Purinyl derivatives and use thereof as potassium channel modulators

FIELD: chemistry.

SUBSTANCE: present invention relates to novel purinyl derivatives of formula or , a stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, where n equals 0, 1, 2 or 3; X is O, S or NR', where R' is hydrogen or methyl; Y is cycloalkyl, phenyl, benzo[1,3]dioxolyl or pyridyl, where the cycloalkyl, phenyl, benzo[1,3]dioxolyl and pyridyl are possibly substituted with one substitute selected from a group consisting of halogen, trifluoromethyl, cyano, nitro and amine; R1 is hydrogen, alkyl or alkoxy-alkyl; and Het is a pyrazolyl group which is substituted twice or more with substitutes selected from a group consisting of alkyl, hydroxy-alkyl, halogen, trifluoromethyl, alkoxy-carbonyl and phenyl. The invention also relates to pharmaceutical compositions which are useful for treating or relieving symptoms of diseases and disorders associated with activity of potassium channels.

EFFECT: novel compounds which can be used as potassium channel modulators are obtained and described.

12 cl, 16 ex

 

The scope of the invention

This invention relates to new derivatives of purine and their use as agents for modulation of potassium channels. In addition, the invention relates to pharmaceutical compositions useful for the treatment or relief of symptoms of diseases or disorders associated with the activity of potassium channels.

Prior art

Ion channels are transmembrane proteins that catalyze the transport of inorganic ions across cell membranes. Ion channels are involved in such diverse processes as the generation and duration of action potentials, synaptic transmission, secretion of hormones, muscle contraction, and so forth.

All mammalian cells Express a potassium (K+) channels in their cell membranes, and these channels play a major role in the regulation of membrane potential. In nerve and muscle cells they regulate the frequency and the shape of the action potential, release of neurotransmitters and the degree of broncho - and vasodilation.

From a molecular point of view,+channels represent the largest and most diverse group of ion channels. In short, they can be divided into five major subfamilies: the potential-activated K+-channels (Kv),+-channels associated with outlining the m QT interval (KvLQT), channels internal straightening (KIR),+-channels with two pore (KTP) and calcium-activated K+-channels (KCA).

The last group, the CA2+-activated K+-view channels, consists of three clearly defined subtypes: SK-channels, C-channels and BK channels. SK, IK and VK are related to the conductivity of a single channel (the channel with a low (small), intermediate and high (big) conductivity). SK, IK and BK-channels are differences, such as sensitivity to the potential and calcium, pharmacological parameters, distribution and operation.

SK-channels are present in many Central neurons and ganglia, where their primary function is to hyperpolarization of nerve cells after one or more action potentials, in order to prevent long-term distribution arising epileptic activity. SK channels are also present in some peripheral cells, including skeletal muscle, glandular cells, liver cells and T-lymphocytes. The value of SK channels in normal skeletal muscle is not clear, but their number significantly increased in denervated muscle, and a large number of SK channels in the muscle of patients with motonishi muscular dystrophy confirms their role in the pathogenesis of this disease.

Studies show that+-channels can imagine with the Oh therapeutic target in the treatment of several diseases, including asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vasospasm, a spasm of coronary arteries, renal disorders, polycystic kidney disease, bladder spasms, overactive bladder, urinary incontinence, syndrome infravesical obstruction, interstitial cystitis, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic heart disease, angina, coronary heart disease, traumatic brain injury, psychosis, anxiety, depression, dementia, disorders of memory and attention, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud's disease, alternating lameness, Sjogren syndrome, migraine, pain, arrhythmias, hypertension, small epileptic seizures, myotonias muscular dystrophy, xerostomia, diabetes type II, hyperinsulinemia, premature labour, alopecia, cancer, and immunosuppression.

A brief description of the invention

The present invention is to offer new chemical compounds capable of modulating SK-channels or subtypes of SK-channels.

Thus, in the first aspect according to the invention proposed new derived purine formula Ia or Ib

its isomer or a mixture of its isomers, N-is xed, its prodrug or pharmaceutically acceptable salt, where

n is 0, 1, 2 or 3;

X represents O, S or NR', where R' represents hydrogen, alkyl, cycloalkyl, phenyl or benzyl;

Y represents alkyl, cycloalkyl, phenyl, benzo[1,3]dioxole or pyridyl, where the alkyl, cycloalkyl, phenyl, benzo[1,3]dioxole and pyridyl possibly substituted by one Deputy, selected from the group consisting of alkyl, cycloalkyl, halogeno, trifloromethyl, triptoreline, hydroxy, alkoxy, cyano, nitro and amino;

R1represents hydrogen, alkyl or alkoxy-alkyl; and

Het represents a heterocyclic group selected from pyrazolyl, imidazolyl, indazole, benzimidazole and pyridine where pyrazolyl, imidazolyl, indazoles, benzimidazolyl and pyridinyl substituted by two or more than two times with substituents selected from the group consisting of alkyl, hydroxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, quinil, halogeno, trifloromethyl, triptoreline, hydroxy, alkoxy, alkoxy-carbonyl, carboxy, cyano, nitro, amino, amino-carbonyl, N,N-dialkyl-amino-carbonyl, phenyl, benzyl and furanyl.

In another aspect according to the invention proposed pharmaceutical composition containing an effective amount of the compounds according to the invention.

In additional aspects, the invention relates the I to the use of a derivative according to the invention for the manufacture of a medicinal product for the treatment or relief of symptoms of diseases or disorders, associated with the activity of potassium channels, and to a method of treating or alleviating the symptoms of disorders or conditions that are sensitive to modulation of potassium channels.

DETAILED description of the INVENTION

Agents modulating potassium channels

In the first aspect according to the invention proposed new derivatives of purine formula Ia or Ib

their stereoisomer or a mixture of their stereoisomers, their N-oxide, prodrug, or their pharmaceutically acceptable salt, where

n is 0, 1, 2 or 3;

X represents O, S or NR', where R' represents hydrogen, alkyl, cycloalkyl, phenyl or benzyl;

Y represents alkyl, cycloalkyl, phenyl, benzo[1,3]dioxole or pyridyl, where the alkyl, cycloalkyl, phenyl, benzo[1,3]dioxole and pyridyl possibly substituted by one Deputy, selected from the group consisting of alkyl, cycloalkyl, halogeno, trifloromethyl, triptoreline, hydroxy, alkoxy, cyano, nitro and amino;

R1represents hydrogen, alkyl or alkoxy-alkyl; and

Het represents a heterocyclic group selected from pyrazolyl, imidazolyl, indazole, benzimidazole and pyridine where pyrazolyl, imidazolyl, indazoles, benzimidazolyl and pyridinyl substituted by two or more than two times with substituents selected from the group consisting the th from alkyl, hydroxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, quinil, halogeno, trifloromethyl, triptoreline, hydroxy, alkoxy, alkoxy-carbonyl, carboxy, cyano, nitro, amino, amino-carbonyl, N,N-dialkyl-amino-carbonyl, phenyl, benzyl and furanyl.

In another embodiment the derivative of the invention is a derivative of purenymphets formula IIa or IIb

it stereoisomer or a mixture of its stereoisomers, its N-oxide, its prodrug or pharmaceutically acceptable salt, where

n, X, Y, and R1are as defined above; and

one of R2, R3and R4represents hydrogen and the other two of R2, R3and R4independently of one another represent alkyl, hydroxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, quinil, halogeno, trifluoromethyl, triptoreline, hydroxy, alkoxy, alkoxy-carbonyl, carboxy, cyano, nitro, amino, amino-carbonyl, N,N-dialkyl-amino-carbonyl, phenyl, benzyl or furanyl.

In another embodiment the derivative of the invention is a derivative polylingual formula IIIa or IIIb

it stereoisomer or a mixture of its stereoisomers, its N-oxide, its prodrug or pharmaceutically acceptable the ol, where n, X, Y, R1, R2, R3and R4are as defined above.

In another embodiment the derivative of the invention is a derivative polylingual formula IVa or IVb

it stereoisomer or a mixture of its stereoisomers, its N-oxide, its prodrug or pharmaceutically acceptable salt, where n, X, Y, R1, R2, R3and R4are as defined above.

In another embodiment the derivative of the invention is a derivative puinirledime.html formula Va or Vb

it stereoisomer or a mixture of its stereoisomers, its N-oxide, its prodrug or pharmaceutically acceptable salt, where n, X, Y, R1, R2, R3and R4are as defined above.

In another embodiment the derivative of the invention is a derivative of polynilpotent formula VIa or VIb

it stereoisomer or a mixture of its stereoisomers, its N-oxide, its prodrug or pharmaceutically acceptable salt, where n, X, Y, R1, R2, R3and R4are as defined above.

In another embodiment the derivative of the invention represents the t of a compound of formula Ia.

In another embodiment the derivative of the invention is a compound of formula Ib.

In another embodiment the derivative of the invention is a compound of formula IIa.

In another embodiment the derivative of the invention is a compound of formula IIb.

In another embodiment the derivative of the invention is a compound of formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa or VIb, where n is 0, 1, 2, or 3.

In another embodiment n is 0, 1 or 2.

In another embodiment n is 0 or 1.

In another embodiment n is 0.

In another embodiment n is 1.

In another embodiment n is 2.

In another embodiment the derivative of the invention is a compound of formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa or VIb, where X represents O, S or NR', where R' represents hydrogen, alkyl, cycloalkyl, phenyl or benzyl.

In another embodiment X represents NR', where R' represents hydrogen, alkyl or cycloalkyl.

In another embodiment X represents NR', where R' represents hydrogen or methyl.

In another embodiment X represents O, S or NH.

In another embodiment X represents O.

In another embodiment X represents S.

In another embodiment X represents NH.

In another embodiment the derivative of the invention is a connection the General formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa or VIb, where Y represents alkyl, cycloalkyl, phenyl, benzo[1,3]dioxole or pyridyl, where the alkyl, cycloalkyl, phenyl, benzo[1,3]dioxole and pyridyl possibly substituted by one Deputy, selected from the group consisting of alkyl, cycloalkyl, halogeno, trifloromethyl, triptoreline, hydroxy, alkoxy, cyano, nitro and amino.

In another embodiment Y represents cycloalkyl, phenyl, benzo[1,3]dioxole or pyridyl, where phenyl and pyridyl may substituted by one Deputy, selected from the group consisting of alkyl, cycloalkyl, halogeno, trifloromethyl, triptoreline, hydroxy, alkoxy, cyano, nitro and amino.

In another embodiment Y represents cycloalkyl, phenyl, benzo[1,3]dioxole or pyridyl, where phenyl and pyridyl may substituted by one Deputy, selected from the group consisting of halogeno, in particular with fluorescent or chloro, and trifloromethyl.

In another embodiment Y represents cycloalkyl, phenyl, benzo[1,3]dioxole or pyridyl, where phenyl and pyridyl may substituted one halogeno, in particular, fluorescent, chloro or bromo.

In another embodiment Y represents cycloalkyl, phenyl, benzo[1,3]dioxole or pyridyl.

In another embodiment Y represents cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In another embodiment the AI Y is cyclohexyl.

In another embodiment Y represents benzo[1,3]dioxole.

In another embodiment Y represents pyridyl, which is possibly substituted by one Deputy, selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano, nitro and amino.

In another embodiment Y represents pyridyl, which is possibly substituted, halogen, in particular, fluorescent, chloro or bromo.

In another embodiment Y represents pyridyl, which is substituted by chloro. In another embodiment Y represents a pyridyl.

In another embodiment Y represents phenyl, which is possibly substituted by one Deputy, selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano, nitro and amino.

In another embodiment Y represents phenyl, which is possibly substituted by one Deputy, selected from the group consisting of halogeno, trifloromethyl, cyano, nitro and amino.

In another embodiment Y represents phenyl, which substituted halogeno, in particular, fluorescent, chloro or bromo.

In another embodiment Y represents phenyl, which may substituted with fluorescent.

In another embodiment Y represents phenyl, substituted with fluorescent.

In another embodiment Y represents phenyl, which is substituted by chloro.

In another embodiment Y represents phenyl, substituted the initial chloro.

In another embodiment Y represents phenyl, which is possibly substituted by trifluoromethyl.

In another embodiment Y represents phenyl substituted by trifluoromethyl.

In another embodiment Y represents phenyl, which is substituted by cyano.

In another embodiment Y represents phenyl, substituted cyano.

In another embodiment Y represents phenyl, which is substituted by nitro.

In another embodiment Y represents phenyl, substituted nitro.

In another embodiment Y represents phenyl, which is possibly substituted amino.

In another embodiment Y represents phenyl, substituted amino.

In another embodiment Y represents phenyl.

In another embodiment the derivative of the invention is a compound of formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa or VIb, where R1represents hydrogen, alkyl or alkoxy-alkyl.

In another embodiment R1represents hydrogen.

In another embodiment R1represents alkyl.

In another embodiment R1represents methyl.

In another embodiment R1represents ethyl.

In another embodiment R1represents an alkoxy-alkyl.

In another embodiment R1is methoxyethyl.

In another embodiment R1represents ataxi the Teal.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents a heterocyclic group selected from pyrazolyl, imidazolyl, indazole, benzimidazole and pyridine where pyrazolyl, imidazolyl, indazoles, benzimidazolyl and pyridinyl substituted by two or more than two times with substituents selected from the group consisting of alkyl, hydroxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, quinil, halogeno, trifloromethyl, triptoreline, hydroxy, alkoxy, alkoxy-carbonyl, carboxy, cyano, nitro, amino, amino-carbonyl, N,N-dialkyl-amino-carbonyl, phenyl, benzyl and furanyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents a heterocyclic group selected from pyrazolyl and pyridinyl where pyrazolyl and pyridinyl substituted by two or more than two times with substituents selected from the group consisting of alkyl, hydroxy-alkyl, halogeno, trifloromethyl, alkoxy, alkoxy-carbonyl, nitro, amino, phenyl and furanyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents a heterocyclic group selected from pyrazolyl and pyridinyl where pyrazolyl and pyridinyl substituted by two or more than two times will replace the guides and selected from the group consisting of alkyl, halogeno, trifloromethyl, nitro, amino and phenyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents a heterocyclic group selected from pyrazolyl and pyridinyl where pyrazolyl and pyridinyl substituted by two or more than two times with substituents selected from the group consisting of alkyl, halogeno and trifloromethyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents a heterocyclic group selected from pyrazolyl and pyridinyl where pyrazolyl and pyridinyl substituted by two or more than two times by alkyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted two or more than two times by alkyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted twice by alkyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted twice the stands.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het performance, which provides pyrazolyl, replaced three times by alkyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted three times the stands.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted two or more than two times halogeno.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted two or more than two times trifluoromethyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted two or more than two times the nitro.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted two or more than two amino times.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted two or more than two times with substituents selected from the group consisting of alkyl, halogeno.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, replacing the military twice substituents, selected from the group consisting of alkyl, halogeno.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted or three times by substituents selected from the group consisting of alkyl, halogeno.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted two times with substituents selected from the group consisting of alkyl and trifloromethyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted two times with substituents selected from the group consisting of alkyl and hydroxy-alkyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted two times with substituents selected from the group consisting of alkyl and alkoxy-carbonyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het represents pyrazolyl, substituted two times with substituents selected from the group consisting of alkyl and phenyl.

In another embodiment the derivative of the invention is a compound of formula Ia or Ib, where Het performance, which provides pyrazolyl, substituted two times with substituents selected from the group consisting of alkyl and furanyl.

In another embodiment the derivative of the invention is a compound of formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa or VIb, where one of R2, R3and R4represents hydrogen and the other two of R2, R3and R4independently of one another represent alkyl, hydroxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, quinil, halogeno, trifluoromethyl, triptoreline, hydroxy, alkoxy, alkoxy-carbonyl, carboxy, cyano, nitro, amino, amino-carbonyl, N,N-dialkyl-amino-carbonyl, phenyl, benzyl or furanyl.

In another embodiment, one of R2, R3and R4represents hydrogen and the other two of R2, R3and R4independently of one another represent alkyl, hydroxy-alkyl, halogeno, trifluoromethyl, triptoreline, alkoxy-carbonyl, nitro, amino, phenyl, benzyl or furanyl.

In another embodiment, one of R2, R3and R4represents hydrogen and the other two of R2, R3and R4independently of one another represent alkyl, halogeno, trifluoromethyl, nitro or amino.

In another embodiment, one of R2, R3and R4represents hydrogen and the other two of R2, R3and R4independently from each other represent the Wallpaper alkyl, phenyl or furanyl.

In another embodiment, one of R2, R3and R4represents hydrogen and the other two of R2, R3and R4independently of one another represent alkyl.

In another embodiment, one of R2, R3and R4represents hydrogen and the other two of R2, R3and R4independently from each other represent halogeno.

In another embodiment of the invention the alkyl represents methyl.

In another embodiment of the invention the alkyl represents ethyl.

In another embodiment of the invention, halogen is fluorescent.

In another embodiment of the invention, halogeno represents chloro.

In another embodiment the derivative of the invention is:

(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine;

cyclohexyl-[2-(3,5-dimethyl-pyrazole-1-yl)-7-methyl-7H-purine-6-yl]-amine;

(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-7-methyl-7H-purine-6-yl]-amine;

(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-ethyl-9H-purine-6-yl]-amine;

benzo[1,3]dioxol-5-yl-[2-(3,5-dimethyl-pyrazole-1-yl)-9-ethyl-9H-purine-6-yl]-amine;

6-(4-chloro-phenylsulfanyl)-2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-9H-purine;

[2-(4-chloro-3-methyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-chloro-phenyl)-amine;

[2-(5-chloro-3-methyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-chloro-phenyl)-amine;

cyclohex is l-[2-(3,5-dimethyl-pyrazole-1-yl)-9H-purine-6-yl]-amine;

[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-fluoro-phenyl)-amine;

(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-isobutyl-N-purine-6-yl]-amine;

(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-(2-ethoxy-ethyl)-N-purine-6-yl]-amine;

[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-pyridine-4-yl-amine;

(5-chloro-pyridine-2-yl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine;

(6-chloro-pyridine-3-yl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-yl]-amine;

[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-8-yl]-(4-nitro-phenyl)-amine;

4-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-ylamino]-benzonitrile;

[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-yl]-phenyl-amine;

[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-phenethyl-amine;

(4-bromo-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine;

(4-chloro-phenyl)-[9-methyl-2-(5-methyl-3-trifluoromethyl-pyrazole-1-yl)-N-purine-6-yl]-amine;

(4-chloro-phenyl)-[2-(3,5-diethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine;

(4-chloro-phenyl)-[9-methyl-2-(3,4,5-trimethyl-pyrazole-1-yl)-N-purine-6-yl]-amine;

[2-(4-chloro-3,5-dimethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-yl]-(4-chloro-phenyl)-amine;

(4-chloro-phenyl)-[9-methyl-2-(5-methyl-3-phenyl-pyrazole-1-yl)-N-purine-6-yl]-amine;

(4-chloro-phenyl)-[2-(3-furan-2-yl-5-methyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine;

ethyl ester of 1-[6-(4-chloro-phenylamino)-9-m is Teal-N-purine-2-yl]-5-methyl-1H-pyrazole-3-carboxylic acid;

[2-(3,5-bis-trifluoromethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-chloro-phenyl)-amine;

N-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-benzene-1,4-diamine;

{2-[6-(4-chloro-phenylamino)-9-methyl-N-purine-2-yl]-5-methyl-2H-pyrazole-3-yl}-methanol;

[2-(3,5-dimethyl-pyrazole-1-yl)-N-purine-6-yl]-phenyl-amine;

[2-(3,5-dimethyl-pyrazole-1-yl)-9-(2-methoxy-ethyl)-9H-purine-6-yl]-phenyl-amine;

or

their stereoisomer or a mixture of their stereoisomers, their N-oxide, prodrug, or their pharmaceutically acceptable salt.

Any combination of two or more embodiments described herein, is considered in the scope of the present invention.

The definition of the substituents

In the context of this invention, halogen is a fluorescent, chloro, bromo or iodo.

In the context of this invention alkyl group means a monovalent saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to eighteen carbon atoms (C1-18alkyl), for example from one to six carbon atoms (C1-6alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary of pentyl, hexyl and isohexyl. In another embodiment alkyl is a1-4alkyl group, including butyl, isobutyl, secondary butyl and tertiary butyl. In another embodiment of this invention the alkyl represents a C1-3al the ilen group, which, in particular, may represent a methyl, ethyl, propyl or isopropyl.

In the context of this invention Alchemilla group means a carbon chain containing one or more than one double bond, including dieny, triene and a polyene. In another embodiment Alchemilla group according to the invention includes from two to eight carbon atoms (C2-8alkenyl), for example from two to six carbon atoms (C2-6alkenyl), including at least one double bond. In another embodiment Alchemilla group according to the invention represents an ethynyl; 1 - or 2-propenyl; 1-, 2 - or 3-butenyl, or 1,3-butenyl; 1-, 2-, 3-, 4 - or 5-hexenyl, or 1,3-hexenyl, or 1,3,5-hexenol; 1-, 2-, 3-, 4-, 5-, 6 - or 7-octenyl, or 1,3-octenyl, or 1,3,5-octenyl, or 1,3,5,7-octenyl.

In the context of this invention Alchemilla group means a straight or branched carbon chain containing one or more than one triple bond, including dieny, triinu and Polyany. In another embodiment Alchemilla group according to the invention includes from two to eight carbon atoms (C2-8quinil), for example from two to six carbon atoms (C2-6quinil), including at least one triple bond. In another embodiment Alchemilla group according to the invention is ethinyl; 1 - or 2-PROPYNYL; 1-, 2 - or 3-butenyl, or 1,3-butadienyl; 1-, 2-, 3-, 4-pentenyl, or 1,3-pentadienyl; 1 - 2-, 3-, 4 - or 5-hexenyl, or 1,3-hexadienyl, or 1,3,5-hexatriene; 1-, 2-, 3-, 4-, 5 - or 6-heptenyl, or 1,3-heptadienyl, or 1,3,5-heptatriene; 1-, 2-, 3-, 4-, 5-, 6 - or 7-octenyl, or 1,3-octadienes, or 1,3,5-octatriene, or 1,3,5,7-octatetraene.

In the context of this invention, hydroxy-alkyl group means an alkyl group as defined above which is substituted one or more than one hydroxy-group. Examples of hydroxy-alkyl groups of the invention include 2-hydroxy-ethyl, 3-hydroxy-propyl, 4-hydroxy-butyl, 5-hydroxy-pentyl and 6-hydroxy-hexyl.

In the context of this invention cycloalkyl group means a cyclic alkyl group, preferably containing from three to ten carbon atoms (C3-10cycloalkyl), for example from three to eight carbon atoms (C3-8cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; or, for example, from three to six carbon atoms (C3-6cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the context of this invention cycloalkyl-alkyl group means cycloalkyl group, as defined above, where cycloalkyl is a Deputy in the alkyl group, also defined above. Examples cycloalkyl-alkyl groups of the invention include cyclopropylmethyl and cyclopropylethyl.

In the Contex the E. of this invention, alkoxygroup means the group "alkyl-O-", where alkyl is as defined above. Examples of alkoxygroup according to the invention include methoxy, ethoxy.

In the context of this invention, alkoxy-alkyl group means the group "alkyl-O-alkyl -, where alkyl is as defined above. Examples of alkoxy-alkyl groups of the invention include methoxy-methyl, methoxy-ethyl, ethoxy-methyl, ethoxy-ethyl.

In the context of this invention alkoxy-carbonyl group corresponds to the group "alkyl-O-CO -, where alkyl is as defined above. Examples of alkoxy-carbonyl groups of the invention include methyl-, ethyl - and propylamino group.

In the context of this invention, amino-carbonyl group means a group of the amino-CO-".

In the context of this invention, N,N-dialkyl-amino-carbonyl group means (tertiary) amino-carbonyl group, a disubstituted alkyl groups defined above.

Isomers

Derivative of the present invention may exist in different stereoisomeric forms, including enantiomers, diastereoisomers and geometric isomers (CIS-TRANS isomers). The invention includes all such isomers and any mixtures thereof, including racemic mixtures.

The racemic forms can be separated into the optical antipodes by known methods and techniques. One way of separating the diastereomeric with whom she is to use optically active acid and the allocation of optically active amino compounds by treatment with base. Another method of separation of racemates on the optical antipodes based on chromatography on optically active matrix. Racemic compounds of the present invention can thus be separated into their optically active antipodes, for example by fractional crystallization of d - or l-salts (tartratami, mandelate or camphorsulfonate), for example.

Chemical compounds of the present invention may also be separated by formation of diastereomeric amides by reacting chemical compounds of the present invention with an optically active activated carboxylic acid such as acid, derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) campanulas acid, or through the formation of diastereomeric carbamates by reacting a chemical compound according to the present invention with an optically active chloroformate or the like.

Other methods of separation of optical isomers are known in the art. Such methods include the methods described Jaques J, Collet A, & Wilen S "Enantiomers, Racemates, and Resolutions". John Wiley and Sons, New York (1981).

In addition, some chemical compounds according to the invention, representing the oximes may thus exist in two forms, SYN - and anti-form (Z - and E-form), depending on the arrangement of the substituents around the war-ties-C=N-. Chemical compound according to the present invention may, thus, represent a SYN - or anti-form (Z - and E-form), or it can represent a mixture.

Pharmaceutically acceptable salt

Derivatives according to the invention can be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre - or proletarienne form chemical compounds according to the invention.

Examples of pharmaceutically acceptable salts of the merger include, without limitation, non-toxic salts of the accession of inorganic and organic acids, such as hydrochloride, obtained from hydrochloric acid, the hydrobromide obtained from Hydrobromic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, formate derived from formic acid, acetate derived from acetic acid, aconitic obtained from amanitowoc acid, the ascorbate derived from ascorbic acid, bansilalpet obtained from benzosulfimide acid, benzoate, obtained of benzoic acid, cinnamate derived from cinnamic acid, the citrate derived from citric acid, embanet obtained from monowai acid, Ananta is, derived from enanthic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, malonate derived from malonic acid, mandelate obtained from almond acid, methanesulfonate, obtained from methanesulfonic acid, econsultant obtained from econsultancy acid, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, the phthalate derived from phthalic acid, the salicylate derived from salicylic acid, sorbate, received from sorbic acid, stearate derived from stearic acid, succinate derived from succinic acid, tartrate derived from tartaric acid, para-toluensulfonate obtained from pair-toluensulfonate acid and the like. Such salts can be formed by methods well known and described in the art.

Other acids, such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in obtaining salts which are useful as intermediates in obtaining the derivative of the invention and its pharmaceutically acceptable salts accession acid.

Metal salts chemical compounds according to the invention VK is ucaut alkali metal salts, such as sodium salt chemical compounds according to the invention containing carboxypropyl.

In the context of this invention "onevia salt" N-containing compounds is also considered as pharmaceutically acceptable salts. Examples onievyh salts include alkyl-onieva salt, cycloalkyl-onieva salt and cycloalkenyl-onieva salt.

The derivative according to the invention can be presented in a soluble or insoluble forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Soluble forms may also include hydrated forms, such as the monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like. In General, soluble forms are considered equivalent to insoluble forms for the purposes of this invention.

Ways to get

Derivatives according to the invention can be obtained by conventional methods of chemical synthesis, such as those described in the demo. Source materials for the methods described in this application are known and can be easily obtained by using common methods from commercially available chemicals.

The final products of the reactions described herein may be allocated in a common manner, for example by extraction, crystallization, distillation, chromatography and so on.

<> Biological activity

Derivatives according to the invention were subjected to in vitro experiments, and they proved to be useful as agents for modulation of potassium channels. Compounds according to the invention is able to selectively modulate SK1-, SK2 and SK3 channels.

Thus, in another aspect the invention relates to the use of the derivatives according to the invention for the production of medicines that can be useful to treat or alleviate symptoms of a disease or disorder associated with the activity of potassium channels, for example SK-channels, for example SK1-, SK2 and SK3 channels.

In another embodiment the disease or disorder associated with the activity of potassium channels is a respiratory disease, epilepsy, convulsions, seizures, small epileptic seizures, vasospasm, a spasm of coronary arteries, renal disorders, polycystic kidney disease, bladder spasms, overactive bladder (OAB), urinary incontinence syndrome infravesical obstruction, interstitial cystitis (IC), erectile dysfunction, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic heart disease, angina, coronary heart disease, autism, ataxia, traumatic brain injury, Parkinson's disease, bipola the Noah disorder, psychosis, schizophrenia, anxiety, depression, mania, mood disorders, dementia, disorders of memory and attention, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, Raynaud's disease, alternating lameness, Sjogren syndrome, arrhythmia, hypertension, myotonias muscular dystrophy, muscle spasticity, xerostomia, diabetes type II, hyperinsulinemia, premature labour, alopecia, cancer, irritable bowel syndrome (IBS), immunosuppression, migraine or pain, such as pelvic pain or abdominal pain, or withdrawal symptoms caused by termination of use of chemicals in particular opioids, heroin, cocaine, morphine, benzodiazepines and benzodiazepinovogo drugs and alcohol.

In another embodiment the disease or disorder associated with the activity of potassium channels is a respiratory disease, urinary incontinence, erectile dysfunction, anxiety, epilepsy, psychosis, schizophrenia, amyotrophic lateral sclerosis (ALS) or pain.

In another embodiment the disease or disorder associated with the activity of potassium channels is a respiratory disease, in particular asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea.

In another embodiment the disease or disorder, as aliowance with the activity of potassium channels, is an overactive bladder, such as incontinence.

In another embodiment the disease or disorder associated with the activity of potassium channels is a incontinence of urine.

In another embodiment the disease or disorder associated with the activity of potassium channels, is an epilepsy, seizures, small epileptic seizures or convulsions.

In another embodiment the disease or disorder associated with the activity of potassium channels is a schizophrenic.

In another embodiment the disease or disorder associated with the activity of potassium channels is a pain.

Tested compounds showed biological activity determined as described herein, in micromolar and submicromolar range, i.e. from less than 1 to about 100 microns, for example from less than 0.1 to about 10 microns.

The pharmaceutical composition

In another aspect according to the invention proposed new pharmaceutical compositions containing a therapeutically effective amount of the derivatives according to the invention.

While derivative according to the invention for use in therapy can be introduced in the form of the raw chemical compound, it is preferable to include the active ingredient, possibly in the Orme physiologically acceptable salts, in the form of pharmaceutical compositions together with one or more than one adjuvant, excipient, the carrier and/or diluent.

In another embodiment according to the invention proposed pharmaceutical composition comprising a derivative according to the invention, or its pharmaceutically acceptable salt, or a derivative thereof together with one or more pharmaceutically acceptable carrier for him and, perhaps, other therapeutic and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense that it must be compatible with other ingredients of the drug and harmless to the recipient host.

The pharmaceutical compositions according to the invention can provide a composition suitable for oral, rectal, bronchial, nasal, local (including transbukkalno and sublingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or compositions in a form suitable for administration by inhalation or insufflation, including the introduction of powders and liquid aerosols or through systems with slow release. Suitable examples of systems with prolonged visvobodi the receiving include semi-permeable matrices of solid hydrophobic polymers, containing compound according to the invention, where these matrices can be represented in the form of products of a certain shape, e.g. films, or microcapsules.

Derivatives according to the invention together with a standard adjuvant, carrier or diluent, thus, can be represented in the form of pharmaceutical compositions and standard dosage forms. Such forms include solid forms, in particular tablets, filled capsules, powders and granules, and liquid formulations, in particular aqueous and non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with them, all for oral administration; suppositories for rectal administration and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and their standard dosage forms may include common ingredients in standard proportions, with an additional active compounds or principles, and such a standard dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended range of daily dosage, which should be used.

The derivative of the present invention can be introduced in a variety of oral and parenteral dosage forms. Specialists in the art bude is clear, that the following dosage forms may contain as an active ingredient or chemical compound according to the invention, or pharmaceutically acceptable salt of a chemical compound according to the invention.

For the manufacture of pharmaceutical compositions of chemical compounds according to the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid dosage forms include powders, tablets, coated tablets, capsules, pills, suppositories, and dispersible granules. A solid carrier can be one or more than one substance, which may also act as a diluent, corrigent, solubilizer, lubricant substance, suspendisse agent, binder, preservative, loosening agent for tablets or encapsulating material.

In powders, the carrier is a finely ground solid material, which is mixed with finely ground active component.

In tablets, the active ingredient is mixed with carrier having the necessary binding capacity in suitable proportions and compacted in the shape desired size.

The powders and tablets preferably contain from five or ten to about seventy percent of the active compounds. Suitable carriers are magnesium carbonate, stearate is Agnes, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. Assume that the term "drug" includes the preparation of the active compound with encapsulating material as a carrier, forming a capsule, where the active ingredient with the carriers, or without them, is surrounded by carrier, which thus is in Association with him. In this way enabled the wafer and pellet. Tablets, powders, capsules, pills, wafers and cakes can be used as solid forms suitable for oral administration.

For the manufacture of suppositories low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, is first melted and the active component is homogeneous dispersed therein by stirring. The molten homogeneous mixture is then poured into molds of suitable size, allow to cool and then harden.

Compositions suitable for vaginal administration, can be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient suitable carrier materials known to specialists in this field of technology.

Liquid preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol RA the works. For example, liquid preparations for parenteral injection can be prepared as solutions in aqueous solution of polyethylene glycol.

Thus, the derivative of the present invention can be manufactured in the form of a preparation for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in a standard dosage form in ampoules, pre-filled syringes, infusion of small volumes or in mnogochasovykh containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous carriers can contain agents for drugs, such as suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic selection of sterile solid or by lyophilization from solution, for dilution with a suitable solvent, such as sterile pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, corrigentov, stabilizing and thickening agents as desired.

Aqueous suspensions suitable the La oral administration, can be prepared by dispersing finely ground active component in water with viscous material, such as natural and synthetic resins, methylcellulose, sodium-karboksimetilcelljuloza or other well-known suspendresume agents.

Also included are solid dosage forms that are designed to turn immediately before use in liquid dosage forms for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient such preparations may contain colouring agents, corrigentov, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents and the like.

For local injection into the epidermis chemical compound according to the invention may be presented as ointments, creams or lotions, or as a transdermal patch. Ointments and creams can be prepared, for example, aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions can be prepared in water or oil-based, and, as a rule, they must also contain one or more than one emulsifying, stabilizing, dispersing, suspendisse, thickening agent or dye.

Compositions suitable DL the local introduction of the oral cavity, include pellet containing the active agent in the flavored basis, usually sucrose and Arabian gum or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerin or sucrose and Arabian gum; and a liquid for rinsing the oral cavity containing the active ingredient in a suitable liquid carrier.

The solutions or suspensions are injected directly into the nasal cavity using standard tools, such as a dropper, pipette or spray. The compositions can be presented in a single dose or mnogochasovykh forms. In the latter case, when using a dropper or pipette, this can be achieved by introducing the patient corresponding to a given volume of solution or suspension. In the case of a spray, this may be achieved, for example, by means of a metering and spray pump.

Introduction to the respiratory tract may also be achieved using an aerosol formulation in which the active ingredient is in a sealed package with a suitable propellant such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Aerosol acceptable may also contain a surfactant such as lecithin. The dose to trainout using a metering valve.

Alternatively, the active ingredients can be represented in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidone (PVP). For convenience powder carrier must form a gel in the nasal cavity. The powder composition may be presented in the form of a standard dose of, for example, capsules or cartridges, for example, from gelatin or blister packs from which the powder can be entered using the inhaler.

In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size, for example of the order of 5 microns or less. This particle size can be achieved by methods known in the art, for example by micronisation.

At desire it is possible to apply compositions made with the possibility of continuous release of the active ingredient.

Pharmaceuticals presents preferably in a standard dosage forms. In such form the preparation is divided into single standard doses containing appropriate quantities of the active component. Form single standard doses can be a drug in the package, tereasa discrete quantities of preparation, such as packaging of tablets, capsules, and powders in vials or ampoules. The standard dosage may be itself a capsule, a tablet, wafer or cake, or the appropriate number of any of them in the package.

In one embodiment according to the invention given tablets or capsules for oral administration.

In another embodiment according to the invention proposed liquid for intravenous injection and continuous infusion.

Additional details concerning methods of manufacture and introduction can be found in the latest edition Remington''s Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

A therapeutically effective dose refers to that amount of active ingredient that relieves the symptoms or condition. Therapeutic efficacy and toxicity, such as ED50and LD50can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is a therapeutic index that can be expressed by the ratio LD50/ED50. The pharmaceutical composition exhibiting a higher therapeutic indices are preferred.

Enter the dose, of course, must be carefully regulated according to age, what assay and condition of the individual, where they treat, as well as by injection, dosage form and scheme of administration and the desired result, and the exact dosage should, of course, be determined by the treating physician.

The actual dosage depends on the nature and severity of the disease, which is treatable and is at the discretion of the attending physician, and it can be varied by titration of the dosage for private embodiments of the present invention to obtain the desired therapeutic effect. However, it is presently envisaged that the pharmaceutical compositions containing from about 0.1 to about 500 mg of the active ingredient on the individual dose, for example from about 1 to about 100 mg, for example from about 1 to about 10 mg, are suitable for therapeutic treatment.

The active ingredient can be introduced in one or several doses per day. Satisfactory results can sometimes be obtained in such low doses as 0.1 µg/kg intravenous (i.v.) and 1 mg/kg oral (r.o.). The upper limit of the range of dosages provided currently as of approximately 10 mg/kg i.v. and 100 mg/kg r.o. Other ranges are from about 0.1 μg/kg to about 10 mg/kg/day i.v. and from about 1 μg/kg to about 100 mg/kg/day r.o.

Methods of treatment

In the other aspect according to the invention, a method for warnings, treat or alleviate symptoms of the disease or disorder, or condition of the body of the living animal, including humans, which is sensitive to modulation of potassium channels, in particular SK channels, including the introduction in the body of the living animal, including humans, in need thereof, a therapeutically effective amount of a derivative according to the invention.

Indications for use provided by this invention are as set forth above.

It is presently envisaged that suitable ranges of dosages range from 0.1 to 1000 milligrams daily, 10-500 milligrams daily, or 30-100 milligrams daily, depending on the exact route of administration, form in which the introduction, indications for which this introduction is intended subject, which is treated and the body weight of the subject, and the preference and experience of the attending physician or veterinarian.

Satisfactory results in some cases can be obtained even at a dose of 0.005 mg/kg i.v. and 0.01 mg/kg r.o. Upper limit of the range of dosage is about 10 mg/kg i.v. and 100 mg/kg r.o. Other ranges are from about 0.001 to about 1 mg/kg i.v. and from about 0.1 to about 10 mg/kg r.o.

EXAMPLES

The invention is additionally illustrated with reference to the following examples, which are not PR is naznaczony to limit in any way the scope of the claimed invention.

Example 1

2,6-Dichloro-9-methyl-9H-purine and 2,6-dichloro-7-methyl-7H-purine

Sodium hydride (60% in mineral oil; 2,53 g, 63.5 mmol) was added to a cooled on ice to a solution of 2,6-dichloropurine (10.0 g; 52,9 mmol) in tetrahydrofuran (75 ml) and the mixture was stirred for 30 minutes. Was added dropwise methyliodide (3,29 ml; 52,9 mmol) and the reaction mixture was stirred over night. Added water and the aqueous phase was twice extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under vacuum. Added dichloromethane and nerastvorimaya substance was collected by filtration. Crystalline compound represented 2,6-dichloro-7-methyl-7H-purine (1.19 g; 11%). The filtrate was concentrated under vacuum and purified by flash chromatography (ethyl acetate/heptane) to give 2,6-dichloro-9-methyl-N-purine (3.0 g; 28%).

2,6-Dichloro-9-ethyl-9H-purine and 2,6-dichloro-7-ethyl-7H-purine

Was obtained according to example 1 using ethyliodide instead of under the conditions.

9-Benzyl-2,6-dichloro-N-purine and 7-benzyl-2,6-dichloro-7H-purine

Was obtained according to example 1 using benzylbromide instead of under the conditions.

2,6-Dichloro-9-tbutyl-9H-purine

Was obtained according to example 1 using 1-bromo-2-methylpropane instead of under the conditions. In this case, was allocated only one isomer.

2,6-Dichloro-9-(2-ethoxy-ethyl)-9H-purine

Was obtained according to example 1 using 2-Bromeliaceae ester instead of under the conditions. In this case, was allocated only one isomer.

Example 2

N-(4-Chloro-sreni)-formamide

4-Chloroaniline (15 g, 117 mmol) and formic acid (25 ml; 663 mmol) was heated to the temperature of reflux distilled for 2 hours. The mixture was concentrated under vacuum. Was added a saturated aqueous sodium bicarbonate and the aqueous phase was twice extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under vacuum to obtain N-(4-chloro-phenyl)-formamide (17.6 g; 97%) as a gray crystalline substance.

N-Benzo[1,3]dioxol-5-yl-formamide

Was obtained according to example 2 of 3,4-(methylenedioxy)aniline and formic acid.

N-(4-Fluoro-phenyl)-formamide

Was obtained according to example 2 from 4-foronline and formic acid.

N-(4-Trifluoromethyl-phenyl)-formamide

Was obtained according to example 2 from 4-(trifluoromethyl)aniline and mu is avinou acid.

N-Pyridin-4-informed

Was obtained according to example 2 from 4-aminopyridine and formic acid.

N-(5-Chloro-pyridine-2-yl)-formamide

Was obtained according to example 2 from 2-amino-5-chloropyridine and formic acid.

N-(6-Chloro-pyridine-3-yl)-formamide

Was obtained according to example 2 from 5-amino-2-chloropyridine and formic acid.

N-(4-Nitro-phenyl)-formamide

Was obtained according to example 2 from 4-nitroaniline and formic acid.

N-(4-Cyano-phenyl)-formamide

Was obtained according to example 2 from 4-cyanoaniline and formic acid.

N-Phenyl-formamide

Was obtained according to example 2 of aniline and formic acid.

N-(4-Bromo-phenyl)-ndimethylacetamide

Was obtained according to example 2 from 4-bromoaniline and formic acid.

Example 3

(2-Chloro-9-methyl-9H-purine-6-yl)-(4-chloro-phenyl)-amine

N-(4-Chloro-phenyl)-formamide (766 mg; is 4.93 mmol) was dissolved in N,N-dimethylformamide (10 ml). Was added sodium hydride (60% in mineral oil, 240 mg; 5,91 mmol) and the mixture was stirred for 30 minutes. Added 2,6-dichloro-9-methyl-N-purine (1.0 g; is 4.93 mmol) and the reaction mixture was heated at 80°C for 2 cha is s, was cooled to room temperature and poured into water. The precipitate was collected by filtration, washed with water and dried to obtain (2-chloro-9-methyl-9H-purine-6-yl)-(4-chloro-phenyl)-amine (1.2 g; 4,08 mmol; 83%).

(2-Chloro-9-ethyl-N-purine-6-yl)-(4-chloro-phenyl)-amine

Was obtained according to example 3 from N-(4-chloro-phenyl)-formamide and 2,6-dichloro-9-ethyl-N-purine.

(2-Chloro-9-isobutyl-9H-purine-6-yl)-(4-chloro-phenyl)-amine

Was obtained according to example 3 from N-(4-chloro-phenyl)-formamide and 2,6-dichloro-9-isobutyl-N-purine.

[2-Chloro-9-(2-ethoxy-ethyl)-9H-purine-6-yl]-(4-chloro-phenyl)-amine

Was obtained according to example 3 from N-(4-chloro-phenyl)-formamide and 2,6-dichloro-9-(2-ethoxy-ethyl)-9H-purine.

(2-Chloro-7-methyl-7H-purine-6-yl)-(4-chloro-phenyl)-amine

Was obtained according to example 3 from N-(4-chloro-phenyl)-formamide and 2,6-dichloro-7-methyl-7H-purine.

Benzo[1,3]dioxol-5-yl-(2-chloro-9-ethyl-N-purine-6-yl)-amine

Was obtained according to example 3 from N-benzo[1,3]dioxol-5-yl-formamide and 2,6-dichloro-9-ethyl-N-purine.

2-Chloro-6-(4-chloro-phenylsulfanyl)-9-methyl-N-purine

Was obtained according to example 3 from 4-chlorbenzoyl and 2,6-dichloro-9-ethyl-9H-purine.

(2-Chloro-9-methyl-9H-purine-6-yl)-(4-fluoro-phenyl)-amine

Was obtained according to example 3 from N-(4-fluoro-phenyl)-formamide and 2,6-dichloro-9-methyl-9H-purine.

(2-Chloro-9-methyl-N-purine-6-yl)-(4-trifluoromethyl-phenyl)-amine

Was obtained according to example 3 from N-(4-trifluoromethyl-phenyl)-formamide and 2,6-dichloro-9-methyl-N-purine.

(2-Chloro-9-methyl-N-purine-6-yl)-pyridin-4-yl-amine

Was obtained according to example 3 from N-pyridin-4-yl-formamide and 2,6-dichloro-9-methyl-9H-purine.

(2-Chloro-9-methyl-9H-purine-6-yl)-(5-chloro-pyridine-2-yl)-amine

Was obtained according to example 3 from N-(5-chloro-pyridine-2-yl)-formamide and 2,6-dichloro-9-methyl-9H-purine.

(2-Chloro-9-methyl-N-purine-6-yl)-(6-chloro-pyridine-3-yl)-amine

Was obtained according to example 3 from N-(6-chloro-pyridine-3-yl)-formamide and 2,6-dichloro-9-methyl-9H-purine.

(2-Chloro-9-methyl-N-purine-6-yl)-(4-nitro-phenyl)-amine

Was obtained according to example 3 from N-(4-nitro-phenyl)-formamide and 2,6-dichloro-9-methyl-N-purine.

4-(2-Chloro-9-methyl-9H-purine-6-ylamino)-benzonitrile

Was obtained according to example 3 from N-(4-cyano-phenyl)-formamide and 2,6-dichloro-9-methyl-9H-purine.

(2-Chloro-9-methyl-9H-purine-6-yl)-phenyl-amine

Was obtained according to example 3 from N-phenyl-formamide and 2,6-dichloro-9-methyl-N-purine.

(4-Bromo-phenyl)-(-chloro-9-methyl-9H-purine-6-yl)-amine

Was obtained according to example 3 from N-(4-bromo-phenyl)-ndimethylacetamide and 2,6-dichloro-9-methyl-N-purine.

(9-Benzyl-2-chloro-N-purine-6-yl)-(4-chloro-phenyl)-amine and (7-benzyl-2-chloro-7H-purine-6-yl)-(4-chloro-phenyl)-amine

A mixture of 9-benzyl-2-chloro-N-purine-6-yl)-(4-chloro-phenyl)-amine and (7-benzyl-2-chloro-7H-purine-6-yl)-(4-chloro-phenyl)-amine was obtained according to example 3 of a mixture of 9-benzyl-2,6-dichloro-9H-purine and 7-benzyl-2,6-dichloro-7H-purine and N-(4-chloro-phenyl)-formamide.

Example 4

(2-Chloro-9-methyl-N-purine-6-yl)-cyclohexyl-amine

2,6-Dichloro-9-methyl-N-purine (1.40 g; 6,93 mmol) was dissolved in acetonitrile (25 ml). Was added triethylamine (4,81 ml, 34.5 mmol) and cyclohexylamine (0,79 ml; 6,90 mmol) and the reaction mixture was stirred at 50°C during the night. The reaction mixture was cooled to room temperature and concentrated under vacuum. Was added water, followed by extraction with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under vacuum to obtain (2-chloro-9-methyl-N-purine-6-yl)-cyclohexyl-amine (1.5 g, 82%) as a crystalline substance.

(2-Chloro-7-methyl-7H-purine-6-yl)-cyclohexyl-amine

Was obtained according to example 4 of 7-methyl-2,6-dichloro-7H-purine and cyclohexylamine.

(-Chloro-9-methyl-N-purine-6-yl)-phenethyl-amine

Was obtained according to example 4 of 9-methyl-2,6-dichloro-9H-purine and phenetylamine.

Example 5

(2-Chloro-N-purine-6-yl)-cyclohexyl-amine

2,6-Dichloropurine (2.5 g; 13,23 mmol) and cyclohexylamine (1,51 ml; 13,2 mmol) was dissolved in acetonitrile (25 ml) and heated to 50°C for 5 days. A white precipitate was collected by filtration and used without further purification.

Example 6

(4-Chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine (compound 6.1)

Sodium hydride (80% in mineral oil, 160 mg; 4.1 mmol) was added to 3,5-dimethylpyrazole (320 mg; 3.4 mmol)dissolved in N,N-dimethylformamide (10 ml)and the mixture was stirred for 30 minutes. Was added (2-chloro-9-methyl-N-purine-6-yl)-(4-chloro-phenyl)-amine (1.0 g; 3,40 mmol) and the reaction mixture was heated at 120°C for 4 hours, cooled and poured into water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (dichloromethane/methanol/ammonia) to give (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine (160 mg, 13%) as a yellow crystalline substance.

Liquid chromatography and high resolution mass with astrometry with ionization elektrorazpredelenie (LC-ESI-HRMS) [M+H]+ shows 354,1227 Yes. Designed 354,123396 Yes, deviation -2 million-1.

Sulfate salt (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine

(4-Chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine (10.0 g; 28.3 mmol) was dissolved in ethanol (200 ml). Was added dropwise sulfuric acid (1.7 ml; 31 mmol). The obtained white crystals were collected by filtration, washed with ethanol and dried to obtain sulfuric acid salt (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine (11.1 g; 87%) as a white crystalline substance. TPL (melting point) to 218°C.

Hydrochloric acid salt of (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine

(4-Chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine (1.4 g; 4.0 mmol) was dissolved in ethanol (25 ml). Was added dropwise concentrated hydrochloric acid (0.4 ml; 4.3 mmol). The obtained white crystals were collected by filtration, washed with ethanol and dried to obtain hydrochloric acid salt (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine (1.3 g; 84%) as a white crystalline substance.

Hydrobromic salt (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine

(4-Chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine (500 mg, 1.4 mmol) was dissolved in ethanol (10 ml). Was added dropwise concentrated of bromilow the portly acid (0,12 ml; 1.6 mmol). The obtained white crystals were collected by filtration, washed with ethanol and dried to obtain Hydrobromic salt (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine (510 mg; 83%) as a white crystalline substance. TPL 235°C.

Cyclohexyl-[2-(3,5-dimethyl-pyrazole-1-yl)-7-methyl-7H-purine-6-yl]-amine (compound 6.2)

Was obtained according to example 6 from (2-chloro-7-methyl-7H-purine-6-yl)-cyclohexyl-amine and 3,5-dimethylpyrazole.

LC-ESI-HRMS of [M+H]+ shows 326,2081 Yes. Designed 326,209318 Yes, the deviation was 3.7 million-1.

(4-Chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-7-methyl-7H-purine-6-yl]-amine (compound 6.3)

Was obtained according to example 6 from (2-chloro-7-methyl-7H-purine-6-yl)-(4-chloro-phenyl)-amine and 3,5-dimethylpyrazole.

LC-ESI-HRMS of [M+H]+ shows 354,1226 Yes. Designed 354,123396 Yes, deviation -2,2 million-1.

(4-Chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-ethyl-9H-purine-6-yl]-amine (compound 6.4)

Was obtained according to example 6 from (2-chloro-9-ethyl-9H-purine-6-yl)-(4-chloro-phenyl)-amine and 3,5-dimethylpyrazole.

LC-ESI-HRMS of [M+H]+ shows 368,1399 Yes. Designed 368,139046 Yes, the deviation of 2.3 million-1.

Benzo[1,3]dioxol-5-yl-[2-(3,5-dimethyl-pyrazole-1-yl)-9-ethyl-N-purine-6-yl]-amine (compound 6.5)

Was obtained according to example 6 of the Benz is[1,3]dioxol-5-yl-(2-chloro-9-ethyl-9H-purine-6-yl)-amine and 3,5-dimethylpyrazole.

LC-ESI-HRMS of [M+H]+ shows 378,1679 Yes. Designed 378,167848 Yes, deviation 0.1 million-1.

6-(4-Chloro-phenylsulfanyl)-2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine (compound 6.6)

Was obtained according to example 6 from 2-chloro-6-(4-chloro-phenylsulfanyl)-9-methyl-N-purine and 3.5-dimethylpyrazole.

LC-ESI-HRMS of [M+H]+ shows 371,0863 Yes. Designed 371,084568 Yes, the deviation of 4.7 million-1.

[2-(4-Chloro-3-methyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-chloro-phenyl)-amine (compound 6.7)

Was obtained according to example 6 from (2-chloro-9-methyl-9H-purine-6-yl)-(4-chloro-phenyl)-amine and 4-chloro-3-methyl-1H-pyrazole.

LC-ESI-HRMS of [M+H]+ shows 374,0692 Yes. Designed 374,068774 Yes, the deviation of 1.1 million-1.

[2-(5-Chloro-3-methyl-pyrazole-1-yl)-9-methyl-9H-purine-6-yl]-(4-chloro-phenyl)-amine (compound 6.8)

Was obtained according to example 6 from (2-chloro-9-methyl-N-purine-6-yl)-(4-chloro-phenyl)-amine and 5-chloro-3-methyl-1H-pyrazole.

LC-ESI-HRMS of [M+H]+ shows 374,0699 Yes. Designed 374,068774 Yes, a deviation of 3 million-1.

Example 7

Cyclohexyl-[2-(3,5-dimethyl-pyrazole-1-yl)-9H-purine-6-yl]-amine (compound 7.1)

(2-Chloro-9H-purine-6-yl)-cyclohexyl-amine (1.0 g; 3,47 mmol), 3,5-dimethyl-pyrazole (834 mg; 8,68 mmol) and acetonitrile (10 ml) were mixed in a tightly closed bottle and heated in a microwave oven at 200°C for 50 min is so Added water and the precipitate was collected by filtration. The crude product was purified by flash chromatography (dichloromethane/methanol) to obtain cyclohexyl-[2-(3,5-dimethyl-pyrazole-1-yl)-9H-purine-6-yl]-amine (210 mg; 19%) as a white powder.

LC-ESI-HRMS of [M+H]+ shows 312,192 Yes. Designed 312,193668 Yes, deviation -5,3 million-1.

Example 8

(4-Chloro-phenyl)-(2-hydrazino-9-methyl-9H-purine-6-yl)-amine

(2-Chloro-9-methyl-9H-purine-6-yl)-(4-chloro-phenyl)-amine (3.58 g; 12.1 mmol) was dissolved in tetrahydrofuran (50 ml). Added hydrazine monohydrate (26 ml; 536 mmol) and the reaction mixture was heated to the temperature of reflux distilled during the night. The next day was added water and the resulting solid was collected by filtration, washed with water and dried to obtain (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purine-6-yl)-amine (3,16 g; 90%) as a white crystalline substance.

(4-Chloro-phenyl)-(2-hydrazino-9-isobutyl-N-purine-6-yl)-amine

Was obtained according to example 8 from (2-chloro-9-isobutyl-9H-purine-6-yl)-(4-chloro-phenyl)-amine and hydrazine monohydrate.

(4-Chloro-phenyl)-[9-(2-ethoxy-ethyl)-2-hydrazino-9H-purine-6-yl]-amine

Was obtained according to example 8 of [2-chloro-9-(2-ethoxy-ethyl)-9H-purine-6-yl]-(4-chloro-phenyl)-amine and hydrazine monohydrate.

(4-Fluoro-phenyl)-(2-hydras the but-9-methyl-N-purine-6-yl)-amine

Was obtained according to example 8 from (2-chloro-9-methyl-9H-purine-6-yl)-(4-fluoro-phenyl)-amine and hydrazine monohydrate.

(2 Hydrazino-9-methyl-9H-purine-6-yl)-(4-trifluoromethyl-phenyl)-amine

Was obtained according to example 8 from (2-chloro-9-methyl-9H-purine-6-yl)-(4-trifluoromethyl-phenyl)-amine and hydrazine monohydrate.

(2 Hydrazino-9-methyl-N-purine-6-yl)-pyridin-4-yl-amine

Was obtained according to example 8 from (2-chloro-9-methyl-N-purine-6-yl)-pyridin-4-yl-amine and hydrazine monohydrate.

(5-Chloro-pyridine-2-yl)-(2-hydrazino-9-methyl-N-purine-6-yl)-amine

Was obtained according to example 8 from (2-chloro-9-methyl-9H-purine-6-yl)-(5-chloro-pyridine-2-yl)-amine and hydrazine monohydrate.

(6-Chloro-pyridine-3-yl)-(2-hydrazino-9-methyl-9H-purine-6-yl)-amine

Was obtained according to example 8 from (2-chloro-9-methyl-9H-purine-6-yl)-(6-chloro-pyridine-3-yl)-amine and hydrazine monohydrate.

(2 Hydrazino-9-methyl-9H-purine-6-yl)-(4-nitro-phenyl)-amine

Was obtained according to example 8 from (2-chloro-9-methyl-9H-purine-6-yl)-(4-nitro-phenyl)-amine and hydrazine monohydrate.

4-(2-Hydrazino-9-methyl-9H-purine-6-ylamino)-benzonitrile

Was obtained according to example 8 from 4-(2-chloro-9-methyl-9H-purine-6-ylamino)-benzonitrile and monohydro is and hydrazine.

(2 Hydrazino-9-methyl-9H-purine-6-yl)-phenyl-amine

Was obtained according to example 8 from (2-chloro-9-methyl-9H-purine-6-yl)-phenyl-amine and hydrazine monohydrate.

(2 Hydrazino-9-methyl-N-purine-6-yl)-phenethyl-amine

Was obtained according to example 8 from (2-chloro-9-methyl-N-purine-6-yl)-phenethyl-amine and hydrazine monohydrate.

(4-Bromo-phenyl)-(2-hydrazino-9-methyl-N-purine-6-yl)-amine

Was obtained according to example 8 from (4-bromo-phenyl)-(2-chloro-9-methyl-9H-purine-6-yl)-amine and hydrazine monohydrate.

(9-Benzyl-2-hydrazino-9H-purine-6-yl)-(4-chloro-phenyl)-amine and (7-benzyl-2-hydrazino-7H-purine-6-yl)-(4-chloro-phenyl)-amine

A mixture of 9-benzyl-2-hydrazino-9H-purine-6-yl)-(4-chloro-phenyl)-amine and (7-benzyl-2-hydrazino-7H-purine-6-yl)-(4-chloro-phenyl)-amine was obtained according to example 8 of a mixture of (9-benzyl-2-chloro-9H-purine-6-yl)-(4-chloro-phenyl)-amine and (7-benzyl-2-chloro-7H-purine-6-yl)-(4-chloro-phenyl)-amine and hydrazine monohydrate.

Example 9

[2-(3,5-Dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-fluoro-phenyl)-amine (compound 9.1)

(4-Fluoro-phenyl)-(2-hydrazino-9-methyl-9H-purine-6-yl)-amine (900 mg; 3,29 mmol) and 2,4-pentandiol (0,47 ml; 4,16 mmol) in ethanol (25 ml) was heated to the temperature of reflux distilled within 20 minutes. Added water and white Crist is licence compound was collected by filtration, washed with water and dried to obtain [2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-yl]-(4-fluoro-phenyl)-amine (1.1 g; 100%).

LC-ESI-HRMS of [M+H]+ shows 338,1526 Yes. Designed 338,152946 Yes, a deviation of -1 million-1.

(4-Chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-isobutyl-N-purine-6-yl]-amine (compound 9.2)

Was obtained according to example 9 from (4-chloro-phenyl)-(2-hydrazino-9-isobutyl-9H-purine-6-yl)-amine and 2,4-pentanedione.

(4-Chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-(2-ethoxy-ethyl)-N-purine-6-yl]-amine (compound 9.3)

Was obtained according to example 9 from (4-chloro-phenyl)-[9-(2-ethoxy-ethyl)-2-hydrazino-9H-purine-6-yl]-amine and 2,4-pentanedione.

[2-(3,5-Dimethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-yl]-(4-trifluoromethyl-phenyl)-amine (compound 9.4)

Was obtained according to example 9 from (2-hydrazino-9-methyl-9H-purine-6-yl)-(4-trifluoromethyl-phenyl)-amine and 2,4-pentanedione.

LC-ESI-HRMS of [M+H]+ shows 388,1517 Yes. Designed 388,149752 Yes, deviation 5 million-1.

[2-(3,5-Dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-pyridine-4-yl-amine (compound 9.5)

Was obtained according to example 9 from (2-hydrazino-9-methyl-N-purine-6-yl)-pyridin-4-yl-amine and 2,4-pentanedione.

LC-ESI-HRMS of [M+H]+ shows 321.1592 Yes. Designed 321,157617 Yes, the deviation of 4.9 million-1.

(5-Chloro-pyridine-2-yl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-mate the-N-purine-6-yl]-amine (compound 9.6)

Was obtained according to example 9 from (5-chloro-pyridine-2-yl)-(2-hydrazino-9-methyl-9H-purine-6-yl)-amine and 2,4-pentanedione.

LC-ESI-HRMS of [M+H]+ shows 355,1204 Yes. Designed 355,118645 Yes, the deviation of 4.9 million-1.

(6-Chloro-pyridine-3-yl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine (compound 9.7)

Was obtained according to example 9 from (6-chloro-pyridine-3-yl)-(2-hydrazino-9-methyl-9H-purine-6-yl)-amine and 2,4-pentanedione.

LC-ESI-HRMS of [M+H]+ shows 355,1179 Yes. Designed 355,118645 Yes, the bias of-2.1 million-1.

[2-(3,5-Dimethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-yl]-(4-nitro-phenyl)-amine (compound 9.8)

Was obtained according to example 9 from (2-hydrazino-9-methyl-N-purine-6-yl)-(4-nitro-phenyl)-amine and 2,4-pentanedione.

LC-ESI-HRMS of [M+H]+ shows 365,1461 Yes. Designed 365,147447 Yes, the deviation was 3.7 million-1.

4-[2-(3,5-Dimethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-ylamino]-benzonitrile (connection 9.9)

Was obtained according to example 9 from 4-(2-hydrazino-9-methyl-9H-purine-6-ylamino)-benzonitrile and 2,4-pentanedione.

LC-ESI-HRMS of [M+H]+ shows 345,1593 Yes. Designed 345,157617 Yes. deviation 4.9 million-1.

[2-(3,5-Dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-phenyl-amine (compound 9.10)

Was obtained according to example 9 from (2-hydrazino-9-methyl-9H-purine-6-yl)-phenyl-and the ins and 2,4-pentanedione.

LC-ESI-HRMS of [M+H]+ shows 320,1629 Yes. Designed 320,162368 Yes deviation 1.7 million-1.

[2-(3,5-Dimethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-yl]-phenethyl-amine (compound 9.11)

Was obtained according to example 9 from (2-hydrazino-9-methyl-N-purine-6-yl)-phenethyl-amine and 2,4-pentanedione.

LC-ESI-HRMS of [M+H]+ shows 348,1941 Yes. Designed 348,193668 Yes, the deviation of 1.2 million-1.

(4-Bromo-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine (compound 9.12)

Was obtained according to example 9 from (4-bromo-phenyl)-(2-hydrazino-9-methyl-9H-purine-6-yl)-amine and 2,4-pentanedione.

(4-Chloro-phenyl)-[9-methyl-2-(5-methyl-3-trifluoromethyl-pyrazole-1-yl)-9H-purine-6-yl]-amine (compound 9.13)

Was obtained according to example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purine-6-yl)-amine and 1,1,1-Cryptor-2,4-pentanedione.

LC-ESI-HRMS of [M+H]+ shows 408,0948 Yes. Designed 408,09513 Yes, a deviation of-0.8 million-1.

(4-Chloro-phenyl)-[2-(3,5-diethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-yl]-amine (compound 9.14)

Was obtained according to example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purine-6-yl)-amine and 3,5-heptanedione.

LC-ESI-HRMS of [M+H]+ shows 382,1542 Yes. Designed 382,154696 Yes, the deviation of 1.3 million-1.

(4-Chloro-phenyl)-[9-methyl-2-(3,4,5-trimethyl-pyrazole-1-yl)-9H-purine-6-yl]-amine (compound 9.15)

Was obtained according to example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-N-purine-6-yl)-amine and 3-methyl-2,4-pentanedione.

LC-ESI-HRMS of [M+H]+ shows 368,1389 Yes. Designed 368,139046 Yes, deviation -0,4 million-1.

[2-(4-Chloro-3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-chloro-phenyl)-amine (compound 9.16)

Was obtained according to example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-N-purine-6-yl)-amine and 3-chloroacetylation.

LC-ESI-HRMS of [M+H]+ shows 388,0852 Yes. Designed 388,084424 Yes, a deviation of 2 million-1.

(4-Chloro-phenyl)-[9-methyl-2-(5-methyl-3-phenyl-pyrazole-1-yl)-9H-purine-6-yl]-amine (compound 9.17)

Was obtained according to example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-N-purine-6-yl)-amine and benzoylacetone.

LC-ESI-HRMS of [M+H]+ shows 416,1393 Yes. Designed 416,139046 Yes, deviation 0.6 million-1.

(4-Chloro-phenyl)-[2-(3-furan-2-yl-5-methyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine (compound 9.18)

Was obtained according to example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-N-purine-6-yl)-amine and 1-(2-furyl)-1,3-butanedione.

LC-ESI-HRMS of [M+H]+ shows 406,1169 Yes. Designed 406,118311 Yes, the deviation is 3.5 million-1.

Ethyl ester of 1-[6-(4-chloro-phenylamino)-9-methyl-N-purine-2-yl]-5-methyl-1H-pyrazole-3-carboxylic acid (compound 9.19)

Was obtained according to example 9 from (4-chloro-FeNi is)-(2-hydrazino-9-methyl-N-purine-6-yl)-amine and ethylacetoacetate.

LC-ESI-HRMS of [M+H]+ shows 412,1308 Yes. Designed 412,128876 Yes, the deviation of 4.7 million-1.

[9-Benzyl-2-(3,5-dimethyl-pyrazole-1-yl)-N-purine-6-yl]-(4-chloro-phenyl)-amine and [7-benzyl-2-(3,5-dimethyl-pyrazole-1-yl)-7H-purine-6-yl]-(4-chloro-phenyl)-amine

A mixture of [9-benzyl-2-(3,5-dimethyl-pyrazole-1-yl)-9H-purine-6-yl]-(4-chloro-phenyl)-amine and [7-benzyl-2-(3,5-dimethyl-pyrazole-1-yl)-7H-purine-6-yl]-(4-chloro-phenyl)-amine was obtained according to example 9 of (9-benzyl-2-hydrazino-N-purine-6-yl)-(4-chloro-phenyl)-amine and (7-benzyl-2-hydrazino-7H-purine-6-yl)-(4-chloro-phenyl)-amine and 2,4-pentanedione.

3-{[6-(4-Chloro-phenylamino)-9-methyl-N-purine-2-yl]-hydrazono}-1,1,1,4,4,4-hexaplar-butane-2-he

Was obtained according to example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-N-purine-6-yl)-amine and hexafluoroacetylacetone.

Example 10

[2-(3,5-Bis-trifluoromethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-yl]-(4-chloro-phenyl)-amine (compound 10.1)

Small pieces of sodium (200 mg; 8,7 mmol) was added to methanol (40 ml) and was stirred for 30 minutes. Was added 3-{[6-(4-chloro-phenylamino)-9-methyl-9H-purine-2-yl]-hydrazono}-1,1,1,4,4,4-hexaplar-butane-2-on (1.3 g; 2.7 mmol) and the reaction mixture was heated at the temperature of reflux distilled during the night. When cooled to precipitate precipitated white solid. The crystals were collected by the filter is tion and recrystallized from methanol to obtain [2-(3,5-bis-trifluoromethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-yl]-(4-chloro-phenyl)-amine (460 mg; 37%) as white crystals.

LC-ESI-HRMS of [M+H]+ shows 462,0668 Yes. Designed 462,066864 Yes, deviation -0,1 million-1.

Example 11

N-[2-(3,5-Dimethyl-pyrazole-1-yl)-9-methyl-9H-purine-6-yl]-benzene-1,4-diamine (compound 11.1)

[2-(3,5-Dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-nitro-phenyl)-amine (2,89 g; of 7.93 mmol) was dissolved in methanol (50 ml) and dichloromethane (50 ml). Added palladium on coal (5%; 600 mg) and the reaction mixture was stirred in an atmosphere of hydrogen for 24 hours. Filtration through celite followed by concentration under vacuum gave N-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-benzene-1,4-diamine (2.6 g; 98%) as a yellow foam.

LC-ESI-HRMS of [M+H]+ shows 335,1733 Yes. Designed 335,173267 Yes, deviation 0.1 million-1.

Example 12

(4-Chloro-phenyl)-{9-methyl-2-[3-methyl-5-(tetrahydro-Piran-2-intoximeter)-pyrazole-1-yl]-N-purine-6-yl}-amine

In nitrogen atmosphere tetrahydro-2-(2-propenyloxy)-2H-Piran (636 ml; to 4.52 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to -78°C. was Added dropwise n-utility (2.5 M in hexano; 2,03 ml; of 5.06 mmol). Was added dropwise zinc chloride (629 mg; 4,51 mmol)dissolved in tetrahydrofuran (5 ml) and the reaction mixture was left to warm to 0°C. was Added acetylchloride (0.35 ml; is 4.93 mmol) followed by heating to 40°C for 45 minutes. The reaction extinguished asystem aqueous ammonium chloride. Added ethyl acetate and the phases were separated. The organic phase was washed with saturated aqueous ammonium chloride (2×) and brine, dried over magnesium sulfate, filtered and concentrated under vacuum to obtain 4-(tetrahydro-Piran-2-yloxy)-but-3-in-2-it is in the form of the crude product.

4-(Tetrahydro-Piran-2-yloxy)-but-3-in-2-it (824 mg; 4.5 mmol) and (4-chloro-phenyl)-(2-hydrazino-9-methyl-N-purine-6-yl)-amine (1.5 g, 5.2 mmol) was dissolved in ethanol (30 ml) and was heated at the temperature of reflux distilled within 24 hours. The reaction mixture was concentrated under vacuum. The crude product was purified by flash chromatography (dichloromethane/methanol/ammonia) to give (4-chloro-phenyl)-{9-methyl-2-[3-methyl-5-(tetrahydro-Piran-2-intoximeter)-pyrazole-1-yl]-N-purine-6-yl}-amine (240 mg, 12%) as a yellow foam.

Example 13

{2-[6-(4-Chloro-phenylamino)-9-methyl-9H-purine-2-yl]-5-methyl-2H-pyrazole-3-yl}-methanol (compound 13.1)

(4-Chloro-phenyl)-{9-methyl-2-[3-methyl-5-(tetrahydro-Piran-2-intoximeter)-pyrazole-1-yl]-N-purine-6-yl}-amine (240 mg; of 0.53 mmol) was dissolved in methanol (30 ml). Added monohydrate para-toluensulfonate acid (90 mg; 0.48 mmol) and the reaction mixture was heated to the temperature of reflux distilled within 24 hours. When cooling was obtained a white crystalline compound. The crystals were stirred with potassium carbonate (2 M), collected by F. is litraly, washed with water and dried to obtain {2-[6-(4-chloro-phenyl-amino)-9-methyl-N-purine-2-yl]-5-methyl-2H-pyrazole-3-yl}-methanol (60 mg, 31%).

LC-ESI-HRMS of [M+H]+ shows 370,1176 Yes. Designed 370,118311 Yes, deviation -1,9 million-1.

Example 14

[2-(3,5-Dimethyl-pyrazole-1-yl)-N-purine-6-yl]-phenyl-amine (compound 14.1)

Ammonia (75 ml) are condensed into the reaction flask, equipped with a mechanical stirrer and cooled in an acetone bath with dry ice. Was added to a mixture of [9-benzyl-2-(3,5-dimethyl-pyrazole-1-yl)-9H-purine-6-yl]-(4-chloro-phenyl)-amine and [7-benzyl-2-(3,5-dimethyl-pyrazole-1-yl)-7H-purine-6-yl]-(4-chloro-phenyl)-amine (1.5 g; 3,49 mmol). With vigorous stirring was added small pieces of sodium (2 equiv.). When the addition was completed, the reaction mixture became dark blue. The mixture was stirred for 2 minutes, followed by careful addition of ammonium chloride. The reaction mixture was left to warm to room temperature. Added water and a small amount of concentrated hydrochloric acid. The obtained solid substance was collected by filtration, washed with water and ether and dried to obtain [2-(3,5-dimethyl-pyrazole-1-yl)-9H-purine-6-yl]-phenyl-amine (590 mg, 50%) as a white solid.

LC-ESI-HRMS of [M+H]+ shows 306,1478 Yes. Designed 306,146718 Yes, the deviation of 3.5 million-1.

Example 15

[2-(3,5-Dimethyl-p is razol-1-yl)-9-(2-methoxy-ethyl)-N-purine-6-yl]-phenyl-amine (compound 15.1)

[2-(3,5-Dimethyl-pyrazole-1-yl)-N-purine-6-yl]-phenyl-amine (300 mg, 0.88 mmol), 2-bromatology ether (0,12 ml; of 1.32 mmol), potassium carbonate (121 mg, 0.88 mmol) and acetonitrile were mixed and heated in a microwave oven at 120°C for 40 minutes. Added water to obtain a white precipitate. The crude product was purified by preparative LC/MS (liquid chromatography/mass spectrometry) to obtain [2-(3,5-dimethyl-pyrazole-1-yl)-9-(2-methoxy-ethyl)-N-purine-6-yl]-phenyl-amine (27 mg, 9%) as a white crystalline substance.

LC-ESI-HRMS of [M+H]+ shows 364,1899 Yes. Designed 364,188583 Yes, the deviation of 3.6 million-1.

Example 16

Biological activity

The example below demonstrates the biological activity of the compounds according to the invention. The flow of ions through the CA2+-activated K+-channels with low conductivity (SK-channels, subtype 3) register using the method of fixing the potential in the whole cell configuration on the classic installation by fixing the potential of using NECK of tissue culture cells expressing hSK3 channels, as described, for example, in WO 2006/100212.

Set value SC100defined as stimulating concentration necessary to improve the original thread at 100%. The following values SC100are SK3-activating properties of the compounds according to the invention.

ConnectionSC100(µm)
6.10,02
6.40,01
9.10,05
9.70,4
9.80,2
9.110,2
9.140,6
9.160,02
9.181,0
13.10,2
14.10,2
15.10,4

1. Derived purine formula Ia or Ib
,
it stereoisomer, or a mixture of its stereoisomers, or its pharmaceutically acceptable salt,
where n is 0, 1, 2 or 3;
X represents O, S or NR', where R' represents hydrogen or methyl;
Y represents cycloalkyl, phenyl, benzo[1,3]dioxole or pyridyl, where cycloalkyl, phenyl, benzo[1,3]dio is salted and pyridyl possibly substituted by one Deputy, selected from the group consisting of halogeno, trifloromethyl, cyano, nitro and amino;
R1represents hydrogen, alkyl or alkoxy-alkyl and
Het represents pyrazolidine group, which is substituted by two or more than two times with substituents selected from the group consisting of alkyl, hydroxy-alkyl, halogeno, trifloromethyl, alkoxy-carbonyl and phenyl.

2. Derived purine according to claim 1, where n is 0, 1 or 2.

3. Derived purine according to claim 2, where n is equal to 0.

4. Derived purine according to claim 1, where X represents NR', where R' represents hydrogen.

5. Derived purine according to claim 1, where Y represents phenyl, which substituted halogeno.

6. Derived purine according to claim 1, where R1represents hydrogen or alkyl.

7. Derived purine according to claim 6, where R1represents alkyl.

8. Derived purine according to claim 1 where Het is pyrazolidine group, which is substituted twice by alkyl.

9. Derived purine according to claim 1, including:
(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine;
cyclohexyl-[2-(3,5-dimethyl-pyrazole-1-yl)-7-methyl-7H-purine-6-yl]-amine;
(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-7-methyl-7H-purine-6-yl]-amine;
(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-ethyl-N-purine-6-yl]-amine;
benzo[1,3]dioxol-5-yl-[2-(3,5-dimethyl-pyrazole-1-yl)-9-ethyl-N-PU is in-6-yl]-amine;
6-(4-chloro-phenylsulfanyl)-2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine;
[2-(4-chloro-3-methyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-chloro-phenyl)-amine;
[2-(5-chloro-3-methyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-chloro-phenyl)-amine;
cyclohexyl-[2-(3,5-dimethyl-pyrazole-1-yl)-N-purine-6-yl]-amine;
[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-fluoro-phenyl)-amine;
(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-isobutyl-N-purine-6-yl]-amine;
(4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-(2-ethoxy-ethyl)-N-purine-6-yl]-amine;
[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-trifluoromethyl-phenyl)-amine;
[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-pyridine-4-yl-amine;
(5-chloro-pyridine-2-yl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine;
(6-chloro-pyridine-3-yl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine;
[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-nitro-phenyl)-amine;
4-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-ylamino]-benzonitrile;
[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-phenyl-amine;
[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-phenethyl-amine;
(4-bromo-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine;
(4-chloro-phenyl)-[9-methyl-2-(5-methyl-3-trifluoromethyl-pyrazole-1-yl)-N-purine-6-yl]-amine;
(4-chloro-phenyl)-[2-(3,5-diethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine;
(4-chloro-phenyl)-[9-methyl-2-(3,4,5-trimethyl-pyrazole-1-yl)-N-purine-6-yl]-amine;
[2-(4-chloro-3,5-dimethyl-is irsol-1-yl)-9-methyl-N-purine-6-yl]-(4-chloro-phenyl)-amine;
(4-chloro-phenyl)-[9-methyl-2-(5-methyl-3-phenyl-pyrazole-1-yl)-N-purine-6-yl]-amine;
ethyl ester of 1-[6-(4-chloro-phenylamino)-9-methyl-N-purine-2-yl]-5-methyl-1H-pyrazole-3-carboxylic acid;
[2-(3,5-bis-trifluoromethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-(4-chloro-phenyl)-amine;
N-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-benzene-1,4-diamine;
{2-[6-(4-chloro-phenylamino)-9-methyl-N-purine-2-yl]-5-methyl-2H-pyrazole-3-yl}-methanol;
[2-(3,5-dimethyl-pyrazole-1-yl)-N-purine-6-yl]-phenyl-amine or
[2-(3,5-dimethyl-pyrazole-1-yl)-9-(2-methoxy-ethyl)-N-purine-6-yl]-phenyl-amine;
or a stereoisomer, or a mixture of its stereoisomers, or its pharmaceutically acceptable salt.

10. Derived purine according to claim 1, where n is equal to 0,
X represents NR', where R' represents hydrogen,
Y represents phenyl, which substituted halogeno,
R1represents alkyl and
Het represents pyrazolidine group, which is substituted twice by alkyl.

11. Derived purine of claim 10, which represents (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazole-1-yl)-9-methyl-N-purine-6-yl]-amine or its pharmaceutically acceptable salt.

12. The pharmaceutical composition capable of modulating SK-channels containing a therapeutically effective amount of a derivative purine according to claim 1 or its pharmaceutically acceptable salts joining together with at least one pharmaceutically who priemlemim carrier or diluent.



 

Same patents:

The invention relates to novel 2,6,9-triple-substituted purine derivative of General formula I, having the effect of selective inhibitors of kinases of the cell cycle, which can be used, for example, for the treatment of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes type I, multiple sclerosis, and for the treatment of cancer, cardiovascular diseases such as restenosis, etc

The invention relates to a method for producing analogues of nucleosides dimethoxyaniline

Compounds // 2461559

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new purine derivatives possessing the properties of an inhibitor of the enzyme CDK specified in CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9. In formula (I): R1 and R2 each independently represents H, C1-6alkyl or C1-6halogenalkyl; R3 and R4 each independently represents H, C1-6-alkyl or C1-6-halogenalkyl; R5 represents C1-6-alkyl or C3-12-cycloalkyl, or C3-12-cycloalkyl-C1-6-alkyl each of which may be optionally substituted by one or more OH groups; R6 represents wherein Y represents N, X and Z represents CR9; R7, R8 and R9 optionally represent H, alkyl or C1-6-halogenalkyl; wherein at least one of R7 , R8 and R9 is other than H. The invention also refers to a pharmaceutical composition containing said compounds, using the compounds for treating alopecia, stroke, a proliferative disease, such as cancer, leukaemia, glomerulonephritis, rheumatoid arthritis, psoriasis, viral diseases, such as a disease caused by human cytomegalovirus, type 1 herpex simplex virus, type 1 human immunodeficiency virus, a neurodegenerative disease, a CNS disease, such as Alzheimer's disease.

EFFECT: preparing new purine derivatives possessing the properties of the inhibitor of the enzyme CDK.

30 cl, 8 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new purine derivatives of formula (I) and to their pharmaceutically acceptable salts exhibiting the properties of adenosine receptor A2A agonists. The compounds can find application for preparing a drug for treating an inflammatory or obstructive respiratory disease. In formula

,

R1, R2 and R3 are those as specified in the patent claim.

EFFECT: preparing new purine derivatives of formula (I) or their pharmaceutically acceptable salts showing the properties of adenosine receptor A2A agonists.

8 cl, 2 tbl, 264 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing abacavir of formula (I) or salts or solvates thereof. Abacavir has strong HIV-1 and HIV-2 selective inhibitor activity and can be used in treating patients infected with HIV. The method involves i) closing the ring in a compound of formula (IV) by first reacting said compound (IV) with an anhydrous hydrochloric acid solution in (C1-C6)-alcohol, preferably isopropanol, and then with tri(C1-C4)-alkylorthoformate in anhydrous conditions to obtain a compound of formula (III), ii) reaction of the compound of formula (III) with cyclopropylamine to obtain a compound of formula (II) and iii) hydrolysis of the compound of formula (II) to obtain abacavir (I) or salt thereof. R1 denotes a (C1-C4)-alkyl radical, preferably isopropyl.

EFFECT: obtaining an end product with higher output and higher quality.

12 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: nucleic base (e.g. uracil, cytosine, adenine, guanine, hypoxanthine, xanthine or similar) reacts with perfluoroalkyl halide in the presence of sulphoxide, peroxide and an iron compound to obtain a perfluoroalkyl-substituted nucleic base.

EFFECT: high cost effectiveness as an intermediate compound for producing medicinal agents.

15 cl, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing abacavir of formula (I) or pharmaceutically acceptable salt thereof, involving reaction of a compound of formula (II), (I) (II), where R denotes H or (C1-C4)-alkyl radical with an inorganic base such as an alkali metal hydroxide in a mixture of (C1-C6)-alcohol and water; and extraction of abacavir of formula (I) in form of a free base or in form of a pharmaceutically acceptable salt by treating said free base with a corresponding acid.

EFFECT: method ensures high degree of conversion without racemation, enables to minimise formation of impurities and considerably shortens reaction time.

19 cl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I in free form or in form of pharmaceutically acceptable salt, which possess properties of adenosine receptor A2A agonists. In formula I , R1 represents (C1-C8)alkylcarbonyl, (C3-C8)cycloalkylcarbonyl, -SO2(C1-C8)alkyl, phenyl(C1-C4)alkylcarbonyl or -(C=O)-C(=O)-NH(C1-C8)alkyl, optionally substituted with R4; R2 represents H or (C1-C8)alkyl, optionally substituted with (C6-C10)aryl; R3 represents halogen or(C2-C8)alkinyl, or R3 stands for aminogroup, optionally substituted with (C3-C8)cycloalkyl, optionally substituted with amino, or R3 represents (C1-C8)alkylaminogroup, optionally substituted with hydroxy, phenyl or R5, or R3 stands for R6, optionally substituted with amino or -NH-C(=O)-NH-R7, or R3 stands for -NH-R6, optionally substituted with -NH-C(=O)-NH-R7, or R3 stands for (C1-C8)alkylaminocarbonyl, optionally substituted with. -NH-C(=O)-NH-R8; R4, R5 and R6 represent independently 5- or 6-member heterocyclic ring, which contains one-two N ring heteroatoms, optionally substituted with amino or (C1-C8)alkyl; and R7 and R8 represent independently 5- or 6-member heterocyclic ring, which contains one-two ring heteroatoms selected from N and S, and is optionally substitutedf with halogen, (C1-C8)alkylsulfonyl or 5- or 6-member aromatic heterocyclic ring, which contains one N ring heteroatom. Invention also relates to pharmaceutical composition and to application of said compounds for treatment of states, mediated by activation of adenosine receptor A2A.

EFFECT: obtaining composition, which possesses properties of adenosine receptor A2A agonists.

10 cl, 3 tbl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel purine derivatives of general formula I in free form or in form of a pharmaceutically acceptable salt which have A2A agonist properties. In formula I , R1 denotes a N-bonded 5-6-member heterocyclic group containing 1-4 nitrogen atoms in the ring, which can be optionally substituted with oxo, phenyl or C1-8-alkyl, optionally substituted with hydroxy; R2 is hydrogen or C1-C8-alkyl, optionally substituted with hydroxy or 1-2 phenyls possibly substituted with hydroxy or C1-C8-alkoxy; R3 is C2-C8-alkynyl or C1-C8-alkoxycarbonyl, or R3 is amino substituted with C3-C8-cycloalkyl, optionally substituted with amino, hydroxy, benzyloxy or NH-C(=O)-NH-R6, or R3 is amino substituted with R4, -R4-benzyl or C5-C10-mono- or bicarbocyclic group, optionally substituted with hydroxy or C1-C8-alkoxycarbonyl, or R3 is aminocarbonyl optionally substituted with R5, or R3 is C1-C8-alkylamino optionally substituted with hydroxy, R5, NH-C(=O)-C1-C8-alkyl, -MH-SO2-C1-C8-alkyl, -NH-C(=O)-NH-R6 or phenyl, optionally substituted with phenyloxy, or R3 is a N-bonded 5-member heterocyclic group containing 1 nitrogen atom in the ring which may optionally be substituted with amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino and other groups.

EFFECT: compounds can be useful in treating conditions mediated by activation of the adenosine A2A receptor, especially inflammatory or obstructive respiratory tract diseases.

9 cl, 5 tbl, 161 ex

FIELD: organic chemistry, heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new compounds - purine derivatives of the general formula (I): in free form or salt wherein X means oxygen or sulfur atom or group NR5; R1 means alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group that can be substituted optionally with hydroxy-, carboxy-group or alkoxycarbonyl; or if X means NR5 then R1 can mean alternatively heterocyclic group taken among benzylpiperidyl or the formula: ; or group of the formula (II): ; R2 means hydrogen atom, alkyl or alkoxy-group; R3 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, alkoxycarbonyl, -N(R9)R10, (C1-C4)-alkylene-SO2N(R11)R12 or -CON(R13)R14; or if two substitutes R2 and R3 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-10 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen and sulfur atom; R4 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, -SO2N(R11)R12, -N(R9)R10 or -CON(R13)R14; or if two substitutes R3 and R4 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen or sulfur atom; R5 means hydrogen atom or alkyl; R6, R7 and R8 mean hydrogen atom, or one of these radicals means -SO2NH2, -N(CH3)COCH3, -CONH2 and two others mean hydrogen atom; R9 means hydrogen atom or alkyl; R10 means hydrogen atom, -COR15 wherein R15 means alkyl, alkoxy-group; or R9 and R10 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R11 means hydrogen atom or alkyl; R12 means hydrogen atom, alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl; or R11 and R12 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R13 and R14 each and independently of one another means hydrogen atom or alkyl with exception of 2-(para-n-butylanilino)-6-methoxypurine, 2-(para-n-butylanilino)-6-(methylthio)purine, 2,6-di-(phenylamino)-purine, 2,6-di-(para-tolylamino)-purine and 2-(para-tolylamino)-6-(phenylamino)-purine.

EFFECT: valuable biochemical properties of compounds.

11 cl, 4 tbl, 221 ex

The invention relates to novel 2,6,9-triple-substituted purine derivative of General formula I, having the effect of selective inhibitors of kinases of the cell cycle, which can be used, for example, for the treatment of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes type I, multiple sclerosis, and for the treatment of cancer, cardiovascular diseases such as restenosis, etc

The invention relates to new compounds of General formula I

< / BR>
where R is chosen from the group comprising R2, R2NH - or R3R4N-R5-, where R2selected from the group including9-C12-alkyl,

< / BR>
and

< / BR>
where each R6independently selected from the group including hydrogen, C3-C8-cycloalkyl,1-C4-alkyl and (CH2)m-phenyl, where m = integer 0-8; x = 1-8 integer; n = 0-8 integer; z is chosen from the group comprising phenyl, heterocycle, cycloalkyl and naphthalene, and M is chosen from the group comprising hydrogen, C1-C4-alkyl,

< / BR>
and

< / BR>
where each R6' are independently selected from the group including hydrogen, C3-C8-cycloalkyl,1-C4-alkyl and (CH2)m-phenyl, where m' = integer 0-8; n' = integer 0-8; x' = 1-8 integer; Q is hydrogen or C1-C4-alkyl, and Z' is chosen from the group comprising phenyl, heterozygote selected from the group including D, E,

< / BR>
and

< / BR>
where each D is independently selected from the group comprising trifluoromethyl, triptoreline and C1-C4-alkoxy; each E is independently selected from the group including Hal, HE and1-C8-alkyl; Z is chosen from the group comprising phenyl, cycloalkyl and naphthalene; each R6"is hydrogen, n = integer 0-8; x" = 1-8 integer, and M' is hydrogen, Z' may be optionally substituted by groups D', E', each D' is independently selected from the group comprising trifluoromethyl, triptoreline and C1-C4-alkoxy; each E' is independently selected from the group including Hal, HE and1-C8-alkyl; R3and R4selected from the group including hydrogen, C1-C4-alkyl and (CH2)y-phenyl, where y = 0-8 integer, provided that R3and R4both denote hydrogen; R5- C1-C8-alkylene and R1selected from the group including cyclopentyl, cyclopentenyl and isopropyl, and their pharmaceutically acceptable salts, optical isomers and hydrates, provided that when R2refers to a group

< / BR>
< / BR>
< / BR>
and

< / BR>
where D, b, R6", x", n", M' and Z" accept above values

the method of treatment of a patient with proliferative disorders by assigning the compounds I, the method of preventing apoptosis of nerve cells, ways of protecting nerve cells from apoptosis and destruction caused by antitumor agents, and pharmaceutical composition

FIELD: medicine.

SUBSTANCE: invention relates to condensed bicyclic compounds, having affinity with mineralocorticoid receptor (VR) of formula [I] and formula [ii], as well as to pharmaceutical compositions on their basis. In general formula [I[ and [ii] ring A represents benzene ring, which has substituent R1, condensed with adjacent 6-membered heterocyclic ring, and said benzene ring additionally optionally is substituted with one or two substituent(s), selected from halogen atom and C1-8-alkyl group, R1 represents C1-8-alkylsulfonyl amino group or C1-8-alkyl aminosulfonyl group, R2 and R3 (a) are similar or different and represent group, selected from hydrogen atom, C1-8-alkyl group, and from 6- to 10-membered monocyclic or bicyclic aryl group (said aryl group is optionally substituted with halogen atom), (b) are combined with each other with formation of oxogroup or (c) are combined with each other on their ends together with adjacent carbon atom with formation of C3-10-cycloalkyl group, X represents the following group =N-, =C(R4)- or -CH(R4)-, R4 represents hydrogen atom, cyanogroup, halogen atom, C1-6-alkyl group, C2-6-alkenyl group, C3-10-dicloalkyl group, C1-7-alkanoyl group, carbamoyl group or C3-8cycloalkenyl group, Ar represents from 6- to 10-membered monocyclic or bicyclic aryl group, optionally containing one or several heteroatom(s), selected from sulphur atom, oxygen atom and nitrogen atom (said aryl group is optionally substituted with similar or different, one or two substituent(s), selected from halogen atom, cyanogroup, C1-8-alkyl group, trihalogen- C1-8-alkyl group and C1-8alkoxygroup), and dotted line represents presence or absence of double bond, Xa represents the following group =N- or =C(CN)-, RZ represents hydrogen atom or halogen atom, R25 and R35 represent alkyl group, and Ar3 represents phenyl group, optionally substituted with one or two group(s), which is(are) selected from halogen atom and trihalogenalkyl group.

EFFECT: compounds can be applied as antihypertensive medication.

15 cl, 18 tbl, 8 dwg, 71 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to 6-substituted isoquinoline and isoquinolinone derivatives of formula or stereoisomer and/or tautomer forms thereof, and/or pharmaceutically acceptable salts thereof, where R1 is H or OH; R2 is R', (C7-C8)alkyl, (C1-C6)alkylene-R', (C2-C6)alkenyl; or R2 is (C1-C6)alkyl, under the condition that in said alkyl residue, at least one hydrogen is substituted with OH or OCH3; or R2 is (C1-C6)alkylene, bonded with cycloalkylamine, where (C1-C4)alkylene forms a second bond with another carbon atom of the cycloalkylamine ring and, together with carbon atoms of the cycloalkyalmine, forms a second 5-8-member ring; R3, R5 and R8 denote H; R4 is H, (C1-C6)alkyl or (C1-C6)alkylene-R'; R6 and R6' independently denote H, (C1-C8)alkyl, (C1-C6)alkylene-R' or C(O)O-(C1-C6)alkyl; R7 is H, halogen or (C1-C6)alkyl; n equals 1; m equals 3 or 5; r equals 0 or 1 and L is O(CH2)p, where p=0; where R' is (C3-C8)cycloalkyl, (C6)aryl; where in residues R2-R8 (C6)aryl is unsubstituted or substituted with one or more suitable groups independently selected from halogen, (C1-C6)alkyl, O-(C1-C6)alkyl, where the alkyl group can be substituted with 1-3 halogen atoms. The invention also relates to use of the compound of formula (I) and a medicinal agent based on the compound of formula (I).

EFFECT: obtaining novel 6-substituted isoquinoline and isoquinolinone derivatives suitable for treating and/or preventing diseases associated with Rho-kinase and/or Rho-kinase-mediated myosin light chain phosphatase phosphorylation.

36 cl, 5 tbl

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to 6-substituted isoquinoline and isoquinolinone derivatives of formula or stereoisomer and/or tautomer forms thereof, and/or pharmaceutically acceptable salts thereof, where R1 is H or OH; R2 is R', (C7-C8)alkyl, (C1-C6)alkylene-R', (C2-C6)alkenyl; or R2 is (C1-C6)alkyl, under the condition that in said alkyl residue, at least one hydrogen is substituted with OH or OCH3; or R2 is (C1-C6)alkylene, bonded with cycloalkylamine, where (C1-C4)alkylene forms a second bond with another carbon atom of the cycloalkylamine ring and, together with carbon atoms of the cycloalkyalmine, forms a second 5-8-member ring; R3, R5 and R8 denote H; R4 is H, (C1-C6)alkyl or (C1-C6)alkylene-R'; R6 and R6' independently denote H, (C1-C8)alkyl, (C1-C6)alkylene-R' or C(O)O-(C1-C6)alkyl; R7 is H, halogen or (C1-C6)alkyl; n equals 1; m equals 3 or 5; r equals 0 or 1 and L is O(CH2)p, where p=0; where R' is (C3-C8)cycloalkyl, (C6)aryl; where in residues R2-R8 (C6)aryl is unsubstituted or substituted with one or more suitable groups independently selected from halogen, (C1-C6)alkyl, O-(C1-C6)alkyl, where the alkyl group can be substituted with 1-3 halogen atoms. The invention also relates to use of the compound of formula (I) and a medicinal agent based on the compound of formula (I).

EFFECT: obtaining novel 6-substituted isoquinoline and isoquinolinone derivatives suitable for treating and/or preventing diseases associated with Rho-kinase and/or Rho-kinase-mediated myosin light chain phosphatase phosphorylation.

36 cl, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to specific compounds of 1-substituted 3,4-tetrahydroisoquinoline derivative. Invention also relates to pharmaceutical composition based on claimed compounds, to blocker of N-type Ca2+- channel based on claimed compounds, to application of claimed compounds, as well as to method of prevention or treatment of some pathologic conditions.

EFFECT: obtained are novel 3,4-tetrahydroisoquinoline derivatives, having substituent in 1-position and possessing blocking action on N-type Ca2+- channels.

15 cl, 129 tbl, 17 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely anaesthesiology and resuscitation, and concerns prevention of heart rhythm disorder in cardiac surgeries with the use of an cardiopulmonary bypass. That is ensured by the introduction of 25% magnesium sulphate 0.05-0.07 mmole/kg of patient's body weight before connection to the cardiopulmonary bypass and 0.05-0.07 mmole/kg before reperfusion through a special medicinal port.

EFFECT: dose schedule of the preparation enables cardiac stabilisation and prevented heart rhythm disorder during cardiac surgery.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely angiology, intensive care, cardiovascular surgery and phlebology, and may be used for integrated treatment of acute thromboembolia of pulmonary artery. That is ensured by prescribing anticoagulants, disaggregants, antibiotic therapy added by thrombolytic therapy by the oral introduction of the preparation Thrombovasim 0.02 mg/kg combined with deobliteration of pulmonary artery or pulmonary trunk by direct surgical thromboembolectomy in complete bypass with retrograde perfusion of pulmonary arteries. Treatment of acute thromboembolia is added by prescribing the preparation Vasaprostan* 60 mcg daily intravenously starting from the moment of diagnosing and up to 7 postoperative days.

EFFECT: method provides higher clinical effectiveness in the patients and preventing developing complications ensured by correction of main pathological links of developing complications of acute thromboembolia of pulmonary artery.

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is the new chemical compound - a 3-(2,2,2-trimethylhydrazinium)propionate derivative - 3-(2,2,2-trimethylhydrazinium)potassium propionate glycinate, (CH3)3N+NHCH2CH2COOKRCOO-, wherein exhibiting endothelioprotective activity. The presented derivative can find application in medicine in the integrated treatment for endothelial dysfunction correction in cardiovascular diseases.

EFFECT: enhanced endothelioprotective properties as compared with previously known mildronat due to the introduction of new functional group showing the most manifested antioxidant properties.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, more specifically to a new 3-(2,2,2-trimethylhydrazinium)propionate derivative, 3-(2,2,2-trimethylhydrazinium)potassium propionate 5-bromnicotinate (CH3)3N+HCH2CH2COOKRCOO- wherein .

EFFECT: preparing the compound showing high endothelioprotective activity.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, more specifically to a new chemical compound, a 3-(2,2,2-trimethylhydrazinium)propionate derivative, namely 3-(2,2,2-trimethylhydrazinium)potassium propionate 5-nicotinate hydroxide showing endothelioprotective activity.

EFFECT: preparing the compound which can find application in medicine in the integrated treatment for endothelial dysfunction correction in cardiovascular diseases.

1 tbl, 2 ex

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