Benzothiazole derivatives

FIELD: medicine, organic chemistry.

SUBSTANCE: the present innovation deals with new benzothiazole derivatives and medicinal preparation containing these derivatives for treating diseases mediated by adenosine receptor A2.A.. The present innovation provides efficient treatment of the above-mentioned diseases.

EFFECT: higher efficiency of therapy.

14 cl, 354 ex

 

The present invention relates to new derivatives of benzothiazole General formula I-A

where R1means hydrogen, (ness.)alkyl, (ness.)alkoxy, benzyloxy, cycloalkane, halogen, hydroxy or cryptometrics,

R2means hydrogen, (ness.)alkyl or (ness.)alkyloxy,

R3means hydrogen, halogen or (ness.)alkyl,

R4means hydrogen, (ness.)alkyl, (ness.)alkenyl, halogen, -C(O)-(ness.)alkyl, -C(O)-halogen(ness.)alkyl, -CH(OH)-halogen(ness.)alkyl, -C(O)O-(ness.)alkyl, -N(O)-(ness.)alkyl, -(CH2)nHE or

means phenyl, which is optionally attached to anthrope via the linker -(O)m-(CH2)n- and optionally substituted by a group N(R5)(R6), halogen or nitro, or

means 2,3-dihydro-1H-indolyl, azepin-1-yl, [1,4]oxazepan-4-yl, or means a five - or six-membered aromatic or nonaromatic a heterocycle, which may be attached to anthrope via the linker -(O)m(CH2)n- or-N=C(CH3)- and optionally substituted by one or two groups R7where R7has the values listed below;

R' means

a) phenyl, optionally substituted by halogen(ness.)by alkyl, -C(O)N or the following groups:

-(CH2)n-C(O)-N(R5)-(CH2)n(ness.)alkoxy,

-(CH2)nO-ha is Agen(ness.)alkyl,

-(CH2)nO-(CH2)n+1O-(ness.)alkyl,

-S(O2)-N(R5)-(CH2)nO-(ness.)alkyl,

-(CH2)n-OR5,

-(CH2)nN(R5)-(CH2)o-(ness.)alkoxy,

-(CH2)nN[(CH2)o-(ness.)alkoxy]2,

-(CH2)nN[S(O)2CH3]2,

-(CH2)nN[R5][S(O)2CH3],

-(CH2)nN(R5)-(ness.)alkenyl,

-(CH2)nN(R5)-(CH2)o-cycloalkyl,

-(CH2)nN(R5)-C(O)O-(ness.)alkyl,

-(CH2)nN(R5)-(CH2)o-S-(ness.)alkyl,

-(CH2)nN(R5)-S(O)2CH3,

-(CH2)nN(R5)-(CH2)o-phenyl,

-(CH2)nN(R5)-(CH2)oOH,

-(CH2)nN(R5)-(CH2)aboutCH(OH)-CF3,

-(CH2)n(R5)-(CH2)about-CF3,

-(CH2)nN(R5)-(CH2)o-O-CH(OH)-C6H3(OCH3)2,

-(CH2)nN(R5)-(CH2)o-O-C(O)-C6H3(OCH3)2,

-N(R5)-C(O)-morpholine,

-N(R5)-C(O)-N(R5)-phenyl, substituted alkoxy,

-S(O)2-morpholine,

or denotes phenyl, which is optionally substituted

-(CR5R6)nfive-semiclean aromatic or neuron is to ensure heterocycle, the heterocycle may optionally be substituted by hydroxy group, -N(R5)(R6or (ness.)the alkyl, or substituted-CH2-N(R5)(CH2)aboutfive - or six-membered aromatic or a non-aromatic heterocycle, and the heterocycle may optionally be substituted by hydroxy group, -N(R5)(R6or (ness.)the alkyl,

or means-N(R5)-phenyl, optionally substituted (ness.)alkoxy,

or means

b) -(CH2)nfive - or six-membered aromatic or nonaromatic a heterocycle, with the exception piperazinilnom and thiazolidine group in case if n=0, and these cycles may not necessarily be substituted by a group

2-oxopyrrolidin, piperidinyl, phenyl, -(CH2)nHE, halogen, CF3, =O, (ness.)alkyl, cycloalkyl, -(CH2)n-O-(ness.)alkyl, -(CH2)nNH2, -(CH2)nCN, -C(O)O-(ness.)alkyl, -CH2-O-S(O)2CH3-C(O)-(ness.)alkyl, -C(O)-(CH2)n-(ness.)alkoxy, -CH2-N(R6)C6H4F, -CH2-N(R6)C(O)O-(ness.)alkyl, -N(R6)-C(O)-N(R5)-(CH2)n-O-(ness.)alkyl or replaced by tetrahydrofuran, substituted by 4-CL-phenyl, or substituted by the group piperazine-1-yl, morpholinyl, thiomorpholine, thiomorpholine-1-oxo, pyrrolidin-1-yl, or substituted piperidine-1-yl, or means benzopyrene the-1-yl or benzothieno-2-yl,

or means

C) -N(R5)(CH2)n+1is phenyl, optionally substituted by group (ness.)alkoxy, or-N(R5)C(O)-phenyl,

or means

g) -N(R5)(CH2)n-5 - or 6-membered aromatic or nonaromatic a heterocycle, optionally substituted by group (ness.)alkyl, -(CH2)n-5 - or 6-membered aromatic or nonaromatic a heterocycle,

or means

e) -O-(CH2)n-(ness.)alkoxy, (ness.)alkyl(ness.)alkoxy, -N(R5)(CH2)nN(R5)(R6), -(CH2)nHE, -(HC=CH)1-4-C(O)O-(ness.)alkyl, octagenarian, 3,4-dihydro-1 H-isoquinoline, 2,3-benzo-1,4-dioxa-8 azaspiro[4,5]decane or 1,4-dioxa-8 azaspiro[4,5]decane;

X is O or S,

R5and R6each independently of one another denotes hydrogen or (ness.)alkyl,

R7means (ness.)alkyl, (ness.)alkoxy, -C(O)-(ness.)alkyl, -C(O)O-benzyl, -C(O)O-(ness.)alkyl, -(CH2)nNR5R6, pyridinyl, optionally substituted (ness.)the alkyl, or means-CH2N(R5)-C(O)O-(ness.)alkyl, -NH-C(phenyl)3pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, optionally substituted (ness.)by alkyl;

n is 0, 1, 2, 3,or 4

m is 0 or 1,

o is 0, 1, 2, 3 or 4;

and their pharmaceutically acceptable salts except for their hydrobromide salts, and with the exception of N-(4-methodology dibenzothiazyl-2-yl)benzamide and provided what R1-R4at the same time does not mean hydrogen when R' represents optionally substituted phenyl.

It has been unexpectedly found that compounds of General formula I are ligands of adenosine receptor.

Adenosine modulates a wide range of physiological functions by interacting with specific receptors on the cell surface. The effectiveness of adenosine receptors as targets of drugs was first described in 1982 in structural and metabolic against adenosine close bioactive nucleotides, such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), a monophosphate (AMP) and zikloadenosinmonofosfat (camp), biochemical metymirumi agent S-adenosine-L-methionine (SAM), structurally similar to the coenzymes NAD, FAD, and coenzyme A, and RNA. Adenosine and listed related compounds play an important role in regulating many aspects of cellular metabolism and modulation of various functions of the Central nervous system.

Adenosine receptors are divided into A1, A2AAnd2Band a3receptors belonging to the family of receptors coupled with G-proteins. Activation of adenosine receptors adenosine initiates the mechanism of signal transmission. These mechanisms are mediated by G-protein associated with receptor is. It is established that each subtype adenosine receptor is characterized by adenylyl cyclase effector system, which as a secondary messenger uses of camp. A1and A3receptors coupled with Gi-proteins inhibit adenylate cyclase, which leads to a reduced level of cellular camp, while A2Aand a2Breceptors coupled with Gs-proteins and activate adenylate cyclase, causing an increase in the level of cellular camp. It is known that the system of receptor-A1includes activation of phospholipase C and modulation of ion channels potassium and calcium. Subtype receptor And3in addition to the Association with the adenylate cyclase also stimulates phospholipase C and thereby activates calcium channels.

The cloned receptor-a1(326-328 amino acids) of different species (dog, human, rat, dog, chicken, cattle, Guinea pigs), while all mammals observed identity 90-95% of the sequence. The cloned receptor-a2A(409-412 amino acids) dog, rat, human, Guinea-pig and mouse. The cloned receptor And2B(332 amino acids) of human and mouse, while there has been gomologichnosti 45% of the receptor And2Bwith receptors man A1and A2A. The cloned receptor And3(317-320 amino acids) of human, rat, dog, rabbit and sheep.

It is assumed that the subtype of the receptor A 1and A2Acomplement each other in the regulation of adenosine software (cell) energy. Adenosine, which is a product of metabolic transformation of ATP diffuses out of the cell and at the local level activates adenosine receptors, reducing the need for oxygen (A1or increasing the supply of oxygen (A2Aand so maintaining a balance between energy supply and consumption in the tissues. The function of the two subtypes is to increase the number of tissue oxygen and protect cells from damage caused by short-term disruption in the supply of oxygen. One of the important functions of endogenous adenosine is the prevention of damage, injury such as hypoxia, ischemia, hypotension, and seizures.

In addition, it is known that the binding of agonist adenosine receptor with fat cells expressing the receptor And3rats, increases the level of Insectivora and concentration of intracellular calcium, which triggers antigen-induced secretion of mediators of the inflammatory response. Therefore, the receptor And3plays an important role in mediating asthma attacks and other allergic reactions.

Adenosine is a neuromodulator that perform key functions in the modulation of molecular m the arrangements, underlying many aspects of the physiological functions of the brain, and adenosine mediates the major inhibitory processes. The increase in the rate of neurotransmitter release occurs when injury such as hypoxia, ischemia and seizures. These neurotransmitters ultimately responsible for the degeneration and death of neurons, which leads to brain damage and death of the organism. Therefore, agonists adenosine receptor (A1simulating the inhibitory processes in the Central nervous system caused by adenosine, can be used as neuroprotective agents. Adenosine is supposed to be used as an endogenous anticonvulsant agent that inhibits the release of glutamate from the excited neurons and inhibitory stimulation of neurons. Therefore, agonists of adenosine can be used as antiepileptic agents. Antagonists of adenosine stimulate the activity of the Central nervous system and has been effective as stimulants cognitive abilities. Selective antagonists of A2Ahave a therapeutic effect in the treatment of various forms of dementia, such as Alzheimer's disease, and are used as neuroprotective agents. Antagonists of adenosine receptor A2Ainhibit the release of dopamine from synaptic nerve endings in the Central nervous system, stimulate whitelow activity and accordingly, weaken the symptoms of Parkinson's disease. The activity of adenosine in the Central nervous system is also evident in the molecular mechanism underlying sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression and addiction. Therefore, drugs acting on adenosine receptors, have a therapeutic effect as a sedative agents, muscle relaxants, antipsychotics, tranquilizers, analgesics, respiratory stimulants and anti-depressants, and can be used to treat ADHD (disorder in the form of increased activity at the lack of attention).

In the cardiovascular system adenosine has an important function as a cardioprotective agent. The level of endogenous adenosine is increased in response to ischemia and hypoxia and protects heart tissue injury and after it (preventive measures). Thus, agonists of adenosine act as cardioprotective agents.

Adenosine modulates many aspects of kidney function, including the release of renin, the rate of glomerular filtration and blood flow to the kidneys. Compounds that counteract the effects of adenosine in the kidney are renal protective agents. In addition, antagonists of adenosine receptors And3and/or And2Bcan be used in the us for the treatment of asthma and other allergic reactions and/or in the treatment of diabetes and obesity.

The latest data on adenosine receptors described in numerous works, for example, in the following publications:

Bioorganic & Medicinal Chemistry, 6, 619-641 (1998),

Bioorganic & Medicinal Chemistry, 6, 707-719 (1998),

J.Med.Chem., 41, 2835-2845 (1998),

J.Med.Chem., 41, 3186-3201 (1998),

J.Med.Chem., 41, 2126-2133 (1998),

J.Med.Chem., 42, 706-721 (1999),

J.Med.Chem., 39, 1164-1171 (1996),

Arch. Pharm. Med.Chem., 332, 39-41 (1999).

The object of the present invention are the compounds of formula I-A and their pharmaceutically acceptable salts for treating diseases mediated by adenosine A2 receptor, methods for their preparation, pharmaceuticals based on compounds according to the invention and their manufacture, as well as the use of compounds of formula I in the treatment and prevention of illnesses based on the modulation of the adenosine system, such as Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, breathing problems, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. In addition, the compounds of the present invention can be used as antianxiety agents, muscle relaxants, protivopsychoticheskogo tools, antiepileptic agents, anticonvulsant agents and cardioprotective agents. The most preferred indications in earnest to the invention are those based on antagonistic activity against receptor A2Aand which include disorders of the Central nervous system, for example, the treatment or prevention of certain depressive States, neuroprotection and Parkinson's disease, and ADHD and diabetes.

The term (ness.)alkyl as used in the text of the application, means a saturated alkyl group with straight or branched chain, containing from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, etc. Preferred (ness.)alkyl groups containing 1-4 carbon atoms.

The term (ness.)alkenyl used in the text of the application, means an unsaturated alkyl group with straight or branched chain, containing from 2 to 6 carbon atoms, for example ethylene, propylene, isopropylene, n-butylene, isobutylene, 2-butylene, tert-butylene, etc. Preferred (ness.)alkeneamine group containing 2-4 carbon atoms.

The term cycloalkyl means a saturated carbocyclic group containing 3-6 carbon atoms.

The term halogen means chlorine, iodine, fluorine and bromine.

The term (ness.)alkoxy means a group where the alkyl has the meanings mentioned above, and is attached via an oxygen atom.

The term five - or six-membered aromatic or nonaromatic a heterocycle means the following group: arene is political heterocyclic group, for example pyrrol-1-yl, tetrazolyl, imidazol-1 - or 2-yl, pyrazole-1-yl, pyridine-1,2,3 - or 4-yl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolin, isoxazolyl, thiazolyl, thienyl or furyl; non-aromatic heterocyclic group, for example pyrrolidinyl, imidazolidinyl, pyrazolidine, piperidine, piperazinil, morpholinyl, thiomorpholine, thiomorpholine-1,1-dioxo or thiomorpholine-1-oxo.

The term pharmaceutically acceptable acid additive salts means salts of inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, para-toluensulfonate acid, etc.

First of all preferred compounds of formula IA, where R1means methoxy, X is oxygen, and R2/R3means hydrogen.

Examples of preferred compounds of formula IA, where R' represents an unsubstituted or substituted five - or six-membered aromatic heterocycle, are the following connections:

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-methylethanolamine,

(4-methoxy-7-phenylbenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid,

(4-methoxy-7-phenylbenzothiazole-2-yl)amide 5-methylfuran-2-carbon is th acid,

N-(4-methoxy-7-phenylbenzothiazole-2-yl)isonicotinamide,

(4-methoxy-7-pyridin-4-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid,

(4-methoxy-7-pyridin-3-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid,

[4-methoxy-7-(2-methylpyridin-4-yl)benzothiazol-2-yl]amide 5-methylthiophene-2-carboxylic acid,

[7-(3-AMINOPHENYL)-4-methoxybenzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid,

N-(4-methoxy-7-thiophene-2-eventhorizon-2-yl)-2-methylethanolamine,

N-[4-methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]-2-methylethanolamine,

N-[4-methoxy-7-(2-pyrrolidin-1-iltiazem-4-yl)benzothiazol-2-yl]-2-methylethanolamine,

N-{4-methoxy-7-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzothiazol-2-yl}-2-methylethanolamine and

N-[4-methoxy-7-(5-methylthiophene-2-yl)benzothiazole-2-yl]-2-methylethanolamine.

In addition, preferred compounds of formula IA are compounds where R is unsubstituted or substituted five - or six-membered nonaromatic a heterocycle, for example the following compounds:

(4-methoxy-7-phenylbenzothiazole-2-yl)amide morpholine-4-carboxylic acid,

(4-methoxy-7-phenylbenzothiazole-2-yl)amide thiomorpholine-4-carboxylic acid,

(4-methoxy-7-phenylbenzothiazole-2-yl)amide 1-oxo-1λ4-thiomorpholine-4-carboxylic acid,

{4-methoxy-7-[2-(6-methylpyridin-3-yl)thiazol-4-yl]benzothiazol-2-yl}amide morpholine-4-CT is about acid,

[4-methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]amide morpholine-4-carboxylic acid,

{4-methoxy-7-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzothiazol-2-yl}amide morpholine-4-carboxylic acid,

[4-methoxy-7-(2-piperidine-1-iltiazem-4-yl)benzothiazol-2-yl]amide morpholine-4-carboxylic acid,

[4-methoxy-7-(5-methylthiophene-2-yl)benzothiazole-2-yl]amide morpholine-4-carboxylic acid,

tert-butyl ester 4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)piperidine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-acetylpiperidine-4-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-oxopiperidin-1-carboxylic acid and

(4-methoxy-7-piperidine-1-eventhorizon-2-yl)amide 1-oxo-1λ4-thiomorpholine-4-carboxylic acid.

Preferred compounds of formula IA are compounds where R' is phenyl, optionally substituted-CH2HE, -CH2N2CH2Och3, -CH2NHCH2CH2OH, -CH2N2-pyridinyl, -CH2NHCH2CH2SCH3, -CH2N(CH3)CH2CH2SCH3,-CH2N(CH3)CH2CH2OCH3, -CH2N(CH2CH3)CH2CH2Och3, -CH2Och3, -CH2Och2CH2Och3or-CH2N(CH3)C(O)och3for example , sleduyusheye:

4-hydroxymethyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

4-[(2-methoxyethylamine)methyl]-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

4-[(2-hydroxyethylamino)methyl]-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-{[(pyridine-4-ylmethyl)amino]methyl}benzamide,

N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-{[(pyridine-3-ylmethyl)amino]methyl}benzamide,

N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-[(2-methylsulfonylamino)methyl]benzamide,

4-{[(2-methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

N-[7-(2-aminothiazol-4-yl)-4-methoxybenzothiazole-2-yl]-4-perbenzoic,

4-fluoro-N-{4-methoxy-7-[2-(6-methylpyridin-3-yl)thiazol-4-yl]benzothiazol-2-yl}benzamide,

4-{[(2-methoxyethyl)methylamino]methyl}-N-{4-methoxy-7-[2-(6-methylpyridin-3-yl)thiazol-4-yl]benzothiazol-2-yl}benzamide,

4-{[(2-methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-thiophene-2-eventhorizon-2-yl)benzamid,

4-{[(2-methoxyethyl)methylamino]methyl}-N-[4-methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]benzamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-4-cryptomelane,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-chloro-3-{[ethyl(2-methoxyethyl)amino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-chloro-3-{[(2-methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-chloro-3-[(2-metakit the laminitis)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

3-[(2-methoxyethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

3-{[(2-methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-[(2-ethoxyethylene)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-4-methylaminoethanol,

4-{[(2-ethoxyethyl)ethylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-{[(2-ethoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-(2-methoxyethoxymethyl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-methoxymethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

N-(4-methoxy-7-thiomorpholine-4-eventhorizon-2-yl)benzamide and

methyl ester [4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)benzyl]methylcarbamate acid.

In addition, preferred compounds of formula IA are compounds where R' is phenyl, substituted by an optionally substituted -(CR5R6)nfive-semiclean aromatic or a non-aromatic heterocycle, for example the following compounds:

4-imidazol-1-ylmethyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

4-(4-hydroxypiperidine-1-ylmethyl)-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

4-[1,4]-diazepan-1-ylmethyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

4-(3(S)-dimetilan eperolehan-1-ylmethyl)-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

N-{4-methoxy-7-[2-(6-methylpyridin-3-yl)thiazol-4-yl]benzothiazol-2-yl}-4-pyrrolidin-1-ylmethylene,

N-(4-methoxy-7-thiophene-2-eventhorizon-2-yl)-4-pyrrolidin-1-ylmethylene,

N-[4-methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]-4-pyrrolidin-1-ylmethylene,

4-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-3-pyrrolidin-1-ylmethylene,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-3-pyrrolidin-1-ylmethylene,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-4-(2-Mei-1-ylmethyl)benzamide and

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-4-(4-methylpiperazin-1-ylmethyl)benzamide.

First of all preferred compounds of formula IA, where R4means optionally substituted five-semicolony aromatic or nonaromatic a heterocycle, which means, for example, morpholine or piperazine.

Compounds of the present invention of formula I-A and their farmatsevticheskii acceptable salts can be obtained by known in the field methods, for example by the methods described below, and the method includes

a) interaction of the compounds of formula

with the compound of the formula

and with the appropriate cyclic amine with the formation of the compounds of formula I-1

in which the group-NR5R6represents a cycle of the ical Amin, where R1-R6and X have the meanings indicated above, or

b) interaction of the compounds of formula

with the compound of the formula

with the formation of the compounds of formula I-A, where R1-R4, R' and X have the meanings indicated above, or

C) modifying one or more substituents R1-R6in accordance with the values specified above, and,

if necessary, the conversion of the compounds obtained into pharmaceutically acceptable acid additive salt.

All stages of the reactions described above are carried out in the usual way and are described in more detail in the examples.

According to the variant of the method a) compound of formula II, for example 2-amino-7-phenyl-4-methoxybenzothiazole, pyridine dissolved in tetrahydrofuran and then treated with phosgene in toluene. The reaction mixture was concentrated twice under reduced pressure, and add the appropriate amine, for example a cyclic amine such as morpholine or thiomorpholine. Received the product emit Express chromatography.

In a variant of the method b) described the method of obtaining the compounds of formula I, where the compound of formula II interacts with the compound of the formula IV. The reaction is carried out for about 10 min in the normal way. Received the product emit Express chromatography.

Getting with the whether was performed at room temperature by known methods, including specialists in this field of technology. Have in view of not only inorganic salts, and organic acid salts. Examples of such salts are hydrochloride, hydrobromide, sulfates, nitrates, citrates, acetates, maleate, succinate, methanesulfonate, para-toluensulfonate etc.

Obtaining compounds of formula I-A are described in more detail in the examples 1-292 and shown in the following schemes 1 and 2.

The parent compound is known or can be obtained well-known in the art methods.

Scheme 1

where 1-6 have the following meanings:

1 - MeO(CO)CL, base,

2 - ICl,

3 - R4-B(OR5)2or R4-Sn(CH3)3Pd-catalyst

4 - KONA,

5 - C(X)Cl2, R5R6NH or R5CX

6 - RC(X)Cl, base.

The substituents have the meanings specified above.

Scheme 2

where 1-6 have the following meanings:

1 - R4-B(OR5)2or R4-Sn(CH3)3Pd-catalyst

2 - H2Pd-C,

3 - Ph(CO)NCS,

4 - NaOMe,

5 - Br2,

6 - RC(X)Cl, base.

The substituents R1-R4, R5X and R have the values specified above.

Scheme 3

The substituents R1-R5have the meanings indicated above, a NBS means-bromosuccinimide.

Scheme 4

The substituents R1-R5and R7have the values specified above.

Scheme 5

The substituents R1-R6have the values specified above.

Scheme 6

The substituents R1-R5have the values specified above.

The reactions shown in schemes 1-6, carried out in normal conditions.

The compounds of formula I-A and their pharmaceutically acceptable acid additive salts have valuable pharmacological properties. First of all, it is established that the compounds of the present invention are ligands of adenosine receptor and have high affinity for adenosine receptor (A2A.

Compounds were analyzed by the following method.

Adenosine receptor-a2Aperson

Adenosine receptor-a2Aman recombinante expressed in cells of the Chinese hamster ovary (Cho) using the expression system of the virus Semliki forest. Cells were collected, washed twice by centrifugation, homogenized and again washed by centrifugation. The washed precipitate the membrane fraction suspended in Tris-buffer solution (50 mm, pH 7.4)containing 120 mm NaCl, 5 mm KCl, 2 mm l2and 10 mm MgCl2(buffer A). Analysis of the binding of [3H]-SCH-5261 (1 nm) (see article Dionisotti, etc., Br. J.Pharmacol., 121, 353 (1997)) was performed in 96-well tablets in the presence of 2.5 μg of membrane protein, 0.5 mg of granules of Ysi-poly-L-lysine-SPA and 0.1% adenozindeaminaza in the final volume of 200 μl of buffer A. non-specific binding was determined using a relative xanthinuria (KHAS, 2 μm). Compounds were analyzed at 10 concentrations in the range of 10 μm to 0.3 nm. All analyses were performed twice, and repeated at least twice. Analytical plates were incubated at room temperature for 1 h, centrifuged, and determined the binding of the ligand on the scintillation counter Packard Topcount. The values of the IC50was calculated using the approximation of a nonlinear curve, and the value Kiwas calculated by the equation of Cheng-Prussoff.

It is established that the compounds of formula I according to the invention have high affinity for the receptor, A2A. The most preferred compounds have affinity for the receptor, A2Aman in the interval pKian 8.5 and 9.3.

Examples of such compounds are included in the table

The compounds of formula I and pharmaceutically acceptable salts of compounds of formula I can be used as medicines, for example, in the form of pharmaceutical preparations. Pharma is iticheskie drugs can be administered orally, for example, in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the introduction can be carried out rectally way, for example, in the form of suppositories and parenteral way, for example, in the form of solutions for injection.

Upon receipt of drugs of compounds of formula I can be processed in a mixture with pharmaceutically inert, inorganic or organic carriers. Upon receipt of tablets, coated tablets, dragées and hard gelatin capsules as these media can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like are Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like, However, depending on the properties of the active substance in the case of soft gelatin capsules usually do not require any media. Suitable carriers for solutions and syrups are, for example, water, polyols, glycerol, vegetable oils, etc. are Suitable carriers for suppositories are, for example, natural or otverzhdennye oils, waxes, fats, semi-liquid or liquid polyols and the like

Moreover, the pharmaceutical preparations can contain preservatives, solubilizing Agay is you, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for regulating the osmotic pressure, buffer substances, masking agents or antioxidants. In addition, they can contain other therapeutically valuable substances.

Drugs containing the compounds of formula I or their pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention as well as the way they are received, which includes processing one or more compounds of formula I and/or pharmaceutically acceptable acid salt additive, if necessary, with one or more therapeutically valuable substances in herbal finished form in a mixture with one or more therapeutically inert carriers.

According to the present invention the compounds of formula I and their pharmaceutically acceptable salts can find primenenie for the treatment or prevention of diseases caused antagonistic activity against adenosine receptor, such as Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, breathing problems, depression, asthma, allergic reaction, hypoxia, ischaemia, seizure and substance abuse. In addition, the compounds of the present invention can be used as a sedative what's agents, muscle relaxants, protivopsychoticheskogo funds, antiepileptic agents, anticonvulsant agents, cardioprotective agents, and for the manufacture of the drugs.

The most preferred indications in the present invention are those which include disorders of the Central nervous system, for example the treatment or prevention of certain depressive States, neuroprotection and Parkinson's disease.

Dosage can vary in a wide interval and must meet the individual requirements in each particular case. When administered orally to adult doses of the compounds of formula I or the corresponding number of its pharmaceutically acceptable salts can vary in the range from about 0.01 mg to about 1000 mg per day. The daily dose can be administered as a single dose or in part and, in addition, the upper limit can also be exceeded in accordance with the indications.

Example 1

N-(4-Methoxy-7-phenylbenzothiazole-2-yl)benzamid

To a solution of 2-amino-4-methoxy-7-phenylbenzothiazole (100 mg, 0.4 mmole) in pyridine (2 ml) was added benzoyl chloride (55 mg, 0.4 mmole) and the mixture was stirred at 20° With during the night. Then to the mixture was added 2 N. Hcl (20 ml) to pH 1 and was twice extracted with EtOAc (20 ml), the extract was washed with saturated solution of NaHCO3 , dried over Na2SO4and the solvent evaporated. The crude product was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution CH2CL2/Meon (98:2). The fractions containing the product were combined and the solvent evaporated, to receive specified in the title compound in the form of solid white (97 mg, yield 69%), MS: m/e 360 (M+).

Compounds described in the examples 2-49 received by the General method described in example 1.

Example 2

(4-Methoxy-7-phenylbenzothiazole-2-yl)amide, furan-2-carboxylic acid

Specified in the title compound was obtained in a solid beige color (yield 41%), MS: m/e 251,3 (M+N+), using the acid chloride furan-2-carboxylic acid.

Example 3

(4-Methoxy-7-phenylbenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid

Specified in the title compound was obtained in a solid beige color (yield 36%), MS: m/e 381,3 (M+N+)using the acid chloride of 5-methylthiocarbamate acid.

Example 4

(4,6-Diferentiator-2-yl)amide, furan-2-carboxylic acid

Specified in the title compound was obtained in the form of a solid gray color (yield 81%), MS: m/e 280 (M+), from 2-amino-4,6-differentiate and acid chloride furan-2-carboxylic acid.

Example 5

(4,6-Diferentiator-2-yl)amide 5-m is titipan-2-carboxylic acid

Specified in the title compound was obtained in the form of a solid yellow (yield 74%), MS: m/e 310 (M+), from 2-amino-4,6-differentiate and the acid chloride of 5-methylthiocarbamate acid.

Example 6

N-(4,6-Diferentiator-2-yl)benzamid

Specified in the title compound was obtained in a solid beige color (yield 82%), MS: m/e 290 (M+), from 2-amino-4,6-differentiate and benzoyl chloride.

Example 7

(4-Methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid

Specified in the title compound was obtained in a solid beige color (yield 95%), MS: m/e 304,1 (M+), when the interaction of 2-amino-4-methoxybenzothiazole and the acid chloride of 5-methylthiocarbamate acid in pyridine.

Example 8

(4-Methoxy-7-phenylbenzothiazole-2-yl)amide 5-methylfuran-2-carboxylic acid

The crude product was obtained from 2-amino-4-methoxy-7-phenylbenzothiazole and freshly prepared acid chloride of 5-methylfuran-2-carboxylic acid. The obtained product was purified by chromatography SiO2(230-400 mesh mesh, Merck) with elution by n-hexane/tO (4:1), to receive specified in the header of the purified compound in the form of solid light yellow (yield 67%), MS: m/e 364,0 (M+).

Example 9

(4-Methoxybenzothiazole-2-yl)amide, furan-2-carboxylic acid

Specified in the header with the Association received in the form of a solid light brown color (yield 100%), MS: m/e 274,1 (M+), when the interaction of 2-amino-4-methoxybenzothiazole and acid chloride furan-2-carboxylic acid in pyridine.

Example 10

Benzothiazole-2-alamid benzo[b]thiophene-2-carboxylic acid

Specified in the title compound was obtained in the form of solid light yellow (yield 86%), MS: m/e 311,1 (M+N+), when the interaction of 2-aminobenzothiazole and acid chloride benzo[b]thiophene-2-carboxylic acid in pyridine.

Example 11

Benzothiazole-2-alamid 3-methylthiophene-2-carboxylic acid

Specified in the title compound was obtained in the form of a solid yellow (yield 69%), MS: m/e 275,1 (M+N+), when the interaction of 2-aminobenzothiazole and the acid chloride of 3-methylthiophene-2-carboxylic acid in pyridine.

Example 12

Benzothiazole-2-alamid 5-methylthiophene-2-carboxylic acid

Specified in the title compound was obtained in the form of a solid yellow (yield 87%), MS: m/e 275,1 (M+N+), when the interaction of 2-aminobenzothiazole and the acid chloride of 5-methylthiophene-2-carboxylic acid in pyridine.

Example 13

N-Benzothiazol-2-yl-6-chloronicotinamide

Specified in the title compound was obtained in a solid white color (yield 97%), MS: m/e 290,1 (M+N+), when the interaction of 2-aminobenzothiazole and the acid chloride of 2-chloropyridin-5-carboxylic acid in pyridine.

Example 14

4-Hydrox is methyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid

To a solution of 4-formyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (194 mg, 0.5 mmole) in THF (40 ml) was added borohydride sodium (19 mg, 0.5 mmole) and the mixture was stirred at RT for 2 h Then was added water (30 ml), 1 N. HCl (4 ml) and the mixture was shaken. The aqueous phase was twice extracted with EtOAc (30 ml), the combined organic extracts were washed with saturated solution of NaCl, dried over Na2SO4, was filtered and was evaporated. The crude residue is suspended in ether and treated with ultrasound for 10 min, the solid was separated by filtration, washed with ether and dried under vacuum (0.05 mm Hg, 50° (C)if this got mentioned in the title compound in the form of a solid light-yellow color (150 mg, yield 77%), MS: m/e 390,0 (M+).

Example 15

4-Formyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid

Specified in the title compound was obtained in the form of solid light yellow (yield 73%), MS: m/e 388,1 (M+N+when using 4-formylbenzoate acid.

Example 16

2-Methoxy-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid

To a solution of 2-amino-4-methoxy-7-phenylbenzothiazole (200 mg, 0.67 mmole) in THF (10 ml) was added DMAP (10 mg, 0.08 mmole), triethylamine (163 μl, of 1.17 mmole) and 2-methoxybenzylamine (136 μl, 1 mmol) in THF (2 ml). The mixture is then boiled under reflux for 2 h, cooled and the allocation of the Yali between AcOEt/THF (1:1, 70 ml) and 5%aqueous solution Panso3(40 ml). The organic phase was washed with saturated NaCl solution (50 ml), dried over Na2SO4was filtered and the solvent evaporated under reduced pressure. The residue is suspended in ether (10 ml), was separated by filtration, washed with ether and dried under vacuum (0.05 mm Hg, 60° (C)if this got mentioned in the title compound in the form of a solid white color (260 mg, yield 85%), MS: m/e 390,0 (M+).

Example 17

3-Methoxy-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid

The crude product was obtained using 3-methoxybenzylamine. The obtained product was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution CH2Cl2/EtOAc (1:1), to receive specified in the header of the purified compound in the form of foam light yellow (75%yield), MS: m/e 390,0 (M+).

Example 18

4-Methoxy-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid

The crude product was obtained using 4-methoxybenzylamine. The obtained product was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution CH2CL2/tO (1:1), to receive specified in the header of the purified compound in the form of a white foam (yield 79%), MS: m/e 390,1 (M+).

Example 19

(4-Methoxy-7-phenylbenzothiazole-2-yl)amide 3-methylthiophene-2-carboxylic key is lots

The crude product was obtained when using the acid chloride of 3-methylthiophene-2-carboxylic acid. The obtained product was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution CH2CL2/tO (1:1), to receive specified in the header of the purified compound in a solid white color (yield 64%), MS: m/e 380,0 (M+).

Example 20

(4-Methoxy-7-phenylbenzothiazole-2-yl)amide 2,5-dimethylfuran-3-carboxylic acid

The crude product was obtained when using the acid chloride 2.5-dimethylfuran-3-carboxylic acid. The obtained product was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution CH2Cl2/EtOAc (1:1), to receive specified in the header of the purified compound in a solid white color (yield 73%), MS: m/e 378,1 (M+).

Example 21

N-(4-Methoxy-7-phenoxybenzamine-2-yl)benzamid

The crude product was obtained from 4-methoxy-7-phenoxybenzamine-2-ylamine and benzoyl chloride. The obtained product was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution CH2Cl2/EtOAc (1:1), to receive specified in the header of the purified compound in a solid white color (yield 72%), MS: m/e 376,1 (M+).

Example 22

N-(4-Methoxy-7-phenylbenzothiazole-2-yl)isonicotinamide

The crude product was obtained from hydro is lorida acid chloride pyridine-4-carboxylic acid in pyridine. The reaction mixture was cooled, precipitated residue triturated with ether (10 ml), collected on a glass Frit and was washed with ether (10 ml). Then the precipitate on the filter is then washed 10%solution PA2CO3(20 ml), water (20 ml), ether (20 ml) and dried under vacuum (0.05 mm Hg, 60°). Specified in the header of the purified compound was obtained in a solid yellow color (188 mg, yield 67%), MS: m/e 361,0 (M+).

Example 23

(4-Methoxy-7-phenoxybenzamine-2-yl)amide 5-methylthiophene-2-carboxylic acid

The crude product was obtained from 4-methoxy-7-phenoxybenzamine-2-ylamine and the acid chloride of 5-methylthiophene-2-carboxylic acid. The obtained product was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution CH2CL2/tO (1:1), to receive specified in the header of the purified compound in the form of solid light yellow (yield 76%), MS: m/e 396,0 (M+).

Example 24

(4-Methoxy-7-morpholine-4-imetelstat-2-yl)amide 5-methylthiophene-2-carboxylic acid

Specified in the title compound was obtained in the form of a solid yellow (yield 53%), MS: m/e 404,4 (M+N+), the interaction of 4-methoxy-7-morpholine-4-imetelstat-2-ylamine and the acid chloride of 5-methylthiophene-2-carboxylic acid in pyridine.

Example 25

Benzothiazole-2-alamid furan-2-Carbo the OIC acid

Specified in the title compound was obtained in a solid white color (yield 83%), MS: m/e 244 (M+), when the interaction of 2-aminobenzothiazole and acid chloride furan-2-carboxylic acid in pyridine.

Example 26

2-Chloro-N-(4-methyl-2-benzothiazolyl)nicotinamide

Specified in the title compound was obtained in the form of a solid yellow (yield 50%), MS: m/e 304 (M+N+), from 4-methylbenzothiazol-2-ylamine and the acid chloride of 2-chloronicotinic acid.

Example 27

2-Chloro-N-(4-methoxy-2-benzothiazolyl)nicotinamide

Specified in the title compound was obtained in the form of a solid off-white color (yield 50%), MS: m/e 320 (M+N+), from 4-methoxybenzothiazole-2-ylamine and the acid chloride of 2-chloronicotinic acid

Example 28

Ethyl ester of 3-(4-methoxybenzothiazole-2-ylcarbonyl)acrylic acid

Specified in the title compound was obtained in the form of a solid off-white color (yield 50%), MS: m/e 307 (M+), from 4-methoxybenzothiazole-2-ylamine and methyl ester 3-chlororesorcinol acid.

Example 29

4-Dimethylamino-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid

The crude product was obtained from hydrochloride of the acid chloride pyridine-2-carboxylic acid in pyridine. The obtained product was purified preparative reversed-phase GHUR in column (2× 5 cm) with sorbent Nucleosil N when e is funding in a gradient of MeCN/water (0.1% of TFU). The fractions containing the product were combined, evaporated, was distributed between EtOAc (30 ml) and 10%solution PA2CO3(30 ml) and the aqueous phase was extracted with EtOAc (30 ml). The combined organic phase was washed with saturated solution of NaCl, dried, filtered and evaporated, to receive specified in the header of the purified compound in the form of solid beige color (110 mg, yield 39%), MS: m/e 361,1 (M+).

Example 30

N-(4-Methoxy-7-phenylbenzothiazole-2-yl)-4-(morpholine-4-sulfonyl)benzamide

Specified in the title compound was obtained in the form of a solid amorphous substance white (yield 32%), MS: m/e 510,3 (M+N+when using 4-(morpholine-4-sulfonyl)benzoic acid.

Example 31

(7-Iodine-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid

Iodination (4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid (5,17 g, 17 mmol) monochloride iodine (and 2.26 ml, 44 mmole) in acetic acid (200 ml) in the presence of sodium acetate (3,63 g, 44 mmole) was performed similarly as described in obtaining methyl ester (4-methoxybenzothiazole-2-yl)carbamino acid. The product was obtained in the form of a solid off-white color (yield 93%), MS: m/e 430 (M+).

Ether (7-aryl-4-methoxybenzothiazole-2-yl)carbamino acid, (7-aryl-4-methoxybenzothiazole-2-yl)amides arylcarbamoyl acid and substituted (4-m is toxi-7-arylbenzothiazoles-2-yl)urea was obtained by the following methods.

General procedure a

Ether (7-iodine-4-methoxybenzothiazole-2-yl)carbamino acid or the corresponding (7-iodine-4-methoxybenzothiazole-2-yl)amide arylcarbamoyl acid or the corresponding (4-methoxy-7-arylbenzothiazoles-2-yl)urea (1 part)corresponding Bronevoy acid (or its ester) (1.5 EQ.), the palladium(II) acetate (of 0.05 equiv.) potassium phosphate (2.5 EQ.) and 2-biphenyldicarboxylic (0.1 EQ.) was placed in toluene (20 parts) and heated in an argon atmosphere at 65° C for 12 h and Then the reaction mixture was evaporated to dryness and the product was isolated by rapid chromatography on silica gel with elution by ethyl acetate/cyclohexane (2:1).

General method B

Ether (7-iodine-4-methoxybenzothiazole-2-yl)carbamino acid or the corresponding (7-iodine-4-methoxybenzothiazole-2-yl)amide arylcarbamoyl acid or the corresponding (4-methoxy-7-arylbenzothiazoles-2-yl)urea (1 part)corresponding to alltimeitem (1.5 equiv.) triphenylarsine (0.5 equiv.) Tris(dibenzylideneacetone)dipalladium(0) (0.8 EQ.) and copper iodide(I) (0.8 EQ.) was placed in dimethylformamide (25 parts) and heated at 80° C for 12 h and Then the reaction mixture was evaporated to dryness and the product was isolated by rapid chromatography on silica gel with elution by ethyl acetate.

Compounds described in the examples 32-39 received by the General method described in example 31.

Example 32

[7-(2-Chlorophenyl)-methoxybenzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid

[7-(2-Chlorophenyl)-4-methoxybenzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid was obtained in the form of solid light yellow (yield 80%), MS: m/e 415 (M+N+), from (7-iodine-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid (100 mg, to 0.23 mmole) and 2-Chlorfenvinphos acid (54 mg, 0.35 mmole) according to the General method A.

Example 33

[4-Methoxy-7-(3-nitrophenyl)benzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid

[4-Methoxy-7-(3-nitrophenyl)benzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid was obtained in the form of crystals pale yellow (yield 42%), MS: m/e 425 (M+), from (7-iodine-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid (155 mg, of 0.36 mmole) and 3-nitrophenylarsonic acid (135 mg, 0,81 mmole) according to the General method A.

Example 34

[7-(3-Dimethylaminophenyl)-4-methoxybenzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid

[7-(3-Dimethylaminophenyl)-4-methoxybenzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid was obtained in the form of a solid light-yellow color (71%yield), MS: m/e 424 (M+N+), from (7-iodine-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid (100 mg, to 0.23 mmole) and 3-dimethylaminopropionic acid (58 mg, 0.35 mmole) according to the General method A.

Example 35

(4-Methoxy-7-pyridin-4-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid

(4-Methoxy-7-pyridin-4-even thiazol-2-yl)amide 5-methylthiophene-2-carboxylic acid was obtained in a solid white color (yield 6%), MS: m/e 381 (M+), from (7-bromo-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid (192 mg, of 0.50 mmole) and 4-pyridylamino acid (92 mg, 0.75 mmole) according to the General method A.

Example 36

(4-Methoxy-7-pyridin-3-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid

(4-Methoxy-7-pyridin-3-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid was obtained in a solid white color (yield 8%), MS: m/e 381 (M+), from (7-bromo-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid (192 mg, of 0.50 mmole) and 4-pyridylamino acid (123 mg, 1.0 mmol) according to General method A.

Example 37

(4-Methoxy-7-pyridin-2-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid

(4-Methoxy-7-pyridin-2-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid was obtained in a solid white color (yield 23%), MS: m/e 382 (M+N+), from (7-iodine-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid (100 mg, to 0.23 mmole) and 2-tri-n-butylstannane (130 mg, 0.35 mmole) according to the General method B.

Example 38

[4-Methoxy-7-(2-methylpyridin-4-yl)benzothiazol-2-yl]amide 5-methylthiophene-2-carboxylic acid

[4-Methoxy-7-(2-methylpyridin-4-yl)benzothiazol-2-yl]amide 5-methylthiophene-2-carboxylic acid was obtained in the form of solid light yellow (yield 50%), MS: m/e 396 (M+N+), from (4-methoxy-7-iodobenzoate-2-yl)amide 5-methyl shall iophen-2-carboxylic acid (260 mg, 0.60 mmole) and 2-methyl-4-trimethylaniline (384 mg, of 0.90 mmole) according to the General method B.

Example 39

[7-(3-AMINOPHENYL)-4-methoxybenzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid

[7-(3-AMINOPHENYL)-4-methoxybenzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid was obtained in the form of a solid light brown color (yield 56%), MS: m/e 396 (M+N+), from (4-methoxy-7-iodobenzoate-2-yl)amide 5-methylthiophene-2-carboxylic acid (300 mg, 0.70 to mmole) and 3-trimethylethylenediamine (291 mg, 1,14 mmole) according to the General method B.

Example 40

(4-Hydroxy-7-phenylbenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid

A solution of (4-methoxy-7-phenylbenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid (630 mg, 1.7 mmole) at 0° was slowly treated with tribromide boron (16 ml, 1.0 M solution in dichlormethane). The reaction mixture was slowly heated to room temperature and was stirred for 72 hours Then the mixture was diluted with ethyl acetate, was extracted twice with water and once with saline, dried over sodium sulfate and the solvent evaporated in vacuum. The residue was purified rapid chromatography on silica gel with elution by ethyl acetate/hexane (1:1). After recrystallization from tetrahydrofuran/hexane received 118 mg (yield 19%) of product as a solid white, MS: m/e 367 (M+N+).

Example 41

Be zilavy ether 4-{4-methoxy-2-[(5-methylthiophene-2-carbonyl)amino]benzothiazol-7-yl}piperazine-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (total yield 12%), MS: m/e 523 (M+N+), from N-benzyloxycarbonylglycine and 4-bromonitromethane, as described in obtaining (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid.

Example 42

[7-(3-Dimethylaminopropan-1-yl)-4-methoxybenzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid

Specified in the title compound was obtained in a solid yellow color (total yield 10%), MS: m/e 417 (M+N+), 3-(dimethylamino)pyrrolidine and 4-bromonitromethane, as described in obtaining (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid.

Example 43

(5-Methoxy-7-phenylbenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid

2-Amino-5-methoxy-7-phenylbenzothiazole (45 mg, of 0.18 mmole) was dissolved in dichloromethane (2 ml) and sequentially treated with triethylamine (0,073 ml of 0.53 mmole) and 5-methylthiophene-2-carbonylchloride (56 mg, 0.35 mmole). After 6 h was added to the second portion of triethylamine (0,073 ml of 0.53 mmole) and 5-methylthiophene-2-carbonylchloride (56 mg, 0.35 mmole) and the mixture was stirred at room temperature for 18 hours Then was added a 0.1 M solution of sodium hydroxide and the mixture was stirred for a further 16 hours the Organic layer was separated, dried and evaporated to dryness. The residue was purified expre the C-chromatography on silica gel with elution by ethyl acetate/cyclohexane (1:1, +0,5% 25%aqueous ammonia solution), received the product in a solid white color (10 mg, yield 5%), MS: m/e 380 (M+).

Example 44

(4,5-Dimethoxybenzoyl-2-yl)amide 5-methylthiophene-2-carboxylic acid

2-Amino-4,5-dimethoxybenzoate (1.1 g, 5.3 mmole) and N,N-dimethylaminopyridine (47 mg, 0.37 mmole) was dissolved in pyridine (17 ml)was slowly added 5-methylthiophene-2-carbonylchloride (1.5 g, 9.0 mmole) and stirred at room temperature for 48 h, then evaporated to dryness. After cleaning, the rapid chromatography on silica gel with elution with diethyl ether/cyclohexane (2:1) received the product in the form of a solid light-yellow color (618 mg, yield 35%).

Example 45

(4-Chlorobenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid

2-Amino-4-chlorobenzothiazole (92 mg, of 0.50 mmole) was dissolved in dichloromethane (10 ml) and treated with pyridine (to 0.060 ml, 0.75 mmole) and 5-methylthiophene-2-carbonylchloride (97 mg, 0.60 mmole). The reaction mixture was stirred at room temperature for 18 h and evaporated to dryness. The residue was dissolved in ethyl acetate and water, the phases were separated, the organic phase was extracted with brine, dried over sodium sulfate and the solvent evaporated in vacuum. After cleaning, the rapid chromatography on silica gel with elution by ethyl acetate/cyclohexane (1:4) received the product VI is e solid white (88 mg, yield 57%), MS: m/e 308 (M+).

Example 46

(7-Bromo-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid

2-Amino-7-bromo-4-methoxybenzothiazole (2,33 g, 9 mmol) was dissolved in dichloromethane (100 ml) and at 0° was treated with pyridine (2.2 ml, 27 mmol) and 5-methylthiophene-2-carbonylchloride (2.2 g, 13.5 mmol). The reaction mixture was heated to room temperature, was stirred for another 18 h and the reaction was stopped by adding water (100 ml). The phases were separated and the aqueous phase was twice extracted with ethyl acetate. The combined organic extracts were washed with saline, dried and evaporated to dryness. After cleaning, the rapid chromatography on silica gel with elution by ethyl acetate/cyclohexane (1:1 to 4:1) and recrystallization from ethyl acetate received the product in a solid off-white color (34 mg, yield 69%), MS: m/e 384 (M+).

Example 47

(4-Fermentational-2-yl)amide 5-methylthiophene-2-carboxylic acid

2-Amino-4-fermentation (84 mg, 0.5 mmole) was dissolved in pyridine (3 ml), was added 4-dimethylaminopyridine (1 mg) and 5-methylthiophene-2-carbonylchloride (161 mg, 1.0 mmole), was stirred at room temperature for 1 h and the reaction mixture was evaporated to dryness. After cleaning, the rapid chromatography on silica gel with elution with diethyl ether/cyclohexane(1:1, +0,5% 25%-aqueous solution of ammonia is) and recrystallization from ethyl acetate received the product in a solid off-white color (34 mg, yield 69%), MS: m/e 292 (M+).

Example 48

(4-Cryptomaterial-2-yl)amide 5-methylthiophene-2-carboxylic acid

2-Amino-4-cryptomaterial (70 mg, 0.30 mmole) was dissolved in pyridine (3 ml), was added 4-dimethylaminopyridine (1 mg) and 5-methylthiophene-2-carbonylchloride (96 mg, 0.60 mmole), was stirred at room temperature for 4 h and the reaction mixture was evaporated to dryness. After cleaning, the rapid chromatography on silica gel with elution by ethyl acetate/cyclohexane (1:2) received the product in a solid white color (42 mg, yield 39%), MS: m/e 358 (M+).

Compounds described in the examples 49-52 received by the General method described in example 1.

Example 49

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid

Specified in the title compound was obtained in the form of a solid yellow (yield 97%), MS: m/e 390 (M+N+), from 5-methylthiophene-2-carbonylchloride and 2-amino-4-methoxy-7-morpholine-4-eventhorizon.

Example 50

(4-Methoxybenzothiazole-2-yl)amide 6-hydroxypyridine-2-carboxylic acid

Specified in the title compound was obtained in the form of a powder beige (5%), MS: m/e 301 (M+), from 2-amino-4-methoxybenzothiazole (450 mg, 2.5 mmole) and the acid chloride 6-hydroxypyridones acid (1.5 g, 10 mmol).

Example 51

(7-Benzyloxy-4-methoxybenzothiazole-2-alamid 5-methylthiophene-2-carboxylic acid

Specified in the title compound was obtained in the form of a solid off-white color (yield 51%), tpl.228-230° C, when using the acid chloride of 5-methylthiophene-2-carboxylic acid.

Example 52

6-Chloro-N-(4-methoxy-7-phenylbenzothiazole-2-yl)nicotinamide

Specified in the title compound was obtained as amorphous solid light yellow (yield 79%), MS: m/e 395,1 (M+when using 6-chloronicotinamide.

Example 53

N-(4-Methoxy-7-phenylbenzothiazole-2-yl)-6-pyrrolidin-1-iniatiated

To a solution of 6-chloro-N-(4-methoxy-7-phenylbenzothiazole-2-yl)nicotinamide (297 mg, 0.75 mmole) in dioxane (10 ml) was added pyrrolidine (266 mg, 3.7 mmole, 5 EQ.) and the mixture was stirred at 100° C for 2 hours After cooling, the solvent evaporated, the residue suspended in methanol (20 ml) at RT, the solid was separated by filtration, washed with methanol and dried under vacuum (0.05 mm RT. senior, 60° (C)if this got mentioned in the title compound in the form of a solid white color (230 mg, 71%yield), MS: m/e 431,4 (M+N+).

The compounds described in examples 54-57 received by the General method described in example 53.

Example 54

(4-Methoxy-7-phenylbenzothiazole-2-yl)amide 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-carboxylic acid

Specified in the title compound was obtained as a solid substance with which ETLO brown (yield 59%), MS: m/e 445,3 (M+N+when using piperidine,

Example 55

N-(4-Methoxy-7-phenylbenzothiazole-2-yl)-6-formalin-4-iniatiated

Specified in the title compound was obtained in a solid white color (yield 82%), MS: m/e 447,2 (M+N+when using the research.

Example 56

N-(4-Methoxy-7-phenylbenzothiazole-2-yl)-6-(4-methylpiperazin-1-yl)nicotinamide

Specified in the title compound was obtained in the form of a solid light brown color (yield 52%), MS: m/e 460,4 (M+N+when using N-methylpiperazine.

Example 57

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-6-thiomorpholine-4-iniatiated (1:1)

Specified in the title compound was obtained in free base form when using thiomorpholine, and then adding 5 N. Hcl/tO, received its hydrochloride in a solid white color (yield 78%), MS: m/e 463,1 (M+N+).

Example 58

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-6-(1-oxo-1,4-thiomorpholine-4-yl)nicotinamide (1:1)

To a solution of the hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-6-thiomorpholine-4-iniatiated (250 mg, 0.54 mmole) in chloroform (12 ml) was added 3-phenyl-2-(phenylsulfonyl)oxaziridine (211 mg, 0,81 mmole) and the mixture was stirred at RT for 2 h After evaporation of the solvent the residue is suspended in CH2CL2was treated with ultrasound,the precipitate was separated by filtration, washed CH2Cl2, ether and was evaporated under vacuum (0.05 mm Hg, 60° (C)if this got mentioned in the title compound in the form of a solid light-yellow color (240 mg, yield 86%), MS: m/e 479,2 (M+N+).

Example 59

4-methyl bromide-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid

To a solution of 4-bromomethylphenyl acid (of 5.45 g of 25.3 mmole) in toluene (60 ml) was added thionyl chloride (18,25 ml, with 25.3 mmole) and the mixture was stirred at 80° C for 16 hours, the Toluene and excess thionyl chloride are evaporated in vacuum and was added THF (100 ml). To the resulting solution were added 2-amino-4-methoxy-7-phenylbenzothiazole (5 g, 19.5 mmole), triethylamine (4,1 ml, 29,2 mmole) and DMAP (238 mg, 2 mmole) as a catalyst, and then the mixture was stirred at 65° C for 4 h After cooling, the reaction mixture was distributed between 10% aqueous solution of Na2CO3(200 ml) and EtOAc (100 ml), the aqueous phase was additionally extracted with EtOAc/THF (1:1) (150 ml), the combined organic phases were washed with saturated NaCl solution (100 ml), dried (Na2SO4), filtered and evaporated in vacuum. Then the residue was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution in a gradient from 100% CH2Cl2until CH2Cl2/EtOAc, 1:1, the fractions containing the product were combined and evaporated in vacuum specified in the title compound was obtained in the form of solid substances is tion of light-yellow color (4.9 g, yield 55%), MS: m/e 452,0 (M+).

Example 60

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-pyrrolidin-1-iletilmesine (1:1)

To a solution of 4-formyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (300 mg, 0.77 mmole) in THF (60 ml) was added pyrrolidine (82 mg, 1.16 mmole), acetic acid (70 mg, 1.16 mmole) and NaBH(OAc)3(246 mg, 1.16 mmole). The resulting mixture was stirred at RT for 16 h, then under vigorous stirring was added a 5%solution Panso3(30 ml) and the mixture was twice extracted with EtOAc (50 ml). The organic phase was washed with saturated solution of NaCl, dried, filtered and evaporated, to receive the crude product, which was converted into hydrochloride and purified preparative reversed-phase GHUR in column (2× 5 cm) sorbent Nucleosil-N (firm Machery-Nagel) with elution in a gradient of MeCN/water (0.1% of TFU). After combining the fractions containing the product, and evaporation has been specified in the title compound in the form of a solid white color (217 mg, yield 59%), MS: m/e 444,4 (M+N+).

Compounds described in the examples 61-64 received by the General method described in example 60.

Example 61

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-piperidine-1-iletilmesine (1:1)

Specified in the title compound was obtained in the form of solid light yellow (yield 78%), MS: m/e 458,4 (M+N+), when using the piperidine.

Example 62

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-morpholine-4-iletilmesine (1:1)

Specified in the title compound was obtained in the form of solid light yellow (yield 23%), MS: m/e 460,5 (M+N+when using the research.

Example 63

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-[(methylpyridin-3-ylmethylamino)methyl]benzamide (1:2)

Specified in the title compound was obtained in the form of solid light yellow (yield 15%), MS: m/e 495,2 (M+N+when using 3-(methylaminomethyl)pyridine.

Example 64

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-(4-methylpiperazin-1-ylmethyl)benzamide (1:2)

Specified in the title compound was obtained in a solid white color (yield 21%), MS: m/e 473,3 (M+N+when using N-methylpiperazine.

Example 65

Hydrochloride 4-[(2-methoxyethylamine)methyl]-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:1)

Specified in the title compound was obtained in the form of solid light yellow (yield 66%), MS: m/e 448,3 (M+N+when using 2-methoxyethylamine in dioxane at 90° C.

Example 66

Hydrochloride 4-[(2-hydroxyethylamino)methyl]-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:1)

Specified in the title compound was obtained in the form of solid light yellow (yield 68%), MS: m/e 434,4 (the+N +when using ethanolamine in dioxane at 90° C.

Example 67

Hydrochloride 4-(benzylamino)-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:1)

Specified in the title compound was obtained in a solid white color (yield 50%), MS: m/e 480,3 (M+N+), when using benzylamine in dioxane at 90° C.

Example 68

Hydrochloride 4-[(benzylmethylamine)methyl]-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:1)

Specified in the title compound was obtained in a solid white color (yield 74%), MS: m/e 494,3 (M+N+when using N-methylbenzylamine in dioxane at 90° C.

Example 69

Hydrochloride 4-[(3-imidazol-1-ylpropionic)methyl]-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:2)

Specified in the title compound was obtained in the form of solid light yellow (yield 58%), MS: m/e 498,2 (M+N+when using 1-(3-aminopropyl)imidazole in dioxane at 90° C.

Example 70

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-{[(pyridine-4-ylmethyl)amino]methyl}benzamide (1:2)

Specified in the title compound was obtained in a solid beige color (yield 33%), MS: m/e 481,2 (M+N+when using 4-(aminomethyl)pyridine in dioxane at 90° C.

Example 71

Hydrochloride 4-{[(2-methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-phenylbenzothiazole-2-is)benzamide (1:1)

Specified in the title compound was obtained in the form of solid light yellow (yield 73%), MS: m/e 462,3 (M+N+when using N-(2-methoxyethyl)of methylamine in dioxane at 90° C.

Example 72

Hydrochloride 4-(1,1-dioxo-4-thiomorpholine-4-ylmethyl)-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:1)

To a solution of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-thiomorpholine-4-iletilmesine (350 mg, 0.73 mmole) in CH2Cl2(10 ml) was added 3-phenyl-2-(phenylsulfonyl)oxaziridine (288 mg, 1.1 mmole) and the mixture was stirred at RT for 2 h Then the reaction mixture was evaporated to dryness, the residue suspended in ether, the solid was separated by filtration, washed with ether and acetone. Then the solid was dissolved in methanol (10 ml)was treated with 5 N. Hcl/Meon at RT for 1 h, the precipitate was separated by filtration, washed with methanol and dried under vacuum (0.05 mm Hg, 60° (C)if this got mentioned in the title compound in the form of a solid white color (270 mg, yield 68%), MS: m/e 508,3 (M+N+).

Example 73

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-thiomorpholine-4-iletilmesine (1:1)

Specified in the title compound was obtained in the form of a solid yellow (yield 68%), MS: m/e 476,1 (M+N+when using thiomorpholine in dioxane at 90° C.

Example 74

Hydrochlo the ID 4-imidazol-1-ylmethyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:1)

Specified in the title compound was obtained in the form of solid light yellow (yield 92%), MS: m/e 441,3 (M+N+when using imidazole in DMF at 90° C.

Example 75

4-(2-Hydroxymethylimidazole-1-ylmethyl)-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid

Specified in the title compound was obtained in the form of solid light yellow (yield 16%), MS: m/e 471,1 (M+N+when using 2-hydroxymethylimidazole in DMF at 90° C.

Example 76

N-(4-Methoxy-7-phenylbenzothiazole-2-yl)- 4-(2-Mei-1-ylmethyl)benzamide

Specified in the title compound was obtained in a solid white color (yield 79%), MS: m/e 455,5 (M+N+when using 2-methylimidazole in DMF at 90° C.

Example 77

4-(4,5-Dimethylimidazole-1-ylmethyl)-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid

Specified in the title compound was obtained in the form of solid light yellow (yield 67%), MS: m/e 469,2 (M+N+when using 4,5-dimethylimidazole in DMF at 90° C.

Example 78

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-piperazine-1-iletilmesine (1:2)

Specified in the title compound was obtained in the form of solid light yellow (yield 80%), MS: m/e 459,5 (M+N+when using 1-tert-butoxycarbonylamino in dioxane at 90° C.

Example 79

Hydra is chloride 4-allelomimetic-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:1)

Specified in the title compound was obtained in the form of solid light yellow (yield 65%), MS: m/e 430,5 (M+N+when using allylamine in dioxane at 90° C.

Example 80

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-{[(pyridine-3-ylmethyl)amino]methyl}benzamide (1:2)

Specified in the title compound was obtained in the form of solid light yellow (yield 28%), MS: m/e 481,3 (M+N+when using 3-(aminomethyl)pyridine in THF at 65° C.

Example 81

The hydrochloride of 4-(4-hydroxypiperidine-1-ylmethyl)-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:1)

Specified in the title compound was obtained in a solid white color (yield 61%), MS: m/e 474,3 (M+N+when using 4-hydroxypiperidine in THF at 65° C.

Example 82

The hydrochloride of 4-(3(S)-hydroxypyrrolidine-1-ylmethyl)-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:1)

Specified in the title compound was obtained in a solid white color (yield 74%), MS: m/e 460,3 (M+N+), using (S)-3-hydroxypyrrolidine in THF at 65° C.

Example 83

Hydrochloride 4-[1,4]-diazepan-1-ylmethyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:2)

Specified in the title compound was obtained in the form of solid light yellow (yield 87%), MS: m/e 473,2 (M+N+), using tert-butyl 1-gomobi is erosioncorrosion in THF at 65° C.

Example 84

The hydrochloride of 4-(3(R)-dimethylaminopyridine-1-ylmethyl)-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:2)

Specified in the title compound was obtained in the form of a solid light brown color (51%yield), MS: m/e 487,3 (M+N+), using (3R)-(+)-3-dimethylaminopyridine in THF at 65° C.

Example 85

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-[(2-morpholine-4-ylethylamine)methyl]benzamide (1:2)

Specified in the title compound was obtained in the form of solid light yellow (yield 44%), MS: m/e 503,3 (M+N+when using 4-(2-amino-ethyl)research in THF at 65° C.

Example 86

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-[(2-pyrrolidin-1 ylethylamine)methyl]benzamide (1:2)

Specified in the title compound was obtained in the form of solid light yellow (yield 37%), MS: m/e 487,3 (M+N+when using N-(2-amino-ethyl)pyrrolidine in THF at 65° C.

Example 87

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-[(2-piperidine-1-ylethylamine)methyl]benzamide (1:2)

Specified in the title compound was obtained in the form of solid light yellow (yield 50%), MS: m/e 501,3 (M+N+when using N-(2-amino-ethyl)piperidine in THF at 65° C.

Example 88

Hydrochloride 4-cyclobutylmethyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (11)

Specified in the title compound was obtained in a solid white color (yield 68%), MS: m/e 444,3 (M+N+), when using cyclobutylamine in THF at 65° C.

Example 89

Hydrochloride 4-cyclopentylmethyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:1)

Specified in the title compound was obtained in the form of a solid light brown color (yield 46%), MS: m/e 458,4 (M+N+), when using cyclopentylamine in THF at 65° C.

Example 90

Hydrochloride 4-{[(furan-2-ylmethyl)amino]methyl}-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:1)

Specified in the title compound was obtained in a solid beige color (yield 57%), MS: m/e 470,2 (M+N+when using 2-(aminomethyl)of furan in THF at 65° C.

Example 91

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-{[(thiophene-2-ylmethyl)amino]methyl}benzamide (1:1)

Specified in the title compound was obtained in the form of solid light yellow (yield 60%), MS: m/e 486,3 (M+N+when using 2-(aminomethyl)of thiophene in THF at 65° C.

Example 92

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-{[methyl(2-pyridin-2-retil)amino]methyl}benzamide (1:2)

Specified in the title compound was obtained in a solid beige color (yield 46%), MS: m/e 509,3 (M+N+when using 2-[(2-(methylamino)ethyl]feast the DIN in THF at 65° C.

Example 93

Hydrochloride 4-[(cyclopropylamino)methyl]-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:1)

Specified in the title compound was obtained in the form of solid light yellow (yield 69%), MS: m/e 444,3 (M+N+), when using aminomethylpropanol in dioxane at 90° C.

Example 94

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-{[2-methylsulfonylamino]methyl}benzamide (1:2)

Specified in the title compound was obtained in the form of solid light yellow (yield 74%), MS: m/e 464,2 (M+N+when using 2-(methylthio)ethylamine in THF at 65° C.

Example 95

The hydrochloride of N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-thiazolidin-3-iletilmesine (1:1)

Specified in the title compound was obtained in a solid white color (yield 48%), MS: m/e 462,2 (M+N+when using thiazolidine in THF at 65° C.

Example 96

The hydrochloride of 4-(3(S)-dimethylaminopyridine-1-ylmethyl)-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamide (1:2)

Specified in the title compound was obtained in the form of a solid light brown color (yield 56%), MS: m/e 487,3 (M+N+), using (3S)-(-)-3-(dimethylamino)pyrrolidine in THF at 65° C.

Example 97

4-Chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamide.

Carried out the reaction of 2-amino-4-methoxy-7-Mohali the-4-eventhorizon (1.0 g, 3.8 mmole), 4-(chloromethyl)benzoyl chloride (810 mg, 4.2 mmole) and pyridine (0,36 ml, 4.5 mmole) in dichloromethane (20 ml) for 18 hours the Reaction was stopped by addition of water (25 ml) was added sodium carbonate to pH 8.0. The resulting mixture was extracted with dichloromethane, the combined organic extracts were dried and evaporated to dryness. After conducting a rapid chromatography on silica gel (elution with dichloromethane containing 2.5% methanol) received the product in the form of white crystals (yield 54%), MS: m/e 418 (M+N+).

Compounds described in the examples 98-102 received by the General method.

Example 98

4-(4-Hydroxypiperidine-1-ylmethyl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

The specified connection was received in the form of a solid white color (yield 73%), MS: m/e 483 (M+N+), from 4-chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamide (84 mg, of 0.20 mmole) and 4-hydroxypiperidine (178 mg, 2.0 mmole) according to the General method C.

Example 99

4-{[(2-Methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

The specified connection was received in the form of a solid white color (yield 55%), MS: m/e 471 (M+N+), from 4-chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamide (84 mg, of 0.20 mmole) and N-(2-methoxyethyl)methylamine (178 mg, 2.0 mmole) according to the General method C.

Example 100

4-{[(2-Hydroxyethyl)methylamino]met the l}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

2- {[4-(4-Methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)benzyl]methylamino} ethyl ester of 3,4-dimethoxybenzoic acid (63 mg, 0.10 mmole) was heated in an aqueous solution of sodium hydroxide (1 M, 0.5 ml) and ethanol (2 ml) at 100° C for 30 minutes Then the mixture was diluted with water and was extracted twice with ethyl acetate. The combined organic layers were extracted with saturated aqueous sodium hydrogen carbonate solution, dried and evaporated to dryness. After conducting a rapid chromatography on silica gel (elution with dichloromethane containing 5% methanol) received the product in the form of white crystals (yield 48%), MS: m/e 457 (M+N+).

Example 101

2-{[4-(4-Methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)benzyl]methylamino} ethyl ester of 3,4-dimethoxybenzoic acid

The specified connection was received in the form of solid light yellow (yield 57%), MS: m/e 621 (M+N+), from 4-chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamide (84 mg, of 0.20 mmole), hydrochloride 2-methylaminoethanol ether 3,4-dimethoxybenzoic acid (96 mg, 0.4 mmole) and N-ethyldiethanolamine (0,14 ml of 0.80 mmole) according to the General method C.

Example 102

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-piperazine-1-ylmethylene

The specified connection was obtained as colorless crystals (yield 72%), MS: m/e 468 (M+N+), the interaction of a 4-hormati is-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamide (84 mg, of 0.20 mmole) of 1-BOC-piperazine (372 mg, 1.9 mmole) according to the General procedure b followed by cleavage of the pure carbamate in triperoxonane acid (1 ml) and neutralized with saturated aqueous solution of sodium carbonate.

Example 103

N-(7-Benzyloxy-4-methoxybenzothiazole-2-yl)-4-chloromethylbenzene.

Specified in the title compound was obtained in the form of solid light yellow (yield 70%), MS (EI): m/e 438 (M+), the General method described in example 1.

Example 104

The hydrochloride of N-(7-benzyloxy-4-methoxybenzothiazole-2-yl)-4-(3-dimethylaminopropan-1-ylmethyl)benzamide.

Specified in the title compound was obtained in the form of a solid light brown color (yield 86%), tpl.195° C (decomp.), according to the General method C.

Obtaining 3-(7-aryl-4-methoxybenzothiazole-2-yl)-1-R3-1-R4-urea.

General method G

The corresponding 2-amino-7-aryl-4-methoxybenzothiazole (1 part) and pyridine (1.2 EQ.) was dissolved in 40 parts of tetrahydrofuran and treated with phosgene (20% solution in toluene, 1 EQ.) at room temperature. After 60 min the reaction mixture was concentrated to half volume under reduced pressure, was added the appropriate amine (1.25 EQ.) and pyridine (1.1 EQ.) and stirred at room temperature for 15 minutes the Reaction mixture was evaporated to dryness, the product was isolated by rapid chromatography is and silica gel (elution with dichloromethane, containing 2.5% methanol).

Compounds described in the examples 135-137 received by the General method.

Example 105

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide thiomorpholine-4-carboxylic acid

The specified connection was received in the form of a solid white color (yield 73%), MS: m/e 395 (M+N+), when the interaction of 2-amino-4-methoxy-7-morpholine-4-eventhorizon (100 mg, 0,377 mmole) with phosgene (20% solution in toluene, 0.2 ml) and thiomorpholine (0,045 ml, 0.47 mmol) by General method,

Example 106

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide morpholine-4-carboxylic acid

The specified connection was received in the form of a solid white color (yield 25%), MS: m/e 379 (M+N+), when the interaction of 2-amino-4-methoxy-7-morpholine-4-eventhorizon (100 mg, 0,377 mmole) with phosgene (20% solution in toluene, 0.2 ml) and morpholine (0,041 ml, 0.47 mmol) by General method,

Example 107

3-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-1-methyl-1-(6-methylpyridin-3-ylmethyl)urea

The specified connection was received in the form of a solid white color (yield 25%), MS: m/e 429 (M+N+), when the interaction of 2-amino-4-methoxy-7-morpholine-4-eventhorizon (100 mg, 0,377 mmole) with phosgene (20% solution in toluene, 0.2 ml) and methyl(6-methylpyridin-3-ylmethyl)amine (0,064 ml, 0.47 mmol) by General method,

Example 108

1-Furan-3-ylmethyl-3-(4-methoxybenzothiazole-2-yl)urea

To rest the ru tert-butyl ester (4-methoxybenzothiazole-2-yl)carbamino acid (80 mg, to 0.29 mmole) in dioxane (2 ml) was added furfurylamine (55 mg, 0.57 mmol) and the mixture was heated at 100° C for 20 hours and Then the reaction mixture was evaporated to dryness and the residue was recrystallized from ether/n-hexane, to receive specified in the title compound in the form of solids beige (80 mg, yield 92%), MS: m/e 303 (M+).

Compounds described in the examples 109-132 received by the General method described in example 108.

Example 109

1-Furan-2-ylmethyl-3-(4-methoxy-7-phenylbenzothiazole-2-yl)urea

Specified in the title compound was obtained in a solid beige color (yield 66%), MS: m/e 380,3 (M+N+), from tert-butyl ether (4-methoxybenzothiazole-2-yl)carbamino acid and furfurylamine.

Example 110

1-(4-Methoxy-7-phenylbenzothiazole-2-yl)-3-thiophene-2-iletilmesine

Specified in the title compound was obtained in a solid beige color (yield 62%), MS: m/e 396,3 (M+N+), from tert-butyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and thiophene-2-methylamine.

Example 111

1-(4-Methoxy-7-phenylbenzothiazole-2-yl)-3-pyridine-2-iletilmesine

Specified in the title compound was obtained in a solid beige color (yield 18%), MS: m/e 391,2 (M+N+), the interaction of tert-butyl methyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and

Example 112

1-(4-Methoxy-7-phenylbenzothiazole-2-yl)-3-pyridin-3-iletilmesine

Specified in the title compound was obtained in a solid beige color (yield 18%), MS: m/e 391,2 (M+N+), the interaction of tert-butyl methyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and 3-(aminomethyl)of pyridine, followed by purification of the product of preparative reversed-phase GHUR on the column 18 ODS-AQ with elution in a gradient of water/acetonitrile.

Example 113

1-(4-Methoxy-7-phenylbenzothiazole-2-yl)-3-pyridin-4-iletilmesine

Specified in the title compound was obtained in a solid beige color (yield 52%), MS: m/e 391,2 (M+N+), from tert-butyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and 4-(aminomethyl)pyridine.

Example 114

3-(4-Methoxy-7-phenylbenzothiazole-2-yl)-1-methyl-1-pyridin-3-iletilmesine

Specified in the title compound was obtained in a solid beige color (yield 23%), MS: m/e 405,4 (M+N+), from tert-butyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and 3-(methylaminomethyl)pyridine.

Example 115

1-(4-Methoxy-7-phenylbenzothiazole-2-yl)-3-phenethylamine

Specified in the title compound was obtained in a solid beige color (yield 77%), MS: m/e 404,5 (M+N+), from tert-butyl ether (4-methoxy-7-phenylbis thiazol-2-yl)carbamino acid and phenetylamine.

Example 116

1-(4-Methoxy-7-phenylbenzothiazole-2-yl)-3-(3-phenylpropyl)urea

Specified in the title compound was obtained in a solid beige color (71%yield), MS: m/e 417,5 (M+N+), from tert-butyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and 3-phenylpropylamine.

Example 117

1-(4-Methoxybenzyl)-3-(4-methoxy-7-phenylbenzothiazole-2-yl)urea

Specified in the title compound was obtained in a solid beige color (yield 60%), MS: m/e 420,3 (M+N+), from tert-butyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and 4-methoxybenzylamine.

Example 118

(4-Methoxy-7-phenylbenzothiazole-2-yl)amide 3,4-dihydro-1H-isoquinoline-2-carboxylic acid

Specified in the title compound was obtained in a solid beige color (yield 31%), MS: m/e 416,3 (M+N+), the interaction of tert-butyl methyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and 1,2,3,4-tetrahydroisoquinoline, followed by purification of the product of preparative reversed-phase GHUR on the column 18 ODS-AQ with elution in a gradient of water/acetonitrile.

Example 119

1-(2-Dimethylaminoethyl)-3-(4-methoxy-7-phenylbenzothiazole-2-yl)urea

Specified in the title compound was obtained in a solid beige color (yield 67%), MS: m/e 371,3 (M+N+), from tert-butyl ether (4-what ethoxy-7-phenylbenzothiazole-2-yl)carbamino acid and 2-diethylaminoethylamine.

Example 120

1-(4-Methoxy-7-phenylbenzothiazole-2-yl)-3-(2-piperidine-1-retil)urea

Specified in the title compound was obtained in a solid beige color (yield 67%), MS: m/e 411,4 (M+N+), from tert-butyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and 1-(2-amino-ethyl)piperidine.

Example 121

1-(4-Methoxy-7-phenylbenzothiazole-2-yl)-3-(2-morpholine-4-retil)urea

Specified in the title compound was obtained in a solid beige color (yield 29%), MS: m/e 413,4 (M+N+), from tert-butyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and 4-(2-amino-ethyl)research.

Example 122

1-(4-Methoxy-7-phenylbenzothiazole-2-yl)-3-(2-pyridin-2-retil)urea

Specified in the title compound was obtained in a solid beige color (yield 88%), MS: m/e 405,4 (M+N+), from tert-butyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and 2-(2-amino-ethyl)pyridine.

Example 123

Hydrochloride of 1-(3-imidazol-1-ylpropyl)-3-(4-methoxy-7-phenylbenzothiazole-2-yl)urea (1:1)

The free base was obtained in the interaction of tert-butyl methyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and N-(3-aminopropyl)imidazole. After processing 5 N. Hcl/tO and crystallization from methanol/ether has been specified in the title compound in the form of solids baie is avago color (yield 72%), MS: m/e 408,3 (M+N+).

Example 124

Hydrochloride of 1-ethyl-3-(4-methoxy-7-phenylbenzothiazole-2-yl)-1-pyridin-4-rocephine (1:1)

The free base was obtained in the interaction of tert-butyl methyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and 4-(N-ethylaminomethyl)pyridine. After processing 5 N. Hcl/tO and crystallization from acetonitrile has been specified in the title compound in the form of solid white (yield 64%), MS: m/e 419,3 (M+N+).

Example 125

Hydrochloride of 1-(2-imidazol-1-retil)-3-(4-methoxy-7-phenylbenzothiazole-2-yl)urea (1:1)

The free base was obtained in the interaction of tert-butyl methyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and N-(2-amino-ethyl)imidazole. After processing 5 N. Hcl/tO and crystallization from acetonitrile has been specified in the title compound in the form of solid light brown color (yield 65%), MS: m/e 393,0 (M+).

Example 126

(4-Methoxy-7-phenylbenzothiazole-2-yl)amide morpholine-4-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 67%), MS: m/e 370,3 (M+N+), from tert-butyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and the research and subsequent crystallization of the product from ether/n-hexane.

Example 127

(4-Methoxy-7-phenylbenzothiazole-2-yl)amide, timoho the Jn-4-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 88%), MS: m/e 386,2 (M+N+), from tert-butyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and thiomorpholine with subsequent crystallization of the product from ether/n-hexane.

Example 128

(4-Methoxy-7-phenylbenzothiazole-2-yl)amide 1-oxo-1λ4-thiomorpholine-4-carboxylic acid

To a solution of (4-methoxy-7-phenylbenzothiazole-2-yl)amide thiomorpholine-4-carboxylic acid (240 mg, of 0.62 mmole) in CH2Cl2(10 ml) was added 3-phenyl-2-(phenylsulfonyl)oxaziridine (244 mg, of 0.92 mmole) and the mixture was stirred at RT for 2 h Then the solvent is evaporated to approximately 2 ml and the mixture was treated with ultrasound for 15 min by adding ether (10 ml). Precipitated precipitated solid substance was separated by filtration and dried under vacuum (0.05 mm Hg, 60° (C)if this got mentioned in the title compound in the form of solid light yellow (yield 90%), MS: m/e 402,9 (M+N+).

Example 129

Hydrochloride of 1-[2-(1,1-dioxo-1λ6-thiomorpholine-4-yl)ethyl]-3-(4-methoxy-7-phenylbenzothiazole-2-yl)urea (1:1)

When interacting tert-butyl ester (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and 2-(1,1-diocletianopolis-4-yl)ethylamine was obtained the free base which was converted into hydrochloride treatment is rigid 5 N. HCl/tO. After drying under vacuum (0.05 mm Hg, 60° (C) has been specified in the title compound in the form of solid beige color (yield 87%), MS: m/e 461,2 (M+N+).

Example 130

Hydrochloride 3-(4-methoxy-7-phenylbenzothiazole-2-yl)-1-methyl-1-(6-methylpyridin-3-ylmethyl)urea (1:2)

When interacting tert-butyl ester (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and methyl(6-methylpyridin-3-ylmethyl)amine was obtained free base which was converted into the hydrochloride by treatment 5 N. Hcl/tO. After recrystallization from acetonitrile and drying under vacuum (0.05 mm Hg, 60° (C) has been specified in the title compound in the form of solid white (yield 61%), MS: m/e 448,9 (M+N+).

Example 131

Hydrochloride 3-(4-methoxy-7-phenylbenzothiazole-2-yl)-1-methyl-1-pyridin-2-iletilmesini (1:2)

When interacting tert-butyl ester (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and methylpyridin-2-ylmethylamino received free base which was converted into the hydrochloride by treatment 5 N. Hcl/tO. After recrystallization from EtOH/ether and drying under vacuum (0.05 mm Hg, 60° (C) has been specified in the title compound in the form of solid white (yield 70%), MS: m/e 494,4 (M+N+).

Example 132

Hydrochloride 3-(4-methoxy-7-phenylbenzothiazole-2-yl)-1-methyl-1-pyridin-4-yl is amylocaine (1:2)

When interacting tert-butyl ester (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid and methylpyridin-4-ylmethylamino received free base which was converted into the hydrochloride by treatment 5 N. Hcl/tO. After recrystallization from tO/ether and drying under vacuum (0.05 mm Hg, 60° (C) has been specified in the title compound in the form of solid white (yield 65%), MS: m/e 480,3 (M+N+).

Example 133

3-(4-Methoxy-7-phenylbenzothiazole-2-yl)-1-methyl-1-(1-oxypyridine-3-ylmethyl)urea

It chilled with ice to a solution of 3-(4-methoxy-7-phenylbenzothiazole-2-yl)-1-methyl-1-pyridin-3-iletilmesini (405 mg, 1 mmol) in CH2Cl2added 3-chlormadinone acid (MSRV) (295 mg, 1.2 mmole) and the mixture was stirred at 0° C for 1 h and then at RT for 1 h Then the reaction mixture is light red, thoroughly washed with 5%aqueous solution Panso3(50 ml), the aqueous phase was extracted with CH2CL2(2× 30 ml), the combined extracts were dried over Na2SO4, filtered and evaporated to dryness. When this was received solid purple color, which was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution in a gradient of CH2Cl2/(2 N. NH3/MeOH) (97:3 to 9:1). Specified in the title compound was obtained in the form of a solid light brown CEE is a (260 mg, yield 62%), MS: m/e 421,3 (M+N+).

Example 134

1-Benzyl-3-(4-methoxybenzothiazole-2-yl)urea

To a solution of 2-amino-4-methoxybenzothiazole (180 mg, 1 mmol) in THF (5 ml) under stirring was added benzylsuccinic (166 mg, 1.25 mmole) and the mixture was heated at 60° C for 3 hours After evaporation of solvent was added ether (5 ml) and the suspension was treated with ultrasound for 10 min by adding n-hexane (5 ml). The suspension was filtered, washed with ether/n-hexane (1:1) and dried under vacuum. Specified in the title compound was obtained in a solid white color (220 mg, yield 70%), MS: m/e 313 (M+).

Example 135

1-Benzyl-3 -(4-methoxy-7-phenylbenzothiazole-2-yl)urea

Specified in the title compound was obtained as amorphous solid white (yield 92%), MS: m/e 389 (M+), from 2-amino-4-methoxy-7-phenylbenzothiazole by the General method described in example 165.

Example 136

1-(4-Methoxy-7-phenylbenzothiazole-2-yl)-3-pyridin-3-ultimatemenu

To a solution of 2-amino-4-methoxy-7-phenylbenzothiazole (80 mg, 0.3 mmol) in dioxane (3 ml) under stirring was added pyridine-3-isothiocyanate (64 mg, of 0.47 mmole) and the mixture was heated at 100° C for 69 hours After cooling to CT the resulting yellow suspension was filtered, washed with ether (5 ml) and dried under vacuum (0.05 mm Hg, 50°). Specified in the header soy is inania received in the form of a solid light-yellow color (98 mg, yield 80%), MS: m/e 393,1 (M+N+).

Example 137

1-Benzoyl-3-(4-methoxy-7-phenylbenzothiazole-2-yl)thiourea

To a suspension of 2-amino-4-methoxy-7-phenylbenzothiazole (1.52 g, 6 mmol) in dioxane (60 ml) was added benzoylisothiocyanate (1.45 g, 8.9 mmole) and the mixture was heated at 100° C for 2 h with the formation of a homogeneous solution. After cooling the mixture, the solvent is evaporated, the solid is suspended in hot acetonitrile (100 ml) and filtered at 50° C. the Solid is collected, washed with acetonitrile (20 ml) and dried under vacuum (0.05 mm Hg, 60°). Specified in the title compound was obtained in the form of a solid amorphous material, light yellow (1,38 g, yield 55%), MS: m/e 419,0 (M+).

Example 138

Benzyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid

To a solution of 2-amino-4-methoxy-7-phenylbenzothiazole (512 mg, 2 mmole) in pyridine under stirring at 90° With three portions over 6 h was added benzylchloride (3,3 ml, 23.4 mmole). Then the reaction mixture was evaporated to dryness and distributed between CH2CL2(50 ml) and saturated aqueous NaCl (50 ml), the aqueous phase was separated and was extracted with CH2Cl2(2× 50 ml). The combined organic phases were dried, filtered and evaporated. The crude residue was purified by chromatography on SiO2(230-400 mesh mesh, Merck,) when suirou the Institute of CH 2CL2/tO (4:1). Specified in the title compound was obtained as white foam (620 mg, yield 79%), MS: m/e 391,2 (M+N+).

Example 139 (intermediate compound)

Methyl ester racemate [7-(2-bromo-1-hydroxyethyl)-4-methoxybenzothiazole-2-yl]carbamino acid

Methyl ester (4-methoxy-7-vinylbenzoate-2-yl)carbamino acid (1.5 g, 0,0057 mol) was dissolved in THF (60 ml)was treated with N2O (6 ml) and NBS (1.0 g, 0,006 mol) at room temperature for 15 minutes Then evaporated the solvent, the residue was transferred into a H2O (30 ml) and was extracted with four portions of ethyl acetate (50 ml). The combined organic phases are washed with saline and dried over MgSO4. After evaporation of the solvent the crude product was purified by chromatography on a column (silica gel, with elution by ethyl acetate). Specified in the title compound was obtained in a solid white color (yield 78%), tpl.150-155° C.

Example 140 (intermediate compound)

Methyl ether [7-(2-bromo-1-hydroxypropyl)-4-methoxybenzothiazole-2-yl]carbamino acid

Specified in the title compound was obtained in the form of foam from the methyl ester (4-methoxy-7-propylbenzoate-2-yl)carbamino acid according to the method described in the above example, and used in the next stage without additional purification and analysis of the.

Example 141 (intermediate compound)

Methyl ester (7-bromoacetyl-4-methoxybenzothiazole-2-yl)carbamino acid

Methyl ester racemate [7-(2-bromo-1-hydroxyethyl)-4-methoxybenzothiazole-2-yl]carbamino acid (1.6 g, 0,0044 mol) was dissolved in l3(100 ml) and treated Mno2(3.8 g, 0,044 mol) at 70° C for 3 hours the Hot reaction mixture was filtered and then concentrated.

The crude product was led from Et2O specified in the title compound was obtained in a solid beige color (yield 73%), tPL. 250-260° C (decomp.).

Example 142 (intermediate compound)

Methyl ether [7-(2-bromopropionyl)-4-methoxybenzothiazole-2-yl]carbamino acid

Methyl ether [7-(2-bromo-1-hydroxypropyl)-4-methoxybenzothiazole-2-yl]carbamino acid (5.0 g, 0,0133 mole) suspended in water (30 ml) and the solution was added SGAs3(2.0 g, of 0.02 mole) in acetic acid (30 ml). The resulting reaction mixture was heated at 70° C for 2 h and then evaporated to dryness. The residue was transferred into a saturated solution Panso3(200 ml), was extracted with four portions of 200 ml of ethyl acetate and the combined organic phases were dried over MgSO4. Specified in the title compound was obtained as orange crystals (yield 74%), tpl.199-201° C.

Example 143

4-Chloromethyl-N-[4-labels and-7-(2-morpholine-4-iltiazem-4-yl)benzothiazol-2-yl]benzamide

4-Methoxy-7-(2-morpholine-4-iltiazem-4-yl)benzothiazol-2-ylamine (0,165 g, 0,00047 mol) was dissolved in dioxane (5 ml) and was mixed with triethylamine (0.1 ml, 0,0007 mol), DMAP (0,006 g, 0,000047 mol) and a solution of 4-(chloromethyl)benzoyl chloride (0,116 g, 0,00062 mol) in dioxane (1 ml). The resulting reaction mixture was stirred at 70° within 6 hours After cooling to room temperature, added water (10 ml) and a saturated solution Panso3(10 ml). The precipitation was separated by filtration, washed with water and dried. The crude product was purified by chromatography on a column (silica gel, eluent CH2CL2/Meon, 19:1). Specified in the title compound was obtained in the form of solid light yellow (yield 65%), tpl.166-168° C.

Compounds described in the following examples were obtained from the corresponding 4-methoxybenzothiazole-2-ylamino, substituted in position 7 by the above method.

Example 144

4-Chloromethyl-N-{4-methoxy-7-[2-(6-methylpyridin-3-yl)thiazol-4-yl]benzothiazol-2-yl}benzamide

The specified connection was received in the form of a solid off-white color (yield 68%), tpl.230-250° C.

Example 145

4-Chloromethyl-N-{4-methoxy-7-[2-(trailmen)thiazol-4-yl]benzothiazol-2-yl}benzamide

The specified connection was received in the form of a solid white color (yield 42%), tpl.163° C (decomp.).

Example 146

4-Charmet the l-N-[7-(2-dimethylaminoethanol-4-yl)-4-methoxybenzothiazole-2-yl]benzamide

The specified connection was received in the form of solid light yellow (yield 36%), tPL. 183-186° C.

Example 147

4-Chloromethyl-N-[4-methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]benzamide

The specified connection was received in the form of a solid light brown color (yield 79%), tpl.195-201° C.

Example 148

4-Chloromethyl-N-[4-methoxy-7-(2-methylthiazole-4-yl)benzothiazol-2-yl]benzamide

The specified connection was received in the form of a solid white color (yield 72%), tpl.140-145° C.

Example 149

4-Chloromethyl-N-[4-methoxy-7-(5-methylthiophene-2-yl)benzothiazole-2-yl]benzamide

The specified connection was received in the form of a solid yellow (yield 93%), tpl.130-146° C.

Example 150

4-{[(2-Methoxyethyl)methylamino]methyl}-N-[4-methoxy-7-(2-morpholine-4-iltiazem-4-yl)benzothiazol-2-yl]benzamide

N-(2-Methoxyethyl)methylamine (0.035 g, 0,00039 mol) and (4-chloromethyl-N-[4-methoxy-7-(2-morpholine-4-iltiazem-4-yl)benzothiazol-2-yl]benzamide (0,064 g, 0,00013 mol) was dissolved in THF (2 ml) and boiled under reflux for 4 hours After cooling to room temperature and the solvent is evaporated, the residue triturated with water (7 ml). The precipitate was separated by filtration, washed with water and dried. Specified in the title compound was obtained in the form of a solid off-white color (yield 79%), tpl.100-110°C.

Compounds described in the following examples was obtained from N-(2-methoxyethyl)methylamine and the corresponding 4-chloromethyl-N-[4-methoxybenzothiazole-2-yl]benzamide, substituted in position 7 by the above method.

Example 151

4-{[(2-Methoxyethyl)methylamino]methyl}-N-{4-methoxy-7-[2-(trailmen)thiazol-4-yl]benzothiazol-2-yl}benzamide

The specified connection was received in the form of a solid white color (yield 79%), tpl.119-128° C.

Example 152

N-[7-(2-Aminothiazol-4-yl)-4-methoxybenzothiazole-2-yl]-4-{[(2-methoxyethyl)methylamino]methyl)benzamide

4-{[(2-Methoxyethyl)methylamino]methyl}-N-{4-methoxy-7-[2-(trailmen)thiazol-4-yl]benzothiazol-2-yl}benzamide (0.1 g, 0,00014 mol) in .l/Meon (0,03 ml:1 ml) was boiled under reflux for 1 h After evaporation of the solvent the residue was transferred into water (10 ml)was treated with a saturated solution of NaHCO3(10 ml) and was extracted with four portions of ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on a column (silica gel, eluent ethyl acetate, CH2Cl2/MeOH, 19:1 and 9:1). Specified in the title compound was obtained in a solid white color (yield 53%), tpl.199-206° C.

Example 153

4-{[(2-Methoxyethyl)methylamino]methyl}-N-{4-methoxy-7-[2-(6-methylpyridin-3-yl)thiazol-4-yl]benzothiazole--yl}benzamide

The specified connection was received in the form of foam light yellow (yield 69%), MS (ISP): m/e 560 (M+N+).

Example 154

N-[7-(2-Dimethylaminoethanol-4-yl)-4-methoxybenzothiazole-2-yl]-4-{[(2-methoxyethyl)methylamino]methyl}benzamide

The specified connection was received in the form of solid light yellow (yield 47%), tpl.85-95° C.

Example 155

4-{[(2-Methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-thiophene-2-eventhorizon-2-yl)benzamid

The specified connection was received in the form of a solid light beige color (yield 44%), tpl.58-78° C.

Example 156

4-{[(2-Methoxyethyl)methylamino]methyl}-N-[4-methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]benzamide

The specified connection was received in the form of solid light yellow (yield 54%), MS (ISP): m/e 546 (M+N+).

Example 157

4-{[(2-Methoxyethyl)methylamino]methyl}-N-[4-methoxy-7-(2-methylthiazole-4-yl)benzothiazol-2-yl]benzamide

The specified connection was received in the form of a solid white color (yield 36%), tpl.140-145° C.

Example 158

4-{[(2-Methoxyethyl)methylamino]methyl}-N-[4-methoxy-7-(5-methylthiophene-2-yl)benzothiazole-2-yl]benzamide

The specified connection was received in the form of a solid light beige color (yield 73%), tpl.83-90° C.

Example 159

N-[4-Methoxy-7-(2-morpholine-4-iltiazem-4-yl)benzothiazol-2-yl]-4-pyrrolidin-1-ylmethylene

Pyrrolidin (0,032 g, 0,00045 mol) and (4-chloromethyl-N-[4-methoxy-7-(2-morpholine-4-iltiazem-4-yl)benzothiazol-2-yl]benzamide (0.075 g, 0,00015 mol) was dissolved in THF (2 ml) and boiled under reflux for 1 h After cooling to room temperature and the solvent is evaporated, the residue triturated with water (7 ml). The precipitate was separated by filtration, washed with water and dried. Specified in the title compound was obtained in the form of a solid off-white color (yield 87%), tpl.120-130° C.

Compounds described in the following examples was obtained from pyrrolidine and the corresponding 4-chloromethyl-N-[4-methoxybenzothiazole-2-yl]benzamide, substituted in position 7 by the above method.

Example 160

N-{4-Methoxy-7-[2-(6-methylpyridin-3-yl)thiazol-4-yl]benzothiazol-2-yl}-4-pyrrolidin-1-ylmethylene

The specified connection was received in the form of a solid light brown color (yield 58%), tpl.230-231° C.

Example 161

N-{4-Methoxy-7-[2-(trailmen)thiazol-4-yl]benzothiazol-2-yl}-4-pyrrolidin-1-ylmethylene

The specified connection was received in the form of solid light yellow (yield 89%), tpl.122-135° C.

Example 162

The hydrochloride of N-[7-(2-aminothiazol-4-yl)-4-methoxybenzothiazole-2-yl]-4-pyrrolidin-1-iletilmesine (1:1)

N-{4-Methoxy-7-[2-(trailmen)thiazol-4-yl]benzothiazol-2-yl}-4-pyrrolidin-1-ylmethyl same (by 0.055 g, 0,000078 mol) was dissolved in Meon/.l (0.5 ml:0,015 ml) and boiled under reflux for 1 h Then the solvent is evaporated, the residue was treated with ethyl acetate, filtered and isolated. The resulting material was triturated with EtOH to form crystals, which were washed Et2Oh and dried. Specified in the title compound was obtained in a solid white color (yield 62%), tpl.228-240° C.

Example 163

N-[7-(2-Dimethylaminoethanol-4-yl)-4-methoxybenzothiazole-2-yl]-4-pyrrolidin-1-ylmethylene

The specified connection was received in the form of solid light yellow (yield 75%), tpl.120-136° C.

Example 164

N-(4-Methoxy-7-thiophene-2-eventhorizon-2-yl)-4-pyrrolidin-1-ylmethylene

The specified connection was received in the form of a solid light beige color (yield 47%), tpl.174-190° C (decomp.).

Example 165

N-[4-Methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]-4-pyrrolidin-1-ylmethylene

The specified connection was received in the form of foam light yellow (yield 48%), MS (ISP): m/e 528 (M+N+).

Example 166

N-[4-Methoxy-7-(5-methylthiophene-2-yl)benzothiazole-2-yl]-4-pyrrolidin-1-ylmethylene

The specified connection was received in the form of a solid light beige color (yield 67%), tpl.140-149° C (decomp.).

Example 167

N-[4-Methoxy-7-(2-methylthiazole-4-yl)besot the azole-2-yl]-4-pyrrolidin-1-ylmethylene

The specified connection was received in the form of solid light yellow (yield 44%), tpl.123-134° C.

Example 168

N-(4-Methoxy-7-thiophene-2-eventhorizon-2-yl)-2-methylethanolamine

A mixture of 4-methoxy-7-thiophene-2-eventhorizon-2-ylamine (0.21 g, 0,0008 mole), triethylamine (0,27 ml of 0.002 mol), DMAP (0.01 g) and the acid chloride isonicotinic acid (0.20 g, about 0.001 mol) in dioxane (10 ml) was boiled under reflux for 20 hours After cooling to room temperature, added water (20 ml) and a saturated solution Panso3(15 ml). The precipitate was separated by filtration, washed with water and dried. The crude product was purified by chromatography on a column (silica gel, eluent - ethyl acetate). Specified in the title compound was obtained in the form of a solid yellow (yield 58%), tpl.203-211° C (decomp.).

Compounds described in the following examples were obtained from the acid chloride of isonicotinic acid and the corresponding 4-methoxybenzothiazole-2-ylamino, substituted in position 7 by the above method.

Example 169

N-[4-Methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]-2-methylethanolamine

The specified connection was received in the form of solid light yellow (yield 38%), MS (ISP): m/e 460 (M+N+).

Example 170

N-[4-Methoxy-7-(2-pyrrolidin-1-iltiazem-4-yl)benzothiazol-2-yl]-2-methylethanolamine

The decree is Noah compound was obtained in the form of a solid yellow (yield 9%), tpl.195-215° C.

Example 171

N-{4-Methoxy-7-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzothiazol-2-yl}-2-methylethanolamine

The specified connection was received in the form of a yellow foam (yield 4%), MS (ISP): m/e 481 (M+N+).

Example 172

N-[4-Methoxy-7-(5-methylthiophene-2-yl)benzothiazole-2-yl]-2-methylethanolamine

The specified connection was received in the form of foam light orange color (yield 65%), MS (ISP): m/e 396 (M+N+).

Example 173

{4-Methoxy-7-[2-(6-methylpyridin-3-yl)thiazol-4-yl]benzothiazol-2-yl}amide morpholine-4-carboxylic acid

4-Methoxy-7-[2-(6-methylpyridin-3-yl)thiazol-4-yl]benzothiazol-2-ylamine (0.1 g, 0,00028 mol) was dissolved in dioxane (2 ml) was added triethylamine (0,047 ml, 0,00034 mol) and phosgene (0,164 ml, 0,00031 mole, 20% solution in toluene). After stirring at room temperature for 2 h was added morpholine (0,122 ml, 0,0014 mol) and the resulting mixture was stirred at room temperature for 16 hours Then was added water (5 ml), precipitated precipitate was separated by filtration, washed with water and dried. The crude product is triturated with hot Meon and after cooling to room temperature was filtered. The filtrate was evaporated, the residue was purified by chromatography on a column (silica gel, eluent CH2CL2/Meon+1% NH4OH). Specified in the title compound was obtained in the form of solid light yellow (yield 7%, MS (ISP): m/e 468 (M+N+).

Example 174

[4-Methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]amide morpholine-4-carboxylic acid

4-Methoxy-7-[2-pyridin-2-yl)thiazol-4-yl]benzothiazol-2-yl]amine (0.1 g, 0,00029 mol) was dissolved in THF (5 ml), was added ethyldiethanolamine (0,063 ml, 0,00037 mol), DMAP (1 mg) and triphosgene (0,029 mg of 0.0001 mol) and boiled under reflux for 30 minutes and Then was added morpholine (0,0322 ml, 0,00037 mol), an additional portion of ethyldiethanolamine (0,062 ml) and the resulting mixture was stirred while boiling under reflux for 16 hours After cooling to room temperature, added water (10 ml) and the reaction mixture was extracted with ethyl acetate (4× 15 ml). The combined organic phases were dried over PA2SO4, was filtered and was evaporated. The residue was purified by chromatography on a column (silica gel, eluent - ethyl acetate). Specified in the title compound was obtained in the form of solid light yellow (yield 7%), tpl.152-178° C (decomp.).

Example 175

[4-Methoxy-7-(2-methylthiazole-4-yl)benzothiazol-2-yl]amide morpholine-4-carboxylic acid

7-(2-Aminothiazol-4-yl)-4-methoxybenzothiazole-2-ylamine (0.07 g, 0,00025 mole) suspended in dioxane (4 ml) and was treated with NaH (0,028 g 0,0006 mol, 60% dispersion in oil) at room temperature for 1 h Then was added triethylamine (of 0.11 ml, 0,00076 mol) and morpholine--carbonylchloride (0,07 ml, 0,0006 mol) and the reaction mixture was stirred at room temperature for 3 hours Then was added water (15 ml) and the reaction mixture was extracted with ethyl acetate (4x20 ml). The combined organic phases were dried over Na2SO4, was filtered and was evaporated. The residue was purified by chromatography on a column (silica gel, eluent - ethyl acetate). Specified in the title compound was obtained in the form of solid light yellow (yield 61%), tpl.223-226° C (decomp.).

Compounds described in the following examples was obtained from morpholine-4-carbonylchloride and the corresponding 4-methoxybenzothiazole-2-ylamino, substituted in position 7 by the above method.

Example 176

{4-Methoxy-7-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzothiazol-2-yl}amide morpholine-4-carboxylic acid

The specified connection was received in the form of a solid beige color (yield 40%), tpl.150-170° C.

Example 177

[4-Methoxy-7-(2-piperidine-1-iltiazem-4-yl)benzothiazol-2-yl]amide morpholine-4-carboxylic acid

The specified connection was received in the form of solid light yellow (yield 25%), tpl.227-234° C.

Example 178

(4-Methoxy-7-thiophene-2-eventhorizon-2-yl)amide morpholine-4-carboxylic acid

The specified connection was received in the form of a solid light beige color (yield 37%), tpl.175-182° C (decomp.).

When the EP 179

[4-Methoxy-7-(5-methylthiophene-2-yl)benzothiazole-2-yl]amide morpholine-4-carboxylic acid

The specified connection was received in the form of a solid light beige color (yield 59%), tpl.173-180° C (decomp.).

Example 180

[4-Methoxy-7-(2-methylthiazole-4-yl)benzothiazol-2-yl]amide of 4-hydroxypiperidine-1-carboxylic acid

To a suspension of 4-methoxy-7-(2-methylthiazole-4-yl)benzothiazole-2-ylamine (0,070 g, 0,00025 mol) in THF (4 ml) at room temperature was added N-ethyldiethanolamine (0,054 ml, 0,00031 mol) and DMAP (0.001 g). Then add triphosgene (0.025 g, 0,000085 mol) and the resulting mixture was heated at 70° C for 1 h and Then added a second portion of N-ethyldiethanolamine (0,054 ml, 0,00031 mol) and 4-hydroxypiperidine (0,031 g, 0,00031 mol) and the reaction mixture was stirred at 70° within 1.5 hours After cooling to room temperature formed a precipitate, which was separated by filtration and washed with THF. The filtrate was evaporated, the residue was purified by chromatography on a column (silica gel, eluent CH2CL2/Meon, 9:1). Specified in the title compound was obtained in a solid white color (yield 11%), tpl.145-150° C.

The connection is described in the following example, was obtained from 4-methoxy-7-(5-methylthiophene-2-yl)benzothiazole-2-yl]amine according to the above method.

Example 181

[4-Methoxy-7-(5-methylthiophene-2-yl)benzothiazole-2-yl]amide of 4-hydrox is piperidine-1-carboxylic acid

The specified connection was received in the form of a solid yellow (yield 10%), tpl.197-204° C (decomp.).

The connection is described in the following example, was obtained from N-methylpiperazine and 4-methoxy-7-(2-methylthiophene-4-yl)benzothiazol-2-yl]amine according to the above method.

Example 182

[4-Methoxy-7-(2-methylthiazole-4-yl)benzothiazol-2-yl]amide of 4-methylpiperazin-1-carboxylic acid

The specified connection was received in the form of a solid white color (yield 8%), tpl.179-181° C.

Example 183

Tert-butyl ether {2-[4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)phenyl]ethyl}methylcarbamate acid

Specified in the title compound was obtained in a solid white color (yield 16%), MS: m/e 527 (M+H+), from tert-butyl ether [2-(4-chlorocarbonyl)ethyl]methylcarbamate acid according to General method described in example 1.

Example 184

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-(1,1,2,2-tetrafluoroethoxy)benzamide

Specified in the title compound was obtained in the form of solid light yellow (yield 35%), MS: m/e 486 (M+N+), from 4-(1,1,2,2-tetrafluoroethoxy)of benzoyl chloride according to General method described in example 1.

Example 185

4-[(2-Methoxyethyl)methylsulfanyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained as a solid substance is Krasnogo color (yield 44%), MS: m/e 521 (M+N+), from the acid chloride (2-methoxyethyl)methylsulfonium acid according to General method described in example 1.

Example 186

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-cryptomelane

Specified in the title compound was obtained in a solid white color (yield 58%), MS: m/e 438 (M+N+), from 4-(trifluoromethyl)benzoyl chloride according to General method described in example 1.

Example 187

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-3-cryptomaterial

Specified in the title compound was obtained in the form of solid light yellow (yield 84%), MS: m/e 454 (M+N+), 3(triptoreline)of benzoyl chloride according to General method described in example 1.

Example 188

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-cryptomaterial

Specified in the title compound was obtained in the form of a solid yellow (yield 77%), MS: m/e 453 (M+), from 4-(triptoreline)of benzoyl chloride according to General method described in example 1.

Example 189

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-methylethanolamine

Specified in the title compound was obtained in a solid white color (yield 72%), MS: m/e 385 (M+N+), from 2-methylisothiourea by the General method described in example 1.

Example 190

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified the title compound was obtained in a solid white color (yield 85%), MS: m/e 370 (M+N+)of benzoyl chloride according to General method described in example 1.

Example 191

4-Chloro-3-{[ethyl(2-methoxyethyl)amino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid off-white color (yield 69%), MS: m/e 519 (M+N+), from 4-chloro-3-chlorodibenzofuran and ethyl(2-methoxyethyl)amine according to the General method C.

Example 192

4-Chloro-3-{[(2-methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid off-white color (yield 54%), MS: m/e 505 (M+N+), from 4-chloro-3-chlorodibenzofuran and (2-methoxyethyl)methylamine according to the General method C.

Example 193

4-Chloro-3-[(2-methoxyethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid off-white color (yield 69%), MS: m/e 491 (M+N+), from 4-chloro-3-chlorodibenzofuran and 2-methoxyethylamine according to the General method C.

Example 194

4-Chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-3-pyrrolidin-1-ylmethylene

Specified in the title compound was obtained in the form of solid light yellow (yield 72%), MS: m/e 487 (M+N+), from 4-chloro-3-chlorodibenzofuran and pyrrolidine according to the General method C.

Prima is 195

Chloride 1-[4-(4-benzyloxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)benzyl]pyridinium

Specified in the title compound was obtained in a solid white color (yield 80%), MS: m/e 538 (M+), from 4-benzyloxy-7-morpholine-4-eventhorizon-2-ylamine, 4-chlorodibenzofuran and pyridine according to the General method C.

Example 196

3-Fluoro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-4-pyrrolidin-1-ylmethylene

Specified in the title compound was obtained in the form of a solid yellow (yield 25%), MS: m/e 471 (M+N+), from 4-chloromethyl-3-tormentilla and pyrrolidine according to the General method C.

Example 197

3-[(2-Methoxyethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of solid light yellow (yield 68%), MS: m/e 457 (M+N+), 3-chlorodibenzofuran and 2-methoxyethylamine according to the General method C.

Example 198

3-{[(2-Methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid yellow (75%yield), MS: m/e 471 (M+N+), 3-chlorodibenzofuran and (2-methoxyethyl)methylamine according to the General method C.

Example 199

Chloride 1-[4-(4-Methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)benzyl]pyridinium

Specified in the header joint is received in the form of a solid white color (yield 33%), MS: m/e 462 (M+), from 4-chlorodibenzofuran and pyridine according to the General method C.

Example 200

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-3-pyrrolidin-1-ylmethylene

Specified in the title compound was obtained in the form of solid light yellow (yield 65%), MS: m/e 454 (M+N+), 3-chlorodibenzofuran and pyrrolidine according to the General method C.

Example 201

4-[(2-Ethoxyethylene)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in a solid white color (yield 18%), MS: m/e 471 (M+N+), from 4-chlorodibenzofuran and 2-ethoxyethylene according to the General method C.

Example 202

(R)-N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-(3-ethoxypyrrolidine-1-ylmethyl)benzamide

Specified in the title compound was obtained in the form of solid light yellow (yield 18%), MS: m/e 483 (M+N+), from 4-chlorodibenzofuran and (R)-3-ethoxypyrrolidine according to the General method C.

Example 203

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-methylaminoethanol

Specified in the title compound was obtained in the form of solid light yellow (yield 63%), MS: m/e 413 (M+N+), from 4-chlorodibenzofuran and methylamine according to the General method C.

Example 204

(S)-N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-(3-ethoxypyrrolidine-1-ylmethyl)Ben the amide

Specified in the title compound was obtained in the form of a solid light brown color (yield 13%), MS: m/e 483 (M+N+), from 4-chlorodibenzofuran and (S)-3-ethoxypyrrolidine according to the General method C.

Example 205

4 Azetidin-1-ylmethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of solid light yellow (yield 33%), MS: m/e 439 (M+N+), from 4-chlorodibenzofuran and azetidine according to the General method C.

Example 206

4-[1-(2-Methoxyethylamine)ethyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid yellow (yield 52%), MS: m/e 471 (M+N+), 4-(1-chloroethyl)benzoyl chloride and 2-methoxyethylamine according to the General method C.

Example 207

4-{1-[(2-Methoxyethyl)methylamino]ethyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid yellow (yield 91%), MS: m/e 485 (M+N+), 4-(1-chloroethyl)benzoyl chloride and (2-methoxyethyl)methylamine according to the General method C.

Example 208

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-(1-pyrrolidin-1-retil)benzamid

Specified in the title compound was obtained in the form of a solid yellow (yield 68%), MS: m/e 467 (M+N+), 4-(1-chloroethyl)benzoyl chloride, pyrrolidin is and according to the General method C.

Example 209

The racemate of N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-4-{[methyl - (4,4,4-Cryptor-3-hydroxybutyl)amino]methyl}benzamide

Specified in the title compound was obtained in a solid white color (yield 89%), MS: m/e 539 (M+N+), from 4-chlorodibenzofuran and racemate 1,1,1-Cryptor-4-methylaminomethyl-2-ol according to the General method C.

Example 210

4-{[Ethyl(2-methoxyethyl)amino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid light brown color (yield 62%), MS: m/e 485 (M+N+), from 4-chlorodibenzofuran and (2-methoxyethyl)ethylamine according to General method C.

Example 211

4-{[(2-Ethoxyethyl)ethylamino]methyl} -N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid light brown color (yield 66%), MS: m/e 499 (M+N+), from 4-chlorodibenzofuran and (2-ethoxyethyl)ethylamine according to General method C.

Example 212

3-Fluoro-4-{[(2-methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid light brown color (yield 52%), MS: m/e 489 (M+N+), from 3-fluoro-4-chloromethylbenzene and (2-methoxyethyl)methylamine according to the General method C.

Example 213

4- {[bis(2-Ethoxyethyl)amino]ethyl} -N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid light brown color (yield 49%), MS: m/e 543 (M+N+), from 4-chlorodibenzofuran and bis(2-ethoxyethyl)amine according to the General method C.

Example 214

4-{[(2-Ethoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in a solid white color (yield 78%), MS: m/e 485 (M+N+), from 4-chlorodibenzofuran and (2-ethoxyethyl)methylamine according to the General method C.

Example 215

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-(4-methoxypiperidine-1-ylmethyl)benzamide

Specified in the title compound was obtained in a solid white color (yield 33%), MS: m/e 497 (M+N+), 4-(1-chloromethyl)benzoyl chloride and 4-methoxypiperidine according to the General method C.

Example 216

4-[(2-Methoxyethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in a solid white color (yield 64%), MS: m/e 457 (M+N+), from 4-chlorodibenzofuran and 2-methoxyethylamine according to the General method C.

Example 217

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-(2-Mei-1-ylmethyl)benzamide

Specified in the title compound was obtained in a solid white color (yield 87%), MS: m/e 464 (M+N+), from 4-chlorodibenzofuran and 2-ethyl-1H-imidazole according to the General method C.

Example 218

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-(4-methylpiperazin-1-ylmethyl)benzamide

Specified in the title compound was obtained in a solid white color (yield 78%), MS: m/e 482 (M+N+), from 4-chlorodibenzofuran and 1-methylpiperazine according to the General method C.

Example 219

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-pyrrolidin-1-ylmethylene

Specified in the title compound was obtained in a solid white color (yield 81%), MS: m/e 454 (M+N+), from 4-chlorodibenzofuran and pyrrolidine according to the General method C.

Example 220

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-morpholine-4-ylmethylene

Specified in the title compound was obtained in a solid white color (yield 83%), MS: m/e 469 (M+N+), from 4-chlorodibenzofuran and research according to the General method C.

Example 221

N-(4-Benzyloxy-7-morpholine-4-eventhorizon-2-yl)-4-{[(2-methoxyethyl)methylamino]methyl}benzamide

Specified in the title compound was obtained in a solid white color (yield 69%), MS: m/e 547 (M+N+), from N-(4-benzyloxy-7-morpholine-4-eventhorizon-2-yl)-4-chloromethylbenzene and (2-methoxyethyl)methylamine according to the General method C.

Example 222

The hydrochloride of N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-4-{[methyl(3,3,3-cryptochromes)amino]methyl}benzamide

N-(4-Methoxy-7-morpholine-4-albenza eazol-2-yl)-4-methylaminoethanol (100 mg, 0.24 mmole), triethylamine (35 mg, 0,34 mmole), potassium iodide (0.4 mg, 0.02 mmole) and 3,3,3-triptorelin (48 mg, of 0.27 mmole) was dissolved in ethanol (1 ml) and dioxane (0.5 ml). The reaction vessel was hermetically closed (sealed) and was heated at 90° C for 18 h After treatment and purification according to the General methodology has been specified in the title compound in the form of solid light brown color (yield 28%), MS: m/e 509 (M+N+).

Example 223

4-(2-Methoxyethoxymethyl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

4-Chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamide (200 mg, 0.48 mmole) and sodium hydride (42 mg, 0.96 mmole, 55% dispersion in mineral oil) was dissolved in 2-methoxyethanol (3.8 ml, 48 mmole) and stirred at room temperature for 18 hours After treatment and purification according to the General methodology has been specified in the title compound in the form of solid white (yield 70%), MS: m/e 458 (M+N+).

Example 224

4-Methoxymethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

4-Chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamide (200 mg, 0.48 mmole) suspended in THF (5 ml) and at 0° With added sodium methoxide (0,27 ml, 1.4 mmole, 5.4 M solution in Meon). Then the mixture was stirred at room temperature for 18 hours After treatment and purification according to the General methodology has been specified in segaloviciene in the form of solid light yellow (yield 41%), MS: m/e 414 (M+N+).

Example 225

N-[4-Methoxy-7-(1-oxo-14-thiomorpholine-4-yl)benzothiazol-2-yl]benzamide

To a solution of N-(4-methoxy-7-thiomorpholine-4-eventhorizon-2-yl)benzamide (80 mg, of 0.21 mmole) in [1,4]dioxane (3 ml) was added periodate sodium (89 mg, at 0.42 mmole) and stirred at room temperature for 20 hours To the mixture was added water (10 ml) and dichloromethane (10 ml), the phases were separated and the aqueous layer was twice extracted with dichloromethane, the combined organic extracts were dried over Na2SO4and the solvent evaporated. After recrystallization from hot THF has been specified in the title compound in the form of solid white (yield 21%), MS: m/e 402 (M+N+).

Example 226

N-(4-Methoxy-7-thiomorpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in a solid white color (yield 15%), MS: m/e 386 (M+N+), from 3-(2-methoxy-5-thiomorpholine-4-ylphenyl)thiourea (which was obtained from 4-bromo-1-methoxy-2-nitrobenzene and thiomorpholine, as described in obtaining 1-benzoyl-3-(2-methoxy-5-morpholine-4-ylphenyl)thiourea) by the General method described in example 403.

Example 227

(4-Methoxy-7-piperazine-1-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid

To a solution of benzyl ester 4-{4-methoxy-2-[(5-methylthiophene-2-carbonyl)amino]benzothiazol-7-yl}piperazine-1-carbon is howling acid (300 mg, 0.57 mmole) in dichloromethane (5 ml) was added diethylether of boron TRIFLUORIDE (to 0.72 ml, 5.7 mmole), ethanthiol (1.2 ml, 17 mmol) and the mixture was stirred for 36 h the Volatile components were evaporated, the residue was twice distilled with toluene. The residue was dissolved in dichloromethane (25 ml)was extracted with 1 N. solution of sodium carbonate and the organic phase was dried over Na2SO4. After removal of solvent and flash-chromatography (silica gel, eluent CH2CL2/Meon/.N4HE, 100:10:1) has been specified in the title compound in the form of solid light yellow (yield 58%), MS: m/e 389 (M+H+).

Example 228

[7-(4-Acetylpiperidine-1-yl)-4-methoxybenzothiazole-2-yl]amide of 2-methylthiophene-2-carboxylic acid

(4-Methoxy-7-piperazine-1-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid (100 mg, 0.26 per mmole) suspended in DMF (2 ml), was added acetylchloride (22 μl, 0.30 mmole) and pyridine (27 μl, of 0.34 mmole) and the mixture was stirred at room temperature for 5 hours After treatment and purification according to the General methodology has been specified in the title compound in the form of solid white (yield 55%), MS: m/e 431 (M+N+).

Example 229

Methyl ester of 4-{4-methoxy-2-[(5-methylthiophene-2-carbonyl)amino]benzothiazol-7-yl}piperazine-1-carboxylic acid

Specified in the title compound was obtained as a solid substance be the CSOs color (yield 26%), MS: m/e 447 (M+N+), from methylcarbamate as described in example 319.

Example 230

[4-Methoxy-7-(4-methylpiperazin-1-yl)benzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid

To a solution of (4-methoxy-7-piperazine-1-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid (100 mg, 0.26 per mmole) in methanol (8 ml) was added formic acid (100 μl, 2.6 mmole) and formaldehyde (23 μl, 0.31 in mmole) and the mixture is boiled under reflux for 18 hours After treatment and purification as described in obtaining (4-methoxy-7-piperazine-1-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid, has been specified in the title compound as light yellow colour powder (yield 34%), MS: m/e 403 (M+N+).

Example 231

[7-(2,3-dihydro-1H-indol-6-yl)-4-methoxybenzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid

Specified in the title compound was obtained as a crystalline substance in a light brown colour (yield 26%), MS: m/e 422 (M+N+), from (7-iodine-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid (100 mg, to 0.23 mmole) and 6-iodine-2,3-dihydro-1H-indole according to the General method B described in example 54.

The intermediate connection

4-(4-Benzyloxy-3-nitrophenyl)morpholine

Specified in the title compound was obtained in the form of a solid yellow (yield 58%), MS: m/e 315 (M+N+), from the research and 1-benzyloxy-4-bromo-2-nitro is Anzola (obtained from 4-bromo-2-nitroanisole and benzylbromide according to the General method described in example 4-(4-methoxy-3-nitrophenyl)of the research.

The intermediate connection

2-Amino-4-morpholine-4-infenal

Specified in the title compound was obtained in the form of a solid gray color (yield 96%), MS: m/e 194 (M+), catalytic hydrogenation of 4-(4-benzyloxy-3-nitrophenyl)research (5 g, 16 mmole) in dichloromethane (500 ml) and ethanol (500 ml) in the presence of palladium on coal (500 mg, 10%).

Example 232

N-(4-Hydroxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid light brown color (total yield 14%), MS: m/e 356 (M+N+), from 2-amino-4-morpholine-4-kilfenora, as described in obtaining N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamide.

Example 233

[7-(3-Dimethylaminopropan-1-yl)-4-methoxybenzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid

Specified in the title compound was obtained in the form of a solid yellow (yield 90%), MS: m/e 417 (M+N+), from 5-methylthiophene-2-carbonylchloride and 7-(3-dimethylaminopropan-1-yl)-4-methoxybenzothiazole-2-ylamine by the General method described in example 1.

The intermediate connection

7-(3-Dimethylaminopropan-1-yl)-4-methoxybenzothiazole-2-ylamine

Specified in the title compound was obtained in a solid white color (yield 25%), MS: m/e 293 (M+N+), from [5-(3-dimethyl inoperative-1-yl)-2-methoxyphenyl]thiourea (obtained from 4-bromo-1-methoxy-2-nitrobenzene and dimethylpyridin-3-ylamine, as described in obtaining (2-methoxy-5-morpholine-4-ylphenyl)thiourea).

Example 234

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide tetrahydropyran-4-carboxylic acid

To a solution of 2-amino-4-methoxy-7-morpholine-4-eventhorizon (100 mg, 0.4 mmole) in tetrahydrofuran (2 ml) was sequentially added N-ethyldiethanolamine (194 μl, 1.1 mmole), tetrahydropyran-4-carbonylchloride (77 mg, of 0.52 mmole, a solution in 0.5 ml of tetrahydrofuran) and the mixture is boiled under reflux for 3 hours Then the mixture was cooled to 0° With added methanol (0.4 ml) and slowly warmed up to 20° C. the Mixture was evaporated dry, was added dichloromethane (3 ml) and was extracted with saturated aqueous sodium carbonate. After back extraction of the aqueous phase of the two portions of 3 ml of dichloromethane the combined organic phases were dried over Na2SO4and the solvent evaporated. The crude product was purified by chromatography on SiO2when the elution of CH2CL2/Meon, 98:2. The fractions containing the product were combined and the solvent evaporated specified in the title compound was obtained in the form of a powder beige (142 mg, yield 76%), MS: m/e 378 (M+N+).

Compounds described in the following examples was obtained by the General method described in example 234.

Example 235

tert-Butyl ester 4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)p is peridin-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 3%), MS: m/e 477 (M+N+), from 2-amino-4-methoxy-7-morpholine-4-eventhorizon and tert-butyl methyl ether 4-chlororespiration-1-carboxylic acid.

Example 236

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-acetylpiperidine-4-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 22%), MS: m/e 419 (M+N+), from 2-amino-4-methoxy-7-morpholine-4-eventhorizon and 1-acetylpiperidine-4-carbonylchloride.

Example 237

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide piperidine-4-carboxylic acid

tert-Butyl ester 4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)piperidine-1-carboxylic acid (95 mg, 0.2 mmole) was dissolved in triperoxonane acid (0.8 ml), the mixture was stirred at room temperature for 1 h and evaporated to dryness. After purification as described in obtaining (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide tetrahydropyran-4-carboxylic acid, has been specified in the title compound in the form of solid white (yield 77%), MS: m/e 377 (M+N+).

General method D (urea)

The corresponding substituted 2-aminobenzothiazole (1 part, usually 500 mg) was dissolved in CH2Cl2(100 parts) and treated with pyridine (3 parts) and phenylcarbamate (1.2 parts). After stirring at room temperature for 30 min the mixture was boiled under reflux for 2 h, and then was added the appropriate amine (5 EQ.). After boiling under reflux for 18 h the mixture was evaporated to dryness, dissolved in CH2CL2and was extracted with an aqueous solution of sodium carbonate. After back extraction of the aqueous phase CH2Cl2the combined organic layers were dried over Na2SO4and was evaporated to dryness.

The product was isolated by rapid chromatography (silica gel, eluent - dichloromethane containing 2.5% methanol).

Compounds described in the examples 238-276 and 279, obtained according to the General method D.

Example 238

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-[(4-forgenerating)methyl]piperidine-1-carboxylic acid

Specified in the title compound was obtained in the form of a solid off-white color (yield 25%), MS: m/e 522 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-[(4-forgenerating)methyl]piperidine.

Example 239

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-hydroxymethyl-4-phenylpiperidine-1-carboxylic acid

Specified in the title compound was obtained in the form of solid light yellow (yield 50%), MS: m/e 483 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-hydroxymethyl-4-phenylpiperidine.

Use the 240

Methyl ester [1-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)piperidine-4-ylmethyl]carbamino acid

Specified in the title compound was obtained in a solid white color (yield 81%), MS: m/e 464 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and methyl ester piperidine-4-iletilerini acid.

Example 241

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-ethylpiperidine-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 26%), MS: m/e 406 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-ethylpiperidine.

Example 242

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-(2-oxopyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (29%), MS: m/e 474 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-(2-oxopyrrolidin-1-ylmethyl)piperidine.

Example 243

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-(2-methoxyethyl)piperazine-1-carboxylic acid

Specified in the title compound was obtained in the form of a solid off-white color (yield 79%), MS: m/e 437 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-(2-methoxyethyl)piperazine.

Example 244

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)and the ID 4-cyanomethylene-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 46%), MS: m/e 416 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-cyanoethylidene.

Example 245

tert-Butyl ether [1-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)piperidine-4-ylmethyl]carbamino acid

Specified in the title compound was obtained in a solid white color (yield 11%), MS: m/e 506 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and tert-butyl methyl ether piperidine-4-iletilerini acid.

Example 246

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-[2-(4-chlorophenyl)tetrahydrofuran-2-yl]piperidine-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 43%), MS: m/e 557 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-[2-(4-chlorophenyl)tetrahydrofuran-2-yl]piperidine.

Example 247

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-(2-hydroxyethyl)piperidine-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 64%), MS: m/e 421 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-(2-hydroxyethyl)piperidine.

Example 248

1-(2-Methoxyethyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine

Specified in the header is Obedinenie received in the form of a solid white color (yield 65%), MS: m/e 381 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and (2-methoxyethyl)methylamine.

Example 249

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-methoxyacetophenone-1-carboxylic acid

Specified in the title compound was obtained in a solid beige color (yield 84%), MS: m/e 450 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-methoxyacetophenone.

Example 250

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-methylpiperidin-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 47%), MS: m/e 391 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-methylpiperidine.

Example 251

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-oxopiperidin-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 38%), MS: m/e 391 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and piperidine-4-it.

Example 252

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-cyclopropyl-4-hydroxypiperidine-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 27%), MS: m/e 434 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-cyclopropyl-4-hydroxypiperidine.

Example 253

(4-Methox the-7-morpholine-4-eventhorizon-2-yl)amide 1,1-dioxo-1λ 6-thiomorpholine-4-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 50%), MS: m/e 427 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 1,1-dioxide thiomorpholine.

Example 254

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-hydroxyethylpiperazine-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 31%), MS: m/e 407 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-hydroxyethylpiperazine.

Example 255

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide, octahedrally-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 79%), MS: m/e 432 (M+H+), 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and octahydrocyclopenta.

Example 256

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2,3-benzo-1,4-dioxa-8 azaspiro[4,5]decane-8-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 63%), MS: m/e 483 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 2,3-benzo-1,4-dioxa-8 azaspiro[4,5]decane.

Example 257

Methyl ester of 4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)piperazine-1-carboxylic acid

Specified in the title compound was obtained as a solid which CSOs substance white (yield 90%), MS: m/e 436 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and methyl ester piperazine-1-carboxylic acid.

Example 258

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide, octahydronaphthalene-2-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 53%), MS: m/e 432 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and octahydronaphthalene.

Example 259

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 3-methylpiperidin-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 50%), MS: m/e 391 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 3-methylpiperidine.

Example 260

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 3-hydroxyethylpiperazine-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 69%), MS: m/e 436 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 3-hydroxyethylpiperazine.

Example 261

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 3,4-benzo-1-oxa-8-azaspiro[4,5]decane-8-carboxylic acid

Specified in the title compound was obtained in the form of solid light yellow (yield 67%), MS: m/e 481 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 3,4-benzo-1-oxa-8-asasp the ro[4,5]decane.

Example 262

tert-Butyl ester 4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)piperazine-1-carboxylic acid

Specified in the title compound was obtained in the form of solid light yellow (yield 66%), MS: m/e 478 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and tert-butyl methyl ether piperazine-1-carboxylic acid.

Example 263

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-hydroxy-4-phenylpiperidine-1-carboxylic acid

Specified in the title compound was obtained in the form of solid light yellow (yield 36%), MS: m/e 469 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-hydroxy-4-phenylpiperidine.

Example 264

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-methylpiperazin-1-carboxylic acid

Specified in the title compound was obtained in a solid beige color (yield 20%), MS: m/e 392 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-methylpiperazine.

Example 265

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-triftormetilfosfinov-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 16%), MS: m/e 445 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-triftormetilfullerenov.

Example 266

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide [14']bipiperidine-1'-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 35%), MS: m/e 461 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and [1,4']bipiperidine.

Example 267

3-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-1-(4-methoxyphenyl)-1-metalmachine

Specified in the title compound was obtained in the form of solid light yellow (yield 40%), MS: m/e 430 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and (4-methoxyphenyl)methylamine.

Example 268

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1,4-dioxa-8 azaspiro[4,5]decane-8-carboxylic acid

Specified in the title compound was obtained in a solid beige color (yield 28%), MS: m/e 435 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 1,4-dioxa-8 azaspiro[4,5]decane.

Example 269

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 3,4-dihydro-1H-isoquinoline-2-carboxylic acid

Specified in the title compound was obtained in the form of a solid orange color (yield 63%), MS: m/e 425 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 1,2,3,4-tetrahydroisoquinoline.

Example 270

3-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-1-methyl-1-phenylacetone

Specified in the title compound was obtained in a solid white color (yield 19%), MS: m/e 399 (M+N+), from 4-methoxy-7-Mohali the-4-eventhorizon-2-ylamine and methylphenylamine.

Example 271

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-hydroxypiperidine-1-carboxylic acid

Specified in the title compound was obtained in the form of a solid yellow (yield 50%), MS: m/e 393 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and piperidine-4-ol.

Example 272

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-methoxypiperidine-1-carboxylic acid

Specified in the title compound was obtained in the form of a solid yellow (yield 33%), MS: m/e 407 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 4-methoxypiperidine.

Example 273

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-oxo-1λ4-thiomorpholine-4-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 87%), MS: m/e 411 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 1-oxide thiomorpholine.

Example 274

1-(4-Methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)piperidine-4-ymetray ether methanesulfonate acid

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-hydroxyethylpiperazine-1-carboxylic acid (300 mg, 0.43 mmole) and N-ethyldiethanolamine (95 μl, of 0.56 mmole) was dissolved in CH2CL2(10 ml), then added methanesulfonamide (36 μl, of 0.47 mmole) and the mixture was stirred at room temperature for 3 days. P the following purification by General method D received the product in a solid white color (yield 34%), MS: m/e 466 (M+N+).

Example 275

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide piperazine-1-carboxylic acid

Specified in the title compound was obtained in the form of solid light yellow (yield 99%), MS: m/e 378 (M+N+), from tert-butyl ether 4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)piperazine-1-carboxylic acid according to General method is described for obtaining (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide piperidine-4-carboxylic acid.

Example 276

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-aminomethylpyridine-1-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 50%), MS: m/e (M+H+), from tert-butyl ether [1-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)piperidine-4-ylmethyl]carbamino acid according to General method is described for obtaining (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide piperidine-4-carboxylic acid.

Example 277

2-Methoxyethylamine ether (4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid

4-Methoxy-7-morpholine-4-eventhorizon-2-ylamine (300 mg, 1.1 mmole) and N-ethyldiethanolamine high (0.56 ml, 3.4 mmole) was dissolved in tetrahydrofuran (11 ml) and within 5 min was added 2-methoxyethylamine (to 0.19 ml, 1.4 mmole). Then the mixture was heated at 70° C for 3 days, cooled to room so the temperature, was added water and was extracted twice with ethyl acetate. The combined organic phases were dried over Na2SO4and was evaporated to dryness. Specified in the title compound was obtained in the form of a solid off-white color (yield 52%), MS: m/e 368 (M+N+).

Example 278

Methyl ester [4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)benzyl]methylcarbamate acid

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-4-methylaminoethanol (100 mg, 0.24 mmole), pyridine (29 μl, of 0.36 mmole) and methylchloroform (24 μl, of 0.32 mmole) was dissolved in dichloromethane (5 ml)and then stirred at room temperature for 18 hours After treatment and purification according to the General methodology has been specified in the title compound in the form of solid light yellow (yield 66%), MS: m/e 471 (M+N+).

Example 279

Hydrochloride (4-methoxy-7-piperidine-1-eventhorizon-2-yl)amide 1-oxo-1λ4-thiomorpholine-4-carboxylic acid

Specified in the title compound was obtained in a solid white color (yield 80%), MS: m/e 409 (M+N+), from 4-methoxy-7-piperidine-1-eventhorizon-2-ylamine and 1-oxide thiomorpholine according to the General method D.

Example 280

[4-Methoxy-7-(4-methoxypiperidine-1-yl)benzothiazole-2-yl]amide morpholine-4-carboxylic acid

Specified in the title compound was obtained in the form of a solid light-reltag the color (the total yield of approximately 10%), MS: m/e 407 (M+N+), from 4-bromo-1-methoxy-2-nitrobenzene and 4-methoxypiperidine, as described in obtaining (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide morpholine-4-carboxylic acid (example 106).

Example 281

(4-Methoxy-7-thiophene-3-eventhorizon-2-yl)amide morpholine-4-carboxylic acid

Specified in the title compound was obtained in the form of a solid light-yellow color (the total yield of approximately 10%), MS: m/e 376 (M+N+), from 4-bromo-1-methoxy-2-nitrobenzene and trimethyltin-3-erstanden, as described in obtaining (4-methoxy-7-phenylbenzothiazole-2-yl)amide morpholine-4-carboxylic acid (example 157).

Example 282

2-Chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-6-methylsalicylic

To a suspension of 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine (13.3 g, 50,1 mmole) in THF (700 ml) with stirring was added N-ethyldiethanolamine (21,3 ml, 125 mmol). Then the mixture was cooled to 5°and dropwise during 2 h was added a solution of 2-chloro-6-methylisothiourea (10.5 g, 55,1 mmole) in dichloromethane (350 ml). The reaction mixture was stirred at 20° during the night, was added methanol (40 ml) and stirring was continued for 10 minutes Then the mixture was concentrated in vacuo and the residue was distributed between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried over Na2SO4and the solvent of viparita is I. The crude product was purified by chromatography on SiO2(230-400 mesh mesh, Merck,) in the elution of CH2CL2/Meon (98:2). The fractions containing the product were combined and the solvent evaporated, to receive specified in the title compound in the form of solids brown (16.0 g, yield 76%), MS: m/e 421 (M{37Cl}+H+), 419 (M{35Cl}+N+).

The connection is described in the following example, received by the General method described in example 282.

Example 283

2-Chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained in a solid brown color (yield 59%), MS: m/e 407 (M{37Cl}+H+), 405 (M{35Cl}+H+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 2-horizontalvelocity.

Example 284

2-Iodine-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-6-methylsalicylic

To a suspension of 2-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-6-methylethanolamine (1,00 g, 2,39 mmole) in ethylmethylketone (10 ml) and dioxane (20 ml) under stirring was added sodium iodide (2.0 g, 13.3 mmole) and idiscovered acid (0.95 ml, 7.2 mmole, 57% solution in water). Then the mixture was heated at 100° C for 96 hours the Mixture was concentrated in vacuo, the residue resuspendable in dichloromethane, then washed with saturated sodium bicarbonate solution, 0,1 is a sodium thiosulfate solution and brine. The organic phase was dried over Na2SO4and the solvent evaporated. The crude product was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution CH2Cl2/MeOH (99:1, then 98:2). The fractions containing the product were combined and the solvent evaporated specified in the title compound was obtained in a solid brown color (80 mg, yield 7%), MS: m/e 511 (M+N+).

Compounds described in the examples 285 and 286, obtained according to the General method D.

Example 285

1-Benzyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine

Specified in the title compound was obtained in the form of a solid off-white color (yield 94%), MS: m/e 413 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and N-benzylmethylamine.

Example 286

3-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-1-methyl-1-phenethylamine

Specified in the title compound was obtained in the form of a solid off-white color (yield 53%), MS: m/e 427 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and N-methyl-2-phenethylamine.

Example 287

The compound described in example 287, received by the General method described in example 282.

Example 288

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-3-phenylpropionamide

Specified in the title compound was obtained in the form of solid light yellow (yield 3%), MS: m/is 398 (M+N +), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 3-phenylpropionylamino.

Compounds described in the examples 392-396, obtained according to the General method D.

Example 289

1-Benzyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)urea

Specified in the title compound was obtained in the form of a solid off-white color (yield 99%), MS: m/e 399 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and benzylamine.

Example 290

1-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-3-phenethylamine

Specified in the title compound was obtained in the form of a solid off-white color (yield 87%), MS: m/e 413 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 2-phenethylamine.

Example 291

1-(2-Methoxyethyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)urea

Specified in the title compound was obtained in the form of a solid off-white color (yield 80%), MS: m/e 367 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 2-methoxyethylamine.

Example 292

1-(2-Dimethylaminoethyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine

Specified in the title compound was obtained in the form of a solid off-white color (yield 61%), MS: m/e 394 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and N,N,N'-trimethylethylenediamine.

Example 293

1-(2-Dimethylaminoethyl)-3-(4-methoxy-7-Maur the Olin-4-eventhorizon-2-yl)urea

Specified in the title compound was obtained in the form of a solid off-white color (yield 79%), MS: m/e 380 (M+N+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 2-diethylaminoethylamine.

The compound described in example 397 received by the General method described in example 379.

The intermediate compounds used in examples 1-138

Example 294

Methyl ester (7-iodine-4-methoxybenzothiazole-2-yl)carbamino acid

Methyl ester (4-methoxybenzothiazole-2-yl)carbamino acid (31.0 g, 130 mmol) and sodium acetate (32,3 g, 394 mmole) was dissolved in 400 ml of glacial acetic acid at 0° was slowly treated with monochloride iodine (13,5 ml, 264 mmole). The reaction mixture was slowly heated to room temperature and was stirred for 15 hours After adding water (1.3 l) formed precipitate was separated by filtration and washed with water. Then the filter cake was dissolved in a minimum amount of tetrahydrofuran (approximately 150 ml) and decolorized by addition of 1 M aqueous solution of sodium thiosulfate. The product precipitated with addition of water (approximately 2.0 l)was separated by filtration and dried at 60° C for 12 hours to receive 42,3 g (yield 89%) solid white, MS: m/e 364 (M+).

Example 295

Methyl ester (4-methoxybenzothiazole-2-yl)carbamino acid

2-Amino-4-methoxybenzothiazole (23,6 g, 131 mmol) and pyridine (of 12.6 ml, 157 mmol) in dichloromethane (230 ml) at 0° was slowly treated with methylchloroform a (10.6 ml, 137 mmol). After 10 min was added an additional portion of methylcarbamate (1.0 ml, 13 mmol) and pyridine (1.0 ml, 12 mmol). After 10 min the mixture was poured into 200 ml of 1 M hydrochloric acid, the organic layer was separated, diluted with dichloromethane (250 ml) and washed with brine (50 ml). The organic phase was dried and the solvent evaporated in vacuum, thus received 31.0 g (yield of 99.4%) solid white, MS: m/e 238 (M+N+).

Example 296

tert-Butyl ester (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid

To a suspension of 2-amino-4-methoxy-7-phenylbenzothiazole (1.0 g, 3.9 mmole) in THF (50 ml) was added di(tert-butoxycarbonyl)anhydride [(VOS)2About] and DMAP (47 mg, 0.04 mmole), the mixture was stirred at RT for 1 h and at 60° C for 3 hours After cooling, the solvent evaporated, the residue was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution in a gradient of EtOAc/cyclohexane (from 10% to 50%). The fractions containing the product were combined and the solvent evaporated specified in the title compound was obtained as white foam (1.1 g, yield 79%), MS: m/e 356 (M+).

Example 297

tert-Butyl ester (4-methoxybenzothiazole-2-yl)carbamino acid

Specified in the title compound was obtained is in the form of a solid white color (yield 60%), MS: m/e 281,2 (M+N+), from 2-amino-4-methoxybenzothiazole.

Example 298

2-Amino-4-methoxy-7-phenylbenzothiazole

Specified in the title compound was obtained as solid white, MS: m/e 256 (M+), tpl.207-208° C, from 3-amino-4-methoxybiphenyl, as described in the patent W.Winter, M.Thiel, A.Roesch and O.H.Wilhelms, N-(Benzothiazol-2-yl)oxamic acid derivatives, DE 2656468 (1978).

Example 299

4-Methoxy-7-phenoxybenzamine-2-ylamine

To a suspension of 2-methoxy-5-phenoxyphenyl)thiourea (8,25 g, 30 mmol) in l3(70 ml) dropwise over 10 min was added bromine (4.8 g, 30 mmol) in l3(10 ml). The mixture is then boiled under reflux for 3 h, cooled to CT, the solvent evaporated and the residue was led from the Meon/ether (1:4). The precipitate on the filter was sequentially washed with a saturated aqueous solution NS3/water (1:1) (100 ml), water (200 ml), 1 N. NaOH (60 ml), water (100 ml) and ether (100 ml). The obtained solid substance was dried under high vacuum (0.05 mm Hg, 60° (C)if this got mentioned in the title compound in the form of a solid white color (6.7 g, yield 82%), MS: m/e 272,1 (M+).

Compounds described in the examples 300-305 received by the General method described in example 299.

Example 300

Methyl ester 2-amino-4-methoxybenzothiazole-7-carboxylic acid

Specified in the title compound was obtained in the form of a solid ve is esta white (yield 55%), MS: m/e 239,2 (M+N+), methyl ester 4-methoxy-3-thioridazine acid.

Example 301

7-Bromo-4-methoxybenzothiazole-2-ylamine

Specified in the title compound was obtained in a solid white color (yield 46%), MS: m/e 258 (M+), from (5-bromo-2-methoxyphenyl)thiourea.

Example 302

7-tert-Butyl-4-methoxybenzothiazole-2-ylamine

Specified in the title compound was obtained in a solid white color (yield 79%), MS: m/e 238,1 (M+), from (5-tert-butyl-2-methoxyphenyl)thiourea.

Example 303

7-Acetylamino-4-methoxybenzothiazole-2-ylamine

Specified in the title compound was obtained in a solid purple color (yield 49%), MS: m/e 238,2 (M+N+), from (5-acetylamino-3-methoxyphenyl)thiourea.

Example 304

4-Methoxy-7-(1H-tetrazol-5-yl)benzothiazol-2-ylamine

Specified in the title compound was obtained in the form of a solid light brown color (yield 54%), MS: m/e 248,2 (M+), from 2-methoxy-5-(1H-tetrazol-5-yl)phenyl]thiourea.

Example 305

(4-Methoxy-7-phenylbenzothiazole-2-yl)methylamine

Specified in the title compound was obtained in the form of a solid white (71%yield), MS: m/e 270,1 (M+), from (4-methoxybiphenyl-3-yl)thiourea.

Example 306

5-Methoxy-7-phenylbenzothiazole-2-ylamine

(5-Methoxybiphenyl-3-yl)thiourea (109 mg, at 0.42 mmole) in chloroform 2 ml) was treated with bromine (22 μl) and the mixture was heated at 61° C for 5 hours After removal of volatiles in vacuo the product was isolated by rapid chromatography (silica gel, eluent - ethyl acetate/cyclohexane, 2:1 to 5:1) solid beige color (93 g, 86%), MS: m/e 256 (M+). Regioniniu cyclization was determined by measuring the transfer nuclear Overhauser effect (NOE).

Example 307

2-Amino-4,5-dimethoxybenzoate

2-Amino-4,5-dimethoxybenzoate, MS: m/e 210 (M+), was synthesized in three stages (with a total yield 72%) of 2,3-dimethoxyaniline (1.0 g, 6.5 mmole) in the same way as described in obtaining 5-methoxy-7-phenylbenzothiazole-2-ylamine.

Example 308

6-Bromo-4-cryptomaterial-2-ylamine

4-Bromo-(2-triptoreline)aniline (768 mg, 3 mmole) and potassium thiocyanate (875 mg, 9 mmol) was dissolved in acetic acid (5 ml) and at 0° slowly added bromine (0,19 ml, 3.6 mmole). After stirring for 1 h was added acetic acid (2 ml) and the mixture was heated at 100° C for 3 hours After cooling to room temperature, to the mixture was added an aqueous solution of sodium hydroxide (10 M, 25 ml) and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saline, dried and the solvent was removed in vacuum. After rapid chromatography (silica gel, eluent ethyl acetate/cyclohexane, 1:4) and recrystallization from ethyl acetate/cyclohexane floor is the beginning of the product in the form of a solid white color (170 mg, yield 18%), MS: m/e 315 (M+N+).

Example 309

4-Methoxy-7-morpholine-4-eventhorizon-2-ylamine

(2-Methoxy-5-morpholine-4-ylphenyl)thiourea (5.0 g, 19 mmol) in chloroform (130 ml) was treated with bromine (960 μl) and the mixture is boiled under reflux for 18 hours After removal of volatiles in vacuo the product was recrystallized from THF (2.8 g, yield 57%), MS: m/e 266 (M+).

Example 310

7-Benzyloxy-4-methoxybenzothiazole-2-ylamine

Specified in the title compound was obtained in a solid beige color (yield 82%), tpl.165° C (decomp.), of (5-benzyl-2-methoxyphenyl)thiourea in the same way as described in obtaining 5-methoxy-7-phenylbenzothiazole-2-ylamine.

Example 311

4-Cryptomaterial-2-ylamine

6-Bromo-4-cryptomaterial-2-ylamine (157 mg, of 0.50 mmole), triethylamine (of 0.21 ml, 1.5 mmole) and palladium on coal (10%, 15 mg) suspended in ethanol (12 ml) and was first made at atmospheric pressure within 96 hours, the Catalyst was separated by filtration and the solution was evaporated to dryness. The residue was dissolved in ethyl acetate, washed three times with water, dried and the solvent was removed in vacuum. The product was obtained in a solid brown color (85 mg, yield 73%), MS: m/e 235 (M+N+).

Example 312

2-Amino-4-methoxybenzothiazole-7-carbaldehyde

Specified in the title compound was obtained in the form of the solid substances beige (yield 70%), MS: m/e 208,0 (M+), of (5-formyl-2-methoxyphenyl)thiourea as described in obtaining 4-methoxy-7-phenoxybenzamine-2-ylamine.

Example 313

4-Methoxy-7-morpholine-4-imetelstat-2-ylamine

To a suspension of 2-amino-4-methoxybenzothiazole-7-carbaldehyde (440 mg, 2.1 mmole) in THF (100 ml) was added morpholine (276 mg, 3.2 mmole), acetic acid (190 mg, 3.2 mmole) and N(SLA)3(672 mg, 3.2 mmole). The resulting mixture was intensively stirred at 20° C for 48 h, then was added water (50 ml), 5% solution of NaHCO3(50 ml) and was intensively shaken. After separation of the organic and aqueous layers, the aqueous phase was extracted with EtOAc (50 ml) and the combined organic phase was washed with saturated NaCl solution (100 ml), dried over Na2SO4, was filtered and was evaporated. The solid residue suspended in ether (20 ml), then separated by filtration, washed on the filter with ether (10 ml) and dried under vacuum (0.05 mm Hg, 50°). Specified in the title compound was obtained in a solid yellow color (430 mg, yield 73%), MS: m/e 280,2 (M+).

Example 314

2-Chloro-4-methoxy-7-phenylbenzothiazole

To a suspension of 2-amino-4-methoxy-7-phenylbenzothiazole (of 5.1 g, 20 mmol) in ethylene glycol (75 ml) was added hydrazinoacetate (4 g, 80 mmol), hydrazinehydrate (4,2 g, 40 mmol) and the suspension was heated at 140° C for 18 hours After cooling to CT is Uspenskiy was filtered, the filter cake was washed with water (200 ml) and ether (100 ml)and then dried under vacuum (0.05 mm Hg, 70°). It was received 2 hydrazino-4-methoxy-7-phenylbenzothiazole in a solid white color (5,2 g, yield 96%). Received 2 hydrazino-4-methoxy-7-phenylbenzothiazole (4.5 g, of 16.6 mmole) in portions over 20 min was added to the mix to thionyl chloride (12 ml, 165 mmol) and the mixture was heated to 50° C for 2 h to complete the reaction. The reaction mixture was cooled, poured into a mixture of water/ice (300 ml) and stirred at 0-10° C for 20 minutes the Mixture was filtered, the filter cake washed with water (100 ml)and then was dissolved in CH2Cl2(250 ml) and washed with saturated solution of NaCl. The organic phase was dried over Na2SO4, was filtered and was evaporated, the thus obtained oil red, which was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with buyrevia CH2CL2. The fractions containing the product were combined and evaporated. Specified in the title compound was obtained in a solid brown color (4,24 g, yield 93%), MS: m/e 275,0 (M+).

Literature: Synth. Commun., 2769-2780 (1992).

Example 315

4-(Morpholine-4-sulfonyl)benzoic acid

To a solution of 4-(chlorosulfonyl)benzoic acid (0.5 g, 2.2 mmole) in THF (20 ml) dropwise over 5 min was added morpholine (0,434 ml, 5 mmol) and the mixture paramesh the Wali at RT for 1 h Then added water (50 ml) and the mixture was shaken, the phases were separated and the aqueous phase was extracted with EtOAc (2× 50 ml). The combined organic phases are washed with saturated aqueous NaCl, dried, filtered and evaporated. The residue was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution l3/(acetone + 10% HCO2N) (9:1). The fractions containing the product were combined, evaporated and dried under vacuum (0.05 mm Hg, 50° (C)if this got mentioned in the title compound in the form of a solid beige color (270 mg, yield 20%), MS: m/e 2 71 (M+).

Compounds described in the examples 316-318 received by the General method described in example 315.

Example 316

4-Dipropyltryptamine acid

Specified in the title compound was obtained as a solid substance beige, MS: m/e 285 (M+), from dipropylamine.

Example 317

4-Metilsulfonilmetane acid

Specified in the title compound was obtained in a solid white color (yield 85%), MS: m/e to 228.1 (M-N)-from ethylamine.

Example 318

4-Diethylaminobenzoic acid

Specified in the title compound was obtained in a solid white color (yield 44%), MS: m/e 257 (M+), from diethylamine.

Example 319

2-(1,1-Diocletianopolis-4-yl)ethylamine

Specified in the title compound was obtained as a description of the but in the patent literature W.R.Baker, S.A.Boyd, A.K.L.Fung, H.H.Stein, J.F.Denissen, C.W.Hutchins and S.H.Rosenberg, WO 9203429 (1992).

Example 320

Methyl(6-methylpyridin-3-ylmethyl)Amin

To a suspension of LiAIH4in THF (120 ml) at 10° C for 45 min was added dropwise and with cooling a solution of methyl-6-methylnicotinate (12 g, 79 mmol) in THF (80 ml). After stirring at 20° C for 1.5 h to the reaction mixture at 0° C for 30 min was added 60 ml of a mixture of THF/water (4:1), and then directly to the mixture under vigorous stirring was added Na2SO4(50 g), filtered and THF was evaporated in vacuum. The residue was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution in a gradient of CH2CL2/Meon (from 97:3 to 9:1), it was obtained a colorless oil (7.5 g, yield 77%). The resulting material was dissolved in l3(100 ml)was added dropwise thionyl chloride (17,2 ml, 237 mmol) and was stirred at a temperature of from 5 to 20° C for 16 hours Then the solvents were removed in vacuum and the residue was distributed between CH2CL2(100 ml) and 5%aqueous solution Panso3(100 ml), the aqueous phase was extracted with CH2Cl2(2× 50 ml), the combined extracts washed with saturated aqueous NaCl (1× 50 ml), dried and the solvent evaporated in vacuum. The resulting oil red was dissolved in EtOH (80 ml), cooled to 0° With dropwise within 1 h was added 33%bromide is in/tO (50 ml) and the mixture was stirred at 20° C for 3 hours After evaporation of all solvents, the residue was distributed between CH2Cl2and water (100 ml each), the aqueous phase was extracted with CH2CL2(2× 100 ml), the extracts were dried (Na2SO4), filtered and the solvent evaporated in vacuum. The oily brown residue was distilled in high vacuum (0.1 mm Hg, 68-70° (C) in column Vigro (Vigreux). Specified in the title compound was obtained in the form of liquid light yellow (6,03 g, 75%yield), MS: m/e 136,1 (M+).

Literature: J. Med. Chem., 5053-63 (1996).

Compounds described in the examples 321-322 received by the General method described in example 320.

Example 321

Methylpyridin-2-ylmethylamino

Specified in the title compound was obtained as a colourless liquid (0.1 mm Hg, 47-48° (C) (yield 20%), MS: m/e br93.1 (M-N3), of the hydrochloride of 2-chloromethylpyridine and 33%methylamine/tO.

Example 322

Methylpyridin-4-ylmethylamino

Specified in the title compound was obtained as a colourless liquid (0.1 mm Hg, 60-62° (C) (yield 79%), MS: m/e 122,1 (M+), of the hydrochloride of 4-chloromethylpyridine and 33%methylamine/tO.

The intermediate compounds used in examples 188-208

Example 323

(2-Methoxy-5-phenoxyphenyl)urea

To a solution of 2-methoxy-5-phenoxyimino (9,9 g, 46 mmol) in acetone (60 ml) was added benzo is isothiocyanate (9 g, 55 mmol) and the mixture is boiled under reflux (56° (C) within 4 hours After cooling to CT, the solvent is evaporated, the oily residue orange besieged from ether (20 ml) with sonication, the solid is washed on the filter with ether/n-hexane (1:3) (50 ml). The obtained solid substance was dried under vacuum (0.05 mm Hg, 50° C)to receive benzopyrano the thiourea in the form of a solid beige color (17,2 g, yield 99%). To a suspension benzopyrano thiourea (14.5 g, 38 mmol) in methanol (70 ml) was added their sodium methoxide (14.5 g, 38 mmol) and the mixture was stirred at RT for 1 h Then was added water (210 ml), the precipitated solid substance was separated by filtration, washed with water (100 ml), ether (100 ml) and dried under vacuum (0.05 mm Hg, 50°). Specified in the title compound was obtained in a solid white color (8.5 g, yield 81%), MS: m/e 274,1 (M+).

Compounds described in the examples 324-329 received by the General method described in example 323.

Example 324

(5-tert-Butyl-2-methoxyphenyl)thiourea

Specified in the title compound was obtained in a solid white color (yield 79%), MS: m/e 238,1 (M+), from 4-tert-butyl-2-methoxyaniline.

Example 325

(5-Acetylamino-2-methoxyphenyl)thiourea

Specified in the title compound was obtained in the de solid gray (yield 69%), MS: m/e 240,3 (M+N+), 3-amino-4-methoxyacetanilide.

Example 326

Methyl ester of 4-methoxy-3-thioridazine acid

Specified in the title compound was obtained in the form of a solid light brown color (yield 78%), MS: m/e 240,0 (M+), methyl ester 3-amino-4-methoxybenzoic acid.

Example 327

(5-Bromo-2-methoxyphenyl)thiourea

Specified in the title compound was obtained in a solid white color (yield 88%), MS: m/e 260 (M+), from 5-bromo-2-methoxyaniline.

Example 328

[2-Methoxy-5-(1H-tetrazol-5-yl)phenyl]thiourea

Specified in the title compound was obtained in the form of a solid light brown color (yield 92%), MS: m/e 250,1 (M+), from 2-methoxy-5-(1H-tetrazol-5-yl)aniline.

Example 329

1-(4-Methoxybiphenyl-3-yl)-3-methylthymidine

Specified in the title compound was obtained in a solid white color (yield 96%), MS: m/e 273,2 (M+N+directly from 4-methoxybiphenyl-3-ylamine and N-methylisothiocyanate.

Example 330

(5-Methoxybiphenyl-3-yl)thiourea

1-Benzoyl-3-(5-methoxybiphenyl-3-yl)thiourea (183 mg, of 0.51 mmole) in methanol (5 ml) was treated with sodium methoxide (5.4 M in methanol, of 0.14 ml), precipitated precipitate was separated by filtration and washed with methanol. The product was obtained in the form of powder off-white color (115 mg, yield 88%), MS: m/e 258 (M+ ).

Example 331

1-Benzoyl-3-(5-methoxybiphenyl-3-yl)thiourea

5-Methoxybiphenyl-3-ylamine (129 mg, 0.65 mmole) was dissolved in acetone (5 ml) and slowly added to the solution benzoylisothiocyanate (0,096 ml of 0.71 mmole) in acetone (2 ml). After stirring at room temperature for 18 h the solvent was removed in vacuo and the residue was led from hexane. The product was obtained as colorless crystals (203 mg, yield 86%), tpl.149° C.

Example 332

(2-Methoxy-5-morpholine-4-ylphenyl)thiourea

To a suspension of 1-benzoyl-3-(2-methoxy-5-morpholine-4-ylphenyl)thiourea (8.0 g, 21 mmol) in methanol (260 ml) was added methanolate sodium (6 ml of a 5.4 M solution in methanol) and stirred until the formation of white precipitate. The mixture was concentrated in vacuo, and the crystals were separated by filtration, washed with methanol and hexane (5.0 g, yield 86%), MS: m/e 268 (M+).

Example 333

1-Benzoyl-3-(2-methoxy-5-morpholine-4-ylphenyl)thiourea

To a solution of 2-methoxy-5-morpholine-4-ilfenomeno (4.6 g, 22 mmole) in acetone (140 ml) solution was added benzoylisothiocyanate (3.4 ml, 25 mmol) in acetone (80 ml) and the reaction mixture was stirred at room temperature for 30 minutes After removal of the volatiles in vacuo the product was isolated by rapid chromatography (silica gel, eluent - ethyl acetate/n-hexane, 1:4, then 1:2) in a solid yellow color (8, g, yield 97%), MS: m/e 272 (M+).

Example 334

(5-Benzyloxy-2-methoxyphenyl)thiourea

Specified in the title compound was obtained as white crystals (total yield 80%), tpl.130° C (decomp.), from 5-benzyloxy-2-methoxyaniline as described in example 427.

Example 335

(5-Formyl-2-methoxyphenyl)thiourea

To a solution of 2-(4-methoxy-3-nitrophenyl)[1,3]dioxolane (13 g, 57,7 mmole)

in the Meon (400 ml) was added catalyst Adams - PT(O2) (700 mg) and the mixture was intensively stirred in hydrogen atmosphere at 20° to the absorption of 4 liters of hydrogen. The catalyst was separated by filtration, the methanol evaporated and was replaced with acetone (150 ml). Then at RT for 15 min was added dropwise benzoylisothiocyanate (8.5 ml, 63,5 mmole) and the mixture is boiled under reflux for 1.5 hours, After cooling the solvent is evaporated, the residue was purified by chromatography on SiO2(230-400 mesh mesh, Merck) with elution CH2Cl2when this received a yellow oil (10 g). The oil obtained was transferred into the Meon (150 ml), was added sodium methoxide (3.7 g, 69 mmol) and the mixture was stirred at 20° C for 1 h, the Solvent evaporated, the residue was dissolved in THF (200 ml), was added 2 N. Hcl (100 ml) and the mixture was stirred for 30 minutes To the mixture was added tO (200 ml), the aqueous phase was separated and was extracted with EtOAc/THF (1:1) (200 ml). The combined organic is their phases are washed with saturated aqueous NaCl (2× 200 ml), dried, filtered and the solvent evaporated. The solid residue suspended in ether (100 ml), was separated by filtration, washed with ether (50 ml) and dried under vacuum (0.05 mm Hg, 50°). Specified in the title compound was obtained in a solid yellow color (4.7 g, yield 39%), MS: m/e 210,1 (M+).

Example 336

2-(4-Methoxy-3-nitrophenyl)[1,3]dioxolane

To a solution of 4-methoxy-3-nitrobenzaldehyde (11.2 g, 61,8 mmole) in toluene (300 ml) was added ethylene glycol (5,2 ml of 92.7 mmole) and the cation of Amberlist And 15 in the acid form (0.6 g) as a catalyst and the resulting mixture was intensively stirred while boiling under reflux for 16 h in the apparatus of the Dean-stark. After cooling, the resin Amberlyst was separated by filtration, the filtrate washed with saturated aqueous NaCl (3× 150 ml), dried over Na2SO4, was filtered and was evaporated. Specified in the title compound was obtained as orange oil (14 g, yield 100%), MS: m/e 224,1 (M-N)-.

Example 337

2-Methoxy-5-(1H-tetrazol-5-yl)aniline

To a solution of 4-methoxy-3-nitrobenzonitrile (2.5 g, 1.4 mmole) in toluene (20 ml) was added sodium azide (1.3 g, 1.8 mmole), triethylamine hydrochloride (1.5 g, 1.8 mmole) and the resulting mixture was stirred at 100° C for 48 hours and Then added to water (200 ml)was shaken and the organic phase was further washed water is (2× 30 ml). The organic phase is acidified to pH 2, the precipitation was separated by filtration, washed with water (100 ml) and dried under vacuum (0.05 mm Hg, 60°). It was obtained the crude tetrazole, which was dissolved in Meon (80 ml), was added Pd/C (10%) (250 mg) and the mixture was stirred in hydrogen atmosphere (1 ATM) at 20° C for 1 h prior to absorption of theoretical amount of hydrogen (about 880 ml). The catalyst was separated by filtration, the solvent is evaporated. Specified in the title compound was obtained in a solid white color (2.2 g, yield 82%), MS: m/e 191,1 (M+).

Literature: Synthesis, 910 (1998).

Example 338

1-Iodine-3-methoxy-5-nitrobenzene

1-Iodine-3,5-dinitrobenzene (1.8 g, 6.1 mmole) was dissolved in methanol (12 ml) and the solution was added sodium methoxide in methanol (5.4 M, 1.2 ml). Then the mixture was stirred at 65° C for 52 h After cooling to room temperature was added water (50 ml) and was extracted three times with ethyl acetate (50 ml). The combined organic phase was extracted with brine (100 ml), dried and evaporated to dryness. After rapid chromatography (silica gel, eluent - ethyl acetate/cyclohexane, 1:1) received the product (1.7 g, yield 99%) as a solid light yellow color, MS: m/e 279 (M+).

Example 339

5-Methoxybiphenyl-3-ylamine

3-Methoxy-5-nitrobiphenyl (176 mg, 0.77 mmole) was first made in e is anole (5 ml) in the presence of palladium on coal (10%, 17 mg) at atmospheric pressure for 2 hours, the Catalyst was separated by filtration, the solvent was removed in vacuum. After rapid chromatography (silica gel, eluent - ethyl acetate/cyclohexane, 1:1) received the product (139 mg, yield 91%) as brown oil, MS: m/e 199 (M+).

Example 340

2-Methoxy-5-morpholine-4-elfenlied

4-(4-Methoxy-3-nitrophenyl)morpholine (6 g) was first made in dichloromethane (100 ml) and methanol (600 ml) in the presence of palladium on coal (10%, 600 mg) for 12 hours, the Catalyst was separated by filtration, the solvent was removed in vacuum. After rapid chromatography (silica gel, eluent - ethyl acetate/n-hexane, 1:1) received the product (4.6 g, yield 88%) as a solid off-white color, MS: m/e 209 (M+N+).

Example 341

4-(4-Methoxy-3-nitrophenyl)morpholine

4-Bromo-2-nitroanisole (8.5 g, 36 mmol), morpholine (3.8 ml, 44 mmole), potassium phosphate (11 g, 51 mmol), 2-biphenyldicarboxylic (960 mg, 2.7 mmole) and palladium (II) acetate (411 mg, 1.8 mmole) was dissolved in dimethoxyethane (80 ml) and stirred at 80° C for 96 hours and Then the mixture was cooled to room temperature, diluted with ethyl acetate (50 ml) and filtered through dicalite. After rapid chromatography (silica gel, eluent - dichloromethane/methanol, 99:1) received the product (6.0 g, yield 69%) as a solid red color, MS: m/e 238 (M+).

Example 342

3-Methoxy-5-n is trouver

1-Iodine-3-methoxy-5-nitrobenzene (279 mg, 1 mmol), phenylboronic acid (146 mg, 1.2 mmole), potassium carbonate (2 M, 1.0 ml) and tetrakis(triphenylphosphine)palladium(0) was dissolved in ethanol (0.5 ml) and toluene (10 ml) and the mixture was heated at 90° C for 24 h the Volatile components were removed in vacuo, the residue was twice distilled with toluene. After rapid chromatography (silica gel, eluent dichloromethane/cyclohexane, 1:2) received the product (185 mg, yield 81%) as a solid light brown, MS: m/e 229 (M+).

Example 343

5-Bromo-2-methoxyaniline

A solution of 4-bromo-2-nitroanisole (7.7 g, 33.1 mmole), triethylamine (4.6 ml, 33.1 mmole) and Raney Nickel as catalyst (4 g) was intensively stirred in ethanol (300 ml) in an atmosphere of hydrogen at 20° C for 1 h During this time he absorbed theoretical amount of hydrogen (2.5 l), after which the catalyst was separated by filtration and the solvent evaporated. Specified in the title compound was obtained in the form of solid light yellow (7 g, exit 104%), MS: m/e 201 (M+).

Intermediate compounds used to obtain benzylamino

Example 344

4-Chloromethyl-N-(4-hydroxy-7-morpholine-4-eventhorizon-2-yl)benzamid

N-(4-Benzyloxy-7-morpholine-4-eventhorizon-2-yl)-4-chloromethylbenzene (1.0 g, 2.0 mmole) was dissolved in CH2CL2(10 ml) and at -78°were treated With Jodi the om tetrabutylammonium (0.95 g, 2.6 mmole) and a solution of trichloride boron in CH2CL2(1 M, 7,4 ml). Then I warmed up to 0°and was stirred for another 2 h, was added ice (2 g), then water (10 ml) and methanol (2 ml), after which the phases were separated. The aqueous phase was twice extracted with CH2Cl2/MeOH, and the combined organic layers were dried over Na2SO4and was evaporated to dryness. After recrystallization from CH2Cl2/MeOH received specified in the title compound in the form of solid off-white color (yield 18%), MS: m/e 403 ([M-H+]-).

Example 345

4-(1-Bromacil)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid yellow (yield 63%), MS: m/e 478 (M+N+), the General method described in example 1.

Example 346

3-Chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of solid light yellow (yield 59%), MS: m/e 418 (M+N+), the General method described in example 1.

Example 347

4-Chloromethyl-3-fluoro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid

Specified in the title compound was obtained in the form of a solid light brown color (yield 99%), MS: m/e 436 (M+N+), the General method described in example 1.

Example 348

4-Chloro-3-chloromethyl-N-(4-methoxy-7-mortal is n-4-eventhorizon-2-yl)benzamid

Specified in the title compound (yield 68%), MS: m/e 452 (M+N+), was obtained with a purity of 75% by the General method described in example 1 and used for the next stage without additional purification.

Example 349

4-[(2-Methoxyethyl)methylsulfanyl]benzoic acid

4-Chlorosulfonylbenzoic acid (100 mg, 0.45 mmole) was dissolved in (2-methoxyethyl)methylamine (1.0 g, 11.2 mmole) and heated at 50° C for 18 hours After removal of volatiles in vacuo and flash-chromatography (silica gel, eluent CH2CL2/Meon/N2O/Asón, 90:10:1:1) received the product in a solid white color (yield 65%), MS: m/e 272 ([M-H]-).

Intermediate compounds used to obtain benzylamino (2-AFP)

Example 350

4-Benzyloxy-7-morpholine-4-eventhorizon-2-ylamine

Specified in the title compound was obtained in the form of a solid off-white color (yield 69%), MS: m/e 342 (M+N+), from (2-benzyloxy-5-morpholine-4-ylphenyl)urea according to the General method described in example 403.

Example 351

N-(4-Benzyloxy-7-morpholine-4-eventhorizon-2-yl)-4-chloromethylbenzene

Specified in the title compound (yield 81%), MS: m/e 494 (M+N+), received in the form of solid light yellow color due to the General method described in example 1.

Intermediate compounds used to obtain benzylamine is in with different substituents in position 7

Example 352

4-Methoxy-7-thiomorpholine-4-eventhorizon-2-ylamine

Specified in the title compound was obtained in the form of a solid light brown color (yield 31%), MS: m/e 282 (M+N+), from (2-methoxy-5-thiomorpholine-4-ylphenyl)thiourea according to the General method described in example 403.

Example 353

Methyl ester [4-methoxy-7-(2-methylpyridin-4-yl)benzothiazol-2-yl]carbamino acid

Specified in the title compound was obtained in a solid white color (yield 8%), MS: m/e 329 (M+), from 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 2-methyl-4-trimethylaniline according to the General method B.

Example 354

4-Methoxy-7-(2-methylpyridin-4-yl)benzothiazol-2-ylamine

Methyl ester [4-methoxy-7-(2-methylpyridin-4-yl)benzothiazol-2-yl]carbamino acid (100 mg, 0.24 mmole) was dissolved in ethylene glycol (3.0 ml)was treated with potassium hydroxide (528 mg, 1.1 mmole) and heated at 100° C for 6.5 h, the Reaction mixture was cooled to room temperature, diluted with water, neutralized 1 N. HCl and was extracted four times with ethyl acetate. The organic layers were combined, washed with water and saturated aqueous NaCl. Then the organic phase was dried and the solvent was removed in vacuum. The product was obtained in the form of a solid light brown color (yield 83%), MS: m/e 272 (M+N+).

Method get

1. Mix components 1, 2, 3 and 4 and granularit in the mixture with purified water.

2. The granules are dried at 50° C.

3. The granules are treated at the appropriate grinding equipment.

4. Add the component 5, stirred for 3 min and pressed tablets on the appropriate media.

Method get

1. Mix components 1, 2 and 3 in an appropriate mixer for 30 minutes

2. Add components 4 and 5 and mix for 3 minutes

3. The mixture is filled capsules.

1. Derivatives of benzothiazole General formula I-A

where

R1means hydrogen, (ness.)alkyl, (ness.)alkoxy, benzyloxy, cycloalkane, halogen, hydroxy or cryptometrics,

R2means hydrogen, (ness.)alkyl or (ness.)alkyloxy,

R3means hydrogen, halogen or (ness.)alkyl,

R4means hydrogen, (ness.)alkyl, (ness.)alkenyl, halogen, -C(O)-(ness.)alkyl, -C(O)-halogen(ness.)alkyl, -CH(OH)-halogen(ness.)alkyl, -C(O)O-(ness.)alkyl, -N(O)-(ness.)alkyl, -(CH2)nHE means or phenyl, which is optionally attached to anthrope via the linker -(O)m-(CH2)n- and optionally substituted by a group N(R5)(R6), Gal the genome or nitro; or means 2,3-dihydro-1H-indolyl, azepin-1-yl, [1,4]oxazepan-4-yl; or

means a five - or six-membered aromatic or nonaromatic a heterocycle, which may be attached to anthrope via the linker -(O)m-(CH2)n- or-N=C(CH3)- and optionally substituted by one or two groups R7where R7has the values listed below;

R' means

a) phenyl, optionally substituted by halogen(ness.)by alkyl, -C(O)N or the following groups:

-(CH2)n-C(O)-N(R5)-(CH2)n(ness.)alkoxy,

-(CH2)nO-halogen(ness.)alkyl,

-(CH2)nO-(CH2)n+1O-(ness.)alkyl,

-S(O)2-N(R5)-(CH2)nO-(ness.)alkyl,

-(CH2)n-OR5,

-(CH2)nN(R5)-(CH2)o-(ness.)alkoxy,

-(CH2)nN[(CH2)o-(ness.)alkoxy]2,

-(CH2)nN[S(O)2CH3]2,

-(CH2)nN[R5][S(Oh)2CH3],

-(CH2)nN(R5)-(ness.)alkenyl,

-(CH2)nN(R5)-(CH2)o-cycloalkyl,

-(CH2)nN(R5)-C(O)O-(ness.)alkyl,

-(CH2)nN(R5)-(CH2)o-S-(ness.)alkyl,

-(CH 2)nN(R5)-S(O)2CH3,

-(CH2)nN(R5)-(CH2)o-phenyl,

-(CH2)nN(R5)-(CH2)oOH,

-(CH2)nN(R5)-(CH2)oCH(OH)-CF3,

-(CH2)nN(R5)-(CH2)about-CF3,

-(CH2)nN(R5)-(CH2)o-O-CH(OH)-C6H3(OCH3)2,

-(CH2)nN(R5)-(CH2)o-O-C(O)-C6H3(Och3)2,

-N(R5)-C(O)-morpholine,

-N(R5)-C(O)-N(R5)-phenyl, substituted alkoxy,

-S(O)2-morpholine, or denotes phenyl, which is optionally substituted

-(CR5R6)nfive-semiclean aromatic or a non-aromatic heterocycle, and the heterocycle may optionally be substituted by hydroxy group,

-N(R5)(R6or (ness.)the alkyl, or substituted-CH2-N(R5)(CH2)aboutfive - or six-membered aromatic or a non-aromatic heterocycle, and the heterocycle may optionally be substituted by hydroxy group, -N(R5)(R6or (ness.)the alkyl,

or means-N(R5)-phenyl, optionally substituted (ness.)alkoxy,

or means

b) -(CH2)nfive - or six-membered aromatics the th or the non-aromatic heterocycle, except piperazinilnom and thiazolidine group in case if n=0, and these cycles may not necessarily be substituted group 2-oxopyrrolidin, piperidinyl, phenyl, -(CH2)nHE, halogen, CF3, =O, (ness.)alkyl, cycloalkyl, -(CH2)n-O-(ness.)alkyl, -(CH2)nNH2, -(CH2)nCN, -C(O)O-(ness.)alkyl, -CH2-O-S(O)2CH3-C(O)-(ness.)alkyl, -C(O)-(CH2)n-(ness.)alkoxy, -CH2-N(R6)C6H4F, -CH2-N(R6)C(O)O-(ness.)alkyl, -N(R6)-C(O)-N(R5)-(CH2)n-O-(ness.)alkyl, or substituted tetrahydrofuran, substituted by 4-CL-phenyl, or substituted by the group piperazine-1-yl, morpholinyl, thiomorpholine, thiomorpholine-1-oxo, pyrrolidin-1-yl, or substituted piperidine-1-yl, or means benzoperylene-1-yl or benzothieno-2-yl, or means

C) -N(R5)(CH2)n+1is phenyl, optionally substituted by group (ness.)alkoxy, or-N(R5)C(O)-phenyl,

or means

g) -N(R5)(CH2)n-5 - or 6-membered aromatic or nonaromatic a heterocycle,

optionally substituted by a group (ness.)alkyl, -(CH2)n-5 - or

6-membered aromatic or nonaromatic a heterocycle, or means

e) -O-(CH2)n-(ness.)alkoxy, (ness.)alkyl(ness.)alkoxy, -N(R5 2)nN(R5)(R6), -(CH2)nHE, -(HC=CH)]1-4-C(O)O-(ness.)alkyl, octagenarian, 3,4-dihydro-1H-isoquinoline, 2,3-benzo-1,4-dioxa-8 azaspiro[4,5]decane or 1,4-dioxa-8 azaspiro[4,5]decane;

X is O or S,

R5and R6each independently of one another denotes hydrogen or (ness.)alkyl,

R7means (ness.)alkyl, (ness.)alkoxy, -C(O)-(ness.)alkyl, -C(O)O-benzyl,

-C(O)O-(ness.)alkyl, -(CH2)nNR5R6, pyridinyl, optionally substituted (ness.)the alkyl, or means-CH2n(R5)-C(O)O-(ness.)alkyl, -NH-C(phenyl)3pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, optionally substituted (ness.)by alkyl;

n is 0,1,2,3 or 4,

m is 0 or 1, o is 0, 1, 2, 3 or 4;

and their pharmaceutically acceptable salts except for their hydrobromide salts, and with the exception of N-(4-methoxybenzothiazole-2-yl)benzamide and provided that R1-R4at the same time does not mean hydrogen when R' represents optionally substituted phenyl.

2. The compounds of formula I-A according to claim 1

where

R1means hydrogen, (ness.)alkyl, (ness.)alkoxy, halogen, hydroxy or cryptometrics,

R2means hydrogen, (ness.)alkyl or (ness.)alkyloxy, R3OSN which denotes hydrogen, halogen or (ness.)alkyl,

R4means hydrogen, (ness.)alkyl, halogen, -C(O)HE, -C(O)O-(ness.)alkyl, -NH-C(O)-(ness.)alkyl, -(CH2)nHE means or phenyl, which is optionally attached to anthrope via the linker -(O)m-(CH2)n- and optionally substituted by a group N(R5)(R6), halogen or nitro, or

means a five - or six-membered aromatic or nonaromatic a heterocycle, which may be attached to anthrope via the linker -(O)m-(CH2)n- and optionally substituted by a group (ness.)alkyl, -C(O)O-benzyl, or-NR5R6,

R' means

a) phenyl, substituted-C(O)N or the following groups:

-(CH2)nHE, -(CH2)nN(R5)-(CH2)about-(ness.)alkoxy,

-(CH2)nN(R5)-(ness.)alkenyl,

-(CH2)nN(R5)-(CH2)about-cycloalkyl,

-(CH2)nN(R5)-(CH2)about-S-(ness.)alkyl,

-(CH2)nN(R5)-(CH2)about-phenyl,

-(CH2)nN(R5)-(CH2)oOH,

-(CH2)nN(R5)-(CH2)about-O-CH(OH)6H3(Och3)2,

-(CH2)nN(R5)-(CH2)o-O-C(O)-C6H3(OCH3)2,

-S(O) 2-morpholine, or denotes phenyl, which is optionally substituted

-(CH2)nfive-semiclean aromatic or a non-aromatic heterocycle, and the heterocycle may optionally be substituted by hydroxy group,

-N(R5)(R6or (ness.)the alkyl, or -(CH2)nN(R5)(CH2)aboutfive - or six-membered aromatic or a non-aromatic heterocycle, and the heterocycle may optionally be substituted by hydroxy group, -N(R5)(R6or (ness.)the alkyl, or means

b) five - or six-membered aromatic or nonaromatic a heterocycle, with the exception of group piperazinil, and aromatic heterocycle substituted by a group piperazine-1-yl, morpholinyl, thiomorpholine, thiomorpholine-1-oxo, pyrrolidin-1-yl, or piperidine-1-yl, or means benzoperylene-1-yl or benzothieno-2-yl,

or means

C) -N(R5)(CH2)n+1is phenyl, optionally substituted by group (ness.)alkoxy,

-O(CH2)n+1phenyl, or

-N(R5)C(O)-phenyl, or means

g) -N(R5)(CH2)n-5 - or 6-membered aromatic or nonaromatic a heterocycle,

optionally substituted by a group (ness.)alkyl, -(CH2)n-5 - or 6-membered aromatic or nonaromatic a heterocycle, or means

d) (ness.)alkyl(ness.)alkoxy, -N(R5)(CH2)nN(R5)(R6), -(CH2)nHE or -(HC=CH)nC(O)O-(ness.)alkyl;

X is O or S,

R5and R6each independently of one another denotes hydrogen or (ness.)alkyl,

n is 0, 1, 2, 3,or 4

m is 0 or 1,

o is 0, 1, 2, 3 or 4;

and their pharmaceutically acceptable salts.

3. The compounds of formula I-A according to claim 1 where R1means methoxy, X is oxygen, and R2/R3mean hydrogen.

4. The compounds of formula I-A according to claim 3, where R' represents an unsubstituted or substituted five - or six-membered aromatic heterocycle.

5. The compounds of formula I-A according to claim 4, and the connections are:

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-methylethanolamine,

(4-methoxy-7-phenylbenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid,

(4-methoxy-7-phenylbenzothiazole-2-yl)amide 5-methylfuran-2-carboxylic acid,

N-(4-methoxy-7-phenylbenzothiazole-2-yl)isonicotinamide,

(4-methoxy-7-pyridin-4-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid,

(4-methoxy-7-pyridin-3-eventhorizon-2-yl)amide 5-methylthiophene-2-carboxylic acid,

[4-methoxy-7-(2-methylpyridin-4-yl)benzothiazol-2-yl]amide 5-methylthiophene-2-carboxylic acid,

[7-(3-AMI is openil)-4-methoxybenzothiazole-2-yl]amide 5-methylthiophene-2-carboxylic acid,

N-(4-methoxy-7-thiophene-2-eventhorizon-2-yl)-2-methylethanolamine,

N-[4-methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]-2-methylethanolamine,

N-[4-methoxy-7-(2-pyrrolidin-1-iltiazem-4-yl)benzothiazol-2-yl]-2-methylethanolamine,

N-{4-methoxy-7-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzothiazol-2-yl}-2-methylethanolamine and

N-[4-methoxy-7-(5-methylthiophene-2-yl)benzothiazole-2-yl]-2-methylethanolamine.

6. The compounds of formula I-A according to claim 1, where R' represents an unsubstituted or substituted five - or six-membered nonaromatic a heterocycle.

7. The compounds of formula I-A according to claim 6, and the connections are:

(4-methoxy-7-phenylbenzothiazole-2-yl)amide morpholine-4-carboxylic acid,

(4-methoxy-7-phenylbenzothiazole-2-yl)mediamorphosis-4-carboxylic acid,

(4-methoxy-7-phenylbenzothiazole-2-yl)amide 1-oxo-1λ4-thiomorpholine-4-carboxylic acid,

{4-methoxy-7-[2-(6-methylpyridin-3-yl)thiazol-4-yl]benzothiazol-2-yl}amide morpholine-4-carboxylic acid,

[4-methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]amemorial-4-carboxylic acid,

{4-methoxy-7-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzothiazol-2-yl}amide morpholine-4-carboxylic acid,

[4-methoxy-7-(2-piperidine-1-iltiazem-4-yl)benzothiazol-2-yl]amemorial-4-carboxylic acid,

[4-meth is XI-7-(5-methylthiophene-2-yl)benzothiazole-2-yl]amemorial-4-carboxylic acid,

tert-butyl ester 4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)piperidine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-acetylpiperidine-4-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-oxopiperidin-1-carboxylic acid and

(4-methoxy-7-piperidine-1-eventhorizon-2-yl)amide 1-oxo-1λ4-thiomorpholine-4-carboxylic acid.

8. The compounds of formula I-A according to claim 1 where R' is phenyl, optionally substituted-CH2HE, -CH2N2CH2Och3, -CH2NH2CH2OH, -CH2NH2-pyridinyl, -CH2NH2CH2SCH3, -CH2N(CH3)CH2CH2S3, -CH2N(CH3)CH2CH2Och3, -CH2N(CH2CH3)CH2CH2OCH3, -CH2Och3, -CH2Och2CH2Och3or-CH2N(CH3)C(O)och3.

9. The compounds of formula I And 8 and the connections are:

4-hydroxymethyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

4-[(2-methoxyethylamine)methyl]-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

4-[(2-hydroxyethylamino)methyl]-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-{[(pyridine-4-ylmethyl)amino]methyl}is ansamed,

N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-{[(pyridine-3-ylmethyl)amino]methyl}benzamide,

N-(4-methoxy-7-phenylbenzothiazole-2-yl)-4-[(2-methylsulfonylamino)methyl]benzamide,

4-{[(2-methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

N-[7-(2-aminothiazol-4-yl)-4-methoxybenzothiazole-2-yl]-4-perbenzoic,

4-fluoro-N-{4-methoxy-7-[2-(6-methylpyridin-3-yl)thiazol-4-yl]benzothiazol-2-yl}benzamide,

4-{[(2-methoxyethyl)methylamino]methyl}-N-{4-methoxy-7-[2-(6-methylpyridin-3-yl)thiazol-4-yl]benzothiazol-2-yl}benzamide,

4-{[(2-methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-thiophene-2-eventhorizon-2-yl)benzamid,

4-{[(2-methoxyethyl)methylamino]methyl}-N-[4-methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]benzamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-4-cryptomelane,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-chloro-3-{[ethyl(2-methoxyethyl)amino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-chloro-3-{[(2-methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-chloro-3-[(2-methoxyethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

3-[(2-methoxyethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

3-{[(2-methoxyethyl)methylamino]methyl}-N-(4-IU the hydroxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-[(2-ethoxyethylene)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-4-methylaminoethanol,

4-{[(2-ethoxyethyl)ethylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-

2-yl)benzamid,

4-{[(2-ethoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-(2-methoxyethoxymethyl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

4-methoxymethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)benzamid,

N-(4-methoxy-7-thiomorpholine-4-eventhorizon-2-yl)benzamide and methyl ester [4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)benzyl]methylcarbamate acid.

10. The compounds of formula I-A according to claim 1 where R' is phenyl, substituted by an optionally substituted -(CR5R6)nfive-semiclean aromatic or a non-aromatic heterocycle.

11. The compounds of formula I-A according to paragraph 10, and the connections are:

4-imidazol-1-ylmethyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

4-(4-hydroxypiperidine-1-ylmethyl)-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

4-[1,4]-diazepan-1-ylmethyl-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

4-(3(S)-dimethylaminopyridine-1-ylmethyl)-N-(4-methoxy-7-phenylbenzothiazole-2-yl)benzamid,

N-{4-methoxy-7-[2-(6-methylpr the DIN-3-yl)thiazol-4-yl]benzothiazol-2-yl}-4-pyrrolidin-1-ylmethylene,

N-(4-methoxy-7-thiophene-2-eventhorizon-2-yl)-4-pyrrolidin-1-ylmethylene,

N-[4-methoxy-7-(2-pyridin-2-iltiazem-4-yl)benzothiazol-2-yl]-4-pyrrolidin-1-ylmethylene,

4-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-3-pyrrolidin-1-ylmethylene,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-3-pyrrolidin-1-ylmethylene,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-4-(2-Mei-1-ylmethyl)benzamide and

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-4-(4-methylpiperazin-1-ylmethyl)benzamide.

12. The compounds of formula I-A according to claim 1, where R4means optionally substituted five or six-membered aromatic or nonaromatic a heterocycle.

13. The compounds of formula I-A according to item 12, where five or six-membered aromatic or nonaromatic a heterocycle means a morpholine or piperazine.

14. Drug containing one or more compounds according to any one of claims 1 to 13 and a pharmaceutically acceptable excipients, for the treatment of diseases mediated by adenosine receptor And2A.



 

Same patents:

The invention relates to new derivatives of benzothiazole General formula (I) or its salt, where p denotes 1; X1and X2together form =O; R1denotes hydrogen, halogen, alkyl, alkoxy; R2denotes hydrogen; R3denotes a-Z4-R6, -Z13-NR7R8; Z4denotes a-Z11-C(O)-Z12-, -Z11-C(O)-O-Z12-; Z11and Z12represent a simple bond or alkylene; Z13denotes a-Z11-C(O)-Z12-; R4denotes hydrogen; R5denotes phenyl, substituted groups Z1, Z2selected from alkyl, halogen, nitro, -HE, hydroxyalkyl, -C(O)Z6, -C(O)OZ6-Z4-NZ7Z8where Z4represents a simple bond; biphenyl, substituted alkyl; naphthalenyl, which optionally can be substituted-HE; chinoline, substituted alkyl; heterocyclics; Z6denotes alkyl which may be optionally substituted by a group-Z4-NZ7Z8, morpholinium; Z7, Z8each independently represents alkyl; R6denotes alkyl optionally substituted by cyano, methoxy, phenyl, -Z4-NZ7Z8and so on; R7denotes hydrogen, alkyl; R8denotes alkyl, the long is Z4-NZ7Z8; and t

The invention relates to the production of derivatives of 3-amino-2-mercaptobenzoic acid of the formula I, in which X represents fluorine, n = 0 or 1, Z represents CO-a or CS-A1A represents hydrogen, halogen, OR1or SR2, A1denotes hydrogen or or1, R1and R2denote hydrogen, substituted or unsubstituted, saturated or unsaturated hydrocarbon radical with an open chain, containing not more than 8 carbon atoms; the interaction of the compounds of formula II in which T represents hydrogen, C1-C6alkyl, C3-C6alkenyl,3-C6quinil,3-C6cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl; with aqueous strong base

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to organic chemistry, in particular to the synthesis of substituted 6-hydroxybenzothiazole containing labile fragments

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which the function of suppressing the production of leukotrienes and thromboxanes are effective

The invention relates to new derivatives of 2-aminobenzothiazole, and to their use in pharmaceutical compositions having activity against convulsions induced by glutamate

The invention relates to the pharmaceutical industry and is used as a means of improving the quality of thinking, memory, the body's resistance to physical and mental stress

The invention relates to new derivatives of 2-aryl-8-oxopiperidine formula (I) having a selective affinity towards BZw3receptor, the method thereof, pharmaceutical composition and means containing it, and also to the intermediate compound of formula (II) to obtain the derivatives of 2-aryl-8-oxopiperidine

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

The invention relates to medicine and relates to the use of 1-hydroxy-4-cyclohexanedimethanol hydrochloride in clinical practice for the treatment of asthenic States, narcolepsy, warnings, and relieve mental and physical fatigue

The invention relates to imidazole derivative of General formula I, where n=0 or 1, R1is hydrogen, alkyl, R2is hydrogen or R2and R3form a double bond, R3is hydrogen, alkyl, R4is hydrogen, alkyl, hydroxy-group, alkoxy, R5is hydrogen or alkyl, or R4and R5form a carboxyl group, R6, R7, R8is hydrogen, alkyl, hydroxy-group, alkoxy, hydroxyalkyl, halogen, X-CHR9-(CHR10)m-, m = 0 or 1, R9and R10is hydrogen or alkyl

The invention relates to medicine, in particular to the composition and method of receiving anticonvulsant and psychotropic drugs

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

Sweetening tool // 2230552
The invention relates to the medical industry, namely the production of therapeutic and medicinal products containing saccharin and used as a sweetener in diet and diabetic diet designed to prevent diseases, diabetes, atherosclerosis, obesity and combat obesity

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to new chemical compounds derived from anthra[2,1-d]isothiazol-3,6,11-trione General formula I, where a is the lowest alkylene, R1and R2(independent) - lower alkyl, or R1and R2together with the nitrogen atom form a six-membered saturated, a heterocycle, which may optionally contain a heteroatom such as oxygen atom, and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzothiazole General formula (I) or its salt, where p denotes 1; X1and X2together form =O; R1denotes hydrogen, halogen, alkyl, alkoxy; R2denotes hydrogen; R3denotes a-Z4-R6, -Z13-NR7R8; Z4denotes a-Z11-C(O)-Z12-, -Z11-C(O)-O-Z12-; Z11and Z12represent a simple bond or alkylene; Z13denotes a-Z11-C(O)-Z12-; R4denotes hydrogen; R5denotes phenyl, substituted groups Z1, Z2selected from alkyl, halogen, nitro, -HE, hydroxyalkyl, -C(O)Z6, -C(O)OZ6-Z4-NZ7Z8where Z4represents a simple bond; biphenyl, substituted alkyl; naphthalenyl, which optionally can be substituted-HE; chinoline, substituted alkyl; heterocyclics; Z6denotes alkyl which may be optionally substituted by a group-Z4-NZ7Z8, morpholinium; Z7, Z8each independently represents alkyl; R6denotes alkyl optionally substituted by cyano, methoxy, phenyl, -Z4-NZ7Z8and so on; R7denotes hydrogen, alkyl; R8denotes alkyl, the long is Z4-NZ7Z8; and t

The invention relates to a derivative of sulfoaluminate and sulphoniumhydroxide acid of formula I, its pharmaceutically acceptable salts, where W is-HE-or-NHOH; X denotes (a) a heterocyclic radical selected from the group comprising imidazolines, dihydrobenzofuranyl and so on, b) -NR1SO2R2where R1denotes a hydrogen atom, R2denotes an unsubstituted phenylalkyl and so on; Y represents carbon or sulfur, with the proviso that when Y represents carbon, n is equal to 2; Z represents phenyl, optionally substituted with halogen, unsubstituted alkoxy, phenyloxy, optionally substituted with halogen, phenylacetonitrile, 4-methylpiperazine, 4-phenylpiperidine, pyridyloxy, -NR'1COR'2, -SO2R'2where R'1denotes a hydrogen atom, R'2denotes phenyl, optionally substituted by hydroxy or phenyl, pyridinyl, substituted-CF3; m denotes an integer from 1 to 4, n represents an integer of 1 or 2
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