1-substituted tetrahydroisoquinoline derivative, based on them pharmaceutical composition and methods of their application. RU patent 2468010.

FIELD: medicine, pharmaceutics.

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

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

15 cl, 129 tbl, 17 ex

The technical field to which the invention relates

The present invention refers to the medicinal product and, particularly, to 1-substituted derivative tetrahydroisoquinoline, which is applicable as an active ingredient in a pharmaceutical composition for prevention and/or treatment of pain, abdominal symptoms, spastic constipatio and irritable bowel syndrome.

The level of technology

Pain is an important mechanism of biological protection, which reflects the emergence of any disease organisms. When pain or dysesthesia still persists, even after tissue injury or disease that causes pain, subjected to treatment, this condition is identified as a disease. Pain in General are classified into nociceptive pain and neuropathic pain. Nociceptive pain involves pain is caused by inflammation of the tissue, the compression of the nerve, induced cancer or the like (inflammatory pain, cancer pain, and so on). Nonsteroidal anti-inflammatory drug (NSAID) or opioids are therapeutically effective for the treatment of nociceptive pain.

On the other hand, neuropathic pain is a chronic pain caused by injury or compression of the nerve tissue, or the like. Symptoms of neuropathic pain include unpleasant dysesthesia, such as continuous or sudden spontaneous pain, numbness, burning sensation, pain experienced when the patient as if cut into small pieces, and pointed pain; state, which is a painful reaction to usually napoletani weak incentive (hyperalgesia); pain due to stimulus that usually does not cause pain (allodynia), such as caused by contact with clothing or changes in temperature, and the like. Specific diseases neuropathic pain include the trigeminal nerve syndrome complex regional pain syndrome after spinal surgery, phantom limb pain, pain after brachial plexus injuries, pain following spinal cord injury, pain after impact, painful diabetic neuropathy, post herpetic neuralgia, HIV-induced neuropathy and, in addition, some cases of cancer pain and lower back pain, which does not have sufficient analgesic action of opioids, in addition to neuropathy induced anti-cancer drugs and medicines against HIV.

Neuropathic pain is known as the pain, the treatment of which NSAID or opioids that are effective in the treatment of nociceptive pain, difficult to achieve therapeutic efficacy. In practical drug therapy pain relief perform hemp, capsaicin cream or intraspinal the introduction of opioids, and antidepressants (DULOXETINE, amitriptyline etc), anti-epileptic drugs (pregabalina, carbamazepine, etc.) or local analgesics (meksiletina etc). Unfortunately, the actions of these drugs is limited because many neuropathic pain are developed through overlapping numerous pathogenic reasons, and some patients have different backgrounds diseases. In addition, there are also problems associated with side effects, characteristic for certain medicines. As a result, there is a huge need in remedy for neuropathic pain, which is more potent and has a wider range of analgesic action and weaker side effects.

The irritable bowel syndrome (IBS) is a syndrome that causes abdominal symptoms such as abdominal pain and bloating, and violations of the chair, such as diarrhoea or a sudden urge to defecate and a higher or difficulty in urinating due to dysfunction of the lower digestive tract about colon, despite the absence of organic changes, such as inflammation and swelling. Depending on the dominant features of the chair, IBS in General subclassification on IBS type of diarrhea (IBS-D), IBS type of constipatio (IBS-C) and IBS mixed type (IBS-M) with alternating diarrhea and higher Gastroenterology 130: 1377-90, 1480-91 (2006)). As means of drug therapy for IBS here you can specify anticholinergic medications for abdominal pain, tricyclic antidepressants (TCA) for improvement (increase) of low threshold of pain sensitivity of the digestive tract and in case of violation of intestinal peristalsis, anti-diarrhoea or gastrointestinal drugs against diarrhea and salt laxatives against konstitutsii, which are the only means allopathic therapies and are also unreliable in their actions (irritable bowel syndrome ~ communication between the brain and gastrointestinal (ISBN4-521-67671-5, 2006)).

As medicines, which recently attracted attention, you can specify alosetron, which is an antagonist of 5-HT 3-receptor, and Tegaserod, which is an agonist of 5-HT 4-receptor, they are used for IBS-D and IBS-C, respectively. However, the use of alosetron limited due to the prevalence of constipatio at 30-35% of patients in combination with serious side effects of ischemic colitis (including fatal cases), even though it shows a relatively high degree of improvement, from 40% to 60%, abdominal symptoms and diarrhea (Drug Today 36: 595-607 (2000), FDA information about lotronex, GlaxoSmithKline press release). Moreover, it is specified that Tegaserod has a minor effect on abdominal symptoms due to a slight weakening the higher-actions that can lead to the risk of occurrence of tahiphylacsii (the phenomenon of inducing resistance to the drug after repeatedly injected doses over a short period of time) (Clinical Therapeutics 25: 1952-1974 (2003)). In addition, the use of Tegaserod severely limited from the point of view of side effects due to existing negative actions on the cardiovascular system (FDA information about zelnorm, Novartis press release).

It is known that opioids, such as morphine, which are usually used as debilitating pain medicines, raise serious dysfunction of the digestive tract, including higher-called opioid dysfunction of the digestive tract (OBD). Among the symptoms OBD have a rapid emergence of constipatio without manifestation of resistance to the drug, unlike other side effects on the Central nervous system induced by opioids, it is therefore necessary to apply the appropriate dose to resolve this problem (American J. Surgery 182: 11S-18S (2001), Jpn. Cancer Chemother. 32: 1377-1383 (2005)). For this reason, in the treatment of opioid, especially patients with cancer pain, essential combined preventive treatment laxative since the introduction of opioid medications, but it is not easy to regulate definatio using laxatives funds (Drugs 63: 649-671 (2003), Pharmacotherapy 22: 240-250 (2002)).

The digestive tract is provided independent neural network, called the ventral nervous system. In the abdominal nervous system there are different types of neurons, they are responsible for regulating the respective functions of the digestive tract. Among these neurons own primary afferent neurons (IPAN) are neurons which are mainly perceived changes in the cavity of the digestive tract. IPAN detects physical or chemical changes in the cavity of the digestive tract and transmit the information of the motor neurons or sensory neurons. Therefore, drugs that alter the activity IPAN, cause changes in the function of the digestive tract, called peristalsis of the bowel, or visceral perception (Progress in Neurobiol. 54: 1-18 (1998)). In addition, on the basis of the fact that CA 2+ channel N-type is expressed in IPAN and promotes activity IPAN (J. Comp. Neurol. 409: 85-104 (1999)), we can assume that the connection blocking CA 2+ -channels N-type, may be applicable in functional diseases of the digestive tract changes in the functions of the digestive tract.

In addition, it is known that the signals abdominal pain, like signals somatic pain, move to the brain through the nerve posterior spinal nerves (DRG) and the spinal cord (Neurogastroentel. Motil. 16: 113-124 (2004)). This way of signaling hipersensibilidad in patients with IBS, suggesting significant manifestation of abdominal symptoms (Gut 53: 1465-1470 (2004)). It is therefore expected that the blocker CA 2+ channel N-type involved in the transmission of pain signals, can be an effective therapeutic agent against abdominal symptoms of IBS. In fact, described that gabapentin or pregabalin, which is a ligand for α2δ-subunit CA 2+ channel, has analgesic actions in animal models of hypersensibility abdominal pain (J. Pharmacol. Exp. Ther. 295: 162-167 (2000), Anesthesiology 98: 729-733 (2003)).

In the cells there are many types of CA 2+ -dependent functional protein, and changes in the concentration of intracellular CA 2+ play an important role in the emergence or regulation of physiological functions, such as neuronal viability, synaptic plasticity and expression of the gene. Among CA 2+ -channels present on the cell membrane, the channel using membrane potential as a trigger at the opening of the channel, called potential-dependent CA 2+ -channel (VDCC), which consists primarily A1-subunit, forming the body of the channel, beta-subunit regulating the expression level A1-subunit or function of the channel and α2δ-subunit (Trends Neurosci. 21 148-154 (1998)). Ca 2+ -channels are classified into Ca 2+ -channels with high potential of activation threshold, such as channels L-type (α1S, C, D, and F), P/Q-type (α1A), N-type (α1B) and R-type (α1E); and Ca 2+ -channels with low potential of activation threshold, such as canals T-type (α1G, H, I), depending on the type A1-subunit and capacity of activation threshold (Rev. Physiol. Biochem. Pharmacol. 139: 33-87 (1999)).

Among CA 2+ -channels with high potential of activation threshold CA 2+ -channels PQ-, N - and R-type present in the synaptic terminala neurons, and serve as the trigger the secretion of neurotransmitters. In particular, Ca 2+ channel N-type much is expressed in the ganglia of the back of the spinal nerve roots (DRG) (J. Neurosci. 15: 4315-4327 (1995)), which is the crush of bodies of cells of the sensory neurons, or posterior horn of the spinal cord (J. Neurosci. 18: 6319-6330 (1998)), which is the area of synaptic ledge sensory neurons. In addition, the back horn of the spinal cord rat models of neuropathic pain found an increased expression of CA 2+ channel N-type synchronous with the development of hyperplasia (Exp. Brain Res. 147: 456-463 (2002)). On the basis of these facts is that the CA 2+ channel N-type plays the role of a trigger that sends excess of pain signals to the brain.

Based on recent surveys that show that the blocking Ca 2+ channel N-type selective peptide, V-conotoxin (W-CTx), shows the analgesic action of a wide range in animal models nociceptive, inflammatory and neuropathic pain, respectively (J. Pharmacol. Exp. Ther. 279: 1243-1249 (1996), J. Pharmacol. Exp. Ther. 287: 232-237 (1998), J. Pharmacol. Exp. Ther. 269: 1117-1123 (1994)) and that is not the case neuropathic pain in mice with a deficit α1B (EMBO J. 20: 2349-2356 (2001)), it is estimated that Ca 2+ channel N-type takes a deep participation in the pathogenesis of neuropathic pain. Indeed, it has been described that the permanent spinal introduction of ziconotide (W-conotoxin MVIIA:V-CTxMVIIA) through implanted pump improves the condition of hyperalgesia and allodinia from immune to morphine patients with neuropathic pain (Clin. J. Pain 13: 256-259 (1997)). In addition, it was shown that gabapentin or pregabalin often used as a means acting against neuropathic pain, binds with high affinity with α2δ-subunit CA 2+ channel, thereby showing analgesic action (J. Pharm. Sci. 100: 471-486 (2006)). According to these discoveries, it is assumed that the blocker Ca 2+ channel N-type is excellent therapeutic tool against pain, especially neuropathic pain. In addition, based on the fact that CA 2+ channel N-type participates in hyperactivity neuronal cell death and the like, it is assumed that the blocker CA 2+ channel N-type is applicable to prevent or treat conditions or diseases associated with activation of CA 2+ channel N-type, in addition to the above pain. In General, it is considered that the connection with the action, blocking CA 2+ channel N-type, can be applied at various pains like neuropathic pain and nociceptive pain, headaches such as migraine and cluster headache, diseases of the Central nervous system, such as anxiety, depression, epilepsy, cerebral stroke and tired leg syndrome, diseases of the digestive system, such as abdominal pain and irritable bowel syndrome and diseases of the urinary tract, such as overactive bladder and interstitial cystitis.

To date, the described connections, blocking CA 2+ -channels N-type. For example, it has been described that the following derivative benzazepines have a blocking action on Sa 2+ -channels N-type and are applicable as a means for preventing and/or treating cerebral infarction, transient disturbance of cerebral circulation, encephalomyelopathy after surgery on the heart, vascular disorders of the spinal cord-induced stress, hypertension, anxiety, epilepsy, asthma, frequent urination and eye diseases, or as medicines for pain (patent document 1).

[Chemical compound 1]

(See in the above document, the values for characters in the formula).

However, there is no specific description of the 1-substituted derivative tetrahydroisoquinoline, which refers to the present invention.

Further, it has been described that the following derivative diarylethene or diarylethene have a blocking action on Sa 2+ -channels N-type and are applicable for the treatment of pain, heart attack brain, cerebral disorders caused acute ischemia after the beginning of intracerebral hemorrhage, Alzheimer's disease associated with AIDS dementia, Parkinson's disease, a progressive degenerative brain diseases, neurological disorders caused by head injury, bronchial asthma, unstable angina, inflammatory diseases irritated colon and withdrawal symptoms excessive use of drugs (patent document 2).

[Chemical compound 2]

(See in the above document, the values for characters in the formula).

However, there is no specific description of the 1-substituted derivative tetrahydroisoquinoline, which refers to the present invention.

Further, it has been described that the following tricyclic heteroaromatic compounds have a blocking action on Sa 2+ -channels N-type and are applicable as medicines, especially analgesic funds (patent document 3)

[Chemical compound 3]

(See in the above document, the values for characters in the formula).

However, there is no specific description of the 1-substituted derivative tetrahydroisoquinoline, which refers to the present invention.

Further, it has been described that the following azetilirovanie are applicable for the treatment or prevention of diseases associated with the flow of sodium ions channel sensory neurons, such as pain, such as chronic and acute pain, allergic diseases, such as diseases of the bladder and irritable bowel syndrome, and danielraysir diseases (patent document 5).

[Chemical compound 5]

(See in the above document, the values for characters in the formula).

However, there is no specific description of the 1-substituted derivative tetrahydroisoquinoline, which refers to the present invention.

Further, it has been described that the following compounds have inhibitory farnesyltransferase activity and are applicable as anticancer agents (patent document 6).

[Chemical compound 6]

(See in the above document, the values for characters in the formula).

However, there is no specific description of the 1-substituted derivative tetrahydroisoquinoline, which refers to the present invention. Moreover, there is no description or assumptions about them blocking the action on Sa 2+ -channels N-type, their effect on pain, including neuropathic pain and diseases of the digestive system, including irritable bowel syndrome.

Further, it has been described that the following compounds have antiarrhythmic action (non-patent document 1).

[Chemical compound 7]

(See in the above document, the values for characters in the formula).

However, English Abstract belonging to the above document does not contain a specific description of the 1-substituted derivative tetrahydroisoquinoline, which refers to the present invention. Moreover, there is no description or assumptions about them blocking the action on Sa 2+ -channels N-type, their effect on pain, including neuropathic pain, and diseases of the digestive system, including irritable bowel syndrome.

Further, it has been described that the following compounds have antiarrhythmic action (non-patent document 2).

[Chemical compound 8]

(See in the above document, the values for characters in the formula).

However, English Abstract belonging to the above document does not contain a specific description of the 1-substituted derivative tetrahydroisoquinoline, which refers to the present invention. Moreover, there is no description or assumptions about them blocking the action on Sa 2+ -channels N-type, their effect on pain, including neuropathic pain, and diseases of the digestive system, including irritable bowel syndrome.

Further, it has been described that the following compounds have a blocking action on Sa 2+ -channels and are applicable as gipotenziveh funds and antiarrhythmic drugs (non-patent document 3).

[Chemical compound 9]

(See in the above document, the values for characters in the formula).

However, English Abstract belonging to the above document does not contain a specific description of the 1-substituted derivative tetrahydroisoquinoline, which refers to the present invention. Moreover, there is no description or assumptions about them blocking the action on Sa 2+ -channels N-type, their effect on pain, including neuropathic pain, and diseases of the digestive system, including irritable bowel syndrome.

Further, it has been described that the following compounds have a blocking action on Sa 2+ -channels, blocking action on Na + channels, and inhibiting calmodulin activity and might be applicable in neuroprotective therapy (non-patent documents 4 and 5).

[Chemical compound 10]

(See in the above document, the values for characters in the formula).

However, there is no specific description of the 1-substituted derivative tetrahydroisoquinoline, which refers to the present invention.

Next, have been described following compounds as the receptor antagonist orexin-2 (non-patent document 6). In addition, it was also suggested that the receptor orexin-2 participates in the transfer of nociceptive stimuli.

[Chemical compound 11]

(IU in the formula is a methyl).

However, there is no specific description of the 1-substituted derivative tetrahydroisoquinoline, which refers to the present invention.

As other links that describe the connection with the skeleton of tetrahydroisoquinoline, there are patent documents 7-9. However, these documents do not contain a specific description of the 1-substituted derivative tetrahydroisoquinoline, which refers to the present invention.

[Patent document 1] JP-A-2002-363163.

[Patent document 2] Bulletin of the international publication No. WO 03/018538.

[Patent document 3] Bulletin of the international publication No. WO 2004/089950.

[Patent document 4] Bulletin of the international publication No. WO 2005/021523.

[Patent document 5] Bulletin of the international publication No. WO 2005/005392.

[Patent document 6] Laid the publication of a European patent application No. EP 0696593.

[Patent document 7] Bulletin of the international publication No. WO 01/85693

[Patent document 8] Bulletin of the international publication No. WO 02/079189.

[Patent document 9] Bulletin of the international publication No. WO 03/082828.

[Non-patent document 1] Fudan University Journal of Medical Science, 1987, 14(1), 15-20.

[Non-patent document 2] Fudan University Journal of Medical Science, 1989, 16(1), 71-74.

[Non-patent document 3] Journal of China Pharmaceutical University, 1993, 24(4), 193-201.

[Non-patent document 4] Biological & Pharmaceutical Bulletin, 2000, 23(3), 375-378.

[Non-patent document 5] Neurochemical Research, 2003, 28(12), 1813-1818.

[Non-patent document 6] Bioorganic & Medicinal Chemistry Letters, 2003, 13(24), 4497-4499.

Description of invention

The problem which must be solved by the invention

The present invention is the provision of drugs having selective blocking action on Sa 2+ -channels N-type, and especially the connection applicable as an active ingredient in a pharmaceutical composition for prevention and/or treatment of pain and irritable bowel syndrome.

The connection of the present invention is a structural characteristic that in formula (1) at least one of the 1a R and R 1b is a Deputy different from the-N and R-22 is a hydroxyl-containing Deputy. In addition, the connection of the present invention has pharmacological properties manifested in the fact that it has the effect of blocking CA 2+ -channels N-type, action against nociceptive pain, action against neuropathic pain, action, inhibiting abdominal pain, and action, improves the state of constipatio induced by opioids.

The way of solving problems

As a result of intensive studies compounds with selective blocking action on Sa 2+ -channels N-type, the authors of the present invention found that the 1-substituted derivative tetrahydroisoquinoline the present invention has effect, selectively blocking CA 2+ -channels N-type, action against nociceptive pain, action against neuropathic pain, action, inhibiting abdominal pain, and action, improves the state of constipatio induced by opioids. The present invention has been completed based on the obtained data.

Then there is the present invention relates to the compound of formula (I) or pharmaceutically acceptable salts and pharmaceutical compositions containing the compound of formula (I) or pharmaceutically acceptable salt and pharmaceutically acceptable excipients.

The compound of formula (I)

[Chemical compound 12]

where the characters in the formula have the following meanings:

R 1a and R 1b are the same or different and are a-H, C 1-6 alkyl that can be substituted, cycloalkyl that can be substituted, aryl, which may be replaced, or aromatic heterocycle that can be substituted, when both of 1a R and R 1b cannot be-H, and R 1a and R 1b , together with the carbon atom to which they are attached, can be cycloalkyl that can be substituted,

R 3a , R 3 , R 4 a and R 4b are the same or different and are a-H or C 1-6 alkyl,

R 5 R 6 -, R-7 and R 8 are the same or different and are a-H, C 1-6 alkyl that can be substituted, -O-(C 1-6 alkyl), which can be substituted, cyano, carbarnoyl that can be substituted for one or two C 1-6 alkelai, or a halogen, and any two neighbouring group R 5 R 6 -, R-7 and R 8 taken together, may form-O-CH 2-O or O-(CH 2 ) 2-O,

R 11 R 12 R 13 R 14 , and R R 15 16 are the same or different and are a-H or C 1-6 alkyl,

R 21 is a-H, C 1-6 alkyl that can be substituted, or cycloalkyl that can be substituted,

R-22 is a

(1) cicloalchil, which is replaced by one or more groups selected from the group consisting of-OH-CH 2 OH, and can be optionally substituted;

(2) (C 1-8 alkyl substituted one or two-OH, where C 1-8 alkyl may have additional Deputy, and one or two methylene groups (-CH 2 -)contained in this alkyl chains, can be replaced with-O-; or

(3) 1-6 C alkyl substituted by cicloalchil, which is replaced by one or more groups selected from the group consisting of-OH-CH 2 OH, and can be optionally substituted, where C 1-6 alkyl can be substituted-OH, and one or two of methylene groups (-CH 2 -)contained in this alkyl chains, can be replaced with-O-;

n and m are the same or different and equal to 0 or 1,

R 12 and R 21 , taken together, can form methylene ethylene or trimethylene and R 11 may be a-OH, or

R 21 R 22 , taken together with the nitrogen atom to which they are attached, can form azetidin, pyrrolidin, piperidine, ASEAN, asokan, morpholine, tetrahydroisoquinoline or thiomorpholine, which substituted-OH or C 1-6-alkyl substituted-OH; or pharmaceutically acceptable salt.

Connection according to [1], where m is 0, n = 0 and each of the R 1a R 3a , R 3b , R 4a , R 4b , R 11 R 12 and R 21 is a-N, or pharmaceutically acceptable salt.

Connection according to [2], where R 1b is an isopropyl, methoxymethyl, phenyl, 2-(trifluoromethyl)benzyl or cyclohexyl, or pharmaceutically acceptable salt.

Connection according to [2] or [3], where R 5 R 6 -, R-7 and R 8 are the same or different and independently selected from the group consisting of Mr., methyl, ethyl, methoxy and fluorine or its pharmaceutically acceptable salt.

Connection according to [2], [3] or [4], where R-22 is a 2-hydroxypropane-1-Il, 2-hydroxy-3-methoxypropan-1-yl or (1-hydroxycyclohexyl)methyl, or pharmaceutically acceptable salt.

Connection according to [1], which is a

1-[({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

(2S)-1-({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)-3-methoxypropan-2-ol,

1-({[2-(1(1S)-isopropyl-6-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

(2R)-1-({2-[(1S)-8-methoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)propan-2-ol,

1-[({2-[(1R)-7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

(2S)-1-methoxy-3-[(2-oxo-2-{1(1S)-[2-(trifluoromethyl)benzyl]-3,4-dihydroisoquinoline-2(1H)-yl}ethyl)amino]propan-2-ol,

1-({[3-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-3-oxopropyl]amino}methyl)cyclohexanol,

(2R)-1-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}propan-2-ol,

(2R)-1-[(2-oxo-2-{1-[2-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-yl}ethyl)amino]propan-2-ol,

(2S)-1-{[2-(1-cyclohexyl-7-methyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}-3-methoxypropan-2-ol,

(2R)-1-({2-oxo-2-[(1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-Il]ethyl}amino)propan-2-ol,

1-[({2-[7-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

1-[({2-[7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

1-({[2-(1-isopropyl-6-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

1-[({2-[5-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

1-[({2-[1-(methoxymethyl)-6-methyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

(1S,2S)-2-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}-1-phenylpropane-1,3-diol,

1-({(2R)-2-[(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)carbonyl]pyrrolidin-1-yl}methyl)cyclohexanol,

(2R)-1-{[2-(1-cyclohexyl-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}propan-2-ol,

1-({[2-(3',4'-dihydro-2'H-Spiro[cyclohexane-1,1'-isoquinoline]-2'-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

(2R)-1-[(2-oxo-2-{1-[2-(cryptonetx)phenyl]-3,4-dihydroisoquinoline-2(1H)-yl}ethyl)amino]propan-2-ol,

(2R)-1-{[2-(1-cyclohexyl-7-ethyl 3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}propan-2-ol,

1-({[2-(6-fluoro-1-isopropyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

1,1-dicyclopropyl-2-({2-[6-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)ethyl alcohol

1-({[2-(1-tert-butyl-8-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

1-({[2-(1-isopropyl-6-methyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

1-({[2-(6-fluoro-1-propyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

1-[({2-[1-(methoxymethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

1-({[2-(5-fluoro-1-propyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

1-[({2-[5-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

1-[({2-[8-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

1-[({2-[1-(ethoxymethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]or cyclohexanol

(1R,2S)-2-({2-[(1R)-1-(2-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)Cyclopentanol or pharmaceutically acceptable salt.

The pharmaceutical composition containing the connection [1] or pharmaceutically acceptable salt and pharmaceutically acceptable excipients.

Blocker CA 2+ channel N-type containing the connection [1] or pharmaceutically acceptable salt.

The pharmaceutical composition for prevention or treatment of pain, neuropathic pain, abdominal symptom, spastic constipatio induced opioid konstitutsii, irritable bowel syndrome or irritable bowel syndrome type of constipatio containing the connection [1] or its pharmaceutically acceptable salt.

The pharmaceutical composition according to [9], which is a pharmaceutical composition for prevention or treatment of pain.

The pharmaceutical composition according to [10], which is a pharmaceutical composition for prevention or treatment of neuropathic pain.

The pharmaceutical composition according to [9], which is a pharmaceutical composition for prevention or treatment of abdominal symptom.

The pharmaceutical composition on [9], which is a pharmaceutical composition for prevention or treatment of spastic constipatio.

The pharmaceutical composition on [13], which is a pharmaceutical composition for prevention or treatment of opioid induced constipatio.

The pharmaceutical composition on [9], which is a pharmaceutical composition for prevention or treatment of irritable bowel syndrome.

The pharmaceutical composition on [15], which is a pharmaceutical composition for prevention or treatment of irritable bowel syndrome type of constipatio.

The pharmaceutical composition containing the connection [1] or pharmaceutically acceptable salt and opioid as active ingredients.

The pharmaceutical composition containing the connection [1] or pharmaceutically acceptable salt as the active ingredient, where the composition is used in combination with opioid.

Application of compounds [1] or pharmaceutically acceptable salts for the manufacture of pharmaceutical composition for prevention or treatment of pain, neuropathic pain, abdominal symptom, spastic constipatio induced opioid konstitutsii, irritable bowel syndrome or irritable bowel syndrome type of constipatio.

The connection [1] for use as an active ingredient in a pharmaceutical composition for prevention or treatment of pain, neuropathic pain, abdominal symptom, spastic constipatio induced opioid konstitutsii, irritable bowel syndrome or irritable bowel syndrome type of constipatio.

Method of prevention or treatment of pain, neuropathic pain, abdominal symptom, spastic constipatio induced opioid konstitutsii, irritable bowel syndrome or irritable bowel syndrome type of konstitutsii, containing an introduction to the patient effective number of connections [1] or pharmaceutically acceptable salts.

In addition, the present invention relates to pharmaceutical compositions for treatment of pain, in a certain variant the implementation of neuropathic pain; abdominal symptoms; spastic konstitutsii, in a certain variant of the implementation of opioid induced constipatio; or irritable bowel syndrome, in a certain embodiment of irritable bowel syndrome type of constipatio containing compound of formula (I) or pharmaceutically acceptable salt, i.e. pharmaceutical composition for prevention and/or treatment of pain, in a particular embodiment, neuropathic pain; abdominal symptoms; spastic konstitutsii, in a particular embodiment, induced opioid constipatio; or irritable bowel syndrome, in a certain embodiment of irritable bowel syndrome type of constipatio containing compound of formula (I) or pharmaceutically acceptable salt.

Further, the present invention relates to the application of the compounds of formula (I) or pharmaceutically acceptable salts for the manufacture of pharmaceutical compositions for treatment of pain, in a particular embodiment, neuropathic pain; abdominal symptoms; spastic konstitutsii, in a certain variant of the implementation of opioid induced constipatio; or irritable bowel syndrome, in a certain embodiment of irritable bowel syndrome type of konstitutsii, and method of treatment of pain, in a particular embodiment, neuropathic pain; abdominal symptoms; spastic konstitutsii, in a certain variant of the implementation of opioid induced constipatio; or irritable bowel syndrome, in a certain embodiment of irritable bowel syndrome type of konstitutsii, containing an introduction to the patient effective number of compounds of formula (I) or pharmaceutically acceptablesalt.

The validity of a patent

The connection of the present invention can be used as a pharmaceutical composition for prevention and/or treatment of various pains like neuropathic pain and nociceptive pain, headaches such as migraine and cluster headache, diseases of the Central nervous system, such as anxiety, depression, epilepsy, cerebral stroke and tired leg syndrome, abdominal symptoms such as abdominal pain and bloating, violations of the chair, such as diarrhoea and higher, diseases of the digestive system, such as irritable bowel syndrome, diseases of the urinary tract, such as overactive bladder and interstitial cystitis, etc.

The best way of carrying out the invention

In the future, the present invention will be described in detail.

In definitions of the present description “From 1-6 alkyl“ means unbranched or branched alkyl, with 1 to 6 carbon atoms, and his examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl n-pentyl, n-hexyl and the like. “With 1-8 alkyl“ means unbranched or branched alkyl, having 1-8 of carbon atoms, and his examples include n-heptyl, n-octyl, Diisopropylamine and the like, in addition to the above With 1-6 Akilov.

“Halogen“ means F, Cl, Br, or I.

“Cycloalkyl” is a group of saturated With 3-10 hydrocarbon rings and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepten, cicloalchil, substituted, and the like. It also includes cyclohexenyl, cyclooctadiene and the like, which contains partially unsaturated bond. In addition, it also includes groups that have one or two methylene groups in the ring is replaced by, for example, tetrahydropyranyl, tetragidrofurane and the like. Next, his ring can be condensed with benzene ring and his examples include indenyl, indanyl, dihydronaphtho and tetrahydronaphtyl.

“Aryl” is a group from monocyclic to tricyclic, aromatic With 6-14 hydrocarbon ring and his examples include phenyl, naphthyl and the like.

“Aromatic heterocycle” is a group of 5 - or 6-membered monocyclic of heterocycle containing 1-3 heteroatoms selected of oxygen, sulphur and nitrogen, and his examples include furyl, tienil, pyrrolyl, pyrazolyl, imidazolyl, oxazoles, thiazolyl, isothiazolin, triazines, pyridyl, Persil, pyrimidinyl, pyridazinyl and the like.

The expression “may be substituted” means that the group is “unsubstituted or substituted 1-5 deputies that are the same or different.” Also, if it has many deputies, deputies may be the same or different from each other.

Examples-of-office “With 1-6 alkyl, which can be substituted”, in the definition of R 1a and R 1b include-OH; -OR z ; or phenyl that can be substituted for one or more of the same or different groups selected from the group consisting of halogen -, R-Y, and-OR Y . R Y is a C 1-6 alkyl, which can be substituted 1-5 with the halogen's atoms, and R z is a C 1-6 alkyl that can be substituted for one or more of the same or different groups selected from the group consisting of-O-(C 1-6 alkyl) and-OR Y (same definition will be applied in the context of further).

Examples of the Deputy for the “cycloalkyl that can be substituted”, in the definition of R 1a and R 1b include-OH, halogen, R Y and-OR Y .

Examples of the Deputy for the “aryl, which may be substituted”and “aromatic heteroclite that can be substituted”, in the definition of R 1a and R 1b include-OH, halogen, R Y , -OR Y-SR Y-cyano and cycloalkyl.

Examples Deputy for “C 1-6 alkyl, which can be substituted”and “-O-(C 1-6 alkyl), which can be substituted”, in the definition of R 5 R 6 -, R-7 and R 8 include-OH, halogen, -OR Y-NHCO-(C 1-6 alkyl).

Examples Deputy for “C 1-6 alkyl, which can be substituted”, in the definition of R 21 include-OH, halogen, -OR Y and cycloalkyl.

Examples of the Deputy for the “cycloalkyl that can be substituted”, in the definition of R 21 include-OH, halogen, R Y and-OR Y .

“Cicloalchil, which is replaced by one or more groups selected from the group consisting of HE and CH 2 HE, and which can be optionally substituted”, in the definition of R 22 means that cycloalkyl has at least one or more of the same or different groups selected from the group consisting of-OH

and-CH 2 OH, as deputies and can optionally be replaced by other deputies. Examples of acceptable additional deputies include halogen, R Y , -OR Y , oxo (=O) and oxo-protected glycol.

“C 1-8 alkyl substituted one or two-OH, where C 1-8 alkyl can optionally have a Deputy and one or two of methylene groups (-CH 2 -)contained in this alkyl chain, may be replaced with the-O”, in the definition of R 22 means that methylene group(s) in the alkyl chain C 1-8 alkyl can be changed with the-O-, and C 1-8 alkyl has at least one or two-OH as Vice and can optionally be replaced by other deputies. Examples of acceptable additional Deputy include halogen; -OR Y ; cycloalkyl or aryl, which may be substituted for one or more of the same or different groups selected from the group consisting of-OH, Halogens R Y and-OR Y .

“C 1-6 alkyl substituted by cicloalchil, which is replaced by one or more groups selected from the group consisting of HE and CH 2 HE, and which can be optionally substituted, where C 1-6 alkyl can be substituted-OH, and one or two of methylene groups (-CH 2 -)contained in this alkyl chains, can be replaced-O”, in the definition of R 22 means, what 1-6 alkyl can be substituted-HE, methylene group(s) in the alkyl chain can be replaced, and 1-6 alkyl has at least cycloalkyl that can be substituted, as Deputy. Cycloalkyl as Deputy C 1-6 alkyl has at least one or more of the same or different groups selected from the group consisting of-OH-CH 2 OH, as Vice, and can optionally be replaced by other deputies. Examples of acceptable additional deputies include halogen, R Y , -OR Y , oxo (=O) and oxo-protected glycol.

“Pain” means different pain, including nociceptive pain and neuropathic pain.

“Nociceptive pain is a pain that is caused by increase of nociceptive stimuli through nociceptors, and examples include pain caused by tissue damage, the pain is caused by inflammation of the tissue (inflammatory pain), pain caused by compression of a nerve, induced cancer (cancer pain).

“Neuropathic pain” is a chronic pain that is caused by damage or compression of the nerve tissue or the like, and examples include the trigeminal nerve syndrome complex regional pain syndrome after spinal surgery, phantom limb pain, pain after brachial plexus injuries, pain following spinal cord injury, pain after impact, painful diabetic neuropathy, post herpetic neuralgia, HIV-induced neuropathy and, in addition, some cases of cancer pain and lower back pain, which does not have sufficient analgesic action of opioids, in addition to neuropathy induced anti-cancer drugs and medicines against HIV.

“Spastic a higher” is a higher-caused spastic dysmotility digestive tract, and examples include opioid induced a higher and higher, find out when irritable bowel syndrome type of constipatio (IBS-C).

“Opioid induced a higher” means a higher-caused by opioids such as morphine.

“Irritable bowel syndrome is a condition that causes abdominal symptoms such as abdominal pain and bloating, and violations of the chair, such as diarrhoea or a sudden urge to defecation and a higher or difficulty in urinating due to dysfunction of the lower digestive tract about colon, despite the absence of organic changes, such as inflammation and swelling, and the like, and is a disease that is classified for IBS type of diarrhea (IBS-D), IBS type of constipatio (IBS-C) and IBS mixed type (IBS-M) with alternating diarrhea and higher, depending on the state of the intestine.

In the future, will be described in some embodiments of the present invention.

(1) In one embodiment, a compound of formula (I)where R 1a is a-N or With 1-6 alkyl that can be substituted. In another embodiment, compound, which R 1a is a-N or methyl. In another embodiment, compound, which 1a R is a

(2) In one embodiment, a compound of formula (I)where R 1b is 1-6 alkyl that can be substituted, cycloalkyl that can be substituted, or aryl, which may be substituted. In another embodiment, compound, which R 1b is an n-propyl, isopropyl, tert-butyl, methoxymethyl, ethoxymethyl, phenyl, 2-methoxyphenyl, 2-(trifluoromethyl)phenyl, 2-(cryptonetx)phenyl, 2-(trifluoromethyl)benzyl or cyclohexyl. In another embodiment, compound, which R 1b is an isopropyl, methoxymethyl, phenyl, 2-(trifluoromethyl)benzyl or cyclohexyl.

(3) In one embodiment, a compound of formula (I)where R 1a and R 1b, together with the carbon atom to which they are attached, are cycloalkyl that can be substituted. In another embodiment, compound, which 1a R and R 1b, together with the carbon atom to which they are attached, are cyclohexyl.

(4) a Compound of formula (I)that each of the R 3a , R 3 , R 4 a and R 4b is a-N.

(5) In one embodiment, a compound of formula (I), where m is 0 and n is 0 or 1. In another embodiment, compound, which m is 0 and n is 0.

(6) In one embodiment, a compound of formula (I)where R 5 R 6 -, R-7 and R 8 are the same or different and independently selected from the group consisting of the-H C 1-6 alkyl-O-(C 1-6 alkyl) and halogen-free. In another embodiment, compound, which R 5 R 6 -, R-7 and R 8 are the same or different, and selected from the group consisting of the-H methyl, ethyl, methoxy and fluorine.

(7) Compound of formula (I)that each of the R 11 R 12 R 13 R 14 , and R R 15 16 is a-H.

(8) In one embodiment, a compound of formula (I), where m is 0, n = 0, R 11 is a-H and R-12 and R 21 , taken together, represent methylene ethylene or trimethylene. In another embodiment, compound, which m is 0, n = 0, R 11 is a-H and R-12 and R 21 , taken together, represent trimethylene.

(9) Connection, which R 21 is a-N.

(10) In one embodiment, compound, which R-22 is cicloalchil, replaced by one or more groups selected from the group consisting of-OH-CH 2 OH. In another embodiment, compound, which R-22 is cyclopentyl or cyclohexyl, replaced by one or more groups selected from the group consisting of-OH-CH 2 OH. In another embodiment, compound, which R-22 is a 2-hydroxycyclohexyl.

(11) In one embodiment, compound, which R-22 is a C 1-8 alkyl, which is replaced by one or two-OH, and optionally substituted by one or more of the same or different groups selected from the group consisting of-O-(C 1-6 alkyl), cycloalkyl and aryl. In another embodiment, compound, which R-22 is a C 1-8 alkyl, which is replaced by one or two-HE and optionally substituted by one or more groups selected from the group consisting of methoxy, cyclopropyl and phenyl. In the next version of the implementation of the compound, which R 22 is an ethyl or propyl, which is replaced by one or two-HE and optionally substituted by one or more groups selected from the group consisting of methoxy, cyclopropyl and phenyl. One more variant of implementation, compound, which R-22 is a 2-hydroxypropane-1-Il, 2-hydroxy-3-methoxypropan-1-Il, 1,3-dihydroxy-1-phenylpropane-2-yl or 2-hydroxy-2,2-dicyclopropyl. One other variant of implementation of the compound, which R-22 is a 2-hydroxypropane-1-yl or 2-hydroxy-3-methoxypropan-1-Il.

(12) In one embodiment, compound, which R-22 is a C 1-6 alkyl substituted by cicloalchil, which is replaced by one or more groups selected from the group consisting of-OH-CH 2 OH. In another embodiment, compound, which R-22 is cyclohexylmethyl, substituted-OH. In another embodiment, compound, which R-22 is a (1-hydroxycyclohexyl)methyl.

(13) In one embodiment, the connection specified in (10), (11) or (12). In another embodiment, the connection specified in (11) or (12).

(14) Connection, which is a combination of any two or more connections, selected from the group consisting of(1), (2), (4), (5), (6), (7), (9) and (13).

(15) the Connection, which is a combination of any two or more connections, selected from the group consisting of(3), (4), (5), (6), (7), (9) and (13).

(16) the Connection, which is a combination of any two or more connections, selected from the group consisting of(1), (2), (4), (6), (8) and (13).

(17) the Connection, which is a combination of any two or more connections, selected from the group consisting of (3), (4), (6), (8) and (13).

(18) In one embodiment, the connection that is any of the connections (14)-(17). In another embodiment, the connection specified in (14).

(19) the Connection, which is a combination of any two or more compounds (1)-(12)that are not incompatible with each other.

Examples of the compounds included this connection include the following connections:

1-[({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

(2S)-1-({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)-3-methoxypropan-2-ol,

1-({[2-(1(1S)-isopropyl-6-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

(2R)-1-({2-[(1S)-8-methoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)propan-2-ol,

1-[({2-[(1R)-7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

(2S)-1-methoxy-3-[(2-oxo-2-{1(1S)-[2-(trifluoromethyl)benzyl]-3,4-dihydroisoquinoline-2(1H)-yl}ethyl)amino]propan-2-ol.

Another option connections, which are included in the present invention, you can specify the following connection:

1-({[3-(1-cyclohexyl-3,4-the dihydroisoquinoline-2(1H)-yl)-3-oxopropyl]amino}methyl)cyclohexanol,

(2R)-1-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}propan-2-ol,

(2R)-1-[(2-oxo-2-{1-[2-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-yl}ethyl)amino]propan-2-ol,

(2S)-1-{[2-(1-cyclohexyl-7-methyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}-3-methoxypropan-2-ol,

(2R)-1-({2-oxo-2-[(1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-Il]ethyl}amino)propan-2-ol,

1-[({2-[7-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

1-[({2-[7-ethyl-1-(methoxymethyl)-3,4-the dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

1-({[2-(1-isopropyl-6-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

1-[({2-[5-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

1-[({2-[1-(methoxymethyl)-6-methyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

(1S,2S)-2-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}-1-phenylpropane-1,3-diol,

1-({(2R)-2-[(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)carbonyl]pyrrolidin-1-yl}methyl)cyclohexanol,

(2R)-1-{[2-(1-cyclohexyl-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}propan-2-ol,

1-({[2-(3',4'-dihydro-2'H-Spiro[cyclohexane-1,1'-isoquinoline]-2'-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

(2R)-1-[(2-oxo-2-{1-[2-(cryptonetx)phenyl]-3,4-dihydroisoquinoline-2(1H)-yl}ethyl)amino]propan-2-ol,

(2R)-1-{[2-(1-cyclohexyl-7-ethyl 3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}propan-2-ol,

1-({[2-(6-fluoro-1-isopropyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

1,1-dicyclopropyl-2-({2-[6-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)ethyl alcohol

1-({[2-(1-tert-butyl-8-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

1-({[2-(1-isopropyl-6-methyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

1-({[2-(6-fluoro-1-propyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

1-[({2-[1-(methoxymethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

1-({[2-(5-fluoro-1-propyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,

1-[({2-[5-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

1-[({2-[8-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

1-[({2-[1-(ethoxymethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,

(1R,2S)-2-({2-[(1R)-1-(2-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)Cyclopentanol.

The connection of the present invention, in some cases, there may be in the form of other tautomers or geometric isomers, depending on the type of deputies. In this connection can only be described in one form isomers, and the present invention includes these isomers, as well as some form or their mixtures.

In addition, the compound of formula I can be in some cases the asymmetric carbon atoms and axial asymmetry and accordingly it can be in the form of optical isomers, such as the R - and S-shape. All possible mixtures of these optical isomers and dedicated optical isomers included in the present invention.

Further, in the present invention also included pharmaceutically acceptable prodrug the compounds of formula (I). “Pharmaceutically acceptable prolekarstvom” is the connection with the group that can be turned into an amino group, hydroxyl group, carboxyl group, or the like, the connection of the present invention a solvolysis or under physiological conditions. Examples of groups for education prodrugs include groups described, for example, in Prog. Med., 5, 2157-2161 (1985) or Iyakuhin no Kaihatsu (Development of Pharmaceuticals)” (Hirokawa Shoten Ltd., 1990), Vol. 7, “Bunshi Sekkei (Molecular Design)”, pp. 163-198.

Next, the connection of the present invention may form acid-additive salt or salt with the basis, depending on the type of deputies, and such salt is included in the present invention, provided that it is pharmaceutically acceptable salt. In particular, examples of such salts include acid-additive salts of inorganic acids such as hydrochloric acid Hydrobromic acid, uudistoodetena acid, sulphuric acid, nitric acid and phosphoric acid, or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, dicloofenac acid, citric acid, methanesulfonate acid, econsultancy acid, benzosulphate acid, para-tauasarova acid, aspartic acid and glutamic acid, inorganic salt grounds such as sodium, potassium, magnesium, calcium and aluminum base, or with organic bases, such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salt with different amino acids, and derivatives of amino acids, such as acetylation, ammonium salt, and the like.

In addition, the present invention includes various hydrates or solvate and crystal polymorphs connection of the present invention, and its pharmaceutically acceptable salts. In addition, at the present invention also included compounds labeled with different radioactive or non-radioactive isotopes.

(Methods of obtaining)

The connection of the present invention, and its pharmaceutically acceptable salt can be obtained through the application of various well-known synthetic methods with the use of performance based on its primary skeleton or the type of deputies. In this case, depending on the type of functional groups, there is effective from the point of view of technology for a way to replace the functional groups with suitable protective group (a group that can easily be turned into a functional group) at the stage of transformation of raw materials into intermediate products. Examples of such protective groups include groups described, for example, in “Protective Groups in Organic Synthesis (3 rd edition, 1999)”, edited by Greene and Wuts, and the like that can properly select and apply depending on the reaction conditions. According to this method, connection required can be obtained by the introduction of protective groups and holding reaction and then, if necessary, removing the protective group.

In addition, the prodrug the compounds of formula (I) can be obtained in the same way as in the case of the above protective bands, the reaction after the introduction of a certain group at the stage of transformation of raw materials into intermediate products or application of the compounds present invention. The reaction can be performed by applying the methods, well-known specialist in this area, such as a normal etherification, amidation, dehydration and the like.

Next will be described representative ways of obtaining connection of the present invention. Each of the ways of getting you to spend according to the references made to the appropriate description. In addition, methods of obtaining of the present invention is not limited to the examples shown below.

(A method of obtaining 1)

[Chemical compound 13]

(In the formula X is a Dating back to the group, and other characters are shown above. The same values will be applied in the future).

This method of production is the way in which connection (I) of the present invention get a reaction connection (1a), Dating back with the group, with the derived Amin (1b).

In this case examples leaving groups include halogen, methanesulfonate and para-colorcontrols.

The reaction can be performed with the use of connection (1A) (1b) in equivalent amounts or by one of them, in excess amounts, in the conditions from cooling to heating, for example, at a temperature from 0 C to 80 C, usually at hashing within 0.1 hour to 5 days, in inert in the conditions of the reaction solvent or solvent-free. There are no specific limits for solvent which can be used in this reaction. Examples of this include solvent aromatic hydrocarbons such as benzene, toluene and xylene; ethers, such as diethyl simple ether, tetrahydrofuran (THF), dioxane and dimethoxyethane (DME); halogenated hydrocarbons, such as dichloromethane (DCM), 1,2-dichloroethane (DCE) and chloroform, and N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, acetonitrile and their mixtures. In some cases, for peaceful development of the reaction can be beneficial carrying out the reactions in the presence of organic bases, such as triethylamine, N,N-Diisopropylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecen or N-methylmorpholine, or inorganic bases, such as potassium carbonate, sodium carbonate, sodium carbonate cesium or potassium hydroxide, or otherwise, in the presence also of interphase catalyst, such as tetrabutylammonium iodide or 18-crown-6 ether.

[Reference literature]

S.R. Sandler and W. Karo, Editors, Organic Functional Group Preparations, 2 nd edition. Vol. 1, Academic Press Inc., 1991.

Courses in Experimental Chemistry, 5 th edition, edited by The Chemical Society of Japan, Vol. 14(2005), Maruzen Co., Ltd.

(A method of obtaining 2)

[Chemical compound 14]

(The symbols in equations have the following values).

This method of production is the way in which connection (I-2) of the present invention get a reaction acrylic connection (2A) derives Amin (1b).

The reaction can be performed with the use of connection (2A) and connection (1b) in equivalent amounts, or use one of them in excess, in conditions from cooling to heating, for example, at a temperature from 0 C to 120 C, usually at hashing within 0.1 hour to 5 days, in inert in the conditions of the reaction solvent or solvent-free. There are no specific limits for solvent which can be used in this reaction. Examples of this include solvent aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols such as methanol, ethanol and 2-propanol, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, acetonitrile and their mixtures. When a derived Amin is in the form of salt, in some cases for peaceful development of the reaction can be beneficial holding reaction conversion of salt in free Amin in the presence of organic bases, such as triethylamine, N,N-Diisopropylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecen or N-methylmorpholine, or inorganic bases, such as potassium carbonate, sodium carbonate or potassium hydroxide.

(A method of obtaining 3)

[Chemical compound 15]

(The characters in the formula are shown above).

This method of production is the way in which connection (I) of the present invention get a reaction derived tetrahydroisoquinoline (3A) derived from amino acids (3b).

The reaction can be performed with the use of connection (3A) (3b) in equivalent amounts, or use one of them in excess, in the presence of the agent condensation, in the conditions from cooling to heating, for example, at a temperature of -20 to 60 C, usually at hashing within 0.1 hour to 5 days, in inert in the conditions of the reaction solvent. There are no specific limits for solvent which can be used in this reaction. Examples of this include solvent aromatic hydrocarbons, halogenated hydrocarbons, ethers, N,N-dimethylformamide (DMF), N is an organic, ethyl acetate, acetonitrile, water and their mixtures. Examples agent condensation include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), diphenylphosphorylacetic and oxychloride phosphorus. In some cases, for peaceful development of the reaction can be beneficial carrying out reactions with application of, for example, supplements, such as 1-hydroxybenzotriazole (HOBt).

In addition, you can also apply the method in which the derivative of the amino acids (3b) (carboxyl group serves as a place reaction) in turn derived reactive and then reactive derived subjected reaction with derivative tetrahydroisoquinoline (3A). In this case examples derived reactive include halides acids, obtained by reaction with halogenation agent such as oxychloride phosphorus or thionyl chloride, anhydrides mixed acids, obtained by reaction with isobutylparaben or the like, and active esters, obtained by the condensation of HOBr or other Reaction between reactive derived compounds (3b) and connection (3A) can be performed in conditions from cooling to heating, for example, at a temperature of -20 to 60 degrees C, in inert under the reaction conditions a solvent such as halogenated hydrocarbons, aromatic hydrocarbons or ethers.

[Reference literature]

In addition to N-alkylation with the use of connection (4b) and (4C), Dating back with the group, this way of getting you to use the N-alkylation with application epoxypropanol corresponding connection (4b) and (4C), and reductive amination with the use of derivative aldehyde, the appropriate connection (4b) and (4C).

N-alkylation with application epoxypropanol corresponding connection (4b) and (4C), you can spend the way in the way of getting 1.

Reductive amination with the use of derivative aldehyde, the appropriate connection (4b) and (4C), can be performed with the use of connection (4A) and derived aldehyde, the appropriate connection (4b) and (4C), equivalent quantities or with the use of one of them, in excess amounts, at temperature from -45 C to heat boiling with reflux in the presence of a reducing agent in solvent inert under the reaction conditions, for example, at a temperature of 0 C to room temperature, usually at hashing within 0.1 hour to 5 days. There are no specific limits for solvent which can be used in the invention. Examples of such solvents include alcohols, ethers and their mixtures. Examples reducing agent include cyanoborohydride sodium, triacetoxyborohydride, detribalized and the like. In some cases, for peaceful development of the reaction can be beneficial carrying out the reactions in the presence of dehydrating agent such as molecular sieves, or acids such as acetic acid, hydrochloric acid, or complex isopropoxide titanium(IV). Depending on the reaction, there is the case when amine connection can be obtained by condensation of compounds (4A) with aldehyde derivatives, the appropriate connection (4b) and (4C), and then you can select in the form of stable intermediate product. In addition, the reaction can be carried out in a solvent such as alcohol or ethyl acetate, in the presence or in the absence of acids, such as acetic acid or hydrochloric acid with the use of a catalyst recovery (such as Pd, besieged on coal (Pd/C), palladium hydroxide or Raney-Nickel) instead of handling regenerating agent. In this case, the reaction can be carried out in conditions from cooling to warming in the atmosphere of hydrogen at pressure from normal to 493,46 x 10 -6 PA (50 atmospheres).

[Reference literature]

A.R. Katritzky and R.J.K. Taylor, Editors, Comprehensive Organic Functional Group Transformation II, Vol. 2, Elsevier Pergamon, 2005.

Courses in Experimental Chemistry, 5 th edition, edited by The Chemical Society of Japan, Vol. 14(2005), Maruzen Co., Ltd.

In addition, the original connection (4A) of this way of receiving you can get removing protection from Amin through reaction connection (1A) - protected derived Amin in the same way as in the process for 1, or remove the protective group amino through reaction connection (3A) with aminosidine a derivative of the amino acids in the same way as in the way of getting 3.

(Synthesis of the parent compounds)

(1) Obtaining compounds (1A) and (2A)

[Chemical compound 17]

(In the formula Hal is a halogen and other characters are shown above. The same values will be applied in the future).

This method of production is the way in which connection (2A) or (1A) get a reaction derived tetrahydroisoquinoline (3A) halogenanion acid (5A) and (5b).

The reaction can be performed with the use of connection (3A) and connection (5A) and (5b) in equivalent amounts or by one of them, in excess amounts, in the conditions from cooling to heating, for example, at a temperature from 0 C to 80 C, usually at hashing within 0.1 hour to 5 days in inert in the conditions of the reaction solvent or solvent-free. There are no specific limits for solvent which can be used in this reaction. Examples of this include solvent aromatic hydrocarbons, ethers, halogenated hydrocarbons, ethyl acetate, acetonitrile and their mixtures. In some cases, for peaceful development of the reaction can be beneficial carrying out the reactions in the presence of organic bases, such as triethylamine, N,N-Diisopropylamine (DIPEA), pyridine or N-methylmorpholine, or inorganic bases, such as potassium carbonate, sodium carbonate, sodium bicarbonate or hydroxide potassium, or water solution, or in the presence of 0,01-0,2 equivalent amounts, preferably 0,05-0,15 equivalent amounts of catalyst, such as N,N-dimethylaminopyridine.

(2) Obtaining connection (3A)-1

[Chemical compound 18]

(In the formula M is an alkali metal and alkaline earth metal and is an anionic salt of metal R 1b , manifesting nucleophilicity in the form R 1b-M, and other characters are shown above. The same values will be applied in the future).

Stage circuit loop connection (6b) can be carried out by mixing compounds (6b) in inert in the conditions of the reaction solvent or without solvent, in the presence derived phosphoric acid, usually within 1 hour to 5 days. The reaction is usually conducted in the conditions from cooling to heating, for example, from room temperature to heat boiling with reflux. In some cases it may be favorable carrying out reactions in the absence of solvent. Solvent if it is used, not specifically limit, but examples include high-boiling aromatic hydrocarbons, such as toluene and xylene. Examples derived phosphoric acid include pentoxide Diaspora, a mixture of pentoxide Diaspora and oxychloride phosphorus, polyphosphoric acid, etiloleat and the like.

Alternatively, this stage can be conducted in such a way that auxililiary subjected reaction with amidon (6b) for the education of the rings 2-chloroquinoline, the resulting product is subjected condensation with the closure of the cycle in the presence of a catalyst acid Lewis, such as ferric chloride, with taking the derivative of 6,10b-dihydro-5H-[1,3]isoxazole[2,3-a]isoquinoline-2,3-dione (6C), and the subsequent solvolysis derived (6C) in the presence of strong acids such as sulphuric acid, or using alkoxide alkali metal such as sodium methoxide, while receiving the connection (6d).

When R 1b is a hydrogen connection (3A), whose R 1b represents hydrogen, you can get a reconnect (6d). The reaction is carried out by treatment of the connection (6d) or equivalent excessive amount of reducing agent in the conditions from cooling to heating, for example, at a temperature of -20 to 80 C, usually within 0.1 hour to 3 days, in inert in the conditions of the reaction solvent. There are no specific limits for solvent which can be used in this reaction. Examples of this include solvent ethers, alcohols, aromatic hydrocarbons, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, and their mixtures. Examples reducing agent include hydride reducing agents, such as sodium borohydride, diisobutylaluminum and socialoriented, metal reducing agents, such as sodium, zinc, and iron, and other reducing agents described in the following literature.

[Reference literature]

M. Hulicky, Reductions in Organic Chemistry, 2nd ed (ACS Monograph:188), ACS, 1996.

R.C. Larock, Comprehensive Organic Transformations, 2 nd ed, VCH Publishers, Inc., 1999.

T.J. Donohoe, Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6), Oxford Science Publications, 2000.

Courses in Experimental Chemistry, 5 th edition, edited by The Chemical Society of Japan, Vol. 14(2005), Maruzen Co., Ltd.

When R 1b is a group that is different from hydrogen, you can apply anionic connection via nucleophilic reagent (6th) for connection (6d). The reaction can be performed with the use of connection (6d) (6th) in equivalent amounts, or use one of them in excess, in conditions from cooling to heating, for example, at the temperature of -78 C to 0 C, usually at hashing within 0.1 hour to 5 days, in inert in the conditions of the reaction solvent. There are no specific limits for solvent which can be used in this reaction. Examples of this include solvent simple esters, aromatic hydrocarbons, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and their mixtures. For the selection of the appropriate connection (6th) appropriately applied R 1b-mineralogiya, R 1b-Li, obtained by the reaction of the corresponding halide with magnesium.

In addition, the provisions 1a R and R 1b in the formula, you can replace one for the other.

(3) Obtaining connection (3A)-2

[Chemical compound 19]

(The characters in the formula are shown above).

This method of production is the way in which connection (3A-2) receive recovery derived acetonitrile (7a).

The reaction can be carried out by mixing compounds (7a) in inert in the conditions of the reaction solvent in the atmosphere of hydrogen in the presence of a metal catalyst, usually within 1 hour to 5 days. The reaction is usually conducted in the conditions from cooling to heating, for example, at room temperature. There are no specific limits for solvent which can be used in this reaction. Examples of such solvent include alcohols, ethers, water, ethyl acetate, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and their mixtures. Examples of metal catalysts, which preferably you can apply include palladium catalysts, such as Pd, besieged on coal (Pd/C), palladium mobile and hydroxide of palladium, platinum catalysts, such as platinum oxide, rhodium catalysts, such as tetranitropentaerithrite, Raney-Nickel, iron catalysts, such as reduced iron and the like. Instead of using gaseous hydrogen as a source of hydrogen can also be applied equivalent or excessive relative to the number of connections (7a), formic acid or ammonium formate.

[Reference literature]

M. Hudlicky, Reductions in Organic Chemistry, 2nd ed (ACS Monograph:188), ACS, 1996.

Courses in Experimental Chemistry, 5 th edition, edited by The Chemical Society of Japan, Vol. 19(2005), Maruzen Co., Ltd.

In addition, R 1a in the formula can also be R 1b .

This method of production is the way in which connection (3A) is produced by condensation derived Amin (6A) ketone (8A).

The reaction can be performed with the use of connection (6A) and connection (8A) in equivalent amounts or one of them abundant in inert in the conditions of the reaction solvent or without solvent, in the presence of dehydrating agent or as a catalyst for a Lewis acid in the conditions from cooling to heating, for example, at a temperature from room up to heating boiling with reflux, usually at hashing within 0.1 hour to 5 days. There are no specific limits for solvent which can be used in this reaction. Examples of this include solvent halogenated hydrocarbons, ethers, and the like. In some cases, for peaceful development of the reaction can be beneficial carrying out the reactions in the presence of strong acids, such as a mixture of formic acid-acetic anhydride and triperoxonane acid. Examples dehydrating agent include acid anhydrides, such as polyphosphoric acid, acetic anhydride and triperoxonane anhydride. Examples of Lewis acid, used as a catalyst include tetraisopropoxide titanium and the like.

The connection of the present invention isolate and purify loose connections or pharmaceutically acceptable salt, hydrate, MES or crystalline polymorpha. Pharmaceutically acceptable salt of the compounds of formula (I) can also be obtained according to the conventional method for the formation of salt.

The selection and cleaning is performed through the application of conventional chemical operations, such as extraction, fractional crystallization and different types of chromatography factions.

Various isomers can be obtained by selecting the appropriate initial connection, or you can select using the differences in physico-chemical properties of the isomers. For example, from the optical isomer you can obtain optically pure isomer using common methods of separation of optical isomers (for example, by fractional crystallization to get diastereomers with optically active grounds or acids, chromatography using chiral columns, etc. and the like). In addition, isomers can also be obtained from the appropriate optically active parent compound.

Pharmacological activity of the connection of the present invention confirmed the following tests.

An example of test 1: Test connections to block CA 2+ channel N-type

Cultivated human fibroblasts (cells IMR-32) and the induction of differentiation conducted a modification of method described in the literature [Carbone et al., Pflugers Arch. Eur. J. Physiol., 416, 170-179 (1990)]. Cells IMR-32 has subcultural in MEM (Invitrogen Corporation, USA)containing 10% fetal bovine serum (FBS), 1% essential amino acids, 1% sodium pyruvate, 100 mg/ml streptomycin and 100 u/ml penicillin. After induction of cellular differentiation to the culture medium was added 1 mm monophosphate of cyclic dibutyltin (dbc) and 2.5 microns 5-bromodeoxyuridine (BrdU) and the cells were cultured for 10-11 days, leading to the expression of CA 2+ channel N-type person.

Cells IMR-32 with induced 10-11 days differentiation planted at a density of 6 x 10 5 cells per well in 96-well tablet, covered with poly-D-lysine. After culturing cells in a culture medium for 3 hours or more in it added Fluo-3 AM, followed by incubation at 37 C for 60 minutes. Culture washed in the buffer for analysis (HBSS, 20 mm HEPES, 2.5 mm probenecid, pH 7,4), which is then added to the solution of the tested compounds in the presence of 1 micron of nitrendipine. After 10 minutes, increasing the concentration of intracellular CA 2+ induced stimulation with high content To + 50 mm KCl solution, determined by applying a set for analysis of calcium FLIPR (Molecular Devices Corporation, USA). Block the activity of the tested compounds in respect of Ca 2+ channel N-type was calculated as a relative value, making the maximum increase in the concentration of intracellular Ca 2+ in the control group at 100%. Then the concentration (the value of the IC 50 ), which is required for 50% inhibition of the increase in the concentration of intracellular Ca 2+ , calculated nonlinear regression analysis.

As a result it was discovered that compounds present invention showed a blocking action on Sa 2+ channel N-type. The value of the IC 50 for multiple connections of the present invention are given below in table 1.

IC 50 (micron)

IC 50 (micron)

IC 50 (micron)

The test example 2: the influence of compounds on the model nociceptive pain (formalin test)

Formalin test on mouse conducted a modification of method described in the literature [Murakami et al., Eur. J. Pharmacol. 419: 175-181 (2001)]. When 20 ml of 2.0% formalin was injected subcutaneously in the pads on the feet of mice (ddY, male, age 5 weeks), processed in the limbs of animals occurred inducing pain behavior (behavior otdergivanija and licking limbs). After 15-25 minutes after administration of formalin measured the time taken for the emergence of pain behaviors in order to assess the inhibitory effect of the tested compounds on pain of animal behavior. Test the connection oral entered 30 minutes prior to the introduction of formalin. Assessment of the tested compounds was performed by calculating the degree of inhibition (%) in the group treated with the test connection, taking the time taken for the emergence of pain behaviors in the group treated with filler, as 100%.

The degree of inhibition (%) = 100-(the average time of occurrence of pain behaviors in the group treated with the test connection)/(average time of occurrence of pain behaviors in the group treated with filler)x 100.

As a result it was discovered that compounds present invention showed the analgesic effect on the pain induced by formalin. The degree of inhibition (%) multiple connections of the present invention at the dose of 100 mg/kg given below in table 2.

The degree of inhibition (%)

The test example 3: the influence of compounds on the model neuropathic pain (action against allodynia in rats with legirovannykh L5/L6 spinal nerves)

One of the main symptoms of neuropathic pain is significantly reduced threshold respond to tactile stimulation (allodynia). Actions against allodynia compounds present invention has confirmed the assessment of the analgesic action in rats with legirovannykh L5/L6 spinal nerves. The evaluation was performed by the method of Kim and Chang (Pain 50, 355-363, 1992) with some modifications.

After anesthesia pentobarbital left L5 L6 and spinal nerves male rats SD (5-6 weeks of age) tightly ligated silk thread. To assess analgesic actions adapted the test von Frey using bristle. That is the tip hind feet pierced bristles and the weakest action bristle at the reaction of otdergivanija limbs meant as a reaction threshold (log grams) to mechanical stimulation. Since the pre-test was confirmed that the threshold response hind legs of the animal, located on the side of the operation of ligation, was significantly lower for 7-14 days after the operation (under condition of mechanical-allodynia), actions against allodynia of the tested compounds were evaluated only in day between days 7 and 14 days after surgery. The day before the evaluation of the test compounds measured the threshold of the reaction before the introduction of the test the connection. Animals were divided into 4-5 groups, so that the differences of mean values of thresholds reaction between groups before the introduction of the test compounds and ranges of values in the group have become small. In the evaluation of the test compounds measured the threshold of the reaction after the introduction of the test the connection. Test the connection was administered orally for 30-60 minutes prior to the measurement of the reaction threshold. The activity against allodynia of the tested compounds were evaluated as the degree of return to normal (restore) (%) in the group treated with the test connection, taking thresholds response feet, located on the side of operation ligation and on the opposite side, in the group treated with filler as 0% and 100%, respectively.

The degree of return to normal (%) = {(average threshold reactions in the group treated with the test connection)-(the average value of the threshold response feet, located on the side of the transactions, in the group treated with filler)}/{(average threshold response feet, located on the side opposite to the operations in the group treated with filler)-(the average value of the threshold response feet, located on the side of the transactions, in the group treated with filler)}x 100.

As a result it was discovered that compounds present invention showed the analgesic effect on the mechanical allodynia in models of neuropathic pain. The degree of return to normal rats (%) for groups with the introduction of the multiple connections of the present invention are given below in table 3.

The degree of return to normal (%) (dose)

95 (30 mg/kg)

97 (30 mg/kg)

100 (10 mg/kg)

80 (10 mg/kg)

156 (10 mg/kg)

83 (10 mg/kg)

The test example 4: the influence of compounds on the model of abdominal pain (definition CDR-induced abdominal pain in rats)

It is known that in response to the stimulation pressure caused by colorectal swelling (CRD), patients with IBS have shown a reduction in the threshold of the digestive perception (allodynia), which causes discomfort compared with the weak stimulus, which is not felt normal individual, and hyperalgesia, which leads to stronger subjective reactions to the digestive perception than normal individual (Gastroenterol. 130: 1377-1390 (2006)), and it is believed that such States are responsible for abdominal symptoms. Improving actions compounds present invention to the pain of the digestive tract confirmed by definition CDR-induced abdominal pain in rats. Determining the CDR-induced abdominal pain in rats conducted a modification of method described in the literature [Neurogastroenterol. Motil. 15: 363-369 (2003)]. When stimulation constant internal pressure applied to the rectal animal inflate its cylinder length of 6 cm, inserted in the anus rats (Wistar male, 250-350 g), behavior abdominal flexion reflex induced due to abdominal pain. The frequency reflex behaviors that occur during stimulation swelling within 5 minutes were calculated to assess inhibitory effect of the tested compounds abdominal pain. Test the connection oral entered 30 minutes before the start of stimulation swelling. Assessment of the tested compounds was performed by calculating the degree of inhibition (%) behaviors abdominal flexion reflex for the group treated with filler.

As a result it was discovered that compounds present invention showed inhibitory effect on abdominal pain. For several compounds present invention at a dose of 10 mg/kg degree of inhibition (%) behaviors abdominal flexion reflex after swelling at the internal pressure 5999,5 PA (45 mm Hg) is shown below in table 4.

The degree of inhibition (%)

The test example 5: the influence of compounds on the model of spastic constipatio (test-induced loperamide delayed migration of balls in the colon)

It is known that usually the appearance of constipatio at IBS-C is called spastic violation of motility of the digestive tract and is similar opioid induced constipatio in terms of the pathophysiology of the disease (Eur. J. Pharmacol. 75: 239-245 (1981), American J. Physiol. 96: 667-676 (1931), Nippon Rinsho 64: 1461-1466 (2006)). Improving effects of the compounds present invention spastic on the higher-was confirmed by the test-induced loperamide delay colorectal transfer balls in mice. Test-induced loperamide delay colorectal migration ball mice conducted a modification of method described in the literature [J. Smooth Muscle Res. 29:47-53 (1993)]. Glass ball with a diameter of 3 mm deeply inserted at a depth of 2 cm into the anus of a mouse (ddY, male, age 6 weeks) and measured the time taken for the excretion of the ball. When 0.3 mg/kg of loperamide subcutaneously injected 30 minutes before inserting the ball, took place inducing delays excretion of the ball. According to enhance action on induced loperamide delayed migration ball evaluated improves intestinal peristalsis effect of the tested compounds on the spastic higher. Test the connection oral introduced simultaneously with the introduction of loperamide (30 minutes before inserting the ball). Assessment of the tested compounds was carried out by calculating the degree of improvement time excretion ball processed the test connection/processed by loperamide group, taking time excretion ball is not processed the test connection/not treated with loperamide (processed filler/processed filler) group at 100% and taking the time excretion ball is not processed the test connection/treated with loperamide (processed filler/processed by loperamide) group at 0%.

As a result it was discovered that compounds present invention showed an improving effect on opioid induced a higher. For several compounds present invention at a dose of 3 mg/kg degree of improvement (%) time excretion ball are given below in table 5.

The degree of inhibition (%)

An example of test 6: Steps compounds in combined use with morphine (1)

It is known that mechanical allodynia observed in rats with legirovaniem L5/L6-spinal nerve, shows only a partial return to normal when processing morphine. On the other hand, as described in the above context, the connection of the present invention show actions with almost 100% back to normal when the mechanical allodynia in rats with legirovaniem L5/L6-spinal nerve. So when the connection of the present invention was used in combination with morphine, strong action against neuropathic pain, comparable to the action or stronger than the effects when introduction only morphine or in the introduction of only compounds the present invention can be confirmed by testing them against allodynia on rats with legirovaniem L5/L6-spinal nerve.

The test example 8: connection when combined application with morphine (3)

Morphine is an agonist at mu-opioid receptor having the same mechanism of action as loperamid, and has delaying effect on the transfer of a ball in the large intestine in mice, similar to the action of loperamide. With the introduction of a dose of morphine, which exerts inhibitory effect on abdominal pain in the test abdominal pains in rats induced CRD, and takes effect on the delay of the transfer in the test for colorectal transfer ball in mice, and doses of the test compound that inhibits the delay transfer of the ball, caused by the above dose of morphine, you can confirm that the combined application of exhibits strong abdominal pain inhibitory effect comparable to or more severe than the effects when introduction only morphine, when determining CRD-induced abdominal pain in rats, and also has an inhibitory effect on morphine-induced delay of transfer when testing for the transfer of the ball.

Alternative, with the introduction of the test connections with a low dose of morphine in which abdominal pain inhibitory action is insufficient in the analysis CRD-induced abdominal pains in rats, but delaying action is not found in a test of the transfer of a ball in the large intestine mouse, you can confirm sufficient abdominal pain inhibitory action that had not received when using a low dose of one of morphine.

On the basis of experimental results described above, it was confirmed that the connection of the present invention possess a blocking action on the Ca 2+ -channels N-type. It is therefore evident that the connection of the present invention is applicable as an active ingredient in a pharmaceutical composition for prevention and/or treatment of various pains like neuropathic pain and nociceptive pain, headaches such as migraine and cluster headache, diseases of the Central nervous system, such as anxiety, depression, epilepsy, cerebral stroke and tired leg syndrome, diseases of the digestive system, such as abdominal pain and irritable bowel syndrome, and urinary tract diseases, such as overactive bladder and interstitial cystitis.

Based on the results of tests with formalin described above, it was confirmed that the connection of the present invention are action against nociceptive pain. In addition, on the basis of the results of action against allodynia in rats with legirovaniem L5/L6 spinal nerve, it was confirmed that the connection of the present invention are action against neuropathic pain. After considering these facts it is clear that the connection of the present invention is applicable as an active ingredient in a pharmaceutical composition for prevention and/or treatment of a variety of pain, including neuropathic pain and nociceptive pain. In addition, clinically shown that pregabalin, which is the ligand subunit α2δ CA 2+ channel and which is used as an agent against neuropathic pain, has a therapeutic effect on fibromyalgia syndrome, having much in common with neuropathic pain in terms of the clinical condition. On the basis of this conclusion, we can assume that the connection of the present invention are also applicable as an active ingredient in a pharmaceutical composition for prevention and/or treatment of fibromyalgia syndrome.

Based on the results of the analysis of the CRD-induced abdominal pain, described above, it was shown that the connection of the present invention are action, inhibiting abdominal pain. It is therefore evident that the connection of the present invention is applicable as an active ingredient in a pharmaceutical composition for prevention and/or treatment of abdominal symptoms, especially abdominal symptoms of IBS.

On the basis of facts showing that the connection of the present invention are effective as the test abdominal pain in rats induced CDR and trial delays colorectal transfer ball mouse, it becomes evident that the connection of the present invention are applicable as the active ingredient excellent pharmaceutical composition for prevention and/or treatment of IBS-C, with a combination of actions that weaken abdominal symptom, and actions that improve the state when constipatio.

It is known that the use of peptide, selectively blocking CA 2+ channel N-type, conotoxin (W-CTx), in combination with increases morphine analgesic actions compared to the analgesic action obtained by applying the only morphine (additional actions) (Pain 84: 271-281 (2000), Life Science 73: 2873-2881 (2003)). Therefore, we can assume that the combined use of compounds present invention and opioids would yield excellent pharmaceutical composition for prevention and/or treatment of pain, which shows a stronger analgesic action than the action when only opioids.

Opioids are used as a therapeutic agent against severe pain, such as cancer pain, but their use is faced with clinical problems associated with dose-dependent side effects on the digestive system, such as vomiting and a higher-Eur. J. Pharmaceutical Sci. 20: 357-363 (2003)). The connection of the present invention are excellent improving actions induced by opioids the higher-OIC). Based on this fact, we can assume that the connection of the present invention when combined with the use of opioids can lead to the creation of a pharmaceutical composition for prevention and/or treatment of pain, which inhibits opioid induced a higher with less side effects. In addition, it can be assumed that the combined use of compounds present invention and low doses of opioids may lead to the creation of superior pharmaceutical composition for prevention and/or treatment of pain, which can be little analgesic action at lower doses of opioids and is able to delay the emergence of constipatio by reducing the dose of the opioid.

The preparation containing one or two or more types of compounds of formula (I) or pharmaceutically acceptable salts as the active ingredient, you can get according to the commonly used method, using a pharmaceutically acceptable carrier, excipient or the like, which are typically used in this field.

The introduction can be orally administered through tablets, pills, capsules, granules, powders, liquid preparations, or the like, or parenteral introduction by injection, such as intra-articular injection, intravenous, intramuscular injection or the like, as well as preparations in the form suppozitoriev, eye drops, eye ointments, percutaneous liquid medicines, ointments, skin patches, liquid preparations for the introduction through the mucous membrane, patches for the introduction through the mucous membrane, preparations for inhalation, and the like.

As a solid songs for oral administration according to the present invention applied tablets, powders, granules or the like. In such a hard song one or two or more types of active ingredients mixed with at least one inert excipients, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polivinilpirrolidon and/or aluminoborosilicate magnesium. According to the conventional method, the composition may contain inert additives such as grease, such as stearate, dezintegrarea substance, such as sodium salt carboxymethyl amylum, stabilising agent and solubilizers auxiliary means. Depending on the specific case of the tablets or pills may be covered with a film or sugar coated or gastro - or enterosolubically coating.

Liquid composition for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs or the like and contain commonly used an inert diluent such as purified water or ethanol. Besides inert solvent, liquid composition may contain adjuvant, such as soljubilizatorami agent, wetting agent and suspendisse agent, sweetener, corrigent, flavouring agent and preservative.

Injections for injecting include sterile water or not water solutions, suspensions and emulsions. Water solvent includes, for example, distilled water for injection and physiological saline. Examples of non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, alcohols such as ethanol, Polysorbate 80 (Japanese Pharmacopeia), and the like. This composition can optionally contain the agent donicetti, preservative, wetting agent, emulsifying agent, dispersant, a stabilizing agent or solubilizers auxiliary means. They are sterilized, for example, by filtration through inhibiting the bacteria filter, enabling sterilizing agent or irradiation. In addition, they can also be applied by manufacture of sterile solid composition and dissolution or suspendirovanie it in sterile water or sterile diluent for injection before applying it.

Preparations for external use include ointments, patches, creams, jellies, adhesive plasters for skin, sprays, lotions, eye drops, eye ointment, and the like. Preparations for external application contain commonly used bases of ointments, lotions, aqueous or non-aqueous liquids, suspensions, emulsions, and the like. Examples of bases of ointments or lotions include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polioksietilirovannogo hydrogenated castor oil, glycerilstearates, stearyl alcohol, cetyl alcohol, eurometropola, sesquioleate sorbitana and the like.

Preparations for the introduction through the mucous membrane, such as preparations for inhalation and preparations for the introduction through the nose, used in solid, liquid or semi-solid form, you can get them as generally known the way. They can appropriately be added, for example, excipient, as well as the agent of the regulation of pH, preservative surfactant, grease, stabilizing agent, thickening agent or the like. For their introduction, you can apply a suitable device for inhalation or injection. For example, a connection can be entered separately or in powder form prepared mixture or solution or suspension in combination with a pharmaceutically acceptable carrier, using the common known device or sprinklers, such as a device for inhalation used for the introduction of measured quantities. Inhaler with dry powder or the like can be used to integrate one or many times, you can use dry powder or capsule containing the powder. Alternatively, it can be in such form, as in pressurised aerosol spray or the like, which apply suitable propellant, such as suitable gas, such as chlorphenesin, gidrotoraks or carbon dioxide.

When administered orally daily dose is usually from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg or more preferably the 0.1-10 mg for body weight, which is injected in the form of one portion or in 2-4 divided doses). In the case of intravenous daily dose is appropriately administered in number from about 0.0001 up to 10 mg/kg of body weight once a day or two or more times a day. In addition, a means of setting through the mucous membrane is administered at the dose from about 0.001 to 100 mg/kg of body weight once a day or two or more times a day. Dose appropriately selected depending on the individual case, taking into account the symptoms, age and sex, and the like.

The connection of the present invention can be used in combination with various methods for treating or preventing disease, for which considered the connection of the present invention are effective. Examples of drugs that can be used in combination with the connection of the present invention, include opioids, such as morphine, antidepressants, such as DULOXETINE and amitriptyline, anti-epileptic drugs such as pregabalin and meksiletin, nonsteroidal anti-inflammatory drugs such as diclofenac, and the like. For such the combined application of the connection of the present invention is made in the composition of the appropriate dosage forms, such as liquid drugs, capsules, granules, pills, powders, tablets, preparations for external use, gels, sprays, patches, suppositories and containing such combinations implantable pumps, and is part of the drug can be administered simultaneously or separately and continuously or after the required time intervals by oral, intravenous, subcutaneous, transnasal, enteral, spinal epidural or spinal subarahnoidalnogo way. The drugs, which is administered jointly, can be a mixture or parts can be produced separately.

EXAMPLES

Rex: number of sample receipt, Ex: the number of example, no: connection number, STRUCTURE: structural formula, Data: physico-chemical data (FAB: FAB-MS[M+H] + , FAN: FAB-MS[M-H] - , FA1: FAB-MS[M] + , FA2: FAB-MS[M+2H] + , ES: ESI-MC[M+H] + , ES1: ESI-MC[M] + , ES2: ESI-MC[M+2H] + , ESNa: ESI-MC[M+Na] + , AP: APCI-MC[M+H] + , AP1: APCI-MC[M] + , CI CI[M+H] + , CIN: CI[M-H] - , CI1: CI[M] + , EI: EI[M+H] + , EIN: EI[M-H] - , EI1: EI[M] + , EIBr: EI[M-Br] - , NMR: δ (ppm) peak 1 H-NMR, in DMSO-d 6 ), N/D: not determined, salt: salt (such term in the blank column or absence column with that term means that the connection is in a free form), CL: hydrochloride, BR: Hydrobromic, OX: oxalate, FM: fumarate, MD: D-mandelate, ML: L-mandelic acid, LL: salt N-acetyl-L-leucine, T1: L-tartrate, T2: D-tartrate, TX: Dibenzoyl-D-tartrate, TY: Dibenzoyl-L-tartrate, TP: dipiradamol-D-tartrate, TQ: dipiradamol-L-tartrate, MA: L-malic acid, MB: D-malic acid), Me: methyl, Et ethyl, nPr: normal propyl, iPr: isopropyl, tBu: tert-butyl, cPr: cyclopropyl, cBu: cyclobutyl, cPen: cyclopentyl, cHex: cyclohexyl Admt: of substituted, Ph: phenyl, Bn: benzyl, Thp: tetrahydropyranyl, pipe: piperidinyl, pipa: piperazinyl, CN: cyano, boc: tert-butiloksianizol, Ac: acetyl, MOM: methoxymethyl, TMS: trimethylsilyl, di: di, THF: tetrahydrofuran, DMF: N,N-dimethylformamide, DMSO: sulfoxide. The number before the Deputy indicates the position of the Deputy and, for example, 6-Cl-2-Py is a 6-chloropyridine-2-yl and 3,3-di-F-cHex represents a 3.3-diverticulosis. Rsyn and Syn: way to obtain (numbers indicate that the compounds were obtained by using of the corresponding source connections the same way of obtaining compounds, respectively, with the number as a number of examples of receipt or numbers of examples). In addition, among the compounds of the examples or examples in the tables for the connection, which configuration of the Deputy in 1-position of tetrahydroisoquinoline not defined, but shows one configuration in any of the parties, the configuration in any of the parties noted and then the sample is received or the number of the example is indicated with the icon *. On the other hand, for a connection, which configuration of the Deputy in 1-position of tetrahydroisoquinoline defined, or compound, which configuration reasonably analgezirutaya on the basis of conduct for chiral column chromatography or activity to test the blocking of CA 2+ channel N-type, configuration only marked.

In addition, compound, which the same number is given after *, means that the connection is received with the use of the connection, which is given the same number and whose configuration Deputy in 1-position of tetrahydroisoquinoline not defined, but one configuration noted in any of the parties, as parent compound.

Example of getting 1

N-(2-Cyclogexa-1-ene-1-ileti)-2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-exoethnonym (431 mg) dissolved in chloroform (12 ml), the solution was added triperoxonane anhydride (0.3 ml) at cooling by ice and subsequent mixing at room temperature for 10 hours and then mixed at 60 C for 2 hours. The solvent is evaporated and to the reaction liquid added saturated aqueous sodium bicarbonate and the mixture was then extracted with chloroform. The reaction liquid washed saturated salt solution and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform), while receiving N-(2-cyclogexa-1-ene-1-ileti)-N-[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]-2,2,2-triptorelin (419 mg).

Example of getting 2

N-(2-Cyclogexa-1-ene-1-ileti)-N-[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]-2,2,2-triptorelin (408 mg) dissolved in a mixture of 3:1 (8 ml) acetone-water. To the reaction liquid added 4-oxide 4-methylmorpholine (200 mg) and a solution of 2.5% osmium tetroxide in tert-butyl alcohol (2,68 ml) followed by mixing at room temperature for 18 hours. Then the reaction solvent evaporated under reduced pressure and the reaction liquid added water with the subsequent extraction of chloroform. The extracts were washed with a saturated solution of salt and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving N-[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]-N-{2-[CIS-1,2-dihydroxytoluene]ethyl}-2,2,2-triptorelin (276 mg).

Example of getting 3

2-(Chloroacetyl)-1-cyclohexyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline (700 mg) dissolved in acetonitrile (15 ml), the solution is then added potassium carbonate (2.1 g), hydrochloride 2-cyclopent-1-ene-1-ratanina 1.6 g and iodide Tetra-n-butylamine (80 mg) followed by stirring at 70 C within 5 hours. Then the solvent is evaporated and to the reaction liquid added water with the subsequent extraction EtOAc. The extracts were washed with a saturated solution of salt and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon).

(L)-Tartrate (1R)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (520 mg) dissolved in the EtOAc (10 ml) and the solution was added saturated aqueous sodium bicarbonate (10 ml). To the reaction of the liquid for 5 minutes at cooling by ice was added dropwise solution chloroacetanilide (0,14 ml) in EtOAc (5 ml) followed by mixing at room temperature for 1 hour. The reaction liquid were extracted EtOAc and dried over magnesium sulfate, while receiving (1R)-2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (415 mg).

Example of getting 5

Hydrochloride 7-chloro-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (899 mg) was added to the saturated water sodium bicarbonate (15 ml), which then further added EtOAc (10 ml). To the reaction of the liquid for 5 minutes was added dropwise solution chloroacetanilide (390 mg) in EtOAc (5 ml). The reaction liquid was stirred for 1 hour, were extracted EtOAc and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 7-chloro-2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (888 mg).

Example of obtaining 6

The mixture of chloroacetanilide (1,03 g) and EtOAc (5 ml) was added dropwise with stirring to mix (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1,58 g), sodium bicarbonate (960 mg), water (25 ml) and EtOAc (25 ml) followed by mixing at room temperature for 2 hours. The reaction liquid were extracted EtOAc and extract washed consistently saturated water bicarbonate of sodium and saturated solution of salt, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (hexane-AcOEt, 4:1), while receiving (1S)-2-(chloroacetyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (2.14 g).

Example of getting 7

Hydrochloride 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (800 mg) dissolved in methylene chloride (12 ml), the solution was added at cooling by ice akrilonitril (0,28 ml), followed by stirring at cooling by ice for 30 minutes and then stirred at room temperature for up to 14 hours. To the reaction liquid added water and the mixture was then extracted with chloroform. The extracts were washed with a saturated solution of salt and dried over magnesium sulfate. The solvent is evaporated, while receiving 2-acryloyl-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (856 mg).

Example of getting 8

1-Benzyl-4-hydroxypiperidine-4-carboxylic acid (951 mg) dissolved in DMF (25 ml) and the solution was added N,N'-carbonyldiimidazole (720 mg), followed by stirring at room temperature for 18 hours. After that to the reaction liquid added N,N-Diisopropylamine (784 mg) and hydrochloride 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (1.22 g), followed by stirring at 60 degrees C for 18 hours. The solvent is evaporated and to the reaction liquid added water and EtOAc. Formed insoluble substances separated by Celica, were extracted EtOAc and dried over magnesium sulfate and the solvent is evaporated. The resulting residue was purified column chromatography on silica gel (chloroform-Meon) and was dissolved in 1,4-dioxane (12 ml) and the solution was added di-tert-BUTYLCARBAMATE (1,3 g) with the subsequent mixing at room temperature for 1 hour. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc and then chloroform-Meon), while receiving 1-benzyl-4-[(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)carbonyl]piperidine-4-ol (115 mg).

Example of obtaining 9

1-Benzyl-4-[(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)carbonyl]piperidine-4-ol (220 mg) dissolved in the Meon (12 ml) and the solution was added 20% palladium hydroxide, besieged on charcoal (360 mg), followed by stirring atmosphere of hydrogen at room temperature and normal pressure for 15 hours. After that, the catalyst separated by Celica. The solvent is evaporated, while receiving 4-[(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)carbonyl]piperidine-4-ol (154 mg).

Example of obtaining 10

N-Methylmorpholine (0,873 ml) was added to a solution of 1-(tert-butoxycarbonyl)-L-Proline (1.28 g) in 1,2-dichloroethane (10 ml) at cooling by ice, and then further adding pualeilani (0,734 ml). The reaction liquid was stirred for 1 hour and then it was added N-methylmorpholine (1,09 ml) and hydrochloride 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (1,00 g). The mixture was stirred at room temperature for 15 hours. To the reaction solution was added EtOAc and water 1 M HCl solution. The organic layer washed with water, saturated aqueous solution of bicarbonate of sodium and saturated solution of salt, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, while receiving tert-butyl(2S)-2-[(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)carbonyl]pyrrolidin-1-carboxylate (1,79 g).

Example of obtaining 11

Hydrochloride 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (1,00 g) dissolved in methylene chloride (20 ml) and cooling with ice to a solution was added pualeilani (0,98 ml) and 4 methylmorpholine (2.2 ml). The reaction liquid stirred at room temperature for 30 minutes and then cooled with ice and to it was added [(tert-butoxycarbonyl)amino]acetic acid (1.54 g). The reaction liquid stirred at room temperature for up to 14 hours and then it was added to the water with the subsequent extraction of chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving tert-butyl-[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]carbamate (1,49 g).

Example 12

4 M HCl/EtOAc (4 ml) was added to solution tert-butyl(2S)-2-[(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)carbonyl]pyrrolidin-1-carboxylate (1,79 g) in EtOAc (4 ml). The mixture was stirred at room temperature for 5 hours. The solvent is evaporated under reduced pressure and the remainder was added chloroform and saturated aqueous solution of sodium bicarbonate. The organic layer is washed with a saturated solution of salt, dried over magnesium sulfate, filtered, and concentrated, while receiving 1-cyclohexyl-2-L-prolyl-1,2,3,4-tetrahydroisoquinoline (1.26 g).

Example of obtaining 13

tert-Butyl-[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]carbamate (1.5 g) dissolved in the EtOAc (20 ml) and to the solution at cooling by ice was added 4 M HCl/EtOAc (3 ml), followed by stirring at 50 C within 5 hours. Then the reaction solvent evaporated. To the reaction liquid added saturated aqueous sodium bicarbonate and then were extracted with chloroform. The extracts were washed with a saturated solution of salt and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving 2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-exoethnonym (1,09 g).

Example of getting 14

2-(1-Cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-exoethnonym (695 mg) dissolved in methylene chloride (12 ml) and the solution was added tetraisopropoxide titanium (1.1 ml) and 1-cyclohexen-1-carbaldehyde (309 mg) followed by mixing at room temperature for 3 hours. Then the solvent is evaporated and to a mix added Meon (15 ml) and then centripetality sodium (190 mg), followed by stirring the mixture within 14 hours. The solvent is evaporated and to a mix added water and EtOAc. The mixture was filtered through celite and were extracted EtOAc. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving N-(cyclohex-1-ene-1-ylmethyl)-2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-exoethnonym (585 mg).

The resulting connection (525 mg) dissolved in 1,4-dioxane (10 ml) and the solution was added di-tert-BUTYLCARBAMATE (312 mg) followed by mixing at room temperature for 4 hours. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving tert-butyl-N-(cyclohex-1-ene-1-ylmethyl)-N-[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]carbamate (564 mg).

Example of obtaining 15

Chloracetophenone (0,151 ml) was added to a solution of 1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (339 mg) and monohydrate para-toluensulfonate (11,3 mg) in toluene (5 ml). The mixture was heated in boiling under reflux for 3 hours. The solvent is evaporated under reduced pressure and the remainder was added EtOAc and water 1 M HCl solution. The organic layer washed with water, saturated aqueous solution of bicarbonate of sodium and saturated solution of salt, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, while receiving 2-(chloroacetyl)-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (452 mg).

The example of 16

10% Pd, besieged on coal (900 mg), was added to a solution of 2-benzyl-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (1,81 g) in a mixture of 2:1 THF-MeOH (30 ml). The mixture was stirred up in the atmosphere of hydrogen at room temperature for 16 hours. Next to a mix added 10% Pd, besieged on coal (900 mg), followed by stirring within 8 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (339 mg).

Example of obtaining 17

In an ice bath when passing a stream of argon 1,07 M solution of fenilmaslanaya in THF (33,2 ml) was added dropwise to the solution hydrobromide 2-benzyl-1-phenyl-3,4-dihydroisoquinoline (8,95 g) in THF (80 ml) for 1 hour. The mixture was stirred at room temperature for 1 hour. To a mix added saturated aqueous solution of ammonium chloride and then were extracted EtOAc. The extracts were washed with water and saturated solution of salt, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 2-benzyl-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (1,81 g).

Sodium borohydride (450 mg) was added with stirring to the solution of 6.8-dimethoxy-1-phenyl-3,4-dihydroisoquinoline (1,96 g) in EtOH (50 ml) for 5 minutes. The reaction mixture was stirred at room temperature for 2 hours and then further stirred at 60 C for 1.5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. It formed the remainder was added water 3 M HCl (60 ml) followed by heating boiling under reflux for 3 minutes. After cooling down to a mix added water 20% NaOH solution to achieve strong alkalinity with the subsequent extraction of chloroform. The organic layer is washed with a saturated solution of salt, dried over magnesium sulfate and concentrated under reduced pressure, while receiving 6,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1.88 g).

Example of obtaining 19

1-Cyclohexyl-6-methyl-3,4-dihydroisoquinoline (4,84 g) dissolved in the Meon (100 ml) and then to the solution was added sodium borohydride (966 mg) followed by mixing at room temperature for 3 hours. The solvent is evaporated under reduced pressure. To the reaction mixture was added to the water and then were extracted with chloroform. The extract is dried over magnesium sulfate and the solvent is evaporated under reduced pressure.

The resulting residue was dissolved in EtOAc (100 ml) and to the solution at ice cooling solution was added 4 M HCl/EtOAc (8 ml), followed by stirring at room temperature. Formed insoluble materials collected and washed EtOAc, while receiving hydrochloride 1-cyclohexyl-6-methyl-1,2,3,4-tetrahydroisoquinoline (3.6 g).

Example of getting 20

Potassium carbonate (92 g) and water (500 ml) was added to the hydrochloride 1-isopropyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (86 g). The reaction mixture was extracted EtOAc and dried over magnesium sulfate and then the solvent is evaporated. It formed the remainder was added iPrOH (1100 ml) and (+)-almond acid (50 g) with the subsequent hashing when heated at 95 degrees With for dissolution. The mixture is left to cool and stirred at room temperature for the night. Formed the solid is collected and recrystallized three times using iPrOH, while receiving (+)-mandelate 1-isopropyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (43) in the form of individual enantiomers.

Example of obtaining 21

1-Cyclohexyl-1,2,3,4-tetrahydroisoquinoline (31.1 g) dissolved in EtOH (1,26 l) at 80 C and the solution is then added (D)-tartaric acid (10,83 g). The reaction mixture was left to cool and stirred at room temperature for the night. Formed insoluble substances (the 16,64 g) collected and dried.

Solid mixed with solid, obtained by the same method as above, and the mixture of 33.26 g) dissolved in EtOH (1 l), followed by stirring boiling under reflux for 2 hours and then mixed at 80 C for 5 hours. The mixture was stirred at room temperature for the night and then insoluble materials collected, while receiving (D)-tartrate (1S)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (30,8 g).

Example of obtaining 22

In argon atmosphere solution of complex 1.0 M borane-THF (110 ml) was added to the mixture (1R,2S)-1-amino-2-Indianola (8,17 g) and diethyl ether (200 ml) at mixing and internal temperature of 5 C or below. The mixture is additionally stirred at room temperature for 1.5 hours. The mixture was cooled to an internal temperature of the 4th C. To the mixture when the internal temperature of 5 C or below gradually added 1-(2-methoxyphenyl)-3,4-dihydroisoquinoline (10 g), followed by stirring at the same temperature for 30 minutes. The mixture was stirred at room temperature for 3 days. To the reaction mixture was added triperoxonane acid (61 ml) for decomposition of excess reagent followed by heating a mixture of boiling under reflux for 3 hours. After cooling, diethyl ether evaporated under reduced pressure and the mixture was heated in boiling under reflux for 10 minutes. The remainder was diluted chloroform were extracted and concentrated water ammonia to make it alkaline. The organic layer is washed with a saturated solution of salt, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (chloroform-EtOH-aqueous ammonia), while receiving 1-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (8,23 g).

1-(2-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (8,227 g) and (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]amber acid (13,282 g) dissolved by stirring in acetonitrile (246 ml) at 70 degrees C. the Mixture slowly cooled with agitation. The resulting crystals were collected by filtration, washed with acetonitrile and dried at low pressure, while receiving (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinate (1S)-1-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (16,193 g).

Example of obtaining 23

N-[2-(4-chlorophenyl)ethyl]ciclohexencarboxilic (2,03 g) dissolved in 1,2-dichloroethane (15 ml) and to the solution at cooling by ice was added oxacillin (0,8 ml). The reaction mixture was stirred at room temperature for 1 hour and then cooled to -20 degrees C. To a mix added the iron chloride(III) (1,49 g) with the subsequent mixing at room temperature for 16 hours. To a mix added water 1 M HCl solution and then stirred at room temperature for 30 minutes followed by extraction with chloroform. The extracts were washed with water and saturated salt solution and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was dried, while receiving 9-chloro-10b-cyclohexyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione (2.38).

Example of getting 25

9-Chloro-10b-cyclohexyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione (2,37 g) dissolved in the Meon (16 ml) and the solution was added to a solution of sulfuric acid (8 ml) in the Meon (24 ml), followed by stirring boiling under reflux for 18 hours. The reaction mixture was left to cool and then the solvent is evaporated. The reaction mixture was neutralized water 1 M sodium hydroxide solution, was extracted with chloroform, washed saturated salt solution and then dried with sodium sulfate. The solvent is evaporated and then the resulting residue was dried, while receiving 7-chloro-1-cyclohexyl-3,4-dihydroisoquinoline (1.78 g).

Example of obtaining 26

N-[2-(2-chlorophenyl)ethyl]ciclohexencarboxilic (2,55 g) dissolved in 1,2-dichloroethane (25 ml) and to the solution at cooling by ice was added oxacillin (1.0 ml). The reaction mixture was stirred at room temperature for 1 hour and then cooled to -20 degrees C. To a mix added the iron chloride (1,87 g) with the subsequent mixing at room temperature for 16 hours. To a mix added water 1 M HCl solution, with subsequent mixing at room temperature for 30 minutes and were extracted with chloroform. The extracts were washed with water and saturated salt solution and dried over magnesium sulfate. Then the solvent is evaporated.

The resulting balance (2,55 g) dissolved in 1,2-dichloroethane (25 ml) and to the solution at cooling by ice was added oxacillin (1.0 ml). The reaction mixture was stirred at room temperature for 1 hour and then cooled to

-20 degrees C. To a mix added the iron chloride (1.78 g) with the subsequent mixing at room temperature for 16 hours. To a mix added water 1 M HCl solution and then stirred at room temperature for 30 minutes followed by extraction with chloroform. The extracts were washed with water and saturated salt solution and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was dissolved in Meon (16 ml) and the solution was added to a solution of sulfuric acid (8 ml) in the Meon (24 ml), followed by stirring boiling under reflux for 18 hours. The reaction mixture was left to cool and then the solvent is evaporated. The reaction mixture was neutralized water 1 M sodium hydroxide solution, was extracted with chloroform, washed saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was dried, while receiving 5-chloro-1-cyclohexyl-3,4-dihydroisoquinoline (2,22 g).

Example of obtaining 27

N-[2-(4-Methoxyphenyl)ethyl]ciclohexencarboxilic (5,56 g) dissolved in toluene (120 ml) and to the solution has consistently added pentoxide Diaspora (3.0 g) and oxychloride phosphorus (6,0 ml), followed by stirring the mixture of boiling under reflux for 5.5 hours. The reaction mixture was left to cool and then the solvent is evaporated. It formed the remainder was added water 8 M solution of potassium hydroxide, water, and chloroform before full dissolution of insoluble substances to achieve a pH of around 8 and subsequent extraction of chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving 1-cyclohexyl-7-methoxy-3,4-dihydroisoquinoline (1,87 g).

Example of obtaining 28

Phosphoric acid (11.9 ml) was added to pentoxide Diaspora (20,0 g) for 5 minutes. The mixture was stirred at 150 C for 0.5 hours. To a mix added 3-fluoro-N-(2-phenylethyl)benzamide (5,00 g), followed by stirring at 160 C during 2,5 hours. After cooling to the reaction solution was added to the water and then added 28% aqueous ammonia, the solution was alkaline. The reaction solution was extracted with EtOAc, washed saturated salt solution and dried over magnesium sulfate. After filtration of the filtrate was concentrated under reduced pressure, while receiving 1-(3-torfanil)-3,4-dihydroisoquinoline (4,87 g).

Example of obtaining 29

Etiolirovannuyu acid (50 ml) was added to 3,3-debtor-N-(2-phenylethyl)ciclohexencarboxilic (6.4 g), followed by stirring when heated at 120 C for 2 hours. The reaction liquid added to ice-cold water (150 ml), were extracted with chloroform and dried over magnesium sulfate. The solvent is evaporated, while receiving 1-(3,3-diverticulosis)-3,4-dihydroisoquinoline (4.1 g).

Example of obtaining 30

Etiolirovannuyu acid (10 ml) was added to the TRANS-4-methyl-N-(2-phenylethyl)ciclohexencarboxilic (2 g), followed by stirring when heated at 120 C for 2 hours. To the reaction liquid added water and the mixture is then were extracted EtOAc. The organic layer is washed with water and saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated. It formed the remainder was added EtOH (10 ml) and then sodium borohydride (0.31 g) when ice cooling with direct the subsequent hashing within 2 hours. To the reaction liquid added water with the subsequent extraction EtOAc. The organic layer is washed with water and saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated, while receiving 1-(TRANS-4-methylcyclohexyl)-1,2,3,4-tetrahydroisoquinoline (2 g).

Example of obtaining 31

N-[2-(2-were)ethyl]butanone (4,58 g) dissolved in xylene (30 ml) and then to the solution was added pentoxide Diaspora (10 g), followed by stirring at 140 degrees C for 4 hours. The reaction mixture was left to cool and then the solvent is evaporated. For the complete dissolution of insoluble substances used water 8 M solution of potassium hydroxide, water, and chloroform. the pH of the reaction mixture is regulated to a value of about 8 and was extracted with chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 5-methyl-1-propyl-3,4-dihydroisoquinoline (2.14 g).

Example of obtaining 32

N-[2-(2-Bromo-5-methoxyphenyl)ethyl]-2-methoxyacetone (7,8 g) dissolved in xylene (80 ml) and the solution was added pentoxide Diaspora (11 grams), followed by stirring at 140 degrees C for 4 hours. Then the solvent is evaporated and the reaction mixture was added water 6 M sodium hydroxide solution to pH mixture was about 8. The reaction mixture was extracted with chloroform, washed saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc).

The resulting connection was dissolved in EtOH (30 ml) and the solution was added N,N-Diisopropylamine and 20% of palladium hydroxide, besieged on charcoal (400 mg), followed by stirring in hydrogen atmosphere at normal pressure and room temperature for 3 hours. Then the reaction mixture was filtered through celite for the Department of catalyst and solvent evaporated.

It formed the remainder was added saturated aqueous sodium bicarbonate (30 ml) and then EtOAc (20 ml). To the reaction of the liquid for 5 minutes was added dropwise solution chloroacetanilide (1,17 ml) in EtOAc (10 ml), followed by stirring for 5 hours. Then the reaction liquid were extracted EtOAc and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 2-(chloroacetyl)-8-methoxy-1-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline (367 mg).

Example of obtaining 33

[2-(4-Chlorophenyl)ethyl]Amin (3.5 g) dissolved in the mixed solution (45 ml) 1:2 EtOAc-saturated aqueous sodium bicarbonate. To the reaction of the liquid for 5 minutes solution was added ciclohexencarboxilic (3,35 ml) in EtOAc (18 ml). After stirring for 1.5 hours reactive liquid were extracted EtOAc, washed with water 1 M sodium hydroxide solution and water and dried with sodium sulfate. The solvent is evaporated and the resulting residue was dried, while receiving N-[2-(4-chlorophenyl)ethyl]ciclohexencarboxilic (5,69 g).

Example of obtaining 34

4,4-Deverticalisation acid (1.48 g) dissolved in methylene chloride (20 ml) and to the solution has consistently added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.68 g), 1-hydroxybenzotriazole (1,21 g) and (2-phenylethyl)Amin (1.2 ml) followed by mixing at room temperature for 18 hours. Then to the reaction liquid added saturated aqueous sodium bicarbonate, and then the mixture was extracted with chloroform. The extracts were washed with water and then with a saturated solution of salt and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 4,4-debtor-N-(2-phenylethyl)ciclohexencarboxilic (1,96 g).

Example of obtaining 35

Triperoxonane acid (27 ml) was added to the 2-[2-(2,2-DIMETHYLPROPANE)-1,2,3,4-tetrahydroisoquinoline-1-yl]propan-2-Ola (2,79 g) with the subsequent mixing at room temperature for 4 hours. Then the solvent is evaporated and the resulting residue was added saturated aqueous sodium bicarbonate with the subsequent extraction EtOAc. The extracts were washed with water and then dried over magnesium sulfate. The solvent is evaporated, while receiving 1-methyl-1-(1,2,3,4-tetrahydroisoquinoline-1-Il)aterpillar.

1-Methyl-1-(1,2,3,4-tetrahydroisoquinoline-1-Il)atypical (2,79 g) dissolved in the mixed solution (30 ml) 1:4 EtOAc-saturated aqueous sodium bicarbonate. To the reaction liquid cooling with ice was added dropwise solution chloroacetanilide (0.9 ml) in EtOAc (6 ml), followed by stirring at room temperature for 2 hours and extraction EtOAc. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 1-[2-(chloroacetyl)-1,2,3,4-tetrahydroisoquinoline-1-yl]-1-methylethylacetate (3,01 g).

Example of obtaining 37

Water (5 ml) and potassium carbonate (1.04 g) was added to solution hydrochloride 6-bromo-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (1,00 g) in 1,2-dichloroethane (5 ml). To the reaction mixture was added di-tert-BUTYLCARBAMATE (726 mg) and then dimethylaminopyridine (36,9 mg). The mixture was stirred at room temperature for 4 hours and was extracted with chloroform. Extract washed saturated aqueous solution of bicarbonate of sodium and saturated solution of salt, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure, while receiving tert-butyl-6-bromo-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1,11 g).

Example of obtaining 38

DMF (20 ml) was added to the mixture tert-butyl-6-bromo-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1,41 g), cyanide zinc (848 mg) and [1,1'-bis(diphenylphosphino)ferrocene]pallidiflora (535 mg), which then blew gaseous argon. Then to a mix added Tris(dibenzylideneacetone)dipalladium (458 mg) and the mixture is then mixed with 120 C in an argon atmosphere within 10 hours. Next to a mix added Tris(dibenzylideneacetone)dipalladium (200 mg), followed by stirring within 10 hours. The reaction mixture was filtered through celite and the filtrate was added EtOAc and water. The organic layer was collected, washed with water and saturated solution of salt, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving tert-butyl-6-cyano-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (361 mg).

Example of obtaining 39

4 M HCl/EtOAc (2 ml) was added to solution tert-butyl-6-cyano-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (361 mg) in EtOAc (1 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture together with the precipitated crystals diluted diethyl ether (5 ml). The crystals were collected by filtration, washed diethyl ether and dried in the air, while receiving hydrochloride 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile (259 mg).

Example of getting 40

Tert-butyl-7-(acetamide)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (861 mg) dissolved in the mixed solution (8 ml) 1:1 EtOAc-Meon, and the solution is then added to the mix 4 M HCl/EtOAc (2,8 ml). The reaction mixture was stirred at 50 C for 6 hours and then the solvent is evaporated.

It formed the remainder was added saturated aqueous sodium bicarbonate (15 ml) and then EtOAc (10 ml). To the reaction of the liquid for 5 minutes was added dropwise solution chloroacetanilide (0.2 ml) in EtOAc (5 ml), followed by stirring for 1 hour. The reaction liquid were extracted EtOAc and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was dried, while receiving N-{[2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline-7-yl]methyl}ndimethylacetamide (655 mg).

Example of obtaining 41

7-Bromo-1-cyclohexyl-3,4-dihydroisoquinoline (for 9.47 g) dissolved in N-methyl-2-pyrrolidone (150 ml), the solution is then added Tris(dibenzylideneacetone)dipalladium (2,97 g), 1,1'-bis(diphenylphosphino)ferrocene (7,19 g) and cyanide zinc (11.5g), followed by stirring at 120 C for 18 hours. Then to the reaction liquid added water and then filtered through celite for separation of insoluble substances. Insoluble substances were extracted EtOAc, washed saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 1-cyclohexyl-3,4-dihydroisoquinoline-7-carbonitril (7,19 g).

Example of obtaining 42

7-Bromo-1-cyclohexyl-3,4-dihydroisoquinoline (4,01 g) dissolved in 1,4-dioxane (100 ml), the solution is then added tributyl-(1-metoxifenil)tin (7,43 g), fluoride potassium (2,39 g) and tetrakis(triphenylphosphine)palladium (1,58 g), followed by stirring mixture at 80 C for 5 hours. After that to the reaction liquid additionally added tributyl-(1-metoxifenil)tin (2,47 g) and tetrakis(triphenylphosphine)palladium (1,58 g), followed by stirring within 14 hours. Then the reaction liquid is filtered through the aims and insoluble substances were separated. To insoluble substances added 4 M HCl/dioxane (20 ml), followed by stirring at 60 C for 30 minutes. The solvent is evaporated and to a mix added water and then were extracted EtOAc. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving 1-(1-cyclohexyl-3,4-dihydroisoquinoline-7-yl)Etalon (2.24 g).

Example of obtaining 43

1-(1-Cyclohexyl-3,4-dihydroisoquinoline-7-yl)Etalon (600 mg) dissolved in the THF (6 ml). To the reaction liquid cooling with ice added 0.5 M reagent Tebbe in toluene (4,7 ml) followed by mixing at room temperature for 45 minutes. Then to the reaction liquid consistently added diethyl ether and 10 drops of water 1 M NaOH solution. The reaction liquid dried with sodium sulfate and filtered through celite.

To the resulting solution added EtOH (8 ml) and 20% of palladium hydroxide, applied to the activated coal (900 mg). The solution was mixed in the atmosphere of hydrogen at room temperature and normal pressure for 13 hours. The catalyst is separated by filtration through celite and then the solvent is evaporated.

It formed the remainder was added saturated aqueous sodium bicarbonate (15 ml) and then EtOAc (10 ml). To the reaction of the liquid for 5 minutes added dropwise solution chloroacetanilide (265 mg) in EtOAc (5 ml), followed by stirring for 1 hour. The reaction liquid were extracted EtOAc and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 2-(chloroacetyl)-1-cyclohexyl-7-isopropyl-1,2,3,4-tetrahydroisoquinoline (186 mg).

Example of obtaining 44

Hydrochloride 6-bromo-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (1.0 g) dissolved in the THF (20 ml). To the reaction liquid at -78°With added 1.6 M solution of n-utility in n-hexane (6 ml), followed by stirring at -78 OC for 0.5 hours. After that to the reaction liquid acetone was added (20 ml), and then further stirring for 2 hours. The solvent is evaporated and to the reaction liquid added water with the subsequent extraction of mixture of chloroform. Extract washed saturated with water solution of sodium chloride and then dried over magnesium sulfate. The solvent is evaporated.

It formed the remainder was added saturated aqueous sodium bicarbonate (15 ml) and then EtOAc (10 ml). To the reaction of the liquid for 5 minutes was added dropwise solution chloroacetanilide (0,24 ml) in EtOAc (5 ml), followed by stirring within 18 hours. The reaction liquid were extracted EtOAc and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 2-[2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline-6-yl]propan-2-ol (646 mg).

Example of obtaining 45

It hydrochloride 5-bromo-1-isopropyl-8-methoxy-1,2,3,4-tetrahydroisoquinoline (3.0 g) was added EtOH (30 ml), triethylamine (1.3 ml) and 10% of palladium, besieged on coal (0,30 g), followed by stirring atmosphere of hydrogen within 2 hours. The reaction liquid is filtered through the aims and the solvent is evaporated. To the reaction liquid added water to 1 M NaOH solution with the subsequent extraction of mixture EtOAc. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was dissolved in EtOAc (30 ml). To a mix added 4 M HCl/EtOAc (5 ml) and besieged the solid is collected, while receiving hydrochloride 1-isopropyl-8-methoxy-1,2,3,4-tetrahydroisoquinoline (2.2 g).

Example of obtaining 46

(2-Bromo-5-were)acetonitrile (8,2 g) dissolved in the THF (60 ml), to a mix added complex borane-dimethyl sulfide (5 ml), followed by stirring at 80 C for 4 hours. The reaction liquid cooled on ice and to it was added the Meon (15 ml), followed by stirring at this time. Then the solvent is evaporated. The remainder was added 4 M HCl/dioxane (30 ml) and then the mixture is stirred when heated at 50 C for 1 hour. After it leaves to cool to a mix added toluene (100 ml) and besieged the solid is collected, while receiving hydrochloride 2-(2-bromo-5-were)of ethanamine (5.5 g).

Example of obtaining 47

Methanesulfonate (3,9 ml) was added to the mixture (2-bromo-5-were)methanol (9,2 g), dichloromethane (100 ml) triethylamine (8 ml) at cooling by ice and subsequent mixing at room temperature for 5 hours. To the reaction liquid added water 1 M HCl solution and the mixture was then extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. Then the solvent is evaporated.

Aluminium chloride (30 g) was added to benzene (60 ml). To the mixture while stirring and ice cooling gradually added 2,6-dimethylbenzoic acid (10 g), followed by stirring within 30 minutes. The temperature returned to room temperature and mix additionally was stirred for 1 hour, followed by stirring boiling under reflux for 4 hours. The reaction liquid was poured into ice-cold water (about 300 ml), filtered through the aims and were extracted with chloroform. The extracts were washed in water to 1 M NaOH solution and then dried over magnesium sulfate. The solvent is evaporated.

The resulting remainder (13 g) dissolved in carbon tetrachloride (150 ml). The solution at stirring and heating boiling with reflux added N-bromosuccinimide (10 g) and 2,2'-azobis(isobutyronitrile) (0.20 g), followed by stirring boiling under reflux for 7 hours. The reaction liquid was left to cool and filter. The resulting liquid is washed saturated aqueous solution of sodium bicarbonate and water solution of sodium thiosulfate and dried over magnesium sulfate. The solvent is evaporated.

It formed the remainder (15 g) was added EtOH (60 ml), water (40 ml) and sodium cyanide (1.5 g), followed by stirring when heated at 80 C for 5 hours. To the reaction liquid added water (200 ml) and then the mixture was extracted EtOAc and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane:chloroform), while receiving (2-benzoyl-3-were)acetonitrile (4.7g).

Example of obtaining 49

(2-benzoyl-3-were)acetonitrile (3,3 g) was added EtOH (40 ml), 4 M HCl/EtOAc (5 ml) and oxide of platinum(IV) (0,53 g), followed by stirring the mixture in the atmosphere of hydrogen for 5 hours. The reaction liquid is filtered through celite and then concentrated. To concentrate added toluene with the subsequent extraction of water 1 M HCl solution. To water layer was added 28% aqueous solution of ammonia and then the mixture were extracted with toluene and dried over magnesium sulfate. The solvent is evaporated and the residue was dissolved in toluene, the solution is then added 4 M HCl/EtOAc (5 ml) with the subsequent concentration. It formed the remainder was added iPrOH and diisopropyl ether and besieged the solid is collected, while receiving hydrochloride 8-methyl-1-phenyl-3,4-dihydroisoquinoline (1.5 g).

Example of getting 50

(2-benzoyl-3-were)acetonitrile (4.6 g) was added EtOH (70 ml), 4 M HCl/EtOAc (15 ml) and oxide of platinum(IV) (0.40 g), followed by stirring the mixture in the atmosphere of hydrogen for 3 days. The reaction liquid is filtered through celite and then concentrated. To concentrate added toluene with the subsequent extraction of mixture of water 1 M HCl solution. To water layer was added 28% aqueous solution of ammonia and then the mixture were extracted with toluene and dried over magnesium sulfate. The solvent is evaporated and the residue was dissolved in toluene. To a mix added 4 M HCl/EtOAc (7 ml) with the subsequent concentration under reduced pressure. It formed the remainder was added iPrOH and diisopropyl ether and besieged the solid is collected, while receiving hydrochloride 1-cyclohexyl-8-methyl-3,4-dihydroisoquinoline (2.2 g).

Example of obtaining 51

The mixture tetralone (1.50 g), 3-methoxyphenethylamine (1.86 g) and tetraisopropoxide titanium (4,55 ml) was mixed in argon atmosphere at 80 C for 1 hour. The reaction mixture was cooled in a bath of ice-Meon. To the reaction mixture while stirring, and internal temperature 0 C or lower was added to a mixture of formic acid (39 ml) and acetic anhydride (97 ml). When you are finished adding the reaction mixture was stirred at 80 C for 2 hours and it was added triperoxonane acid (158 ml), followed by stirring when the internal temperature of 70 C for 3 hours. After the reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The remainder did alkalescent with application of saturated aqueous solution of sodium bicarbonate and were extracted EtOAc. The organic layer is washed with a saturated solution of salt, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 6-methoxy-3,3',4,4'-tetrahydro-2H,2'H-Spiro[isoquinoline-1,1'-naphthalene]-2-carbaldehyde (1.86 g).

To polyphosphoric acid, obtained from 80% phosphoric acid (25 g) and pentoxide Diaspora (25 g), was added to the mix 3-methoxyphenethylamine (5,2 g) and tetrahydro-4H-4-pyrone (4,13 g) when the internal temperature of 90oC for 5 minutes. Then the reaction mixture was stirred for 40 minutes, cooled to room temperature and then poured into ice-cold water (500 ml). To the reaction mixture was added concentrated aqueous ammonia, that it was strongly alkaline, with the subsequent extraction EtOAc. The extracts were washed with water and saturated solution of salt, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (chloroform-EtOH-aqueous ammonia), while receiving 6-methoxy-2',3,3',4,5',6'-hexahydro-2H-Spiro[ethanole-1,4'-charge] (2.36 in).

Example of obtaining 53

When cooled in a bath of ice-Meon to lucialamorenita (3.03 g) was added THF (80 ml) with reception of suspensions. The suspension was added dicyclopropyl[(trimethylsilyl)oxy]acetonitrile (at 8.36 g). The mixture was stirred at room temperature for 20 hours and cooled in an ice bath. To a mix added sodium fluoride (3,35 g) and more water (4,23 ml) followed by mixing at room temperature for 1 hour. After that the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, while receiving oily substance (of 4.38 g). To oily substance added EtOAc (80 ml) and the mixture is then cooled ice. To a mix added 4 M HCl/EtOAc (8 ml) and then mixed together with precipitated solids at room temperature for 1 hour. After that the solid is collected by filtration, washed EtOAc and dried at low pressure and 90 C, while receiving hydrochloride 2-amino-1,1-dicyclopentyl (3,68 g).

Example of obtaining 54

In an ice bath in argon atmosphere zinc iodide (290 mg) was added to solution of Dicyclopentadiene (5,00 g) in 1,2-dichloroethane (50 ml). Then during 10 minutes to the mixture was added dropwise trimethylsilane (6,84 ml). The mixture was stirred at room temperature for 4 hours and it was further added trimethylsilane (1,71 ml) followed by mixing at room temperature for 20 hours. The reaction mixture was poured into the saturated aqueous solution of sodium bicarbonate and were extracted EtOAc. Extract washed saturated aqueous solution of sodium bicarbonate and saturated salt solution and dried over magnesium sulfate. To a mix added activated charcoal and then filtered through celite. The filtrate was concentrated under reduced pressure, while receiving dicyclopropyl[(trimethylsilyl)oxy]acetonitrile (at 8.36 g).

Example of obtaining 55

10% of palladium, besieged on coal (300 mg)was added to a solution of 2-benzyl-1-(1-methoxy-1-methylethyl)-1,2,3,4-tetrahydroisoquinoline (1,17 g) in MeOH (12 ml). The reaction mixture was stirred in the atmosphere of hydrogen at room temperature for 8 hours. The reaction liquid is filtered through the aims and the filtrate was concentrated under reduced pressure, while receiving 1-(1-methoxy-1-methylethyl)-1,2,3,4-tetrahydroisoquinoline (770 mg).

Example of obtaining 56

When cooled in a bath of ice-Meon in argon atmosphere solution 2-(2-benzyl-1,2,3,4-tetrahydroisoquinoline-1-yl)propan-2-ol (1.27 g) in THF (7 ml) was added dropwise sodium hydride sodium (60%, 199 mg) in THF (5 ml) followed by mixing at room temperature for 0.5 hours. Then the reaction liquid cooled on ice and to it was added mutiliated (0,42 ml). The mixture was stirred at room temperature for 8 hours. To a mix added sodium hydride (60%, 199 mg) and mutiliated (0,42 ml) followed by mixing at room temperature for 12 hours. To the reaction solution was added to the water with the subsequent extraction EtOAc. The extracts were washed with a saturated solution of salt, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 2-benzyl-1-(1-methoxy-1-methylethyl)-1,2,3,4-tetrahydroisoquinoline (1,17 g).

Example of getting 57

On the bath dry ice-acetone in argon atmosphere of 1.0 M solution metallitia in diethyl ether (16,2 ml) was added dropwise to the solution of ethyl-2-benzyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylate (1,99 g) in THF (20 ml) for 15 minutes. The reaction liquid into the bath dry ice-acetone was stirred for 0.5 hour and then further stirred in an ice bath for 1 hour. The reaction liquid again cooled in the bath dry ice-acetone and to it was added 1,04 M solution motility in diethyl ether (3,24 ml). The reaction liquid into the bath dry ice-acetone was stirred for 0.5 hour and then mixed in an ice bath for 1 hour. To the reaction liquid added water with the subsequent extraction of mixture EtOAc. The extracts were washed with a saturated solution of salt, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 2-(2-benzyl-1,2,3,4-tetrahydroisoquinoline-1-yl)propan-2-ol (1.27 g).

Example of obtaining 58

Triacetoxyborohydride sodium (6.11 g) was added to solution hydrochloride ethyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylate (4,98 g) and benzaldehyde (2,72 d) acetic acid (50 ml) in an ice bath. The mixture was stirred at room temperature for 15 hours. To the reaction liquid added 1 M aqueous solution of NaOH and the mixture was extracted with chloroform. The extracts were washed with water and saturated solution of salt, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving the ethyl-2-benzyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylate (1,99 g).

Example of getting 59

Solution 5-bromo-7,8-dimethoxy-1-phenyl-3,4-dihydroisoquinoline (450 mg), EtOH (30 ml), 10% of palladium, besieged on coal (80 mg), and 28% solution of sodium methoxide in Meon (0.1 ml) was mixed in the atmosphere of hydrogen at room temperature during the night. Insoluble substances separated by filtration, and the filtrate was concentrated, while receiving 7,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (350 mg).

The solution chloroacetanilide (177 mg) in EtOAc (12 ml) was added dropwise to the mixture 7,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (350 mg), saturated aqueous solution of sodium bicarbonate (50 ml) and EtOAc (50 ml) with stirring. When you are finished adding drop by drop the mixture was stirred for 2 hours and were extracted EtOAc. Extract washed consistently saturated aqueous solution of bicarbonate of sodium and saturated solution of salt, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (chloroform-EtOH), while receiving 2-(chloroacetyl)-7,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (349 mg).

Example of getting 60

1-Cyclohexyl-N-isobutyl-3,4-dihydroisoquinoline-7-carboxamide (689 mg) dissolved in MeOH (12 ml). To the reaction mixture was added sodium borohydride (100 mg) followed by mixing at room temperature for 5 hours. The solvent evaporated. It formed the remainder was added water and chloroform. The rest were extracted with chloroform and dried over magnesium sulfate. Then the solvent is evaporated under reduced pressure, while receiving 1-cyclohexyl-N-isobutyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide.

It formed the remainder was added saturated aqueous sodium bicarbonate (10 ml) and then EtOAc (5 ml). To the reaction of the liquid for 5 minutes was added dropwise solution chloroacetanilide (0,19 ml) in EtOAc (5 ml), followed by stirring the mixture for 1 hour. Then the reaction liquid were extracted EtOAc and dried over magnesium sulfate. The solvent is evaporated, while receiving 2-(chloroacetyl)-1-cyclohexyl-N-isobutyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (410 mg).

Example of getting 61

5-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinoline (1.7 g) dissolved in MeOH (15 ml), the solution is then added sodium borohydride (376 mg) followed by mixing at room temperature for 5 hours. Under reduced pressure evaporated solvent and to a mix added water and chloroform. The mixture was extracted with chloroform and dried over magnesium sulfate. The solvent is evaporated.

It formed the remainder was added saturated aqueous sodium bicarbonate (20 ml) and then EtOAc (15 ml). To the reaction liquid drops for 5 minutes solution was added to chloracetophenone (0,66 ml) in EtOAc (5 ml), followed by stirring the mixture for 1 hour. The reaction liquid were extracted EtOAc

and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 2-(chloroacetyl)-5-methoxy-1-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline (550 mg).

Example of obtaining 62

5-Bromo-8-methoxy-1-propyl-1,2,3,4-dihydroisoquinoline (5.5 g) dissolved in EtOH (30 ml). To the reaction mixture was added DMF (3.4 ml) and 10% of palladium, besieged on coal (500 mg), followed by stirring in hydrogen atmosphere at normal pressure and room temperature for 3 hours. After that the catalyst was separated by filtration through celite and to the reaction mixture was added sodium borohydride (740 mg), followed by stirring the mixture at room temperature for 2 hours. The solvent is evaporated under reduced pressure and the resulting residue was added water and chloroform. The mixture was extracted with chloroform and dried over magnesium sulfate. The solvent is evaporated under reduced pressure.

The resulting residue was dissolved in EtOAc (10 ml) and then to the solution at cooling by ice was added 4 M HCl/EtOAc (15 ml), followed by stirring the mixture at room temperature. Formed insoluble materials collected and washed EtOAc, while receiving 8-methoxy-1-propyl-1,2,3,4-tetrahydroisoquinoline (3,67 g).

Example of obtaining 63

The resulting residue (1 g) was dissolved in THF (30 ml) with subsequent cooling at -78°North To the reaction mixture was added 2.6 M solution of n-utility in n-hexane (a 3.7 ml), followed by stirring within 30 minutes. To mix at -78°With acetone was added (30 ml) and the temperature was raised to room temperature with the subsequent hashing within 1 hour. Then the solvent is evaporated under reduced pressure. It formed the remainder was added water and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and then the solvent is evaporated under reduced pressure.

The resulting residue was dissolved in the mixed solution EtOAc (10 ml) and saturated aqueous sodium bicarbonate (15 ml). To the reaction mixture was added dropwise solution chloroacetanilide (683 mg) in EtOAc (5 ml) followed by mixing at room temperature for two days. Then to a mix added water with the subsequent extraction EtOAc. The organic layer is washed with a saturated solution of salt and dried over magnesium sulfate. Then the solvent is evaporated under reduced pressure. The resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 2-[2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline-7-yl]propan-2-ol (606 mg).

Example of obtaining 64

1-Cyclohexyl-3,4-dihydroisoquinoline-7-carbonitril (1.01 g) dissolved in EtOH (15

ml), the solution is then added 6 M aqueous solution of NaOH (7,0 ml), followed by stirring the mixture of boiling under reflux for 6 hours. To a mix added water and then washed EtOAc. To a mix added 1 M aqueous solution of HCl to achieve a pH of about 3, and then added saturated aqueous solution of sodium sulfate. The mixture was extracted mixed solution 4:1 chloroform-iPrOH, washed saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated, while receiving 1-cyclohexyl-3,4-dihydroisoquinoline-7-carboxylic acid (1,09 g).

Example of obtaining 65

1-Cyclohexyl-3,4-dihydroisoquinoline-7-carboxylic acid (1,15 g) dissolved in methylene chloride (15 ml). The solution was added hexaphosphate About-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (2,03 g), N,N-Diisopropylamine (1,55 ml) and 2-methyl-1-propanamine (0,87 ml), followed by stirring the mixture at room temperature for 18 hours. Then to a mix added water with the subsequent extraction of chloroform. The extracts were washed with a saturated solution of salt and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving 1-cyclohexyl-N-isobutyl-3,4-dihydroisoquinoline-7-carboxamide (700 mg).

Example of obtaining 66

The sodium methoxide (9,46 g) was added to the suspension 10b-(chloromethyl)-9-ethyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione (14,0 ml) in MeOH (140 ml) at cooling by ice. The mixture was stirred at room temperature for 0.5 hour and then heated in boiling under reflux for 3 hours. To a mix added EtOAc and water with subsequent filtering. The organic layer of leachate collected, washed saturated salt solution and dried over magnesium sulfate. Were added activated carbon and silica gel with subsequent filtering mixture. The filtrate was concentrated under reduced pressure, while receiving 7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinoline (4,75 g).

Example of obtaining 67

Sodium borohydride (900 mg) was added to mixed solution solution 5,8-dimethoxy-1-phenyl-2-TRIFLUOROACETYL-1,2,3,4-tetrahydroisoquinoline (4,21 g) in THF (30 ml) and EtOH (100 ml) at room temperature and at hashing. The reaction mixture was stirred at room temperature for 3 hours and then mixed at 40 degrees C for 30 minutes and concentrated under reduced pressure. It formed the remainder was added 3 M aqueous solution of HCl (30 ml) with the subsequent boiling under reflux for about 5 minutes. After cooling the mixture was doing strongly alkaline using 20% aqueous solution of NaOH and was extracted with chloroform. The organic layer is washed with a saturated solution of salt, dried over magnesium sulfate and concentrated under reduced pressure, while receiving 5,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (3,05 g).

Example of obtaining 68

In argon atmosphere solution 2.5-dimethoxyphenethylamine (3,175 g) in benzene (4 ml) was added with stirring to suspension of benzaldehyde (1.86 g) and magnesium sulfate (3,89 g) in benzene (10 ml). Took place exothermic reaction, the reaction mixture is then mixed throughout the night. Once the reaction is the reaction liquid is filtered and the filtrate was concentrated under reduced pressure, while receiving 2-(2,5-acid)-N-[(1E)-phenylethylene]ananamin (4.72 in).

Example of getting 69

2-(2,5-Acid)-N-[(1E)-phenylethylene]ananamin (4,719 g) dissolved in triperoxonane acid, followed by boiling solution under reflux for 2 days. The reaction mixture was cooled to room temperature, and it was gradually added triperoxonane anhydride (55 ml). The mixture was heated under reflux for 3 days, cooled to room temperature, and concentrated under reduced pressure. The resulting balance was extracted saturated aqueous solution of sodium bicarbonate and chloroform. The organic layer washed saturated aqueous solution of bicarbonate of sodium and saturated solution of salt, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving 5,8-dimethoxy-1-phenyl-2-(TRIFLUOROACETYL)-1,2,3,4-tetrahydroisoquinoline (4,168 g).

Example of getting 70

tert-Butyl-7-cyano-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (2,38 g) dissolved in methylene chloride (40 ml). The solution was added 0,99 M solution of sibutramine.meridia in n-hexane (7,8 ml) followed by stirring at -78 OC for 4 hours. Then the reaction mixture was further added 0,99 M solution of sibutramine.meridia in n-hexane (28 ml). To stop reaction was added saturated aqueous solution Rochelle salt with the subsequent mixing of the mixture during the night. The mixture was extracted EtOAc. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (benzene-EtOAc).

The resulting residue was dissolved in mixed solvent (90 ml) 8:1 EtOH-acetic acid-water. The solution was added hydroxylamine hydrochloride (812 mg) and sodium acetate (930 mg) followed by stirring the solution at room temperature for 28 hours. Then the solvent is evaporated. To a mix added water and the mixture was then extracted with chloroform, washed saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated, while receiving tert-butyl-1-cyclohexyl-7-[(hydroxyimino)methyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (2,03 g).

Example of getting 71

tert-Butyl-1-cyclohexyl-7-[(hydroxyimino)methyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.04 g) dissolved in the mixed solvent (20 ml) 8:1:1 EtOH-acetic acid-water. The solution was added 10% of palladium, besieged on activated carbon (500 mg), followed by stirring the mixture in the atmosphere of hydrogen at room temperature and normal pressure within 4 hours. Then the reaction mixture was filtered through celite and the solvent is evaporated.

The resulting residue was dissolved in methylene chloride (12 ml), the solution is then added triethylamine (880 mg), acetic anhydride (385 mg) and 4-dimethylaminopyridine (70 mg), followed by stirring the mixture at room temperature for 16 hours. Then to a mix added water and were extracted with chloroform. The extracts were washed with a saturated solution of salt and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform), while receiving tert-butyl-7-(atsetamidometil)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (875 mg).

Example of obtaining 72

tert-Butyl-1-cyclohexyl-7-[(hydroxyimino)methyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (995 mg) dissolved in a mixture of EtOH-acetic acid-water (8:1:1, 20 ml). To the reaction mixture was added 10% of palladium, besieged on coal (480 mg), followed by stirring atmosphere of hydrogen at room temperature and normal pressure within 4 hours. Then the reaction mixture was filtered through celite and the solvent is evaporated, while receiving tert-butyl-7-(aminomethyl)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (956 mg).

Example of getting 73

tert-Butyl-7-(aminomethyl)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (999 mg) dissolved in methylene chloride. The solution was added somaclonal acid (0,33 ml), triethylamine (1,2 ml) and hexaphosphate About-(benzotriazol-1-yl)-N,N,N',N'-tetranitramene (1,32 g) with the subsequent mixing at room temperature for 18 hours. To a mix added water and then were extracted with chloroform. Extract washed 1 M aqueous solution of NaOH and saturated salt solution and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel, while receiving tert-butyl-1-cyclohexyl-7-[(isobutylamino)methyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (468 mg).

Example of getting 74

1-Cyclohexyl-3,4-dihydroisoquinoline-7-ol (2 g) dissolved in MeOH (40 ml), the solution is then added sodium borohydride (396 mg) followed by mixing at room temperature for 4 hours. Then the solvent is evaporated. To a mix added water and were extracted with chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated.

tert-Butyl-1-cyclohexyl-7-(2-oxopropoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (808 mg) dissolved in methylene chloride (15 ml). To the reaction mixture dropwise at -78°With added bis-(2-methoxyethyl)aminomercaptan (0,65 ml) methylene chloride (5 ml) followed by mixing at room temperature for up to 14 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate and then were extracted with chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc), while receiving tert-butyl-1-cyclohexyl-7-(2,2-diffiplomacy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (747 mg).

Example of obtaining 77

1 M aqueous solution of NaOH was added to the hydrochloride (1S)-1-isopropyl-8-methoxy-1,2,3,4-tetrahydroisoquinoline (808 mg). The reaction mixture was extracted with chloroform and the organic layer was dried over magnesium sulfate. The solvent is evaporated under reduced pressure. Mixed solution of 1 M solution tribromida boron in dichloromethane (13.4 ml) and dichloromethane (10 ml) was cooled to -78 C and to it was added dropwise solution residue extraction in dichloromethane (10 ml). The temperature is gradually increased, and the reaction mixture was stirred at room temperature for 24 hours. Then the reaction mixture was added saturated aqueous sodium bicarbonate, and chloroform. After the separation of the liquid layer water layer is applied in the following reaction.

The established water layer was added di-tert-BUTYLCARBAMATE with subsequent mixing at room temperature for 5 hours. The mixture was neutralized 1 M aqueous solution of HCl and was extracted with chloroform. The organic layer was rinsed with water and dried over magnesium sulfate. Then the solvent is evaporated under reduced pressure, while receiving tert-butyl-(1S)-8-hydroxy-1-isopropyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (973 mg).

Example of obtaining 78

tert-Butyl-(1S)-8-hydroxy-1-isopropyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (973 mg) dissolved in the mixed solution iPrOH (6 ml) and 30% aqueous solution of potassium hydroxide (3 ml). To the reaction mixture was added Chlorodifluoromethane by injection, followed by stirring at 70 C for 20 hours. To a mix added water and then were extracted with chloroform. The organic layer was dried over magnesium sulfate. The solvent is evaporated under reduced pressure and then the residue was purified column chromatography on silica gel (hexane-EtOAc).

The resulting balance (790 mg) dissolved in the EtOAc. The solution was added 4 M HCl/EtOAc (5.8 ml), followed by stirring at 60 degrees C for 18 hours. Then the solvent is evaporated under reduced pressure, while receiving hydrochloride (1S)-8-(deformitate)-1-isopropyl-1,2,3,4-tetrahydroisoquinoline (642 mg).

Example of getting 79

1 M aqueous solution of NaOH was added to the hydrochloride (1S)-8-methoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1,81 g). The reaction mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent is evaporated under reduced pressure. Mixed mortar solution of 1 M tribromida boron in dichloromethane (26,3 ml) and dichloromethane (30 ml) was cooled to -78 C and to it was added dropwise solution residue extraction in dichloromethane (10 ml). The temperature is gradually increased, and the reaction mixture was stirred at room temperature for 24 hours. Then the reaction mixture was added saturated aqueous sodium bicarbonate, and chloroform. After the separation of the liquid at the layers of organic layer was dried over magnesium sulfate. The solvent is evaporated under reduced pressure.

The resulting balance (1.48 g) dissolved in the THF (50 ml). The solution was added to 1 M aqueous solution of NaOH (8 ml) and di-tert-BUTYLCARBAMATE (2,87 g), followed by stirring the mixture at room temperature for 5 hours. Then the solvent is evaporated under reduced pressure. It formed the remainder was added water and 1 M aqueous solution of HCl and the mixture was extracted with chloroform. The organic layer was rinsed with water and dried over magnesium sulfate. Then the solvent is evaporated under reduced pressure and the resulting residue was purified column chromatography on silica gel (hexane-EtOAc).

The resulting balance (1.24 g) dissolved in the mixed solution iPrOH (20 ml) and the 50% aqueous sodium hydroxide solution (10 ml). To the reaction mixture was added Chlorodifluoromethane injection, followed by stirring at 70 C for 14 hours. To a mix added water and then it was extracted with chloroform. The organic layer was dried over magnesium sulfate. The solvent is evaporated under reduced pressure and then the resulting residue was purified column chromatography on silica gel (hexane-EtOAc).

The resulting balance (927 mg) dissolved in the EtOAc (25 ml) and the solution is then added 4 M HCl/EtOAc (6,2 ml), followed by stirring at 60 degrees C for 18 hours. Then the solvent is evaporated under reduced pressure, while receiving hydrochloride (1S)-8-(deformitate)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (770 mg).

Example of getting 80

28% aqueous ammonia is added to 1-oxirane-2-illlogical with the subsequent hashing for 11 hours. The solvent is evaporated under reduced pressure and then water was removed by azeotropic distillation with toluene.

The resulting residue was dissolved in the mixed solution EtOH-diethyl ether. The solution was added oxalic acid, followed by stirring for some time. Formed insoluble materials collected, while receiving oxalate 1-(2-amino-1-hydroxyethyl)cyclohexanol (853 mg).

Example of getting 81

(1R,2S)-1-amino-2-indanol (511 mg) dissolved in toluene (60 ml). The solution was added when the ice cooling solution of the complex is 1 M borane-THF in THF (8,16 ml) followed by mixing at room temperature for 1 hour. Then to a mix added 7-bromo-1-cyclohexyl-3,4-dihydroisoquinoline (1 g), followed by stirring at room temperature for 3 days. The reaction was stopped by adding triperoxonane acid, followed by additional hashing at 60 degrees C for 1 hour. The solvent is evaporated. To a mix added 1 M aqueous solution of sodium hydroxide and then were extracted with chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving raw (1S)-7-bromo-1-cyclohexyl-3,4-tetrahydroisoquinoline (1.06 g). The resulting raw product (203 mg) dissolved in EtOH (9 ml). To a mix added D-(-)-tartaric acid (104 mg) at 80 C. the Mixture gradually cooled to room temperature, with the subsequent hashing within 12 hours. Formed insoluble materials collected, while receiving (1S)-7-bromo-1-cyclohexyl-3,4-tetrahydroisoquinoline (72 mg).

Example of getting 82

In argon atmosphere to suspension (1R,2S)-1-aminoindan-2-ol (3.04 from g) in toluene (60 ml) and ice cooling solution was added 1,09 M borane-THF (18,7 ml) followed by mixing at room temperature for 1 hour. Then the reaction mixture at ice cooling solution was added 1-[2-[(trifluoromethyl)benzyl]-3,4-dihydroisoquinoline (4,00 g) in toluene (20 ml). The mixture was stirred at 4 OC for 45 hours. To stop reaction was added triperoxonane acid (20 ml). The mixture was heated in boiling under reflux for 1 hour and then cooled. To a mix added 28% aqueous ammonia (30 ml)to make it more alkaline. The mixture was extracted EtOAc. The extracts were washed 3 times and additionally washed saturated solution of salt, dried over magnesium sulfate and then filtered. The filtrate is concentrated, while receiving a yellow oily substance (4.11 g). Oily substance dissolved in acetonitrile (80 ml). To a mix added N-acetyl-L-leucine (2,39 g) at 80 degrees C. the Mixture gradually cooled, followed by stirring at 60 C for 2 hours at room temperature for 12 hours. When the crystals besieged, crystals were collected by filtration, was chilled on ice, washed with acetonitrile and dried in the air, while receiving crystals (2,48 g). Crystals recrystallized from acetonitrile (50 ml), while receiving salt N-acetyl-L-leucine 1-[2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydroisoquinoline (1,72 g).

Example of getting 83

In argon atmosphere solution 1,09 M borane-THF (48,8 ml) was added to suspension (1R,2S)-1-aminoindan-2-ol (3,79 g) in toluene (60 ml) at cooling by ice and subsequent mixing at room temperature for 1 hour. Then the reaction mixture at ice cooling solution was added 7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinoline (4,70 g) in THF (40 ml). The mixture was stirred at 4 OC for 8 hours. To stop reaction was added triperoxonane acid (15 ml). The mixture was heated in boiling under reflux for 1 hour. To a mix added chloroform and 28% aqueous ammonia. The organic layer washed 3 times with water, and were extracted 5% aqueous solution of acetic acid. The extract did alkaline add 28% aqueous ammonia and were extracted EtOAc. The extracts were washed twice with water and then washed with a saturated solution of salt, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, while receiving a yellow oily substance (3.15 in). Oily substance dissolved in iPrOH (63 ml), to the solution gradually at 90oC added (2S,3S)-2,3-bis(benzoyloxy)succinic acid (4,14 g) at 90 C. the Mixture was heated in boiling under reflux for 1 hour and gradually cooled to room temperature, with the subsequent mixing at room temperature for 3 hours. When the crystals are deposited, the crystals were collected by filtration, washed iPrOH and simple ether and dried at low pressure, while receiving (2S,3S)-2,3-bis(benzoyloxy)succinate (7-ethyl-1-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline (5,54 g).

Example of getting 84

Example of obtaining 85

Tert-butyl-(1S)-8-hydroxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1,53 g) dissolved in dichloromethane (20 ml). The solution at -78°With added 2,6-lutidine (1.1 ml) and anhydride triftormetilfullerenov acid (0.9 ml) followed by mixing at room temperature for 16 hours. Then to a mix added saturated aqueous sodium bicarbonate and then were extracted with chloroform. Extract washed saturated with water solution of sodium chloride and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (ethyl acetate, hexane), while receiving tert-butyl (1S)-1-phenyl-8-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydroisoquinoline-2(1H)-carboxylate (2,08 g).

Example of obtaining 86

To N-[2-(2-bromo-5-were)ethyl]-2-methoxyacetone (3,9 g) was added xylene (50 ml), followed by stirring when heated at 60 C. To the reaction mixture while stirring was added phosphorus pentoxide (7,0 g), followed by stirring at 140 degrees C for 3 hours. After leaving the reaction mixture to cool the supernatant reaction mixture was unloaded. The mixture was dissolved in a mixture of water, toluene and aqueous sodium hydroxide solution and the solution was extracted with toluene. The extract is additionally were extracted 1 M aqueous solution of HCl. Selected water layer is neutralized, was extracted with toluene and dried over magnesium sulfate. After filtering layer solution was added 4 M HCl/EtOAc (5 ml) and the solvent is evaporated under reduced pressure. It formed the remainder was added EtOH (50 ml), toluene (10 ml) and sodium borohydride (1.0 g), followed by stirring the mixture within 4 days. To the reaction mixture was added to 1 M aqueous solution of HCl, followed by stirring for 5 hours. After that to a mix added aqueous solution of sodium hydroxide and then were extracted with chloroform. The solvent is evaporated. It formed the remainder was added sodium carbonate (1.0 g), water (30 ml), toluene (30 ml) and chloracetophenone (0.3 ml) at cooling by ice, followed by stirring the mixture at room temperature for 17 hours. To the reaction liquid added water and the mixture is then were extracted with chloroform. Extract washed 1 M aqueous solution of HCl and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified by chromatography on silica gel, while receiving 5-bromo-2-(chloroacetyl)-1-(methoxymethyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline (0,323 g).

Example of obtaining 87

Hydrochloride 8-ethyl-5-methoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline from 2.06 g) dissolved in methylene chloride (40 ml). To the reaction mixture was added to the solution of tribromida boron in dichloromethane (13,6 ml) at -78°With subsequent mixing at room temperature for 16 hours. After that to the reaction mixture was added saturated aqueous solution of sodium bicarbonate to the reaction mixture to make alkaline. Then to the reaction solution was added di-tert-BUTYLCARBAMATE (2,96 g) with the subsequent mixing at room temperature for 3 hours. The reaction liquid were extracted with chloroform, washed saturated with water solution of sodium chloride and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was dissolved in dichloromethane (20 ml). To a mix added 2,6-lutidine (1.8 ml) and anhydride triftormetilfullerenov acid (1,55 ml) followed by mixing at room temperature for 18 hours. After that to a mix added water and then were extracted with chloroform. Extract washed saturated with water solution of sodium chloride and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (EtOAc:hexane). The resulting residue was dissolved in DMF (30 ml). To a mix added the palladium(II) acetate (305 mg), triethylsilane (5,4 ml) and 1,1'-bis(diphenylphosphino)ferrocene (750 mg) followed by stirring at 70 C for 20 hours. Then to a mix added water and the mixture is then filtered through celite and was extracted with diethyl ether. Extract washed saturated with water solution of sodium chloride and dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (EtOAc:hexane), while receiving tert-butyl-8-ethyl-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (to 2.29 g).

Example of obtaining 88

When cooled in an ice bath to methoxyethanol (100 ml) at hashing for 20 minutes were added to the mix hydride sodium (suspension 8 g hydride sodium mineral oil (60%), washed with hexane) and THF (10 ml) with a 2-methoxyethoxide sodium and subsequent additional stirring for 2 hours. When mixing a solution of 2-methoxyethoxide sodium 2-methoxyethanol (55 ml) was added to the solution hydrochloride-1-(chloromethyl)-7-ethyl-3,4-dihydroisoquinoline (8.5 g) methoxyethanol (50 ml) with cooled in an ice bath for 5 minutes. The reaction mixture was heated at 60 C, followed by stirring for 3 hours in argon atmosphere. The reaction mixture was cooled to room temperature and diluted THF (150 ml) with subsequent filtering. The filtrate was concentrated under reduced pressure. It formed the remainder was added saturated aqueous solution of ammonium chloride and the rest were extracted EtOAc. The organic layer is washed with water and saturated with water solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (hexane:EtOAc), while receiving 7-ethyl-1-[(2-methoxyethyl)methyl]-3,4-dihydroisoquinoline (2,13 g).

Example of getting 89

tert-Butyl-(1S)-1-phenyl-8-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.75 g) dissolved in N,N-dimethylacetamide (40 ml). To the reaction mixture was added zinc (537 mg), cyanide zinc (1,15 g), triveratech palladium(II) (682 mg) and biphenyl-2-yl(di-tert-butyl)phosphine (1.22 g). The temperature was increased from room temperature up to 95 degrees C for 45 minutes and then the mixture was stirred at 95 degrees C for 18 hours. To a mix added water and then filtered through celite. Then the solution was extracted with diethyl ether. Extract washed saturated with water solution of sodium chloride and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (EtOAc-hexane), while receiving tert-butyl-(1S)-8-cyano-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (796 mg).

Example of getting 90

1,55 M solution of n-utility in hexane (10,94 ml) was added with stirring to a solution of 1(methoxymethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline (3,07 g) in THF (60 ml) in argon atmosphere for about 8 minutes at -70 degrees or below, followed by additional hashing within 30 minutes. To the reaction mixture was added with stirring the solution (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-4-methylbenzenesulfonyl (3,375 g) in THF (25 ml) for 5 minutes at -70 C or below, followed by further stirring for 1 hour. After that to the mix at the same temperature added saturated centripetal and the temperature was increased up to room temperature. The mixture was extracted simple ether. The organic layer washed saturated with water solution of sodium chloride and dried over magnesium sulfate and then the solvent is evaporated. The resulting residue was purified column chromatography on silica gel (hexane:EtOAc), while receiving (1R)-1-(methoxymethyl)-5-methyl-2-[(R)-(4-were)sulfinil]-1,2,3,4-tetrahydroisoquinoline (2,144 g) (value Rf = 0,14).

Example of getting 91

A blended solution (1R)-1-(methoxymethyl)-5-methyl-2-[(R)-(4-were)sulfinil]-1,2,3,4-tetrahydroisoquinoline (2,47 g) in EtOH (45 ml) and THF (10 ml) was added to concentrated hydrochloric acid (3,1 ml) was mixed at 0 C, and then further stirring, for 10 minutes. To a mix added saturated aqueous solution of sodium carbonate (50 ml) with subsequent extraction EtOAc. The organic layer was rinsed 1 M aqueous solution of sodium hydroxide and saturated with water solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (chloroform:EtOH:aqueous ammonia), while receiving (1R)-1-(methoxymethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline (1,276 g).

Chemical structure of compounds obtained by means of the above examples obtain shown in tables 6 to 12 (see below). In addition, in the same way as the ways of the above examples obtain, connection examples obtain shown in tables 13-35 (see below), receive, applying the original compounds. The data of instrumental analysis of these compounds examples obtain shown in tables 36-42 (see below).

Example 1

(1S)-2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (4,496 g) dissolved in acetonitrile (100 ml). To a mix added potassium carbonate (6.25 g), iodide Tetra-n-butylamine (679 mg) and hydrochloride, 1-(aminomethyl)cyclohexanol (4,50 g), followed by stirring at 60 C for 6 hours. Then the solvent is evaporated and the reaction mixture was added to the water with the subsequent extraction of mixture of chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel, while receiving 1-[({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol (3,02 g).

2-Acryloyl-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (516 mg) dissolved in the iPrOH (15 ml). To the reaction mixture was added hydrochloride, 1-(aminomethyl)cyclohexanol (635 mg) and triethylamine (0,59 ml), followed by stirring boiling under reflux for 16 hours. Then the solvent is evaporated and to a mix added water with the subsequent extraction of chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon) and then further purified column chromatography on alkaline silica gel (chloroform), while receiving 1-({[3-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-3-oxopropyl]amino}methyl)cyclohexanol (214 mg).

The resulting connection (214 mg) dissolved in EtOH (8 ml). To the reaction mixture was added oxalic acid (51 mg), while receiving oxalate 1-({[3-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-3-oxopropyl]amino}methyl)cyclohexanol (229 mg).

Example 3

1-Cyclohexyl-7-isopropoxide-3,4-dihydroisoquinoline (245 mg) dissolved in MeOH (6 ml). After that to the reaction liquid added sodium borohydride (40 mg), followed by stirring the mixture at room temperature for 4 hours. The solvent is evaporated under reduced pressure and to a mix added water and chloroform. The reaction liquid were extracted with chloroform and dried over magnesium sulfate. Then the solvent is evaporated under reduced pressure.

It formed the remainder was added saturated aqueous sodium bicarbonate (6 ml), to a mix added EtOAc (3 ml). To the reaction of the liquid for 5 minutes was added dropwise solution chloroacetanilide (102 mg) in EtOAc (3 ml), followed by stirring the mixture for 1 hour. After the reaction liquid were extracted EtOAc and dried over magnesium sulfate and then the solvent is evaporated.

The resulting residue was dissolved in 1,4-dioxane (8 ml). The solution was added (2R)-1-amino-2-propanol (180 mg) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (146 mg) followed by stirring at 50 C for 3 hours. Then the solvent is evaporated and to the reaction liquid added water with the subsequent extraction of mixture EtOAc. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon).

The resulting balance (211 mg) dissolved in the mixed solution 1:4 iPrOH-diethyl ether. To the reaction liquid added oxalic acid (49 mg), while receiving oxalate (2R)-1-{[2-(1-cyclohexyl-7-isopropoxide-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}propan-2-ol (223 mg).

Example 4

N-(2-Cyclogexa-1-ene-1-ileti)-N-[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]-2,2,2-triptorelin (210 mg) dissolved in methylene chloride (5 ml). The solution was added 75% of the 3-chloroperbenzoic acid (152 mg) followed by mixing at room temperature for 18 hours. After that to the reaction liquid added saturated aqueous solution of sodium sulfite, followed by stirring for some time. The reaction liquid were extracted with chloroform and extract washed 1 M aqueous solution of NaOH and saturated salt solution and then dried over magnesium sulfate.

The solvent is evaporated and the resulting residue was dissolved in mixed solvent (7.5 ml) 4:1 THF-1,5% aqueous solution of sulfuric acid with subsequent mixing with boiling under reflux for 5 hours. To the reaction liquid added water and then were extracted EtOAc. The extracts were washed with saturated salt solution and then dried over magnesium sulfate.

The solvent is evaporated and the resulting residue was dissolved in Meon (6 ml). To the reaction liquid added potassium carbonate (304 mg), followed by stirring at 60 degrees C within 5 hours. Then the solvent is evaporated and to the reaction liquid added water and then were extracted with chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving TRANS-1-(2-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}ethyl)cyclohexane-1,2-diol (93 mg).

The resulting connection (93 mg) dissolved in the mixed solvent chloroform-EtOH. To the reaction liquid added oxalic acid (22 mg), while receiving oxalate TRANS-1-(2-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}ethyl)cyclohexane-1,2-diol (66 mg).

Example 5

A mixture of 1-({[2-(5-bromo-1-isopropyl-8-methyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol (0.14 g), EtOH (10 ml), triethylamine (0.05 ml) and 10% of palladium, besieged on coal (10 mg), mixed in the atmosphere of hydrogen within 6 hours. The reaction liquid is filtered and the solvent is evaporated. To the resulting residue added 1 M aqueous solution of NaOH with the subsequent extraction of mixture of chloroform. The organic layer was dried over magnesium sulfate and then the solvent is evaporated. The resulting residue was purified column chromatography on silica gel (chloroform-Meon). The resulting residue was dissolved in 2-propanol (0,8 ml). To the reaction liquid added oxalic acid (23 mg) and diethyl ether (5 ml) and besieged the solid is collected by filtration and dried, while receiving oxalate 1-({[2-(1-isopropyl-8-methyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol (of 0.066 g).

Example 7

2-(1-Cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-exoethnonym (400 mg) dissolved in EtOH (10 ml). To the reaction liquid added 2-methyl-1-exaspere[2.5]octane (555 mg) and water (5 ml), followed by stirring boiling under reflux for 2 days. The solvent is evaporated and to the reaction liquid added water with the subsequent extraction of chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving 1-(1-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}ethyl)cyclohexanol (585 mg).

The resulting connection (325 mg) dissolved in the mixed solvent EtOH-acetonitrile. To the reaction liquid added oxalic acid (80 mg), while receiving oxalate 1-(1-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}ethyl)cyclohexanol (292 mg).

Example 8

2-{[2-(1-Cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}ethanol (342 mg) dissolved in EtOH (5 ml). The solution was added 1 exaspere[2.5]octane (363 mg) and water (5 ml), followed by stirring boiling under reflux for 2 days. The solvent is evaporated and to the reaction liquid added water with the subsequent extraction of mixture of chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving 1-({[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl](2-hydroxyethyl)amino}methyl)cyclohexanol (346 mg).

The resulting connection (346 mg) dissolved in EtOH (10 ml). To the reaction liquid added oxalic acid (76 mg), while receiving oxalate 1-({[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl](2-hydroxyethyl)amino}methyl)cyclohexanol (210 mg).

Example 9

N-[2-(1-Cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]-N-{2-[CIS-1,2-dihydroxytoluene]ethyl}-2,2,2-triptorelin (255 mg) dissolved in MeOH (10 ml). The solution was added potassium carbonate (345 mg), followed by stirring at 60 degrees C for 4 hours. The solvent is evaporated and to the reaction liquid added water with the subsequent extraction of mixture of chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving CIS-1-(2-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}ethyl)cyclohexane-1,2-diol (212 mg).

The resulting connection (212 mg) dissolved in EtOH. To the reaction liquid added oxalic acid (46 mg), while receiving oxalate CIS-1-(2-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}ethyl)cyclohexane-1,2-diol (170 mg).

Example 10

tert-Butyl-[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]{[CIS-1,2-dihydroxytoluene]methyl}carbamate (92 mg) dissolved in the EtOAc (4 ml). The solution was added 4 M HCl/EtOAc (0,45 ml) followed by mixing at room temperature for up to 14 hours. The solvent is evaporated and the resulting residue added 1 M aqueous solution of NaOH with the subsequent extraction of mixture of chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform), while receiving CIS-1-({[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexane-1,2-diol (174 mg).

The resulting connection (174 mg) dissolved in the iPrOH. To the reaction liquid added oxalic acid (43 mg), while receiving oxalate CIS-1-({[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexane-1,2-diol (88 mg).

Example 11

1-[2-(Chloroacetyl)-1,2,3,4-tetrahydroisoquinoline-1-yl]-1-methylethylacetate (1.2 g) dissolved in acetonitrile (20 ml). The solution was added potassium carbonate (2.36 in), hydrochloride, 1-(aminomethyl)cyclohexanol (2.26 and g) and iodide Tetra-n-butylamine (126 mg), followed by stirring at 60 degrees C within 5 hours. To the reaction liquid added water with the subsequent extraction EtOAc. The extracts were washed with saturated salt solution and then dried with sodium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon).

The resulting balance (USD 1.43 g) dissolved in methylene chloride (20 ml). To the reaction liquid solution was added 1.01 M diisobutylaluminum/n-hexane (of 9.55 ml) at -78°C, followed by stirring at -78 OC for 5 hours. After that the temperature was increased up to 0 C during 2 hours. To the reaction liquid added saturated aqueous solution Rochelle salt with the subsequent mixing of the mixture within 20 minutes. Then to the reaction liquid added celite and then she was subjected to division by filtration, followed by extraction with chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving 1-[({2-[1-(1-hydroxy-1-methylethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol (118 mg).

The resulting connection (150 mg) dissolved in acetonitrile. To the reaction liquid added oxalic acid (41 mg), while receiving oxalate 1-[({2-[1-(1-hydroxy-1-methylethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]of cyclohexanol (151 mg).

Example 13

2-(1-Cyclohexyl-7-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-N-(2-{[CIS-2-(methoxyethoxy)cyclopentyl]oxy}ethyl)-2-exoethnonym (500 mg) dissolved in MeOH (8 ml). To the reaction liquid cooling with ice added 4 M HCl/EtOAc (0,8 ml), followed by stirring the mixture at 60 degrees C within 5 hours. The solvent is evaporated and the resulting residue was added saturated aqueous sodium bicarbonate with the subsequent extraction of chloroform. The extracts were washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving CIS-2-(2-{[2-(1-cyclohexyl-7-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}etoxi)Cyclopentanol (380 mg).

The resulting connection (380 mg) dissolved in the iPrOH. To the reaction liquid added oxalic acid (80 mg), while receiving oxalate CIS-2-(2-{[2-(1-cyclohexyl-7-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}etoxi)Cyclopentanol (384 mg).

Example 14

Hydrochloride, 1-(4-chloropyridine-2-yl)-1,2,3,4-tetrahydroisoquinoline (200 mg) and potassium carbonate (344 mg) dissolved in a mixture EtOAc-water (1:1, 4 ml) at cooling by ice. The solution was added chloracetophenone (0,85 ml) and gidrobromid of benzyldimethylamine (9,2 mg) followed by mixing at room temperature for 1 hour. To a mix added hydrochloride 2-amino-1,1-dicyclopentyl (190 mg) and potassium carbonate (246 mg). The mixture was stirred at 50 C for 8 hours. The organic layer was collected, washed saturated solution of salt, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified column chromatography on silica gel (chloroform-Meon), while receiving 2-({2-[1-(4-chloropyridine-2-yl)-3,4-dihydroisoquinoline-2(1H)-Il-2-oxoethyl]amino}-1,1-dicyclopentyl (143 mg) in the form of a yellow oily substances. Oily substance dissolved in the mixed liquid (4 ml) 3:1 diethyl ether-iPrOH. To the reaction mixture was added oxalic acid (30,2 mg), while receiving oxalate 2-({2-[1-(4-chloropyridine-2-yl)-3,4-dihydroisoquinoline-2(1H)-Il-2-oxoethyl]amino}-1,1-dicyclopentyl (128 mg).

Example 15

The solution 8-({[2-(1-cyclohexyl-3,4-dihydro-2(1H)-sochinyenii)-2-oxoethyl]amino}methyl)-1,4-dioxaspiro[4.5]Dean-8-Ola (324 mg) in THF (2 ml) was added to the water (1 ml) and concentrated hydrochloric acid (1 ml). The reaction mixture was heated under reflux for 5 hours. The temperature was lowered to room temperature and mix added sodium bicarbonate to make her alkaline, with the subsequent extraction of chloroform. The extract is purified column chromatography on silica gel (chloroform-Meon), while receiving the required Amin (176 mg).

Amin was dissolved in iPrOH (3 ml), the solution was added oxalic acid (41,7 mg) followed by mixing at room temperature for 2 hours. The resulting crystals were collected by filtration, washed simple ether and dried at 90 C and under reduced pressure, while receiving oxalate 4-({[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)-4-hydroxycyclohexanone (139 mg).

Example 16

The solution of 2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (12 mg) in acetonitrile (0.5 ml) was added potassium carbonate (3 mg) and hydrochloride (S)-(+)-2-amino-3-cyclohexyl-1-propanol (15 mg) followed by stirring mixture at 80 C for 4 hours. After that to the reaction liquid added saturated aqueous solution of ammonium chloride with the subsequent extraction of chloroform. The solvent is evaporated and the resulting residue was purified preparative HPLC, while receiving (2S)-3-cyclohexyl-2-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}propan-1-ol (4,1 mg).

Example 17

2-(Isobutylamino)ethanol (26 mg) was added to a solution of 2-acryloyl-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (7 mg) in iPrOH (0.1 ml), followed by stirring at 90 OC for 10 hours. After the reaction liquid purified preparative HPLC, while receiving 2-[[3-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-3-oxopropyl]-(3-methylbutyl)amino]ethanol (3 mg).

Chemical structure of compounds obtained by the above examples, it is shown in tables 43 and 44 (see below). In addition, in the same way as in the ways of the above examples, the connection of the examples shown in tables 45-110, obtained with application of the corresponding compounds. The data of instrumental analysis of these compounds examples shown in tables 111-125 (see below).

In addition, the tables 126 and 127 (see below) shows the structure of other compounds present invention. These connections can be easily obtained by these methods in the methods of obtaining and examples and methods, well-known specialist in this area, or of their modifications.

Further, in tables no means the connection number.

The results of the analysis of multiple connections examples obtaining chiral column chromatography shown in tables 128 and 129 (see below).

In addition, the tables RT is the retention time (min) and the PR means of optical purity (%).

Industrial applicability

The connection of the present invention can be used in composition the pharmaceutical composition for prevent and/or treat various pain, including neuropathic pain and nociceptive pain, headaches such as migraine and cluster headache, diseases of the Central nervous system, such as anxiety, depression, epilepsy, cerebral stroke and tired leg syndrome, abdominal symptoms such as abdominal pain and bloating, violations of the chair, such as diarrhoea and higher, diseases of the digestive system, such as irritable bowel syndrome, and urinary tract diseases, such as overactive bladder and interstitial cystitis.

1. The connection is selected from the group consisting of: 1-[({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol, (2S)-1-({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)-3-methoxypropan-2-ol, 1-({[2-(1(1S)-isopropyl-6-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol, (2R)-1-({2-[(1S)-3-methoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)propan-2-ol, 1-[({2-[(1R)-7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol, (2S)-1-methoxy-3-[(2-oxo-2-{1(1S)-[2-(trifluoromethyl)benzyl]-3,4-dihydroisoquinoline-2(1H)-yl}ethyl)amino]propan-2-ol, 1-({[3-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-3-oxopropyl]amino}methyl)cyclohexanol, (2R)-1-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-Il)-2-oxoethyl]amino}propan-2-ol, (2R)-1-[(2-oxo-2-{1-[2-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-yl}ethyl)amino]propan-2-ol, (2S)-1-{[2-(1-cyclohexyl-7-methyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}-3-methoxypropan-2-ol, (2R)-1-({2-oxo-2-[(1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-Il]ethyl}amino)propan-2-ol, 1-[({2-[7-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol, 1-[({2-[7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol, 1-({[2-(1-isopropyl-6-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol, 1-[({2-[5-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol, 1-[({2-[1-(methoxymethyl)-6-methyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol, (1S,2S)-2-{[2-(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}-1-phenylpropane-1,3-diol, 1-({(2R)-2-[(1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-yl)carbonyl]pyrrolidin-1-yl}methyl)cyclohexanol, (2R)-1-{[2-(1-cyclohexyl-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}propan-2-ol, 1-({[2-(3',4'-dihydro-2 N-Spiro[cyclohexane-1,1'-isoquinoline]-2'-yl)-2-oxoethyl]amino}methyl)cyclohexanol, (2R)-1-[(2-oxo-2-{1-[2-(cryptonetx)phenyl]-3,4-dihydroisoquinoline-2(1H)-yl}ethyl)amino]propan-2-ol, (2R)-1-{[2-(1-cyclohexyl-7-ethyl 3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}propan-2-ol, 1-({[2-(6-fluoro-1-isopropyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol, 1,1-dicyclopropyl-2-({2-[6-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)ethanol, 1-({[2-(1-tert-butyl-8-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol, 1-({[2-(1-isopropyl-6-methyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol, 1-({[2-(6-fluoro-1-propyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol, 1-[({2-[1-(methoxymethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol, 1-({[2-(5-fluoro-1-propyl-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol, 1-[({2-[5-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol, 1-[({2-[8-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol, 1-[({2-[1-(ethoxymethyl)-7-methyl-3,4-dihydroisoquinoline-2(1H)-Il]-2-oxoethyl}amino)methyl]cyclohexanol or (1R,2S)-2-({2-[(1R)-1-(2-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-yl]-2-oxoethyl}amino)Cyclopentanol, or pharmaceutically acceptable salt.

2. Compound according to claim 1, which is a

or pharmaceutically acceptable salt.

3. The pharmaceutical composition with blocking CA 2+ -channels N-type activity, containing the compound according to claim 1 or 2 or pharmaceutically acceptable salt mixed with pharmaceutically acceptable carrier and excipients.

4. Blocker CA 2+ channel N-type containing compound according to claim 1 or 2 or pharmaceutically acceptable salt.

5. The pharmaceutical composition for prevention or treatment of pain, neuropathic pain, abdominal symptom, spastic constipatio induced opioid konstitutsii, irritable bowel syndrome or irritable bowel syndrome type of constipatio containing compound according to claim 1 or 2 or pharmaceutically acceptable salt.

6. The pharmaceutical composition according to claim 5, which is a pharmaceutical composition for prevention or treatment of pain.

7. The pharmaceutical composition according to claim 6, which is a pharmaceutical composition for prevention or treatment of neuropathic pain.

8. The pharmaceutical composition according to claim 5, which is a pharmaceutical composition for prevention or treatment of abdominal symptom.

9. The pharmaceutical composition according to claim 5, which is a pharmaceutical composition for prevention or treatment of spastic constipatio.

10. The pharmaceutical composition on item 9 which is a pharmaceutical composition for prevention or treatment of opioid induced constipatio.

11. The pharmaceutical composition according to claim 5, which is a pharmaceutical composition for prevention or treatment of irritable bowel syndrome.

12. The pharmaceutical composition on paragraph 11, which is a pharmaceutical composition for prevention or treatment of irritable bowel syndrome type of constipatio.