Cycloalkylamine derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of formula (1) , in form of trans- or cis-isomers, or their mixture, where R1 is selected from , and ; R7 stands for lower alkyl; R8 stands for lower alkyl; X represents >C=O or >SO2; R9 and R11 represent hydrogen or together form double bond; R10 and R12 are independently selected from hydrogen or lower alkyl; m stands for 1 or 2; n stands for 0, 1 or 2 and their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition and to application of said compounds, as well as compounds of formula (I), where R1 represents (R2, R3, R4, R5 and R6 each is independently selected from hydrogen, lower alkyl, lower alkoxy group or halogen; on condition that R2, R3, R4, R5 and R6 do not represent hydrogen), for treatment and/or prevention of DPP-IV-associated diseases.

EFFECT: obtaining novel compounds for treatment and/or prevention of DPP-IV-associated diseases.

14 cl, 1 tbl, 33 ex

 

The present invention relates to new derivatives of cyclooctylamine, their reception and their use as medicines. In particular, the invention relates to compounds of formula (I)

where R1choose from

,,and,

where R2, R3, R4, R5and R6each independently selected from hydrogen, lower alkyl, halogenated lower alkyl, lower alkoxygroup or halogen, provided that R2, R3, R4, R5and R6not all are hydrogen;

R7denotes lower alkyl;

R8denotes lower alkyl;

X represents >C=O or >SO2;

R9and R11denote hydrogen or together form a double bond;

R10and R12independently selected from hydrogen or lower alkyl;

m denotes 1 or 2;

n denotes 0, 1 or 2;

and their pharmaceutically acceptable salts for use in therapy.

The enzyme dipeptidyl peptidase IV (EC, abbreviated as DPP-IV) participates in the regulation of the activity of several hormones. In particular, DPP-IV results in an effective and rapid degradation of glucagon like peptide 1 (GLP-1), which is one of the most potential is in General stimulant production and secretion of insulin. Inhibition of DPP-IV may potentiate the effects of endogenous GLP-1 and leads to higher concentrations of insulin in plasma. In patients suffering from reduced glucose tolerance and diabetes mellitus type 2, elevated concentration of plasma insulin can mitigate dangerous hyperglycemia and thereby reduce the risk of tissue damage. Therefore, DPP-IV inhibitors are considered as candidates for drugs to treat low glucose tolerance and diabetes mellitus type 2 (for example, Villhauer, WO 98/19998). Other related description of the prior art may be found in WO 99/38501, DE 19616486, DE 19834591, WO 01/40180, WO 01/55105, US 6110949, WO 00/34241 and US 6011155.

In addition, DPP IV contributes to the generation and modulation of T-cell immune response. DPP IV (also known as CD26) plays a significant role in immune regulation as T-cell activation molecule and regulator of chemokine function, inducing thus, the idea about the role of DPP-IV in the pathophysiology immunomodulirutaya disorders, and autoimmune diseases (Hosano O. et al., Modern Rheumatology 2003, 13(3), 199-204). Abnormal expression of DPP-IV was detected in the case of autoimmune diseases, HIV-related illnesses and cancer. Natural substrates for DPP-IV is included in immunomodulirutaya, psycho/neuronal modulation and General physiological processes (Boonacker E.; Van Noorden who .J. F, European Journal of Cell Biology, 2003, 82(2), 53-73). In addition, it was shown that there is a correlation between DPP-IV and key nuclear protein topoisomerase alpha (Aytac u, Dang, N.., Current Drug Targets: Immune, Endocrine and Metabolic Disorders 2004, 4(1), 11-18). Thus, DPP-IV inhibitors can be used as drugs for the treatment of various diseases associated with DPP-IV.

We have found new DPP-IV inhibitors that effectively reduce the levels of glucose in plasma. Therefore, the compounds of the present invention are used for treatment and/or prevention of diabetes, particularly non-insulin dependent diabetes mellitus, and/or decreased glucose tolerance, as well as other States, where the amplification action of the peptide, normally inactivating DPP-IV, brings therapeutic benefit. In addition, the compounds of the present invention can be applied in the treatment and/or prophylaxis of obesity, metabolic syndrome, β-cell protection, autoimmune diseases such as inflammatory bowel disease, encephalitis paraxially sclerosis and rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, planus and/or benign prostatic hypertrophy. Connections can also be used for the prevention of AIDS (acquired immunodeficiency syndrome) or for prevention and metastasis, in particular metastasis of breast cancer and prostate cancer in the lungs. In addition, the compounds of the present invention can be used as diuretic agents and for the treatment and/or prophylaxis of hypertension.

Compounds of the present invention showed superior therapeutic and pharmacological properties, comparable with other DPP-IV inhibitors, known from the technical field, for example, in the context of pharmacokinetics and bioavailability.

Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, as such and as pharmaceutically active substances, their receipt of the medicinal product on the basis of the compounds of formula I and their production, as well as the use of compounds of the formula I according to the invention in the control or prevention of the diseases mentioned above, and accordingly, when receiving the drugs.

If not indicated otherwise, the following definitions for illustrations and definitions of the value and volume of various terms used in the description of this invention.

In this description, the term "lower" is used to refer to groups containing from one to six, preferably one to four, carbon atoms.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine are the two who are preferred. Most preferred is chlorine.

The term "alkyl", alone or in combination with other groups, refers to a branched or linear monovalent saturated aliphatic hydrocarbon radical containing from one to twenty carbon atoms, preferably from one to sixteen carbon atoms, more preferably one to ten carbon atoms. The term "lower alkyl", alone or in combination with other groups, refers to a branched or linear monovalent alkyl, the radical containing from one to six carbon atoms, preferably from one to four carbon atoms. This term is further illustrated by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl and the like. Preferred lower alkyl radicals are methyl and ethyl, with methyl is especially preferred.

The term "halogenated lower alkyl" refers to lower alkyl group where at least one of the hydrogen atoms of the lower alkyl groups substituted by a halogen atom, preferably fluorine or chlorine, most preferably fluorine. The preferred halogenated lower alkyl groups are trifluoromethyl, deformity, forme the silt and chloromethyl, especially preferred is permetrina group.

The term "alkoxygroup" refers to the group R'-O-, where R' represents alkyl. The term "lower alkoxygroup" refers to the group R'-O-, where R' denotes a lower alkyl. Examples of the lower alkoxygroup serve as a methoxy group, ethoxypropan, propoxylate, isopropoxide, butoxypropan, isobutoxide and hexyloxy, especially preferred is a methoxy group.

The term "pharmaceutically acceptable salt" includes salts of compounds of formula (I) with inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, malic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonate acid, salicylic acid, p-toluensulfonate acid and the like, which are non-toxic to living organisms. The preferred salts are the formate, maleate, citrates, hydrochloride, hydrobromide and salt methanesulfonic acid, the most preferred are hydrochloride.

In one embodiment, the present invention relates to compounds for use in therapy, having the formula (I)

where R1choose from

,,and

where R2, R3, R4, R5and R6each independently selected from hydrogen, lower alkyl, halogenated lower alkyl, lower alkoxygroup or halogen, provided that R2, R3, R4, R5and R6not all are hydrogen;

R7denotes lower alkyl;

R8denotes lower alkyl;

X represents >C=O or >SO2;

R9and R11denote hydrogen or together form a double bond;

R10and R12independently selected from hydrogen or lower alkyl;

m denotes 1 or 2;

n denotes 0, 1 or 2;

and their pharmaceutically acceptable salts for use in therapy.

In the following embodiment, the invention relates to compounds of formula I for use in therapy, where R1means

,

where R2, R3, R4, R5and R6each independently selected from hydrogen, lower alkyl, halogenated lower alkyl, lower alkoxygroup or halogen, provided that R2, R3, R4, R5and R6not all are hydrogen.

R preferably denotes hydrogen, lower alkyl or halogen, more preferably hydrogen, methyl or x is op.

R3, R4, R5and R6preferably selected from hydrogen, lower alkyl, lower alkoxygroup or halogen. The most preferred lower alkyl is methyl, most preferred lower alkoxygroup is a methoxy group, and most preferred halogen is selected from fluorine, chlorine and bromine.

In one preferred embodiment, R2, R3, R4and R5represent hydrogen and R6denotes lower alkyl, lower alkoxygroup or halogen, more preferably methyl, a methoxy group or chlorine.

In another preferred embodiment, R2, R3, R5and R6represent hydrogen and R4denotes lower alkyl or halogen, more preferably methyl, fluorine, chlorine or bromine.

In another preferred embodiment, R2, R4and R5represent hydrogen, and R3and R6each independently represent lower alkyl or halogen, more preferably methyl, fluorine or chlorine.

In another preferred embodiment, R3, R4and R5represent hydrogen, and R2and R6each independently represent lower alkyl or halogen, more preferably methyl or chlorine.

In another embodiment, the present invention relates to compounds of formula I for use in therapy, where R1means

,

where R7denotes lower alkyl.

Preferred lower alkyl radical, R7are methyl and ethyl, especially preferred is methyl.

In another embodiment, the present invention relates to compounds of formula I for use in therapy, where R1means

,

where R8denotes lower alkyl.

Preferred lower alkyl radical, R8is methyl.

In another embodiment, the present invention relates to compounds of formula I for use in therapy, where R1means

,

where X represents >C=O or >SO2;

R9and R11denote hydrogen or together form a double bond;

R10and R12independently selected from hydrogen or lower alkyl and

m denotes 1 or 2.

In one preferred embodiment, X represents >SO2, R9, R10, R11and R12represent hydrogen and m is 2.

In another preferred embodiment, X represents >C=O, R9and R11together form a double bond, R10and R12represent hydrogen and m is 2.

In another preferred embodiment, X represents >C=O, R9and R11denote hydrogen or together form a double bond, R10indicates the lowest Alki is, preferably methyl, R12denotes hydrogen and m is 1 or 2, more preferably m is 1.

The preferred compound of formula 1 for use in therapy is such a connection, where n denotes 1.

The compounds of formula I, where n denotes 2, are also preferred for use in therapy.

Preferred compounds of General formula I for use in therapy are compounds selected from the group including:

TRANS-2-m-tollcollection,

CIS-2-m-tollcollection,

TRANS-2-o-tollcollection,

CIS-2-o-tollcollection,

TRANS-2-(2-methoxyphenyl)cyclohexylamine,

TRANS-2-(2,5-dichlorophenyl)cyclohexylamine,

CIS-2-(2,5-dichlorophenyl)cyclohexylamine,

TRANS-2-(2,4-dimetilfenil)cyclohexylamine,

CIS-2-(3-bromophenyl)cyclohexylamine,

TRANS-2-(3-bromophenyl)cyclohexylamine,

TRANS-2-(2-fluoro-5-were)cyclohexylamine,

CIS-2-(5-methylthiophene-2-yl)cyclohexylamine,

TRANS-2-(5-methylthiophene-2-yl)cyclohexylamine,

CIS-2-(2,4-dichlorophenyl)cyclohexylamine,

TRANS-2-(2,4-dichlorophenyl)cyclohexylamine,

CIS-2-(3-forfinal)cyclohexylamine,

TRANS-2-(2-chlorophenyl)cyclohexylamine,

TRANS-2-(2,5-dimetilfenil)cyclohexylamine,

(CIS/TRANS)-2-(2-forfinal)cyclohexylamine,

TRANS-2-(2-forfinal)cyclohexylamine,

CIS-2-(3-CHL is henyl)cyclohexylamine,

TRANS-2-(3-chlorophenyl)cyclohexylamine,

CIS-2-(2,5-dichlorophenyl)cycloheptylamine,

TRANS-2-(2,5-dichlorophenyl)cycloheptylamine,

CIS-2-(2,5-dichlorophenyl)cyclopentylamine,

TRANS-2-(3-methylpyrrole-1-yl)cyclohexylamine,

TRANS-2-(3-acylpyrrole-1-yl)cyclohexylamine,

TRANS-2-(1,1-dioxo[1,2]diazinon-2-yl)cyclohexylamine,

TRANS-1-(2-aminocyclohexanol)-5,6-dihydro-1H-pyridine-2-it,

TRANS-1-(2-aminocyclohexanol)-4-methyl-1,5-dihydropyrrol-2-it,

TRANS-1-(2-aminocyclohexanol)-4-methyl-5,6-dihydro-1H-pyridine-2-it,

TRANS-1-(2-aminocyclohexanol)piperidine-2-it,

TRANS-1-(2-aminocyclohexanol)-4-methylpyrrolidine-2-he

their pharmaceutically acceptable salts.

The compounds of formula I have two or more asymmetric atoms and can exist in the form of optically pure enantiomers, mixtures of diastereoisomers, racemates or mixtures diastereoisomeric racemate. The invention includes all these forms.

In a preferred embodiment, R1and the amino group in 1-position of cyclooctylamine are in the TRANS configuration, for example,

or

In a preferred embodiment, R1and the amino group in 1-position of cyclooctylamine are in CIS-configuration, for example,

It should be noted that compounds of General formula (I) according to this invention mouthbut derivatively functional groups with obtaining derivatives, who can turn again to the parent compound in vivo.

The present invention relates also to compounds of formula (I)

where R1choose from

where R2, R3, R4, R5and R6each independently selected from hydrogen, lower alkyl, halogenated lower alkyl or halogen, provided that R2, R3, R4, R5and R6not all are hydrogens;

R7denotes lower alkyl;

R8denotes lower alkyl;

X represents >C=O or >SO2;

R9and R11denote hydrogen or together form a double bond;

R10and R12independently selected from hydrogen or lower alkyl;

m denotes 1 or 2;

n represents 0,1 or 2;

and their pharmaceutically acceptable salts,

with the additional condition that excludes the following connections:

2-(m-tolyl)cyclohexylamine, 2-(p-tolyl)cyclohexylamine, 2-(o-tolyl)cyclohexylamine, 2-(2-chlorophenyl)cyclohexylamine, 2-(3-chlorophenyl)cyclohexylamine, 2-(4-chlorophenyl)cyclohexylamine, 2-(2-bromophenyl)cyclohexylamine, 2-(o-tolyl)cyclopentylamine, 2-(p-tolyl)cyclopentylamine, 2-(4-chlorophenyl)cyclopentylamine, 2-(3,5 - differenl)cyclopentylamine, 2-(3-forfinal)cyclopentylamine, 2-(4-forfinal)cyclopentylamine, 2-(4-bramp the Nile)cyclopentylamine and 2-(4-tert-butylamine)cyclopentylamine.

2-(m-Tolyl)cyclohexylamine and 2-(p-tolyl)cyclohexylamine described as intermediates for the synthesis of phenanthridine derivatives in J. Chem. Soc. 1956, 4280-4283. The synthesis of all the isomeric forms of 2-(o-tolyl)cyclohexylamine, 2-(p-tolyl)cyclohexylamine, 2-(2-chlorophenyl)cyclohexylamine, 2-(3-chlorophenyl)cyclohexylamine and 2-(4-chlorophenyl)cyclohexylamine to study their spectra proton magnetic resonance described in J. Org. Chem. 1962, 27, 3006-3010. In J. Org. Chem. 1971, 36, 3046-3048 described the syntheses of all isomers of 2-(2-bromophenyl)cyclohexylamine and their NMR spectra.

2-(o-Tolyl)cyclopentylamine known from WO 2004/016601 as a reagent to obtain aminohydroxylation used as agonists of β3 adrenergic receptors. 2-(p-Tolyl)cyclopentylamine, 2-(4-chlorophenyl)cyclopentylamine, 2-(3,5-differenl)cyclopentylamine, 2-(3-forfinal)cyclopentylamine, 2-(4-forfinal)cyclopentylamine, 2-(4-bromophenyl)cyclopentylamine and 2-(4-tert-butylphenyl)cyclopentylamine disclosed in WO 2001/042203 as intermediates for the synthesis of N-(vinylcyclopentane)of sulfonamides with activity potentiating the function of glutamate receptor.

Preferred compounds of formula I are those compounds in which R1means

,

where R2, R3, R4, R5and R6each independently selected from hydrogen, lower alkyl, Gal is generowania lower alkyl, low alkoxygroup or halogen, provided that R2, R3, R4, R5and R6not all are hydrogen.

R2preferably represents hydrogen, lower alkyl or halogen, more preferably hydrogen, methyl or chlorine.

R3, R4, R5and R6preferably selected from hydrogen, lower alkyl, lower alkoxygroup or halogen. The most preferred lower alkyl is methyl, most preferred lower alkyl group is a methoxy group, and most preferred halogen is selected from fluorine, chlorine and bromine.

In one preferred embodiment, R2, R3, R4and R5represent hydrogen and R6denotes lower alkyl, lower alkoxygroup or halogen, more preferably methyl, a methoxy group or chlorine.

In another preferred embodiment, R2, R3, R5and R6represent hydrogen and R4denotes lower alkyl or halogen, more preferably methyl, fluorine, chlorine or bromine.

In another preferred embodiment, R2, R4and R5represent hydrogen and R3and R6each independently represent lower alkyl or halogen, more preferably methyl, fluorine or chlorine.

In still another preferred embodiment, R3, R4and R5denote the waters of the genus and R 2and R6each independently represent lower alkyl or halogen, more preferably methyl or chlorine.

In addition, preferred compounds of formula I of the present invention are such compounds in which R1means

,

where R7denotes lower alkyl.

Preferred lower alkyl radicals R are methyl and ethyl, especially preferred is methyl.

In another embodiment of the present invention, the preferred compounds of formula I are those compounds in which R1means

,

where R8denotes lower alkyl.

Preferred lower alkyl radical, R8is methyl.

Also preferred compounds of formula I of the present invention are the compounds where R1means

where X represents >C=O or >SO2;

R9and R11denote hydrogen or together form a double bond;

R10and R12independently selected from hydrogen or lower alkyl and

m denotes 1 or 2.

In one preferred embodiment, X represents >SO2, R9, R10, R11and R12represent hydrogen and m is 2.

In another preferred embodiment, will Chobotnice > C=O, R9and R11together form a double bond, R10and R12represent hydrogen and m is 2.

In another preferred embodiment, X represents >C=O, R9and R11denote hydrogen or together form a double bond, R10denotes lower alkyl, preferably methyl, and m is 1 or 2, more preferably 1. Preferred compounds of formula I are those compounds in which n denotes 1.

Especially preferred compounds of General formula I is chosen from the group including:

TRANS-2-(2-methoxyphenyl)cyclohexylamine,

TRANS-2-(2,5-dichlorophenyl)cyclohexylamine,

CIS-2-(2,5-dichlorophenyl)cyclohexylamine,

TRANS-2-(2,4-dimetilfenil)cyclohexylamine,

CIS-2-(3-bromophenyl)cyclohexylamine,

TRANS-2-(3-bromophenyl)cyclohexylamine,

TRANS-2-(2-fluoro-5-were)cyclohexylamine,

CIS-2-(5-methylthiophene-2-yl)cyclohexylamine,

TRANS-2-(5-methylthiophene-2-yl)cyclohexylamine,

CIS-2-(2,4-dichlorophenyl)cyclohexylamine,

TRANS-2-(2,4-dichlorophenyl)cyclohexylamine,

CIS-2-(3-forfinal)cyclohexylamine,

TRANS-2-(2-chlorophenyl)cyclohexylamine,

TRANS-2-(2,5-dimetilfenil)cyclohexylamine,

(CIS/TRANS)-2-(2-forfinal)cyclohexylamine,

TRANS-2-(2-forfinal)cyclohexylamine,

CIS-2-(2,5-dichlorophenyl)cycloheptylamine,

TRANS-2-(2,5-dichlorophenyl)cycloheptylamine,

p> CIS-2-(2,5-dichlorophenyl)cyclopentylamine,

TRANS-2-(3-methylpyrrole-1-yl)cyclohexylamine,

TRANS-2-(3-ethyl-pyrrol-1-yl)cyclohexylamine,

TRANS-2-(1,1-dioxo[1,2]diazinon-2-yl)cyclohexylamine,

TRANS-1-(2-aminocyclohexanol)-5,6-dihydro-1H-pyridine-2-it,

TRANS-1-(2-aminocyclohexanol)-4-methyl-1,5-dihydropyrrol-2-it,

TRANS-1-(2-aminocyclohexanol)-4-methyl-5,6-dihydro-1H-pyridine-2-he

TRANS-1-(2-aminocyclohexanol)piperidine-2-it,

TRANS-1-(2-aminocyclohexanol)-4-methylpyrrolidine-2-he

their pharmaceutically acceptable salts.

The present invention relates also to a method for producing compounds of formula I.

In General, the compounds of formula I can be obtained either

a) through reductive amination of the ketone of formula II

where R1and n are defined above, or

b) by removing the protection in a complex ester of the formula III

where R1and n are defined above, and Rpdenotes an amino protective group.

Rpdenotes the corresponding group protecting the amino group, such as benzyloxycarbonyl (Z or Cbz), allyloxycarbonyl (Aloka), 9-fluorenylmethoxycarbonyl (Fmoc), preferably tert-butoxycarbonyl (Side).

The compounds of formula (I) can be obtained by the methods given below, by the methods given in the examples, or analogicamegas. Appropriate reaction conditions for the individual reaction stages known to experts in the field of engineering. The initial substance either commercially available or can be obtained by methods similar to the methods below, or by methods described in the examples or by methods known from the prior art.

Obtaining the compounds of the present invention is illustrated in the diagrams below.

Compounds of General formula Ia, where R1connected with cycloalkanones ring through a carbon atom, is obtained from the ketone II by methods known from the prior art, such as reductive amination with the preferred use of ammonium acetate and laborgerate sodium (scheme 1).

Scheme 1

Ketones of General formula II can be obtained from the corresponding alcohol by oxidation using methods known from the prior art, preferably using Martin reagent (Dess Martin Reagent). The alcohol can be obtained from the corresponding epoxide using methods known from the prior art, preferably using ORGANOMETALLIC reagent, such as an appropriate organolithium reagent or the corresponding Grignard reagent.

Compounds of General formula IB, in which R1associated with cycloalkanones number of the CMA through the nitrogen atom, can be synthesized from complex ether of carbamino acid III by methods known from the prior art. When Rpis tert-butoxycarbonyl, the reaction is preferably carried out in the presence of hydrogen chloride in dioxane or triperoxonane acid in dichloromethane. Ester carbamino acid III may be obtained from the complex ether carboxylic acids IV via hydrolysis and subsequent rearrangement of kurzius using methods known from the prior art (scheme 2).

Scheme 2

(Racorresponds to the stands or ethyl; Rpcorresponds to a group protecting the amino group, such as benzyloxycarbonyl, allyloxycarbonyl, preferably tert-butoxycarbonyl).

Synthesis lactamase or Sultanovich derived In exercise based on cycloalkylation V, as shown in the following scheme 3. Compound V is introduced into the reaction with the acid chloride of acetic acid or sulphonylchloride VII in the presence of a base (e.g. triethylamine)to give amide or sulfanilamide V. Then cyclization of compound V using a base such as sodium hydride, in a solvent such as N,N-dimethylformamide, optionally in the presence of sodium iodide leads to V ester carbamino acid can be converted into the free amine as shown in scheme 2.

Scheme 3

(Rpcorresponds to a group protecting the amino group, such as benzyloxycarbonyl, allyloxycarbonyl, preferably tert-butoxycarbonyl; Hal denotes halogen, preferably chlorine).

Unsaturated lactams of the formula IB where R9and R10form a double bond, and X represents >C=O, can be synthesized from cycloalkylation VI according to scheme 4. Thus, alkylation of compound VI with alkenylsilanes IX (in the presence of a base, for example triethylamine), followed by acylation (in the presence of a base, for example triethylamine) with acylhalides X leads to amide VIII. Compound VIII can be entered into the exchange reaction with the circuit loop (ACC. Chem. Res. 2001, 34, 18) using a ruthenium catalyst, for example dichloride bis(tricyclohexylphosphine)benzyladenine(IV), and optionally a Lewis acid, such as tetraisopropyl-orthotitanate, obtaining connection Iك. Ester carbamino acid can be converted into the free amine as shown in scheme 2.

Scheme 4

(Rpcorresponds to a group protecting the amino group, such as benzyloxycarbonyl, allyloxycarbonyl, preferably tert-butoxycarbonyl; Hal denotes halogen, preferably chlorine).

The invention relates gave the e to compounds of formula (I) as defined above, obtained in accordance with the method according to the above definition.

As described above, the compounds of formula I of the present invention can be used as drugs for the treatment and/or prevention of diseases associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, and/or decreased glucose tolerance, inflammatory bowel disease, ulcerative colitis, Crohn's disease, obesity and/or metabolic syndrome, β-cell protection, preferably non-insulin dependent diabetes mellitus, and/or decreased glucose tolerance. In addition, the compounds of the present invention can be used as diuretic agents or for the treatment and/or prophylaxis of hypertension.

The invention therefore relates also to pharmaceutical compositions comprising the compounds of formula I

where R1choose from

R2, R3, R4, R5and R6each independently selected from hydrogen, lower alkyl, halogenated lower alkyl, lower alkoxygroup or halogen, provided that R2, R3, R4, R5and R6not all represent hydrogen;

R7denotes lower alkyl;

R8denotes lower alkyl;

Will chobotnice > C=O or >SO2;

R9and R11denote hydrogen or together form a double bond;

R10and R12independently selected from hydrogen or lower alkyl;

m denotes 1 or 2;

n denotes 0, 1 or 2;

their pharmaceutically acceptable salts

and pharmaceutically acceptable carriers and/or adjuvants.

In addition, the invention relates to compounds defined above for use as therapeutically active substances for the treatment and/or prevention of diseases associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, decreased glucose tolerance, inflammatory bowel disease, ulcerative colitis (Colitis Ulcerosa, Crohn's disease, obesity and/or metabolic syndrome or β-cell protection, preferably for use as therapeutically active substances for the treatment and/or prophylaxis of non-insulin-dependent diabetes mellitus and/or decreased glucose tolerance. In addition, the invention relates to compounds defined above for use as a diuretic agents or for use as therapeutically active substances for the treatment and/or prophylaxis of hypertension.

In another embodiment, the invention relates to a method of treatment and/or prevention of diseases associated with DPP-V, such as diabetes, particularly non-insulin dependent diabetes mellitus, decreased glucose tolerance, inflammatory bowel disease, ulcerative colitis (Colitis Ulcerosa, Crohn's disease, obesity and/or metabolic syndrome or β-cell protection, preferably for the treatment and/or prophylaxis of non-insulin-dependent diabetes mellitus and/or decreased glucose tolerance, comprising introducing the compound according to the above definition a person or an animal. In addition, the invention relates to a method of treatment and/or prophylaxis according to the above definition of the disease, which is hypertension, or disease, diuretic where the agent has a positive effect.

The invention relates further to the use of compounds according to the definition above for the treatment and/or prevention of diseases associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, decreased glucose tolerance, inflammatory bowel disease, ulcerative colitis (Colitis Ulcerosa, Crohn's disease, obesity and/or metabolic syndrome or β-cell protection, preferably for the treatment and/or prophylaxis of non-insulin-dependent diabetes mellitus and/or decreased glucose tolerance. In addition, the invention relates to the use as defined above, when the disease is hypertension, or is on a label as a diuretic agent.

In addition, the invention relates to the use of the compounds defined above to obtain drugs for the treatment and/or prevention of diseases associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, decreased glucose tolerance, inflammatory bowel disease, ulcerative colitis (Colitis Ulcerosa, Crohn's disease, obesity and/or metabolic syndrome or β-cell protection, preferably for the treatment and/or prophylaxis of non-insulin-dependent diabetes mellitus and/or decreased glucose tolerance. Such drugs include the connection definition above. In addition, the invention relates to the use as defined above, when the disease is hypertension, or applying to obtain a diuretic agents.

In the context of the methods and application of the definition above, preferred are the following diseases: diabetes, particularly non-insulin dependent diabetes mellitus, decreased glucose tolerance, obesity and/or metabolic syndrome or β-cell protection, preferably non-insulin dependent diabetes mellitus and/or decreased glucose tolerance.

To determine the activity of compounds of formula 1 were carried out the following tests.

The activity of DPP-IV inhibitors tested in Nata is real human DPP-IV, selected from a pool of human plasma or recombinant human DPP-IV. Human citrate plasma from different donors is collected, filtered through a membrane with a thickness of 0.2 micron sterile conditions, and aliquot in 1 ml frozen and stored until use at a temperature of -120°C. as the source of enzyme used in the calorimetric DPP-IV analysis from 5 to 10 μl of human plasma, and in the spectral analysis of the use of 1.0 µl human plasma total analyzed volume of 100 μl. The amino acid sequence of cdnc human DPP-IV from 31-766, subject to the restriction on the N-terminal and transmembrane domain, clone in Pichia pastoris. Human DPP-IV Express and isolated from the culture medium using standard column chromatography, including pressure, anionic and cationic chromatography. The purity obtained by Coomassie blue SDS-PAGE of the final enzyme is >95%. In colorimetric DPP-IV analysis is used as a source of enzyme, 20 ng rec.-h DPP-IV, and spectral analysis of 2 ng rec.-h DPP-IV total target volume of 100 μl.

In fluorometric analysis of Ala-Pro-7-amido-4-triptorelin (Calbiochem No 125510) is used as the substrate. 20 mm initial solution in 10% DMF/N2About stored at -20°C until use. When IC50determine eniah use final substrate concentration of 50 μm. In the analyses for the determination of kinetic parameters, such as KmVmax, Kithe substrate concentration range from 10 μm to 500 μm.

In colorimetric analysis as the substrate using H-Ala-Pro-pNA.HCl (Bachem L-1115). 10 mm initial solution in 10% Meon/H2O store at -20°C until use. When IC50the definitions use the final substrate concentration of 200 μm. In the analyses for the determination of kinetic parameters, such as KmVmaxToithe substrate concentration range from 100 μm to 2000 μm.

The fluorescence detected on a Perkin Elmer luminescence spectrometer LS 50B when the wavelength of excitation 400 nm and emission wavelength of 505 nm continuously every 15 seconds for 10 to 30 minutes the rate Constant of excitation is calculated using the method of linear regression.

The absorbance of pNA released from the colorimetric substrate to be detected on a Packard SpectraCount at 405 nm continuously every 2 min for 30 to 120 minutes, the rate Constant of excitation is calculated using the method of linear regression.

Analysis of DPP-IV activity is carried out in a 96-cellular tablets at a temperature of 37°C and analyzed with the General volume of 100 μl. Buffer for analysis consists of 50 mm Tris/HCl, pH 7.8, containing 0.1 mg/ml BSA and 100 mm NaCl. Test compounds dissolved in 100% DMSO, diluted to the required to the ncentratio in 10% DMSO/H 2O. the Final concentration of DMSO in the analysis is 1% (vol./vol.). At this concentration, inactivation of the enzyme DMSO is <5%. Connections are taken from pre-incubation with the enzyme for 10 min at 37°C) and without it. Enzyme reactions begin with the use of the substrate followed by immediate mixing.

IC50values of the test compounds is calculated using non-linear regression DPP-IV inhibiting at least 5 different concentrations of compounds. Kinetic parameters of enzymatic reactions calculate at least 5 different concentrations of substrates and at least with 5 different concentrations of the tested compounds.

Compounds of the present invention have the IC50values from 0.1 μm to 50 μm, more preferably from 0.1 μm to 1 μm, as shown in the following table:

ExampleIC50[µm]
70,13
180,16
240,72
300,73

The compounds of formula I and/or their pharmaceutically acceptable salts can be IP is alsomany as medicines, for example in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered orally, for example in the form of pills, tablets in the shell, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or tapicerki, for example in the form of ointments, creams or oils. It is preferable to oral administration.

The pharmaceutical preparation carried out by a method known to anyone skilled in the art, including the introduction of the described compounds of formula I and/or their pharmaceutically acceptable salts, optionally in combination with other farmatsevticheskii valuable substances in pharmaceutically accepted insertion form together with suitable non-toxic inert, therapeutically compatible solid or liquid carriers and, if desired, usual pharmaceutical adjuvants.

Suitable carriers can serve not only inorganic materials, but also organic media. So, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carriers in the manufacture of tablets, pills in Obolo is e, dragées and hard gelatin capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, regardless of the nature of the active ingredient in the case of hard gelatin capsules any media may not be required). Suitable carriers for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and the like. Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable carriers for suppositories are, for example, natural or hydrogenated oils, waxes, fats and semi-solid or liquid polyols. Suitable carriers for topical preparations are, for example, glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

Conventional stabilizers, preservatives, wetting and emulsion agents, agents for improving the consistency, flavor agents, salts for varying the osmotic pressure, buffer substances, solvents, dyes and masking agents and antioxidants are considered as pharmaceutical adjuvants.

Dosing is connected to the I of the formula (I) can vary within wide limits depending on the controlled disease, age and individual condition of the patient and the route of administration and must comply with, of course, the individual requirements in each particular case. For adult patients, the daily dose is from about 1 mg to 1000 mg, in particular from about 1 mg to 100 mg depending on the severity of the disease and specific pharmacokinetic profile of the compound can be introduced in the form of one or more daily unit doses, for example from 1 to 3 single doses.

The pharmaceutical preparations normally contain about 0.1-500 mg, preferably 1-100 mg, of the compounds of formula (I).

The following examples illustrate in more detail the present invention. They are, however, in no way limit its scope.

Examples

Example 1 and 2: TRANS-2-m-tollcollection and CIS-2-m-tollcollection

To a solution of 1-bromo-3-methyl-benzene in THF at -78°C is added dropwise a solution of n-BuLi (1.6 M in THF, and 12.4 ml) and the reaction mixture stirred at -78°C for 30 minutes After this 7-oxabicyclo[4.1.0]heptane (3.4 g) is added slowly to the reaction mixture, and then add portreporter (2.5 ml). The reaction mixture was stirred at -78°C for additional 2 h, then allowed to warm to room temperature, and then treated with a solution of ammonium chloride (25 ml), the phases are separated and twice the extras is Giroud with ethyl acetate. The combined organic extracts are then washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography, obtaining 2.9 g of (CIS/TRANS) 2-o-taillecavat.

MS (EI) 190,1 (M+).

(CIS/TRANS) 2-o-taillecavat (1 g) in dichloromethane (30 ml) is added a reagent Dess-Martin periodinane (company Aldrich 27,462-3) at room temperature. The reaction mixture was allowed to mix at room temperature for 16 h, after which add diethyl ether. The volume of solvent reduced in vacuo to approximately one-quarter of the initial volume. Add another 87 ml of diethyl ether and the solution washed with 10%sodium thiosulfate solution (87 ml), saturated sodium bicarbonate solution (87 ml), brine (100 ml) and water (100 ml). The organic phase is then dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography, obtaining of 0.54 g of 2-o-taillecavat.

MS (EI) 188,2 (M+).

To 2-o-taillecavat (0,22 g) in methanol (30 ml) is added ammonium acetate (0,90 g) and leave the reaction under stirring at room temperature for 16 hours then added to the reaction mixture Lamborghini sodium (91 mg) and stirred for 10 minutes, the Reaction mixture was treated then with saturated aqueous concrete is NaHCO 3and extracted with ethyl acetate (twice 50 ml). The combined organic phases are dried over sodium sulfate, concentrated in vacuo and purified by column chromatography, obtaining CIS-2-m-tollcollection (35 mg), MS (ISP) 190,3 (M+N)+and TRANS 2-m-tollcollection MS (ISP) 190,3 (M+N)+. Compounds of the following examples are obtained analogously to examples 1 and 2:

ExampleThe systematic nameThe original connectionMMMM (found.) (MN+)
3TRANS-2-o-tollcollection1-bromo-2-methylbenzoyl189,3190,2
4CIS-2-o-tollcollection1-bromo-2-methylbenzoyl189,3190,2
5TRANS-2-(2-methoxyphenyl)cyclohexylamine1-bromo-2-methoxybenzoyl205,3206,1
6Tran is-2-(2,5-dichlorophenyl)cyclohexylamine 2-bromo-1,4-dichlorobenzene244,2244,2
7CIS-2-(2,5-dichlorophenyl)cyclohexylamine2-bromo-1,4-dichlorobenzene244,2244,2
8TRANS-2-(2,4-dimetilfenil)cyclohexylamine1-bromo-2,4-xylene203,3to 204.1
9CIS-2-(3-bromophenyl)cyclohexylamine1,3-dibromobenzyl254,2254,0
10TRANS-2-(3-bromophenyl)cyclohexylamine1,3-dibromobenzyl254,2254,0
11TRANS-2-(2-fluoro-5-were)cyclohexylamine2-bromo-1-fluoro-4-methylbenzoyl207,3244,2
12CIS-2-(5-methylthiophene-2-yl)cyclohexylamine2-bromo-5-methylthiophene 196,2
13TRANS-2-(5-methylthiophene-2-yl)cyclohexylamine2-bromo-5-methylthiophene195,3196,1
14CIS-2-(2,4-dichlorophenyl)cyclohexylamine1-bromo-2,4-dichlorobenzene244,2244,2
15TRANS-2-(2,4-dichlorophenyl)cyclohexylamine1-bromo-2,4-dichlorobenzene244,2244,2
16CIS-2-(3-forfinal)cyclohexylamine1-bromo-3-torbenson193.3 M.194,2
17TRANS-2-(2-chlorophenyl)cyclohexylamine1-chloro-2-iadanza209,7210,2
18TRANS-2-(2,5-dimetilfenil)cyclohexylamine2-bromo-1,4-xylene203,3204,3
19 (CIS/TRANS)-2-(2-forfinal)cyclohexylamine1-bromo-2-torbenson193.3 M.for 194.3
20TRANS-2-(2-forfinal)cyclohexylamine1-bromo-2-torbenson193.3 M.194,2
21CIS-2-(3-chlorophenyl)cyclohexylamine1-bromo-3-chlorobenzene209,7210,2
22TRANS-2-(3-chlorophenyl)cyclohexylamine1-bromo-3-chlorobenzene209,7210,2
23CIS-2-(2,5-dichlorophenyl)cycloheptylamine2-bromo-1,4-dichlorobenzene and 8-oxa-icicle[5.1.0]octane258,2258,1
24TRANS-2-(2,5-dichlorophenyl)cycloheptylamine2-bromo-1,4-dichlorobenzene and 8-oxa-bicyclo[5.1.0]octane258,2258,1
25CIS-2-(2,5-dichlorophenyl)cyclopent the Lamin 2-bromo-1,4-dichlorobenzene and 6-oxa-bicyclo[3.1.0]hexane230,1230,1

Example 26: TRANS-2-(3-methylpyrrole-1-yl)cyclohexylamine

a) tert-Butyl ether TRANS-[2-(3-formylphenol-1-yl) cyclohexyl] carbamino acid

A solution of tert-butyl ether TRANS-(2-aminocyclohexanol) carbamino acid (Tetrahedron Lett. 2000, 41, 9607; 400 mg of 1.87 mmole) and 2,5-dimethoxy-3 - tetrahydrobenzaldehyde (365 mg, of 2.05 mmole) in pyridine (0.5 ml) and acetic acid (0,82 ml) is heated at 100°C for 4.5 hours After cooling, the reaction mixture is distributed between ethyl acetate and 10%citric acid solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (silica gel, gradient heptane-ethyl acetate) gives named the title compound (yield 334 mg, 61%) as a bright solid, MS (ISP) 293,3 (M+N)+.

b) TRANS-2-(3-Methylpyrrole-1-yl)cyclohexylamine

Triethylsilane (368 mg, 3.16 mmol) is added at 0°C. to a solution of tert-butyl ether TRANS-[2-(3-formylphenol-1-yl)cyclohexyl]carbamino acid (330 mg, of 1.13 mmole) in triperoxonane acid (5.1 ml). After 90 min the reaction mixture is evaporated and distributed between ethyl acetate and 2-molar aqueous solution of sodium hydroxide. The organic layer was washed with brine, you is sutured (MgSO 4) and evaporated. Chromatography (silica gel, CH2Cl2/MeOH/NH4OH in the ratio 90:10:0.25 in) network named the title compound (yield 163 mg, 81%) as a yellow oil.

MC(ISP) 179,1 (M+N)+.

Example 27: TRANS-2-(3-acylpyrrole-1-yl)cyclohexylamine

a) tert-Butyl ether TRANS-[2-(3-acylpyrrole-yl)cyclohexyl]carbamino acid

The solution methylacrylamide (3-molar in THF, 0,23 ml, 0.68 mmole) is added at -78°C to a solution of tert-butyl ether TRANS-[2-(3-formylphenol-1-yl)cyclohexyl]carbamino acid (example 26a, 100 mg to 0.34 mmole) in tetrahydrofuran (2 ml), then after 3.5 h the reaction stopped by the addition of saturated aqueous solution of ammonium chloride and the reaction mixture is extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting crude product (103 mg) was dissolved in dichloromethane (2 ml) and treated with triethylsilane (58 mg, of 0.50 mmole) and triperoxonane acid (190 mg, 1,67 mmole). The reaction mixture is left to warm to 0°C for 3 h, then evaporated and chromatographic the residue (silica gel, gradient heptane-ethyl acetate), obtaining mentioned in the title compound (yield 27 mg, 28%) as a yellow solid. MS (ISP) 293,2 (M+N)+.

b) TRANS-2-(3-Acylpyrrole-1-yl)cyclohexylamine

A solution of tert-butyl ether TRANS-[2-(-acylpyrrole-1-yl)cyclohexyl] carbamino acid (24 mg, 82 mmol) in hydrochloric acid (4-molar in 1,4-dioxane) and stirred for 90 min at room temperature, and then evaporated. The residue is transferred into a solution of CH2Cl2/MeOH/NH4OH in the ratio 90:10:0.25 and concentrate the solution in vacuo. Chromatography (silica gel, CH2Cl2/MeOH/NH4OH in the ratio 90:10:0.25 in) network named the title compound (5 mg, 32%) as a slightly yellow solid, MS (ISP) 193,4 (M+N)+.

Example 28: TRANS-2-(1,1-dioxo[1,2]diazinon-2-yl)cyclohexylamine

a) tert-Butyl ether TRANS-[2-(4-chlorobutane-1 sulfonylamino)cyclohexyl]carbamino acid

4-Chlorobutyronitrile (178 mg, of 0.93 mmole) is added at 0°C. to a solution of tert-butyl ether TRANS-(2-aminocyclohexanol) carbamino acid (200 mg, of 0.93 mmole) and triethylamine (94 mg, of 0.93 mmole) in dichloromethane (2 ml) and the reaction mixture left to warm to room temperature over 3 h, and then partitioned between dichloromethane and 10%aqueous citric acid solution. The organic layer was washed with 1-molar aqueous solution of sodium carbonate and brine, dried (MgSO4) and evaporated. Chromatography (silica gel, gradient heptane-ethyl acetate) gives named the title compound (yield 130 mg, 38%) as a light solid compound, MS(ISP) 367,2(M-H)-.

b) tra is s-2-(1.1-Dioxo[1,21]diazinon-2-yl)cyclohexylamine

Sodium hydride (60%dispersion in mineral oil, 15 mg, or 0.38 mmole) is added at 0°C. to a solution of tert-butyl ether TRANS-[2-(4-chlorobutane-1 sulfonylamino)cyclohexyl]carbamino acid (125 mg, 0.34 in mmole) and sodium iodide (51 mg, 0.34 in mmole) and the reaction mixture was stirred at room temperature for 24 h, then add another portion of sodium hydride (15 mg, or 0.38 mmole) and the reaction mixture is heated at 60°C for 3 hours After cooling, the solution is partitioned between a mixture of heptane/ethyl acetate (1:1 ratio) and water. The organic layer was washed with brine, evaporated and chromatographic (silica gel, gradient heptane-ethyl acetate). Named in the header connection receive in accordance with the General method shown in example b, in the form of a bright solid, MS (ISP) to 233.1 (M+N)+.

Example 29: TRANS-1-(2-aminocyclohexanol)-5,6-dihydro-1H-pyridine-2-he

a) tert-Butyl ether TRANS-(2-but-3-enemyoccupied) carbamino acid

Named in the header connection receive in accordance with the General method shown in example 30A, from tert-butyl ether TRANS-(2-aminocyclohexanol)carbamino acid and 4-bromo-1-butene in the form of a brown solid, MS (ISP) 269,3 (M+N)+.

b) tert-Butyl ether TRANS-[2-(akrilovye-3-enylamine)cyclohexyl]carbamino acid

Chlorohydrin acrylic acid (47 mg, of 0.50 mmole) is added at 0°C. to a solution of tert-butyl ether TRANS-(2-but-3-enemyoccupied)carbamino acid (123 mg, and 0.46 mmole) and triethylamine (51 mg, of 0.51 mmole) in dichloromethane (3 ml) and leave the reaction mixture to warm to room temperature within 3 hours After the distribution of the reaction mixture between dichloromethane and 10%aqueous citric acid solution the organic layer was washed with 1-molar aqueous solution of sodium carbonate and brine, dried (MgSO4) and evaporated. Chromatography (silica gel, gradient heptane-ethyl acetate) gives named the title compound (yield 103 mg, 70%) as a yellowish solid, MS (ISP) 323,3 (M+N)+.

C) tert-Butyl ether TRANS-[2-(6-oxo-3,6-dihydro-2H-pyridine-1-yl)cyclohexyl]carbamino acid

Bis(tricyclohexylphosphine)benzylidene ruthenium(IV)dichloride (13 mg, 16 mcmole) are added to a solution of tert-butyl ether TRANS-[2-(akrilovye-3-enylamine)cyclohexyl]carbamino acid (50 mg, 0.16 mmole) and tetraisopropyldisiloxane (8,8 mg, 31 mcmole) in dichloromethane (2.5 ml) and the reaction mixture stirred for 1 h at room temperature. The solvent is then evaporated and the residue chromatographic (silica gel, gradient heptane-ethyl acetate), obtaining mentioned in the title compound (yield 44 mg, 96%) as a solid light substances, MS (ISP) 295,2(M +N)+.

d) TRANS-1-(2-Aminocyclohexanol)-5,6-dihydro-1H-pyridine-2-he

Named in the header connection receive in accordance with the General method shown in example b, from tert-butyl ether TRANS-[2-(6-oxo-3,6-dihydro-2H-pyridine-1-yl)cyclohexyl]carbamino acid in the form of a yellow liquid, MS (ISP) 195,3 (M+N)+.

Example 30: TRANS-1-(2-aminocyclohexanol)-4-methyl-1,5-dihydropyrrol-2-he

a) tert-Butyl ether TRANS-[2-(2-methylethylamine)cyclohexyl]carbamino acid

Metalibrary (139 mg, of 1.03 mmole) is added at 0°C. to a solution of tert-butyl ether TRANS-(2-aminocyclohexanol)karamanova acid (200 mg, 25 of 0.93 mmole) and triethylamine (113 mg, 1.12 mmole) in tetrahydrofuran (4 ml).

The reaction mixture was stirred for 16 h at room temperature, and then distributed between ethyl acetate and 1 molar aqueous solution of sodium hydroxide. The organic layer was washed with brine, dried (MgSO4) and evaporated. Chromatography (silica gel, CH2Cl2/MeOH/NH4OH in the ratio 90:10:0.25 in) network named the title compound (yield 177 mg, 71%) as a solid orange substance, MS (ISP) 269,3 (M+N)+.

b) tert-Butyl ether TRANS-{2-[acryloyl(2-methylallyl)amino]cyclohexyl}carbamino acid

Named in the header connection receive in accordance with the General method is m, shown in example 29b, from tert-butyl ether TRANS-[2-(2-methylethylamine)cyclohexyl]carbamino acid and akriloilkhlorida in the form of a solid light substances, MS (ISP) 323,3 (M+N)+.

C) tert-Butyl ether TRANS-[2-(4-methyl-2-oxo-2,5-dihydropyrrol-1-yl)cyclohexyl]carbamino acid

Named in the header connection receive in accordance with the General method shown in example V, from tert-butyl ether TRANS-{2-[acryloyl-(2-methylallyl)amino]cyclohexyl}carbamino acid in the form of a black solid, MS (ISP) 295,2 (M+N)+.

d) TRANS-1-(2-Aminocyclohexanol)-4-methyl-1,5-dihydropyrrol-2-he

Named in the header connection receive in accordance with the General method shown in example b, from tert-butyl ether TRANS-[2-(4-methyl-2-oxo-2,5-dihydropyrrol-1-yl)cyclohexyl]carbamino acid in the form of hard yellow substance, MS (ISP) 195,2 (M+N+).

Example 31: TRANS-1-(2-aminocyclohexanol)-4-methyl-5,6-dihydro-1H-pyridine-2-he

a) tert-Butyl ether TRANS-[2-(3-methylbut-3-enylamine)cyclohexyl]carbamino acid

Named in the header connection receive in accordance with the General method shown in example 30A, from tert-butyl ether TRANS-(2-aminocyclohexanol)carbamino acid and 4-bromo-2-methyl-1-butene (J. Org. Chem. 1997, 62, 1536) in the form of a solid brown is the first substance, MS (ISP) is 283.3 (M+N)+.

b) tert-Butyl ether TRANS-{2-[acryloyl-(3-methylbut-3-enyl)amino]cyclohexyl}carbamino acid

Named in the header connection receive in accordance with the General method shown in example 29b, from tert-butyl ether TRANS-[2-(3-methylbut-3-enylamine)cyclohexyl]carbamino acid and akriloilkhlorida in the form of a bright solid, MS (ISP) 337,4 (M+N)+.

C) tert-Butyl ether TRANS-[2-(4-methyl-6-oxo-3,6-dihydro-2H-pyridine-1-yl)cyclohexyl]carbamino acid

Dichloro(1,3-dimetil-4,5-dihydroimidazole-2-ilidene)(phenylmethylene)-(tricyclohexylphosphine)ruthenium (54 mg, 63 mcmole) are added to a solution of tert-butyl ether TRANS-{2-[acryloyl-(3-methylbut-3-enyl)amino]cyclohexyl}carbamino acid (212 mg, 0,63 mmole) and tetraisopropyldisiloxane (36 mg, of 0.13 mmole) in chloroform (11 ml) and the reaction mixture is heated under reflux for 72 hours, the Solvent is then evaporated and the residue chromatographic (silica gel, gradient heptane-ethyl acetate), obtaining mentioned in the title compound (yield 120 mg, 62%) as a bright solid, MS (ISP) 309,1 (M+N)+.

d) TRANS-1-(2-Aminocyclohexanol)-4-methyl-5,6-dihydro-1H-pyridine-2-he

Named in the header connection receive in accordance with the General method shown in example b, from tert-butyl what about the ether of TRANS-[2-(4-methyl-6-oxo-3,6-dihydro-2H-pyridine-1-yl)cyclohexyl]carbamino acid in the form of a brown liquid, MS (ISP) 209,2 (M+N)+.

Example 32: TRANS-1-(2-aminocyclohexanol)piperidine-2-he

Named in the header connection receive in accordance with the General method shown in example 28, from tert-butyl ether TRANS-(2-aminocyclohexanol)carbamino acid and the acid chloride of 5-haralanova acid as colorless liquid, MS (ISP) 197,2 (M+N)+.

Example 33: 1-(2-aminocyclohexanol)-4-methylpyrrolidine-2-he

a) Ethyl ester of CIS-2-(4-chloro-3-methylbutylamine)cyclohexanecarbonyl acid

Getting ethyl-CIS-2-amino-1-cyclohexanecarboxylate

Hydrochloride ethyl-CIS-2-amino-1-cyclohexanecarboxylate (750 mg) is suspended in 1 normal NaOH solution (pH 12). The aqueous layer was extracted with CH2Cl2, washed with brine, dried over Na2SO4and evaporated, to give crude ethyl-CIS-2-amino-1-cyclohexanecarboxylate (570 mg).

Crude ethyl-CIS-2-amino-1-cyclohexanecarboxylate (570 mg) was dissolved in dichloromethane (15 ml) in an argon atmosphere and cooled to 0°C in an ice bath, and then added dropwise a triethylamine (0.51 ml) for 10 minutes the Mixture is stirred for 30 min and then treated dropwise within 10 min 4-chloro-3-methylbutyraldehyde (568 mg)to give a white suspension (synthesis according to the method of Chem. Ber., 97, 1964, 2544-2550). The resulting mixture is left to reach room temperature peremeshivayte for 30 min, then transferred into a mixture of ice/brine and the aqueous layer was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4and evaporated. The residue is purified using accelerated chromatography (heptane/ethyl acetate in the ratio 7:3)to give the product, which is a mixture (1:1) epimeres, in the form of a yellowish oil (yield 913 mg). MS (EPI): 290,1 (M+N+).

b) Ethyl ester of TRANS-2-(4-methyl-2-oxopyrrolidin-1-yl)-cyclohexanecarboxylic acid

Ethyl ester of CIS-2-(4-chloro-3-methylbutylamine)cyclohexanecarboxylic acid (895 mg) was dissolved in absolute DMF (20 ml) in an argon atmosphere at room temperature, then add sodium iodide (463 mg) and sodium hydride (55%) (270 mg)to give a white suspension. The reaction mixture was stirred for 2H at room temperature, and then transferred into a mixture of ice and water containing a saturated solution of NH4Cl, and extracted the aqueous layer with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4and evaporated. The residue is purified using accelerated chromatography (CH2Cl2/MeOH/NH3in relation 95/5/0,5), receiving a product that is a mixture (1:1) epimeres, in the form of a yellowish liquid (exit 402 mg). MS (EPI): 254,1 (M+H+).

b) TRANS-2-(4-Methyl-2-oxopyrrolidin-1-yl)cyclohexan robonova acid

Ethyl ester of TRANS-2-(4-methyl-2-oxopyrrolidin-1-yl)cyclohexanecarboxylic acid (395 mg) was dissolved in absolute THF (15 ml) and add 1-normal solution of lithium hydroxide (5,12 ml). The resulting mixture is heated under reflux during the night. The reaction mixture is cooled to room temperature, and then add concentrated HCl solution (1.80 ml) (pH 2). The mixture is evaporated and then diluted with toluene and using azeotropic distillation to remove water. The residue is purified by rapid chromatography (AcOEt/MeOH in a ratio of 85/15)to give the product, which is a mixture (1:1) epimeres, in the form of a yellowish foam (yield 435 mg). MS (EPI): 224,3 (M+N+-).

g) Benzyl ether TRANS-2-(4-methyl-2-oxopyrrolidin-1-yl)cyclohexyl]carbamino acid

TRANS-2-(4-Methyl-2-oxopyrrolidin-1-yl)cyclohexanecarbonyl acid (100 mg), diphenylphosphoryl (DFFA) (183 mg), benzyl alcohol (China 0,686 ml) and triethylamine (0,062 ml) dissolved in absolute toluene (1.0 ml) and heat the mixture at 80°C during the night. After that, the reaction mixture is immediately evaporated. The residue is purified using accelerated chromatography (ethyl acetate/heptane in the ratio 80:20)to give the product, which is a mixture (1:1) epimeres, in the form of a white foam (yield 42 mg). MS (EPI): 331,2 (M+H+).

d) TRANS-1-(2-Aminocyclohexanol)-4-methylpyrrolidine-2-it

To a solution of benzyl ester, TRANS-[2-(4-methyl-2-oxopyrrolidin-1-yl)cyclohexyl]carbamino acid (34 mg) in absolute ethanol (4.0 ml) is added 10%Pd on coal (5 mg). Atmosphere of hydrogen create alternating insertion and removal of gas. The suspension is vigorously stirred overnight, then filtered off the catalyst, and the filtrate was concentrated in vacuo.

The residue is purified using accelerated chromatography (CH2Cl2/MeOH/NH3in the ratio of 93:7:0.5), and getting a product that is a mixture (1:1) epimeres, in the form of a colorless liquid (yield 15 mg). MS (EPI): 197,3 (M+N+). Pharmaceutical examples

Example

The coated tablets containing the following ingredients can be obtained with the standard method:

IngredientsPills
Core:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Water lactose60,0 mg
Polydon K3012.5 mg15,0 mg
Alkaline starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(Earth core)120,0 mg350,0 mg
Shell:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredients are screened, mixed with microcrystalline cellulose and granularit mixture in a solution of polyvinylpyrrolidone in water. The granulate is mixed with alkaline g is costom starch and magnesium stearate and pressed, getting the core tablets weighing 120 or 350 mg, respectively. The core varnished using an aqueous solution/suspension of the above-mentioned film shell.

Example B

Capsules containing the following ingredients can be obtained with the standard method:

IngredientsOn capsule
The compound of formula (I)25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg

Components sift, mix and make into capsules of size 2.

The example In

Injectable solutions may have the following composition:

Ingredients
The compound of formula (I)3.0 mg
The polyethylene glycol 400150,0 mg
Acetic acidto pH 5.0
Water for injection solutionsto 1.0 ml

The act is wny ingredient dissolved in a mixture of polyethylene glycol 400 and water for injection (part). Bring the pH to 5.0 with acetic acid. The volume was adjusted to 1.0 ml by adding the remaining amount of water. The solution is filtered, filled into vials, using the appropriate device, and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can be obtained with the standard method:

Ingredients

The contents of the capsules

The compound of formula (I)5.0 mg
Yellow wax8.0 mg
Gidrirovannoe soybean oil8.0 mg
Partially hydrogenated vegetable oil34,0 mg
Soybean oil110,0 mg
Mass content capsules165,0 mg

Gelatin capsule

Gelatin75,0 mg
Glycerol 85%32,0 mg
The Karion 838.0 mg (dry matter)
Titanium dioxide 0.4 mg
Iron oxide (yellow)1.1 mg

The active ingredient is dissolved in warm melt the other ingredients and the mixture is filled soft gelatin capsules of appropriate size. Filled soft gelatin capsules are processed using conventional methods.

Example D

A wafer containing the following ingredients can be obtained with the standard method:

Ingredients
The compound of formula (I)50.0 mg
Lactose, finely ground powder1015,0 mg
Microcrystalline cellulose (AVICEL PH 102)1400,0 mg
The sodium carboxymethyl cellulose14,0 mg
Polyvinylpyrrolidone K 3010.0 mg
Magnesium stearate10.0 mg
Flavorings1.0 mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose, and then pellet the shape with a mixture of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavors and bring in Sasha.

1. The use of compounds of formula (I) in the form of TRANS - or CIS-isomers, or mixtures thereof

where R1choose from
,,and,
R2, R3, R4, R5and R6each independently selected from hydrogen, lower alkyl, lower alkoxygroup or halogen, provided that R2, R3, R4, R5and R6not all represent hydrogen;
R7denotes lower alkyl;
R8denotes lower alkyl;
X represents >C=O or >SO2;
R9and R11denote hydrogen or together form a double bond;
R10and R12independently selected from hydrogen or lower alkyl;
m denotes 1 or 2;
n denotes 0, 1 or 2;
and their pharmaceutically acceptable salts to obtain drugs for the treatment and/or prevention of diseases associated with DPP-IV.

2. The use of compounds of the formula I according to claim 1, where R1does
,
and where R2, R3, R4, R5and R6each independently selected from hydrogen, lower alkyl, lower alkoxygroup or halogen, provided that R2, R3, R4, R5 and R6not all represent hydrogen.

3. The use of compounds of the formula I according to claim 1, where R1does
,
and where R7denotes lower alkyl.

4. The use of compounds of the formula I according to claim 1, where R1does
,
and where R8denotes lower alkyl.

5. The use of compounds of the formula I according to claim 1, where R1does
,
and where X represents >C=O or >SO2;
R9and R11denote hydrogen or together form a double bond;
R10and R12independently selected from hydrogen or lower alkyl and
m denotes 1 or 2.

6. The use of compounds of the formula I according to claim 1, selected from the group including:
TRANS-2-m-tollcollection,
CIS-2-m-tollcollection,
TRANS-2-o-tollcollection,
CIS-2-o-tollcollection,
TRANS-2-(2-methoxyphenyl)cyclohexylamine,
TRANS-2-(2,5-dichlorophenyl)cyclohexylamine,
CIS-2-(2,5-dichlorophenyl)cyclohexylamine,
TRANS-2-(2,4-dimetilfenil)cyclohexylamine,
CIS-2-(3-bromophenyl)cyclohexylamine,
TRANS-2-(3-bromophenyl)cyclohexylamine,
TRANS-2-(2-fluoro-5-were)cyclohexylamine,
CIS-2-(5-methylthiophene-2-yl)cyclohexylamine,
TRANS-2-(5-methylthiophene-2-yl)cyclohexylamine,
CIS-2-(2,4-dichlorophenyl)cyclohexylamine,
TRANS-2-(2,4-dichlorophenyl)cyclohexylamine, CIS-2-(3-forfinal)cyclohexylamine,
TRANS-2-(2-chlorophenyl)cyclohexylamine,
TRANS-2-(2,5-dimetilfenil)cyclohexylamine,
(CIS/TRANS)-2-(2-forfinal)cyclohexylamine,
TRANS-2-(2-forfinal)cyclohexylamine,
CIS-2-(3-chlorophenyl)cyclohexylamine,
TRANS-2-(3-chlorophenyl)cyclohexylamine,
CIS-2-(2,5-dichlorophenyl)cycloheptylamine,
TRANS-2-(2,5-dichlorophenyl)cycloheptylamine,
CIS-2-(2,5-dichlorophenyl)cyclopentylamine,
TRANS-2-(3-methylpyrrole-1-yl)cyclohexylamine,
TRANS-2-(3-acylpyrrole-1-yl)cyclohexylamine,
TRANS-2-(1,1-dioxo[1,2]diazinon-2-yl)cyclohexylamine,
TRANS-1-(2-aminocyclohexanol)-5,6-dihydro-1H-pyridine-2-it,
TRANS-1-(2-aminocyclohexanol)-4-methyl-1,5-dihydropyrrol-2-it,
TRANS-1-(2-aminocyclohexanol)-4-methyl-5,6-dihydro-1H-pyridine-2-it,
TRANS-1-(2-aminocyclohexanol)piperidine-2-it,
TRANS-1-(2-aminocyclohexanol)-4-methylpyrrolidine-2-it,
and their pharmaceutically acceptable salts.

7. The compounds of formula (I) in the form of TRANS - or CIS-isomers, or mixtures thereof

where R1choose from
,and;
R7denotes lower alkyl;
R8denotes lower alkyl;
X represents >C=O or >SO2;
R9and R11denote hydrogen or together form a double bond;
R10and R12independently selected from the waters of the genus or lower alkyl;
m denotes 1 or 2;
n denotes 0, 1 or 2;
and their pharmaceutically acceptable salts.

8. The compounds of formula I according to claim 7, where R1does

and where R7denotes lower alkyl.

9. The compounds of formula I according to claim 7, where R1does
,
and where R8denotes lower alkyl.

10. The compounds of formula I according to claim 7, where R1does
,
X represents >C=O or >SO2;
R9and R11denote hydrogen or together form a double bond;
R10and R12independently selected from hydrogen or lower alkyl and
m denotes 1 or 2.

11. The compounds of formula I according to claim 7, selected from the group including:
CIS-2-(5-methylthiophene-2-yl)cyclohexylamine,
TRANS-2-(5-methylthiophene-2-yl)cyclohexylamine,
TRANS-2-(3-methylpyrrole-1-yl)cyclohexylamine,
TRANS-2-(3-acylpyrrole-1-yl)cyclohexylamine,
TRANS-2-(1,1-dioxo[1,2]diazinon-2-yl)cyclohexylamine,
TRANS-1-(2-aminocyclohexanol)-5,6-dihydro-1H-pyridine-2-it,
TRANS-1-(2-aminocyclohexanol)-4-methyl-1,5-dihydropyrrol-2-it,
TRANS-1-(2-aminocyclohexanol)-4-methyl-5,6-dihydro-1H-pyridine-2-it,
TRANS-1-(2-aminocyclohexanol)piperidine-2-it,
TRANS-1-(2-aminocyclohexanol)-4-methylpyrrolidine-2-he
their pharmaceutically acceptable salts.

12. Compounds according to one of claims 7-11, designed on what I use as therapeutically active substances for the treatment and/or prevention of diseases, associated with DPP-IV.

13. Pharmaceutical composition having any abscopal properties in relation to DPP-IV, comprising the compound according to one of claims 7 to 11 in an effective amount and a pharmaceutically acceptable carrier and/or adjuvant.

14. Use according to one of claims 1 to 6 to obtain drugs for the treatment and/or prevention of diabetes, particularly non-insulin dependent diabetes mellitus, decreased glucose tolerance.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel bioisosteres of actinonin of general formula (I) , as well as to pharmaceutically acceptable salts thereof and pharmaceutical compositions based on said compounds, with peptide deformylase (PDF) inhibitory activity, as well as to use of the compounds or pharmaceutical compositions based on said compounds to prepare medicinal agents. In general formula (I) R1 is a hydrogen atom, R2 is a hydrogen atom, (C1-C6)alkyl residue, hetero(C1-C6)alkylphenyl residue, where the heteroatom is sulphur, R3 is a hydrogen atom, R4 is (C1-C6)alkyl residue, (C3-C7)cycloalkyl residue, R6 is a hydrogen atom, n is 1, 2 or 3. Values of substitute R5 are given in the formula of invention.

EFFECT: new compounds have useful biological activity.

8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-substituted aniline and diphenylamine analogues, chosen from 3,4-bisdifluoromethoxy-(3-carboxyphenyl)-N-(5-(2-chloropyridinylmethyl))-aniline, 3,4-bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(3-(2-chloropyridylmethyl))-aniline, 3,4 - bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(4-(3,5-dimethylisoxazolylmethyl)) aniline, 3 - cyclopentyloxy - 4-methoxy - N-(3-aminocarbonylphenyl) - N-(3-pyridylmethyl) aniline and other compounds given in paragraph 1 of the formula of invention and to their pharmaceutically acceptable salts as inhibitors of PDE4 enzyme.

EFFECT: compounds can be used for treating and preventing diseases caused by activity of the PDE4 enzyme.

15 cl, 8 dwg, 58 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed method of producing (+)duloxetine or its acid-additive salt, including (i) isolation of racemic (±)duloxetine with chiral acid thus producing chiral acid salt and (+)duloxetine, essentially free from (-)duloxetine; and (ii) if desired, transformation of the salt produced at the stage (i) into free base or other acid-additive salt if reasonable. Additionally, method of producing (+)duloxetine or its acid-additive salt can include intermediate process stage that is O-alkylilation enabled with the base or phase-transfer catalyst added.

EFFECT: specified method allows for production of receive enantiomer-pure (+)duloxetine.

17 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new derivative of cyclic amine or its salts with the following formula (I): (where symbols stand for the following: A: 5-8-member cyclic amine, which may contain a double bond, a bridged structure and may contain substitutes R7-R11 in the ring, or -NH2, -NH(inferior alkyl), -N(inferior alkyl)2 or ) morpholin-1-yl; ring B: benzole, thiophene, furane, pyrrole, 5-7-member cycloalkane or 5-7-member cycloalkene; X1: a bond or inferior alkylene; X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -CO-, -CH(OH)-, -N(R14)- (CR12R13)n-, (CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -n(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13)n-CON(R14)-, -CO-(CR12R13)n- or -(CR12R13)n-CO-; Y1: -OH, -O-inferior alkyl, NH2 or -N3; R1 and R2: are identical or different and stand for a halogen atom, inferior alkyl or inferior alkylene-OH; R3-R6: are identical or different and stand for a hydrogen atom, a halogen atom, inferior alkyl, inferior alkenyl, inferior alkynyl, -O-inferior alkyl, -OH, -NH2, -NH(inferior alkyl), -N(inferior alkyl)2, -NH-CO- inferior alkyl, -N(inferior alkyl)-CO- inferior alkyl, -CN-, -NO2, -CF3, -O-inferior alkylene-OH, -inferior alkylene-OH, -inferior alkylene-halogen, -inferior alkylene-O-inferior alkyl, -CO-5-8-member cyclic amine, -COOH-inferior alkyl, -COO-inferior alkylene-aryl, pyridine, thiophene, -inferior alkylene-morpholine, aryl, which may contain a substitute: -O-inferior alkyl or -CF3; R7: hydrogen atom, inferior alkyl, -inferior alkylene-aryl or -inferior alkylene-pyridine: R7 is substitute on the nitrogen atom of the cyclic amine; R8-R14: are identical or different and stand for a hydrogen atom or inferior alkyl; n: is an integer, equal to 1, 2 or 3; where R5 and R6, R4 and R5 or R3 and R4 can form an inferior alkylene together, -O-inferior alkylene-O-, -O-inferior alkylene-, -inferior alkylene-O-, -C(R15)=C(R16)-O-, -O-C(R15)=C(R16)-, -C(R15)=C(R16)-C(R17)=C(R18)-; R3 and Y1 together can form -O-inferior alkylene-O- or -inferior alkylene-O-; R1 and Y1 together can form -inferior alkylene-O-; and Y1 and a branch on - X1-A together can form -O- or -O-inferior alkylene; R15-R18 stand for a hydrogen atom, under the condition that, 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol is not included in the group of compounds). The invention also pertains to a derivative of cyclic amine or its salts with formula (II), to a derivative of cyclic amine or its salts with formula (III), to pharmaceutical composition, as well as their use.

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on these compounds, with antagonist effect on NMDA receptors NMDA.

7 cl, 160 ex, 45 tbl

FIELD: chemistry.

SUBSTANCE: method of enantiomeric obtaining aminoalcohols of formula I in which R1, R2 and n have values given in invention formula, lies in enantioselective hydration of aminoketones in presence of non-racemic catalyst, representing complex of transitive metal, which contains one or more metals and its salts, selected from group, including rhodium, iridium, ruthenium and palladium, in which transitive metal forms complex with chiral diphosphine ligand A.

EFFECT: improvement of synthesis of aminoalcohols, which are acceptable as precursors for obtaining anti-depressants.

11 cl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new compositions of general formula (I): where R1 and R2 mean H; R3 means H; R4 means lower alkyl; n is equal to 1-6; X means O; formula group =N-D (where D means H, lower alkyl); Y means ethylene group, ethynylene group, formula group -E-CH2 - (where E means carbonyl, formula group -CH(OH)-), C6-C10arylen C6-C10arylen group substituted with 1-3 substitutes, selected from Group (a) of substitutes; Z means single bond, C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain; R5 means H, C3-C10cycloalkyl group, C6-C10aryl, C6-C10aryl group substituted with 1-3 substitutes selected from Group (a) of substitutes; R6 and R7 are identical or different and represent each H, lower alkyl; Group (a) of substitutes represents group consisting of halogen, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, lower alkylthio group; provided when R5 represents H, Z represents branched C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain, or it pharmacologically acceptable salt.

EFFECT: high immunosuppressive activity of compounds and their effective application for pharmaceutical compositions and for methods of preventive rheumatoid arthritis treatment.

51 cl, 13 tbl, 91 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

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

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: chemistry.

SUBSTANCE: invention refers to cyclic sulphonamide derivatives of general formula I where bonds indicated with wavy lines represent mutually cis- in relation to cyclohexane ring; R3 represents H or hydrocarbon group having up to 10 carbon atoms; Ar1 and Ar2 independently represent phenyl which carries 0-3 substitutes independently selected from halogen, CF3, CHF2; or its pharmaceutically acceptable salt. Besides, invention refers to technology of compounds of general formula I and to pharmaceutical composition based on compounds of general formula I and applied as gamma-secretase inhibitor.

EFFECT: new derivatives of cyclic sulphonamide, activating gamma-secretase inhibition and suitable for treatment and prevention of Alzheimer's disease.

9 cl, 7 ex

The invention relates to new derivatives of phenylsulfonylacetate General formula (I), which are herbicide and regulating plant growth properties and can find application in agriculture

The invention relates to new heterocyclic compounds with valuable biological properties, in particular derived dioxide benzothiazine, the pharmaceutical compositions based on them having inhibitory receptor endothelin activity, and to a method of inhibiting endothelin receptor

The invention relates to organic chemistry, in particular to an improved method for the preparation of 3-alkoxycarbonyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-1,1 - dioxides of the formula

< / BR>
where

R - CH3C2H5

The invention relates to new chemical compounds derived benzothiazine responsible of General formula I

where R1lower alkyl WITH1-C4

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I), their obtaining and application as elastase inhibitors, and can be applied in medicine, where Y = CH; R№ represents H or alkyl; RІ represents phenyl or 5-6-memner heteroaryl, G1 represents phenyl; R5 represents H, halogen, alkyl, CN or fluorinated alkyl; n=1-3; R4 = H; L represents bond, O, NR29 or alkyl; or R4 and L are bound together in such way that group -NR4L- represents 5-7-member asacyclic ring; G2 represents phenyl, 5-6-member heteroaryl, cycloalkyl, C4-7-heterocycle, bicycle from two condensed, bound with direct bond or separated with O atom rings, selected from phenyl, 5-6-member heteroaryl, cycloalkyl or C4-7-heterocycle; or when L does not represent bond, G2 represents H; s = 0-2; R25 represents H, alkyl or cycloalkyl; R29 represents H or alkyl.

EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new 2-pyridone derivatives of formula (I): where R1, R2, R4, R5, G1, G2, L, Y and n are as specified in the invention formula, and their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and their application in therapy. These compounds have neutrophil elastase inhibition effect.

EFFECT: new compounds with useful biological properties.

7 cl, 1 tbl, 150 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the 2-pyridone derivatives with the common formula where X, Y1, R1, Y2, G1, R5, R4, L, G2 are as specified in the invention formula. The invention also relates to the pharmaceutical agent which inhibits the human neutrophil elastase activity and which contains the compound with the formula (I), in drug manufacturing, and to the method of producing the compound with formula (I).

EFFECT: producing novel compounds which inhibit neutrophil elastase activity.

8 cl, 1 tbl, 96 ex

The invention relates to a method for connection of a new class of organic chemistry - 2,3,5,6-tetraoxa - 4-nitropyridine ammonium of formula I:

< / BR>
The known method for obtaining compounds of similar class - alloxan formula II, which is obtained by the oxidation of urea with malonic ester (Chichibabin A. E.

The invention relates to new derivatives of pyridone F.-ly (I'), where R1- C1- C4-alkyl, R2is hydrogen, R3- SC6H5, R4- CH2OR13where R13is hydrogen, benzyl, R'- tetrazolyl, which have high antagonistic activity against receptor antiotensin II and can find application in medicine

The invention relates to medicine, namely to funds with anticommuting action
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