Derivatives of alpha-(n-sulfonamido)acetamide as inhibitors of beta-amyloid


FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

 

The SCOPE TO WHICH the INVENTION RELATES.

This invention covers a new connection α-(N-sulphonamido)ndimethylacetamide, have medicinal and bioactive properties, their pharmaceutical compositions and methods of use. In particular, the invention relates to α-(N-arylsulfonamides)acetamide. These compounds have the unique property of inhibiting the production of β-amyloid peptide (β-AR), thereby prevent the accumulation of amyloid peptide in the brain. More specifically, the present invention relates to the treatment of Alzheimer's disease (AD).

BACKGROUND of INVENTION

Alzheimer's disease is a progressive neurodegenerative disease characterized by memory impairment and cognitive dysfunction. AD is characterized by the pathological accumulation of senile (Narineh) plaques, neurofibrillary tangles, amyloid deposits in neural tissues and blood vessels, loss of synaptic contacts and death of neurons. It is the most common form of dementia and is currently the third leading cause of death after cardiovascular diseases and cancer. The cost of Alzheimer's huge (in the U.S. more than $100 billion annually). With increasing life expectancy in society, the frequency of AD is noticeable. P is the estimated if the methods of prevention and treatment will not be found, by 2020, more than 10 million Americans will suffer from AD. At the present time believe that Alzheimer's disease (AD) affected 10% of the population aged over 65 and up to 50% over the age of 85 years. There is currently no treatment that effectively warned AD or reduced (negated) clinical symptoms and the basic pathophysiology (for review see Selkoe, D.J. Ann. Rev. Cell Biol., 1994, 10:373-403).

There are many theories regarding the etiology and pathogenesis of AD. These theories are either based on analogy with other diseases and conditions (e.g., theory of slow virus "aluminum") or on observations of pathology (e.g., cholinergic, amyloid or glomerular theory). Genetic analysis will probably help to make the choice between competitive theories. Identification of mutations in the predecessor β-amyloid protein (β-ARR) individuals predisposed to early forms of AD and rodstvennym diseases, largely confirms amyloidogenic theory.

Histopathological examination of brain tissue obtained at autopsy or in the study of neurosurgical samples of affected people, reveals the presence of amyloid plaques and neurofibrillary glomeruli in the cortex of these patients. Similar izmenenyaya in patients with trisomy 21 (down syndrome). Biochemical and immunological studies show that the dominant protein component of amyloid plaques is a protein with a size of about 4.2 kilodaltons, containing about 39-43 amino acids. This protein is called Aβ, β-amyloid peptide and sometimes β/4; in this description it is called Aβ. In addition to deposits in amyloid plaques Andβ found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries and sometimes venules. Irrefutable evidence accumulated over the last decade show that Aβ an internal polypeptide derived from a type 1 integral membrane protein, called protein precursor β-amyloid peptide (β-amyloid) (APP) (Selkoe, D. Physiol. Rev. 2001, 81, 741-766; Wolfe, M. J. Med. Chem. 2001, 44, 2039-2060). βAPP usually is produced by many cells in vivo and cultured cells of various animals and people. Some proteolytic fragments of APP formed in the presence of proteases, called secretase. A subpopulation of these proteolytic fragments, called β-amyloid peptide (aβ), contains 39-43 amino acids and is obtained by joint participation β-secretase and γ-secretase. β-Secretase is a membrane-bound, aspartyl-proteinase, which forms the N-end Andβ peptide. S-Con is C Andβ peptide formed with the participation of γ-secretase, apparently, the oligomeric complex, which includes presenilin-1 and/or presenilin-2. Presenilin-1 and presenilin-2 represent polytope filling the membrane (integrated into the membrane) proteins, which may contain catalytic components γ-secretase (Seiffert, D., Bradley, J. et al. J. Biol. Chem. 2000, 275, 34086-34091).

Numerous data, taken together, steadily suggest that the lower levels Andβ in the brain prevents initiation and progression of AD. First, Aβ is the main component of plaques in the parenchyma of the brain observed in all patients with AD and amyloid deposits in cerebral vessels observed in 90% of patients with AD (review Selkoe, D. Physiol. Rev. 2001, 81, 741-766; Wolfe, M. J. Med. Chem. 2001, 44, 2039-2060). These plaques are formed by aggregation of soluble Andβthe level of which in the brain is clearly correlated with the severity of AD neurodegeneration (McLean, S., Cherny, R. et al. Ann. Neurol. 1999, 46, 860-866). Secondly, mutations in three genes (APP, PS-1 or PS-2), which increase the level Andβcause family AD (FAD), in which the beginning of the AD is accelerating at least a decade. Including mutations that increase the level Andβlead to trisomy of chromosome 21 that causes down syndrome. Third, transgenic mice whose cells Express one or more mutant genes FAD, in which there is oveseny level Aβ the formation of plaques in the brain parenchyma and cerebral vascular deposits containing Aβexhibit memory impairment (Chapman, P., White, G. et al. Nature Neurosci. 1999, 2, 271-276) and, as a consequence, neurofibrillary degeneration in mice whose cells also sverkhekspressiya mutant Tau protein (Lewis, J.; Dickson, D. et al. Science 2001, 293, 1487-1491). Fourthly, Andβ is toxic to cultured cells (Dahlgren, K; Manelli, A. et al. J. Biol. Chem. 2002, 277, 32046-32053), causes the formation of neurofibrillary glomeruli in mice with mutant Tau (Gotz, J., Chen, F. et al. Science 2001, 293, 1491-1495) and prevent long-lasting potentiation, a likely component of memory (Walsh, D., Klyubin, I. et al. Nature 2002, 416, 535-539 and are listed in the article link). Together, these data lead specialist in this field to conclude that excess products Andβ and/or reduced clearance Andβ causes AD. From this it follows that reducing Aβ in the brain through inhibition γ-secretase warns the beginning and progression of AD.

In addition to AD, excessive production and/or lower clearance Andβ causes cerebral amyloid angiopathy (CAA) (review Thal, D., Gherbremedhin, E. et al., J. Neuropath, exp. Neuro. 2002, 61, 282-293). In these patients, vascular amyloid deposits cause degeneration of the walls of blood vessels and aneurysms, which may be responsible for 10-15% of cases of hemorrhage in elderly patients. As p and AD, mutations in the gene, encoding Aβlead to an early form of CAA, called intracerebral hemorrhage with amyloidosis of the Dutch type, and in mice expressing this mutant protein, develops CAA, similar to the human one.

The hypothesis that inhibition of the production Andβ prevents and reduces neurodegeneration, reducing neurotoxicity and, as a rule, mediating the pathology associated with producing Andβ. Methods of treatment can be aimed at education Andβ with the participation of enzymes included in the proteolytic processing β-amyloid protein precursor. Compounds that inhibit βor γ-secretshow activity, directly or indirectly, can control the production Andβ. Favorable is that compounds that are aimed at specific γ-secretase, can control the production Andβ. This inhibition βor γ-secretase can thus reduce the production Andβcan reduce or prevent the neurological disorders associated with protein Andβ.

In the International application WO 00/50391, published August 31, 2000, describes a number of sulfonamidnuyu compounds that can modulate production of amyloid β protein, as a means to treat various C the problems especially Alzheimer's disease and other diseases associated with amyloid deposits. In Japanese patent 11343279 published December 14, 1999, describes a number of sulfonamidnuyu derivatives, which are inhibitors of TNF-alpha, applicable to the treatment of autoimmune diseases.

Nothing in these references cannot be interpreted as describing or suggesting new connections according to this invention and their use for inhibiting the production of βAR.

The INVENTION

Synthesized a number of derivatives α-(N-sulphonamido)ndimethylacetamide. These compounds inhibit specific production β-amyloid peptide (β-AR) of protein-predecessor β-amyloid protein (β-ARR). Pharmacological action of these compounds makes them applicable for treating conditions responsible for the inhibition β-AR patients, such as Alzheimer's disease (AD) and down syndrome. Therapy using the introduction of these compounds to patients suffering from these diseases or exposed to them, includes a reduction in the β-AR in the brain of these patients.

DETAILED description of the INVENTION

The present invention includes compounds of Formula I, their pharmaceutical preparations and their use for inhibiting (suppressing) production β-AR in patients suffering from AD or at risk of AD or other naru is eniam, the resulting accumulation β-AR in the brain. The compounds of Formula I, which include non-toxic pharmaceutically acceptable salts and/or hydrates, have the following formula, and the following notation:

where R1selected from the group consisting of

(a) a linear or branched C1-6the alkyl or C2-6alkenyl, optionally having substituents selected from the group consisting of hydroxy, C3-7cycloalkyl,1-4alkoxy, C1-4alkylthio and halogen;

(b)3-7cycloalkyl, optionally substituted by hydroxy or halogen;

R denotes hydrogen or R1and R together denote C2-5alkylen;

R2selected from the group consisting of

(a) a linear or branched C1-6the alkyl or C3-6alkenyl having optionally substituents selected from the group consisting of halogen, C1-4alkoxy and NR4R5;

(b)3-7cycloalkenyl having optionally substituents selected from the group consisting of amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, With1-4alkyls(=O)NH - and C1-4alkimos(=O)NH-;

(b) a linear or branched C1-6alkyl-C(=O)-A;

(g) In-naphthyl;

(d)

D and E each independently represent a simple link to the e l e C linear or branched C1-6alkyl, C2-6alkenyl or3-7cycloalkyl;

Z is chosen from the group consisting of hydrogen, C1-4of alkyl, C1-4alkoxy, halogen, cyano, hydroxy, -OCHF2, -OCF3, -CF3and-CHF2;

X and Y each independently selected from the group consisting of hydrogen, hydroxy, halogen, (halogen)3C-, (halogen)2CH-, C1-4S-From1-4S(O)-, C1-4SO2-, nitro, F3S -, and cyano; OR6; -NR4R5; -NR7C(=O)R8; -NR7C(=O)OR8; NHSO2C1-4alkyl; -N(SO2C1-4alkyl)2; C(=O)W, where W is chosen from the group consisting of hydroxy, C1-4alkyl, C1-4alkoxy, phenoxy and-NR4R5; -OC(=O) C1-4of alkyl; phenyl, and specified phenyl optionally may be substituted by cyano, halogen, C1-4alkoxy, C1-4S-, CH3C(=O), C1-4S(O)- or1-4SO2-, and heterocyclic group, where the specified heterocyclic group selected from a set consisting of furanyl, thiopurine, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl and thiazolyl, and specified heterocyclic group optionally substituted by substituents selected from the group consisting of the C cyano, halogen, C1-4of alkyl, (halogen)1-4the alkyl and CO2C1-4of alkyl;

(e)-(heterocycle), where the heterocycle is chosen from the group consisting of furanyl, thiopurine, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl and thiazolyl, and said heterocycle optionally has substituents selected from the group consisting of cyano, halogen, C1-4of alkyl, CO2C1-4of alkyl, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

(W) -To-(piperidine-4-yl), where the specified piperidine-4-yl optionally has substituents selected from the group consisting of linear or branched C1-6of alkyl, CH2C(=O)phenyl, phenyl and phenylmethyl, with the specified C1-6alkyl and said phenyl optionally have substituents selected from the group consisting of cyano, halogen, benzimidazole-2-yl, pyridyl and tetrahydrofuran-2-yl, and-C(=O)W', where W' is chosen from the group consisting of C1-4alkoxy, R9and-NR4R5;

And denotes hydroxy, C1-4alkoxy or NR4R5;

In denotes a linear or branched C1-6alkyl or C3-6alkenyl;

R3denotes phenyl or pyridyl having optionally substituents selected from the group consisting of halogen, hydroxy, C1-4alkoxy, C1-4of alkyl, (halogen)3C-, (halogen)2SN - and Halogens2-;

R4and R5, each independently, represent hydrogen, linear or branched C1-6alkyl, C3-6alkenyl,3-6quinil,3-7cycloalkyl,3-7cycloalkenyl, C1-4alkoxy, phenyl, benzyl, pyridyl, piperidine-4-yl, indan-1-yl, indan-2-yl, tetrahydrofuran-3-yl or pyrrolidin-3-yl, where each optionally have substituents selected from the group consisting of hydroxy, cyano, halogen, (halogen)3C-, (halogen)2CH-, Halogens2hydroxymethyl, benzoyloxymethyl, phenyl, pyridyl, C1-4of alkyl, C1-4alkoxy, (halogen)3With-O-, (halogen)2CH-O-, C1-4alkylthio, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl, 4-(C1-6alkyl)piperazine-1-yl, 4-phenylpiperazin-1-yl, 4-benzylpiperazine-1-yl, 4-pyridineboronic-1-yl, CO2N, CO2With1-4of alkyl, C(=O)NHC1-4the alkyl and C(=O)N(C1-4alkyl)2;

R4and R5together may denote morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, 1,2,3,4-tetrahydroisoquinoline-2-yl, decahydro the quinoline-1-yl, piperidine-1-yl, piperazine-1-yl, [1,4]oxazepan-4-yl, azetidin-1-yl, 2,3-dihydro-1H-isoindole-2-yl or 2,3-dihydro-1H-indol-1-yl, where each optionally have substituents selected from the group consisting of hydroxy, cyano, halogen, (halogen)3C-, (halogen)2CH-, Halogens2-, phenyl, pyridyl, benzyl, C1-6of alkyl, C3-7cycloalkyl, C1-4alkoxy, C1-4alkylthio, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, CO2H, CO2With1-4alkyl, C(=O)NHC1-4alkyl and C(=O)N(C1-4alkyl)2;

R6denotes a linear or branched C1-6alkyl, C3-6alkenyl, benzyl or phenyl, where each optionally have substituents selected from the group consisting of halogen, C1-4of alkyl, C1-4alkoxy, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, (C1-4alkyl)(phenyl)N-, morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

R7denotes a linear or branched C1-6alkyl;

R8denotes a linear or branched C1-6alkyl, C3-7cycloalkyl, phenyl, pyridyl or furanyl, where each optionally have substituents selected from the group consisting of halogen, C1-4of alkyl, C1-4alkoxy, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, calm surroundings is Holin-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

R9denotes a linear or branched C1-6alkyl, C3-6alkenyl, benzyl, phenyl, oxazolyl or pyridyl, where each optionally have substituents selected from the group consisting of halogen, (halogen)3C-, (halogen)2CH-, Halogens2-With1-4of alkyl, C1-4alkoxy, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

or their non-toxic pharmaceutically acceptable salt.

The present invention also encompasses a method of treating or alleviating disorders associated with β-amyloid peptide, particularly Alzheimer's disease, which is the introduction, together with a conventional adjuvant, carrier or diluent a therapeutically effective amount of the compounds of formula I or its non-toxic pharmaceutically acceptable(th) salt, MES or hydrate.

The term "C1-6alkyl", as used in this description and in the claims (unless the text indicates otherwise)means a linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 3-methylbutyl, hexyl and the like, the Term "C2-6al is Anil, denotes a linear or branched alkeneamine groups such as ethynyl (i.e. vinyl), propenyl, allyl, butenyl, 3-methylbutanal, pentanal, hexanal, etc. Unless otherwise specified, the term "halogen", involves bromine, chlorine, iodine and fluorine, whereas the term "halide" implies anion bromide, chloride and iodide.

The term "C3-7cycloalkyl" denotes the carbon cycle, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "C1-4halogenated" denotes a linear or branched C1-4alkyl group containing 1-3 halogen atoms, such as trifluoromethyl, foradil, 1,2-dichloroethyl, trichloroethyl etc.

The term "C2-5alkylene" denotes a linear or branched alkylenes group such as methylene, ethylene, propylene, mutilation, butylene, methylpropene, pentile, methylbutyl and adipophilin.

Since the compounds according to this invention contain asymmetric carbon atom, the present invention includes the racemate and individual enantiomers of compounds of Formula I according to this description, and in accordance with the invention. It is assumed that a single-letter designation (R) or (S) includes predominantly one stereoisomer. A mixture of isomers into the individual isomers by methods known in themselves, such as fractional Chris what alsatia, adsorption chromatography or other appropriate methods division. Resulting racemates can be separated into the antipodes in the usual way by the introduction of suitable salt-forming groups, for example, obtaining a mixture diastereoisomeric salts with optically active salt-forming agents, separating the mixture into individual diastereoisomeric salts and converting the separated salts into the free compounds. Possible enantiomeric forms can also be divided by fractionation on columns for chiral liquid chromatography high pressure.

The term "nontoxic pharmaceutically acceptable salt" implies a non-toxic salt of attaching the base. Such salts include salts formed from organic and inorganic acids, such as, but without limitation, hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonate acid, acetic acid, tartaric acid, lactic acid, Sultanova acid, citric acid, maleic acid, fumaric acid, sorbic acid, konitova acid, salicylic acid, phthalic acid, etc.

In the method according to this invention, the term "therapeutically effective amount" means the total amount of each active component in this method, which is enough to Ovide the ü significant improvement in the condition of the patient, i.e. healing of acute conditions characterized by suppression (inhibition) products β-amyloid peptide. If the individual give one active ingredient, the term refers to a single ingredient. If you give a combination, the term refers to the total number of active ingredients, which gives a therapeutic effect, administered in combination, intermittently or simultaneously. The terms "treat, cure, therapy, treatment"as used in this description and in the claims, refer to the prevention or reduction of intensity of disease due to β-amyloid peptide.

The General scheme of reactions

General procedure for the synthesis of compounds of Formula I described in the Reaction schemes 1-23. It is assumed that reasonable variations of the described methods obvious to a person skilled in the art, are included in the scope of the present invention.

Reaction scheme 1

Source (α-amino)acetamide Formula II used in the form of racemates or in the form of pure enantiomers, manufactured, or get them on the well-known literaturnyi methods of the commodity (commercially available) (α-amino)acids (a General reference for obtaining amides: R.C.Larock "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp.972-976; see also Reaction scheme 18 the transformation of the acid is ormula XLVIII in amide of Formula XLIX). The compound of Formula II is treated with an appropriate base and sulfonylureas agent such as sulphonylchloride, in an aprotic solvent such as CH2Cl2at room temperature, receiving (α-sulphonamido)ndimethylacetamide Formula III. Appropriate bases include triethylamine and pyridine.

One method of transformation of compounds of Formula III in the sulfonamide of the Formula I compound of Formula III is treated with an appropriate base and an alkylating agent in an aprotic solvent under heating or without heating. Appropriate bases for this reaction include potassium carbonate and cesium carbonate. Alkylating agents include alkylhalogenide (for example, alkyl chloride, alkyl bromide or alkyl iodide and alkyl sulphonates (tozilaty, mesylates, triftoratsetata). Preferred solvents include DMF and acetonitrile. The temperature range for this reaction, as a rule, is 20-100°C.

An alternative method of transformation of compounds of Formula III to the compound of Formula I comprises treating compound of Formula III with triphenylphosphine, dialkyldithiocarbamato and alcohol in an inert solvent under heating or without heating.

Reaction scheme 1 on solid media

The compounds of Formula I can also be obtained using the UYa methodology solid-phase synthesis. For example, FMOC-protected amide resin Rinca treated with piperidine in DMF to remove the FMOC-group. Then the resin is condensed with a protected amine (α-amino)acid in the presence of a condensing agent such as 1-hydroxybenzotriazole and dialkylated in an inert solvent, such as DMF, under heating or without heating. Deprotecting amino receive associated with the polymer amide of Formula IV. In the case of FMOC-protected amino acids unlocks can be carried out by treatment with piperidine in DMF.

The reaction of the compound of Formula IV with an appropriate base, such as pyridine, and sulfonylureas agent such as sulphonylchloride, in an inert solvent receive associated with resin sulfonamide of Formula V. Alkylation of compounds of Formula V alkylhalogenide (for example, alkyl chloride, bromide, an alkyl or alkyl iodide) or alkylsulfonates (tosylates, mesilate, triftoratsetata) is carried out in the presence of a base in an inert solvent at room temperature. The preferred base is 2-tert-butylamino-2-diethylamino-1,3-dimethylpyridine-1,2,3-datafactory. Removing the polymer substrate gives the sulfonamide of Formula I. In the case of amide resin Rinca removal is preferably carried out triperoxonane acid in an inert solvent such as CH Cl2.

Reaction scheme 2

The compounds of Formula I can also be obtained as shown in Reaction scheme 2. Reductive alkylation of an amine of the Formula I in order to obtain an amine of Formula VI is carried out, processing aldehyde and a reducing agent is a hydride in the presence of an acidic catalyst under heating or without heating. The preferred reducing agent is cyanoborohydride sodium. The preferred acid catalyst is a Lewis acid, such as ZnCl2. A preferable solvent in this reaction is methanol. Then the amine of Formula VI is treated sulfonylureas agent such as sulphonylchloride, in the presence of an amine such as triethylamine. This reaction is carried out in an inert solvent such as CH2Cl2when heated or unheated, getting the product of Formula I. the Reaction is generally carried out at room temperature.

Reaction scheme 3

where the linker is a linear or branched C1-6alkyl or C3-6alkenyl;

LG = leaving group.

Obtaining compounds of Formula VIII are being performed, as shown in Reaction scheme 3, reaction of the compound of Formula VII with an amine in the presence of an acid acceptor, such as triethylamine, in an inert solvent such as CH2C 2when heated or unheated. Compound of Formula VII receive consecutive reactions (chain reaction), depicted in Reaction scheme 1 or Reaction scheme 2.

Reaction scheme 4

The compounds of Formula XI and XII are given as shown in Reaction scheme 4. The restoration of the nitro group in the compound of Formula IX (obtained by consecutive reactions depicted in Reaction scheme 1 or 2) with gaseous hydrogen under pressure in the presence of a palladium catalyst, acid and in a solvent such as methanol, gives the aniline derivative of Formula X. Monomethylamine the compounds of Formula X in order to obtain the compounds of Formula XI carried out by reaction with 1.1 equivalent of methylchloride or methylsulfonate, such as dimethylsulfate, in the presence of a base, such as triethylamine, in an inert solvent, such as DMF. The reaction monomethylamine, as a rule, carried out at a temperature of 20-40°C. Dimethylaniline of the Formula XII receiving, processing aniline of the Formula X excess methylglucamide, such as methyl iodide, or methylsulfonate in the presence of a base such as cesium carbonate, in a solvent such as DMF, under heating or without heating.

Reaction scheme 5

In Reaction scheme 5 shows the synthesis of esters of Formula XIII, acids of Formula XIV and amides of Formula XV. The reaction of the compound of Formula III with ether haloalkylthio acid, for example tert-butyl ether bromoxynil acid, in the presence of a base such as potassium carbonate, in an inert solvent, such as DMF, to give an ester of Formula XIV. Deprotecting ester groups by methods known to experts in the art (reference: T.W. Greene and P.G.M. Wuts, "Protecting Groups in Organic Synthesis", Wiley Interscience, New York, 1999, pp.373-442). For example, in the case of tert-butyl methyl ether cleavage with the formation of the acid of Formula XIV is carried out, processing triperoxonane acid in a solvent such as CH2Cl2. The transformation of the acid amide of the Formula XV is conducted according to conventional methods reactions of amides, well izvestnim specialists in the art (reference: R.C. Larock "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp.972-976). In the preferred method, the acid of Formula XIV is treated with a primary or secondary amine in the presence of 1-hydroxybenzotriazole and 1,3-dicyclohexylcarbodiimide in an aprotic solvent such as CH2Cl2or DMF.

Reaction scheme 6

.

Obtain the acid of Formula XVII and amides of Formula XVIII is shown in Reaction scheme 6. The transformation of complex EPE is and Formula XVI (obtained as shown in Reaction schemes 1 or 2) to the acid of Formula XVII is performed in standard conditions, cleavage of ethers, well-known to experts in the art (reference: T.W. Greene and P.G.M. Wuts, "Protecting Groups in Organic Synthesis", Wiley Interscience, New York, 1999, pp.373-442). In the case of methyl ester of Formula XVI by treatment with an aqueous solution of sodium hydroxide in a solvent such as methanol or a mixture of methanol/THF, at 20-40°get the acid of Formula XVII. The transformation of the acid of Formula XVII in amide of Formula XVII carried out by conventional methods of obtaining amides, well known to experts in the art (reference: R.C. Larock "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp.972-976). In the preferred method, the acid of Formula XIV is treated with a primary or secondary amine in the presence of 1-hydroxybenzotriazole and a carbodiimide, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in a solvent such as DMF or CH2Cl2. As the acid acceptor can be added base, such as diisopropylethylamine.

Reaction scheme 7

The synthesis of piperidine derivatives of the Formula XIX, XX, XXI and XXIII shown in Reaction scheme 7. The reaction of the compound of Formula III with N-protected piperidine with 4-haloalkyl or 4-sulfonylamino group as a substituent, such as 4-(toluensulfonate)-1-(tert-butoxycarbonyl)piperidine), in the presence of a base such as cesium carbonate, in a solvent such as DMF, at which the agrevanie or in the absence of heating, get the carbamate of Formula XIX. Dissociation of urethane groups is carried out in standard conditions, well known to experts in the art (reference: T.W. Greene and P.G.M. Wuts, "Protecting Groups in Organic Synthesis", Wiley Interscience, New York, 1999, pp.503-550), receiving a piperidine of Formula XX. If (tert-butoxycarbonyl)piperidine cleavage is carried out in the presence of triperoxonane acid in CH2Cl2.

The conversion of piperidine of Formula XX in amide of Formula XXI carried out by conventional methods of obtaining amides, well known to experts in the art (reference: R.C. Larock "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp.972-976). The preferred method piperidine of Formula XX is treated with acylchlorides in the presence of an amine, such as triethylamine, and an inert solvent such as CH2Cl2when heated or unheated. Or a piperidine of Formula XX can be condensing the acid in the presence of a condensing agent, such as hydroxybenzotriazole and carbodiimide getting amide of Formula XXI. Urea of Formula XXII receive, treating the amine of Formula XX with isocyanate and a base, such as triethylamine, in a solvent such as CH2Cl2when heated or unheated. Alkylation of the piperidine of Formula XX receive N-substituted piperidine Formula XXIII. As a rule, treated with piperidine alkylhalogenide or Alki what sulfonate in the presence of a base, such as triethylamine and a solvent such as CH2Cl2.

Reaction scheme 8

The alcohols of Formula XXV and amines of Formula XXV and amines of Formula XXVI are synthesized as shown in Reaction scheme 8. The protected alcohol of Formula XXIV get the Reaction schemes 1 or 2. Removing protection from an alcohol group (deprotection) in the conditions corresponding to the selected protective group (reference: T.W. Greene and P.G.M. Wuts, "Protecting Groups in Organic Synthesis", Chapter 2) gives the alcohol of Formula XXV. For example, if the protecting group is tetrahydropyranyl group, a free alcohol group receive the reaction of the compounds of Formula XXIV with p-toluensulfonate in a solvent such as methanol. Hydroxyl group of compounds of Formula XXV is transformed into a leaving group (e.g. halide or sulphonate), and then treated with a primary or secondary amine, getting amine of Formula XXVI. For example, the alcohol can be converted into mesilate reaction with methanesulfonanilide and a base, such as CH2Cl2. Subsequent reaction of nelfinavir with primary or secondary amine in the presence of a base, such as triethylamine, in a solvent such as CH2Cl2receive amine of Formula XXVI.

Reaction scheme 9

Amides of Formula XXVIII is obtained from the amines of Formula XXVII, as shown on P is a promotional scheme 9. Amines of Formula XXVII, where D denotes a simple link, get the Reaction scheme 1 or 4. Amines of Formula XXVII, where D has a different meaning than simple communication, get in Reaction scheme 8. The conversion of amines of Formula XXVII in the amides of Formula XXVIII is carried out in the conditions of obtaining the amides, well known to experts in the art (reference: R.C. Larock "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp.972-976). For example, the reaction of the amine of Formula XXVII with an acid chloride of the acid in the presence of a base, such as triethylamine, in a solvent such as CH2Cl2get amide of Formula XXVIII. The conversion of amines of Formula XXVII in the carbamates can be performed under conditions well known to experts in the art (reference: T.W. Greene and P.G.M. Wuts, "Protecting Groups in Organic Synthesis", Wiley Interscience, New York, 1999, pp.503-550). Sulfonamides can also be obtained from the amine of Formula XXVII by the methods described for the conversion of the intermediate of Formula II in the sulfonamide of Formula III.

Reaction scheme 10

Synthesis of pyridines of Formula XXX are being performed, as shown in the Reaction scheme. Chloropyridin Formula XXIX get the methods described in Reaction schemes 1 or 2. The reaction of the compound XXIX with a primary or secondary amine in a solvent such as THF, at temperatures from 20 to 100°s in a sealed vessel under pressure get aminopyridin the Formula XXX.

Reaction scheme 11

Aminosilane ethers of phenols of Formula XXXII is obtained from (O-allyl)phenol, as shown in Reaction scheme 11. Source allyl ethers of Formula XXXI receive, as shown in Reaction schemes 1 or 2. The reaction of the compound of Formula XXXI with osmium tetroxide and trimethylamine-N-oxide in a solvent such as acetone, followed by treatment with periodate sodium get the intermediate aldehyde, which, as a rule, used without further purification. Reaction of the crude aldehyde with a primary or secondary amine and a reducing agent, such as triacetoxyborohydride sodium in a solvent such as ethanol, when heated or in the absence of heating, receive amine of Formula XXXII.

Reaction scheme 12

The transformation of ester of Formula XXXIII in the tertiary alcohol of Formula XXXIV is conducted, as shown in Reaction scheme 12. The reaction of the ester of Formula XXXIII with an excess methylethanolamine reagent, such as methylmagnesium, in a solvent such as THF, in a temperature range 0-25°gives the alcohol of Formula XXXIV.

Reaction scheme 13

1,3,4-Oxadiazol Formula XXXVI receive, as shown in Reaction scheme 13, using methods well known in the art in question is the field of technology (reference: Joule, J.A.; Mills, K; Smith, G.F. Heterocyclic Chemistry, 3rded., Chapman & Hall: London, 1995; 452-456 and cited references). For example, the ester of Formula XXXV is treated with hydrazine in methanol at boiling. The obtained intermediate acylhydrazides used without purification in the subsequent reaction with alkylolamides in pyridine boiling, getting oxadiazol Formula XXXVI.

Reaction scheme 14

Synthesis of 1,2,4-oxadiazole Formula XXXVI is conducted, as shown in Reaction Scheme 14, using methods well known to experts in the art (reference: Joule, J.A.; Mills, K; Smith, G.F. Heterocyclic Chemistry, 3rded., Chapman & Hall: London, 1995; 452-456 and cited references). For example, treatment of the acid of Formula XVII-hydroxybenzotriazole, carbodiimide and acetamidoxime (N-hydroxyethylamide) in the presence of a base, such as triethylamine, receive intermediate, which upon heating in boiling pyridine gives oxadiazol Formula XXXVII.

The reaction scheme 15

1,2,4-Oxadiazol Formula XXXIX is obtained from the nitrile of Formula XXXVIII (Reaction scheme 15) by methods well known to experts in the art (reference: Joule, J.A.; Mills, K; Smith, G.F. Heterocyclic Chemistry, 3rded., Chapman & Hall: London, 1995; 452-456 and cited references). For example, the reaction of a nitrile of Formula XXXVI with hydroxylamine in a solvent such as ethanol, n and temperatures up to the boiling point receive the intermediate N-hydroxyamides, which is then treated with acetyl chloride in the presence of a base, such as triethylamine, in a solvent such as CH2Cl2getting 1,2,4-oxadiazol Formula XXXIX.

Reaction scheme 16

In Reaction scheme 16 shows the conversion of the amide of Formula XL in the ketone of Formula XLI. Amide of Formula XL, which is obtained, as shown in Reaction scheme 6, is treated with methyl ORGANOMETALLIC reagent, such as methylmagnesium, in a solvent such as THF, getting a ketone of Formula XLI. Interval the reaction temperature is -20÷25°C.

The reaction scheme 17

β-Aminoamide Formula XLIII is obtained from acrylamido Formula XLII, as shown in Reaction scheme 17. For example, the acrylamide of Formula XLII, which is obtained as described in Reaction scheme 9, is treated with a primary or secondary amine in a solvent such as toluene, receiving β-aminoamide Formula XLIII.

The reaction scheme 18

Intermediate sulfonamide of Formula XLIX (one enantiomer of the compounds of Formula (III) are obtained in accordance with Reaction scheme 18. Reaction α-anion intermediate of Formula XLIV (link: Josien, H.; Martin, A; Chassing, G. Tetrahedron Lett. 1991, 32, 6547) alkylating agent, such as alkylhalogenide (for example, chloride Alki is, methyl alkyl or alkyl iodide) or alkylsulfonate (for example, alkalmazasa, alkyllithium or alkylarylsulfonate), gives the intermediate of Formula XLV. α-Anion compounds of Formula XLIV is formed by processing a strong base, such as alkylate (e.g. n-BuLi) or dialkylamide lithium (for example, diisopropylamide lithium), in a solvent such as THF, with a co-solvent, such as NMR, or without it. The reaction temperature generally is -78÷25°C. removing the protective benzhydrylidene group in the compound of Formula XLV carried out under conditions well known to experts in the art (reference: T.W. Greene and P.G.M. Wuts, "Protecting Groups in Organic Synthesis", Wiley Interscience, New York, 1999, pp.587-588). For example, the compound of Formula XLV is treated with acid, such as HCl in water, in a solvent such as THF, to hydrolyze benzhydrylidene protective group. The obtained amine of Formula XLVI process sulfonylureas agent, as described for Reaction scheme 1, get a sulfonamide of Formula XLVII. Hydrolysis of arylsulfonamides Formula XLVII with the formation of the acid of Formula XLVIII is done processing its hydroxide ion, such as lithium hydroxide, in the presence of additives, such as lithium bromide and tetrabutylammonium. The acid of Formula XLVIII is transformed into amide of formula XLIX under conditions well known in the art given in the second field of machinery (common reference for obtaining amides: R.C. Larock "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp.972-976). For example, the reaction of the compound of Formula XLVIII with ammonium chloride in the presence of 1-hydroxybenzotriazole, carbodiimide and a base-amine, such as diisopropylethylamine, gives the amine of Formula XLIX. This reaction is usually carried out in a polar solvent such as DMF, at the reaction temperature 0-40°C. Amide of Formula XLIX is transformed into the compounds of Formula I according to the method described in Reaction scheme 1.

The reaction scheme 19

The reaction scheme 19 illustrates one method for the synthesis of α-substituted intermediate (N-sulphonamido)ndimethylacetamide Formula III in terms of an activated derivative of glycine of Formula L. the Reaction of the compound of Formula L (reference: Haufe, G.; Laue, K.W.; Thriller, M.U.; Takeuchi, Y.; Shibata, N. Tetrahedron 1998, p.5929-5938; Kroger, S.; Haufe, G. Ammo Acids 1997, 12, p.363-372) with an alkylating agent such as alkylhalogenide (alkylchloride, allylbromide or alkylated) or alkylsulfonates (for example, alkylsilanes, alkyllithium or alkylarylsulfonates) in the presence of a base such as potassium carbonate, and additives, such as tetrabutylammonium, in an inert solvent, such as acetonitrile, at a temperature of 25-70°gives compound of Formula LI. Removing benzhydrylidene protective group is carried out under conditions well known to specialists in the field of technical and (link: T.W. Greene and P.G.M. Wuts, "Protecting Groups in Organic Synthesis", Wiley Interscience, New York, 1999, pp.587-588). For example, a solution of the compounds of Formula LI in a solvent such as diethyl ether, treated with an aqueous acid solution (e.g., aqueous HCl), usually at a temperature of 0-30°receive aminoether Formula LII. The transformation of the ester of Formula LII in amide of Formula II is carried out by methods well known to specialists in this field of technology. For example, if the compound of Formula LII is an ethyl ester, hydrolysis of this complex ester is carried out, the processing solution in diethyl ether acid, such as HCl, typically by heating the reaction mixture in a boiling solvent. Then the intermediate acid is transformed into methyl ester with the transfer to the acid chloride acid under standard conditions (for example, by treatment with thionyl chloride and methanol), followed by reaction with aqueous ammonia solution in a solvent such as toluene (reference: R.C. Larock. "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp.972-976). Amine of the Formula II into a compound of Formula I, as described in Reaction scheme 1.

The reaction scheme 20

Obtaining the compounds of Formula VI shown in Reaction scheme 20. Alkene LIII receive, as described in Reaction scheme 18, the intermediate of Formula (LIV and 1-bromo-2-methyl-2-propene). The reaction of the alkene of Formula LIII with complex F· pyridine in a solvent such as THF, at a temperature of 0-25°alkyl fluoride gives the compound of Formula LIV. The transformation of compounds of Formula LIV in amide of Formula LV is done, as shown in Reaction scheme 18. The transformation of the amide of Formula LV compound LVI carried out as shown in Reaction scheme 1.

The reaction scheme 21

The synthesis of compounds of Formula LXII and Formula LXIV shown in Reaction scheme 21. Ethyl ester of 2-amino-4-methyl-4-pentenol acid (obtained according to Reaction scheme 19 of ethyl ether (benzhydrylidene)acetic acid and 1-bromo-2-methyl-2-propene) process sulfonylureas agent such as sulphonylchloride, in the presence of a base, such as triethylamine, in an inert solvent such as CH2Cl2getting ether of Formula LVII. The reaction of the ester of Formula LVII with complex HF·pyridine in a solvent such as THF and at a temperature of 0-25°C gives a mixture of alkyl fluoride derivative of Formula LVIII and lactone of Formula LIX. These products are divided and separately carried out subsequent reactions.

The ester of Formula LVIII hydrolyzing to the acid of Formula LX by methods well known to experts in the art (reference: T.W. Greene and P.G.M. Wuts, "Protecting Groups in Organic Synthesis", Wiley Interscience, New York, 1999, pp.373-442). For example, treatment of the ester of Formula LVIII water hydroxide hydroxide is I in the solvent, such as methanol, get acid LXVI.

The conversion of an alkene of Formula LXVI in the aldehyde of Formula LX. The acid of Formula LX is transformed into amide of Formula LXI according to the method described in Reaction scheme 18 to obtain the amide of Formula XLIX. Obtain the amide of Formula LXII of the compounds of Formula LXI is conducted, as shown in Reaction scheme 1.

Treatment of the lactone of Formula LIX aqueous ammonia gives the amide of Formula LXIII. This reaction is usually carried out by heating in a sealed ampoule. The reaction temperature is 40 to 80°C. Further conversion of the intermediate of Formula LXIII in the sulfonamide of Formula LXIV carried out as shown in Reaction scheme 1.

The reaction scheme 22

Multistage synthesis of differenciated Formula LXIX is shown in Reaction scheme 22. The compound of Formula L is treated with 4-bromo-1-butene in the presence of a base such as potassium carbonate, in the presence of salt - of tetraalkylammonium halide, such as tetrabutylammonium, in a solvent such as CH3CN at a temperature of 20-70°C. removing the protective benzhydrylidene group as described in Reaction scheme 19, gives the amine intermediate, which is then treated sulfonylureas agent such as sulphonylchloride, receiving an ester of Formula LXV. Alkylation of the nitrogen atom in the sulfonamide performed according to the method described in R. the promotional scheme 1, get the compound of Formula LXVI. The conversion of an alkene of Formula LXVI in the aldehyde of Formula LXVII is carried out on the reaction of the alkene with osmium tetroxide and trimethylamine-N-oxide in a solvent such as acetone, followed by treatment with periodate sodium. The reaction temperature is usually 20-40°C. the reaction of the aldehyde of Formula LXVII with a fluorinating agent such as DAST, in a solvent such as CH2Cl2gives diferuloylmethane Formula LXVIII. The compound of Formula LXVIII turns into an amide of Formula LXIX hydrolysis of ester to acid in the presence of a base such as sodium hydroxide, in a solvent such as methanol. The intermediate acid is transformed into amide under conditions well known to experts in the art (reference: R.C. Larock. "Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp.972-976). For example, the reaction of the acid with ammonium chloride in the presence of hydroxybenzotriazole and a carbodiimide and a base-amine, such as diisopropylethylamine, gives the amide of Formula LXIX. This reaction is usually carried out in a polar solvent such as DMF, at a temperature of 0-40°C.

The reaction scheme 23

α-Aminoamide Formula LXXI get the reaction depicted in Reaction scheme 23. Amide of Formula LXX receive, as described in Reaction scheme 9. Treatment of compounds of Formula LXX secondary isotretionin the amine in the solvent, such as THF, at a temperature of 20-40°To give the amine of Formula LXXI.

In a preferred embodiment, the present invention includes compounds of Formula Ia and pharmaceutically acceptable salts

where R1selected from the group consisting of

(a) a linear or branched C1-6the alkyl or C2-6alkenyl having optionally substituents selected from the group consisting of hydroxy, C3-7cycloalkyl,1-4alkoxy, C1-4alkylthio and halogen;

(b)3-7cycloalkyl, substituted, optionally, hydroxy or halogen;

R2selected from the group consisting of

(a) a linear or branched C1-6the alkyl or C3-6alkenyl having optionally substituents selected from the group consisting of halogen, C1-4alkoxy and NR4R5;

(b)3-7cycloalkenyl having optionally substituents selected from the group consisting of amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, With1-4alkyls(=O)NH - and C1-4alkimos(=O)NH-;

(b) a linear or branched C1-6alkyl-C(=O)-A;

(g) In-naphthyl;

(d)

D and E each independently represent a simple bond, a linear or branched C1-6alkyl, C2-6alkenyl or 3-7cycloalkyl;

Z is chosen from the group consisting of hydrogen, C1-4of alkyl, C1-4alkoxy, halogen, cyano, hydroxy, -OCHF2, -OCF3, -CF3and-CHF2;

X and Y each independently selected from the group consisting of hydrogen, hydroxy, halogen, (halogen)3C-, (halogen)2CH-, C1-4S-, C1-4S(O)-, C1-4SO2-, nitro, F3S - and cyano;

-OR6;

-NR4R5;

-NR7C(=O)R8;

-NR7C(=O)OR8;

NHSO2C1-4alkyl;

-N(SO2C1-4alkyl)2;

C(=O)W, where W is chosen from the group consisting of hydroxy, C1-4of alkyl, C1-4alkoxy, phenoxy and-NR4R5;

-OC(=O)C1-4of alkyl;

phenyl, and specified phenyl optionally substituted by cyano, halogen, C1-4alkoxy, C1-4S-, CH3C(=O)1-4S(O)- or C1-4SO2-and

heterocyclic group, where the specified heterocyclic group selected from a set consisting of furanyl, thiopurine, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl and thiazolyl, and specified heterocyclic group optionally has substituents selected from the group consisting of cyano, halogen, C1-4of alkyl, (Galaga is) 1-4the alkyl and CO2C1-4of alkyl;

(e)-(heterocycle), where the heterocycle is chosen from the group consisting of furanyl, thiopurine, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl and thiazolyl, and said heterocycle optionally has substituents selected from the group consisting of cyano, halogen, C1-4of alkyl, CO2C1-4of alkyl, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

(W) -To-(piperidine-4-yl), where the specified piperidine-4-yl optionally has substituents selected from the group consisting of linear or branched C1-6of alkyl, CH2C(=O)phenyl, phenyl and phenylmethyl, with the specified C1-6alkyl and said phenyl optionally have substituents selected from the group consisting of cyano, halogen, benzimidazole-2-yl, pyridyl and tetrahydrofuran-2-yl; and-C(=O)W', where W' is chosen from the group consisting of C1-4alkoxy, R9and-NR4R5;

And denotes hydroxy, C1-4alkoxy or NR4R5;

In denotes a linear or branched C1-6alkyl or C3-6alkenyl;

R3denotes phenyl or pyridyl,optionally having substituents, selected from the group consisting of halogen, hydroxy, C1-4alkoxy, C1-4of alkyl, (halogen)3C-, (halogen)2SN - and Halogens2-;

R4and R5, each independently, represent hydrogen, linear or branched C1-6alkyl, C3-6alkenyl,3-6quinil,3-7cycloalkyl,3-7cycloalkylation,1-4alkoxy, phenyl, benzyl, pyridyl, piperidine-4-yl, indan-1-yl, indan-2-yl, tetrahydrofuran-3-yl or pyrrolidin-3-yl, where each optionally have substituents selected from the group consisting of hydroxy, cyano, halogen, (halogen)3C-, (halogen)2CH-, Halogens2hydroxymethyl, benzoyloxymethyl, phenyl, pyridyl, C1-4of alkyl, C1-4alkoxy, (halogen)3With-O-, (halogen)2CH-O-, C1-4alkylthio, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl, 4-(C1-6alkyl)piperazine-1-yl, 4-phenylpiperazin-1-yl, 4-benzylpiperazine-1-yl, 4-pyridineboronic-1-yl, CO2N, CO2C1-4of alkyl, C(=O)NHC1-4the alkyl and C(=O)N(C1-4alkyl)2;

R4and R5together may denote morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, 1,2,3,4-tetrahydroisoquinoline-2-yl, decahydroquinoline-1-yl, piperidine-1-yl, piperazine-1-yl, [1,4]oxazepan-4-yl, azetidin-1-yl, 2,3-d the hydro-1H-isoindole-2-yl or 2,3-dihydro-1H-indol-1-yl, where each optionally have substituents selected from the group consisting of hydroxy, cyano, halogen, (halogen)3C-, (halogen)2CH-, Halogens2-, phenyl, pyridyl, benzyl, C1-6of alkyl, C3-7cycloalkyl, C1-4alkoxy, C1-4alkylthio, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, CO2N, CO2C1-4of alkyl, C(=O)NHC1-4the alkyl and C(=O)N(C1-4alkyl)2;

R6denotes a linear or branched C1-6alkyl, C3-6alkenyl, benzyl or phenyl, where each optionally have substituents selected from the group consisting of halogen, C1-4of alkyl, C1-4alkoxy, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, (C1-4alkyl)(phenyl)N-, morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

R7denotes a linear or branched C1-6alkyl;

R8denotes a linear or branched C1-6alkyl, C3-7cycloalkyl, phenyl, pyridyl or furanyl, where each optionally have substituents selected from the group consisting of halogen, C1-4of alkyl, C1-4alkoxy, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

R9about who appoints a linear or branched C 1-6alkyl, C3-6alkenyl, benzyl, phenyl, oxazolyl or pyridyl, where each optionally have substituents selected from the group consisting of halogen, (halogen)3C-, (halogen)2CH-, Halogens2-C1-4of alkyl, C1-4alkoxy, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

or their non-toxic pharmaceutically acceptable salt.

In another preferred embodiment, the invention encompasses the compounds of Formula I or their pharmaceutically acceptable salt, where R3denotes phenyl, optionally having substituents selected from the group consisting of halogen, hydroxy, C1-4alkoxy, C1-4of alkyl, (halogen)3C-, (halogen)2SN - and Halogens2-.

In another preferred embodiment, the invention includes compounds of Formula Ia or pharmaceutically acceptable salt, where R2means

METHODS of BIOLOGICAL TESTING

It is expected that the compounds of Formula (I) possess the ability to inhibit γ-secretshow activity. To detect γ-secretase activity need tests that can reliably, accurately and conveniently almost to detect cleavage products by the th γ -secretase, especially Asβ. Inhibition γ-secretase activity of the compounds according to this invention is demonstrated using assays for such activity, for example, assays described below. Analyses by definition this activity shows that the compounds included in the scope of the present invention, blocks the activity γ-secretase. Compounds covered by this invention will also be applicable as standards and reagents in determining the ability of a potential pharmaceutical compounds to inhibit (block, suppress) Andβ products. They should be included in commercial kits containing compound according to this invention.

In vitro analysis of the binding for the identification of inhibitors γ-secretase.

To identify molecules that inhibit the binding of labeled radioactive label inhibitor γ-secretase and, therefore, block γ-secretshow activity, you can apply competitive analysis link. For example, [3H]-connection And can be used for analysis of binding to membranes TNR-cells (Seiffert, D.; Bradley, J. et al., J. Biol. Chem. 2000, 275, 34086-34091). The compound a is a (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)butanediamine, the synthesis of which is described in U.S. Patent 6331408 (12/18/2001); published the Anna International PCT application WO 00/28331; published International PCT application WO 00/07995 and article Seiffert, D., Bradley, J. et al., J. Biol. Chem. 2000, 275. 34086-34091.

For these analyses TNR-1 cells grown in the spin-cultures in medium RPMI 1640 containing L-glutamine and 10 microns β-mercaptoethanol, to a density of 5×105cells/ml Cells are harvested by centrifugation, cellular precipitate quickly frozen in a mixture of dry ice/ethanol and stored at -70°C. the Residue, about 2×104TNR-cells homogenized in a homogenizer (Brinkman transmitter station at position 6 within 10 seconds. The homogenate was centrifuged at 48000×g for 12 minutes and the precipitate washed by repeating the homogenization and centrifugation. End-cellular precipitate again suspended in the buffer, receiving a protein concentration of about 0.5 mg/ml Analyses begin by adding 150 μl of membrane suspension in 150 ál of buffer for analysis containing 0,064 µci radioactive ligand and various concentrations of unlabeled compounds. Analyses linking is performed in the double repetition in polypropylene 96-well tablets a final volume of 0.3 ml containing 50 mm Hepes, pH 7.0, and 5% dimethyl sulfoxide. Non-specific binding determine using incubation with 300 nm of compound A (Seiffert, D.; Bradley, J. et al., J. Biol. Chem. 2000, 275, 34086-34091). After incubation at 23°With over 1.3 hours associated Li gang is separated from free labeled ligand by filtration through GFF glass filters, pre-moistened with 0.3% solution of polymer etilenimina. The filters three times washed with ice-cold phosphate buffered saline, pH 7.0, containing 0.1% Triton X-100. Associated with the filter radioactivity is measured by scintillation counter. Then determine the values of the IC50and use them to calculate the values of Kithrough an amendment Cheng-Prusoff (Cheng-Prusoft) for values of IC50. Compounds assessed as active inhibitors γ-secretase, if the values of Kiless than 10 microns.

Examples of the results obtained in the analysis of compounds according to the invention as described above, are given in table 1. In table inhibitory concentration (IC50) less than or equal to 50 nm is indicated by +++; inhibitory concentration of 50-500 nm indicated ++; inhibitory concentration 500-10000 nm is indicated with +.

TABLE 1. Examples of activity in the in vitro analysis of binding
EXAMPLEEVALUATION ACTIVITYa
96+++
123+++
159+++
315++
341++
357++
362+++
365+++
366+++
367+
376++
379+++
385+++
389+++
394+++
403++
405+++
408+
409++
437+++
441+++
443++
445+++
447+++
450++
451+
452++
457++
464+
474+++
476+++
479++
486+++
andActivity based on the values of IC50:

+++=<50 nm

++=50-500 nm

+=>500 nm and <10000 nm

In vitro identification of inhibitor γ-secretase. based on education Andβ from membrane preparations

The selected membrane fraction, which contains functionally active γ-secretase and β-ARR substrates can generate products which you splitting using γ -secretase, including Aβ (Roberts, S.B.; Hendrick, J. P.; Vinitsky, A.; Lewis, M.; Smith, D.W.; Pak, R. Published international PCT application WO 01/0175435; Fechteler, K.; Kostka, M.; Fuchs, M. Patent application Germany 99-19941039; Shearman, M.; Beher, D. et al., Biochemistry, 2000, 39, 8698-8704; Zhang, L.; Song, L. et al., Biochemistry 2001, 40, 5049-5055). The selected membrane fraction can be obtained from human cell lines such as HeLa or H4, which transferout when using β-ARR wild-type or mutant forms β-the RDA, or chimeric constructs of human alkaline phosphatase-β-RDAs and which stably Express high levels of substrates γ-secretase. Endogenous γ-secretase present in the selected membranes prepared at 0-4°splits β-ARR substrates, when the temperature of the membrane rises from 0-4°to 37°C. Detection of cleavage products, including Aβ can be monitored by standard methods, such as immunoprecipitate (Citron, M.; Diehl, T.S. et al., Proc. Natl. Acad. Sci. USA, 1996, 93, 13170-13175), Western blotting (Klafki, H.-W.; Ambramowski, D. et al., J. Biol. Chem., 1996, 271, 28655-28659), enzyme-linked immunosorbent assay (ELISA ), as shown Seubert, P.; Vigo - Pelfrey, C. et al., Nature, 1992, 359, 325-327, or the preferred method, using frameratelimit fluorescent analysis of homogeneous sample containing membrane and Aβ (Roberts, S.B.; Hendrick, J.P.; Vinitsky, A.; Lewis, M.; Smith, D.W.; Pak, R. Published international application PCTWO 01/0175435; Shearman, M.; Beher, D. et al., Biochemistry, 2000, 39, 8698-8704). Andβ in a homogeneous sample containing membrane can be detected frameratelimit fluorescent analysis with two antibodies that recognize different epitopes Andβ. One of the antibodies recognizes an epitope that is present in Aβbut not in fragments predecessor; preferably the antibody binds to the carboxyl end of Aβformed by splitting γ-secretases. The second antibody binds to any other epitope, present in Aβ. For example, known antibodies that bind to N-terminal region (for example, 26D6-B2-B3®SIBIA Neurosciences, La Jolla, CA) or associated with the end of Aβ peptide. Antibodies have been labelled by a pair of fluorescent adducts that transfer of fluorescent energy when the adducts are in close proximity as a result of binding of the N - and C - ends or end regions Andβ. The absence of fluorescence is indicative of the absence of fission products as a result of inhibition γ-secretase. The analysis of isolated membranes can be used to identify agents of the candidates that inhibit the activity of the fission γ-secretases and products Andβ.

For analysis of membranes typically requires 45 μg of membrane protein per well in 96 - or 384-well format. Membrane in neutral buffer merge the Ute with the test compound and from 0-4° With the lead up to 37°C. Agents for testing can typically be composed of synthetic compounds, secondary metabolites from extracts obtained when bacterial or fungal fermentation, or from extracts of samples of terrestrial and marine plants. All synthetic agents are first subjected to screening at doses of 10-100 μm, or, in the case of extracts, with sufficient dilution to minimize cytotoxicity. Incubation of the membranes with the test agent lasts about 90 minutes, then fluorescently labeled antibody is added to each well for the quantitative determination of Aβ. Detection and calculation Andβ using preparednesses fluorescence analysis are described elsewhere (Roberts, S.B.; Hendrick, J.P.; Vinitsky, A.; Lewis, M.; Smith, D.W.; Pak, R. Published international PCT application WO 01/0175435; Shearman, M.; Beher, D. et al. Biochemistry, 2000, 39, 8698-8704). The results obtained by the analysis of the tablet with a microplate fluorescence reader and comparison with model membranes and samples, to which is added a known quantity of Aβ to plot a standard curve concentrations. Positive current connection is one which inhibits Aβ relative to a reference sample, of at least 50% at the start of the investigated concentrations. If detected that the connection is active, then spend experiment to study the effect of dose to determine the lowest dose of a compound, necessary for determining the inhibition of the production Andβ. Compounds assessed as active inhibitors γ-secretase, if the values of Kibelow 10 microns.

Examples of the results obtained in the analysis of compounds according to the invention as described above, are given in table 2. In table inhibitory concentration (IC50), less than or equal to 50 nm, indicated by +++; inhibitory concentration of 50-500 nm indicated ++; inhibitory concentration 500-10000 nm is indicated with +.

TABLE 2. Examples of activity in in vitro analysis, based on the inhibition of education Andβ in cultured cells
EXAMPLEEVALUATION ACTIVITYa
1+++
2+++
3+++
4+++
5+++
6+++
7+++
8+++
9+++
10+++
11+++
12+++
13+++
14+++
15+++
16+++
17+++
18++
19++
20++
21+++
22+++
23+++
24+++
25+++
26+++
27++
28++
29+++
30++
31++
32+++
33+++
34+++
35++
36++
37+++
38+++
39+++
40+++
41+++
42+++
43+++
44+++
45+++
46+++
47+++
48+++
49++
50+++
51+++
52 +++
59++
61+++
83+
85+
87+++
89+++
95+++
103+++
113++
122+
133+++
153++
andActivity based on the values of IC50:

+++=<50 nm

++=50-500 nm

+=>500 nm and <10000 nm

In vitro identification of inhibitor γ-secretase on the basis of inhibition of education Andβ in cultured cells

Cultured human cell lines, such as cell NECK and H4, which Express ARR and γ-secretshow activity, or transfetsirovannyh cell lines, sverkhekspressiya RDAs wild-type, mutant APP or chimeric proteins of the RDA, secrete into the culture medium Andβ peptides, which can be quantitatively determined, as described in the previous technique (Dovey, H., John, V. et al., J. Neurochem. 2001, 76, 173-181). Incubation of these cultured cells with inhibitors γ-secretase lowers production Andβ peptides. For example, H4 cells stably transfetsirovannyh order from the expression of a chimeric (merged) protein HPLAP-APP described above, is grown, as indicated previously, produce and bring up the level 2×105cells/ml and Then 100 μl of the resulting suspension added to each well of 96-well plate. After 4 hours, the medium removed and replaced with 100 μl serum-free medium containing the test compound at various dilutions. Then the tablets incubated for 18 h at 37°and select an aliquot of 100 ál of supernatant tissue culture to determine the levels Andβ method preparednesses fluorescence analysis of homogeneous sample, as described above. Or you can use other methods described above definitions Andβ. The degree (magnitude) of inhibition Andβ used for calculating the value of the IC50for the test connection.

The compounds of this invention are considered to be active if you checked the above method of analysis the value of the IC50less than 50 microns.

Examples of the results obtained in the analysis of compounds according to the invention as described above, are given in table 3. In table inhibitory concentration (IC50), less than or equal to 50 nm, indicated by +++; inhibitory concentration of 50-500 nm indicated ++; inhibitory concentration 500-10000 nm is indicated with +.

TABLE 3. Examples of activity in in vitro analysis, based naimisaranya education Andβ in cultured cells
EXAMPLEEVALUATION ACTIVITYa
1+++
5+++
19++
26+++
38+++
41+++
51+++
55+++
61+++
72+++
80+++
89+++
96+++
101+++
123+++
127++
143+++
147++
158+++
171++
193+++
203+++
205++
207+++
245+++
246+++
249++
254+++
256+++
260+++
272+++
280++
282 +++
288++
301++
302+++
321++
322+++
329+++
330++
331+
340+++
341++
342+++
349+++
352++
358++
359+++
366+++
367+
378+++
383+++
394+++
403++
416+++
418+++
424+++
433+++
434+++
439+++
442+++
472+++
481+
492++
495+++
497+++
andActivity on the basis of the values of the IC 50:

+++=<50 nm

++=50-500 nm

+=>500 nm and <10000 nm

It is shown that the value of the IC50compounds according to this invention is less than 10 microns in one or all of the above analyses. Therefore, the compounds of Formula I or pharmaceutical compositions suitable for the treatment, cure, mitigate or eliminate diseases or other disorders associated with inhibition β-amyloid peptide.

In addition to cleavage of APP, γ-secretase cleaves other substrates, including a family of transmembrane receptor Notch (review in: Selkoe, D. Physiol. Rev. 2001, 81, 741-766; Wolfe, M. J. Med. Chem. 2001, 44, 2039-2060); protein related LDL (LDL) receptor (May, P, Reddy, Y.K, Herz, J. J. Biol. Chem. 2002, 277, 18736-18743); ErbB-4 (Ni. C.Y, Murphy, M.P., Golde, IE, Carpenter, G. Science 2001, 294, 2179-2181); E-cadherin (Marambaud, P., Shioi, J. et al., EMBO J. 2002, 21, 1948-1956) and CD44 (Okamoto, I., Kawano, Y., et al., J. Cell Biol. 2001, 155, 755-762). If the inhibition of cleavage of the non-APP substrates has an unwanted effect on people, then set the inhibitors γ-secretase mainly inhibit cleavage of APP associated with resultline substrates. Cleavage of transmembrane receptors of the Notch family can be monitored directly by measuring the amount of cleavage product, or indirectly, by determining the product of the cleavage of the transcription (Mizutani, T., Tanigutchi, Y. et al. Proc. Natl. Acad. Sci. USA 2001, 98, 9026-9031).

In vivo about what the definition of reduce Andβ using inhibitors γ-secretase.

In vivo analyses applicable to demonstrate inhibition γ-secretase activity. In these analyses to demonstrate the suitability of inhibitors γ-secretase you can use animals, such as mice, which Express normal levels of APP and, therefore, Aβ (Dovey, H., John, V. et al., J. Neurochem. 2001, 76, 173-181). In these analyses inhibitors γ-secretase injected animals and the above-described methods of monitoring levels Andβ in many departments, such as plasma, cerebral spinal fluid (CSF) and brain extracts. For example, the Tg2576 mice, sverkhekspressiya human RDAs, via a stomach tube orally administered inhibitory γ-secretase in doses that cause a measurable decrease in the level Andβusually less than 100 mg/kg After three hours after a dose collect samples of plasma, brain and CSF (cerebrospinal fluid), frozen in liquid nitrogen and stored at -80°C until analysis. To detect Andβ plasma diluted 15-fold in PBS with 0.1% Chaps with protease inhibitors (5 μg/ml leupeptin, 10 μg/ml Aprotinin, 1 mm phenylmethylsulfonyl, 1 μm of pepstatin). Brain tissue is homogenized in 1% Chaps with protease inhibitors using 24 ml/g brain tissue. Then the homogenates centrifuged at 100000×g for 1 hour at 4°C. Then 10 times Rabaul who have received supernatant in 1% Chaps with protease inhibitors. Levels Aβ in plasma, CSF and brain lysate was measured using preparednesses fluorescence analysis of homogeneous sample or one of the other above methods.

Inhibitor γ-secretase is aktivnim in one of the above-described in vivo analyses, if its introduction in a dose of 100 mg/kg reduces the level of Aβat least 50%.

Therefore, the compounds of Formula I or a pharmaceutical composition suitable for treatment, mitigation or elimination disorders or other disorders associated with inhibition β-amyloid peptide.

In another embodiment, the invention encompasses pharmaceutical compositions containing at least one compound of Formula I in combination with a pharmaceutical adjuvant, carrier or diluent.

In another embodiment, this invention relates to a method of inhibiting β-amyloid peptide in an organism in need thereof of a mammal, consisting in the introduction to the specified mammal a therapeutically effective amount of the compounds of Formula I or its non-toxic(CSOs) are pharmaceutically acceptable(CSOs) salt, MES or hydrate.

In another embodiment, the present invention relates to a method of treatment of Alzheimer's disease and down syndrome in need of this mammal, which is the introduction of UCU is anomo the mammal a therapeutically effective amount of the compounds of Formula I or its non-toxic(CSOs) are pharmaceutically acceptable(CSOs) salt, the MES or hydrate.

For therapeutic use of pharmacologically active compounds of the Formula I is usually administered in the form of a pharmaceutical composition containing as a main active ingredient (or one of the main active ingredients), at least one such compound in combination with a solid or liquid pharmaceutically acceptable carrier and optionally with pharmaceutically acceptable adjuvants and excipients using standard and convenient methods.

Pharmaceutical compositions include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous), bronchial or nasal applications. So, if you use solid media, the drug may be in the form of tablets can be placed in a hard gelatin capsule in powder or granules, or in the form of tablets or cakes. A solid carrier can include the appropriate excipients, such as binders, fillers, lubricant for tableting, substances that contribute to crushing, moisturizer, etc. the Tablet, if desired, conventional methods can be covered with a sheath. If you use a carrier liquid, the drug may be in the form of a syrup, emulsion, soft gelatin capsules of the drug with sterile media and is yacci, aqueous or non-aqueous suspension in the liquid, or may be in the form of a solid product, which is dissolved in water or other suitable carrier prior to use. Liquid preparations can contain conventional additives, such as suspendresume agents, emulsifying agents, moisturizing agents, non-aqueous media (including edible oils), preservatives and substances that give the taste and smell, and/or dyes. For parenteral administration the carrier typically contains sterile water, at least mostly, though, you can use saline solutions, glucose solutions and the like Can be applied injectable suspension, in this case, you can use a regular suspendresume agents. In the dosage form for parenteral administration can also add standard preservatives, bothersome agents and other Pharmaceutical compositions have the usual methods appropriate to the desired preparation containing appropriate quantities of the active ingredient, i.e. the compounds of Formula I according to the invention. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 17thedition, 1985.

The dosage of the compounds of Formula I for therapeutic effect depends not only on such factors as age, weight and sex of the patient and the method of application, but also on the desired degree β-AR inhibition and efficiency specifically what about the connection, used for specific disorders in this disease. Also taken into account, which can be treated using the dosage of a particular compound by introducing a single dose, and that a single dose may adjust the specialist in the art, given the relative level of activity. The decision about what specific dose to be used (and how many times a day), is the responsibility of the attending physician, and these values can be changed by selecting dose to the specific conditions of the present invention to achieve the desired therapeutic effect.

A suitable dose of a compound of Formula I or pharmaceutical composition to a mammal, including humans, suffering from or suspected of suffering from any violation related products β-AR according to this description, as a rule, is: a daily dose of about 0.05-10 mg/kg and preferably about 0.1-2 mg/kg for parenteral administration. Oral spacing of doses is about 1-75 mg/kg, and preferably 0.1 to 10 mg/kg of body weight. The active ingredient is preferably administered in the same doses one to four times per day. However, usually take a small dose and gradually increase the dose until you determine the optimal treatment of the master dose. In accordance with established clinical p is acticoa is preferred to introduce the considered compounds at these concentrations, which has a effective anti-amyloid remedy action without causing any harmful or adverse side effects. It is clear however, that the actual number of input connections is determined by the physician in light of the relevant circumstances, including the subject of treating a condition selected for the introduction of the compound, chosen route of administration, age, weight and individual response of the patient and the severity of the patient's symptoms.

The following examples are given to illustrate, but in no way claim to be limiting of the invention, since many possible variants of the invention, without departing from its essence.

DESCRIPTION of SPECIFIC OPTIONS INVENTIONS

In the examples below, all temperatures are given in degrees Celsius. The melting temperature determined in a capillary tube on the instrument Thomas Scientific Unimelt and do not adjust. The spectra of nuclear magnetic resonance (1H NMR) recorded on the following instruments : Bruker Avance 300, Bruker Avance 400 or Bruker Avance 500. All spectra are taken in the specified solvent and chemical shifts are given in units of the scale δ in the weaker field relative to the internal standard tetramethylsilane (TMS, TMS), and the constant of spin-spin interaction is given in Hertz (Hz).

Multipletness and the nature of the signals denoted as follows: C (s, singlet; d, doublet; t (t), I is t; kV (q, Quartet; m (m), multiplet; ush (br), broadened signal; DD (dd), doublet of doublets; ush. d (br d), broadened doublet; dt (dt), doublet of triplets; ush. (br s), broadened singlet; DQC (dq), doublet of quartets. Infrared (IR) spectra in the film (between the plates) of potassium bromide (KBR) or sodium chloride in the region from 4000 to 400 cm-1remove spectrometer Jasco FT/IR-410 or Perkin Elmer 2000 FT-IR calibrated to the absorption band of the film of polystyrene at 1601 cm-1and expressed in reciprocal centimeters (cm-1). Optical rotation [α]Ddetermine on a Rudolph polarimeter Scientific Autopol IV in these solvents; the concentrations indicated in mg/ml. mass spectra of low-resolution (MS) and average molecular mass (MH+) or (M-N)+register on the device Finnegan SSQ7000. Mass spectra of high resolution register on the device Finnegan MAT900. The / mass spectrometry (liquid chromatography (LC)/mass spectrum) performed on a liquid chromatograph Shimadzu LC connected to a mass-spectrometer Water Micromass ZQ.

The following abbreviations are used: DMF DMF (dimethylformamide); THF (tetrahydrofuran); DMSO (dimethylsulfoxide), Leu (leucine); TFA (TFA) (triperoxonane acid); DAST [(diethylamino)sulphur TRIFLUORIDE], ghvd (liquid chromatography high pressure); rt (room temperature); aq. (aq.) (water).

Examples of making connections on P is a promotional scheme 1

Amide and (2R)-2-(4-chlorobenzenesulfonamide)-4-methylpentanoic acid:

To a solution of (D)-leucinamide hydrochloride (0.25 g, 1.5 mmol) and Et3N (0.43 ml, 3.0 mmol) in CH2Cl2(150 ml) is added 4-chlorobenzenesulfonamide (380 mg, 1.8 mmol). The resulting solution was stirred at rt for 18 hours. Then the reaction mixture was diluted with CH2Cl2(200 ml) and washed with H2Oh, 0.5 N HCl, brine and dried with MgSO4get the title compound (410 mg) as a white solid with a yield of 90%. MS (ESI, electrospray ionization), (M+N)+305.2;1H NMR (DMSO-d6) δ 7.77 (d, 2H, J=8.7), 7.62 (d, 2H, J=8.7), 6.90 (ush. s, 1H), 3.67 (m, 1H), 1.54 (m, 1H), 1.31 (m, 2H), 0.81 (d, 3H, J=7.0), 0.71 (d, 3H, J=7.0).

Method And conversion of III to I

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-methoxybenzyl)amino]-4-methylpentanoic acid (Example 1)

Amide and (2R)-2-(4-chlorobenzenesulfonamide)-4-methylpentanoic acid (300 mg, 1 mmol), K2CO3(170 mg, 1.2 mmol) and 4-methoxybenzylamine (170 mg, 1.1 mmol) in DMF (25 ml) is heated at 60°C for 18 hours. Then the reaction mixture was added EtOAc (150 ml) and washed with H2O, brine, dried with MgSO4and evaporated, get the crude product as a white wax. Additional cleaning flash chromatography (SiO2, 25% EtOAc/mixture hexanol) gives the title soybeans is inania (297 mg) as a white solid connection with the release of 70%. [α]D=+44.2 (1.00, Meon); MS (ESI) (M-N)-422.9;1H NMR(CDCl3) δ 7.63 (d, 2H, J=7.0), 7.42 (d, 2H, J=7.0), 7.25 (d, 2H, J=8.0), 6.79 (d, 2H, J=8.0), 6.25 (ush. s, 1H), 5.35 (ush. s, 1H), 4.36 (dd, 2H, J=50,15), 4.26 (t, 1H, J=7.2), 3.78 (s, 3H), 1.83 (s, 1H), 1.18-1.34 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0); IR (KBr) 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm-1.

Method In the conversion of III to I

Methyl ester of 6-dimethylaminoethanol acid

A solution of methyl ester of 6-chloronicotinic acid (4.0 g, 23 mmol) in a solution of dimethylamine/Meon (2 M, 80 ml, 160 mmol) in a pressure vessel stirred at 95°C for 2 h, cooled to rt and evaporated. The residue is dissolved in EtOAc (250 ml), washed with water (2×150 ml), dried with Na2SO4and evaporated, to obtain the title compound in the form of solid, yellowish-brown (4.1 g, 98%). MS (ESI) (M+H)+181.24;1H NMR (CDCl3) δ 8.79 (s, 1H), 7.99 (d, 1H. J=9.2), 6.45 (d, 1H, J=9.2), 3.85 (s, 3H), 3.15 (s, 6N).

2-Dimethylamino-5-hydroxymethyluracil

A solution of methyl ester of 6-dimethylaminoethanol acid (4.14 g, 23.0 mmol) in dry ether (80 ml) at 0°treated with lydialydia (1 M in ether, 20 ml, 20 mmol). The mixture was stirred at rt for 0.5 hour, again cooled to 0°and slowly add us. aq. NaHCO3(10 ml). The resulting mixture was stirred at rt for 0.5 hour, filter the Ute and washed with ether. The combined filtrates are dried over Na2SO4and evaporated, obtaining the title compound in the form of waxy substances beige (3.5 g, 100%). MS (ESI) (M+H)+153.4;1H NMR (CDCl3) δ 8.06 (d, 1H, J=2.4), 7.47 (DD, 1H, J=2.4, 8.8), 6.45 (d, 1H, J=8.8), 4.50 (s, 2H), 3.06 (s, 6N), 1.98 (ush. s, 1H).

Salt TFA (TFA) and amide (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(2-dimethylaminopyridine-5-yl)amino]-4-fluoro-4-methylpentanoic acid (Example 459)

To turbid solution of amide (2R)-2-[(4-chlorobenzenesulfonyl)-4-fluoro-4-methylpentanoic acid (obtained according to Reaction scheme 20 or methyl ester γ-fluoro-D-Leu-OH, Papageorgiou et. al., Bioorg. & Med. Chem. Lett. 1994, Vol.4, p.p.267-272; 0.060 u, 0.18 mmol), 2-dimethylamino-5-hydroxymethylbilane (71 mg, 0.46 mmol), triphenylphosphine (122 mg, 0.464 mmol) in CH2Cl2(9.5 ml) at rt is added dropwise diisopropyl ester of azodicarboxylic acid (75 μl, 0.46 mmol). The resulting pale yellow solution was stirred at rt for 2 h and evaporated in vacuum. The residue is dissolved in methanol and purified by reversed-phase preparative ghvd (YMC S5 ODS, Meon-water-TFA), receive the title compound as a white foam (90 mg, 85%). MS (ESI) (M+H)+457.2;1H NMR (CDCL3) δ 8.11 (s, 1H), 7.95 (d, 1H, J=9.6), 7.77 (d, 2H, J=6.8), 7.51 (d, 2H, J=6.8), 6.76 (d, 2H, J=9.6), 6.34 (s, 1H), 6.02 (s, 1H), 4.58 (ush. d, 1H, J=8.4), 4.46 (d, 1H, J=16.0), 4.06 (d, 1H, J=16), 3.29 (s, 6N), 2.50 (m, 1H), 1.39 (m, 1H, 1.25 (d, 3H, J=22.0), 1.17 (d, 3H, J=22.0).

Examples of the application of the Reaction scheme 1 on solid media

Associated with the polymer (immobilized on the polymer) D-Leu-NH2

FMOC-protected amide resin Rinca (30 g, 0.61 mmol/g, 18 mmol) is treated with a solution of piperidine/DMF (250 ml). The mixture is shaken at rt for 24 hours, drain the liquid, washed with DMF (5×200 ml), CH2Cl2(5×200 ml) and dried in vacuum. Then the resin was treated with FMOC-D-Leu-OH (22 g, 62 mmol), 1-hydroxybenzotriazole hydrate (2.5 g, 18 mmol), 1,3-diisopropylcarbodiimide (9.8 ml, 62 mmol) and DMF (250 ml). The mixture is shaken for 20 hours, the liquid is decanted, washed with DMF (4×200 ml), a mixture of DMF-water (1:1, 3×200 ml), DMF (3×200 ml), Meon (3×200 ml), CH2Cl2(3×200 ml) and dried. The completion of the reaction and deposition (load) associated with the resin FMOC-D-Leu-NH2(0.56 mmol/g) determine processing 52 mg of the resin 10% vol. TFA/CH2Cl2(2 ml), get 11 mg of FMOC-D-Leu-NH2. Associated with the resin FMOC-D-Leu-NH2deprotection 20% vol. a solution of piperidine/DMF (250 ml)are associated with the polymer (immobilized on the polymer) D-Leu-NH2(20 g).

Associated with the polymer amide (R)-2-(4-chlorobenzenesulfonamide)-4-methylpentanoic acid

Obtained above is associated with the polymer (habilitowany on the polymer) D-Leu-NH 2(20 g) is treated with CH2Cl2(150 ml), pyridine (100 ml) and 4-chlorophenylsulfonyl (20.0 g, 94.8 mmol). The mixture is shaken for 24 hours, decanted, washed with DMF (4×200 ml), CH2Cl2(4×200 ml) and evaporated, getting associated with the polymer amide (R)-2-(4-chlorobenzenesulfonamide)-4-methylpentanoic acid in the form of a yellow polymer (22 g). The completion of the reaction and load resin (0.57 mmol/g) is determined by processing 50 mg resin 10% vol. TFA/CH2Cl2(2 ml), get 8.7 mg amide (R)-2-(4-chlorobenzenesulfonamide)-4-methylpentanoic acid.

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-methylbenzyl)amino]-4-methylpentanoic acid (Example 60)

To the mixture immobilized on a polymeric amide resin (2R)-2-[N-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid (0.45 mmol/g, 50.0 mg, 0.0225 mmol), 4-methylbenzylamine (44 mg, 0.24 mmol) and DMF (1.5 ml) was added 2-tert-butylamino-2-diethylamino-1,3-dimethylpyridine-1,2,3-datafactory (0.10 ml, 0.34 mmol). The resulting mixture is shaken at rt for 2 days, then decanted and washed with DMF (4×2 ml), Meon (4×2 ml) and CH2Cl2(4×2 ml).

Then the resin is treated with 10% vol. a solution of TFA/CH2Cl2. The mixture is shaken for 1 hour, filtered and washed with CH2Cl2(2×0.5 ml). The combined filtrates evaporated vacuume and get the title compound in the form of solid beige color (7.7 mg, 100%, Ehud purity >95%). HRMS (mass spectrometry high resolution) (ESI) (M-N)-for C20H24SClN2O3calculated 407.1206 found 407.1201;1H NMR (CDCl3) δ 7.64 (d, 2H, J=8.0), 7.44 (d, 2H, J=8.0), 7.22 (d, 2H, J=8.0), 7.08 (d, 2H, J=8.0), 6.29 (ush. s, 1H), 5.34 (ush. s, 1H), 4.53 (d, 1H, J=15.2), 4.34 (d, 1H, J=15.2), 4,27 (t, 1H, J=7.2), 2.32 (s, 3H), 1.84 (m, 1H), 1.30 (m, 1H), 1.21 (m, 1H), 0.75 (d, 3H, J=6.8), 0.67 (d, 3H, J=6.8); IR (KBr) 3467, 3367, 2956, 2869, 1694; 1670, 1340, 1160 cm-1.

Examples of the application of the Reaction scheme 2

Amide and (2R)-2-(4-methoxybenzylamine)-4-methylpentanoic acid

A solution of D-leucinamide hydrochloride (2.8 g, 16.8 mmol) and p-anisaldehyde (2.29 g, 16.8 mmol) in methanol (150 ml) is treated with anhydrous ZnCl2(538 mg, 5 mmol). Then the resulting suspension is treated with NaCNBH3(1.05 g, 16.8 mmol), adding parts, and boiled for 3 hours. The reaction mixture was cooled to rt, was added a saturated solution of NaHCO3(3 ml), add EtOAc (500 ml) and washed with brine. The process of evaporation receive raw benzylamine in the form of wax, which is then used without further purification (3.57 g, 84%). MS (ESI) (M+H)+251.4;1H NMR (CDCl3) δ 7.20 (d, 2H, J=6.6), 7.10 (ush. s, 2H), 6.88 (d, 2H, J=8.4), 5.30 (ush. s, 1H), 3.80 (s, 3H), 3.63 (DD, 2H, J=4.5, 12), 1.44-1.65 (m, 3H), 0.95 (d, 3H, J=6.3), 0.80 (d, 3H, J=6.3).

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-methoxybenzyl)amino]-4-methylp Stanovoy acid (Example 1)

Amide and (2R)-2-[N-(4-methoxybenzyl)amino]-4-methylpentanoic acid (3.57 g, 14.3 mmol) dissolved in CH2Cl2(100 ml) and treated with Et3N (4.2 ml, 29 mmol) and 4-chlorobenzenesulfonamide (3.6 g, 17 mmol) at rt for 18 hours. The solvent is distilled off and the residue is dissolved in EtOAc (500 ml). The organic solution was washed with H2O, brine, dried with MgSO4and evaporated. Then the residue is optionally purified flash chromatography (SiO2, 1% MeOH/CH2Cl2)to give the title compound (2.4 g) in the form of slightly colored solid with a yield of 40%. MS (ESI), (M-H)-422.9;1H NMR (CDCl3) δ 7.63 (d, 2H, J=7.0), 7.42 (d, 2H, J=7.0), 7.25 (d, 2H, J=8.0), 6.79 (d, m, J=8.0), 6.25 (ush. s, 1H), 5.35 (ush. s, 1H), 4.36 (DD, 2H, J=5.0, 15), 4.26 (t, 1H, J=7.2), 3.78 (s, 3H), 1.83 (m, 1H), 1.18-1.34 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0). IR (KBr) 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm-1.

The application example of the Reaction scheme 3

Amide and (2R)-2-[N-(4-morpholinoethyl)-N-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid (Example 25)

A solution of amide (2R)-2-[N-(4-bromohexyl)-N-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid (Example 24; obtained as described in Scheme 1; 0.20 g, 0.44 mmol), Et3N (0.25 ml, 1.7 mmol) and research (150 mg, 1.7 mmol) in CH2With2(2 ml) was stirred at rt for 18 hours. Then the reaction mixture is evaporated, get soggy white wax (resin), which cleaned the Ute flash chromatography (SiO 2, 85% EtOAc/5% mixture of hexanol/10% Meon)to give the title compound (112 mg) as a white solid with a yield of 54%. MS (ESI) (M+N)+474.4;1H NMR (DMSO-d6) δ 7.82 (1, 2N J=8.0), 7.64 (d, 2H, J=8.0), 7.42 (ush. s, 1H), 6.99 (s, 1H), 4.25 (m, 1H), 3.51-3.60 (ush s, 4H), 3.18-3.41 (m, 2H), 2.25-2.35 (ush s, 4H), 2.27 (m, 2H), 1.15-1.62 (m, N), 0.80 (d, 6N, J=6.0).

The application example of the Reaction scheme 4

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methylpentanoic acid (Example 48)

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-nitrobenzyl)amino]-4-methylpentanoic acid (Compound of Example 24; obtained as described in Reaction scheme 1; 2.8 g, 6.6 mmol) is suspended with 10% Pd/C (1 g) and conc. HCl (1 ml) in the Meon (100 ml) and placed in an atmosphere of hydrogen at a pressure 27.79 kPa (40 psi) for 1 hour. The suspension is filtered through celite and then evaporated, obtaining the title compound as a yellow-brown solid (2.4 g, yield 88%). MS (ESI) (M+H)+410.1;1H NMR (CDCl3) δ 7 80 (d, 2H, J=8.5), 7.63 (d, 2H, J=8.5), 7.52 (ush. s, 1H), 7.46 (d, 1H, J=8.0), 7.26 (d, 1H, J=8.0), 7.02 (ush. s, 1H), 4.70 (DD, 2H, J=50, 18), 4.30-4.41 (m, 1H), 3.67 (ush. s, 2H), 1.28-1.33 (m, 3H), 0.86 (d, 3H, J=7.0), 0.57 (d, 3H, J=7.0).

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-methylaminomethyl)amino]-4-methylpentanoic acid (Example 51)

A solution of amide (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methylphe Lanovoy acid (Example 48, 400 mg, 1 mmol), Et3N (0.16 ml, 1.1 mmol), dimethylsulfate (139 mg, 1.1 mmol) in 25 ml of toluene was stirred at rt for 18 hours. The reaction mixture was evaporated, then dissolved in EtOAc and washed with H2Oh, brine, dried To2CO3and evaporated, to give crude mixture of source and product. The mixture is then purified on a flash chromatography (SiO2, 35% EtOAc/mixture hexanol)to give the title compound 195 mg, yield 46%. MS (ESI) (M+N)+424.1;1H NMR (CDCl3) δ 7.65 (d, 2H, J=8.0), 7.58 (d, 2H, J=8.2), 7.47 (d, 2H, J=8.0), 7.31 (d, 2H, J=8.5), 6.24 (ush. s, 1H), 5.16 (ush. s, 1H), 4.50 (DD, 2H, J=50, 17), 4.27 (t, 1H, J=10), 2.44 (m, 3H), 1.74-1.83 (m, 1H), 1.25-1.33 (m, 1H), 0.93-1.01 (m, 1H), 0.74 (d, 3H, J=7.0), 0.63 (d, 3H, J=7.0).

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-dimethylaminobenzoyl)amino]-4-methylpentanoic acid (Example 65)

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methylpentanoic acid (Example 48, 0.10 g, 0.22 mmol) dissolved in DMF (5 ml). To this solution add logmean (62 mg, 0.44 mmol) and cesium carbonate (220 mg, 0.66 mmol). Then the reaction mixture was stirred at 40°C for 18 hours. The reaction mixture was poured into EtOAc and water. The organic extracts are combined, dried MgSO4and evaporated, receiving the remainder in the form of oil. The residue is optionally purified (Biotage 40S, application in CH2Cl2, elution with 25% EtOAc/mixture hexanol), receives a yellow powder (15 mg, 16%). MS ESI), (M+N)+438.1;1H NMR (DMSO-d6, 500 MHz) δ 7.74 (DD, 2H, J=1.9, 6.7), 7.54 (DD, 2H, J=1.9, 6.8), 7.43 (s, 1H), 7.16 (d, 2H, J=8.6), 7.01 (s, 1H), 6.61 (d, 2H, J=8.8), 4.59 (q, 2H, J=16, 25), 4.34 (DD, 1H, J=5.0, 9.3), 2.85 (s, 6N), 1.27-1.47 (m, 3H), 0.80 (d, 3H, J=5.9), 0.52 (d, 3H, J=6.1).

Examples of the application of Reaction scheme 5

tert-Butyl ether {N-[(1R)-1-carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino}acetic acid (Example 46)

Amide and (2R)-2-(4-chlorobenzenesulfonamide)-4-methylpentanoic acid (3.00 g, 9.87 mmol) dissolved in DMF (50 ml). To the solution was added potassium carbonate (6.0 g, 39 mmol) and tert-butyl methyl ether bromoxynil acid (6.0 ml, 39 mmol). The solution is heated at 70°C for 3 hours. To the solution was added EtOAc and a saturated solution of NaHCO3. The organic extracts washed with brine, dried with MgSO4and evaporated. The crude product in the form of oil cleanse next on the system Biotage 40M (load in CH2Cl2the elution of 30% EtOAc/mixture hexanol), get white powder (1.2 g, 35%). MS (ESI) (M+H)+446.3;1H NMR (CDCl3) δ 7.76 (d, 2H, J=8.0), 7.52 (d, 2H, J=8.0), 6.61 (ush. s, 1H), 5.45 (s, 1H), 4.15-4.18 (m, 1H), 3.09-3.24 (m, 2H), 2.50-2.58 (m, 4H), 2.31-2.39 (m, 2H), 1.92-1.99 (m, 1H), 1.15-1.59 (m, 8H), 1.00-1.04 (m, 7H), 0.71-0.74 (m, 6N).

{N-[(1R)-1-Carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino}acetic acid (Example 59)

Triperoxonane acid (15 ml) was added to a solution of the pet-butyl ester {N-[(1R)-1-carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino}acetic acid (0.50 g, 1.2 mmol) in CH2Cl2(15 ml). The reaction mixture was stirred at rt for 4 hours. Then the reaction mixture is evaporated, get a solid white color (0.40 g, 92%), which is used without further purification. MS (ESI) (M+H)+363.1;1H NMR (DMSO-d6, 500 MHz) δ 7.90 (DD, 2H, J=2.0, 6.8), 7.65 (DD, 2H, J=2.0, 6.8), 7.60 (s, 1H), 7.06 (s, 1H), 4.32 (d, 1H, J=18), 4.12 (t, 1H, J=8.0), 4.02 (d, 1H, J=18), 1.55-1.65 (m, 1H), 1.35-1.45 (m, 2H), 0.78 (d, 3H, J=6.1), 0.73 (d, 3H, J=6.1).

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(cyclopropanecarbonyl)amino]-4-methylpentanoic acid (Example 88)

To a solution of {N-[(1R)-1-carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino}acetic acid (Example 59, 175 mg, 0.480 mmol), cyclopropylamine (41 ml, 0.58 mmol) in CH2With2(3 ml) was added 1-hydroxybenzotriazole (47 mg, 0.72 mmol) and 1,3-dicyclohexylcarbodiimide (144 mg, 0.720 mmol). The reaction mixture was stirred for 18 h at rt, and then poured into a mixture of EtOAc/water. The organic layer is separated, dried with MgSO4and evaporated, receiving the remainder in the form of a clear oil. The residue is optionally purified on column (Biotage 40S (elute with a mixture of 40% EtOAc in a mixture of hexanol), receiving solid white (54 mg, 29%). MS (ESI) (M+H)+402.2;1H NMR (CDCl3, 500 MHz) δ 7.85 (DD, 2H, J=1.9, 8.9), 7.50 (DD, 2H, J=2.0, 8.7), 7.40 (ush. s, 1H), 6.55 (ush. s, 1H), 6.30 (ush. s, 1H), 4.23 (DD, 1H, J=2.9, 8.9), 3.92 (d, 1H, J=17), 3.8 (d, 1H, J=17), 2.68-2.73 (m, 1H), 1.75-1.83 (m, 1H), 1.50-1.57 (m, 1H), 1.40-1.49 (m, 1H), 0.88 (d, 3H, J=6.4), 0.87 (d, 3H, J=6.7), 0.80 (d, 2H, J=7.0), 0.51 (t, 2H, J=4.0).

Examples of the application of Reaction scheme 6

4-{[N-[(1R)-1-Carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino]methyl}benzoic acid (Example 89)

The compound of Example 61 [methyl ester [4-{[N-[(1R)-1-carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino]methyl}benzoic acid, 354 mg, 0.782 mmol] is dissolved in methanol (4 ml). Add 5 N NaOH solution (1 ml), and then THF, sufficient to make the solution was homogenen (1 ml). After 1 hour, add an additional aliquot of 5 N NaOH (1 ml) and continue stirring for 2.5 hours. The solution is acidified to pH 2 by adding 1 N HCl, and extracted with CHCl3(2). The combined organic extracts dried (Na2SO4) and evaporated, getting a solid white color (343 mg, 100%). MS (ESI) (M+H)+439.17;1H NMR (CDCl3, 300 MHz) δ 7.91 (d, 2H, J=8.2), 7.81-7.84 (m, 3H), 7.56 (d, 2H, J=8.6), 7.49 (d, 2H, J=8.2), 6.55 (ush. s, 1H), 5.10 (d, 1H, J=15.4), 4.23 (DD, 1H, J=4.6, 9.7), 4.05 (d, 1H,J=15.4), 2.04-2.14 (m, 1H), 1.20-1.31 (m, 1H), 0.80-0.89 (m, 1H), 0.74 (d, 3H, J=6.6), 0.68 (d, 3H, J=6.6).

Amide and (2R)-2-{N-(4-chlorobenzenesulfonyl)-N-[4-(morpholine-4-carbonyl)benzyl]amino}-4-methylpentanoic acid (Example 101)

To a solution of 4-{[N-[(1R)-1-carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino]METI the}benzoic acid (50.0 mg, 0.114 mmol) in DMF (0.3 ml) was added morpholine (12.9 mg, 0.148 mmol)and then 1-hydroxybenzotriazole (18.5 mg, 0.137 mmol), 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.2 mg, 0.137 mmol) and iPr2NEt (26 μl, 0.15 mmol). After 2 hours the temperature of the solution is brought to rt. After 4 hours the solution is poured into 10% aq. citric acid and extracted with EtOAc (2x). The combined organic extracts are washed sequentially us. aq. NaHCO3, then dried (MgSO4) and evaporated. Column flash chromatography (SiO2, 40-100% EtOAc/mixture hexanol) get the title compound in the form of solid white (46.0 mg, 79%). MS (ESI) (M+H)+508.22;1H NMR (CDCl3, 300 MHz) δ 7.68 (d, 2H, J=8.6), 7.29-7.47 (m, 6N), 6.38 (ush. s, 1H), 5.75 (ush. s, 1H), 4.65 (d, 1H, J=16.0), 4.42 (d, 1H, J=16.0), 4.32 (t, 1H, J=7.5), 3.30-3.85 (ush. m, 8H), 1.69-1.78 (m, 1H), 1.28-1.37 (m, 1H), 1.08-1.14 (m, 1H), 0.76 (d, 3H, J=6.5), 0.63 (d, 3H, J=6.6).

Examples of the application of Reaction scheme 7

tert-Butyl ether 4-{[N-[(1R)-1-carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino]methyl}piperidine-1-carboxylic acid (Example 92)

To a solution of amide (2R)-2-(4-chlorobenzenesulfonamide)-4-methylpentanoic acid (4.2 g, 14 mmol) in DMF (50 ml) was added cesium carbonate (13.6 g, 417 mmol). To this reaction mixture was added tert-butyl ester 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylic acid (reference: Gilissen, S.; Borans, G.; De Groot, T.; Verbruggen, A.J.Labeled Cmpd. Radiopharm. 1999, 42, 1289;. 10.4 g, 282 mmol). The reaction mixture was stirred at 70°C for 18 hours. Then the reaction mixture was diluted with us. aq. NaHCO3and extracted with EtOAc. The organic extracts are combined, washed with brine, dried with MgSO4and evaporated, getting a clear oil. The oil is then purified on a Biotage 40S (eluent 30% EtOAc in a mixture of hexanol), get a solid white color (3.0 g, 44%). MS (ESI) (M+H)+502.1;1H NMR (DMSO-d6, 500 MHz) δ 7.86 (DD, 2H, J=2.0, 6.8), 7.65 (DD, 2H, J=2.0, 6.8), 7.37 (ush. s, 1H), 7.07 (ush. s, 1H), 4.19 (t, 1H, J=7.6), 3.92 (ush. s, 2H), 3.35 (DD, 1H, J=15, 6.8), 3.05 (DD, 1H, J=15, 8.1), 1.85 (ush. s, 1H), 1.50-1.70 (m, 4H), 1.38 (s, N), 1.10-1.20 (m, 1H), 0.80-1.00 (m, 3H), 0.82 (d, 6N, J=7.6).

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidine-4-ylmethyl)amino]-4-methylpentanoic acid (Example 126)

To a solution of tert-butyl ester 4-{[N-[(1R)-1-carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino]methyl}piperidine-1-carboxylic acid (Example 92, 2.6 g, 5.2 mmol) in CH2Cl2(25 ml) was added triperoxonane acid (10 ml). The reaction mixture is stirred for 1 hour, and then evaporated, getting a solid white color (1.6 g, 84%). MS (ESI) (M+H)+402.15;1H NMR (DMSO-d6, 500 MHz) δ 7.87 (d, 2H, J=8.5), 7.66 (d, 2H, J=8.6), 7.41 (s, 1H), 7.04 (s, 1H), 4.17 (t, 1H, J=7.3), 3.40-3.50 (m, 1H), 3.20-3.25 (m, 1H), 3.03-3.10 (m, 1H), 2.65-2.80 (m, 2H), 1.85-2.00 (m, 1H), 1.20-1.85 (m, 2H), 1.45-1.60 (m, 1 is), 1.30-1.40 (m, 1H), 1.10-1.30 (m, 4H), 0.75-0.90 (m, 1H), 0.82 (d, 3H, J=7.3), 0.80 (d, 3H, J=7.0).

Amide and (2R)-2-{N-(4-chlorobenzenesulfonyl)-N-[1-(pyridine-4-carbonyl)piperidine-4-ylmethyl]amino}-4-methylpentanoic acid (Example 278)

To a solution of amide (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidine-4-ylmethyl)amino]-4-methylpentanoic acid (Example 126, 0.10 g, 0.22 mmol) and Et3N (0.06 ml, 0.5 mmol) in CH2Cl2(3 ml) was added the acid chloride isonicotinic acid hydrochloride (56 mg, 0.32 mmol). The reaction mixture was stirred at rt for 18 h, and then poured into a mixture of EtOAc and us. aq. NaHCO3. The organic layer is separated and washed with brine, dried with MgSO4and evaporated, receiving the remainder in the form of oil. The residue is purified on Biotage 10M (elution with 80% EtOAc/mixture hexanol), get a solid white color (36 mg, 30%). MS (ESI) (M+N)+509.20;1H NMR (CDCl3, 500 MHz) δ 8.66 (ush. s, 2H), 7.80 (d, 1H, J=8.6), 7.73 (d, 2H, J=8.5), 7.51 (d, 2H, J=7.6), 7.41 (ush. s, 1H), 6.64 (ush. s, 1H), 5.35 (ush. s, 1H), 4.70 (ush. s, 1H), 4.10 (ush. s, 1H), 3.71 (ush. s, 1H), 3.33 (ush. s, 1H), 3.02 (DD, 2H, J=4.8, 16), 2.70-2.85 (ush. s, 1H), 1.50-2.09 (m, 5H), 1.18-1.33 (m, 4H), 0.73 (d, 3H, J=6.7), 0.68 (d, 3H, J=6.5).

Ventilated 4-{[N-[(1R)-1-carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino]methyl}piperidine-1-carboxylic acid (Example 256)

To a solution of amide (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidine-4-ylmethyl)amino]-4-methylp Stanovoy acid (Example 126, 0.10 g, 0.22 mmol) and Et3N (32 μl, 0.25 mmol) in CH2Cl2(3 ml) was added (2-isocyanatomethyl)benzene (0.040 ml, 0.30 mmol). The reaction mixture was stirred at rt for 18 h, and then poured into a feast upon. aq. NaHCO3and extracted with EtOAc. The organic layer was washed with brine, dried with MgSO4and evaporated, receiving the remainder in the form of oil. The residue is purified on Biotage system (elution with 75% EtOAc/mixture hexanol)obtain the target product as a solid white (67 mg, 52%). MS (ESI) (M+H)+549.00;1H NMR (CDCl3, 500 MHz) δ 7.71 (d, 2H, J=8.6), 7.71 (d, 2H, J=8.9), 7.15-7.35 (m, 5H), 6.64 (s, 1H), 5.86 (s, 1H), 4.15 (DD, 1H, J=5.2, 9.5), 3.88 (d, 1H, J=13), 3.76 (d, 1H, J=13), 3.46 (t, 2H, J=6.7), 3.21-3.29 (m, 1H), 2.97 (DD, 1H, J=4.6, 14), 2.65-2.85 (m, 4H), 1.75-1.95 (m, 3H), 1.00-1.30 (m, 5H), 0.75-0.80 (m, 1H), 0.72 (d, 3H, J=6.7), 0.67 (d, 3H, J=6.7).

Amide and (2R)-2-{N-(4-chlorobenzenesulfonyl)-N-{[2-(4-cyanophenyl)-2-oxoethyl]piperidine-4-ylmethyl}amino)-4-methylpentanoic acid (Example 286)

To a solution of amide (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidine-4-ylmethyl)amino]-4-methylpentanoic acid (Example 126, 0.050 g, 0.12 mmol) and Et3N (0.040 ml, 0.30 mmol) in CH2Cl2(2 ml) was added 4-(2-chloroacetyl)benzonitrile (55 mg, 0.30 mmol). The reaction mixture was stirred at rt for 18 h, and then evaporated. The residue is purified on Biotage system (elution with 80% EtOAc/mixture hexanol)obtain 29 mg (48%) of the desired product as a solid in the society of white. MS (ESI) (M+H)+545.16;1H NMR (CDCl3, 500 MHz) δ 7.72 (d, 2H, J=8.5), 7.50-7.65 (m, 2H), 7.50 (d, 2H, J=7.0), 7.35-7.45 (m, 2H), 6.67 (s, 1H), 5.32 (s, 1H), 4.14 (DD, 1H, J=5.0, 9.0), 3.52 (ush. s, 1H), 3.28 (t, 1H, J=14), 2.97 (DD, 1H, J=3.5, 14), 2.82 (ush. s, 1H), 1.00-2.00 (m, 10H), 0.71 (d, 3H, J=6.5), 0.66 (d, 3H, J=6.5).

Examples of the application of Reaction scheme 8

Amide and (2R)-2-{N-(4-chlorobenzenesulfonyl)-N-[4-(tetrahydropyran-2-intoximeter)benzyl]amino}-4-methylpentanoic acid

Amide and (2R)-2-(4-chlorobenzenesulfonamide)-4-methylpentanoic acid (6.35 g, 196 mmol), CsCO3(5.62 g, 196 mmol) and 2-[(4-methyl bromide)benzyl]oxy)tetrahydropyran (5.62 g, 196 mmol) in acetonitrile (200 ml), boiled for 1 hour. The reaction mixture is filtered under vacuum through celite. The filtrate is evaporated in vacuum, obtaining a white foam (9.5 g, 96%). The foam used without purification in subsequent reactions. MS (ESI) (M+N)+510.9;1H NMR (CDCl3) δ 7.83 (d, 2H, J=8.0), 7.75 (d, 2H, J=8.0), 7.39 (d, 2H, J=8.0), 7.24 (d, 2H, J=8.0), 6.25 (ush. s, 1H), 5.35 (ush. s, 1H), 4.82 (d, 1H, Jab=12), 4.65 (m, 1H), 4.52 (d, 1H, Jab=12), 4.30 (d, 1H, Jab=16), 4.20 (d, 1H, Jab=16), 3.74 (m, 2H), 3.46 (m, 1H), 1.89 (m, 1H), 1.66 (m, 6N), 0.97 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0).

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-hydroxymethyl)benzylamino]-4-methylpentanoic acid (Example 95)

To a solution of amide (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-[4-(tetrahydropyran-2-intoximeter)benzylamino]-4-methylpentanoate (9.5 g, 186 mmol) in methanol (200 ml) was added a catalytic amount of p-toluenesulfonic acid. The mixture is stirred over night at rt. The solvent is removed in vacuum. The resulting foam was dissolved in CH2Cl2(100 ml), washed with 1 N NaOH, H2O and dried MgSO4. The filtrate is evaporated in vacuum. The resulting foam is crystallized from hot hexane, receive the product in a solid white color (7.7 g) with a yield of 92%. MS (ESI) (M+H)+425.17;1H NMR (CDCl3) δ 7.68 (d, 2H, J=7.0), 7.46 (d, 2H, 7=7.0), 7.33 (d, 2H, J=8.0), 7.28 (d, 2H, J=8.0), 6.26 (ush. s, 1H), 5.35 (ush. s, 1H), 4.67 (ush. s, 2H), 4.59 (d, 1H, Jab=16), 4.37 (d, 1H, Jab=16), 4.26 (t, 1H, J=7.0), 1.86-1.80 (m, 2H), 1.34-1.28 (m, 1H), 1.16-1.10 (m, 1H), 0.96 (d, 3H, J=7.0), 0.93 (d, 3H, J=7.0).

4-{[N-[(1R)-1-Carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino]methyl}benzyl ether methanesulfonate

To a cooled to 0°With the solution of amide (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-hydroxymethylbenzene)amino]-4-methylpentanoic acid (1.5 g, 3.5 mmol) in CH2Cl2(15 ml) under stirring add Et3N (0.74 ml, 5.3 mmol). Added dropwise a solution of methanesulfonamide (0.29 ml, 3.5 mmol) in 5 ml of CH2Cl2and the reaction mixture is stirred 1 hour at 0°C. To the reaction mixture was added 25 ml of CH2Cl2quickly washed with 1 N HCl, brine and dried, passing the organic phase through the cotton fabric is the same filter. The solvent is distilled in vacuum, obtaining the title compound in quantitative yield. The resulting foam is used without purification in subsequent reactions. MS (ESI) (M-95)+409.15;1H NMR (CDCl3) δ 7.70 (d, 2H, J=8.0), 7.48 (d, 2H, J=8.0), 7.41 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 6.27 (ush. s, 1H), 5.32 (ush. s, 1H), 5.24 (s, 2H), 4.64 (d, 1H, Jab=16), 4.43 (d, 1H, Jab=16), 4.33 (t, 1H, J=6), 2.90 (s, 3H), 1.90 (m, 1H), 1.60 (m, 2H), 0.96 (d, 3H, J=7.0), 0.91 (d, 3H, J=7.0).

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-dimethylaminomethylene)amino]-4-methylpentanoic acid (Example 110)

To a solution of 4-{[N-((1R)-1-carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino]methyl}benzyl ether methanesulfonate (150 mg, 0.298 mmol) in CH2Cl2(3 ml) at 0°under stirring was added 1 equivalent of Et3N, a then dimethylamine (0.3 ml, 2 M in THF). The reaction mixture was stirred over night at room temperature. To the mixture was added CH2Cl2, washed with water, brine, dried with MgSO4and evaporated, get glassy product amber color. Clean flash chromatography (SiO2, 10% MeOH/CH2Cl2) gives the title compound (95 mg) with a yield of 71%. MS (ESI) (M+H)+452.23;1H NMR (CDCl3) δ 7.94 (d, 2H, J=8.0), 7.74 (d, 2H, J=8.0), 7.63 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 6.23 (ush. s, 1H), 5.35 (ush. s, 1H), 4.22 (d, 1H, Jab=16), 4.14 (d, 1H, Jab=16), 3.28-3.23 (m, 3H), 2.17 (ush. C, 6N) 1.95 (m, 1H), 1.55 (m, 2H), 0.96 (d, 3H, J=7.0), 0.93 (d, 3H, J=7.0).

Examples of the application of the Reaction scheme 9

Amide and (2R)-2-[N-(4-acetylaminobenzoic)-N-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid (Example 163)

To a solution of the compound from Example 48 [amide (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methylpentanoic acid (250 mg, 0.60 mmol) and Et3N (120 mg, 1.2 mmol) in CH2Cl2(20 ml) was added acetyl chloride (56 mg, 0.72 mmol). Stirred for 18 h, the reaction mixture is evaporated, chromatographic (flash-chromatography on silica gel, 1% methanol/CH2Cl2) get the title compound (110 mg, 41%). MS (ESI), (M-H)-422.9;1H NMR (CDCl3) δ 7.67 (d, 2H, J=8.0), 7.28-7.46 (m, 6N), 7.12 (ush. s, 1H), 6.24 (ush. s, 1H), 5.19 (ush. s, 1H), 4.48 (DD, 2H, J=50, 15), 4.27 (t, 1H, J=7.0), 2.18 (s, 3H), 1.80-2.01 (m, 1H), 1.12-1.32 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0).

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-{[(2-dimethylaminoacetyl)methylamino]methyl}benzyl)amino]-4-methylpentanoic acid (Example 272)

Amide and (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-methylaminomethyl)amino]-4-methylpentanoic acid (75 mg, 0.17 mmol), (α-dimethylamino)acetic acid (18 mg, 0.17 mmol), 1-hydroxybenzotriazole (24 mg, 0.17 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol) are mixed in CH2Cl2(3 ml) and lane is mesilat during the night. To the reaction mixture add 5 ml of CH2Cl2and washed with 1 N NaOH and brine. The organic layer is dried by filtering through a cotton filter, and the solvent is removed in vacuum. Purified preparative Ehud receive the title compound (61 mg) with a yield of 68%. MS (ESI)523.4 (M+N)+;1H NMR (CDCl3) δ 8.02 (d, 2H, J=8.0), 7.71 (d, 2H, J=8.0), 7.37 (d, 2H, J=8.0), 7.28 (d, 2H, J=8.0), 6.23 (ush. s, 1H), 5.51 (ush. s, 1H), 4.46 (s, 2H), 4.70 (d, 1H, Jab=16), 4.33 (d, 1H, Jab=16), 3.25 (t, 1H, J=6.0), 2.69 (s, 3H), 2.63 (s, 2H), 2.20 (s, 6N), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0).

The application example of the Reaction scheme 10

Salt TFA (TFA) and amide (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(2-dimethylaminopyridine-5-ylmethyl)amino]-4-methylpentanoic acid (Example 254)

A solution of amide (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(2-chloropyridin-5-ylmethyl)amino]-4-methylpentanoic acid (obtained according to Reaction scheme 1, 18 mg, 41 mmol) in a solution of dimethylamine/THF (2 M, 20 ml, 40 mmol) was stirred at 95°C for 30 h in a pressure vessel. 5 ml of the reaction mixture (25% of total) purified by reversed-phase preparative ghvd (YMC S5 ODS, Meon-water-TFA), receive the title compound as a white foam (17 mg, 30%yield). HRMS (ESI) (M-N)-for C20H26SCIN4O3calculated 437.1426 found 437.1420;1H NMR (CDCl3): δ 8.04 (s, 1H), 8.03 (d, 1H, J=9.8), 7.76 (d, 2H, J=7.6), 7.54 (d, 2 is, J=7.6), 6.83 (d, 1H, J=9.8), 6.62 (ush. s, 1H), 6.40 (ush. s, 1H), 4.64 (d, 1H, J=15.9), 4.29 (m, 1H), 4.18 (d, 1H, J=15.9), 3.30 (s, 6N), 1.84 (m, 1H), 1.29 (m, 1H), 0.93 (m, 1H), 0.77 (d, 3H, J=6.5), 0.72 (d, 3H, J=6.5).

Examples of the application of the Reaction scheme 11

Amide and (2R)-2-[N-(4-allyloxy-3-terbisil)-N-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid

To a solution of amide (2R)-2-(4-chlorobenzenesulfonamide)-4-methylpentanoic acid (1.00 g, 3.29 mmol) and CsCO3(1.29 g, 3.95 mmol) in DMF (25 ml) was added 1-allyloxy-4-methyl bromide-2-torbenson (reference: Graham, Samuel L; European patent application (1992): EP 487270; 0.88 g, 3.67 mmol). The resulting solution was stirred at rt for 18 hours. Then to the reaction mixture was added EtOAc/mixture hexanol (9:1, 350 ml) and washed with H2About (4×200 ml), brine and dried with Na2SO4get the title compound (393 mg) as a solid white color with a yield of 26%. MS (ESI) (M+H)+469.1;1H NMR (CDCl3) δ 7.66 (d, 2H, J=8.1), 7.45 (d, 2H, J=8.1), 7.11 (d, 1H, J=12.0), 6.98 (m, 1H), 6.84 (t, 1H, J=8.0), 6.22 (ush. s, 1H), 6.04 (m, 2H), 5.42 (m, 1H), 5.16 (ush. s, 1H), 4.59 (m, 2H), 4.40 (m, 3H), 1.83 (m, 1H), 1.32 (m, 1H), 1.14 (m, 1H), 0.76 (d, 3H, J=7.0), 0.68 (d, 3H, J=7.0).

Amide and (2R)-2-{N-(4-chlorobenzenesulfonyl)-N-[3-fluoro-4-(2-morpholine--4-ylethoxy)benzyl]amino}-4-methylpentanoic acid (Example 427)

A mixture of intermediate aliakseyeu (0.39 g, 0.84 mmol)obtained above, Tetrao the led osmium (0.01, 0.04 mmol) and trimethylamine-N-oxide (0.140 g, 1.81 mmol) dissolved in acetone (10 ml) and stirred for 4 h at room temperature (rt). The solution is evaporated in vacuum and dissolved again in a mixture of dioxane : H2O (1.5:1, 15 ml). Add periodate sodium (0.22 g, 1.0 mmol) and the solution stirred at rt for 18 hours. Then the reaction mixture was added EtOAc (200 ml) and washed with H2O, brine, dried with Na2SO4and evaporated, receiving (2R)-{N-(4-chlorobenzenesulfonyl)-N-[3-fluoro-4-(2-oksidoksi)benzyl]amino}-4-methylpentanol acid. This raw material is used in the next stage without additional purification. Amide and (2R)-2-{N-(4-chlorobenzenesulfonyl)-N-[3-fluoro-4-(2-oksidoksi)benzyl]amino}-4-methylpentanoic acid (0.16 g, 0.34 mmol) and morpholine (0.090, 1.0 mmol) dissolved in EtOH (5 ml) and heated at 80°within about 15 minutes I put the oil bath, was added sodium triacetoxyborohydride (0.290 g, 1.36 mmol) and stirred suspension at rt for 16 hours. The solution is evaporated to dryness, add the brine, extracted with EtOAc (2×100 ml), dried with Na2SO4and evaporated in vacuum to get the crude product as an orange precipitate. Further purification preparative ghvd (column YMC S5 ODS C-18, 20×100 mm, 25 ml/min, 0-100% Meon/H2About 0.1% TFA, 15 min) to give the title compound (69.5 mg) as a solid pale yellow color with a yield of 31%. [α D+23 (6.4, CH2Cl2); LCMS (M+H)+542.25;1H NMR (CDCl3) δ 7.71 (d, 2H, J=8.0), 7.50 (d, 2H, J=8.0), 7.16 (d, 1H, J=12.0), 7.05 (d, 1H, J=8.0), 6.87 (t, 1H, J=8.0), 6.38 (ush. s, 1H), 5.91 (ush. s, 1H), 4.41 (Avcv, 2H, J=16, Jab=176), 4.45 (m, 2H), 4.27 (t, 1H, J=8.0), 4.03 (m, 4H), 3.70 (m, 2H), 3.51 (m, 2H), 3.10 (m, 2H), 1.83 (m, 1H), 1.29 (m, 1H), 1.05 (m, 1H), 0.75 (d, 3H, J=8.0), 0.68 (d, 3H, J=8.0).

The application example of the Reaction scheme 12

Amide and (2R)-2-{N-(4-chlorobenzenesulfonyl)-N-[4-(1-hydroxy-1-methylethyl)benzyl]amino}-4-methylpentanoic acid (Example 287)

A solution of the compound from Example 61 [methyl ester [4-{N-[(1R)-1-carbarnoyl-3-methylbutyl]-N-(4-chlorobenzenesulfonyl)amino]methyl}benzoic acid, 101 mg, 0.221 mmol] cooled to 0°in THF (2 ml). Added dropwise a solution of methylacrylamide (1.4 M in a mixture of toluene/THF, 0.50 ml, 0.71 mmol). Dark yellow solution was stirred at 0°and after 30 minutes add the additional amount of methylacrylamide. After 1 hour the solution is allowed to warm to room temperature. After 3.5 hours the reaction is stopped by adding us. aq. NH4Cl, and the mixture is extracted with EtOAc (2x). The combined organic extracts dried (Na2SO4) and evaporated. Flash chromatography on a column (SiO2, 20-100% EtOAc/mixture hexanol) gives the title compound as a white foam (62 mg, 62%). MS (ESI) (M+N)+453.16;1H NMR (CDCl3, 300 MHz) δ 7.61 (d, 2H, J=8.7), 7.40 d, 2H, J=8.7), 7.37 (d, 2H, J=8.4), 7.26 (d, 2H, J=8.4), 6.28 (ush. s, 1H), 5.25 (ush. s, 1H), 4.49 (d, 1H, J=15.9), 4.41(d, 1H, J=15.9), 4.33 (t, 1H, J=6.6), 1.73-1.80 (m, 1H), 1.55 (s, 6N), 1.28-1.35 (m, 1H), 1.20-1.25 (m, 1H), 0.77 (d, 3H, J=6.5), 0.66 (d, 3H, J=6.6).

The application example of the Reaction scheme 13

Amide and (2R)-2-{N-(4-chlorobenzenesulfonyl)-N-[4-(5-methyl[1,3,4]oxadiazol-2-yl)benzyl]amino}-4-methylpentanoic acid (Example 436)

Stage 1. To the compound of Example 61 [methyl ester [4-{[N-((1R)-1-carbarnoyl-3-methylbutyl)-N-(4-chlorobenzenesulfonyl)amino]methyl}benzoic acid, 0.500 mg, 1.10 mmol] was added methanol (10 ml)and then hydrazine (2 ml). Source dissolves slowly over 5 minutes. After 30 min the solution heated to boiling. After 22 hours, the solution is cooled to rt. Add water, a white precipitate is formed. The mixture is extracted with EtOAc (2x). The combined organic extracts washed with brine, dried (Na2SO4) and evaporated receive appropriate acylhydrazides in the form of a white foam, which is injected directly into the stage cyclization without further purification.

Stage 2. Raw (untreated) acellerated (0.150 g, 0.331 mmol) dissolved in pyridine (2.2 ml) and added acetimidate hydrochloride (60.0 mg, 0.364 mmol). The mixture is boiled for 1.25 hour. The solution is cooled to rt and evaporated with the purpose of distillation of pyridine. The residue is dissolved in EtOAc and washed successively with water, 1 N HCl (2x), us. aq. NaHCO3and assolombarda dried (MgSO 4) and evaporated. After flash chromatography on a column ((SiO2, 50-100% EtOAc/mixture hexanol) get the specified compound in the form of solid white (138 mg, 88% over 2 stages). [α]D+11.1 (7.0 mg/ml CHCl3); MS (ESI) (M+H)+477.22;1H NMR (CDCl3, 300 MHz) δ 7.94 (DD, 2H, J=1.8, 8.4), 7.69 (DD, 2H, J=1.8, 8.7), 7.45-7.50 (m, 4H), 6.23 (ush. s, 1H), 5.19 (ush. s, 1H), 4.65 (d, 1H, J=15.9), 4.46 (d, 1H, J=15.9), 4.31 (DD, 1H, J=6.6, 7.8), 2.61 (s, 3H), 1.75-1.85 (m, 1H), 1.28-1.35 (m, 1H), 1.08-1.15 (m, 1H), 0.76 (d, 3H, J=6.6), 0.64 (d, 3H, J=6.6).

The application example of the Reaction scheme 14

Amide and (2R)-2-{N-(4-chlorobenzenesulfonyl)-N-[4-(3-methyl[1,2,4]oxadiazol-5-yl)benzyl]amino}-4-methylpentanoic acid (Example 437)

Stage 1. To a solution of compound from Example 89 [[4-{[N-((1R)-1-carbarnoyl-3-methylbutyl)-N-(4-chlorobenzenesulfonyl)amino]methyl}benzoic acid, 520 mg, 1.2 mmol) in DMF (2.4 ml) and CH2Cl2(7.1 ml) was added 1-hydroxybenzotriazole (192 mg, 1.42 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (272 mg, 1.42 mmol) and iPr2NEt (0.31 ml, 1.8 mmol). Also add N-hydroxyacetamido (105 mg, 1.42 mmol). After 21 hours, the original is still present, so periodically add additional servings of all reagents, in order to bring the reaction to the end (move to the right). After 3 days the mixture was evaporated and partitioned between us. aq. NaHCO3and EtOAc (2x). The combined organic the latter is Ki washed with brine, dried (MgSO4) and evaporated, receiving a yellow oil, which enter into the next stage without additional purification.

Stage 2. Raw acetamidoxime dissolved in toluene (10 ml) and the solution heated to boiling. After 1 hour, add pyridine (2 ml) and continue heating for 15 hours. The mixture was evaporated and dissolved in EtOAc. The organic phase is successively washed with water, 1 N HCl (2x), us. aq. NaHCO3and brine, then dried (MgSO4) and evaporated. After flash chromatography on a column (SiO2, 10-40% EtOAc/mixture hexanol) get the title compound in the form of solid pale yellow color (238 mg, 42% in two stages). [α]23D+9.30 (5.93 mg/ml CHCl3); MS (ESI) (M+H)+477.18;1H NMR (CDCl3, 300 MHz) δ 8.04 (d, 2H, J=8.4), 7.70 (DD, 2H, J=1.8, 8.4), 7.45-7.52 (m, 4H), 6.23 (ush. s, 1H), 5.19 (ush. s, 1H). 4.67 (d, 1H, J=16.2), 4.47 (d, 1H, J=15.9), 4.31 (t, 1H, J=7.2), 2.47 (s, 3H), 1.75-1.85 (m, 1H), 1.28-1.35 (m, 1H), 1.08-1.15 (m, 1H), 0.76 (d, 3H, J=6.6), 0.64 (d, 3H, J=6.6).

The application example of the Reaction scheme 15

Amide and (2R)-2-{N-(4-chlorobenzenesulfonyl)-N-[4-(5-methyl[1,2,4]oxadiazol-3-yl)benzyl]amino}-4-methylpentanoic acid (Example 465)

To a solution of the compound from Example 6 [amide (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-cyanobenzyl)amino]-4-methylpentanoic acid (0.20 g, 0.47 mmol] in ethanol (6 ml) was added hydroxylamine (50% solution in water, 0.050 ml, 0.71 mmol). actionnow the warm mixture at 80° C for 18 hours. The reaction mixture is evaporated, the residue is recrystallized from a mixture of EtOAc/mixture hexanol, getting a solid white color (136 mg, 51%). Then this solid (0.18 mmol) is dissolved in chloroform and add Et3N (0.030 ml, 0.24 mmol) and acetylchloride (0.020 ml, 0.18 mmol). The reaction mixture was stirred at rt for 2 h, and then poured into EtOAc and brine. The organic layer is separated, dried with MgSO4and evaporated. The residue is dissolved in toluene and boiled for 24 hours. The reaction mixture was evaporated and purified on the Biotage system (elution of EtOAc/mixture hexanol, 1:1)get the specified product in the form of a solid white color (yield 35 mg, 39%). MS (ESI) (M+H)+477.13;1H NMR (CDCl3, 500 MHz) δ 7.98 (d, 2H, J=8.2), 7.68 (d, 2H, J=8.9), 7.45 (d, 4H, J=8.5), 6.21 (s, 1H), 5.19 (s, 1H). 4.62 (d, 1H, J=15), 4.48 (d, 1H, J=16), 4.31 (t, 1H, J=7.0), 2.65 (s, 3H), 1.75-1.85 (m, 1H), 1.20-1.35 (m, 4H), 1.10-1.17 (m, 1H), 0.85-0.90 (m, 1H), 0.75 (d, 3H, J=6.7), 0.64 (d, 3H, J=6,4).

The application example of the Reaction scheme 16

Amide and (2R)-2-[N-(4-acetylphenyl)-N-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid (Example 273)

A solution of the compound from Example 251 [4-{[N-((1S)-1-carbarnoyl-3-methylbutyl)-N-(4-chlorobenzenesulfonyl)amino]methyl}-N-methoxy-N-methylbenzamide, 0.100 g, 0.207 mmol] in THF (2.1 ml) cooled to 0°C. added dropwise a solution of methylacrylamide (1.4 M in a mixture of toluene/THF, 0.178 ml, .249 mmol). The resulting solution is stirred for 3 hours at 0°C, add more solution methylacrylamide (0.178 ml, 0.249 mmol). After another 30 minutes add the last portion of a solution of MeMgBr (0.3 ml). After 15 min to the reaction mixture add us. aq. NH4Cl and 1 N HCl and the mixture extracted with EtOAc (2x). The combined organic extracts washed us. aq. NaHCO3and brine, dried (Na2SO4). Flash chromatography on a column (SiO2, 20-60% EtOAc/mixture hexanol) get the specified compound in the form of yellowish-white foam (79 mg, 87%). [α]23D+20.4 (7.57, CHCl3); MS (ESI) (M+N)+437.13;1H NMR (CDCl3, 300 MHz) δ 7.87 (d, 2H, J=8.4), 7.67 (DD, 2H, J=1.8, 8.7), 7.42-7.46 (m, 4H), 6.21 (ush. s, 1H), 5.28 (ush. s, 1H), 4.64 (d, 1H, J=15.9), 4.45 (d, 1H, J=15.9), 4.31 (t, 1H, J=6.6), 2.58 (s, 3H), 1.73-1.80 (m, 1H), 1.25-1.35 (m, 1H), 1.05-1.14 (m, 1H), 0.74 (d, 3H, J=6.5), 0.65 (d, 3H, J=6.6).

The application example of the Reaction scheme 17

Amide and (2R)-2-{N-(4-chlorobenzenesulfonyl)-N-[4-(3-piperidine-1-ylpropionic)benzyl]amino}-4-methylpentanoic acid (Example 274)

To a solution of N-(4-{[N-((1S)-1-carbarnoyl-3-methylbutyl)-N-(4-chlorobenzenesulfonyl)amino]methyl}phenyl)acrylamide (0.10 g, 0.22 mmol) in toluene (5 ml) was added piperidine (20 mg, 0.24 mmol). The mixture is heated at a low boil for 1 hour and then the solvent is removed in vacuum. Clean flash chromatography (SiO2 10% of the Meon/CH2Cl2) gives the title compound with a yield of 86% (105 mg). MS (ESI) (M+H)+449.16;1H NMR (CDCl3, 400 MHz) δ 7.69 (d, 2H, J=8.0), 7.63 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 7.23 (d, 2H, J=8.0), 6.25 (ush. s, 1H), 5.35 (ush. s, 1H), 4.75 (d, 1H, J=16), 4.38 (d, 1H, J=16), 3.25 (t, 1H, J=6.0), 2.65 (t, 2H, J=6.0), 2.56-2.44 (m, 6N), 1.95 (m, 1H), 1.68-1.45 (m, 8H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0).

Examples of the application of the Reaction scheme 18

(2R)-2-(Benzhydrylidene)-1-{(1'S),(5'S)-10',10'-dimethyl-3',3'-deoxo-3'λ6-thia-4'-azatricyclo[5.2.1.0.1,5]Dec-4'-yl}-4-verboten-1-he

To a solution of N-2-(benzhydrylidene)-1-{(1'S),(5'S)-10',10'-dimethyl-3',3'-deoxo-3'λ6-thia-4'-azatricyclo[5.2.1.0.1,5]Dec-4'-yl}ethanone (link: Josien, H.; Martin, A.; Chassing, G. Tetrahedron Lett. 1991, 32, 6547; 30.0 g, 68 mmol) in NMR (60 ml) and THF (300 ml) at -78°With added dropwise n-BuLi (1.6 M in hexane, 42.4 ml, 68 mmol), keeping the temperature below -65°C. the Temperature of the reaction mixture is brought to room dropwise at rt was added a solution of 1-bromo-3-floridana (17.4 g, 137 mmol) in THF (30 ml). After 18 h, the reaction mixture was poured into H2O/SPLA (200 ml/2 ml), add EtOAc and the organic extracts washed with a saturated solution of NH4Cl, brine, dried with MgSO4and evaporated. The obtained orange oil is then purified by chromatography on silica gel (25% EtOAc/mixture hexanol), get a solid white color that cross stilizovala from 15% EtOAc/mixture hexanol, get a specified substance (24.4 g, 70%). MS (ESI) (M+N)+483.27;1H NMR (CDCl3) δ 7.66 (d, 2H, J=7.2), 7.13-7.44 (m, 8H), 4.82-4.83 (m, 2H), 4.39-4.81 (m, 2H), 3.84-3.87 (m, 1H), 3.28 (Avcv, 2H, J=18, 10) 2.33-2.41 (m, 2H), 2.02-2.04 (m, 2H), 1.84-1.87 (m, 2H), 1.32-1.39 (m, 2H), 1.10 (s, 3H), 0.91 (s, 3H).

(2R)-2-Amino-1-{(1'S),(5'S)-10',10'-dimethyl-3',3'-deoxo-3'λ6-thia-4'-azatricyclo[5.2.1.01,5]Dec-4'-yl}-4-verboten-1-he

To a solution of (2R)-2-(benzhydrylidene)-1-{(1'S),(5'S)-10',10'-dimethyl-3',3'-deoxo-3'λ6-thia-4'-azatricyclo[5.2.1.01,5]Dec-4'-yl}-verboten-1-it (20.0 g, 41 mmol) in THF (400 ml) was added 1 N HCl (200 ml). After 3 hours the reaction mixture are added water and extracted with Et2O. the Aqueous phase is then neutralized by adding 0.5 N NaOH. The basic solution is extracted with CH2Cl2, dried with MgSO4and evaporated, getting solid white (11.9 g, 90%).1H NMR (CDCl3) δ 4.56-4.71 (m, 2H), 4.23-4.31 (m, 1H), 3.40-3.49 (m, 3H), 3.11 (d, 2H, J=4.4), 1.17-2.23 (m, 8H), 1.13 (s, 3H), 0.93-1.12 (m, 3H).

(2R)-2-(4-Chlorobenzenesulfonamide)-1-{(1'S),(5'S)-10',10'-dimethyl-3',3'-deoxo-3'λ6-thia-4'-azatricyclo[5.2.1.01,5]Dec-4'-yl}-4-verboten-1-he

To a solution of (2R)-2-Amin-1-{(1'S),(5'S)-10',10'-dimethyl-3',3'-deoxo-3'λ6-thia-4'-azatricyclo[5.2.1.01,5]Dec-4'-yl}-4-verboten-1-it (12 g, 36 mmol) and Et3N (10.4 ml, 72.0 mmol) in CH2Cl2(350 ml) is added if all estvo 4-chlorobenzenesulfonamide (9.1 g, 43 mmol). After 18 h, the reaction mixture was evaporated, the obtained residue was dissolved in EtOAc and washed with H2Oh, brine, dried with MgSO4and evaporated. Then the product is purified by chromatography on silica gel (SiO2, 30% EtOAc/mixture hexanol)obtain the title compound (16.0 g, 92%) as a white wax.1H NMR (CDCl3) δ 7.79 (d, 2H, J=8.0), 7.43 (d, 2H, J=8.0), 5.69 (ush. d, J=8.0), 4.42-4.77 (m, 4H), 3.71-3.72 (m, 1H), 3.10 (Avcv, 2H, J=9, 4.4) 2.11-2.29 (m, 2H), 1.33-1.99 (m, 6N), 1.04 (s, 3H), 0.91 (s, 3H).

(2R)-2-(4-Chlorobenzenesulfonamide)-4-terbutalina acid

To a solution of (2R)-2-(4-chlorobenzenesulfonamide)-1-{(1'S),(5'S)-10',10'-dimethyl-3',3'-deoxo-3'λ6-thia-4'-azatricyclo[5.2.1.01,5]Dec-4'-yl}-4-verboten-1-it (16 g, 32 mmol) in acetonitrile (200 ml) with vigorous stirring was added LiBr (13.9 g, 16 mmol), tetrabutylammonium (4.13 g, 12.8 mmol) and LiOH (5.45 g, 0.130 mol). After 4.5 hours the reaction mixture is evaporated to half volume, add H2O and extracted with CH2Cl2. The aqueous phase is acidified with 1 N HCl and extracted with EtOAc. EtOAc extracts are combined, dried MgSO4and evaporated, get a solid white color, 9.4 g of this amount directly enter into the next stage.1H NMR (DMSO-d6) δ 8.39 (d, 1H, J=9.0), 7.76 (d, 2H, J=6.8), 7.64 (d, 2H, J=6.8), 7.00 (ush. s, 1H), 4.29-4.48 (m, 2H), 3.80-3.88 (m, 1H), 1.66-1.96 (m, 2H).

Amide and (2R)-2-(4-chlorobenzenesulfonamide)-4-torbutrol acid

To a solution of (2R)-2-(4-chlorobenzenesulfonamide)-4-torbutrol acid (9.0 g, 31 mmol) in DMF (250 ml) in an atmosphere of N2added sequentially 1-hydroxybenzotriazole hydrate (6.2 g, 46 mmol), N,N-diisopropylethylamine (23 ml, 124 mmol), ammonium chloride (3.34 g, 62 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.8 g, 46 mmol). The resulting solution was stirred at rt for 18 hours. The solution is poured into ice water (500 ml), the solid precipitate is filtered off and dried. The product is then precipitated with 10% EtOAc/mixture hexanol, get a clean solid white color (4.5 g) with a yield of 50%. [α]D=-21 (C 1.00, DMF); MS (ESI) (M-N)-293.01;1H NMR (DMSO-d6) δ 8.12 (d, 1H, J=8.8), 7.77 (d, 2H, J=7.0), 7.62 (d, 2H, J=7.0), 7.38 (ush. s, 1H), 7.03 (ush. s, 1H), 4.22-4.47 (m, 2H), 3.71-3.85 (m, 1H), 1.65-1.92 (m, 2H).

(2R)-2-(4-Chlorobenzenesulfonyl)-(4-cyanobenzyl)amino]-4-ferroceramic (Example 360)

(2R)-2-(4-Chlorobenzenesulfonamide)-4-ferroceramic (20 mg, 0.7 mmol) is transformed into the title compound by Reaction scheme 1, method A. Obtain 208 mg (73%) of the title compound. MS (ESI) (M-N)-407.99; [α]D= +39.13 (1.00, Meon);1H NMR (CDCl3) δ 7.72 (d, 2H, J=8.4), 7.58 (d, 2H, J=8.4), 7.50 (d, 2H, J=8.4), 7.45 (d, 2H, J=8.4), 6.29 (ush. s, 1H), 5.21 (ush. s, 1H), 4.19-4.67 (m, 5H), 2.17-2.28 (m, 1H), 1.49-1.61 (m, 1H).

When the minimum level of application of the Reaction scheme 19

Amide 2-(4-chlorobenzenesulfonamide)-6-ftaleksonami acid (III)

A mixture of ethyl ether (benzhydrylidene)acetic acid (8.6 g, 32 mmol), 4-bromo-1-verboten (10.0 g, 64.5 mmol), K2CO3(13.4 g, 96.9 mmol), tetrabutylammonium (2.1 g, 6.5 mmol) and acetonitrile (300 ml) is boiled for 72 hours. The reaction mixture was cooled to rt and filtered through a glass filter. The filtrate is evaporated in vacuum. The residue is dissolved in diethyl ether (250 ml)of saliva. The precipitate is filtered off under vacuum. To the filtrate containing the crude product ethyl ester (2-(benzhydrylidene)-6-ftaleksonami acid, add 1 N HCl solution (100 ml). The resulting biphasic mixture was vigorously stirred for 3 hours. The mixture is transferred into a separating funnel. The aqueous layer was separated. The organic layer is extracted with 1 N HCl (30 ml). The combined aqueous phases are washed with 200 ml of diethyl ether. To the aqueous phase was added concentrated HCl (10.8 ml) and the resulting solution is boiled for 6 hours. The reaction mixture was cooled to rt and evaporated in vacuum. To the residue was added toluene and the mixture is again evaporated in vacuum, receive hydrochloride 2-amino-6-ftaleksonami acid in a solid white color. The crude product is a salt of the amino acids - used without cleaning and without characterization. GI is rochloride 2-amino-6-ftaleksonami acid (32.3 mmol, theoretically) is suspended in dry methanol (300 ml) and cooled to 0°C. Slowly over 5 min add chloride thionyl (10.3 ml, 129 mmol). The resulting solution was brought to rt and stirred for 18 hours. The reaction mixture is evaporated in vacuum, receive hydrochloride 2-amino-6-ftaleksonami acid. To the crude aminoether added toluene (100 ml) and 28% ammonia solution in water (75 ml). The resulting biphasic mixture was vigorously stirred at rt for 24 hours. The reaction mixture is evaporated in vacuum. The remainder in the form of solids suspended in toluene (200 ml) and again evaporated in vacuum, get amide 6-ftaleksonami acid (II) in a solid white color. The crude amide amino acids dissolved in dry DMF (50 ml) and CH2Cl2(350 ml) and conduct its reaction with 4-chlorobenzenesulfonamide (82 g, 32.3 mmol) and Et3N (13.5 ml, 96.9 mmol). After 2 hours add the second portion of 4-chlorobenzenesulfonamide (1.70 g, 8.1 mmol). After 18 h the resulting mixture was poured into 1 N HCl (500 ml). The organic layer is separated and washed with water (2×500 ml). To the organic phase was added hexane (600 ml). A white precipitate is formed. The precipitate is filtered under vacuum, washed with cold ethanol (50 ml) and dried in vacuum. Obtain 4.95 g (yield 48% 6 stages) amide 2-(4-chlorobenzenesulfonamide)-4-ftaleksonami acid (III). LCMS (M+Na)+345.2; 1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, 1H, J=8.8), 7.77 (d, 2H, J=8.8), 7.62 (d, 2H, J=8.8), 7.29 (s, 1H), 6.95 (s, 1H), 4.34 (dt, 2H, Jd=47.5, Jt=6.1), 3.65 (dt, 1H, Jd=5.6, Jt=8.6), 1.60-1.39 (m, 4H), 1.36-1.15 (m, 2H). Elemental analysis: calculated for C12H16ClFN2O3S: 44.65; N, 4.99; N, 8.67. Found: 44.61; H 5.08; N, 8.75.

Amide 2-(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)amino)-6-ftaleksonami acid (Example 333)

Amide 2-(4-chlorobenzenesulfonamide)-6-ftaleksonami acid (0.500 g, 1.55 mmol) is transformed into the title compound (360 mg, yield 59%)as described in Reaction scheme 1, method A. LCMS (M+Na)+459.9;1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, 2H, J=8.8), 7.79 (d, 2H, J=8.5), 7.63 (d, 2H, J=8.8), 7.58 (d, 2H, J=8.3), 7.52 (s, 1H), 7.09 (s, 1H), 4.82 (Avcv, 2H, Δν=37.2, Jab=17.6), 4.34 (DD, 1H, J=8.0, 6.6), 4.25 (dt, 2H, Jd=47.2, Jt=5.7), 1.58 (m, 1H), 1.49-1.12 (m, 5H). Elemental analysis: calculated for C20H21ClFN3About3S: 54.85; N, 4.83; N, 9.59. Found: 54.92; H 4.76; N, 9.54.

Examples of the application of the Reaction scheme 20

(2R)-2-(4-Chlorobenzenesulfonamide)-1-{(1'S),(5'S)-10',10'-dimethyl-3',3'-deoxo-3'λ6-thia-4'-azatricyclo[5.2.1.01,5]Dec-4'-yl}-4-fluoro-4-methylpentan-1-he

To a solution of (2R)-2-(4-chlorobenzenesulfonamide)-1-{(1'S),(5'S)-10',10'-dimethyl-3',3'-deoxo-3'λ6-thia-4'-azatricyclo[5.2.1.01,5]Dec-4'-yl}methylpentan-1-he is [500 mg, 1 mmol, obtained according to Reaction scheme 18 of N-2-(benzhydrylidene)-1-{(1'S),(5'S)-10',10'-dimethyl-3',3'-deoxo-3'λ6-thia-4'-azatricyclo[5.2.1.01,5]Dec-4'-yl}ethanone (link: Josien, H.; Martin, A.; Chassing, G. Tetrahedron Lett. 1991, 32, 6547) and 1-bromo-2-methyl-2-propene] in THF (5 ml) at 0°With added HF·pyridine (10 ml). The reaction mixture was brought to rt and stirred for 18 h.

The contents of the reaction flask is gently added to aqueous solution of NaHCO3(300 ml). Extracted with EtOAc (3×100 ml). The combined organic extract is successively washed with 1 N HCl (200 ml) and brine (100 ml). The organic phase is dried MgSO4, filtered and evaporated in vacuum, get 490 mg (94%) of the title compound in the form of a solid white color.1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, 2H, J=8.8), 7.45 (d, 2H, J=8.8), 5.37 (d, 1H, J=8.1), 4.65 (m, 1H), 3.64 (t, 1H, J=6.4), 3.43 (Avcv, 2H, Δν=5.4, Jab=13.7), 2.19-1.83 (m, 7H), 1.41-1.31 (m, 8H), 1.04 (s, 3H), 094 (s, 3H).

Amide and (2R)-2-(4-chlorobenzenesulfonamide)-4-fluoro-4-methylpentanoic acid

(2R)-2-(4-Chlorobenzenesulfonamide)-1-{(1'S),(5'S)-10',10'-dimethyl-3',3'-deoxo-3'λ6-thia-4'-azatricyclo[5.2.1.01,5]Dec-4'-yl}-4-fluoro-4-methylpentan-1-he is transformed into the title compound in two stages according to the Reaction scheme 18 (165 mg, yield 55%); LCMS (M+Na)+345.1;1H NMR (500 MHz, DMSO-d6) δ 8.10 (d, 1H, J=9.2), 7.77 (d, 2H, J=8.5), 7.62 (d, N, J=8.9), 7.34 (s, 1H), 6.92 (s, 1H), 3.85 (m, 1H), 1.89 (m, 1H), 1.74 (m, 1H), 1.31 (d, 3H, J=21.7), 1.29 (d, 3H, J=21.9).

Examples of the application of the Reaction scheme 21

Ethyl ester of 2-(4-chlorobenzenesulfonamide)-4-methyl-4-pentanol acid

A solution of ethyl ester of 2-amino-4-methyl-4-pentanol acid (2.84 g, 18.1 mmol, obtained according to Reaction scheme 19 of ethyl ether (benzhydrylidene)acetic acid and 1-bromo-2-methyl-2-propene) in CH2Cl2(250 ml) is reacted with 4-chlorobenzenesulfonamide (4.20 g, 19.9 mmol) and Ee3N (3.78 ml, 27.2 mmol). After 4 hours the resulting mixture was poured into 1 N aqueous HCl solution (500 ml) and extracted with EtOAc (3×150). The organic extracts washed with brine (50 ml), dried (MgSO4), filtered and evaporated in vacuum. The crude concentrate is purified column chromatography on silica gel (gradient from 10:1 to 5:1, the mixture of hexanol/EtOAc)obtain 3.04 g (3 phase 25%) of the ethyl ester of 2-(4-chlorobenzenesulfonamide)-4-methyl-4-pentanol acid. LCMS (M+Na)+354.2;1H NMR (400 MHz, CDCl3) δ 7 77 (d, 2H, J=9.1), 7.46 (d, 2H, J=8.8), 5.07 (d, 1H, J=9.0), 4.84 (c, 1H), 4.73 (s, 1H), 4.05 (m, 1H), 3.95 (q, 2H, J=7.1), 2.40 (m, 2H), 1.66 (s, 3H), 1.13 (t, 3H, J=7.1).

Ethyl ester of 2-(4-chlorobenzenesulfonamide)-4-fluoro-4-methylpentanoic acid and 4-chloro-N-(5,5-dimethyl-2-oxitetraciclina-3-yl)benzosulfimide

Fluorohydrogen&#jed (10 ml) at 0° With added to a solution of ethyl ester of 2-(4-chlorobenzenesulfonamide)-4-methyl-4-pentanol acid (1.0 g, 3.0 mmol) in THF (15 ml). The reaction mixture was brought to rt. After 5 hours add a new portion fluorohydrogen·pyridine (10 ml). The mixture is stirred for 24 hours, then added a third portion fluorohydrogen·pyridine (10 ml). The total mixing time is 53 hours. Then the reaction quenched by adding crushed ice (20 ml). The crude mixture was poured into ice water (500 ml) and extracted with CH2Cl2(2×200 ml). The combined organic extracts washed us. aq. NaHCO3(100 ml) and evaporated in vacuo. The crude concentrate is purified column chromatography on silica gel (gradient from 10:1 to 5:1, the mixture of hexanol/EtOAc), get 0.395 g (yield 37%) of ethyl ester of 2-(4-chlorobenzenesulfonamide)-4-fluoro-4-methylpentanoic acid and 0.425 g (yield 46%) of 4-chloro-N-(5,5-dimethyl-2-oxitetraciclina-3-yl)benzosulfimide. Characteristics of the ethyl ester of 2-(4-chlorobenzenesulfonamide)-4-fluoro-4-methylpentanoic acid. LCMS (M+Na)+374.1;1H NMR (500 MHz, CDCl3) δ 7.78 (d, 2H, J=8.9), 7.47 (d, 2H, J=8.5), 5.19 (d, 1H, J=7.9), 4.08 (m, 1H), 3.93 (m, 2H), 2.09-1.94 (m, 2H), 1.42 (d, 3H, J=21.6), 1.37 (d, 3H, J=21.6), 1.12 (t, 3H, J=7.0). Features 4-chloro-N-(5,5-dimethyl-2-oxitetraciclina-3-yl)benzosulfimide. LCMS (M+Na)+326.0;1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, 1H, J=9.1), 7.86 (d, 2H, J=8.6), 7.67 (d, 2 is, J=8.8), 4.57 (m, 1H), 2.22 (DD, 1H, J=12.4, 9.0), 1.72 (t, 1H, J=12.0), 1.33 (s, 3H), 1.31 (s, 3H).

Amide 2-(4-chlorobenzenesulfonamide)-4-fluoro-4-methylpentanoic acid

A solution of ethyl ester of 2-(4-chlorobenzenesulfonamide)-4-fluoro-4-methylpentanoic acid (457 mg, 1.30 mmol) in Meon (20 ml) is treated with 10 N NaOH solution (780 μl, 7.8 mmol) at rt for 18 hours. The crude reaction mixture is evaporated in vacuum. To the residue was added water (50 ml) and 1 N HCl (20 ml). The aqueous solution is extracted with EtOAc (3×100 ml). The combined organic extracts washed with brine (50 ml), dried with MgSO4, filtered and evaporated in vacuum, get a solid white color, containing 2-(4-chlorobenzenesulfonamide)-4-fluoro-4-methylpentanol acid. A mixture of crude solid product, 1-hydroxybenzotriazole (263 mg, 1.95 mmol), Diisopropylamine (670 mg, 5.2 mmol), ammonium chloride (140 mg, 2.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (373 mg, 1.95 mmol) and DMF (20 ml) was stirred at rt for 24 hours. The crude reaction mixture was poured into water (500 ml). The aqueous solution is extracted with a mixture of EtOAc/mixture hexanol (90:10, 3×150 ml). The combined organic extracts washed with brine (50 ml), dried with MgSO4, filtered and evaporated in vacuum. The crude concentrate is purified column chromatography on silica gel (chloroform/Meon, 95:5), receive 0.426 g (yield 100%) of falnoga connection. LCMS (M+Na)+345.3;1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, 1H, J=9.2), 7.77 (d, 2H, J=8.5), 7.62 (d, 2H, J=8.9), 7.34 (s, 1H), 6.92 (s, 1H), 3.85 (m, 1H), 1.89 (m, 1H), 1.74 (m,1H), 1.31 (d, 3H, J=21.7), 1.29 (d, 3H, J=21.9).

Amide 2-(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)amino]-4-fluoro-4-methylpentanoic acid (Example 357)

Amide 2-(4-chlorobenzenesulfonamide)-4-fluoro-4-methylpentanoic acid is transformed into the title compound by Reaction scheme 1, method A. LCMS (M+Na)+460.2;1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, 2H, J=8.5), 7.75 (d, 2H, J=8.3), 7.68 (s, 1H), 7.64 (d, 2H, J=8.6), 7.49 (d, 2H, J=8.1), 7.20 (s, 1H), 4.67 (Avcv, 2H, Δν=28.3, Jab=17.3), 4.54 (DD, 1H, J=9.3, 3.2), 2.23 (m, 1H), 1.42 (m, 1H), 1.25 (d, 3H, J=21.6), 1.21 (d, 3H, J=21.7).

Amide 2-(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)amino]-4-hydroxy-4-methylpentanoic acid (Example 443)

Sealed ampoule containing a mixture of 4-chloro-N-(5,5-dimethyl-2-oxitetraciclina-3-yl)benzosulfimide (0.20 g, 0.66 mmol) and 28% ammonia solution in water (3 ml), heated in a microwave reactor at 80°C for 40 minutes, the Reaction mixture was cooled to rt and evaporated to dryness in a vacuum, get a solid white color containing amide 2-(4-chlorobenzenesulfonamide)-4-hydroxy-4-methylpentanoic acid. The crude solid product is transformed into the title compound (98 mg, 34%) according to Reaction scheme 1, method A. LCMS (M+Na)+458.2; 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, 2H, J=8.6), 7.76 (d, 2H, J=8.3), 7.62 (d, 2H, J=8.8), 7.51 (d, 2H, J=8.3), 7.40 (s, 1H), 7.11 (s, 1H), 4.63 (Avcv, 2H, Δν=5.9, Jab=17.6), 4.56 (DD, 1H, J=8.3, 2.5), 4.54 (s, 1H), 1.95 (DD, 1H, J=13.7, 8.6), 1.26 (DD, 1H, J=13.6, 2.4), 1.04 (s, 3H), 0.99 (s, 3H). Elemental analysis: calculated for C20H22ClN3O4S: at 55.10; H 5.08; N, 9.64. Found: 54.96; H 5.14; N, 9.58.

Examples of the application of the Reaction scheme 22

Ethyl ester of 2-(4-chlorobenzenesulfonyl)-5-hexenoic acid

A mixture of ethyl ether (benzhydrylidene)acetic acid (20 g, 74.8 mmol), 4-bromo-1-butene (10.1 g, 74.8 mmol), K2CO3(31.0 g, 224 mmol), tetrabutylammonium (2.41 g, 7.48 mmol) and acetonitrile (150 ml) is boiled for 6 hours. The reaction mixture was cooled to rt and filtered through a funnel with a glass filter. The filtrate is evaporated in vacuum. The residue is dissolved in diethyl ether (250 ml)of saliva. The precipitate is filtered off under vacuum. To the filtrate containing the crude product (ethyl ester of 2-(benzhydrylidene)-Gex-5-ene acid), was added 1 N HCl (150 ml). The resulting biphasic mixture was vigorously stirred for 18 hours. The mixture is transferred into a separating funnel. The aqueous phase are combined and evaporated in vacuum. The residue is dissolved in toluene (2×200 ml) and again evaporated. Crude aminoether dissolved in CH2l 2and conduct its reaction with 4-chlorobenzenesulfonamide (15.8 g, 74.8 mmol) and Et3N (31.2 ml, 224 mmol). After 18 h the resulting mixture was poured into 1 N HCl (500 ml). The organic layer was separated and sequentially washed with 1 N HCl (500 ml) and brine (50 ml). The organic layer is dried with MgSO4, filtered and evaporated in vacuum. The crude concentrate is purified column chromatography on silica gel (5:1 mixture of hexanol/EtOAc), get 5.57 g (stage 3 23%) of the title compound. LCMS (M+Na)+454.0;1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, 1H, J=8.8), 7.76 (d, 2H, J=8.8), 7.66 (d, 2H, J=8.8), 5.69 (m, 1H), 4.95-4.88 (m, 2H), 3.86 (q, 2H, J=7.1), 3.76 (m, 1H), 1.98 (m, 2H), 1.71-1.54 (m, 2H), 1.03 (t, 3H, J=7.1).

Ethyl ester of 2-[(4-chlorobenzenesulfonyl)-(4-panamensis)amino]-Gex-5-ene acid

Ethyl ester of 2-[(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)amino]-Gex-5-ene acid get a similar Reaction scheme 1, as the initial charge ethyl ester 2-(4-chlorobenzenesulfonamide)-Gex-5-ene acid. Ethyl ester of 2-[(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)amino]-Gex-5-ene acid is isolated in the form of a crude solid yellow (1.14 g) and used in the next stage without additional purification.1H NMR (CDCl3) δ 7.71 (d, 2H, J=8.0), 7.61 (d, 2H, J=8.0), 7.53 (d, 2H, J=8.0), 7.46 (d, 2H, J=8.0), 5.54 (m, 2H), 4.90 (m, 2H), 4.74 (d, 1H, J=16.0), 4.48 (m, 2H), 3.90 (m, N), 1.95 (m, 2H), 1.81 (m, 1H), 1.48 (m, 1H), 1.11 (t, 3H, J=8.0).

Ethyl ester of 2-[(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)amino]-5-oxopentanoic acid

A mixture of ethyl ester of 2-[(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)amino]-Gex-5-ene acid (1.14 g, 2.56 mmol), osmium tetroxide (0.030 g, 0.13 mmol) and trimethylamine-N-oxide (0.41 g, 5.5 mmol) dissolved in acetone (50 ml) and stirred for 4 h at rt. Upon completion of the reaction solution is evaporated in vacuum and dissolved again in a mixture of dioxane : H2O (1.5:1, 50 ml). To this solution is added periodate sodium (0.66 g, 3.07 mmol) and stirred for 18 h at rt. Then the reaction mixture was added EtOAc (500 ml) and washed with H2Oh, brine, dried with Na2SO4and evaporated. Get a crude colorless oil. Further purification via flash chromatography (SiO2, 5-75% EtOAc/mixture hexanol) receive the ethyl ester of 2-[(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)amino]-5-oxopentanoic acid (yield 0.26 g, 23%) as a colourless oil.1H NMR (CDCl3) δ 9.57 (s, 1H), 7.69 (d, 2H, J=8.0), 7.51 (m, 6N), 5.99 (Avcv, 2H, Δν=16, Jab=168), 4.47 (m, 1H), 3.89 (m, 2H), 2.53 (m, 1H), 2.32 (m, 1H), 2.11 (m, 1H), 1.61 (m, 1H), 1.06 (t, 3H, J=8.0).

Ethyl ester of 2-[(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)amino]-5,5-differentyou acid

Ethyl ester of 2-[(4-chlorobenzenesulfonyl)-(4-tzia is benzyl)amino]-5-oxopentanoic acid (0.05 g, 0.11 mmol) is slowly added to a solution of DAST (0.020 ml, 0.11 mmol) in CH2Cl2(2 ml) at rt and stirred for 16 hours. To the reaction mixture add CH2Cl2and extracted with water (2×25 ml). The combined organic extracts washed with water, brine, dried with Na2SO4and evaporated, obtaining the ethyl ester of 2-[(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)amino]-5,5-differentyou acid in the form of a crude yellow residue. This crude residue used in the next stage without additional purification.

Amide 2-[(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)amino]-5,5-differentyou acid (Example 377)

The crude ethyl ester of 2-[(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)amino]-5,5-differentyou acid (0.061 g, 0.13 mmol) dissolved in Meon (2 ml). To this mixture was added 10 N NaOH (0.052 ml, 0.52 mmol) and the resulting solution stirred at rt for 16 hours. The reaction mixture was diluted with water (25 ml), acidified with 1 N HCl and extracted with CH2Cl2(4×100 ml). The combined organic extracts are dried Na2SO4and evaporated in vacuum, get a carboxylic acid in the form of a crude colorless oil. Then the intermediate carboxylic acid was dissolved in DMF (10 ml) and mixed 1-hydroxybenzotriazole (0.030 g, 0.20 mmol), iPrNEt (0.090 ml, 0.52 mmol), NH4Cl (0.01 g, mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.04 g, 0.20 mmol) and stirred at rt for 72 hours. To the reaction mixture was added EtOAc (150 ml) and washed with water (4×50 ml). The organic extract is dried Na2SO4and evaporated in vacuum, obtaining the crude yellowish-white solid. Further purification of flash chromatography (SiO2, 5-85 EtOAc/mixture hexanol) gives the title compound (yield 10.7 mg, 19%) as a solid white color. LCMS (M+Na)+464.01;1H NMR (CDCl3) δ 7.69 (d, 2H, J=8.3), 7.60 (d, 2H, J=8.3), 7.49 (m, 4H), 6.18 (ush. s, 1H), 5.67 (TT, 1H, J=56, 4.0), 5.22 (ush. s, 1H), 4.52 (Avcv, 2H, Δν=16, Jab=100), 4.34 (m, 1H), 2.03 (m, 1H), 1.68 (m, 1H), 1.38 (m, 1H), 0.86 (m, 1H).

Examples of the application of the Reaction scheme 23

Amide and (2R)-2-[[4-(2-bromoacetamide)benzyl]-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid

To a solution of amide (2R)-2-[(4-amino)benzyl)-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid (248 mg, 0.56 mmol) and Et3N (176 mg, 1.74 mmol) in CH2Cl2(3 ml) was added bromocatechol (105 mg, 0.67 mmol). The reaction mixture was stirred over night at rt. To the reaction mixture add CH2Cl2(5 ml), washed with 1 N HCl, brine and dried by passing through a cotton filter. The solvent is distilled off in vacuum. Clean flash chromatography (SiO210% acetone/CH2 Cl2) give 124 mg (42%) of the title compound. MS (ESI) (M+N)+531.86;1H NMR(CDCl3, 400 MHz) δ 78 (ush. s, NH), 7.95 (d, 2H, J=8.0), 7.82 (d, 2H, J=8.0), 7.42 (d, 2H, J=8.0), 7.33 (d, 2H, J=8.0), 6.20 (ush. s, 1H), 5.20 (ush. s, 1H), 4.30 (s, 2H), 4.22 (d, 1H, Jab=16), 4.14 (d, 1H, Jab=16), 3.25 (t, 1H, J=6.0), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0)

Amide and (2R)-2-{(4--chlorobenzenesulfonyl)-[4-(2-diethylaminoethylamine)benzyl]amino}-4-methylpentanoic acid (Example 308)

To a solution of amide (2R)-2-[[4-(2-bromoacetamide)benzyl]-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid (41 mg, 0.77 mmol) in CH2Cl2(2 ml) was added an excess of 2.0 M solution of dimethylamine in THF. The reaction mixture was stirred over night. The solvent is distilled off in vacuum. Clean flash chromatography (SiO210% of the Meon/CH2Cl2) give 24 mg (63%) of the title compound. MS (ESI) (M+N)+495.14;1H NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.02 (d, 2H, J=8.0), 7.75 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 7.29 (d, 2H, J=8.0), 6.23 (ush. s, 1H), 5.39 (ush. s, 1H), 4.62 (m, 4H), 3.25 (t, 1H, J=6.0), 2.95 (s, 6N), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0).

Educt

Below α-amino acids are commercially available or they are obtained by standard methods:

Amide 5,5,5-Cryptor-2-aminopentanoic acid and 6,6,6-Cryptor-2-aminohexanoic acid is obtained by Ojima, I.; Kato, K.; Nakahashi, K. J. Org. Chem. 1989, 54, 4511.

Benzylbromide used in the synthesis of compounds of Examples 100 and 155, receive Ishihara, Y.; Fujisawa, Y.; Furuyama, N. international application PCT WO 9846590; Senanayake, C.H.; Fang, O.K.; Wilkinson, S.H. international application PCT WO 9833789.

Aldehydes for the synthesis of compounds of Examples 91, 248, 249, 289, 290, and 300 (see Reaction scheme 2) receive, as shown in example 4-(piperidine-1-yl)benzaldehyde. A suspension of 4-forventelige (0.48 ml, 4 mmol), K2CO3(522 mg, 4 mmol), piperidine (340 mg, 4 mmol) in DMSO (5 ml) is heated in a sealed vial at 150°C for 18 h, after which the reaction mixture is evaporated and purified by chromatography on silica gel (CH2Cl2then 2% Meon/CH2Cl2receive 4-(piperidine-1-yl)benzaldehyde, 748 mg, yield 98%.

The aldehydes used in the synthesis of compounds of Examples 317, 318, and 320, receive, as shown in example 4-(piperidine-1-yl)-3-forventelige. A suspension of 4.3-diferentialglea (500 mg, 3.5 mmol), K2CO3(483 mg, 3.5 mmol), piperidine (298 mg, 3.5 mmol) in DMSO (5 ml) is agreat in a sealed ampoule at 130° C for 18 hours. The reaction mixture was cooled to rt, evaporated and purified by chromatography on silica gel (CH2Cl2then 2% MeOH/CH2Cl2receive 4-(piperidine-1-yl)-3-fermentology, 740 mg, yield 99%.

Benzylchloride used to obtain the compounds of Examples 433, 474, 480, 500, receive according to the following procedure. To a solution of 2-[(4-chloromethyl)phenyl]propan-2-ol (769 mg, 4.16 mmol) (reference: Seago, X.; Mehrsheikh-Mohammadi, M.E.; McDonald, S. J. Org. Chem. 1987, 52, 3254) in CH2Cl2(14 ml) at -78°With added DAST (0.72 ml, 5.4 mmol). After 1.5 hours the solution was added water and bring to room temperature. The mixture is extracted with CH2Cl2(3). The combined organic extracts dried (Na2SO4) and evaporated. Flash chromatography on a column (SiO2, 0-5% EtOAc/mixture hexanol) gives the chloride in the form of a pale yellow liquid (512 mg, 66%).1H NMR (CDCl3, 300 MHz) δ 7.30-7.48 (m, 4H), 4.58 (s, 2H), 1.70 (s, 3H), 1.63 (s, 3H).

Getting 2-trimethylsilylacetamide ether 4-bromomethylphenyl acid used in the synthesis of compounds of Example 470, described Graffner-Nordberg, M.; Sjoedin, L.; Tunek, A.; Hallberg, A. Chem. Pharm. Bull. 1998, 46, 591.

Conditions chromatographic separation of enantiomeric mixtures

Condition 1. The substance of Example 345 divided by the following method. Column Chiracel OJ, 4.6 X 250 mm, 10 ám 1.0 ml/min, 85% hexane/EtOH with 0.1% DEA, for 20 minutes

Condition 2. The compound of Example 346 section is aout the following method. Column Chiralpak AD, 4.6 x 250 mm, 10 ám 1.0 ml/min, 80% hexane/EtOH 0.15% DEA, for 20 minutes

Condition 3. The compound of Example 347 share the following method. Column Chiralpak AD, 4.6 x 250 mm, 10 ám 1.0 ml/min, 65% hexane/IPA 0.1% DEA, 18 minutes

Condition 4. Compounds of Examples 365 and 366 are divided by the following method. Column Chiralpak AD, 4.6 x 250 mm, 10 ám 1.0 ml/min, 75% hexane/EtOH 0.15% DEA, for 25 minutes

Condition 5. Compounds of Examples 408 and 409 are divided by the following method. Column Chiracel OD, 4.6 x 250 mm, 10 ám 1.0 ml/min, 90% hexane/EtOH 0.15% DEA, 36 minutes

1. The compound of formula I or its optical isomer

where R1selected from the group consisting of

(a) a linear or branched C1-6the alkyl or C2-6alkenyl having optionally substituents selected from the group consisting of hydroxy, C3-7cycloalkyl,1-4alkoxy, C1-4alkylthio and halogen;

(b)3-7cycloalkyl, substituted, optionally, hydroxy or halogen;

R denotes hydrogen

R2selected from the group consisting of

(a) a linear or branched C1-6the alkyl or C3-6alkenyl having optionally substituents selected from the group consisting of halogen, C1-4alkoxy and NR4R5;

(b)3-7cycloalkenyl having optionally substituents selected from the group, with Toyama from amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-;

(b) a linear or branched C1-6alkyl-C(=O)-A;

(g) In-naphthyl;

(d)

D and E each independently represents a simple (ordinary) correlation, linear or branched C1-6alkyl, C2-6alkenyl;

Z is chosen from the group consisting of hydrogen, C1-4of alkyl, C1-4alkoxy, halogen, cyano, hydroxy, -OCHF2, -OCF3, -CF3and-CHF2;

X and Y each independently selected from the group consisting of hydrogen, hydroxy, halogen, (halogen)3C-, (halogen)2CH-, C1-4S-, C1-4SO2-, nitro, F3S - and cyano;

-OR6;

-NR4R5;

-NR7C(=O)R8;

-C(=O)W, where W is chosen from the group consisting of hydroxy, C1-4of alkyl, C1-4alkoxy, phenoxy and-NR4R5;

-OC(=O) C1-4of alkyl;

phenyl, and specified phenyl, optionally, has as Deputy cyano; and

heterocyclic group, where the specified heterocyclic group is chosen from the series consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and specified heterocyclic group optionally has substituents selected from the group consisting of ishalgen, C1-4of alkyl, (halogen)1-4the alkyl and CO2C1-4of alkyl;

(e)-(heterocycle), where the heterocycle is chosen from the group consisting of furanyl, thiopurine, imidazolyl, pyridinyl, oxazolyl, isoxazolyl and thiazolyl, and said heterocycle optionally has substituents selected from the group consisting of halogen, C1-4of alkyl, CO2C1-4of alkyl, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl;

(W) -To-(piperidine-4-yl), where the specified piperidine-4-yl optionally has substituents selected from the group consisting of linear or branched C1-6of alkyl, CH2C(=O) phenyl, phenylmethyl, which optionally have substituents selected from the group consisting of cyano, halogen, benzimidazole-2-yl, pyridyl and tetrahydrofuran-2-yl; and-C(=O)W', where W' is chosen from the group consisting of C1-4alkoxy, R9and-NR4R5;

And denotes hydroxy, C1-4alkoxy or NR4R5;

In denotes a linear or branched C1-6alkyl or C3-6alkenyl;

R3denotes phenyl or pyridyl having optionally substituents selected from the group consisting of halogen, C1-4of alkyl, (halogen)3C-, (halogen)2SN - and Halogens2-;

R4and R5each independently represents hydrogen, linear or branched C1-6alkyl, C3-6alkenyl,3-6quinil,3-7cycloalkyl,3-7cycloalkenyl, C1-4alkoxy, phenyl, benzyl, piperidine-4-yl, where each optionally have substituents selected from the group consisting of hydroxy, cyano, halogen, (halogen)3C-, (halogen)2CH-, Halogens2hydroxymethyl, phenyl, pyridyl,1-4of alkyl, C1-4alkoxy, (halogen)3With-O-, (halogen)2CH-O-, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, piperidine-1-silt, CO2N, CO2C1-4of alkyl;

R4and R5together may denote morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, 1,2,3,4-tetrahydroisoquinoline-2-yl, decahydroquinoline-1-yl, piperidine-1-yl, piperazine-1-yl, where each optionally have substituents selected from the group consisting of hydroxy, pyridyl, benzyl, C1-6of alkyl, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, CO2N, CO2With1-4alkyl;

R6denotes a linear or branched C1-6alkyl, C3-6alkenyl, benzyl or phenyl, where each optionally have substituents selected from the group consisting of halogen, C1-4of alkyl, C1-4alkoxy, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, (C14 alkyl)(phenyl)N-, morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

R7denotes hydrogen, a linear or branched C1-6alkyl;

R8denotes a linear or branched C1-6alkyl, pyridyl or furanyl;

where each optionally have substituents selected from the group consisting of (C1-4alkyl)NH-, di(C1-4alkyl)N-, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

R9denotes a linear or branched C1-6alkyl, C3-6alkenyl, benzyl, phenyl, oxazolyl or pyridyl; where each optionally have substituents selected from the group consisting of halogen, (halogen)3C-, (halogen)2CH-, Halogens2-With1-4alkoxy, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, thiomorpholine-4-yl, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

or its non-toxic pharmaceutically acceptable salt.

2. The compound according to claim 1, having the formula

where R1selected from the group consisting of

linear or branched C1-6the alkyl or C2-6alkenyl having optionally substituents selected from the group consisting of hydrox is, With3-7cycloalkyl, C1-4alkoxy, C1-4alkylthio and halogen;

R2selected from the group consisting of

(a) a linear or branched C1-6the alkyl or C3-6alkenyl having optionally substituents selected from the group consisting of halogen, C1-4alkoxy and NR4R5;

(b)3-7cycloalkenyl having optionally substituents selected from the group consisting of amino, (C1-4alkyl)NH-, di(C1-4alkyl)N;

(b) a linear or branched C1-6alkyl-C(=O)-A;

(g) In-naphthyl;

(d)

D and E each independently represents a simple (ordinary) correlation, linear or branched C1-6alkyl, C2-6alkenyl;

Z is chosen from the group consisting of hydrogen, C1-4of alkyl, C1-4alkoxy, halogen, cyano, hydroxy, -OCHF2, -OCF3, -CF3and-CHF2;

X and Y each independently selected from the group consisting of hydrogen, hydroxy, halogen, (halogen)3C-, (halogen)2CH-, C1-4S-, C1-4SO2-, nitro, F3CS -, and cyano;

-OR6;

-NR4R5;

-NR7C(=O)R8;

-C(=O)W, where W is chosen from the group consisting of hydroxy, C1-4of alkyl, C1-4alkoxy, penokie-NR 4R5;

-OC(=O) C1-4of alkyl;

phenyl, and specified phenyl, optionally, has as Deputy cyano; and

heterocyclic group, where the specified heterocyclic group is chosen from the series consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and specified heterocyclic group optionally has substituents selected from the group consisting of halogen, C1-4of alkyl, (halogen)1-4the alkyl and CO2C1-4of alkyl;

(e)-(heterocycle), where the heterocycle is chosen from the group consisting of furanyl, thiopurine, imidazolyl, pyridinyl, oxazolyl, isoxazolyl and thiazolyl, and said heterocycle optionally has substituents selected from the group consisting of halogen, C1-4of alkyl, CO2C1-4of alkyl, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl;

(W) -To-(piperidine-4-yl), where the specified piperidine-4-yl optionally has substituents selected from the group consisting of linear or branched C1-6of alkyl, CH2(=O) phenyl, phenylmethyl, which optionally have substituents selected from the group consisting of cyano, halogen, benzimidazole-2-yl, pyridyl and tetrahydrofuran-2-yl; and-C(=O)W, where W s is given from the group consisting of C1-4alkoxy, R9and-NR4R5;

And denotes hydroxy, C1-4alkoxy or NR4R5;

In denotes a linear or branched C1-6alkyl or C3-6alkenyl;

R3denotes phenyl or pyridyl having optionally substituents selected from the group consisting of halogen, C1-4of alkyl, (halogen)3C-, (halogen)2SN - and Halogens2-;

R4and R5each independently represents hydrogen, linear or branched C1-6alkyl, C3-6alkenyl,3-6quinil,3-7cycloalkyl,3-7cycloalkenyl, C1-4alkoxy, phenyl, benzyl, piperidine-4-yl, where each optionally have substituents selected from the group consisting of hydroxy, cyano, halogen, (halogen)3C-, (halogen)2CH-, Halogens2hydroxymethyl, phenyl, pyridyl,1-4of alkyl, C1-4alkoxy, (halogen)3With-O-, (halogen)2CH-O-, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, piperidine-1-silt, CO2N, CO2With1-4of alkyl;

R4and R5together may denote morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, 1,2,3,4-tetrahydroisoquinoline-2-yl, decahydroquinoline-1-yl, piperidine-1-yl, piperazine-1-yl, where each optionally have substituents, selected the C group, consisting of hydroxy, pyridyl, benzyl, C1-6of alkyl, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, CO2N, CO2C1-4alkyl;

R6denotes a linear or branched C1-6alkyl, C3-6alkenyl, benzyl or phenyl, where each optionally have substituents selected from the group consisting of halogen, C1-4of alkyl, C1-4alkoxy, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, (C1-4alkyl)(phenyl)N-, morpholine-4-yl, thiomorpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

R7denotes hydrogen, a linear or branched C1-6alkyl;

R8denotes a linear or branched C1-6alkyl, pyridyl or furanyl; where each optionally have substituents selected from the group consisting of (C1-4alkyl)NH-, di(C1-4alkyl)N-, piperidine-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-yl;

R9denotes a linear or branched C1-6alkyl, C3-6alkenyl, benzyl, phenyl, oxazolyl or pyridyl; where each optionally have substituents selected from the group consisting of halogen, (halogen)3C-, (halogen)2CH-, Halogens2-With1-4alkoxy, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, thiomorpholine-4-yl, p is peridin-1-yl, piperazine-1-yl and 4-(C1-6alkyl)piperazine-1-Il,

or its non-toxic pharmaceutically acceptable salt.

3. The compound according to claim 2, in which R1denotes a linear or branched C1-6alkyl having optionally as a Deputy With3-7cycloalkyl.

4. The compound according to claim 2, in which R1denotes a linear or branched C1-6alkyl having optionally as Deputy halogen.

5. The compound according to claim 2, in which R3denotes a phenyl having optionally substituents selected from the group consisting of halogen, C1-4of alkyl, (halogen)3C-, (halogen)2SN - and Halogens2-.

6. The compound according to claim 2, in which R3denotes a pyridyl having optionally substituents selected from the group consisting of halogen, C1-4of alkyl, (halogen)3C-, (halogen)2SN - and Halogens2-.

7. The compound according to claim 5, in which R3denotes phenyl, optionally substituted with halogen.

8. The compound according to claim 2, in which R2denotes a linear or branched C1-6alkyl or C3-6alkenyl having optionally substituents selected from the group consisting of halogen, C1-4alkoxy and NR4R5.

9. The compound according to claim 2, in which R2stands With3-7cycloalkylation with neobyazatel is, substituents selected from the group consisting of amino, (C1-4alkyl)NH -, di(C1-4alkyl)N-.

10. The compound according to claim 2, in which R2denotes a linear or branched C1-6alkyl-C(=O)-A.

11. The compound according to claim 2, in which R2means-In-naphthyl.

12. The compound according to claim 2, in which R2means

13. The compound according to claim 2, in which R2means- (heterocycle, where the heterocycle is chosen from the group consisting of furanyl, thiopurine, imidazolyl, pyridinyl, oxazolyl, isoxazolyl and thiazolyl, and said heterocycle optionally has substituents selected from the group consisting of halogen, C1-4of alkyl, CO2With1-4of alkyl, amino, (C1-4alkyl)NH-, di(C1-4alkyl)N-, morpholine-4-yl, pyrrolidin-1-yl, piperidine-1-Il.

14. The compound according to claim 2, in which R2means- (piperidine-4-yl), where the specified piperidine-4-yl optionally has substituents selected from the group consisting of linear or branched C1-6of alkyl, CH2C(=O) phenyl and phenylmethyl, which optionally have substituents selected from the group consisting of cyano, halogen, benzimidazole-2-yl, pyridyl and tetrahydrofuran-2-yl; and-C(=O)W', where W' is chosen from the group consisting of C1-4alkoxy, R9and-NR4R5.

15. The connection section 12, in which a denotes a linear or branched C1-4alkyl or C3-6alkenyl.

16. The connection 15 in which Z represents hydrogen.

17. The connection indicated in paragraph 15, in which X represents-C(=O)W, E denotes simple (ordinary) correlation and Y denotes hydrogen.

18. The connection indicated in paragraph 15, in which X represents-NR4R5E denotes the ordinary communication and Y denotes hydrogen.

19. The connection indicated in paragraph 15, in which X denotes-OR6E denotes the ordinary communication and Y denotes hydrogen.

20. The connection indicated in paragraph 15, in which X represents-NR7C(=O)R8E denotes the ordinary communication and Y denotes hydrogen.

21. The pharmaceutical composition inhibiting the production β-amyloid peptide containing a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier or diluent.

22. A method of inhibiting the production β-amyloid peptide, which is specified in the introduction to the mammal a therapeutically effective amount of a compound according to claim 1



 

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The invention relates to Hinayana and hinokitiol, compositions containing them, and methods of producing these compounds

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 5-amino-1-pentene-3-ol of the general formula (I)

as a free form or as their physiologically compatible salts possessing the analgesic effect. In general formula (I) each R1 and R2 means independently of one another (C1-C6)-alkyl that can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or multi-substituted; or R1 and R2 form in common -(CH2)2-9-mono- or bicyclic ring; each R3 and R4 means independently of one another (C1-C6)-alkyl, or R3 and R4 form in common a ring and mean the group -CH2CH2NR22CH2CH2 wherein R22 represents (C1-C10)-alkyl; R5 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched, mono- or multi-substituted or unsubstituted, (C3-C9)-cycloalkyl that is saturated or means phenyl, heteroaryl that can be condensed with benzene ring and chosen from 5-membered heteroaryl with sulfur or oxygen atom as a heteroatom bound through saturated (C1-C3)-alkyl, phenyl bound through saturated (C1-C3)-alkyl-(C3-C10)-cycloalkyl wherein each among all these alkyl, phenyl, heteroaryl and cycloalkyl residues and independently of others can be unsubstituted or mono- or multi-substituted residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, groups -OR18, (C1-C3)-alkyl) that is saturated or branched or unbranched, mono- or multi-substituted halide, or unsubstituted and wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or unbranched; R6 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched and unsubstituted, phenyl or heteroaryl that is chosen from 5-membered heteroaryl with oxygen atom as a heteroatom wherein each of them is unsubstituted or mono- or multi-substituted as indicated above; R7 means H. Also, invention relates to a medicinal agent based on proposed compounds and to a method for their synthesis.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

10 cl, 493 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 1-aminobutane-3-ol of the general formula (I): and their physiologically acceptable salts possessing analgesic effect and capacity for binding habapentin-site. In the general formula (I) R1 and R2 form in common (CH2)2-9-ring; each R3 and R4 independently of one another means (C1-C6)-alkyl that is branched or direct, saturated or unsubstituted, benzyl or phenethyl that are unsubstituted; R5 means (C1-C10)-alkyl that can be saturated, unsaturated, branched or direct or unsubstituted, (C3-C9)-cycloalkyl that is saturated, phenyl or 5-membered sulfur-containing heteroaryl possibly condensed with benzene ring, (C3-C6)-cycloalkyl bound through saturated or unsaturated (C1-C3)-alkyl, 5-membered possibly condensed with benzene ring sulfur-containing heteroaryl bound through saturated or unsaturated (C1-C3)-alkyl wherein each aryl, heteroaryl and cycloalkyl residue independently of one another can be unsubstituted or mono- or multi-substituted with residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct and can be mono- or multi-substituted with halogen atoms wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or direct or unsubstituted; R6 means H; R7 means (C1-C6)-alkyl that is branched or direct, saturated or unsaturated or unsubstituted, (C3-C9)-cycloalkyl that is saturated or unsubstituted, phenyl that is unsubstituted or mono- or multi-substituted or phenyl bound through saturated (C1-C3)-alkyl that can be unsubstituted or mono- or multi-substituted wherein these substitutes can be chosen independently from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct, in free form as their physiologically acceptable salts. Proposed compounds can be used in treatment of pain and first of all neuropathic, chronic and acute pain. Also, invention relates to a method for synthesis of compounds and preparing a medicinal agent.

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

9 cl, 89 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new N-(2-arylpropionyl)-sulfonamides of the formula (1): wherein R2 means phenyl, thiophenyl optionally substituted with 1-3 substitutes taken independently among halogen atom, (C1-C4)-alkyl, phenyl, phenoxy-group, benzyl, benzoyl, (C1-C7)-acyloxy-group, 2-thienoyl or 1-oxo-2-isoindolyl; R means linear or branched (C1-C16)-alkyl, trifluoromethyl, cyclohexyl, o-tolyl, 3-pyridyl, p-cyanophenylmethyl, p-aminomethylphenylmethyl, 2-cyano-1-propyl, alkoxyethylene group CH3-(CH2)ni-(OCH2CH2)mi- wherein ni and mi mean a whole number from 1 to 3, or the group P1P2N-CH2-CH2- wherein P1 and P2 represent independently hydrogen atom (H), (C1-C3)-alkyl, benzyloxycarbonyl, α-, β- or γ-pyridocarbonyl, carboxycarbonyl or carbalkoxycarbonyl; or R1 and P2 in common with nitrogen atom to which they are bound form morpholino-group; R' means hydrogen atom (H) or linear or branched (C1-C3)-alkyl, or their salts with strong or mean bases. Compounds of the formula (1) show inhibitory activity with respect to chemotaxis and degranulation of neutrophiles induced with interleukin-8 and can be used in pharmaceutical composition used for prophylaxis and treatment of tissue injures.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 dwg, 2 tbl, 18 ex

The invention relates to new derivatives of N, S-substituted N'-1-[(hetero)aryl] -N'-[(hetero)aryl] methylisothiazoline General formula I or their salts with pharmacologically acceptable acids HX in the form of a racemic mixture or in the form of a mixture of stereoisomers, which can be used for the treatment and prevention of diseases associated with dysfunction glutamatergic nanoperiodic

The invention relates to new nitromethylene formula (I)

< / BR>
in which A represents C6-C10aryl, thienyl, benzothiazyl; X denotes halogen, cyano, C1-C7alkyl, trifluoromethyl, C2-C7alkoxy, or cryptometer; p is chosen from 0, 1, 2, 3, 4, or 5; Z represents a bond, -CO-NH-, SO2-NH-, a sulfur atom, sulfinyl group or a C2-C7alkenylamine radical; R1, R2, R3and E indicated in paragraph 1

The invention relates to a method for producing derivatives of 2-aminothiazoline formula I, in which R1represents C1-5alkyl straight or branched chain, R2is1-3alkyl, by reacting the compounds of formula II in which R3represents phenyl which may be optionally mono-pentamidine independently chlorine, methoxy, ethoxy, phenoxy or nitro, with the compound of the formula III in which Y represents a leaving group, in a solvent and in the presence of a base

The invention relates to new derivatives of tamilcanadian with the General formula (I) wherein R' represents 2-thienyl or 3-thienyl radical, R represents ceanorhaditis or a radical of the formula-C(O) - and R2 is optional saturated or unsaturated cyclic hydrocarbon radical or aryl radical

The invention relates to the field of pharmaceutical chemistry and synthetic organic chemistry and represents the asymmetric synthesis of the key intermediate compound in obtaining DULOXETINE - antidepressant tools

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to arylated amides of furan and thiophene carboxylic acids of the formulae (Ia) and (Ib) wherein W means oxygen or sulfur atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x means 0, 1, 2 or 3; R(14) means phenyl, and to their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition and using proposed compounds a medicinal agents. Compounds can be used as anti-arrhythmic biologically active substances and especially in treatment and prophylaxis of atrium arrhythmia.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 29 ex

FIELD: organic chemistry, agriculture, insecticides.

SUBSTANCE: invention relates to a substituted anilide derivative of the formula (I): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2; Z represents oxygen atom; Q means a substitute represented by any of the following formulae: Q1-Q3, Q6, Q8-Q12, Q14-Q19, Q21 and Q23 (wherein each among Y1 that can be similar or different represents halogen atom, (C1-C6)-alkyl group, and so on); Y2 represents (C1-C6)-alkyl group or halogen-(C1-C6)-alkyl group; Y3 represents (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl group or substituted phenyl group; p represents a whole number from 1 to 2; q represents a whole number from 0 or 2; r represents a whole number from 0 to 2. Also, invention proposes a chemical for control of pests of agricultural and fruit crops. The chemical comprises substituted anilide derivative of the formula (I) as an active component and represents insecticide, fungicide or acaricide. Also, invention proposes a method for addition of the chemical for control of pests of agricultural and fruits crops. Also, invention proposes aniline derivative represented by the general formula (II): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2. Invention provides the development of anilide derivative as insecticide, fungicide and acaricide against pests of agricultural and fruit crops.

EFFECT: valuable properties of compound.

5 cl, 6 tbl, 27 ex

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

The invention relates to new chemical compounds, namely, esters of 2-furfurylamine-2-tsianuksusnogo acid of General formula

< / BR>
where R: CH2CF3(Ia), CH(CF3)2(IB), CH2(CF2)2CF3(IB), CH2(CF2)4H (Iك), CH2PhX (Ia), CH2C(CH3)(X)2(S), CH2C2H5)(X)2(AI), CH2WITH(X)3(IK),

when X

< / BR>
These compounds can be used as an inhibitor to prevent premature polymerization of unsaturated compounds in their synthesis, processing and storage, such as methyl methacrylate, styrene, dimethylphenylcarbinol, ethyl-2-cyanoacrylate and other

The invention relates to dimethylpolysiloxene General formula

< / BR>
in which the radicals R1and R2may be the same or different, represents hydrogen, C2-C6- alkyl, C3-C6-cycloalkyl, C3-C6alkenyl,

C2-C6-quinil, C1-C3-halogenated, benzoyloxy group containing substituents, benzoylamino, which can also contain one or two Deputy, C2-C6-alkanolamines, C3-C6-cycloalkylcarbonyl, benzyl group which may contain substituents, the phenyl group with possible alternates, and other substituents, provided that at the same time R1and R2are not hydrogen atoms, the second condition is that one of R1and R2is not unsubstituted phenyl group when the other one represents a hydrogen atom, and the third condition is one of R1and R2in anthopology is not an aniline ring, C2-C6-alkyl, C3-C6-cycloalkyl or C2-C6-alkoxygroup when the other one represents a hydrogen atom
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