in the mix, which will eventually lead to the formation of the specified and/or required product.

In General, used in this application, the nomenclature is based on AUTONOM™ v.4.0, automated system Institute Beylshtein to create systematic IUPAC nomenclature. Shown here chemical structure obtained using ISIS® version 2.2. Any open valence on a carbon atom, oxygen, sulfur or nitrogen in the structures presented here indicates the presence of a hydrogen atom.

When the chemical structure is chiral carbon, it is assumed that the structure encompasses all stereoisomers, the associated chiral carbon.

All patents and publications cited here, fully included here by reference.

Compounds according to the invention are compounds of formula I as described above.

In specific embodiments of formula I, Ar is:

possibly substituted indolyl;

possibly substituted indazoles;

perhaps C is displaced 2,3-dihydro-indolyl;

possibly substituted 1,3-dihydro-indol-2-he-Il;

possibly substituted benzothiophenes;

possibly substituted chinoline;

possibly substituted 1,2,3,4-tetrahydroquinolines;

possibly substituted azaindole;

possibly substituted naphthalenyl;

possibly substituted benzothiazolyl;

possibly substituted benzisothiazole;

possibly substituted thiophenyl or possibly substituted phenyl.

In specific embodiments of formula I, Ar is:

possibly substituted indolyl or possibly substituted indazoles.

In specific embodiments of formula I, Ar is:

possibly substituted naphthalenyl or possibly substituted phenyl.

In specific embodiments of formula I, Ar represents a possibly substituted indolyl.

In specific embodiments of formula I, Ar represents a possibly substituted indazoles.

In specific embodiments of formula I, Ar represents a possibly substituted azaindole.

In specific embodiments of formula I, Ar represents a possibly substituted benzothiophenes.

In specific embodiments of formula I, Ar represents a possibly substituted benzimidazolyl.

In specific embodiments of formula I, Ar represents a possibly substituted benzoxazolyl.

In specific embodiments of formula I, Ar represents a possibly substituted Ben is thiazolyl.

In specific embodiments of formula I, Ar represents a possibly substituted chinoline.

In specific embodiments of formula I, Ar represents a possibly substituted ethenolysis.

In specific embodiments of formula I, Ar represents a possibly substituted naphthalenyl.

In specific embodiments of formula I, Ar represents a possibly substituted 2,3-dihydro-indolyl.

In specific embodiments of formula I, Ar represents a possibly substituted azaindole.

In specific embodiments of formula I, Ar represents a possibly substituted pyridinyl.

In specific embodiments of formula I, Ar represents a possibly substituted thiophenyl.

In specific embodiments of formula I, Ar represents a possibly substituted pyrrolyl.

In specific embodiments of formula I, Ar represents a possibly substituted benzothiazolyl.

In specific embodiments of formula I, Ar represents a possibly substituted benzisothiazole.

In specific embodiments of formula I, Ar represents a possibly substituted phenyl.

In specific embodiments of formula I, Ar is a substituted phenyl.

In specific embodiments of formula I, Ar is a phenyl, substituted two or three times.

In specific embodiments of formula I, Ar is an indole-2-yl, indol-3-yl, indol-4-yl, indol-5-yl and is and indol-6-yl, every possible replaced.

In specific embodiments of formula I, Ar is an indole-2-yl, indol-5-yl or indol-6-yl, each possibly substituted.

In specific embodiments of formula I, Ar represents a possibly substituted indol-5-yl.

In specific embodiments of formula I, Ar represents a possibly substituted indazol-5-yl.

In specific embodiments of formula I, Ar represents a possibly substituted benzothiophen-5-yl.

In specific embodiments of formula I, Ar represents a possibly substituted benzothiophen-2-yl.

In specific embodiments of formula I, Ar represents a possibly substituted benzothiophen-3-yl.

In specific embodiments of formula I, Ar represents a possibly substituted benzothiophen-5-yl.

In specific embodiments of formula I, Ar represents a possibly substituted benzothiophen-6-yl.

In specific embodiments of formula I, Ar represents a possibly substituted Tien-2-yl.

In specific embodiments of formula I, Ar represents a possibly substituted Tien-3-yl.

In specific embodiments of formula I, Ar represents a possibly substituted benzothiazol-2-yl.

In specific embodiments of formula I, Ar represents a possibly substituted benzisothiazol-3-yl.

In specific embodiments of formula I, Ar represents a possibly substituted naphthalene-2-yl.

The spiral is different embodiments of formula I, Ar represents a possibly substituted quinoline-6-yl.

In specific embodiments of formula I, Ar represents a possibly substituted quinoline-2-yl.

In specific embodiments of formula I, Ar represents a possibly substituted isoquinoline-6-yl.

In specific embodiments of formula I, Ar represents a possibly substituted 2,3-dihydro-indol-5-yl.

In specific embodiments of formula I, Ar represents a possibly substituted 1,3-dihydro-indol-2-one-5-yl.

In specific embodiments of formula I, Ar represents a possibly substituted benzimidazole-5-yl.

In specific embodiments of formula I, Ar represents a possibly substituted benzoxazol-5-yl.

In specific embodiments of formula I, Ar represents a possibly substituted benzothiazol-5-yl.

In specific embodiments of formula I, Ar represents a possibly substituted 1,2,3,4-tetrahydroquinolin-6-yl.

In specific embodiments of formula I, Ar represents a possibly substituted quinoline-2-one-6-yl.

In specific embodiments of formula I, Ar represents a possibly substituted pyridine-2-yl.

In embodiments of formula I, where Ar represents a possibly substituted azaindole, such isoindolyl preferably is pyrrolo[2,3-b]pyridinyl.

In specific embodiments of formula I, where Ar represents a possibly substituted azaindole, such isoindolyl preferably is pyrrolo[2,3-b]pyridine-ILOM.

When Ar is any of indolyl, indazole, isoindolyl, azaindole, 2,3-dihydro-indolyl, 1,3-dihydro-indol-2-he-Il, benzothiophene, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, chinoline, 1,2,3,4-tetrahydroquinoline, quinoline-2-he-Il, izochinolina, pyridinyl, thiophenyl, pyrrolyl, naphthalenyl or phenyl, which may be substituted, possible substituents can be one, two or three groups, each of which is independently selected from:

halo;

With1-6of alkyl;

halo-C1-6of alkyl;

halo-C1-6alkoxy;

With1-6alkoxy;

hydroxy;

hetero-C1-6of alkyl;

cyano;

nitro;

amino;

N-C1-6alkyl-amino;

N,N-di-C1-6alkylamino or

-(CH2)r-Y-(CH2)s-Z-(CH2)t-Q-(CH2)u-Rc;

where

each r, s, t and u independently represents 0 or 1;

Z represents-C(O)- or-SO2-;

each X and Y independently represents-O-, -NRdor communication;

Rcrepresents:

hydrogen;

With1-6alkyl;

halo-C1-6alkyl;

halo-C1-6alkoxy;

With1-6alkoxy;

hydroxy;

hetero-C1-6alkyl;

cyano;

amino;

With1-6alkyl-amino or

N,N-di-C1-6alkylamino; and

Rdrepresents the t other:

hydrogen or

With1-6alkyl.

When Ar is any of indolyl, indazole, isoindolyl, azaindole, 2,3-dihydro-indolyl, 1,3-dihydro-indol-2-he-Il, benzothiophene, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, chinoline, 1,2,3,4-tetrahydroquinoline, quinoline-2-he-Il, izochinolina, pyridinyl, thiophenyl, pyrrolyl, naphthalenyl or phenyl, which may be substituted, possible substituents can be one, two or three groups, each of which is independently selected from:

halo;

C1-6of alkyl;

halo-C1-6of alkyl;

halo-C1-6alkoxy;

With1-6alkoxy;

hydroxy;

hetero-C1-6the alkyl selected from:

hydroxy-C1-6of alkyl;

With1-6alkylsulfonyl-C1-6the alkyl and

With1-6alkoxy-C1-6of alkyl;

cyano;

nitro;

amino;

N-C1-6alkyl-amino;

N,N-di-C1-6alkylamino;

C1-6alkyl-sulfonyl or

-C(O)Rcwhere Rcrepresents:

With1-6alkyl;

amino;

With1-6alkyl-amino or

N,N-di-C1-6alkylamino.

When Ar is any of indolyl, indazole, isoindolyl, azaindole, 2,3-dihydro-indolyl, 1,3-dihydro-indol-2-he-Il, benzothiophene, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, Benito Azolla, chinoline, 1,2,3,4-tetrahydroquinoline, quinoline-2-he-Il, izochinolina, pyridinyl, thiophenyl, pyrrolyl, naphthalenyl or phenyl, which may be substituted, possible substituents can be one or two groups, each of which is independently selected from:

halo;

amino;

C1-6of alkyl;

halo-C1-6of alkyl;

C1-6alkoxy;

hydroxy or

cyano.

Preferably, when Ar is any of indolyl, indazole, isoindolyl, azaindole, 2,3-dihydro-indolyl, 1,3-dihydro-indol-2-he-Il, benzothiophene, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, chinoline, 1,2,3,4-tetrahydroquinoline, quinoline-2-he-Il, izochinolina, pyridinyl, thiophenyl, pyrrolyl, naphthalenyl or phenyl, which may be substituted, possible substituents can be one or two groups, each of which is independently selected from halo, amino, C1-6-alkyl and halo-C1-6the alkyl. In some embodiments Ar is substituted one or two times with halo, preferably fluorine.

In specific embodiments of formula I, Ar is a phenyl substituted one, two or three groups independently selected from:

halo;

amino;

C1-6of alkyl;

With3-6cycloalkyl;

C1-6alkylcarboxylic;

C1-6alkylsulfonyl;

Csub> 1-6alkylsulfanyl;

halo-C1-6of alkyl;

C1-6alkoxy;

halo-C1-6alkoxy;

C1-6alkoxy-C1-6of alkyl;

hydroxy;

cyano;

possibly substituted phenyl;

possibly substituted, phenoxy;

phenylsulfonyl or

possibly substituted heteroaryl.

In specific embodiments of formula I, Ar is a phenyl, substituted two or three groups independently selected from:

halo;

amino;

C1-6of alkyl;

halo-C1-6of alkyl;

C1-6alkoxy;

hydroxy or

cyano.

In specific embodiments of formula I, Ar is a phenyl, substituted two or three times a halo.

In specific embodiments of formula I, Ar is a phenyl substituted at the 3 - and 4-positions and possibly substituted in the 2 - or 5-position by groups independently selected from:

halo;

amino;

C1-6of alkyl;

With3-6cycloalkyl;

C1-6alkylcarboxylic;

C1-6alkylsulfonyl;

C1-6alkylsulfanyl;

halo-C1-6of alkyl;

C1-6alkoxy;

halo-C1-6alkoxy;

C1-6alkoxy-C1-6of alkyl;

hydroxy;

cyano;

possibly substituted phenyl;

possibly substituted, phenoxy or

possibly substituted heteroaryl.

In specific embodiments of formula I, Ar is a phenyl, samisen the th 3 - and 4-positions and possibly substituted in the 2 - or 5-position groups, independently chosen from:

halo;

amino;

C1-6of alkyl;

halo-C1-6of alkyl;

C1-6alkoxy;

hydroxy or

cyano.

In specific embodiments of formula I, Ar is a phenyl substituted at the 3 - and 4-positions and possibly substituted in the 2 - or 5-position with halo.

In specific embodiments of formula I, Ar is a phenyl substituted at the 3 - and 4-positions and possibly substituted in the 2 - or 5-position with halo or amino.

In specific embodiments of formula I, Ar is a pyridinyl, substituted once or twice by groups independently selected from:

halo;

amino;

C1-6of alkyl;

With3-6cycloalkyl;

C1-6alkylcarboxylic;

C1-6alkylsulfonyl;

C1-6alkylsulfanyl;

halo-C1-6of alkyl;

C1-6alkoxy;

halo-C1-6alkoxy;

C1-6alkoxy-C1-6of alkyl;

hydroxy;

cyano;

possibly substituted phenyl;

possibly substituted, phenoxy or

possibly substituted heteroaryl.

In specific embodiments of formula I, Ar is a pyridinyl, substituted once or twice by groups independently selected from:

halo;

amino;

C1-6of alkyl;

halo-C1-6of alkyl;

C1-6alkoxy;

hydroxy or

cyano.

In specific embodiments of formula I, Ar is a tee is phenyl, substituted one, two or three groups independently selected from:

halo;

amino;

C1-6of alkyl;

With3-6cycloalkyl;

C1-6alkylcarboxylic;

C1-6alkylsulfonyl;

C1-6alkylsulfanyl;

halo-C1-6of alkyl;

C1-6alkoxy;

halo-C1-6alkoxy;

C1-6alkoxy-C1-6of alkyl;

hydroxy;

cyano;

possibly substituted phenyl;

possibly substituted, phenoxy or

possibly substituted heteroaryl.

In specific embodiments of formula I, Ar is thiophenyl substituted once or twice by groups independently selected from:

halo;

amino;

C1-6of alkyl;

halo-C1-6of alkyl;

C1-6alkoxy;

hydroxy or

cyano.

In specific embodiments of formula I, Ar is thiophenyl substituted one or two times with halo.

In specific embodiments of formula I, Ar is a thiophene-2-yl, substituted at the 4 - and 5-positions and possibly substituted in 3-position by groups independently selected from:

halo;

amino;

C1-6of alkyl;

With3-6cycloalkyl;

C1-6alkylcarboxylic;

C1-6alkylsulfonyl;

C1-6alkylsulfanyl;

halo-C1-6of alkyl;

C1-6alkoxy;

halo-C1-6alkoxy;

C1-6alkoxy-C1-6of alkyl;

hydroxy;

C is ANO;

possibly substituted phenyl;

possibly substituted, phenoxy or

possibly substituted heteroaryl.

In specific embodiments of formula I, Ar is a thiophene-2-yl, substituted at the 4 - and 5-positions and possibly substituted in 3-position by groups independently selected from:

halo;

amino;

C1-6of alkyl;

halo-C1-6of alkyl;

C1-6alkoxy;

hydroxy or

cyano.

In specific embodiments of formula I, Ar is a thiophene-2-yl, substituted at the 4 - and 5-positions and possibly substituted in 3-position a halo.

In specific embodiments of formula I, Ar is a thiophene-2-yl, substituted at the 4 - and 5-positions and possibly substituted in 3-position with halo or amino.

In specific embodiments of formula I, Ar is pyrrolyl substituted one, two or three groups independently selected from:

halo;

amino;

C1-6of alkyl;

With3-6cycloalkyl;

C1-6alkylcarboxylic;

C1-6alkylsulfonyl;

C1-6alkylsulfanyl;

halo-C1-6of alkyl;

C1-6alkoxy;

halo-C1-6alkoxy;

C1-6alkoxy-C1-6of alkyl;

hydroxy;

cyano;

possibly substituted phenyl;

possibly substituted, phenoxy or

possibly substituted heteroaryl.

In specific embodiments of formula I, Ar represents Erroll, substituted once or twice by groups independently selected from:

halo;

amino;

C1-6of alkyl;

halo-C1-6of alkyl;

C1-6alkoxy;

hydroxy or

cyano.

In specific embodiments of formula I, Ar is pyrrolyl substituted one or two times with halo.

In specific embodiments of formula I, Ar is a pyrrol-2-yl, substituted at the 4 - and 5-positions and possibly substituted in 3-position by groups independently selected from:

halo;

amino;

C1-6of alkyl;

With3-6cycloalkyl;

C1-6alkylcarboxylic;

C1-6alkylsulfonyl;

C1-6alkylsulfanyl;

halo-C1-6of alkyl;

C1-6alkoxy;

halo-C1-6alkoxy;

C1-6alkoxy-C1-6of alkyl;

hydroxy;

cyano;

possibly substituted phenyl;

possibly substituted, phenoxy or

possibly substituted heteroaryl.

In specific embodiments of formula I, Ar is a pyrrol-2-yl, substituted at the 4 - and 5-positions and possibly substituted in 3-position by groups independently selected from:

halo;

amino;

C1-6of alkyl;

halo-C1-6of alkyl;

C1-6alkoxy;

hydroxy or

cyano.

In specific embodiments of formula I, Ar is a pyrrol-2-yl, substituted at the 4 - and 5-positions and possibly substituted in 3-position a halo.

<> In specific embodiments of formula I, Ar is a pyrrol-2-yl, substituted at the 4 - and 5-positions and possibly substituted in 3-position with halo or amino.

In specific embodiments of formula I, Ar is a pyridinyl substituted one or two times with halo.

In specific embodiments of formula I, Ar is a: 3,4-dichloro-phenyl; 4-methoxy-phenyl; 4-methyl-phenyl; 4-fluoro-phenyl; 3-chlorophenyl; 4-chlorophenyl; 4-iodine-phenyl; 4-cyano-phenyl; 4-isopropyl-phenyl; 4-phenyl-phenyl (biphenyl-4-yl); 4-pyrazole-3-yl-phenyl; 4-chloro-3-methoxy-phenyl; 4-chloro-3-ethyl-phenyl; 4-chloro-3-cyano-phenyl; 4-chloro-3-phenyl-phenyl (6-chloro-biphenyl-3-yl); 3-chloro-4-methoxy-phenyl; 3-chloro-4-methoxymethyl-phenyl; 3-chloro-4-hydroxy-phenyl; 3-chloro-4-methylsulfanyl-phenyl; 3-chloro-4-methylsulphonyl-phenyl; 4-acetyl-3-chloro-phenyl; 4-chloro-3-fluoro-phenyl; 4-chloro-3-cyclopropyl-phenyl; 4-chloro-3-acetyl-phenyl; 4-chloro-3-cyano-phenyl; 3-chloro-4-fluoro-phenyl; 3-chloro-5-fluoro-phenyl, 2,3-dichloro-phenyl; 3,5-dichloro-phenyl; 3,4-debtor-phenyl; 3,4-dibromo-phenyl; 3,4-dicyano-phenyl; 3-chloro-4-methyl-phenyl; 3-bromo-4-chloro-phenyl; 4-chloro-3-methyl-phenyl; 4-chloro-3-trifluoromethyl-phenyl; 4-trifluoromethyl-phenyl; 4-triptoreline-phenyl; 3,4,5-Cryptor-phenyl; 3,4,5-trichloro-phenyl; 3,4-dichloro-5-fluoro-phenyl; 3,4-dichloro-5-methyl-phenyl; 4,5-dichloro-2-fluoro-phenyl; 4-bromo-3-chloro-phenyl; 4-chloro-3-isopropoxy-phenyl; 3-(4-fluoro-phenoxy)-phenyl; 4-amino-3-chloro-phenyl; 4-amino-3-fluoro-phenyl; 4-bromo-3-methyl-phenyl; 4-amino-3-chlorine is-5-fluoro-phenyl; 2-amino-3,4-dichloro-phenyl; 4-bromo-3-chloro-5-fluoro-phenyl; 3-chloro-5-fluoro-4-hydroxy-phenyl; 4-chloro-3-phenoxy-phenyl or 3-chloro-4-phenoxy-phenyl.

In specific embodiments of formula I, Ar is a: 3,4-dichloro-phenyl; 4-chloro-3-fluoro-phenyl; 3-chloro-4-fluoro-phenyl; 3,4-debtor-phenyl; 3,4-dibromo-phenyl; 3-bromo-4-chloro-phenyl; 3,4,5-Cryptor-phenyl; 3,4,5-trichloro-phenyl; 3,4-dichloro-5-fluoro-phenyl; 4,5-dichloro-2-fluoro-phenyl; 4-bromo-3-chloro-phenyl; 4-chloro-3-isopropoxy-phenyl; 4-amino-3-chloro-phenyl; 4-amino-3-fluoro-phenyl; 4-amino-3-chloro-5-fluoro-phenyl; 2-amino-3,4-dichloro-phenyl, or 4-bromo-3-chloro-5-fluoro-phenyl.

In specific embodiments of formula I, Ar is a: 3,4-dichloro-phenyl; 3,4-dichloro-5-fluoro-phenyl; 4-amino-3-chloro-phenyl or 4-amino-3-chloro-5-fluoro-phenyl.

In specific embodiments of formula I, Ar is a 3,4-dichloro-phenyl.

In specific embodiments of formula I, Ar is a 3,4-dichloro-5-fluoro-phenyl.

In specific embodiments of formula I, Ar is a 4-amino-3-chloro-phenyl.

In specific embodiments of formula I, Ar is a 4-amino-3-chloro-5-fluoro-phenyl.

In specific embodiments of formula I, Ar is: indol-5-yl; 1-methyl-indol-5-yl; 7-fluoro-indol-5-yl; 2-methyl-indol-5-yl; indol-4-yl; 7-chloro-indol-5-yl; indol-3-yl; 7-trifluoromethyl-indol-5-yl; 6-fluoro-indol-5-yl; 6,7-debtor-indol-5-yl; indol-2-yl; 5-fluoro-indol-2-yl; 1-phenylsulfonyl-indol-2-yl; 1-methyl-indol-2-yl; 6-fluoro-indol-2-yl; -fluoro-indol-2-yl or 4-fluoro-indol-2-yl.

In specific embodiments of formula I, Ar is benzothiophen-5-yl; benzothiophen-2-yl; benzothiophen-3-yl; 5-fluoro-benzothiophen-2-yl; 6-fluoro-benzothiophen-2-yl; 5-chloro-benzothiophen-2-yl; 7-fluoro-benzothiophen-2-yl or 4-fluoro-benzothiophen-2-yl.

In specific embodiments of formula I, Ar is: 4,5-dichloro-thiophene-2-yl; 4-chloro-thiophene-2-yl; 3-chloro-thiophene-2-yl or 4-chloro-5-methyl-thiophene-2-yl.

In specific embodiments of formula I, R2represents hydrogen.

In specific embodiments of formula I, R2represents a C1-6alkyl.

In specific embodiments of formula I, R2represents methyl.

In specific embodiments of formula I, where Ar represents a possibly substituted phenyl, Ar is preferably a phenyl substituted one, two or three times, and more preferably two or three times, any halo, C1-6by alkyl, halo,-C1-6the alkyl, C1-6alkoxy, hydroxy or cyano.

In specific embodiments of formula I, m is 1, n is 1, Ar represents a possibly substituted indol-5-yl, R1represents a possibly substituted benzyl and R2represents hydrogen.

In specific embodiments of formula I, m is 1, n is 1, Ar represents a possibly substituted indol-5-yl, R1represents a C3-6al the silt and R 2represents hydrogen.

In specific embodiments of formula I, m is 1, n is 2, Ar represents a possibly substituted indol-5-yl, R1represents a possibly substituted benzyl and R2represents hydrogen.

In specific embodiments of formula I, m is 1, n is 2, Ar represents a possibly substituted indol-5-yl, R1represents a C3-6alkyl, and R2represents hydrogen.

In specific embodiments of formula I, m represents 2, n represents 1, Ar represents a possibly substituted indol-5-yl, R1represents a possibly substituted benzyl and R2represents hydrogen.

In specific embodiments of formula I, m represents 2, n represents 1, Ar represents a possibly substituted indol-5-yl, R1represents a C3-6alkyl, and R2represents hydrogen.

In specific embodiments of formula I, m is 1, n is 1, Ar represents a possibly substituted indazol-5-yl, R1represents a possibly substituted benzyl and R2represents hydrogen.

In specific embodiments of formula I, m is 1, n is 1, Ar represents a possibly substituted indazol-5-yl, R represents a C3-6alkyl, and R2represents hydrogen.

In specific embodiments of formula I, m is 1, n is 2, Ar represents a possibly substituted indazol-5-yl, R1represents a possibly substituted benzyl and R2represents hydrogen.

In specific embodiments of formula I, m is 1, n is 2, Ar represents a possibly substituted indazol-5-yl, R1represents a C3-6alkyl, and R2represents hydrogen.

In specific embodiments of formula I, m represents 2, n represents 1, Ar represents a possibly substituted indazol-5-yl, R1represents a possibly substituted benzyl and R2represents hydrogen.

In specific embodiments of formula I, m represents 2, n represents 1, Ar represents a possibly substituted indazol-5-yl, R1represents a C3-6alkyl, and R2represents hydrogen.

In specific embodiments of formula I, m is 1, n is 1, Ar represents a possibly substituted phenyl, R1represents a possibly substituted benzyl and R2represents hydrogen.

In specific embodiments of formula I, m is 1, n is 1, Ar represents the t of a possibly substituted phenyl, R1represents a C3-6alkyl, and R2represents hydrogen.

In specific embodiments of formula I, m is 1, n is 2, Ar represents a possibly substituted indazol-5-yl, R1represents a possibly substituted benzyl and R2represents hydrogen.

In specific embodiments of formula I, m is 1, n is 2, Ar represents a possibly substituted phenyl, R1represents a C3-6alkyl, and R2represents hydrogen.

In specific embodiments of formula I, m represents 2, n represents 1, Ar represents a possibly substituted phenyl, R1represents a possibly substituted benzyl and R2represents hydrogen.

In specific embodiments of formula I, m represents 2, n represents 1, Ar represents a possibly substituted phenyl, R1represents a C3-6alkyl, and R2represents hydrogen.

In specific embodiments of formula I, Raand Rbrepresents hydrogen.

In specific embodiments of formula I one of Raand Rbrepresents hydrogen and the other represents C1-6alkyl, halo, oxo or hydroxy.

In specific embodiments of formula I, Raand Rbtogether form a C1-6and the kilen.

In specific embodiments of formula I compounds according to the invention may be of formula II:

where:

p represents 0-3;

X represents N or CRe;

R3represents:

hydrogen or

C1-6alkyl;

each R4, R5and Reindependently represents:

hydrogen;

halo;

C1-6alkyl;

halo-C1-6alkyl;

halo-C1-6alkoxy;

C1-6alkoxy;

hydroxy;

hetero-C1-6alkyl;

cyano;

nitro;

amino;

N-C1-6alkyl-amino;

N,N-di-C1-6alkylamino or

-(CH2)r-Y-(CH2)s-Z-(CH2)t-Q-(CH2)u-Rc;

where

each r, s, t and u independently represents 0 or 1;

Z represents-C(O)- or-SO2-;

each X and Y independently represents-O-, -NRdor communication;

Rcrepresents:

hydrogen;

C1-6alkyl;

halo-C1-6alkyl;

halo-C1-6alkoxy;

C1-6alkoxy;

hydroxy;

hetero-C1-6alkyl;

cyano;

amino;

C1-6alkyl-amino or

N,N-di-C1-6alkylamino; and

Rdrepresents:

hydrogen or

C1-6alkyl and

m, n and R1are as defined here for formula I.

In specific embodiments of formula II X pre is is a n

In specific embodiments of formula II, X represents CRe.

In specific embodiments of formula II, X represents CH.

In specific embodiments of formula II, R3represents hydrogen.

In specific embodiments of formula II, R3represents a C1-6alkyl.

In specific embodiments of formula II, R3represents methyl.

In specific embodiments of formula II, m represents 1, n represents 1, X represents CH, R1represents a possibly substituted benzyl and R3represents hydrogen.

In specific embodiments of formula II, m represents 1, n represents 1, X represents N, R1represents a C3-6alkyl, and R3represents hydrogen.

In specific embodiments of formula II, m represents 1, n represents 1, X represents CH, R1represents a possibly substituted benzyl and R3represents hydrogen.

In specific embodiments of formula II, m represents 1, n represents 1, X represents N, R1represents a C3-6alkyl, and R3represents hydrogen.

In specific embodiments of formula I compounds according to the invention may be of formula III:

where m, n, p, R1, R4The R 5are as defined here for formula I.

In specific embodiments of formula II or III, R represents 0, 1 or 2.

In specific embodiments of formula II or III, R represents 0, 1 or 2 and R6is a halo.

In specific embodiments of formula II or III, R represents 0, 1 or 2 and R6represents fluorine.

In specific embodiments of formula II or III, R represents 1 and R6represents fluorine.

In specific embodiments of formula I or III, R represents 0.

In specific embodiments of formula I compounds according to the invention may be of formula IV:

where:

q represents 0 or 1;

each R6, R7and R8independently represents:

halo;

amino;

C1-6alkyl;

With3-6cycloalkyl;

C1-6alkylsulphonyl;

C1-6alkylsulfonyl;

C1-6alkylsulfanyl;

halo-C1-6alkyl;

C1-6alkoxy;

halo-C1-6alkoxy;

C1-6alkoxy-C1-6alkyl;

hydroxy;

cyano;

possibly substituted phenyl;

possibly substituted, phenoxy or possibly substituted heteroaryl;

or R6and R7together form1-2alkylen or1-2alkylen-dioxy;

or R7and R8together form1-2alkylen or 1-2alkylen-dioxy;

and where m, n and R1are as defined here for formula I.

In specific embodiments of formula IV, each R6, R7and R8independently is: halo; amino; C1-6alkyl, C1-6alkylsulphonyl; halo-C1-6alkyl, C1-6alkoxy; halo-C1-6alkoxy; hydroxy or cyano.

In specific embodiments of formula IV, one of R6, R7and R8represents amino and the other is halo.

In specific embodiments of formula IV, q represents 1, one of R6, R7and R8represents amino and the other is halo.

In specific embodiments of formula IV, q represents 1, and R6, R7and R8represent halo.

In specific embodiments of formula IV, q represents 0, one of R6and R7represents amino and the other is halo.

In specific embodiments of formula IV, q represents 0, and R6and R7represent halo.

In specific embodiments of formula IV, one of R6, R7and R8represents fluorine, and the other is chlorine.

In specific embodiments of formula IV, q represents 1, one of R6, R7and R8represents amino and the other is chlorine or fluorine.

In specific embodiments of formula IV q of t is made a 0.

In specific embodiments of formula IV, q represents 1.

In specific embodiments of formula IV, R6, R7and R8represent halo.

In specific embodiments of formula IV, q represents 1, R7represents amino, and R6and R8independently represent a fluorine or chlorine.

In specific embodiments of formula IV, q represents 0, R7represents amino, and R6represents fluorine or chlorine.

In specific embodiments of formula I compounds according to the invention can be of the formula V:

where:

each R6, R7and R8independently represents:

hydrogen;

halo;

amino;

C1-6alkyl;

With3-6cycloalkyl;

C1-6alkylsulphonyl;

C1-6alkylsulfonyl;

C1-6alkylsulfanyl;

halo-C1-6alkyl;

C1-6alkoxy;

halo-C1-6alkoxy;

C1-6alkoxy-C1-6alkyl;

hydroxy;

cyano;

possibly substituted phenyl;

possibly substituted, phenoxy or

possibly substituted heteroaryl;

or R7and R8together form1-2alkylen or1-2alkylen-dioxy;

and where m, n and R1are as defined here for formula I.

In specific embodiments of formula V, R8represents odor is d, and each R6and R7independently is: halo; amino; C1-6alkyl, C1-6alkylsulphonyl; halo-C1-6alkyl, C1-6alkoxy; halo-C1-6alkoxy; hydroxy or cyano.

In specific embodiments of formula V, R8represents hydrogen, and R6and R7represent halo.

In specific embodiments of formula V, R8represents hydrogen, and R6and R7represent chlorine or fluorine.

In specific embodiments of formula V, R8represents hydrogen, and R6and R7represent chlorine.

In specific embodiments of formula V, R8represents hydrogen, one of R6and R7represents amino and the other represents a halo.

In specific embodiments of formula V, R6represents halo, and R7and R8represent hydrogen.

In specific embodiments of formula V, one of R6, R7and R8represents amino and the other represents a halo.

In particular embodiments of any of formulas I, II, III, IV or V m is 0.

In particular embodiments of any of formulas I, II, III, IV or V m is 1.

In particular embodiments of any of formulas I, II, III, IV or V m is 2.

In particular embodiments of any of formulas I, II, III, IV or V m is the th 3.

In particular embodiments of any of formulas I, II, III, IV or V n is 0.

In particular embodiments of any of formulas I, II, III, IV or V n represents 1.

In particular embodiments of any of formulas I, II, III, IV or V n represents 2.

In particular embodiments of any of formulas I, II, III, IV or V m represents 1 and n represents 1.

In particular embodiments of any of formulas I, II, III, IV or V m is 2 and n is 1.

In particular embodiments of any of formulas I, II, III, IV or V m is 2 and n is 0.

In particular embodiments of any of formulas I, II, III, IV or V m is 3 and n is 0.

In particular embodiments of any of formulas I, II, III, IV or V m represents 1 and n represents 0.

In particular embodiments of any of formulas I, II, III, IV or V m represents 1 and n represents 2.

In particular embodiments of any of formulas I, II, III, IV or V m represents 0 and n represents 1.

In particular embodiments of any of formulas I, II, III, IV or V R1represents:

C1-6alkyl;

C1-6alkenyl;

C1-6quinil;

C1-6alkoxy;

With3-7cycloalkyl-C1-6alkyl;

hetero-C1-6alkyl;

halo-C1-6alkyl;

possibly substituted aryl;

aryl-C1-3alkyl, where aryl is Naya part possibly substituted;

heteroaryl-C1-3alkyl, where the heteroaryl portion may substituted.

In particular embodiments of any of formulas I, II, III, IV or V R1represents:

C1-6alkyl;

C1-6alkenyl or

aryl-C1-3alkyl, where the aryl part may substituted.

In particular embodiments of any of formulas I, II, III, IV or V R1represents:

With3-6alkyl;

With3-6haloalkyl;

With3-6cycloalkyl-C1-3alkyl;

With1-2alkoxy-C1-3alkyl;

With1-2alkyl-C3-6cycloalkyl-C1-3alkyl;

possibly substituted benzyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents: n-propyl; isopropyl; tert-butyl; n-butyl; isobutyl; n-pentyl; isopentyl; 2,2-dimethyl-propyl; 3,3-dimethyl-butyl; cyclopentyl; cyclopropyl-methyl; cyclobutyl-methyl; cyclopentyl-methyl; cyclohexyl-methyl; cyclopropyl-ethyl; cyclohexyl-ethyl; 2-(1-methyl-cyclopropyl)-ethyl; 3-(1-methyl-cyclopropylmethyl; 3,3,3-Cryptor-propyl; 4,4,4-Cryptor-butyl; 3,3-debtor-allyl; benzyl; 3-fluoro-benzyl; 4-fluoro-benzyl; 3-methoxy-benzyl; 4-methoxy-benzyl; 3,4-dichloro-benzyl; 3,4-debtor-benzyl; pyrazin-2-yl-methyl; thiazol-4-yl-methyl; pyrazole-1-yl-methyl; methoxy-methyl; ethoxy-methyl; isopropoxy-methyl; 2-methoxy-ethyl; 2-ethoxy-ethyl; 3-methoxy-3-methyl-butyl; 3-econsultancy-methyl or tetrahydropyran-4-elmet the L.

In particular embodiments of any of formulas I, II, III, IV or V R1represents: n-propyl; isopropyl; tert-butyl; n-butyl; isobutyl; n-pentyl; isopentyl; 2,2-dimethyl-propyl; 3,3-dimethyl-butyl; cyclopentyl; cyclopropyl-methyl; cyclobutyl-methyl; cyclopentyl-methyl; cyclohexyl-methyl; cyclopropyl-ethyl; cyclohexyl-ethyl; 2-(1-methyl-cyclopropyl)-ethyl; 3-(1-methyl-cyclopropylmethyl; 3,3,3-Cryptor-propyl or 4,4,4-Cryptor-butyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents: n-propyl; isopropyl; tert-butyl; n-butyl; isobutyl; isopentyl; 2,2-dimethyl-propyl; 3,3-dimethyl-butyl; cyclopentyl; cyclopropyl-methyl; cyclobutyl-methyl; cyclopentyl-methyl; cyclohexyl-methyl; cyclopropyl-ethyl; cyclohexyl-ethyl; 2-(1-methyl-cyclopropyl)-ethyl or 3-(1-methyl-cyclopropylmethyl.

In particular embodiments of any of formulas I, II, III, IV or V, where R1is heteroaryl-C1-3alkyl, heteroaromatic, heteroaryl-C1-6alkoxy, heteroaryl group may be a pyridinyl, pyrazinyl, thiazolyl or pyrazolyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a C1-6alkyl; aryl-C1-6alkyl; C3-6cycloalkyl-C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl or C1-6alkyl-C1-3cycloalkyl-C1-6alkyl.

In to skretny embodiments of any of formulas I, II, III, IV or V R1represents a C1-6alkyl; aryl-C1-6alkyl; C3-6cycloalkyl-C1-6alkyl or C1-6alkyl-C1-3cycloalkyl-C1-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a C3-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a C3-6alkenyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a C3-6quinil.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a C2-6alkoxy.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a C3-7cycloalkyl-C1-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a C3-7cycloalkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a C1-6alkyl-C3-6cycloalkyl-C1-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a hetero-C1-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents heterocyclyl - C1-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents heterocyclyl-C1-6alkyl, in which the last of tetrahydropyranyl, tetrahydrofuranyl and piperidinylmethyl.

In particular embodiments of any of formulas I, II, III, IV or V R1is tetrahydropyranyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a hetero-C1-6alkyl selected from:

hydroxy-C1-6of alkyl;

C1-6alkylsulfonyl-C1-6of alkyl;

C1-6alkylsulfanyl-C1-6the alkyl and

C1-6alkoxy-C1-6the alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a hydroxy-C1-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a C1-6alkylsulfonyl-C1-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a C1-6alkylsulfanyl-C1-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a C1-6alkoxy-C1-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents halo,-C1-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a possibly substituted aryl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a possibly substituted heteroaryl.

In specific embodiments Liu the Oh of formula I, II, III, IV or V R1represents aryl-C1-3alkyl, where the aryl part may substituted.

In particular embodiments of any of formulas I, II, III, IV or V R1is heteroaryl-C1-3alkyl, where the heteroaryl portion may substituted.

In particular embodiments of any of formulas I, II, III, IV or V R1is heteroaryl-C1-3alkyl selected from pyridinyl-C1-3of alkyl, pyrazinyl-C1-3of alkyl, thiazolyl-C1-3the alkyl and pyrazolyl-C1-3the alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or isopentyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents n-propyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents isopropyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents n-butyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents isobutyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents tert-butyl.

In particular embodiments of any of formulas I, II, III, IV or V R1is a n-pentyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents the t isopentyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents 2,2-dimethyl-propyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents 3,3-dimethyl-butyl.

In particular embodiments of any of formulas I, II, III, IV or V R1is cyclopropyl-methyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a 2-(1-methyl-cyclopropyl)-ethyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a 3-(1-methyl-cyclopropyl)-methyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents:

possibly substituted benzyl;

triazolylmethyl;

personality;

possibly substituted phenyl or

C1-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents:

possibly substituted benzyl;

possibly substituted phenyl or

With3-6alkyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a possibly substituted benzyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a possibly substituted phenyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a C3-6alkyl.

In particular embodiments of any of the of oral I, II, III, IV or V R1represents a possibly substituted phenylethyl.

In particular embodiments of any of formulas I, II, III, IV or V R1represents a possibly substituted heteroaryl-C1-6alkyl selected from triazolylmethyl and parasaissetia.

In specific embodiments of formula II, preferably each R4, R5and Rwithindependently chosen from:

halo;

C1-6of alkyl;

halo-C1-6of alkyl;

halo-C1-6alkoxy;

C1-6alkoxy;

hydroxy;

hetero-C1-6the alkyl selected from:

hydroxy-C1-6of alkyl;

C1-6alkylsulfonyl-C1-6the alkyl and

C1-6alkoxy-C1-6of alkyl;

cyano;

nitro;

amino;

N-C1-6alkyl-amino;

N,N-di-C1-6alkylamino;

C1-6alkyl-sulfonyl or

-C(O)Rcwhere Rcrepresents:

C1-6alkyl;

amino;

C1-6alkyl-amino or

N,N-di-C1-6alkylamino.

In particular embodiments of any of formulas II, more preferably each R4, R5and Rcindependently chosen from:

halo;

C1-6of alkyl;

halo-C1-6of alkyl;

C1-6alkoxy;

hydroxy or

cyano.

In the embodiments of formulas I, II, III, IV or V, when R1represents a possibly substituted aryl, possibly substituted heteroaryl, possibly substituted aryls 1-3alkyl (including possibly substituted benzyl) or possibly substituted heteroaryl-C1-3alkyl, such possible substituents can be one, two or three groups, each of which is independently selected from:

halo;

C1-6of alkyl;

halo-C1-6of alkyl;

halo-C1-6alkoxy;

C1-6alkoxy;

hydroxy;

hetero-C1-6of alkyl;

cyano;

nitro;

amino;

N-C1-6alkyl-amino;

N,N-di-C1-6alkylamino or

-(CH2)r-Y-(CH2)s-Z-(CH2)tQ-(CH2)u-Rc;

where

each r, s, t and u independently represents 0 or 1;

Z represents-C(O)- or-SO2-;

each X and Y independently represents-O-, -NRdor communication;

Rcrepresents:

hydrogen;

C1-6alkyl;

halo-C1-6alkyl;

halo-C1-6alkoxy;

C1-6alkoxy;

hydroxy;

hetero-C1-6alkyl;

cyano;

amino;

C1-6alkyl-amino or

N,N-di-C1-6alkylamino; and

Rdrepresents:

hydrogen or

C1-6alkyl.

In the embodiments of formulas I, II, III, IV or V, when R1represents a possibly substituted aryl, possibly substituted heteroaryl, possibly substituted aryl-C1-3alkyl (including possibly substituted benzyl) or possibly substituted heteroaryl-C 1-3alkyl, such possible substituents preferably comprise one, two or three groups, each of which is independently selected from:

halo;

C1-6of alkyl;

halo-C1-6of alkyl;

halo-C1-6alkoxy;

C1-6alkoxy;

hydroxy;

hetero-C1-6the alkyl selected from:

hydroxy-C1-6of alkyl;

C1-6alkylsulfonyl-C1-6the alkyl and

C1-6alkoxy-C1-6of alkyl;

cyano;

nitro;

amino;

N-C1-6alkyl-amino;

N,N-di-C1-6alkylamino;

C1-6alkyl-sulfonyl or

-C(O)Rcwhere Rcrepresents:

C1-6alkyl;

amino;

C1-6alkyl-amino or

N,N-di-C1-6alkylamino.

In the embodiments of formulas I, II, III, IV or V, when R1represents a possibly substituted aryl, possibly substituted heteroaryl, possibly substituted aryl-C1-3alkyl (including possibly substituted benzyl) or possibly substituted heteroaryl-C1-3alkyl, such possible more substituents are preferably one or two groups, each of which is independently selected from:

halo;

C1-6of alkyl;

halo-C1-6of alkyl;

C1-6alkoxy;

hydroxy or

cyano.

In specific embodiments of formula I compounds according to the invention can be in particular of the formula VI:

where Ar and R1are as defined here for formula I.

In specific embodiments of formula VI compounds according to the invention can be in particular of the formula VIa or formula VI:

where Ar and R1are as defined here for formula I.

In specific embodiments of formula I compounds according to the invention can be in particular of the formula VII:

where Ar and R1are as defined here for formula I.

In specific embodiments of formula VII, the compounds according to the invention can be in particular of the formula VIIa or formula VII:

where Ar and R1are as defined here for formula I.

In specific embodiments of formula I compounds according to the invention can be in particular of the formula VIII:

where Ar and R1are as defined here for formula I.

In specific embodiments of formula VIII compounds according to the invention can be in particular of the formula VIIIa or formula VIII:

where Ar and R1are as defined here for formula I.

In specific embodiments of formula I compounds according to the invention can be frequent in the spine of formula IX:

where Ar and R1are as defined here for formula I.

In specific embodiments of formula I compounds according to the invention can be in particular of the formula X:

where Ar and R1are as defined here for formula I.

In specific embodiments of formula X compounds according to the invention can be in particular of the formula Ha or formula HB:

where Ar and R1are as defined here for formula I.

Typical compounds according to the methods of the invention are shown in table 1. Unless otherwise stated, the melting temperature (in °C) in table 1 are given for chlorotoluron salts.

Synthesis

Compounds of the present invention can be obtained during a number of methods depicted in the illustrative schemes reactions of synthesis, shown and described below.

Source materials and reagents used in the preparation of these compounds generally are either available from trade suppliers, such as Aldrich Chemical Co., either get them by methods known to the skilled person skilled in the art following procedures set forth in references such as Fieser and Fieser''s Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, volumes 1-15; Rodd''s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, volumes 1-5, dopolneniya; and Organic Reactions, Wiley & Sons: New York, 1991, volumes 1-40. The following scheme of reactions for the synthesis of only illustrate some of the ways according to which compounds of the present invention can be synthesized, and various modifications to these schemes reactions of synthesis can be done and will be offered to a qualified specialist in the art by reference to the disclosure of the entities contained in this proposal.

Source materials and intermediate compounds according to the schemes of synthesis reactions can be isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography and the like, Such substances can be characterized using conventional methods, including physical constants and spectral data.

Unless otherwise stated, the reactions described herein, preferably in an inert atmosphere at atmospheric pressure in the reaction temperature range from about -78°to about 150°C., more preferably from about 0°C. to about 125°C. and most preferably and conveniently at about room (or ambient) temperature, for example about 20°C.

Below is a diagram And illustrates one procedure for the synthesis suitable for producing compounds according to the invention, where X represents the Oh halo or other leaving group and may be the same or different in each case, 3G is a protective group, and m, n, Ar and R1are as defined here.

Scheme And

In stage 1 scheme And aryl compound a, such as the aryl halide, interacts with the N-protected heterocyclic amide compound b in the presence of a strong base, such as alkyllithium reagent that gives heterocyclic aryl ketone century, the values of m and n in the compound b can be chosen in such a way as to ensure pyrrolidinyl, piperidinyl, azetidine, azepine or similar heterocyclic group. In stage 2, the alkylation is carried out in the course of the reaction heterocyclic aryl ketone with an alkylating agent g that gives compound D. Alkylating agent g may include, for example, a benzyl halide, alkenyl the halide or other alkylating reagents. Then remove the protective group in the compound and at stage 3, that gives compound e, which is a compound of formula I according to the invention.

Numerous variants of the procedures of the scheme As possible and will be obvious to a qualified specialist in this field of technology. For example, N-alkylation of compound e can give compounds where R2represents alkyl. When the group R1introduced in stage 2, represents alkenyl or quinil, the hydrogenation reaction can be performed, h the Oba change R 1on alkyl.

Diagram B shows another method of synthesis of compounds according to the invention, where R is a lower alkyl, 3G is a protective group, X is a leaving group and m, n, Ar and R1are as defined here.

Scheme B

In stage 1 scheme B ether carboxylic acid cyclic amine W is treated with an alkylating agent of C in the presence of a strong base, such as alkyllithium reagent, getting alkilirovanny cyclic amine I. Cyclic amine W can be pyrrolidinyl, piperidinyl, azetidine, azepine or the like according to the values of m and n, as noted above. In stage 2 of the ester group of the compounds and to restore the connection to the primary alcohol. Recovery stage 2 may be performed, for example, when using LiAlH4. Then the alcohol connection is subjected to partial oxidation in stage 3, receiving aldehyde compound L. the Oxidation stage 3 may be performed, for example, using periodinane dessa-Martin or chromate. The alkylation is carried out in stage 4 by the reaction of the aldehyde compound l with arellanobond m getting connection n aryl alcohol. Stage 5 alcohol n oxidized to the corresponding connections on arylketones. The oxidation may be performed, for example, using MnO , reagent Swarna or similar oxidizing agents. On stage 6 remove the protective group in the compound d arylketones, receiving the connection e, which is a compound of formula I according to the invention.

Numerous variants of the procedures of scheme B is possible, it is believed that they are within the scope of this invention. For example, ability can be used in stage 4. The characteristic details of preparing compounds according to the invention described in the Examples below.

Utility

Compounds according to the invention are suitable for treating diseases or conditions associated with neurotransmission serotonin, neurotransmission norepinephrine and/or neurotransmission dopamine. Such diseases and conditions include depressive and anxiolytic disorders, and schizophrenia and other psychosis, dyskinesia, drug dependence, cognitive disorders, Alzheimer's disease, attention deficit disorder, such as ADHD, obsessive-compulsive behaviour, panic attacks, sociophobia, eating disorders such as obesity, anorexia, bulimia and compulsive overeating, stress, hyperglycemia, hyperlipidemia, ainsliezubaida diabetes, epileptic diseases, such as epilepsy, and treatment of conditions associated with neurological damage resulting from stroke, brain injury, is Enebrales ischemia, head injuries and bleeding.

Compounds according to the invention is also suitable for the treatment of diseases and painful conditions of the urinary tract, such as stress incontinence, urgency urinary incontinence, benign prostatic hyperplasia (BPH), prostatitis, detrusor hyperreflexia, obstruction of the outlet, frequent urination, nocturia, urgency urge to urination, overactive bladder, pelvic hypersensitivity, urethritis, prostatodynia, cystitis, idiopathic hypersensitivity of the bladder.

Compounds according to the invention also have anti-inflammatory and/or analgesic properties in vivo, and, therefore, expected to find application in the treatment of painful conditions associated with painful conditions in a variety of cases, including, but not limited to, neuropathic pain, pain caused by inflammation, pain during surgery, visceral pain, dental pain, premenstrual pain, Central pain, pain due to burns, migraine or histamine headaches, nerve damage, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injuries (including fractures and sports injuries), and Bo is e l e C associated with functional bowel disorders such as irritable bowel syndrome.

Compounds according to the invention are also useful in the treatment of arthritis, including, but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic condition.

Introduction and pharmaceutical composition

The invention includes pharmaceutical compositions containing at least one compound of the present invention, or individual isomers, racemic or prizemistuyu mixture of isomers, or pharmaceutically acceptable salt or MES together with at least one pharmaceutically acceptable carrier, and possibly other therapeutic and/or prophylactic ingredients.

In General, the compounds according to the invention are introduced in a therapeutically effective amount of any generally accepted method of administration of agents that satisfy such use. Suitable dosage ranges are usually 1-500 mg / day, preferably 1-100 mg per day and most preferably 1-30 mg / day depending on a number of factors, such as the severity subjected to treatment of the disease, the age and relative health of the subject, the activity of the used connection method and forms of introduction, indications as to which is the introduction, and the preference and experience caused by the doctor. Any average specialist in the treatment of such diseases are able, without undue experimentation, relying on personal knowledge and the essence of this proposal to establish a therapeutically effective amount of the compounds of the present invention for a given disease.

Compounds according to the invention can be introduced in the form of pharmaceutical preparations, including suitable for oral (including transbukkalno and sublingual), rectal, nasal, local, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for introduction during inhalation or insufflation. The preferred method of introduction, as a rule, is oral using a convenient daily dosage regimen which can be adjusted depending on the extent of disease.

The compound or compounds according to the invention together with one or more conventional adjuvants, carriers or diluents may be put into the form of pharmaceutical compositions and standard dosage forms. Pharmaceutical compositions and a standard dosage form may consist of conventional components in tra the investment proportions with or without additional active compounds or substrates, standard dosage forms may contain any suitable effective amount of the active component in accordance with the intended daily dosage range to be used. The pharmaceutical compositions can be used in the form of solids, such as tablets or filled capsules, semi-solid substances, powders, drugs with a slow release, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral administration; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Drugs, containing approximately one (1) milligrams of active ingredient or, more commonly from about 0.01 to about one hundred (100) milligrams per tablet are, thus, suitable typical standard dosage forms.

Compounds according to the invention can be created in a large variety of dosage forms for oral administration. Pharmaceutical compositions and dosage forms may contain a compound or compounds of the present invention or their pharmaceutically acceptable salts as the active ingredient. Pharmaceutically acceptable carriers can be either solid or liquid. Drugs t is erday forms include powders, tablets, pills, capsules, pills, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilization, lubricants, suspendida agents, binding agents, preservatives, dezintegriruetsja agents or encapsulating substances. In powders, the carrier is usually a powdered solid substance which is a mixture with finely ground active ingredient. For tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in appropriate proportions and pressed into the desired shape and size. The powders and tablets preferably contain from about one (1) to about (70) percent of the active compounds. Suitable carrier materials include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, carboxymethylcellulose sodium, low melting wax, cocoa butter, etc. it is Assumed that the term "drug" includes the composition of the active compound with encapsulating material in the form of media, providing a capsule in which the active component with or without carriers, is surrounded by carrier, which is associated with them. Similarly comprise a wafer, and lollipops. Tablets, powders, capsules, pills, wafers and candies can be in the form of solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid preparations of forms, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are supposed to translate directly before applying the medication liquid form. The emulsion can be obtained in solutions, for example, aqueous propylene glycol solutions, or they may contain emulsifying agents such as lecithin, monooleate sorbitan or gum Arabic. Aqueous solutions can be obtained by dissolving the active component in water and adding suitable colorants, corrigentov, stabilizers and thickeners. Aqueous suspensions can be obtained by dispersing finely ground active component in water with viscous substance, such as natural or synthetic resins, resinous substances, methylcellulose, carboxymethylcellulose sodium, and other well-known suspendresume agents. The solid form preparations include solutions, suspensions and emulsions can contain, in addition to the active component, colorants, corrigentov, stabilizers, buffers, artificial and natural podla the Fort worth, dispersing agents, thickeners, soljubilizatory etc.

Compounds according to the invention can be created for parenteral administration (for example, during injection, for example bolus injection or continuous injection) and can be represented in the form of a single dose in ampoules, pre-filled syringes, infusion of a small volume or in containers for repeated dosing with added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous fillers, such as solutions in aqueous polyethylene glycol. Examples of oil or non-aqueous carriers, diluents, solvents or excipients include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil) and injectable organic esters (for example, etiloleat) and may contain additional agents such as preserving, wetting, emulsifying or suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic allocation of sterile solid or during lyophilization from solution, for merging before use with a suitable filler, such as sterile pyrogen-free water.

Compounds according to the invention which may be prepared for the local introduction to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams can be, for example, based on the aqueous or oily base with the addition of suitable thickeners and/or gelling agents. Lotions may be water or oil based and also typically contain one or more emulsifiers, stabilizers, dispersing agents, suspendida agents, thickeners or dyes. Drugs suitable for local injection in the mouth include lozenges containing the active agent is a flavored basis, usually sucrose and gum Arabic or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerol or sucrose and gum Arabic; and dental elixirs containing the active ingredient in a suitable liquid carrier.

Compounds according to the invention can be designed for administration in the form of suppositories. First, low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, melt, and the active component is dispersed to a homogeneous mass, for example, with stirring. The molten homogeneous mixture is then poured into a suitable size, shape, cooled and allowed to harden.

Compounds according to the invention can be designed for vaginal insertion. Suitable pessaries, tampons, creams, gels, pastes, foams or sprays containing in opalanie to the active component carriers, known in this field.

Compounds according to the invention can be designed for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, using a dropper, pipette or spray. Drugs can be created in the form of single or multiple dosing. In the case of a dropper or pipette, this can be accomplished by the patient at the input of the corresponding pre-defined volume of solution or suspension. In the case of spray this is done, for example, by spray dosing pump.

Compounds according to the invention can be created for aerosol administration, particularly to the respiratory tract and including intranasal administration. Typically, the connection has a small particle size, for example of the order of five (5) microns or less. Such particle size can be obtained well-known in this field of ways, for example by micronization. The active ingredient is placed in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may contain a surfactant such as lecithin. The dose can be adjusted using dairou is it valve. Alternatively, the active components can be created in the form of a dry powder, for example a powder mix of a compound corresponding to the powder base such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidone (PVP). Powdered media will form a gel in the nasal cavity. Powder composition may be presented in the form of a single dose, for example, capsules or cartridges, for example, gelatin or blister packs from which the powder can be introduced through the inhaler.

If desired, the preparations can be obtained intersolubility coating, suitable for introduction of the active component with a slow or controlled release. For example, the compounds of the present invention can be created for transdermal or subcutaneous delivery system for drugs. These delivery systems are useful when you want slow release of the connection, and when it is crucial to the patient's consent to treatment. Connection in transdermal delivery systems are often mounted on sticking to the skin of solid media. Of interest, the connection can also be combined with promoting the penetration of a substance, such as azone (1-dodecylsulfate-2-one). The system is of supplying delayed release subcutaneously in the subdermal layer by surgery or during injection. Subcutaneous implants encapsulate the fat-soluble compound in the membrane, for example silicon rubber, or biodegradable polymer such as polylactic acid.

The pharmaceutical preparations are preferably in a standard dosage forms. In such form the preparation is divided into single doses containing appropriate quantities of the active component. Standard dosage form can be a packaged preparation, where the package contains a specific quantity of the drug, such as packaged tablets, capsules, and powders in vials or ampoules. Standard dosage form can be a capsule, tablet, wafer or toffee as such, or may constitute an appropriate number of any of these in packaged form.

Other suitable pharmaceutical carriers and their preparations are described in Remington; The Science and Practice of Pharmacy 1995, published E.W.Martin, Mack Publishing Company, 19th-oe edition, Easton, Pennsylvania. Typical pharmaceutical preparations containing the compound of the present invention, is described below.

Examples

The following preparations and examples are given in order to give the opportunity to a qualified specialist in this area to more clearly understand and practice the present invention. It should be assumed that they do not limit the scope of izobreteny is, but only illustrate and represent it. In the examples can be used the following abbreviations.

ABBREVIATIONS

AsónAcetic acid
BnBenzil
(VOS)2Odi-tert-BUTYLCARBAMATE
t-BuLitert-Utility
t-BuOHtert-Butyl alcohol :
m-SRV3-Chloroperoxybenzoic acid
DHMDichloromethane/methylene chloride
DejaDiethylamin
DIPEADiisopropylethylamine
DIBALHDiisobutylaluminum
DMFN,N-Dimethylformamide
DMPPeriodinane dessa-Martin (1,1-diacetoxy-3-oxo-lambda*5*-iodine-2-oxa-indan-1-silt ether acetic acid)
Dppf1,1'-Bis(diphenylprop the but)ferrocene
EDC1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EtOAcThe ethyl acetate
HPLCHigh performance liquid chromatography
HOBt1-Hydroxybenzotriazole
'lahAlumoweld lithium
LHMDSBis(trimethylsilyl)amide lithium
MeonMethanol
MsClMethanesulfonanilide
NBSN-bromosuccinimide
PFBSFPerformancemonitoring
TBAFTetrabutylammonium fluoride
TBAHSTetrabutylammonium the hydrosulfate
TBDMStert-Butyldimethylsilyl
TMSIEdotreotide
The teaThe triethylamine
TIPSTriisopropylsilyl
TFUTriperoxonane acid
THFTetrahydrofuran
TMAPTetramethylammonium fluoride
TMSTrimethylsilyl

Getting 1

5-Bromo-1-triisopropylsilyl-1H-indol

Bis(trimethylsilyl)amide lithium (1.0 M in THF, 28 ml, 28 mmol) was slowly added to a solution of 5-bromoindole (of 5.00 g, 25.5 mmol) in THF (60 ml) at -78°C under nitrogen atmosphere. The reaction mixture was stirred at -78°C for 20 minutes, then added triisopropylsilane (5.7 ml, 26.8 mmol). The resulting mixture was stirred at -78°C for 20 minutes, then was heated to room temperature within 1 hour. The reaction was suppressed by adding a saturated aqueous solution of NH4Cl, diluted with water and the resulting mixture was extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and evaporated under reduced pressure, which gave a crude oil which was purified using flash chromatography (100% hexane)to give to 8.94 g (yield 99%) 5-bromo-1-triisopropylsilyl-1H-indole as a colorless oil.

Similarly, COI is lsua appropriate starting material, received the following connections:

5-Bromo-1-triisopropylsilyl-1H-indazol (yield 86%, yellow solid);

5-Bromo-1-triisopropylsilyl-1H-pyrrolo[2,3-b]pyridine (yield 87%, yellow solid);

5-Bromo-2-methyl-1-triisopropylsilyl-1H-indole;

5-Bromo-1-triisopropylsilyl-2,3-dihydro-1H-indole (yield 100%, white solid);

5-Bromo-1-(tert-butyl-dimethyl-silanol)-1H-indole and

5-Bromo-7-fluoro-1-triisopropylsilyl-1H-indole.

Getting 2

1-tert-Butyl ester 2-methyl ester (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid

Synthesis of 1-tert-butyl ester 2-methyl ester (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid were performed according to the method shown in scheme C.

Schema

Stage 1 1-tert-Butyl ether (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid

A mixture of (R)-2-benzyl-pyrrolidin-2-carboxylic acid (2,07 g, 10.1 mmol) and hydroxide pentahydrate of Tetramethylammonium (1,83 g, 10.1 mmol) in acetonitrile (100 ml) was stirred in nitrogen for 90 minutes, then was added (BOC)2O (of 3.31 g of 15.2 mmol). After 48 hours was added to the second part (Vos)2O (1.10 g, 5.0 mmol). After 24 hours the reaction mixture was concentrated in vacuo, then was divided between ether (100 ml) and water (50 ml). The aqueous phase was washed with ether (50 ml), then acidified to pH 4 with 10% aqueous citric acid (20 ml). P is obtained in the resulting solution was extracted with EtOAc and the combined extracts washed with brine (30 ml), dried over MgSO4), filtered and concentrated in vacuo, which gave 1-tert-butyl ether (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid (1.26 g, 4,13 mmol, 41%) as a foam.

Stage 2 1-tert-Butyl ester 2-methyl ester (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid

To a stirred solution of 1-tert-butyl ether (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid (1.23 g, 4.00 mmol) in THF (10 ml) and methanol (10 ml) at 0°C in nitrogen was added TMS-diazomethane (5.0 ml of 2.0 M solution in hexano, 5.0 mmol) dropwise. The reaction mixture was heated to ambient temperature, then concentrated in vacuo to an oil (about 1.36 g). Purification via chromatography (silica, 5-15% EtOAc in hexano) gave 1-tert-butyl ester 2-methyl ester (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid (1,03 g of 3.23 mmol, 81%) as oil.

Getting 3

tert-Butyl ester 2-n-butyl-2-formyl-pyrrolidine-1-carboxylic acid

Synthesis of tert-butyl methyl ether 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid were performed according to the method shown in the diagram,

Scheme G

Stage 1 1-tert-Butyl ester 2-methyl ester 2-n-butyl-pyrrolidine-1,2-dicarboxylic acid

To a stirred solution of 1-tert-butyl ester 2-methyl ester pyrrolidine-1,2-dicarboxylic acid (3.00 g, of 13.1 mmol) in THF (50 ml) at -78°C and the nitrogen was added LHMDS (hexamethyldisilazide lithium 14.4 ml of 1.0 M solution in THF, 14.4 mmol) dropwise. After 30 minutes, was added dropwise a solution of 1-idbutton (2,23 ml of 19.7 mmol) in THF (1 ml). The reaction mixture was stirred for 30 minutes at -78°C., was heated to ambient temperature for 90 minutes then extinguished by adding saturated aqueous NH4Cl, and extracted with EtOAc. The combined extracts were washed with saturated aqueous NaHCO3and brine, then dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (4.5 g). Purification via chromatography (silica, 10% EtOAc in hexano) gave 1-mpem-butyl ester 2-methyl ester 2-butyl-pyrrolidine-1,2-dicarboxylic acid (to 2.57 g, 9,01 mmol, 69%) as a clear, colourless oil.

Using the above procedure and the appropriate source materials, likewise received:

1-tert-Butyl ester 2-methyl ester 2-propyl-pyrrolidine-1,2-dicarboxylic acid (colorless oil, 85%), using 1-jumprope;

1-tert-Butyl ester 2-methyl ester 2-ethoxymethyl-pyrrolidine-1,2-dicarboxylic acid (colorless oil, 76%), using chloromethoxy-ethane;

1-tert-Butyl ester 2-methyl ester 2-(3,3-debtor-allyl)-pyrrolidine-1,2-dicarboxylic acid (colorless oil, 11%), using 1,1,1-Cryptor-3-jumprope;

1-tert-Butyl ester 2-ethyl ester 2-isopropoxyphenyl-pyrrolidin-1,2-dicarbo the howling acid (colorless oil, 49%) of chloretocsitiodiasole ether and 1-tert-butyl ester 2-ethyl ester pyrrolidine-1,2-dicarboxylic acid;

1-tert-Butyl ester 2-ethyl ester of 2-isobutyl-pyrrolidine-1,2-dicarboxylic acid (colorless oil, 67%) of 1-iodine-2-methylpropane and 1-tert-butyl ester 2-ethyl ester pyrrolidine-1,2-dicarboxylic acid;

1-tert-Butyl ester 2-ethyl ester 2-cyclopropylmethyl-pyrrolidine-1,2-dicarboxylic acid (colorless oil, 50%) from cyclopropanemethylamine and 1-tert-butyl ester 2-ethyl ester pyrrolidine-1,2-dicarboxylic acid;

1-tert-Butyl ester 2-methyl ester of 5,5-dimethyl-2-propyl-pyrrolidine-1,2-dicarboxylic acid (colorless oil, 76%) of 1-jumprope and 1-tert-butyl ester 2-methyl ester of 5,5-dimethyl-pyrrolidine-1,2-dicarboxylic acid;

1-tert-Butyl ester 2-methyl ester (2R,4R)-4-(tert-butyl-dimethyl-silyloxy)-2-propyl-pyrrolidine-1,2-dicarboxylic acid (colorless oil, 26%) and 1-tert-butyl ester 2-methyl ester (2S,4R)-4-(tert-butyl-dimethyl-silyloxy)-2-propyl-pyrrolidine-1,2-dicarboxylic acid (colorless oil, 30%) of 1-jumprope and 1-tert-butyl ester 2-methyl ester (2S,4R)-4-(tert-butyl-dimethyl-silyloxy)-pyrrolidine-1,2-dicarboxylic acid;

1-tert-Butyl ester 2-methyl ester 2-propyl-azetidine-1,2-dicarboxylic acid (colorless oil, 80%) of 1-itpro the Ana and 1-tert-butyl ester 2-methyl ester azetidine-1,2-dicarboxylic acid;

1-tert-Butyl ester 2-ethyl ester 2-propyl-piperidine-1,2-dicarboxylic acid (colorless oil, 38%) of 1-jumprope and 1-tert-butyl ester 2-ethyl ester piperidine-1,2-dicarboxylic acid and

1-tert-Butyl ester 2-methyl ester 2-(tetrahydro-Piran-4-ylmethyl)-pyrrolidine-1,2-dicarboxylic acid.

Step 2 tert-Butyl ester 2-n-butyl-2-hydroxymethyl-pyrrolidin-1-carboxylic acid

To a stirred solution of 1-tert-butyl ester 2-methyl ester 2-butyl-pyrrolidine-1,2-dicarboxylic acid (0,842 g, 2,95 mmol) in THF (30 ml) at 0°C in nitrogen was added LiAlH4(2,95 ml of 1.0 M solution in THF, 2,95 mmol) dropwise. After 15 minutes the reaction mixture was suppressed by adding decahydrate sodium sulfate (2.5 g), then filtered. The filter cake was washed DHM (50 ml), then the combined filtrates were concentrated in vacuo, obtaining tert-butyl ester 2-butyl-2-hydroxymethyl-pyrrolidin-1-carboxylic acid (0,763 g) as a clear, colourless oil, which was directly used without further purification.

Using the above procedure and the appropriate source materials, likewise received:

tert-Butyl ester 2-hydroxymethyl-2-propyl-pyrrolidin-1-carboxylic acid (yellow oil, 94%);

tert-Butyl ester 2-hydroxymethyl-2-isopropoxyphenyl-pyrrolidin-1-carboxylic acid (bestv is the based oil, 89%);

tert-Butyl ester 2-hydroxymethyl-2-isobutyl-pyrrolidin-1-carboxylic acid (colorless oil, 100%);

tert-Butyl ester 2-cyclopropylmethyl-2-hydroxymethyl-pyrrolidin-1-carboxylic acid (colorless oil, 100%);

tert-Butyl ester 2-hydroxymethyl-5,5-dimethyl-2-propyl-pyrrolidin-1-carboxylic acid (colorless oil, 100%);

tert-Butyl ester (2S,4R)-2-hydroxymethyl-2-propyl-4-(1,1,2,2-tetramethyl-propoxy)-pyrrolidin-1-carboxylic acid (colorless oil, 100%), and

tert-Butyl ester 2-hydroxymethyl-2-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-1-carboxylic acid.

Step 3 tert-Butyl ester 2-n-butyl-2-formyl-pyrrolidine-1-carboxylic acid

To a stirred solution of tert-butyl methyl ether 2-butyl-2-hydroxymethyl-pyrrolidin-1-carboxylic acid (0,763 g, about 2,95 mmol) in DHM (30 ml) at 0°C in nitrogen was added DMP (2.50 g, 5,90 mmol) in one part, then the reaction mixture was heated to ambient temperature. After 14 hours the reaction mixture was diluted DHM (70 ml), washed with 1 N. NaOH (2×30 ml) and brine (30 ml), then dried (MgSO4), filtered and concentrated in vacuum. Purification via chromatography (silica, 10-20% EtOAc in hexano) gave tert-butyl ester 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid (0,359 g of 1.41 mmol, 48%) as a pale yellow oil.

Using visiprise the military procedure and relevant source materials, in this way received:

tert-Butyl ester 2-formyl-2-propyl-pyrrolidin-1-carboxylic acid (colorless oil, 92%);

tert-Butyl ester 2-formyl-2-isopropoxyphenyl-pyrrolidin-1-carboxylic acid (colorless oil, 77%);

tert-Butyl ester 2-formyl-2-isobutyl-pyrrolidin-1-carboxylic acid (colorless oil, 79%);

tert-Butyl ester 2-cyclopropylmethyl-2-formyl-pyrrolidine-1-carboxylic acid (yellow oil, 85%);

tert-Butyl ester 2-formyl-5,5-dimethyl-2-propyl-pyrrolidin-1-carboxylic acid (colorless oil, 85%);

tert-Butyl ester (2S,4R)-4-(tert-butyl-dimethyl-silyloxy)-2-formyl-2-propyl-pyrrolidin-1-carboxylic acid (colorless oil, 63%), and

tert-Butyl ester 2-formyl-2-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-1-carboxylic acid.

Getting 4

tert-Butyl ester 2-ethoxymethyl-2-formyl-pyrrolidine-1-carboxylic acid.

Synthesis procedure for the receipt shown in scheme D below.

Scheme D

To a stirred solution of 1-tert-butyl ester 2-methyl ester 2-ethoxymethyl-pyrrolidine-1,2-dicarboxylic acid (1,00 g of 3.48 mmol, obtained using the procedure of stage 1 receiving 3) in THF (40 ml) at -78°C in nitrogen was added DIBALH (4.09 to ml, 1.7 M solution in PhCH3, of 6.96 mmol) dropwise within 15 minutes so that the internal temperature is ur did not exceed -75°C. After 4.5 hours the reaction mixture was suppressed by adding decahydrate sodium sulfate (4 g) and Meon (0.5 ml)and then heated to ambient temperature. The reaction mixture was diluted with EtOAc (50 ml) and filtered. The filter cake washed with EtOAc (200 ml) and the combined filtrates were concentrated in vacuo to a colorless oil. Purification via chromatography (silica, 10-30% EtOAc in hexano) gave tert-butyl ester 2-ethoxymethyl-2-formyl-pyrrolidine-1-carboxylic acid (0,528 g, 2.05 mmol, 59%) as a clear, colourless oil.

Using the above procedure and the appropriate source materials, likewise received:

tert-Butyl ester 2-(3,3-debtor-allyl)-2-formyl-pyrrolidine-1-carboxylic acid (colorless oil, 100%);

tert-Butyl ester (2R,4R)-4-(tert-butyl-dimethyl-silyloxy)-2-formyl-2-propyl-pyrrolidin-1-carboxylic acid (colorless oil, 36%);

tert-Butyl ester 2-formyl-2-propyl-azetidin-1-carboxylic acid (colorless oil, 53%), and

tert-Butyl ester 2-hydroxymethyl-2-propyl-piperidine-1-carboxylic acid (colorless oil, 72%).

Getting 5

tert-Butyl ether 4-formyl-4-propyl-piperidine-1-carboxylic acid synthesis Procedure for the receipt shown in scheme E below.

Scheme E

Stage 1 1-tert-Butyl ester 4-ethyl ester 4-propyl-piperidin-1,4-dicarboxylic acid

To a solution of hexamethyldisilazide potassium (29,1 g, 146 mmol) in THF (200 ml) at -78°C was added ethyl N-BOC-piperidine-4-carboxylate (25 g, 97 mmol). The reaction mixture was stirred at -78°C for 30 minutes, then was slowly added 1-jumprope (of 14.2 ml, 146 mmol). The reaction mixture was stirred at -78°C for an additional 20 minutes, then was heated to room temperature and was stirred for 1 hour. The reaction was suppressed by adding a saturated aqueous solution of NH4Cl, and extracted with EtOAc. The combined organic extracts were washed with saline, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified using flash chromatography (0% to 50% EtOAc in hexano), which gave 19.3 g (66%) of 1-tert-butyl ester 4-ethyl ester 4-propyl-piperidine-1,4-dicarboxylic acid as a yellow oil.

Step 2 tert-Butyl ether 4-formyl-4-proper-piperidine-1-carboxylic acid

To a solution of 1-tert-butyl ester 4-ethyl ester 4-propyl-piperidine-1,4-dicarboxylic acid (19.3 g, and 64.3 mmol) in THF (120 ml) at 0°C was slowly added alumoweld lithium (1.0 M in THF, 65 ml, 65 mmol). The reaction mixture was stirred at 0°C for one hour, then extinguished by slowly adding solid Na2SO4·10H2O, and stirred intensively at room temperature for one hour. Solid matter is removed by filtering through celite, washing EtOAc. The filtrate was concentrated under reduced pressure, giving a yellow oil.

In a separate flask was dissolved oxalyl chloride (5.4 ml, and 64.3 mmol) in dichloromethane (150 ml) and cooled to -78°C. dimethyl Sulfoxide (9.1 ml, 130 mmol) was slowly added and the reaction mixture was stirred at -78°C for 15 minutes. The above yellow oil is dissolved in dichloromethane (50 ml)was slowly added. After stirring at -78°C for 15 minutes Et3N (45 ml, 322 mmol) was added. The reaction mixture was heated to room temperature within one hour, and then extinguished with H2O and was extracted with dichloromethane. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (0% to 50% EtOAc in hexano), which gave 12.3 g (75%) of tert-butyl methyl ether 4-formyl-4-propyl-piperidine-1-carboxylic acid as a colourless oil.

Example 1

(3-Benzyl-pyrrolidin-3-yl)-(1H-indol-5-yl)-methanon

The synthesis procedure described in this example was carried out according to the method shown in scheme J.

Scheme W

Step 1 tert-Butyl ether 3-(methoxy-methyl-carbarnoyl-pyrrolidin-1-carboxylic acid

tert-Butyl ether pyrrolidine-1,3-dicarboxylic acid (3.00 g, 13,93 mmol), N,O-dimethylhydrogen the min hydrochloride (1.63 g, 16,72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2,94 g, 15,32 mmol) and 1-hydroxybenzotriazole (2,07 g, 15,32 mmol) were placed in a 100 ml round bottom flask and dissolved in DMF (30 ml). Diisopropylethylamine (6,1 ml, 34,82 mmol) was slowly added and the reaction mixture was stirred at room temperature for 24 hours. The reaction was suppressed by adding water, and was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure, which gave 2,60 g (yield 72%) of tert-butyl methyl ether 3-(methoxy-methyl-carbarnoyl-pyrrolidin-1-carboxylic acid as a pale yellow oil, which was used in the next stage without additional purification.

Similarly, when using the procedure of stage 1 were obtained:

tert-Butyl ester 4-(methoxy-methyl-carbarnoyl)-piperidine-1-carboxylic acid;

tert-Butyl ether 3-(methoxy-methyl-carbarnoyl)-piperidine-1-carboxylic acid;

tert-Butyl ester 2-(methoxy-methyl-carbarnoyl)-azetidin-1-carboxylic acid and

tert-Butyl ether 3-(methoxy-methyl-carbarnoyl-azepin-1-carboxylic acid.

Step 2 tert-Butyl ether 3-(1-triisopropylsilyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid

tert-Utility (1.7 M in pentane, 13 ml, 22,13 mmol) was added to p is the target 5-bromo-1-triisopropylsilyl-1H-indole (3,54 g, 10,06 mmol) in THF (35 ml) at -78°C under nitrogen atmosphere. The pale yellow reaction mixture was stirred at -78°C for 15 minutes, then a solution of tert-butyl methyl ether 3-(methoxy-methyl-carbarnoyl-pyrrolidin-1-carboxylic acid (2,60 g, 10,06 mmol) in THF (5 ml) was slowly added. The resulting mixture was stirred at -78°C for 30 minutes, then was heated to room temperature within 1 hour. The reaction was suppressed by adding a saturated aqueous solution of NH4Cl, and was divided between water and EtOAc. The organic layer was dried over MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified using flash chromatography (10% to 25% EtOAc in hexane)gave 2.66 g (yield 56%) of tert-butyl methyl ether 3-(1-triisopropylsilyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid as a colourless oil.

Step 3 tert-Butyl ether 3-benzyl-3-(1-triisopropylsilyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid

Bis(trimethylsilyl)amide lithium (1.0 M in THF, 12.1 ml) was added to a solution of tert-butyl methyl ether 3-(1-triisopropylsilyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid (1.90 g, a 4.03 mmol) in THF (25 ml) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 0°C for 10 minutes and then benzylbromide (1.9 ml, 16,12 mmol) was added. The resulting mixture was heated to room temperature the market and was stirred for 1.5 hours. The reaction was suppressed by adding a saturated aqueous solution of NH4Cl, then was diluted with water and was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified using flash chromatography (10% to 20% EtOAc in hexane)gave 1.55 g (yield 69%) of tert-butyl methyl ether 3-benzyl-3-(1-triisopropylsilyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid as a white foam.

Stage 4 tert-Butyl ether 3-benzyl-3-(1H-indol-5-carbonyl)-pyrrolidin-1-carboxylic acid

A solution of tetrabutylammonium fluoride (1.0 M in THF, 1.2 ml) was slowly added at 0°C. to a solution of tert-butyl methyl ether 3-benzyl-3-(1-triisopropylsilyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid (670 mg, 1,19 mmol) in THF (15 ml). The resulting bright yellow mixture was stirred at 0°C for 20 minutes, then extinguished, adding water. The resulting mixture was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified using flash chromatography (30% to 50% EtOAc in hexane), giving 447 mg (yield 93%) of tert-butyl methyl ether 3-benzyl-3-(1H-indol-5-carbonyl)-pyrrolidin-1-carboxylic acid as a white foam.

Stage 5 Division tert-butyl ether (+)-3-benzyl-3-(1H-indol-5-carbonyl)-pyrrolidin-1-carboxylic acid and tert-butyl methyl ether (-)-3-benzyl-3-(1H-indol-5-carbonyl)-pyrrolidin-1-carboxylic acid

Two enantiomers of tert-butyl methyl ether 3-benzyl-3-(1H-indol-5-carbonyl)-pyrrolidin-1-carboxylic acid were separated using chiral HPLC (using a column Chiralpak IA with 90/10 hexane/EtOH, of 1.4 ml/min).

Enantiomer A:

[α]D=+8,6° (5.2 mg/1.0 ml EtOH).

Enantiomer In:

[α]D=-10,2° (5.2 mg/1.0 ml EtOH).

Stage 6 (+)-(3-Benzyl-pyrrolidin-3-yl)-(1H-indol-5-yl)-methanon and (-)-(3-Benzyl-pyrrolidin-3-yl)-(1H-indol-5-yl)-methanon

A solution of HCl (1.0 M in Meon, 12 ml) was added to a solution of enantiomer And tert-butyl methyl ether 3-benzyl-3-(1H-indol-5-carbonyl)-pyrrolidin-1-carboxylic acid (257 mg, 0,635 mmol) in Meon (5 ml). The resulting pale yellow solution was stirred at room temperature for 6 hours, then was cooled to 0°C and was suppressed by adding aqueous NaOH (1.0 M). The mixture was diluted with water and was extracted with DHM. The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified using flash chromatography (5% to 10% Meon in DHM with 0.5% NH4OH, that would give 179 mg (yield 93%) of (3-benzyl-pyrrolidin-3-yl)-(1H-indol-5-yl)-methanon, which was dissolved in a mixture DHM/Meon. A solution of HCl (1 M in Et2O) was added, the resulting mixture is evaporated under reduced pressure and the residue triturated with Et2O that would give 173 mg of enantiomer And hydrochloride (3-benzyl-pyrrolidin-3-yl)-(1H-indol-5-yl)-methanone in the ideal of a white powder. MS=305 [M+H]+; [α]D=-26,3° (to 5.40 mg/1.0 ml Meon).

In this way received enantiomer B hydrochloride (3-benzyl-pyrrolidin-3-yl)-(1H-indol-5-yl)-methanone: [α]D=+24,4° (the 5.45 mg/1.0 ml Meon).

Using the procedure of example 1 with the corresponding original substance, received the following connections:

Hydrochloride (3-benzyl-pyrrolidin-3-yl)-(7-fluoro-1H-indol-5-yl)-methanone, rose powder, MS=324 [M+H]+;

Hydrochloride (1H-indol-5-yl)-[3-(3-methoxy-benzyl)-pyrrolidin-3-yl]-methanone, light pink powder, MS=335 [M+H]+;

Hydrochloride 3-[3-(1H-indol-5-carbonyl)-pyrrolidin-3-ylmethyl]-benzonitrile, white solid, MS=330 [M+H]+;

Hydrochloride [3-(3-fluoro-benzyl)-pyrrolidin-3-yl]-(1H-indol-5-yl)-methanone, orange-pink solid, MS=323 [M+H]+;

Hydrochloride [3-(4-fluoro-benzyl)-pyrrolidin-3-yl]-(1H-indol-5-yl)-methanone, red powder, MS=323 [M+H]+;

Hydrochloride (1H-indol-5-yl)-[3-(4-methoxy-benzyl)-pyrrolidin-3-yl]-methanone, MS=335 [M+H]+;

Hydrochloride [3-(3,4-dichloro-benzyl)-pyrrolidin-3-yl]-(1H-indol-5-yl)-methanone, off-white powder, MS=374 [M+H]+;

Hydrochloride [3-(2-fluoro-benzyl)-pyrrolidin-3-yl]-(1H-indol-5-yl)-methanone, pink solid, MS=323 [M+H]+;

Hydrochloride (3-benzyl-pyrrolidin-3-yl)-(2-methyl-1H-indol-5-yl)-methanone, yellow solid, MS=319 [M+H]+;

Hydrochloride (3-benzyl-Pirro is one-3-yl)-(2,3-dihydro-1H-indol-5-yl)-methanone, light yellow powder, MS=307 [M+H]+;

(4-Benzyl-piperidine-4-yl)-(1H-indol-5-yl)-methanon, off-white powder, MS=319 [M+H]+;

(3-Benzyl-piperidine-3-yl)-(1H-indol-5-yl)-methanon, white solid, MS=319 [M+H]+two enantiomers were separated using chiral HPLC on a column Chiralpak IB with 65/35 hexane/EtOH+0.1% of deja, 1.0 ml/min;

Chloromethane salt of the enantiomer A (white powder), [α]D=-126,4° (5,12 mg/1,024 ml Meon),

Chloromethane salt of the enantiomer B (white powder), [α]D=+129,4° (5,26 mg/1,052 ml Meon),

Hydrochloride (1H-indol-5-yl)-[3-(4-methoxy-benzyl)-piperidine-3-yl]-methanone, pale yellow powder, MS=349 [M+H]+.

Hydrochloride [3-(3-fluoro-benzyl)-piperidine-3-yl]-(1H-indol-5-yl)-methanone, white solid, MS=337 [M+H]+

Additional compounds obtained according to the above procedure are shown in table 1.

Example 2

5-(3-Benzyl-pyrrolidin-3-carbonyl)-1H-indol-3-carbonitril

The synthesis procedure described in this example was carried out according to the method shown in scheme 3.

Scheme 3

Step 1 tert-Butyl ether 3-(1-benzazolyl-3-iodine-1H-indole-5-carbonyl)-3-benzyl-pyrrolidin-1-carboxylic acid

Svejeispechennyi potassium hydroxide (35 mg, 0,617 mmol) was added to a solution of tert-butyl methyl ether 3-benzyl-3-(1H-indol-5-carbonyl)-pyrrolidin-1-carboxylic key is lots (100 mg, 0,247 mmol) in DMF (1.5 ml). Then a solution of iodine (63 mg, 0,247 mmol) in DMF (0.5 ml) was added dropwise and the reaction mixture was stirred at room temperature for 45 minutes. The reaction was suppressed by adding an aqueous solution of Na2S2O3, and was diluted with water. The resulting mixture was extracted with EtOAc, the combined organic extracts were washed with water, dried over MgSO4, filtered and evaporated under reduced pressure. Immediately the residue was dissolved in DMF (2 ml) and NaH (60% in mineral oil, 12 mg, 0,296 mmol) was added to the solution. The resulting mixture was stirred for 20 minutes, then was added dropwise benzazolyl chloride (38 μl, 0,296 mmol). The reaction mixture was stirred for 30 minutes, then extinguished, adding water. The resulting mixture was extracted with EtOAc, the combined organic extracts were washed with water, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified using flash chromatography (10% to 30% EtOAc in hexane)gave 150 mg (yield 91%) of tert-butyl methyl ether 3-(1-benzazolyl-3-iodine-1H-indole-5-carbonyl)-3-benzyl-pyrrolidin-1-carboxylic acid as a white foam.

Step 2 tert-Butyl ether 3-(1-benzazolyl-3-cyano-1H-indole-5-carbonyl)-3-benzyl-pyrrolidin-1-carboxylic acid

The copper cyanide (I) (76 mg, 0,852 mmol) dobavlyali 25 ml round bottom flask, filled tert-butyl ether 3-(1-benzazolyl-3-iodine-1H-indole-5-carbonyl)-3-benzyl-pyrrolidin-1-carboxylic acid (143 mg, 0,213 mmol), then 1,1'-bis(diphenylphosphino)ferrocene (24 mg, 0,043 mmol) and Tris(dibenzylideneacetone) dipalladium (0) (10 mg, to 0.011 mmol). Then 1,4-dioxane (1.5 ml) was added and the mixture was heated under reflux in nitrogen atmosphere for one hour. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filter cake washed with EtOAc and the filtrate was concentrated under reduced pressure. The residue was purified using flash chromatography (30% EtOAc in hexane)gave 115 mg (yield 95%) of tert-butyl methyl ether 3-(1-benzazolyl-3-cyano-1H-indole-5-carbonyl)-3-benzyl-pyrrolidin-1-carboxylic acid as pale yellow foam.

Step 3 tert-Butyl ether 3-benzyl-3-(3-cyano-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid

Water (1 ml) was added to a solution of tert-butyl methyl ether 3-(1-benzazolyl-3-cyano-1H-indole-5-carbonyl)-3-benzyl-pyrrolidin-1-

carboxylic acid (100 mg, 0,175 mmol) in Meon (4 ml), then potassium carbonate (73 mg, 0,525 mmol). The reaction mixture was heated at 50°C for 10 minutes, then cooled to room temperature and was diluted with water and saline solution. The resulting mixture was extracted with DHM, dried over MgSO4was filtered and the issue is ivali under reduced pressure. The residue was purified using flash chromatography (30% to 50% EtOAc in hexane)gave tert-butyl ether 3-benzyl-3-(3-cyano-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid as a white foamy solid.

Stage 4 of 5-(3-Benzyl-pyrrolidin-3-carbonyl)-1H-indol-3-carbonitril

A solution of HCl (1.0 M in Meon, 8 ml) was slowly added at 0°C. to a solution of tert-butyl methyl ether 3-benzyl-3-(3-cyano-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid (169 mg, 0,393 mmol) in Meon (2 ml). The resulting pale yellow mixture was stirred at room temperature for 4 hours, then extinguished, adding cooled to 0°C. aqueous NaOH (1.0 M). The resulting mixture was diluted with water and was extracted with DHM. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The crude substance was purified using flash chromatography (Meon in DHM with 0.5% NH4OH), which gave 42 mg of 5-(3-benzyl-pyrrolidin-3-carbonyl)-1H-indol-3-carbonitrile in the form of a white foamy solid. This product was dissolved in DHM and a solution of HCl (1.0 M in Et2O, 1 equivalent) was added. Meon was added and the resulting mixture was evaporated under reduced pressure. The residue is triturated with Et2O and 32 mg hydrochloride 5-(3-benzyl-pyrrolidin-3-carbonyl)-1H-indol-3-carbonitrile was collected as below the solids, MS=330 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 3

Hydrochloride (1H-indazol-5-yl)-(3-propyl-pyrrolidin-3-yl)-methanone

The synthesis procedure described in this example were carried out according to the method shown in scheme I.

Scheme And

Step 1 tert-Butyl ester 5-(3-propyl-pyrrolidin-3-carbonyl)-indazol-1-carboxylic acid

tert-Butyl ester 5-(3-allyl-pyrrolidin-3-carbonyl)-indazol-1-carboxylic acid was obtained as described in stages 3 and 4 of example 1, but substituting benzyl bromide, allyl bromide. Pd/C (10%, catalyst from Degussa type E101 NE/W, 100 mg) was added to a solution of tert-butyl ester 5-(3-allyl-pyrrolidin-3-carbonyl)-indazol-1-carboxylic acid (200 mg, 0,56 mmol) in Meon (10 ml). The resulting mixture was stirred in an atmosphere of hydrogen (pressure cylinder) for 2.5 hours. Then the reaction mixture was filtered through a pad of celite and the filtrate evaporated under reduced pressure, which gave 207 mg of the crude tert-butyl ester 5-[hydroxy-(3-propyl-pyrrolidin-3-yl)-methyl]-indazol-1-carboxylic acid as off-white foam. This substance was dissolved in toluene (8 ml) was added activated manganese dioxide (85%, 240 mg, 2,80 mmol). The resulting mixture was heated at 100°C in the tip is of 3 hours, then cooled to room temperature and filtered through a pad of celite. The filtrate is evaporated under reduced pressure and the resulting residue was purified using flash chromatography, which gave 86 mg tert-butyl ester 5-(3-propyl-pyrrolidin-3-carbonyl)-indazol-1-carboxylic acid as a white foamy solid.

Stage 2 Hydrochloride (1H-indazol-5-yl)-(3-pooper-pyrrolidin-3-yl)-methanone

Remove the protective group, tert-butyl ester 5-(3-propyl-pyrrolidin-3-carbonyl)-indazol-1-carboxylic acid, following the procedure described in stage 4 of example 2, hydrochloride (1H-indazol-5-yl)-(3-propyl-pyrrolidin-3-yl)-methanone received in the form of a white powder, MS=258 [M+H]+.

Using the above procedure and appropriate starting material, was obtained the following compounds:

hydrochloride (1H-indol-5-yl)-(3-propyl-pyrrolidin-3-yl)-methanone, MS=257 [M+H]+;

hydrochloride (3-butyl-pyrrolidin-3-yl)-(1H-indol-5-yl)-methanone, MS=271 [M+H]+and

hydrochloride (1H-indol-5-yl)-[3-(3-methyl-butyl)-pyrrolidin-3-yl]-methanone, MS=285 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 4

(1H-Indol-5-yl)-(3-phenyl-pyrrolidin-3-yl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in the Hema K.

Scheme To

Stage 1 Methyl ester of 6-phenyl-7-oxa-3-Aza-bicyclo[4.1.0]heptane-3-carboxylic acid

The triethylamine (2.6 ml, 19,15 mmol) was added to a suspension of the hydrochloride of 4-phenyl-1,2,3,6-tetrahydropyridine (1.50 g, 7,66 mmol) in DHM (30 ml). The resulting mixture was stirred for 5 minutes to dissolve the solids, then cooled to 0°C. and was added dropwise methyl chloroformate (0,65 ml, 8,43 mmol). Formed viscous white precipitate. The reaction mixture was heated to room temperature and was stirred for 1 hour, then extinguished, adding water, and was extracted with DHM. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure, which gave a 1.75 g of methyl ester of 4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid as a pale yellow oil. This crude product (7,66 mmol) was dissolved in chloroform (30 ml) was added 3-chloroperoxybenzoic acid (77%, 2,22 g, 9,95 mmol). The resulting solution was stirred at room temperature for 18 hours. Was added an aqueous solution of Na2SO3(20%, 30 ml) and the resulting mixture was intensively stirred for 1 hour. The phases were separated and the aqueous layer was extracted with DHM. The combined organic extracts washed with saturated aqueous NaHCO , dried over MgSO4, filtered and evaporated under reduced pressure, giving a pale yellow oil. This crude oil was purified using flash chromatography (10% to 20% EtOAc in hexane)gave 1.68 g (output 2 stages 94%) of methyl ester of 6-phenyl-7-oxa-3-Aza-bicyclo[4.1.0]heptane-3-carboxylic acid as a colourless oil.

Stage 2 Methyl ether 3-formyl-3-phenyl-pyrrolidin-1-carboxylic acid

Athirat of boron TRIFLUORIDE (1,82 ml, 14,40 mmol) was slowly added at room temperature to a solution of methyl ester of 6-FINEP-7-oxa-3-Aza-bicyclo[4.1.0]heptane-3-carboxylic acid (1.68 g, 7.20 mmol). Was observed weakly exothermic reaction, and after 5 minutes the reaction mixture was extinguished by slowly adding saturated aqueous NaHCO3(50 ml). The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with water, dried over MgSO4, filtered and evaporated under reduced pressure, which gave 1.63 g (yield 97%) of methyl ester of 3-formyl-3-phenyl-pyrrolidin-1-carboxylic acid as a pale yellow oil which was used without further purification.

Stage 3 Methyl ether 3-[hydroxy-(1-triisopropylsilyl-1H-indol-5-yl)-methyl]-3-phenyl-pyrrolidin-1-carboxylic acid

tert-Utility (1.7 M in pentane, 8,9 ml, 15,10 mmol) was added at -78°C. in a nitrogen atmosphere to a solution of 5-bromo-triisopropylsilyl-1H-indole (2,42 g, 6,86 mmol) in THF (25 ml). The resulting pale yellow solution was stirred at -78°C for 15 minutes, then a solution of methyl ester of 3-formyl-3-phenyl-pyrrolidin-1-carboxylic acid (1.60 g, 6,86 mmol) in THF (5 ml) was slowly added. The reaction mixture was stirred at -78°C for 30 minutes and then heated to room temperature within 1 hour. The reaction was suppressed by adding a saturated aqueous solution of NH4Cl and diluted with water. The resulting mixture was extracted with EtOAc and the combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified using flash chromatography (10% to 50% EtOAc in hexane), giving of 1.76 g (yield 51%) of the methyl ester of 3-[hydroxy-(1-triisopropylsilyl-1H-indol-5-yl)-methyl]-3-phenyl-pyrrolidin-1-carboxylic acid as a white foamy solid.

Stage 4 Methyl ether 3-(1H-indol-5-carbonyl)-3-phenyl-pyrrolidin-1-carboxylic acid

Manganese dioxide (85%, 256 mg, 2,95 mmol) was added to a solution of methyl ester of 3-[hydroxy-(1-triisopropylsilyl-1H-indol-5-yl)-methyl]-3-phenyl-pyrrolidin-1-carboxylic acid (300 mg, 0.59 mmol) in toluene (8 ml). The reaction mixture was heated at 100°C for 2 hours, then cooled to room temperature and filtered through a pad of celite. The filtrate is evaporated under pengendalian, that would give 326 mg of methyl ester of 3-phenyl-3-(1-triisopropylsilyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid as colorless foamy oil. Part of this product (298 mg, 0.59 mmol) was dissolved in THF (8 ml) and the solution was added tetrabutylammonium fluoride (1.0 M in THF, of 0.60 ml, 0.59 mmol) at 0°C. the Reaction mixture was stirred at 0°C for 20 minutes, then extinguished, adding water. The resulting mixture was extracted with EtOAc and the combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified using flash chromatography (30% to 50% EtOAc in hexane)gave 167 mg (yield 2 stages 81%) of methyl ester of 3-(1H-indol-5-carbonyl)-3-phenyl-pyrrolidin-1-carboxylic acid as a white foam.

tert-Butyl ester 4-(1H-indol-5-carbonyl)-4-phenyl-piperidine-1-carboxylic acid was obtained by following the procedure described above, using tert-butyl ester 4-formyl-4-phenyl-piperidine-1-carboxylic acid (obtained as described in Obtaining 5).

Stage 5 (1H-Indol-5-yl)-(3-phenyl-pyrrolidin-3-yl)-methanon

Attentional sodium (113 mg, 1.35 mmol) was added to a solution of methyl ester of 3-(1H-indol-5-carbonyl)-3-phenyl-pyrrolidin-1-carboxylic acid (157 mg, 0.45 mmol) in DMF (3 ml). The resulting mixture was heated at 100°C for 2 hours and then at 120°C during the course the e 2 additional hours. The reaction mixture was cooled to room temperature and was suppressed by adding water. The resulting mixture was extracted with EtOAc, the combined organic extracts were washed with water, dried over MgSO4, filtered and evaporated under reduced pressure, which gave 230 mg of an oil which was purified using flash chromatography (Meon/DHM/NH4OH), which gave 15 mg (1H-indol-5-yl)-(3-phenyl-pyrrolidin-3-yl)-methanone; MS=291 [M+H]+.

In this way received (1H-indol-5-yl)-(4-phenyl-piperidine-4-yl)-methanon, MS=305 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 5

(3-Benzyl-pyrrolidin-3-yl)-(1-methyl-1H-indol-5-yl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in scheme L.

Scheme L

Step 1 tert-Butyl ether 3-benzyl-3-(1-methyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid

Sodium hydride (60% in mineral oil, 12 mg, 0,296 mmol) was added at room temperature to a solution of tert-butyl methyl ether 3-benzyl-3-(1H-indol-5-carbonyl)-pyrrolidin-1-carboxylic acid (100 mg, 0,247 mmol) in DMF (3 ml). The resulting mixture was stirred at room temperature for 20 minutes and then added methyliodide (18 μl, 0,296 mmol). Then reacciona the mixture was stirred for 30 minutes, then extinguished, adding water, and was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure, which gave 105 mg of tert-butyl methyl ether 3-benzyl-3-(1-methyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid as a white foam which was used without further purification.

Stage 2 (3-Benzyl-pyrrolidin-3-yl)-(1-methyl-1H-indol-5-yl)-methanon

Remove the protective group in tert-butyl methyl ether 3-benzyl-3-(1-methyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid, as described in stage 4 of example 1, which gave (3-benzyl-pyrrolidin-3-yl)-(1-methyl-1H-indol-5-yl)-methanon as chloroethanol salt, MS=319 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 6

(3-Benzyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in the diagram M

Scheme M

Step 1 tert-Butyl ether 3-(3.4-dichloro-benzoyl)-pyrrolidin-1-carboxylic acid

tert-Utility (1.7 M in pentane, 2.5 ml, of 4.25 mmol) was added at -78°C to a solution of 4-bromo-1,2-dichlorobenzene (435 mg, of 1.93 mmol) in THF (10 ml) under nitrogen atmosphere. The resulting solution was stirred at -78°C in ECENA 15 minutes and then slowly added a solution of tert-butyl methyl ether 3-(methoxy-methyl-carbarnoyl-pyrrolidin-1-carboxylic acid (500 mg, of 1.93 mmol) in THF (2 ml). The reaction mixture was stirred at -78°C for 20 minutes and then heated to room temperature within 30 minutes. The reaction was suppressed by adding saturated aqueous NH4Cl, then was diluted with water and was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure, which gave an oil which was purified using flash chromatography (10% to 30% EtOAc in hexane)gave 143 mg (yield 22%) of tert-butyl methyl ether 3-(3,4-dichloro-benzoyl)-pyrrolidin-1-carboxylic acid as a colourless oil.

Step 2 tert-Butyl ether 3-benzyl-3-(3,4-dichloro-benzoyl)-pyrrolidin-1-carboxylic acid

Benzyl bromide (0,19 ml of 1.60 mmol) was added to a solution of tert-butyl methyl ether 3-(3,4-dichloro-benzoyl)-pyrrolidin-1-carboxylic acid (138 mg, 0.40 mmol) in THF (5 ml) and then bis(trimethylsilyl)amide lithium (1.0 M in THF, 1.2 ml, 1.20 mmol) was slowly added at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours, then was suppressed by adding saturated aqueous NH4Cl, diluted with water and was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified using flash chromatography (10% to 20% EtOAc in hexane)gave 40 mg (yield 23%) of tert-butyl what about the ether of 3-benzyl-3-(3,4-dichloro-benzoyl)-pyrrolidin-1-carboxylic acid as a colourless oil.

Stage 3 (3-Benzyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanon

Triperoxonane acid (0.3 ml) was added at room temperature to a solution of tert-butyl methyl ether 3-benzyl-3-(3,4-dichloro-benzoyl)-pyrrolidin-1-carboxylic acid (40 mg, 0,092 mmol) in DHM (3 ml). The reaction mixture was stirred at room temperature for 1 hour, then poured into aqueous NaOH (1.0 M), diluted with water and was extracted with DHM. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified using flash chromatography (3% to 10% Meon in DHM+0.5% of NH4OH), which gave 15 mg (yield 48%) of (3-benzyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanone in the form of a yellow oil. This substance was dissolved in DHM and a solution of HCl (1.0 M in Et2O, 1.1 equivalent) was added, the resulting mixture was concentrated under reduced pressure and the residue triturated with Et2O that gave 17 mg of the hydrochloride (3-benzyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanone in the form of a white solid; MS=334 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 7

Hydrochloride 5-(3-benzyl-pyrrolidin-3-carbonyl)-1,3-dihydro-indol-2-it

The synthesis procedure described in this example were carried out according to the method shown in scheme N.

Scheme N

Step 1 tert-Butyl ether 3-benzyl-3-(3,3-dibromo-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid tert-butyl ester 3-benzyl-3-(3-bromo-2-oxo-2,3-dihydro-1H-indol-5-carbonit)-pyrrolidin-1-carboxylic acid

Svejeprigotovlenny N-bromosuccinimide (278 mg, 1.56 mmol) was added in portions during 5 minutes at room temperature to a solution of tert-butyl methyl ether 3-benzyl-3-(1H-indol-5-carbonyl)-pyrrolidin-1-carboxylic acid (210 mg, 0.52 mmol) in a mixture of t-BuOH/water (5% water, to 8.40 ml). The reaction mixture was stirred for 1.5 hours at room temperature and then concentrated under reduced pressure. The residue was separated between water and DHM, and the combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified using flash chromatography (30% to 60% EtOAc in hexane)gave 129 mg (yield 43%) of tert-butyl methyl ether 3-benzyl-3-(3,3-dibromo-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid as a pale yellow foamy solid and 67 mg (yield 26%) of tert-butyl methyl ether 3-benzyl-3-(3-bromo-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid as a pale yellow foamy solid.

Step 2 tert-Butyl ether 3-benzyl-3-(2-oxo-2,3-dihydro-1H-indol-5-carbon is l)-pyrrolidin-1-carboxylic acid

Zinc powder (130 mg, 2.00 mmol) was added to a solution of tert-butyl methyl ether 3-benzyl-3-(3,3-dibromo-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid (115 mg, 0.20 mmol) in acetic acid (4 ml). The reaction mixture was intensively stirred at room temperature for 1 hour. Solids removed during filtration and the filtrate was concentrated under reduced pressure, which gave tert-butyl ether 3-benzyl-3-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid in the form of foam. The same procedure was repeated, using tert-butyl ether 3-benzyl-3-(3-bromo-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid, which gave an additional tert-butyl ether 3-benzyl-3-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid.

Stage 3 Hydrochloride 5-(3-benzyl-pyrrolidin-3-carbonyl)-1,3-dihydro-indol-2-it

Remove the protective group in tert-butyl methyl ether 3-benzyl-3-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid, following the procedure described in example 3, which gave the hydrochloride of 5-(3-benzyl-pyrrolidin-3-carbonyl)-1,3-dihydro-indol-2-it is in the form of off-white powder; MS=321 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 8

(2-Benzyl-pyrrolidin-2-yl)-(1H-indol-5-yl)-meth is non -

The synthesis procedure described in this example were carried out according to the method shown in scheme O.

Scheme About

Step 1 tert-Butyl ester 2-benzyl-2-(1-triisopropylsilyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid

To a stirred solution of 5-bromo-1-triisopropylsilyl-1H-indole (0.55 g, 1.57 mmol) in THF (10 ml) at -78°C in an atmosphere of nitrogen was added tert-utility (2,02 ml of 1.55 M solution in pentane, 3,13 mmol) dropwise. After one hour the reaction mixture was quickly added to a cold (-78°C) solution of 1-tert-butyl ester 2-methyl ester (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid (0.50 g, of 3.13 mmol) in THF (10 ml). The reaction mixture was stirred at -78°C for one hour, then heated to room temperature and was stirred for two hours. The reaction mixture was suppressed by adding saturated aqueous NH4Cl (20 ml), then was extracted with EtOAc. The combined extracts were washed with saline, then was dried (MgSO4), filtered and concentrated in vacuum. Purification via chromatography (silica, 0-20% EtOAc in hexano) gave tert-butyl ester 2-benzyl-2-(1-triisopropylsilyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid (0,145 g, 0,259 mmol, 16%) as a colourless resin.

Using the appropriate source materials, were also received after the respective connection:

tert-butyl ester 2-butyl-2-(1-triisopropylsilyl-1H-indazol-5-carbonyl)-pyrrolidin-1-carboxylic acid (yellow oil, 31%).

Step 2 tert-Butyl ester 2-benzyl-2-(1H-indol-5-carbonyl)-pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl methyl ether 2-benzyl-2-(1-triisopropylsilyl-1H-indole-5-carbonyl)-pyrrolidin-1-carboxylic acid (0,145 g, 0,259 mmol) in THF (5 ml) at ambient temperature under nitrogen atmosphere was added TMAP (0,026 g, 0,285 mmol). After one hour the reaction mixture was concentrated in vacuum. Purification of the residue by chromatography (silica, 25-50% EtOAc in hexano) gave tert-butyl ester 2-benzyl-2-(1H-indol-5-carbonyl)-pyrrolidin-1-carboxylic acid (0,045 g, 0,111 mmol, 43%) as a colourless foam.

Using the appropriate initial matter, also received the following connection:

tert-butyl ester 2-butyl-2-(1H-indazol-5-carbonyl)-pyrrolidin-1-carboxylic acid (yellow solid, 25%).

Stage 3 (2-Benzyl-pyrrolidin-2-yl)-(1H-indol-5-yl)-methanon

A solution of tert-butyl methyl ether 2-benzyl-2-(1H-indol-5-carbonyl)-pyrrolidin-1-carboxylic acid (0,045 g, 0,111 mmol) in 1 N. HCl in the Meon (2.2 ml) was stirred for 14 hours at ambient temperature under nitrogen atmosphere. Aqueous NaOH (4 N., 0.6 ml) was added and the reaction mixture was extracted with DHM. The combined extracts washed the Li salt solution, then was dried (MgSO4), filtered and concentrated in vacuum. Purification of the residue by chromatography (silica, 0-10% 9:1 MeOH:NH4OH solution in DHM) gave (2-benzyl-pyrrolidin-2-yl)-(1H-indol-5-yl)-methanon (0,021 g, 0,069 mmol, 62%) as a colourless solid, MS=305 [M+H]+.

Using the appropriate initial matter, also received the following connection:

(2-Butyl-pyrrolidin-2-yl)-(1H-indazol-5-yl)-methanon (yellow solid, 100%), MS=306 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 9

(2-Butyl-pyrrolidin-2-yl)-(3,4-dichloro-phenyl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in scheme P.

Scheme P

Step 1 tert-Butyl ester 2-butyl-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl methyl ether 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid (0,753 g, 2,95 mmol) in THF (12 ml) at 0°C and under nitrogen atmosphere was added 3,4-dichlorophenylamino (11.8 ml of 0.5 M solution in pentane, 5.9 mmol) dropwise over 10 minutes. After 20 minutes the reaction mixture was suppressed by adding saturated aqueous NH4Cl (30 ml), then was extracted with EtOAc. The combined extracts were washed with sollevamento, then was dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (1.9 g). Purification via chromatography (silica, 5-20% EtOAc in hexano) gave tert-butyl ester 2-butyl-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyrrolidin-1-carboxylic acid (0,548 g of 1.36 mmol, 46%) as a colourless resin and in the form of an inseparable mixture of diastereoisomers.

Using the appropriate initial matter, also received the following connections:

tert-Butyl ester 2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-2-propyl-pyrrolidin-1-carboxylic acid (pale yellow oil, 47%);

tert-Butyl ester 2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-2-ethoxymethyl-pyrrolidin-1-carboxylic acid (colorless oil, 59%);

tert-Butyl ester 2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-2-(3,3-debtor-allyl)-pyrrolidine-1-carboxylic acid (colorless resin, 42%);

tert-Butyl ester 2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-5,5-dimethyl-2-propyl-pyrrolidin-1-carboxylic acid (colorless foam, 81%);

tert-Butyl ester (2R,4R)-4-(tert-butyl-dimethyl-silyloxy)-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-2-propyl-pyrrolidin-1-carboxylic acid (colorless resin, 70%);

tert-Butyl ester (2S,4R)-4-(tert-butyl-dimethyl-silyloxy)-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-2-propyl-pyrrolidin-1-carboxylic acid (colorless oil, 45%);

tert-Butyl ester 2-[(3,4-dichloro-phenyl)-Hydra is XI-methyl]-2-propyl-azetidin-1-carboxylic acid (colorless oil, 21%) as single diastereoisomer;

tert-Butyl ester 2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-2-propyl-piperidine-1-carboxylic acid (colorless oil, 10%).

Step 2 tert-Butyl ester 2-butyl-2-(3,4-dichloro-benzoyl)-pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl methyl ether 2-butyl-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyrrolidin-1-carboxylic acid (0,520 g, 1,29 mmol) in DHM (20 ml) at 0°C under nitrogen atmosphere was added DMP (0,658 g, 1.55 mmol) at once. The reaction mixture was heated to ambient temperature and was stirred for 30 minutes, then diluted DHM, washed with 1 n NaOH and brine, then dried (MgSO4), filtered and concentrated in vacuo, giving a yellow oil (0,62 g). Purification via chromatography (silica, 10-20% EtOAc in hexano) gave tert-butyl ester 2-butyl-2-(3,4-dichloro-benzoyl)-pyrrolidin-1-carboxylic acid (0,441 g, 1.10 mmol, 85%) as a colorless transparent resin.

Using the appropriate initial matter, also received the following connections:

tert-Butyl ester 2-(3,4-dichloro-benzoyl)-2-propyl-pyrrolidin-1-carboxylic acid (white solid, 88%);

tert-Butyl ester 2-(3,4-dichloro-benzoyl)-2-ethoxymethyl-pyrrolidin-1-carboxylic acid (colorless residue, 75%);

tert-Butyl ester 2-(3,4-dichloro-benzoyl)-2-(3,3-debtor-allyl)-the feast of alidin-1-carboxylic acid (yellow oil, 81%);

tert-Butyl ester 2-(3,4-dichloro-benzoyl)-5,5-dimethyl-2-propyl-pyrrolidin-1-carboxylic acid (colorless resin, 83%);

tert-Butyl ester (2R,4R)-4-(tert-butyl-dimethyl-silyloxy)-2-(3,4-dichloro-benzoyl)-2-propyl-pyrrolidin-1-carboxylic acid (colorless resin, 73%);

tert-Butyl ester (2S,4R)-4-(tert-butyl-dimethyl-silyloxy)-2-(3,4-dichloro-benzoyl)-2-propyl-pyrrolidin-1-carboxylic acid (colorless oil, 83%);

tert-Butyl ester 2-(3,4-dichloro-benzoyl)-2-propyl-azetidin-1-carboxylic acid (colorless residue, 58%);

tert-Butyl ester 2-(3,4-dichloro-benzoyl)-2-propyl-piperidine-1-carboxylic acid (colorless oil, 80%).

Stage 3 (2-Butyl-pyrrolidin-2-yl)-(3,4-dichloro-phenyl)-methanon

A solution of tert-butyl methyl ether 2-util-2-(3,4-dichloro-benzoyl)-pyrrolidin-1-carboxylic acid (0,435 g of 1.09 mmol) in 1 N. HCl in the Meon (10.9 ml) was stirred at ambient temperature under nitrogen atmosphere for 14 hours. The reaction mixture was concentrated in vacuo, then dissolved in DHM and concentrated in vacuum to remove excess HCl. Purification via chromatography (silica, 0-10% Meon in DHM) gave (2-butyl-pyrrolidin-2-yl)-(3,4-dichloro-phenyl)-methanon (0,249 g, 0,740 mmol, 68%) as a white powder, MS=300 [M+H]+.

Using the appropriate initial matter, likewise received the following connections:

(3,4-is ALOR-phenyl)-(2-propyl-pyrrolidin-2-yl)-methanon (off-white solid, 81%); MS=286 [M+H]+;

(3,4-Dichloro-phenyl)-(2-ethoxymethyl-pyrrolidin-2-yl)-methanon (white solid, 99%); MS=302 [M+H]+;

(3,4-Dichloro-phenyl)-[2-(3,3-debtor-allyl)-pyrrolidin-2-yl]-methanon (white powder, 97%); MS=320 [M+H]+;

(3,4-Dichloro-phenyl)-(5,5-dimethyl-2-propyl-pyrrolidin-2-yl)-methanon (pale yellow powder, 97%); MS=314 [M+H]+;

(3,4-Dichloro-phenyl)-(2-propyl-azetidin-2-yl)-methanon (white powder, 30%) after analytical HPLC purification; MS=272 [M+H]+and

(3,4-Dichloro-phenyl)-(2-propyl-piperidine-2-yl)-methanon (yellow solid, 97%); MS=300 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 10

(4-Amino-3-chloro-phenyl)-(2-butyl-pyrrolidin-2-yl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in scheme R.

Scheme P

Step 1 tert-Butyl ester 2-butyl-2-{[3-chloro-4-(1,1,1,3,3,3-HEXAMETHYL-disilane-2-yl)-phenyl-hydroxy-methyl}-pyrrolidine-1-carboxylic acid

To a stirred solution of 2-(4-bromo-2-chloro-phenyl)-1,1,1,3,3,3-HEXAMETHYL-disilane (0,484 g, 1.38 mmol) in ether (14 ml) at -78°C and in an atmosphere of nitrogen was added tert-utility (2,03 ml, 1.43 M solution in pentane, only 2.91 mmol) dropwise. After 90 minutes a solution of tert-butyl methyl ether 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid is (0,353 g, 1.38 mmol) in ether (3 ml) was added to the reaction mixture dropwise. After one hour the reaction mixture was heated to ambient temperature and was stirred at ambient temperature for 30 minutes. The reaction mixture was suppressed by adding saturated aqueous NH4Cl (10 ml)and was extracted with EtOAc. The combined extracts were washed with saline, then was dried (MgSO4), filtered and concentrated in vacuo to an oil (0.75 g). Purification via chromatography (silica, 5-20% EtOAc in hexano) gave tert-butyl ester 2-butyl-2-{[3-chloro-4-(1,1,1,3,3,3-HEXAMETHYL-disilane-2-yl)-phenyl]-hydroxy-methyl}-pyrrolidine-1-carboxylic acid (0,357 g, 0,678 mmol, 49%) as a colourless oil.

Using the appropriate initial matter, also received the following connections:

tert-Butyl ester 2-{[3-chloro-4-(1,1,1,3,3,3-HEXAMETHYL-disilane-2-yl)-phenyl]-hydroxy-methyl}-2-propyl-pyrrolidin-1-carboxylic acid (colorless foam,43%);

tert-Butyl ester 2-[hydroxy-(1-triisopropylsilyl-1H-indazol-5-yl)-methyl]-2-propyl-pyrrolidin-1-carboxylic acid (yellow foam, 50%);

tert-Butyl ester 2-{[1-(tert-butyl-dimethyl-silanol)-7-fluoro-1H-indol-5-yl]-hydroxy-methyl}-2-propyl-pyrrolidin-1-carboxylic acid (white solid, 49%) and

tert-Butyl ester 2-cyclopropylmethyl-2-[hydroxy-(1-triisopropylsilyl-1H-inditop-5-yl)-IU is Il]-pyrrolidin-1-carboxylic acid (colorless resin, 62%).

Step 2 tert-Butyl ester 2-butyl-2-[3-chloro-4-(1,1,1,3,3,3-HEXAMETHYL-disilane-2-yl)-benzoyl]-pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl methyl ether 2-butyl-2-{[3-chloro-4-(1,1,1,3,3,3-HEXAMETHYL-disilane-2-yl)-phenyl]-hydroxy-methyl}-pyrrolidine-1-carboxylic acid (0,357 g, 0,678 mmol) in DHM (10 ml) at ambient temperature under nitrogen atmosphere was added DMP (0,575 g of 1.36 mmol) at once. After one hour the reaction mixture was diluted DHM, washed with 1 N. NaOH and brine, then dried (MgSO4), filtered and concentrated in vacuo to a brown residue (0,290 g). Purification via chromatography (silica, 10% EtOAc in hexano) gave tert-butyl ester 2-butyl-2-[3-chloro-4-(1,1,1,3,3,3-HEXAMETHYL-disilane-2-yl)-benzoyl]-pyrrolidin-1-carboxylic acid (0,208 g, 0,397 mmol, 58%) as a clear, colorless residue.

Using the appropriate initial matter, also received the following connections:

tert-Butyl ester 2-[3-chloro-4-(1,1,1,3,3,3-HEXAMETHYL-disilane-2-yl)-benzoyl]-2-propyl-pyrrolidin-1-carboxylic acid (yellow oil, 96%);

tert-Butyl ester 2-propyl-2-(1-triisopropylsilyl-1H-indazol-5-carbonyl)-pyrrolidin-1-carboxylic acid (yellow foam, 77%);

tert-Butyl ester 2-[1-(tert-butyl-dimethyl-silanol)-7-fluoro-1H-indole-5-carbonyl]-2-propyl-pyrrolidin-1-carboxylic acid (jaltemba, 75%);

tert-Butyl ester 2-cyclopropylmethyl-2-(1-triisopropylsilyl-1H-indazol-5-carbonyl)-pyrrolidin-1-carboxylic acid (colorless resin, 27%).

Stage 3 (4-Amino-3-chloro-phenyl)-(2-butyl-pyrrolidin-2-yl)-methanon

A solution of tert-butyl methyl ether 2-butyl-2-[3-chloro-4-(1,1,1,3,3,3-HEXAMETHYL-disilane-2-yl)-benzoyl]-pyrrolidin-1-carboxylic acid (0,205 g, 0,391 mmol) in methanol 1 N. HCl (7.8 ml) was stirred at 50°C. in a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated in vacuo, which gave (4-amino-3-chloro-phenyl)-(2-butyl-pyrrolidin-2-yl)-methanon (0,249 g, quantitative yield) as a light brown powder and monochloroborane salt.

Using the appropriate initial matter, also received the following compounds according to the above procedure:

(4-amino-3-chloro-phenyl)-(2-propyl-pyrrolidin-2-yl)-methanon, (beige solid, 83%), MS=267 [M+H]+;

(1H-Indazol-5-yl)-(2-propyl-pyrrolidin-2-yl)-methanon, (yellow solid, 57%), MS=258 [M+H]+;

(7-Fluoro-1H-indol-5-yl)-(2-propyl-pyrrolidin-2-yl)-methanon, (light brown foam, 60%), MS=275 [M+H]+;

(2-Cyclopropylmethyl-pyrrolidin-2-yl)-(1H-indazol-5-yl)-methanon, (white powder, 99%), MS=270 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 11

(2-Propyl-pyrrolidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in scheme C.

Scheme

Step 1 tert-Butyl ester 2-[hydroxy-(1-triisopropylsilyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-methyl]-2-propyl-pyrrolidin-1-carboxylic acid

To a stirred solution of 5-bromo-1-triisopropylsilyl-1H-pyrrolo[2,3-b]pyridine (0,587 g of 1.66 mmol) in ether (20 ml) at -78°C and in an atmosphere of nitrogen was added tert-utility (2.30 ml 1,51 M solution in pentane, to 3.49 mmol) dropwise. After 90 minutes a solution of tert-butyl methyl ether 2-formyl-2-propyl-pyrrolidin-1-carboxylic acid (0.400 g, of 1.66 mmol) in ether (1 ml) was added to the reaction mixture dropwise. After stirring for one hour the reaction mixture was heated to ambient temperature for 30 minutes. The reaction mixture was suppressed by adding saturated aqueous NH4Cl (20 ml), then was extracted with EtOAc. The combined extracts were washed with saturated aqueous NaHCO3and brine, then dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (0,90 g). Purification via chromatography (silica, 5-20% EtOAc in hexano) gave tert-butyl ester 2-[hydroxy-(1-triisopropylsilyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-methyl]-2-propyl-pyrrolidin-1-carboxylic acid (0,576 g, 1.12 mmol, 53%) as a colourless resin.

Using the appropriate initial matter, also received the following connections:

tert-Butyl ester 2-[hydroxy-(1-triisopropylsilyl-1H-indazol-5-yl)-methyl]-2-isopropoxyphenyl-pyrrolidin-1-carboxylic acid (yellow oil, 79%), and

tert-Butyl ester 2-[hydroxy-(1-triisopropylsilyl-1H-indazol-5-yl)-methyl]-2-isobutyl-pyrrolidin-1-carboxylic acid (colorless oil, 56%).

Step 2 tert-Butyl ester 2-propyl-2-(1-triisopropylsilyl-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl methyl ether 2-[hydroxy-(1-triisopropylsilyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-methyl]-2-propyl-pyrrolidin-1-carboxylic acid (0,528 g of 1.03 mmol) in DHM (15 ml) at ambient temperature under nitrogen atmosphere was added DMP (0,652 g, 1.54 mmol) at once. After 90 minutes the reaction mixture was diluted DHM, washed with 1 N. NaOH and brine, then dried (MgSO4), filtered and concentrated in vacuo to a brown oil. Purification via chromatography (silica, 5-10% EtOAc in hexano) gave tert-butyl ester 2-propyl-2-(1-triisopropylsilyl-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-pyrrolidin-1-carboxylic acid (0,415 g, 0,809 mmol, 79%) as a yellow resin.

Using the appropriate initial matter, also received the following connections:

tert-Butyl ester 2-isopropoxyphenyl-2-(1-triisopropylsilyl-1H-indazol-5-carbonyl)-pyrrolidin-1-carboxylic acid (yellow solid, 96%) and

tert-Butyl ester 2-isobutyl-2-(1-triisopropylsilyl-1H-indazol-5-carbonyl)-pyrrolidin-1-carboxylic acid (colorless resin, 49%).

Step 3 tert-Butyl ester 2-propyl-2-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl methyl ether 2-propyl-2-(1-triisopropylsilyl-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-pyrrolidin-1-carboxylic acid (0,415 g, 0,809 mmol) in THF (7.5 ml) at ambient temperature under nitrogen atmosphere was added TMAP (0,753 g of 8.09 mmol). The reaction mixture was stirred for one hour, then was diluted with saturated aqueous NaHCO3(30 ml) and water (15 ml) and was extracted with EtOAc. The combined organic extracts were washed with saline, dried (MgSO4), filtered and concentrated in vacuo to a pale yellow resin. Purification via chromatography (silica, 50-100% EtOAc in hexano) gave tert-butyl ester 2-propyl-2-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-pyrrolidin-1-carboxylic acid (0,247 g, 0,692 mmol, 86%) as a colourless foam.

Using the appropriate initial matter, also received the following connections:

tert-Butyl ester 2-(1H-indazol-5-carbonyl)-2-isopropoxyphenyl-pyrrolidin-1-carboxylic acid (white foam, 68%);

tert-Butyl ester 2-(1H-indazol-5-carbonyl)-2-isobutyl-pyrrolidin-1-carboxylic acid (is ELTA foam, 30%);

tert-Butyl ester (2R,4R)-2-(3,4-dichloro-benzoyl)-4-hydroxy-2-propyl-pyrrolidin-1-carboxylic acid (colorless residue, 79%);

tert-Butyl ester (2S,4R)-2-(3,4-dichloro-benzoyl)-4-hydroxy-2-propyl-pyrrolidin-1-carboxylic acid (colorless resin, 79%).

Stage 4 (2-Propyl-pyrrolidin-2-yl)-(1H-pyrrolo[2,3-b]pyridine-5-yl)-methanon

A solution of tert-butyl methyl ether 2-propyl-2-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-pyrrolidin-1-carboxylic acid (0,240 g, 0,672 mmol) in 1 N. methanolic HCl (10.1 ml) was stirred at 20°C. in a nitrogen atmosphere for 18 hours. The reaction mixture was concentrated in vacuo, then triturated with DHM (5 ml) and concentrated in vacuum, obtaining (2-propyl-pyrrolidin-2-yl)-(1H-pyrrolo[2,3-b]pyridine-5-yl)-methanon (0,215 g, 0,652 mmol, 97%) as a white powder and as monochloromethane salt, MS=258 [M+H]+.

Using the appropriate initial matter, also received the following connections:

(1H-Indazol-5-yl)-(2-isopropoxyphenyl-pyrrolidin-2-yl)-methanon (white solid, 94%), MS=288 [M+H]+;

(1H-Indazol-5-yl)-(2-isobutyl-pyrrolidin-2-yl)-methanon (yellow powder, 100%), MS=272[M+H]+;

(3,4-Dichloro-phenyl)-((2R,4R)-4-hydroxy-2-propyl-pyrrolidin-2-yl)-methanon (white solid, 61%), MS=302 [M+H]+and

(3,4-Dichloro-phenyl)-((2S,4R)-4-hydroxy-2-propyl-pyrrolidin-2-yl)-methanon (white solid, 97%), MS=302 [M+H]+.

Consequently, the sustained fashion connection obtained according to the above procedure are shown in table 1.

Example 12

(5,6-Dichloro-pyridine-2-yl)-(2-propyl-pyrrolidin-2-yl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in scheme I.

The T

Step 1 tert-Butyl ester 2-[(5,6-dichloro-pyridine-2-yl)-hydroxy-methyl]-2-propyl-pyrrolidin-1-carboxylic acid

To a stirred solution of 2-bromo-5,6-dichloro-pyridine (0,500 g of 2.20 mmol) in THF (6 ml) at 0°C and under nitrogen atmosphere was added isopropylaniline (1,21 ml of 2 M solution in THF, to 2.42 mmol) dropwise. After 2 hours a solution of tert-butyl methyl ether 2-formyl-2-propyl-pyrrolidin-1-carboxylic acid (MX 0.317 g of 1.32 mmol) in THF (1 ml) was added to the reaction mixture dropwise. After 30 minutes the reaction mixture was heated to ambient temperature and was stirred for one hour, then extinguished by adding saturated aqueous NH4Cl (10 ml)and was extracted with EtOAc. The combined organic extracts were washed with saline, dried (MgSO4), filtered and concentrated in vacuum. Purification of the residue by chromatography (silica, 0-40% EtOAc in hexano) gave tert-butyl ester 2-[(5,6-dichloro-pyridine-2-yl)-hydroxy-methyl]-2-propyl-pyrrolidin-1-carboxylic acid (0,289 g, 0,745 mmol, 56%) as a yellow oil and as ner is delimas a mixture of diastereoisomers.

Using the appropriate source materials, tert-butyl ester 2-[(4,5-dichloro-pyridine-2-yl)-hydroxy-methyl]-2-propyl-pyrrolidin-1-carboxylic acid (orange oil, 19%) was also obtained using the above procedure.

Step 2 tert-Butyl ester 2-(5,6-dichloro-pyridine-2-carbonyl)-2-propyl-pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl ester 2-[(5,6-dichloro-pyridine-2-yl)-hydroxy-methyl]-2-propyl-pyrrolidin-1-carboxylic acid (in 0.288 g, 0,742 mmol) in DHM (12 ml) at 0°C under nitrogen atmosphere was added DMP (0,315 g, 0,742 mmol) at once. The reaction mixture was stirred for one hour, then extinguished with a mixture of 1:1 10% aqueous Na2S2O3and saturated aqueous NaHCO3(50 ml) and was extracted with DHM (3×30 ml). The combined organic phases were concentrated in vacuo, which gave tert-butyl ester 2-(5,6-dichloro-pyridine-2-carbonyl)-2-propyl-pyrrolidin-1-carboxylic acid (0,280 g, 0,725 mmol, 98%) as a yellow solid, which was directly used without further purification.

Using the appropriate source materials, tert-butyl ester 2-(4,5-dichloro-pyridine-2-carbonyl)-2-propyl-pyrrolidin-1-carboxylic acid (colorless oil, 43%) was also obtained.

Stage 3 (5,6-Dichloro-pyridine-2-yl)-(2-propyl-pyrrolidin-2-yl)-methanon

A solution of tert-butyl methyl ether 2-(5,6-dichloro-PI is one-2-carbonyl)-2-propyl-pyrrolidin-1-carboxylic acid (0,280 g, 0,725 mmol) in 1 N. HCl in the Meon (3 ml) was stirred at ambient temperature under nitrogen atmosphere for 20 hours. The reaction mixture was concentrated in vacuo and the resulting residue was purified by chromatography (silica, 0-30% Meon in DHM), which gave (5,6-dichloro-pyridine-2-yl)-(2-propyl-pyrrolidin-2-yl)-methanon (0.167 g, 0,522 mmol, 72%) as a yellow solid and as monochloromethane salt, MS=287 [M+H]+.

Using the appropriate starting material, (4,5-dichloro-pyridine-2-yl)-(2-propyl-pyrrolidin-2-yl)-methanon (yellow resin, 37%) was also obtained, MS=287 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 13

(3,4-Dichloro-5-fluoro-phenyl)-(2-propyl-pyrrolidin-2-yl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in the diagram U.

Scheme

Step 1 tert-Butyl ester 2-[(3,4-dichloro-5-fluoro-phenyl)-hydroxy-methyl]-2-propyl-pyrrolidin-1-carboxylic acid

Stir a mixture of 3,4-dichloro-5-forprivate (1,38 g, to 5.66 mmol) and magnesium turnings (0,145 g, 5,94 mmol) in THF (8 ml) was heated under reflux in nitrogen atmosphere for 30 minutes, then was cooled to 0°C. To the reaction mixture solution was added tert-butyl ester 2-formyl-2-propyl-feast is ridin-1-carboxylic acid (0,682 g, of 2.38 mmol) in THF (2 ml) dropwise within 15 minutes. The cold reaction mixture was stirred for one hour, then extinguished by adding saturated aqueous NH4Cl (20 ml)and was extracted with EtOAc. The combined organic extracts were washed with saline, dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (1.7 g). Purification via chromatography (silica, 0-20% EtOAc in hexano) gave tert-butyl ester 2-[(3,4-dichloro-5-fluoro-phenyl)-hydroxy-methyl]-2-propyl-pyrrolidin-1-carboxylic acid (0,571 g of 1.41 mmol, 50%) as a white solid.

Step 2 tert-Butyl ester 2-(3,4-dichloro-5-fluoro-benzoyl)-2-propyl-pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl ester 2-[(3,4-dichloro-5-fluoro-phenyl)-hydroxy-methyl]-2-propyl-pyrrolidin-1-carboxylic acid (of 0.533 g of 1.31 mmol) in DHM (20 ml) at 0°C under nitrogen atmosphere was added DMP (0,557 g, 1.55 mmol) in one part. The reaction mixture was heated to ambient temperature and was stirred for 90 minutes. Added the second part of the DMP (0,110 g, 0.26 mmol) and the reaction mixture was stirred for 30 minutes, then diluted DHM, washed with 1 N. NaOH, brine (20 ml), dried (MgSO4), filtered and concentrated in vacuo to a clear, colorless oil (0.55 g). Purification via chromatography (silica, 5-20% EtOAc is hexano) gave tert-butyl ester 2-(3,4-dichloro-5-fluoro-benzoyl)-2-propyl-pyrrolidin-1-carboxylic acid (0,358 g, 0,886 mmol, 68%) as a colorless transparent resin.

Stage 3 (3,4-Dichloro-5-fluoro-phenyl)-(2-propyl-pyrrolidin-2-yl)-methanon

A solution of tert-butyl methyl ether 2-(3,4-dichloro-5-fluoro-benzoyl)-2-propyl-pyrrolidin-1-carboxylic acid (0,346 g, 0,856 mmol) in 1 N. methanolic HCl (8.6 ml) was stirred at ambient temperature under nitrogen atmosphere for 15 hours. The reaction mixture was concentrated in vacuo, then dissolved in DHM and again concentrated in vacuo to remove excess HCl, receiving (3,4-dichloro-5-fluoro-phenyl)-(2-propyl-pyrrolidin-2-yl)-methanon (0,294 g, quantitative yield) as a white powder, MS=304 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 14

(3,4-Dichloro-phenyl)-((2R,4S)-4-fluoro-2-propyl-pyrrolidin-2-yl)-methanon and

(3,4-dichloro-phenyl)-((2S,4S)-4-fluoro-2-propyl-pyrrolidin-2-yl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in scheme F.

Scheme f

Step 1 tert-Butyl ether (R)-4-(tert-butyl-dimethyl-Tepanyaki)-2-propyl-2-[(3,4-dichloro-phenyl)-hydroxy-methyl-pyrrolidin-1-carboxylic acid

tert-Butyl ether (R)-4-(tert-butyl-dimethyl-silyloxy)-2-propyl-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyrrolidin-1-carboxylic acid was obtained by the reaction of 3,4-DIH is organicmineral with tert-butyl ether (R)-4-(tert-butyl-dimethyl-silyloxy)-2-formyl-2-propyl-pyrrolidin-1-carboxylic acid, following the procedure of stage 1 of example 11.

Step 2 tert-Butyl ether (R)-4-(tert-butyl-dimethyl-silyloxy)-2-propyl-2-(3,4-dichloro-benzoyl)-pyrrolidin-1-carboxylic acid

tert-Butyl ether (R)-4-(tert-butyl-dimethyl-silyloxy)-2-propyl-2-(3,4-dichloro-benzoyl)-pyrrolidin-1-carboxylic acid was obtained during the oxidation of the tert-butyl ester (R)-4-(tert-butyl-dimethyl-silyloxy)-2-propyl-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyrrolidin-1-carboxylic acid with DMP, following the procedure of step 2 of example 11.

Step 3 tert-Butyl ether (R)-2-(3,4-dichloro-benzoyl)-4-hydroxy-2-propyl-pyrrolidin-1-carboxylic acid

tert-Butyl ether (R)-2-(3,4-dichloro-benzoyl)-4-hydroxy-2-propyl-pyrrolidin-1-carboxylic acid was obtained by treatment of tert-butyl methyl ether (R)-4-(tert-butyl-dimethyl-silyloxy)-2-propyl-2-(3,4-dichloro-benzoyl)-pyrrolidin-1-carboxylic acid with TMAP, following the procedure of stage 3 of example 11.

Stage 4 tert-Butyl ether (S)-2-(3,4-dichloro-benzoyl)-4-fluoro-2-propyl-pyrrolidin-1-carboxylic acid

To a stirred solution of tert-butyl methyl ether (R)-2-(3,4-dichloro-benzoyl)-4-hydroxy-2-propyl-pyrrolidin-1-carboxylic acid (0,222 g, 0,554 mmol) in THF (3 ml) at ambient temperature under nitrogen atmosphere was added performancemonitoring (of € 0.195 ml, 1.11 mmol), digidropiridilidyen (0,181 ml, 1.11 mmol) and triethylamine (and 0.46 ml of 3.32 mmol. The reaction mixture was stirred for 18 hours, then filtered through a pad of silica, washed with EtOAc and concentrated in vacuo, which gave tert-butyl ether (S)-2-(3,4-dichloro-benzoyl)-4-fluoro-2-propyl-pyrrolidin-1-carboxylic acid (0,222 g, 0,551 mmol, 99%) as a yellow foam which was used directly in the next stage without additional purification.

Stage 5 (3,4-Dichloro-phenyl)-((2R,4S)-4-fluoro-2-propyl-pyrrolidin-2-yl)-methanon and (3,4-dikhlaa-phenyl)-((2S,4S)-4-fluoro-2-propyl-pyrrolidin-2-yl)-methanon

A solution of tert-butyl methyl ether (S)-2-(3,4-dichloro-benzoyl)-4-fluoro-2-propyl-pyrrolidin-1-carboxylic acid (0,220 g, 0,545 mmol) in 1 N. methanolic HCl (3 ml) was stirred at 20°C. in a nitrogen atmosphere for 18 hours. The reaction mixture was concentrated in vacuo, then purified via chromatography (silica, 0-20% Meon in DHM), which gave (3,4-dichloro-phenyl)-((2R,4S)-4-fluoro-2-propyl-pyrrolidin-2-yl)-methanon (0,048 g, 0,158 mmol, 29%) as the first fraction (yellow oil), then (3,4-dichloro-phenyl)-((2S,4S)-4-fluoro-2-propyl-pyrrolidin-2-yl)-methanon (0,072 g, 0,238 mmol, 44%) as the second fraction (yellow oil), each in the form of monochloroborane salt, MS=304 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 15

(1H-Indol-5-yl)-(2-propyl-pyrrolidin-2-yl)-methanon

The% is ur synthesis, described in this example was carried out according to the method shown in scheme X.

Scheme X

Step 1 tert-Butyl ester 5-[(1-tert-butoxycarbonyl-2-propyl-pyrrolidin-2-yl)-hydroxy-methyl]-indole-1-carboxylic acid

To a stirred solution of tert-butyl ester 5-bromo-indole-1-carboxylic acid (0,700 g, is 2.37 mmol) in ether (20 ml) at -78°C and in an atmosphere of nitrogen was added tert-utility (3,64 ml 1.43 M solution in pentane, to 5.21 mmol) dropwise. After 30 minutes a solution of tert-butyl methyl ether 2-formyl-2-propyl-pyrrolidin-1-carboxylic acid (0,569 g, is 2.37 mmol) in ether (5 ml) was added to the reaction mixture dropwise. The reaction mixture was stirred for one hour, then extinguished by adding saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3and brine, then dried (MgSO4), filtered and concentrated in vacuum. Purification via chromatography (silica, 0 to 60% EtOAc in hexano) gave tert-butyl ester 5-[(1-tert-butoxycarbonyl-2-propyl-pyrrolidin-2-yl)-hydroxy-methyl]-indole-1-carboxylic acid (0,466 g of 1.02 mmol, 43%) as a yellow oil.

Step 2 tert-Butyl ester 5-(1-tert-butoxycarbonyl-2-propyl-pyrrolidin-2-carbonyl)-indole-1-carboxylic acid

To a stirred solution of tert-is etilovogo ester 5-[(1-tert-butoxycarbonyl-2-propyl-pyrrolidin-2-yl)-hydroxy-methyl]-indole-1-carboxylic acid (0,460 g, 1.00 mmol) in DHM (10 ml) at 0°C under nitrogen atmosphere was added DMP (0,652 g, 1.54 mmol) at once. The reaction mixture was heated to ambient temperature and was stirred for 90 minutes, then diluted DHM, washed with a mixture of 1:1 10% aqueous Na2S2O5and NaHCO3(50 ml), then brine, then dried (MgSO4), filtered and concentrated in vacuo to a yellow oil. Purification via chromatography (silica, 0-80% EtOAc in hexano) gave tert-butyl ester 5-(1-tert-butoxycarbonyl-2-propyl-pyrrolidin-2-carbonyl)-indole-1-carboxylic acid (0,132 g, 0,289 mmol, 29%) as a yellow oil.

Stage 3 (1H-Indol-5-yl)-(2-propyl-pyrrolidin-2-yl)-methanon

To a stirred solution of tert-butyl ester 5-(1-tert-butoxycarbonyl-2-propyl-pyrrolidin-2-carbonyl)-indole-1-carboxylic acid (0,132 g, 0,289 mmol) in DHM (3 ml) at 20°C in an atmosphere of nitrogen was added TFU (1 ml). After 14 hours the reaction mixture was extinguished saturated aqueous NaHCO3and were extracted DHM. The combined organic phases were concentrated in vacuo, then purified via chromatography (silica, 0-30% Meon in DHM), receiving (1H-indol-5-yl)-(2-propyl-pyrrolidin-2-yl)-methanon (0,053 g, 0,207 mmol, 72%) as a beige foam, MS=257 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

P the emer 16

Exo-(3,4-Dichloro-phenyl)-(2-propyl-8-Aza-bicyclo[3.2.1]Oct-2-yl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in scheme C.

Scheme C

Step 1 tert-Butyl ester 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid

Hydrochloride 8-azabicyclo[3.2.1]Octan-3-one (hydrochloride of nortropinone, 10.0 g, 62 mmol) was dissolved in 1,4-dioxane (200 ml) and water (50 ml). N,N-diisopropylethylamine (20,0 g, 155 mmol) and di-tert-BUTYLCARBAMATE (20,3 g, 93 mmol) was added and the reaction mixture was stirred at room temperature for three hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (silica gel, ethyl acetate/hexane)gave tert-butyl ester 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid as off-white solids, 14 g (yield 99%).

Stage 2 8-tert-Butyl ester 2-methyl ester of 3-hydroxy-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid

tert-Butyl ester 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid from step 1 (14.1 g, 62 mmol) was dissolved in cyclohexane (550 ml)to which was added dimethylcarbonate (12.4 g, mol), then sodium hydride (5.0 g, 125 mmol) and methanol (0.2 ml). The reaction mixture was stirred at reflux for 15 hours, then cooled to room temperature and added water (25 ml). The reaction mixture was concentrated under reduced pressure to a volume of 50 ml, which was then divided between ethyl acetate and saturated aqueous ammonium chloride. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (silica gel, ethyl acetate/hexane)gave 8-tert-butyl ester 2-methyl ester of 3-hydroxy-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid as a pale yellow oil (15,4 g, yield 87%).

Stage 3 8-tert-Butyl ether Exo-2-methyl ester of endo-3-hydroxy-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid

8-tert-Butyl ester 2-methyl ester of 3-hydroxy-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid from stage 2 (15,4 g, 54 mmol) was dissolved in methanol (350 ml). The resulting solution was cooled in a bath of dry ice/acetonitrile (-45°C). Sodium borohydride (5,15 g, 136 mmol, 10-40 mesh) was added and the reaction mixture was stirred at -45°C for 1.5 hours, after which was added a saturated aqueous ammonium chloride (50 ml). The mixture was heated to room is temperature and then concentrated under reduced pressure to a volume of 50 ml, which was then divided between dichloromethane and saturated aqueous ammonium chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (silica gel, ethyl acetate/hexane)gave 8-tert-butyl ether Exo-2-methyl ester of endo-3-hydroxy-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid as a colourless oil (8.1 g, yield 52%).

Stage 4 8-tert-Butyl ester 2-methyl ester 8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid

8-tert-Butyl ether Exo-2-methyl ester of endo-3-hydroxy-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid from step 3 (8,1 g, 28 mmol) was dissolved in 1,2-dichloroethane (120 ml)to which was added triethylamine (17,2 g, 170 mmol) and triperoxonane anhydride (17.8 g, 85 mmol). The reaction mixture was stirred at room temperature for 15 hours, then was added aqueous saturated sodium bicarbonate (150 ml) and dichloromethane (280 ml). The organic phase was separated and washed with saline. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (silica gel, ethyl acetate/hexane)gave 8-tert-butyl ester 2-methyl ester 8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid in the form of altago oil (6.0 g, yield 79%).

Stage 5 8-tert-Butyl ester 2-methyl ester 8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid

8-tert-Butyl ester 2-methyl ester 8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid from step 4 (5.9 g, 22 mmol) was dissolved in ethanol (100 ml)to which was added palladium (10% on charcoal, 0,59 g). The resulting mixture was shaken in a hydrogen atmosphere (50 psi) for 2 hours at room temperature, then filtered through a layer of celite, which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the resulting residue was purified using flash chromatography (silica gel, ethyl acetate/hexane)gave 8-tert-butyl ester 2-methyl ester 8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid in a mixture of endo and Exo isomers as a colorless oil (5.8 g, yield 97%).

Stage 6 8-tert-Butyl ester 2-propyl-8-Aza-bicyclo[3.2.1]octane-2,8-dicarboxylic acid

8-tert-Butyl ester 2-methyl ester 8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid in a mixture of endo and Exo isomers from step 5 (1.0 g, 3.7 mmol) was dissolved in tetrahydrofuran (30 ml) was added 1-jumprope (3.2 g, 19 mmol). The resulting solution was cooled to -76°C. and treated dropwise over 15 minutes a solution of bis(trimethylsilyl)amide potassium in toluene (0.5 M, 11,1 ml, 5.6 mmol). Continued to be stirred at -76°C within 1.5 hours and then the reaction mixture was slowly heated to 0°C for 3 hours. Was added a saturated aqueous ammonium chloride and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (silica gel, ethyl acetate/hexane)gave 8-tert-butyl ester 2-methyl ester 2-propyl-8-Aza-bicyclo[3.2.1]octane-2,8-dicarboxylic acid in a mixture of endo and Exo isomers in the form of a pale yellow oil (0,99 g, yield 85%).

Stage 7 tert-Butyl ester 2-hydroxymethyl-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid

8-tert-Butyl ester 2-methyl ester 2-propyl-8-Aza-bicyclo[3.2.1]octane-2,8-dicarboxylic acid (mixture of endo and Exo isomers from step 6, and 0.98 g, 3.1 mmol) was dissolved in tetrahydrofuran (15 ml) and the resulting mixture was cooled to 0°C. a Solution of lithium aluminum hydride in tetrahydrofuran (1 M, 3.3 ml, 3.3 mmol) in tetrahydrofuran was added dropwise within 10 minutes and continued to stir at 0°C for 1.5 hours. A saturated aqueous solution of tartrate of potassium-sodium (10 ml) was added, and the mixture was heated to room temperature and was stirred for 15 hours. Additional saturated aqueous solution of tartrate of potassium-sodium (10 ml) was added and the mixture was extracted with ethyl acetate. Obyedinenny the organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (silica gel, ethyl acetate/hexane)gave tert-butyl ester 2-hydroxymethyl-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid in the form of a separable mixture of endo and Exo isomers, both as colourless oils (0,68 g and 0.17 g, yield 76% and 19%, respectively).

Stage 8 tert-Butyl ether Exo-2-formyl-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid

tert-Butyl ether Exo-2-hydroxymethyl-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid from step 7 (of 0.67 g, 2.4 mmol) was dissolved in dichloromethane (25 ml). The solution was cooled to 0°C and added periodinane dessa-Martin (1.0 g, 2.4 mmol). Continued to stir for 5 minutes at 0°C., then 1.5 hours at room temperature. To the reaction mixture were added diethyl ether (50 ml) and aqueous sodium hydroxide (1 M, 20 ml), then additional diethyl ether (30 ml). The phases were separated and the organic phase is washed with water and brine. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified using flash chromatography (silica gel, ethyl acetate/hexane)gave tert-butyl ether Exo-2-formyl-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid as a colorless oil (0.6 g, yield 90%).

Stage 9 tert-Butyl ether Exo-2-[(3,4-dichlorophenyl)-hydroxymethyl]-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid

tert-Butyl ether Exo-2-formyl-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid from step 8 (0.45 g, 16 mmol) was dissolved in tetrahydrofuran (4 ml). The resulting solution was cooled to 0°C and a solution of 3,4-dichlorophenylisocyanate in tetrahydrofuran (0.5 M, 6.4 ml, 3.2 mmol) was added dropwise over 10 minutes. Continued to stir at 0°C for 1.5 hours, then was added aqueous saturated ammonium chloride (20 ml). The resulting mixture was extracted with ethyl acetate, the combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (silica gel, ethyl acetate/hexane)gave tert-butyl ether Exo-2-[(3,4-dichlorophenyl)-hydroxymethyl]-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid in the form of a mixture of epimeres in the form of a white solid substance (or 0.57 g, yield 83%).

Stage 10 tert-Butyl ether Exo-2-(3,4-dichlorobenzoyl)-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid

tert-Butyl ether Exo-2-[(3,4-dichlorophenyl)-hydroxymethyl]-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid in the form of a mixture of epimeres with stage 9 (0.56 g, 1.3 mmol suspended in acetonitrile (14 ml). Added dichloromethane (4 ml) and the resulting homogeneous solution was added periodinane dessa-Martin (0.56 g, 1.3 mmol), then stirred at room temperature for 1 hour. To the reaction mixture were added diethyl ether (80 ml) and aqueous sodium hydroxide (1 M, 20 ml). The phases were separated, and the combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (silica gel, ethyl acetate/hexane)gave tert-butyl ether Exo-2-(3,4-dichlorobenzoyl)-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid as off-white solids (0,53 g, yield 95%).

Stage 11 Exo-(3,4-Dichloro-phenyl)-(2-propyl-8-azabicyclo[3.2.1]Oct-2-yl)methanon

tert-Butyl ether Exo-2-(3,4-dichlorobenzoyl)-2-propyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid from step 10 (0.15 g, 0.35 mmol) was dissolved in a solution of hydrogen chloride in methanol (1 M, 3.5 ml) and the resulting solution was stirred at 40°C for two hours. The reaction mixture was concentrated under reduced pressure, obtaining hydrochloride Exo-(3,4-dichloro-phenyl)-(2-propyl-8-azabicyclo[3.2.1]Oct-2-yl)methanone in the form of a white foam (0,13 g, yield 99%).

This way of tert-butyl methyl ether, endo-2-hydroxymethyl-2-propyl-8-azabicyclo[3.2.1]octane-8-arbonboy acid with stage 7, following stages 8-11, got hydrochloride endo-(3,4-dichloro-phenyl)-(2-propyl-8-azabicyclo[3.2.1]Oct-2-yl)methanone, MS=326 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 17

(5-fluoro-1H-indol-2-yl)-(4-propyl-piperidine-4-yl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in scheme H.

Scheme H

Stage 1 1-Benzazolyl-5-fluoro-1H-indol

To a cooled to 0°C solution of 5-farindola (10 g, 74 mmol) and tetrabutylammonium hydrosulfate (3.8 g, 11 mmol) in 200 ml of toluene was added 200 ml of 50% aqueous NaOH was then added benzosulphochloride (14 ml, 111 mmol). The reaction mixture was heated to room temperature over night. The reaction mixture was extracted with ethyl acetate and washed with 1 M HCl, aqueous sodium bicarbonate, water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The remaining residue was recrystallized from ethyl acetate and hexanol, receiving 19 g (yield 96%) 1-benzazolyl-5-fluoro-1H-indole as a white crystalline solid.

Step 2 tert-Butyl ester 4-[(1-benzazolyl-5-fluoro-1H-indol-2-yl)-hydroxy-methyl]-4-propyl-piperidine-1-carboxylic acid

To a cooled to -78°C rest the ru 1-benzazolyl-5-fluoro-1H-indole (539 mg, a 1.96 mmol) in 30 ml THF was slowly added t-BuLi (1.5 ml, 2.54 mmol). The reaction mixture was stirred for 30 minutes, then the solution was added tert-butyl ester 4-formyl-4-propyl-piperidine-1-carboxylic acid (500 mg, a 1.96 mmol) in 5 ml of THF. The reaction mixture was stirred for 2 hours at -78°C, then warmed up to -20°C and extinguished saturated aqueous ammonium chloride. The reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with saline, dried (MgSO4), filtered and concentrated on the silicon dioxide. Substance chromatographically through 25 g column from Thomson, elwira 20% ethyl acetate, 80% hexane getting tert-butyl ester 4-[(1-benzazolyl-5-fluoro-1H-indol-2-yl)-hydroxy-methyl]-4-propyl-piperidine-1-carboxylic acid (319 mg, 0.6 mmol) with a yield of 53% in the form of a beige foam.

Step 3 tert-Butyl ester 4-(1-benzazolyl-5-fluoro-1H-indole-2-carbonyl)-4-propyl-piperidine-1-carboxylic acid

To a solution of tert-butyl ester 4-[(1-benzazolyl-5-fluoro-1H-indol-2-yl)-hydroxy-methyl]-4-propyl-piperidine-1-carboxylic acid (319 mg, 0.6 mmol) in 20 ml of dichloromethane was added periodinane dessa-Martin (255 mg, 0.6 mmol). The reaction mixture was stirred for 30 minutes at room temperature, then put the mixture 1:1 with 5% aqueous Na2S2O3: saturated aqueous NaHCO3 . The mixture was stirred to dissolve all solids, then was extracted with diethyl ether. The combined organic layers were washed with saturated aqueous NaHCO3and brine, dried (MgSO4), filtered and concentrated in vacuo gave the crude tert-butyl ether 4-(1-benzazolyl-5-fluoro-1H-indole-2-carbonyl)-4-propyl-piperidine-1-carboxylic acid (300 mg, or 0.57 mmol) as a beige solid with a yield of 95%.

Stage 4 tert-Butyl ester 4-(5-fluoro-1H-indole-2-carbonyl)-4-propyl-piperidine-1-carboxylic acid

To a solution of tert-butyl ester 4-(1-benzazolyl-5-fluoro-1H-indole-2-carbonyl)-4-propyl-piperidine-1-carboxylic acid (290 mg, 0.55 mmol) in 30 ml of methanol was added 10 ml of 1 M NaOH. The reaction mixture was heated up to 80°C and was stirred for one hour, then concentrated in vacuo to remove the methanol. The remaining residue was extracted with ethyl acetate and the combined organic layers were washed with saline, dried (MgSO4), filtered and concentrated in vacuum, receiving a yellow oil. The oil was chromatographically through 12 g SiO2column elwira 20% ethyl acetate, 80% hexane getting 162 mg tert-butyl ester 4-(5-fluoro-1H-indole-2-carbonyl)-4-propyl-piperidine-1-carboxylic acid as a white solid with a yield of 76%.

One hundred is s 5 (5-fluoro-1H-indol-2-yl)-(4-propyl-piperidine-4-yl)-methanon

162 mg of tert-Butyl ester 4-(5-fluoro-1H-indole-2-carbonyl)-4-propyl-piperidine-1-carboxylic acid was dissolved in 1 M methanolic HCl and stirred at room temperature for 24 hours. The solvent was removed, getting the oil, which was besieging of diethyl ether, which gave 132 mg hydrochloride (5-fluoro-1H-indol-2-yl)-(4-propyl-piperidine-4-yl)-methanone in the form of a solid substance with a yield of 97%, MS=289 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 18

(4-Propyl-piperidine-4-yl)-quinoline-2-yl-metano

The synthesis procedure described in this example were carried out according to the method shown in scheme W.

Scheme sh

Stage 1 2-Athineon

2-Athineon received according to the procedure Kimber et al. (Tetrahedron 2000, 56, 3575). To a solution of 2-chlorhydrin (10.0 g, is 61.5 mmol) in CH3CN (100 ml) was added sodium iodide (14 g, 92,3 mmol) and acetylchloride (8,8 ml, 123 mmol). The reaction mixture was stirred at 100°C for 5 hours, then cooled to room temperature and extinguished 10% aqueous K2CO3(100 ml) and 5% aqueous NaHSO3(50 ml). The aqueous layer was extracted twice with dichloromethane, then the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified using the fluorescence is W-chromatography (0% to 20% EtOAc in hexano), getting 9.7 g (70%) of 2-athineon in the form of a yellow solid.

Step 2 tert-Butyl ester 4-(hydroxy-quinoline-2-yl-methyl)-4-propyl-piperidine-1-carboxylic acid

To a solution of 2-athineon (670 mg, 2.6 mmol) in THF (10 ml) at 0°C was slowly added isopropylaniline (2.0 M in THF, 1.6 ml, 3.2 mmol). The reaction mixture was stirred at 0°C for 30 minutes, then a solution of tert-butyl methyl ether 4-formyl-4-propyl-piperidine-1-carboxylic acid (670 mg, 2.6 mmol) in THF (3 ml) was slowly added. The reaction mixture was stirred at 0°C for 30 minutes, then was heated to room temperature, reduce saturated aqueous NH4Cl and extracted with EtOAc. The combined organic extracts were washed with saline, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (0% to 20% EtOAc in hexano), which gave 190 mg (19%) of tert-butyl ester 4-(hydroxy-quinoline-2-yl-methyl)-4-propyl-piperidine-1-carboxylic acid as a yellow oil.

Step 3 tert-Butyl ether 4-propyl-4-(quinoline-2-carbonyl)-piperidine-1-carboxylic acid

To a solution of tert-butyl ester 4-(hydroxy-quinoline-2-yl-methyl)-4-propyl-piperidine-1-carboxylic acid (190 mg, 0.5 mmol) in toluene (5 ml) was added manganese oxide (IV) (activated, 260 mg, 3.0 mmol). The reaction mixture is load the Wali at 100°C for 3 hours, then cooled to room temperature and filtered through celite, washing EtOAc. The filtrate was concentrated and purified using flash chromatography (0% to 20% EtOAc in hexano), which gave 124 mg (67%) of tert-butyl methyl ether 4-propyl-4-(quinoline-2-carbonyl)-piperidine-1-carboxylic acid as a colourless oil.

Stage 4 (4-Propyl-piperidine-4-yl)-quinoline-2-yl-metano

tert-Butyl ether 4-propyl-4-(quinoline-2-carbonyl)-piperidine-1-carboxylic acid (124 mg, 0.32 mmol) was dissolved in a solution of anhydrous 1.0 M HCl in the Meon (5 ml). The reaction mixture was stirred at room temperature for 15 hours, then concentrated under reduced pressure, which gave 82 mg (80%) of hydrochloride (4-propyl-piperidine-4-yl)-quinoline-2-yl-methanone in the form of a yellow solid, MS=283 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 19

[3-(3,3-Dimethyl-butyl)-pyrrolidin-3-yl]-(5-fluoro-benzo[b]thiophene-3-yl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in the diagram S

Scheme Shch

Step 1 tert-Butyl ether 3-(3,3-dimethyl-butyl)-3-[(5-fluoro-benzo[b]thiophene-3-yl)-hydroxy-methyl]-pyrrolidin-1-carboxylic acid

A mixture of 3-bromo-5-fluoro-benzothiophene (0.4 g, of 1.73 mmol), magnesium (0,051 g, 2.1 mmol) and a few hours the CI of iodine in anhydrous tetrahydrofuran (10 ml) was heated under reflux for 7 hours and then cooled in a bath with ice. To the reaction mixture was slowly added a solution of tert-butyl methyl ether 3-(3,3-dimethyl-butyl)-3-formyl-pyrrolidine-1-carboxylic acid (0.39 g, 1.38 mmol) in anhydrous tetrahydrofuran (9 ml). The reaction mixture was stirred at a bath temperature with ice for one hour and extinguished saturated aqueous ammonium chloride. The aqueous solution was extracted with ethyl acetate, which was washed with saline and dried over anhydrous sodium sulfate. After removal of the desiccant organic solution was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 to 20% ethyl acetate in hexane)gave tert-butyl ether 3-(3,3-dimethyl-butyl)-3-[(5-fluoro-benzo[b]thiophene-3-yl)-hydroxy-methyl]-pyrrolidin-1-carboxylic acid as a yellow foam (0,13 g, 21%), MS=436 [M+H]+.

Step 2 tert-Butyl ether 3-(3,3-dimethyl-butyl)-3-(5-fluoro-benzo[b]thiophene-3-carbonyl)-pyrrolidin-1-carboxylic acid

tert-Butyl ether 3-(3,3-dimethyl-butyl)-3-(5-fluoro-benzo[b]thiophene-3-carbonyl)-pyrrolidin-1-carboxylic acid was obtained from tert-butyl ether 3-(3,3-dimethyl-butyl)-3-[(5-fluoro-benzo[b]thiophene-3-yl)-hydroxy-methyl]-pyrrolidin-1-carboxylic acid by the oxidation with MnO2using the procedure of stage 3 of example 18.

Stage 3 [3-(3,3-Dimethyl-butyl)-pyrrolidin-3-yl]-(5-fluoro-benzo[b]thiophene-3-yl)-methanon

[3-(3,3-Dimethyl-butyl)pyrrolidin-3-yl]-(5-fluoro-benzo[b]thiophene-3-yl)-methanon was obtained from tert-butyl ether 3-(3,3-dimethyl-butyl)-3-(5-fluoro-benzo[b]thiophene-3-carbonyl)-pyrrolidin-1-carboxylic acid, using the procedure of stage 4 of example 18, MS=334 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 20

(7-Fluoro-benzo[b]thiophene-2-yl)-[3-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-3-yl]-methanon

The synthesis procedure described in this example were carried out according to the method shown in scheme E.

Scheme e

Step 1 tert-Butyl ester 3-[(7-fluoro-benzo[b]thiophene-2-yl)-hydroxy-methyl]-3-(tetrahydro-broan-4-ylmethyl)-pyrrolidin-1-carboxylic acid

To a solution of 7-fluoro-benzothiophene (0,22 g, 1.44 mmol) in anhydrous tetrahydrofuran (10 ml) at -78°C was added dropwise a solution of n-BuLi in hexane (1.6 M, 0.9 ml, 1.44 mmol). The reaction mixture was stirred at -78°C for one hour and then a solution of tert-butyl methyl ether 3-formyl-3-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-1-carboxylic acid (0.3 g, 1.01 mmol) in anhydrous tetrahydrofuran (5 ml) was added. The reaction mixture was stirred at -78°C for 3 hours, reduce saturated aqueous ammonium chloride and was divided between ethyl acetate and saturated aqueous ammonium chloride. The organic phase is washed with saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 to 45% ethyl acetate in hexane), that gave tert-butyl ester 3-[(7-fluoro-benzo[b]thiophene-2-yl)-hydroxy-methyl]-3-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-1-carboxylic acid as colorless semi-solid substances (was 0.138 g, 30%). MS=450 [M+H]+.

Step 2 tert-Butyl ether 3-(7-fluoro-benzo[b]thiophene-2-carbonyl)-3-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-1-carboxylic acid

tert-Butyl ether 3-(7-fluoro-benzo[b]thiophene-2-carbonyl)-3-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-1-carboxylic acid was obtained from tert-butyl ether 3-[(7-fluoro-benzo[b]thiophene-2-yl)-hydroxy-methyl]-3-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-1-carboxylic acid by the oxidation with MnO2using the procedure of stage 3 of example 18.

Stage 3 (7-Fluoro-benzo[b]thiophene-2-yl)-[3-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-3-yl]-methanon

(7-Fluoro-benzo[b]thiophene-2-yl)-[3-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-3-yl]-methanon was obtained from tert-butyl ether 3-(7-fluoro-benzo[b]thiophene-2-carbonyl)-3-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-1-carboxylic acid using the procedure of stage 4 of example 18, MS=348 [M+H]+.

Additional compounds obtained according to the above procedure are shown in table 1.

Example 21

(4-Chloro-5-methyl-thiophene-2-yl)-(3-propyl-pyrrolidin-3-yl)-methanon

The synthesis procedure described in this example were carried out according to the method shown in scheme Y.

Scheme Yu

Step 1 tert-Butyl ester 3-[(4,5-dichloro-thiophene-2-yl)-hydroxy-methyl]-3-propyl-pyrrolidin-1-carboxylic acid

tert-Butyl ester 3-[(4,5-dichloro-thiophene-2-yl)-hydroxy-methyl]-3-propyl-pyrrolidin-1-carboxylic acid was obtained from 2,3-dichloro-thiophene and tert-butyl methyl ether 3-formyl-3-propyl-pyrrolidin-1-carboxylic acid using the procedure of stage 1 of example 20.

Step 2 tert-Butyl ether 3-(4,5-dichloro-thiophene-2-carbonyl)-3-propyl-pyrrolidin-1-carboxylic acid

A mixture of tert-butyl ester 3-[(4,5-dichloro-thiophene-2-yl)-hydroxy-methyl]-3-propyl-pyrrolidin-1-carboxylic acid (0,423 g, 1.07 mmol) and manganese oxide (IV) (1.3 g, 12.7 mmol) in toluene (20 ml) was heated under reflux for 2 hours and filtered through a pad of celite. The filtrate was washed with saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10% ethyl acetate in hexane)gave tert-butyl ether 3-(4,5-dichloro-thiophene-2-carbonyl)-3-propyl-pyrrolidin-1-carboxylic acid as a pale yellow solid (0.27 g, 64%). M+Na: 414.

Step 3 tert-Butyl ether 3-(4-chloro-5-methyl-thiophene-2-carbonyl)-3-propyl-pyrrolidin-1-carboxylic acid

A mixture of tert-butyl methyl ether 3-(4,5-dichloro-thiophene-2-carbonyl)-3-propyl-pyrrolidin-1-carboxylic acid is you (0.2 g, 0,512 mmol), trimethylboroxine (0.24 g, at 1.91 mmol), potassium carbonate (0,22 g, to 1.59 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.06 g, 0,051 mmol) in dioxane (10 ml) was heated under reflux for three hours, then cooled to room temperature. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 to 10% ethyl acetate in hexane)gave tert-butyl ether 3-(4-chloro-5-methyl-thiophene-2-carbonyl)-3-propyl-pyrrolidin-1-carboxylic acid in the form of solids (0,166 g, 87%). M+Na: 394.

Stage 4 (4-Chloro-5-methyl-thiophene-2-yl)-(3-propyl-pyrrolidin-3-yl)-methanon

A solution of tert-butyl methyl ether 3-(4-chloro-5-methyl-thiophene-2-carbonyl)-3-propyl-pyrrolidin-1-carboxylic acid (0.16 g, 0.43 mmol) in a mixed solvent of methanol and dichloromethane (3 ml/3 ml) was added to a solution of hydrochloric acid in anhydrous ether (1 M, 10 ml). The solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue is triturated with hexane and diethyl ether gave the hydrochloride (4-chloro-5-methyl-thiophene-2-yl)-(3-propyl-pyrrolidin-3-yl)-methanone in the form of solids (0,129 g, 97%). [M+H]+: 272.

Similarly, skipping stage 3, received (4,5-dichloro-thiophene-2-yl)-(3-propyl-pyrrolidin-3-yl)-methanon, MS=292 [M+H]+.

An additional with the unity, obtained according to the above procedure are shown in table 1.

Example 22

Drugs

Pharmaceutical preparations for delivery in different ways made, as shown in the following tables. "Active ingredient" or "active compound", as used in the tables means one or more compounds of formula I.

Composition for oral administration
Ingredient% wt./wt.
The active ingredient20,0%
Lactose79,5%
Magnesium stearate0,5%

The ingredients are mixed and dosed in capsules, containing about 100 mg each; one capsule almost corresponds to the full daily dose.

Composition for oral administration
Ingredient% wt./wt.
The active ingredient20,0%
Magnesium stearate0,5%
Crosscare the vine sodium 2,0%
Lactose76,5%
PVP (polyvinylpyrrolidone)1,0%

The ingredients are combined and granularit using a solvent, such as methanol. Then the product is dried and pressed into tablets (containing about 20 mg of active compound) to the appropriate tablet press machine.

Composition for oral administration
IngredientNumber
Active connection1.0 g
Fumaric acid0.5 g
Sodium chloride2.0 g
Methylparaben0.15 g
Propylparaben0.05 g
Granulated sugar25,5 g
Sorbitol (70% solution)is 12.85 g
Veegum K (Vanderbilt Co.)1.0 g
Flavor a 0.035 ml
Dyes0.5 mg
Distilled waterto 100 ml

The ingredients are mixed before formation of a suspension for oral administration.

The preparation for parenteral administration
Ingredient% wt./wt.
The active ingredient0.25 g
Sodium chlorideenough to make isotonic
Water for injections100 ml

The active ingredient is dissolved in parts of water for injection. Then add with stirring, a quantity of sodium chloride sufficient to make the solution isotonic. The solution is brought to a weight with the rest of the water for injection, filtered through the 0.2 micron membrane filter and packaged under sterile conditions.

The composition of the suppository
Ingredient% wt./wt.
The active ingredient 1,0%
Polyethylene glycol 100074,5%
Polyethylene glycol 400024,5%

The ingredients are melted together, mixed in a steam bath and poured into molds containing 2.5 g total mass.

The preparation for external use
Ingredientsgrams
Active connection0,2-2
Span 602
Twin 602
Mineral oil5
Vaseline10
Methylparaben0,15
Propylparaben0,05
BHA (Butylhydroxyanisole)0,01
Water100

All the ingredients except water are combined and heated to approximately 60°C under stirring. Then add priblizitelen is at 60°C under intensive stirring, a quantity of water sufficient from ingredients to obtain an emulsion, and then add water to approximately 100 g

Nasal sprays

Some water suspension containing approximately 0,025-0,5% of the active compounds are in the form of nasal sprays. Drugs may contain inactive ingredients, such as, for example, microcrystalline cellulose, carboxymethylcellulose sodium, dextrose, etc. Can be added hydrochloric acid to adjust the pH. Nasal sprays can be fed through a nasal injection metering pump normally supplying about 50-100 microliters drug for injection. The usual dosage is 2-4 injection every 4 to 12 hours.

Example 23

Screening of antagonists vector serotonin person (hSERT from Human Serotonin Transporter) using scintillation proximal analysis (SPA from Scintillation Proximity Assay)

In this example, to determine the affinity of ligands to hSERT-carrier used in a screening analysis based on competition with [3N]-citalopram.

Scintillation proximal analysis (SPA) is based on the fact that for the stimulation of light emission from radioligand must be in the immediate vicinity of the scintillator beads. In this analysis, the receptor-containing membrane is pre-tied with SPA beads and measured the binding is their right radioligand with the carrier. Light emission was proportional to the number associated radioligand. Due to the large distance from the scintillator unbound radioligand did not give any signal (due to the absence of energy transfer).

Cells of SOME 293 (Tatsumi et al., Eur. J. Pharmacol. 1997, 30, 249-258), stably expressing recombinant hSERT, supported with medium (DMEM (modified by way of Dulbecco environment Needle) with high glucose with 10% FBS (fetal calf serum), 300 μg/ml G418 and 2 mm L-glutamine) and incubated at 37°C With 5% CO2. Cells were washed from the culture flasks using PBS (phosphate-saline buffer) for 1-2 minutes. Then the cells were centrifuged at 1000×g in second for 5 minutes and resuspendable in PBS before use in the preparation of membranes.

Cell membranes were obtained using a buffer for the preparation of membranes 50 mm Tris (pH 7.4). Cell membranes were obtained from 1 cm3(the total number of cells of 7.5×109). Cells are homogenized using a homogenizer transmitter station (average mode opening within 4 seconds). Then the homogenate was centrifuged at 48000×g for 15 minutes, then the supernatant was removed and discarded, and the precipitate resuspendable in fresh buffer. After the second centrifugation the precipitate is again homogenized and brought to the final volume, which is about Regaleali during analysis. Typically, portions of the membranes were stored in aliquot at 3 mg/ml (weight: volume) at -80°C.

To determine IR50/Ki by scintillation proximal analysis used a buffer of 50 mm Tris-HCl and 300 mm NaCl (pH of 7.4). Compounds according to the invention were diluted to the final of the analyzed concentration (FAC) from 10 mm to 0.1 nm (10 points on a curve, logarithmic (log) dilution/semi-log (half-log dilutions) using a Beckman Biomek 2000 using Protocol serial dilution. Then tested compound was transferred into a tablet (20 µl/well), and added radioligand [3N]-citalopram in the amount of 50 µl/well. The membrane and the balls were taken in the ratio of 10 µg: 0.7 mg, was added 0.7 mg PVT-WGA (polyvinyltoluene - agglutinin from wheat germ) Amersham beads (cat. No. RPQ0282V) per well. In the analysis tablet was added to 130 μl of a mixture of membrane balls. The mixture was kept at room temperature for one hour and then counted on a Packard TopCount LCS using a common Protocol settings for scintillation counting proximal analysis (energy range: low; mode efficiency: normal; range: 1,50-35,00; range: 1,50-256,00; counting time (min): 0,40; subtract background: none; correction to the half-life: none; indicator blanking: tSIS, background subtraction on the map tablet: none; subtract crosstalk: off is expected).

The percentage of inhibition was calculated for each tested compound [(number of pulses per minute (CPM from counts per minute) connections at the highest concentrations, non - specific CPM)/total CPM×100]. The concentration providing 50% inhibition (IC50), was determined using an iterative method of selection of parameters of nonlinear equations of the curve using Activity Base/Xlfit by the following equation:

where max = total binding, min = nonspecific binding, x = concentration (M) of the investigated compounds and n = hill coefficient. The dissociation constant for inhibition of binding (Ki) were determined for each connection in accordance with the method of Cheng-Prusova and then calculate the negative logarithm (pKi) from Ki.

When using the above method it was found that the compounds according to the invention have affinity to the carrier serotonin person. For example, using the above analysis naphthalene-2-yl-(3-propyl-pyrrolidin-3-yl)-methanon showed pKi approximately 9,82.

Example 24

Screening of compounds with activity against carrier norepinephrine person (hNET from Human Norepinephrine Transporter), using scintillation proximal analysis (SPA)

To determine the affinity of ligands to hNET-carrier used given the initial analysis, based on competition with [3N]-nisoxetine. As in hSERT-analysis of the above example, the receptor-containing membrane is pre-tied with SPA beads and measured the binding of a suitable radioligand with the carrier. Light emission was proportional to the number associated radioligand and unbound radioligand did not give any signal.

Cells of SOME 293 (Tatsumi et al., Eur. J. Pharmacol. 1997, 30, 249-258), stably expressing recombinant hNET (Clone: HEK-hNET No. 2), supported with medium (DMEM high glucose with 10% FBS, 300 μg/ml G418 and 2 mm L-glutamine) and incubated at 37°C With 5% CO2. Cells were washed from the culture flasks using PBS for 1-2 minutes. Then the cells were centrifuged at 1000×g in second for 5 minutes and resuspendable in PBS before use in the preparation of membranes.

Cell membranes were obtained using a buffer for the preparation of membranes 50 mm Tris (pH 7.4). Cell membranes were obtained from 1 cm3(the total number of cells of 7.5×109). Cells are homogenized using a homogenizer transmitter station (average mode opening within 4 seconds). Then the homogenate was centrifuged at 48000×g for 15 minutes, then the supernatant was removed and discarded, and the precipitate resuspendable in fresh buffer. After the second centrifugation the precipitate again homogenizer is whether and brought up to final volume, which was determined in the analysis. Typically, portions of the membranes were stored in aliquot at 3-6 mg/ml (weight: volume) at -80°C.

To determine IR50/Ki by scintillation proximal analysis used radioligand3[N]-nisoxetine (Amersham cat. No. TRK942 or Perkin Elmer cat. No. NET1084, specific activity: 70-87 CI/mmol, initial concentration: 1,22E-5 M, final concentration: 8,25th-9 M) and a buffer of 50 mm Tris-HCl, 300 mm NaCl (pH 7.4). Compounds according to the invention were diluted to FAC from 10 mm to 0.1 nm (10 points on a curve, logarithmic (log) dilution/semi-log (half-log dilutions) using a Beckman Biomek 2000 using Protocol serial dilution. Then tested compound was transferred into a tablet (20 μl/well) was added radioligand in the amount of 50 µl/well. The membrane and the balls were taken in the ratio of 10 µg: 0.7 mg, was added 0.7 mg PVT-WGA Amersham beads (cat. No. RPQ0282V) per well. In the analysis tablet was added to 130 μl of a mixture of membrane balls. The mixture was kept at room temperature for one hour and then counted on a Packard TopCount LCS with typical settings Protocol count for SPA (energy range: low; mode efficiency: normal; range: 1,50-35,00; range: 1,50-256,00; counting time (min): 0,40; subtract background: none; correction to the half-life: none; indicator blanking: tSIS, subtraction of background on CarteBlanche: none; subtract crosstalk: off).

The percentage of inhibition was calculated for each tested compound [(CPM at a maximum concentration of the compound - non-specific CPM)/total CPM×100]. The concentration providing 50% inhibition (IC50), was determined using an iterative method of selection of parameters of nonlinear equations of the curve using Activity Base/Xlfit using the following equation:

where max = total binding, min = nonspecific binding, x = concentration (M) of the investigated compounds and n = hill coefficient. The dissociation constant for inhibition of binding (Ki) were determined for each connection in accordance with the method of Cheng-Prusova and then calculate the negative logarithm (pKi) from Ki.

When using the above method it was found that the compounds according to the invention have affinity to the carrier norepinephrine person. For example, using the above analysis of (7-fluoro-1H-indol-5-yl)-[(S)-3-(3-methyl-butyl)-pyrrolidin-3-yl]-methanon showed pKi approximately 9,2.

Example 25

Screening of compounds with activity against dopamine carrier person, using scintillation proximal analysis (SPA)

To determine the affinity of ligands to the carrier dopamine IP who was olovely this analysis, based on competition with [3N]-vanoxerine.

Cells of SOME 293 (Tatsumi et al., Eur. J. Pharmacol. 1997, 30, 249-258), stably expressing recombinant hDAT, supported with medium (DMEM high glucose with 10% FBS, 300 μg/ml G418 and 2 mm L-glutamine) and incubated at 37°C With 5% CO2. Cells were cultivated for four hours before the experiment, placing approximately 30,000 cells per well (PBS) on white, opaque Cell-Tak 96-well plates. Special buffer washed cellular tablets, using a machine for washing tablets EL×405.

To determine IR50/Ki by scintillation proximale analysis used radioligand [3N]-vanoxerine (GBR 12909), specific activity approximately 59 CI/mmol, initial concentration: 400 nm, and a buffer of 50 mm Tris-HCl, 300 mm NaCl (pH of 7.4). Compounds according to the invention were diluted to FAC from 10 mm to 0.1 nm (10 points on a curve, logarithmic (log) dilution/semi-log (half-log dilutions) using a Beckman Biomek 2000 using Protocol 10-point dilution. The mixture was kept at room temperature for 30 minutes and then counted on a Packard TopCount LCS with typical settings Protocol count for SPA (counting time (min): 0,40; subtract background: none; correction to the half-life: none; indicator blanking: tSIS, background subtraction on the map tablet: none; in the subtraction of crosstalk: off).

The percentage of inhibition was calculated for each tested compound [(CPM at a maximum concentration of the compound - non-specific CPM)/total CPM×100]. The concentration providing 50% inhibition (IC50), was determined using an iterative method of selection of parameters of nonlinear equations of the curve using Activity Base/Xlfit using the following equation:

where max = total binding, min = nonspecific binding, x = concentration (M) of the investigated compounds and n = hill coefficient. The dissociation constant for inhibition of binding (Ki) were determined for each connection in accordance with the method of Cheng-Prusova and then calculate the negative logarithm (pKi) from Ki.

When using the above method it was found that the compounds according to the invention have affinity to the carrier dopamine person. For example, using the above analysis of [(S)-3-(3,3-dimethyl-butyl)-pyrrolidin-3-yl]-(7-fluoro-1H-indol-5-yl)-methanon showed pKi approximately 9,2.

Example 26

Analysis of pain syndrome when using formalin

Male rats Sprague, doli (180-220 g) is placed in a separate chamber made of plexiglass and allowed to adapt to the conditions of the test within 30 minutes. Filler, medicine or positive the initial control (2 mg/kg of morphine) is injected subcutaneously at 5 ml/kg 15 minutes after dosing formalin (5% in 50 µl) was injected into the plantar surface of the right hind paw using a needle of No. 26. Immediately rats return in the observation chamber. Mirrors placed around the camera, allow you to freely observe the paw, which was introduced formalin. The duration of nociceptive behavior of each animal is registered blinded observer using automated behavioral timer. Licking and shaking/lifting of the hind legs is registered separately in the container every 5 minutes for 60 minutes. The amount of time spent licking or shaking, in seconds, from 0 to 5 minutes is considered an early stage, whereas for slow-motion stage is the number of seconds spent licking or shaking, from 15 to 40 minutes. Plasma samples collected.

Example 27

Analysis of pain in the colon

1-2 adult male rats Sprague, doli (350-425 g; Harlan, Indianapolis, IN) was placed in a cage with the animal care. Rats make deep anesthesia with pentobarbital sodium (45 mg/kg)injected intraperitoneally. The electrodes are placed and fixed in the outer oblique muscles for electromyographic (EMG) registration. The electrode wires include subcutaneous and display to the back of the neck for the future is the start. After surgery, rats are placed separately and allowed to recover for 4-5 days before the test.

The descending colon and rectum expand when inflated with adjustable pressure with 7-8 inch flexible latex probe tied around the flexible tube. Probe grease, is inserted into the colon through the anus and fix, tying a balloon catheter to the base of the tail. Colorectal bloat (CRD from colorectal distension) reach, opening solenoid valve air reservoir with constant pressure. Vnutritelostnoe pressure regulate and continuously monitored using a pressure sensor. The response is quantitatively measured as visceromotor response (VMR from the visceromotor response), reduction of abdominal muscles and muscles of the hind limbs. EMG activity, caused by the contraction of the external oblique muscle is quantitatively measured using Spike2 software (Cambridge Electronic Design). The analysis of each blow lasts 60 seconds, and EMG activity quantitatively measured for 20 seconds to inflation (baseline), within 20 seconds of inflating and 20 seconds after inflation. The increase in the total number of registered units during inflation above the baseline is defined as the response. Stable baseline responses to CRD (10, 20, 40 and 80 mm Hg, 20 seconds, with 4-mi is cozy interval) is obtained from the waking posibleng rats before any processing.

Assess the effect of compounds on the response to inflation of the colon in the initial stage in a model of acute visceral nociception and hypersensitivity of the colon caused vnutripoliticheskoi treatment with simhasanam (1 ml, 25 mg/ml), moulded drop in the colon with a needle probe power, inserted to a depth of about 6 cm, Each experimental group will consist of 8 rats.

Acute visceral nociception: To investigate the effects of drugs on acute visceral nociception at 1 of 3 doses of a medicinal product, filler or positive control (morphine, 2.5 mg/kg) was injected, and then set the background response, determine the response to inflation in the next 60-90 minutes.

Visceral hypersensitivity: To investigate the effects of a drug or filler after vnutripoliticheskoi processing simhasanam vnutriserdecnuu treatment is carried out after determining the background response. To test medicines in 4 hours assess responses to inflation in order to establish the presence of hypersensitivity. Treated with simhasanam rats injected with 1 of 3 doses of a medicinal product, filler or positive control (morphine, 2.5 mg/kg) after 4 hours after treatment with simhasanam and responses to bloat about Radelet through the following 60-90 minutes.

Example 28

Cold allodynia in rats with chronic damage when hauling sciatic nerve

The influence of the compounds according to this invention on cold allodynia determine, using a model of neuropathic pain as a result of chronic damage when hauling (CCIS from chronic constriction injury) in rats when cold allodynia is measured in a bath of ice water, with a bottom of the metal plate, water at a depth of 1.5-2.0 cm and a temperature of 3-4°C (Gogas, K.R. et al., Analgesia, 1997, 3, 1-8).

Namely, CCl, rats do anesthesia, where the triple branching of the sciatic nerve, 4 ligation (4-0 or 5-0 chromed catgut) have a circumference around the sciatic nerve close to the triple fork. Then the rats allowed to recover from surgery. 4-7 days after surgery rats first estimate for induced cold allodynia, individually placing animals in a bath of ice water, and registering the total number of lifts damaged feet for 1 minute: invalid paw rises out of the water. Rises feet associated with movement or change of position of the body, are not registered. It is believed that rats, which show 5 times for a minute or more 4-7 days after surgery, have a cold allodynia and used for subsequent studies. When studying the situation of the immediate effects of the filler, reference compound or compounds according to this invention is injected subcutaneously (s/C) for 30 minutes prior to the study. The influence of repeated administration of compounds according to this invention on cold allodynia determine through 14, 20 or 38 hours after the last perorally dose according to the following mode: oral (p/o) introduction of filler, reference compound or compounds according to this invention at ~ 12-hour intervals (twice a day) for 7 days.

Although the present invention is described with reference to its specific embodiments, a qualified person skilled in the art should understand that various changes may be made and equivalents may be substituted, without departing from the true nature and scope of the invention. In addition, can be made numerous modifications to adapt a particular situation, substance, mixture of substances, the way, the stage or stages of the method to the true nature and scope of the present invention. It is implied that all such modifications are within the scope of the attached claims.

1. The use of the compounds of formula I

or its pharmaceutically acceptable salt,
where
m is 0-3;
n is 0-2;
AG is a
possibly substituted indolyl;
possibly substituted indazoles;
isoindolyl;
2,3-dihydro-indolyl;
1,3-dihydro-indol-2-he-Il;
possibly substituted benzothiophenes;
benzothiazolyl;
benzisothiazolin;
possibly substituted chinoline;
1,2,3,4-tetrahydroquinoline;
the quinoline-2-he-Il;
possibly substituted naphthalenyl;
possibly substituted pyridinyl;
possibly substituted thiophenyl or
possibly substituted phenyl;
R1represents a
C1-6alkyl;
hetero-C1-6alkyl;
halo-C1-6alkyl;
halo-C2-6alkenyl;
With3-7cycloalkyl;
With3-7cycloalkyl-C1-6alkyl;
With1-6alkyl-C3-6cycloalkyl-C1-6alkyl;
With1-6alkoxy;
With1-6alkylsulfonyl;
phenyl;
tetrahydropyranyl-C1-6alkyl;
phenyl-C1-3alkyl, where the phenyl portion may substituted;
heteroaryl-C1-3alkyl;
R2represents a
hydrogen or
With1-6alkyl; and
each Raand Rbindependently represents a
odor is d;
With1-6alkyl;
With1-6alkoxy;
halo;
hydroxy or
oxo;
or Raand Rbtogether form1-2alkylen;
provided that, when m represents 1, n represents 2, and ar represents a possibly substituted phenyl, then R1is not the stands or ethyl, and
where possible replaced means one to three substituent selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamines, dialkylamines, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Rior -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rgand Rhindependently represents hydrogen or alkyl, and each Riindependently represents alkyl, and where "heteroaryl" means a monocyclic radical of 5-6 ring atoms containing one, two ring heteroatoms selected from N or S, with remaining ring atoms are C, "heteroalkyl" means an alkyl radical, including branched C4-C7-alkyl, where one hydrogen atom is substituted by substituents selected from the group consisting of-ORa, -NRbH, on the assumption that the accession hetaeras the alkyl radical is through a carbon atom, where Rarepresents hydrogen or C1-6alkyl, Rbrepresents a C1-6alkyl,
for the manufacture of drugs to treat depression, anxiety or both of them.

2. The compound of the formula I

or its pharmaceutically acceptable salt,
where
m represents 1;
n represents 1;
AG represents a possibly substituted phenyl;
R1represents a
C1-6alkyl;
hetero-C1-6alkyl;
halo-C1-6alkyl;
With3-7cycloalkyl;
With3-7cycloalkyl-C1-6alkyl;
With1-6alkyl-C3-6cycloalkyl-C1-6alkyl;
tetrahydropyranyl-C1-6alkyl;
phenyl-C1-3alkyl;
C1-6alkoxy;
heteroaryl-C1-3alkyl;
R2represents a
hydrogen or
With1-6alkyl; and each Raand Rbindependently represents hydrogen;
where possible replaced means one to three substituent selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, acylamino and where "heteroaryl" means a monocyclic radical with 5 ring atoms, containing two ring heteroatoms selected from N;
"heteroalkyl" means an alkyl radical, including branched C4-C7-alkyl, where one hydrogen atom is substituted by substituents selected from the group consisting of-or SIGa, -NRbH IP is odya of assumptions, that the accession of heteroalkyl radical is through a carbon atom, where Rarepresents hydrogen or C1-6alkyl, Rbrepresents a C1-6alkyl.

3. The compound according to claim 2, where AG represents 3,4-dichloro-phenyl, or its pharmaceutically acceptable salt.

4. The compound according to claim 2 of formula IV

where
q represents 0 or 1;
each R6, R7and R8independently represents a
halo;
amino;
C1-6alkyl;
C1-6alkoxy;
halo-C1-6alkoxy;
and where m, n and R1are as defined in claim 2.

5. The compound according to claim 2, where R1represents a
With3-6alkyl;
phenyl-C1-3alkyl;
With3-6cycloalkyl-C1-6alkyl;
hetero-C1-6alkyl;
halo-C1-6alkyl or C1-6alkyl-C1-3cycloalkyl-C1-6alkyl.

6. The compound according to claim 2, where R1represents a
With3-6alkyl;
With3-6cycloalkyl-C1-6alkyl or C1-6alkyl-C1-3cycloalkyl-C1-6alkyl.

7. The compound according to claim 2, where R1represents a C3-6alkyl.

8. The compound according to claim 2, where R2represents hydrogen.

9. The compound according to claim 2, where Raand Rbrepresent hydrogen.

10. The compound according to claim 2, where the specified compound is a compound of formula VI

where AG and R1are as specified in item 2.

11. The compound according to claim 2, representing hydrochloride compound selected from the group including
(3-benzyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanon,
phenyl-(3-propyl-pyrrolidin-3-yl)-methanon,
(4-methoxy-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(4-fluoro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3-chloro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-phenyl)-(3-ethoxymethyl-pyrrolidin-3-yl)-methanon,
(4-chloro-3-methoxy-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
N-[2-chloro-4-(3-propyl-pyrrolidin-3-carbonyl)-phenyl]-acetamide", she
(3-chloro-4-methoxy-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-phenyl)-((R)-3-propyl-pyrrolidin-3-yl)-methanon,
(4-chloro-3-fluoro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3-chloro-4-fluoro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3,5-dichloro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3,4-debtor-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-phenyl)-(3-isopropoxyphenyl-pyrrolidin-3-yl)-methanon,
(3-butyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanon,
(4-chloro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3-chloro-4-methyl-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(4-chloro-3-methyl-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3-propyl-pyrrolidin--yl)-(4-triptoreline-phenyl)-methanon,
(4-chloro-3-trifluoromethyl-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3-propyl-pyrrolidin-3-yl)-(3,4,5-Cryptor-phenyl)-methanon,
(3,4-dichloro-5-fluoro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(4-bromo-3-chloro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(4-chloro-3-isopropoxy-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
[3-(2-cyclohexyl-ethyl)-pyrrolidin-3-yl]-(3,4-dichloro-phenyl)-methanon,
(3,4-dichloro-phenyl)-[3-(3,3-dimethyl-butyl)-pyrrolidin-3-yl]-methanon,
(4-amino-3-chloro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(2,3-dichloro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3-propyl-pyrrolidin-3-yl)-(3,4,5-trichloro-phenyl)-methanon,
(3,4-dibromo-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-phenyl)-[3-(4,4,4-Cryptor-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-5-fluoro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-5-fluoro-phenyl)-((R)-3-propyl-pyrrolidin-3-yl)-methanon,
(4-chloro-3-ethyl-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3-bromo-4-chloro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3-cyclopropylmethyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanon,
(3,4-dichloro-phenyl)-[3-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-3-yl]-methanon,
(4-bromo-3-methyl-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(4-amino-3-chloro-5-fluoro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(4-bromo-3-chloro-5-fluoro-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3-butyl-pyrrolidin-3-yl)-(3,4-dichloro-5-fluoro-phenyl)-methanon,
((R)--butyl-pyrrolidin-3-yl)-(3,4-dichloro-5-fluoro-phenyl)-methanon,
((S)-3-butyl-pyrrolidin-3-yl)-(3,4-dichloro-5-fluoro-phenyl)-methanon,
((S)-3-butyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanon,
((R)-3-butyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanon,
(3,4-dichloro-phenyl)-(3-isobutyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-5-fluoro-phenyl)-(3-isobutyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-phenyl)-[(S)-3-(3-methyl-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-phenyl)-(3-isopropyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-phenyl)-[(S)-3-(3,3-dimethyl-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-phenyl)-[(R)-3-(3,3-dimethyl-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-phenyl)-((S)-3-isobutyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-5-fluoro-phenyl)-[3-(3-methyl-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-phenyl)-((R)-3-isobutyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-5-fluoro-phenyl)-[3-(3,3-dimethyl-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-phenyl)-[(R)-3-(3-methyl-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-5-fluoro-phenyl)-[(R)-3-(3-methyl-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-5-fluoro-phenyl)-[(S)-3-(3-methyl-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-phenyl)-[3-(2-ethoxy-ethyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-phenyl)-{3-[2-(1-methyl-cyclopropyl)-ethyl]-pyrrolidin-3-yl}-methanon,
(3,4-dichloro-5-fluoro-phenyl)-[(R)-3-(3,3-dimethyl-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-5-fluoro-phenyl)-[(S)-3-(3,3-dimethyl-butyl)-pyrrolidin-3-yl]-methanon,
(4-amino-3-chloro-5-fluoro-phenyl)-[3-(3,3-dimethyl-butyl)-pyrrolidin-3-yl]-Manon,
(4-amino-3-chloro-5-fluoro-phenyl)-(3-isobutyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-5-fluoro-phenyl)-[3-(tetrahydro-Piran-4-ylmethyl)-pyrrolidin-3-yl]-methanon,
(4-amino-3-chloro-phenyl)-[3-(3,3-dimethyl-butyl)-pyrrolidin-3-yl]-methanon,
(4-amino-3-chloro-phenyl)-(3-isobutyl-pyrrolidin-3-yl)-methanon,
(3,4-dichloro-phenyl)-(3-pyrazole-1-ylmethyl-pyrrolidin-3-yl)-methanon,
(3-cyclopentyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanon,
(4-amino-3-chloro-phenyl)-[3-(3-methyl-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-5-fluoro-phenyl)-((S)-3-isobutyl-pyrrolidin-3-yl)-methanon,
(4-amino-3-chloro-5-fluoro-phenyl)-[3-(3-methyl-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-phenyl)-[3-(2,2-dimethyl-propyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-phenyl)-[3-(3-methoxy-3-methyl-butyl)-pyrrolidin-3-yl]-methanon,
(2-amino-3,4-dichloro-phenyl)-(3-isobutyl-pyrrolidin-3-yl)-methanon,
(3-chloro-4-methyl-phenyl)-[3-(3,3-dimethyl-butyl)-pyrrolidin-3-yl]-methanon,
(2-amino-3,4-dichloro-phenyl)-((S)-3-ethyl-pyrrolidin-3-yl)-methanon,
(4-amino-3-chloro-phenyl)-[(S)-3-(3,3-dimethyl-butyl)-pyrrolidin-3-yl]-methanon,
(4-amino-3-chloro-phenyl)-[(R)-3-(3,3-dimethyl-butyl)-pyrrolidin-3-yl]-methanon,
(2-amino-3,4-dichloro-phenyl)-((R)-3-ethyl-pyrrolidin-3-yl)-methanon,
(4-amino-3-chloro-phenyl)-[(S)-3-(3-methyl-butyl)-pyrrolidin-3-yl]-methanon,
(4-amino-3-chloro-phenyl)-[(R)-3-(3-methyl-butyl)-pyrrolidin-3-yl]-methanon,
(3,4-dichloro-phenyl)-[3-(1-methyl-cyclopropylmethyl)-pyrrolidin-3-yl]-methanon,
(2,4-di the ENT-phenyl)-(3-propyl-pyrrolidin-3-yl)-methanon,
(3-cyclopentylmethyl-pyrrolidin-3-yl)-(3,4-dichloro-phenyl)-methanon,
(3,4-dichloro-phenyl)-[3-(2-methoxy-2-methyl-propyl)-pyrrolidin-3-yl]-methanon.

12. The Union, representing (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanon or its pharmaceutically acceptable salt.

13. The connection section 12, representing hydrochloride (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone.

14. Pharmaceutical composition for treating depression, anxiety or both, comprising the compound according to any one of claim 2 to 13 and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to producing new 5,8,9,10-tetrahydropyrimido[4,5-d]azocine derivatives having triflate, secondary and tertiary amino groups in the 4th position of general formula specified below. In general structural formula: 2-12 2 X=OTf (Tf means triflate), X means NR1R22 related to the groups 3-12

.

The method consists in the fact that 6-isopropyl-2-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one reacts with methyl propyolate in methanol at room temperature to produce methyl 8-isopropyl-4-oxo-2-phenyl-5,8,9,10-tetrahydropyrimido[4,5-d]azocine-6-carboxylate (1). Thereafter, the prepared compound reacts with triftalane hydride in dichloromethane in the presence of pyridine at t°=-10°C; it is recovered and purified with by means of column chromatography to prepare methyl 8-isopropyl-2-phenyl-4-{[(trifluoromethyl)sulphonyl]oxy}-5,8,9,10-tetrahydropyrimido[4,5-d]azocine-6-carboxylate (2); then the solution I mmole of the prepared product (2) in absolute dioxide is added with 2 mmole of K2CO3 and 1.5 mmole of appropriate amine. After being boiled for two hours and removing the solvent, respective 4-amino substituted 5,8,9,10-tetrahydropyrimido[4,5-d]azocine of formula 3-12 is prepared. The method is directed to prepare the products in the form of white or yellow powder, or in the form of drying oil.

EFFECT: after the primary screening, the compounds appeared to be acetyl- and butyrylcholin esterase inhibitors and can find application as scaffolds in searching the preparations for treating neurodegenerative diseases.

10 ex

FIELD: medicine, pharmaceutics.

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

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

17 cl, 2 tbl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new halogenised pyrazolo[1,5-a]-pyrimidines of general formula (I) and their pharmaceutically acceptable salts possessing affinity with respect to α1-,α2 subunits of a GABAA receptor. In formula R represents alkyl(C1-C6); R1 is specified in a group consisting of alkyl(C1-C6) and alkinyl(C1-C6); X represents a halogen atom, and Y is specified in a group consisting of -CO- and -SO2. The invention refers to intermediate enamine compounds and methods for preparing them.

EFFECT: invention also refers to a method for preparing the compounds of formula (I), the based pharmaceutical compounds, to the use of said compounds for preparing said drug preparation for treating or preventing anxiety, epilepsy, sleep disorders, including insomnia, as well as for inducing a sedative-hypnotic effect, anaesthesia and muscular relaxation.

23 cl, 6 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (VIII):

X represents NR7; Y represents O or N-(CH2)nR19; n is equal to 1 or 2; m is equal to 1 or 2; R1 represents H or C1-6alkyl; R2 independently represents H, C1-6alkyl or C5-6cycloalkyl; each of R4 and R4 independently represents H or C1-6alkyl; or R4 and R4 together form spiro-C3-6cycloalkyl group; R19 represents H, C1-6alkyl, C6aryl or C3cycloalkyl group; R6 represents OR8 ; and each of R7 and R8 independently represents H or C1-6alkyl. The invention also refers to compounds of formula VI, VII, a pharmaceutical composition containing said compounds, and a method of treating a proliferative disease, such as cancer.

EFFECT: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a PLK1 kinase inhibitor.

24 cl, 8 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein m is equal to 0, 1, 2; n is equal to 0, 1, 2, 3; each p, s, t is equal to 0 or 1; X represents CHR8 wherein R8 represents hydrogen; represents -CR9=C<, and then a dash line represents a bond, R9 independently represents hydrogen or C1-6-alkyl, or wherein R9 together with one of R2 or R20 forms a direct bond; R1 represents hydrogen; R2 and R20 are specified in: halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl, C1-6-alkyloxy with any of said groups is optionally and independently substituted by hydroxy, NR21R22 wherein R21 and R22 are independently specified in hydrogen, C1-6-alkylcarbonyl; or R2 and R20 together with a phenyl cycle whereto attached form a naphthaline group; or one of R2 or R20 have the values specified above, and the other of R2 or R20 together with R9 form a direct bond; R3 represents hydrogen; R4 and R5 independently represent hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6-alkenyl or C1-6-alkyloxy; or R6 represents hydrogen; when p is equal to 1, then R7 represents hydrogen; Z represents one of the radicals presented in the patent claim. Also, the invention refers to a based pharmaceutical composition, using the compounds of formula (I) for producing the drug preparation for treating the disorders medicated by p53-MDM2 interaction for treating cancer, and to methods for producing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) as p53-MDM2 interaction inhibitors.

13 cl, 5 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

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

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

16 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new crystalline form 1 of 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide, to a based composition, the use of said crystalline form 1, methods for preparing it.

EFFECT: what is prepared is the new crystalline form 1 of 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide effective for treating cancer.

10 cl, 9 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I:

,

where X1 denotes a bond, NR8 or S; Y1 denotes O or NR ; R1 denotes C1-10alkyl, C6-10aryl or a 5-10-member heteroaryl containing 1-3 heteroatoms which are independently selected from N or S; where said R1 is optionally substituted with 0-2 J1; R2 denotes H or C1-10alkyl; each of R3, R4, R5 and R6 independently denotes H or C1-10alkyl; and R7 denotes C1-10alkyl, C3-10cycloalkyl, phenyl, 5-6-member heterocyclyl containing 1-3 heteroatoms independently selected from O and N, - (C1-6alkyl) -(C3-10cycloalkyl), - (C1-6alkyl) - (phenyl) or -(C1-6alkyl)-(6-member heterocyclyl containing 2 heteroatoms selected from O and N); where said R7 is optionally substituted with 0-5 J7; or R3 and R4, together with a carbon atom with which they are bonded, optionally form a 3-4-member saturated or partially unsaturated monocyclic fragment; R3 and R5, together with carbon atoms with which they are bonded, optionally form a 5-member monocyclic fragment; R8 denotes H; R9 denotes H or unsubstituted C1-6alkyl; or R2 and R9, together with atoms with which they are bonded, optionally form a 5-member aromatic monocyclic fragment containing 3 nitrogen atoms; each J1 independently denotes C1-6halogenalkyl, halogen, NO2, CN, Q or -Z-Q; or two J1 together can optionally form =O; Z denotes C1-6alkyl, wherein 0-3 carbon atoms are optionally substituted with -NR-, -O-, -C(O)- or -SO2-; wherein each Z is optionally substituted with 0-2 J2; Q denotes H; C1-6alkyl; 3-8-member aromatic or non-aromatic monocyclic fragment containing 0-3 heteroatoms independently selected from O, N and S; or an 8-10-member aromatic bicyclic system; each Q is optionally substituted with 0-2 JQ; each J7 independently denotes C1-6alkyl or halogen(C1-4alkyl); each of JQ and J7 independently denotes M or -Y-M; each Y independently denotes an unsubstituted C1-6alkyl, wherein 0-3 carbon atoms are optionally substituted with -O-, -C(O)- or -SO2-; each M independently denotes H, C1-6alkyl, C3-6cycloalkyl; halogen (C1-6alkyl), phenyl, halogen, CN, OH, OR1; or two M together can optionally form =O; R denotes H or an unsubstituted C1-6alkyl; R' denotes an unsubstituted C1-6alkyl. The invention also relates to methods of producing said compounds and a pharmaceutical composition for inhibiting PLK based on said compounds.

EFFECT: novel compounds which can be used in medicine as inhibitors of protein kinase are obtained.

34 cl, 1 tbl, 279 ex

FIELD: chemistry.

SUBSTANCE: method involves heating cyclic thiourea at temperature from higher than 200°C to 250°C in a solvent which is selected from ethers, alcohols or mixtures thereof, to form bicyclic guanidines.

EFFECT: method enables to obtain a product with high output.

13 cl, 2 ex

FIELD: chemistry.

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

EFFECT: high efficiency of using the compounds.

2 cl, 20 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to methods of producing 3-endo(8-azabicyclo[3.2.1]oct-3-yl)benzamide of formula 1 . The methods are realised via hydrogenation of an intermediate product, amine-protected 3-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzamide of formula 3, in the presence of hydrochloric or trifluoroacetic acid, where the amine-protective group is a removable by catalytic hydrogenation. The invention also relates to intermediate compounds 2, 3 and 5, a method of producing a compound of formula 3 and a method of increasing stereospecifity for endo-orientation of a 3-endo(8-azabicyclo[3.2.1]oct-3-yl)benzamide sample.

EFFECT: improved methods of producing 3-endo(8-azabicyclo[3,2,1]oct-3-yl)benzamide.

14 cl, 1 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a crystalline salt form representing a sulphate salt of 3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxypropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide or its hydrate which are used as mu-opioid receptor antagonists, to a based pharmaceutical composition, to applying them for preparing a drug, as well as to a method of treating, improving gastrointestinal motility and mu-opioid receptor antagonisation.

EFFECT: invention refers to versions of the method for preparing the crystalline sulphate salt of 3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxypropionyl)amino]ethyl}-8-azabicyclo[3,2,1]oct-3-yl)benzamide and to a bisulphite adduct of benzene ester of N-cyclohexylmethyl-(2-oxoethyl)carbamic acid.

26 cl, 26 ex, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

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

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

13 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where the dotted line in the 6-member nitrogen-containing ring Z of formula (I) (said ring Z consists of ring atoms numbered 1 to 6) indicates that a double bond is either present in the 3,4-position of the ring Z of formula (I), or a double bond is absent in ring Z of formula (I); and where the double bond may be present in the 3,4-position of the ring Z of formula (I); or: the double may be absent in ring Z of formula (I) if: i) X denotes N or N+-O-, or ii) V denotes -O-CH2-Q-, or iii) W denotes para-substituted phenyl or para-substituted pyridinyl, and V denotes pyrrolidinyl of formula:

X denotes CH, N, or N+-O-; W denotes para-substituted phenyl or para-substituted pyridinyl; V denotes -O-CH2-Q-, where Q is bonded with a group U of formula (I), or V denotes pyrrolidinyl of formula:

U denotes mono-, di-, tri- or tetra-substituted aryl, where the substitutes are independently selected from C1-7-alkyl and halogen; Q denotes a five-member heteroaryl with two or three heteroatoms independently selected from O and N; R1 denotes C1-7-alkyl or cycloalky; R2 denotes halogen or C1-7-alkyl; R3 denotes halogen or hydrogen; R4 denotes C1-7-alkyl-O-(CH2)0-4-CH2-; R'R"N-(CH2)0-4-CH2-, where R' and R" are independently selected from a group consisting of hydrogen, C1-7-alkyl (optionally substituted with one-three fluorine atoms), cyclopropyl (optionally substituted with one-three fluorine atoms), cyclopropyl- C1-7-alkyl (optionally substituted with one-three fluorine atoms) and -C(=O)-R"', where R'" denotes C1-4-alkyl, C1-4-alkoxy, -CH2-CF3, or cyclopropyl; or R12NH-C(=O)·(O)0-1-(CH2)0-4-, where R12 denotes C1-4-alkyl or cyclopropyl; and n equals 0; and salts thereof. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having inhibiting effect on renin.

21 cl, 112 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): , where: R1 is selected from -ORa, -C(O)NRaRb, -NHS(O)2Rc, -C(O)ORa; A means C1-4alkylenyl; R2 means C3-12cycloalkyl or C6-10aryl which is optionally substituted by one -ORa, one or two halogen atoms, one or two C1-3alkyls substituted by two or three halogen atoms; or one, two, three or four C1-3alkyls; G means C1-4alkylenyl; R3 is selected from hydrogen, -C(O)R4, -C(O)NHR5, -S(O)2Rc and -S(O)2NRaRb; R4 means C3-6cycloalkyl or C1-6alkyl, C3-6cycloalkyl is optionally substituted by one -ORa, and C1-6alkyl is optionally substituted by one or two substitutes selected from -ORa, -C(O)ORa, -S(O)2R6, -C(O)NRaRb, -NRaRb, -CN, C3-6cycloalkyl and phenyl; or by one -D-(CH2)j-R7 where D means , j is equal to 1, n is equal to 1 or 2; R6 means C1-3alkyl optionally substituted by R7; R7 means -C(O)ORa; R5 means C1-6alkyl, benzo[1.3]dioxole or -(CH2)q-phenyl; where phenyl is optionally substituted by one or two substitutes selected from halogen, -ORa, C1-3alkiyl and C1-3alkoxy where C1-3alkyl and C1-3alkoxy optionally substituted by 2 or 3 halogen atoms, and q is equal to 0, 1; Ra and Rb independently mean hydrogen or C1-4alkyl; and Rc means C1-3alkyl; provided when R2 means phenyl substituted in position 4, R3 is not -C(O)R4 where R4 means C1-4alkyl substituted by C(O)ORa; to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition, to a method of preparing the compound of formula (I), to compounds of formula (II), (III), to application of the compounds on any claim 1-14, to a method of analysing a biological system or a sample containing a mu-opioid receptor, and also to a method of treating a mammal suffering a disease caused by mu-opioid receptor activity.

EFFECT: production of the new biologically active compounds exhibiting mu-opioid receptor antagonist activity.

26 cl, 204 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new tartrate salts of (1R,2R,3S,5S)-2-methoxymethyl-3-(3,4-difluorophenyl)-8-azabicyclo[3.2.1]octane, such as L-tartrate monohydrates and anhydrates.

EFFECT: application as inhibitors of monoamine neurotransmitter reuptake.

8 cl, 8 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 8-ethyl-6,7-fullero[60]-3-oxa-8-azabicyclo[3.2.1]octane of the general formula (1): . Method involves interaction of fullerene[60] with N-ethylmorpholine in the mole ratio fullerene-C60 : N-ethylmorpholine = 0.01:(0.01-0.011) in the presence of Cp2TiCl2 as a catalyst taken in the amount 15-25 mole% with respect to fullerene[60], in toluene medium as a solvent at temperature ˜20°C for 18-30 h. The yield of the end product is 73-90%. Synthesized compound can be used as chelating agent, sorbent, biologically active compound and in creature of novel materials with desired electronic, magnetic and optical properties.

EFFECT: improved method of synthesis.

1 tbl, 1 ex

FIELD: organic chemistry.

SUBSTANCE: claimed method includes reaction of C60-fullerene with dipiperidine methane in presence of Cp2TiCl2 as catalyst in toluene medium at room temperature (approximately 20°C) for 15-25 hours. Yield of target product is 70-90 %. Compound of present invention is useful as chelating agent, sorbent, biologically active compound and for production of new materials with desired electronic, magnetic and optical properties. .

EFFECT: new compound; method of increased yield and selectivity.

1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a 2-aza-bicyclo[3.3.0]octane derivative of formula , with stereogenic centres in a (1S,3S,5S)-configuration, where A is a thiazolyl which is unsubstituted or monosubstituted, where the substitute is independently selected from a group comprising C1-4alkyl, C3-6cycloalkyl and NH2; B is phenyl which is unsubstituted or mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, trifluoromethyl, NHC(O)CH3 and halogen; and R1 is an imidazo[2,1·b]thiazolyl or benzoisoxazolyl group, where said groups are independently unsubstituted or monosubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl; or R1 is a 2,3-dihydrobenzofuranyl group; or a pharmaceutically acceptable salt. The 2-aza-bicyclo[3.3.0]octane derivative of formula (I) is as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: obtaining novel 2-aza-bicyclo[3,3,0]octane derivatives as orexin receptor antagonists.

8 cl, 1 tbl, 26 ex

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