Thiomorpholine compound and method for making thereof

FIELD: medicine.

SUBSTANCE: there is described thiomorpholine compound presented by formula (I) wherein the ring A represents benzene ring; the ring B represents benzene ring; R1 represents hydrogen atom, R2 represents C1-6-alkyl group; R3a and R3b are identical or different, each representing hydrogen atom or C1-6-alkyl group, and n represents an integer equal to 2, or its pharmaceutically acceptable salt. There is also described method for making the compound of formula (1), a pharmaceutical composition and application of the compound of formula (1) for making a medical product used for treatment and prevention of the disease chosen from inflammation, allergic diseases, pain, migraine, neuralgia, itch, cough, central nervous system diseases, alimentary organ diseases, nausea, vomiting and urological disorders.

EFFECT: compounds exhibits affinity to neurokinine-1 receptor.

6 cl, 4 tbl, 16 ex

 

The scope to which the invention relates

The present invention relates to a new connection thiomorpholine with excellent antagonistic activity against tachykinin receptors, and to receive the connection of piperidine.

The level of technology

Tachykinin is the common name for a group of neuropeptides, and a known substance P (hereafter referred to as "SP"), neurokinin and neurokinin In mammals. It is known that these peptides have different biological activity by binding their respective receptors, which arein vivo(neurokinin-1, neurokinin-2, neurokinin-3). Among them, the SP is one of the peptides, who studied the longest and detail. Its existence is confirmed in the hood intestinal probe horses in 1931 and he is a peptide consisting of 11 amino acids, the structure of which was determined in 1971.

SP is widely distributed in the Central and peripheral nervous systems, and it has a physiological activity, such as a vasodilator effect, improved vascular permeability, smooth muscle contraction, stimulation of neurons, sljunootdelitelnoe action, diuretic action, immunological effects, etc. and function of neurotransmitter primary sensory neuron. In particular, the world is but that SP released from the end of the posterior horn of the spinal cord, pain impulse transmits pain information secondary sensory neuron, and that SP released from peripheral endings, causes an inflammatory response through their receptors. These facts believe that SP is involved in various diseases (for example, pain, inflammation, allergies, pollakiuria, incontinence, respiratory disease, mental disorder, depression, anxiety, vomiting, and so on), and, in addition, believe that SP is involved in the dementia type [Review: Physiological Reviews, vol.73, pp.229-308 (1993) (non-Patent literature 1), Journal of Autonomic Pharmacology, vol.13, pp.23-93 (1993) (non-Patent literature 2)].

Currently, as the compounds having antagonistic activity to theminimum receptor, in WO 2003/011860 describe the compound represented by the following formula:

in which R1represents hydrogen or fluorine,

and its pharmaceutically acceptable additive salt of the acid.

In addition, in WO 2002/032867 describe the compound represented by the following formula:

in which R represents a halogen atom or C1-4alkyl group;

R1represents a C1-4alkyl group;

R2presented yet a hydrogen or C 1-4alkyl group;

R3represents hydrogen or C1-4alkyl group;

R4represents triptorelin group;

R5represents hydrogen, C1-4alkyl group, or C(O)R6;

R6represents a C1-4alkyl, C3-7cycloalkyl, NH(C1-4alkyl) or N(C1-4alkyl)2;

m is 0 or an integer from 1 to 3;

n is an integer from 1 to 3,

or its pharmaceutically acceptable salt or solvated connection.

In WO 2003/066589 describe the compound represented by the formula:

in which:

R represents halogen or C1-4alkyl;

R1represents hydrogen or C1-4alkyl;

R2represents hydrogen, C1-4alkyl, or R2and R3combined with the formation of C3-7cycloalkyl;

R3represents hydrogen, C1-4alkyl, C3-7cycloalkyl or C3-6alkenyl; or

R1and R3form a 5 - or 6-membered heterocyclic group with the nitrogen atoms and the carbon to which they are linked in combination;

R4represents trifluoromethyl, C1-4alkyl, C1-4alkoxy, triptoreline or halogen;

R5represents hydrogen, and R6represents NR7R8or R 5represents NR8R9and R6represents hydrogen;

R7represents hydrogen or C1-4alkyl, or R7and R8form a saturated 5-7 membered heterocyclic group containing oxygen, nitrogen, with which they are associated in combination;

R8represents hydrogen, phenyl, C3-7cycloalkyl, (CH2)pC(O)NR10R11saturated 5-7 membered heterocyclic group (which may be substituted C1-4the alkyl, S(O)2C1-4the alkyl or C(O)C1-4by alkyl)containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, 5-membered heteroaryl group which may be substituted C1-4the alkyl, S(O)2C1-4the alkyl or C(O)C1-4by alkyl)containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, or R8represents a 6-membered heteroaryl group which may be substituted C1-4the alkyl, S(O)2C1-4the alkyl or C(O)C1-4by alkyl)containing 1 to 3 nitrogen atoms; or R8represents a C1-6alkyl group which may be optionally substituted 1 or 2 groups selected from fluorine, phenyl (which may be substituted C1-4the alkyl, C(O)C1-4by alkyl or halogen), =O, C3-7cycloalkyl, hydroxy, amino, dimethylamino, Aminata is bonila, C1-4alkoxy and trifloromethyl;

R9represents hydrogen or C1-4alkyl, or R9and R8may form a 5-7-membered heterocyclic group with astami with which they are associated, which may contain another heteroatom selected from oxygen, sulfur and nitrogen, and may be substituted by 1 or 2 groups selected from C1-4of alkyl, =O, S(O)2C1-4of alkyl, C(O)C3-7cycloalkyl and C(O)C1-4of alkyl;

R10and R11each independently represents hydrogen or C1-4alkyl group,

X represents a nitrogen atom, and Y represents CH, or X represents CH and Y represents a nitrogen atom;

m is 0 or an integer from 1 to 3;

n is an integer from 1 to 3,

p is 0, 1 or 2,

or its pharmaceutically acceptable salt or solvated connection.

In addition, in WO 2003/099787 describes piperidine derivative represented by the formula:

in which ring A represents an optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, R1represents an optionally substituted alkyl group, optionally substituted hydroxyl group, substituted Tilney group, substituted carbonyl group, a substituted sulfide is inuu group, substituted sulfonyloxy group or a group represented by the formula:

R11and R12may be the same or different from each other, and each of them represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyloxy group optionally substituted alkyl group or heterocyclic group containing from 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfur atom as the heteroatom(s)and specified heterocyclic group may be optionally substituted, and optionally a nitrogen atom contained in the specified heterocyclic group may be oxidized, or may be connected at its ends with the adjacent nitrogen atom to form heterocyclic group selected from piperidinium, azacycloheptane group, pyrrolidinone, imidazolidinyl group, hexahydropyridine group, thiazolidine group morpholinopropan, triazolines group, tetrazolyl group and parinello group, and specified heterocyclic group optionally can be substituted, in addition to the nitrogen atom contained in the specified heterocyclic group may be oxidized, R2represents a hydrogen atom, optionally substituted hydroxyl group, optionally Zam is on the amino group, optionally substituted alkyl group, substituted carbonyl group or a halogen atom, Z represents an oxygen atom or a group represented by-N(R3)-, R3represents a hydrogen atom or optionally substituted alkyl group, R4represents a hydrogen atom or optionally substituted alkyl group, or its pharmaceutically acceptable salt.

Description of the invention

Currently, as a therapeutic agent for the above-mentioned various diseases (especially, vomiting, depression, urological disorders and so on) still has not been found any compound which has an excellent antagonistic action on tachykinin receptors (specifically, an antagonistic effect on the SP receptor) and with satisfactory safety and sustainability (metabolism, dynamicsin vivoand absorption), etc. Therefore, was carried out search for compounds with excellent antagonistic action on tachykinin receptors and has a satisfactory clinical effect as a therapeutic agent.

The present invention relates to the connection thiomorpholine represented by the formula (I):

in which ring A represents an optionally substituted benzo what aspects of the ring;

ring B represents an optionally substituted benzene ring;

R1represents a hydrogen atom, optionally substituted hydroxyl group, optionally substituted by an amino group, an optionally substituted alkyl group, substituted carbonyl group or a halogen atom;

R2represents a hydrogen atom or optionally substituted alkyl group;

R3aand R3bmay be the same or different from each other, and each of them represents a hydrogen atom or optionally substituted alkyl group, or attached to each other at both of their ends with the formation of alkalinous group, and

n is an integer equal to 1 or 2,

or its pharmaceutically acceptable salt.

The effects of the invention

The present invention consists in the join clause, which has an excellent antagonistic action on tachykinin receptors and has a satisfactory clinical effect, such as security and sustainability (metabolism, dynamicsin vivoand absorption), etc.

The preferred embodiment of the invention

In the present invention, the ring A represents an optionally substituted benzene ring, and as the substituent(s) benzene Kohl is and you can specify alkyl group, halogen atom, cyano, optionally protected hydroxyl group, or alkoxygroup. Ring A may have 1 to 3 identical or different from each other substituents selected from these substituents.

In the present invention ring B represents an optionally substituted benzene ring, and as the substituent(s), benzene ring, you can specify trigalogenmetany group, halogen atom, cyano, phenyl group, heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, alkyl group, optionally protected hydroxyl group, or alkoxygroup. Ring B may have 1 to 3 identical or different from each other substituents selected from these substituents.

As preferred examples of ring A and ring B in the compound of the present invention it is possible to specify a connection in which, for example, ring A is a benzene ring represented by the formula:

ring B is a benzene ring represented by the formula:

Vice-A1, A2and A3may be the same or different from each other, and each of them represents a hydrogen atom, halogen atom, alkyl group, n is necessarily protected hydroxyl group, or alkoxygroup, B1B2and B3may be the same or different from each other, and each of them represents a hydrogen atom, trigalogenmetany group, halogen atom, cyano, phenyl group, heterocyclic group, containing from 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfur atom as the heteroatom(s), alkyl group, optionally protected hydroxyl group, or alkoxygroup. As trihalogenmethanes group, you can specify, for example, triptorelin group or trichlorethylene group, etc. as the heterocyclic group, containing from 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfur atom as the heteroatom(s), you can specify, for example, tetrazolyl group.

In the present invention as a protective group for optionally protected hydroxyl group, you can specify commonly used protective group, such as optionally substituted arylalkyl group, optionally substituted silyl group, acyl group, etc. Of the data groups as the preferred, you can specify, for example, arylalkyl group such as benzyl group, penicilina group, etc.; substituted silyl group such as tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, etc.; acyl groups is, such as formyl group, acetyl group, propylaniline group, melonella group, calolina group, benzoline group, etc.

In the present invention as R1you can specify a hydrogen atom, optionally substituted hydroxyl group, optionally substituted by an amino group, an optionally substituted alkyl group, substituted carbonyl group or a halogen atom.

In the present invention as Deputy optionally substituted hydroxyl group, R1you can specify alkyl group.

In the present invention as Deputy optionally substituted amino group, R1you can specify alkyl group.

In the present invention as Deputy optionally substituted alkyl group, R1you can specify alkoxygroup.

In the present invention as the substituent of the substituted carbonyl group, R1you can specify a hydroxyl group, alkoxygroup or alkylamino.

In the present invention as R2you can specify a hydrogen atom or optionally substituted alkyl group. As Deputy optionally substituted alkyl group, R2you can specify a hydroxyl group, alkanoyloxy group, halogen atom, alkoxygroup or alkylamino.

In this izobreteny the R 3aand R3bare the same or different from each other, and each of them represents a hydrogen atom or optionally substituted alkyl group, or a group that forms alkylenes group by linking all R3aand R3b. As Deputy optionally substituted alkyl group, you can specify a hydroxyl group, etc.

In the present invention, n can be specified as an integer equal to 1 or 2.

As the compound (I) according to the present invention, preferred is a compound in which ring A is a benzene ring represented by the formula:

in which A1represents an alkyl group, and A2represents a halogen atom,

ring B is a benzene ring represented by the formula:

B1represents trigalogenmetany group, B2represents trigalogenmetany group, R1represents a hydrogen atom, R2represents an alkyl group, R3aand R3bmay be the same or different from each other, and each of them represents a hydrogen atom or alkyl group. In addition, as the compound (I) of the present invention predpochtite is determined as being in a join, in which n is 2.

In addition, the compounds according to the present invention, preferred is a compound selected from the following list (a) to (g), or its pharmaceutically acceptable salt.

(a) 1,1-dioxo-4-(S)-[1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine,

(b) 1,1-dioxo-4-(R)-[1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine,

(c) 1,1-dioxo-4-(S)-[1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine,

(d) 1,1-dioxo-4-(R)-[1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine,

(e) 1,1-dioxo-4-(S)-[1-{N-(3,5-bistrifluormethylbenzene)methyl-N-methyl}-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine,

(f) 1,1-dioxo-4-(R)-[1-{N-(3,5-bistrifluormethylbenzene)methyl-N-methyl}-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine and

(g) 4-(S)-[1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]-1-Osotimehin.

The compound (I) of the present invention can be used for pharmaceutical purposes or in free form or in the form of pharmaceutically acceptable salts.

As pharmaceutically acceptable salts of the compounds is based (I) of the present invention can be specified for example, salt of an inorganic acid such as hydrochloride, sulfate, phosphate and hydrobromide; and salt of organic acid such as acetate, fumarate, oxalate, citrate, methanesulfonate, bansilalpet, tosylate, maleate, succinate and tartrate.

In addition, compound (I) of the present invention or its pharmaceutically acceptable salt includes its any internal salt, MES and hydrate, etc.

Although optical isomer based on an asymmetric carbon atom may be present in the compound (I) of the present invention, the present invention includes any data optical isomers and their mixtures. In the present invention among these optical isomers preferred is a compound having the R configuration at 2-position piperidino ring (connecting position of ring A).

The compound (I) or its pharmaceutically acceptable salt according to the present invention has an excellent antagonistic action on tachykinin receptors, in particular an antagonistic effect on the SP receptor, causing it applies as a safe drug for the prevention and treatment of inflammatory or allergic diseases (e.g. atopic dermatitis, dermatitis, herpes, psoriasis, asthma, bronchitis, expectoration, rhinitis, rheumatoid arthritis, osteoarthritis, is teoporosis, multiple sclerosis, conjunctivitis, OFTAL, cystitis etc), pain, migraine, neuralgia, pruritus, cough and, in addition, diseases of the Central nervous system (e.g., schizophrenia, Parkinson's disease, depression, anxiety, psychosomatic disorders, marvinney addiction, dementia (such as Alzheimer's disease, etc. and so on), digestive diseases (e.g., irritable bowel syndrome, ulcerative colitis, Crohn's disease, disorders (e.g., gastritis, gastric ulcers and so on)related to urease-positiveSpirillum(for example,helicobacter pylorietc), and so on), nausea, vomiting, urinary disorders (for example, pollakiuria, involuntary urination and so on), circulatory diseases (e.g., angina, hypertension, heart failure, thrombosis etc) and immune disorders, etc. in mammals (e.g., mice, Guinea pigs, clawed Mongolian gerbil, ferret, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc). In particular, since the compound (I) or its pharmaceutically acceptable salt, which are the active ingredient of the present invention, has a high penetration in the brain and has a low toxicity (high security), showing almost complete absence of side effects, it is applicable as Ter is non-therapeutic or prophylactic agent for diseases of the Central nervous system, such as vomiting, depression and the like, or urological disorders, such as pollakiuriya etc.

Measurements with the compound of the present invention or its pharmaceutically acceptable salt can be hold by the method described in European Journal of Pharmacology, vol. 254, pp. 221-227 (1994) relative to the binding action of the receptor neirokinina-1, by the method described in European Journal of Pharmacology, vol. 265, pp. 179-183 (1994) relative antagonistic action on the receptor neirokinina-1, and the method described in the Journal of Urology, vol. 155, No. 1, pp. 355 to 360 above (1996) regarding the overwhelming effects on pollakiuria.

The compound (I) or its pharmaceutically acceptable salt according to the present invention can be administered orally or parenterally, and it can be a suitable formulation of the drug, using traditionally applied pharmaceutical carrier for oral or parenteral administration. As such a pharmaceutical carrier, you can specify, for example, binder (syrup, Arabian gum, gelatin, sorbitol, tragacanth gum, polyvinylpyrrolidone, etc.), filler (lactose, sugar, corn starch, potassium phosphate, sorbitol, glycine, etc.), lubricating agent (magnesium stearate, talc, polyethylene glycol, silicon dioxide and so on), a substance that promotes raspadaemosti dosage forms (potato starch, etc. and flaneuse agent (anhydrous sodium dodecyl sulfate, etc. and similar. In addition, when the data of pharmaceutical drugs administered orally, they may be a solid preparation such as tablets, granules, capsules, and powders, or liquid preparation, such as solution, suspension and emulsion. On the other hand, when they are administered parenterally, they can be administered, for example, in the form of solution for injection or infusion solution using distilled water for injection, physiological saline, aqueous glucose solution, etc. or you can enter them in the form of a suppository and similar dosage forms.

The dose of compound (I) or its pharmaceutically acceptable salt according to the present invention may vary depending on the method of administration, age, body mass or condition of the patient, etc. and, for example, in the case of oral administration injected dose is usually from 0.01 to 20 mg/kg per day, and especially preferably from 0.01 to 10 mg/kg per day, and in the case of parenteral administration the usual dose is from 0.01 to 10 mg/kg / day, particularly preferably from 0.01 to 1 mg/kg per day.

[Method A]

The preferred compound (I) of the present invention can be obtained, for example, by the interaction of the compounds represented by formula (II):

in which ring A represents an optionally substituted benzene ring;

to Liza B represents an optionally substituted benzene ring;

R1represents a hydrogen atom, optionally substituted hydroxyl group, optionally substituted by an amino group, an optionally substituted alkyl group, substituted carbonyl group or a halogen atom;

R2represents a hydrogen atom or optionally substituted alkyl group; and

R3aand R3bmay be the same or different from each other, and each of them represents a hydrogen atom or optionally substituted alkyl group, or a group that forms alkylenes group at the ends,

in the presence of an oxidant.

[Method B]

The preferred compound (I) of the present invention can be obtained, for example, by the interaction of the compounds represented by formula (III):

in which ring A, R1and n have the same meanings as defined above,

with the compound represented by formula (IV):

in which ring B, R2, R3aand R3bhave the same meanings as defined above,

in the presence of the reagent, forming a urea bond.

[Method C]

The preferred compound (I) of the present invention can be obtained, for example, by the interaction of the compounds represented by formula (V)or its salt:

in which ring A, ring B, R1, R2, R3aand R3bhave the same meanings as defined above,

with the compound represented by formula (VI):

in which n has the same meaning as defined above, in the presence of a base.

These methods [method A]-[method C] can be carried out as follows.

[Method A]

This method of obtaining can be accomplished by interaction of the compound (II) in the presence of an oxidant in a suitable solvent. As oxidant here you can specify, for example, 3-chloroperbenzoic acid, peracetic acid, periodate sodium, OXONE, etc. in Addition, the solvent can be any solvent provided that it does not exert any harmful influence on the reaction, and, for example, optional can be used dichloromethane, chloroform, acetonitrile, dimethoxyethane, tetrahydrofuran, water, etc. This reaction can be performed, for example, at temperatures from -80°C to 150°C, preferably from 0°C to 50°C.

[Method B]

The interaction of the compound (III) with compound (IV) can be performed in the presence of compounds forming a urea bond, in a suitable solvent. As a compound forming a urea bond, here you can specify the connection represented by the formula:

in which group W1and W2may be the same or different from each other, and each of them represents a leaving group.

W1and W2may be the same or different from each other, and each of them can be imidazolidinyl group, halogen atom or fenoxaprop. Specifically, preferred are 1,1'-carbonyldiimidazole, phosgene, etc. and, for example, you can use carbonylchloride, such as 1,1'-carbonyldiimidazole, triphosgene or phosgene, etc. in Addition, the solvent can be any solvent provided that it does not exert any harmful influence on the reaction, and, for example, optional can be used acetonitrile, dichloromethane, tetrahydrofuran, etc. This reaction can be performed, for example, at a temperature from 0°C to 80°C, preferably from 0°C to 50°C.

Moreover, this reaction can be accomplished by the interaction of the compound (III) with the compound, forming a urea bond represented by the formula:

in which group W1and W2have the same meanings as defined above,

receiving the compound represented by formula (VII):

in which ring A, R1, W2and n have the same meanings as defined above,/p>

then the compound (VII) is converted into its reactive derivative, and implement its interaction with the compound (IV), or interaction of the compound (IV) with the compound, forming a urea bond represented by the formula:

in which W1and W2have the same meanings as defined above,

receiving the compound represented by formula (VIII):

in which ring B, R2, R3a, R3band W2have the same meanings as defined above,

then the compound (VIII) is converted into its reactive derivative and implement its interaction with the compound (III)to give compound (I).

As reactive derivatives can specify, for example, compound (VII) or compound (VIII), the compound in which W2turn to the group represented by the formula:

The interaction between the compound (III) or compound (IV) and the reagent, forming a urea bond can be carried out for example at temperatures from 0°C to 80°C, preferably from 0°C to 50°C. in Addition, the solvent can be any solvent provided that it does not exert any harmful influence on the reaction, and, for example, optional can be used acetonitrile, dig orotan, tetrahydrofuran, etc.

The reaction which converts the compound (VII) or compound (VIII) in their reactive derivatives can be carried out, for example, using reactive giver derived reagent, such as methyliodide, at a temperature from 0°C to 80°C, preferably from 0°C to 50°C. in Addition, the solvent can be any solvent provided that it does not exert any harmful influence on the reaction, and optionally can be used, for example, acetonitrile, dichloromethane, tetrahydrofuran, etc.

The interaction of the corresponding reactive derivative and the compound (III) or compound (IV) can be performed, for example, in the presence of a base at a temperature from 0°C to 80°C, preferably from 0°C to 50°C. in Addition, as a base, you can use any substance, such as triethylamine, etc. and the solvent can be used any substance, provided that it does not exert any harmful effects on the reaction and, for example, optional can be used toluene, acetonitrile, dichloromethane, tetrahydrofuran, etc.

[Method C]

The interaction of compounds (V) and compound (VI) can be performed in the presence of a base in a suitable solvent. As a basis you can specify, for example, organic base, tacocat the triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 1,8-diazabicyclo-[5.4.0]undec-7-ene, etc. or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, tert-piperonyl potassium, etc. in Addition, the solvent can be any solvent provided that it does not exert any harmful influence on the reaction, and optionally can be used, for example, methanol, ethanol, isopropanol, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, ethyl acetate, toluene, etc. or a mixed solvent or mixture of solvents, or a mixed solvent and water. As the salt of compound (V) can be specified, for example, salt of an inorganic acid such as hydrochloride, hydrobromide, sulfate, etc., and salt of organic acid, such as methanesulfonate, p-toluensulfonate, acetate, carbonate, triptorelin etc. This reaction can be performed, for example, at a temperature from 10°C to temperature flavobacteria, preferably, from 50°C to 120°C.

In particular, the compound represented by formula (IX):

in which ring A, ring B, R1, R2, R3aand R3bhave the same meanings as defined above,

or its optical isomer can be prepared by the method described in WO 2003/099787.

The is a group (II) can be obtained subjecting a mixture of the compound (IX) or its salt and thiomorpholine in a suitable solvent recovery aminating. This reductive amination can be performed under acidic conditions, conducting the hydrogenation reducing agent such as sodium borohydride, triacetoxyborohydride sodium, cyanoborohydride sodium, etc. or regenerating a catalyst, such as palladium, etc. as the solvent can be any solvent provided that it does not exert any harmful influence on the reaction, and optionally can be used, for example, dichloromethane, acetic acid, ethanol, methanol, etc. as a salt of compound (IX) is optional, you can use the hydrochloride, acetate, etc. This reaction can be performed, for example, at a temperature of from -10°C to 80°C, preferably from 0°C to 30°C.

In addition, the compound represented by formula (X):

in which R4represents a hydrogen atom or a protective group for the amino group, the ring A and R1have the same meanings as defined above,

or its optical isomer can be prepared by the method described in WO 2002/032867.

As a protective group for amino group, R4you can specify alkoxycarbonyl group, such as tert-butoxycarbonyl group, etc. and arillas carbonyloxy group, such as benzyloxycarbonyl group, etc.

The compound (III) can be obtained by subjecting a mixture of the compound (X) or its salt and thiomorpholine recovery aminating in a suitable solvent, and when R4represents a protective group for the amino group, the protective group is then removed. Reductive amination can be performed under acidic conditions, conducting the hydrogenation reducing agent such as sodium borohydride, triacetoxyborohydride sodium, cyanoborohydride sodium, etc. or regenerating a catalyst, such as palladium, etc. as the solvent can be any solvent provided that it does not exert any harmful influence on the reaction, and optionally can be used, for example, dichloromethane, acetic acid, ethanol, methanol, etc. as a salt of compound (X) is optional, you can use the hydrochloride, acetate, etc. This reaction can be performed, for example, at temperatures from -10°C to 80°C, preferably from 0°C to 30°C. in Addition, the removal of the protective group of the amino group can be performed in the traditional way.

In addition, the compound represented by formula (XI):

in which ring A, ring B, R1, R2, R3aand R3bhave the same meanings as defined above,

or opt the ical isomer can be prepared by the method, described in WO 2003/099787.

The compound represented by formula (XII):

in which ring A, ring B, R1, R2, R3aand R3bhave the same meanings as defined above,

or its optical isomer can be prepared by the method described in WO 2003/099787.

In addition, the compound (III) can be prepared in the same way the above-mentioned method C, for example, by the interaction of the compounds represented by formula (XIII)or its salt:

in which ring A, R1and R4have the same meanings as defined above,

and compounds represented by the formula (VI):

in which n has the same meanings as defined above, in the presence of a base, and then removing the protective group of amino group (R4), if desired.

In addition, to achieve the desired connection and the source connection of the present invention, when the starting compound or the corresponding intermediate compounds have functional group(s)to the appropriate functional group(s) enter an appropriate protective group conventional methods of synthetic chemistry, other than those specified above, and, if they are not necessary, these protective groups can optionally be removed.

In the present description, the alkyl gr what PLR means, for example, an alkyl group with straight or branched chain, containing from 1 to 6 carbon atoms, such as methyl group, ethyl group, through the group, isopropyl group, bucilina group, isobutylene group, tert-bucilina group, isopentyl group, etc. are preferably groups containing from 1 to 4 carbon atoms. Alchemilla group denotes, for example, alkenylphenol group with a straight or branched chain, containing from 2 to 7 carbon atoms, such as vinyl group, allyl group, protanilla group, isopropylene group, etc. are preferably groups containing from 2 to 5 carbon atoms. Alkoxygroup means, for example, alkoxygroup straight or branched chain, containing from 1 to 6 carbon atoms, such as methoxy group, ethoxypropan, propoxylate, isopropoxide, butoxypropan etc. preferably groups containing from 1 to 4 carbon atoms. Alcoolica group denotes, for example, alkanoyloxy group with a straight or branched chain, containing from 1 to 6 carbon atoms, such as formyl group, acetyl group, propylaniline group, Butyrina group, valerina group, tert-butylcellosolve group, etc. are preferably groups containing from 1 to 4 carbon atoms. Cycloalkyl group denotes, for example, cycloalkyl group is, containing from 3 to 8 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, etc. are preferably groups containing from 3 to 6 carbon atoms. In addition, the halogen atoms are illustrated by a chlorine atom, a bromine atom, a fluorine atom or iodine atom.

[Example]

Example 1

To 2 ml of dichloromethane solution containing 90 mg of 4-(S)-[1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine, was added to 0.02 ml methanesulfonic acid and 105 mg of meta-chloroperbenzoic acid and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added aqueous sodium thiosulfate solution and the resulting mixture was stirred at room temperature for 30 minutes. To the mixture were added water and chloroform, the liquid was separated and the aqueous layer was again extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified primary column chromatography on silica gel (n-hexane:ethyl acetate=3:1) and then column chromatography on silica gel (chloroform:ethyl acetate=3:1)to give 44 mg of 1,1-dioxo-4-(S)-[1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}--methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine, shown in the following table 1.

Examples 2-6

Using the appropriate source materials, was carried out by the same procedure as in example 1, obtaining the compounds shown in the following tables 1 and 2.

Example 7

To 5 ml of a dichloromethane solution containing 80 mg of 4-(S)-[1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine was added dropwise 0,034 ml of 4M hydrochloric acid solution in 1,4-dioxane), then to this mixture was added 33 mg of meta-chloroperbenzoic acid (70%) at -10°C and the resulting mixture was stirred for one hour. To the reaction mixture was added aqueous sodium hydrogen carbonate solution and dichloromethane and then the liquid was separated. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and the residue was purified column chromatography on silica gel (chloroform: methanol=19:1). The product was liofilizovane tert-butanol, receiving 50 mg of 4-(S)-[1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]-1-Osotimehin shown in the following table 2.

Example 8

To 15 ml of 1,4-dioxane containing 11.3 g of (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-tert-butoxycarbonylamino-2-(4-ft is R-2-were)piperidine, was added dropwise in 45 ml of 4M hydrochloric acid solution in 1,4-dioxane) and the resulting mixture was stirred for two hours at room temperature. The solvent was removed under reduced pressure and the residue was dried under vacuum. To 50 ml of ethanol containing this residue was added 3 g of diphenylsulfone and 5.1 g of triethylamine, and the resulting mixture was stirred for two and a half hours while boiling under reflux. The solvent was removed under reduced pressure and the residue was led from diisopropyl ether, receiving 10.3 g of the same compounds as in the above example 1.

Comparative example 1

To 60 ml of tetrahydrofuran containing 3,91 g of N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methylamine was added 2,34 g of 1,1'-carbonyldiimidazole, and the mixture was stirred at 40°C during the night. After removal of the solvent from the reaction mixture, to the residue was added ethyl acetate and the organic layers were washed with water and saturated salt solution, dried and the solvent drove away. The residue was led from diisopropyl ether and collected by filtration. The obtained white crystals were dissolved in 60 ml of acetonitrile, and then to the solution was added 3.4 ml of methyliodide, cooperated mixture at 60°C for 2 hours and the solvent drove away. Estato is dissolved in 40 ml dichloromethane and cooled in an ice bath, the solution was added 3,47 g of 2-(4-fluoro-2-were)-4,4-dimethoxypyridine and 3,82 ml of triethylamine and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, liquids were separated, and the aqueous layer was extracted with dichloromethane. All organic layers were washed with water and saturated salt solution, dried and the solvent drove away. The residue was dissolved in 90 ml of tetrahydrofuran, while cooling in an ice bath, the solution was added 30 ml of a 1M aqueous solution of sulfuric acid and the mixture was stirred at room temperature for 5 hours. After adjusting the pH of the mixture up to 8-9 using 1M aqueous solution of sodium hydroxide tetrahydrofuran drove away, to the residue were added water and ethyl acetate and the liquids were separated, and the aqueous layer was again extracted with ethyl acetate. All organic layers were washed with water and saturated salt solution, dried and the solvent drove away. The residue was purified column chromatography on silica gel (hexane: ethyl acetate=2:1), receiving a 2.12 g of (2R)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-were)-4-oxopiperidine shown in the following table 3.

Comparative examples 2 and 3

Using the appropriate source materials, was carried out by the same procedure as in comparative example 1, obtaining the compounds shown in the following table 3.

Comparative example 4

To 15 ml of dichloromethane solution containing 504 mg (2R)-1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarb the Il-2-(4-fluoro-2-were)-4-oxopiperidine, 155 mg thiomorpholine and 0,057 ml of acetic acid was added 446 mg triacetoxyborohydride sodium and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 52 mg thiomorpholine and 112 mg of triacetoxyborohydride sodium and the mixture was additionally stirred at room temperature for 3 hours. To the mixture were added water and chloroform, the liquid was separated and the aqueous layer was again extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified primary column chromatography on silica gel (n-hexane: ethyl acetate=3:1) and then column chromatography on silica gel (chloroform: ethyl acetate=3:1)to give 92 mg (a) 4-(S)-[2-(R)-(4-fluoro-2-were)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-yl]thiomorpholine and 164 mg (b) 4-(R)-[2-(R)-(4-fluoro-2-were)-1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-yl]thiomorpholine shown in the following table 3.

Comparative examples 5 and 6

Using the appropriate source materials, was carried out by the same procedure as in comparative example 4, when receiving the connection shown in the following table 4.

Comparative example 7

To a solution of N,N-dimethylformamide, containing 280 mg of (2R,4R)-1-[N-{1-()-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]aminocarbonyl-4-bromo-2-(4-fluoro-2-were)piperidine, was added 0.2 ml thiomorpholine and the mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (n-hexane: ethyl acetate=1:3)to give 80 mg of the same compounds as in the above comparative example 4(a).

Table 1

Table 2

Table 3

Table 4

Industrial applicability of the invention

Compounds of the present invention have an excellent antagonistic action on tachykinin receptors. In addition, the compounds of the present invention have high safety and excellent in absorption, penetration into the brain, stability, metabolism, blood concentrations, stability, etc. and, thus, have excellent medical action.

Example 9

In accordance with the method described in European Journal of Pharmacology, vol 254, str-227 (1994), the cells IM-9 (4×106cells in vitro) with 0.3 nm [3H] (Sar9, Met11(O2)) substance P (constant Kd=0,17 nm) and 10 nm analyte is incubated in 0.5 ml of 50 mm Tris-HCl (pH of 7.4, 25°C)containing 150 mm NaCl, 3 mm MnCl2, 40 μg/ml bacitracin, 4 μg/ml leupeptin, 4 is kg/ml hemostasia, 4 μg/ml of phosphoramidon and 0.02% bovine serum albumin at room temperature for 60 minutes. After incubation, the cells were collected by vacuum filtration through a glass filter GF/C, pre-treated with 0.3% polyethylenimine. Cells were washed two times with 3 ml ice-cold reagent buffer in the absence of bovine serum albumin and various protease inhibitors. Radioactivity (dpm = number of polarizado per minute) of the filter was determined with a liquid scintillation counter. The exact binding amount was determined by subtracting nonspecific binding (receptor antagonist neirokinina-1 L-703606, 2 ál) of the total linking number. Used to calculate the degree of inhibition of the compounds (10 nm) on the specificity of binding of the labeled ligand.

The results of the study are given in table 5.

Table 5.
Room dimensionsThe degree of inhibition (%)
189
286
378
464
94
675

Example 10

Getting pills.

Got a tablet weighing 180 mg standard technology components 1-6, as described below.

IngredientAmount (mg)
1. connection example 140
2. lactose38
3. hydroxypropylcellulose2
4. cross-linked carboxymethyl cellulose sodium9
5. DILACTOSE®89,2
6. magnesium stearate1,8

1. Connection thiomorpholine represented by the formula (I)

in which ring a is a benzene ring represented by the formula

in which And1represents a C1-6is an alkyl group, and2represents a halogen atom,
the ring is a benzene ring represented by the formula
,
which1is trihalogen-C1-6is an alkyl group, and2is trihalogen-C1-6is an alkyl group,
R1represents a hydrogen atom, R2represents a C1-6is an alkyl group, R3aand R3bare the same or different from each other, and each of them represents a hydrogen atom or a C1-6is an alkyl group and
n is an integer equal to 2
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, selected from the following list (a) to (f):
(a) 1,1-dioxo-4-(S)-[1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine,
(b) 1,1-dioxo-4-(R)-[1-[N-{1-(R)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine,
(c) 1,1-dioxo-4-(S)-[1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine,
(d) 1,1-dioxo-4-(R)-[1-[N-{1-(S)-(3,5-bistrifluormethylbenzene)ethyl}-N-methyl]-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine,
(e) 1,1-dioxo-4-(S)-[1-{N-(3,5-bistrifluormethylbenzene)methyl-N-methyl}-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]thiomorpholine,
(f) 1,1-dioxo-4-(R)-[1-{N-(3,5-bistrifluormethylbenzene)methyl-N-methyl}-2-(R)-(4-fluoro-2-were)aminocarbonylmethyl-4-yl]imartin or its pharmaceutically acceptable salt.

3. The method of obtaining compounds of thiomorpholine represented by the formula (I)

in which ring a is a benzene ring represented by the formula

in which And1represents a C1-6is an alkyl group, and2represents a halogen atom,
the ring is a benzene ring represented by the formula
,
which1is trihalogen-C1-6is an alkyl group, and2is trihalogen-C1-6is an alkyl group,
R1represents a hydrogen atom, R2represents a C1-6is an alkyl group, R3aand R3bare the same or different from each other, and each of them represents a hydrogen atom or a C1-6is an alkyl group and
n is an integer equal to 2
or its pharmaceutically acceptable salt,
which includes the interaction of the compounds represented by formula (II)

in which ring A, ring B, R1, R2, R3aand R3bhave the same meanings as defined above,
in the presence of an oxidant, and then the transformation of the product into its pharmaceutically acceptable salt, if desired.

4. Pharmaceutical HDMI is tion for the treatment and prevention of diseases, selected from inflammation, allergic diseases, pain, migraine, neuralgia, pruritus, cough, Central nervous system diseases, diseases of the digestive system, nausea, vomiting, urological disorders, comprising a compound according to any one of claims 1 or 2, in a clinically effective amount and a pharmaceutically acceptable carrier.

5. The use of compounds according to any one of claims 1 or 2 for the preparation of drugs for treatment and prophylaxis of diseases selected from inflammation, allergic diseases, pain, migraine, neuralgia, pruritus, cough, Central nervous system diseases, diseases of the digestive system, nausea, vomiting, urological disorders.

6. The use according to claim 5, in which the disease is a urological disorder.



 

Same patents:

Gsk-3 inhibitors // 2379300

FIELD: medicine.

SUBSTANCE: invention concerns GSK-3 inhibitors of general formula (I), method for making thereof and based pharmaceutical compositions which can be used in medicine: formula I, where R1 means an organic group containing at least 8 atoms, chosen of C or O, including aromatic ring of phenyl, naphthyl or methylene dioxypjenyl, which is not bound directly with N through -C(O)- or oxygen; Ra, Rb, Rz, R3, R4, R5 and R6 represent hydrogen.

EFFECT: production of new biologically active compounds for treatment of GSK-3 mediated diseases.

28 cl, 13 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzyloxy-derivatives of general formula (I) , where R1 is a halogen; R2 is a 5-member heteroaryl group containing 2 or 3 heteroatoms selected from a group consisting of N, O or S, which can be substituted with R3, where R3 is a lower alkyl or -C(O)R; R is -NR'R" or lower alkoxy; R'/R" independently represent H; as well as to their pharmaceutically acceptable salts. Formula I compounds inhibit monoamine oxidase B.

EFFECT: compounds can be used for preparing a medicinal agent.

5 cl, 15 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of aryl and heteroarylpiperidinecarboxylates, of formula (I): , where: type means integer numbers from 1 to 3, such that m+n is integer number from 2 to 5; p means integer number from 1 to 7; A means simple connection or is selected from one or several groups X, Y; X means -CH2-; Y means C2-alkynilene group; R1 means group R5, substituted with one or several groups R6 and/or R7; R2 means H, F, OH; R3 means H; R4 means H, C1-6-alkyl; R5 means group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinolynyl, tetrahydrochinolinyl, isochinolinyl, tetrahydroisochinolinyl, indolyl, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzizoxazolyl, benzothiazolyl, benzithiazolyl, benzotriazolyl, benzoxadiazolyl, pyrrolopyridinyl; R6 means halogen, CN, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, OH, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, or cycle selected from pyrrolidine and piperidine cycle, besides this cycle is unnecessarily substituted with C1-6-alkyl group; R7 means phenyl group, besides group or groups R7 may be substituted with one or several groups R6, identical or differing from each other, selected from halogen, C1-6-alkyl and C1-6-fluoroalkyl, C1-6-alkoxy, in the form of pharmaceutically acceptable base or acid-additive salt.

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10 cl, 1 tbl, 7 ex

FIELD: medicine.

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10 cl, 1 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I) , A means phenyl or pyridyl cycle, R1 and R3 each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R4 means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO2 possibly substituted with ketogroup, R5 means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y1, Y2, Y3, Y4 and Y5 each means CH-group. Invention is also related to pharmaceutical composition.

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8 cl, 1 dwg, 111 ex

FIELD: medicine.

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16 cl, 5 tbl, 40 ex

FIELD: medicine.

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EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

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9 cl, 170 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2-heteroaryl derivatives of benzothiazole and benzoxazole of formula by boiling amine with general formula with acid chloride of general formula , where R=2-furyl or 2-thienyl, X = S or O, in 1-methyl-2-pyrrolidone.

EFFECT: method increases output of product to 78 to 90% and environmental friendliness of the process.

1 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

Novel insecticides // 2379301

FIELD: chemistry.

SUBSTANCE: compounds with formula I are described, where each of E and Z is oxygen; A is C1-C6alkylene or a 3-member monocyclic ring system, which can be monosubstituted; Y is C1-C6alkylene; p equals 0; q equals 0 or 1; B represents a 3- or 4-member ring system which is completely or partially saturated and can contain a heteroatom selected from oxygen, possibly substituted; each R1 independently represents halogen, nitro group, C1-C6alkyl; or each R1 independently represents an amino group; n equals 1, 2; each of R2 and R3 represents hydrogen; D represents a group and agronomically acceptable salts of said compounds. Also described is a method of producing formula I compounds, intermediate compounds, a pesticide composition containing a formula I compound, as well as an insect control method and a method of protecting plant propagation material.

EFFECT: novel anthranylamide derivatives have good insecticidal activity.

16 cl, 8 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: chemistry.

SUBSTANCE: novel isoquinoline derivatives are described by general formula I, where q equals zero; p equals zero or one; Ra is -COOH or WR8; under the condition that, if Ra is -COOH, then p equals zero, and if Ra is -WR8, then p equals one; W is selected from an oxygen atom and -NR9-, where R9 is selected from a group consisting of a hydrogen atom, acyl and alkyl; and R8 is selected from a group consisting of a hydrogen atom and alkyl; R1 is selected from a group consisting of a hydrogen atom, alkyl, alkyl substituted with one group selected from alkoxy and dialkylamino, a halogen atom, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl substituted with alkyl, and -XR6, where X is an oxygen atom, -S(O)n- or -NR7, where n equals zero, one or two, R6 is selected from a group consisting of alkyl, aryl, aryl substituted with one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamide, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, and R7 is a hydrogen atom or aryl; R2 and R3 are independently selected from a group consisting of a hydrogen atom, amino, amino substituted with alkoxy-substituted phenylsulfonyl, alkyl, alkyl substituted with up to three times by a halogen atom, aryl, halogen atom -NR6C(O)NR6R6, and -XR6, where X is an oxygen atom or -S(O)n-, where n equals zero, one or two, each of the substitutes R6 is independently selected from a group consisting of hydrogen, alkyl, alkyl substituted with aryl, aryl , aryl substituted with one or two groups selected from a halogen atom, alkyl, alkyl substituted with up to three times by a halogen, alkoxy, alkoxy substituted with up to three times by a halogen, aryloxy substituted with a halogen, nitro, alkylsulfonamide, arylsulfonamide and alkyl-substituted arylsulfonamide, cycloalkyl, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, under the condition that if X is -SO2-, R6 cannot be a hydrogen atom; or R2 and R3 together with carbon atoms to which they are bonded, are bonded with formation of an aryl group; R4 and R5 are independently selected from a hydrogen atom or aryl; R is selected from a group which includes a hydrogen atom, deuterium and methyl; R' is selected from a group consisting of a hydrogen atom, deuterium, alkyl or alkyl substituted with one group selected from hydroxyl, amino, carboxyl, aryl, aryl substituted with one hydroxyl and heteroaryl, containing up to five carbon atoms, two of which can be nitrogen; on the other hand, R and R' and the carbon atom to which they are bonded can be bonded with formation of cycloalkyl; R" is formed from a hydrogen atom and alkyl, or R" together with R' and the nitrogen atom to which they are bonded can be bonded with formation of a heterocyclic group containing up to six carbon atoms, one of which is nitrogen; R'" is selected from a group consisting of hydroxyl, alkoxy, alkoxy substituted with aryl, acyloxy, aryl, -S(O)n-R10, where R10 is hydrogen, and n is zero; or its pharmaceutically acceptable salts, esters or amides; under the condition that restrictive conditions given in paragraph 1 of the formula of invention are met. The invention also relates to specific produced and described compounds, a pharmaceutical composition based on compounds with general formula I, a method of treating, preventing and pretreatment using said pharmaceutical composition, a method of inhibiting activity of hydrolase enzyme, based on taking an effective amount of a formula I compound, a composition for preventing and pretreatment, based on formula I compound and erythropoietin.

EFFECT: new isoquinoline derivatives have useful biological properties.

53 cl, 4 tbl, 253 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted derivatives of N-(3-benzoylaminophenyl)-4-pyridyl-2-pyrimidine amine of general formula (I), with inhibitory activity towards protein kinase, method of producing said derivatives and pharmaceutical compositions based on the derivatives. In the compound of formula 1 R1 is hydrogen and R2 is NR5R6, or R1 is NR5R6 and R2 is hydrogen; R3 is trifluoromethyl; R4 is lower alkyl; and R5 and R6 are independently hydrogen, lower alkyl, di(lower alkyl)amino-lower alkyl, N-lower alkylpiperidinyl, N-lower alkylpyrrolidinyl, or lower alkyl, or NR5R6 together represent pyrrolidino, piperidino, morpholino, N-lower alkylpiperazino, 1N-imidazolyl, 1H-2-lower alkylimidazolyl, 1H-4-lower alkylimidazolyl or 1H-2,4-di-lower alkylimidazolyl, or a pharmaceutically acceptable salt of such a compound.

EFFECT: compounds can be used in treating diseases related to inhibition of protein kinase activity, such as neoplastic diseases or leukaemia.

13 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) , where R1 is hydrogen, C1-C7 alkyl; R2 is C1-C7 alkyl, aryl, C1-C7 haloalkyl or C3-C8 cycloalkyl; R3, R4 each independently represents hydrogen, halogen, C1-C7 alkoxy, C1-C7 alkylsuphonyl; R5 is hydrogen, halogen, C1-C7 alkyl, C1-C7 haloalkoxy, or aryloxy, or is -NR7R8, where R7 and R8 represent C1-C7 alkyls, or R7 and R8 together with the nitrogen atom to which they are bonded can form a 4-7-member heterocycloalkyl group, which can be substituted with one or more substitutes selected from a group consisting of halogen, C1-C7 alkyl, C1-C7 alkoxy, hydroxyl, phenyl and di(C1-C7)alkylamino; R6 is hydrogen or together with R5 can form a 5- or 6-member heterocycloalkyl group which can be substituted with one or more halogens; and their pharmaceutically acceptable salts of acid compound, except the range of compounds given in paragraph 1 of the formula of invention. The invention also relates to medicine based on said compounds, with activity of allosteric enhancer of GABA-B receptors and use of compounds of the formula to prepare medicines used in treating central nervous system disorders, including anxiety and depression.

EFFECT: novel compounds are obtained and described, which can be used for preparing medicines used in treating central nervous system disorders, including anxiety and depression.

14 cl, 58 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of aryl and heteroarylpiperidinecarboxylates, of formula (I): , where: type means integer numbers from 1 to 3, such that m+n is integer number from 2 to 5; p means integer number from 1 to 7; A means simple connection or is selected from one or several groups X, Y; X means -CH2-; Y means C2-alkynilene group; R1 means group R5, substituted with one or several groups R6 and/or R7; R2 means H, F, OH; R3 means H; R4 means H, C1-6-alkyl; R5 means group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinolynyl, tetrahydrochinolinyl, isochinolinyl, tetrahydroisochinolinyl, indolyl, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzizoxazolyl, benzothiazolyl, benzithiazolyl, benzotriazolyl, benzoxadiazolyl, pyrrolopyridinyl; R6 means halogen, CN, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, OH, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, or cycle selected from pyrrolidine and piperidine cycle, besides this cycle is unnecessarily substituted with C1-6-alkyl group; R7 means phenyl group, besides group or groups R7 may be substituted with one or several groups R6, identical or differing from each other, selected from halogen, C1-6-alkyl and C1-6-fluoroalkyl, C1-6-alkoxy, in the form of pharmaceutically acceptable base or acid-additive salt.

EFFECT: compounds are applicable as inhibitors of FAAH ferment.

10 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds of formula I , or its pharmaceutically acceptable salt of this, in which: R1 means C1-6-aliphatic group, besides, R1 may be substituted with substituents in number of up to 2 groups, independently selected from -OR or -C1-3 halogenalkyl; each R independently means hydrogen or C1-4-aliphatic group; R2 means R, fluorine or chlorine; m means 0, 1 or 2; and R3 means hydrogen, C1-3-aliphatic group, fluorine or chlorine, to composition for inhibition of activity of protein kinase ERK1 or ERK2, on the basis of these compounds, to method for inhibition of activity of protein kinase ERK1 or ERK2, and also to use of compounds of formula I or composition on their basis, for treatment or reduction of disease severity.

EFFECT: new compounds are produced and described, which may be used as inhibitors of protein kinases.

11 cl, 7 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I) , A means phenyl or pyridyl cycle, R1 and R3 each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R4 means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO2 possibly substituted with ketogroup, R5 means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y1, Y2, Y3, Y4 and Y5 each means CH-group. Invention is also related to pharmaceutical composition.

EFFECT: possibility of application for treatment of chronic obstructive lung diseases, acute coronary syndrome, acute myocardial infarction and progressing cardiac decompensation.

8 cl, 1 dwg, 111 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

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