Fluoro-substituted 2-oxo-azepane derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

where there are R3/R3', R4/R4' and R5/R5' where at least one of either R4/R4' or R5/R5' always represents a fluorine atom, and the other radical values are disclosed in the description.

EFFECT: making the compounds which are γ-secretase inhibitors, and can be effective in treating Alzheimer's disease or advanced cancers, including but not limited to carcinoma of uterine cervix and breast carcinoma and malignant tumours of hematopoietic system.

15 cl, 3 tbl, 18 ex

 

The invention relates to compounds of General formula

where

R1represents lower alkyl substituted by halogen, or represents aryl or heteroaryl, unsubstituted or substituted with halogen;

R2is heteroseksualci, aryl or heteroaryl, which are unsubstituted or substituted by one or more than one Deputy, selected from the group consisting of halogen, lower alkyloxy, lower alkyl substituted by halogen, O-lower alkyl substituted by halogen, or substituted by the group C(O)-NR2, (CR2)m-C(O)-R', heteroaryl or S(O)2is lower alkyl;

R3/R3', R4/R4'and R5/R5'represent independently each other a hydrogen atom or fluorine, where at least one of R4/R4'or R5/R5'always represents fluorine;

R' represents an aryl or hydroxy;

R" represents a hydrogen atom, cycloalkyl or is heteroseksualci;

R represents a hydrogen atom or lower alkyl;

m is 0, 1, 2 or 3;

and their pharmaceutically acceptable salts accession acid, optically pure enantiomers, racemates or diastereomeric mixtures.

As used here, the term "lower alkyl" means a saturated straight the chain or branched group, containing from 1 to 7 carbon atoms, for example: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and the like. Preferred alkyl groups are groups with 1-4 carbon atoms.

The term "lower alkoxy" means a group where the alkyl residue is as defined above, attached via an oxygen atom.

The term "halogen" means chlorine, iodine, fluorine and bromine.

The term "aryl" means a monovalent cyclic aromatic hydrocarbon radical consisting of one ring or more condensed rings, in which at least one ring is aromatic in nature, for example phenyl or naphthyl. The preferred aryl group is phenyl.

The term "heteroaryl" means the monovalent aromatic carbocyclic radical containing at least one heteroatom selected from the group consisting of N, O or S, such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, tetrazolyl, [1,2,4]triazolyl, [1,2,4]oxadiazolyl, oxazolyl or isoxazolyl. Preferred heteroaryl groups are pyridyl, thienyl, triazinyl, furyl or thiazolyl.

The term "heteroseksualci" means a non-aromatic hydrocarbon radical containing at IU is greater least one heteroatom, selected from the group consisting of N, O or S, for example: oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidine, pyrrolidine, piperidinyl, piperazinil, morpholinyl or thiomorpholine. Preferred heteroseksualnymi groups are morpholinyl, piperidinyl or pyrrolidinyl.

The term "cycloalkyl" means a saturated carbocyclic ring containing 3-7 carbon atoms.

The term "pharmaceutically acceptable salts join acid" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, para-toluensulfonate acid and the like.

Found that compounds of General formula I are inhibitors of γ-secretase, and related compounds may be useful in the treatment of Alzheimer's disease or common cancers, including, but not limited to, carcinoma of the cervix and breast carcinoma, and malignant tumors of the hematopoietic system.

Alzheimer's disease (ad) is the most common dementia in the elderly. Ad is characterized pathologically by the deposition in the brain and is eloida in the extracellular plaques and intracellular neurofibrillary tangles. Amyloid plaques are mainly composed of amyloid peptide (A-beta peptides), which are formed from β-amyloid protein precursor (APP) through a series of stages proteolytic cleavage. Identified several forms of ADR, of which the most common are the proteins by the length of 695, 751 and 770 amino acids. They all originate from a single gene by differential splicing. A-beta peptides originate from the same domain of APP, but differ in their N - and C-ends, the main types of which have a length of 40 and 42 amino acids.

A-beta peptides are produced from the RDA through the sequential action of two proteolytic enzymes called β - and γ-secretases. First, β-secretase cleaves the extracellular domain of APP directly from outside the transmembrane domain (TM) with the formation of the C-terminal fragment of APP containing the TM and cytoplasmic domain (CTFβ). CTFβ is a substrate for γ-secretase, which breaks down at several nearby locations inside the TM with the formation of β peptides and cytoplasmic fragment. The majority of A-beta peptides have a length of 40 amino acids (β40), minor species are two additional amino acids at its C-end. Assume that the last amyloid peptides in more pathogenic.

β-Secretase performance, which provides a typical aspirinplease. γ-Secretase is a proteolytic activity consisting of several proteins, and its exact composition is not fully understood. However presenilin are essential components of this activity and may represent a new group of atypical aspartate, which decompose inside TM their substrates, and which are themselves polititicheskie membrane proteins. Other essential components of the γ-secretase can be presenilin, nicastrin and the products of the genes aph1 and pen-2. Proven substrates for γ-secretase are RDAs and proteins of the family of Notch receptors, however, γ-secretase has a loose substrate specificity and can split additional membrane proteins that are not related to the RDA and Notch. It was demonstrated genetic methods, i.e. by removing or genes presenilin 1 and 2, a gene nicastrin that γ-secretase absolutely necessary for signal transmission Notch. This was subsequently confirmed by treatment of specific inhibitors of γ-secretase.

The Notch receptors are not only essential in embryonic development, but also play a critical role in several tissues of an adult organism, which continue to undergo proliferation and differentiation, such as hematopoietic cells and the epithelium of the intestine and skin. Signaling receptors Notch p is oshodi through an ordered sequence of events: the binding of ligand group Delta or Jagged, cleavage of the extracellular domain of the ADAM protease (TACE) and subsequent cleavage of γ-secretases within the transmembrane domain of Notch. Last cleavage results in the release of the cytoplasmic domain, which then moves into the nucleus where it acts with other proteins as a regulator of specific groups of genes.

The role of Notch in tumorigenesis person most clearly established for acute T-cell lymphoblastic leukemia (T-ALL). In some rare cases of T-ALL shown chromosomal translocation (7:9), which leads to constitutive activation of Notch1. Recently reported that approximately 50% of all cases of T-ALL there is a point mutation in the receptor Notch1, which also causes hyperactivation. It was shown that the growth of some cell lines derived from such leukemia, was sensitive to treatment with inhibitors of γ-secretase, which confirms its important role for signal transmission Notch1.

More extensive role of Notch in tumorigenesis are discussed in several recent articles, which described that his signal necessary for the maintenance of the neoplastic phenotype in ras-transformed cells. Dysregulation of biochemical route of transmission of the signal ras is detected when the number of common cancers, including carcinoma of the cervix and breast carcinoma.

The asset is ity γ secretase absolutely necessary for the production of A-beta peptides. This is shown by genetic methods, i.e. by removing genes presenilin and using low molecular weight inhibitory compounds. Since, according to the amyloid hypothesis BA production and deposition of A-beta is the final cause of the disease, believe that selective and effective inhibitors of γ-secretase useful for the prevention and treatment of ad.

Thus, the compounds of this invention should be useful in the treatment of BA or common cancers by blocking the activity of γ-secretase and reduce or prevent the formation of various amyloidogenic A-beta peptides and, in addition, by blocking biochemical by transmitting a signal Notch they may interfere with the pathogenesis of cancer.

In the various documents described the current knowledge on the inhibition of γ-secretase, for example, in the following publications:

The EMBO Journal (2204), 23, 483-488,

Biochemistry (2004), 43 (30), 9774-9789,

Nature Reviews/Neuroscience, Vol.3, April 2002/281,

Biochemical Society Transactions (2002), Vol.30, part 4,

Current Topics in Medicinal Chemistry, 2002, 2, 371-383,

Current Medicinal Chemistry, 2002, Vol.9, No. 11, 1087-1106,

Drug Development Research, 56, 211-227, 2002,

Drug Discovery Today, Vol.6, No. 9, May 2001, 459-462,

FEBS Letters, 483, (2000), 6-10,

Science, Vol.297, 353-356, July 2002,

Journ. of Medicinal Chemistry, Vol.44, No. 13, 2001, 2039-2060,

Nature Cell Biology 2, 461-462, 2000,

Nature 398, 518-522, 1999,

Nature Cell Biology 3, 1129-1132, 2001,

PNAS98, 7487-7491, 2001,

ancer Cell 1, 75-87, 2002,

Science 306, 269-271, 2004,

Mol Cell Biol 23, 655-664, 2003,

Nature Medicine 8, 979-986, 2002 and

Oncogene 22, 6598-6608, 2003.

Objects of the present invention are the compounds of formula I as such, the use of compounds of the formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases associated with inhibition of γ-secretase, their manufacture, medicaments based on a compound in accordance with the invention and their manufacture, as well as the use of compounds of formula I in the fight against Alzheimer's disease or with common cancers, including, but not limited to, carcinoma of the cervix and breast carcinoma, or when their warning.

The next object of the invention is any form of optically pure enantiomers, racemates or diastereomeric mixture of compounds of formula I.

The most preferred compounds of formula I are compounds where R4/R4'both represent fluorine and R1represents phenyl, substituted with halogen.

Preferred compounds from this group are compounds where R2represents phenyl, substituted with halogen and/or C(O)-N(R')2for example the following compounds:

4-{[(4-chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-N-cyclopropylbenzene or

4-{[(4-chlorobenz sulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-3-fluoro-N-pyrrolidin-1-ylbenzene.

The following preferred compounds from this group are compounds where R2represents phenyl substituted by halogen and lower alkoxy, for example the connection

4-chloro-N-(2,3-debtor-4-methoxybenzyl)-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide.

Preferred compounds from this group are compounds where R2represents phenyl, substituted with halogen and heteroaryl, for example, the following connection

4-chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-[2-fluoro-4-(2H-[1,2,4]triazole-3-yl)-benzyl]-benzosulfimide.

Preferred compounds from this group are compounds where R2represents phenyl, substituted (CR2)mC(O)-R', for example the following compounds

3-(4-{[(4-chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-phenyl)-propionic acid, or

3-(4-{[(4-chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-phenyl)-3-matlakala acid.

Preferred compounds are compounds where R1is heteroaryl, substituted with halogen, or R1represents lower alkyl substituted by halogen.

These compounds of formula I and their pharmaceutically acceptable salts can be obtained by methods known in the art, e.g. the measures using the following processes, which include

a) interaction of the compounds of formula

with the compound of the formula

obtaining the compounds of formula

where R1, R2, R3/R3', R4/R4'and R5/R5'you have such a value as described above, or

b) interaction of the compounds of formula

with the compound of the formula

in the presence of base or with the compound of the formula

in the presence of Ph3P and DIAD

obtaining the compounds of formula

where R1, R2, R3/R3', R4/R4'and R5/R5'you have such a value as described above, and if desired, the conversion of the compounds obtained into pharmaceutically acceptable salts accession acid.

Detailed processes for producing compounds of formula I described in schemes 1 and 2 and in Examples 1-18. Educt of formula VII, VIII, IX, X and XI are known compounds or can be obtained by methods well known in the art.

Used the following abbreviations:

DIAD - diethylazodicarboxylate

DMAP - 4-dimethylaminopyridine

EDC - etyl-3-(3-dimethylaminopropyl)carbodiimide

TATU - 1,1,3,3-tetramethyl-2-(1H-1,2,3-triazolo[5,4-b]pyridin-1-yl)Urania tetrafluoroborate

TPTU - O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N'N'-tetramethylurea tetrafluoroborate

DMB - 2,4-dimethoxybenzyl

DAST - diethylaminoethyl TRIFLUORIDE

DMF - N,N-dimethylformamide

Deoxofluor - [bis(2-methoxyethyl)amino]sulfur TRIFLUORIDE

Scheme 1

where R1, R2, R3/R3', R4/R4'and R5/R5'you have such a value as described above, and Ph3P is a triphenylphosphine.

Aminoethan-2-it formula VII is treated with an aldehyde and a suitable regenerating reagent, such as triacetoxyborohydride sodium or cyanoborohydride sodium, to obtain the amine compound of the formula II. The solution of this amine in dichloromethane can be subjected to interaction with one equivalent of an aromatic sulphonylchloride in the presence of a base, such as base Hunga or triethylamine, and a catalytic amount of DMAP to obtain after column chromatography the pure compounds of formula I. the Alternate connection of the formula VII can be engaging first sulphonylchloride, resulting in sulfonamidnuyu compounds of formula IV, which are amenable to further conversion using, for example, Protocol Mitsunobu, through the m which the alcohol R 2CH2OH, triphenylphosphine and aminobutiramida or diethylazodicarboxylate subjected to interaction at low temperature in an inert atmosphere in a dry solvent such as tetrahydrofuran. The reaction mixture is allowed to warm, and then stirred at room temperature for several hours to obtain after column chromatography of the compounds of formula I. Intermediate compounds of formula IV can also be used in the reaction, where the halide R2CH2hal is subjected to interaction in the presence of excess potassium carbonate, a catalytic amount of potassium iodide in dry DMF solvent and at elevated temperature. Then the reaction mixture is filtered, acidified and purified using column chromatography, to obtain the compounds of formula I.

3-Aminoethan-2-ones, substituted by a fluorine atom in the ring, of the formula VII can be obtained by various methods described in the literature, and specifically one approach, shown in diagram 2.

Amine of the formula X (which can be obtained by reacting a substituted benzaldehyde with allylamine in reducing conditions) can be combined with the derived amino acid of formula XI using standard reagents peptide combinations such as EDC or TATU, obtaining at high outputs bi is-allyl derivatives of formula XII. The metathesis circuit cycle compounds of formula XII can be achieved using catalysts based on ruthenium, such as described by Grubbs. The Grubbs catalyst 2nd generation was more effective for producing compounds of formula XIII. The resulting alkenes of formula XIII can be oxidized to 5.6-oxo-regioisomers of formula XIV by palladium complexes in the environment rich in oxygen. Regioisomeric mixture of ketones of the formula XIV are not easily separated by chromatography. This mixture can be further converted into paired dipteronia the compounds of formula XV using commercial compounds such as DAST or deoxofluor. The compounds of formula XV can be adequately separated by chromatography on silica gel. In the result of the removal of the protective group in terms of acidalia get 3-aminoethan-2-ones, substituted by a fluorine atom in the ring, of the formula VII.

A detailed description can be found in Examples a-K and 1-18.

If the compounds of formula I are basic, they can be converted into the corresponding salt accession acid.

This conversion is carried out by processing at least the stoichiometric amount of the appropriate acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and the organization is organic acid, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, para-toluensulfonate acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and add the acid in this solvent. The temperature of the support between 0°C and 50°C. the resulting salt spontaneously precipitates, or can be deduced from the solution of the less polar solvent.

Salt accession acid compounds of the formula I can be converted into the corresponding free base by treating at least a stoichiometric amount of the appropriate base, such as sodium hydroxide or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia and the like.

The compounds of formula I and their pharmaceutically applicable salt accession acids have valuable pharmacological properties. Specifically, it was found that the compounds of the present invention can in order to inhibit γ-secretase.

Compounds were investigated in accordance with the test described here below.

Description of analysis for γ-secretase

The activity of test compounds can be evaluated in assays that measure the proteolytic cleavage of the respective substrates, the activity of γ-secretase. These tests can be a cellular analyses where, for example, the substrate γ-secretase hybridized in its cytoplasmic domain transcription factor. Cells transferout this hybrid gene and gene-reporter, for example, Firefly luciferase, the expression of which is enhanced by this transcription factor. Cleavage of the hybrid substrate of γ-secretases should lead to gene expression reporter, monitoring which can be done in the respective analyses. The activity of γ-secretase can also be determined in cell-free assays in vitro, where, for example, cell lysate containing γ-Secretary complex, incubated with the appropriate substrate, representing a derivative of the RDA, which breaks down to A-beta peptides. The number of produced peptides can be determined using specific analyses ELIZA. Cell lines of neural origin secrete A-beta peptides, which can measure specific analysis ELIZA. Treatment with compounds that inhibit γ-secretase, leads to a reduction of the structure secreted A-beta peptides providing, thus, the measurement of inhibition.

In the analysis of the activity of γ-secretase in vitro with the use of membrane fraction NECK as the source of γ-secretase and recombinant substrate ARR. The latter consists of 100 C-terminal amino acids of the human ear, which hybridized with histidinol "tail" for cleaning, which Express in E. coli in the regulated expression vector, for example pEt15. This recombinant protein corresponds to a shortened fragment of APP, which is formed in the decomposition of γ secretases extracellular domain, which is the substrate of γ-secretase. The principle of this analysis is described in Li Y. M. et al., PNAS 97 (11), 6138-6143 (2000). The Hek293 cells mechanically destroy, and microsome fraction allocate by differential centrifugation. Membrane solubilizing in detergent (of 0.25% CHAPSO) and incubated with the RDA substrate. A-beta peptides, which are produced in the cleavage of this substrate γ-secretases find using specific analyses ELIZA, as described (Brockhaus M, et al., Neuroreport 9 (7), 1481-1486 (1998)).

The preferred compounds show IC50<10 nm. The following list describes some of the data on the inhibition of γ-secretase:

The compounds of formula I and pharmaceutically acceptable salts connection the settings of the formula I can be used as drugs for example, in the form of pharmaceutical preparations. These pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. Introduction you can, however, also to carry out rectally, for example in the form of suppositories, parenterally, e.g. in the form of injection solutions.

The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or their salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance, however, usually does not require any media in the case of soft gelatin capsules. Suitable carriers for the manufacture of solutions and syrups are, for example, water, polyols, glycerine, vegetable oil, and the like. Suitable carriers for suppositories are, for example, natural or hardened mA is La, waxes, fats, semi-solid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives, soljubilizatory, stabilizers, moistening agents, emulsifiers, sweeteners, colorants, corrigentov, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

Drugs, containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention, as the method of their production, which comprises bringing one or more than one compounds of formula I and/or pharmaceutically acceptable salts accession acid and, if desired, one or more than one other therapeutically valuable substances into a form Galanova preparation for the introduction together with one or more therapeutically inert carrier.

In accordance with the invention the compounds of formula I and their pharmaceutically acceptable salts useful in the fight against diseases which are useful in the inhibition of γ-secretase, such as Alzheimer's disease, or warning.

The dosage may vary within wide limits, and, of course, need to be adjusted according to the individual needs of the each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of the compounds of General formula I or the corresponding amount of its pharmaceutically acceptable salts. The daily dosage can be entered as a single dose or in fractional doses, and, in addition, the upper limit can also be exceeded when this is considered shown.

The method of production

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add PP and 5 and mix for 3 minutes.

3. Fill in the appropriate capsule.

Example

4-Chloromethyl-N-cyclopropylbenzene

4-Chlorodibenzofuran (2,82 g, 15 mmol) and cyclopropylamine (1,26 ml, 18 mmol) was subjected to interaction in CH2Cl2(30 ml) and in the presence of a base Hunya (3.1 ml, 18 mmol) for 1 h Formed a precipitate, which was re solubilizers by adding ethyl acetate. The reaction mixture was washed with a solution of 5% KHSO4/10% K2SO4, saturated NaCl, and dried (Na2SO4). The organic phase was filtered and concentrated under reduced pressure to obtain a semi-solid substance, which was ground in hexano: solid 3.1 g (95%);1H NMR (CDCl3) δ 0.60-0.64 (m, 2H), 0.85-of 0.90 (m, 2H), 2.89-2.92 (m, 1H), 4.60 (s, 2H), .20 (br, 1H), 7.44 (d, 2H), 7.71-7.74 (m, 2H); MS: m/e=210.2 (MH+)

The example In

(6-Methoxypyridine-3-yl)-methanol

To lithium aluminum hydride (0.68 g, 18 mmol)suspended in dry THF (10 ml), was added dropwise a solution of methyl-6-methoxynicotinate (1 g, 6 mmol) in dry THF (5 ml). The reaction mixture was stirred for 2 h at RT, then cooled (ice bath) and extinguished with water (2 ml) followed by addition of 1 N. NaOH (6 ml) and water (2 ml). The cooling bath was removed and the mixture was stirred for 30 min at RT, filtered and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3x). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure to get crude oil, which was purified on silica gel (ethyl acetate/n-heptane 1:1): colorless oil, 0.45 g (51%);1H NMR (COCl3) δ 1.69 (t, 1H), 3.94 (s, 3H), 4.62 (d, 2H), 6.75 (d, 1H), 7.62 (dd, 1H), 8.13 (d, 1H); MS: m/e=139,0 (M+)

The example

1-methyl bromide-4-deformational

To a solution of 4-bromocinnamaldehyde (1.0 g, 5.2 mmol) in CH2Cl2(60 ml) was added [bis(2-methoxyethyl)amino]sulfur TRIFLUORIDE (50% solution in toluene, 14 ml), and the light yellow reaction mixture was stirred for 4 hours at 40°C in argon atmosphere. The reaction mixture is the end of what was tarawali under reduced pressure, and the oily residue was added dropwise to cooled in ice to a solution of NaHCO3(half saturated, 50 ml). The resulting mixture was extracted with ethyl acetate (3x)and the combined organic extracts washed with aqueous NaHCO3, brine, dried (MgSO4·2H2O), filtered and concentrated under reduced pressure to obtain a yellow oil: 1,03 g, 85%; MS: m/e=220,0 (M), 141,0 (M-Br);1H NMR (400 MHz, CDCl3) δ million-14.50 (s, 2H), 6.64 (t, JHF=51 Hz, 1H), 7.49 (s, 4H).

Example D

{(R)-1-[Allyl-(2,4-dimethoxybenzyl)-carbarnoyl]-but-3-enyl}-carbamino acid tert-butyl methyl ether

(R)-N-BOC-allylglycine (2.3 g, 9.9 mmol) was dissolved in dimethylformamide (20 ml) and activated with a reagent combination TATU (3.5 g, 10.9 mmol) and the base Hunya (3.8 ml, 21.9 mmol) for 2 minutes Allyl-(2,4-dimethoxybenzyl)-amine (2.1 g, 9.9 mmol)dissolved in dimethylformamide (20 ml)was added to a chilled (ice bath-water) of the reaction mixture, and stirring was continued over night. The solvent is evaporated, and the residue was dissolved in ethyl acetate, washed with saturated solution of NaHCO3, 1 m solution of KHSO4, brine, dried (MgSO4·2H2O), filtered and concentrated under reduced pressure and purified on silica gel (ethyl acetate/n-heptane 1:4): colorless resin 2.6 g (62%); MS: m/e=to 405.5 (MH+).

[(R)-1-(2,4-Dimethoxybenzyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl]-carbamino acid tert-butyl methyl ether

(R)-1-[Allyl-(2,4-dimethoxybenzyl)-carbarnoyl]-but-3-enyl}-carbamino acid tert-butyl ester (2.6 g, 6.4 mmol) was dissolved in CH2Cl2(200 ml), was added the catalyst is [1,3-bis-(2,4,6-trimetilfenil)-2-imidazolidinone]dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium] Grubbs II (0.55 g, 0.64 mmol)and the reaction mixture is boiled under reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate and washed with a solution of NaHCO3, 1 m solution of KHSO4, brine, dried (MgSO4·2H2O), filtered, concentrated under reduced pressure and purified on silica gel (ethyl acetate/n-heptane 1:4->1:2): dark brown solid of 1.93 g (80%); MS: m/e=377,4 (MH+), Making Up 277.3 (M-Boc).

Example F

A mixture of [(R)-1-(2,4-dimethoxybenzyl)-2,6-diocesean-3-yl]-carbamino acid tert-butyl ester; compound with [(R)-1-(2,4-dimethoxybenzyl)-2,5-diocesean-3-yl]-carbamino acid tert-butyl ether

[(R)-1-(2,4-Dimethoxybenzyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl]-carbamino acid tert-butyl ester (5.4 g, of 14.3 mmol) was dissolved in DMF/water (10:1 V/V), and then added Pd(ll)l 2(1 g, 5.7 mmol) and Cu(l)Cl (7.2 g, to 72.4 mmol). The reaction mixture was evacuated and filled About2and then was heated at 50°C for 48 hours while the reaction used additional Pd(ll)Cl2(3×0.4 equivalent). The reaction mixture was diluted with water (400 ml) and filtered through cellit. The filtrate was extracted with ethyl acetate (5x), and the combined organic extracts were washed with a solution of NaHCO3, 1 m solution of KHSO4, brine, dried (MgSO4·2H2O), filtered, concentrated under reduced pressure and purified on silica gel (ethyl acetate/n-heptane 1:2->1:1) to give a mixture of [(R)-1-(2,4-dimethoxybenzyl)-2,6-diocesean-3-yl]-carbamino acid tert-butyl ester and [(R)-1-(2,4-dimethoxybenzyl)-2,5-diocesean-3-yl]-carbamino acid tert-butyl ether in the ratio 1:2: white solid 3.8 g (67%); MS: m/e=392,9 (MH+).

Example G

[(R)-1-(2,4-Dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-carbamino acid tert-butyl methyl ether

[Bis(2-methoxyethyl)amino]sulfur TRIFLUORIDE (3.5 g, 15.8 mmol) was dissolved in dry toluene (30 ml) and cooled (ice bath) in an argon atmosphere. Was added dropwise telefonat of boron TRIFLUORIDE (0.16 g, 1.13 mmol)and the mixture was stirred for 30 min at 5°C. Then was added a mixture of 1:2 [(R)-1-(2,4-dimethoxybenzyl)-2,6-diocesean-3-yl]-carbamino is islote tert-butyl ester and [(R)-1-(2,4-dimethoxybenzyl)-2,5-diocesean-3-yl]-carbamino acid tert-butyl ester (4.44 g, 11.3 mmol)dissolved in toluene (15 ml), the cooling bath was removed and the reaction mixture was slowly heated to 50°C., and then was stirred for 5 hours at this elevated temperature. The reaction mixture was poured chilled in ice, a half-saturated solution of NaHCO3and were extracted with ethyl acetate (3x). The combined organic extracts were washed with water, brine, dried (MgSO4·2H2O), filtered, concentrated under reduced pressure and purified on silica gel (ethyl acetate/n-heptane 1:4->1:3) to give [(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-carbamino acid tert-butyl ester: foam 1,32 g (25%); Rfof 0.4 (hexane/ethyl acetate, 1:1 V/V); MS: m/e=415,1 (MH+), 437,1 (MNa+)

1H NMR (400 MHz, CDCl3) δ million-11.45 (s, 9H), 1.54-1.69 (m, 1H), 1.75-1.98 (m, 1H), 2.00-2.16 (m, 1H), 2.49-2.65 (m, 1H), 3.34-3.44 (m, 1H), 3.47-3.60 (m, 1H), 3.80 (s, 3H), 3.81 (s, 3H), 4.49 (d, J=14.2 Hz, 1H), 4.52-4.56 (m, 1H), 4.69 (d, J=14.5 Hz, 1H), 5.97 (d, J=5.4 Hz, 1H), 6.42-6.48 (m, 2H), 7.19 (d, J=8.9 Hz, 1H).

Example H

[(R)-1-(2,4-Dimethoxybenzyl)-6,6-debtor-2-oxazepan-3-yl]-carbamino acid tert-butyl methyl ether

The connection is allocated when the output of 6.5% as a byproduct in the synthesis of another regioisomer [(R)-1-(2,4-dimethoxybenzyl)-6,6-debtor-2-oxazepan-3-yl]-carbamino acid tert-butyl ether.

Rfto 0.45 (hexane/ethyl acetate, 1:1 V/V); MS: m/e=415.3 MH +), when 432,2 (MNH4+).

1H NMR (400 MHz, CDCl3) δ million-11.41 (s, 9H), 1.54-1.56 (m, 1H), 2.1-2.3 (m, 3H), 3.6-3.8 (m, 2H), 3.80 (s, 3H), 3.82 (s, 3H), 4.21 (d, J=14 Hz, 1H), 4.38 (dd, J=6/8 Hz, 1H), 5.0 (d, J=14 Hz, 1H), 6.05 (b, 1H), 6.45-6.48 (m, 2H), 7.3 (d, J=8 Hz, 1H).

Example I

4-Chloro-N-[(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-benzosulfimide

(R)-1-(2,4-Dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-carbamino acid tert-butyl ether (0,77 g of 1.86 mmol) was dissolved in 4 M HCl/1,4-dioxane (20 ml) and was allowed to go reaction for 1 h, the Reaction mixture was concentrated under reduced pressure and once concentrated from acetonitrile. To the resulting hydrochloride salt was added CH2Cl2(30 ml) followed by adding dropwise base Hunya (1 ml, 5.6 mmol). Solution was added 4-chlorobenzenesulfonamide (0,59 g, 2.8 mmol) in CH2Cl2(4 ml)and the reaction mixture (pH 8) was stirred further for 1.5 hours the Reaction mixture was diluted with CH2Cl2and washed with a solution of NaHCO3, 1 M solution of KHSO4, brine, dried (MgSO4·2H2O), filtered, concentrated under reduced pressure and purified on silica gel (ethyl acetate/n-heptane 1:2): white crystals 0.74 g (78%);

MS: m/e=487,1 (MH-);

1H NMR (400 MHz, CDCl3) δ million-11.46-1.65 (m, 1H), 1.87-2.11 (m, 2H), 2.51-2.62 (m, 1H), 3.27-3.32 (m, 2H), 3.77 (s, 3H), 3.81 s, 3H), 3.96-4.04 (m, 1H), 4.38 (d, J=14.2 Hz, 1H), 4.62 (d, J=14.5 Hz, 1H), 6.33 (d, J=5.6 Hz, 1H), 6.41-6.46 (m, 2H), 6.91-6.95 (m, 1H), 7.45-7.50 (m, 2H), 7.78-7.83 (m, 2H).

Example J

4-Chloro-N-[(R)-1-(2,4-dimethoxybenzyl)-6,6-debtor-2-oxazepan-3-yl]-benzosulfimide

The connection specified in the header, MS: m/e=487,2 (MH+), obtained analogously to example I, starting with [(R)-1-(2,4-dimethoxybenzyl)-6,6-debtor-2-oxazepan-3-yl]-carbamino acid tert-butyl ether.

Example

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide

A mixture containing 40% triperoxonane acid, 1% triftormetilfullerenov acid in CH2Cl2(20 ml)was added to 4-chloro-N-[(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-benzosulfimide (0.5 g, 1.0 mmol). After 30 min the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate and washed with water, a solution of NaHCO3, 1 m solution of KHSO4, brine, dried (MgSO4·2H2O), filtered, concentrated under reduced pressure and purified on silica gel (CH2Cl2/Meon 95:5 V/V): white solid 0.74 g (78%); MS: m/e=sauce 337,1 (MH-).

Example 1

4-{[(4-Chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-N-cyclopropylbenzene

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide (0.05 g, 0.15 mmol), 4-chloromethyl-N-cyclopropylbenzene (0,05 is, 0.22 mmol), K2CO3(0.20 g, 1.5 mmol), KI (0.005 g, 0.03 mmol) was added to dry DMF (2.5 ml)and the resulting reaction mixture was stirred for 3.5 h at 65°C in argon atmosphere. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate and washed with 5% KHSO4/10% K2SO4(2x), water, brine, dried (MgSO4), filtered, concentrated under reduced pressure and purified on silica gel (ethyl acetate/n-heptane 3:2 V/V), and the purified product liofilizirovanny: white lyophilisate 60 mg; MS: m/e=512,3 (MN+), 534,2 (MNH4+)

1H NMR (400 MHz, CDCl3) δ million-10.57-0.69 (m, 2H), 0.79-0.94 (m, 2H), 1.78-1.95 (m, 1H), 1.98-2.14 (m, 1H), 2.19-2.32 (m, 2H), 2.88-2.94 (m, J=7.1, 7.1, 7.0, 3.8 Hz, 1H), 3.16-3.25 (m, J=13.2, 7.9, 5.2, 2.5, 2.5 Hz, 1H), 3.37-3.47 (m, 1H), 4.52 (d, J=17.2 Hz, 1H), 4.77-4.95 (m, 2H), 5.78 (dd, J=7.7, 5.2 Hz, 1H), 6.11-6.24 (m, 1H), 7.40-7.46 (m, 3H), 7.65-7.74 (m, 3H).

Example 2

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-(4-isoxazol-5-ylbenzyl)-benzosulfimide

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide alkilirovanie, using 5-(4-bromomethylphenyl)-isoxazol, analogously to Example 1 to obtain 4-chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-(4-isoxazol-5-ylbenzyl)-benzosulfimide: MS: m/e=496,0 (MN+), 513,2 (MNH4+).

Example 3

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-(6-methoxypyridine-3-ylmethyl)benzosulfimide

a) 4-Chloro-N-[(R)-1-(2,4-dimethoxy the ZIL)-5,5-debtor-2-oxazepan-3-yl]-N-(6-methoxypyridine-3-ylmethyl)-benzosulfimide

4-Chloro-N-[(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-benzosulfimide (0.04 g, 0.07 mmol), (6-methoxypyridine-3-yl)-methanol (of 0.014 g, 0.10 mmol), triphenylphosphine (0.04 g, 0.13 mmol) was dissolved in dry THF (3 ml) at 0-5°C. (ice bath-water) in an argon atmosphere followed by the addition dropwise of diisopropylcarbodiimide (28 mg, 0.13 mmol) in dry THF (0.5 ml). The reaction mixture was stirred for 1 h at RT, and then concentrated under reduced pressure. The crude yellow oil was purified on silica gel (ethyl acetate/n-heptane 1:2): colorless resin 23 mg (52%); MS: m/e=610,3 (MN+).

b) 4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-(6-methoxypyridine-3-ylmethyl)benzosulfimide

A mixture containing triperoxonane acid/triftormetilfullerenov acid (10:1 V/V, 4 ml)was added to 4-chloro-N-[1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-N-(6-methoxypyridine-3-ylmethyl)-benzosulfimide (21 mg, 0.03 mmol). After 1 h the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with 5% KHSO4/10% K2SO4(2x), water, brine, dried (MgSO4), filtered, concentrated under reduced pressure and purified on silica gel (ethyl acetate/n-heptane 3:2 V/V), and the purified product liofilizirovanny: white lyophilisate of 15.3 mg; MS: m/e=460,1 (MH+).

Example 4

4-Chloro-N-(2,3-debtor-4-methoxybenzyl)-N-((R)-5,5-d is fluoro-2-oxazepan-3-yl)-benzosulfimide

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide alkilirovanie, using 1-methyl bromide-2,3-debtor-4-methoxybenzoyl, analogously to Example 1 to obtain 4-chloro-N-(2,3-debtor-4-methoxybenzyl)-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide: MS: m/e=495,1 (MH+), 512,1 (MNH4+).

Example 5

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-(2-fluoro-4-methoxybenzyl)-benzosulfimide

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide were subjected to interaction with the (2-fluoro-4-methoxyphenyl)-methanol analogously to Example 3A to obtain 4-chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-(2-fluoro-4-methoxybenzyl)-benzosulfimide: MS: m/e=477,1 (MH+), 494,3 (MNH4+).

Example 6

4-{[(4-Chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-3-Formentera acid

a) 4-{[(4-Chloro-benzazolyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-3-fermenting acid methyl ester

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide alkilirovanie, using 4-methyl bromide-3-fermenting acid methyl ester, as in Example 1 to obtain 4-{[(4-chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-3-fermenting acid methyl ester: MS: m/e=504,9 (MH+), 522,1 (MNH4+).

b) 4-{[(4-Chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-3-Formentera acid

4-{[(4-Harbe solarpanel)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-3-fermenting acid methyl ester (130 mg, 0.26 mmol) was dissolved in THF/Meon (5 ml) and treated with 1 N. NaOH (1.2 ml) for 1.5 hours the Reaction mixture was concentrated under reduced pressure, diluted with the water, and was extracted with diethyl ether. The aqueous phase was acidified using a mixture of 5% KHSO4/10% K2SO4, and was extracted with ethyl acetate (3x). The combined organic fractions were washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure (103 mg). The crude product (50 mg) was purified using preparative chromatography OF (C18) (reversed-phase): lyophilized 22 mg; MS: m/e=489,0 (MH-).

Example 7

4-{[(4-Chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-3-fluoro-N-pyrrolidin-1-ylbenzene

4-{[(4-Chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-3-fermenting acid (50 mg, 0.10 mmol) was dissolved in DMF (1 ml) and activated with a reagent combination TPTU (33 mg, 0.11 mmol) and the base Hunga one (0.03 ml, 0.26 mmol) for 2 minutes was Added 1-aminopyrrolidine hydrochloride (0,013 g, 0.22 mmol) and the additional amount of base Hunga one (0.03 ml, 0.26 mmol). After 1 h the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with 5% KHSO4/10% K2SO4(2x), water, brine, dried (MgSO4), filtered, concentrated under reduced pressure, the Institute and was purified on silica gel (ethyl acetate-> the ethyl acetate/5% Meon), and the purified product liofilizirovanny: white lyophilisate 32 mg; MS: m/e=559,3 (MH+), 581,2 (MNa+).

Example 8

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-(4-methanesulfonylaminoethyl)-benzosulfimide

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide alkilirovanie using 4-methylsulfonylbenzoyl, analogously to Example 1 to obtain 4-chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-(4-methanesulfonylaminoethyl)-benzosulfimide: MS: m/e=507,2 (MN+), 524,1 (MNH4+).

Example 9

4-Chloro-N-(4-deformational)-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide alkilirovanie, using 4-(deformedarse)benzylbromide, analogously to Example 1 to obtain 4-chloro-N-(4-deformational)-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide: MS: m/e=495,1 (MH+), 512,1 (MNH4+).

Example 10

4-Chloro-N-(4-deformational)-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide alkilirovanie, using 1-methyl bromide-4-deformational, analogously to Example 1 to obtain 4-chloro-N-(4-deformational)-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide: MS: m/e=479,1 (MH+), 496,0 (MNH4+).

Example 11

N-(1-Benzoylpiperidine-4-ylmethyl)-4-chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzene is sulfonamid

a) 4-{[(4-Chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl methyl ether

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide alkilirovanie, using 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester, as in Example 1 to obtain 4-{[(4-chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester: MS: m/e=536,3 (MN+), 553,2 (MNH4+).

b) 4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-piperidine-4-ylmethylphosphonate

4-{[(4-Chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ether (0,105 g, 0.2 mmol) was dissolved in a mixture triperoxonane acid and dichloromethane (1:1) and stirred over night. After extraction with aqueous sodium bicarbonate solution the organic layer was dried (MgSO4) and evaporated to obtain 80 mg (94%) of 4-chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-piperidine-4-ylmethylphosphonate; MS: m/e=436,2 (MH+).

C) N-(1-Benzoylpiperidine-4-ylmethyl)-4-chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-piperidine-4-ylmethylphosphonate (0.04 g, 0.09 mmol) and triethylamine (19 mg, 0.18 mmol) was dissolved in dichloromethane (1.5 ml). Then was added benzoyl chloride (0.08 g, 0.13 mmol)and the mixture was stirred over night at room temperature. The reaction mixture was distributed between aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified on silica gel (heptane/ethyl acetate 1:1) to give 29 mg (58%) of the compound indicated in the title; MS: m/e=540,3 (MN+), 557,1 (MNH4+).

Example 12

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-[2-fluoro-4-(2H-[1,2,4]triazole-3-yl)-benzyl]-benzosulfimide

a) 4-Chloro-N-(4-cyano-2-terbisil)-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide alkilirovanie, using 4-methyl bromide-3-perbenzoate, analogously to Example 1 to obtain 4-chloro-N-(4-cyano-2-terbisil)-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide: MS: m/e=472,2 (MH+).

b) 4-{[(4-Chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-3-persensitivity ethyl ester hydrochloride

4-Chloro-N-(4-cyano-2-terbisil)-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide (to 0.23 g, 0.49 mmol) suspended in dry ethanol (10 ml) and cooled to 0°C. Dry HCl gas was carefully barbotirovany for 30 min in the suspension. This light-red reaction mixture was stirred at room temperature for 20 hours the resulting transparent the initial yellow solution was concentrated under reduced pressure, and the crude product used directly in the next stage: 0.28 g; MS: m/e=516,2 (MN-).

b) 4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-[2-fluoro-4-(2H-[1,2,4]triazole-3-yl)-benzyl]-benzosulfimide

The crude hydrochloride salt (0.27 g, approximately 0.49 mmol) and formylhydrazine (purity 90%, 36 mg, 0.54 mmol) was dissolved in pyridine (7.3 ml) and was stirred for 3 h in argon atmosphere. The reaction mixture was concentrated under reduced pressure and added xylenes (12.1 ml)and the reaction mixture was heated at 145°C for 30 minutes the Reaction mixture was concentrated under reduced pressure and the crude yellow solid was purified on silica gel (CH2Cl2/Meon 95:5), and the purified product liofilizirovanny: white lyophilized 75 mg; MS: m/e=514,2 (MH+), 531,0 (MNH4+).

Example 13

4-{[(4-Chlorobenzenesulfonyl)-((R)-6,6-debtor-2-oxazepan-3-yl)-amino]-methyl}-N-cyclopropylbenzene

4-Chloro-N-[(R)-1-(2,4-dimethoxybenzyl)-6,6-debtor-2-oxazepan-3-yl]-benzosulfimide was subjected to removal of the protective group dimethoxybenzyl analogously to Example K, and then alkilirovanie using chloromethyl-N-cyclopropylbenzene, similar to the Protocol in Example 1 to obtain 4-{[(4-chlorobenzenesulfonyl)-((R)-6,6-debtor-2-oxazepan-3-yl)-amino]-methyl}-N-cyclopropylbenzene. MS: m/e=512,1 (MH+);

1H NMR (400 MHz, CDCl3) δ million-10.56-0.68 (m, 2H), 0.81-0.91 (m, 2H), 1.72-1.87 (m, 2H, 1.95-2.14 (m, 1H), 2.17-2.27 (m, 1H), 2.91 (qd, J=7.1, 3.8 Hz, 1H), 3.31-3.50 (m, 1H), 3.54-3.67 (m, 1H), 4.51-4.62 (m, 1H), 4.82-4.94 (m, 2H), 5.51-5.62 (m, 1H), 6.16 (s, 1H), 7.41-7.52 (m, 3H), 7.65-7.72 (m, 3H).

Example 14

3-(4-{[(4-Chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-phenyl)-propionic acid

a) 3-(4-{[(4-Chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-phenyl)-propionic acid methyl ester

4-Chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide alkilirovanie, using 3-(4-bromomethylphenyl)-propionic acid methyl ester, as in Example 1 to obtain 3-(4-{[(4-chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-phenyl)-propionic acid methyl ester: MS: m/e=515,1 (MN+), 532,1 (MNH4+).

b) 3-(4-{[(4-Chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-phenyl)-propionic acid

3-(4-{[(4-Chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-phenyl)-propionic acid methyl ester (65 mg, 0.13 mmol) was dissolved in methanol (0.5 ml) and was treated with 2 N. LiOH in water (0.25 ml, 0.5 mmol) overnight at 40°C. the Reaction mixture was distributed between 4 N. HCl and ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude product (50 mg) was purified using column chromatography (dichloromethane/methanol 90:10), to obtain 45 mg (71%); MS: m/e=499,0 (MH-).

Example 15

3-(4-{[(4-what lebensalter)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-phenyl)-3-matlakala acid

This compound is obtained analogously to Example 14, using 3-(4-bromomethylphenyl)- 3-methylmalonic acid methyl ester at the stage 14a), to obtain 3-(4-{[(4-chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-phenyl)-3-methylmalonic acid: MS: m/e=527,1 (MN-).

Example 16

3,3,3-Cryptochrome-1-sulfonic acids ((R)-5,5-debtor-2-oxazepan-3-yl)-(6-methoxypyridine-3-ylmethyl)-amide

a) 3,3,3-Cryptochrome-1-sulfonic acids [(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-amide

[(R)-1-(2,4-Dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-carbamino acid tert-butyl ester (0.85 grams, of 1.85 mmol) was dissolved in 38 ml of dichloromethane. 4 M HCl/1,4-dioxane (20 ml) was added dropwise, and the mixture was allowed to react for 1 h the Reaction mixture was concentrated under reduced pressure and concentrated once from acetonitrile. To 291 mg of the resulting hydrochloride salt was added CH2Cl2(20 ml) followed by adding dropwise base Hunya (of 0.36 ml, 2.1 mmol). Solution was added 3,3,3-cryptochrome-1-sulphonylchloride (to 0.19 g, 0.9 mmol) in CH2Cl2(5 ml)and the reaction mixture (pH 8) was stirred further for 1.5 hours, the Reaction mixture was purified on silica gel (heptane-ethyl acetate, 95:5-0:100): white solid of 0.30 g (77%); MS: m/e=473,1 (M-H-).

b) 3,3,3-Cryptochrome-1-sulfonic acids [(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxeas the pan-3-yl)-(6-methoxypyridine-3-ylmethyl)-amide

3,3,3-Cryptochrome-1-sulfonic acids [(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-amide (0.15 g, 0.31 mmol), (6-methoxypyridine-3-yl)-methanol (0.06 g, 0.38 mmol), triphenylphosphine (0.17 g, of 0.62 mmol) was dissolved in dry THF (15 ml) at 0-5°C. (ice bath-water) in an argon atmosphere followed by the addition dropwise of diisopropylcarbodiimide (0,12 ml of 0.62 mmol) in dry THF (1.5 ml). The reaction mixture was stirred for 1 h at RT, and then concentrated under reduced pressure. The crude oil was purified on silica gel (first: heptane-ethyl acetate, 97:3-0:100; then: dichloromethane-methanol, 98:2-90:10): white solid 214 mg (81%); MS: m/e=654,2 (M+CH3Soo-).

C) 3,3,3-Cryptochrome-1-sulfonic acids ((R)-5,5-debtor-2-oxazepan-3-yl)-(6-methoxypyridine-3-ylmethyl)-amide

A mixture containing triperoxonane acid/triftormetilfullerenov acid (5:2 V/V, from 0.76 ml)was added 3,3,3-cryptochrome-1-sulfonic acids [(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-(6-methoxypyridine-3-ylmethyl)-amide (0.2 g, 0.24 mmol) in dichloromethane (10 ml). After 2 h the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified on silica gel (heptane-ethyl acetate, 9:1-0:1): white solid fuel is the substance 72 mg (69%); MS: m/e=446,2 (MH+).

Example 17

5-Chlorothiophene-2-sulfonic ((R)-5,5-debtor-2-oxazepan-3-yl)-(6-methoxypyridine-3-ylmethyl)-amide

a) 5-Chlorothiophene-2-sulfonic acids [(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-amide

[(R)-1-(2,4-Dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-carbamino acid tert-butyl ester (0.85 grams, of 1.85 mmol) was dissolved in 38 ml of dichloromethane. 4 M HCl/1,4-dioxane (20 ml) was added dropwise, and the mixture was allowed to react for 1 h the Reaction mixture was concentrated under reduced pressure and concentrated once from acetonitrile. To 291 mg of the resulting hydrochloride salt was added CH2Cl2(20 ml) followed by adding dropwise base Hunya (of 0.36 ml, 2.1 mmol). Solution was added 5-chlorothiophene-2-sulphonylchloride (0.21 g, 0.9 mmol) in CH2Cl2(5 ml)and the reaction mixture (pH 8) was stirred further for 1.5 hours, the Reaction mixture was purified on silica gel (heptane-ethyl acetate, 95:5-0:100): white solid 0.40 g (97%); MS: m/e=493,1 (M-H-).

b) 5-Chlorothiophene-2-sulfonic acids [(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl-(6-methoxypyridine-3-ylmethyl)-amide

5-Chlorothiophene-2-sulfonic acids [(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-amide (0.20 g, 0.40 mmol), (6-methoxypyridine-3-yl)-methanol (0.07 g, 0.48 mmol), triphenylphosphine (0,22 g, 0.80 mmol) was dissolved in dry THF (15 ml) at 0-5°C. (ice bath in the (a) in an argon atmosphere followed by the addition dropwise of diisopropylcarbodiimide (0.16 ml, 0.80 mmol) in dry THF (1.5 ml). The reaction mixture was stirred for 1 h at RT, and then concentrated under reduced pressure. The crude oil was purified on silica gel (first: heptane-ethyl acetate, 97:3-0:100; then: dichloromethane-methanol, 98:2-90:10): white solid 0,19 g (53%); MS: m/e=674,2 (M+CH3Soo-).

C) 5-Chlorothiophene-2-sulfonic ((R)-5,5-debtor-2-oxazepan-3-yl)-(6-methoxypyridine-3-ylmethyl)-amide

A mixture containing triperoxonane acid/triftormetilfullerenov acid (5:2 V/V, 0.62 ml)was added to 5-chlorothiophene-2-sulfonic acids [(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-(6-methoxypyridine-3-ylmethyl)-amide (0.17 g, 0,19 mmol) in dichloromethane (10 ml). After 2 h the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified on silica gel (heptane-ethyl acetate, 9:1-0:1): white solid 69 mg (77%); MS: m/e=466,1 (MH+).

Example 18

5-Chloropyridin-2-sulfonic acids (4-deformational)-((R)-5,5-debtor-2-oxazepan-3-yl)-amide

a) 5-Chloropyridin-2-sulfonic acids [(R)-1-(2,4-dimethoxybenzyl)-5.5-debtor-2-oxazepan-3-yl]-amide

[(R)-1-(2,4-Dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-carbamino acid tert-butyl ether (0,46 g ,0 mmol) was dissolved in 20 ml of dichloromethane. 4 M HCl/1,4-dioxane (20 ml) was added dropwise, and the mixture was allowed to react for 1 h the Reaction mixture was concentrated under reduced pressure and concentrated once from acetonitrile. To the resulting hydrochloride salt was added CH2Cl2(15 ml) followed by adding dropwise base Hunya (of 0.44 ml, 2.5 mmol). Solution was added 5-chloropyridin-2-sulphonylchloride (0.33 g, 1.1 mmol) in CH2Cl2(5 ml)and the reaction mixture (pH 8) was stirred further for 1.5 hours, the Reaction mixture was purified on silica gel (heptane-ethyl acetate, 95:5-0:100): white solid of 0.37 g (76%); MS: m/e=490,2 (MH+).

b) 5-Chloropyridin-2-sulfonic ((R)-5,5-debtor-2-oxazepan-3-yl)-amide

A mixture containing triperoxonane acid/triftormetilfullerenov acid (5:2 V/V, 2,44 ml), was added to 5-Chloropyridin-2-sulfonic acids [(R)-1-(2,4-dimethoxybenzyl)-5,5-debtor-2-oxazepan-3-yl]-amide (0,37 g, from 0.76 mmol) in dichloromethane (20 ml). After 2 h the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified on silica gel (heptane-ethyl acetate, 1:1-0:1): white solid 0,22 g (84%); MS: m/e=340,0 (MH+).

C) 5-Chloropyridin-2-sulfonic acids (4-diformate dibenzyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amide

5-Chloropyridin-2-sulfonic ((R)-5,5-debtor-2-oxazepan-3-yl)-amide (0.21 g, 0.61 mmol), 4-(deformedarse)benzylbromide (0,23 g of 0.91 mmol), K2CO3(0.85 grams, between 6.08 mmol), KI (0.02 g, 0.12 mmol) was added to dry DMF (10 ml)and the resulting reaction mixture was stirred for 1.5 h at 65°C and for an additional 3 h at room temperature in argon atmosphere. The solvent was removed under reduced pressure, and the residue was purified on silica gel (first: ethyl acetate/n-heptane 1:2 V/V; then: dichloromethane/Meon, 100:0-95:5): brownish oil, 0,23 g; MS: m/e=496,1 (MH+).

1. Compounds of General formula

where R1represents a C1-7alkyl substituted by halogen, or represents aryl or heteroaryl, unsubstituted or substituted with halogen, where aryl hereinafter means a monovalent cyclic aromatic hydrocarbon radical consisting of one ring or more condensed rings, in which at least one ring is aromatic in nature, and heteroaryl hereinafter means a monovalent aromatic carbocyclic radical containing at least one heteroatom selected from N, O or S;
R2is heteroseksualci where heteroseksualci hereinafter means a non-aromatic hydrocarbon glad the feces, containing at least one heteroatom selected from N, O or S, aryl or heteroaryl, which are unsubstituted or substituted by one or more than one Deputy, selected from the group consisting of halogen, C1-7alkyloxy,1-7of alkyl, substituted with halogen, O-(C1-7)alkyl, substituted with halogen, or substituted by the group C(O)-NR2, (CR2)m-C(O)-R', heteroaryl or S(O)2-(C1-7)alkyl;
R3/R3', R4/R4'and R5/R5'represent independently each other a hydrogen atom or fluorine, where at least one of R4/R4'or R5/R5'always represents a fluorine atom;
R' represents an aryl or hydroxy;
R" represents a hydrogen atom, a C3-7cycloalkyl or is heteroseksualci;
R represents a hydrogen atom or a C1-7alkyl;
m is 0, 1, 2 or 3;
and their pharmaceutically acceptable salts accession acid, optically pure enantiomers, racemates or diastereomeric mixture.

2. Compounds according to claim 1 of formula I, where R4/R4'both represent fluorine and R1represents phenyl, substituted with halogen.

3. Compounds according to claim 2 of formula I, where R2represents phenyl, substituted with halogen and/or C(O)-N(R')2.

4. Compounds according to claim 3 of the formula I, which is s represent 4-{[(4-chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-N-cyclopropylbenzene or
4-{[(4-chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-3-fluoro-N-pyrrolidin-1-ylbenzene.

5. Compounds according to claim 2 of formula I, where R2represents phenyl, substituted with halogen and C1-7alkoxy.

6. Compounds according to claim 5 of the formula I, which represent 4-chloro-N-(2,3-debtor-4-methoxybenzyl)-N-((R)-5,5-debtor-2-oxazepan-3-yl)-benzosulfimide.

7. Compounds according to claim 2 of formula I, where R2represents phenyl, substituted with halogen and heteroaryl.

8. Compounds according to claim 7 of formula I, where the compound is a 4-chloro-N-((R)-5,5-debtor-2-oxazepan-3-yl)-N-[2-fluoro-4-(2H-[1,2,4]triazole-3-yl)-benzyl]-benzosulfimide.

9. Compounds according to claim 2 of formula I, where R2represents phenyl, substituted (CR2)mC(O)-R'.

10. Compounds according to claim 9 of the formula I, which are
3-(4-{[(4-chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-phenyl)-propionic acid, or
3-(4-{[(4-chlorobenzenesulfonyl)-((R)-5,5-debtor-2-oxazepan-3-yl)-amino]-methyl}-phenyl)-3-methylmalonyl acid.

11. Compounds according to claim 1 of formula I, where R1is heteroaryl, substituted with halogen.

12. Compounds according to claim 1 of formula I, where R1represents a C1-7alkyl, substituted with halogen.

13. Medicine, with the ability to inhibit γ-secretase containing one or more than one soy is inania according to claim 1 and pharmaceutically acceptable excipients.

14. Medicine for 13 for the treatment of Alzheimer's disease or common types of cancer.

15. The use of compounds according to claim 1 for the manufacture of medicaments for the treatment of Alzheimer's disease or common cancers.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 3,4-substituted pyrrolidine derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is an acyl selected from values given paragraph 1 of the formula of invention; R2 is unsubstituted C1-C4-alkyl or C3-C7-cycloalkyl; R3 is a fragment selected from a group of fragments of formulae: (a), (b),

(c) and (f), where any of the fragments of formulae given above (a), (b) and (f), the star (*) indicates a bond of the corresponding fragment R3 with the molecule residue in formula I; Ra denotes N-C1-C4-alkylaminocarbonyl, N-phenylaminocarbonyl, N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl- C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(C3-C7-cycloalkyl-C1-C4-alkyl)aminocarbonyl, N,N-di-(C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl)aminocarbonyl or hydrogen; Rb and Rc are independently selected from a group comprising unsubstituted C1-C4-alkyl, unsubstituted monocyclic aryl, unsubstituted monocyclic heterocyclyl, unsubstituted or substituted monocyclic C3-C7-cycloalkyl, unsubstituted aryl- C1-C4-alkyl, usubstituted monocyclic C3-C7-cycloalkyl- C1-C4-alkyl, hydrogen or acyl, where the acyl is selected from values given in paragraph 1 of the formula of invention; or Rb and Rc together may form a 6-member nitrogen-containing ring which may be unsubstituted or disubstituted with =O; Rd in the fragment of formula (c) denotes a phenyl or phenyl-C1-C4-alkyl; Re denotes hydrogen or C1-C4-alkyl; and m equals 2; each of R4 and R5 denotes hydrogen; and T denotes methylene. The invention also relates to the pharmaceutical composition based on the compound of formula I and a method of treating hypertension using the compound of formula I.

EFFECT: novel pyrrolidine derivatives having renin inhibiting activity are obtained.

7 cl, 19 tbl, 37 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to oxazole compound represented by formula (1) and its pharmaceutically acceptable salts. In formula (1) R1 represents phenyl group, which can contain one or two substituents, selected from the following groups (1-1)-(1-11): (1-1) hydroxy groups, (1-2) unsubstituted or halogen-substituted lower alkoxy groups, (1-3) lower alkenyloxy-groups, (1-4) lower alkinyloxy groups, (1-5) cycloC3-8alkyl (lower) alkoxy groups, (1-6) cycloC3-8alkyloxy groups, (1-7) cycloC3-8alkenyloxy groups, (1-8) dihydroindenyloxy groups, (1-9) hydroxyl-(lower)ankoxy groups, (1-10) oxiranyl(lower)alkoxy groups, and (1-11) phenyl(lower)-alkoxy groups; R2 represents phenyl group or heterocyclyl group, selected from pyridine, pyrasine, isoquinoline, pyrrolidine, piperazine, morpholine, each of which can contain one or two substituents, selected from the following groups (2-1)-(2-10):(2-1) hydroxy groups, (2-2) unsubstituted or halogen-substituted lower alkoxy groups, (2-3) unsubstituted or halogen-substituted lower alkyl groups, (2-4) lower alkenyloxy groups, (2-5) halogen atoms, (2-6) lower alkanoyl groups, (2-7) lower alkylthio groups, (2-8) lower alkylsulphonyl groups, (2-9) oxo groups and (2-10) groups lower alkoxy-lower alkoxy; and W represents bivalent group represented by formula (i) or (ii): formula (i) -Y -A -, formula (ii) -Y2-C(=O)-, where A1 represents lower alkenylene group or lower alkylene group, which can contain one substitutent, selected from group, consisting from hydroxy group and lower alkoxicarbonyl group, Y1 represents simple bond, -C(=O)-, -C(=O)-N(R3)-, -N(R4)-C(=O)-, -S(O)m-NH- or -S(O)n-, where R3 and R4, each independently, represent a hydrogen atom or lower alkyl group, and m and n, each independently, represent integer, which has value 2, and Y represents pyperazine-diyl group, or bivalent group, represented by formula (iii) or (iv): formula (iii) -C (=O)-A2-N(R5)-, formula (iv) A3-N(R6)-, where A2 and A3, each independently, represent lower alkylene group, and R5 and R6, each independently, represent a hydrogen atom. Invention also relates to pharmaceutical composition, containing the invention compound as an active ingredient, to pharmaceutical composition for treatment or prevention of atopic dermatitis, which includes the invention compound, to application of the compound as medication, to application of the compound as phosphodiesterase 4 inhibitor and/or as inhibitor of production of tumour necrosis factor α and to method of treatment or prevention of diseases, mediated by phosphodiesterase 4 or mediated by tumour necrosis factor α, including introduction of efficient dose of the compound.

EFFECT: creation of pharmaceutical composition for treatment or prevention of diseases mediated by phosphodiesterase 4 or mediated by tumour necrosis factor, as well as for treatment or prevention of atopic dermatitis.

12 cl, 42 tbl, 486 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (3-trifluromethylphenyl)amide 6-(6-hydroxymethylpyrimidin-4-yloxy)naphthalene-1-carboxylic acid or tautomer or salt thereof. The invention also relates to a pharmaceutical composition which has protein kinase inhibiting activity, based on the said compound and use of the said compound to prepare pharmaceutical compositions for use in treating protein kinase dependent diseases, preferably proliferative diseases, particularly tumorous diseases.

EFFECT: improved properties of compounds.

6 cl, 115 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

Aromatic compound // 2416608

FIELD: chemistry.

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

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

62 cl, 2717 ex, 432 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzo[d]isoxazol-3-ylamine compounds of formula I in free form or in form of salts with physiologically compatible acids, having antagonistic effect on KCNQ2/3 ion channel. In formula I , R1, R2, R3 and R4 independently denote H, F, CI, Br, I, -NR7R8, -OR9 or C1-C10alkyl, R5 denotes -C(=S)NR21R22 or (CHR6)n-R25, where n equals 1, 2 or 3, R6 denotes H or C1-C6 alkyl, R25 denotes aryl or heteroaryl, R7 and R8 independently denote H or C1-C10 alkyl, R9 denotes H, C1-C10alkyl or -(C1-C5alkylene)aryl, R21 denotes H, R22 denotes C1-C10alkyl, C2-C10alkenyl, C3-C8cycloalkyl, -(C1-C5alkylene)-C3-C8cycloalkyl, -(C1-C3alkylene)heterocycloalkyl, aryl, heteroaryl or -(C1-C5alkylene)aryl, wherein each of the heterocycloalkyl residues has 5-6 members, contains 1 or 2 heteroatoms in the ring, independently selected from oxygen and nitrogen, each of the aryl residues is phenyl, anthracenyl or naphthyl, each of the heteroaryl residues has 5 or 6 members and contains 1 or 2 heteroatoms in the ring, independently selected from oxygen, sulphur and nitrogen.

EFFECT: said compounds can be used to prepare a medicinal agent for curing pain, migraine, anxiety, uroclepsia or epilepsy.

17 cl, 203 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1, compounds of formula 5 and pharmaceutically acceptable salts thereof. In formulae 1 5 Y denotes -C(O)-, X denotes -N(R11)-, R1 denotes a residue of formula 1a or 1b - for formula 1 or residue of formulae 5a or 5b - for formula 5 1a 1b 5a 5b, R2 and R7 independently denote H, hydroxyl or (C1-C6)alkyl; R3 and R6 each independently denotes H, hydroxyl or (C1-C6)alkyl; R4 and R5 each independently denotes H or (C1-C6)alkyl; the rest of the radicals are described in the formula of invention. The invention also relates to separate compounds given in the formula of invention, a pharmaceutical composition having Bcl bound protein inhibiting properties, which contains a therapeutically effective amount of the disclosed compound, a method of treating a bc1 mediated disorder, involving introduction of a therapeutically effective amount of the disclosed compound and a method of treating a bc1 mediated disorder involving administration to a patient in need of treatment of an effective amount of camptothecin and therapeutically effective amount of the disclosed compound.

EFFECT: high efficiency of the composition.

84 cl, 12 tbl, 1 dwg, 217 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a heterocyclic compound or salt thereof, having formula (1): where R2 is hydrogen or a lower alkyl group; A is a lower alkylene group or a lower alkenylene group and R1 is a cyclo(C3-C8)alkyl group, an aromatic group or a heterocyclic group selected from a group consisting of groups (I)-(IV), defined in the formula of invention. The invention also relates to a pharmaceutical composition, having activity as a partial agonist of dopamine D2 receptors and/or a serotonin 5-HT2A receptor antagonist and/or an adrenalin α1 receptor antagonist and/or a serotonin absorption inhibitor and/or serotonin reuptake inhibitor based on said compounds, a method of preparing a pharmaceutical composition, use of said compounds as a partial agonist of dopamine D2 receptors and/or a serotonin 5-HT2A receptor antagonist and/or an adrenalin α1 receptor antagonist and/or a serotonin absorption inhibitor and/or serotonin reuptake inhibitor, as well as a method of producing formula I compounds.

EFFECT: novel compounds are obtained and described, which have a wide range of curative effect on mental disorders, including central nervous system disorders, without side effects and with high degree of safety.

22 cl, 3110 ex, 314 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopenta[b]benzofuranyl derivatives of formula wherein substitutes R1, R2, R3, R4, R5, R6 and R7 and n are specified in the patent clam. These compounds exhibit properties of NF-kB-activity and/or AP-1 inhibitor/modulator. Also, the inventive subject matter are methods for preparing intermediate compounds thereof, a pharmaceutical composition containing them, administration thereof for prevention and/or treatment of inflammatory and autoimmune diseases, neurodegenerative diseases and hyperproliferative diseases caused by NF-kB- and/or AP-1-activity, and a method for prevention and/or treatment of said diseases.

EFFECT: preparation of new cyclopenta[b]benzofuranyl derivatives.

21 cl, 3 tbl, 151 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described 3,4-substituted piperidines applicable in diagnostics and drug therapy of a warm-blooded animal, preferentially for therapy of a disease which depends on renin activity; application of a compound of such kind for preparing a pharmaceutical composition for therapy of the disease which depends on renin activity; application of the compound of such kind for therapy of the disease which depends on renin activity; the pharmaceutical compositions containing 3,4-substituted piperidine, and/or a therapeutic mode involving administration of 3,4-substituted piperidine, a method for producing 3,4-substituted piperidine. The preferential compound (which also can be presented in the form of salts) are described by formula I' wherein R1, R2, T, R3 and R4 are such as described by the patent claim.

EFFECT: production of the compounds for therapy of the disease which depends on renin activity.

28 cl, 1 tbl, 375 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of formula I in which cycle A represents unsaturated carbocycle with double bonds, which is selected from phenyl or naphtyl; 1 can take value from 1 to 3; m can take value 0, 2 or 3; n can take value 0 or 2; R1 represents a hydrogen atom, (C1-3)alkyl group; R2 represents(C1-6)alkyl group, which is possibly substituted with substituent, selected from C6-cycloalkyl, monocyclic heteroaryl, selected from thiophene, aryl group, selected from phenyl, in form of base or salt of bonding with an acid. Invention also relates to pharmaceutical composition, based on formula I compound, to application of formula I compound for obtaining medication, to method of obtaining formula I compound and to application of formula compound for obtaining formula 1 compound.

EFFECT: obtained are novel isoquinoline and benzo[h]isoquinoline derivatives, possessing properties of antagonists of histamine type H3 receptor.

9 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula 2: and to its pharmaceutically acceptable salts and their mixtures, where values of R, M, Q, Z, W, D radicals are described in i.1 of the invention formula. Invention also relates to pharmaceutical compositions, which possess inhibiting activity with respect to Btk, based on formula 2 compounds.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions which can be applied in medicine for treatment of patients with diseases associated with inhibiting Btk activity and/or B-cell activity.

55 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, in which X is or ; Y is H; Z is -C(O)-; R1 and R3 each independently denotes H or (C1-C4) alkyl; R2 and R4 each independently denotes , , or ; R5 denotes H or (C1-C6) alkyl; R8 and R9 each independently denote (C1-C6) alkyl; and Q is H.

EFFECT: possibility of use in stimulating the growth hormone in a subject based on the said compounds.

49 cl, 2 tbl, 57 ex

Aromatic compound // 2416608

FIELD: chemistry.

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

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

62 cl, 2717 ex, 432 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds described by formula in which radical and symbol values are specified in the patent claim, and their pharmaceutically acceptable salts. These compounds inhibit tompomyosine-related kinases (Trk), and can find application in treating a malignant growth, such as breast cancer, rectal cancer and prostate cancer. Also, the invention relates to a method for producing these compounds, a based pharmaceutical composition and to methods of application thereof.

EFFECT: preparation of the pharmaceutical composition which can find application in treating a malignant growth.

18 cl, 134 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), where R2 denotes H, [(C1-C6) alkylene]0-1-R'; R3 denotes H; R4 denotes H, halogen or (C1-C6) alkyl; R5 denotes H or halogen; R6 denotes H, (C1-C8) alkyl, R', (C1-C6) alkylene-R'; R7 and R8 independently denote H, halogen, (C1-C6) alkyl, O-(C1-C6) alkyl, R'; R9 denotes (C1-C6)alkyl; n equals 0 or 1; L denotes O or O-(C1-C6)alkylene; where R' denotes (C3-C8) cycloalkyl; (C5-C10)heterocyclyl, which denotes an aromatic or saturated mono- or bicyclic ring system which, besides a carbon atom, includes one or more heteroatoms such as nitrogen, oxygen and sulphur atoms; or (C6-C10) aryl; where in the heterocyclyl is unsubstituted or substituted with (C1-C6)alkyl, and the aryl is unsubstituted or substituted with a halogen, (C1-C4)alkyl, -O-(C1-C4)alkyl, SO2- (C1-C4) alkyl or N[(C1-C4) alkyl]2; and where in groups R4, R6 and R7 the alkyl can be halogenised in one or more positions; or pharmaceutically acceptable salts and/or stereo isomer forms thereof. The invention also relates to use of formula (I) compounds, as well as a medicinal agent.

EFFECT: obtaining novel biologically active compounds having Rho-kinase inhibiting activity.

21 cl, 320 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrazole derivatives of formula (I) or pharmaceutically acceptable salts thereof, having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths accompanied by high level of Trk, to a method of producing said derivatives, use thereof to prepare a medicinal agent, pharmaceutical compositions based on said derivatives, a method of inhibiting Trk activity and a method of obtaining antiproliferative action. where A denotes a single bond or C1-2alkylene; where the said C1-2alkylene can be optionally substituted with one R22; ring C is a phenyl or a 5-6-member heterocyclic ring with 1-2 heteroatoms selected from N or S. Values of R1-R7, R22 and n are given in the formula of invention.

EFFECT: obtaining pharmaceutically acceptable salts having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths.

20 cl, 5 dwg, 193 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 3,4-substituted pyrrolidine derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is an acyl selected from values given paragraph 1 of the formula of invention; R2 is unsubstituted C1-C4-alkyl or C3-C7-cycloalkyl; R3 is a fragment selected from a group of fragments of formulae: (a), (b),

(c) and (f), where any of the fragments of formulae given above (a), (b) and (f), the star (*) indicates a bond of the corresponding fragment R3 with the molecule residue in formula I; Ra denotes N-C1-C4-alkylaminocarbonyl, N-phenylaminocarbonyl, N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl- C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(C3-C7-cycloalkyl-C1-C4-alkyl)aminocarbonyl, N,N-di-(C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl)aminocarbonyl or hydrogen; Rb and Rc are independently selected from a group comprising unsubstituted C1-C4-alkyl, unsubstituted monocyclic aryl, unsubstituted monocyclic heterocyclyl, unsubstituted or substituted monocyclic C3-C7-cycloalkyl, unsubstituted aryl- C1-C4-alkyl, usubstituted monocyclic C3-C7-cycloalkyl- C1-C4-alkyl, hydrogen or acyl, where the acyl is selected from values given in paragraph 1 of the formula of invention; or Rb and Rc together may form a 6-member nitrogen-containing ring which may be unsubstituted or disubstituted with =O; Rd in the fragment of formula (c) denotes a phenyl or phenyl-C1-C4-alkyl; Re denotes hydrogen or C1-C4-alkyl; and m equals 2; each of R4 and R5 denotes hydrogen; and T denotes methylene. The invention also relates to the pharmaceutical composition based on the compound of formula I and a method of treating hypertension using the compound of formula I.

EFFECT: novel pyrrolidine derivatives having renin inhibiting activity are obtained.

7 cl, 19 tbl, 37 ex

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