Guanidin derivatives and their application as neuropeptide ff receptor antagonists

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

 

This invention relates to guanidine derivative of General formula

where

And circuit means from 3-6 possibly substituted With atoms, one of

which can be replaced by-N(R') -, or-O-; and

R' means hydrogen or Deputy;

moreover, cyclic fragment contains two double bonds only thiazole structural element;

and to pharmaceutically acceptable acid additive salts of compounds of formula I of the main character, to pharmaceutically acceptable salts of the compounds of formula I containing an acid group with a base to a pharmaceutically acceptable esters of compounds of formula I containing a hydroxy - or carboxypropyl, and their hydrate or solvate.

Derivatives of guanidine of the formula I which contain one or more asymmetric centers may be in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates or, if necessary, in the form of optically pure diastereomers, mixtures of diastereomers in the form of diastereomeric racemates or mixtures of diastereomeric racemates.

Certain substances are partly known and partly new, and they exhibit valuable pharmacological properties, namely act as receptor antagonists of neuropeptide FF.

In the first aspect of this invention relates to the use of the above defined compounds of formula I, defined above and salts, esters, hydrates and solvate as receptor antagonists of neuropeptide FF or to obtain the appropriate medicines, in particular for the treatment of pain and increased pain sensitivity, inflammation in alcoholic, psychopharmaceuticals and nicotine dependence and to improve or resolve these dependencies, to regulate the release of insulin, food intake, memory function, blood pressure, and electrolyte and energy metabolism and for the treatment of urinary incontinence or for the manufacture of the drugs.

Treatable pain can be chronic, acute, lasting or transient, and these pains can be surgical, traumatic or pathological origin; the advantage according to the invention consists in the prevention of tolerance to opioids and/or opioid dependence.

Already in 1985, were discovered neuropeptide FF (NPFF; H-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2[99566-27-5]), oktapeptid and neuropeptide AF (NPAF; H-Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Pro-Gln-Arg-Phe-NH2[99588-52-0]), related octadecane as neurotransmitters of the Central nervous system in a bullish goal who ate the brain (Yang and others, Proc. Natl. Acad. Sci. USA 1985, 82(22), 7757-61) and originally described as antiopioid peptides. Carboxyterminal amidarone neuropeptides on the basis of their reactivity towards anti-Phe-Met-Arg-Phe-NH2anticigarette were assigned to FMRF peptides. Both peptides exhibit the properties of modulating pain, and oktapeptid has a stronger effect. Both peptides play an important role in opioidnaive analgesia and the development of tolerance to opioids (review article: Roumy and Zajac, Europ. J. Pharm. 1998, 345, 1-11; Panula and others, Prog. Neurobiol. 1996, 48, 461-87). Interestingly, in animal experiments NPFF depending on the method of introduction are as protivootechenoe and propionate actions. So NPFF can pay acute effects of opioids and their increased concentration in the brain may be responsible for the development of tolerance to opioids and addiction. In rats, for example, intracerebroventricular (i.c.v.) introduction reduces the pain threshold and reduces morphine-induced analgesia. Introduction NPFF tolerant to morphine to rats causes symptoms of inflammatory phenomena. The tolerance to morphine in rats after i.c.v injection. anti-NPFF IgG was again apparent analgesic effect of morphine. (Lake and others, Neurosci. Lett. 1991, 132, 29-32). Immunoneutralization NPFF by podvoloshino (i.t.) introduced anti-NPFF antibodies increases the em analgesia, caused by endogenous and exogenous opioids. By direct injection of NPFF or similar NPFF in the spinal cord (i.t.) received propionate action with long apiognomonia the analgesia and enhanced the effect of alleviating pain by morphine (Gouarderes and others, Eur. J. Pharmacol. 1993, 237, 73-81; Kontinen and Kalso, Peptides 1995, 16, 977).

Additional messages indicate that NPFF also play an important role in physiological processes such as the release of insulin, regulation of digestion, memory function, regulation of blood pressure and electrolyte metabolism (Panula and others, Prog. Neurobiol. 1996, 48, 461-487).

In different species of mammals such as human, rat, mouse and the bull was proved by the discovery of the gene that encodes as a common precursor proteins NPFF and NPAF, resulting in a split both active peptide (Perry and others, FEBS Lett. 1997, 409, 426-30; Vilim, etc., Mol. Pharmacol. 1999, 55,804-11). In humans the gene specified predecessor is expressed in various peripheral organs and the Central nervous system, primarily in the cerebellum (Elshourbagy, etc., J. Biol. Chem. 2000, 275 (34), 25965-71), whereas expression in rats is limited solely to specific areas of the Central nervous system, such as the hypothalamus, bone marrow and the dorsal process of the spinal cord. On the basis of evidence for the presence of NPFF in the plasma of human blood, it is assumed that peptides per vericheck additionally responsible for hormone-like activity (Sundblom and others, Peptides 1998, 19, 1165-70).

In tissue samples of human and rat were identified two receptors associated with G-protein (GPCR), NPFF1 and NPFF2 (Bonini and others, J. Boil. Chem. 2000, 275 (50), 39324-31; Kotani, etc., Br. J. Pharmacol. 2001, 133, 138-44), and NPFF2 identical to the originally described as a single receptor HLWAR77 (Elshourbagy, etc., J. Biol. Chem. 2000, 275 (34), 25965-71). NPFF1 and NPFF2 can be characterized as specific receptors with affinity in the nanomolar and subnanomolar area for both neuropeptides FF and AF. NPFF associated with NPFF1 the coupling constant Kd = 1,13 nm and NPFF2 Kd = 0,37 nm. Identity NPFF1 and NPFF2 is approximately 50%. Comparison of amino acid sequences with known GPCRs shows 30-40%similarity with orixinal-1, orixinal-2, neuropeptide Y (NPY) Y2, cholecystokinin AND NPY Y1 receptor proactiveimageuse hormone and NPY Y4 person. Distribution NPFF1 and NPFF2 in different tissue samples of human and rat was established by the definition of m-RNA by RT-PCR (reaction reversible transcription polymerase chain). This NPFF1 was found predominantly in the Central nervous system (CNS). In contrast NPFF2 found predominantly in the spinal cord. These data were based on autoradiographically methods using selective radio-NPFF1 and NPFF2 (Allard and others, Brain Res. 1989, 500, 169-176; Neuroscience 1992, 49, 106-116; Gouarderes and others, Neyroscience 2002 115:2 349-61).

Neuropeptides SF (NPSF, 37 and is of inoculat) and neuropeptide VF (NPVF, oktapeptid), described as akin NPFF peptide is localized in the so-called NPVF-gene, are associated with relatively high affinity and selectivity with NPFF1 receptor as NPFF and NPAV. NPVF-peptide also blocks morphine-induced analgesia in acute and inflammatory aches and pains, expressed NPFF, and emphasizes the importance of NPVF/FF1-systems as part of the endogenous antiopioid mechanism (Q. Liu and others, J. Biol. Chem. 2002, 276 (40). 36961).

The presence of functional receptors NPFF1 and NPFF2 in adipocytes and the effect of NPFF and NPAF on the key position signal in the metabolism of fats means that both peptides along with their original modulating effect on pain additionally can influence the accumulation and expenditure of energy of the body (I. Lefrere, etc., J. Biol. Chem. 2002, 277 (42), 39169).

The peptide of desamino-Tyr-Phe-Leu-Phe-Gln-Pro-Gln-Arg-NH2was the first for which were described NPFF-effects of anti NPFF receptor antagonist. After i.c.v. injection of the indicated peptide weakened inflammatory effects of morphine dependence (Malin and others, Peptides 1991, 12, 1011-1014). However, this peptide in no way demonstrates the biocompatibility of the Central nervous system. Optimization of Tripeptide Pro-Gln-Arg-NH2when the combinatorial preparation led to dansyl-Pro-Gln-Arg-NH2or dansyl-Pro-Ser-Arg-NH2both with improved properties, which passiver the Wali blood-brain barrier, after systemic injections to rats resulted in improved antagonistic effect against induced NPFF antibiogram symptoms (Prokai, etc., J. Med. Chem. 2001, 44, 1623-1626).

Arg-Tyr-amide peptoid BIBP3226, described originally as NPY Y1 selective receptor antagonist, shows 10-60-fold increased affinity for NPFF1-receptor of human and rat compared to the NPFF2 receptors (Bonini and others, J. Biol. Chem. 2000, 275 (50), 39324-31). Of a series of compounds that occur from NPY Y1 selective antagonist BIP3226 received selective antagonists hNPFF1 receptor, which showed affinity 40-80 nm (Mollereau, etc., Europ. J. Pharmacol. 2002, 45, 245-56).

Both neuropeptide FF-analog 1DME ([D-Tyr1,(Nme)Phe3]NPFF) and Nic-1DME (nicotinoyl-Pro-1DME) exhibit various pharmacological properties when Tail-flick test in mice, although both compounds are associated with NPFF1 and NPFF2 with comparable affinity and selectivity. As 1DME and Nic-1DME increase after i.t. and I.P. Pavlova. (vnutribruchinnogo) introduction analgesia morphine, but Nic-1DME may, after i.c.v. and I.P. Pavlova. the introduction is not to suppress morphine-induced analgesia (Quelven and others, Europ. J. Pharmacol. 2002, 449, 91-98).

In the application WO 02/24192 A1 describes the structure of synthetic peptide NPFF-ligand on the basis of arginine as a Central structural element.

Certain substances are potent and specific molecular the antagonist is istemi receptor cells with FF1 ones or nepetoideae structures.

Conventional treatment of chronic pain based on NSAIDs (non-steroid anti-means), cannabinoid and opioids. So, for example, derivatives of morphine bind μ-opioid receptors and act because of this analgesic. The binding of opioids μ-opioid receptor comes with the release of neuropeptide FF. Based on tests performed on animals, it was assumed that released NPFF weakens analgesic effect introduced opioid use leads to tolerance to opioids. In order for the long term treatment to get permanent analgesic effect, due to the mentioned tolerance had to enter all higher doses of opioid, which eventually could lead to serious side effects. As already mentioned above, to date, there are two known receptor for neuropeptide FF, and the receptor NPPF1 mainly localized in the Central nervous system, and NPFF2 receptors (localized) predominantly in the spinal cord. The activation of NPFF2 receptor has apiognomonia analgiziruyuschee action. Blocking receptor NPPF1 antagonist makes the development of tolerance to opioids and enhances their effect.

As mentioned above, certain substances there are partly known and partly new, and he shall differ valuable pharmacological properties, block the interaction of neuropeptide FF with neuropeptide receptor subtype FF1.

If one or more C-atoms of the chain And in the formula I is replaced by(s), then

one C-atom may have one or two (end) are the same or different substituent; or

several C-atoms can have each one or two (end) are the same or different substituent.

In the formula I together with thiazole cycle can form cyclopentadienyl, benzothiazolyl, cycloheptadecane, paranoiacally, triazolopyridines, thiazoleethanol or thiazoleacetate fragments that contain both double bonds only thiazole structural element, such as, for example, 4,5,6,7-tetrahydroindazole, 5,6,7,8-tetrahydro-4H-cycloheptatriene, 5,6-dihydro-4H-cyclopentadienyl, 6,7-dihydro-4H-pyrano[4,3-d]thiazole or 5,6,7,8-tetrahydro-4H-thiazolo[4,5-c]againby fragments.

A subgroup of compounds of formula I may be represented by the General formula (II)

where R1-R6represent hydrogen, alkyl, alkanoyl, alkenyl, alkoxygroup, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkylamides, alkylaminocarbonyl, alkylarylsulfonate, allylcarbamate, alkylthio mail, alkylsulphonyl, alkylcarboxylic, alkylenedioxy, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, allylthiourea, alkylsulfonamides, alkylthiomethyl, quinil, amino group, aminoalkyl, aminoalkyl, aminoacyl, alkylamino, acylaminoalkyl, acylaminoalkyl, aminocarbonyl, aminocarbonylmethyl, aminocarbonylmethyl, alkylaminocarbonyl, alkoxycarbonyl, aryl, arylalkyl, arylalkylamine, arylalkyl, arylalkylamines, arylalkyl, arylamidase, killingray, allumination, arylcarbamoyl, aristochromis, alloctype, aryloxyalkyl, aryloxyalkanoic, aryloxyalkyl, aryloxyalkanoic, aryloxyalkanoic, aryloxyalkyl, aryloxyalkyl, aryloxyalkanoic, aryloxypropanolamine, aryloxyalkanoic, aryloxyalkanoic, arylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonamides, arylsulfonamides, killigrew, alltoall, arylthioureas, carboxypropyl, carboxyl, carboxylic, carboxyethylidene, cyano, cianelli, cyanoacetamide, cyanoalanine, cycloalkyl, cycloalkylation, cycloalkenyl, cycloalkylation, cycloalkyl aminocarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, dialkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkyl, diarylamino, formyl, formylalkyl, halogen, halogenlampe, halogenated, galgenlieder, halogenoalkanes, halogenosilanes, geteroarilsulfoksidu, heteroanalogues, geterotsiklicheskikh, heteroarylboronic, heteroarylboronic, heteroatomcontaining, heteroarylboronic, heterocyclyl, heterocyclisation, heterocyclisation, geterotsiklicheskikh, heterocyclisation, heterocyclisation, geterotsiklicheskikh, heteroallyl, heteroarylboronic, heteroarylboronic, heteroarylboronic, geterotsiklicheskikh, geterotsiklicheskikh, geterotsiklicheskikh, geterotsiklicheskikh, geterotsiklicheskikh, the hydroxy-group, hydroxyalkyl, hydroxyalkyl, mercaptopropyl or nitrogroup.

Preferred values for R1are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1,1-dimethylpropyl or Fanelli R 2-R6different from hydrogen, they are preferably methyl or other lower alkyl residue.

Further subgroup of compounds of formula I may be represented by the General formula III

where R' represents alkyl, alkanoyl, alkenyl, quinil, alkoxycarbonylmethyl, alkoxycarbonylmethyl, allylcarbamate, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkylthiomethyl, mono - or disubstituted aminoalkyl, aryl, arylalkyl, arylethoxysilanes, arylalkyl, arylcarbamoyl, alkoxyalkyl, alkylsulfonyl, aristochromis, aryloxyalkyl, aryloxyalkanoic, aryloxyalkanoic, aryloxyalkanoic, arylsulfonyl, cycloalkyl, cycloalkenyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, heteroallyl, geterotsiklicheskikh, geterotsiklicheskikh, geterotsiklicheskikh, geterotsiklicheskikh, geterotsiklicheskikh, heteroarylboronic, heteroarylboronic or heteroaryl carbonyldiimidazole.

Thus preferably R' represents methyl, ethyl, propyl, hexyl, 2,2-dimethylpropionic, cyclopropylmethyl, 2-cyclohexylethyl, PROPYNYL, ethoxycarbonylmethyl, benzyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, 3-methylbutyryl, pentanoyl, phenylacetyl, 2-propylpentanoic, cyclopropanecarbonyl, isobutyryl, but-3-enoyl, 2-methoxyacetyl, propane-2-sulfonyl, butane-1-sulfonyl, methanesulfonyl, tert-butyloxycarbonyl or 4-dimethylaminobutyric.

Preferably the application of the following compounds of the formula III:

tert-butyl ester 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid;

N-(5-hexyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine;

N-[5-(2-cyclohexylethyl)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine;

N-(5-ethyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine;

Butyl ether 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid;

N-[5-(propane-2-sulfonyl)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine;

N-(5-phenylacetyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine;

Benzyl ether of 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid;

N-(5-pentanoyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine;

Propelled 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-thiocarbonic acids;

N-[5-(2-propylpentanoic)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine;

N-(5-benzyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine;

N-(5-prop-2-inyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine;

N-(5-cyclopropanecarbonyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine;

N-[5-(butane-1-sulfonyl)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine;

N-(5-isobutyryl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine;

N-[5-(2,2-dimethylpropionic)-4,5,6,7-tetrahydrothieno[5,4-c]pyridyl-2-yl]guanidine;

benzylated 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-thiocarbonic acids;

tert-butylamide 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid;

N-(5-but-3-enoyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine;

N-(5-benzyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-c]azepin-2-yl)guanidine;

Ethyl ester of 3-(2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-yl)propionic acid;

Pencilled 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid;

N-[5-(2-methoxyacetyl)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine;

N-(5-cyclopropylmethyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine;

N-(5-methanesulfonyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine;

N-[5-(3-methylbutyryl)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine;

(2-methoxy-1-methylethyl)amide 2-guanidino-6,7-dihydro-thiazolo[5,4-c]pyridine-5-thiocarbonic acid;

phenylamide 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid;

tert-butyl ether [3-(2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-yl)-3-oxopropyl]carbamino acids;

N-[5-(4-dimethylaminobutyric)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine;

N-(5-propyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine; and

isopropylated 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-thiocarbonic acid.

New connections are defined above for the formula I, where a is a chain of 3 to 6, if necessary substituted With atoms, one of which may be replaced by-O-; and cyclic fragment contains two double bonds only thiazole structural element;

as well as pharmaceutically acceptable acid additive salts of compounds of the main character, pharmaceutically acceptable salts of compounds containing acid groups, bases, pharmaceutically acceptable esters of compounds containing hydroxy or carboxypropyl and their hydrate or solvate;

except:

- N-(4,5,6,7-tetrahydroindazole-2-yl)guanidine;

ethyl ether (2-guanidino-4,5,6,7-tetrahydroindazole-4-yl)acetic acid;

- N-(4-hydroxymethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

- N-(4-tosyloxy-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

- N(-azidomethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

- N-(4-aminomethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine; and

- N-(6-acetamidomethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine.

In the following aspect, the invention encompasses accordingly, these new compounds as such and as therapeutically active substances; the retrieval method; drug containing one of the above new compounds; the receipt of the medicines; and the use of these novel compounds as receptor antagonists of neuropeptide FF or to obtain the appropriate drugs according to the above first aspect of the present invention.

In certain above new compounds of the formula I in the circuit a-C-atom may have one or two (end) are the same or different substituent; or

several C-atoms can have each one or two (end) are the same or different substituent.

Moreover, the substituent(s) may(may) be selected(s) from the following groups:

alkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, aralkyl, alkoxycarbonyl, carboxamido, cyano or cianelli and/or polymethene groups attached to the same C-atom.

In particular, the substituent(s) may(gut) selected(s) from the following groups:

is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-Buti is, tert-butyl, 1,1-dimethylpropyl, allyl and cyclohex-1-enyl;

and/or

- phenyl, ortho-tolyl, meta-tolyl, para-tolyl, 2-ethylphenyl, 3-forfinal, 4-forfinal, 4-chlorophenyl, 4-cyanophenyl, 4-benzyloxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-acid, 3,4-methylenedioxyphenyl and

bis-3,5-triptoreline; and/or

- thiophene-2-yl and benzyl; and/or

- ethoxycarbonyl groups; and/or

'n ' propylamino, benzylamino-, N-methyl-N-phenethylamine-, 3-methylbutylamine, phenylamino-, N-butyl-N-ethylamino-, di-n-propylamino-allylamino, piperidine-1 - morpholine-4-carbonyl groups; and/or

- cyano - and cyanoethylene groups; and/or

- pentamethylenebis group, prisoedinenii to the same C-atom.

Preferred such new connections to the same C-atom attached to the phenyl and, on the other hand, etoxycarbonyl, cyano or phenyl.

Absolutely new preferred compounds are:

N-(5-ethyl-5-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(5,5-dimethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(5,5-dimethyl-6-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(4-tert-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(6-isopropyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(5,5,7-trimethyl-4,5,6,7-tetrahydroindazole-2 - yl)guanidine;

-(6,6-dimethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(5-butyl-5,6,7,8-tetrahydro-4H-cycloheptatrien-2-yl)guanidine;

N-(4-ethyl-4-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-[6-(3,4-acid)-4,5,6,7-tetrahydroindazole-2-yl]guanidine and its formate;

N-(5-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(6-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(5-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(4-methyl-4-propyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(6-propyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(4-cyclohex-1-enyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(4-sec-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate; and

N-(4-isobutyl-4-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine.

Further particularly preferred new compounds are:

N-(6-tert-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

ethyl ester of 2-guanidino-6-phenyl-4,5,6,7-tetrahydroindazole-6-carboxylic acid and its formate;

N-[6-(1,1-dimethylpropyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine;

N-(7-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-[6-(3-methoxyphenyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine and its formate;

N-(6-thiophene-2-yl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(5,5,7,7-tetramethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-[6-(4-forfinal)-4,5,6,7-those whom rehydrogenation-2-yl]guanidine and its hydrobromide;

ethyl ester of 2-guanidino-4,5,6,7-tetrahydroindazole-6-carboxylic acid and its hydrobromide;

N-(4,4-dimethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(4-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(4,5,6,7-tetrahydroindazole-2-yl-4-Spiro-cyclohexane)guanidine and its formate;

N-(5,6,7,8-tetrahydro-4H-cycloheptatrien-2-yl)guanidine;

N-(4-allyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(6-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-[6-(3-forfinal-4,5,6,7-tetrahydroindazole-2-yl]guanidine and its formate;

N-(6-cyano-6-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its hydrobromide;

N-(4-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate; and

N-(6,6-diphenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate.

Also preferred new connections:

N-[6-(4-methoxyphenyl-4,5,6,7-tetrahydroindazole-2-yl]guanidine and its hydrobromide;

N-(5-phenyl-5,6,7,8-tetrahydro-4H-cycloheptatrien-2-yl)guanidine and its hydrobromide;

N-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)guanidine;

N-(6-benzo[1,3]dioxol-5-yl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

propelled 2-guanidino-4,5,6,7-tetrahydroindazole-6-carboxylic acid and its formate;

N-[6-(4-cyanophenyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine and its formate;

N-(4-benzyl-4,5,6,7-Tetra robinsoniana-2-yl)guanidine and its formate;

N-(5-methyl-5-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-[6-(3,5-bis-triptoreline)-4,5,6,7-tetrahydroindazole-2-yl]guanidine and its formate;

N-(6-ortho-tolyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(6-meta-tolyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-[6-(2-ethylphenyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine and its formate;

N-[6-(4-chlorophenyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine and its formate;

benzylated 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid and its formate;

N-(5,6-dihydro-4H-cyclopentadiene-2-yl)guanidine;

N-[6-(4-benzyloxyphenyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine and its hydrobromide;

methylphenethylamine 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid and its formate;

N-(6-phenyl-4,5,6,7-tetrahydroindazole-2-yl-4-Spiro-cyclohexane)guanidine and its hydrobromide;

N-(6-para-tolyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

(3-methylbutyl)amide 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid and its formate; and

N-(4-tert-butyl-6-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine.

Other representative (examples) new compounds are:

phenylamide 2-guanidino-4,5,6,7-tetrahydroindazole-6-carboxylic acid and its formate;

butylacrylamide 2-guanidino-4,5,6,7-those whom rehydrogenation-4-carboxylic acid and its formate;

N-[4-(2-cyanoethyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine and its formate;

ethyl ester of 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid and its hydrobromide;

DIPROPYLENE 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid and its formate;

phenylamide 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid and its formate;

Alleluia 2-guanidino-4,5,6,7-tetrahydroindazole-6-carboxylic acid and its formate;

propelled 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid and its formate;

N-[4-(piperidine-1-carbonyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine and its formate;

Alleluia 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid and its formate;

(3-methylbutyl)amide 2-guanidino-4,5,6,7-tetrahydroindazole-6-carboxylic acid and its formate;

N-[4-(morpholine-4-carbonyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine and its formate; and

diisopropylamide 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid and formate.

The term "alkyl", single or in combination, means an unbranched or branched hydrocarbon residue with 1 to 8 C-atoms. Representative, but not limiting examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or 2-methylpropyl), n-pentyl (or n-amyl), isopentyl (or isoamyl), n-gecsi is, n-heptyl, n-octyl and the like. The alkyl residue may have one or more substituents, which independently of each other selected from alkenyl, alkoxygroup, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkylcarboxylic, alkylcarboxylic, alkylcarboxylic, alkylenedioxy, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, allylthiourea, alkylthiomethyl, quinil, amino, aminoalkyl, aminocarbonyl, aminocarbonylmethyl, aryl, arylalkyl, arylalkylamine, arylalkyl, alloctype, aryloxyalkyl, aryloxyalkyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, aristocraty, alltoall, carboxypropyl, carboxyethyl, ceanography, cyanoalanine, formyl, formylalkyl, halogen, halogenlampe, halogenoalkane, heterocyclyl, hydroxy-group, hydroxyalkyl, mercaptopropyl, nitro and the like and which can be attached to any C-atom alkyl groups.

The term "lower alkyl", single or in combination, signifies an alkyl group with 1-4 C-atoms. Representative, but not limiting examples of lower alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like.

The concept of "alkenyl", single or in combination, means non-branched and the branched hydrocarbon residue with 2 to 8 C-atoms, in which there is at least one carbon-carbon double bond (RaRbC=CRcRd). Ra-Rdmean substituents, which independently of each other selected from hydrogen, alkyl, alkoxygroup, alkoxyalkyl and the like. Representative, but not limiting examples of alkenyl are ethynyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.

The concept of "alkylenedioxy", single or in combination, means a group- (CH2)nO-where n is 1 or 2; and O atoms are bound to two adjacent C-atoms of the main fragment of the molecule. Representative, but not limiting examples of alkylenedioxy are methylendioxy, atlantoxerus and the like.

The concept of "quinil", single or in combination, means an unbranched or branched uglevodorodnyi residue with 2 to 8 C-atoms, which contains at least one carbon-carbon triple bond (Ra-C≡C-Rb). Raand Rbmean substituents, which independently of each other selected from hydrogen, alkenyl, alkoxygroup, alkoxyalkyl and the like. Representative, but not limiting examples of quinil are acetylenyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 3-butynyl, 2-pentenyl and the like.

The concept of "alkoxygroup"or one in whom is inali, means an alkyl group that is attached through an oxygen bridge. Representative, but not limiting examples of alkoxygroup are a methoxy group, ethoxypropan, propoxylate, 2-propoxylate, butoxypropan, tert-butoxypropan, pentyloxy and hexyloxy.

The concept of "alkoxyalkyl", single or in combination, means alkoxygroup, which is attached via an alkyl residue. Representative, but not limiting examples of alkoxyalkyl are tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl and ethoxymethyl.

The concept of "alkoxycarbonyl", single or in combination, means alkoxygroup, which is attached via a carbonyl group. Representative, but not limiting examples of alkoxycarbonyl are methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl and the like.

The concept of "alkoxycarbonyl", single or in combination, means alkoxycarbonyl group that is attached via an alkyl residue. Representative, but not limiting examples of alkoxycarbonylmethyl are methoxycarbonylpropionyl, ethoxycarbonylbutyl, 2-tert-butoxycarbonylamino and the like.

The concept of "alkylaryl", single or in combination, means an alkyl group that is attached through a carbonyl group. Representative, but not ogranicheniyami of alkylcarboxylic are acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, 1-oxobutyl and the like.

The concept of "alkylcarboxylic", single or in combination, means alkylcarboxylic group that is attached through an alkyl group. Representative, but not limiting examples of alkylcarboxylic are 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, 3-oxobutyl and the like.

The concept of "alkylcarboxylic", single or in combination, means alkylcarboxylic group that is attached through an oxygen bridge. Representative, but not limiting examples of alkylcarboxylic are acetyloxy, ethylcarboxylate, tert-butylcarbamoyl and the like.

The concept of "alkylsulfonyl", single or in combination, means an alkyl group attached through sulfonyloxy group. Representative, but not limiting examples of alkylsulfonyl are methylsulfinyl, ethylsulfinyl and the like.

The concept of "alkylsulfonyl", single or in combination, means alkylsulfonyl group attached through an alkyl group. Representative, but not limiting examples of alkylsulfonyl are methylsulfonylmethyl, ethylsulfinyl and the like.

The term "alkylsulfonyl", single or in combination, means an alkyl group attached jerusalemonline group. Representative, but not limiting examples alkylsulfonyl are methylsulphonyl, ethylsulfonyl and the like.

The concept of "alkylsulfonyl", single or in combination, means alkylsulfonyl group attached through an alkyl group. Representative, but not limiting examples of alkylsulfonyl are methylsulfonylmethyl, ethylsulfonyl and the like.

The concept of "allylthiourea", single or in combination, means an alkyl group attached through tigroup. Representative, but not limiting examples of ancilliary are methylsulfonyl, ethylsulfonyl, tert-butylsulfonyl, hexylsilane and the like.

The concept of "alkylthiomethyl", single or in combination, means allylthiourea attached through an alkyl group. Representative, but not limiting examples of alkylthiomethyl are methylsulfonylmethyl, 2-(ethylsulfanyl)ethyl and the like.

The term "amino group", single or in combination, signifies a group-NReRfand Reand Rfindependently from each other selected from hydrogen, alkyl, aryl, arylalkyl, acyl, alkylsulphonyl, arylcarbamoyl, carbamoyl, raidgroup, formyl, alkylsulfonyl, arylsulfonyl and the like.

The concept of "aminoalkyl", single or in combination, means an amino group attached across the alkyl group. Representative, but not limiting examples of aminoalkyl are aminomethyl, 2-amino-ethyl, N-benzyl-N-methylaminomethyl, dimethylaminomethyl and the like.

The concept of "aminocarbonyl", single or in combination, means an amino group attached through a carbonyl group. Representative, but not limiting examples of aminocarbonyl are dimethylaminoethyl, benzylaminocarbonyl, acylaminoalkyl and the like.

The concept of "aminocarbonyl", single or in combination, means aminocarbonyl group attached through an alkyl group. Representative, but not limiting examples of aminocarbonylmethyl are 2-amino-2-oxoethyl, 2-(benzylamino)-2-oxoethyl, 2-(methylamino)-2-oxoethyl, 4-amino-4-oxobutyl, 4-(dimethylamino)-4-oxobutyl and the like.

The term "aryl", single or in combination, means an aromatic carbocyclic group containing at least one aromatic cycle, for example, phenyl or biphenyl, or a condensed cyclic system in which at least one cycle is aromatic, for example, 1,2,3,4-tetrahydronaphthyl, naphthyl, antril, tenantry, fluorenyl and the like. The aryl group may have one or more substituents, which independently of each other selected from alkenyl, alkoxygroup, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl,alkyl, alkylcarboxylic, alkylcarboxylic, alkylcarboxylic, alkylenedioxy, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, allylthiourea, alkylthiomethyl, quinil, amino, aminoalkyl, aminocarbonyl, aminocarbonylmethyl, arylalkyl, arylalkylamine, arylalkyl, alloctype, aryloxyalkyl, aryloxyalkyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, aristocraty, alltoall, carboxypropyl, carboxyethyl, ceanography, cyanoalanine, formyl, formylalkyl, halogen, halogenlampe, halogenoalkane, heterocyclyl, hydroxy-group, hydroxyalkyl, mercaptopropyl, nitro and the like.

The concept of "arylalkyl", single or in combination, means an aryl group attached through alkenylphenol group. Representative, but not limiting examples arylalkyl are 2-phenylethenyl, 3 phenylpropan-2-yl, 2-naphthas-2-retinyl and the like.

The concept of "arielalexisxrp", single or in combination, means an aryl group attached through alkoxygroup. Representative, but not limiting examples of arialcategory are 2-venlafaxina, 5-phenylphenoxide, 3-naphthas-2-lpropecia and the like.

The concept of "arylalkyl", single or in combination, means arilin the th group, attached via the alkyl group. The aryl group may be substituted or unsubstituted. Representative, but not limiting examples of arylalkyl are benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphthas-2-retil and the like.

The concept of "alloctype", single or in combination, means an aryl group attached through an oxygen bridge. The aryl group may be substituted or unsubstituted. Representative, but not limiting examples of alloctype are fenoxaprop, naphthyloxy, 3-bromophenoxy, 4-chlorphenoxy, 4-methylphenoxy, 3,4-dimethoxyphenoxy and the like. The aryl group can be unsubstituted or substituted according to the definition.

The concept of "carbarnoyl", single or in combination, signifies a group-C(O)NReRf.

The concept of "thiocarbamoyl", single or in combination, signifies a group-C(S)NReRf.

The term "carbonyl", single or in combination, signifies a group-S(O).

The concept of "carboxypropyl", single or in combination, signifies a group-CO2N.

The concept of "carboxylic", single or in combination, means carboxypropyl that is attached through an alkyl group. Representative, but not limiting examples of carboxyethyl are carboxymethyl, 2-carboxyethyl, 3-carboxypropyl and the like.

The term "cyano groups is", single or in combination, signifies a group- ≡N.

The concept of "cianelli", single or in combination, means cyano, which is attached via the alkyl group. Representative, but not limiting examples of cyanoalanine are cyanomethyl, 2-cyanoethyl, 3-cyanopropyl and the like.

The concept of "cycloalkyl", single or in combination, means a saturated cyclic hydrocarbon residue with 3 to 15 C-atoms, which may have one or more substituents. Substituents independently of one another selected from alkenyl, alkoxygroup, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkyl, alkylsulphonyl, alkylcarboxylic, alkylcarboxylic, alkylenedioxy, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, allylthiourea, alkylthiomethyl, quinil, amino, aminoalkyl, aminocarbonyl, aminocarbonylmethyl, aryl, arylalkyl, arylalkylamine, arylalkyl, alloctype, aryloxyalkyl, aryloxyalkyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, aristocraty, alltoall, carboxypropyl, carboxyethyl, ceanography, cyanoalanine, formyl, formylalkyl, halogen, halogenlampe, halogenoalkane, heterocyclyl, hydroxy-group, hydroxyalkyl, mercaptopropyl, nitro and the like is. Representative, but not limiting examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. In polycyclic cycloalkyl remains one of the condensed cycles may be aromatic, such as, for example, 1 indanyl, 2-indanyl, tetrahydronaphthyl and the like.

The concept of "cycloalkenyl and cycloalkenyl" means a cyclic hydrocarbon residues containing at least one carbon-carbon double or triple bond. These residues, as cycloalkyl residues may have one or more deputies.

The term "formyl", single or in combination, signifies a group-C(O)N.

The concept of "formylalkyl", single or in combination, means a formyl group attached through an alkyl group. Representative, but not limiting examples of formylalkyl are formylmethyl, 2-formylated and the like.

The notion of "halogen" or "halogen", single or in combination, refers to fluorine, bromine, chlorine and iodine.

The concept of "halogenated", single or in combination, means an alkyl group in which at least one hydrogen atom replaced by a halogen. Representative, but not limiting examples of halogenoalkane are chloromethyl, 2-foretel, trifluoromethyl, pentafluoroethyl, 2-chloro-3-terpencil and the like.

The concept of "halogenlampe is, single or in combination, means alkoxygroup, in which at least one hydrogen atom replaced by a halogen. Representative, but not limiting examples of halogenlampe are climatograph, 2-veracocha, tripterocarpa, pentaceratops and the like.

The concept of "heterocyclyl", single or in combination, means a monocyclic, bicyclic or polycyclic ring system with the number of atoms in a loop until 15 containing at least one heteroatom independently selected from nitrogen, oxygen, or sulfur; ring(a) can(may) be saturated, partially unsaturated or unsaturated or aromatic(and). Representative, but not limiting examples heterocyclyl are furyl, imidazolyl, imidazolyl, imidazolidinyl, isothiazolin, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxazolyl, oxazolidinyl, piperazinil, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolidyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothieno, thiadiazolyl, thiazolyl, thiazolyl, diazolidinyl, thienyl, thiomorpholine, 1,1-dioxothiazolidine, benzimidazolyl, benzothiazolyl, benzothiazyl, benzoxazolyl, benzofuranyl, indolyl, indolinyl, isobenzofuranyl, isobenzofuranyl, isoindolyl, isoindolines, Itoh Nalini, chinoline and the like. Heterocyclic residues may have one or more substituents and are independently from each other selected from alkenyl, alkoxygroup, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, alkyl, alkylsulphonyl, alkylcarboxylic, alkylcarboxylic, alkylenedioxy, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, allylthiourea, alkylthiomethyl, quinil, amino, aminoalkyl, aminocarbonyl, aminocarbonylmethyl, aryl, arylalkyl, arylalkylamine, arylalkyl, alloctype, aryloxyalkyl, aryloxyalkyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, aristocraty, alltoall, carboxypropyl, carboxyethyl, ceanography, cyanoalanine, cycloalkyl, formyl, formylalkyl, halogen, halogenlampe, halogenoalkane, hydroxy-group, hydroxyalkyl, mercaptopropyl, nitro and the like.

The concept of "heteroaryl", single or in combination, is a special case heterocyclyl and means a monocyclic, bicyclic or polycyclic ring system in which at least one cycle is heteroaromatic.

The concept of "heterocyclisation", single or in combination, means heterocyclyl group attached through alkenyl the th group. Representative, but not limiting examples geterotsiklicheskikh are 2 pyrid-3-retinyl, 3-quinoline-3-improper-2-yl, 5-pyrid-4-rintelen-4-yl and the like.

The concept of "geterotsiklicheskikh", single or in combination, means heterocyclyl group attached through alkoxygroup. Representative, but not limiting examples of geterotsiklicheskikh are 2 pyrid-3-yletoxarap, 3-quinoline-3-lpropecia, 5-pyrid-4-rintracciata and the like.

The concept of "geterotsiklicheskikh", single or in combination, means heterocyclyl group attached through a higher alkyl group. Representative, but not limiting examples of geterotsiklicheskikh are 2 pyrid-3-ylmethyl, 2-pyrimidine-2-ylpropyl and the like.

The concept of "geterotsiklicheskikh", single or in combination, means heterocyclyl group attached through an oxygen bridge. Representative, but not limiting examples of geterotsiklicheskikh are pyrid-3-roxyrama, quinoline-3-roxyrama and the like.

The term "hydroxy-group" or "hydroxyl", alone or in combination, means a group-IT.

The concept of "hydroxyalkyl", single or in combination, means an alkyl group in which at least one hydrogen atom is replaced by a hydroxyl group. Representative is, but non-limiting examples of hydroxyalkyl are 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyethyl and the like.

The term "nitro-group, one or in combination, signifies a group-NO2.

The concept of "oxoprop", single or in combination, means a group =O.

The concept of "oxygraph", single or in combination, signifies a group-O-.

The concept of "mercaptopropyl" and "thiol" refers to the group-SH.

The concept of "tighrope", "sulfinil and sulfonyl"means the group-S(O)nc n = 0, 1, and 2.

As defined above, the compounds of formula I can be represented in a free form, in the form of a pharmaceutically acceptable acid additive salts, in the form of pharmaceutically acceptable salts of acidic compounds of formula I with bases, in the form of pharmaceutically acceptable esters of compounds of formula I containing a hydroxy - or carboxypropyl, as well as in the form of hydrate or solvate. The term "pharmaceutically acceptable salt" refers to salts that do not reduce the biological activity and properties of the free bases and are not undesirable biological or other point of view.

Acid additive salts formed from the free bases by inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like is, preferably, hydrochloric acid and Hydrobromic acid, or by organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, salicylic acid, citric acid, benzoic acid, mandelic acid, methanesulfonate, p-toluensulfonate and the like.

The compounds of formula I which contain acidic groups can form salts with inorganic bases or organic bases. The preferred salts with inorganic bases are, but not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium and the like. The preferred salts with organic bases are, but not limited to, salts of primary, secondary and tertiary, if necessary, substituted amines including all substituted amines of natural origin, cyclic amines and basic ion-exchange resins of the character, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polianinova resin and the like. The compounds of formula I which contain acidic groups can also be represented in the form zwitterions.

The above also f is rmaceuticals acceptable esters of compounds of formula I, containing hydroxy or carboxypropyl. "Pharmaceutically acceptable ester" means that the corresponding functional groups in the compounds of the formula I is converted into ester groups in such a way that in vivo they turn back into their active form. On the one hand, can be tarifitsirovana COOH-group. Examples of suitable esters of this kind are alkalemia and Arakelova esters. Preferred esters of this kind are methyl, ethyl, propyl, butyl and benzyl esters, and (R/S)-1-[(isopropoxycarbonyl)oxy]ethyl ester. Especially preferred ethyl ester and isomeric butyl esters. On the other hand, can be tarifitsirovana Oh-group. For example, such compounds contain physiologically acceptable and metabolically labile ester groups, such as methoxymethyl ester, methylthiomethyl ester, pivaloyloxymethyl ester and the like of the ester group.

The compounds of formula I were tested for their affinity to the NPFF receptors in the following tests:

To study the binding of the receptor neuropeptide FF suitable hamster cells (cells of the ovary of the Chinese hamster, CHOSP10), which as required produce NPFF1 receptors or NPFF2, were propagated under standard conditions for tile is cnyh cultures. The cell culture medium was aspirated and added to 5 ml of buffer A (5 mm Tris pH 7.4, 1 mm MgCl217 cm Petri dish. Cells are scraped from the plates with cell cultures and transfusional in the vessel Falcon with a capacity of 50 ml and Then the cells were centrifuged for 5 minutes at 450 g, again suspended in buffer solution and within 30 seconds was stirred at Polytron (transmitter station) Vortex. After centrifugation at 30,000 g for 20 minutes upper part was discarded and the membrane pellets were consumed 500 ál buffer (75 mm Tris pH 7.4, 25 mm MgCl2, 250 mm sucrose, 0.1 mm PMSF, 0.1 mm phenanthroline). A mixture of buffer solution with membranes were then divided into aliquots and subjected to deep freezing. The protein content in each sample was determined by the Lowry method.

Test linking was performed in a final volume of 250 μl. 100 μl of a buffer mixture membranes, corresponding to 35 μg of protein was mixed with 95 μl of binding buffer (50 mm Tris pH 7.4, 60 mm NaCl, 0.1% BSA, free from protease, of 0.01% NaN3). After adding 5 μl of the test substance in the desired concentration was added 0.2 nm125I-Tyrl-NPFF (NEN, NEX381) at the measurement point 50 µl. After 90 minutes incubation at room temperature, the sample was aspirated through the filter GF/C (Millipore (MAHFCH60)) and the filter was washed 3 times with 300 ál of ice binding buffer dissolve the (Packard Filtermate). After addition of 55 μl acquired scintillation fluid Microscint 40 (Packard 6013641) point of measurement was kvantovoi in a gamma counter (Packard Top Count NXT).

In the presence of 1 μm unlabelled neuropeptide FF specific binding was not detected. Specific binding was defined as the difference between total and nonspecific binding. The value of the IC50was defined as the concentration of antagonist that displaces 50%125I-labeled neuropeptide FF. The specified concentration was determined by linear regression analysis logically after logarithmic transformation (Logit/log Transformation) values of the binding.

The preferred proposed compounds shown in the above test on receptor binding values IC50below 1000 nm, especially preferred compounds show values of the IC50below 100 nm, very particularly preferred below 50 nm.

The results of the above biological testing of representative compounds of formula I are presented in the following table 1.

Table 1

Linking NPFF1 receptor
ConnectionBinding

NPFF-1

IC50 [μm]
N-(5-ethyl-5-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidineis 0.0002
N-(5,5-dimethyl-4,5,6,7-tetr hydrobenzoin-2-yl)guanidine 0,002
N-(4-tert-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,002
N-(5,5-dimethyl-6-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,002
N-(6-isopropyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,004
N-(6,6-dimethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,004
N-(5,5,7-trimethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,004
N-(5-butyl-5,6,7,8-tetrahydro-4H-cycloheptatrien-2-yl)guanidine0,005
N-(5-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,005
N-(4-ethyl-4-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,005
N-[6-(3,4-acid)-4,5,6,7-tetrahydroindazole-2-yl]guanidine0,005
N-(5-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,006
N-(6-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,006
N-(6-propyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,007
N-(4-methyl-4-propyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,007
N-(4-cyclohex-1-enyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,008
N-(4-second- butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,009
N-(4-isobutyl-4-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,009
N-(6-tert-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine0,010

As mentioned above, these substances due to their ability to block receptors neuropeptide FF are valuable for the treatment of pain, hypersensitivity to pain (hyperalgesia) and chronic, acute, prolonged or transient pain, and these pains can be surgical, traumatic or pathological origin. First of all, they complement conventional methods of treatment of chronic pain with the advantage that they prevent unwanted tolerance to opioids and/or opioid dependence. In addition, the compounds can be administered to regulate the release of insulin, digestion, memory function, blood pressure, as well as electrolyte and energy exchanges and for the treatment of urinary incontinence.

Defined above substances may be used are well known and commonly used for each specialist ways in suitable galenic forms. Such applications are, for example, tablets, pills with sheath, coated tablets, capsules, injectable solutions, etc. made For what I mentioned galenical forms application use suitable fillers and excipients, also widely known and familiar to any person skilled in the art. In addition to one or more defined above substances specified forms of application may also contain additional pharmacologically active compounds.

The dosage of the above defined compounds or containing their applications determined by the physician depending on the patient's needs. Usually, the daily dose may be about 0.1-20 mg, preferably 0.5 to 5 mg defined above substance per 1 kg of body weight of the patient.

Derivatives of guanidine of the General formula I, as well as the appropriate source and intermediate products can be obtained by methods known in organic synthesis, and isolated and purified using conventional techniques such as precipitation, chromatography, crystallization, preparationa HPLC with reversed phases, etc. In all cases, the resulting mixture of stereoisomers, such as racemates, can be separated by the usual conventional methods, preferably by chromatographytandem on chiral phase.

Getting guanidine derivatives of General formula I is carried out according to the following scheme 1:

Scheme 1

The compound of formula 1, in which in And secured all the available nitrogen atoms, halogenous in α-position to a carbonyl group, then the obtained compounds is their formula 2 using a derivative of thiourea, such as 2-imino-4-taburet formula 3,subjected to cyclocondensation, if necessary, of the compounds obtained otscheplaut are all nitrogen atoms of the protective group, if necessary, these nitrogen atoms, respectively, replace R' by using tools, giving R', and, if necessary, the obtained compound of the main character is transformed into pharmaceutically acceptable acid additive salt or a resulting compound containing an acid group is converted into pharmaceutically acceptable salt with a base or a derived compound containing hydroxy or carboxypropyl, turns into a pharmaceutically acceptable ester and, if necessary, the resulting product is converted into a hydrate or MES.

Since the new compounds of the formula I circuit And may not contain a nitrogen atom, the previous guidance on the N-protective group, its removal and possible N-substitution of the target product to obtain these new connections are unnecessary. Accordingly, proposed new products can be obtained simply, by halogenation of the compounds of the above formula 1 α-position to a carbonyl group, the cyclocondensation of the obtained compound of the above formula 2 with 2-imino-4-cibeureum the above formula 3 and, if necessary, prevremeni the compounds of basic character in pharmaceutically acceptable acid additive salt or transformation of the obtained compound, containing acid group, a pharmaceutically acceptable salt with a base or transformations of the obtained compounds containing hydroxy or carboxypropyl, pharmaceutically acceptable ester and, if necessary, conversion of the resulting product in the hydrate or MES.

Usually syntheses as guanidine derivatives of the formula I and the corresponding intermediate products, carried out in a solution using an organic solvent. The introduction and removal of protective groups make in the usual well-known experts in this field (T.W. Greene &P.G.M. Wuts in Protective Groups in Organic Synthesis, third edition, John Wiley & Sons, 1999). Usually cycloalkanones (1) halogenous in α-position to a carbonyl group by known methods. Subsequent cyclocondensation α-halogenoalkane (2) with a derivative of thiourea, as, for example, with 2-imino-4-tobirama (3), carried out in a known manner, which leads to the desired guanidine derivative of the formula I (J. Med. Chem. 1991, 34(3), 914-918; J. Med. Chem. 1994, 37(8), 1189-1199). In General, the heterocyclic exocoetidae (1) similarly can be converted into the corresponding target compounds of formula I. it should be noted that present in the original product-NH-group (cf. the subsequent formula 4) must be submitted with a conventional protecting group (PG), see sleduushuu the scheme 2:

Scheme 2

The required cyclic ashkelony formula 4 can partially be received is known in the literature (methods) (Yokoo and others, Bull. Chem. Soc. Japan 1959, 29, 631; Griss, and others, patent DE 2206385, published February 10, 1972) or similar to the first stage of example N-07.

Halogenoalkane 5 and cyclocondensation 6 with 2-imino-4-tobirama (3) with the formation of the corresponding N-protected bicyclic guanidinate 7 is carried out in known conditions. After removal of protective groups, which leads to 8, enter the above-defined balance R' in certain circumstances by an appropriate reagent, giving R', such as, for example, alkylhalogenide, halogenmethyl or carboxylic acid anhydride or carboxylic acid, in the presence of the agent combinations and bases as an auxiliary reagent, CHLOROFORMATES, sulphonylchloride, isocyanates, isothioscyanates and the like, with the formation of the corresponding compounds of formula III.

Suitable organic rastvoritelyami are those which are inert under the chosen reaction conditions. Preferred ethers, such as diethyl ether, dioxane, tetrahydrofuran or a simple dimethyl ether glycol; or alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, Isobutanol or tert-butanol; or equal to the hydrogens, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions; or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene; or also ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, acetonitrile, acetone or nitromethane. Can also be used mixtures of the mentioned solvents.

Bases which can be used for the described processes are the customary inorganic or organic bases. Preferred hydroxides of alkali metals such as sodium hydroxide or potassium hydroxide, hydroxides of alkaline-earth metals such as barium hydroxide, carbonates of alkali metals such as sodium carbonate or potassium carbonate, carbonates of alkaline-earth metals such as calcium carbonate or alcoholate of an alkaline or alkaline-earth metals, such as methylate sodium or potassium, utility sodium or potassium or tert-butyl potassium, or organic amines, for example, trialkyl-(C1-C6)-amines, such as triethylamine, or heterocyclic amines, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine, N-methylpiperidine or N-methylmorpholine. You can also use alkaline metals such as sodium, and the and their hydrides, such as sodium hydride. The aforesaid grounds, if necessary, can be used as auxiliary tools for connecting acid.

As agents of the combination can serve as a dehydrating reagents, for example carbodiimide, such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, or carbonyl compounds, such as carbonyldiimidazole or compounds 1,2-oxazole, such as 3-sulfonate 2-ethyl-5-phenylisoxazole or anhydride papapostolou acid or isobutylparaben or hexaphosphate benzothiazolinone-Tris(dimethylamino)phosphonium (THIEF) or diphenylimidazole or methansulfonate in the case of use in the presence of a base such as triethylamine or N-or N ethylmorpholine-metapopulation or diisopropylethylamine.

The following examples should serve to illustrate this invention, but they in no way limit it. The products obtained are given in the following tables 3 and 4.

Example C-01

Rat.-N-(6-isopropyl-4,5,6,6-tetrahydrobenzoic-2-yl)guanidine

To a solution of 2-bromo-4-isopropylcyclohexane (5 mmol) in ethanol (10 ml) under stirring was added 2-imino-4-taburet (5 mmol) and the reaction mixture is boiled for 16 hours with a reverse holodilniki is. After evaporation of the solvent the residue was mixed with ethyl acetate and the precipitated product was filtered: tRa 2.75 min (LC-1, single peak); ESI-MS (+/-): m/z 239,25 [M+H]+/ 237,24 [M-H]-.

2-Bromo-4-isopropylcyclohexane(starting material for example-01)

To a solution of 4-isopropylcyclohexane (5 mmol) in diethyl ether (10 ml) at room temperature was added dropwise bromine (5 mmol). After the addition, the reaction mixture continued to stir for 30 minutes After addition of a saturated aqueous solution of sodium sulfite (5 ml) was extracted with diethyl ether, the combined organic phase after drying over sodium sulfate, evaporated. Obtained as a crude product Bratton used in the next stage for reaction with 2-imino-4-tobirama without additional purification.

Similarly, to obtain example-01 based on relevant α-bromo - or α-chloroethanol received connection examples with C-02 to C-73, shown in table 3.

Bromination used in examples C-02 to C-17 ketone was carried out as described above to obtain 2-bromo-4-isopropylcyclohexane. Usually α-brometane used as crude products without additional parameters.

3-Butylcyclohexanone(intermediate for example-05)

A solution of copper iodide (6.3 m is ol) in dimethyl sulfide (12 ml) was cooled to 50° C. With stirring was added dropwise a solution of bullimia (6.2 mmol) and stirred for 5 to 15 minutes, the Reaction mixture was cooled to -78°and then was slowly added dropwise a pre-cooled to -78°With solution cyclohex-2-Aenon (6 mmol) in dimethyl sulfide (1 ml). After stirring for one hour at -78°extinguished With a saturated aqueous solution of horida ammonium. Warmed to room temperature, the reaction mixture was extracted with diethyl ether. The combined ether phases were washed with saturated aqueous solution of ammonium chloride and dried over sodium sulfate. After evaporation of the solvent, the obtained residue was made in hexane, the solution was filtered and evaporated. After chromatography was carried out of the residue on silica gel with a mixture of ethyl acetate/hexane 1:4 was obtained pure 3-butylamine (Tetrahedron 1989, 45 (2), 425-434).

2-Bromo-5-butylcyclohexanone(the original product for example-05)

Bromination of 3-butylcyclohexanone was performed similarly to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound in the form of crude product used without further purification.

2-tert-Butyl-6-chlorocyclohexane(starting material for example-07

To a cooled to 0°With the solution Diisopropylamine (5.5 mmol) in dry tetrahydrofuran was added on the aplam N-utillity. After the addition was cooled to -78°and made a solution of 2-tert-butylcyclohexanone (5 mmol) in dry tetrahydrofuran (50 ml), followed by addition of para-toluensulfonate (5 mmol), dissolved in dry tetrahydrofuran (50 ml). The reaction mixture was heated to room temperature and after stirring for 30 min, filtered through silica gel with simple ether as eluent. After evaporation in vacuum was obtained 2-tert-butyl-6-chlorocyclohexane (760 ml) to yield 81% (Tet. Lett. 1999, 40(12), 2231-2234).

4,4-Dimethylcyclohexanone(intermediate for example C-11)

A solution of 4,4-dimethylcyclohex-2-Aenon (3 mmol) in ethyl acetate was first made over night at room temperature over Pd/C (0.05 mmol) with hydrogen under normal pressure. Filtration through celite and the subsequent evaporation of the obtained 4,4-dimethylcyclohexanone (355 mg) with a yield of 94% (J. Org. Chem. 2001, 66 (3), 733-738).

2-Bromo-4,4-dimethylcyclohexanone(starting material for example C-11)

Bromination of 4,4-dimethylcyclohexanone was similar to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound in the form of crude product used without additional parameters.

2-sec-butyl-6-chlorocyclohexane(starting material for example C-18)

Chlorination of 2-second-butilka is hexanone was similar to that described above to obtain 2-tert-butyl-6-chlorocyclohexanone. Specified in the title compound in the form of crude product used without additional parameters.

3-Globallogic-1'-EN-2-he(starting material for example C-19)

Chlorination of 2-(1-cyclohexenyl)cyclohexanone was similar to that described above to obtain 2-tert-butyl-6-chlorocyclohexanone. Specified in the title compound in the form of crude product used without additional parameters.

2-Benzyl-6-chlorocyclohexane(starting material for example C-20)

Chlorination of 2-benzylchloride was similar to that described above to obtain 2-tert-butyl-6-chlorocyclohexanone. Specified in the title compound in the form of crude product used without additional parameters.

2-Allyl-6-chlorocyclohexane(starting material for example C-21

Chlorination of 2-allylcyclohexane was similar to that described above to obtain 2-tert-butyl-6-chlorocyclohexanone. Specified in the title compound in the form of crude product used without additional parameters.

2-Chloro-6-phenylcyclohexanone(starting material for example C-22)

Chlorination of 2-phenylcyclohexanone was similar to that described above to obtain 2-tert-butyl-6-chlorocyclohexanone. Specified in the title compound in the form of raw was productionvalue without additional parameters.

Ethyl ester of (3-chloro-2-oxocyclohexyl)acetic acid(the original product, for example C-23)

Chlorination of ethyl ether (2-oxocyclohexyl)acetic acid was similar to that described above to obtain 2-tert-butyl-6-chlorocyclohexanone. Specified in the header of the connection used in the form of a crude product without additional parameters.

3-(3-Chloro-2-oxocyclohexyl)propionitrile(the original product, for example C-24)

Chlorination of 2-oxo-1-cyclohexanecarbonitrile was similar to that described above to obtain 2-tert-butyl-6-chlorocyclohexanone. Specified in the title compound in the form of crude product used without additional parameters.

2-Chloro-6-methylcyclohexane(the original product for example-25)

Chlorination of 2-methylcyclohexanone series was similar to that described above to obtain 2-tert-butyl-6-chlorocyclohexanone. Specified in the title compound in the form of crude product used without additional parameters.

2.2-Dimethylcyclohexane(intermediate for example C-26)

A suspension of potassium hydride (5.5 mmol) and 2-methylcyclohexanone series (5 mmol) in dry tetrahydrofuran (10 ml) was stirred at room temperature for 30 minutes was Slowly added dropwise, triethylborane (at 6.25 mmol) and stirred at room is temperature for 16 hours. After the addition under the conditions was stirred for 8 hours, then the reaction is extinguished saturated aqueous ammonium chloride and was extracted twice with diethyl ether. The combined organic phases were dried over sodium sulfate, evaporated in vacuum to dryness and got mentioned in the title compound, which could be used further without additional purification (JACS 1985, 107, 19, 5391-5396).

6-Bromo-2,2-dimethylcyclohexanone(the original product, for example C-26)

Bromination of 2,2-dimethylcyclohexanone was similar to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound in the form of crude product used without additional parameters.

2-Ethyl-2-methylcyclohexane(intermediate for example C-27)

Alkylation of 2-methylcyclohexanone series by ethyliodide was similar to that described above to obtain 2,2-dimethylcyclohexanone.

6-Bromo-2-ethyl-2-methylcyclohexane(the original product, for example C-27)

Bromination of 2-ethyl-2-methylcyclohexanone series was similar to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound in the form of crude product used without additional parameters.

2-Isobutyl-2-methylcyclohexane(intermediate for example C-28)

Alkilirovan the s 2-methylcyclohexanone series 1-iodine-2-methylpropanol was similar to that described above to obtain 2,2-dimethylcyclohexanone.

6-Bromo-2-isobutyl-2-methylcyclohexane(the original product, for example C-28)

Bromination of 2-isobutyl-2-methylcyclohexanone series was similar to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound in the form of crude product used without additional parameters.

2-Methyl-2-propylcyclohexane(intermediate for example C-29)

Alkylation of 2-methylcyclohexanone series 1-iodopropane was similar to that described above to obtain 2,2-dimethylcyclohexanone.

6-Bromo-2-methyl-2-propylcyclohexane(the original product, for example C-29)

Bromination of 2-methyl-2-propylcyclohexanone was similar to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound in the form of crude product used without additional parameters.

Example-30

Ethyl ester of 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid

Similarly, to obtain example-01 ethyl ester 3-bromo-2-oxocyclohexanecarboxylic acid was converted to the specified in the title compound interaction with 2-imino-4-tobirama.

Ethyl ester of 3-bromo-2-oxocyclohexanecarboxylic acid(the original product for example-30)

Bromination of ethyl ester of 2-oxocyclohexanecarboxylic acid wire, and similarly described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound in the form of crude product used without additional parameters.

Guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid

A suspension of ethyl ester of 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid (5 mmol) and sodium hydroxide (20 mmol) in methanol/water (4:1, 10 ml) was stirred overnight at room temperature. Addition of 25%hydrochloric acid was established pH 5 and the precipitated product was filtered. By the above method has been specified in the title compound (671 mg) with a yield of 56%: TR0,64 min (LC-1); ESI-MS (+/-); m/z 241,49 [M+H]+/ 239,37 [M-H]-.

Example C-31

Benzylated 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid and formate

2-Guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid (0.1 mmol), diisopropylethylamine (0.2 mmol), hexaflurophosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (0.1 mmol) and benzylamine (0.2 mmol) was dissolved in dimethylformamide (0.5 ml) and was stirred over night at room temperature. After removal of the solvent in vacuo the residue was distributed in ethyl acetate (1 ml) and 1M aqueous caustic soda (0.5 ml). The phases were separated, the organic phase was dried over sodium sulfate, the solvent was evaporated and received net specified in the header of the connection using the drug the main HPLC (column Waters Prep LC, equipped with a Waters 600 Controller, Waters 2767 Sample Manager, Waters 996 mass spectrometer and photodiode array detector).

Analogously to example 31 was obtained compounds are shown in table 3 as examples with C-32 C-41, by reacting 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid with the appropriate amines in the presence of the agent combinations, such as hexaphosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea.

Example 42

Ethyl ester of 2-guanidino-4,5,6,7-tetrahydroindazole-6-carboxylic acid

Similarly, to obtain a sample s-1 conducted the reaction of the ethyl ester of 3-bromo-4-oxocyclohexanecarboxylic acid with 2-imino-4-tobirama education specified in the connection header.

Ethyl ester of 3-bromo-4-oxocyclohexanecarboxylic acid(the original product for example-42)

Bromination of ethyl ester of 4-oxocyclohexanecarboxylic acid was similar to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound in the form of crude product used without additional parameters.

2-Guanidino-4,5,6,7-tetrahydroindazole-6-carboxylic acid

Similarly, to obtain 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid ethyl ester 2-guanidino-4,5,6,7-tetrahydroindazole-6-carboxylic acid omilami d is specified in the connection header: t R2,49 min (LC-1); ESI-MS (+/-): m/z 241,04 [M+H]+/ 238,39 [M-2H]-.

Analogously to example C-31 the interaction of 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid with the appropriate amines in the presence of the agent combinations, such as hexaphosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylthiourea got connections, which are shown in table 3 as examples with C-43 C-46.

Example C-47

N-(tetrahydrobenzoic-2-yl-4-Spiro-cyclohexane)guanidine and its formate

Similarly, to obtain example-01 conducted the reaction of 2-bromo-Spiro[5.5]undecane-1-it with 2-imino-4-tobirama education specified in the connection header.

2-Bromo-Spiro[5.5]undecane-1-he(the original product for example a C-47)

Bromination Spiro[5.5]undecane-1-it was similar to the described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound in the form of crude product used without additional parameters.

Spiro[5.5]undecane-1-he(intermediate for example-47)

To a solution of cyclohexanone (5 mmol) and of potassium tert-butylate (10 mmol) in toluene (7.5 ml) were added dibromethane (5 mmol) and the reaction mixture is boiled under reflux for 48 hours. After cooling to room temperature was added 25%hydrochloric acid and was extracted with diethyl ether. Joint the United organic phases are dried over sodium sulfate, the solvent was removed in vacuo and the residue was chromatographically on silica gel (mixture of ethyl acetate/heptane, 1:5), (receiving) pure Spiro[5.5]undecane-1-he (Tetrahedron 1964, 20, 2553-2573): tR1,90 min (LC-2); ESI-MS (+): m/z 167,27 [M+H]+.

Example 48

N-(6-phenyl-4,5,6,7-tetrahydroindazole-2-yl-4-Spiro-cyclohexane)guanidine and its Hydrobromic salt

Specified in the title compounds were obtained on the basis of 4-phenyl-Spiro[5.5]undecane-1-she instead Spiro[5.5]undecane-1-it, similarly, N-(tetrahydrobenzoic-2-yl-4-Spiro-cyclohexane)guanidino.

4-Phenyl-Spiro[5.5]undecane-1-he(intermediate for example C-48)

Obtaining specified in the title compound was carried out as described above to obtain Spiro[5.5]undecane-1-it: tR1,92 min (LC-2); ESI-MS(+): m/z 243,36 [M+H]+.1H NMR (ppm, CDCl3): 7,3 (5H); 3,25 (1H); 2,8 (1H); 2,35 (1H); 2,2 (2H); 1,95 (3H); OF 1.75 (2H); OF 1.65 (2H); 1,4 (4H); 1,15 (1H).

4,4-diphenylsiloxane(intermediate for example-49)

Getting 4,4-diphenylsiloxane was performed similarly to that described above to obtain 4,4-dimethylcyclohexanone: tR3,68 min (LC-1); ESI-MS(-): m/z 249,00 [M-H]-.

2-Bromo-4,4-diphenylsiloxane(the original product for example-49)

Bromination of 4,4-diphenylsiloxane was similar to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound as crude product IP is was olovely without additional parameters.

Ethyl ester of 3-bromo-4-oxo-1-phenylcyclohexanecarboxylic acid(the original product for example-50)

Bromination of ethyl ester of 4-oxo-1-phenylcyclohexanecarboxylic acid was similar to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound in the form of crude product used without additional parameters.

3-Bromo-4-oxo-1-phenylcyclohexanecarboxylic(the original product for example-51)

Bromination of 4-oxo-1-penicillinsusceptible was similar to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound in the form of crude product used without additional parameters.

3-Bromo-4-arylcyclohexylamine(source products for examples with C-52 C-66)

Bromination of derivatives of 4-arylcyclohexylamine (intermediates for examples with C-52 C-66) was similar to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound in the form of crude product used without additional parameters.

Preparation of derivatives of 4-arylcyclohexylamine (intermediates for examples with C-54 C-66):

Ether 1,4-dioxaspiro[4.5]Dec-7-EN-8-intraformational acid

To a cooled to -78°With a solution of bis(trimethyl who ilil)lithium amide (1M in tetrahydrofuran, 1.1 mmol) in dry tetrahydrofuran was added 1,4-dioxaspiro[4.5]decane-8-he (1 mmol)dissolved in tetrahydrofuran (2 ml). Was stirred at -78°C for 1.5 hours and then was added dropwise a solution of N-phenyltrichlorosilane (1.07 mol) in tetrahydrofuran (2 ml). Then was stirred overnight at room temperature and then the solvent was removed in vacuum. After drying the residue in vacuum received the ether of 1,4-dioxaspiro[4.5]Dec-7-EN-8-intraformational acid, which is immediately used further without additional purification (Tetrahedron1999,55, 14479-14490):1H NMR (ppm, CDCl3): THE 5.65 (1H); 4 (4H); TO 2.55 (2H); 2,4 (2H); 1,9 (2H).

4-(4-Forfinal)cyclohexanone(intermediate for example-54)

a) 8-(4-forfinal)-1,4-dioxa-Spiro[4.5]Dec-7-EN:

In filled with argon, the flask was mixed 2M sodium carbonate (4.8 mmol), 1,2-dimethoxyethane (8 ml), 4-ftorhinolonovy acid (2.8 mmol), lithium chloride (6 mmol), ether of 1,4-dioxa-Spiro[4.5]Dec-7-EN-8-intraformational acid (2 mmol) and tetrakis(triphenylphosphine)palladium (0.1 mmol) and stirred at 80°With during the night. The reaction mixture was concentrated in vacuo and the residue was distributed in a mixture of dichloromethane/2M aqueous solution of sodium carbonate. The aqueous phase was extracted with dichloromethane. The combined organic phases are then dried over sodium sulfate and the solvent Privalov vacuum. From the residue after chromatography was carried out on a column of silica gel (a mixture of ethyl acetate/heptane 1:4) was isolated pure 8-(4-forfinal)-1,4-dioxa-Spiro[4.5]Dec-7-ene (Synthesis1993,735-762): tR3,61 min (LC-1); ESI-MS(+): m/z 235,34 [M+H]+.1H NMR (ppm, CDCl3): TO 7.35 (2H); 6,95 (2H); 5,9 (1H); OF 4.05 (4H); TO 2.65 (2H); OF 2.45 (2H); 1,9 (2H).

b) 8-(4-Forfinal)-1,4-dioxaspiro[4,5]Decan:

8-(4-Forfinal)-1,4-dioxa-Spiro[4,5]Dec-7-ene was first made with hydrogen over Pd/C. After filtering off the catalyst through celite and evaporation of the solvents was obtained 8-(4-forfinal)-1,4-dioxa-Spiro[4,5]decane with quantitative yield: tRthe 3.65 min (LC-1); ESI-MS(+): m/z 237,26 [M+H]+.

C) 4-(4-Forfinal)cyclohexanone:

8-(4-forfinal)-1,4-dioxa-Spiro[4,5]decane (2 mmol) was dissolved in dioxane (6.5 ml) and was treated with 3 ml of 50%aqueous sulfuric acid under stirring at room temperature for 5 hours. After dilution with water (12 ml) was twice acciaioli dichloromethane. From the combined organic phase after drying over sodium sulfate and evaporation of the solvent in vacuo got wet specified in the title compound (Tetrahedron1998, 54, 15509-15524): tR3,44 min (LC-1): ESI-MS(+): m/z 193,29 [M+H]+.

Obtaining intermediates for examples with C-55 C-66 was carried out similarly to the method described for 4-(4-forfinal)cyclohexanone.

4-ortho-Tollcollection(intermediate for example-55)

p> 1H NMR (ppm, CDCl3): 7,3 (2H); AND 7.1 (2H); 3.15 IN (1H); OF 2.45 (4H); 2,35 (3H); 2,1 (2H); 1.85 TO (2H); OF 1.65 (2H); 1,4 (4H); 1,15 (1H).

4-(2-Ethylphenyl)cyclohexanone(intermediate for example-56) tR3,62 min (LC-1); ESI-MS (+): m/z 203,29 [M+H]+.

4-(3,4-Acid)cyclohexanone(proproach for example-57)

tR3,43 min (LC-1); ESI-MS (+): m/z 235,28 [M+H]+.

4-(4-Cyanophenyl)cyclohexanone(intermediate for example-58)

tR1,92 min (LC-2); ESI-MS (+): m/z 200,33 [M+H]+.

4-(3,5-Bis-triptoreline)cyclohexanone(intermediate for example-59)

tRthe 2.46 min (LC-2); ESI-MS (+): m/z 311,29 [M+H]+.

4-pair-Tollcollection(intermediate for example-60)

tR2,11 min (LC-2); ESI-MS (+): m/z 189,32 [M+H]+.

4-meta Tollcollection(intermediate for example-61)

tR2,12 min (LC-2); ESI-MS (+): m/z 189,32 [M+H]+.

4-(3-Methoxyphenyl)cyclohexanone(intermediate for example-62)

tR2,08 min (LC-2); ESI-MS (+): m/z205,35 [M+H]+.

4-(4-Chlorophenyl)cyclohexanone(intermediate for example-63)

tRof 2.26 min (LC-2); ESI-MS (+): m/z 209,23 [M+H]+.

4-(3-Forfinal)cyclohexanone(intermediate for example-64)

tR2,11 min (LC-2); ESI-MS (+): m/z 193,26 [M+H]+.

4-Thiophene-2-illlogical(intermediate for example-65)

tR2,05 min (LC-2); ESI-MS (+): m/z 219,29 [M+H]+.

4-Benzo[1,3]dioxol-5-illlogical(paludi the product of example S-66)

tR2,05 min (LC-2); ESI-MS (+): m/z181,23 [M+H]+.

2-Bromo-5,5-dimethylcyclohexane(the original product for example-67);

2-Bromo-5-ethyl-5-methylcyclohexanone(the original product for example-64)

2-Bromo-5-methyl-5-phenylcyclohexane(the original product for example-69)

Bromination of 3,3-dimethylcyclohexanone, 3-ethyl-3-methylcyclohexanone series or 3-methyl-3-phenylcyclohexanone (intermediates for examples with C-67 C-69) was performed in a manner analogous to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the header of the compounds used as starting substances without additional parameters.

2-Bromo-5,5-dimethyl-4-phenylcyclohexanone(the original product for example-70)

Bromination of 3,3-dimethyl-4-phenylcyclohexanone carried out in a manner analogous to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound was used as the starting material without additional parameters.

3,3-Dimethyl-4-phenylcyclohexanone(intermediate for example-70)

The lithium chloride (0.6 mmol)and copper iodide (0.3 mmol) in argon atmosphere were made in dry tetrahydrofuran (18 ml). When 0°C was added 3-methyl-4-phenylcyclohexyl-2-northward (3 mmol) and continued stirring for 10 min at the same temperature. Then m is Glenna was added dropwise a solution of methylacrylamide (3.6 mmol) and the reaction mixture was stirred for 3 hours at 0° C. the Reaction was stopped by adding a saturated aqueous solution of ammonium chloride. The mixture was extracted with diethyl ether. From the combined organic phase after drying over sodium sulfate and evaporation of the solvent in vacuum has been specified in the header connection (J. Organom.Chem.1995,502, C5-C7): tRat 2.36 min (LC-2); ESI-MS (+): m/z 203,35 [M+H]+.

2-Bromo-3-methylcyclohexane(the original product for example-71)

A solution of N-bromosuccinimide (0.48 mmol) and sodium acetate (0.04 mmol) in a mixture of THF/water (1:1, and 5.2 ml) was cooled to 0°and dropwise added to trimethyl-(3-methylcyclohex-1 enyloxy)silane (0.4 mmol, 80%purity). The reaction mixture was left to warm to room temperature and continued stirring overnight. After addition of water were extracted with ethyl acetate. From the combined organic phase after drying over sodium sulfate and evaporation of the solvent in vacuum has been specified in the header connection (JOC1997,62, 19, 6692-6696).

Trimethyl-(3-methylcyclohex-1 enyloxy)silane(intermediate for example-71)

The lithium chloride (2 mmol) and copper iodide (1 mmol) in an argon atmosphere was introduced in tetrahydrofuran and cooled to -78°C. was Added cyclohex-2-Aenon (1 mmol), and trimethylsilane (1.1 mmol) and stirred solution for 10 minutes Then slowly added to cap the pits solution methylacrylamide (1.2 mmol). After stirring for 3 hours at -78°To these were added a saturated aqueous solution of ammonium chloride and was extracted with simple ether. The combined organic phase was dried over sodium sulfate and the solvent was removed in vacuum. The resulting crude product according to LC-MS contained 80% of trimethyl-(3-methylcyclohex-1 enyloxy)silane and 20% of the parent compound without further purification was used in subsequent reactions (J. Organom. Chem.1995, 502, C5-C7):1H NMR (ppm, CDCl3): 4,75(1H); 2,25(1H); 1,95(2H); OF 1.75(2H); 1,05(1H); OF 0.95 (3H); 0,2 (9H).

2-Bromo-6-phenylcyclohexanone(the original product, for example C-72)

Bromination of 3-phenylcyclohexanone carried out in a manner analogous to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the title compound used as an intermediate without further specification.

2-tert-Butyl-6-chloro-4-phenylcyclohexanone(the original product for example-73)

Chlorination of 2-tert-butyl-4-phenylcyclohexanone carried out in a manner analogous to that described above to obtain 2-tert-butyl-6-chloro-cyclohexanone. Specified in the header of the compound used as the raw product without additional parameters.

2-tert-Butyl-4-phenylcyclohexane(intermediate for example-73)

a) Trimethyl-(4-fenil logex-1 enyloxy)silane:

To a solution of 4-phenylcyclohexanone (10 mmol) in hexane (10 ml) was added dropwise at room temperature dissolved in acetonitrile (12,4 ml), sodium iodide (12.4 mmol) followed by addition of triethylamine (12.4 mmol) and trimethylchlorosilane (12.4 mmol). After stirring for two hours was added cold pentane and ice water. The aqueous phase was extracted with hexane. The combined organic phases are washed with ice water, dried over sodium sulfate and the solvent was removed in vacuum. Received net trimethyl-(4-phenylcyclohexyl-1 enyloxy)silane (1.8 g) with a yield of 73% (Tetrahedron1987, 43, 9, 2075-2088): tRto 2.29 min (LC-2); ESI-MS (+): m/z 247,27 [M+H]+.

b) 2-tert-Butyl-4-phenylcyclohexane:

Trimethyl-(4-phenylcyclohexyl-1 enyloxy)silane (7,27 mmol) and tert-butyl chloride (7.85 mmol) under nitrogen atmosphere were placed in dichloromethane and cooled to -45°C. was Added also cooled to -45°With a solution of titanium tetrachloride (7,63 mmol) in dichloromethane (3.6 ml) and continued stirring at the same temperature for 3 hours. The reaction mixture was diluted with dichloromethane and washed with ice water. The organic phase was dried over sodium sulfate and the solvent was removed in vacuum. Chromatographytandem residue on a column (a mixture of ethyl acetate/heptane) were obtained is indicated in the title compound (250 mg) with a yield of 15% (Angew Chem Int EdEng 1978, 17, 1, 48-49).1H NMR (ppm, CDCl3): TO 7.35 (5H); 3.15 IN (1H); TO 2.55 (1H); 2,4 (3H); 2,25 (1H); 2 (1H); 1.8 M (1H); OF 1.05 (9H).

Example N-01

Tert-Butyl ester 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid

Similarly, to obtain a sample s-1 conducted the reaction of tert-butyl ester 3-bromo-4-oxopiperidin-1-carboxylic acid with 2-imino-4-tobirama education specified in the connection header. tRto 2.55 min (LC-1); ESI-MS (+):m/z298,25 [M+H]+.

Tert-Butyl ester 3-bromo-4-oxopiperidin-1-carboxylic acid(the original product for example N-01)

Bromination tert-butyl ether 4-oxopiperidin-1-carboxylic acid was performed in a manner analogous to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the header of the compound used as the raw product without additional parameters.

N-(4,5,6,7-Tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine(cleavage of the protective groups of the product of example N-01,tert-butyl ester 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid)

Tert-butyl ether 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid (9.6 mmol) suspended in ethanol (10 ml) and concentrated hydrochloric acid (3.8 ml) and stirred at room temperature during the course the e 3 hours. After filtration by adding ethyl acetate to the transparent solution of ethyl acetate was besieging the product. The white precipitate was filtered, washed with ethyl acetate and then dried in vacuum. Received net specified in the title compound (1.63 g) in the form of the dihydrochloride with a yield of 62%: tR0,83 min (LC-1); ESI-MS (-): m/z 232,23 [M-H]-.

Example N-02

N-(5-Hexyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine

To a suspension of N-(4,5,6,7-tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine (0.1 mmol) and cesium carbonate (0.22 mmol) in dimethylformamide (0.3 ml) was added 1-bromhexin (0.11 mmol) and the reaction mixture was stirred at room temperature overnight. After addition of 2M sodium alkali (1 ml) the mixture was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate and then evaporated, thus obtaining specified in the title compound in pure form.

Analogously to example N-02 connection examples with N-03 N-10, which is shown in table 4, were obtained by interaction of N-(4,5,6,7-tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine with relevant alkylhalogenide ("R'-reagents").

Example N-07

N-(5-benzyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-c]azepin-2-yl)guanidine

By an alternative method as in example 1 carried out the reaction of 1-benzyl-4-bromazepam-3-one with 2-imino-4-tobirama with the formation of the decree is tion in the connection header.

1-Benzylation-3-one(intermediate for example N-07)

a) 5-(Benzenedicarbonitrile)pentane acid:

Ethyl ester of N-benzylglycine (1,87 ml) and ethyl ester of 5-bombalurina acid (1,92 ml) was dissolved in dimethylformamide (100 ml) and in the presence of potassium carbonate (1.66 g) was stirred for 2 days at room temperature. The reaction extinguished saturated aqueous ammonium chloride and was extracted with ethyl acetate. After drying over sodium sulfate the combined organic phase was evaporated. From the resulting residue by chromatographytandem on silica gel (mixture of ethyl acetate/heptane 1:5) were isolated 5-(benzenedicarbonitrile)pentane acid with 30%yield.

b) 1-Benzylation-3-one:

A suspension of potassium tert-butylate (336 mg) in toluene (2.5 ml) was boiled under reflux for 10 minutes and Then the suspension was slowly added

5-(benzenedicarbonitrile)pentane acid (695 mg) in toluene (1 ml) and after adding boiled for 1.5 hours. After cooling to room temperature was added 25%hydrochloric acid (1 ml). The organic phase was separated and washed with 25%hydrochloric acid (4×1 ml). United by means of hydrochloric acid of the aqueous phase is then boiled under reflux for 5 hours. After cooling to room temperature, R is the target were podlachian (to pH 11) 2n. soda lye and extracted with ethyl acetate. The combined organic phase after drying over sodium sulfate, evaporated. The obtained residue was chromatographically on silica gel (mixture of ethyl acetate/heptane 1:5) and received the desired specified in the title compound (197 mg) with a yield of 45% (Bull. Chem. Soc. Jpn.1956, 29, 631-632; patent DE 2206385).

1-Benzyl-4-bromazepam-3-one(the original product for example N-07)

Bromination of 1-benzylation-3-it was carried out in a manner analogous to that described above to obtain 2-bromo-4-isopropylcyclohexane. Specified in the header of the compound used as the raw product without additional parameters.

Example N-11

N-(Pentanoyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine

To a stirred suspension of the hydrochloride of N-(4,5,6,7-tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine (0.1 mmol) in dimethylformamide (0.7 ml) were added diisopropylethylamine (0.22 mmol) and then pentanoate (0.11 mmol) and the reaction mixture then was stirred for 16 hours at room temperature. After addition of 2M sodium alkali (1 ml) were extracted with ethyl acetate. The combined organic phase after drying over sodium sulfate and evaporation to dryness gave a clear specified in the header of the connection.

Analogously to example N-11 the interaction of N-(4,5,6,7-tetrahydropyrazolo[,4-c]pyridine-2-yl)guanidine with the corresponding acid anhydrides (R'-reagents") received connection examples with N-13 N-33, shown in table 4.

Example N-12

N-(5-but-3-enoyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine

To a stirred suspension of the hydrochloride of N-(4,5,6,7-tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine (0.1 mmol) in dimethylformamide (0.7 ml) was sequentially added diisopropylethylamine (0.22 mmol), vinyloxy acid (0.11 mmol) and hexaphosphate benzothiazolinone-Tris(dimethylamino)phosphonium (0.11 mmol) and the reaction mixture was stirred at room temperature for 16 hours. After addition of 2 M sodium alkali (1 ml) were extracted with ethyl acetate. From the combined organic phases after drying over sodium sulfate and evaporation to dryness received net specified in the header of the connection.

Analogously to example N-12 interaction of N-(4,5,6,7-tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine with the corresponding carboxylic acids (R'-reagents") in the presence of hexaflurophosphate benzothiazolinone-Tris(dimethylamino)phosphonium as agent combinations (received) connection examples with N-19 N-21, are shown in table 4.

Example N-22

Benzyl ether of 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid

To a stirred suspension of N-(4,5,6,7-tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine (0.1 mmol) and diisopropylethylamine (0.22 mmol) in dimethylformamide (0.7 ml) was added bansidhar Ormat and the mixture is then stirred for 3 hours at room temperature. After addition of saturated aqueous sodium carbonate solution was extracted with ethyl acetate; the combined organic phases after drying over sodium sulfate and complete evaporation of solvent received net specified in the header of the connection.

Analogously to example N-22 interaction of N-(4,5,6,7-tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine with butylchloroformate ("R'-reagent") received the compound of example N-23, are shown in table 4.

Example N-24

N-[5-(Propane-2-sulfonyl)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)]guanidine

To a stirred suspension of N-(4,5,6,7-tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine (0.1 mmol) and diisopropylethylamine (0.22 mmol) in dimethylformamide (0.7 ml) was added propan-2-sulphonylchloride and the mixture is then stirred for 16 hours at room temperature. After addition of 2 M sodium alkali (1 ml) were extracted with ethyl acetate; the combined organic phases after drying over sodium sulfate and complete evaporation of solvent received net specified in the header of the connection.

Analogously to example N-24 interaction of N-(4,5,6,7-tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine with relevant sulphonylchloride ("R'-reagents") received connection examples N-25 N-26, are shown in table 4.

Example N-27

Phenylamide 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-to benovoy acid

To a suspension of the dihydrochloride of N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-yl)guanidine (0.1 mmol) in dimethylformamide (0.5 ml) were added diisopropylethylamine (0.2 mmol) and after 5 min phenylisocyanate (0.11 mmol). The reaction mixture was stirred for 3 hours at room temperature. Then was added a saturated aqueous solution of sodium carbonate and was extracted with ethyl acetate. After drying the combined organic phases over sodium sulfate and removal of solvent in vacuo received net specified in the header of the connection.

Analogously to example N-27 the interaction of the dihydrochloride of N-(4,5,6,7-tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine with an ' R'-reagents" tert-utilitarianism or intilization received connection examples N-28 N-29, are shown in table 4.

Example N-30

Benzylated 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-thiocarbonic acid

Benzylamine (0.1 mmol)dissolved in dimethylformamide (0.3 ml)in an argon atmosphere was added to a solution of 1'-thiocarbonyldiimidazole (0.1 mmol) in dimethylformamide (0.5 ml). After stirring for 2.5 hours at room temperature to the reaction mixture was sequentially added a solution of dihydrochloride of N-(4,5,6,7-tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine (0.1 mmol) and diisopropylethylamine (0.2 mmol) in dimethylformamide. The mixture was stirred for another during the 16 hours at room temperature and then extinguished saturated aqueous sodium carbonate. Were extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate. After removal of solvents in vacuo received net specified in the header connection (Bioorg. Med. Chem, Lett. 2002, 12, 337-340).

Analogously to example N-30 by the interaction of the dihydrochloride of N-(4,5,6,7-tetrahydropyrazolo[5,4-c]pyridine-2-yl)guanidine with appropriate amines in the presence of 1'-thiocarbonyldiimidazole received connection examples with N-31 N-33, are shown in table 4.

Preparative LC-MS

Preparative separation of mixtures of substances produced by preparative system LC-MS (Waters Prep LC-MS, equipped with a regulator Waters 600, sampler Waters 2767, a mass spectrometer Waters 996 photodiode and a matrix detector). Used column Xterra Prep MS C18 (particle size 5 mm, length 50 mm, diameter 19 mm) with a linear gradient elution of water/0,06% formic acid (a) and acetonitrile/0.06% of formic acid (V) at a flow rate of 20 ml/min

Analytical methods

Spectra1H NMR was measured on the spectrometer Varian Oxford 300 at 300 K; the chemical shift δ in ppm is shifted towards the strong field from the signal tetramethylsilane given as a reference; as internal standard were used as signals residues deuterated dimethyl sulfoxide (δ (H) 2,49 ppm), deuterated chloroform (δ (H) of 7.24 ppm) and deuterium oxide.

Table 2

Data1H NMR for the selected soedinenii formula I
ExampleChemical shift in ppm (integral)Solvent
C-028 (4H); TO 2.65 (3H); TO 2.15 (1H); 1.85 TO (2H); 1,4 (1H); 1 (3H)DMSO-d6
C-056,8 (4H); 2,5 (4H); 2,05 (1H); OF 1.85 (1H); 1,65 (1H); 1,3 (6N), OF 0.95 (3H)DMSO-d6
C-066,8 (4H); 2,75 (1H); OF 2.45 (4H); 1.8 M (2H); TO 1.45 (2H); 1,2 (6N), OF 0.95 (3H)D2O
C-098,1 (4H); AND 7.3 (4H); 7,2 (1H); 2.95 AND (2N); A 2.75 (3H); 2 (3H)DMSO-d6
C-127 (4H); 2,75 (1H); 2,45 (1H); 2,25 (1H); 1.55V (1H); 1,15 (1H); 1,1 (3H); 1 (3H); 0,85 (3H)DMSO-d6
C-24of 8.3 (4H); TO 7.4 (5H); 4,35 (2H); 4.25 IN (2N); 3,55 (2H); 2,9 (2H); 2,1 (2N)DMSO-d6
C-388,1 (1H); THE 7.65 (1H); 6,9 (4H); 3,5 (1H); 3,3 (1H); 1,95-1,5 (10H); 1,15 (5H)DMSO-d6
S-428,1 (4H); TO 4.1 (2H); 2,85 (3H); TO 2.65 (2H); 2,1 (1H); OF 1.85 (1H); TO 1.15 (3H)DMSO-d6
C-508,1 (4H); AND 7.3 (5H); OF 4.05 (2H); OF 3.45 (1H); 3,1 (1H); TO 2.65 (1H); 2,4 (3H); OF 1.05 (3H)DMSO-d6
C-548,1 (4H); 7,35 (2N); AND 7.1 (2H); 3 (2H); 2,7 (3H); 2 (2N)DMSO-d6
C-578,1 (4H); 6,85 (3H); 3.75 TO 3H); of 3.7 (3H); 2.95 AND (2N); 2,7 (3H); 2 (2N)DMSO-d6
C-712,8 (1H); 2,5 (2H); 1.85 TO (2H); 1,6 (1H); 1,3 (1H); TO 1.15 (3H)CDCl3
N-07of 8.3 (4H); TO 7.4 (5H); 4,35 (2H); 4.25 IN (2N); 3,55 (2H); 2,9 (2H); 2.05 IS (2N)D2O
N-086,8 (4H); 3,05 (2N); 3 (2H); 2,7 (3H); 2,5 (2N)DMSO-d6
N-136,8 (4H); 4.5 M (2H); 3.75 TO (2H); 2.95 AND (1H); 2,6 (1H); 2,5 (1H); 1 (6N)DMSO-d6
N-22of 7.3 (5H); 6,8 (4H); 5,1 (2H); OF 4.45 (2H); 3,7 (2H); 2,55 (2N)DMSO-d6
N-267 (4H); 4,2 (2H); TO 3.45 (2H); 2,9 (3H); 2,65 (2N)DMSO-d6
N-296,8 (4H); 6,55 (1H); 4,3 (2H); 3,6 (2H); 3 (2H); 2,5 (2H); 1,4 (2H); 1,25 (4H); 0,85 (3H)DMSO-d6
N-308,35 (1H); TO 7.25 (5H); 6,8 (4H); 4,85 (2N); AND 4.8 (2H); TO 4.1 (2H); 2,6 (2N)DMSO-d6

The obtained compounds were analyzed by reversed-phase HPLC using column Waters Alliance LC, equipped with a UV detector and a mass spectrometer MassLynx NT.

LC-1: column HPLC GROM-SIL 120 ODS-4 (particle size 3 μm, the column length 30 mm, diameter 2 mm) with a linear gradient elution of water/0,06% formic acid (a) and acetonitrile/0.06% of formic acid (B)from 5% to 95% b for 3 min, at a flow rate of 0.75 ml/min

LC-2: column HPLC XTrra MS C18 (particle size 5 μm, the column length 50 mm, diameter 2.1 mm) with a linear gradient elution of water/0,06% formic acid (a) and acetonitrile/0.06% of formic acid (B)from 5% to 95% In 2.5 min, at a flow rate of 0.75 ml/min

Table 3< / br>
Analytical data for examples C01 C-73
When-MerStructureNameSource< / br>
product
Total formula< / br>
Molecular mass
tR[min] (method< / br>
HPLC)
Data< / br>
MS m/z< / br>
[M+H]+/< / br>
[M-H]-
C-01N-(6-isopropyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine4-isopropyl-cyclohexanoneWith11H18N4S

238,4
2,75

(LC-1)
239,25/237,24
C-02N-(5-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine3-methyl-cyclohexanoneWith9H14N4S

210,3
2,86 (LC-1)211,25/209,26
C-03N-(6-propyl-4,5,6,7-t is trihydrobromide-2-yl)guanidine 4-n-propyl-cyclohexanoneWith11H18N4S

238,4
2,79 (LC-1)239,2/237,27
C-04N-(6-tert-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine4-tert-butyl-cyclohexanoneWith12H20N4S

252,4
3,06 (LC-1)253,28/251,36
C-05N-(5-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine3-butyl-cyclohexanoneWith12H20N4S

252,4
3,19 (LC-1)253,31/251,32
C-06N-(5-butyl-5,6,7,8-tetrahydro-4H-cyclohepta-thiazol-2-yl)guanidine3-butyl-CycloheptaneWith13H22N4S

266,4
3,2

(LC-1)
267,35/265,36
C-07N-(4-tert-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine2-tert-butyl-cyclohexanoneWith12H20N4S

252,4
3,51 (LC-1)253,37/251,45
C-08N-[6-(1,1-dimethyl-propyl)4,5,6,7-tetrahydroindazole-2-yl]guanidine 4-tert-amyl-cyclohexanoneWith13H22N4S

266,4
2,82 (LC-1)267,24/265,36
C-09N-(6-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine4-phenyl-cyclohexanoneWith14H16N4S

272,4
2,74 (LC-1)273,20/271,30
C-10N-(6-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine4-methyl-cyclohexanoneWith9H14N4S

210,3
2,7

(LC-1)
211,24/209,19
C-11N-(6,6-dimethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine4,4-dimethyl-cyclohexanoneWith10H16N4S

224,3
3,28 (LC-1)225,36/223,37
C-12N-(5,5,7-trimethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine3,3,5-trimethyl-cyclohexanoneWith11H18N4S

238,4
3,34 (LC-1)239,33/237,36
C-13N-(5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzo the evils-2-yl)guanidine 3,3,5,5-tetramethyl-cyclohexanoneWith12H20N4S

252,4
2,73 (LC-1)253,21/251,26
C-14N-(5,6-dihydro-4H-cyclopentadiene-2-yl)guanidineCyclopentanoneWith7H10N4S

of 182.2
2,83 (LC-1)183,31/181,32
C-15N-(4,5,6,7-tetrahydroindazole-2-yl)guanidineCyclohexanoneWith8H12N4S

196,3
2,75 (LC-1)197,22/195,34
C-16N-(5,6,7,8-tetrahydro-4H-cycloheptatrien-2-yl)guanidineCycloheptaneWith9H14N4S

210,3
2,89 (LC-1)211,25/209,26
C-17N-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)guanidineTetrahydropyran-4-oneWith7H10N4OS

198,2
1,76 (LC-1)199,27/197,31
C-18Formate N-(4-sec-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine2-Deut-bucilla-GE is Canon With13H22N4O2S

298,4
3,09 (LC-1)253,28/251,36
C-19Formate N-(4-cyclohex-1-enyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine2-(1-cyclo-hexenyl)-cyclohexanoneWith15H22N4O2S

322,4
3,13 (LC-1)277,25/275,39
C-20Formate N-(4-benzyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine2-benzyl-cyclohexanoneWith16H20N4O2S

332,4
3,09 (LC-1)287,25/285,27
C-21Formate N-(4-allyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine2-allyl-cyclohexanoneWith12H18N4O2S

of 282.3
to 2.99

(LC-1)
237,26/235,71
S-22Formate N-(4-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine2-phenyl-cyclohexanoneWith15H18N4O2S

318,4
3,05 (LC-1)273,66
S-23Ormat ethyl ether (2-guanidino-4,5,6,7-tetrahydroindazole-4-yl)-acetic acid Ethyl-(2-oxo-cyclohexyl)acetateWith13H20N4O4S

328,4
1,54 (LC-1)283,08
S-24Formate N-[4-(2-cyanoethyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine2-oxo-1-cyclohexane-propionitrileWith12H17N5O2S

295,3
2,81 (LC-1)250,08
C-25< / br>
Formate N-(4-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine2-methyl-cyclohexanoneWith10H16N4O2S

256,3
2,87 (LC-1)211,33
C-26N-(4,4-dimethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine2,2-dimethyl-cyclohexanoneWith10H16N4S

224,3
2,95 (LC-1)225,92
C-27N-(4-ethyl-4-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine2-ethyl-2-methylcyclohexaneWith11H18N4S

238,3
2,99 (LC-1)239,7
C-28 N-(4-isobutyl-4-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine2-isobutyl-2-methyl-cyclohexanoneWith13H22N4S

266,4
3,11 (LC-1)267
S-29N-(4-methyl-4-propyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine2-methyl-2-propyl-cyclohexanoneWith12H20N4S

252,4
3,07 (LC-1)253,67
S-30The ethyl ester hydrobromide 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acidEthyl ester of 2-oxo-cyclohexane-carboxylic acidWith11H17BrN4O2S 349,21,54 (LC-2)269,01/267,22
C-31Formate of benzylamine 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acidWith17H21N5O3S

375,4
1,45 (LC-2)330,26/328,16
C-32Formate of allylamine 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acidWith13H19N5O3S

325,4
1,18 (LC-2)280,18/278,18
C-33Formate (3-IU-terbutyl)amide 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acidWith15H25N5O3S

355,5
1,43 (LC-2)310,27/308,23
C-34Formate of propylamide 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid2-guanidino-4,5,6,7-tetrahydrobenzo-thiazole-4-carboxylic acidWith13H21N5O3S

327,4
1,25 (LC-2)282,19/280,21
C-35Formate of phenylamide 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acidWith16H19N5O3S

361,4
1.44MB (LC-2)316,19/314,15
C-36Formate di-Isopropylamine 2-guanidino-4,5,6,tetrahydrobenzoic-4-carboxylic acid 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acidWith16H27N5O3S

369,488
1,53 (LC-2)324,15/n.a.
S-37Formate of dipropylamine 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acidWith16H27N5O3S

369,5
1,53 (LC-2)324,28/322,24
C-38Formate N-[4-(piperidine-1-carbonyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acidWith15H23N5O3S

353,4
1,37 (LC-2)308,29/306,26
S-39Formate of methylphenethylamine 2-guanidino-4,5,6,7-tetrahydroindazole-4-carboxylic acid2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acidWith19H25N5O3S

403,5
1.55V (LC-2)358,22/356,25
S-40Formate of butylacrylamide 2-guanidino-4,5,6,7-tet is ierobezotiba-4-carboxylic acid 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acidWith16H27N5O3S

369,5
1,51 (LC-2)324,28/322,24
S-41Formate N-[(4-morpholine-4-carbonyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acidWith14H21N5O4S

355,4
1,21 (LC-2)310,20/308,23
S-42The ethyl ester hydrobromide 2-guanidino-4,5,6,7-tetrahydroindazole-6-carboxylic acidEthyl ester of 4-oxo-cyclohexane-carboxylic acidWith11H17BrN4O2S 349,2was 2.76 (LC-1)270,59/266,22
C-43Formate of allylamine 2-guanidino-4,5,6,7-tetrahydroindazole-6-carboxylic acid2-guanidino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acidWith13H19N5O3S

325,4
1,2

(LC-2)
280,15/278,18
C-44Formate (3-methyl-butyl)amide 2-guanidino-4,5,6,7-tetrahydro isothiazol-6-carboxylic acid 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acidWith15H25N5O3S

355,5
1,46 (LC-2)310,33/308,29
C-45Formate of propylamide 2-guanidino-4,5,6,7-tetrahydroindazole-6-carboxylic acid2-guanidino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acidWith13H21N5O3S

327,4
1.27mm (LC-2)282,12
C-46Formate of phenylamide 2-guanidino-4,5,6,7-tetrahydroindazole-6-carboxylic acid2-guanidino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acidWith16H19N5O3S

361,4
1,46 (LC-2)316,25/314,15
C-47N-(tetrahydrobenzoic-2-yl-4-Spiro-cyclohexane)guanidineSpiro[5.5]-undecane-1-heWith13H20N4S

264,4
1,69 (LC-2)265,63/263,24
C-48The hydrobromide of N-(6-phenyl-4,5,6,7-tetrahydroindazole-2-yl-4-spirocyclohexane)-guanidine4-phenyl-Spiro[5.5]-undecane-1-he With19H25BrN4S

421,4
1,85 (LC-2)341,54/339,24
C-49Formate N-(6,6-diphenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine4,4-diphenyl-cyclohexanoneWith21H22N4O2S

394,5
3.15 in (LC-1)349,24/347,44
C-50Formate, ethyl ester 2-guanidino-6-phenyl-4,5,6,7-tetrahydroindazole-6-carboxylic acidEthyl ester of 4-oxo-1-phenyl-cyclohexane-carboxylic acidWith18H22N4O4S

390,5
1,75 (LC-2)345,36
C-51The hydrobromide of N-(6-cyano-6-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine4-cyano-4-phenylcyclohexanoneWith15H16BrN5S

378,3
2,92 (LC-1)298,1/295,97
C-52The hydrobromide of N-[6-(4-methoxyphenyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine4-(4-methoxyphenyl)-

cyclohexanone
With15H19BrN4OS

383,3
3,0

(LC-1)
303,25/301,26
C-53The hydrobromide of N-[6-(4-benzyloxy-phenyl)-4,5,6,7-tetrahydrobenzo-thiazol-2-yl]guanidine4-(4-benzyloxyphenyl)-cyclohexanoneWith21H23BrN4OS 459,43,24

(LC-1)
379,26
C-54The hydrobromide of N-[6-(4-forfinal)-4,5,6,7-tetrahydroindazole-2-yl]guanidine4-(4-forfinal)-cyclohexanoneWith14H16BrFN4S

371,3
3.04 from

(LC-2)
291,26/289,33
C-55formate N-(6-ortho-tolyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine4-ortho-tolyl-cyclohexanoneWith16H20N4O2S

332,4
3,42

(LC-2)
286,25
C-56formate N-[6-(2-ethylphenyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine4-(2-ethylphenyl)-cyclohexanoneWith17H22N4O2S

346,4
3,13

(LC-2)
301,33/299,4
C-57formate N-[6-(3,4-acid)-4,5,6,7-tetrahydroindazole-2-yl]Guan is Dina 4-(3,4-acid)-cyclohexanoneWith17H22N4O4S

378,4
3,44 (LC-2)333,2
C-58formate N-[6-(4-cyanophenyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine4-(4-oxo-cyclohexyl)-

benzonitrile
With16H17N5O2S

343,4
1,59 (LC-2)298,17/296,26
C-59formate N-[6-(3,5-bis-triptoreline)-4,5,6,7-tetrahydrobenzo-thiazol-2-yl]guanidine4-(3,5-bis-triptoreline)-

cyclohexanone
With17H16F6N4O2S

454,4
1,88 (LC-2)408,99/407,15
C-60formate N-(6-para-tolyl-4,5,6,7-tetrahydrobenzo-thiazol-2-yl)guanidine4-pair-Talyzina-hexanonWith16H20N4O2S

332,4
1,68 (LC-2)287,15
C-61formate N-(6-meta-tolyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine3-meta-Talyzina-hexanonWith16H20N4O2S

332,4
1,73 (LC-2)287,22
C-62formate N-[6-(3-methoxyphenyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine4-(3-methoxyphenyl)-cyclohexanoneWith16H20N4O3S

348,4
1,73 (LC-2)303,2/301,35
C-63formate N-[6-(4-chlorophenyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine4-(4-chlorophenyl)-cyclohexanoneWith15H17ClN4O2S of 352.81,85 (LC-2)307,15/305,13
C-64formate N-[6-(3-forfinal)-4,5,6,7-tetrahydroindazole-2-yl]guanidine4-(3-forfinal)-cyclohexanoneWith15H17FN4O2S

336,4
1.55V (LC-2)290,91/289,25
C-65formate N-(6-thiophene-2-yl-4,5,6,7-tetrahydroindazole-2-yl)guanidine4-thiophene-2-yl-cyclohexanoneWith13H16N4O2S2< / br>
324,4
1,61 (LC-2)279,13/277,22
C-66formate N-(6-benzo[1,3]di-oxol-5-yl-4,5,6,7-Tetra is hydrobenzoin-2-yl)guanidine 4-benzo[1,3]-dioxol-5-yl-cyclohexanoneWith16H18N4O4S

362,4
1,66 (LC-2)317,02
C-67formate, N-(5,5-dimethyl-4,5,6,7-tetrahydrobenzo-thiazol-2-yl)guanidine3,3-dimethyl-cyclohexanoneWith11H18N4O2S

270,3
2,92 (LC-2)225,34
C-68formate N-(5-ethyl-5-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine3-ethyl-3-methylcyclohexaneWith12H20N4O2S

284,4
2,97 (LC-1)239,25/USD 237.2
C-69formate N-(5-methyl-5-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine3-methyl-3-phenylcyclohexanoneWith16H20N4O2S

332,4
3,01 (LC-2)286,45
C-70formate, N-(5,5-dimethyl-6-phenyl-4,5,6,7-Tetra-hydrobenzoin-2-yl)guanidine3,3-dimethyl-4-phenylcyclohexanoneWith17H22N4O2S

346,4
1,85 (LC-2)301,33/299,35
formate N-(7-methyl-4,5,6,7-Tetra-hydrobenzoin-2-yl)guanidine2-bromo-3-methylcyclohexaneWith10H16N4O2S

256,3
2,84 (LC-2)211,24
C-72the hydrobromide of N-(5-phenyl-5,6,7,8-tetrahydro-4H-cycloheptatrien-2-yl]-guanidine2-bromo-6-phenylcyclohexanoneWith15H19BrN4S

367,3
3,05 (LC-2)287,34/285,42
C-73N-(4-tert-butyl-6-phenyl-4,5,6,7-tetrahydroindazole-2-yl]guanidine2-tert-butyl-6-chloro-4-phenylcyclohexanoneWith18H24N4S

328,5
1,85 (LC-2)329,25/327,27

With12H19N5O2S

297,4
Table 4< / br>
Analytical data for the samples with N-01 N-33
When-< / br>
measures
StructureNameR'-reagentTotal formula Molecular masstR[min]< / br>
(HPLC< / br>
method)
Data< / br>
MSm/z[M+H]+/ [M-H]
N-01Tert-butyl ester 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acidWith12H19N5O2S

297,4
2,88 (LC-1)298,22/296,29
N-02N-(5-hexyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine1 bromhexinWith13H23N5S

281,4
0,94 (LC-1)282,18/280,33
N-03N-(5-propyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine1-bromopropaneWith10H17N5S

239,3
0,85 (LC-1)240,18/238,31
N-04N-[5-(2-cyclohexyl-ethyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine(2-bromacil)-cyclohexaneWith15H25N5S

307,5
0,95 (LC-1)308,28/306,42
N-05N-(5-cyclopropylmethyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidineBromelicolaWith11H17Nsub> 5S

251,3
0,86 (LC-1)252,16/250,25
N-06N-(5-benzyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidineBenzylbromideWith14H17N5S

287,4
2,67 (LC-1)288,22/286,16
N-07N-(5-benzyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-c]azepin-2-yl)guanidineBenzylbromideWith15H19N5S

301,4
0,9

(LC-1)
302,12/300,02
N-08N-(5-prop-2-inyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidinePropylbromideWith10H13N5S

235,3
0,83 (LC-1)236,16/234,25
N-09N-(5-ethyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidine1-bromatanWith9H15N5S

225,3
0,86 (LC-1)226,20/227,07
N-10Ethyl ester of 3-(2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-yl)propionic acidEthyl-3-bromopropionate0,84 (LC-1)298,18/296,35
N-11N-(5-pentanoyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidinePentonvilleWith12H19N5OS

281,4
2,46 (LC-1)282,21/280,32
N-12N-(5-but-3-enoyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidineFeniluksousna acidWith11H15N5OS

265,3
0,82 (LC-1)266,21/264,29
N-13N-(5-isobutyryl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidineIsobutyrateWith11H17N5OS

267,3
0,81 (LC-1)268,20/266,32
N-14N-[5-(2-propyl-pentanoyl)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine2-propylpentanoic-chlorideWith15H25N5OS

323,5
2,56 (LC-1)324,28/322,31
N-15N-[5(-2,2-dimethyl-propionyl)-4,5,6,7-tetrahydrate the olo[5,4-c]pyridine-2-yl]guanidine 2,2-dimethyl-propionateWith12H19N5OS

281,4
2,47 (LC-1)282,18/280,31
N-16N-(5-cyclopropane-carbonyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidineCyclopropanecarbonyl-chlorideWith11H15N5OS

265,3
0,82 (LC-1)266,19/264,24
N-17N-[5-(3-methylbutyryl)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine3-methyl-butyrylcholineWith12H19N5OS

281,4
0,83 (LC-1)282,25/280,33
N-18N-(5-phenylacetyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidinePhenylacetyleneWith15H17N5OS

315,4
2,49 (LC-1)316,15/314,25
N-19N-[5-(2-methoxyacetyl)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidineMethoxy-acetic acidWith10H15N5O2S

269,3
0,83 (LC-1)270,20/268,34
N-20 Tert-butyl ether [3-(2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-yl)-3-oxopropyl]carbamino acidBOC-beta-alanineWith15H24N6O3S

368,5
0,81 (LC-1)369,13/367,27
N-21N-[5-(4-dimethyl-aminobutyryl)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine4-dimethyl-aminobutyric acidWith13H22N6OS

310,4
0,82 (LC-1)311,16/309,15
N-22Benzyl ether of 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acidBenzylchlorideWith15H17N5O2S

331,4
2,7

(LC-1)
332,17/330,24
N-23Butyl ether 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acidButylchloroformateWith12H19N5O2S

297,4
2,67 (LC-1)298,25/296,28
N-24N-[5-(propane-2-sulfonyl)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine2-propanesulfonyl-chloride With10H17N5O2S2< / br>
303,4
0,81 (LC-1)304,08/302,25
N-25N-[5-(butane-1-sulfonyl)-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl]guanidine1-butanesulfonyl-chlorideWith11H19N5O2S2< / br>
317,4
0,84 (LC-1)318,11/316,28
N-26N-(5-methanesulfonyl-4,5,6,7-tetrahydrothieno[5,4-c]pyridine-2-yl)guanidineMethanesulfonanilideWith8H13N5O2S2< / br>
275,3
0,83 (LC-1)276,11/274,25
N-27Phenylamide 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acidPhenylisocyanateWith14H16N6OS

316,4
was 2.76 (LC-1)317,19/315,33
N-28Tert-butylamide 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acidTert-utilitzantWith12H20N6OS

usd296.4
2,73 (LC-1)297,25/295,4
N-29Pencilled 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acidIntilizationWith13H22N6OS

310,4
2,81 (LC-1)311,23/309,37
N-30Benzylated 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-thiocarbonic acidBenzylamineWith15H18N6S2< / br>
346,5
2.91 in (LC-1)346,82/345,09
N-31Isopropylated 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-thiocarbonic acidIsopropylamineWith11H18N6S2< / br>
298,4
2,94 (LC-1)298,86/296,29
N-32Propelled 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-thiocarbonic acidPropylamineWith11H18N6S2< / br>
298,4
2,78 (LC-1)299,11/291,7
N-33(2-methoxy-1-methylethyl)amide 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-thiocarbonic acid2-amino-1-IU is oxypropane With12H20N6OS2< / br>
328,4
2,72 (LC-1)329,38/326,93

1. The compound of General formula II

where And with thiazole ring forms 4,5,6,7-tetrahydroindazole, 5,6,7,8-tetrahydro-4H-cycloheptatriene, 5,6-dihydro-4H-cyclopentadienyl fragments;

R1represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1,1-dimethylpropyl or phenyl;

R2-R6each represent hydrogen or methyl;

or pharmaceutically acceptable acid additive salts of basic compounds of formula II.

2. The compounds of formula II according to claim 1 or a pharmaceutically acceptable acid additive salts of basic compounds of formula II, selected from the group consisting of

N-(5-ethyl-5-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(5,5-dimethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(5,5-dimethyl-6-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(4-tert-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(6-isopropyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(5,5,7-trimethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(6,6-dimethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(5-butyl-5,6,7,8-tetrahydro-4H-cycloheptatrien-2-yl)guanidine;

N-(4-ethyl-4-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(5-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(6-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(5-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(4-methyl-4-propyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(6-propyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(4-sec-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate; and

N-(4-isobutyl-4-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine.

3. The compounds of formula II according to claim 1 or a pharmaceutically acceptable acid additive salts of basic compounds of formula II, selected from the group consisting of

N-(6-tert-butyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-[6-(1,1-dimethylpropyl)-4,5,6,7-tetrahydroindazole-2-yl]guanidine;

N-(7-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(5,5,7,7-tetramethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(4,4-dimethyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine;

N-(4-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate;

N-(5,6,7,8-tetrahydro-4H-cycloheptatrien-2-yl)guanidine;

N-(6-methyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate; and N-(4-phenyl-4,5,7-tetrahydrobenzoic-2-yl)guanidine and its formate.

4. The compounds of formula II according to claim 1 or a pharmaceutically acceptable acid additive salts of basic compounds of formula II, selected from the group consisting of

N-(5-phenyl-5,6,7,8-tetrahydro-4H-cycloheptatrien-2-yl)guanidine and its hydrobromide;

N-(5-methyl-5-phenyl-4,5,6,7-tetrahydroindazole-2-yl)guanidine and its formate.

5. The drug, which has antagonistic activity against receptor neuropeptide FF, containing the compound of formula II according to claim 1 or a pharmaceutically acceptable acid additive salts of basic compounds of formula II and an inert carrier.

6. The use of the compounds of formula II according to claim 1 or a pharmaceutically acceptable acid additive salts of basic compounds of formula II to obtain drugs for the treatment of pain and hyperalgesia, urinary incontinence, to eliminate syndromes that occur when alcohol, psychotropic and nicotine dependency, to regulate the release of insulin, digestion, memory function, blood pressure or electrolyte and energy metabolism.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention was targeted at obtaining crystals of acetonitrile solvate of 6-fluor-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (compound B), which is an intermediate compound in obtaining crystals of 6-fluor-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid of III type (compound A). Compound B crystals are mostly precipitated by regulation of super-saturation during crystallisation involving acetonitrile as a solvent. Then compound A crystals of III type are obtained crystal desolvation.

EFFECT: increased efficiency of compounds.

6 cl, 4 dwg, 4 tbl, 4 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

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), -(CH2)3-, -(CH2)4-, -CH2-S-CH2-, -S-CH2-CH2-; R2 is chosen from group consisting of nitrogen (N), sulfur (S) atom; n = 0 or 1; Z is chosen from group consisting of (C2-C10)-alkyl; R3 is chosen from group consisting of H; m = 0-2; R4 is chosen from group consisting of oxygen atom (O), -CH2-; R5 is chosen from group consisting of the following groups:

wherein R6 is chosen from group consisting of H, alkyl-(C1-C5)-alkoxyl; W is chosen from group consisting of -NH wherein each "alkyl" can be linear or branched and can be also cyclic or linear, or branched and comprises such cyclic residues, and each "aryl" comprises monocyclic aromatic group comprising 5-12 carbon atoms bound with one or some heteroatoms chosen from N, O or S atoms, and to their salts and solvates. Also, invention relates to a pharmaceutical composition, to a method for their synthesis and using compounds by claims 1-6. Invention provides synthesis of novel active compounds and pharmaceutical compositions based on thereof that possess affinity to serotonin receptors of subtype 5-HT1A.

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

10 cl, 4 tbl, 26 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention proposes use of 2-amino-7-bromo-4-acetylazo[5,4-b]indol depicted by formula: against hyperbaric and hematic hypoxia and protection of liver against carbon tetrachloride poisoning. Use of this compound reduces concentration of AlAT by a factor of 2.6 and that of AcAT by a factor of 1.67.

EFFECT: increased therapeutic activity.

3 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the formula (I): and their salts, to methods for their preparing, compositions containing thereof and their using in medicine, in particular, for prophylaxis or treatment of clinical state wherein a selective agonist of β2-adrenoceptors is prescribed.

EFFECT: valuable medicinal properties of compound and compositions.

32 cl, 4 dwg, 82 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new compounds of formula I , or stereoisomers, or pharmaceutically acceptable salts thereof, wherein Q is SO2; n = 2 or 3; each R1 and R2 is independently H, halogen, OR22 or C1-C6-alkyl; each R3 and R4 is H; each R5 and R6 is independently H or C1-C6-alkyl optionally substituted with phenyl or R5 and R6 together with together with atom to which they are attached may form 5-7-membered ring optionally containing N as the second heteroatom optionally substituted with COOH or C1-C6-alkyl; R7 is H; R7 is optionally substituted 8013-membered bicyclic or tricyclic ring system, containing N in bridge bond and optionally 1, 2 additional heteroatoms selected from N, S wherein substituent represent 1 or 2 halogen atoms; R22 is H or C1-C6-phenyl optionally substituted with C1-C6-alkyl. Compounds of present invention specifically bond to 5-HT6 receptor and are useful in pharmaceutical compositions.

EFFECT: compounds with specific bonding to 5-HT6 receptor.

10 cl, 3 tbl, 45 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula I and pharmaceutically acceptable salt thereof, wherein R1, R3, R4, R5, and R10 are independently H, halogen, C1-C4-alkyl, etc.; R2 is H, halogen, NO2, etc.; R6 is H, C1-C6-alkyl, C1-C6-alkoxy-substituted C1-C4-alkyl, etc.; R7 is H, C1-C4-alkyl or C2-C4-alkenyl, optionally substituted with halogen; R8 and R9 are H, R11 and R12; meanings of the rest substituents are as define in specification.

EFFECT: new compounds with value biological properties and useful as drug having activity in relates to progesterone receptor.

15 cl, 3 tbl, 80 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to bicyclic 1,4-piridotiazine-1,1-dioxides of general formula I wherein R1 is chlorine or fluorine; R2 is linear or branched alkyl, cycloalkyl, optionally reduced aryl or heteroaryl, etc. Method for production of said compounds includes reaction of acyclic sulfones with primary alcohols, preferably in presence of inorganic or organic such as carbonates or alkali metal hydroxides tertiary organic amines or base mixtures, preferably in aprotic bipolar media without solvents, or mixture thereof with water.

EFFECT: safe method for production of new compounds useful as drugs.

2 cl, 2 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds of the formula (I) and their pharmaceutically acceptable salts in the capacity of modulators of receptors CB1 and to the pharmacological composition on their basis. Bonds can be used for treatment and prophylaxis of diseases, which are associated with the modulation of receptor CB1, for example, obesity and diabetes of type II. In the general formula (I) R1 means hydrogen or the lowest alkyl; R2 means hydrogen, the lowest alkyl, the lowest alkenyl, the lowest alkoxy-lowest alkyl, the lowest alkoxycarbonilamino-group or - (CH2)m-R2a; or R1 and R2 form together with atom of nitrogen to which they are attached, a 5-or 6-member saturated heterocyclic ring; R2a means cycloalkyl, which is not necessarily mono- or tetra-substituted independently by hydroxy-group, the lowest alkyl; C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen; 5- or 6-member monovalent heteroaromatic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heteroaromatic ring is not necessarily mono-substituted independently with the lowest alkyl; or phenyl which is not necessarily mono- or di-substituted independently with the lowest of the alkoxy group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy group or nitro-group; R3 means the lowest alkyl, the lowest alkoxy-lowest alkyl, diphenyl-lowest alkyl or - (CH2)n-R3a; R3a means C3-6cycloalkyl which can be not necessarily condensed with the phenol ring; or C3-6cycloalkyl, which can be not necessarily mono-, di- or trisubstituted independently hydroxy-group, the lowest alkyl, C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heterocyclic rings are not necessarily mono-substituted independently by the lowest alkyl, 5- or 6-member monovalent heteroaromatic ring containing one heteroatom, independently selected from oxygen and sulfur, the aforesaid heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, or the phenyl, which can be not necessarily mono-, di- or trisubstituted independently by the hydroxy-group, lowest alkyl, lowest alkoxy-group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; R4 means the lowest alkyl the lowest alkoxycarbonyl; C3-6 cycloalkyl, 5- or 6-member monovalent heteroaromatic ring, which contains one or two heteroatoms, independently selected from nitrogen, the said heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, lowest alkoxy-group; phenoxy-lowest alkyl, in which the phenyl part is not necessarily mono-, di- or trisubstituted independently by the lowest alkoxy-group; or the phenyl, which not necessarily can be mono-, di- or trisubstituted independently, by the lowest alkyl, by the lowest alkoxy-group, by halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; or two adjusted substitutes of the said phenyl remainder indicate together -O-(CH2)p-O- or -(CH2)2-O-; R5 and R6 each indicates a substitute independently selected from hydrogen of lowest alkyl; R7 indicates hydrogen; m indicates 0,1 or 2; n indicates 1.

EFFECT: new bonds possess useful biological properties.

28 cl, 4 dwg, 380 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel derivatives of 1,2,4-triazole of the general formula (I): wherein A and b can be taken separately or in common being when they are taken separately then A means (C1-C6)-alkyl or phenyl, and B means (C1-C6)-alkyl; A and B taken in common mean (C2-C5)-alkanediyl, and they form with C-atoms 3-6-membered cycle optionally substituted with (C1-C4)-alkylene, oxo, ethylenedioxy group, (C1-C4)-alkyl, 1-2 halogen atoms, (C1-C3)-alkoxy-(C1-C3)-alkoxy or hydroxy group; each R1 means independently hydrogen atom, -OH, halogen atom, (C3-C6)-cycloalkyl, (C1-C6)-alkyl optionally substituted with 1-3 halogen atoms; or two R1 groups near adjacent carbon atoms form 6-membered aryl cycle; R2 and R3 can be taken in common or separately, and when they are taken in common then they represent (C3-C8)-alkanediyl that forms condensed 5-10-membered nonaromatic cycle; when R2 and R3 are taken separately then R2 means (C1-C6)-alkyl possibly substituted with 1-3 halogen atoms or cyclopropyl, and R3 means cyclopropyl possibly substituted with (C1-C4)-alkyl, naphthyl, phenyl possibly substituted with halogen atom, -OH, (C1-C6)-alkyl wherein indicated (C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, -O-(C1-C6)-alkyl wherein indicated -O-(C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, phenyl or benzyloxy group, dihydrobenzofuranyl, benzothiadiazolyl or benzoimidazolyl possibly substituted with (C1-C6)-alkyl, their pharmaceutically acceptable salts or solvates, and pharmaceutical composition based on thereof. Proposed compounds are inhibitor of 11β-hydroxysteroid dehydrogenase I, and can be used in medicine in treatment of diabetes mellitus, obesity and dyslipidemia.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

19 cl, 17 tbl, 4 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and/or stereomer form of compound of the formula (I), and/or physiologically compatible salt of compound of the formula (I) wherein X and M are similar or different and mean independently of one another nitrogen atom (N) or -CH; R1 and R11 are similar or different and mean independently of one another: (1.) hydrogen atom; (2.) fluorine (F), chlorine (Cl), iodine (J) or bromine (Br) atom; R2 means: (1.) heteroaryl residue of group comprising 1,3,4-oxadiazole, oxadiazolylidinedione, oxadiazolone, thiazole, and heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another: (1.1.) keto-group; (2) -C(O)-R5 wherein R5 means hydrogen atom or -(C1-C4)-alkyl, or (3.) -C(O)-N(R7)-R8 wherein R7 and R8 mean independently of one another hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl; R3 means hydrogen atom or -(C1-C4)-alkyl; R4 means: (1.) heteroaryl residue of group comprising thiazole, isothiazole, pyridine, pyrazine, pyrimidine wherein heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another with -(C1-C5)-alkyl, halogen atom, trifluoromethyl, or (2.) aryl residue of group comprising phenyl. Also, invention relates to a method for preparing a medicinal agent and to using compounds based on the formula (I) possessing activity with respect to IkB kinase. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical agent.

6 cl, 67 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of carboxylic acid represented by the general formula (I): , their pharmaceutically acceptable salts or esters wherein values Y, L, X, T, Z, M, R1, W and are given in the invention claim. Proposed compounds possess insulin-sensitizing effect and they are double agonists with respect to PPARα and γ, and triple agonists with respect to PPARα, β(δ) and γ. Except for, the invention relates to a medicinal agent and pharmaceutical compositions based on the claimed derivatives of carboxylic acid, to methods for prophylaxis or treatment of diseases, and to using derivatives carboxylic acid for preparing a medicinal agent.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

56 cl, 2 tbl, 609 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 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.

SUBSTANCE: invention relates to using compounds of the general formula (I): and their pharmaceutically acceptable acid-additive salts. Compounds are used for preparing medicinal agents used in treatment diseases and state associated with system of adenosine receptors A2A, such as Alzheimer's disease, Parkinson's diseases, Huntington's syndrome, schizophrenia, anxiety state, pain, depression, narcomania to such substances as amphetamine, cocaine, opioides, ethyl alcohol, nicotine, cannabinoids, or in treatment of hypoxia, ischemia, epileptic attack. Also, proposed compounds exert neuroprotective effect and can be used as sedative, antipsychotic or anti-epileptic agents.

EFFECT: valuable medicinal properties of compounds.

18 cl, 1 tbl, 49 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. Method involves the following successive steps: (i) interaction of bromine with 4-acetamidocyclohexanone an aqueous solution to yield 2-bromo-4-acetamidocyclohexanone; (ii) addition of thiourea to yield 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole; (iii) addition of hydrobromic acid an aqueous solution to yield 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole without isolation of 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole synthesized at stage (ii); (iv) isolation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole and if necessary separation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole isolated at stage (iv) for R-(+)- and S-(-)-enantiomers, and isolation of R-(+)- and/or S-(-)-enantiomer. 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole is used for synthesis of pramipexole. Also, invention relates to a method for synthesis of pramipexole by synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole by using the method said and its conversion to pramipexole and if necessary by separation of pramipexole for its R-(+)- and S-(-)-enantiomers and isolation of R-(+)- and/or S-(-)-enantiomer.

EFFECT: improved method of synthesis.

15 cl, 1 sch, 3 ex

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