N-substituted 2-cyanopyrrolidine

 

(57) Abstract:

The invention relates to N-(N'-substituted glycyl)-2-cyanopyrrolidine formula I, where R denotes: a)1R1aN (CH2)m-, where R1means pyridinoline or pyrimidinyl fragment, optional one - or disubstituted independently of one another by halogen, trifluoromethyl, cyano - or nitro-group; R1adenotes hydrogen or C1-C8alkyl, m is equal to 2,3, b)3-C12cycloalkyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl,) R2(CH2)n- where either R2denotes phenyl, optional one-, two - or tizamidine selected independently of each1-C4alkoxygroup, halogen or phenylthiourea, optional one-deputizing in the phenyl ring with hydroxymethyl; or denotes a C1-C8alkyl, [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8the alkyl, pyridinoline or nattily fragment, or cyclohexenyl, or substituted and n is 1-3, or R2denotes fenoxaprop; and n is 2; d) (R3)2CH(CH2)2-, where each R3independently of alkoxy; and p is 2-4, e) isopropyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl, W) R5that means indanyl piperidinyl fragment, optionally substituted benzyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8by alkyl, substituted or1-C8alkyl, optionally one or mnogozalny independently from each other hydroxy-group, hydroxymethyl or phenyl, optional one - or disubstituted independently selected from each other WITH1-C4the alkyl, C1-C4alkoxygroup or halogen, in free form or in the form of an acid additive salt. The compound of formula I used in the pharmaceutical composition that inhibits DPP-IV, in particular for the treatment of diabetes independent of insulin, and conditions caused by a decreased glucose tolerance (IGT). 2 c. and 4 C.p. f-crystals, 2 PL.

The technical field to which the invention relates

The invention relates to N-substituted 2-cyanopyrrolidine. In particular, it relates to new derivatives of N-glycyl-2-cyanopyrrolidine.

Background of the invention

To date, described a large number of inhibitorsthose, stability or toxicity. There is therefore a need for new inhibitors of DPP-IV, suitable for treating conditions mediated by inhibition of DPP-IV, devoid of the above limitations.

Summary of the invention

The invention relates to new N-(N'-substituted glycyl)-2-cyanopyrrolidines, effective as inhibitors of DPP-IV in the treatment of conditions mediated by DPP-IV. It also applies to the respective pharmaceutical compositions, method of production thereof, to a method of inhibiting DPP-IV comprising the administration to a patient in need of such treatment, a therapeutically effective amount of such compositions, to compounds intended for use as a pharmaceutical preparation, and to their use in the method of manufacturing a medicinal product intended for the treatment of a condition mediated by DPP-IV.

Detailed description of the invention

The invention relates to N-(N'-substituted glycyl)-2-cyanopyrrolidines, briefly referred to in the present description "connections according to the invention, and in particular to compounds of the formula I:

< / BR>
where R denotes:

a) R1R1a(CH2)m- where

R1bassima from each other WITH1-C4the alkyl, C1-4alkoxygroup, halogen, trifluoromethyl, cyano - or nitro-group, or denotes phenyl, optional one - or disubstituted independently selected from each other WITH1-C4the alkyl, C1-C4alkoxygroup or halogen,

R1adenotes hydrogen or C1-C8alkyl and

m is 2 or 3,

b)3-C12cycloalkyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl,

C) R2(CH2)n- where

R2denotes phenyl, optional one-, two - or tizamidine selected independently of each1-C4the alkyl, C1-C4alkoxygroup, halogen or phenylthiourea, optional one-deputizing in the phenyl ring with hydroxymethyl, or denotes a C1-C8alkyl, [3.1.1]bicyclic carbocyclic fragment, optional single or mnogozalny1-C8the alkyl, pyridinoline or nattily fragment, optional one - or disubstituted independently selected from each other C1-C4the alkyl, C1-C4alkoxygroup or halogen, cyclohexane or substituted and

n is 1-3, or

R1-C4alkoxygroup or halogen, and

n is 2 or 3,

g) (R3)2CH(CH2)2- where

R3in each case independently denotes phenyl, optional one - or disubstituted independently selected from each other1-C4the alkyl, C1-C4alkoxygroup or halogen,

d) R4(CH2)p- where

R4denotes 2-oxopyrrolidin or2-C4alkoxy and

p is 2-4,

e) isopropyl, optional one-deputizing in position 1 C1-C3hydroxyalkyl,

W) R5that means indanyl, pyrrolidinyl or piperidinyl fragment, optionally substituted benzyl; [2.2.1] or [3.1.1]bicyclic carbocyclic fragment, optional single or mnogozalny1-C8by alkyl, substituted or1-C8alkyl, optionally one or mnogozalny selected independently from each other hydroxy-group, hydroxymethyl or phenyl, optional one - or disubstituted independently selected from each other C1-C4the alkyl, C1-C4alkoxygroup or halogen,

in free form or in the form of an acid additive salt.

is to be obtained in a known manner from the free form, and Vice-versa. Acid additive salts may, for example, be a salt of pharmaceutically acceptable organic or inorganic acids. Although the preferred acid additive salts are hydrochloride can be used in salt methansulfonate, sulfuric, phosphoric, citric, lactic and acetic acid.

Compounds according to the invention can exist in the form of optically active isomers or diastereoisomers and can be separated and selected by standard methods such as chromatography.

The term "alkyl" or "alkoxy" refers to radicals having a straight or branched chain; examples of the latter include isopropyl and tertbutyl.

R preferably has the values listed above in PP (a), b) or d). R1preferably indicates pyridinoline or pyrimidinyl fragment, optionally substituted as indicated above. R1apreferably denotes hydrogen. R2preferably denotes phenyl, optionally substituted as indicated above. R3preferably denotes unsubstituted phenyl. R4preferably represents alkoxy. R5preferably means are not nezamescennych 2. R preferably is 2 or 3, most preferably 3.

Pyridinyl preferably denotes pyridine-2-yl, more preferably it is unsubstituted or one-deputizing, preferably in position 5. Pyrimidinyl preferably denotes pyrimidine-2-yl. Preferably it is unsubstituted or one-deputizing, preferably in position 4. Preferred substituents for pyridine and pyrimidine are halogen, cyano and nitro-group is most preferable Deputy is chlorine.

In the presence of the phenyl substituents is preferably one-deputizing, while it is preferably substituted with halogen, more preferably chlorine, or methoxy group. Preferably it is substituted in position 2, 4 and/or 5, most preferably in position 4.

WITH3-C12cycloalkyl preferably denotes cyclopentyl or cyclohexyl. In the presence of deputies it is preferably substituted with hydroxymethyl. WITH1-C4alkoxy preferably has 1 or 2 carbon atoms, most preferably represents methoxy. WITH2-C4alkoxy preferably has 3 carbon atoms, most preferably denotes isolino chlorine. WITH1-C8the alkyl preferably has from 1 to 6, preferably from 1 to 4, or from 3 to 5 carbon atoms, most preferably 2 or 3 carbon atoms, or represents methyl. WITH1-C4alkyl preferably denotes methyl or ethyl, most preferably methyl. C1-C3hydroxyalkyl preferably represents hydroxymethyl.

[3.1.1] bicyclic carbocyclic fragment, optionally substituted as indicated above, preferably denotes a bicyclo[3.1.1]hept-2-yl, optionally substituted in position 6 stands, or bicyclo[3.1.1] hept-3-yl, optionally tizamidine one methyl group in position 2 and the two methyl groups in position 6. [2.2.1]bicyclic carbocyclic fragment, optionally substituted as indicated above, preferably denotes a bicyclo[2.2.1]hept-2-yl.

Naphthyl, preferably denotes 1-naphthyl. Cyclohexen preferably denotes cyclohex-1-EN-1-yl. Of substituted preferably represents 1 - or 2-substituted.

Pyrrolidinyl or piperidinyl fragment, optionally substituted as indicated above, preferably denotes pyrrolidin-3-yl or piperidine-4-yl. If there zamastil includes compounds of formula I, where R denotes R' (compounds Ia), and R' denotes:

- R1'NH(CH2)2-, where R1' denotes a pyridinyl, optional one - or disubstituted selected independently of one another by halogen, trifluoromethyl, cyano - or nitro-group, or denotes an unsubstituted pyrimidinyl,

- C3-C7cycloalkyl, optional one-deputizing in position 1 C1-C3hydroxyalkyl,

- R4'(CH2)3-, where R4' matches WITH2-C4alkoxy, or

- R5where R5has the above values,

in free form or in the form of an acid additive salt.

More preferred compounds according to the invention are the compounds of formula I, where R denotes R (compounds Ib), and R" means:

- R1"NH(CH2)2-, where R1" refers to pyridinyl, one - or disubstituted selected independently of one another by halogen, trifluoromethyl, cyano - or nitro-group,

- C4-C6cycloalkyl, one-deputizing in position 1 WITH1-C3hydroxyalkyl,

- R4'(CH2)3-, where R4' has the above meanings, or

- R5'where R5' denotes a [2.2.1] or [3.1.1], what if denotes substituted,

in free form or in the form of an acid additive salt.

Even more preferred compounds according to the invention are the compounds of formula I, where R denotes the R"' (compounds IC), and R"' denotes:

- R1"NH(CH2)2-, where R1" have the above values,

- C4-C6cycloalkyl, one-deputizing in position 1-hydroxymethyl,

- R4'(CH2)3-, where R4' has the above meanings, or

- R5"where R5" means substituted,

in free form or in the form of an acid additive salt.

Another group of compounds according to the invention includes compounds of IP, where R denotes the Rpthat means:

a) R1pNH(CH2)2-, where R1pmeans pyridinoline or pyrimidinyl fragment, optional one - or disubstituted selected independently of one another by halogen, trifluoromethyl, cyano - or nitro-group,

b)3-C7cycloalkyl, optional one-deputizing in position 1 C1-C3hydroxyalkyl,

C) R2p(CH2)2-, where R2pdenotes phenyl, optional one-, BR> g) (R3p)2CH(CH2)2-, where each R3pindependently denotes phenyl, optional one-deputizing halogen or1-C3alkoxygroup,

d) R4(CH2)3-, where R4has the above values, or

e) isopropyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl,

in free form or in the form of an acid additive salt.

Another group of compounds according to the invention includes the compound Is where R denotes the Rsthat means:

a) R1sR1as(CH2)ms-, where R1srepresents pyridinyl, optionally one or disubstituted independently selected from each other, chlorine, trifluoromethyl, cyano - or nitro-group, pyrimidinyl, optional one-deputizing chlorine or trifluoromethyl, or denotes phenyl,

R1asdenotes hydrogen or methyl and

ms is 2 or 3,

b)3-C12cycloalkyl, optional one-deputizing in position 1-hydroxymethyl,

C) R2s(CH2)ns- or

R2sdenotes phenyl, optional one-, two - or tizamidine chosen independently desannoy phenyl ring with hydroxymethyl, WITH1-C6alkyl, 6,6-dimethylbicyclo[3.1.1]hept-2-yl, pyridinyl, naphthyl, cyclohexen, or substituted, and ns is equal to 1-3, or

R2sindicates phenoxy, and ns is equal to 2,

g) (3,3-diphenyl) propyl,

d) R4s(CH2)pswhere R4sdenotes 2-oxopyrrolidin-1-yl or isopropoxy and ps is 2 or 3,

e) isopropyl, optional one-deputizing in position 1-hydroxymethyl,

W) R5swhere R5smeans of indanyl, pyrrolidinyl or piperidinyl fragment, optionally N-substituted by benzyl, bicyclo [2.2.1] hept-2-yl, 2,6,6-trimethylbicyclo[3.1.1] hept-3-yl, substituted or1-C8the alkyl, optional one - or disubstituted selected independently from each other hydroxy-group, hydroxymethyl or phenyl,

in free form or in the form of an acid additive salt.

Compounds according to the invention can be obtained by a process comprising a combination of a reactive (2-cianergoline) carbonylmethyl connection with the appropriate substituted amine, in particular, to obtain the compounds of formula I it includes the interaction of the compounds of formula II

< / BR>
where X represents a reactive group,

the gosia the compounds of formula I in free form or in the form of an acid additive salt.

X preferably represents halogen, such as bromine, chlorine or iodine.

The method according to the invention can be carried out in the usual way.

The compound of formula II is preferably subjected to interaction with at least 3 equivalents of a primary amine of the formula III. The interaction should be carried out in the presence of an inert organic solvent, preferably a cyclic simple ether, such as tetrahydrofuran. The temperature is preferably in the range from approximately 0oWith up to approximately 35oC, preferably from about 0oWith up to approximately 25oC.

Compounds according to the invention can be isolated from the reaction mixture and purified by standard methods, e.g. by chromatography.

Original products can also be obtained in the conventional way.

The compounds of formula II can, for example, be obtained according to the following two-step reaction scheme presented in the end of the description.

Stage 1 includes the interaction of pyrrolidine formula IV with a small molar excess of halogenacetylenes such as bromoacetamide or chlorocatechol, and triethylamine is under an inert organic solvent, preferably chlorinated aliphatic hydrocarbons, such as methylene chloride, at a temperature of from about 0oWith up to approximately 25oC, preferably at a temperature in the range from approximately 0oWith up to approximately 15oC.

Stage 2 involves dehydration of the compounds of formula V obtained in stage 1, using at least 2 equivalents triperoxonane anhydride (TFW). The dehydration is preferably carried out in the presence of an inert organic solvent, such as tetrahydrofuran or a chlorinated aliphatic hydrocarbon, such as methylene chloride, at a temperature of from about 0oWith up to approximately 25oC, preferably from about 0oWith up to approximately 15oC.

If the original product is not specifically presented in this description, the compound used as the source of the product is known or can be obtained from known compounds in a known manner either by analogy with known methods or analogously to the methods described in the examples.

Below the invention is illustrated in the examples. All temperatures are listed in gradusa 500 ml added 16.6 g of 2-[(5-chloropyridin-2-yl)amino] ethylamine and 100 ml of tetrahydrofuran and the mixture is cooled in an ice bath. To a chilled mixture of 7.0 g (2-cianergoline)carbonylmethyl-(S)-bromide, dissolved in 30 ml of tetrahydrofuran. The resulting mixture is stirred for 2 h at 0oWith, the solvent is removed on a rotary evaporator and the mixture was separated between ethyl acetate and water. The product is then extracted with an ethyl acetate layer, after which the aqueous layer was washed twice with ethyl acetate. The combined organic layers are successively washed with water and with brine, dried over sodium sulfate and concentrated, obtaining the desired compound in free base form in the form of a crude product. Then the crude product is purified on silica gel, using as eluent a mixture of 5% methanol in methylene chloride and getting mentioned in the title compound in free base form in the form of butter a light brown color.

After dissolving the free base in 30 ml of anhydrous tetrahydrofuran solution bubbled with gaseous hydrogen chloride for 5 C. the Resulting whitish precipitate is filtered, washed with anhydrous tetrahydrofuran and the solvent is removed by pumping at high vacuum, getting mentioned in the title compound in the form of acid-additive with the Itza).

The original product is obtained in the following way.

a) In 200 ml of methylene chloride is dissolved 22,37 g (S)-2-carbamoylpiperidino, 30,1 ml of triethylamine and 30.0 mg of dimethylaminopyridine (DMAP) and then the resulting solution for 60 min are added dropwise in the presence of a drying tube with calcium sulfate to chilled on ice, the solution containing 18.8 ml of bromoacetamide in 192 ml of methylene chloride. The resulting solution is stirred for 2 hours at a temperature of a mixture of ice-water in the presence of a drying tube with calcium sulfate, and then poured into 3.5 l of ethyl acetate. The formed precipitate is filtered, washed with ethyl acetate and the filtrate is concentrated and receiving (2-carbamoylpiperidino)carbonylmethyl-(S)-bromide (solid sticky yellow substance).

b) 50.0 g prosteradlo compound obtained above in stage a), is dissolved in 300 ml of methylene chloride and the solution is cooled in a bath of ice water in the presence of a drying tube with calcium sulfate. Then cooled the solution for 2 minutes and drain on a 60.2 ml triperoxonane anhydride, the resulting solution is stirred for 4 hours at a temperature of a mixture of ice-water in the presence of a drying tube with calcium sulfate and distribute between metranil the first layer is washed twice with methylene chloride. The combined organic layers are successively washed with water and with brine and then dried over sodium sulfate. The solution is filtered and the solvent is removed by rotary evaporator and pumping at high vacuum, receiving (2-cyanopyrrolidine)carbonylmethyl-(S)-bromide (solid dark yellow color).

See the table below for the compounds of formula I according to the invention have a similar way by reacting the corresponding compounds of formula II with an appropriate compound of formula III (in the table below, if just a form of acid additive salts of the compounds according to the invention, a connection is obtained from the free base without highlighting it).

Compounds according to the invention in free form or in the form of a pharmaceutically acceptable acid salt additive, briefly referred to below in the present description "agents according to the invention, in particular the compounds of formula I in free form or in the form of a pharmaceutically acceptable acid additive salts, possess pharmacological activity. Therefore they can be used as pharmaceuticals.

In particular, they inhibit DPP-IV. This activity can be progesterone compounds to inhibit the activity of DPP-IV from extracts of cells of carcinoma of the colon. The cell line of SASO-2 carcinoma of the colon of a person can be obtained from the American type culture collection (ATSC NRT 37). Differentiation of cells for the induction of expression of DPP-IV is carried out according Reisher and others, Proc. Natl. Acad. Sci. USA 90 (1993) 5757-5761. Extract cells obtained from cells solubilizing in a buffer comprising 10 mm Tris-HCl, 0.15 M NaCl, 0.04 to t.i. u. (tripterygiidae units) Aprotinin, 0.5% nonionic detergent R40, pH 8.0, centrifuged at 35000xg for 30 min at 4oC to remove cellular debris. The analysis is performed by adding to the wells tiralongo microplate 20 µg solubilizing protein, SASO-2, diluted to a final volume of 125 μl of buffer for analysis (25 mm Tris-Hcl pH 7.4, 140 mm NaCl, 10 mm KCl, 1% bovine serum albumin). The reaction is initiated by adding 25 μl of 1 mm substrate (H-alanine-Proline-PNA, where the PNA denotes para-nitroaniline). The reaction is carried out at room temperature for 10 minutes, then add 19 ál of 25% glacial acetic acid to terminate the reaction. The test compounds, as a rule, add portions by volume of 30 μl and the volume of buffer for analysis is brought to 95 µl. A standard curve for the free para-nitroaniline receive inani, and it is used for interpolation of the absorption of the substrate (catalytic activity in nolah decomposed substrate/min). The end point is determined by measuring the absorbance at 405 nm using a reader for titrating microplate type Molecular Devices UV Max. The activity of test compounds as inhibitors of DPP-IV, expressed as IC50derived from dependency dose-response received on 8 points, using a four-parameter logarithmic function.

In the above analysis for the agents according to the invention receives the values of the IC50from approximately 10 nm to approximately 900 nm, e.g., 22 nm for the agent from example 3.

Inhibition of DPP-IV can also be demonstrated by measuring the effects of test compounds on the activity of DPP-IV in the plasma of humans and rats using a modified version of the analysis described Kubota and others in Clin. Exp. Immunol. 89 (1992) 192-197. In General, this analysis is that 5 ál of plasma added to 96-well flat-bottomed titration microplates (Falcon), and then add 5 ál of 80 mm MgCl2in the buffer for incubation (25 mm HEPES, 140 mm NaCl, 1% BSA with purity for RIA (radioimmunoassay analysis), pH 7,8). After 5 min incubation PR the strata (N-glycine-Proline-AMC, where AMK denotes 7-amino-4-methylcoumarin). The tablets covered with aluminum foil (or kept in the dark) and incubated at room temperature for 20 minutes After the reaction for 20 min measure fluorescence using fluorimetry type CytoFluor 2350 (excitation at 380 nm, emission at 460 nm, set the sensitivity level 4). Test compounds generally added in portions of 2 ml and the volume of buffer for analysis of the lead up to 13 ál. The dependence of the fluorescence-concentration of free AMC is obtained using 0-50 μm solutions AMK buffer for analysis. The obtained dependence is linear, and it is used for interpolation of the absorption of the substrate (catalytic activity in nolah decomposed substrate/min). As in the previous analysis, the activity of the test compounds as inhibitors of DPP-IV, expressed as IC50derived from dependency dose-response, constructed by 8 points, using a four-parameter logarithmic function.

In the above analysis of the gain values IC50in plasma from about 7 nm to about 2000 nm, and in the plasma of the rat, from about 3 nm to priblizitelino.

The agents according to the invention due to its ability to inhibit DPP-IV can be used in the treatment of conditions mediated by DPP-IV. It should be expected that the compounds described in the present description, are suitable for the treatment of diabetes independent of insulin, arthritis, obesity and osteoporosis, such as osteoporosis, independent of calcitonin. The agents according to the invention improve the initial insulin response to a glucose oral route and, therefore, the most suitable for the treatment of diabetes independent of insulin, and other conditions caused by a decreased glucose tolerance (IGT).

The ability of the agents according to the invention to improve the initial insulin response to a glucose oral route can be estimated, for example, resistant to insulin rats in accordance with the following method.

Male rats Sprague-Dawley, who was on a diet with a high content of fat (saturated fat = 57% of calories) in 2-3 weeks, on the day of the experience immobilizes approximately 2 h, divided into groups of 8-10 individuals and introduce oral route 10 mcmole/kg of the test compounds in the carboxymethyl cellulose (CMC). A bolus of glucose 1 g/kg, intended for oral wegrowe, taken at different points in time using a catheter, is continuously introduced into the jugular vein, analyze for the presence of glucose in plasma, evaluate immunoreactive concentration of insulin (IRI) and the activity of DPP-IV in the plasma. The levels of insulin in plasma assessed using radioimmunoassay (RIA) for the two antibodies using specific rat insulin antibodies supplied by the company Linco Research (St. Louis, MO, USA). RIA has a lower detection limit of 0.5 microengines/ml at variations within one experiment and between experiments less than 5%. The results are expressed as % increase in average compared with that for control animals.

It was found that after oral administration of each of the tested compounds enhances the initial insulin response, resulting in improved glucose tolerance resistant to insulin experimental animals. The following results were obtained, are given in table.2.

The exact dose of the agents according to the invention, which should be used for treating conditions mediated by inhibition of DPP-IV, depends on several factors, including the host, the nature and severity of the condition to be treated, method of administration and specifically Ave is if the agent according to the invention is administered enterline, for example, orally or parenterally, for example intravenously, preferably orally, in a daily dose of from about 0.002 mg/kg to about 5 mg/kg, preferably from about 0.02 mg/kg to about 2.5 mg/kg body weight or, for most larger primates, a daily dosage of from about 0.1 mg to about 250 mg, preferably from about 1 mg to about 100 mg standard dose for oral administration is from about 0.01 mg/kg to about 0.75 mg/kg and applied one to three times a day. As a rule, first enter a small dose and then gradually increase the dose up until not determine the optimal dose for the owner, subject to treatment. The upper limit is determined by the dose that causes side effects, and it can be evaluated through experiments on the host to be treated.

The agents according to the invention can be combined with one or more pharmaceutically acceptable carriers and optionally with one or more other conventional pharmaceutical adjuvants and you can enter them enterline, for example, orally in the form of tablets, capsules, capleton, etc. or parenterally, for example, nutriv the th introduction can be obtained by standard methods.

The agents according to the invention can be incorporated into pharmaceutical compositions for enteral or parenteral administration containing an active ingredient in amount effective for treating conditions mediated by DPP-IV, and such compositions can be a standard dosage form and may include a pharmaceutically acceptable carrier.

The agents according to the invention, which are, for example, the compounds of formula I may be administered in the form of pure (S)-enantiomer (e.g., with a purity of 98%, preferably with a purity of 99%) or together with the other enantiomer, for example, in the form of racemic mixtures. The above dose ranges specified for compounds of formula I (excluding the amount of R-enantiomer).

Thus, the object of the invention is also the agent according to the invention, in particular compound of formula I, as defined above, in free form or in the form of a pharmaceutically acceptable acid salt additive designed for use as a pharmaceutical preparation. In addition, the object of the invention is a pharmaceutical composition comprising the agent according to the invention, in particular compound of formula I, as defined above, in free whitesky acceptable carrier or diluent. In addition, the object of the invention is the use of an agent according to the invention, in particular the compounds of formula I, as defined above, in free form or in the form of a pharmaceutically acceptable acid salt additive to obtain drugs for inhibition of DPP-IV or treating conditions mediated by DPP-IV, the process comprising mixing agent according to the invention with a pharmaceutically acceptable carrier or diluent. In addition, the invention proposes a method of inhibiting DPP-IV or treating conditions mediated by DPP-IV, comprising the administration to a patient in need of such treatment, a therapeutically effective amount of the compounds according to the invention, in particular the compounds of formula I in free form or in the form of a pharmaceutically acceptable acid additive salt.

Agents of examples 1, 3, 5, 8 and 12 are the preferred agents according to the invention, first and foremost agents of examples 1, 3, 5 and 12, preferably in the form of an acid additive salts, such as hydrochloride, the most preferable is the agent of example 3, namely 1-[2-[(5-lepirudin-2-yl) amino]ethylamino] acetyl-2-cyan-(S)- pyrrolidin, preferably in the form of an acid additive salt, such as digit using cell line, SASO-2, respectively, 36, 22, 26, 8, and 279 nm, and the results of the analysis using the above modified method Kubota values IC50for DPP-IV in human plasma and rat respectively 27 and 22 nm (example 1), 7 and 6 nm (example 3), 37 and 18 nm (example 5), 12 and 11 nm (example 8), 95 and 38 nm (example 12). Therefore, for the aforementioned purposes, the compounds of examples 1, 3, 5, 8 and 12 can be larger mammals, for example, a person using such methods of administration and approximately the same doses that are typically used in the case of the use of Metformin.

The example of the pharmaceutical composition

Tablets, each containing 50 mg of active ingredient, for example, 1-[2-[(5-chloropyridin-2-yl)amino]ethylamino]-2-cyano-(S)-pyrrolidin, can be prepared as follows.

Composition (for 10,000 tablets), g:

Active ingredient - 500,0

Lactose - 500,0

Potato starch - 352,0

Gelatin - 8,0

Talc - 60,0

Magnesium stearate - 10,0

Silicon dioxide (fine) - 20,0

Ethanol - q.s. (enough)

The active ingredient is mixed with the lactose and 292 g of potato starch, the mixture moisturize alcoholic solution of gelatin and the edge of aspersky silicon dioxide, the mixture is pressed with getting pills weight 145,0 mg each at the concentration of active ingredient 50,0 mg If needed on the resulting tablets can be coated with dividing notches for finer control of the dose.

1. N-(N'-substituted glycyl)-2-cyanopyrrolidine formula I

< / BR>
where R denotes: a) R1R1aN(CH2)m-, where R1means pyridinoline or pyrimidinyl fragment, optional one - or disubstituted selected independently of one another by halogen, trifluoromethyl, cyano - or nitro-group; R1adenotes hydrogen or C1-C8alkyl and m = 2 or 3, b)3-C12cycloalkyl, optional one-deputizing in position 1 C1-C3hydroxyalkyl,) R2(CH2)n- where either R2denotes phenyl, optional one-, two - or tizamidine selected independently of each1-C4alkoxygroup, halogen or phenylthiourea, optional one-deputizing in the phenyl ring with hydroxymethyl; or denotes a C1-C8alkyl, [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8the alkyl, pyridinoline or nattily frag>H(CH2)2-, where each R3independently represents phenyl; d) R4(CH2)p-, where R4denotes 2-oxopyrrolidin or2-C4alkoxy; and p = 2-4, s) isopropyl, optional one-deputizing in position 1 C1-C3hydroxyalkyl, W) R5that means indanyl, piperidinyl fragment, optionally substituted benzyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny C1-C8by alkyl, substituted or C1-C8alkyl, optionally one or mnogozalny selected independently from each other hydroxy-group, hydroxymethyl or phenyl, optional one - or disubstituted independently selected from each other WITH1-C4the alkyl, C1-C4alkoxygroup or halogen;

in free form or in the form of an acid additive salt.

2. Connection on p. 1 (IP connection), where R denotes the Rpthat means a) R1pNH(CH2)2-, where R1pmeans pyridinoline or pyrimidinyl fragment, optional one - or disubstituted selected independently of one another by halogen, trifluoromethyl, cyano - or nitrogroup the kilometres, C) R2p(SN2)2-, where R2pdenotes phenyl, optional one-, two - or tizamidine selected independently of one another by halogen or C1-C3alkoxygroup, g) (R3p)2CH(CH2)2-, where each R3pindependently denotes phenyl, d) R4(CH2)3-, where R4has the above significance, or (e) isopropyl, optional one-deputizing in position 1 C1-C3hydroxyalkyl, in free form or in the form of an acid additive salt.

3. Connection on p. 1 (the connection Is), where R denotes the Rsthat means a) R1sR1as(CH2)ms-, where R1srepresents pyridinyl, optionally one or disubstituted independently selected from each other, chlorine, trifluoromethyl, cyano - or nitro-group, pyrimidinyl, optional one-deputizing chlorine or trifluoromethyl, or phenyl; R1asdenotes hydrogen or methyl; and ms = 2 or 3, b)3-C12cycloalkyl, optional one-deputizing in position 1-hydroxymethyl, C) R2s(CH2)ns- where either R2sdenotes phenyl, optional one-, two - or tizanidinebuy, one-deputizing in the phenyl ring with hydroxymethyl; C1-C6alkyl; 6,6-dimethylbicyclo[3.1.1] hept-2-yl; pyridinyl; naphthyl; cyclohexenyl; or substituted, a ns = 1-3, or R2sindicates phenoxy, and ns = 2, d) (3,3-diphenyl)propyl, d) R4s(CH2)ps-, where R4sdenotes 2-oxopyrrolidin-1-yl or isopropoxy and ps = 2 or 3, e) isopropyl, optional one-deputizing in position 1-hydroxymethyl, W) R5sthat means indanyl, piperidinyl fragment, optionally N-substituted by benzyl; bicyclo[2.2.1] hept-2-yl, 2,6,6-trimethylbicyclo[3.1.1] hept-3-yl, substituted or1-C8the alkyl, optional one - or disubstituted selected independently from each other hydroxy-group, hydroxymethyl or phenyl, in free form or in the form of an acid additive salt.

4. Connection on p. 1, where R is 2-[(5-lepirudin-2-yl)amino] ethyl, namely, 1-[2[(5-lepirudin-2-yl)amino] ethylamino] acetyl-2-cyan-(S)-pyrrolidin, in free form or in the form of an acid additive salt, particularly preferably in the form of the dihydrochloride.

5. Connection on p. 1, which is the compound of formula I, where R stands for either 2-[(5-chloropyridin-2-yl)amino] ethyl, (1-hydroxynonenal form or in the form of an acid additive salt.

6. Pharmaceutical composition for inhibiting DPP-IV, and for treating conditions mediated by DPP-IV, in particular, for the treatment of diabetes independent of insulin, and conditions caused by a decreased glucose tolerance (IGT), including a pharmaceutically effective amount of the compounds according to paragraphs. 1-5 in free form or in the form of a pharmaceutically acceptable acid additive salts together with at least one pharmaceutically acceptable carrier or diluent.

 

Same patents:

The invention relates to 4-(allumination)-2,4-dihydropyrazol-3-Onam General formula I, where R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, unsubstituted or substituted once to three - fold amino, acyl, halogen, nitro, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium (with 1-6 C-atoms in the alkyl part), A-CO-NH-, AND-O-CO-NH-, AND-O-CO -, NA-, SO2NR4R5(R4and R5can denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, or O, which may be substituted),-CO-NH-SO2-, A-CO-NA-SO2- (AND-SO2-)2N-, tetrazolium phenyl; or pyridyl; R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl; R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3and their salts

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new derivatives of carboxylic acids of General formula I containing heterocyclic ring

The invention relates to new 1-(biphenyl-4-yl)methyl-1H-1, 2,4-triazole compounds and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole compounds, and each of them has as a substituent in the 2'-position (2,4-dioxopyrimidine-5-ilidene)methyl or (2,4-dioxotetrahydrofuran-5-ilidene)methyl, and their salts

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (IX):

< / BR>
in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

< / BR>
in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

< / BR>
in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

< / BR>
in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>
in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):

O=C=N-R6' (XV)

in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):

< / BR>
in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

< / BR>
in which R1', R4'Hal and R3" have the above values, the compound obtained is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of formula (IVa') (IVb'), (IVc'), (IVd') or (IVe') defined above, to obtain a product of formula (I7):

< / BR>
in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

C) transforming functions of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

a) transforming radical

< / BR>
in radical

< / BR>
p) conversion of the acid function in function

< / BR>
q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic cisisomer, enantiomers and diastereoisomers

The invention relates to new sulfonamidnuyu derivatives or their pharmaceutically acceptable salts, which have the properties of inhibitor action of endothelin receptors and can find application in the treatment of diseases associated with disorders in the circulatory system, such as hypertension, ischemia, angina, spasms of the blood vessels as well as to pharmaceutical drugs based on them

The invention relates to new pyrimidine compounds or their salts with pharmaceutically acceptable acids and pharmaceutical compositions based on them

The invention relates to 4-(allumination)-2,4-dihydropyrazol-3-Onam General formula I, where R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, unsubstituted or substituted once to three - fold amino, acyl, halogen, nitro, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium (with 1-6 C-atoms in the alkyl part), A-CO-NH-, AND-O-CO-NH-, AND-O-CO -, NA-, SO2NR4R5(R4and R5can denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, or O, which may be substituted),-CO-NH-SO2-, A-CO-NA-SO2- (AND-SO2-)2N-, tetrazolium phenyl; or pyridyl; R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl; R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3and their salts

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to new sulfonamidnuyu derivatives or their pharmaceutically acceptable salts, which have the properties of inhibitor action of endothelin receptors and can find application in the treatment of diseases associated with disorders in the circulatory system, such as hypertension, ischemia, angina, spasms of the blood vessels as well as to pharmaceutical drugs based on them

The invention relates to derivatives of N-heteroaryl-pyridinesulfonamide General formula I, in which one of the A1and A3represents nitrogen and the other represents CH; each of the A3and A4represents CH; Ar represents a phenyl group which is either not replaced, or has one Deputy; W, X, Y, Z can be nitrogen or a CH group; R1is hydrogen or halogen, and their pharmaceutically acceptable salts

The invention relates to new pyrimidine compounds or their salts with pharmaceutically acceptable acids and pharmaceutical compositions based on them

The invention relates to novel triazole compounds of the General formula (1), where a denotes a linear or branched C1-C18-alkylenes group which may comprise at least one group which is selected from O, S, CONH, COO,3-C6-cycloalkene or double or triple bond; In denotes the radical of formula (a), (b) or (C); R1denotes H, NH2WITH3-C6-cycloalkyl or1-C8-alkyl, which is not substituted or substituted OS1-C8-alkyl; R2denotes H, HE, C1-C8-alkyl, C3-6-cycloalkyl, CF3, CN, NR3R4, SR3or CO2R3where R3denotes N or C1-C8-alkyl, a R4denotes H, C1-C8-alkyl, or COR3where R3stands WITH1-C8-alkyl; Ar represents naphthyl, phenyl with 1-2 substituent selected from C1-C8-alkyl, CF3, CHF2, NO2, SR3, SO2R3where R3means1-C8-alkyl; and pyridyl, pyrimidyl or triazinyl, which have from 1 to 3 substituents selected from C1-C8-alkyl, C2-C6-alkenyl, C2-C6-quinil, halogen, CN, CF3, OR4where R43-C6-lalouche possibly condensed, phenylalkylamine or 5-membered aromatic heterocycle with 1 to 2 nitrogen atoms, which may be condensed with a benzene ring

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of piperidine F.-ly (I), where R1- aryl, heterocyclyl, R2is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridine, diazines, triazoles, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl or furyl which may be substituted with halogen, hydroxy, cyano, CF3, alkyl, R3-H, hydroxy, alkoxy, alkenylacyl, R4-H, alkyl, alkenyl, alkoxy, benzyl, oxo, Q is ethylene or absent, X is a bond, oxygen, sulfur, W is oxygen or sulfur, Z - alkylen, albaniles, -Oh, -S; n = 1, m = 0 or 1

The invention relates to new derivatives carbapenem formula I, where R1and R2may be the same or different, and each represents a modifiable group that can be hydrolyzed in the body, selected from 1-alkanoyloxy, 1-alkoxycarbonylmethyl, 5-methyl-1,3-dioxolan-2-he-4-ylmethyl; R3and R4may be the same or different and each represents lower alkyl, or R3and R4together with the adjacent nitrogen atom form a cyclic amino; or pharmaceutically acceptable salts
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