Pyrrole and pyrazole daao inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) , where R1 and R2 are independently chosen from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5; X and Y are independently chosen from O and (CR6R7)n; R3 represents hydrogen, alkyl or M; M represents an ion, chosen from aluminium, calcium, lithium, magnesium, potassium, sodium, zinc or their mixture; Z represents CR4; R4 is chosen from hydrogen, halogen, alkyl, alkylaryl and XYR5; R5 is chosen from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently chosen from hydrogen and alkyl; n is an integer from 1 to 6; at least one of R1 and R2 represents XYR5, and at least one of X and Y represents (CR6R7)n. The invention also pertains to the method of increasing concentration of D-serine and/or reducing concentration of toxic products of D-serine oxidation under the effect of DAAO in mammals, involving introduction into a subject of a therapeutically effective amount of a formula I compound, to the method of treating schizophrenia, treating or preventing loss of memory and/or cognitive ability, to the method of improving learning ability, method of treating neuropathic pain, as well as to a pharmaceutical composition, with DAAO inhibitory activity, based on these compounds.

EFFECT: obtained are new compounds and a pharmaceutical composition based on these compounds.

27 cl, 4 tbl, 72 ex

 

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is nepredvidatelne and claims priority under provisional application U.S. No. 60/532979, filed December 29, 2003, a Full description of the provisional application U.S. No. 60/532979 incorporated herein by reference.

BACKGROUND of INVENTION

The enzyme oxidase D-amino acids (DAAO) is metabolized to D-amino acids, in particular, it is metabolized to D-serine in vitro at physiological pH values. DAAO is expressed in the brain and peripheral systems of mammals. D-serine as a neurotransmitter plays an important role in the activation of N-methyl-D-aspartate (NMDA)-selective subtype of glutamate receptor ion channel expressed in neurons, which in this document is known as the NMDA receptor. Small organic molecules that inhibit the enzymatic cycle DAAO, can control the levels of D-serine and thus to influence the activity of the NMDA receptor in the brain. The activity of the NMDA receptor

plays an important role in a number of illnesses, such as schizophrenia, psychosis, ataxia, ischemia, some types of pain, including neuropathic pain, as well as deficits in memory and cognitive abilities.

Small organic molecules that inhibit the enzymatic cycle DAAO, can also regulate the production of toxic metabolite is, resulting from the oxidation of D-serine, such as hydrogen peroxide and ammonia. Thus, these molecules may influence the progressive loss of cells in neurodegenerative diseases. Neurodegenerative diseases are diseases in which there is progressive loss of neurons in the CNS and/or peripheral neurons, usually accompanied by (and may be called) physical disruption of the structure or of neurons themselves, or surface contact with other neurons. Such conditions include Parkinson's disease, Alzheimer's disease, Huntington's disease and neuropathic pain. Glutamate receptors N-methyl-D-aspartate (NMDA) expressed in excitatory synapses throughout the Central nervous system (CNS). These receptors mediate a wide range of processes in the brain, including synaptic plasticity, which are associated with certain types of memory formation and cognitive abilities. To influence neuropterida, NMDA glutamate receptors must contact the two agonists. One of these agonists is a stimulating amino acid L-glutamate, whereas the second, communicating on the so-called "glycine site, insensitive to strychnine", as now believe, is a D-serine. The animal is D-serine is synthesized from L-serine by the action of serine-racemase and decomposes to the corresponding keto-acid under the action of DAAO. I believe that the serine-racemase and DAAO together play a key role in the modulation of NMDA-mediated nanoperiodic by regulating the concentrations of D-serine in the Central nervous system.

Alzheimer's disease is manifested as a form of dementia, which usually involves mental disturbance, accompanied by memory loss, confusion and disorientation. In the context of the present invention dementia is defined as a syndrome of progressive deterioration in different areas of cognitive function, which ultimately leads to an inability to maintain normal social and/or professional activities. Early symptoms include memory loss and moderate but progressive deterioration of specific cognitive functions such as language (aphasia), motor skills (apraxia) and recognition (agnosia). The early manifestation of Alzheimer's disease is often poor memory, which is a necessary condition for the diagnosis of dementia according to the criteria of the National Institute of neurological and communicative diseases and the Association for the impact of Alzheimer's disease and Alzheimer's disease and related diseases (Stroke-Alzheimer's Disease and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) (McKhannet al., 1984, Neurology 34: 939-944)that specialize in Alzheimer's disease, as well as on the criteria diag is sticheskogo and statistical manual of mental disorders of the American psychiatric Association, fourth edition (DSM-IV), which applies to all forms of dementia. Cognitive function of the patient can be assessed by cognitive podskali scale for the assessment of Alzheimer's disease (ADAS-cog; Rosen et al., 1984, Am. J. Psychiatry 141: 1356-1364). Alzheimer's disease is usually treated with acetylcholinesterase inhibitors, such as hydrochloride of tacrine or donepezil. Unfortunately, several ways to treat loss of memory and deterioration of cognitive abilities that exist at the present time, are not considered effective enough and does not allow to achieve significant changes in the condition of the patient, at the present time also there is a lack of standard nootropic drugs for use in such treatment methods.

Neuropsychiatric disorders include schizophrenia, autism and disorder with attention deficit. Clinicians known features, which differ in these diseases, as well as numerous schemes of classification. As the basis of the experts in this field use a standard diagnostic system outlined in the revised fourth edition of the Diagnostic and statistical manual of mental disorders (DSM-IV-R), published by the American psychiatric Association, which is included in this description by reference. In accordance with DSM-IV mental ill the of axis I include: violations diagnosed in children (such as disorder attention deficit (ADD) and hyperactivity disorder and attention deficit (ADHD)), and disorders diagnosed in adults. Disorders diagnosed in adults, include (1) schizophrenia and mental disorders; (2) cognitive disorders; (3) mood disorders; (4) disorders associated with anxiety; (5) eating disorders; (6) violations related to drug dependence; (7) personality disorders; and (8) "diseases are not yet included in this schema.

ADD and ADHD are diseases that occur most often in children and is associated with increased physical activity and reduced concentration. These diseases are usually treated by injection of psychostimulants, such as methylphenidate and dextroamphetamine sulfate.

Schizophrenia refers to a group of neurological diseases characterized by disorders of the thinking process, such as delusions, hallucinations and extensive branch of patients ' interests from the interests of other people. Approximately one percent of the world's population suffers from schizophrenia, and this disease is characterized by a high percentage of morbidity and mortality. The so-called negative symptoms of schizophrenia include emotional stupor, energy is, alogia and social isolation, which can be measured using SANS (just dragging, 1983, scale for assessment of negative symptoms (Scales for the Assessment of Negative Symptoms) (SANS), Iowa City, Iowa). Positive symptoms of schizophrenia include delusions and hallucinations, which can be measured using the PANSS scale (positive and negative syndromes (Positive and Negative Syndrome Scale)) (Kay et al., 1987, Schizophrenia Bulletin 13: 261-276). Cognitive symptoms of schizophrenia include worsening of acquisition, organization and use of intellectual knowledge, which can be measured using cognitive podskalny scale positive and negative syndrome (PANSS-cognitive podskalo) (Lindenmayer et al., 1994, J. Nerv. Ment. Dis. 182: 631-638) or with cognitive tasks, such as test card sorting Wisconsin. For the treatment of the positive symptoms of schizophrenia, such as delusions and hallucinations, you can use the traditional neuroleptic drugs that act on the receptor dopamine D2. In most cases, traditional neuroleptics and atypical neuroleptic drugs that act on the receptors of dopamine D2and serotonin 5HT2have a limited ability to treat cognitive deficits and negative symptoms such as emotional stupor (i.e. loss of facial expression), anergy and social isolation.

Other conditions that p is ablauts in the form of deficits in memory and cognitive abilities, include mild form of unconsciousness and closed head injury. A mild form of unconsciousness refers to a moderate loss of the ability to restore in memory or recall of information that has already been zapechetlena learned and stored in memory (e.g., ability to remember where people put the keys or zaparkoval machine). A mild form of unconsciousness usually occurs in people older than 40 years, it can be diagnosed using standard analytical tools, such as scale memory Veksler. Closed head injury refers to a clinical condition after damage or head trauma. This condition, which is characterized by deterioration of cognitive abilities and memory, can be diagnosed as "amnesia due to a General medical condition" in accordance with the DSM-IV.

Known DAAO inhibitors include benzoic acid, pyrrole-2-carboxylic acid and indole-2-carboxylic acid, as described Frisell, et al., J. Biol. Chem., 223: 75-83 (1956) and Parikh et al., JACS, 80: 953 (1958). The literature describes that indole derivatives and, particularly, some indole-2-carboxylates are used for the treatment of neurodegenerative diseases and neurotoxic damage. EP 396124 discloses indole-2-carboxylates and their derivatives for the treatment or therapy neurotoxic damage caused by disease of the Central nervous system or herbs is eticheskim event in the treatment or therapy of neurodegenerative diseases. Some examples of traumatic events that can lead to neurotoxic damage, including hypoxia, anoxia and ischemia associated with perinatal asphyxia, cardiac arrest or stroke. The neurodegeneration associated with diseases of the Central nervous system as convulsions and epilepsy. U.S. patent No. 5373018; 5374649; 5686461; 5962496 and 6100289, Cugola, open treatment of neurotoxic injury and neurodegenerative diseases indole derivatives. None of the above references do not mention improvement or learning ability, memory, or cognitive abilities.

WO 03/039540 reveals the improvement of learning ability, memory, or cognitive understanding and treatment of neurodegenerative diseases using DAAO inhibitors, including indole-2-carboxylic acid. However, there remains a need for new drugs, clinically effective in the treatment of defects of memory, impaired learning ability and loss of cognitive abilities, as well as other symptoms associated with activity or loss of the NMDA receptor.

van Herk et al. (J. Med. Chem., 46 (18): 3945-51(2003)has described some of the pyrazole-3-carboxylic acid as a partial agonist of the receptor for nicotinic acid. Described synthetic method of obtaining data connection is on and set, these compounds inhibit the binding of nicotinic acid. The activity of the NMDA receptor or inhibition of DAAO in this work is not mentioned.

BRIEF description of the INVENTION

Unexpectedly, it was found that some of pyrrole and pyrazole nucleus derived more effectively inhibit the activity of DAAO than known inhibitors. It was shown that these compounds inhibit DAAO in vitro at very low concentrations, especially in comparison with the known DAAO inhibitors, such as benzoic acid, pyrrole-2-carboxylic acid and indole-2-carboxylic acid. Due to its ability to inhibit the activity of DAAO, some of pyrrole and pyrazol derivatives can be used to treat a number of diseases and/or conditions in which modulation of the level of D-serine and/or its oxidation products leads to an effective improvement of symptoms while reducing unwanted side effects. In particular, these compounds can be used to raise levels of D-serine and reduce levels of toxic oxidation products of D-serine; thus, these compounds can be used to improve learning ability, memory, and cognitive ability, or for the treatment of schizophrenia, for treating or preventing loss of memory and/or cognition associated with Alzheimer's disease, on the I treatment of ataxia or for preventing loss of neuronal function, characteristic of neurodegenerative diseases.

Accordingly, in one aspect this invention relates to methods for increasing the level of D-serine and reduce the level of toxic oxidation products of D-serine, to methods of improving learning ability, memory, and/or ability to knowledge, to methods of treatment of schizophrenia, treatment or prevention of memory loss and/or loss of cognitive ability associated with Alzheimer's disease, treatment of ataxia, neuropathic pain or for preventing loss of neuronal function characteristic of neurodegenerative diseases.

These methods include introduction to the subject a therapeutic amount of the compounds of formula I or its pharmaceutically acceptable salt or MES

where

R1and R2independently selected from hydrogen, halogen, nitro, alkyl, acyl, alkylaryl and XYR5; or R1and R2together form a 5-, 6-, 7 - or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group;

X and Y independently selected from O, S, NH, and (CR6R7)n;

R3denotes hydrogen, alkyl or M+;

M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof;

R6and R7independently selected from hydrogen and alkyl;

Z represents N or CR4;

R4selected from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5;

R5selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;

n denotes an integer from 1 to 6;

at least one of R1, R2and R4different from hydrogen, and

at least one of X and Y denotes (CR6R7)n.

In the second aspect of this invention relates to methods for treating autism, schizophrenia, Alzheimer's disease, ataxia, neuropathic pain or neurodegenerative diseases, including the introduction of a therapeutically effective amount of the above-mentioned inhibitor oxidase D-amino acids (DAAO) of formula I to a subject in need of treatment one or more of these conditions.

In preferred embodiments of the compounds of formula I are substituted pyrrole-2-carboxylic acid, or a pyrazole-3-carboxylic acid, for example:

DETAILED description of the INVENTION

The present invention relates to methods for increasing the level of D-serine and reduce the level of toxic oxidation products of D-serine, to methods of improving learning ability, memory, and/or ability to knowledge or to methods of treatment of schizophrenia, treatment or prevention of memory loss and/or loss of cognitive ability is, associated with Alzheimer's disease, treatment of ataxia, neuropathic pain or for preventing loss of neuronal function characteristic of neurodegenerative diseases. These methods include introduction to the subject a therapeutic amount of the compounds of formula I

or its pharmaceutically acceptable salt or MES, where

R1and R2independently selected from hydrogen, halogen, nitro, alkyl, acyl, alkylaryl and XYR5; or R1and R2together form a 5-, 6-, 7 - or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group;

X and Y independently selected from O, S, NH, and (CR6R7)n;

R3denotes hydrogen, alkyl or M+;

M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof;

R6and R7independently selected from hydrogen and alkyl;

Z represents N or CR4;

R4selected from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5;

R5selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;

n denotes an integer from 1 to 6;

at least one of R1, R2and R4different from hydrogen, and

at least one of X and Y denotes (CR6R7)n.

Therapeutic treatment of a compound of formula I Ave the leads to improved memory and improve and/or enhance learning ability and cognitive abilities, especially in subjects suffering from neurodegenerative diseases such as Alzheimer's disease, Huntington's disease or Parkinson's disease. These connections also facilitate cognitive dysfunction associated with aging, and improve the condition with catatonic schizophrenia.

The compounds of formula I possess unique pharmacological characteristics in relation inhibition of DAAO and influence the activity of the NMDA receptor in the brain, in particular through the regulation of the levels of D-serine. Therefore, these compounds can be used effectively to treat conditions and diseases, especially diseases related to the Central nervous system and is mediated by the activity of DAAO, D-serine and/or NMDA receptor, and these compounds have reduced side effects compared to existing standard drugs. These conditions and diseases include, but are not limited to, neurological diseases such as schizophrenia, autism, disorder attention deficit (ADD and ADHD) and impaired learning ability in children, and neurodegenerative diseases and disorders such as MLS (cerebellar ataxia), Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, down's syndrome, neuropathic pain, preinfarction dementia, the epila is this, contusion injuries (e.g. spinal cord injury and head), neurodegeneration, caused by a viral infection such as AIDS, encephalopathies), epilepsy, mild form of unconsciousness and closed head injury. The compounds of formula I can also be used for treatment of neurotoxic injury accompanying cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, spasm of cerebral vessels, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest.

Accordingly, the present invention relates to methods for increasing the concentration of D-serine and/or reduce the concentration of toxic oxidation products of D-serine under the action of DAAO in mammals, to methods of treatment of schizophrenia, treatment, or prevention of loss of memory and/or cognition associated with Alzheimer's disease, treatment, or prevention of loss of neuronal function characteristic of neurodegenerative diseases, to methods of improving learning ability, memory and/or cognitive abilities or treatment of neuropathic pain. Each of these methods includes introduction to the subject in need of such treatment, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt or MES

where

R1and R2independently selected from hydrogen, halogen, nitro, alkyl, acyl, alkylaryl, arylalkyl and XYR5; or R1and R2together form a 5-, 6-, 7 - or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group;

X and Y independently selected from O, S, NH, and (CR6R7)n;

R3denotes hydrogen, alkyl or M+;

M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof;

Z represents N or CR4;

R4selected from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5;

R5selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;

R6and R7independently selected from hydrogen and alkyl;

n denotes an integer from 1 to 6;

at least one of R1, R2and R4different from hydrogen, and

at least one of X and Y denotes (CR6R7)n.

In some embodiments D-serine or cycloserine you can enter together with compound (compounds) of formula I.

The compounds of formula I are typically more selective than known DAAO inhibitors, including indole-2-carboxylates, and have a higher selectivity for inhibition of DAAO than for binding to the binding site of D-serine NMDA receptor. These compounds are also areas which indicate the preferred profile activity including a good bioavailability. Accordingly, their use has advantages compared to many known in the field methods of treatment of diseases mediated by the activity of DAAO, D-serine or NMDA. For example, unlike many traditional neuroleptic funds, DAAO inhibitors can cause the desired reduction of the cognitive symptoms of schizophrenia. Traditional neuroleptic drugs often cause unwanted side effects, including late dyskinesia (irreversible violation of involuntary movements), extrapyramidal symptoms and akathisia, which can reduce or limit by introducing the compounds of formula I.

In another aspect, the present invention also relates to compounds of formula IA or pharmaceutically acceptable salts or solvate and to pharmaceutical compositions containing these compounds

where

R1a, R2aand R4independently selected from hydrogen, halogen, nitro, alkyl, alkylaryl, arylalkyl and XYR5;

X and Y independently selected from O, S, NH, and (CR6R7)n;

R3denotes hydrogen, alkyl or M+;

M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof;

R5selected from aryl, substituted aryl, heteroaryl and substituted g is tetraaryl;

R6and R7independently selected from hydrogen and alkyl;

Z represents N or CR4;

n denotes an integer from 1 to 6;

at least one of R1Aand R2Ameans XYR5and

at least one of X and Y denotes (CR6R7)n;

provided that formula 1A does not include 5-phenethyl-1H-pyrazole-3-carboxylic acid, i.e. if R1adenotes hydrogen, R2ameans XYR5; X and Y denote (CR6R7)n; R3denotes hydrogen, R6and R7represent hydrogen; Z represents N; n is 2, R5cannot denote phenyl.

The compounds of formula IA form a subclass of compounds of formula I and, therefore, can be used in the methods of the present invention without limitation.

In preferred embodiments of compounds of formulas I and IA represent pyrrole-2-carboxylic acid, substituted at the 4 position, or pyrazole-3-carboxylic acid, substituted at the 5 position. Preferred substituents for compounds of formulas I and IA, 4-substituted pyrrole-2-carboxylic acid and 5-substituted pyrazole-3-carboxylic acids are arylalkyl, substituted arylalkyl and higher alkyl (C6C20). Preferred arylalkyl substituents are arylamidine group, especially phenethyl, in this case, the compounds of formulas I and IA is predstavlyaet a pyrrole-2-carboxylic acid, substituted 4-position substituted or unsubstituted aryl group connected to the 4-position of the pyrrole through diatomic linker, or a pyrazole-3-carboxylic acid, substituted at the 5-position substituted or unsubstituted aryl group connected to the 5-position of the pyrrole through diatomic linker. In other preferred embodiments of compounds of formulas I and IA, pyrrole-2-carboxylic acid and pyrazole-3-carboxylic acid R1and R2together form a 5-, 6-, 7 - or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group.

Especially preferred pyrrole and pyrazole nucleus inhibitors oxidase D-amino acids include:

The invention includes compounds of formulas I and IA, and pharmaceutically acceptable salt and solvate of these compounds. The term "compound or pharmaceutically acceptable salt or solvate of this compound" means containing the value "or", that includes the substance in the form of salt and MES is. Pharmaceutically acceptable salts include, without limitation, inorganic salts of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts of lysine, N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine)and procaine and tromethamine.

Compounds of formulas I and IA can be obtained by known methods, using the methods described in the Examples section, or by using the methods depicted in schemes 1-5.

Scheme 1

The method of synthesis of the starting compounds: esters of 3-substituted 1H-pyrrole-2-carboxylic acid

Scheme 1 R1denotes hydrogen, halogen, nitro, alkyl, acyl, alkylaryl, arylalkyl or XYR5; and R5denotes aryl, substituted aryl, heteroaryl or substituted heteroaryl.

Scheme 2

The method of synthesis of the starting compounds: esters of 5-substituted 1H-pyrrole-2-carboxylic acid

Scheme 3

The method of synthesis of 4-substituted, 3,4-disubstituted-, 4,5-disubstituted or 3,4,5-triple-substituted 1H-pyrrole-2-carboxylic acid

Note: all the anhydrides of the acids used as starting substances, either obtained from commercial sources or synthesized from commercially available corresponding carboxylic what the slot using thionyl chloride or oxalicacid. You can use the following standard experimental conditions: a solution of the desired acid in thionyl chloride (or in toluene containing 10 equivalents of thionyl chloride) is heated at 60°C for 1-4 hours to obtain the corresponding acylchlorides, then the solvent evaporated in vacuum. The anhydrides of the acids used in the acylation reactions without additional purification.

Scheme 4

The method of synthesis of amine-substituted 1H-pyrrole-2-carboxylic acid using reductive amination

Note: this diagram Ar denotes an aromatic group such as phenyl, or substituted aromatic group, such as 4-chlorophenyl, or heteroaryl, or substituted heteroaryl. Instead of acetylchloride you can also use other acid anhydrides, such as, for example, propionitrile.

Scheme 5

The method of synthesis of 3,4-disubstituted 1H-pyrrole-2-carboxylic acid according to Barton-Zarda

Note: this diagram Ar denotes an aromatic group such as phenyl, or substituted aromatic group, such as 4-chlorophenyl, n=0, 1, or 2, or heteroaryl, or substituted heteroaryl, and R=hydrogen, halogen, nitro, alkyl or acyl.

The treatment methods of the present invention can be applied to subjects, including all the I people (patients) and other mammals treatment of this condition. Patients in need of treatment to improve or enhance learning ability and memory, are patients with symptoms of dementia or loss of learning ability and memory. Subjects suffering from amnesia, have degraded the ability to perceive new information or are not able to recall previously learned information or recent events. The memory bottleneck is most clearly detected using tasks that require spontaneous recall, he also evident when the examiner gives the subject a stimulus for recall at a later time. Memory impairment must be severe enough to cause significant impairment of social or professional activity with a significant deviation from the original level. The memory deficit may be associated with age, or it can occur as a result of illness or some other factor. Dementia is characterized by several clinically significant deficits in cognitive abilities that cause a significant deviation from the previous level of activity, including memory impairment, including the inability to learn new material or forgetting previously learned material. Memory can be formally tested by measuring the ability bakes avati, save, remember and learn. For the diagnosis of dementia also requires the presence of at least one of the following cognitive disturbances: aphasia, apraxia, agnosia or disturbance operations. These speech disorders, motor activity, learning objects, and abstract thinking must be severe enough in combination with memory deficiency causes impaired occupational or social activities that deviate from the previous higher level of operations.

The compounds of formula I and IA can also be used in combination with therapy, including the introduction of D-serine or its equivalent, such as a salt of D-serine, an ester of D-serine, alkilirovanny D-serine, or a precursor of D-serine, or in conjunction with therapy involving the introduction of neuroleptic agents, antidepressants, psychostimulants and/or drugs used to treat Alzheimer's disease.

Developed several animal models of learning and memory to determine the beneficial effects of treatment associated with higher cognitive functions, and side effects associated with potential. Description tests that can be used to assess changes in cognitive abilities in species other than person listed in Sartr, Martin, Intern. J. Neuroscience, 32: 765-774 (1987). These tests include water maze Morris (Stewart and Morris, Behavioral Neuroscience, R. Saghal, Ed., p. 107 (1993)), the model delayed nonmatching sample and social discrimination.

Water maze Morris is one of the best approved models of learning and memory, it is possible to determine the effect of several pharmacological agents associated with higher cognitive functions. The task in the maze is very dependent on the manipulation of the hippocampus, a brain region important for spatial learning in animals and enhance memory in people. Moreover, improving the implementation of the water maze Morris suggests possible clinical efficacy of compounds as amplifier cognitive function. For example, treatment with cholinesterase inhibitors or selective muscarinic cholinergic agonists reduces the deficit in the ability to learn a maze Morris in animal models of learning and memory, as well as in clinical populations with dementia. In addition, this animal model accurately reproduces the degree of deterioration with age and the increased sensitivity of ingrami delay or disturbing effects before testing, which are characteristic of amnestic patients. This test is a simple task about transtorno training for which the animal is placed in a tank with lukewarm water, which give the turbidity by adding powdered milk. Animals learn to find the position of the platform using visual landmarks, located in the maze and location for testing; this skill is called the ability to find the location of the subject. The group of animals receiving the control solution or the dose of the drug for a certain time before the test or after a certain time after the test. Three days after the start of the test control animals, as a rule, reach the platform within five to ten seconds. The action of the medicinal product associated with the modulation of memory is determined by the change in a given period of time. In the second or pilot testing phase animals trained to find the platform position, is placed in a tank from which removed the platform. Animals who remember the position of the platform, spend more time in the sector, in which there was a platform, and make more intersections the place previously occupied by the platform. Improving memory or cognitive abilities observed in animals spend more time in the right sector or doing more intersections the place previously occupied by the platform, compared to control animals. Wow what denie memory or cognitive abilities observed in animals, spending less time in the right sector or committing fewer intersections the place previously occupied by the platform, compared to control animals.

In the model of delayed nonmatching sample of animals provide an incentive (e.g., A lever). After some time, give the animal the opportunity to choose between two options (e.g., arm A and arm B). Choose an option that does not coincide with the initial stimulus (arm B), accompanied by a reward. If the frequency of the selection exceeds the random value, then the initial stimulus forgotten. With increasing time between providing incentives and choice task deteriorates and the choice boils down to pure chance. The number of correct choices for a certain period of time associated with the cognitive ability. The deficit in cognitive ability or memory can be obtained by physical methods, biochemical methods or by the use of older animals.

In the social interaction test in the test cell of the animal (animal A) enter someone else's pet (animal). Animal And recognizes the entered animal as alien and examines it. If the animal B to delete and re-enter it after a while, the test animal (animal A) will spend less time exploring the new inhabitant of cells, which since it remembers from the previous administration. With increasing time between the introduction of the tested animal spends more time on re-investigation of a new animal, because worse remembers it. The time spent on the study of the new inhabitant of the cells with the re-introduction, is inversely proportional to cognitive abilities. The deficit in cognitive ability or memory can be obtained by physical methods, biochemical methods or by the use of older animals.

Ways to improve learning ability and memory in humans can be assessed using such tests as the scale memory at the Veksler and minimental test (Minimental test). Standard clinical test for determining deterioration of learning and memory in a patient is minimental test for learning and memory (Folstein et al., J Psychiatric Res. 12: 185, 1975), in particular it is used for patients suffering from trauma to the head, Korsakov's syndrome or stroke. The result of the test is an indicator of short-term, working memory, which is rapidly deteriorating in the early stages of diseases associated with dementia or amnesia. The patient read ten pairs of unrelated words (e.g., army-style). Then the patient read the first word of each pair and asked to recall the second. Reduced the number of recall of paired words compared to the control GRU who sing indicates a worsening of memory. Conclusion about improving learning ability and memory do on the basis of either (a) statistically significant differences in test performance of patients receiving drug compared with the group receiving placebo; or (b) statistically significant deviation in test performance from standard corresponding to this model of the disease. Animal models or clinical cases of the disease have symptoms, which by definition can be distinguished from normal controls. Thus, the measure of effective pharmacotherapy is essential, but not necessarily full, reduced symptoms. Improvement in animals and human models of pathology of memory can be achieved by using the clinically effective "increase cognitive ability" of medicines that improve the task to remember. For example, a means of improving cognitive ability, which is used as a cholinomimetic replacement therapy for patients suffering from dementia and memory loss in medical literature type, significantly improves short-term working memory in these models, as the task of pairwise associations. Another potential use as a therapeutic treatment of memory loss features associated with the age of the deficit which execution efficiency is but is modulated by long study short-term memory in aging mice.

Scale memory Veksler is a widespread testing using paper and pencil cognitive function and memory capacity. In normal populations, standardized test gives a value of 100 and standard deviation 15, therefore, easy amnesia can be detected with decreasing values on a scale of 10-15 units, more severe amnesia - decreasing 20-30 units, and so forth. In clinical survey for diagnosing symptomatic loss of memory used by several tests, including, without limitation, minimental test, scale memory Veksler or task of pairwise associations. These tests give an idea how about a General tendency to deterioration of cognitive functions, and specific loss of learning ability and memory (Squire, 1987). In addition to the specific diagnosis of diseases associated with dementia or amnesia, clinical data also enable you to identify age-related deterioration of cognitive function, which reflects a real decrease in mental function that accompanies the aging process, that is, within the normal range indicates the age of the subject (DSM IV, 1994). As described above, an improvement of learning ability and memory in the context of the present invention occurs when there is statistically significant is e difference in the test of paired associations, for example, the task of patients receiving the drug, compared with members of the group receiving placebo, or when performing sequential tests for one patient.

Test rapid suppression can be used to identify compounds effective for the treatment of schizophrenia. This test is based on the observation that animals or people when exposed to loud sound startle reflex, and that if animals or humans exposed to several sounds of lower intensity, they will not startle reflex after exposure experienced more intense sound. This phenomenon is called preemptive suppression. Patients with a diagnosis of schizophrenia are observed defects ahead of suppression, that is, the leading pulses of lower intensity already not inhibit the startle reflex when exposed to intense experimental sound. Such defects can be caused animal drugs (scopolamine, ketamine, PCP or MK801) or brood rearing in isolation. These defects ahead of inhibition in animals can be partially mitigated with the help of medicines, is effective in schizophrenia. It is obvious that animal models ahead of inhibition have significant value for predicting efficiency with the unity in the treatment of patients with schizophrenia.

If desired, compounds of formulas I and IA can also be used in combination with therapy, including the introduction of D-serine or its equivalent, such as a salt of D-serine or an ester of D-serine, alkylated D-serine, or a precursor of D-serine. These compounds can also be used in combination with therapy, including the introduction of neuroleptic funds (for the treatment of schizophrenia and other psychotic States), psychostimulants (for the treatment of attention deficit disorder, depression or learning disabilities), antidepressants, nootropic means (e.g., piracetam, oksiratsetam or aniracetam), acetylcholinesterase inhibitors (for example, compounds related to physostigmine, tacrine or donepezil) and/or drugs against Alzheimer's disease (for treatment of Alzheimer's disease). Such methods of joint treatment included in the scope of this invention.

The phrase "therapeutically effective amount" in this description refers to the number of compounds, substances or compositions containing the compound of the present invention, providing some desired therapeutic effect by inhibition of DAAO in at least a subpopulation of cells in an animal and thereby blocking the biological consequences of that pathway in the treated cells, with acceptable from what achenium benefit/risk, suitable for any medical use.

The term "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Suitable pharmaceutically acceptable basic additive salts of the compounds of the present invention include salts of metals such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts, such as salts of lysine, N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine(N-methylglucamine)and procaine and tromethamine.

In General, the compounds of the present invention are commercially available or can be obtained using methods well known to specialists in this field. In addition, you can use the following methods or their modifications with the use of readily available starting materials, reagents and conventional synthesis methods. In these reactions it is also possible to use variants which are in themselves known, but are not mentioned in this document.

In the context of the present invention is meant that the alkyl includes linear, branched, or cyclic hydrocarbon structures and combinations thereof, including lower alkyl and higher alkyl. Preferred alkyl groups I have are C 20or below. The term lower alkyl refers to alkyl groups containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl and n-, sec - and t-butyl. The term higher alkyl refers to alkyl groups containing seven or more carbon atoms, preferably 7-20 carbon atoms and includes, for example, n-, sec - and t-heptyl, octyl and dodecyl. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups containing 3 to 8 carbon atoms. Examples cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and norbornyl.

The term aryl and heteroaryl refers to 5 - or 6-membered aromatic or heteroaromatic cycle-containing 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur, a bicyclic 9 - or 10-membered aromatic or heteroaromatic system containing 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur; or a tricyclic 13 - or 14-membered aromatic or heteroaromatic system containing 0-3 heteroatoms selected from nitrogen, oxygen or sulfur. Aromatic 6-14-membered carbocyclic fragments include, for example, benzene, naphthalene, indan, tetralin and fluoran; and 5-10-membered aromatic heterocyclic fragments include, e.g. the, the imidazole, pyridine, indole, thiophene, benzopyrane, thiazole, pyrrole, furan, benzimidazole, quinoline, isoquinoline, cinoxacin, pyrimidine, pyrazin, tetrazole and pyrazole.

The term arylalkyl refers to an alkyl residue attached to the aryl cycle. Examples are benzyl and phenethyl. The term heteroaromatic refers to an alkyl residue attached to a heteroaryl cycle. Examples include pyridinylmethyl and pyrimidinyl. The term alkylaryl refers to an aryl residue containing one or more alkyl groups. Examples are tolyl and mesityl.

The term alkoxy or alkoxyl refers to groups containing from 1 to 8 carbon atoms having a linear, branched or cyclic configuration or a combination of these configurations, attached to the main structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropylamine, cyclohexyloxy. The term lower alkoxy refers to groups containing one to four carbon atoms.

The term acyl refers to groups containing from 1 to 20 carbon atoms having a linear, branched or cyclic configuration, which are saturated, unsaturated and aromatic or contain a combination of these fragments and which is attached to the main structure through CT is onilne functional group. One or more of the carbon atoms in the acyl residue may be replaced by nitrogen, oxygen or sulfur, but the attachment point to the main fragment is carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl and benzyloxycarbonyl. The term lower acyl refers to a group containing from one to four carbon atoms.

The term heterocycle or heterocyclic refers to cycloalkyl or aryl residue in which one or two carbon atoms replaced by a heteroatom, such as oxygen, nitrogen or sulfur. Examples of heterocycles that fall within the scope of the present invention include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when he is present as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazol, dioxane and tetrahydrofuran.

The term substituted refers to the remains, including, without limitation, alkyl, alkylaryl, aryl, arylalkyl and heteroaryl, where up to three H atoms substituted lower alkyl, substituted alkyl, substituted quinil, halogenation, alkoxy, carbonyl, carboxy, carboxylate, carboxamido, acyloxy, amidino, nitro, halogen, guy is Roxie, OCH(COOH)2, cyano, primary amino group, secondary amino group, acylamino, alkylthio, sulfoxide, sulfonal, phenyl, benzyl, phenoxy, benzyloxy, heteroaryl or heteroaromatic.

The term halogenated refers to an alkyl residue in which one or more H atoms are replaced by halogen atoms; the term halogenated includes perhalogenated. Examples halogenating groups included in the scope of the present invention include CH2F, CHF2and CF3.

Oxaalkyl refers to an alkyl residue in which one or more carbon atoms replaced by oxygen atom. It is attached to the main structure via an alkyl residue. Examples include methoxypropane, 3,6,9-trioxadecyl etc. is Understood that the term oxaalkyl has a value that is typically used in this area [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, ¶196, but without limitation, ¶127(a)], i.e. it refers to compounds in which the oxygen is linked to adjacent atoms through a simple connection with the formation of simple essential communication); this term does not apply to compounds containing oxygen, connected by a double bond, as in carbonyl groups. Similarly, the terms thiaalkyl and isoalkyl refer to alkyl residues in which one or more carbon atoms replaced by gray is whether nitrogen, respectively. Examples include acylaminoacyl and metaltipped.

In the context of the present invention compounds having the activity of DAAO inhibitors, are compounds that inhibit the enzymatic cycle DAAO by 50% (IC50) at a concentration of approximately ≤100 μm, preferably approximately ≤10 microns and more preferably approximately ≤1 ám.

Many of these compounds can contain one or more asymmetric centers and therefore, can form enantiomers, diastereomers, and other stereoisomeric forms that terminology absolute stereochemistry is defined as (R)- or (S)-isomers. Understood that this invention includes all such possible isomers, including racemic mixtures and optically pure forms. Optically active (R)- and (S)-isomers can be obtained by using chiral synthons or chiral reagents, or by splitting traditional methods. If the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, it is believed that these compounds, unless otherwise specified, include geometric isomers E and z Similarly, the scope of the present invention also includes all tautomeric forms.

Although the compounds of formulas I and IA can be entered as raw the chemicals it is preferable to provide them in the form of pharmaceutical compositions. In accordance with another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula I or IA or pharmaceutically acceptable salt or MES in combination with one or more pharmaceutically acceptable carriers and, optionally, one or more other therapeutic ingredients. The carrier(s) must be "acceptable", that is, it must be compatible with other ingredients of the composition and do not adversely impact on the recipient.

The compositions include compositions suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and local (including dermal, buccal, sublingual and intraocular) administration. The most suitable method is selected depending on condition and disease of the recipient. Typically, the compositions obtained using any of the widely known in the pharmaceutical field methods, and provide in the form of unit dosage forms. All methods include the stage of mixing the compound or its pharmaceutically acceptable salt or MES ("active ingredient") with the carrier, which consists of one or more accessory ingredients. Usually is oppozitsii produced by uniform and homogeneous mixing of the active ingredient with liquid carriers, or powdered solid carriers, or both, and then, if necessary, by molding product with obtaining the target composition. Compositions for oral administration are well known to specialists in this area and General methods for their preparation can be found in any standard textbook on the pharmaceutical industry, for example, in Remington: The Science and Practice of Pharmacy., A. R. Gennaro, ed. (1995), the complete disclosure of which is incorporated in this description by reference.

Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, pills or tablets, each of which contains a certain amount of the active ingredient; as a powder or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an emulsion oil-in-water" or "water in oil". The active ingredient may also be presented as a bolus, electuary or paste.

The tablet can be obtained by extrusion or molding, optionally in the presence of one or more accessory ingredients. Molded tablets can be obtained by molding in a suitable machine the active ingredient in free-flowing form such as powder or granules, optionally mixed with a binder agent, lubricant, inert diluent, lanaudit means, surface-active or dispersing agent. Molded tablets can be obtained by molding in a suitable machine a mixture of the powdered compound moistened inert liquid diluent. Tablets may not necessarily have the floor or notches and may have a composition that provides slow, delayed or controlled release of the active ingredient. Oral and parenteral delivery system drug delayed release is well known to specialists in this field, and General ways to achieve slow release of drugs, administered orally or parenterally, can be found, for example, in Remington: The Science and Practice of Pharmacy, pages 1660-1675 (1995).

Compositions for parenteral administration include aqueous and non-aqueous sterile solutions for injection, which may contain antioxidants, buffers, bacteriostatic and substances that make the composition isotonic with respect to blood of the intended recipient. Compositions for parenteral administration include aqueous and non-aqueous sterile suspensions, which may contain suspendresume and thickening means. The composition can be in containers containing one or more doses, for example, sealed ampoules and vials and may be stored in the dried the C frozen state (dried), in this case, to the composition immediately before use you need to add the sterile liquid carrier, such as saline, phosphate buffered saline (PBS) and the like, Solutions and suspensions for immediate introduction can be obtained from sterile powders, granules and tablets of the type indicated above. Compositions for rectal injection can be presented in the form of suppositories containing traditional media, such as coconut oil or polyethylene glycol. Compositions for local insertion through the mouth, such as buccal or sublingual include tablets containing the active ingredient in a flavored basis such as sucrose and gum Arabic or tragakant, and flavoured tablets containing the active ingredient in such manner as gelatin and glycerol or sucrose and gum Arabic.

Pharmaceutical compositions containing compounds of formula I or IA may be presented in unit dosage form and may be obtained using methods well known in the pharmaceutical field. Preferred unit dosage forms contain an effective dose or an appropriate part of the effective dose of the active ingredient or its pharmaceutically acceptable salt. The magnitude of prophylactic or therapeutic dose usually varies depending the nature and severity of the condition, subject to treatment as well as way of introduction. Dose and possibly frequency of the dose also varies depending on age, weight and response of the individual patient. Generally, the total daily dose ranges from about 1 mg / day to 7000 mg per day, preferably from about 1 mg / day to 100 mg / day and more preferably from about 25 mg / day to 50 mg per day, and this dose can be administered in one or several stages. In some embodiments the total daily dose may vary from approximately 50 mg to 500 mg per day and preferably from about 100 mg to 500 mg per day. Children, patients over 65 years of age and patients with renal or hepatic insufficiency, it is recommended to first take a low dose with subsequent selection of the dose depending on individual response and blood levels. In some cases, if necessary, you can use doses outside these intervals, which is obvious for specialists in this field. In addition, it should be noted that the Clinician or treating physician according to the individual response of the patient may determine how and when to interrupt, adjust, or terminate treatment.

It should be understood that except as specifically mentioned above ingredients the composition of this invention may contain other tools traditionally used in the Noi area, in accordance with the type of the obtained compositions, such as compositions suitable for oral administration may include flavouring tools.

EXAMPLES

METHODS of OBTAINING PYRAZOLES

Example 1

Synthesis of 6,6-dimethyl-1,4,5,6-tetrahydrocyclopent-3-carboxylic acid (3)

Synthesis of (3,3-dimethyl-2-oxocyclopent)octoxynol acid ethyl ester (1)

Sodium hydride (0,428 g, 17.8 mmol) is slowly added to EtOH (5,4 ml, 3,3M), with stirring in an atmosphere of N2while cooling in a bath with ice and NaCl. 2.2-Dimethylcyclopentane (2.00 g, 17,83 mmol) and diethyloxalate (2,42 ml, 17.8 mmol) are mixed and then added to a chilled solution of NaOEt. After stirring for 15 minutes the reaction mixture is heated to room temperature and stirred for 6 hours, after which the completion of the reaction is confirmed by TLC. The reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2O, dried with Na2SO4filter and concentrate, receiving 3,4084 g (90,0%) of the crude compound 2, which according to NMR data is clean enough to be used in the next stage without additional purification. Note: instead of NaOEt, obtained from Aldrich, you can use NaOEt, synthesized in situ.

H (CDCl3, 400 MHz): δ the 4.29 (2H, q, J=7,3 Hz), 2,82 (2H, t, J=7,3 Hz)of 1.76 (2H, t, J=7,3 Hz), 1, 32 (3H, t, J=7,3 Hz)of 1.07 (6H, c) ppm13C (CDCl3, 100 MHz): δ 218, 162,89, 153,15, 115,98, 62,12, 46,16, 36,39, 23,98, 23,87, 14,22 ppm

Synthesis of 6,6-dimethyl-1,4,5,6-tetrahydrocyclopent-3-carboxylic acid ethyl ester (2)

The hydrazine hydrate (0,229 ml, 4,71 mmol) are added to stir at room temperature to a solution of compound 1 (0,9961 g, 4,71 mmol) in EtOH (4,7 ml, 1 M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction according to TLC (2 h). The reaction mixture was concentrated and purified by chromatography on silica gel (Combiflash column, 70:30:2 hexane:CH2Cl2:2 N. of NH3in EtOH). Pure fractions are combined and concentrated, obtaining 0,6955 g (71.2 percent) of compound 2.

1H (CDCl3, 400 MHz): δ 11,04 (1H, Sirs), to 4.33 (2H, q, J=7,3 Hz), was 2.76 (2H, t, J=6.8 Hz), and 2.26 (2H, t, J=6,8 Hz)of 1.33 (3H, t, J=7,3 Hz)is 1.31 (6H, c) ppm13C (CDCl3, 100 MHz): δ 168,08, 160,61, 128,73, 127,27, 61,15, 47,22, 38,64, 27,57, 22,00, 14,48 ppm

Synthesis of 6,6-dimethyl-1,4,5,6-tetrahydrocyclopent-3-carboxylic acid (3)

Their aqueous solution of NaOH (10M in H2O, 15.1 mmol) are added to stir at room temperature to a solution of compound 2 (0,6289 g, to 3.02 mmol) in MeOH (7,6 ml, 0,4M) in the atmosphere N2. Then the reaction mixture is heated at boiling under reflux until completion of the reactions which according to TLC (2.5 hours). The reaction mixture is concentrated and again dissolved in EtOAc and H2O and extracted with EtOAc. Added dropwise a 10% aqueous solution of HCl to obtain pH=4, after which the organic layer removed and the aqueous layer was again extracted with EtOAc. The combined organic layers are dried Na2SO4filter and concentrate. A small amount of CH2Cl2and hexane add to colored solid product and colored impurity is removed by pipette. The remaining solid is dried, receiving 0,2371 g (43,6%) of compound 3 in the form of not-quite-white solid. Note: as used below, the deposition method is the preferred method.

1H (CD3OD, 400 MHz): δ of 2.75 (2H, t, J=6,8 Hz)to 2.29 (2H, t, J=6,8 Hz)of 1.29 (6H, c) ppm13C (CD3OD, 100 MHz): δ 166,15, 162,23, 130,46, 126,93, 47,10, 38,22, 26,62, 21,52 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 26,62; CH2carbon atoms: 47,10, 21,52 ppm JHMS: 181,4 (M+1); 163,6 ((M+1)-18), HPLC: 7,538 minutes

Example 2

Synthesis of 3-methyl-1,4,5,6-tetrahydrocyclopent-3-carboxylic acid (6)

Synthesis of (3-methyl-2-oxocyclopent)octoxynol acidethyl ether (1)

2-Methylcyclopentanone (1,0058 g, 10.2 mmol) and diethyloxalate (1,38 ml, 10.2 mmol) are mixed and then added to a solution of NaOEt (~3M, 3.4 ml), with stirring in an atmosphere of N2while cooling in a bath with ice. After the lane is masiania within 15 minutes the reaction mixture is heated to room temperature and stirred over night. The reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2O, dried with Na2SO4, filtered and concentrated, obtaining the crude compound 4. The crude substance is purified using a gradient from 98:2 to 96:4 hexane:EtOAc, getting 0,5635 g (27.7%) connections 4.

1H (CDCl3, 400 MHz): δ the 4.29 (2H, q, J=7,1 Hz), 2,96 (1H, DDD, J=17,6, to 8.1, 1.5 Hz), 2,69 (1H, DDD, J=17,6 of 9.5 and 8.1 Hz), 2.57 m-2,47 (1H, m), 2,24 (1H, DTD, J=12,5, to 8.3, 2.4 Hz), 1,49 (1H, DTD, J=12,5, 10,3, 8,4 Hz)of 1.34 (3H, t, J=7,1 Hz)of 1.13 (3H, d, J=7.0 Hz) ppm13C (CDCl3, 100 MHz): δ 164,09, 153,19, 117,67, 62,92, 44,76, 30,60, 30,36, 26,55, 14,63, 14,37 ppm

Synthesis of 6-methyl-1,4,5,6-tetrahydrocyclopent-3-carboxylic acid ethyl ester (5)

The hydrazine hydrate (0,101 ml, 2.05 mmol) are added to stir at room temperature to a solution of compound 4 (0,4055 g, 2.05 mmol) in EtOH (2.0 ml, 1M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction according to TLC. The reaction mixture was concentrated and purified by chromatography on silica gel (Combiflash column, 96:4 hexane:2 N. of NH3in EtOH). Pure fractions are combined and concentrated, obtaining 0,2003 g (50.4 percent) of compound 5.

1H (CDCl3, 400 MHz): δ of 9.55 (1H, Sirs), 4,35 (2H, q, J=7,1 Hz), 3,26-and 3.16 (1H, m), 2,89-2,63 (3H, m), 2,09-to 1.98 (1H, m)to 1.37 (3H, t, J=7.2 Hz), of 1.30 (3H, d, J=6.9 Hz) ppm Partial13C (CDCl3, 100 MHz): δ 128,67, 61,32, 39,73,32,64, 22,94, 19,62, 14,52 ppm HPLC: 8,901 minutes

Synthesis of 6-methyl-1,4,5,6-tetrahydrocyclopent-3-carboxylic acid (6)

Their aqueous solution of NaOH (10M in H2O 5,02 mmol) are added to stir at room temperature to a solution of compound 5 (0,1949 g, 1.00 mmol) in MeOH (12.5 ml, 0,4M) in the atmosphere N2. Then the reaction mixture is heated at boiling under reflux until completion of the reaction according to TLC (0.5 h). The reaction mixture was concentrated and then dissolved in 2 ml of H2O. added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting 0,1223 g (73,3%) of compound 6.

1H (CD3OD, 400 MHz): δ 3,18-of 3.07 (1H, m), 2,84-2,62 (3H, m), 2,08 is 1.96 (1H, m), 1,25 (3H, d, J=6.8 Hz) ppm13C (CD3OD, 100 MHz): δ 164,49, 163,43, 131,67, 129,41, 40,87, 33,40, 23,61, 19,73 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 19,73; CH2carbon atoms: 40,87, 23,61; CH carbons: 33,40 ppm HPLC: 7,006 minutes

Example 3

Synthesis of 4-methyl-1,4,5,6-tetrahydrocyclopent-3-carboxylic acid (11) and 5-methyl-1,4,5,6-tetrahydrocyclopent-3-carboxylic acid (12)

Synthesis of (2-methyl-5-oxocyclopent)octoxynol acid ethyl ester (7) and (4-methyl-2-oxocyclopent)oxoxox the second acid ethyl ester (8)

Sodium hydride (0,122 g 5,09 mmol) is slowly added to EtOH (1,54 ml of 3.3 M), with stirring in an atmosphere of N2while cooling in a bath with ice and NaCl. 3-Methylcyclopentanone (0,500 g 5,09 mmol) and diethyloxalate (0,ml, 5,09 mmol) are mixed and then added to a chilled solution of NaOEt. After stirring for 15 minutes the reaction mixture is heated to room temperature and stirred for 6 hours, after which the completion of the reaction is confirmed by TLC. The reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2Oh, dried Na2SO4filter and concentrate, receiving 0,5591 g (55.4 per cent) of the crude compounds 7 and 8 in the form of a mixture of approximately 1:1,1. Although conditions for separation of the isomers is not selected, the mixture is sufficiently pure according to NMR data, to be used in the next stage without additional purification. Note: instead of NaOEt, obtained from Aldrich, you can use NaOEt, synthesized in situ.

1H (CDCl3, 400 MHz): δ 4,33 and or 4.31 (2H, q, J=7,3 Hz, 3,54-3,45, 3,20-3,08, 2,64-2,30, 2,15-2,04, 1,74-1,66, 1,35 and 1.34 (3H, t, J=7,3 Hz, 1.16 and of 1.10 (3H, d, J=7.3 and 6.4 Hz) ppm13C (CDCl3, 100 MHz): δ 214,05, 162,98, 152,36, 117,34, 62,23, 46,44, 35,92 and 35,76, 29,45 and 28,65, 21,00 and to 20.91, 14,25 and 14,17 ppm

Synthesis of 4-methyl-1,4,5,6-tetrahydrocyclopent-3-carboxylic acid (9) and 5-methyl-1,4,5,6-tetrahydrocyclopent-3-to benovoy acid ethyl ester (10)

The hydrazine hydrate (to 0.127 ml, 2,62 mmol) are added to stir at room temperature to a solution of compounds 7 and 8 (0,5064 g, 2,62 mmol) in EtOH (2.6 ml, 1M) in an atmosphere of N2. Then the reaction mixture is heated at boiling under reflux until complete according to TLC (2,3 h). The reaction mixture was concentrated and purified by chromatography on silica gel (Combiflash column, 70:30:2 hexane:CH2Cl2:2 N. of NH3in EtOH). Pure fractions are combined and concentrated, obtaining 0,3132 g (63,1%) of compounds 9 and 10. Conditions of separation of the isomers was not found.

1H (CDCl3, 400 MHz): δ of 11.26 and 11,18 (1H, Sirs), 4,35 and 4.34 (2H, q, J=7,3 Hz), 3,28-3,18 (0,48H, m), 3,02-2,90 (1,5H, m), 2,86 was 2.76 (0,52H, m), 2,74-2,61 (1H, m), 2,09-of 1.88 (1H, m), 2,15-1,80 (0,52H, m), of 1.36 and 1.35 (3H, t, J=7,3 Hz), 1,28 and to 1.19 (3H, d, J=6.3 Hz for 1,28 and 4.4 Hz for 1,19) ppm Partial13C (CDCl3, 100 MHz): δ 133,67, 128,61, 61,12, 40,25 and 39,35, 33,24 and 32,46, 32,30 and 23,91, 21,69 and 20,55, 14, 48mm and of 14.46 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 21,69 and 20,55, 14, 48mm and of 14.46; CH2carbon atoms: 61,12, 39,35, 33,24 and 32,46, 23,91; CH carbons: 40,25, 32,30 ppm HPLC: 8,974 minutes

Synthesis of 4-methyl-1,4,5,6-tetrahydrocyclopent-3-carboxylic acid (11) and 5-methyl-1,4,5,6-tetrahydrocyclopent-3-carboxylic acid (12)

Their aqueous solution of NaOH (10M in H2O 8,07 mmol) are added to stir at room temperature to a solution of compounds 9 and 10 (0,3132 g of 1.61 mmol) in MeOH (4.0 ml of 0.4 M) in the atmosphere is ore N 2. Then the reaction mixture is heated at boiling under reflux until completion of the reaction according to TLC. The reaction mixture was concentrated and then dissolved in 3 ml of H2O. added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting 0,1781 g (66,4%) of a mixture of compounds 11 and 12.

1H (CD3OD, 400 MHz): δ 3,34-3,16, 3,02-2,84, 2,80-2,58, 2,40-2,26, 2,10-1,98, 1,28 and 1.20 (3H, d, J=7.0 and 6.3 Hz) ppm13C (CD3OD, 100 MHz): δ 162,36 and 162,19, 158,43 and 158,43, 133,52, 128,16, 40,37 and 39,18, 32,39 and 32,06, 32,03 and 22,91, 20,61 and 19,68 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 20,61 and 19,68; CH2carbon atoms: 39,18, 32,39 and 32,06, 22,91; CH carbons: 40,37, 32,03 ppm JHMS: 167,4 (M+1); 149,4 ((M+1)-18), HPLC: 6,984 minutes

Example 4

Synthesis 1,4,5,6,7,8-hexahydroterephthalate-3-carboxylic acid (15)

Synthesis of oxo-(2-oxocyclohexyl)acetic acid ethyl ester (13)

Cycloheptanone (1,9998 g, 17.8 mmol) and diethyloxalate (2,42 ml, 17.8 mmol) are mixed and then added to a solution of NaOEt (~3M, 5,94 ml)while stirring in an atmosphere of N2while cooling in a bath with ice. After stirring for 15 minutes the reaction mixture is heated to room temperature and stirred over night. The reaction mixture g is placed at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2O, dried with Na2SO4, filtered and concentrated, obtaining the crude compound 13. The crude substance is cleaned with a mixture of 1:1 hexane:CH2Cl2getting 1,9775 g (52.3%), the connection 13. Note: the product is not completely purified, but it is used in the next stage.

1H (CDCl3, 400 MHz): δ or 4.31 (2H, q, J=7,3 Hz), 2,66-of 2.58 (2H, m), 2,48 is 2.43 (2H, m), 1.77 in-to 1.59 (6H, m)of 1.34 (3H, t, J=7,3H) ppm

Synthesis 1,4,5,6,7,8-hexahydroterephthalate-3-carboxylic acid ethyl ester (14)

The hydrazine hydrate (0,142 ml, to 2.94 mmol) are added to stir at room temperature to a solution of compound 13 (0,6229 g, to 2.94 mmol) in EtOH (2.9 ml, 1M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction according to TLC (4.5 hours). The reaction mixture was concentrated and purified by chromatography on silica gel (Combiflash column, 70:30:2 hexane:CH2Cl2:2 N. of NH3in EtOH). Pure fractions are combined and concentrated, obtaining 0,4428 g (72,3%) of compound 14.

1H (CDCl3, 400 MHz): δ 8,56 (1H, Sirs), 4,30 (2H, q, J=7,1 Hz), 2,92-of 2.86 (2H, m), 2,73-2,78 (2H, m), 1,84 to 1.76 (2H, m), 1,65-of 1.57 (4H, m)of 1.30 (3H, t, J=7,1 Hz) ppm13C (CDCl3, 100 MHz): δ 162,11, 150,70, 134,97, 124,58, 60,85, 32,33, 28,63, 28,32, 27,39, 24,42, 14,47 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 14,7; CH2the carbon atoms: 60,85, 32,33, 28,63, 28,32, 27,39, 24,42; ppm HPLC: 9,19 minutes

Synthesis 1,4,5,6,7,8-hexahydroterephthalate-3-carboxylic acid (15)

Their aqueous solution of NaOH (10M in H2O, to 9.66 mmol) are added to stir at room temperature to a solution of compound 14 (0,4029 g of 1.93 mmol) in MeOH (4.8 ml, 0,4M) in the atmosphere N2. The reaction mixture is then heated at the boil under reflux to complete the reaction according to TLC (0.5 h). The reaction mixture was concentrated and then dissolved in 3.8 ml of H2O added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, receiving the connection 15. Note: an undesired impurity, which is not removed from the solution by the addition of HCl, has a retention time 8,708 min according to the HPLC data.

1H (CD3OD, 400 MHz): δ 2,98-2,90 (2H, m), 2,80-of 2.72 (2H, m), 1,92-to 1.82 (2H, m), 1.70 to was 1.58 (4H, m) ppm13C (CD3OD, 100 MHz): δ 164,81, 151,31, 136,87, 125,13, 33,36, 29,73, 28,78, 28,49, 25,17 ppm DEPT (CD3OD, 100 MHz): CH2the carbon atoms: 33,36, 29,73, 28,78, 28,49, 25,17 ppm HPLC: 7,545 minutes

Example 5

Synthesis of 5-(4-methylpentyl)-1H-pyrazole-3-carboxylic acid (18)

Synthesis of 8-methyl-2,4-dioxanonane acid ethyl ester (16)

6-methyl-2-g is planon (0,9981 g, 7,80 mmol) and diethyloxalate (of 1.06 ml, 7,80 mmol) are mixed and then added to a solution of NaOEt (~3M, and 2.6 ml), with stirring in an atmosphere of N2while cooling in a bath with ice. After stirring for 15 minutes the reaction mixture is heated to room temperature and stirred over night. The reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2O, dried with Na2SO4, filtered and concentrated, obtaining the crude compound 16. The crude substance is cleaned with a mixture of 1:1 hexane:CH2Cl2getting 0,8342 g (46,9%) of compound 16.

1H (CD3OD, 400 MHz): δ 6,36 (1H, c), 4,30 (2H, q, J=7,1 Hz)of 2.50 (2H, t, J=7,3 Hz), 1,68-to 1.59 (2H, m), 1,61 of 1.50 (1H, m)of 1.33 (3H, t, J=7,1 Hz), 1,25-1,17 (2H, m)to 0.89 (6H, d, J=7.0 Hz) ppm13C (CD3OD, 100 MHz): δ 204,41, 166,93, 163,28, 102,66, 63,29, 41,89, 39,41, 28,92, 23,65, 22,89, 14,33 ppm

Synthesis of 5-(4-methylpentyl)-1H-pyrazole-3-carboxylic acid ethyl ester (17)

The hydrazine hydrate (0,943 ml, at 1.91 mmol) are added to stir at room temperature to a solution of compound 16 (0,4354 g, at 1.91 mmol) in EtOH (1.9 ml, 1M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction according to TLC. The reaction mixture was concentrated and purified by chromatography on silica gel (Combiflash column, 96:4 hexane:2 N. of NH3in EtOH). Pure fractions obyedinyaytes concentrate, getting 0,3132 g (63,1%) of compound 17.

1H (CDCl3, 400 MHz): δ 9,60 (1H, Sirs), to 6.58 (1H, c), 4,34 (2H, q, J=7.2 Hz), to 2.66 (2H, t, J=7,7 Hz), 1,67-of 1.57 (2H, m), 1,58 (1H, m)of 1.36 (3H, t, J=7.2 Hz), 1,24-of 1.15 (2H, m)of 0.85 (6H, d, J=6.5 Hz) ppm Partial13C (CDCl3, 100 MHz): δ 162,22, 106,59, 61,17, 38,58, 27,99, 27,20, 26,57, 22,72, 14,48 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 22,72, 14, 48mm; CH2carbon atoms: 61,17, 38,58, 27,20, 26,57; CH carbons: 106,59, 27,99 ppm HPLC: 10,072 minutes

Synthesis of 5-(4-methylpentyl)-1H-pyrazole-3-carboxylic acid (18)

Their aqueous solution of NaOH (10M in H2O, equal to 4.97 mmol) are added to stir at room temperature to a solution of compound 17 (0,2229 g, 0,994 mmol) in MeOH (12,4 ml, 0,4M) in the atmosphere N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC (20 min). The reaction mixture was concentrated and then dissolved in 2.0 ml of H2O. added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting 0,1565 g (80.2 per cent) of compound 18.

1H (CD3OD, 400 MHz): δ 6,56 (1H, c), 2,68 (2H, t, J=7,6 Hz), 1,67 (2H, q, J=7.8 Hz), 1,63-is 1.51 (1H, m)of 1.23 (2H, dt, J=8,8, 7,1 Hz)to 0.89 (6H, d, J=6.4 Hz) ppm13C (CD3OD, 100 MHz): δ 163,79, 149,69, 142,80, 107,65, 39,46, 28,92, 28,11, 26,90, 22,91 ppm DEPT (CD3OD, 100 MHz): CH 3carbon atoms: 22,91; CH2carbon atoms: 39,46, 28,11, 26,90; CH carbons: 107,65, 28,92 ppm HPLC: 8,579 minutes

Example 6

Synthesis of 5-phenethyl-1H-pyrazole-3-carboxylic acid (21)

Synthesis of 2,4-dioxo-6-phenylhexanoic acid ethyl ester (19)

Benzylacetone (1.0 g, of 6.75 mmol) and diethyloxalate (0,92 ml of 6.75 mmol) are mixed and then added to a solution of NaOEt (~3M, 2,3 ml)while stirring in an atmosphere of N2while cooling in a bath with ice. After stirring for 15 minutes the reaction mixture is heated to room temperature and stirred over night. The reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2O, dried with Na2SO4, filtered and concentrated, obtaining the crude compound 19. The crude substance is cleaned with a mixture of 1:1 hexane:CH2Cl2getting 0,7348 g (43,9%) of compound 19.

1H (CD3OD, 400 MHz): δ 7,27 for 7.12 (5H, m), 4.26 deaths (2H, q, J=7.2 Hz), 2,89 (2H, t, J=7,3 Hz), of 2.81 (2H, t, J=7,3 Hz)of 1.30 (3H, t, J=7,1 Hz) ppm Partial13C (CD3OD, 100 MHz): δ 163,32, 141,74, 129,43, 129,29, 127,16, 126,95, 103,06, 63,34, 43,46, 31,34, 14,24 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 14.24 from; CH2carbon atoms: 63,34, 43,46, 31,34; CH carbons: 129,43, 129,29, 127,16, 103,06 ppm HPLC: 10,279 minutes

Synthesis of 5-phenethyl-1H-pyrazole-3-carboxylic acid ethyl ester (20)

is igrat hydrazine (0,109 ml, 2,24 mmol) are added to stir at room temperature to a solution of compound 19 (0,5570 g, 2,24 mmol) in EtOH (2.2 ml, 1M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC. The reaction mixture was concentrated and purified by chromatography on silica gel (Combiflash column, 70:30:2 hexane:CH2Cl2:2 N. of NH3in EtOH). Pure fractions are combined and concentrated, obtaining 0,2983 g (54,4%) of compound 20.

1H (CDCl3,400 MHz): δ 11,7 (1H, Sirs), 7,30-7,11 (5H, m), 6,60 (1H, c), 4,32 (2H, q, J=7,1 Hz), 3,07 of 2.92 (4H, m)is 1.31 (3H, t, J=7,1 Hz) ppm Partial13C (CDCl3, 100 MHz): δ 162,13, 147,42, 140,97, 128,72, 128,59, 126,48, 106,79, 61,16, 35,63, 28,18, 14,47 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,47; CH2carbon atoms: 61,16, 35,63, as opposed to 28.18 per; CH carbons: 128,72, 128,59, 126,48, 106,79 ppm HPLC: 9,299 minutes

Synthesis of 5-phenethyl-1H-pyrazole-3-carboxylic acid (21)

Their aqueous solution of NaOH (10M in H2O, of 5.06 mmol) are added to stir at room temperature to a solution of compound 17 (0,2477 g, 1.01 mmol) in MeOH (2.5 ml, 0,4M) in the atmosphere N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC (30 min). The reaction mixture was concentrated and then dissolved in 2.0 ml of H2O added dropwise 10% aqueous HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, receiving the connection 21. Note: an undesired impurity, which is not removed from the solution by the addition of HCl, has a retention time 8,919 min according to the HPLC data.

1H (CD3OD, 400 MHz): δ 7,28-7,20 (2H, m), 7,20-6,92 (3H, m), of 6.66 (1H, c), 3,02 of 2.92 (4H, m) ppm13C (CD3OD, 100 MHz): δ 164,79, 148,33, 142,96, 142,11, 129,45, 129,43, 127,21, 107,51, 36,56, 28,97 ppm DEPT(CD3OD, 100 MHz): CH2carbon atoms: 36,50, 28,91; CH carbons: 129,45, 129,43, 127,24, 107,60 ppm HPLC: 8,050 minutes

Example 7

Synthesis of 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-3-carboxylic acid (24)

Synthesis of 6-(4-methoxyphenyl)-2,4-docohexaenoic acid ethyl ester (22)

4-(4-methoxyphenyl)-2-butanone (14,9908 g, 84,2 mmol) and diethyloxalate (12,3434 g, 84,2 mmol) are mixed and then added to a solution of NaOEt (~3 M, 28,1 ml), with stirring in an atmosphere of N2while cooling in a bath with ice. After stirring for 15 minutes the reaction mixture is heated to room temperature and stirred. After 10 min the reaction mixture completely cures. Add 100 ml of EtOH, and then the reaction mixture was shaken on a mechanical shaker overnight. The reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2 . The combined organic layers washed with H2O, dried with Na2SO4, filtered and concentrated, obtaining the crude compound 22. The crude substance is cleaned with a mixture of 1:1 hexane:CH2Cl2receiving a connection 22.

1H (CDCl3, 400 MHz): δ 14,39 (1H, Sirs), 7,10 (2H, d, J=7,1 Hz), PC 6.82 (2H, d, J=6.3 Hz), 6,34 (1H, c)to 4.33 (2H, q, J=7,1 Hz), of 3.77 (3H, c), only 2.91 (2H, t, J=7,3 Hz), 2,78 (2H, t, J=7,3 Hz)of 1.36 (3H, t, J=7,1 Hz) ppm13C (CDCl3, 100 MHz): δ 202,53, 166,46, 162,29, 158,36, 132,36, 129,44, 114,20, 102,11, 62,75, 55,47, 43,02, 29,94, 14,27 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 55,47, 14,27; CH2carbon atoms: 62,75, 43,02, 29,94; CH carbons: 129,44, 114,20, EUR 102.11 ppm HPLC: 10,12 minutes (starting material: HPLC: 9,10 minutes)

Synthesis of 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-3-carboxylic acid ethyl ester (23)

The hydrazine hydrate (0,513 ml, 10.6 mmol) are added to stir at room temperature to a solution of compound 22 (2,9241 g, 10.5 mmol) in EtOH (10,6 ml, 1M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC (45 min). The reaction mixture was concentrated and crystallized from EtOH, receiving the connection 23.

1H (CDCl3, 400 MHz): δ 11,67 (1H, Sirs), 7,06 (2H, d, J=8,3 Hz), 6,78 (2H, d, J=8,3 Hz), to 6.57 (1H, c), 4,30 (2H, q, J=7.0 Hz), 3,76 (3H, c), 2,98 (2H, t, J=7,7 Hz), is 2.88 (2H, t, J=7,7 Hz)of 1.30 (3H, t, J=7,1 Hz) ppm13C (CDCl3,100 MHz): δ 162,20, 158,13, 147,05, 141,79, 132,94 129,42, 113,98, 106,61, 61,02, 55,36, 34,65, 28,23, 14,37 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 55,36, 14,37; CH2carbon atoms: 61,02, 34,65, 28,23; CH carbons: 129,42, 113,98, 106,61 ppm HPLC: 9,200 minutes

Synthesis of 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-3-carboxylic acid (24)

Their aqueous solution of NaOH (10M in H2O, and 25.4 mmol) are added to stir at room temperature to a solution of compound 23 (1,391 g 5,07 mmol) in MeOH (12,7ml, 0,4M) in the atmosphere N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC (30 min). The reaction mixture was concentrated and then dissolved in 10 ml of H2O. the Reaction mixture is extracted with a small amount of EtOAc, and then the aqueous layer was acidified (pH=2) by adding dropwise a 10% aqueous solution of HCl. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting 0,3771 grams of relatively pure compound 24, which is then purified by recrystallization from warm MeOH, getting 0,1317 g of pure compound 24. Attempts to extract the remainder of the connection 24 from the mother liquor does not take.

1H (CD3OD, 400 MHz): δ 7,07 (2H, d, J=8,2 Hz), at 6.84 (2H, d, J=8.6 Hz), 6,53 (1H, c), of 3.73 (3H, c), 2,97-2,84 (4H, m) ppm13C (CD3OD, 100 MHz): δ 164,86, 159,60, 148,26, 143,15, 134,01, 130,36, 11481, 107,50, 55,60, 35,67, 29,10 ppm

Example 8

Synthesis of 4-benzyl-1H-pyrrole-2-carboxylic acid methyl ester (26)

Synthesis of 4-benzyl-1H-pyrrole-2-carboxylic acid methyl ester (25)

Triethylsilane (0,215 ml, 1.35 mmol) are added to stir at room temperature to a solution of methyl-4-benzoyl-1H-pyrrole-2-carboxylate (0,1118 g, 0,488 mmol) in triperoxonane acid (TFU) (1,04 ml of 0.47 M) in an atmosphere of N2. After stirring over night the reaction is completed, as confirmed by HPLC. TFU is removed in vacuum, the crude product is placed in EtOAc, washed with saturated salt solution, dried with Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, 95:5 hexane:EtOAc)to give pure compound 25 (0,0604 g, 57.5%, respectively).

1H (CDCl3, 400 MHz): δ 9,44 (1H, Sirs), 7,34-7,21 (5H, m), 6,78 (1H, c), of 6.75 (1H, c)3,853 (2H, c)3,846 (3H, c) ppm13C (CDCl3, 100 MHz): δ 162,09, 141,68, 128,85, 128,70, 126,25, 125,55, 122,67, 121,86, 115,74, 51,70, 33,41 ppm HPLC: 9,693 minutes (starting material: 8,611 minutes)

Synthesis of 4-benzyl-1H-pyrrole-2-carboxylic acid methyl ester (26)

Their aqueous solution of NaOH (10M in H2O, of 1.40 mmol) are added to stir at room temperature to a solution of compound 25 (0,0602 g, 0,280 mmol) in MeOH (0,70 ml, 0,4M) in the atmosphere N2. Add 0.7 ml of MeOH from the deposition source in the society and the reaction mixture is heated at boiling under reflux to complete the reaction, which register using HPLC. The reaction mixture was concentrated and then dissolved in 0,55 ml H2O. added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting 0,0495 g (94,5%) of compound 26.

1H (CD3D, 400 MHz): δ 10,83 (1H, Sirs), 7,27-7,11 (5H, m), of 6.71 (1H, c), of 6.66 (1H, c), of 3.78 (2H, c) ppm13C (CD3OD, 100 MHz): δ 164,45, 143,25, 129,58, 129,31, 126,81, 126,18, 123,70, 122,96, 116,68, 34,03 ppm DEPT (CD3OD, 100 MHz): CH2carbon atoms: 34,03; CH carbon atoms: 129,58, 129,31, 126,81, 122,96, 116,68 ppm HPLC: 8,647 minutes

Example 9

Synthesis of 4-Phenethyl-1H-pyrrole-2-carboxylic acid (28)

Synthesis of 4-phenethyl-1H-pyrrole-2-carboxylic acid methyl ester (27)

Triethylsilane (0,323 ml, 2.03 mmol) are added to stir at room temperature a solution of methyl-4-phenylacetyl-1H-pyrrole-2-carboxylate (0,1593 g, 0,655 mmol) in triperoxonane acid (TFU) (1,47 ml, 0,45M) in the atmosphere N2. After stirring over night the reaction is completed, as confirmed by HPLC. TFU is removed in vacuum, the crude product is placed in EtOAc, washed with saturated salt solution, dried with Na2SO4filter, concentrate and purify by chromatography on silica gel (column Combifash, 95:5 hexane:EtOAc)to give pure compound 27 (0,0755 g, 50.3 per cent).

1H (CDCl3, 400 MHz): δ 9,17 (1H, Sirs), 7,32-of 7.25 (2H, m), 7.23 percent-7,17 (3H, m), to 6.80 (1H, c), 6,69 (1H, c), 3,85 (3H, c), 2,93-to 2.85 (2H, m), 2,84 is 2.75 (2H, m) ppm13C (CDCl3, 100 MHz): δ 161,97, 142,15, 128,70, 128,55, 126,13, 125,96, 122,40, 121,26, 115,28, 51,67, 37,57, 28,92 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 51,67; CH2carbon atoms: 37,57, 28,92; CH carbon atoms: 128,70, 128,55, 126,13, 121,26, 115,28 ppm HPLC: 10,033 minutes (starting material: 8,751 minutes)

Synthesis of 4-phenethyl-1H-pyrrole-2-carboxylic acid (28)

Their aqueous solution of NaOH (10M in H2O, of 1.65 mmol) are added to stir at room temperature to a solution of compound 27 (0,0755 g, 0,329 mmol) in MeOH (of 0.82 ml, 0,4M) in the atmosphere N2. Add 0.7 ml MeOH due to the deposition of source materials, after which the reaction mixture is heated at boiling under reflux until completion of the reaction, which is recorded by means of HPLC (2 hours). The reaction mixture was concentrated and then dissolved in 0,55 ml H2O. added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting a net connection 28.

1H (CDCl3,400 MHz): δ 10,87 (1H, Sirs), 7,25-to 7.18 (2H, m), 7,17-of 7.69 (3H, m), 6,70 (1H, c), to 6.67 (1H, c), and 2.83 (2H, t, J=7,6 Hz), is 2.74 (2H, t, J=7,6 Hz) ppm13C (CDCl3 , 100 MHz): δ 164,53, 143,39, 129,50, 129,21, 126,76, 126,38, 123,49, 122,85, 116,48, 38,68, 29,94 ppm DEPT (CDCl3, 100 MHz): CH2carbon atoms: 38,68, 29,94; CH carbon atoms: 129,50, 129,21, 126,76, 122,85, 116,48 ppm HPLC: 8,579 minutes

Example 10

Synthesis of 5-benzyl-1H-pyrrole-2-carboxylic acid (32)

Synthesis of 5-benzoyl-1H-pyrrole-2-carboxylic acid ethyl ester (29) and 4-benzoyl-1H-pyrrole-2-carboxylic acid ethyl ester (30)

Acylpyrrole-2-carboxylate (1,0013 g, 7.20 mmol) in a minimal amount (2.5 ml) of dichloroethane is added to a cooled on ice, and stir the mixture of zinc chloride (1,96 g, 14.4 mmol) and benzoyl chloride (1,67 ml, 14.4 mmol) in dichloroethane (10.9 ml, 0,66M) in an atmosphere of N2. After stirring for 10 min bath with ice is removed and the reaction mixture is heated at 50°C until completion of the reaction according to TLC (35 min, 9:1 hexane:EtOAc). The reaction mixture was cooled and carefully poured into ice water. The reaction mixture was extracted with CH2Cl2using 3 portions of solvent. The combined organic layers washed with H2O, dilute HCl and saturated saline, then dried with Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, 95:5 to 50:50 hexane:EtOAc)to give compound 29 (higher Rf value) and a pure compound 30 (lower Rf value, 0,5646 g, 32,3%): 29 Ni is sustained fashion purify by chromatography on silica gel (Combiflash column, 100% CH2Cl2), receiving 0,6168 g (35,2%) of compound 29.

The results of spectral analysis of compound 29:

1H (CDCl3, 400 MHz): δ 10,19 (1H, Sirs), of 7.90 (2H, d, J=7,6 Hz), to 7.59 (1H, t, J=7,3 Hz), 7,49 (2H, t, J=7,3 Hz)6,94 (1H, DD, J=3,9, 2.4 Hz), 6,83 (1H, DD, J=3,9, 2.4 Hz), to 4.38 (2H, q, J=7,0 Hz)to 1.38 (3H, t, J=7,1 Hz) ppm13C (CDCl3, 100 MHz): δ 185,37, 160,56, 137,69, 133,30, 132,72, 129,27, 128,69, 127,97, 118,75, 115,72, 61,39, 14,55 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,55; CH2carbon atoms: 61,39; CH carbon atoms: 132,72, 129,27, 128,69, 118,75, 115,72 ppm HPLC: 9,792 minutes (starting material: at 8.36 minutes)

The results of spectral analysis of compound 30:

1H (CDCl3, 400 MHz): δ 10,29 (1H, Sirs), to 7.84 (2H, DD, J=8,0, 1.2 Hz), to 7.59-7,53 (2H, m), of 7.48 (2H, t, J=7,6 Hz), was 7.36 (1H, DD, J=2,4, 1.5 Hz), to 4.38 (2H, t, J=7,3 Hz)of 1.35 (3H, t, J=7,3 Hz) ppm13C (CDCl3, 100 MHz): δ 190,93, 161,47, 139,21, 132,23, 129,22, 128,77, 128,61, 124,35, 116,91, 112,82, 61,30, 14,55 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,55; CH2carbon atoms: 61,30; CH carbon atoms: 132,23, 129,22, 128,77, 128,61, 116,91 ppm HPLC: 9,048 minutes

Synthesis of 5-benzyl-1H-pyrrole-2-carboxylic acid ethyl ester (31)

Triethylsilane (0,323 ml, 2.03 mmol) are added to stir at room temperature solution of 5-benzoyl-1H-pyrrole-2-carboxylic acid ethyl ester (29) (0,4180 g, 1,72 mmol) in triperoxonane acid (TFU) (4,1 ml, 0,42M) in the atmosphere N2. After stirring over night the HPLC analysis shows that the reaction does not end the. Adding additional quantities of triethylsilane does not lead to any change according to HPLC, so the reaction mixture and begin to process. TFU is removed in vacuum, the crude product is placed in EtOAc, washed with saturated salt solution, dried with Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, from 98:2 to 95:5 hexane:EtOAc)to give pure compound 31 (0,2190 g, 55.6 per cent).

1H (CDCl3, 400 MHz): δ 9,05 (1H, Sirs), 7,35-7,28 (2H, m), 7,28-of 7.23 (1H, m), 7.23 percent-to 7.18 (2H, m), 6,85 (1H, t, J=3.2 Hz), 6,0 (1H, t, J=3.2 Hz), 4,27 (2H, q, J=7,1 Hz), 4,00 (2H, c), of 1.32 (3H, t, J=7,3 Hz) ppm Partial13C (CDCl3, 100 MHz): δ 138,51, 136,86, 128,99, 128,88, 126,98, 122,26, 116,08, 109,41, 60,39, 34,37, 14,70 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,70; CH2carbon atoms: 60,39, 34,37; CH carbon atoms: 128,99, 128,88, 126,98, 116,08, 109,41 ppm HPLC: 10,014 minutes

Synthesis of 5-benzyl-1H-pyrrole-2-carboxylic acid (32)

Their aqueous solution of NaOH (10M in H2O, 4,78 mmol) are added to stir at room temperature to a solution of compound 31 (0,2190 g, 0,955 mmol) in MeOH (2.4 ml, 0,4M) in the atmosphere N2. The reaction mixture is heated at boiling under reflux until completion of the reaction, which is recorded by means of HPLC (40 min). The product is concentrated and then dissolved in 1.9 ml of H2O added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid in the society, precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, receiving the connection 32 in the form of pale pink, dirty solids (0,0845 g). The connection 32 additionally cleaned by adding CHCl3, mixing and filtering, and then get a pure compound 32 white (0,0445 g). Note: an undesired impurity has a retention time 9,643 min according to HPLC. In addition, when analyzing the connection 32 method13C NMR at room temperature are observed doublets for the peaks corresponding to the carbon atoms of the pyrrole, the carbon atoms of the benzyl and acidic carbon atoms. If the NMR probe is heated to 28°C, all double peaks merge into a single, as described below.

1H (CD3OD, 400 MHz): δ 11,04 (1H, Sirs), 7,27-7,13 (5H, m), to 6.80 (1H, d, J=3,4 Hz), by 5.87 (1H, d, J=3,4 Hz) 3,93 (2H, c) ppm13C (CD3OD, 100 MHz): δ 164,52, 140,71, 139,04, 129,56, 129,42, 127,27, 122,77, 117,59, 109,66, 34,65 ppm DEPT (CD3OD, 100 MHz): CH2carbon atoms: 34,65; CH carbon atoms: 129,56, 129,42, 127,27, 117,59, 109,66 ppm HPLC: 8,698 minutes

Example 11

Synthesis of 5-phenethyl-1H-pyrrole-2-carboxylic acid (36)

Synthesis of 5-phenylacetyl-1H-pyrrole-2-carboxylic acid ethyl ester (33) and 4-phenylacetyl-1H-pyrrole-2-carboxylic acid ethyl ester (34)

Acylpyrrole-2-carboxylate (2,5182 g, 18.1 m is ol) in a minimal amount of dichloroethane is added to a cooled on ice, and stir the mixture of zinc chloride (4,9891 g, 36.6 mmol) and phenylacetylene (4,76 ml, compared with 35.9 mmol) in dichloroethane (25 ml, 0,72M) in an atmosphere of N2. After stirring for 10 min bath with ice is removed and the reaction mixture is heated at 50°C until completion of the reaction according to TLC (30 min, 9:1 hexane:EtOAc). The reaction mixture was cooled and carefully poured onto ice water. The reaction mixture was extracted with CH2Cl2using 3 portions of solvent. The combined organic layers washed with H2O, dilute HCl and saturated saline, then dried with Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, 90:10 to 60:40 hexane:EtOAc)to give compound 33 (lower Rf value) and 34 ((higher Rf value): detected that the connection 33 contains colored admixture, which is easily removed by adding hexanol and removal of the colored solution. After processing hexane connection 33 (0,7239 g, 15.5 per cent) is sufficiently pure for use in the next stage.

The results of spectral analyses of the connections 33:

1H (CDCl3, 400 MHz): δ 9,87 (1H, Sirs), 7,35-of 7.23 (5H, m), 6,92-6,87 (2H, m), 4,34 (2H, q, J=7,1 Hz), 4.09 to (2H, c), of 1.36 (3H, t, J=7,1 Hz) ppm13C (CDCl3, 100 MHz): δ 188,72, 160,49, 134,40, 133,63, 129,57, 128,96, 127,82, 127,32, 116,60, 115,73, 61,39, 45,59, 14,54 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,54; CH2carbon atoms: 61,39, 45,59; CH atoms angle of the ode: 129,57, 128,96, 127,32, 116,60, 115,73 ppm HPLC: 9,714 minutes (starting material: at 8.36 minutes)

The results of spectral analyses of the connections 34:

1H (CDCl3, 400 MHz): δ 10,16 (1H, Sirs), 7,74 (1H, c), 7,72 (1H, c), 7,44-of 7.23 (5H, m)to 4.33 (2H, q, J=7,1 Hz), 4,18 (2H, c), of 1.34 (3H, t, J=7,1 Hz) ppm Partial13C (CDCl3, 100 MHz): δ 193,45, 160,64, 61,43, 47,97, 14,49 ppm HPLC: 10,7 minutes

Synthesis of 5-phenethyl-1H-pyrrole-2-carboxylic acid ethyl ester (35)

Triethylsilane ones (0.46 ml, is 2.88 mmol) are added to stir at room temperature solution of 5-phenylacetyl-1H-pyrrole-2-carboxylic acid ethyl ester (33) (0,240 g, 0,929 mmol) in triperoxonane acid (TFU) (2.2 ml, 0,42M) in the atmosphere N2. According to HPLC, the reaction is terminated after 3.5 h TFU removed in vacuo, the crude product is placed in EtOAc, washed with saturated salt solution, dried with Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, 60:40 hexane:CH2Cl2receiving a connection 35, which according to TLC is clean, and according to HPLC has impurities. Net connection 35 is obtained after preparative HPLC with reversed phase under the following conditions: from 0 to 10 min: 35:65 H2O:CH3CN; 10-11 min: from 35:65 to 0:100 H2A:CH3CN; 20 ml/min; λ=254 nm; 50,8 mg/ml, 0.8 ml/input sample.

1H (CDCl3, 400 MHz): δ 9,46 (1H, Sirs), 7,33-7,16 (5H, m), 6,85 (1H, t, J=2,9 Hz), of 5.99 (1H, t, J=2,9 Hz), the 4.29 (2H, q, J=7,1 Hz), 2,97 (4H, c), of 1.33(3H, t, J=7,1 Hz) ppm13C (CDCl3, 100 MHz): δ 161,76, 141,16, 138,18, 128,69, 128,52, 126,46, 121,52, 116,06, 108,46, 60,36, 35,89, 29,83, 14,67 ppm DEPT (CDCl3,100 MHz): CH3carbon atoms: 14,67; CH2carbon atoms: 60,36, 35,89, 29,83; CH carbon atoms: 128,69, 128,52, 126,46, 116,06, 108,46 ppm HPLC: over 10,392 minutes

Synthesis of 5-phenethyl-1H-pyrrole-2-carboxylic acid (36)

Their aqueous solution of NaOH (10M in H2O, to 1.67 mmol) are added to stir at room temperature to a solution of compound 35 (0,0814 g of 0.333 mmol) in MeOH (0,83 ml, 0,4M) in the atmosphere N2. To dissolve the connection 35, add 0.4 ml of iPrOH. The reaction mixture is heated at boiling under reflux until completion of the reaction, which is recorded by means of HPLC. The product is concentrated and dissolved in 1.9 ml of H2O added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night and get a connection 36 in the form of a pale pink solid. (Note: an undesired impurity has a retention time 12,055 min according to HPLC. In addition, when analyzing the connection 36 method13C NMR at room temperature are observed doublets for the peaks corresponding to the carbon atoms of the pyrrole, the carbon atoms of the benzyl and acidic carbon atoms. If the NMR probe heating of the Ute to 28°C, all double peaks merge into a single, as described below.)

1H (CD3OD, 400 MHz): δ 10,97 (1H, Sirs), 7,25-7,20 (2H, m), 7.18 in-7,11 (3H, m), 6,76 (1H, d, J=3,4 Hz), 5,90 (1H, d, J=3,4 Hz), 2,94-2,84 (4H, m) ppm13C (CD3OD, 100 MHz): δ 164,51, 142,68, 139,79, 129,40, 129,30, 126,98, 122,36, 117,47, 108,90, 37,00, 30,67 ppm DEPT (CDCl3, 100 MHz): CH2carbon atoms: 37,00, 30,67; CH carbon atoms: 129,40, 129,30, 126,98, 117,47, 108,90 ppm, HPLC: 11,239 minutes

Example 12

Synthesis of 4-[2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (39)

Synthesis of 4-[2-(4-chlorophenyl)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (37)

Acylpyrrole-2-carboxylate (1,0195 g, 7,33 mmol) in a minimal amount of dichloroethane is added to a cooled on ice, stir a mixture of aluminium chloride (1,934 g, 14.5 mmol) and 4-chlorobenzotrichloride (2,7841 g, 14,73 mmol) in dichloroethane (10.9 ml, 0,67M) in an atmosphere of N2. After stirring for 10 min bath with ice is removed and the reaction mixture was stirred at room temperature for 60 minutes, after which there is a slight change in TLC (9:1 hexane:EtOAc). After heating at 60°C for one hour with TLC discover that there was only a small amount of substance. The reaction mixture is cooled to room temperature, add the resin PS-TrisamineTM(6,3954 g, 24,30 mmol) and dichloroethane (10 ml) and stirred for 3 hours. C is the reaction mixture was filtered through a funnel with a porous glass filter directly on the water with ice. The resin was washed with CH2Cl2, then the organic layers are removed, dried Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, 95:5 to 50:50 hexane:EtOAc)to give 1,0345 g (48.4%) of compound 37 as a pale orange solid. Note: before applying on a column with silica to solubilize the crude product you want to add a small amount of CH2Cl2.

1H (CDCl3, 400 MHz): δ 10,07 (1H, Sirs), 7,55-7,52 (1H, m), 7,33-7,30 (1H, m), 7,27 (2H, d, J=8,3 Hz), 7,14 (2H, d, J=8,3 Hz), 4,35 (2H, q, J=7.0 Hz), Android 4.04 (2H, c), of 1.37 (3H, t, J=7,1 Hz) ppm13C (CDCl3,100 MHz): δ 192,55, 160,97, 133,10, 132,75, 130,76, 128,69, 126,80, 126,25, 124,30, 114,95, 61,06, 45,79, 14,31 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,31; CH2carbon atoms: 61,06, 45,79; CH carbons: 130,76, 128,69, 126,80, 114,96 ppm HPLC: 10,049 minutes

Synthesis of 4-[2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (38)

Triethylsilane (1.13 ml, was 7.08 mmol) are added to stir at room temperature to a solution of 4-[2-(4-chlorophenyl)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (37) (0,6662 g, 2.28 mmol) in triperoxonane acid (TFU) (5,54 ml, 0,42M) in the atmosphere N2. After stirring at room temperature for 4 hours TFU removed in vacuo, the crude product is placed in EtOAc, washed with saturated salt solution, dried with Na2SO4, Phi is trout, concentrated and purified preparative HPLC with reversed phase under the following conditions: from 0 to 12 min: 35:65 H2O:CH3CN; 12-13 min: from 35:65 to 0:100 H2A:CH3CN; 20 ml/min; λ=254 nm; 137 mg/ml, 1.0 ml/input sample. Get 0,2704 g (42.6%) compound 38 in the form of a friable white solid. (Note: an undesired impurity has a retention time 12,055 min according to HPLC.)

1H (CDCl3, 400 MHz): δ 8,99 (1H, Sirs), of 7.23 (2H, d, J=8,3 Hz), to 7.09 (2H, d, J=8,3 Hz), 6,76 (1H, c), only 6.64 (1H, c), 4,30 (2H, q, J=7.0 Hz), 2,84 (2H, t, J=7,6 Hz)of 2.75 (2H, t, J=7,6 Hz)of 1.35 (3H, t, J=7,1 Hz) ppm13C (CDCl3, 100 MHz): δ 161,14, 140,25, 131,52, 129,80, 128,32, 125,17, 122,62, 120,66, 114,73, 60,25, 36,62, 28,53, 14,43 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,43; CH2carbon atoms: 60,25, 36,62, 28,53; CH carbons: 129,80, 128,32, 120,66, 114,73 ppm HPLC: 11,049 minutes

Synthesis of 4-[2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (39)

Their aqueous solution of NaOH (10M in H2O, 4,84 mmol) are added to stir at room temperature to a solution of compound 38 (0,2689 g, 0,968 mmol) in MeOH (2,42 ml, 0,4M) in the atmosphere N2. The reaction mixture is heated at boiling under reflux until completion of the reaction, which is recorded by means of HPLC (30 min). The product is concentrated and then dissolved in 5 ml of H2O. the Product is extracted with EtOAc, and then the aqueous layer was acidified (pH=2)by adding dropwise a 10% aqueous solution of HCl. White solid, about arausiaca from the reaction mixture, filtered off and washed with cold H2O. the Solid is dried in vacuum over night, receiving the connection 39 in the form of a pale pink solid (note: an undesired impurity has a retention time 10,956 min according to HPLC.)

1H (CD3OD, 400 MHz): δ 10,89 (1H, Sirs), 7,22 (2H, d, J=8,3 Hz), 7,13 (2H, d, J=8,3 Hz), 6,69 (1H, c), of 6.66 (1H, c), 2,82 (2H, t, J=7,1 Hz), 2,73 (2H, t, J=7,1 Hz) ppm13C(CD3OD, 100 MHz): δ 164,48, 142,15, 132,49, 131,15, 129,21, 125,97, 123,60, 122,88, 116,44, 37,92, 29,70 ppm DEPT (CDCl3, 100 MHz): CH2carbon atoms: 37,92, 29,70; CH carbons: 131,15, 129,21, 122,88, 116,44 ppm HPLC: 9,996 minutes

Example 13

Synthesis of 5-phenoxymethyl-1H-pyrazole-3-carboxylic acid (42)

Synthesis of 2,4-dioxo-5-Phenoxyethanol acid ethyl ester (40)

PHENOXYACETIC (5,0240 g, 33,46 mmol) and diethyloxalate (4.52 ml, 33,29 mmol) are mixed and then added to a solution of NaOEt (~3M, 11,1 ml), with stirring in an atmosphere of N2while cooling in a bath with ice N2. After stirring for 15 minutes the reaction mixture is heated to room temperature and stirred over night. The reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2O, dried with Na2SO4, filtered and concentrated, obtaining the crude compound 40. The crude substance is cleaned with a mixture of 1: hexane:CH 2Cl2getting 1,3490 g (15,4%) of compound 40.

1H (CDCl3, 400 MHz): δ 7,31 (2H, t, J=7.5 Hz), 7,01 (1H, t, J=7,3 Hz)6,91 (2H, d, J=8,8 Hz), 6,76 (1H, c), of 4.67 (2H, c), of 4.35 (2H, q, J=7,1 Hz)to 1.38 (3H, t, J=7,1 Hz) ppm13C (CDCl3, 100 MHz): δ 199,61, 166,38, 161,55, 157,37, 129,63, 121,89, 114,48, 98,97, 70,13, 62,60, 13,90 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 13,90; CH2carbon atoms: 70,13, 62,60; CH carbons: 129,63, 121,89, 114,48, 98,97 ppm, HPLC: 10,180 minutes (starting material: 9,053 minutes)

Synthesis of 5-phenoxymethyl-1H-pyrazole-3-carboxylic acid ethyl ester (41)

The hydrazine hydrate (0,197 ml, 4,06 mmol) are added to stir at room temperature to a solution of compound 40 (1,0163 g 4,06 mmol) in EtOH (4,1 ml, 1M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC. The reaction mixture was concentrated and purified by chromatography on silica gel (Combiflash column, 92:4:4 hexane:CH2Cl2:2 N. of NH3in EtOH). Pure fractions are combined and concentrated, obtaining 0,5474 g (54,7%) of compound 41.

1H (CDCl3, 400 MHz): δ 12,12 (1H, Sirs), 7,28 (2H, t, J=7.8 Hz), 7,01-6,94 (3H, m)6,91 (1H, c)to 5.17 (2H, c), 4,36 (2H, q, J=7.0 Hz), of 1.36 (3H, t, J=7,1 Hz) ppm Partial13C (CDCl3, 100 MHz): δ 158,11, 129,48, 121,26, 114,71, 107,83, 62,61, 61,31, 14,17 ppm HPLC: 9,505 minutes

Synthesis of 5-phenoxymethyl-1H-pyrazole-3-carboxylic acid (42)

Their water dissolve the NaOH (10M in H 2O, 10,49 mmol) are added to stir at room temperature to a solution of compound 41 (0,5164 g, 2.10 mmol) in MeOH (5.2 ml, 0,4M) in the atmosphere N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC (20 min). The reaction mixture was concentrated and then dissolved in 4.2 ml of H2Oh, and then added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting 0,4044 g (88,4%) of compound 42 as a white solid. Note: an undesired impurity, which is not removed from the solution by the addition of HCl, has a retention time 9,127 min according to the HPLC data.

1H (CDCl3, 400 MHz): δ 7,26 (2H, t, J=8.0 Hz), of 6.99 (2H, d, J=8,3 Hz)6,94 (1H, t, J=7,3 Hz), 6,85 (1H, c), 5,10 (2H, c) ppm13C (CDCl3, 100 MHz): δ 163,68, 159,73, 146,60, 141,13, 130,51, 122,27, 115,83, 108,88, 63,06 ppm DEPT (CDCl3, 100 MHz): CH2carbon atoms: 63,06; CH carbons: 130,51, 122,27, 115,83, 108,88 ppm HPLC: 8,272 minutes

Example 14

Synthesis of 4-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid (45)

Synthesis of 4-(3-phenylpropionyl)-1H-pyrrole-2-carboxylic acid ethyl ester (43)

Acylpyrrole-2-carboxylate (1,6236 g, 11,67 mmol) in a minimal amount is chlorethane add to cooled on ice, stir a mixture of aluminium chloride (3,1085 g, 23,30 mmol) and hydrocinnamaldehyde (3,9058 g, 23,16 mmol) in dichloroethane (17,7 ml, 0,67M) in an atmosphere of N2. After stirring for 10 min bath with ice is removed and the reaction mixture was stirred at room temperature for 60 minutes, then see a small change by TLC (9:1 hexane:EtOAc). After heating at 60°C for one hour with TLC discover that only a small amount of the original substance. The reaction mixture is cooled to room temperature, add poliaminov resin HL (2,60 mmol/g, 16,41 g, 42,67 mmol) and dichloroethane (10 ml) and the reaction mixture is stirred for 3 hours. Then the reaction mixture was filtered through a funnel with a porous glass filter directly on the water with ice. The resin was washed with CH2Cl2, then the organic layers are removed, dried Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, 92:8:4 Hexane:CH2Cl2:2 N. of NH3in EtOH), receiving 0,5501 g (14,1%) of compound 43 as a pale orange solid.

1H (CDCl3,400 MHz): δ 10,70 (1H, Sirs), 7,56 (1H, c), of 7.36-7,17 (6H, m), 4,35 (2H, q, J=7.0 Hz), 3,18-3,10 (2H, m), 3,10-a 3.01 (2H, m)to 1.37 (3H, t, J=7,1 Hz) ppm13C (CDCl3, 100 MHz): δ 194,98, 161,18, 141,13, 128,31, 128,20, 126,64, 126,42, 125,92, 123,96, 114,72, 60,84, 41,19, 30,04, 14,16 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,16; CH2the carbon atoms is kind: 60,84, 41,19, 30,04; CH carbon atoms: 128,31, 128,20, 126,64, 125,92, 114,72 ppm HPLC: 9,975 minutes

Synthesis of 4-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (44)

Triethylsilane (0,776 ml, to 4.87 mmol) are added to stir at room temperature to a solution of compound 43 (0,5266 g, 1.57 mmol) in triperoxonane acid (TFU) (3,74 ml, 0,42M) in the atmosphere N2. After stirring at room temperature for 4 hours TFU removed in vacuo, the crude product is placed in EtOAc, washed with saturated salt solution, dried with Na2SO4, filtered, concentrated and purified preparative HPLC with reversed phase under the following conditions: from 0 to 11 min: 35:65 H2A:CH3CN; 11,5-20 min from 35:65 to 0:100 H2O:CH3CN; 20 ml/min; λ=254 nm; 200 mg/ml, 0.7 ml/input sample. 0,2455 g (48.7 percent) of compound 44 receive in the form of a friable white solid. (Note: an Undesired impurity has a retention time 12,062 min according to HPLC.)

1H (CDCl3, 400 MHz): δ 9,27 (1H, Sirs), 7,34-7,26 (2H, m), 7.24 to 7,17 (3H, m), for 6.81 (1H, c), of 6.75 (1H, c)to 4.33 (2H, q, J=7,1 Hz)to 2.67 (2H, t, J=7.8 Hz), 2,53 (2H, t, J=7.8 Hz), of 1.93 (2H, q, J=7,8 Hz)to 1.37 (3H, t, J=7,1 Hz) ppm13C (CDCl3, 100 MHz): δ 161,34, 142,31, 128,40, 128,22, 125,99, 125,64, 122,47, 120,73, 114,82, 60,17, 35,33, 32,47, 26,17, 14,41 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,41; CH2carbon atoms: 60,17, 35,33, 32,47, 26,17; CH carbon atoms: 128,40, 128,22, 125,64, 120,73, 114,82 ppm HPLC: 11,140 minutes

Synthesis of 4-(3-Fe is ylpropyl)-1H-pyrrole-2-carboxylic acid (45)

Their aqueous solution of NaOH (10M in H2Oh, 3,82 mmol) are added to stir at room temperature to a solution of compound 44 (0,2455 g, 0,7644 mmol) in MeOH (1.9 ml, 0,4M) in the atmosphere N2. The reaction mixture is heated at boiling under reflux until completion of the reaction, which is recorded by means of HPLC (25 min): Product is concentrated and then dissolved in 1.5 ml H2O. the Product is extracted with EtOAc, and then the aqueous layer was acidified (pH=2) by adding dropwise a 10% aqueous solution of HCl. Add EtOAc and the product is extracted in the organic layer. The organic layer is dried Na2SO4filter and concentrate, getting to 56.1 mg of product, which according to HPLC contains several minor impurities. The product is placed into the minimum number of CHCl3when heated and then add a small amount of hexanol to precipitate the product. The product is filtered and dried, obtaining 16,0 mg of compound 45. (Note: an undesired impurity has a retention time 10,843 min according to HPLC.)

1H (CD3OD, 400 MHz): δ 7,24 (2H, t, J=7,3 Hz), 7,16 (2H, d, J=7,3 Hz), 7,13 (1H, t, J=7,3 Hz), to 6.75 (1H, c), of 6.71 (1H, c), 2,61 (2H, t, J=7.8 Hz), the 2.46 (2H, t, J=7.8 Hz), to 1.86 (2H, q, J=7,8 Hz) ppm13C (CD3OD, 100 MHz): δ 164,54, 143,73, 129,47, 129,27, 126,73, 126,66, 123,49, 122,56, 116,34, 36,41, 34,23, 27,21 ppm DEPT (CDCl3, 100 MHz): CH2carbon atoms: 36,41, 34,23, 27,21; CH carbon atoms: 129,47, 129,27, 126,66, 122,56, 116,34 ppm is ASH: 9,845 minutes

Example 15

Synthesis of 5-(3-methylbutyl)-1H-pyrazole-3-carboxylic acid (48)

Synthesis of 7-methyl-2,4-dioxopentanoate acid ethyl ester (46)

5-Methyl-2-hexanone (5,0084 g and 43.9 mmol) and diethyloxalate (5,95 ml that 43.8 mmol) are mixed and then added to a solution of NaOEt (~3M, 14,6 ml)while stirring in an atmosphere of N2while cooling in a bath with ice. After stirring for 15 minutes the reaction mixture is heated to room temperature and stirred over night. The reaction mixture was quenched at 0°C 1N HCl and extracted 2×CH2Cl2. The combined organic layers washed with H2O, dried with Na2SO4, filtered and concentrated, obtaining the crude compound 46. The crude substance is cleaned with a mixture of 1:1 hexane:CH2Cl2getting 6,6035 g (70,3%) of compound 46.

1H (CDCl3, 400 MHz): δ 6,28 (1H, c), of 4.25 (2H, q, J=7.0 Hz), 2.40 a (2H, t, a 7.6 Hz), 1,54-of 1.41 (3H, m)of 1.27 (3H, t, J=7,3 Hz)of 0.82 (6H, d, J=6.3 Hz) ppm13C (CDCl3, 100 MHz): δ 203,40, 166,27, 161,85, 101,37, 62,15, 38,74, 33,39, 27,46, 21,99, 13,77 ppm DEPT (CDCl3,100 MHz): CH3carbon atoms: 21,99, 13,77; CH2carbon atoms: 62,15, 38,74, 33,39; CH carbons: 101,37, 27,46 ppm HPLC: 11,038 minutes

Synthesis of 5-(3-methylbutyl)-1H-pyrazole-3-carboxylic acid ethyl ester (47)

The hydrazine hydrate (1,43 ml, 2,95 mmol) are added to stir at room temperature the solution connect the tion 46 (6,3112 g, 2,95 mmol) in EtOH (29.5 ml, 1M) in an atmosphere of N2. Then the reaction mixture was stirred at room temperature until completion of the reaction, which is recorded by means of HPLC (35 min). The reaction mixture was concentrated and purified by chromatography on silica gel (Combiflash column, 96:4 hexane:2 N. of NH3in EtOH). Pure fractions are combined and concentrated, obtaining 4,3911 g (70,9%) of compound 47.

1H (CDCl3, 400 MHz): δ 13,01 (1H, Sirs), of 6.52 (1H, c), the 4.29 (2H, q, J=7,1 Hz)of 2.64 (2H, t, J=7.8 Hz), 1,57-of 1.41 (3H, m)of 1.26 (3H, t, J=7,1 Hz), 5,85 (6H, d, J=5,9 Hz) ppm13C (CDCl3, 100 MHz): δ 162,37, 146,26, 143,1, 105,73, 60,53, 37,88, 27,35, 23,42, 22,11, 14,06 ppm HPLC: 10,006 minutes

Synthesis of 5-(3-methylbutyl)-1H-pyrazole-3-carboxylic acid (48)

Their aqueous solution of NaOH (10M in H2Oh, to 80.85 mmol) are added to stir at room temperature to a solution of compound 47 (3,40 g, 16,17 mmol) in MeOH (40,4 ml, 0,4M) in the atmosphere N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC (6 min): the Reaction mixture was concentrated and then dissolved in 14 ml of H2O. added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting 2,8753 g (97,6%) of compound 48. (Note: undesired hair the first impurity has a retention time 9,522 min according to HPLC.)

1H (CDCl3, 400 MHz): δ is 6.61 (1H, c), 2,70 (2H, t, J=7.8 Hz), 1,63-is 1.51 (3H, m)to 0.94 (6H, d, J=6.3 Hz) ppm13C (CDCl3, 100 MHz): δ 164,35, 149,48, 143,00, 107,34, 39,35, 28,71, 24,69, 22,65 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 22,65; CH2carbon atoms: 39,35, 24,69; CH carbons: 107,34, 28,71 ppm HPLC: 9,522 minutes

Example 16

Synthesis of 5-(4-Methylpent-3-enyl)-1H-pyrazole-3-carboxylic acid (51)

Synthesis of 8-methyl-2,4-dioxane-7-ene acid ethyl ester (49)

Sodium hydride (0,465 g, and 19.4 mmol) is slowly added to EtOH (5,ll, 3,3M), with stirring in an atmosphere of N2while cooling in a bath with ice and NaCl. 6-Methylhept-5-ene-2-he (2,4412 g, and 19.3 mmol) and diethyloxalate (2,63 ml of 19.4 mmol) are mixed and then added to a chilled solution of NaOEt. After stirring for 15 minutes the reaction mixture is heated to room temperature and stirred for 6 hours, after which record the completion of the reaction using TLC. The reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2O, dried with Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, 70:30:3 Hexane:CH2Cl2:2n NH3in EtOH). Pure fractions are combined and concentrated, obtaining 1,9190 g (43,8%) of compound 49.

1H (CDCl3, 400 MHz): δ 14,44 (1H, Sirs, 6,34 (1H, c), is 5.06 (1H, t, J=7,3 Hz, to 4.33 (2H, q, J=7,1 Hz), 2.49 USD (2H, t, J=7,3 Hz), 2,31 (2H, q, J=7,3 Hz)of 1.66 (3H, c)to 1.60 (3H, c), of 1.35 (3H, t, J=7,1 Hz) ppm13C (CDCl3, 100 MHz): δ 202,83, 166,39, 162,08, 133,42, 121,90, 101,64, 62,40, 40,92, 25,59, 23,34, 17,61, 13,96 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 25,59, 17,62, 13,97; CH2carbon atoms: 62,40, 40,92, 23,34; CH carbons: 121,90, 101,64 ppm HPLC: 11,007 minutes

Synthesis of 5-(4-Methylpent-3-enyl)-1H-pyrazole-3-carboxylic acid ethyl ester (50)

The hydrazine hydrate (0,41 ml, 8,48 mmol) are added to stir at room temperature to a solution of compound 49 (0,1,9190 g, 8,48 mmol) in EtOH (8.5 ml, 1M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC (1/2 h). The reaction mixture was concentrated and purified by chromatography on silica gel (Combiflash column, 96:4 hexane:2n NH3in EtOH).

1H (CDCl3, 400 MHz): δ of 12.73 (1H, Sirs), to 6.57 (1H, c), 5,09 (1H, t, J=6.8 Hz), 4,32 (2H, q, J=7,1 Hz), 2,70 (2H, t, J=7.5 Hz), to 2.29 (2H, q, J=7.5 Hz), and 1.63 (3H, c), of 1.52 (3H, c), of 1.30 (3H, t, J=7,1 Hz) ppm Partial13C (CDCl3, 100 MHz): δ 162,27, 106,11, 60,65, 31,49, 27,53, 25,52, 17,51, 13,10 ppm HPLC: 9,986 minutes

Synthesis of 5-(4-Methylpent-3-enyl)-1H-pyrazole-3-carboxylic acid (51)

Their aqueous solution of NaOH (10M in H2O 11,85 mmol) are added to stir at room temperature to a solution of compound 50 (0,0,5269 g, is 2.37 mmol) in MeOH (5,9 ml, 0,4M) in the atmosphere is e N 2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC (5 min). The reaction mixture was concentrated, dissolved again in H2O and extracted with EtOAc. 10% aqueous HCl solution are added dropwise to the aqueous layer to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting 0,4034 g (87,6%) of compound 51.

1H (CD3OD, 400 MHz): δ 6,56 (1H, c), 5,14 (1H, t), 2,68 (2H, t, J=7,3 Hz), 2,33 (2H, q, J=7,3 Hz), 1,67 (3H, c), and 1.56 (3H, c) ppm13C (CD3OD, 100 MHz): δ 164,94, 148,55, 143,23, 123,94, 107,32, 28,89, 27,04, 25,85, 17,69 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 25,85, 17,69; CH2carbon atoms: 28,89, 27,04; CH carbons: 123,94, 107,32 ppm: HPLC: 8,475 minutes

Example 17

Synthesis of 5-[2-(2,2,6-trimethylcyclohexyl)ethyl]-1H-pyrazole-3-carboxylic acid (54)

Synthesis of 2,4-dioxo-6-(2,2,6-trimethylcyclohexyl)hexanoic acid ethyl ester (52)

Sodium hydride (0,6447 g, 25,52 mmol) is slowly added to EtOH (10 ml, 2,6M), with stirring in an atmosphere of N2while cooling in a bath with ice and NaCl. 4-(2,2,6-Trimethylcyclohexyl)butane-2-he (5,0072 g is 25.50 mmol) and diethyloxalate (3,7241 g, 25,48 mmol) are mixed and then added to a chilled solution of NaOEt. After paramasivan what I'm in for 5 minutes the reaction mixture is heated to room temperature. Then the reaction mixture cures quickly. Add another 10 ml of EtOH and the reaction mixture is left to stand for a further 3 hours, the Reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2O, dried with Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, 1:1 hexane:CH2Cl2). Pure fractions are combined and concentrated, obtaining the connection 52.

1H (CDCl3, 400 MHz): δ 14,51 (1H, Sirs), 6,34 (1H, c), 4,34 (2H, q, J=7,1 Hz), 2,44 (2H, t, J=8,3 Hz), 1,96-of 1.84 (1H, m), 1,68-1,22 (m)of 1.36 (3H, t, J=7,1 Hz), 1.18 to 0,98 (m)to 0.94 (3H, c), of 0.87 (3H, c), of 0.85 (3H, d, J=7,3 Hz) ppm Partial13C (CDCl3, 100 MHz): δ 203,45, 167,17, 162,40, 101,80, 62,71, 49,28, 42,60, 30,46, 20,86, 14,27 ppm Partial DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,27; CH2carbon atoms: 62,71; CH carbons: 101,80 ppm HPLC: 12,576 minutes

Synthesis of 5-[2-(2,2,6-trimethylcyclohexyl)ethyl]-1H-pyrazole-3-carboxylic acid ethyl ester (53)

The hydrazine hydrate (0,867 ml of 17.9 mmol) are added to stir at room temperature to a solution of compound 52 (5,2981 g of 17.9 mmol) in EtOH (to 17.9 ml, 1M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC. The reaction mixture was concentrated and purified by chromatography on silica gel (Combiflash column, 97:3 Gex is HN:2 N. NH3in EtOH), receiving 1,6604 g (31,8%) of compound 53.

Partial1H (CDCl3, 400 MHz): δ 12,45 (1H, Sirs), to 6.58 (1H, c), 4,32 (2H, q, J=7,1 Hz), 2,63 (2H, t, J=8,3 Hz)is 1.31 (3H, t, J=7,1 Hz)of 0.90 (3H, c), or 0.83 (3H, c)to 0.78 (3H, d, J=6.8 Hz) ppm Partial13C (CDCl3, 100 MHz): δ 106,04, 60,66, 48,99, 34,03, 30,10, 24,89, 14,17 ppm HPLC: 12,000 min

Synthesis of 5-[2-(2,2,6-trimethylcyclohexyl)ethyl]-1H-pyrazole-3-carboxylic acid (54)

Their aqueous solution of NaOH (10M in H2O, by 2.73 mmol) are added to stir at room temperature to a solution of compound 53 (0,1594 g, 0,5451 mmol) in MeOH (1,36 ml, 0,4M) in the atmosphere N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC (5 min). The reaction mixture was concentrated, dissolved again in H2O and extracted with EtOAc. To the water layer added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting 0,0119 g (8,2%) of compound 54. From the EtOAc layer receive 0,0590 g (40,9%) of compound 54, though not quite clean.

1H (CD3OD, 400 MHz): δ 6,56 (1H, c), of 2.64 (2H, t, J=7.8 Hz), 2,03-1,89 (1H, m), 1,69-of 1.53 (2H, m), 1,55-of 1.41 (2H, m), 1,39-of 1.27 (2H, m), 1,20 was 1.06 (3H, m)to 0.97 (3H, c), of 0.91 (3H, c)0,86 (3H, d, J=6.8 Hz) ppm13C (CD3OD, 100 MHz): δ 165,07, 149,02, 143,33, 107,26, 50,24, 37,04, 35,11, 31,58, 31,33, 29,00, 2887, 28,37, 26,30, 22,13, 18,90 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 29,00, 28,87, 18,90; CH2the carbon atoms: 37,04, 31,33, 28,37, 26,30, 22,13; CH carbon atoms: 107,26, 50,24, 31,58 ppm HPLC: 10,497 minutes

Example 18

Synthesis of 5-(2-Phenylpropyl)-1H-pyrazole-3-carboxylic acid (58)

Synthesis of 4-phenylpentane-2-she (55)

1,6 M Motility (22,8 ml of 36.5 mmol) added dropwise within 1 hour to stir at 0°C solution of 3-phenylalkanoic acid (1,8298 g, 11,14 mmol) in dry Et2O (56 ml, 0,2M). Bath ice is removed and the reaction mixture is allowed to mix at room temperature for another 2 and 2/3 hours. Add 0.8 ml MeLi (1.12 mmol, of 0.10 equiv.) and the reaction mixture is stirred for further 30 minutes. Then the reaction mixture was poured in intensively mix the water with ice, containing an aqueous solution of HCl. The organic layer is removed, washed with NaHCO3and saturated saline, then dried with Na2SO4, filtered and concentrated, obtaining a pure compound 55 (1,2324 g, 68,2%).

1H (CDCl3, 400 MHz): δ 7,30 (2H, t, J=7,3 Hz), 7,22 (2H, d, J=7,3 Hz), 7,20 (2H, t, J=7,3 Hz), 3,37-of 3.27 (1H, m), was 2.76 (1H, DD, J=16,1, 6.3 Hz), to 2.66 (1H, DD, J=16,1, and 7.8 Hz), was 2.05 (3H, s)of 1.28 (3H, d, J=7,3 Hz) ppm13C (CDCl3, 100 MHz): δ 208,01, 146,42, 128,80, 127,03, 126,57, 52,16, 35,67, 30,77, 22,28 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 30,77, 22,28; CH2carbon atoms: 52,16; CH carbons: 128,80, 127,03, 126,57, 35,6 ppm HPLC: 10,017 minutes (note: SM has a retention time 9,041 min according to HPLC.)

Synthesis of 2,4-dioxo-6-phenylheptanoic acid ethyl ester(56)

Sodium hydride (0,1702 g, to 7.09 mmol) is slowly added to EtOH (2.6 ml, 2,7M) with stirring in an atmosphere of N2while cooling in a bath with ice and NaCl,. 4-Phenylpentane-2-he (55) (1,0493 g, 6,47 mmol) and diethyloxalate (0,88 ml, 6,47 mmol) are mixed and then added to a chilled solution of NaOEt. After stirring for 5 minutes the reaction mixture is heated to room temperature. After 90 min the reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2O, dried with Na2SO4, filtered, and concentrated, obtaining compound 56 (0,7230 g, 42.6 per cent), which is used in the next stage without additional purification.

1H (CDCl3, 400 MHz): δ 7,34-1,16 (5H, m), 6,30 (1H, s)to 4.33 (2H, q, J=7.0 Hz), 3,39-3,26 (1H, m), 2,82 (1H, DD, J=15,1, 6,8 Hz), of 2.72 (1H, DD, J=15,1, and 7.8 Hz), of 1.36 (3H, t, J=7.0 Hz), 1,32 (3H, d, J=6.8 Hz) ppm HPLC: 10,934 minutes

Synthesis of 5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid ethyl ester (57)

The hydrazine hydrate (0,134 ml, was 2.76 mmol) are added to stir at room temperature to a solution of compound 56 (0,7230 g, was 2.76 mmol) in EtOH (2.8 ml, 1M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, to the register which by HPLC (50 min). The reaction mixture was concentrated and purified preparative HPLC with reversed phase, using the following conditions: from 0 to 24 min: 55:45 H2A:CH3CN; 24-25 min: from 55:45 to 0:100 H2A:CH3CN; 20 ml/min; λ=214 nm; 100 mg/ml, 0.2 ml/input sample. Get 0,0489 g of compound 57.

1H (CDCl3, 300 MHz): δ 10,77 (1H, Sirs), was 7.36-7,14 (5H, m), of 6.49 (1H, s)to 4.33 (2H, q, J=7.0 Hz), 3,16-of 2.86 (3H, m)of 1.33 (3H, t, J=7,0 Hz)of 1.27 (3H, d, J=5,9 Hz) ppm13C (CDCl3, 75 MHz): δ 162,01, 145,94, 145,75, 141,50, 128,43, 126,76, 126,32, 106,98, 60,87, 39,94, 34,64, 21,34, 14,12 ppm DEPT (CDCl3, 75 MHz): CH3carbon atoms: 21,34, 14,12; CH2carbon atoms: comparison with 60.87, 34,64; CH carbon atoms: 128,43, 126,77, 126,32, 106,98, 39,94 ppm HPLC: 10,052 minutes

Synthesis of 5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid (58)

Their aqueous solution of NaOH (10M in H2O, 0,947 mmol) are added to stir at room temperature to a solution of compound 57 (0,0489 g, 0,1893 mmol) in MeOH (of 0.47 ml, 0,4M) in the atmosphere N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, registered by HPLC (8 min). The reaction mixture was concentrated, dissolved again in H2O and extracted with EtOAc (1 ml). To the water layer added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum for but and, getting 0,0298 g (68,3%) of compound 58.

1H (CD3OD, 400 MHz): δ 7,24 (2H, t, J=7,3 Hz), 7,18 (2H, d, J=7,3 Hz), 7,14 (1H, t, J=7,3 Hz), 6.42 per (1H, s), 3,11-a 3.01 (1H, m), 2,95 (1H, DD, J=14,1, 7,3 Hz), 2,89 (1H, DD, J=14,1, 7,8 Hz)of 1.26 (3H, d, J=6.8 Hz) ppm13C (CD3OD, 100 MHz): δ 164,83, 147,35, 147,13, 143,02, 129,45, 127,92, 127,35, 108,07, 41,46, 35,58, 22,05 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 22,05; CH2carbon atoms: 35,58; CH carbon atoms: 129,45, 127,92, 127,35, 108,07, 41,46 ppm HPLC: 8,764 minutes

Example 19

Synthesis of 5-(1-methyl-2-phenylethyl)-1H-pyrazole-3-carboxylic acid (62)

Synthesis of 3-methyl-4-phenylbutane-2-she (59)

1,4M Motility (34.8 ml, 48,72 mmol) is added over 70 min to stir at 0°C solution of α-methylhydroquinone acid (4,0019 g, 24,36 mmol) in dry Et2O (122 ml of 0.2 M). Bath ice is removed, and the reaction mixture is allowed to mix at room temperature for another 2 hours. The reaction mixture is poured into intensively mix the water with ice, containing an aqueous solution of HCl. The organic layer is removed, washed with NaHCO3and saturated saline, then dried with Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, 95:5 hexane:EtOAc)to give pure compound 59 (2,3038 g, 58.3 percent).

1H (CDCl3, 400 MHz): δ 7,28 (2H, t, J=7,3 Hz), 7,20 (1H, t, J=7,3 Hz), 7,16 (2H, d, J=7,3 Hz)of 3.00 (1H, DD, J=13,7, 6,8 Hz), and 2.83 (1H, app sex, 7,0 Hz), 2,56 (1, DD, J=13,7, 7,8 Hz), of 2.08 (3H, s)of 1.09 (3H, d, J=6.8 Hz) ppm13C (CDCl3, 100 MHz): δ 211,99, 139,53, 128,79, 128,28, 126,10, 48,65, 38,75, 28,74, 16,10 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 28,74, 16,10; CH2carbon atoms: 38,75; CH carbons: 128,79, 128,28, 126,10, 48,65 ppm HPLC: 10,229 minutes (note: SM has a retention time 9,225 min according to HPLC.)

Synthesis of 5-methyl-2,4-dioxo-6-phenylhexanoic acid ethyl ester (60)

Sodium hydride (0,3965 g, 16,52 mmol) is slowly added to EtOH (5.6 ml, 2,6M), with stirring in an atmosphere of N2cooling in a bath with ice, containing NaCl. Compound 59 (2,2727 g, 14,01 mmol) and diethyloxalate (2,0649 g, 14,13 mmol) are mixed and then added to a chilled solution of NaOEt. After stirring for 5 minutes the reaction mixture is heated to room temperature. After stirring for 5 h the reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2O, dried with Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, 67:30:3 hexane:CH2Cl2:2n NH3in EtOH). Pure fractions are combined and concentrated, obtaining a connection 60.

1H (CDCl3, 400 MHz): δ 14,55 (1H, Sirs), 7,32 for 7.12 (5H, m), 6,36 (1H, s)to 4.33 (2H, q, J=7.0 Hz), 3,05 (1H, DD, J=13,5 that 6.8 Hz), 2,84 (1H, app sex, J=7,0 Hz)to 2.67 (1H, DD, J=13,5, and 7.8 Hz), of 1.36 (3H, t, J=7,1 Hz), 2,33 (3H, d, J=7.0 Hz) ppm13C (CDCl3, 100 Hz): δ 205,78, 166,96, 161,88, 138,75, 128,80, 128,30, 126,29, 100,75, 62,32, 46,35, 39,10, 16,51, 13,88 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 16,51, 13,88; CH2carbon atoms: 62,32, 39,10; CH carbon atoms: 128,80, 128,30, 126,29, 100,75, 46,35 ppm HPLC: 11,084 minutes

Synthesis of 5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid ethyl ester (61)

The hydrazine hydrate (0,1564 ml of 3.23 mmol) are added to stir at room temperature to a solution of compound 60 (0,8460 g, AZN 3.223 bn mmol) in EtOH (3.2 ml, 1M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC. The reaction mixture was concentrated and purified by chromatography on silica gel (Combiflash column, 87:7:4 hexane:CH2Cl2:2 N. of NH3in EtOH), receiving 0,6423 g (77,1%) of compound 61.

1H (CDCl3, 300 MHz): δ 7,26-7,14 (3H, m), was 7.08 (2H, d, J=7,0 Hz), is 6.61 (1H, c), 4,34 (2H, q, J=7.2 Hz), 3,23 (1H, app sex, J=7,1 Hz)of 3.00 (1H, DD, J=13,5, 6,7 Hz), 2,77 (1H, DD, J=13,5, 8.0 Hz), of 1.34 (3H, t, J=7,1 Hz), 1.26 in (3H, d, J=7,3 Hz) ppm Partial13C (CDCl3, 75 MHz): δ 161,86, 139,47, 128,99, 128,20, 126,14, 104,99, 60,80, 43,37, 33,39, 19,60, 14,18 ppm DEPT (CDCl3, 75 MHz): CH3carbon atoms: 19,60, 14,18; CH2carbon atoms: 60,80, 43,37; CH carbon atoms: 128,99, 128,20, 126,14, 104,99, 33,39 ppm HPLC: 10,129 minutes

Synthesis of 5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid(62)

Their aqueous solution of NaOH (10M in H2O, 1.01 mmol) is added to the mix in to matnog temperature to a solution of compound 61 (0,0523 g, 0,2024 mmol) in MeOH (0.51 ml, 0,4M) in the atmosphere N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, registered by HPLC (9 min). The reaction mixture was concentrated, dissolved again in H2O and extracted with EtOAc. To the water layer added dropwise 10% aqueous solution of HCl to obtain pH=2. If white solid does not fall as expected, add EtOAc, the organic layer removed, dried Na2SO4filter and concentrate, getting a net connection 62.

1H (CD3OD, 400 MHz): δ 7.24 to to 7.18 (2H, m), 7,17-7,05 (3H, m), 6,56 (1H, c), 3,17 (1H, app sex, J=7,3 Hz), 2,96 (1H, DD, J=13,6, 7,3 Hz), 2,80 (1H, DD, J=13,7, 7,8 Hz), 1,25 (3H, d, J=6.8 Hz) ppm13C (CD3OD, 100 MHz): δ 164,88, 153,40, 142,91, 140,97, 130,09, 129,25, 127,21, 106,11, 44,41, 34,96, 20,35 ppm DEPT (CD3OD, 100 MHz): CH3the carbon atom: 20,35; CH2the carbon atom: 44,41; CH carbon atoms: 130,09, 129,25, 127,21, 106,11, 34,96 ppm HPLC: 8,849 minutes

Example 20

Synthesis of 4-[2-(2-bromophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (65)

Synthesis of 4-[2-(2-bromophenyl)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (63)

Acylpyrrole-2-carboxylate (1,9428 g, 13,96 mmol) in a minimal amount (~5 ml) of dichloromethane is added to a cooled on ice, stir a mixture of aluminium chloride (4,0458 g, 30,34 mmol) and 2-bromophenylacetonitrile (6,7116 g, 28,74 mmol) in dichloromethane (44 ml, 0,66M) and in the atmosphere N 2. Bath ice is removed and the reaction mixture was stirred at room temperature for 2 hours Add 19,2977 g (2.6 mmol/g) polyominoes resin HL (200-400 mesh) and dichloromethane (20 ml), after which the reaction mixture is stirred for ~100 minutes Then the reaction mixture was filtered through a funnel with a porous glass filter directly on the water with ice. The resin was washed with CH2Cl2, then the organic layers are removed, dried Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, from 80:20 to 60:40 hexane:EtOAc)to give 2,5751 g (54,9%) of compound 63 as a white solid. Note: Before applying on a column with silica to solubilize the crude product you want to add a small amount of CH2Cl2.

1H (CDCl3, 400 MHz): δ 10,32 (1H, Sirs), EUR 7.57-7,53 (2H, m), 7,38-7,37 (1H, m), 7,29-7,21 (2H, m), 7,13-7,07 (1H, m), 4,35 (2H, q, J=7.2 Hz), 4,25 (2H, s)of 1.36 (3H, t, J=7.2 Hz) ppm13C (CDCl3, 100 MHz): δ 191,78, 161,04, 134,91, 132,62, 131,66, 128,59, 127,40, 126,95, 126,25, 124,98, 124,17, 114,88, 60,92, 46,56, 14,26 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,26; CH2carbon atoms: 60,92, 46,56; CH carbon atoms: 132,62, 131,66, 128,59, 127,40, 126,95, 114,88 ppm HPLC: 10,078 minutes

Synthesis of 4-[2-(2-bromophenyl)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (64)

Triethylsilane (2.25 ml, 14.1 mmol) are added to stir at room temperature the re solution of compound 63 (1,5291 g, 4,55 mmol) in triperoxonane acid (TFU) (10,8 ml, 0,42M) in the atmosphere N2. After stirring at room temperature for 3 hours the reaction mixture is heated at 35°C for 35 min, then TFU removed in vacuo, the crude product is placed in EtOAc, washed with saturated salt solution, dried with Na2SO4, filtered, concentrated and purified preparative HPLC with reversed phase, using the following conditions: from 0 to 12 min: 35:65 H2A:CH3CN; 14-15 min: from 35:65 to 0:100 H2A:CH3CN; 20 ml/min; λ=254 nm; 3,67 g/ml, 0.2 ml/input sample. Get 0,8402 g (57.3 per cent) connection 64 in the form of a friable white solid. (Note: an Undesired impurity has a retention time 12,281 min according to HPLC).

1H (CDCl3, 400 MHz): δ 9,07 (1H, Sirs), 7,55 (1H, DD, J=8,0, 1.3 Hz), 7,21 (1H, TD, J=7,3, 1.3 Hz), 7,17 (1H, DD, J=7,6, 2.4 Hz), 7,06 (1H, DDD, J=7,9, 7,0, 2.3 Hz), PC 6.82 (1H, s), 6,72 (1H, s), 4,32 (2H, t, J=7.2 Hz), 2,99 (2H,, t, J=8.0 Hz), 2,78 (2H, t, J=7.9 Hz), of 1.36 (3H, t, J=7.2 Hz) ppm13C (CDCl3, 100 MHz): δ 161,21, 141,03, 132,75, 130,41, 127,63, 127,32, 125,31, 124,43, 122,66, 120,68, 114,83, 60,22, 37,78, 27,03, 14,48 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14, 48mm; CH2carbon atoms: 60,22, 37,78, 27,03; CH carbon atoms: 132,75, 130,41, 127,63, 127,32, 120,68, 114,83 ppm HPLC: 11,355 minutes

Synthesis of 4-[2-(2-bromophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (65)

Their aqueous solution of NaOH (10M in H2O, 13,04 mmol) is added to the mix when the room is Noah temperature to a solution of compound 64 (0,8402 g, 2,608 mmol) in MeOH (6.5 ml, 0,4M) in the atmosphere N2. The reaction mixture is heated at boiling under reflux until completion of the reaction, which is recorded by means of HPLC (10 min): the Product is concentrated and then dissolved in 10 ml of H2O. the Product is extracted with EtOAc until the organic layer will not cease to be painted in yellow, then the aqueous layer was acidified (pH=2)by adding dropwise a 10% aqueous solution of HCl. The product oil is separated from the solution, therefore, add EtOAc, the organic layer removed, dried Na2SO4, filtered and concentrated, obtaining compound 65 (0,3934 g, 51,3%) as a white solid (note: an Undesired impurity has a retention time 11,066 min according to HPLC).

1H (CD3OD, 400 MHz): δ 7,51 (1H, d, J=7.8 Hz), 7.24 to 7,16 (2H, m), 7,05 (1H, DDD, J=8,2, 6,3, 2,9 Hz), 6,72 (1H, s)of 6.71 (1H, s), 2,96 (2H, t, J=8.0 Hz), 2,73 (2H, t, J=7.8 Hz) ppm13C (CD3OD, 100 MHz): δ 164,48, 142,42, 133,71, 131,80, 128,79, 128,53, 125,89, 125,20, 123,54, 122,61, 116,38, 38,99, 28,20 ppm DEPT (CDCl3, 100 MHz): CH2carbon atoms: 38,99, 28,20; CH carbon atoms: 133,71, 131,80, 128,79, 128,53, 122,61, 116,38 ppm HPLC: 10,035 minutes

Example 21

Synthesis of 5-[2-(4-chlorophenyl)ethyl]-1H-pyrazole-3-carboxylic acid (69)

Synthesis of 4-(4-chlorophenyl)butane-2-she (66)

1,6M Motility (33.9 ml, 54,17 mmol) is added over 70 min to stir at 0°C solution of 3-(4-chlorophenyl)propionic what Islami (5,0072 g, 27,08 mmol) in dry Et2O (135 ml, 0,2M): Bath with ice is removed and the reaction mixture is allowed to mix at room temperature over night. The reaction mixture is poured into intensively mix the water with ice, containing an aqueous solution of HCl. The organic layer is removed, washed with NaHCO3and saturated saline, then dried with Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, from 98:2 to 95:5 hexane:EtOAc)to give pure compound 66 (2,4253 g, 49,0%).

1H (CDCl3, 400 MHz): δ 7,14 (2H, d, J=8,3 Hz), 7,03 (2H, d, J=8,3 Hz), 2,77 (2H, t, J=7.5 Hz), of 2.64 (2H, t, J=7.5 Hz), 2,04 (3H, s) ppm13C (CDCl3, 100 MHz): δ 207,12, 139,38, 131,59, 129,55, 128,35, 44,62, 29,82, 28,78 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 29,82; CH2carbon atoms: 44,62, 28,78; CH carbons: 129,55, 128,35 ppm HPLC: 10,361 minutes (note: SM has a retention time 9,409 min according to HPLC.)

Synthesis of 6-(4-chlorophenyl)-2,4-docohexaenoic acid ethyl ester (67)

Sodium hydride (0,4163 g of 17.35 mmol) is slowly added to EtOH (5,3 ml, 2.5m), with stirring in an atmosphere of N2while cooling in a bath with ice and NaCl. Compound 66 (2,4253 g, 13,28 mmol) and diethyloxalate (1,803 g, 13,28 mmol) are mixed and then added to a chilled solution of NaOEt. After stirring for 5 minutes the reaction mixture is heated to room temperature. After 10 minutes the reaction is ionic mixture cures, then add another 10 ml of EtOH. After stirring for ~5 h, the reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2O, dried with Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash column, 1:1 hexane:CH2Cl2). Pure fractions are combined and concentrated, obtaining compound 67 (1,7561 g, 46,8%).

1H (CDCl3, 400 MHz): δ 14,27 (1H, Sirs), 7,22 (2H, d, J=8,3 Hz), 7,10 (2H, d, J=8,3 Hz), 6,32 (1H, s), or 4.31 (2H, q, J=7.2 Hz), of 2.92 (2H, t, J=7.8 Hz), 2,78 (2H, t, J=7,8 Hz)of 1.34 (3H, t, J=7.2 Hz) ppm13C (CDCl3, 100 MHz): δ 201,59, 166,07, 161,79, 138,51, 132,00, 128,53, 128,54, 101,72, 62,38, 42,08, 29,60, 13,88 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 13,88; CH2carbon atoms: 62,38, 42,08, 29,60; CH carbons: 129,53, 128,54, 101,72 ppm HPLC: 11,103 minutes

Synthesis of 5-[2-(4-chlorophenyl)ethyl]-1H-pyrazole-3-carboxylic acid ethyl ester (68)

The hydrazine hydrate (0,300 ml, 6,18 mmol) are added to stir at room temperature to a solution of compound 67 (0,1,7484 g, 6,18 mmol) in EtOH (6.2 ml, 1M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC (40 min). Upon cooling of the reaction mixture, the precipitated white crystalline solid. The solid is separated by filtration, washed with EtOH and dried, the floor is th net connection 68 (0,9092 g, 52,7%).

1H (CDCl3, 300 MHz): δ to 12.44 (1H, Sirs), 7,21 (2H, d, J=8,3 Hz), was 7.08 (2H, d, J=8.1 Hz), to 6.58 (1H, s)to 4.33 (2H, q, J=7,0 Hz)of 3.00 (2H, t, J=7.0 Hz), with 2.93 (2H, t, J=7,0 Hz)of 1.33 (3H, t, J=7.0 Hz) ppm Partial13C (CDCl3, 75 MHz): δ 139,12, 131,93, 129,67, 128,50, 106,49, 60,94, 34,72, 14,20 ppm HPLC: 10,269 minutes

Synthesis of [2-(4-chlorophenyl)ethyl]-1H-pyrazole-3-carboxylic acid (69)

Their aqueous solution of NaOH (10M in H2O, to 16.31 mmol) are added to stir at room temperature to a solution of compound 68 (0,9092 g, 3,26 mmol) in MeOH (8.2 ml, 0,4M) in the atmosphere N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC (7 min). The reaction mixture was concentrated, dissolved again in H2O (5 ml) and extracted with EtOAc (2 ml). To the water layer added dropwise 10% aqueous solution of HCl to obtain pH=2. The precipitated white solid is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting 0,7543 g (92,2%) of compound 69. Because the connection 69 still contains a small amount of impurities, it is dissolved in 38 ml of toluene containing 10 ml of EtOAc and 14 ml of EtOH, when heated at the boil under reflux. After standing over night from the reaction mixture precipitates pure white solid (0,4052 g). (Note: an Undesired impurity has a retention time 9,904 minpo HPLC data.).

1H (CD3OD, 400 MHz): δ of 7.24 (2H, d, J=8,3 Hz), to 7.15 (2H, d, J=8,3 Hz), is 6.54 (1H, s), 2,95 (4H, s) ppm13C (CD3OD, 100 MHz): δ 164,68, 148,23, 142,84, 140,91, 133,00, 131,08, 129,46, 107,59, 35,83, 28,78 ppm DEPT (CD3OD, 100 MHz): CH2carbon atoms: 35,83, 28,78; CH carbons: 131,08, 129,46, 107,59 ppm HPLC: 9,026 minutes

Example 22

Synthesis of 5-bromo-4-[2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (70)

Synthesis of 5-bromo-4-[2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (70)

Bromine (0,049 ml, 0,962 mmol) is added dropwise during 5 minutes to a stirred solution of compound 39 (0,200 g, 0,802 mmol) in acetic acid (2.5 ml). After completion of the reaction, registered by HPLC (30 min)add H2Oh, and the precipitated solid is filtered off and washed with N2O. Received light purple solid was dissolved in EtOAc, washed with Na2SO3and H2O, then dried with Na2SO4filter and concentrate. The product was then purified preparative HPLC with reversed phase, elwira mixture 40:60 H2A:CH3CN (w/0,05% TFU); 20 ml/min; λ=214 nm. Get 0,1520 g (57,7%) of compound 70 in the form of a friable white solid.

1H (CD3OD, 400 MHz): δ 7,22 (2H, d, J=8,8 Hz), 7,12 (2H, d, J=8,8 Hz), of 6.65 (1H, s), of 2.81 (2H, t, J=7,3 Hz)to 2.67 (2H, t, J=7,3 Hz) ppm Partial13C (CD3OD, 100 MHz): δ 163,33, 141,42, 132,54, 131,03, 129,18, 124,73, 117,15, 105,84, 36,72, 29,04 ppm DEPT (CD3OD, 100 MG what): CH 2carbon atoms: 36,72, 29,04; CH carbons: 131,03, 129,18, 117,15 ppm HPLC: 10,484 minutes

Example 23. Synthesis of 4-(2-(2-bromophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (73)

Synthesis of 4-[2-(4-forfinal)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (71)

Acylpyrrole-2-carboxylate (2,0589 g, 14,80 mmol) in a minimal amount of dichloroethane is added to a cooled on ice and stir a mixture of aluminium chloride (3,9913 g, 29,93 mmol) and 4-perforazione (5,1338 g, 29,75 mmol) in dichloroethane (22 ml, 0,66M) in an atmosphere of N2. Bath ice is removed and the reaction mixture was stirred at room temperature for 3.5 hours Add 20,6195 g (2.6 mmol/g) polyominoes resin HL (200-400 mesh) and dichloroethane (20 ml), after which the reaction mixture is stirred for ~60 minutes Then the reaction mixture was filtered through a funnel with a porous glass filter directly on the water with ice. The resin was washed with CH2Cl2, then the organic layers are removed, dried Na2SO4filter and concentrate. With the addition of 6.5 ml of a mixture of 80:20 hexane:EtOAc the organic layer becomes yellow and remains yellow-brownish solid. The solid is removed by filtration, washed with a mixture of 80:20 hexane:EtOAc and dried, obtaining a pure compound 71 (2,1838 g, 53.6 per cent).

1H (CDCl3, 400 MHz): δ there is a 10.03 (1H, Sirs), 7,54 (1H, s), 7,32 1H, C)of 7.23 (2H, DD, J=8,6,5,3 Hz), 6,99 (2H, t, J=8.6 Hz), 4,35 (2H, q, J=7,1 Hz), Android 4.04 (2H, s)to 1.37 (3H, t, J=7,1 Hz) ppm13C (CDCl3, 100 MHz): δ 192,81, 161,84 (d, J=244 Hz), 160,95, 130,89 (d, J=7.8 Hz), 130,37 (d, J=3.2 Hz), 126,72, 126,36, 124,30, 115,40 (d, J=21,4 Hz), 114,96, 61,02, 45,63, 14,29 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,29; CH2carbon atoms: 61,02, 45,63; CH carbons: 130,89 (d, J=7.8 Hz), 126,72, 115,40 (d, J=21,4 Hz), 114,96 ppm HPLC: 9,689 minutes

Synthesis of 4-[2-(4-forfinal)ethyl]-1H-pyrrole-2-carboxylicacid ethyl ester (72)

Triethylsilane (3,84 ml, 24,1 mmol) are added to stir at room temperature to a solution of compound 71 (2,1400 g, to 7.77 mmol) in triperoxonane acid (TFU) (18.5 ml, 0,42M) in the atmosphere N2. After completion of the reaction, which is recorded by using HPLC, TFU removed in vacuo, the crude product is placed in EtOAc, washed with saturated salt solution, dried with Na2SO4, filtered, concentrated and purified preparative HPLC with reversed phase under the following conditions: from 0 to 12 min: 35:65 H2A:CH3CN; 14-15 min: from 35:65 to 0:100 H2O:CH3CN; 20 ml/min; λ=254 nm; 3,67 g/ml, 0.2 ml/input sample. Get 1,1571 g (57,0%) of compound 72 in the form of a friable white solid. (Note: an Undesired impurity has a retention time 11,414 min according to HPLC).

1H (CDCl3, 400 MHz): δ was 9.33 (1H, Sirs), 7,13 (2H, DD, J=8,5, 5.6 Hz), of 6.96 (2H, t, J=8,8 Hz), 6,79 (1H, s), of 6.66 (1H, s)to 4.33 (2H, t, J=7,1 Hz), of 2.86 (2H, t, J=7 Hz), 2,77 (2H, t, J=7,1 Hz)of 1.36 (3H, t, J=7,1 Hz) ppm13C (CDCl3, 100 MHz): δ 161,31, 161,22 (d, J=242 Hz), 137,46 (d, J=3.2 Hz), 129,71 (d, J=7,7 Hz), 125,22, 122,52, 120,84, 114,89 (d, J=21,9 Hz), 114,79, 60,19, 36,44, 28,73, 14,37 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,37; CH2carbon atoms: 60,19, 36,44, 28,73; CH carbons: 129,71 (d, J=7,7 Hz), 120,84, 114,89 (d, J=21,9 Hz), 114,79 ppm HPLC: 10,797 minutes

Synthesis of 4-[2-(4-forfinal)ethyl]-1H-pyrrole-2-carboxylic acid (73)

Their aqueous solution of NaOH (10M in H2O, 22,14 mmol) are added to stir at room temperature a solution of 72 (1,1571 g 4,428 mmol) in MeOH (11,1 ml, 0,4M) in the atmosphere N2. The reaction mixture is heated at boiling under reflux until completion of the reaction, registered by HPLC (10 min). Upon cooling, the reaction mixture solidifies. The product is concentrated and then dissolved in H2O. the Product is extracted with EtOAc, and then the aqueous layer was acidified (to pH=2) by adding dropwise a 10% aqueous solution of HCl. The product is released from the solution in the form of oil, so add EtOAc, the organic layer removed, dried Na2SO4filter and concentrate the receiving connection 73 (0,8724 g, 84.4 per cent) in the form of not-quite-white solid. The product is optionally purified by repeating the above procedure. The product is dissolved in 10% NaOH, washed with EtOAc and then acidified with 10% HCl. As before, the product is released in the form of oil, and it is xtraceroute in EtOAc, dried Na2SO4filter and concentrate.

1H (CD3OD, 400 MHz): δ 7,14 (2H, DD, J=8,8, 5,4 Hz)6,94 (2H, t, J=8,8 Hz), of 6.68 (1H, d, J=1.7 Hz), of 6.66 (1H, d, J=7,1 Hz), 2,82 (2H, t, J=7,3 Hz), of 2.72 (2H, t, J=7,3 Hz) ppm13C (CD3OD, 100 MHz): δ 164,48, 162,69 (d, J=241 Hz), 139,28 (d, J=3.2 Hz), 131,08 (d, J=8,2 Hz), 126,08, 123,47, 122,68, 116,41, 115,68 (d, J=21,0 Hz), 37,77, 29,94 ppm DEPT (CDCl3, 100 MHz): CH2carbon atoms: 37,77, 29,94; CH carbons: 131,08 (d, J=8,2 Hz), 122,68, 116,41, 115,68 (d, J=21,0 Hz) ppm HPLC: 9,575 minutes

Example 24

Synthesis of 4-(3-Cyclopentylpropionyl)-1H-pyrrole-2-carboxylic acid (76)

Synthesis of 4-(3-cyclopentylpropionyl)-1H-pyrrole-2-carboxylic acid ethyl ester (74)

Acylpyrrole-2-carboxylate (1,8593 g, made 13.36 mmol) in a minimal amount of dichloroethane is added to a cooled on ice, stir a mixture of aluminium chloride (3,5756 g, 26,82 mmol) and 3-cyclopentylpropionate (4,1 ml, 26,59 mmol) in dichloroethane (20 ml of 0.66 M) in an atmosphere of N2. Bath ice is removed and the reaction mixture was stirred at room temperature for 4 hours Add 18,18 g (2.6 mmol/g) polyominoes resin HL (200-400 mesh) and dichloromethane (20 ml), after which the reaction mixture is stirred for ~60 minutes Then the reaction mixture was filtered through a funnel with a porous glass filter directly on the water with ice. The resin was washed with CH2Cl2, then the organic layers are removed is, dried Na2SO4filter and concentrate. The crude product is recrystallized from a mixture of hexane/ethyl acetate. The crude compound was dissolved in a minimum quantity of hot EtOAc, then leave to cool slowly to room temperature. If the product does not crystallize, a small amount of hexanol make the eyedropper on the sides of the flask. Pure crystals of the target product (2,3068 g, 65.6 per cent) receive after standing over night.

1H (CDCl3, 400 MHz): δ 10,04 (1H, Sirs), 7,55 (1H, s), 7,29 (1H, s), 4,34 (2H, q, J=7,1 Hz), 2,77 (2H, t, J=7,6 Hz), 1.85 to to 1.67 (5H, m), 1,64 of 1.46 (4H, m)of 1.36 (3H, t, J=7,1 Hz), 1,78 was 1.06 (2H, m) ppm13C (CDCl3, 100 MHz): δ 196,38, 161,09, 127,03, 126,14, 124,05, 114,76, 60,91, 39,82, 39,06, 32,53, 30,82, 25,11, 14,31 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,31; CH2the carbon atoms: 60,91, 39,06, 32,53, 30,82, 25,11; CH carbon atoms: to 126.14, 114,76, 39,82 ppm HPLC: 10,800 minutes

Synthesis of 4-(3-cyclopentylpropionyl)-1H-pyrrole-2-carboxylic acid ethyl ester (75)

Triethylsilane (4,28 ml, 26,86 mmol) are added to stir at room temperature to a solution of compound 74 (2,2816 g, 8,66 mmol) in triperoxonane acid (TFU) (20,6 ml, 0,42M) in the atmosphere N2. After completion of the reaction, recorded using HPLC, TFU removed in vacuo, the crude product is placed in EtOAc, washed with saturated salt solution, dried with Na2SO4filter, concentrate and purify the preparative HPLC with reversed phase under the following conditions: 30:70 H 2A:CH3CN; 20 ml/min; λ=254 nm. Connection 75 receive in the form of a friable white solid.

1H (CDCl3, 400 MHz): δ 9,43 (1H, Sirs), 6,77 (1H, s), 6,74 (1H, s), 4,32 (2H, q, J=7,1 Hz), the 2.46 (2H, t, J=7,6 Hz), 1,83-1,71 (3H, m), 1,64 of 1.46 (6H, m)of 1.35 (3H, t, J=7,1 Hz), 1,36 to 1.31 (2H, m), 1,14-1,02 (2H, m) ppm13C (CDCl3, 100 MHz): δ 161,46, 126,62, 122,33, 120,74, 114,86, 60,10, 40,00, 35,82, 32,65, 30,14, 26,94, 25,13, 14,39 ppm DEPT (CDCl3, 100 MHz): CH3carbon atoms: 14,39; CH2the carbon atoms: 60,10, 35,82, 32,65, 30,14, 26,94, 25,13; CH carbon atoms: 120,74, 114,86, 40,00 ppm HPLC: 12,379 minutes

Synthesis of 4-(3-cyclopentylpropionyl)-1H-pyrrole-2-carboxylic acid (76)

Their aqueous solution of NaOH (10M in H2O, 11,23 mmol) is added at room temperature to a stirred solution of compound 75 (0.56 g, 2.25 mmol) in MeOH (5.6 ml, 0,4M) in the atmosphere N2. The reaction mixture is heated at boiling under reflux until completion of the reaction, which is recorded by means of HPLC (10 min). Upon cooling, the reaction mixture solidifies. The product concentrate and add H2O. If the product is not soluble in H2O add EtOAc and then with 10% HCl to acidification of the aqueous layer. Then the organic layer is removed, dried Na2SO4, filtered, concentrated and purified preparative HPLC with reversed phase, using the following conditions: 30:70 H2A:CH3CN; 20 ml/min; λ=254 nm. The connection 76 receive in the form of friable white is solid substances. (Note: an Undesired impurity has a retention time 12,073 min according to HPLC.).

1H (CD3OD, 400 MHz): δ 10,80 (1H, s), 6,72 (1H, s), of 6.68 (1H, s), 2,43 (2H, t, J=7,6 Hz), 1,82 is 1.70 (3H, m), 1,64 of 1.46 (6H, m), 1,38-of 1.29 (2H), 1,14-1,02 (2H, m) ppm13C (CD3OD, 100 MHz): δ 164,45, 127,29, 122,45, 116,39, 41,31, 37,00, 33,73, 31,43, 27,96, 26,11 ppm DEPT (CDCl3, 100 MHz): CH2the carbon atoms: 37,00, 33,73, 31,43, 27,96, 26,11; CH carbon atoms: 122,45, 116,39, 41,31 ppm HPLC: 10,977 minutes

Example 25

Synthesis of (S)-5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid (80)

Synthesis of (S)-4-phenylpentane-2-she (77)

1,6M Motility (17,8 ml, 24,9 mmol) added dropwise within 1 hour to stir at 0°C a solution of (S)-3-phenylalkanoic acid (2,0147 g, 12,18 mmol) in dry Et20 (61 ml of 0.2 M): Bath with ice is removed and the reaction mixture is allowed to mix at room temperature for another 1 and 1/2 hours. Then the reaction mixture was poured into rapidly stirred ice water containing an aqueous solution of HCl. The organic layer is removed, washed with NaHCO3and saturated saline, then dried with Na2SO4, filtered and concentrated, obtaining a pure compound 77 (2,0487 g, ~100%): HPLC: 10,081 minutes (note: SM has a retention time 9,127 min according to HPLC)/

Synthesis of (S)-2,4-dioxo-6-phenylheptanoic acid ethyl ester (78)

Sodium hydride (0,3790 g, 15.8 mmol) slowly to ablaut to EtOH (4,9 ml, 2,5M), with stirring in an atmosphere of N2while cooling in a bath with ice and NaCl. (S)-4-Phenylpentane-2-he (78) (2,0487 g, 12,63 mmol) and diethyloxalate (1,67 ml, 12,30 mmol) are mixed and then added to a chilled solution of NaOEt. After stirring for 5 minutes the reaction mixture is heated to room temperature. After 60 min the reaction mixture was quenched at 0°C 1 N. HCl and extracted with 2×CH2Cl2. The combined organic layers washed with H2Oh, dried Na2SO4filter, concentrate and purify a mixture of from 1:1 to 1:3 hexane:CH2Cl2receiving a connection 78 (0,6895 g, 20,8%): HPLC: 10,940 minutes

Synthesis of (S)-5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid ethyl ester (79)

The hydrazine hydrate (0,126 ml, at 2.59 mmol) are added to stir at room temperature to a solution of compound 78 0,0,6895 g, 2,63 mmol) in EtOH (2.6 ml, 1M) in an atmosphere of N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, which is recorded by means of HPLC (45 min). The reaction mixture was concentrated and purified using a gradient from 9:1 to 8:1 hexane:(3:1 CH2Cl2:2n NH3in EtOH), and get 0,6153 g (90,6%) of compound 79. HPLC: 10,001 minutes

Synthesis of (S)-5-(2-phenylpropyl)-1H-pyrazole-3-carboxylic acid (80)

Their aqueous solution of NaOH (10M in H2Oh, to 11.9 mmol) is added to the mix in to the room temperature to a solution of compound 79 (0,6153 g, 0,2,38 mmol) in MeOH (6 ml, 0,4M) in the atmosphere N2. The reaction mixture is then heated at the boil under reflux to complete the reaction, registered by HPLC (7 min). The reaction mixture was concentrated, dissolved again in H2O and extracted with EtOAc (1 ml). To the water layer added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting 0,250 g (45,6%) of compound 80.

1H (CD3OD, 400 MHz): δ 7,30-of 7.23 (2H, m), 7,22-7,13 (3H, m), 6,62 (1H, s), 3,14 (1H, app sex, J=7,3 Hz), 3,03 (2H, d, J=7.8 Hz), is 1.31 (3H, d, J=6.8 Hz) ppm13C (CD3OD, 100 MHz): δ 162,00, 149,20, 146,35, 141,76, 129,62, 127,93, 127,64, 109,16, 41,21, 35,22, 22,11 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 22,11; CH2carbon atoms: 35,22; CH carbon atoms: 129,62, 127,93, 127,64, 109,16, 41,21 ppm HPLC: 8,771 minutes

Conditions for analytical HPLC: Analytical column with reversed phase. A linear gradient that starts with a 95:5 H2A:CH3CN at time = 0, and is changed to 60:40 H2A:CH3CN for 4 minutes

Example 26

The determination of the activity of DAAO in vitro

Purified pork DAAO added to the buffer mixture containing 50 mm D-serine, produces H2About2in stoichiometric quantities for each oxidizable molecules D with the Rina. The formation of H2About2you can register using a commercially available dye Amplex Red, which in the presence of H2About2turns into a fluorescent compound resorufin. For each of the described inhibitor fluorescence is also measured by adding 80 μm H2About2in the absence of DAAO to control artificial inhibition of the conversion of the dye and to determine the amount of formed H2About2. In the alternative analysis of the activity of DAAO purified pork DAAO add to buffer mixture containing 1 mm phenylglycine in the presence of compounds. The DAAO activity determined by the spectrophotometric method, registering the enzymatic conversion of phenylglycine in benzoylamino acid by optical absorption at 252 nm.

Receive serial dilution of inhibitors of the enzymatic cycle DAAO with reduced levels of inhibition. The parameters of nonlinear equations fit to the resulting series of levels of inhibition to extrapolate the concentration providing 50% inhibition (IC50). These values are averaged by the number (n) of independent measurements (carried out in different days) inhibition. The values of inhibition are shown in table 1.

Table 1
No. or the structure of connectionsInhibition of DAAO, IC50No. or the structure of connectionsInhibition of DAAO, IC50
3<10 microns45<100 mm
6<10 microns48<10 microns
11+12<10 microns51<1 μm
15<10 microns54<100 mm
18<1 μm58<1 μm
21<1 μm62<1 μm
24<1 μm65<1 μm

26<100 mm69 <1 μm
32>100 mm70<100 mm
36<100 mm73<1 μm
39<1 μm76<10 microns
42<1 μm80<10 microns
<1 μm<100 mm
<1 μm<100 mm
<1 μm<100 mm
<1 μm<100 mm
<1 μm<100 mm
<1 μm<100 mm
<10 microns<100 mm

<10 microns<100 mm
<10 microns<100 mm
<10 microns<100 mm
<10 microns <100 mm
<10 microns<100 mm
<10 microns>100 mm
<10 microns>100 mm
<10 microns

From table 1 we can see that the values of the IC50all previously described DAAO inhibitors exceed the concentration is 1 μm with the inhibition of DAAO activity by more than 50%. Pyrrole and pyrazol derivatives of the present invention have at least the same inhibitory activity, and the activity of some compounds isolated examples 5 or more times higher, i.e., for inhibition of DAAO activity by 50% is required less than 200 nm connection.

Example 27

Determination of affinity to the NMDA receptor

To measure the affinity of the compounds described in the Anna of the application the binding site of D-serine NMDA receptor (also known as "glycine site" or "strychnine-independent glycine site"), analyze the binding of the radioactive ligand to the membrane obtained from the cerebral cortex of rats. Radioactive ligand is [3H]MDL105,519. The amount of radioactivity which is replaced with the connection, judged by the number of scintillations. The nonspecific binding determined in the presence of 1 mm glycine. The affinity is calculated as % inhibition of specific binding of [3H]MDL105,519 test the connection.

Indole-2-carboxylic acid inhibits specific binding radioactiveman connection to 77% at a concentration of 100 μm, whereas the following compounds, examples of the substituted pyrrole and pyrazoles, have no affinity (when tested at a concentration of 100 μm is achieved in less than 20% inhibition of specific binding of [3H]MDL-509,519) the binding site of D-serine receptor NMDA:

Example 28

Determination of absorption by rat brain

Experiments on determination of the penetration test compounds in the rat brain, make use of a perfusion system in which the left carotid artery insert the cannulae and artery branches off bandage. Test the connection with internal controls introduced during the course the e 30 seconds in the left hemisphere in phosphate buffered saline solution at pH of 7.4. As internal controls use atenolol (low absorption by the brain) and antipyrine (with high absorption by the brain). After washing the perfusion solution for 30 seconds, the brain is removed surgically. The left hemisphere homogenized; the tested compounds (including internal controls) extracted from the homogenate of the brain and analyze by LC/MS/MS to determine the concentration of the tested compounds and internal controls in the brain. Rate of absorption of the brain selected compounds, expressed in pmol/g brain/sec ± SD (standard deviation) for n=4 rats, are shown in table 2.

Table 2
No. (example) or the structure of connectionsThe absorption rate of the rat brain, pmol/g brain/sec
1817
216
39204
6

Example 29

Determination of the levels of D-serine in the brain

Determining the level of D-serine in the brain of mammals shows that the endogenous production of ravnovesie the W decay of D-serine. D-serine is formed from L-serine by the action of serine-racemase and metabolism of D-serine is carried out under the action of DAAO. Introduction of exogenous D-serine, a short-term, due to the activity of DAAO, raising the level of D-serine in the brain. Similarly, in this invention it is shown that the DAAO inhibitors several times increase the levels of D-serine in the brain. It is shown that introduction of exogenous D-serine is used in the clinic for the treatment of schizophrenia; see Coyle, Joseph J., Ann. N.Y Acad. Sci., 1003: 318-327 (2003) and U.S. patent No. 6227875; 6420351; and 6667297. Therefore, the levels of D-serine in rat brain can be used to assess the potential therapeutic effects of DAAO inhibitors to increase the level of D-serine in the treatment of schizophrenia.

In vivo increased levels of D-serine in the brain

Compounds suspended in phosphate buffered saline solution (pH of 7.4, containing 2% tween 80) and injected intraperitoneally to adult male rats Sprague Daly (age 40-60 days, Charles River Laboratories, Inc.), during the experiment with the weight 185-225, After a few hours of rats killed by decapitation, the brain quickly removed and frozen at -80°C for subsequent analysis. The rest of the brain is removed and frozen. On the day of analysis of brain tissue homogenized in 5 times the volume of chilled on ice for 5% trichloroacetic acid. The homogenate was centrifuged at 18000 g for 30 mi the ut. Precipitation drop. The supernatant is washed 3 times with water-saturated diethyl ether and the organic layer discarded. After filtration, the aqueous layer through a filter membrane with a pore size of 0.45 μm samples ready for derivatization o-phthaldialdehyde (OPA) and BOC-L-Cys-OH by the way Hashimoto and co-authors (Hashimoto A, et al., J Chromatogr., 582 (1-2): 41-8 (1992)). Briefly, 50 mg of each derivatizing reagent dissolved in 5 ml of methanol. An aliquot of the resulting solution volume of 200 μl is added to 100 μl of the sample solution in 700 μl of borate buffer (0,4M, pH adjusted to 9.0 using sodium hydroxide). Then the levels of D-serine determine fluorometrically method (wavelength of 344 nm excitation, the wavelength of emission of the 443 nm) by introducing aliquot of 10 µl of a system for carrying out high-performance liquid chromatography.

Compounds, examples of which are described in this patent application, cause a steady and significant increase in levels of D-serine in rat brain. In particular, pyrrole derivatives, administered in two separate doses (125 mg/kg and 3 hours 75 mg/kg) caused a 4-fold increased levels of D-serine in the brain after 6 hours after the first dose.

Example 30

Reducing neuropathic pain in animal models (model with legirovaniem spinal cord (SNL)) under the action of DAAO inhibitors

Animals: AMCOW rats Sprague-Dawley (Hsd:Sprague-Dawley®™ SD®™, Harlan, Indianapolis, Indiana, U.S.A.) weighing 232±2 g / day of testing behavior is placed in a cell for three animals in each. Throughout the study the animals had free access to food and water and a 12:12-hour cycle of light/dark. Animals are kept at 21°C and 60% humidity. All experiments are carried out in accordance with the guidelines of the International Association for the study of pain (International Association for the Study of Pain) and have the permission of the Committee on the application and animal care (Animal Care and Use Committee).

Induction of chronic neuropathic pain: For the induction of chronic neuropathic pain using the model with legirovaniem spinal cord (SNL) (Kim and Chung, 1992). Animals anaesthetize with isoflurane, the left transverse process of L5 is removed and the spinal nerves L5 and L6 are ligated tightly silk surgical thread 6-0. Then the wound is closed with internal sutures and external brackets. Brackets removed at 10-11 days after the operation.

Testing the mechanical allodynia: Background values harmless mechanical sensitivity, its value after damage and after treatment assessed using 8 threads Semmes-Weinstein (Stoelting, Wood Dale, IL, USA) with different density(0,4, 0,7, 1,2, 2,0, 3,6, 5,5, 8,5 and 15 g) by the method of up-down up-down method (Chaplan et al., 1994). Animals are placed on the perforated metal platform and allowed to habituate to the environment for as mini is the mind, 30 minutes before testing. For each animal in each experimental group to determine the average value and the standard error of the mean (SEM). Since this incentive, as a rule, is not considered painful, a significant increase in sensitivity induced damage, is interpreted as a measure of the mechanical allodynia.

The experimental group:

No.SurgeryProcessingDose (mg/kg)Route of administrationWednesdayInjected volume (ml/kg)Int. time (hours)n
1SNL4-[2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (39)125V.B.PBS2BL, 2, 4, 6, 810
1SNLGabapentin100V.B.Saline 5BL, 0,5, 1, 2, 410
3SNLSaline-V.B.2BL, 2, 4, 6, 88

Schedule time:

4-[2-(4-Chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (39) and (environment)

(1) test von Frey (von Frey) (background level)

(2) 0 min: introduction of the medicinal product

(3) 120 min: test von Frey

(4) 240 min: test von Frey

(5) 360 min: test von Frey

(6) 480 min: test von Frey

(7) 495 min: collect plasma

The implementation of a "blind" experiment: Drug enters the experimenter, who is not involved in the testing of conduct. The distribution of administration of drugs in animals is not revealed until the end of the study.

Analytical dataStatistical analyses performed using Prism™ 4.01 (GraphPad, San Diego, CA, USA). Mechanical hypersensitivity damaged paws determined by comparing the values for the opposite legs and values for feet that are on the same side in the group receiving environment. Data analyzed using a dough is Anna Whitney. Temporal stability values for damaged paws in the group receiving environment, determined using two-factor analysis of variance Friedman by ordering values. The effect of the drugs analyzed at each time point using one-factor analysis of variance the Kruskal-Wallis and then "post hoc" test Dunn or signed rank criterion of Mann-Whitney.

Results: 4-[2-(4-Chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid causes a significant decrease in the mechanical allodynia, which is statistically significant at time 240 and 360 minutes Maximum effect is observed after 360 minutes after administration of the dose.

Links:

Chaplan SR, Bach FW, Pogrel JW, Chung JM and Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55 to 63.

Kim SH and Chung JM (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.Pain50:355-63.

Example 31

Dosage forms

Dosage form tablets do not contain lactose

Table 3 reveals the ingredients for dosage forms as tablets do not contain lactose, the compounds of formula I

Table 3
IngredientQuantity per tablet (mg)
5-phenethyl-1H-pyrazole-3-carboxylic acid75
Microcrystalline cellulose125
Talc5,0
Water (per thousand tablets)30,0 ml*
Magnesium stearate0,5
* Water pariveda in the process of receiving

The active ingredient is mixed with cellulose to obtain a homogeneous mixture. A small amount of corn starch mixed with a suitable amount of water to obtain a paste of corn starch. Then it is mixed with the homogeneous mixture to form a homogeneous wet mass. The remaining corn starch is added to the obtained wet mass and mix until homogeneous granules. Then the granules are sifted through a suitable milling machine using a 1/4-inch stainless steel sieve. Milled granules are then dried in a suitable drying oven to obtain the desired moisture content. The dried granules were then milled in a suitable grinding machine using a 1/4-inch stainless steel sieve. Then the granules are mixed with magnesium stearate and the mixture p will assult into tablets of the desired shape, thickness, hardness and friability. Tablet cover, using standard aqueous or non-aqueous method.

Dosage form tablets

Table 4 shows the different composition of the dosage form tablet suitable for use with the active ingredients of this invention.

Table 4
IngredientQuantity per tablet (mg)
Composition AndCompositionComposition
5-phenethyl-1H-pyrazole-3-carboxylic acid2040100
Microcrystalline cellulose134,5114,5309,0
Starch BP303060
Relatively maize starch BP151530
Magnesium stearate 0,50,51,0
Mass in Presolana200200500

The active ingredient is sifted and mixed with cellulose, starch and gelatinising maize starch. Add the appropriate volume of purified water and powders granularit. After drying, the granules are sieved and mixed with magnesium stearate. Then the granules are pressed into tablets using a punch press.

Tablet other efficiency can be obtained by varying the ratio of the active ingredient and pharmaceutically acceptable carrier, masses pressed, or by applying other punch presses.

Example 32

Synthesis of 4-[2-(4-chlorophenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (87)

Synthesis of (toluene-4-sulfonylamino)acetic acid ethyl ester (81)

Taillored (14,75 g, 77,37 mmol) are added to stir the mixture of the hydrochloride of the ethyl ester of glycine (9.0 g, 64,48 mmol) and pyridine (11,45ml, 141,85 mmol) in 100 ml of dichloromethane. After stirring overnight the mixture was washed with water and dilute NaOH. The combined organic layers are dried Na2SO4, fil the shape, evaporated under reduced pressure, getting 16.0 g (96%) of compound 81, which is used without purification in the next stage.

1H-NMR (400 MHz, CDCl3): δ of 1.18 (t, 3H), 2,42 (s, 3H), 3,76 (d, 2H), 4,08 (kV, 2H), 5,22 (m, 1H), 7,30 (m, 2H), of 7.75 (d, 2H) ppm13C-NMR (100 MHz, CDCl3): δ 13,99, 21,55, 44,19, 61,89, 127,28, 129,76, 136,20, 143,81, 168,87 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 13,99, 21,55; CH2carbon atoms: 44,19, 61,89; CH carbons: 127,28, 129,76 ppm LC/MS: 95%, m/z=257.

Synthesis of 3-hydroxy-3-methyl-1-(toluene-4-sulfonyl)pyrrolidin-2-carboxylic acid ethyl ester (82)

1,8-Diazabicyclo[5,4,0]undec-7-ene (DBU) (7 ml, 47,08 mmol) is added to a mixed solution of ethylvanillin (1.75 ml, with 21.4 mmol) and ethyl N-p-toluensulfonate 81 (5.5 g, 21,4 ml) in THF (50 ml). The resulting mixture is stirred over night at room temperature. The mixture is diluted with ether, washed with 5% aqueous HCl solution, 5% sodium bicarbonate solution and water. The combined organic layers are dried Na2SO4, filtered, evaporated under reduced pressure, obtaining the crude compound 82 (5,3 g, 76%) as a yellow oil (mixture of diastereomers).

1H-NMR (400 MHz, CDCl3): δ of 1.29 (m, 6H), of 1.75 (m, 1H), 2,09 (m, 1H), 2,43 (s, 3H), 3,40 (m, 1H), of 3.56 (m, 1H), Android 4.04 (s, 1H), 4,20 (m, 2H), 7,30 (m, 2H), of 7.75 (d, 2H) ppm13C-NMR (100 MHz, CDCl3): δ 14,12, 15,28, 23,04, 25,60, 26,27, 38,20, 38,86, 46,26, 46,46, 61,49, 61,65, 69,10, 71,69, 127,51, 129,70, 134,83, 134,91, 143,58, 143,84, 170,03, 170,45 ppm DEPT (00 MHz, CDCl3): CH3the carbon atoms: 14,12, 15,28, 23,04, 25,60, 26,27; CH2the carbon atoms: 38,20, 38,86, 46,26, 46,46, 61,49, 61,65; CH carbon atoms: 69,10, 71,69, 127,51, 129,70 ppm

Synthesis of 3-methyl-1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid ethyl ester (83)

Pyrolidine oil 82 (10.5 g, 32,11 mmol) dissolved in pyridine (86 ml). Added dropwise POCl3(of 7.48 ml, 80,27 mmol) and the resulting mixture is stirred over night at room temperature. The mixture was poured on ice, extracted with ether and washed with 5% aqueous HCl solution, 5% sodium bicarbonate solution and water. The ether layer is dried over sodium sulfate, filtered and evaporated under reduced pressure, obtaining the crude solid 83 (8,80 g, 88%).

1H-NMR (400 MHz, CDCl3): δ of 1.28 (t, 3H), 1.69 in (m, 3H), 2,43 (s, 3H), 4,10 (m, 1H), 4,20 (kV, 2H), 4,21 (m, 1H), 7,31 (d, 2H), of 7.75 (d, 2H) ppm13C-NMR (100 MHz, CDCl3): 8 13,58, 14,10, 21,56, 54,64, 61,62, 70,55, 110,02, 122,51, 127,51, 129,73, 169,87 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: of 13.58, 14,10, 21,56; CH2carbon atoms: 54,64, 61,62; CH carbons: 70,55, 122,51, 127,51, 129,73 ppm LC/MS: 100%, m/z=309.

Synthesis of 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84)

Pyrrolin 83 (8,80 g, 28,48 mmol) dissolved in THF (70 ml). Added dropwise DBU (9,78 ml, 65,50 mmol) and the resulting solution was stirred under heating at boiling under reflux overnight. The mixture is cooled to room is based temperature diluted with ether and washed with 5% aqueous HCl solution, 5% sodium bicarbonate solution and water. The organic layer is dried over sodium sulfate, filtered and evaporated under reduced pressure, obtaining the crude solid 84 (4,30 g, 98%).

1H-NMR (400 MHz, CDCl3): δ of 1.37 (t, 3H), of 2.35 (s, 3H), or 4.31 (q, 2H), between 6.08 (d, 1H), for 6.81 (d, 1H), 8,90 (Sirs, 1H) ppm13C-NMR (100 MHz, CDCl3): δ 12,76, 14,53, 59,96, 112,58, 119,35, 121,53, 127,96, 162,01 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 12,76, 14,53; CH2carbon atoms: 59,96; CH carbons: 112,58, 121,53 ppm LC/MS: 90,74%, m/z=153.

Synthesis of 4-[2-(4-chlorophenyl)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (85)

A solution of (4-chlorophenyl)acetylchloride (3 mmol) in dichloromethane or 1,2-dichloroethane (4 ml) is added to cooled to-40 ° C to a solution of compound 84 (0,229 g, 1.5 mmol) and add AlCl3(0.400 g, 3 mmol). The reaction mixture is stirred for 30 minutes at the same temperature. The reaction mixture is poured on ice water and extracted with ethyl acetate. The organic layer was washed with NaOH (2M) and saturated saline solution, dried over Na2SO4and evaporated in vacuum to dryness, obtaining the crude product 85. The yield of crude product: 96%

1H-NMR (400 MHz, CDCl3): δ of 1.37 (t, 3H), 2,60 (s, 3H), 4.00 points (s, 2H), 4,35 (kV, 2H), 7,27 (m, 4H), 7,49 (d, 1H), 8,83 (Sirs, 1H) ppm13C-NMR (100 MHz, CDCl3): δ 11,81, 14,38, 46,52, 60,94, 121,65, 124,57, 127,46, 128,81, 130,81, 33,54, 162,13, 193,36 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 11,81, 14,38; CH2carbon atoms: 46,52, 60,94; CH carbons: 121,65, 128,81, 130,81 ppm LC/MS: 90,32%, m/z=305.

Synthesis of 4-[2-(4-chlorophenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (86)

Triethylsilane (3 equivalents) are added to a solution of compound 85 in triperoxonane acid (2 ml per mmol). The mixture is stirred for 48 h at room temperature. TFU is removed in vacuum, the crude product is placed in AcOEt, washed with NaOH (2M), saturated salt solution, dried with Na2SO4, filtered and concentrated, obtaining the crude product. The residue is purified by HPLC. Yield: 46% from two stages.

1H-NMR (400 MHz, CDCl3): δ of 1.35 (t, 3H), and 2.26 (s, 3H), 2,69 (m, 2H), 2,78 (m, 2H), or 4.31 (q, 2H), 6,55 (d, 1H), was 7.08 (d, 2H), 7,22 (d, 2H), 8,86 (Sirs,1H) ppm

Synthesis of 4-[2-(4-chlorophenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (87)

Their aqueous solution of NaOH (1M in H2O, 10 equivalents) is added at room temperature to a stirred solution of compound 86 (1 equivalent) in a mixture of 1,4-dioxane and H2About (./about. 3:1). The reaction mixture is heated at 80°C until completion of the reaction, which register with TLC. The product is extracted with Et2O, and then the aqueous layer was acidified (pH=1)by adding dropwise a 10% aqueous solution of HCl. The solid is filtered off and washed with water. Solid substances which has dried in vacuum over night, getting 87. Yield: 66%.

1H-NMR (400 MHz, CD3OD): δ 2,19 (s, 3H), 2,69 (m, 2H), 2,78 (m, 2H), return of 6.58 (d, 1H), 7,11 (d, 2H), 7,22 (d, 2H) ppm LC/MS: 100%, m/z=263, HPLC (200-400 nm): 95,93%.

Example 33

Synthesis of 4-[2-(4-methoxyphenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (90)

Synthesis of 4-[2-(4-methoxyphenyl)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (88)

4-[2-(4-Methoxyphenyl)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (88) synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) according to the method described in example 32. The yield of crude product: 97%.

1H-NMR (400 MHz, CDCl3): δ of 1.36 (t, 3H), 2,61 (s, 3H), 3,79 (s, 3H), of 3.97 (s, 2H), 4,33 (kV,2H), 6,50 (d, 2H), 7,16 (d, 2H), 7,46 (d, 1H), 9,27 (Sirs, 1H) ppm13C-NMR (100 MHz, CDCl3): 511,75, 14,41, 46,60, 55,27, 60,68, 114,07, 127,09, 130,43, 158,45, 194,19 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 11,75, 14,41, 55,27; CH2carbon atoms: 46,60, 60,68; CH carbons: 114,07, 127,09, 130,43 ppm LC/MS: 76.86 euros%, m/z=301.

Synthesis of 4-[2-(4-methoxyphenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (89)

4-[2-(4-Methoxyphenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (89) synthesized from 4-[2-(4-methoxyphenyl)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (88) according to the method described in example 32. Yield: 23%.

1H-NMR (400 MHz, CDCl3): δ of 1.36 (t, 3H), and 2.27 (s, 3H), 2,69 (m, 2H), 2.76 m, 2H), 3,79 (s, 3H), or 4.31 (q, 2H), 6,59 (d, 1H), PC 6.82 (m, 2H), was 7.08 (m, 2H), 8,70 (Sirs, 1H) ppm

13C-NMR (100 MHz, CDCl3): δ 10,23, 14,56, 27,34, 35,78, 55,27, 59,85, 113,70, 119,69, 129,35, 134,14, 157,81 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 10,23, 14,56, 55,27; CH2carbon atoms: 27,34, 35,78, 59,85; CH carbons: 113,70, 119,69, 129,35, 134,14 ppm LC/MS: 100%, m/z=287.

Synthesis of 4-[2-(4-methoxyphenyl)ethyl]-2-methyl-1H-pyrrole-2-carboxylic acid (93)

4-[2-(4-Methoxyphenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (93) synthesized from 4-[2-(4-methoxyphenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (92) according to the method described in example 32. Yield: 66%.

1H-NMR (400 MHz, CD3OD): δ 2,19 (s, 3H), 2,65 (m, 2H), 2,72 (m, 2H, in), 3.75 (s, 3H), 6,59 (d, 1H), 6,79 (m, 2H),? 7.04 baby mortality (m, 2H) ppm13C-NMR (100 MHz, CDCl3): δ 10,46, 28,51, 37,32, 55,62, 114,64, 121,89, 125,45, 127,46, 130,44, 135,54, 165,07 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 10,46, 55,62; CH2carbon atoms: 28,51, 37,32; CH carbons: 114,64, 121,89, 130,44 ppm LC/MS: 100%, m/z=259. HPLC (200-400 nm): 94,17%.

Example 34

Synthesis of 4-(2-(3-methoxyphenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (90)

Synthesis of 4-[2-(3-methoxyphenyl)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (91)

4-[2-(3-Methoxyphenyl)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (91) synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-methoxyphenyl)is ethylchloride on the way, described in example 32. The yield of crude product: 95%.

1H-NMR (400 MHz, CDCl3): δ of 1.36 (t, 3H), 2,61 (s, 3H), of 3.77 (s, 3H), 3,99 (s, 2H), 4,32 (kV, 2H), for 6.81 (m, 3H), 7,24 (m, 1H), 7,45 (d, 1H), 9,41 (Sirs, 1H) ppm13C-NMR (100 MHz, CDCl3): δ 11,75, 14,40, 47,59, 55,19, 60,66, 112,19, 115,04, 121,71, 127,22, 129,58, 136,75, 159,75, 193,65 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 11,75, 14,40, 55,19; CH2carbon atoms: 47,59, 60,66; CH carbons: 112,19, 115,04, 121,71, 127,22,129,58 ppm LC/MS: 60,20%, m/z=301.

Synthesis of 4-[2-(3-methoxyphenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (92)

4-[2-(3-Methoxyphenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (92) synthesized from 4-[2-(3-methoxyphenyl)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (91) according to the method described in example 32. Yield: 18%.

1H-NMR (400 MHz, CDCl3): δ of 1.36 (t, 3H), of 2.28 (s, 3H), of 2.72 (m, 2H), and 2.79 (m, 2H), 3,79 (s, 3H), or 4.31 (q, 2H), is 6.61 (d, 1H), 6,67 (m, 3H), 7,20 (m, 1H), 8,72 (Sirs,1H) ppm

13C-NMR (100 MHz, CDCl3): δ 10,24, 14,56, 26,99, 36,73, 55,16, 59,87, 111,11, 114,27, 119,65, 120,89, 129,28, 159,04 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 10,24, 14,56, 55,16; CH2carbon atoms: 26,99, 36,73, 59,87; CH carbon atoms: 111,11, 114,27, 119,65, 120,89, 129,28 ppm LC/MS: 100%, m/z=287.

Synthesis of 4-[2-(3-methoxyphenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (93)

4-[2-(3-Methoxyphenyl)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (93) synthesized from 4-[2-(3-methoxyphenyl)ethyl]-3-methyl-1H-pyrrol-2-carbon is Oh acid ethyl ester (92) according to the method, described in example 32. Yield: 57%.

H-NMR (400 MHz, CD3OD): δ of 2.20 (s, 3H), 2,70 (m, 2H), was 2.76 (m, 2H), of 3.73 (s, 3H), of 6.61 (d, 1H), 6,72 (m, 3H), 7,13 (m, 1H) ppm13C-NMR (100 MHz, CDCl3): δ 10,48, 28,18, 38,25, 55,51, 112,30, 115,17, 121,95, 125,37, 130,18, 145,05, 161,10 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 10,48, 55,51; CH2carbon atoms: as opposed to 28.18 per, 38,25; CH carbons: 112,30, 115,17, 121,95, 130,18 ppm LC/MS: 93,45%, m/z=259, HPLC (200-400 nm): 69,03%.

Example 35

Synthesis of 4-[2-(4-Forfinal)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (96)

Synthesis of 4-[2-(4-forfinal)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (94)

4-[2-(4-Forfinal)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (94) synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (4-forfinal)acetylchloride according to the method described in example 32. [MLG-INCOMP.SENTENCE?] The yield of crude product: 94%.

1H-NMR (400 MHz, CDCl3): δ of 1.36 (t, 3H), 2,61 (s, 3H), 4,01 (s, 2H), 4,35 (kV, 2H), 7,01 (m, 2H), 7,22 (m, 2H), 7,50 (d, 1H), 9,70 (Sirs, 1H) ppm13C-NMR (100 MHz, CDCl3): δ 11,79, 14,38, 46,36, 60,89, 115,51, 127,27, 129,93, 130,77, 162,04, 193,62 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: to 11.79, 14,38; CH2carbon atoms: 46,36, 60,89; CH carbons: 115,51, 127,27, 129,93, 130,77 ppm LC/MS: 77,48%, m/z=289.

Synthesis of 4-[2-(4-forfinal)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (95)

4-[2-(4-Forfinal)ethyl]-3-methyl-1H-pyrrol-2-to benovoy acid ethyl ester (95) synthesized from 4-[2-(4-forfinal)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (94) according to the method, described in example 32. Yield: 23%.

1H-NMR (400 MHz, CDCl3): δ of 1.36 (t, 3H), and 2.26 (s, 3H), 2,69 (m, 2H), 2,78 (m, 2H), or 4.31 (q, 2H), to 6.57 (d, 1H), 6,95 (m, 2H), 7,10 (m, 2H), 8,70 (Sirs, 1H) ppmI3C-NMR (100 MHz, CDCl3): δ 10,21, 14,55, 27,20, 35,90, 59,89, 114,89, 115,10, 119,70, 124,60, 129,77, 137,58, 160,00 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: of 10.21, 14,55; CH2carbon atoms: 27,20, 35,90, 59,89; CH carbons: 121,65, 128,81, 130,81 ppm LC/MS: 100%, m/z=275.

Synthesis of 4-[2-(4-forfinal)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (96)

4-[2-(4-Forfinal)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (96) synthesized from 4-[2-(4-forfinal)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (95) according to the method described in example 32. Yield: 22%.

1H-NMR (400 MHz, CDCl3): δ 2,19 (s, 3H), 2,68 (m, 2H), 2,77 (m, 2H), return of 6.58 (d, 1H), 6,95 (m, 2H), 7,12 (m, 2H) ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 10,43; CH2carbon atoms: weighing 28.32, 37,31; CH carbons: 115,61, 121,90, 131,11 ppm LC/MS: 100%, m/z=247, HPLC (200-400 nm): 98,44%.

Example 36

Synthesis of 4-[2-(3-forfinal)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (99)

Synthesis of 4-[2-(3-Forfinal)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (97)

4-[2-(3-Forfinal)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-forfinal)acetylchloride by the way, opisannogo example 32. The yield of crude product: 93%.

1H-NMR (400 MHz, CDCl3): δ of 1.37 (t, 3H), 2,61 (s, 3H), a 4.03 (s, 2H), 4,35 (kV, 2H), 7,00 (m, 3H), 7,27 (m, 1H), 7,49 (d, 1H), to 9.57 (Sirs, 1H) ppm13C-NMR (100 MHz, CDCl3): δ 11,76, 14,38, 46,93, 60,84, 113,64, 116,30, 125,13, 127,17, 129,94, 137,42, 161,64, 193,02 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 11,76, 14,38; CH2carbon atoms: 46,93, 60,84; CH carbons: 116,30, 125,13, 127,17, 129,94 ppm LC/MS: 91,29%, m/z=289.

Synthesis of 4-[2-(3-forfinal)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (98)

4-[2-(3-Forfinal)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (98) synthesized from 4-[2-(3-forfinal)acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (98) according to the method described in example 32. Yield: 27%.

1H-NMR (400 MHz, CDCl3): δ of 1.36 (t, 3H), and 2.27 (s, 3H), of 2.72 (m, 2H), 2,81 (m, 2H), or 4.31 (q, 2H), 6,59 (d, 1H), to 6.88 (m, 3H), 7,22 (m, 1H), 8,79 (Sirs, 1H) ppm13C-NMR (100 MHz, CDCl3): δ 10,22, 14,55, 26,80, 36,43, 59,93, 112,64, 115,18, 119,72, 124,16, 129,72, 144,51, 161,65 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 10,22, 14,55; CH2carbon atoms: 26,80, 36,43, 59,93; CH carbon atoms: 112,64, 115,18, 119,72, 124,16, 129,72 ppm LC/MS: 100%, m/z=275.

Synthesis of 4-[2-(3-forfinal)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (99)

4-[2-(3-Forfinal)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (99) synthesized from 4-[2-(3-forfinal)ethyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (98) according to the method described in example 32. Yield: 55%.

p> 1H-NMR (400 MHz, CDCl3): δ of 2.20 (s, 3H), 2,69 (m, 2H), 2,81 (m, 2H), is 6.61 (d, 1H), 6.87 in (m, 2H), 6,95 (m, 1H), 7,24 (m, 1H) ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 10,43; CH2carbon atoms: 27,95, 37,84; CH carbon atoms: 113,53, 116,27, 121,87, 125,48, 130,79 ppm LC/MS: 100%, m/z=247, HPLC (200-400 nm): 80,81%.

Example 37

Synthesis of 3-methyl-4-[2-(4-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid (93)

Synthesis of 3-methyl-4-[2-(4-triptoreline)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (100)

3-Methyl-4-[2-(4-triptoreline)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (100) synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (4-triptoreline)acetylchloride according to the method described in example 32. The yield of crude product: 96%.

1H-NMR (400 MHz, CDCl3): δ to 1.38 (t, 3H), 2,61 (s, 3H), 4,11 (s, 2H), 4,35 (kV, 2H), 7,37 (m, 2H), 7,51 (d, 1H), 7,58 (m, 2H), 9,29 (Sirs, 1H) ppm13C-NMR (100 MHz, CDCl3): δ 11,71, 14,41, 46,90, 60,78, 123,70, 124,70, 125,49, 126,75, 129,41, 129,85, 130,00, 161,98, 193,49 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 11,71, 14,41; CH2carbon atoms: 46,90, 60,78; CH carbon atoms: 123,70, 124,70, 125,49, 126,75, 129,41, 129,85, 130,00 ppm LC/MS: 73,23%, m/z=339.

Synthesis of 3-methyl-4-[2-(4-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (101)

3-Methyl-4-[2-(4-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (101) Sintesi the jut of 3-methyl-4-[2-(4-triptoreline)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (100) according to the method, described in example 32. Yield: 22%.

1H-NMR (400 MHz, CDCl3): δ of 1.36 (t, 3H), and 2.27 (s, 3H), by 2.73 (m, 2H), 2,87 (m, 2H), or 4.31 (q, 2H), 6,56 (d, 1H), 7,26 (m, 2H), 7,52 (m, 2H), 8,72 (Sirs, 1H) ppm13C-NMR (100 MHz, CDCl3): δ 10,21, 14,54, 26,78, 36,51, 59,95, 119,70, 124,23, 125,18, 128,81, 161,68 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: of 10.21, 14,54; CH2carbon atoms: 26,78, 36,51, 59,95; CH carbons: 119,70, 124,23, 125,18, 128,81 ppm

LC/MS:100%, m/z=325

Synthesis of 3-methyl-4-[2-(4-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid (102)

3-Methyl-4-[2-(4-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid (102) synthesized from 3-methyl-4-[2-(4-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (101) according to the method described in example 32. Yield: 60%.

1H-NMR (400 MHz, CDCl3): δ of 2.20 (s, 3H), by 2.73 (m, 2H), 2,89 (m, 2H), 6,59 (d, 1H), 7,32 (m, 2H), 7,54 (m, 2H) ppm13C-NMR (100 MHz, CDCl3): δ 10,42, 27,84, 37,90, 120,14, 121,92, 124,74, 126,04, 127,37, 130,26, 148,11, 164,99 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 10,42; CH2carbon atoms: of 27.84, 37,90; CH carbons: 121,92, 126,04, 130,27 ppm LC/MS: 100%, m/z=297, HPLC (200-400 nm): 94,63%.

Example 38

Synthesis of 3-methyl-4-[2-(3-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid (96)

Synthesis of 3-methyl-4-[2-(3-triptoreline)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (105)

3-Methyl-4-[2-(3-triptoreline)acetyl]-1H-pyrrole-2-carboxylic sour the s ethyl ester (103) synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-triptoreline)acetylchloride on the way, described in example 32. The yield of crude product: 97%.

1H-NMR (400 MHz, CDCl3): δ to 1.38 (t, 3H), 2,62 (s, 3H), 4,11 (s, 2H), 4,35 (kV, 2H), 7,45 (m, 2H), 7,51 (m, 3H), 9,40 (Sirs, 1H) ppm13C-NMR (100 MHz, CDCl3): δ 11,73, 14,40, 46,73, 60,78, 123,70, 124,70, 126,82, 128,93, 129,71, 133,01, 135,85, 161,61, 192,58 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 11,73, 14,40; CH2carbon atoms: 46,73, 60,78; CH carbon atoms: 123,70, 126,82, 128,93, 129,71, 133,01 ppm LC/MS: 79,18%, m/z=339.

Synthesis of 3-methyl-4-[2-(3-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (104)

3-Methyl-4-[2-(3-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (104) synthesized from 3-methyl-4-[2-(3-triptoreline)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (103) according to the method described in example 32. Yield: 16%.

1H-NMR (400 MHz, CDCl3): δ of 1.36 (t, 3H), and 2.26 (s, 3H), 2,74 (m, 2H), 2,87 (m, 2H), or 4.31 (q, 2H), return of 6.58 (d, 1H), 7,38 (m, 4H), 8,72 (Sirs, 1H) ppm13C-NMR (100 MHz, CDCl3): δ 10,20, 14,54, 26,87, 35,56, 59,93, 119,67, 122,77, 124,25, 125,16, 128,67, 131,95, 142,77 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: 10,20, 14,54; CH2carbon atoms: 26,87, 35,56, 59,93; CH carbon atoms: 119,67, 122,77, 125,16, 128,67, 131,95 ppm LC/MS: 100%, m/z=325.

Synthesis of 3-methyl-4-[2-(3-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid (105)

3-Methyl-4-[2-(3-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid (105) synthesized from 3-methyl-4-[2-(3-triptoreline)ethyl]-1H-pyrrole-2-carboxylic KIS is the notes ethyl ester (104) according to the method, described in example 32.

1H-NMR (400 MHz, CDCl3): δ to 2.18 (s, 3H), by 2.73 (m, 2H), 2,89 (m, 2H), 6,60 (d, 1H), 7,42 (m, 4H) ppm13C-NMR (100 MHz, CDCl3): δ 10,39, 27,93, 37,87, 121,93, 123,57, 124,69, 126,22, 127,40, 129,94, 133,52, 144,72, 165,01 ppm DEPT (100 MHz, CDCl3): CH3carbon atoms: accounted for 10.39; CH2carbon atoms: 27,93, 37,87; CH carbon atoms: 121,93, 123,57, 126,22, 129,94, 133,52 ppm LC/MS: 100%, m/z=297, HPLC (200-400 nm): 96,89%.

Example 39

4-2-(4-Chlorophenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (110)

Synthesis of 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107)

Sodium nitrite (11.5g; 0,160 mol) in water (20 ml) is added dropwise to a cooled on ice stir the solution ethylacetoacetate (20.7 g; strength of 0.159 mol) in acetic acid (20 ml). The reaction temperature kept lower than 10°C. the Mixture is stirred for another 1 h at 5°C and stored over night at 0°C, receiving the oxime 97 in the form of orange-red solution. This solution is added to a mixture of acetoacetanilide of dimethylacetal (21 g; strength of 0.159 mol) and glacial acetic acid (35 ml)previously heated to 60°C, and immediately begin to slowly added to a mixture of zinc dust (30 g; 0,459 mol) and sodium acetate (30 g; 0,364 mol). After complete addition, the mixture is stirred for further 2 hours, then the mixture is poured into ice water (300 ml)to give a yellow precipitate. After filtration and recrystallization from whom thou methanol/water get 3.5 g (27%) 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107), in the form of a cream-colored needles.

1H-NMR (CDCl3, 400 MHz): δ 9,10 (NH, Sirs), PC 6.82 (1H, d), 5,95 (1H, s), the 4.29 (2H, q), 2,31 (3H, s)of 1.35 (3H, t) ppmI3C (CDCl3, 100 MHz): δ 161,5, 134,1, 121,2, 116,1, 101,8, 60,1, 15,5, 13,1 ppm LC/MS: 97%.

Synthesis of 4-[2-(4-chlorophenyl)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (108)

4-[2-(4-Chlorophenyl)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (108) are synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-chlorophenyl)acetylchloride according to the method described in example 32. Reaction conditions: 1,2-dichloroethane/CT. Purification: recrystallization from a mixture of ether/pentane. Yield: 83%.

1H (CDCl3, 400 MHz): δ 9,65 (NH, Sirs), 7,28 (3H, m), 7,2 (2H, d), 4,35 (2H, HF), Android 4.04 (2H, s), to 2.57 (3H, s)to 1.38 (3H, t) ppm13C (CDCl3, 100 MHz): δ 193,7, 161,5, 141,0, 133,5, 132,6, 130,9, 130,7, 128,9, 128,6, 121,4, 120,5, 116,9, 61,0, 46,1, 14,4, 14,0 ppm LC/MS: 100%.

Synthesis of 4-[2-(4-chlorophenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (109)

4-[2-(4-Chlorophenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (109) synthesized from 4-[2-(4-chlorophenyl)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (108) according to the method described in example 32. Purification: recrystallization from a mixture of ether/pentane. Yield: 82%.

1H (CDCl3, 400 MHZ): δ 9,65 (NH, Sirs), 7,20 (2H, d),? 7.04 baby mortality (2H, d), 6,72 (1H, s), the 4.29 (2H, q), 2,78 (2H, DD), of 2.64 (2H, DD), 2,04 (3H, s)of 1.35 (3H, t) ppm13C (CDCl3, 100 MHz): δ 161,6, 140,4, 131, 5mm, 131,2,129,9, 128,3, 121,3, 119,8, 115,7, 60,1, 36,7, 27,8 14,5, 11,0 ppm LC/MS: 96%.

Synthesis of 4-[2-(4-chlorophenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (110)

To a solution of 4-[2-(4-chlorophenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (109) in dioxane is added 10 equivalents of aqueous NaOH (1,5M), then the mixture is heated at 80°C for 3 hours. Then register the completion of the reaction, the solvents are removed in vacuo, add H2Oh and equal volume of Et2O. the Organic layer is removed, and then the aqueous layer was acidified with HCl (1M). If the product precipitates, it is filtered off, washed with H2O and dried, obtaining the pure target product. If the product is not precipitated upon acidification of the aqueous layer, add Et2O and the organic layer removed (2×). The organic layer is dried Na2SO4, filtered and concentrated, obtaining the target product. Cleaning: the deposition. Quantity: to 20.6 mg

1H (400 MHz, MeOD): δ 7,2 (2H, DD), was 7.08 (2H, DD), 6,59 (1H, s), was 2.76 (2H, DD), 2,63 (2H, DD), of 1.97 (3H, s) ppm DEPT (CD3OD, 100 MHz): CH3: δ 10,8, CH2: δ 28,9, 38,0, CH: 116,4, 129,1, 131,3 ppm HPLC (20 minutes): 97.8 per cent, LC/MS: 100%.

Example 40

Synthesis of 4-[2-(4-Forfinal)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (113)

Synthesis of 4-[2-(4-forfinal)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (111)

4-[2-(4-Forfinal)acetyl]-5-methyl-1H-pyrrole-2-carboxylic key is lots ethyl ester (111) are synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-forfinal)acetylchloride on the way, described in example 32. Reaction conditions: 1,2-dichloroethane/CT. Purification: recrystallization from a mixture of ether/pentane. Yield: 76%.

1H (CDCl3)400 MHz): δ 10,5 (NH, Sirs), 7,31 (1H, s), 7,22 (2H, DD), of 6.99 (2H, DD), 4,36 (2H, HF), 4,06 (2H, s), 2,58 (3H, s)of 1.39 (3H, t) ppm13C (CDCl3, 100 MHz): δ 194,1, 163,0, 161,5, 160,6, 141,0, 131,1, 130,7, 121,5, 120,5, 116,9, 115,4, 115,2, 61,0, 45,9, 14,4, 14,0 ppm LC/MS: 100%.

Synthesis of 4-[2-(4-forfinal)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (112)

4-[2-(4-Forfinal)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (112) synthesized from 4-[2-(4-forfinal)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (111) according to the method described in example 32. Purification: recrystallization from a mixture of ether/pentane. Yield: 86%.

1H (CDCl3, 400 MHz): δ 9,45 (NH, Sirs), 7,06 (2H, m)6,94 (2H, m), 6,72 (1H, s), the 4.29 (2H, q), 2,78 (2H, DD), of 2.64 (2H, DD), 2,03 (3H, s)of 1.34 (3H, t) ppm13C (CDCl3, 100 MHz): δ 162,5, 160,1, 137,6, 131,1, 129,9, 121,4, 119,8, 115,7, 115,0, 60,0, 36,5, 28,0 14,5, 11,0 ppm LC/MS: 100%.

Synthesis of 4-[2-(4-forfinal)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (113)

4-[2-(4-Forfinal)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (113) synthesized from 4-[2-(4-forfinal)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (112) according to the method described in example 39. Cleaning: the deposition. Quantity: 21,5 mg

1N(CD3D, 400 MHz): δ 7,10 (2H, DD), 6,94 (2H, DD), 6,60 (1H, s), 2,77 (2H, DD), of 2.64 (2H, DD), of 1.97 (3H, s) ppm13C (CD3OD, 100 M is C): δ 166,0, 161,5, 139,4, 131,5, 131,3, 131,2, 122,5, 121,9, 116,6, 115,8, 115,5, 37,8, 29,1, 10,8 ppm HPLC (20 minutes): 96,6%, LC/MS: 100%.

Example 41

Synthesis of 4-[2-(3-forfinal)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (116)

Synthesis of 4-[2-(3-forfinal)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (114)

4-[2-(3-Forfinal)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (114) are synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (3-forfinal)acetylchloride according to the method described in example 32. Reaction conditions: 1,2-dichloroethane/CT. Purification: recrystallization from a mixture of ether/pentane. Yield: 78%.

1H(CDCl3, 400 MHz): δ 10,6 (NH, Sirs), 7,30 (1H, s), 7,26 (1H, DD),? 7.04 baby mortality (1H, d), of 6.99 (1H, d), 6,92 (1H, DD), 4,37 (2H, HF), 4,07 (2H, s), 2,58 (3H, s)of 1.39 (3H, t) ppm13C (CDCl3, 100 MHz): δ 193,5, 164,0, 161,6, 141,0, 137,4, 130,0, 125,3, 121,5, 120,5, 116,9, 116,4, 113,7, 61,0, 46,4, 14,4, 14,0 ppm LC/MS: 98%.

Synthesis of 4-[2-(3-forfinal)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (115)

4-[2-(3-Forfinal)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (115) synthesized from 4-[2-(3-forfinal)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (114) according to the method described in example 32. Purification: recrystallization from a mixture of ether/pentane. Yield: 79%.

1H (CDCl3, 400 MHz): δ of 9.55 (NH, Sirs), 7,19 (1H, m)6,86 (3H, m), 6,72 (1H, s), the 4.29 (2H, q), 2,80 (2H, DD), to 2.66 (2H, DD), 2,07 (3H, s)of 1.34 (3H, t) ppm3 C (CDCl3, 100 MHz): δ 164,1, 161,6, 144,6, 131,1, 129,7, 124,2, 121,3, 119,8, 115,6, 115,2, 112,6, 60,1, 37,1, 27,6, 14,5, 11,0 ppm LC/MS: 93%.

Synthesis of 4-[2-(3-forfinal)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (116)

4-[2-(3-Forfinal)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (117) synthesized from 4-[2-(3-forfinal)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (116) according to the method described in example 39. Cleaning: extraction. Quantity: 10 mg

1H (MeOD, 400 MHz): δ 7.23 percent (1H, m)6,94 (1H, d), at 6.84 (2H, m), of 6.65 (1H, s), and 2.79 (2H, DD), to 2.66 (2H, DD), 2,0 (3H, s) ppm DEPT (MeOD, 100 MHz): CH3: δ 10,8, CH2: 28,7, 38,3, CH: 113,3, 116,3, 117,4, 125,5, 130,7 ppm HPLC (20 mn): 96,4%, LC/MS: 94%.

Example 42

Synthesis of 5-methyl-4-[2-(4-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid (119)

Synthesis of 5-methyl-4-[2-(4-triptoreline)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (117)

5-Methyl-4-[2-(4-triptoreline)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (117) synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-triptoreline)acetylchloride according to the method described in example 32. Reaction conditions: 1,2-dichloroethane/-40°C. Cleaning: prep./HPLC. Yield: 33%.

1H (CDCl3, 400 MHz): δ 10,5 (NH, Sirs), 7,56 (2H, d), 7,34 (2H, d), 7,32 (1H, s), 4,37 (2H, q), is 4.15 (2H, s)at 2.59 (3H, s)to 1.38 (3H, t) ppm13C (CDCl3, 100 MHz): δ 193,3, 161,5, 141,0, 139,0, 130,9, 125,5, 128,6, 121,4, 120,6, 114,0 61,0, 46,5, 14,5, 14,0 ppm LC/MS: 98%.

<> Synthesis of 5-methyl-4-[2-(4-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (118)

5-Methyl-4-[2-(4-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (118) are synthesized from 5-methyl-4-[2-(4-triptoreline)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (117) according to the method described in example 32. Cleaning: prep./HPLC. Yield: 50%.

1H (CDCl3, 400 MHz): δ 9,35 (NH, Sirs), to 7.50 (2H, d), of 7.23 (2H, d), 6,72 (1H, s), the 4.29 (2H, q), 2,85 (2H, DD), to 2.66 (2H, DD), 2,03 (3H, s)of 1.34 (3H, t) ppm HPLC: 100%.

Synthesis of 5-methyl-4-[2-(4-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid (119)

5-Methyl-4-[2-(4-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid (119) synthesized from 5-methyl-4-[2-(4-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (118) according to the method described in example 39. Cleaning: extraction. Quantity: 11,6 mg

1H (CDCl3, 400 MHz): δ 9.15, with (NH, Sirs), to 7.50 (2H, d), from 7.24 (2H, d), 6,86 (1H, s), 2,89(2H, DD), 2,68 (2H, DD), 2,04 (3H, s) ppm13C (CDCl3, 100 MHz): δ 165,7, 145,9, 132,5, 128,4, 128,13, 125,2, 122,0, 118,8, 117,9, 37,0, 27,5, 11,2 ppm HPLC (20 minutes): 94,5%, LC/MS: 97%.

Example 43

Synthesis of 5-methyl-4-[2-(3-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid (122)

Synthesis of 5-methyl-4-[2-(3-triptoreline)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (120)

5-Methyl-4-[2-(3-triptoreline)acetyl]-1H-pyrrol-2-carbon is howling acid ethyl ester (120) are synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (3-triptoreline)acetylchloride on the way, described in example 32. Reaction conditions: 1,2-dichloroethane/-40°C. Cleaning: prep./HPLC. Yield: 16%.

1H (CDCl3, 400 MHz): δ 10,7 (NH, Sirs), of 7.48 (4H, m), 7,34 (1H, s), 4,37 (2H, q), is 4.15 (2H, s)at 2.59 (3H, s)of 1.39 (3H, t) ppm13C(CDCl3, 100 MHz): δ 193,3, 161,6, 141,2, 136,0, 133,2, 131,2, 128,8, 128,2, 126,4, 123,6, 121,4, 120,6, 116,9, 61,0, 46,3,1 4,3, 13,9 ppm LC/MS: 100%.

Synthesis of 5-methyl-4-[2-(3-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (121)

5-Methyl-4-[2-(3-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (121) are synthesized from 5-methyl-4-[2-(3-triptoreline)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (120) according to the method described in example 32. Cleaning: prep./HPLC.

1H (CDCl3, 400 MHz): δ 9,25 (NH, Sirs), and 7.4 (4H, m), 6,72 (1 H, s), 4,30 (2H, HF), 2,87 (2H, DD), 2,68 (2H, DD), 2,03 (3H, s)of 1.35 (3H, t) ppm13C (CDCl3, 100 MHz): δ 161,5, 142,8, 132,0, 130,9, 130,7, 130,4, 128,7, 125,2, 122,7, 121,0, 120,0, 115,6, 60,1, 37,2, 27,7, 14,5, 11,0 ppm LC/MS: 94%.

Synthesis of 5-methyl-4-[2-(3-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid (122)

5-Methyl-4-[2-(3-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid (122) are synthesized from 5-methyl-4-[2-(3-triptoreline)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (121) according to the method described in example 39. Cleaning: extraction. Quantity: 9,5 mg

1H (CD3OD, 400 MHz): δ of 7.4 (4H, m), of 6.65 (1 H, s), 2,87 (2H, DD), 2,69 (2H, DD), of 1.95 (3H, s) ppm13C (CD3OD, 100 MHz): δ 164,5, 144,7, 133,6, 132,6, 131,3, 129,9, 126,3 123,6, 121,8, 121,0, 117,4, 38,3, 28,7, 10,7 ppm HPLC (20 minutes): 95,6%, LC/MS: 100%.

Example 44

Synthesis of 4-[2-(4-methoxyphenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (125)

Synthesis of 4-[2-(4-methoxyphenyl)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (123)

4-[2-(4-Methoxyphenyl)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (123) synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-methoxyphenyl)acetylchloride according to the method described in example 32. Reaction conditions: 1,2-dichloroethane/-40°C. Cleaning: prep./HPLC. Yield: 72%.

1H (CDCl3, 400 MHz): δ 10,45 (NH, Sirs), 7,31 (1H, s), 7,18 (2H, d), at 6.84 (2H, d), 4,37 (2H, kV)to 4.01 (2H, s), 3,74 (3H, s), to 2.57 (3H, s)to 1.38 (3H, t) ppm13C (CDCl3, 100 MHz): δ 194,7, 161,5, 158,4, 140,8, 130,5, 127,1, 121,6, 120,4, 117,1, 114,0, 60,8, 55,2, 46,0, 14,4, 14,0 ppm LC/MS: 100%.

Synthesis of 4-[2-(4-methoxyphenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (124)

4-[2-(4-Methoxyphenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (124) synthesized from 4-[2-(4-Methoxyphenyl)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (123) according to the method described in example 32. Purification: recrystallization from a mixture of ether/pentane. Yield: 75%.

1H (CDCl3, 400 MHz): δ 9,0 (NH, Sirs), 7,05 (2H, d), PC 6.82 (2H, d), 6,74 (1H, s), the 4.29 (2H, q), of 3.78 (3H, s)of 2.75 (2H, DD), of 2.64 (2H, DD), was 2.05 (3H, s)of 1.34 (3H, t) ppm13C (CDCl3, 100 MHz): δ 158,8, to 135.2, 131,7, 1304, 122,9, 120,8, 116,6, 114,7, 63,0, 61,0, 56,3, 37,4, 29,2, 12,2 ppm

Synthesis of 4-[2-(4-methoxyphenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (125)

4-[2-(4-Methoxyphenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (125) synthesized from 4-[2-(4-methoxyphenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (124) according to the method described in example 39. Cleaning: the deposition. Quantity: 27,4 mg.

1H (CD3OD 400 MHz): δ 7,01 (2H, DD), 6,78 (2H, DD), only 6.64 (1H, s), 3,30 (3H, s), a 2.71 (2H, DD), 2,62 (2H, DD), to 1.98 (3H, s) ppm13C (CD3OD, 100 MHz): δ 159,3, 135,5, 132,7, 130,5, 122,7, 120,7, 117,5, 114,6, 55,6, 37,8, 29,3, 10,8 ppm HPLC (20 minutes): 95,6%, LC/MS: 100%.

Example 45

Synthesis of 4-[2-(3-methoxyphenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (128)

Synthesis of 4-[2-(3-methoxyphenyl)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (126)

4-[2-(3-Methoxyphenyl)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (126) synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (3-methoxyphenyl)acetylchloride according to the method described in example 32. Reaction conditions: 1,2-dichloroethane/-40°C. Purification: recrystallization from a mixture of ether/pentane. Yield: 50%.

1H (CDCl3, 400 MHz): δ 10,80 (NH, Sirs), 7,32 (1H, s), 7,18 (1H, DD), 6,85 (1H, d), 6,83 (1H, s), of 6.75 (1H, d), to 4.33 (2H, q), Android 4.04 (2H, s), 3,74 (3H, s)to 2.55 (3H, s)of 1.36 (3H, t) ppm13C (CDCl3, 100 MHz): δ 194,3, 161,5, 159,7, 141,1, 136,7, 129,4, 121,9, 121,6, 120,4, 117,2, 115,2, 112,1, 60,8, 55,1, 4,0, 14.4V, to 13.9 ppm LC/MS: 100%.

Synthesis of 4-[2-(3-methoxyphenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (127)

4-[2-(3-Methoxyphenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (127) synthesized from 4-[2-(3-methoxyphenyl)acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (126) according to the method described in example 32. Purification: recrystallization from a mixture of ether/pentane. Yield: 82%.

1H (CDCl3, 400 MHZ): δ 9,40(NH, Sirs), 6,74 (4H, m), 4,30 (2H, q), of 3.77 (3H, s), 2,78 (2H, DD), to 2.67 (2H, DD), of 2.08 (3H, s)of 1.34 (3H, t) ppm13C (CDCl3, 100 MHz): δ 161,5, 159,6, 143,7, 131,0, 129,3, 121,8, 121,0, 119,8, 115,7, 114,3, 111,2, 60,0, 55,2, 37,4, 27,9, 14,5, 11,1 ppm LC/MS: 93%.

Synthesis of 4-[2-(3-methoxyphenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (128)

To a solution of 4-[2-(3-methoxyphenyl)ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (127) in EtOH added 3 equivalents of aqueous NaOH (3M), then the mixture is heated at 80°C for 1 hour. After completion of the reaction the solvent is removed in vacuo, add H2O and equal volume of Et2O. the Organic layer is removed, after which the aqueous layer was acidified with HCl (1M). If the product precipitates, it is filtered off, washed with H2O and dried, obtaining the pure target product. If the product is not precipitated upon acidification of the aqueous layer, add Et2O and the organic layer removed (2×). The organic layer is dried Na2SO4 , filtered and concentrated, obtaining the target product. Cleaning: extraction. Quantity: 37 mg.

1H (CDCl3, 400 MHz): δ 8,90 (NH, Sirs), 7,19 (1H, DD), to 6.88 (1H, s), 6.75 in (2H, m)6,94 (1H, s), of 3.78 (3H, s), 2,80 (2H, DD), 2,68 (2H, DD), of 2.08 (3H, s) ppm13C (CDCl3, 100 MHz): δ 165,5, 159,6, 143,5, 132,3, 129,3, 122,6, 121,0, 118,7, 117,8, 114,2, 111,2, 55,2, 37,3, 27,8, 11,3 ppm HPLC (20 minutes): to 91.6%, LC/MS: 97%.

Example 46

Synthesis of 5-methyl-4-(2-naphthalen-1-retil)-1H-pyrrole-2-carboxylic acid (131)

Synthesis of 5-methyl-4-(2-naphthalen-1-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (129)

5-Methyl-4-(2-naphthalen-1-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (129) synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) according to the method described in example 32. Reaction conditions: 1,2-dichloroethane/-40°C. Cleaning: prep./HPLC. Yield: 52%. LC/MS: 62%.

Synthesis of 5-methyl-4-(2-naphthalen-1-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (130)

5-Methyl-4-(2-naphthalen-1-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (130) are synthesized from 5-methyl-4-(2-naphthalen-1-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (129) according to the method described in example 32. Cleaning: no cleaning.

Synthesis of 5-methyl-4-(2-naphthalen-1-retil)-1H-pyrrole-2-carboxylic acid (131)

5-Methyl-4-(2-naphthalen-1-retil)-1H-pyrrole-2-carboxylic acid (131) synthesized from 5-methyl-4-(2-naphthalen-1-ileti-1H-pyrrole-2-carboxylic acid ethyl ester (130) according to the method, described in example 45. Cleaning: prep./HPLC. Quantity: 5,2 mg

1N (CD3OD 400 MHz): δ of 8.06 (1H, d), of 7.82(1H, d), to 7.67 (1H, d), was 7.45 (2H, m), 7,31 (1H, DD), 7,18 (1H, d), 6,72 (1H, s), 3,24 (2H, DD), was 2.76 (2H, DD), of 1.84 (3H, s) ppm DEPT (CD3OD, 100 MHz): CH3: δ 10,8, CH2: δ 28,4, 35,9, CH: 116,8, 124,8, 126,4, 126,5, 126,7, 127,4, 127,6, 129,8 ppm HPLC (20 minutes): 98,6%, LC/MS: 100%.

Example 47

Synthesis of 5-methyl-4-(3-naphthalen-2-ylpropyl)-1H-pyrrole-2-carboxylic acid (134)

Synthesis of 5-methyl-4-(3-naphthalen-2-ylacrylic)-1H-pyrrole-2-carboxylic acid ethyl ester (132)

5-Methyl-4-(3-naphthalen-2-yl-acryloyl)-1H-pyrrole-2-carboxylic acid ethyl ester (132) are synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and 3-naphthalen-2-electrologica according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40°C→CT. Cleaning: no cleaning. LC/MS: 40%.

Synthesis of 5-methyl-4-(3-naphthalen-2-ylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (133)

5-Methyl-4-(3-naphthalen-2-ylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (133) are synthesized from 5-methyl-4-(3-naphthalen-2-ylacrylic)-1H-pyrrole-2-carboxylic acid ethyl ester (132) according to the method described in example 32. When reconnecting 132 is restored carbonyl and double bond. Cleaning: no cleaning. Output: 100% according to LC/MS.

Synthesis of 5-methyl-4-(3-naphthas the flax-2-ylpropyl)-1H-pyrrole-2-carboxylic acid (134)

5-Methyl-4-(3-naphthalen-2-ylpropyl)-1H-pyrrole-2-carboxylic acid (134) are synthesized from 5-methyl-4-(3-naphthalen-2-ylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (133) according to the method described in example 45. Cleaning: extraction and ven. HPLC. Quantity: 20 mg

1H (CDCl3, 400 MHz): δ 8,95 (NH, Sirs), to 7.77 (3H, m), 7,60 (1H, s), 7,42 (2H, m), 7,32 (1H, d), 6.89 in (1H, s), 2,80 (2H, m), 2,46 (2H, m)to 2.18 (3H, s)a 1.96 (2H, m) ppm DEPT (CDCl3, 100 MHz): CH3: δ 11,6, CH2: δ 25,2, 32,0, 35,5, CH: 117,9, 125,0, 125,9, 126,4, 127,4, 127,6, 127,7, 127,8 ppm HPLC (20 min): 88,4%, LC/MS: 94%.

Example 48

Synthesis of 5-methyl-4-(2-naphthalen-2-retil)-1H-pyrrole-2-carboxylic acid (137)

Synthesis of 5-methyl-4-(2-naphthalen-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (135)

5-Methyl-4-(2-naphthalen-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (135) synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and naphthalen-2-Elaterid according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40°C→CT. Cleaning: no cleaning. LC/MS: 80%.

Synthesis of 5-methyl-4-(2-naphthalen-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (136)

5-Methyl-4-(2-naphthalen-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (136) are synthesized from 5-methyl-4-(2-naphthalen-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (135) according to the method described in example 32. Cleaning: without the cleaning.

Synthesis of 5-methyl-4-(2-naphthalen-2-retil)-1H-pyrrole-2-carboxylic acid (137)

5-Methyl-4-(2-naphthalen-2-retil)-1H-pyrrole-2-carboxylic acid (137) synthesized from 5-methyl-4-(2-naphthalen-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (136) according to the method described in example 45. Cleaning: the Rev. HPLC. Quantity: 12,6 mg

1H (CD3OD;400 MHz): δ to 7.77 (1H, d), 7,73 (2H, m), 7,54 (1H, s), 7,38 (2H, m), 7,28 (1H, DD), of 6.68 (1H, s), 2,95 (2H, DD), is 2.74 (2H, DD) ppm13C (CD3OD, 100 MHz): δ 165,8, 141,04, 135,15, 133,6, 131,9, 128,7, 128,6, 128,5, 128,4, 127,6, 126,7, 126,1, 122,3, 122,0, 116,9, 38,8, 29,0, 10,9 ppm HPLC (20 minutes): 99,0%. LC/MS: 100%.

Example 49

Synthesis of 5-methyl-4-(2-phenylpropyl)-1H-pyrrole-2-carboxylic acid (140)

Synthesis of 5-methyl-4-(2-phenylpropionyl)-1H-pyrrole-2-carboxylic acid ethyl ester (138)

5-Methyl-4-(2-phenylpropionyl)-1H-pyrrole-2-carboxylic acid ethyl ester (138) synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and 2-phenylpropionylamino according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40°C→CT. Cleaning: no cleaning. LC/MS: 86%.

Synthesis of 5-methyl-4-(2-phenylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (139)

5-Methyl-4-(2-phenylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (139) synthesized from 5-methyl-4-(2-phenylpropionyl)-1H-pyrrole-2-carboxylic acid ethyl ester (138) according to the method, opican the mu in example 32. Cleaning: no cleaning.

Synthesis of 5-methyl-4-(2-phenylpropyl)-1H-pyrrole-2-carboxylic acid (140)

5-Methyl-4-(2-phenylpropyl)-1H-pyrrole-2-carboxylic acid (140) are synthesized from 5-methyl-4-(2-phenylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (139) according to the method described in example 45. Cleaning: the Rev. HPLC. Number: 13 mg.

1H (CDCl3400 MHz): δ 8,7 (NH, Sirs), 7,27 (3H, m), 7,18 (2H, m), 6,77 (1H, s), 2,90 (1H, m), 2,62 (2H, m)of 1.97 (3H, s)of 1.27 (3H, d) ppm DEPT (CDCl3, 100 MHz): CH3: δ 11,3, 20,9 CH2: δ 35,0, CH: 41,4, 118,6, 126,0, 127,1, 128,3 ppm HPLC (20 minutes): 93.1%of, LC/MS: 96%.

Example 50

Synthesis of 4-(2-naphthalen-2-retil)-1H-pyrrole-2-carboxylic acid (128)

Synthesis of 4-(2-naphthalen-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (141)

4-(2-Naphthalen-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (141) are synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester and naphthalen-2-Elaterid according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40°C→CT. Cleaning: no cleaning. LC/MS: 78%.

Synthesis of 4-(2-naphthalen-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (142)

4-(2-Naphthalen-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (142) synthesized from 4-(2-naphthalen-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (141) according to the method described in example 32. Cleaning: no cleaning.

Sint is C 4-(2-naphthalen-2-retil)-1H-pyrrole-2-carboxylic acid (143)

4-(2-Naphthalen-2-retil)-1H-pyrrole-2-carboxylic acid (143) synthesized from 4-(2-naphthalen-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (142) according to the method described in example 45. Purification: chromatography on silica gel (eluent: CH2Cl2→AcOEt).

1H (MeOD, 400 MHz): δ to 7.77 (3H, m), to 7.61 (1H, s), 7,54 (1H, s), 7,38 (3H, m), 7,34 (1H, s), of 6.68 (1 H, s), 3,01 (2H, DD), of 2.86 (2H, DD) ppm DEPT (MeOD, 100 MHz): CH2: δ 29,8, 38,9, CH: 116,4, 122,7, 126,1, 126,8, 127,5, 128,4, 128,5, 128,6, 128,7 ppm HPLC (20 mn): 96.9% of the LC/MS: 100%.

Example 51

Synthesis of 4-(2-[4-bromophenyl]ethyl)-1H-pyrrole-2-carboxylic acid (146)

Synthesis of 4-(2-[4-bromophenyl]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (144)

4-(2-[4-Bromophenyl]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (144) are synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester and 4-bromophenyl-2-Elaterid according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40°C→CT. Cleaning: no cleaning.

Synthesis of 4-(2-[4-bromophenyl]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (145)

4-(2-[4-Bromophenyl]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (145) synthesized from 4-(2-[4-bromophenyl]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (144) according to the method described in example 32. Cleaning: no cleaning.

Synthesis of 4-(2-[4-bromophenyl]ethyl)-1H-pyrrole-2-carboxylic acid (146)

4-(2-[4-Brough the phenyl]ethyl)-1H-pyrrole-2-carboxylic acid (146) synthesized from 4-(2-[4-bromophenyl]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (145) according to the method, described in example 45. Purification: crystallization from water.

1H NMR (CD3OD, 400 MHz): δ was 7.36 (2H, d), 7,07 (2H, d), 6,69 (1H, s); to 6.67 (1H, s); of 2.81 (2H, m); of 2.72 (2H, m) ppm13C NMR (CD3OD, 100 MHz): 164,5, 142,7, 132,26, 131,6, 125,9, 123,5, 122,8, 120,4, 116,4, 38,0, 29,7 ppm HPLC (20 mn): 92,75% yield 91%.

Example 52

Synthesis of 4-(2-[2-forfinal]ethyl)-1H-pyrrole-2-carboxylic acid (149)

Synthesis of 4-(2-[4-forfinal]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (147)

4-(2-[4-Forfinal]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (147) are synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester and (4-forfinal)-2-Elaterid according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40°C→CT. Cleaning: no cleaning.

Synthesis of 4-(2-[4-forfinal]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (148)

4-(2-[4-Forfinal]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (1481) synthesized from(2-[4-forfinal]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (147) according to the method described in example 32. Cleaning: no cleaning.

Synthesis of 4-(2-[4-forfinal]ethyl)-1H-pyrrole-2-carboxylic acid (149)

4-(2-[4-Forfinal]ethyl)-1H-pyrrole-2-carboxylic acid (149) synthesized from 4-(2-[4-forfinal]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (148) according to the method described in example 45. Purification: crystallization and is water.

1H NMR (CDCl3, 400 MHz): δ 7,16 (2H, m), 7,03 (2H, m), 6,70 (2H, m); 2,87 (2H, m), 2,73 (2H, m) ppm13C NMR (CD3OD 100 MHz): 164,4, 161,4, 132,0, 130,0, 128,8, 126,0, 125,0, 123,5, 122,8, 116,4, 115,8, 31,8, 28,5 ppm, a 71%Yield,HPLC 20 minutes: 97,76%.

Example 53

Synthesis of 4-(2-[4-were]ethyl)-1H-pyrrole-2-carboxylic acid (152)

Synthesis of 4-(2-[4-were]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (150)

4-(2-[4-Were]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (150) are synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester and p-tolyl-2-Elaterid according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40°C→CT. Cleaning: no cleaning.

Synthesis of 4-(2-[4-were]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (151)

4-(2-[4-Were]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (151) synthesized from 4-(2-[4-were]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (150) according to the method described in example 32. Cleaning: no cleaning.

Synthesis of 4-(2-[4-were]ethyl)-1H-pyrrole-2-carboxylic acid (152)

4-(2-[4-Were]ethyl)-1H-pyrrole-2-carboxylic acid (152) synthesized from 4-(2-[4-were]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (151) according to the method described in example 45. Purification: Crystallization from water.

1H NMR (CDCl3)400 MHz): δ? 7.04 baby mortality (4H, m), of 6.68(1H, with); to 6.67 (1H, s); 2,78 (2H, m), of 2.72 (2H, m), and 2.27 (3H, s) ppm13C NMR (CD3OD 100 MHz): 164,5, 140,3, 136,2, 129,9, 129,4, 126,5, 123,3, 122,7, 116,5, 38,3, 30,1, 21,1 ppm Output is 55%. HPLC 20 mn: 96,23%.

Example 54

Synthesis of 4-(2-[2-were]ethyl)-1H-pyrrole-2-carboxylic acid (155)

Synthesis of 4-(2-[2-were]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (153)

4-(2-[2-Were]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (153) synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester and o-tolyl-2-Elaterid according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40 ° C→CT. Cleaning: no cleaning.

Synthesis of 4-(2-[2-were]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (154)

4-(2-[2-Were]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (154) synthesized from 4-(2-[2-were]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (153) according to the method described in example 32. Cleaning: no cleaning.

Synthesis of 4-(2-[2-were]ethyl)-1H-pyrrole-2-carboxylic acid (155)

4-(2-[2-Were]ethyl)-1H-pyrrole-2-carboxylic acid (155) synthesized from 4-(2-[2-were]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (153) according to the method described in example 45. Purification: crystallization from water.

1H NMR (CDCl3, 400 MHz): δ was 7.08 (4H, m), of 6.71 (1H, s); 6,69 (1H, s); and 2.83 (2H, m), 2,69 (2H, m), and 2.27 (3H, s) ppm13/sup> C NMR (CD3OD 100 MHz): 164,5, 141,5, 136,9, 131,0, 130,0, 127,0, 126,9, 126,58, 123,4, 122,6, 116,4, 63,1, 28,9, 19,4 ppm Output 73% HPLC 20 mn: 96,95%.

Example 55

Synthesis of 4-(2-[3-were]ethyl)-1H-pyrrole-2-carboxylic acid (158)

Synthesis of 4-(2-[3-were]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (156)

4-(2-[3-Were]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (156) are synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester and m-tolyl-2-Elaterid according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40°C→CT. Cleaning: no cleaning.

Synthesis of 4-(2-[3-were]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (157)

4-(2-[3-Were]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (157) synthesized from 4-(2-[3-were]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (156) according to the method described in example 32. Cleaning: no cleaning.

Synthesis of 4-(2-[3-were]ethyl)-1H-pyrrole-2-carboxylic acid (158)

4-(2-[3-Were]ethyl)-1H-pyrrole-2-carboxylic acid (158) synthesized from 4-(2-[3-were]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (157) according to the method described in example 45. Purification: crystallization from water.

1H NMR (CDCl3, 400 MHz): δ 9,00 ( 1H, Sirs), 7,18 (1H, m)to 7.00 (3H, m)6,91 (1H, s), of 6.75 (1H, s), 2,82 (4H, m), of 2.38 (3H, s) ppm LC/MS: 100%, m/z=229 g/mol. Yield=72%.

Example 56

Synthesis of 4-(2-[2-chloro-4-forfinal]ethyl)-1H-pyrrole-2-carboxylic acid (161)

Synthesis of 4-(2-[2-chloro-4-forfinal]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (159)

4-(2-[2-chloro-4-forfinal]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (159) synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester and (2-chloro-4-forfinal)-2-Elaterid according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40°C→CT. Cleaning: no cleaning.

Synthesis of 4-(2-[2-chloro-4-forfinal]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (160)

4-(2-[2-chloro-4-forfinal]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (160) synthesized from 4-(2-[2-chloro-4-forfinal]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (159) according to the method described in example 32. Cleaning: no cleaning.

Synthesis of 4-(2-[2-chloro-4-forfinal]ethyl)-1H-pyrrole-2-carboxylic acid (161)

4-(2-[2-chloro-4-forfinal]ethyl)-1H-pyrrole-2-carboxylic acid (161) synthesized from 4-(2-[2-chloro-4-forfinal]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (160) according to the method described in example 45. Cleaning: the deposition from the water.

1H NMR (CDCl3, 400 MHz): δ 7,19 (2H, m), of 6.96 (1H, m); 6,70 (2H, m); 2,95 (2H, m), 2,73 (2H, m) ppm13C NMR (CD3OD 100 MHz): 164,4, 161,2, 136,9, 135,4, 132,9, 125,7, 123,6, 122,7, 117,4, 116,4, 114,7, 35,7, 28,0 ppm Output 51%e HPLC 20 mn: 98,85%.

Example 57

Synthesis of 4-(2-[2,4-dichlorophenyl]ethyl)-1H-pyrrole-2-carboxylic acid (164)

Synthesis of 4-(2-[2,4-dichlorophenyl]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (162)

4-(2-[2,4-dichlorophenyl]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (162) are synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester and o,p-dichlorophenyl-2-Elaterid according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40°C→CT. Cleaning: no cleaning.

Synthesis of 4-(2-[2,4-dichlorophenyl]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (163)

4-(2-[2,4-dichlorophenyl]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (163) synthesized from 4-(2-[2,4-dichlorophenyl]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (162) according to the method described in example 32. Cleaning: no cleaning.

Synthesis of 4-(2-[2,4-dichlorophenyl]ethyl)-1H-pyrrole-2-carboxylic acid (164)

4-(2-[2,4-dichlorophenyl]ethyl)-1H-pyrrole-2-carboxylic acid (164) are synthesized from 4-(2-[2,4-dichlorophenyl]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (163) according to the method described in example 45 (note: used in the reaction, the solvent was replaced by ethanol). Cleaning: the deposition from the water.

1H NMR (CD3OD 400 MHz): δ the 7.43 (1H, s), 7,20 (2H, m), 6,69 (2H, s), 2,96 (2H, t), 2,78 (2H, t) ppm Yield=46%.

Example 58

Synthesis of 4-(2-[3,4-dichlorophenyl]this is)-1H-pyrrole-2-carboxylic acid (167)

Synthesis of 4-(2-[3,4-dichlorophenyl]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (165)

4-(2-[3,4-dichlorophenyl]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (165) are synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester and m,p-dichlorophenyl-2-Elaterid according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40°C→CT. Cleaning: no cleaning.

Synthesis of 4-(2-[3,4-dichlorophenyl]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (166)

4-(2-[3,4-dichlorophenyl]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (166) synthesized from 4-(2-[3,4-dichlorophenyl]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (165) according to the method described in example 32. Cleaning: no cleaning.

Synthesis of 4-(2-[3,4-dichlorophenyl]ethyl)-1H-pyrrole-2-carboxylic acid (167)

4-(2-[3,4-dichlorophenyl]ethyl)-1H-pyrrole-2-carboxylic acid (167) synthesized from 4-(2-[3,4-dichlorophenyl]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (166) according to the method described in example 45 (note: used in the reaction, the solvent was replaced by ethanol). Cleaning: the deposition from the water.

1H NMR (CD3OD 400 MHz): δ was 7.36 ( 2H, m), was 7.08 (1H, m), of 6.68 (2H, m), and 2.83 (4H, m) ppm Yield=87%.

Example 59

Synthesis of 4-(2-[2,4-differenl]ethyl)-1H-pyrrole-2-carboxylic acid (170)

Synthesis of 4-(2-[2,4-debtor enyl]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (168)

4-(2-[2,4-Differenl]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (168) are synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester and o,p-differenl-2-Elaterid according to the method described in example 32. Reaction conditions: 1,2-dichloromethane/-40°C→CT. Cleaning: no cleaning.

Synthesis of 4-(2-[2,4-differenl]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (169)

4-(2-[2,4-differenl]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (169) synthesized from 4-(2-[2,4-differenl]-2-ylacetic)-1H-pyrrole-2-carboxylic acid ethyl ester (168) according to the method described in example 32. Cleaning: no cleaning.

Synthesis of 4-(2-[2,4-differenl]ethyl)-1H-pyrrole-2-carboxylic acid (170)

4-(2-[2,4-differenl]ethyl)-1H-pyrrole-2-carboxylic acid (170) synthesized from 4-(2-[2,4-differenl]-2-retil)-1H-pyrrole-2-carboxylic acid ethyl ester (169) according to the method described in example 45. Cleaning: the deposition from the water.

1H NMR (CDCl3i400 MHz): δ 6,76 (2H, m), 6,70 (3H, m); 2,87 (2H, m)of 2.75 (2H, m) ppm13C NMR (CD3OD 100 MHz): 165,6, 164,5, 163,2, 148,0, 125,6, 123,6, 122,7, 116,3, 112,4, 112,2, 101,9, 38,3, 29,2 ppm Output 70%. HPLC 20 mn: 99,05%.

Example 60

Synthesis of 4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (172)

Synthesis of 4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid ethyl ester (171)

1,8-Diazabicyclo[5,4,0]-undec-7-ene (6.2 ml, 41.5 mmol)in 2-propanol (45 ml) is added through a funnel over ~25 minutes to a stirred solution of 1-nitrocyclohexane (5,0441 g, 39,67 mmol) and ethylisothiocyanate (4,3340 g, 37,16 mmol) in THF (45 ml). After stirring overnight at room temperature, record the completion of the reaction. Add 2 N. HCl (~100 ml) and EtOAc (~50 ml). The organic layer is removed, then washed with H2O, 5% NaHC3and H2O. the Crude product is dried Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash Column, 100% CH2Cl2), receiving the connection 171 containing a minor impurity. Attempts to remove the mixture by recrystallization from hexanol did not succeed, so the product is used in the next stage without additional purification.

1H (CDCl3, 400 MHz): δ 9,01 (1H, Sirs), only 6.64 (1H, s), or 4.31 (3H, q, J=7.2 Hz), 2,82 (2H, t, J=5.6 Hz), to 2.55 (2H, t, J=5.6 Hz), 1,80 by 1.68 (4H, m)of 1.36 (3H, t, J=7.2 Hz) ppm13C (CD3OD, 100 MHz): δ 161,71, 128,06 and 127,84, 121,98 and 121,96, 118,74 and 118,55, 118,03 and 117,71, 59,62, 23,41 and 23,39, 23,36 and 23,33, 23,16 and 23,13, 21,88 and 21,86, 14, 48mm ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 14, 48mm; CH2carbon atoms: 59,62, 23,41 and 23,39, 23,36 and 23,33, 23,16 and 23,13, 21,88 and 21,86; CH carbons: 118,74 and 118,55 ppm HPLC: 10,689 minutes

Synthesis of 4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (172)

Their aqueous solution of NaOH (10M in H2O, to 10.3 mmol) are added to stir at room temperature to a solution of compound 171 (0,3966 g, 2.05 mmol) in MeOH (5.1 ml, 0,4M) in the atmosphere N2. The reaction mixture ZAT is m heated at the boil under reflux for 20 minutes. There is a small amount of substance. The HPLC analysis shows the presence of a large number of non-target product and a small amount of the target product. The reaction mixture was concentrated, dissolved again in H2O and extracted with EtOAc (1 ml). To the water layer added dropwise 10% aqueous solution of HCl to obtain pH=2. White solid precipitated from the reaction mixture, is filtered off and washed with cold H2O. the Solid is dried in vacuum over night, getting 0,0076 g (11.6%) of compound 172.

1H (CD3OD, 400 MHz): δ 5,62 (1H, s), 2,77 (2H, t, J=5.6 Hz), 2,52 (2H, t, J=5.4 Hz), 1,78-of 1.66 (4H, m) ppm13C (CD3OD, 100 MHz): δ 164,87, 129,69, 122,48, 120,57, 118,42, 24,74, 24,69, 24,35, 22,94 ppm DEPT (CD3OD, 100 MHz): CH2carbon atoms: 24,74, 24,69, 24,35, 22,94; CH carbons: 120,57 ppm HPLC: 8,896 minutes

Example 61

Synthesis of 5-bromo-4-[2-(2-bromophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (173)

Synthesis of 5-bromo-4-[2-(2-bromophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (173)

Bromine (0,021 ml, 0,414 mmol) added dropwise over 5 minutes to a stirred solution of compound 65 (0,1014 g, 0,345 mmol) in acetic acid (1.1 ml). After completion of the reaction, which is recorded by means of HPLC (20 min)add H2Oh, and the precipitated solid is filtered off and washed with H2O. Received light purple solid substances is about dissolved in EtOAc, washed Na2SO3and H2O, then dried with Na2SO4filter and concentrate. The product was then purified preparative HPLC with reversed phase, elwira 40:60 H2O:CH3CN (mass./0.05% of TFU); 20 ml/min; λ=214 nm. Get 0,0574 g (44.6 per cent) connection 173 in the form of friable pale pink solid.

1H (CD3OD, 400 MHz): δ 7,50 (1H, d, J=7.8 Hz), 7.24 to to 7.00 (3H, m), of 6.68 (1H, s), of 2.92 (2H, t, J=~7,8 Hz)to 2.67 (2H, t, J=~7,8 Hz) ppm Partial13C(CD3OD, 100 MHz): δ 163,25, 141,86, 133,73, 131,85, 128,89, 128,54, 125,26, 124,68, 117,16, 105,89, 37,91, 27,62 ppm DEPT (CD3OD, 100 MHz): CH2carbon atoms: 37,91, 27,62; CH carbon atoms: 133,73, 131,85, 128,89, 128,54, 117,16 ppm HPLC: 10,473 minutes

Example 62

Synthesis of 5-bromo-4-[2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (174)

Synthesis of 5-bromo-4-[2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (174)

5-Bromo-4-[2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid is obtained according to the method of example 61.

1H (CD3OD, 400 MHz): δ 7,22 (2H, d, J=8,8 Hz), 7,12 (2H, d, J=8,8 Hz), of 6.65 (1H, s), of 2.81 (2H, t, J=7,3 Hz)to 2.67 (2H, t, J=7,3 Hz) ppm13C (CD3OD, 100 MHz): δ 163,33, 141,42, 132,54, 131,03, 129,18, 124,73, 117,46, 105,84, 36,72, 29,04 ppm

Example 63

Synthesis of 5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid (177)

Synthesis of 5-(3-phenylpropionyl)-1H-pyrrole-2-carboxylic acid ethyl ester (175) and 4-(3-phenylpropionyl)-1H-pyrrole-2-carboxylic what islote ethyl ester (43)

Acylpyrrole-2-carboxylate (2,0211 g, 14.5 mmol) in a minimal amount of dichloroethane (2 ml) is added to a cooled on ice, stir a mixture of zinc chloride (4,0151 g, 29.5 mmol) and hydrocinnamaldehyde (5,0348 g, and 29.9 mmol) in dichloroethane (20 ml, 0,66M) in an atmosphere of N2. After stirring for 10 min bath with ice is removed and the reaction mixture is left at room temperature until completion of the reaction, registered by HPLC (2 h 45 min). Add resin PS-Trisamine™ (13,44 g) and the reaction mixture was stirred at room temperature for approximately 1.5 hours, the Reaction mixture was filtered through a Frit into a flask containing ice water. The Frit was washed with CH2Cl2, then the combined organic layers washed with H2Oh, dried Na2SO4filter, concentrate and purify by chromatography on silica gel (Combiflash Column, 25:75 hexane:CH2Cl2), receiving 0,5374 g (14%) of compound 175 (lower Rf-value). Attempts to allocate the connection 43 (higher Rf value) does not take. HPLC: of 10.58 minutes (starting material: 8,90 minutes).

Synthesis of 5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (176)

Triethylsilane (0,977 ml, 6,14 mmol) are added to stir at room temperature solution of 5-(3-phenylpropionyl)-1H-pyrrole-2-carboxylic acid ethyl ester (175) (0,5374 g of 1.98 mmol) in trip oruktusai acid (TFU) (4.72 in ml, 0,42M) in the atmosphere N2. After stirring at room temperature overnight using HPLC register the completion of the reaction. TFU is removed in vacuum and the crude product purified preparative HPLC with reversed phase, using the following conditions: 35:65 H2A:CH3CN; 20 ml/min; λ=254 nm. HPLC: 11,12 minutes

Synthesis of 5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid (177)

Their aqueous solution of NaOH (10M in H2O, 1,22 mmol) are added to stir at room temperature solution of 5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (85) (0,0629 g, 0,244 mmol) in MeOH (0,61 ml, 0,4M) in the atmosphere N2. The reaction mixture is heated at boiling under reflux until completion of the reaction, which is recorded by means of HPLC. The product concentrate and then add 2 ml of diethyl ether and 2 ml of H2O. the Organic layer is removed and discarded, then add 2 ml of diethyl ether and 10% are added dropwise an aqueous solution of HCl to obtain pH=2. A layer of diethyl ether was removed and the aqueous extracted with another portion of diethyl ether. The combined organic layers are dried and concentrated, obtaining the target product. (Note: an undesired impurity has a retention time 10,85 min according to HPLC. HPLC: minutes to 9.91

Example 64

The transformation of 4-(2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic KIS is the notes in sodium salt (178)

Obtaining the sodium salt of 4-[2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (178)

4-[2-(4-Chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid (39) (4,2668 g, 17,09 mmol) dissolved in 60 ml (0,17M) MeOH. The solution is cooled in a bath of ice at 0°C, then while mixing, slowly add aqueous sodium hydroxide solution (0,6872 g, 17,09 mmol NaOH, 2,7M). White solid separated from the solution in the form of oil. The methanol is removed on a rotary evaporator, then add 32 ml of H2Oh and the flask contents are well stirred at room temperature until dissolution. The disappearance of light pink staining observed in the dissolution of the original acid in methanol occurs after filtration through filter paper. After lyophilization colorless solution get 4,5345 g (97.7 percent) of friable white solid.

Example 65

Synthesis of 4-methyl-2-phenethyl-1H-pyrrole-2-carboxylic acid ethyl ester (182)

Synthesis of 4-nitro-1-phenylpentane-3-ol (179)

Method One et al, J. Hetercyclic Chem., 1994, 31, 707-710, which is included in this description by reference, nitroethane (10 ml, 139,2 mmol, 96%) and 3-phenylpropionaldehyde (be 18.49 ml, 139,9 mmol) dissolved in THF (70 ml, 2M). After cooling the reaction mixture to -10°C in a bath containing a saturated salt solution, there was added 18-diazabicyclo[5,4,0]-undec-7-ene (DBU) (1,46 ml, 9,74 mmol) and the mixture allowed to mix until completion of the reaction, registered by HPLC (75 min). The reaction mixture was diluted with diethyl ether and H2O, after which the organic layer is removed and washed with saturated aqueous NaHCO3and saturated salt solution. Water layers again extracted with diethyl ether and the combined organic layers are dried Na2SO4filter and concentrate the receiving connection 179, which is used in the next stage without additional purification. HPLC: 9,68 minutes (note: the Original substances have the following meanings retention time: nitroethane: minutes of 6.49; 3-phenylpropionaldehyde: 9,45 min).

Synthesis of acetic acid 2-nitro-1-ventiltruemogo ether (180)

Obtained in the previous phase of the crude 4-nitro-1-phenylpentane-3-ol (179) dissolved in CH2Cl2(60 ml) and cooled in a bath with ice in a nitrogen atmosphere. Slowly add concentrated sulfuric acid (0,76 ml of 14.2 mmol)and then acetic anhydride (13,83 ml, 146,2 mmol), after which the reaction mixture is left to warm to room temperature and stirred until completion of the reaction, registered with poosu HPLC (3 h, 40 min). (Note: Soon after adding acetic anhydride begins the reverse reaction). The reaction is quenched slowly pouring the reaction mixture into water, then the organic layer is removed, washed with aqueous solution of NaHCO3, dried, filtered and concentrated. The crude product is purified by chromatography on silica gel (Combiflash column, 95:5 hexane:EtOAc) and get a pure compound 180 (21,4447 g, 65.5 per cent, stage 2). HPLC: 10,45 minutes

Synthesis of 4-methyl-2-phenethyl-1H-pyrrole-2-carboxylic acid ethyl ester (181)

Acetic acid 2-nitro-1-phenotypicaly ether (180) (10,4302 g, a 44.2 mmol) and utilitarianistic (4,957 g, a 44.2 mmol) is weighed into a round bottom flask of 250 ml Flask sealed with a membrane, rinsed with nitrogen, then dissolved in a mixture of THF and isopropyl alcohol (1,6:1, 44 ml, 1M). The reaction mixture is cooled in a bath with ice, then add DBU (to 13.6 ml, 2.05 mmol). The reaction mixture was left to warm to room temperature and allowed to mix at room temperature until completion of the reaction, which is recorded by means of HPLC (2 h, 25 min). The reaction mixture was diluted with H2O and diethyl ether, the organic layer removed, extracted with 2 N. HCl, H2O and NaHCO3. The combined organic layers are dried Na2SO4filter and concentrate. The crude product is purified by chromatography on silica gel (Combiflash column, 95:5 hexane:EtOAc). The product is crystallized from combined fractions Combiflash receiving portion 3,3224 g (29%) of pure compound 181 and 3,7709 g of compound 181, containing small amounts of the impurities. HPLC: 11,27 minutes

Synthesis of 4-methyl-2-phenethyl-1H-pyrrole-2-carboxylic acid (182)

4-Methyl-2-phenethyl-1H-pyrrole-2-carboxylic acid ethyl ester (181) hydrolyzing the above-described method, receiving the pure target product.

1H (CD3OD, 400 MHz): δ or 10.60 (1H, Sirs), 7,24-7,00 (5H, m), 6,62 (1H, s)to 2.99 (2H, DD, J=9,6, 7,3 Hz)to 2.67 (2H, DD, J=9,6, 7,8 Hz)and 1.83 (3H, s) ppm13C (CD3OD, 100 MHz): δ 164,75, 143,86, 132,12, 129,58, 129,10, 126,61, 122,27, 122,10, 120,68, 38,32, 28,61, 9,80 ppm DEPT (CD3OD, 100 MHz): CH2carbon atoms: 38,32, 28,61; CH carbons: 129,58, 129,10, 126,61, 122,27 ppm HPLC: 9,947 minutes

Example 66

Synthesis of 4-[2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (38)

Synthesis of 4-[2-(4-chlorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid amide (38)

To a solution of compound 39 (0,5026 g, a 2.01 mmol) in CH2Cl2(8,4 ml, 0,24M) was added 1-[3-(dimethylamine)propyl]-3-ethylcarbodiimide (EDCI, 0,4700 g, 2,42 mmol), 4-(dimethylamino)pyridine (DMAP, 0,0270 g, 0.20 mmol) and EtOH (0,352 ml, 6,04 mmol) and the reaction mixture was stirred at room temperature overnight. Solid by-product is filtered off and washed with CH2Cl2, then the combined organic layers washed with 5% aqueous solution of NaHCO3a 5% aqueous solution of HCl and H2O. the combined organic layers are dried Na2SO4filter and concentrate. The product was then purified XP is matography on silica gel (Combiflash Column, 90:10 hexane:EtOAc)to give 0,2974 g (53,2%) of compound 38. Analytical data for compound 38 coincide with the data obtained for the compounds synthesized previously in another way. HPLC: 11,261 minutes (note: the retention time of the parent substance by HPLC=10,028 minutes)

Example 67

Synthesis of 4-phenyliminomethyl-1H-pyrrole-2-carboxylic acid (184)

Synthesis of 4-phenyliminomethyl-1H-pyrrole-2-carboxylic acid ethyl ester (183)

0,2012 g (1.20 mmol) of 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester is dissolved in 4.8 ml (0,25M) 5% solution of acetic acid in methanol. Add aniline (0,13 ml g, 1.44 mmol) and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 45 minutes, then slowly add cyanoborohydride sodium (0,1244 g of 1.98 mmol) and the reaction mixture is allowed to mix at room temperature over night. Add approximately 2 ml of a saturated solution of K2CO3and the reaction mixture is extracted twice with ethyl acetate. The combined organic layers washed with aqueous solution of NaHCO3(~3 ml) and saturated salt solution (~3 ml), then dried with Na2SO4, filtered and concentrated in vacuo. The crude product is purified by chromatography on silica gel (Combiflash column, 85:15 hexane:ethyl acetate), obtaining 0,2663 g (91%) 4-phenylamino ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (183) in the form of a colorless viscous oil. Note: the starting material 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester has a retention time on HPLC=7,337 minutes

1H (CDCl3, 400 MHz): δ 9,49 (1H, Sirs), 7,19 (2H, DD, J=8,6, and 7.3 Hz), was 6.73 (1H, TT, J=7,3, 1.1 Hz), 6,66 (2H, DD, J=8,6, 1,1 Hz)6,91 (1H, d, J=2.0 Hz), 6.90 to (1H, d, J=2.0 Hz), to 4.33 (2H, q, J=7.2 Hz), 4,19 (2H, s), 3,90 (1H, Sirs), of 1.36 (3H, t, J=7.2 Hz) ppm HPLC: 6,936 minutes

Synthesis of 4-phenyliminomethyl-1H-pyrrole-2-carboxylic acid (184)

4-Phenyliminomethyl-1H-pyrrole-2-carboxylic acid ethyl ester (183) (0,0773 g, 0,316 mmol) is weighed into a round bottom flask. Flask equipped with a stirrer, a refrigerator and a membrane and blow N2. The ester was dissolved in EtOH (0,70 ml, 0,45M) and then to a solution of ether was added with stirring their aqueous solution of NaOH (0,0354 g, 0,283 ml H2About). Immediately after the reaction flask is immersed in an oil bath heated to 85°C, and the reaction mixture is heated and stirred in an atmosphere of N2until completion of the reaction, which is recorded by means of HPLC (15 min). The solvent is removed on a rotary evaporator and add 0.8 ml H2O. the Aqueous layer was slowly and carefully acidified with 10% aqueous HCl solution. The product was then purified preparative HPLC with reversed phase (45:55 H2Oh, containing 0.05% TFU:CH3CN containing 0.05% TFU) and get a clean 4-phenyliminomethyl-1H-pyrrole-2-carboxylic acid.

1H (CD3OD, 400 MHz): δ 7,51-7,40 (5H, m), of 6.99 (1H, d, J=5 Hz), 6,86 (1H, d, J=1.5 Hz), to 4.46 (2H, s) ppm13C(CD3OD, 100 MHz): δ 163,92, 137,17, 131,10, 129,97, 125,95, 125,07, 123,71, 117,37, 115,77, 49,38 ppm DEPT (CD3OD, 100 MHz): CH2carbon atoms: 49,38; CH carbon atoms: 131,10, 129,97, 125,94, 123,71, 117,37 ppm HPLC: 5,724 minutes

Example 68

Synthesis of 4-[(acetylamino)methyl]-1H-pyrrole-2-carboxylic acid (186)

Synthesis of 4-[(acetylamino)methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (185)

4-Phenyliminomethyl-1H-pyrrole-2-carboxylic acid ethyl ester (183) (0,1523 g, 0,623 mmol) is weighed into a flask with a volume of 10 ml. Flask equipped with a stirrer and a membrane and rinsed with nitrogen. The amine is dissolved in methylene chloride (1.6 ml, 0,4M) and then the flask was cooled to 0°C. Add N,N-diisopropylethylamine (0,1194 ml, China 0,686 mmol), then stirred at 0°C. the solution through the syringe slowly add acetylchloride (0,0488 ml, China 0,686 mmol). Then the reaction mixture was left to warm to room temperature. After completion of the reaction, registered by HPLC (35 min), the reaction mixture is diluted with methylene chloride and quenched with water. The organic phase is removed, washed with saturated salt solution, dried with Na2SO4, filtered and concentrated in vacuo. According to HPLC and NMR of the crude product is sufficiently pure to be used in the next stage without additional purification (0,1625 g, 91%, be the CSOs crystalline solid).

1H (CD3OD, 400 MHz): δ 11,22 (1H, Sirs), 7,43-7,31 (3H, m), was 7.08 (2H, DD, J=7,0, 1.5 Hz), to 6.75 (1H, d, J=1.5 Hz), of 6.68 (1H, d, J=1.5 Hz), 4,70 (2H, s), are 4.24 (2H, q, J=7.0 Hz), is 1.81 (3H, s)is 1.31 (3H, t, J=7.0 Hz) ppm13C (CD3OD, 100 MHz): δ 172,47, 162,64,1 43,86, 130,68, 129,34, 129,27, 124,50, 124,33, 122,19, 116,72, 61,16, 46,60, 22,64, 14,75 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 22,64, 14,75; CH2carbon atoms: 61,16, 46,60; CH carbon atoms: 130,68, 129,34, 129,27, 124,33, 116,72 ppm HPLC: 8,738 minutes

Synthesis of 4-[(acetylamino)methyl]-1H-pyrrole-2-carboxylic acid (186)

4-[(Acetylamino)methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (185) (0,1353 g, 0,473 mmol) is weighed into a round bottom flask. Flask equipped with a stirrer, a refrigerator and a membrane and blow N2. The ester was dissolved in EtOH (1,05 ml, 0,45M) and then to a solution of ether was added with stirring their aqueous solution of NaOH (0,0529 g of 0.42 ml of H2About). Immediately after the reaction flask is immersed in an oil bath heated to 85°C, and the reaction mixture is heated and stirred in an atmosphere of N2until completion of the reaction, which is recorded by means of HPLC (45 min). The solvent is removed on a rotary evaporator and add 1.0 ml of CH2Cl2and 1.0 ml of H2O. the Aqueous layer was slowly and carefully acidified with 10% aqueous HCl solution. Although the aqueous layer was cloudy precipitation is not observed. The product is extracted from the aqueous layer with three portions of CH2Cl2dried Na 2SO4, filtered and concentrated in vacuo, obtaining pure 4-[(acetylamino)methyl]-1H-pyrrole-2-carboxylic acid (186, 0,0968 mg; 79%).

1H (CD3OD, 400 MHz): δ of 11.11 (1H, Sirs), 7,46-7,31 (3H, m), to 7.09 (2H, DD, J=7,0, 1.5 Hz), 6,74 (1H, s), of 6.68 (1H, s), 4,71 (2H, s), equal to 1.82 (3H, s) ppm13C (CD3OD, 100 MHz): δ 172,49, 164,19, 143,87, 130,69, 129,37, 129,28, 124,41, 124,24, 122,14, 116,88, 46,64, 22,64 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 22,64; CH2carbon atoms: 46,64; CH carbon atoms: 130,69, 129,37, 129,28, 124,24, 116,88 ppm HPLC: 7,518 minutes

Example 69

Synthesis of 4-[(4-chlorpheniramine)methyl]-1H-pyrrole-2-carboxylic acid (188)

Synthesis of 4-[(4-chlorpheniramine)methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (187)

0,5052 g (to 3.02 mmol) of 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester is dissolved in 12.0 ml (0,25M) 5% solution of acetic acid in methanol. Add 4-Chloroaniline (0,4633 g, 3.63 mmol) and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes, then slowly add cyanoborohydride sodium (0,3013 g, 4,79 mmol) and the reaction mixture is allowed to mix at room temperature over night. Add approximately 5 ml of a saturated solution of K2CO3and the reaction mixture is extracted twice with ethyl acetate. The combined organic layers washed with saturated solution of NaHCO3(~6 ml)and saturated salt solution (~6 ml), then dried Na2SO4, filtered and concentrated in vacuo. The crude product is purified by chromatography on silica gel (Combiflash column, 85:15 hexane:ethyl acetate) and get 0,5806 g (69%) of 4-[(4-chlorpheniramine)methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (187) in the form of light yellowish-brown solid. Note: the starting material 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester has a retention time on HPLC=7,337 minutes HPLC: 8,543 minutes

Synthesis of 4-[(4-chlorpheniramine)methyl]-1H-pyrrole-2-carboxylic acid (188)

4-[(4-Chlorpheniramine)methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (187) (0,1070 g, 0.384 mmol) is weighed into a round bottom flask. Flask equipped with a stirrer, a refrigerator and a membrane and blow N2. The ester was dissolved in EtOH (0,85 ml, 0,45M) and then to a solution of ether was added with stirring their aqueous solution of NaOH (0,0432 g, 0,123 ml H2About). Immediately after the reaction flask is immersed in an oil bath heated to 85°C, and the reaction mixture is heated and stirred in an atmosphere of N2until completion of the reaction, which is recorded by means of HPLC (30 min). The solvent is removed on a rotary evaporator and add 0.8 ml H2O. the Aqueous layer was slowly and carefully acidified with 10% aqueous HCl solution. The product was then purified preparative HPLC with reversed phase (45:55 H2Oh, containing 0.05% TF is:CH 3CN containing 0.05% TFU) and get pure 4-[(4-chlorpheniramine)methyl]-1H-pyrrole-2-carboxylic acid (188).

1H (CD3OD, 400 MHz): δ for 7.12 (2H, d, J=8,4 Hz), 6,92 (1H, s), 6,85 (1H, s), to 6.95 (2H, d, J=8,4 Hz)to 4.16 (2H, s) ppm13C (CD3OD, 100 MHz): δ 164,24, 146,44, 129,96, 124,87, 124,15, 123,56, 122,98, 117,22, 116,24, 43,18 ppm DEPT (CD3OD, 100 MHz): CH2carbon atoms: 43,18; CH carbons: 129,96, 123,56, 117,22, 116,24 ppm HPLC: 7,137 minutes

Example 70

Synthesis of 4-[(acetyl(4-chlorophenyl)amino)methyl]-1H-pyrrole-2-carboxylic acid (190)

Synthesis of 4-[(acetyl(4-chlorophenyl)amino)methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (189)

4-[(4-Chlorpheniramine)methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (187) (0,2868 g of 1.03 mmol) is weighed into a flask with a volume of 10 ml. Flask equipped with a stirrer and a membrane and rinsed with nitrogen. The amine is dissolved in methylene chloride (2.6 ml, 0,4M) and then the flask was cooled to 0°C. Add N,N-diisopropylethylamine (0,1971 ml, 1.13 mmol), then stirred at 0°C. the solution through the syringe slowly add acetylchloride (0,0805 ml, 1.13 mmol). Then the reaction mixture was left to warm to room temperature. After completion of the reaction, detected by HPLC (90 min), the reaction mixture is diluted with methylene chloride and quenched with water. The organic phase is removed, washed with saturated salt solution, dried with Na2SO4the filter is t, and concentrated in vacuo. The crude product is purified by chromatography on silica gel (Combiflash column, 2:1 hexane:ethyl acetate) and get pure 4-[(acetyl(4-chlorophenyl)amino)methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (189, 0,2701 g, 82%) as a sticky white solid.

1H (CD3OD, 400 MHz): δ 11,25 (1H, Sirs), 7,35 (2H, d, J=8,4 Hz), 7,05 (2H, d, J=8,4 Hz), 6,76 (1H, s), 6,69 (1H, s), and 4.68 (2H, s), 4,22 (2H, q, J=7,1 Hz), is 1.81 (3H, s)of 1.29 (3H, t, J=7,1 Hz) ppm13C (CD3OD, 100 MHz): δ 172,17, 162,50, 142,39, 134,87, 130,94, 130,70, 124,46 and 124,30, 123,94, and 121,91 121,88, 116,64, 61,13, 46,43, 22,70, 14,75 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 22,70, 14,75; CH2carbon atoms: 61,13, 46,43; CH carbons: 130,94, 130,70, 124,46 and 124,30, 116,64 ppm HPLC: 9,247 minutes

Synthesis of 4-[(acetyl(4-chlorophenyl)amino)methyl]-1H-pyrrole-2-carboxylic acid (190)

4-[(Acetyl(4-chlorophenyl)amino)methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0,2701 g, 0,842 mmol) is weighed into a round bottom flask. Flask equipped with a stirrer, a refrigerator and a membrane and blow N2. The ester was dissolved in EtOH (of 1.87 ml, 0,45M) and then to a solution of ether was added with stirring their aqueous solution of NaOH (0,0943 g, 0.75 ml of H2About). Immediately after the reaction flask is immersed in an oil bath heated to 85°C, and the reaction mixture is heated and stirred in an atmosphere of N2until completion of the reaction, which is recorded by means of HPLC (11 min). The solvent is removed on a rotary COI is retele and add 1.6 ml of CH 2Cl2and 1.6 ml of H2O. the Aqueous layer was slowly and carefully acidified with 10% aqueous HCl solution. The product is released in the form of oil. The product is extracted from the aqueous layer with three portions of CH2Cl2, dried Na2SO4, filtered and concentrated in vacuo, obtaining pure 4-[(acetyl(4-chlorophenyl)amino)methyl]-1H-pyrrole-2-carboxylic acid (190, 0,2242 mg; 91%).

1H (CD3OD, 400 MHz): δ 11,14 (1H, Sirs), 7,38 (2H, d, J=8,4 Hz), 7,07 (2H, d, J=8,4 Hz), to 6.75 (1H, s), 6,69 (1H, s), 4,69 (2H, s), equal to 1.82 (3H, s) ppm13C(CD3OD, 100 MHz): δ 172,32, 164,16 and 164,13, 142,41, 134,98, 131,02, 130,74, 124,43, 124,27, 121,90 and 121,86, 116,85 and 116,81, 46,49, one-22.67 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: one-22.67; CH2carbon atoms: 46,49; CH carbons: 131,02, 130,74, 124,27 and 124,09, 116,85 and 116,81 ppm HPLC: 8,077 minutes

Example 71

Synthesis of 4-{[(4-chlorophenyl)methylamino]methyl]-1H-pyrrole-2-carboxylic acid (192)

Synthesis of 4-{[(4-chlorophenyl)methylamino]methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (191)

4-chloro-N-methylaniline (0,225 ml of 1.86 mmol) are added to stir at room temperature to a solution of 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester (0,2585 g, 1.55 mmol) in 5% acetic acid solution in methanol in an atmosphere of N2. After stirring at room temperature for 30 minutes add cyanoborohydride sodium (0,1585 g, 2,52 mmol) and the reaction mixture per mesilat at room temperature over night. Add approximately 3 ml of a saturated solution of K2CO3and the reaction mixture is extracted twice with ethyl acetate. The combined organic layers washed with saturated solution of NaHCO3(~4 ml) and saturated salt solution (~4 ml)then the combined organic layers are dried Na2SO4, filtered and concentrated in vacuo. The crude product is purified by chromatography on silica gel (Combiflash column, 85:15 hexane:ethyl acetate), obtaining 0,3419 g (76%) of 4-{[(4-chlorophenyl)methylamino]methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (191) in the form of light yellowish-brown solid. Note: the starting material 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester has a retention time on HPLC=7,337 minutes HPLC: 8,478 minutes

Synthesis of 4-{[(4-chlorophenyl)methylamino]methyl]-1H-pyrrole-2-carboxylic acid (192)

4-{[(4-Chlorophenyl)methylamino]methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (191) (0,3419 g at 1.17 mmol) is weighed into a round bottom flask. Flask equipped with a stirrer, a refrigerator and a membrane and blow N2. The ester was dissolved in EtOH (2.6 ml, 0,45M) and then to a solution of ether was added with stirring their aqueous solution of NaOH (0,1336 g, 1.0 ml H2About). Immediately after the reaction flask is immersed in an oil bath heated to 85°C, and the reaction mixture is heated and stirred in an atmosphere of N2on the completion of the reaction, which register using HPLC (15 min). The solvent is removed on a rotary evaporator and the crude product purified preparative HPLC with reversed phase (45:55 H2Oh, containing 0.05% TFU:CH3CN containing 0.05% TFU)to give pure 4-{[(4-chlorophenyl)methylamino]methyl]-1H-pyrrole-2-carboxylic acid (192).

1H(CD3OD, 400 MHz): δ 7,22 (2H, d, J=9,2 Hz), to 6.95 (2H, d, J=9,2 Hz), for 6.81 (1H, d, J=1.5 Hz), 6,70 (1H, d, J=1.5 Hz), 4,43 (2H, s)of 3.00 (3H, s) ppm Partial13C (CD3OD, 100 MHz): δ 130,12, 124,02, 117,99, 116,47, 52,37, 39,91 ppm DEPT (CD3OD, 100 MHz): CH3carbon atoms: 14, 48mm; CH2carbon atoms: 59,62, 23,41 and 23,39, 23,36 and 23,33, 23,16 and 23,13, 21,88 and 21,86; CH carbons: 118,74 and 118,55 ppm

Example 72

Synthesis of 4-benzyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (198)

Synthesis of 4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid methyl ester (193)

A solution of 4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carbonitrile (4.5 g, 28.1 mmol, obtained according to the method described in Synth. Comm. 1995, 25, 507-514) in methanol saturated with gaseous HCl (200 ml) is heated at boiling under reflux for 6 days. The solvent is removed in vacuum. The NMR analysis shows that the obtained product (3.5 g) is a blend of 65/35 target of ether and the original substances. This mixture is used to the comfort to the next stage without additional purification.

Synthesis of 4-oxo-1-(2-trimethylsilylethynyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid diethyl ester (194)

A solution of ester (500 mg, 2.6 mmol) in DMF (3 ml) is added to a chilled (0°C) suspension of sodium hydride (114 mg, 60% in oil, 2.8 mmol) in DMF (2 ml). After 10 minutes add the SEM-Cl (550 μl, 3.1 mmol). The mixture is then stirred at room temperature for 2 h, then poured into ice water and extracted with ethyl acetate. After concentrating obtain the target compound in the form of crude oil (930 mg).

1H NMR (CDCl3, 400 MHz): δ 7,27 ( 1H, s), 5,78 (2H, s), 3,61 (2H, m)to 2.94 (2H, m)of 2.50 (2H, m)to 2.18 (2H, m)to 0.92 (2H, m) ppm

LC/MS:60%

Synthesis of 4-benzylidene-1-(2-trimethylsilylethynyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid methyl ester (195)

A solution of the protected ester (900 mg, 2,78 mmol) in dry THF (7 ml) are added to a solution of benzylmagnesium (3.4 ml, 2M in THF, 6.8 mmol) in THF (10 ml). The reaction mixture is allowed to stand for 2 h at room temperature, after which add more a certain amount of benzylacrylamide (1.7 ml, 2M in THF, 3.4 mmol). The mixture is then heated at the boil under reflux for 1 night. Then water is added and the reaction mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over Na2SO4and concentrate under reduced giving the situation, getting listed in the title compound (900 mg). LC/MS: 50%, m/z=397 g/mol.

Synthesis of 4-benzylidene-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid methyl ester (196)

To a solution of ester (900 mg, and 2.26 mmol) in THF cooled (0°C) for 5 min add tetrabutylammonium fluoride (23 ml, 1M in THF, 23 mmol). Then the reaction mixture is heated for 4 hours at 80°C. After 48 h at room temperature the reaction mixture is partitioned between ether and water. The organic layer is dried over MgSO4and concentrate under reduced pressure, obtaining mentioned in the title compound in crude form. After chromatography on silica gel (eluent cyclohexane/cOEt:80/20) get pure starting material (100 mg) and the corresponding nitrile with remote protective groups (80 mg). Clean air, still containing protective group (100 mg, 0.25 mmol) is mixed with TBAF (750 μl, 0.75 mol). THF is removed in vacuo. After concentrating the reaction mixture is heated with Ethylenediamine (0.25 ml) in DMF (1 ml) for 16 hours After preconcentration get mentioned in the title compound as an oil (80 mg). LC/MS: 76%, m/z=267 g/mol.

Synthesis of 4-benzyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid methyl ester (197)

A saturated solution of ester derived hydronaut at normal pressure over Pd in EtOH for 3 h the Catalyst was removed by filtration and actuarial evaporated under reduced pressure, getting listed in the title compound which is purified by chromatography on silica gel (eluent cyclohexane/CH2Cl2: 50/50). Yield: 20 mg LC/MS: 60%, m/z=269 g/mol.

Synthesis of 4-benzyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (198)

Their aqueous solution of NaOH (1M in H2O, 0.8 ml, 0.8 mmol) is added at room temperature to a stirred solution of the ester (20 mg, 0.08 mmol) in EtOH (5 ml). The reaction mixture is heated at 80°C until completion of the reaction, detected by TLC. The product is extracted with Et2O, and then the aqueous layer was acidified (pH=1)by adding dropwise a 10% aqueous solution of HCl. The solid is filtered off and washed with water. The solid is dried in vacuum over night, getting mentioned in the title compound (19 mg).

1H NMR (CDCl3, 400 MHz): δ 8,8 (1H, Sirs), 7,3-7,33 (2H, m), 7,2-7,26 (3H, m), for 6.81 (1H, s)to 3.09 (1H, DD), 2,9 (1H, m), 2,55-to 2.65 (3H, m), 1,9-2,0 (1H, m), 1,6-1,8 (2H, m), to 1.3-1.4 (1H, m), LC/MS: 89%, m/z=255 g/mol.

1. The compound of formula IA, or pharmaceutically acceptable salt or MES

where R1aand R2aindependently selected from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5;
X and Y independently selected from O and (CR6R7)n;
R3denotes hydrogen, alkyl or M;
M represents an ion selected from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or aspesi;
Z represents CR4;
R4selected from hydrogen, halogen, alkyl, alkylaryl and XYR5;
R5selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R6and R7independently selected from hydrogen and alkyl;
n denotes an integer from 1 to 6;
at least one of R1aand R2ameans XYR5;
at least one of X and Y denotes (CR6R7)n.

2. The compound according to claim 1, where R3denotes hydrogen.

3. The compound according to claim 1, where R1adenotes hydrogen, a R2ameans XYR5.

4. The compound according to claim 3, where X and Y denote CR6R7.

5. The compound according to claim 3, where R5denotes a substituted aryl.

6. The compound according to claim 4, where R6and R7denote hydrogen.

7. The compound according to claim 1, where the compound is selected from


and

8. The compound according to claim 1, where the connection is a

9. Method of increasing concentrations of D-serine and/or reduce the concentration of toxic oxidation products of D-serine under the action of DAAO in a mammal, comprising administration to the subject a therapeutically effective amount of the compounds of formula I or its farmaceuticas is acceptable salt or MES

where R1and R2independently selected from hydrogen, halogen, nitro, alkyl, alkylaryl, and XYR5;
X and Y independently selected from O and (CR6R7)n;
R3denotes hydrogen, alkyl or M;
M represents an ion selected from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof;
Z represents CR4;
R4selected from hydrogen, halogen, alkyl, alkylaryl and XYR5;
R5selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R6and R7independently selected from hydrogen and alkyl;
n denotes an integer from 1 to 6;
at least one of R1and R2means XYR5;
at least one of X and Y denotes (CR6R7)n.

10. Method for the treatment of schizophrenia, treatment, or prevention of loss of memory and/or cognition associated with Alzheimer's disease, treatment of ataxia or preventing loss of neuronal function characteristic of neurodegenerative diseases, comprising the administration to a subject in need, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt or MES

where R1and R2independently selected from hydrogen, halogen, nitro, alkyl, alkylaryl, and XYR5 ;
X and Y independently selected from O and (CR6R7)n;
R3denotes hydrogen, alkyl or M;
M represents an ion selected from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof;
Z represents CR4;
R4selected from hydrogen, halogen, alkyl, alkylaryl and XYR5;
R5selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R6and R7independently selected from hydrogen and alkyl;
n denotes an integer from 1 to 6;
at least one of R1and R2means XYR5;
at least one of X and Y denotes (CR6R7)n.

11. Method for improving learning ability, memory and/or cognitive abilities, including introduction to the subject in need, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt or MES

where R1and R2independently selected from hydrogen, halogen, nitro, alkyl, alkylaryl, and XYR5;
X and Y independently selected from O and (CR6R7)n;
R3denotes hydrogen, alkyl or M;
M represents an ion selected from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof;
Z represents CR4;
R4selected from hydrogen, halogen, alkyl, alkylaryl and XYR ;
R5selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R6and R7independently selected from hydrogen and alkyl;
n denotes an integer from 1 to 6;
at least one of R1and R2means XYR5;
at least one of X and Y denotes (CR6R7)n.

12. A method of treating neuropathic pain comprising the administration to a subject in need, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt or MES

where R1and R2independently selected from hydrogen, halogen, nitro, alkyl, alkylaryl, and XYR5;
X and Y independently selected from O and (CR6R7)n;
R3denotes hydrogen, alkyl or M;
M represents an ion selected from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof;
Z represents CR4;
R4selected from hydrogen, halogen, alkyl, alkylaryl and XYR5;
R5selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R6and R7independently selected from hydrogen and alkyl;
n denotes an integer from 1 to 6;
at least one of R1and R2means XYR5;
at least one of X and Y denotes (CR6R7)n.

13. The way in which the yubom of PP-12, where R3denotes hydrogen.

14. The method according to any of PP-12, where n denotes 1 or 2.

15. The method according to any of PP-12, where X and Y denote (CR6R7)na n denotes 1.

16. The method according to any of PP-12, where R6and R7denote hydrogen.

17. The method according to any of PP-12, where R1denotes hydrogen, and R2means XYR5.

18. The method according to any of PP-12, where the compound of formula I selected from

and

19. The method according to any of PP-12, where the compound of formula I is a

20. Pharmaceutical composition having DAAO inhibitory activity containing a compound of formula I and a pharmaceutically acceptable carrier

where R1and R2independently selected from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5;
X and Y independently selected from O and (CR6R7)n;
R3denotes hydrogen, alkyl or M;
M represents an ion selected from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof;
Z represents CR4;
R4selected from hydrogen, halogen, alkyl, alkylaryl and XYR5;
R5selected from aryl, substituted aryl, and g is tetraaryl and substituted heteroaryl;
R6and R7independently selected from hydrogen and alkyl;
n denotes an integer from 1 to 6;
at least one of R1and R2means XYR5;
at least one of X and Y denotes (CR6R7)n.

21. The pharmaceutical composition according to claim 20, where R3denotes hydrogen.

22. The pharmaceutical composition according to claim 20, where n denotes 1 or 2.

23. The pharmaceutical composition according to claim 20, where X and Y denote (CR6R7)na n denotes 1.

24. The pharmaceutical composition according to claim 20, R6and R7denote hydrogen.

25. The pharmaceutical composition according to claim 20, where R1denotes hydrogen.

26. The pharmaceutical composition according to claim 20, where the compound of formula I selected from

and

27. The pharmaceutical composition according to claim 20, where the compound of formula I is a



 

Same patents:

FIELD: pharmacology.

SUBSTANCE: invention relates to novel compounds - tetrahydronaphthyridine derivatives of formula (I) or their pharmaceutically acceptable salts, where R1 represents C1-6alkoxycarbonyl group optionally substituted with 1-5 substituents, etc; R2 represents C1-6alkyl group; R3 represents hydrogen or and all; R4 represents C1-4alkylene group; R5 represents optionally substituted unsaturated 5-8-member heterocyclic group containing 1-4 heteroatoms independently selected from oxygen and nitrogen atoms; R6, R7 and R8 represent independently hydrogen atom, hydroxygroup, cyanogroup, C1-6alkyl group, C1-6alkoxygroup, mono- or di- C1-6alkylcarbamoyl group or mono- or di- C1-6alkylaminogroup, optionally substituted with 1-6 substituents independently selected from halogen atom, C1-6alkoxygroup and aminogroup; R10 represents optionally substituted with 1-2 substituents phenyl group; which possess inhibiting activity with respect to cholesteryl ester transfer protein (CETP).

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

FIELD: chemistry; pharmacology.

SUBSTANCE: invention refers to new quinazoline derivative or its pharmaceutically acceptable acid-additive salt. Quinazoline derivative is described with general formula (I): , where Z is NH; m is 2; the first R1 group located in 5th position is chosen from isopropoxy and tetrahydropyran-4-yloxy; the second R1 group located in 7th position is chosen from ethoxy or propoxy substituted with chlorine or certain substituted or unsubstituted heterocycles containing at least one or two N atoms and at least one O atom together with N atom; n is 0 or 1; R3 group located in 5th or 6th position of 2,3-methylenedioxypyridine-4-yl group, is chosen from Cl or Br. Besides, there is disclosed pharmaceutical composition used as antiinvasive agent to control distribution and/or treat solid cancer, containing this quinazoline derivatives combined with pharmaceutically acceptable diluent or carrier. Declared quinazoline derivatives possess considerable antineoplastic action ensured with effective inhibition of one or more nonreceptor protein kinases, specific to tyrosine, referring to Src linase family.

EFFECT: treatment of cancer in homoiotherms and human.

11 cl, 2 tbl, 22 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new annelated asaheterocycles include pyrimidine fragment of general formula I in the form of free bases or pharmaceutically acceptable salts. Compounds of this invention possess properties of PI3 kinase inhibitors. In general formula I X represents oxygen atom or sulphur atom; Z represents oxygen atom, R1 represents hydrogen atom or optionally substituted C1-C6alkyl, or Z represents nitrogen atom together with bound carbon atom forming through Z and R1 optionally substituted annelated imidazoline cycle; R2 represents optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, possibly annelated with 5-6-term heterocyclyl containing heteroatoms chosen from oxygen and nitrogen, optionally substituted 5-6-term heterocyclyl containing heteroatoms chosen from nitrogen, oxygen and/or sulphur, possibly annelated with phenyl ring. Invention also concerns method of production of compounds, pharmaceutical compositions and medical products.

EFFECT: effective application for preparation of medical products for oncologic therapy.

14 cl, 3 dwg, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: in general formula I

R1 is phenyl or 5-6-member heterocycle, containing one N atom and/or one O atom; R2 is imidazole or annelated imidazole, selected from group, including a), b), c), d) and e); and R3 stands for hydrogen, phenyl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, benzo[b]thiophen-3-yl, 3-methylbenzo[b] thiophen-2-yl, thiophen-2-yl or thiophen-2-ylmethyl, R4 is hydrogen or lower alkyl, R5 is hydrogen, lower alkyl, halogen, morpholinyl, -NR'R", piperydinyl, optionally substituted with hydroxy-group, or is pyrrolidin-1-yl; R6 is hydrogen or -(CH2)nO-lower alkyl, R7 is hydrogen, -C(O)O-lower alkyl, -C(O)-C6H4-halogen, -C(O)-C6H4-lower alkyl, -C(O)-lower alkyl, -C(O)-cycloalkyl, -C(O)-NR'R", -C(O)-(CH2)nO-lower alkyl, -S(O)2-lower alkyl, -(CH2)nO-lower alkyl, -C(O)-pyridin-4-yl, whose ring can contain as substituents lower alkyl, halogen-lower alkyl or pyrrolidin-1-ylmethyl or is -(CH2)n-C(O)-NR'R"; R'/R" independently on each other stand for hydrogen, lower alkyl or -(CH2)n-tetrahydropyran-4-yl, X is -CH2-, -NR'''- or -O-; R''' is hydrogen, -C(O)-lower alkyl, -C(O)O-lower alkyl, -C(O)-C6H4CH3 or benzyl; n is 1 or 2.

EFFECT: increase of composition and treatment method efficiency.

14 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of formula (I) as well as to synthesis procedure and application for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis where R1-R11, t, X, Y, Z and n have values specified in the description.

EFFECT: production of macrocyclic compounds used for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis.

41 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

The invention relates to new compounds of the formula (I), where a represents the group CH2or atom That denotes H or halogen, D is CH2, OCH2, NHCH2CH2CH2, R denotes phenyl, benzothiazolyl, indolyl, indazoles, purinol, pyridyl, pyrimidyl, thiophenyl, each of these groups may be substituted or unsubstituted

The invention relates to new tricyclic pyrazole derivative or its pharmaceutically acceptable salt

The invention relates to tricyclic pyrazole derivative of the General formula I, where R1-R4denote hydrogen, halogen, lower alkyl or lower alkoxy; R5denotes lower alkyl; R6denotes hydrogen, lower alkyl or lower alkoxy; X represents -(CR7R8)nor-CH=CH-; R7and R8represent hydrogen or lower alkyl and n = 1 or 2, or pharmaceutically applicable salts of basic compounds of General formula (I)

The invention relates to 3-oxo-propanenitrile derived condensed pyrazole, method of production thereof and to pharmaceutical compositions containing them

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 represents halogen atom; R2 represents halogen atom; R3 represents (C1-C4)-alkyl; X represents nitrogen atom (N) or -CH; n = 0-3 under condition that when X represents -CH then n= 1 at least. Also, invention relates to novel compounds of the formula (II): wherein R1 represents halogen atom; R2 represents halogen atom; R3 represents hydrogen atom (H) or (C1-C4)-alkyl; X represents N or -CH; n = 0-3 under condition that when X represents -CH then n = 1 at least. Also, invention relates to a method for synthesis of compound of the formula (I), a method for synthesis of compound of the formula (II) and to a method for synthesis of compound of the formula (III) given in the invention description. Also, invention describes intermediate compounds of the formula (4) given in the invention description. Invention provides synthesis of novel biologically active compounds that can be used as insecticides, and a method for their synthesis.

EFFECT: valuable properties of compounds.

24 cl, 3 tbl, 19 ex

Up!