Novel 2-heteroaryl-substituted benzothiophenes and benzofurans 709

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2-heteroaryl-substituted benzothiophene and benzofuran, precursors thereof and therapeutic use of said compounds, having structural formula (1a) where R1, R2, X9 and Q assume values given in the description, and pharmaceutically acceptable salts thereof, which are suitable for imaging amyloid deposits in living patients. The invention also relates to pharmaceutical compositions based on compounds of formula 1a, use and methods of producing said compounds. More specifically, the present invention relates to a method of imaging brain amyloid deposits in vivo for intravital diagnosis of Alzheimer's disease, and measuring clinical efficiency of therapeutic agents against Alzheimer's disease.

EFFECT: high efficiency of using said compounds.

15 cl, 1 tbl, 14 ex

 

The invention relates to new 2-heteroaryl-substituted derivatives of benzothiophene and benzofuran and therapeutic applications of these compounds. Moreover, this invention relates to new 2-heteroaryl-substituted derivatives of benzothiophene and benzofuran that are suitable for imaging amyloid deposits in living patients, their compositions, methods of use and methods of producing such compounds. More specifically the present invention relates to a method of imaging amyloid deposits in the brain in vivo for in vivo diagnosis of Alzheimer's disease, and measuring the clinical effectiveness of therapeutic agents against Alzheimer's disease.

Prior art

Amyloidosis is a progressive, incurable metabolic disorder with an unknown cause, characterized by abnormal deposits of protein in one or more than one organ or system of the body. Amyloid proteins are produced, for example, bone marrow with impaired function. Amyloidosis, which occurs when the accumulation of amyloid deposits, disrupts the normal functions of the body, can cause lesions or death. This disease is rare, occurring in approximately eight out of every 1,000,000 people. It affects men and women equally in the th least and usually develops after the age of 40 years. Were identified at least 15 types of amyloidosis. Each of them is associated with deposits of different kinds of proteins.

The main forms are the primary systemic amyloidosis, secondary and familial or hereditary amyloidosis. There is also another form of amyloidosis associated with Alzheimer's disease. Primary systemic amyloidosis usually develops between the ages of 50 and 60 years. Among the approximately 2000 annually diagnosed new cases of primary systemic amyloidosis is the most common form of this disease in the United States. Being also known as amyloidosis associated with light chains, it can occur even in Association with multiple myeloma (cancer of bone marrow). Secondary amyloidosis is the result of chronic infection or inflammatory disease. It is often associated with hereditary Mediterranean fever (bacterial infection characterized by fever, weakness, headache and recurrent fever), a granulomatous eleita (inflammation of the small intestine), Hodgkin's disease, leprosy, osteomyelitis, and rheumatoid arthritis.

Familial or hereditary amyloidosis is the only inherited form of this disease. He meets members of the majority ethnic groups, and each semester is ustwo has a specific pattern of symptoms and the involvement of the authorities. Hereditary amyloidosis is an autosomal dominant, which means that only one copy of the defective gene is needed to cause the disease. The child of a parent with hereditary amyloidosis is a disease risk 50 to 50.

Amyloidosis can affect any organ or system in the body. Heart, kidneys, gastrointestinal system and nervous system are affected most often. Other common areas of accumulation of amyloid include the brain, joints, liver, spleen, pancreas, respiratory system and skin.

Alzheimer's disease (AD) is the most common form of dementia, a neurologic disease characterized by loss of mental abilities severe enough to interfere with normal activities of daily living, lasting at least six months and is not present at birth. BA usually occurs in old age and is accompanied by a decline in cognitive functions such as learning, reasoning and planning.

From two and up to four million Americans have AD, and it is expected that this number will increase to 14 million by the middle of the 21st century as the aging population in General. Though at the age of 40-50 years, this disease develops in a small number of people, BA predominantly affects the elderly. BA porage is approximately 3% of the total population aged 65 to 74 years, approximately 20% aged 75 to 84 years and approximately 50% over the age of 85 years. BA occurs in women more often than men, even taking into account the fact that women tend to live longer, so in the most susceptible age groups more women.

The accumulation of amyloid β-peptide in the brain is a pathological hallmark of all forms of BA. It is generally accepted that the deposition of cerebral amyloid β-peptide is a primary factor in the pathogenesis of AD (Hardy J and D.J. Selkoe, Science. 297: 353-356, 2002).

Methods of imaging, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), effective in monitoring the accumulation of amyloid deposits in the brain and their correlation with progression BA (Shoghi-Jadid et al. The American journal of geriatric psychiatry 2002, 10, 24; Miller, Science, 2006, 313, 1376; Coimbra et al. Curr. Top. Med. Chem. 2006, 6, 629; Nordberg, Lancet Neurol. 2004, 3, 519). The application of these techniques requires the development of radio, which easily penetrate into the brain and selectively associated with amyloid deposits in vivo.

There is a need for such compounds bind to amyloids, which can cross the blood-brain barrier and, therefore, can be used in diagnosis. Moreover, significant is the possibility of monitoring the effectiveness of treatment, recip is imago patients with BA, by measuring the effect of the specified treatment by determining the change in the level of medical literature plaques.

The properties of the detected binding amyloid compounds of particular interest include, in addition to the high affinity to amyloid deposits in vivo and high level and the rate of supply to the brain, low nonspecific binding to normal tissue and rapid elimination from it. These properties usually depend on the lipophilicity of the compound (Coimbra et al. Curr. Top. Med. Chem. 2006, 6, 629). Among the proposed small molecules for imaging amyloid plaques were synthesized some have potential applicability uncharged analogues of thioflavin T (Mathis et al. J. Med. Chem. 2003, 46, 2740). There are reports of different isothermic the heterocycles as potential binding amyloid ligands (Cai et al. J. Med. Chem. 2004, 47, 2208; Kung et al. J. Med. Chem. 2003, 46, 237). The previously described derivatives benzofuran for use as agents of imaging amyloid (Ono et al. J. Med. Chem. 2006, 49, 2725; Lockhart et al. J. Biol. Chem. 2005, 280(9), 7677; Kung et al. Nuclear Med. Biol. 2002, 29(6), 633; WO 2003051859) and for use in preventing aggregation of a-beta (Twyman et al. Tetrahedron Lett. 1999, 40(52), 9383; Hewlett et al. Biochemical Journal, 1999, 340(1), 283; Choi et al. Archives of Pharmacal Research, 2004, 27(1), 19; Twyman et al. Bioorg. Med. Chem. Lett. 2001, 11(2), 255; WO 9517095).

Previously described derivatives benzothiophene for use as agents of imaging amyloid is in (Chang et al. Nuclear Medicine and Biology, 2006, 33, 811) and for use as neuroprotective agents from the toxicity of β-amyloid (JP 11116476). There is a need for improved compounds for obtaining the ratio of signal and noise, high enough for detailed detection of amyloid deposits in all parts of the brain for increased reliability of quantitative research load amyloid plaques in connection with medical treatment. In the present invention proposed new 2-heteroaryl-substituted derivatives of benzothiophene and benzofuran for use as agents of imaging amyloid and treatment of diseases associated with amyloid.

Description of the invention

The proposed compounds of formula (Ia):

,

where R1 is selected from H, halogen, methyl,1-5foralkyl, groups C1-3alkylene1-3alkyl, C1-3alkylene1-3foralkyl,1-3N2C1-3N1-3alkyl, C1-3N(C1-3alkyl)2With1-3N1-3foralkyl,1-3N(C1-3foralkyl)2With1-3N(C1-3alkyl)1-3foralkyl, hydroxy, methoxy,1-5feralcode,1-5alkylthio,1-5coralcalcium, amino, NHC1-3alkyl, NHC1-3foralkyl, N(C1-3alkyl)2N(C1-3alkyl)1-3FPO is alkyl, NH(CO)1-3alkyl, NH(CO)1-3foralkyl, NH(CO)1-3alkoxy, NH(CO)1-3feralcode, NHSO2C1-3alkyl, NHSO2C1-3foralkyl, (CO)1-3alkyl, (CO)1-3foralkyl, (CO)C1-3alkoxy, (CO)1-3feralcode, (CO)NH2, (CO)NHC1-3alkyl, (CO)NHC1-3foralkyl, (CO)N(C1-3alkyl)2, (CO)N(C1-3alkyl)1-3foralkyl, (CO)N(C4-6alkylene), (CO)N(C4-6peralkaline), cyano, SO2NHC1-3foralkyl, nitro and SO2NH2;

R2 is selected from H, halogen, methyl,1-5foralkyl, groups C1-3alkylene1-3alkyl, C1-3alkylene1-3foralkyl,1-3N2C1-3N1-3alkyl, C1-3N(C1-3alkyl)2With1-3N1-3foralkyl,1-3N(C1-3foralkyl)2With1-3N(C1-3alkyl)1-3foralkyl, hydroxy, methoxy,1-5feralcode,1-5alkylthio,1-5coralcalcium, amino, NHC1-3alkyl, NHC1-3foralkyl, N(C1-3alkyl)2N(C1-3alkyl)1-3foralkyl, NH(CO)1-3alkyl, NH(CO)1-3foralkyl, NH(CO)1-3alkoxy, NH(CO)1-3feralcode, NHSO2C1-3alkyl, NHSO2C1-3foralkyl, (CO)1-3alkyl, (CO)1-3foralkyl, (CO)C1-3alkoxy, (CO)1-3feralcode, (CO)NH21-3alkyl, (CO)NHC1-3foralkyl, (CO)N(C1-3alkyl)2, (CO)N(C1-3alkyl)1-3foralkyl, (CO)N(C4-6alkylene), (CO)N(C4-6peralkaline), cyano, SO2NHC1-3foralkyl, nitro and SO2NH2; or

R1 and R2 together form a ring

;

X9selected from O and S;

Q represents a nitrogen-containing aromatic heterocycle selected from Q1-Q10:

where Q2 represents a 6-membered aromatic heterocycle containing one or two atoms of N, where X1, X2, X3and X4independently selected from N or S; and where one or two of X1, X2, X3and X4is(are) a N, and the rest are With, and where the atom X1represents s, and the specified substituted With R4; and where the atom X2represents s, and the specified substituted With R5;

R3 is selected from methoxy,1-4feralcode, amino, NHC groups1-3alkyl, NHC1-3foralkyl, N(C1-3alkyl)2N(C1-3alkyl)1-3foralkyl, NH(CO)1-3alkyl, NH(CO)sub> 1-3foralkyl, NH(CO)G2, (CO)NH2, (CO)1-3alkoxy, methylthio, C1-6coralcalcium, SO2NH2N(C4-6alkylen) and G1:

;

X5selected from Oh, NH, groups NC1-3alkyl and N(CO)O-tert-butyl;

G2 represents a phenyl or 5 - or 6-membered aromatic heterocycle, possibly substituted by one Deputy, selected from fluorine, C1-3alkoxy, C1-3feralcode and iodo;

R4 is selected from H, halogeno;

R5 is selected from H, fluorescent, bromo and iodo;

R6 is selected from H, methyl and (CH2)0-4CH2F;

one or more of its constituent atoms may represent the detected isotope;

in the form of free base or its pharmaceutically acceptable salt, MES or MES salt;

provided that the following compounds are excluded:

.

In one aspect of the compounds of formula (Ia)where R4 is selected from H, fluorescent, bromo and iodo.

In another aspect of the proposed compounds of formula (Ia), where R1 is selected from H, halogen, methyl,1-5foralkyl, hydroxy, methoxy,1-5feralcode, methylthio,1-5coralcalcium, amino, groups NH, NHC1-3foralkyl, N(CH3)CH3N(C1-3alkyl)1-3foralkyl, NH(CO)1-3alkyl, NH(CO)C1-3foralkyl, NH(CO)1-3alkoxy, NH(CO)1-3feralcode, NHSO2C1-3alkyl, NHSO2C1-3foralkyl, (CO)1-3foralkyl, (CO)1-3alkoxy, (CO)C1-3feralcode, (CO)NH2, (CO)NHC1-3foralkyl, cyano, SO2NHC1-3foralkyl, nitro and SO2NH2; or

R1 and R2 together form a number of the TSO:

.

In another aspect of the proposed compounds of formula (Ia), where R1 is selected from H, fluorescent, iodo, methyl,1-5foralkyl, hydroxy, methoxy, cyano, C1-5feralcode, methylthio, amino, groups, NH-methyl, NHC1-3foralkyl, NH(CO)C1-3alkyl, NH(CO)1-3foralkyl, NH(CO)1-3feralcode, (CO)1-3alkoxy and (CO)NH2.

In another aspect of the proposed compounds of formula (Ia), where R1 is selected from H, hydroxy and methoxy.

In another aspect of the proposed compounds of formula (Ia)where R2 is selected from H, fluorescent, iodo, With1-5foralkyl, hydroxy, methoxy, (CO)NH2, cyano and methylthio.

In another aspect of the proposed compounds of formula (Ia)where R2 is selected from H, fluorescent, hydroxy and methoxy.

In another aspect of the proposed compounds of formula (Ia)where R2 represents N.

In another aspect of the proposed compounds of formula (Ia), where Q represents Q1.

In another aspect of the proposed compounds of formula (Ia), where Q is a Q2.

In another aspect of the proposed compounds of formula (Ia), where Q is selected from Q3-Q10.

In another aspect of the proposed compounds of formula (Ia), where Q2 represents a pyridine ring, where X3and X4independently selected from N or s and where one of X3and X4represents N and the other of X1, X2, X3and X4represent C.

2and X4are N and where X1and X3represent C.

In another aspect of the proposed compounds of formula (Ia), where Q2 represents a pyrimidine ring, where X1and X3are N and where X2and X4represent C.

In another aspect of the proposed compounds of formula (Ia), where Q2 is pyridazinone ring, where X3and X4are N and where X1and X2represent C.

In another aspect of the proposed compounds of formula (Ia), where Q2 is pyrazinone ring, where X1and X4are N and where X2and X3are C; or where X1and X4are With, and where X2and X3represent N.

In another aspect of the proposed compounds of formula (Ia), where R3 is selected from methoxy,1-4feralcode, amino, NHC groups1-3alkyl, NHC1-3foralkyl, N(C1-3alkyl)2N(C1-3alkyl)1-3foralkyl, NH(CO)1-3alkyl, NH(CO)1-3foralkyl, (CO)NH2, (CO)1-3alkoxy, methylthio, C1-6coralcalcium, SO2NH2and G1; where X5selected from O, NH and N-methyl.

In another aspect of the proposed compounds of formula (Ia), where R3 is selected from amino, NH-methyl, and (CO)NH2.

p> In another aspect of the proposed compounds of formula (Ia)where R4 is selected from H, fluorescent.

In another aspect of the proposed compounds of formula (Ia)where R4 represents N.

In another aspect of the proposed compounds of formula (Ia)where R4 is a fluorescent.

In another aspect of the proposed compounds of formula (Ia)wherein R5 is selected from H, fluorescent.

In another aspect of the proposed compounds of formula (Ia)wherein R5 represents N.

In another aspect of the proposed compounds of formula (Ia)wherein R5 is a fluorescent.

In another aspect of the proposed compounds of formula (Ia), where R6 is selected from H and methyl.

In another aspect of the proposed compounds of formula (Ia), where R6 represents N.

In another aspect of the proposed compounds of formula (Ia), where R6 represents methyl.

In another aspect of the proposed compounds of formula (Ia)represents:

2-[6-(methylamino)pyridine-3-yl]-1-benzofuran-5-ol
5-(5-methoxy-1-benzofuran-2-yl)pyridine-2-carboxamide

6-(5-hydroxy-1-benzofuran-2-yl)Niko is inamed
5-(5-hydroxy-1-benzofuran-2-yl)pyridine-2-carboxamide
5-(5-methoxy-1-benzofuran-2-yl)-N-methylpyridin-2-amine
6-(5-methoxy-1-benzofuran-2-yl)pyridazin-3-amine
2-(1-benzofuran-2-yl)-6-methoxyimino[1,2-a]pyridine
5-(1-benzothieno-2-yl)pyridine-2-carboxamide
5-(1-benzofuran-2-yl)pyridine-2-carboxamide
6-(5-methoxy-1-benzofuran-2-yl)nicotinamide
2-(6-aminopyridin-3-yl)-1-benzofuran-5-ol.

In another aspect of the proposed compounds of formula (Ia)represents:

2-(2-fluoro-6-methylamino-pyridine-3-yl)-benzofuro the-5-ol
2-(6-fluoro-5-methylamino-pyridine-2-yl)-benzofuran-5-ol
2-(5-fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol.

In another aspect of the proposed connection, where from one to six of its constituent atoms is(are) a detected isotope3H, or anywhere from one to three of its constituent atoms is(are) a detected isotope13With or where one of the constituent atoms represents the detected isotope selected from the18F,11C,75Br,76Br,120I123I125I131I and14C, and the connection specified is chosen from:

.

In one of the embodiments of this aspect one of its constituent atoms represents the detected isotope11C. In yet another embodiment of this aspect one of its constituent atoms represents the detected isotope18F.

In another aspect of the proposed compounds of formula (Ia), where one or more than one atom of the molecule represents the detected isotope.

In another aspect of the proposed compounds of formula (Ia), where from one to six of its constituent atoms is(are) a detected isotope3H, or anywhere from one to three of its constituent atoms is(are) a detected isotope selected from the19F and13With or where one of the constituent atoms represents detective the initial isotope, selected from the18F,11C,75Br,76Br,120I123I125I131I and14C.

In another aspect of the proposed compounds of formula (Ia), where from one to six of its constituent atoms is(are) a detected isotope3H, or anywhere from one to three of its constituent atoms is(are) a detected isotope19F, or where one of the constituent atoms represents the detected isotope selected from the18F,11C and123I.

In another aspect of the proposed compounds of formula (Ia), where from one to six of its constituent atoms is(are) a detected isotope3N, or anywhere from one to three of its constituent atoms is(are) a detected isotope19F, or where one of the constituent atoms represents the detected isotope selected from the18F and11C.

In another aspect of the proposed compounds of formula (Ia), where one of its constituent atoms represents the detected isotope11C.

In another aspect of the proposed compounds of formula (Ia), where one of its constituent atoms represents the detected isotope18F.

In another aspect of the proposed compounds of formula Ib:

,

where Z represents clanny aromatic heterocycle, containing one or two atoms(a) N, where X6, X7and X8independently selected from N or s and where one or two of X6X7and X8is(are) a N, and the rest(s) is(are) themselves, and where X6is, moreover, indicated With possibly substituted by R9;

X10selected from O and S;

R8 is selected from OSi(G3)3, OCH2G4, OG5, H, bromo, fluorescent, hydroxy, methoxy, Sn(C1-4alkyl)3N(CH3)3+, IG6+N2+and nitro;

R9 is selected from H, bromo, fluorescent, Sn(C1-4alkyl)3N(CH3)3+, IG6+N2+and nitro;

R10 selected from amino, methylamino, NH(CH2)2-4G7, dimethylamino, methoxy, hydroxy, (CO)NH2and O(CH2)2-4G7;

R11 is selected from OSi(G3)3, OCH2G4, OG5, H, bromo, fluorescent, hydroxy, methoxy, Sn(C1-4alkyl)3N(CH3)3+, IG6+N2+and nitro;

G3 is selected from C1-4the alkyl and phenyl;

G4 is selected from 2-(trimethylsilyl)ethoxy, C1-3alkoxy, 2-(C1-3alkoxy)ethoxy, C1-3alkylthio, cyclopropyl, vinyl, phenyl, para-methoxyphenyl, ortho-nitrophenyl and 9-Anttila;

G5 is selected from tetrahydropyranyl, 1-ethoxyethyl, Fenella, 4-bratinella, cyclohexyl, tert-butyl, tert-butoxycarbonyl, 2,2,2-trichlorethylene and triphenylmethyl;

IG6+ represents a part of idoneous salt, in which the iodine atom is hypervalency and has a positive formal charge and in which G6 is a phenyl, possibly substituted by one Deputy, selected from methyl and bromo;

G7 is selected from bromo, iodo, OSO2CF3, OSO2CH3and OSO group2phenyl, and specified phenyl possibly substituted by stands or bromo;

with reference to formula Ib, one or more substituents selected from R8, R9, R10 and R11 is(are) one of the functional groups selected from bromo, fluorescent, hydroxy, Sn(C1-4alkyl)3N(CH3)3+, IG6+N2+, nitro, amino, methylamino, NH(CH2)2-4G7;

in the form of free base or its salt, MES or MES salt;

provided that the following compounds are excluded:

.

In another aspect of the proposed compounds of formula Ib, where X7is, moreover, indicated With possibly substituted by R9, and where X8predstavljaet themselves, and specified With possibly substituted by R9.

In another aspect of the proposed compounds of formula Ib, where R9 is selected from H, bromo, fluorescent, chloro, iodo, Sn(C1-4alkyl)3N(CH3)3+, IG6+N2+and nitro.

In another aspect of the proposed compounds of formula Ib, where with reference to formula Ib, one or more of the substituents selected(e) of R8, R9, R10 and R11 is(are) one of the functional groups selected from bromo, fluorescent, hydroxy, Sn(C1-4alkyl)3N(CH3)3+, IG6+N2+, nitro, amino, methylamino, NH(CH2)2-4G7, N(CH3)SNO, N(CH3Of PINES3group N(CH3)CO2tert-butyl, (CO)NH2, O(CH2)2-4G7, OSi(G3)3and OCH2G4.

In another aspect of the proposed compounds of formula Ib, where R10 is selected from amino, methylamino, NH(CH2)2-4G7, dimethylamino, N(CH3)SNO, N(CH3Of PINES3group N(CH3)CO2tert-butyl, methoxy, hydroxy, (CO)NH2and O(CH2)2-4G7.

In another aspect of the proposed compounds of formula Ib, where R8 is H; R10 is selected from amino, methylamino, dimethylamino and NH(CH2)2-4G7; R11 is selected from OSi(CH3)2C(CH3)3, H, fluorescent, hydroxy, methoxy, Sn(C1-4alkyl)3and N2+.

In another aspect of the proposed connection Faure the uly Ib, where R8 represents H; R9 represents H, F, NO2; R10 is selected from amino, methylamino, dimethylamino, NH(CH2)2-4G7, N(CH3)SNO, N(CH3Of PINES3group N(CH3)CO2tert-butyl, (CO)NH2and O(CH2)2-4G7; R11 is selected from OSi(CH3)2C(CH3)3, H, fluorescent, hydroxy, methoxy, OCH2G4, Sn(C1-4alkyl)3and N2+.

In another aspect of the proposed compounds of formula Ib where Z is a pyridine ring, where X6and X7are With, and where X8represents N.

In another aspect of the proposed compounds of formula Ib where Z is a pyridine ring, where X6and X8are With, and where X7represents N.

In another aspect of the proposed compounds of formula Ib where Z is a pyrimidine ring, where X6and X8are N, and where X7is a C.

In another aspect of the proposed compounds of formula Ib where Z is pyrazinone ring, where X6and X7are N, and where X8is a C.

In another aspect of the proposed compounds of formula Ib where Z is pyridazinone ring, where X7and X8are N, and where X6is a C.

In another aspect of the proposed compounds of formula Ib, represents:

2-[6-(methylamino)pyridine-3-yl]-1-benzofuran-5-ol
5-(5-methoxy-1-benzofuran-2-yl)pyridine-2-carboxamide
6-(5-hydroxy-1-benzofuran-2-yl)nicotinamide
5-(5-hydroxy-1-benzofuran-2-yl)pyridine-2-carboxamide
5-(5-methoxy-1-benzofuran-2-yl)-N-methylpyridin-2-amine
6-(5-methoxy-1-benzofuran-2-yl)pyridazin-3-amine
5-(1-benzothieno-2-yl)pyridine-2-carboxamide
5-(1-benzofuran-2-yl)pyridine-2-carboxamide
6-(5-methoxy-1-benzofuran-2-yl)nicotinamide
2-(6-aminopyridin-3-yl)-1-benzofuran-5-ol.

In another aspect of the proposed compounds of formula Ib represents:

2-(2-fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol
2-(6-fluoro-5-methylamino-pyridine-2-yl)-benzofuran-5-ol
2-(5-fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol
tert-butyl ether [6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridine-2-yl]-carbamino acid
6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridine-2-ylamine
2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridine-3-ylamine
tert-butyl ether [6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridine-2-yl]-methyl-carbamino acid.

In another aspect of the proposed use of compounds of the formula Ib is as a synthetic precursor in the method of obtaining labeled compounds with the specified label is one of [11C]methyl group.

In another aspect of the proposed use of compounds of the formula Ib as a synthetic precursor in the method of obtaining labeled compounds, and the specified label is one atom18F.

In another aspect of the proposed use of compounds of the formula Ib as a synthetic precursor in the method of obtaining labeled compounds, and the specified label is one atom selected from the120I123I125I and131I.

In another aspect of the proposed pharmaceutical composition comprising a compound of formula (Ia) together with a pharmaceutically acceptable carrier.

In another aspect of the proposed pharmaceutical composition for imaging amyloid deposits in vivo, containing radiolabelled compound of formula (Ia) together with a pharmaceutically acceptable carrier.

In another aspect, a method for measuring amyloid deposits in a subject in vivo, comprising the stage of: (a) the introduction of the detected amount of the pharmaceutical composition containing the radiolabelled compound of formula (Ia), and (b) detecting binding of the compound to amyloid Deposit in the subject.

In one of the embodiments of this aspect of the specified detection carried out by the group of methods, you the security of gamma imaging, magnetic resonance imaging and magnetic resonance spectroscopy.

In another embodiment of this aspect of the subject suspected of having the disease or syndrome is selected from the group consisting of Alzheimer's disease, hereditary Alzheimer's disease, down syndrome, and homozygosity for allele E4 of apolipoprotein.

In another aspect of the proposed compound of formula (Ia) for use in treatment.

In another aspect of the proposed use of the compounds of formula (Ia) in the manufacture of a medicine for the prevention and/or treatment of Alzheimer's disease, hereditary Alzheimer's disease, down syndrome, and homozygosity for allele E4 of apolipoprotein.

In another aspect, a method for prevention and/or treatment of Alzheimer's disease, hereditary Alzheimer's disease, down syndrome, and homozygosity for allele E4 of apolipoprotein, including the introduction of a mammal, including man, in need of such prevention and/or treatment, a therapeutically effective amount of the compounds of formula (Ia).

Definition

When used here "alkyl", "alkylene" or "alkylene"used alone or as suffix or prefix, includes saturated aliphatic hydrocarbon group with a branched and non-branched chain, having from to 12 carbon atoms or, if conceived a specific number of carbon atoms, this specific number must be specified. For example, "C1-6alkyl" denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. When a specific number in the designation of the alkyl groups is an integer of 0 (zero), the hydrogen atom is designed as a Deputy in the position of the alkyl group. For example, "N(C0alkyl)2" equivalent "NH2" (amino). When a specific number in the designation alkylene or alkylene is an integer of 0 (zero), the link is for linking groups, which are substituted group alkylaryl or alkylen. For example, "NH(C0alkylene)NH2" equivalent "NHNH2(hydrazino). When using a group here related group alkylen or alkylaryl, are designed for connection to the first and to the last carbon atom of the group alkylen or alkylaryl. In the case of methylene first and last carbon is the same. For example, "N(C4alkylen), N(C5alkylen)and N(C2alkylen)2NH" is equivalent to pyrrolidinyl, piperidinyl and piperazinil respectively.

Examples of alkyl include, without limiting them, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

Examples of alkylene or alkylene include, without limitation, methylene, ethylene,propylene and butylene.

When used here "alkoxy" or "alkyloxy" represents an alkyl group, as defined above, with the specified number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, without limiting them, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentox, isopentane, cyclopropylmethoxy, allyloxy, propargyloxy. Similarly "alkylthio" or "dialkoxy" represent an alkyl group, as defined above, with the specified number of carbon atoms attached through the bridge, represents a sulfur atom.

When used here "foralkyl", "foralkyl and feralcode"used alone or as suffix or prefix, refers to groups in which one, two, or three atoms of hydrogen attached(e) to the atom(s) of the corresponding carbon alkyl group, alkylene, alkoxy, substituted(s) atom(s) of fluoride. Examples of foralkyl include, without limitation, trifluoromethyl, deformity, vermeil, 2,2,2-triptorelin, 2-foradil and 3-forproper.

Examples of peralkaline include, without limitation, deformation, permatile, 2,2-deformation and 2,2,3-triptorelin.

Examples of feralcode include, without limiting them, triptoreline, 2,2,2-triptoreline, 3,3,3-cryptochromes and 2,2-diffiplomacy.

When used is here "aromatic" refers to hydrocarbon groups, having one or more unsaturated carbon ring having aromatic characteristics (e.g. 4n+2 delocalized electrons, where "n" is an integer) and containing up to about 14 carbon atoms. In addition, "heteroaromatic" refers to groups having one or more unsaturated ring containing a carbon atom, and one or more than one heteroatom such as nitrogen atom, oxygen or sulfur, which has aromatic character (e.g. 4n+2 delocalized electrons).

When used herein, the term "aryl" refers to aromatic ring structure, consisting of 5-14 carbon atoms. Ring structure containing 5, 6, 7 and 8 carbon atoms, must be an aromatic group having a single ring, for example phenyl. Ring structure containing 8, 9, 10, 11, 12, 13 or 14 carbon atoms, must be polycyclic, for example to represent a naphthyl. The aromatic ring may be substituted by one or more than one position of the ring substituents described above. The term "aryl" also includes polycyclic ring systems having two or more than two cyclic rings in which two or more than two carbon atoms are common to two adjoining rings (the rings are "condensed ring"), and at least the bottom ring is aromatic, and the other cyclic rings can represent, for example, cycloalkyl, cycloalkenyl, cycloalkenyl, Ariely and/or heterocyclyl. The terms ortho, meta, and para refers to 1,2-, 1,3 - and 1,4-the disubstituted benzenes, respectively. For example, 1,2-xylene and ortho-xylene are synonymous.

When used herein, the term "cycloalkyl" is intended to include saturated ring groups, having the specified number of carbon atoms. They may include condensed or connected by bridges polycyclic system. Preferred cycloalkyl have in the ring structure of 3 to 10 carbon atoms and, more preferably, are in the ring structure 3, 4, 5 and 6 carbon atoms. For example, "C3-6cycloalkyl" refers to such groups as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

When used here "halogen" or "halogen" refers to a fluorescent, chloro, bromo and iodo. "Counterion" is used, for example, to denote a small negatively charged structures such as chloride, bromide, hydroxide, acetate, sulfate, tosylate, bansilalpet and the like.

When used herein, the term "heterocyclyl" or "heterocyclic" or "heterocycle" refers to a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring(unless otherwise specified), containing from 3 to 20 atoms, of which 1, 2, 3, 4 or 5 atom(s) of the ring selected from nitrogen atom, sulfur or oxygen, which may, if not specified otherwise, to be bound with the carbon atom or nitrogen, and the group-CH2- may be replaced by a group-C(O)-; and if not stated otherwise, the atom of nitrogen or sulfur in the ring, possibly oxidized with the formation of N-oxide or S-oxide(s), or the nitrogen atom in the ring is probably the Quaternary; and-NH-in the ring possibly substituted by acetyl, formyl, stands or mesilim; and ring possibly substituted by one or more than one halogen. We must understand that, when the total number of atoms S and About in heterocyclyl exceeds 1, then these heteroatoms are not adjacent to each other. If the specified heterocyclyl group is bi - or tricyclic, at least one ring may be possible heteroaromatic or aromatic ring, provided that at least one ring is heteroaromatic. If the specified heterocyclyl group is monocyclic, it should not be aromatic. Examples heterocyclyl include, without limitation, piperidinyl, N-acetylpiperidine, N-methylpiperidine, N-formylpiperazine, N-methylpiperazine, homopiperazine, piperazinil, azetidine, oxetane, morpholinyl, tetrahydroisoquinoline, tetrahydroquinoline, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl and 2.5-dioxoimidazolidin.

When used here "heteroaryl" refers to heteroaromatic the heterocycle having at least one member ring, represents a heteroatom, such as sulfur atom, oxygen or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 of the condensed ring system. Examples of heteroaryl groups include, without limitation, pyridyl (pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (i.e., furanyl), hinely, ethanolic, thienyl, imidazolyl, thiazolyl, indolyl, peril, oxazolyl, benzofuran, benzothiazyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazoles, 1,2,4-thiadiazolyl, isothiazolin, benzothiazyl, purinol, carbazolyl, benzimidazolyl, indolyl and the like.

When using the phrase "protective group" or "protecting group" refers to temporary deputies, which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protective groups include esters of carboxylic acids, Silovye esters of alcohols and acetals and ketals of aldehydes and ketones, respectively. Subgroup protective groups are those that protect nucleophile the second group (for example an aromatic hydroxy group) from alkylation and thus make possible the selective N-alkylation of amino groups, present in the same molecule, in alkaline conditions. Examples of such protective groups include, without limiting them, methyl, 2-(trimethylsilyl)ethoxymethyl, alkoxymethyl and tert-butyldimethylsilyl.

When used here "pharmaceutically acceptable" refers to those compounds, substances, compositions and/or dosage forms which are, within the measure of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and meet a reasonable balance between benefits and risks.

When used here "pharmaceutically acceptable salts" refer to derivatives disclosed here connection and the source connection is modified by the receipt of its salts with an acid or a base. Examples of pharmaceutically acceptable salts include, without limitation, their salts with mineral or organic acids with basic residues such as amines; salts with alkalis or salts of organic compounds with acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or the Quaternary ammonium salt and the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, the conventional non-toxic salts include those which are derived from inorganic acids, such as chloromethane, phosphoric and the like; and salts derived from organic acids such as lactic, maleic, citric, benzoic, methanesulfonate and the like.

Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic group, conventional chemical methods. Typically, such salts can be obtained by the interaction of forms of these compounds representing the free acid or base, with the stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or a mixture of both of them; usually used non-aqueous environment, such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.

When used herein, the term "precursor, a hydrolyzable in vivo" denotes a hydrolyzable (or split) in vivo ester compounds according to this invention, which contains a carboxy group or hydroxy. For example: esters of amino acids; C1-6alkoxymethyl esters, such as methoxymethyl; C1-6alkanoyloxy esters, such as pivaloyloxymethyl; C3-8cycloalkylcarbonyl1-6alkalemia esters such as 1-cyclohexylcarbodiimide, acetoxymethyl or phosphoramide ilycheskie esters.

When used here "tautomer" means other structural isomers that exist in equilibrium, resulting from migration of a hydrogen atom. For example, keto-enol tautomerism, when the resulting compound has the properties of a ketone and an unsaturated alcohol.

When used here "stable compound" and "stable structure" refers to a compound which is sufficiently stable for preservation in the allocation of the reaction mixture to a useful degree of purity and subsequent long-term storage in cold weather or when ambient temperature and possibly in the preparation in the form of effective therapeutic or diagnostic agent.

Compounds according to this invention further include a hydrate and a solvate.

The present invention includes labeled with isotopes of the compounds according to this invention. "Isotope-labeled", "radiolabelled", "tagged", "detective" or "detective bind to amyloid" connection or "radioligand" represents a connection according to this invention, where one or more than one atom is replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number, in typical cases detected(CSOs) in nature (i.e., naturally occurring). One of Neagra Iceweasel exception is 19F, which allows the detection molecule that contains this element without upgrading to a higher degree than that which occurs in nature. Compounds bearing Deputy19F can thus also be referred to as a "probe" or the like. Suitable radionuclides (i.e., "detected isotopes")that can be included in the composition of the compounds of the present invention, include, without limitation, their,2H (also denoted as D, which means deuterium),3H (also denoted as T, which means tritium),11C,13C,14C,13N15N15Oh,17Oh,18O,18F,35S36Cl82Br,75Br,76Br,77Br,123I124I125I and131I. we Must understand that the labeled isotopes connection according to this invention must be enriched detektivami isotope to or higher degree, which makes possible the detection method suitable for the particular application, for example in detektiruya connection according to this invention, the labeled carbon atom11With the carbon atom labeled group labeled compounds can include12With or other isotopes of carbon in some fraction of these molecules. The radionuclide, which is included in the composition representing an example of radiolabelled compounds is avisit from the specific application of this radiolabelled compounds. For example, for in vitro on a plaque or a receptor on the label or competition most useful should generally be compounds that contain3H,14With or125I. For use in in vivo imaging is most useful usually must be11C,13C,18F,19F,120I123I131I75Br or76Br.

Examples of "effective amount" includes the amount that makes possible the visualization of amyloid(s) adjournment(s) in vivo, which provide acceptable for pharmaceutical applications the levels of toxicity and bioavailability and/or prevent cell degeneration and toxicity associated with the formation of fibrils.

This invention also suggested radiolabelled 2-heteroaryl-substituted derivatives of benzothiophene and benzofuran as agents of imaging amyloid and connections, representing a synthetic precursors from which they receive.

Applications

Compounds of the present invention can be used to determine the presence, location and/or quantity of one or more than one amyloid deposits in an organ or area of the body, including the brain, of an animal or human. Amyloid(s) deposition(I) include, without limitation, the deposition of(I) β. Allowing monitored the performance by a temporal sequence of amyloid deposits, compounds according to the invention may further be used to correlate amyloid deposits since the beginning of clinical symptoms associated with a disease, disorder or condition. Compounds according to the invention can ultimately be used for the treatment and diagnosis of disease, disorder or condition characterized by amyloid, such as Alzheimer's disease (ad), hereditary BA, down syndrome, amyloidosis and homozygosity for allele E4 of apolipoprotein.

The method according to this invention determines the presence and location of amyloid deposits in an organ or area of the body, preferably the brain of the patient. This method includes the introduction of a detected amount of the pharmaceutical composition comprising communicating with amyloid compound of the present invention, called "detective connection, or its pharmaceutically acceptable water-soluble salt, the patient. "Detective number" means the number of detected compound that is administered is sufficient to detect binding of the compound to amyloid. "Effective to render the number" means the number of detected compound that is administered is sufficient to render binding compounds the Oia with amyloid.

In this invention used probes for amyloid, which in combination with non-invasive methods of imaging such as magnetic resonance spectroscopy (Mrs) or imaging (MRI), or gamma imaging, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), are used to quantify amyloid deposits in vivo. The term "visualization " in vivo" or "visualization" refers to any method that allows the detection described here labeled heteroaryl-substituted derivatives of benzofuran or benzothiophene. For gamma-ray imaging radiation emitted from the examined organ or area is measured and expressed either as total binding, or as a ratio in which the total binding in the same fabric normalize (such as division) relative to the total binding in another tissue of the same subject during the same imaging procedures in vivo. Total binding in vivo is defined as a full signal, detected in the tissue by the method of in vivo imaging without the need for correction the second injection of the same amount of labeled compounds along with a large excess of unlabeled, but otherwise chemically identical compounds. "Subject" is a mammal, preferably human, and n is andmore preferably, person with suspected dementia.

For visualization purposes, in vivo the main factors for choosing this label is available type detecting device. For example, particularly suitable in the methods of the present invention for imaging in vivo are radioactive isotopes and19F. Type of the apparatus used should determine the choice of a radionuclide or stable isotope. For example, the selected radionuclide must have a type of decay detected by this device type.

Another consideration relates to the half-life of the radionuclide. The half-life must be so long that it was still detektivami to the time of maximum uptake by the target, but short enough so that the owner did not experience harmful radiation. Radiolabelled compounds according to this invention can be detected using gamma imaging, which detects the emitted gamma radiation of an appropriate wavelength. How gamma-ray imaging include, without limiting them, SPECT and PET. Preferably, the detection method SPECT selected radioactive label must not emit particles, but must generate a large number of photons in the range of 140-200 Kev.

For detection by way of PET radioactive label must be a emitting poses the thrones radionuclide, such as18F or11With that should annihilate to form two gamma rays, which must be detectivesyme PET camera.

In the present invention obtained to bind to the amyloid connection/probes that are useful for in vivo imaging and quantification of amyloid deposits. These compounds are intended for use in combination with non-invasive methods of imaging such as magnetic resonance spectroscopy (Mrs) or imaging (MRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT). In accordance with this invention, 2-heteroaryl-substituted derivatives of benzothiophene and benzofuran you can mark isotopes19F or13For Mrs/MRI conventional methods of organic chemistry known in this field. Connections can also be marked with radioactive isotopes, such as18F,11C,75Br,76Br or120I, for PET by techniques well known in the field and exposed Fowler, J. and Wolf, A. "Positron Emission Tomography and Autoradiography" 391-450 (Raven Press, 1986). Connections can also be marked with radioactive isotopes123I and131I for SPECT any of several methods known in this field. See, for example, Kulkarni, Int. J. Rad. Appl. & Inst. (Part B) 18: 647 (1991). Connections can also marks the known radioactive labels, representing a radioactive metal, such as technetium-99m (99mTc). Modification of the substituents for the introduction of ligands that bind with ions of such metal may be carried out without undue experimentation ordinary specialist in the field of injection of radioactive labels. The compound labeled with a radioactive metal, can then be used to detect amyloid deposits. Getting radiolabelled derivatives of TC-99m is well known in this field. See, for example, Zhuang et al. Nuclear Medicine & Biology 26(2): 217-24, (1999); Oya et al. Nuclear Medicine & Biology 25(2): 135-40, (1998), and Hom et al. Nuclear Medicine & Biology 24(6): 485-98, (1997). In addition, the compounds can mark3H,14C and125I ways, well known to the specialist for detection of amyloid plaques in vitro and in post-mortem samples. Moreover, the fluorescent compounds of the present invention can be used for detection of plaques present in vitro and in post-mortem samples, using well known techniques based on the detection of fluorescence.

In the methods of the present invention for the purpose of imaging and spectroscopy in vivo can be used isotopes detected nuclear magnetic resonance spectroscopy. Items that are particularly useful in magnetic resonance spectroscopy include19F and13C.

Approaching the s radioisotopes for the purposes of this invention include sources of beta radiation, gamma rays and positrons and x-ray radiation. These radioisotopes include120I123I131I125I18F,11C,75Br and76Br. Suitable stable isotopes for use in magnetic resonance imaging (MRI) or spectroscopy (Mrs) in accordance with this invention include19F and13C. Suitable radioisotopes for the quantitative determination of amyloid in vitro in homogenates of biopsy or post-mortem tissue samples include125I14C and3H. Preferred radioactive labels are11C and18F for use in PET imaging in vivo,123I for use in SPECT imaging,19F for Mrs/MRI and3H and14For in vitro studies. However, in accordance with this invention can be used any conventional method of imaging diagnostic probes.

Compounds of the present invention can be entered by any method known to the person skilled in the art. For example, the introduction of the animal can be local or systemic, and it can be done orally, parenterally, by inhalation spray, topically, rectally, nose, mouth, vagina, or implantable reservoir. The term "parenteral" when used here includes subcutaneous, intravenous, intraarterial, vnutrimyshecnam is, intraperitoneal, intrathecal, intraventricular, vnutrigrudne, intracranial and intraosseous injection and infusion techniques.

The exact Protocol introduction will vary depending on various factors, including the age, body weight, General health, sex and diet of the patient; determining the specific techniques should be familiar to any ordinary specialist in the field.

Useful for methods of the invention are the dose levels of the compounds according to the invention is from about 0.001 microg/kg/day to about 10,000 mg/kg/day. In one of the embodiments of the dose represents from about 0.001 microg/kg/day to about 10 g/kg/day. In another embodiment the dose represents from about 0.01 μg/kg/day to about 1.0 g/kg/day. In another embodiment the dose represents from about 0.1 mg/kg/day to about 100 mg/kg/day.

The specific dose level for any particular patient will vary depending on various factors, including the activity and potential toxicity of the compound; the age, body weight, General health, sex and diet of the patient; the time of administration; rate of excretion; the combination of drugs and the form of administration. In typical cases useful guidance on the proper doses for administration to the patient the results of the dependence of the effect of the dosage in vitro. Also help research in animal models. Considerations to determine appropriate dose levels are well known in this field and are within the ordinary skill of the doctor.

In the methods according to the invention for the implementation of treatment can be used and repeated as necessary any known injection mode for regulating the timing and sequence of drug delivery.

The mode may include prior and/or concurrent introduction of additional(s) therapeutic(s) agent(s).

In one embodiments of the compounds according to the invention is administered to an animal, who suspect the presence or risk of developing a disease, disorder or condition characterized by amyloid deposits. For example, such animals may be an old man.

In yet another embodiment of the proposed compounds useful as precursors, and methods for their preparation. Such precursors can be used as starting substances for the synthesis for the introduction of labeled molecular fragments resulting radiolabelled 2-heteroaryl-replaced derivatives benzothiophene and benzofuran as agents of imaging amyloid.

Method of detecting amyloid deposits in vitro

This invention is additionally a method detected the I amyloid(s) adjournment(s) in vitro, includes: (1) bringing the tissue into contact with an effective amount of the compounds according to the invention, and the connection is associated with any(and) amyloid(s) deposition(s) in the tissue; and (2) detecting binding of the compound to amyloid(s) deposition(s) in the tissue.

Binding can be detected by any method known in this field. Examples of detection methods include, without limitation, microscopic techniques, such as svetovalna, fluorescent, laser confocal and cross-polarization microscopy.

The pharmaceutical composition

This invention additionally proposed pharmaceutical composition comprising: (1) an effective amount of at least one compound according to the invention; and (2) pharmaceutically acceptable carrier.

The composition may contain one or more than one additional pharmaceutically acceptable ingredient, including, without limitation, one or more than one wetting agent, buffer agent, suspendisse agent, lubricating agent, emulsifier, baking powder, absorbent, preservative, surfactant, colorant, corrigent, sweetener and a therapeutic agent.

The composition can be prepared in the form of solids, liquid, gel or suspension for: (1) oral administration, such as, for example, p is lecanium (aqueous or nonaqueous solution or suspension), the tablet (for example, intended for transbukkalno, sublingual or systemic absorption), bolus, powder, granule, paste for application to the tongue, hard gelatin capsule, soft gelatin capsule, a spray for the mouth, emulsion and microemulsion; (2) parenteral administration, subcutaneous, intramuscular, intravenous or epidural injection, for example, a sterile solution, suspension or composition with prolonged release; (3) local application, e.g., cream, ointment, patch, adjustable release or spray applied to the skin; (4) vnutrivlagalishnogo or intrarectal injection, for example, vaginal pessary, cream or foam; (5) sublingually introduction; (6) eye of administration; (7) TRANS-dermal; or (8) introduction in the nose.

In one embodiments the composition is prepared for intravenous administration, and the carrier includes a liquid and/or wspanialy nutrients. In yet another embodiment, the composition capable of specific binding to amyloid in vivo, capable of crossing the blood-brain barrier, is non-toxic when appropriate dose levels and/or has a satisfactory effect duration. In yet another embodiment, the composition contains about 10 mg of human serum albumin and from about 0.0005 to 500 mg connection to us is oedema invention 1 ml phosphate buffer, containing NaCl.

The present invention additionally proposed composition containing the compound of the formula Ia and at least one pharmaceutically acceptable carrier, diluent or excipient.

The present invention additionally methods of treating or preventing associated with β pathology in a patient, comprising the administration to a patient a therapeutically effective amount of the compounds of formula Ia.

In the present invention is additionally described here proposed connection for use as pharmaceuticals.

The present invention additionally proposed is described here is the link for the manufacture of a medicinal product.

Some compounds of formula Ia and Ib may have stereogenic centers and/or geometric isomerism (E - and Z-isomers), and it should be understood that this invention encompasses all such optical isomers, enantiomers, diastereoisomers, atropoisomeric and geometric isomers.

The present invention relates to the use of compounds of formula Ia, as defined here above, and their salts. Salts for use in pharmaceutical compositions should be pharmaceutically acceptable salts, but other salts may be useful in obtaining the compounds of formula Ia.

Compounds according to this invention can be used as carstone funds. In some embodiments of the present invention proposed the compounds of formula Ia or pharmaceutically acceptable salts, tautomers or hydrolyzable in vivo precursors for use as medicines. In some embodiments of the present invention described here proposed compounds for use as pharmaceuticals for the treatment or prevention of pathologies associated with β. In some additional embodiments, the pathology associated with β, is a syndrome, β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, lku ("mild cognitive impairment"), Alzheimer's disease, memory loss, symptoms of attention deficit associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, presenilny dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

Ways to get

The present invention also relates to methods for obtaining compounds of formula Ia and Ib in the form of their free bases, acids or salts Throughout the following description of such methods it is necessary to understand that, where appropriate, suitable protective groups must be attached to various reagents and intermediate connections and then remove them as it will be easily understandable to the expert in the field of organic synthesis. Conventional methods of use of such protective groups, and examples of suitable protective groups are disclosed, for example, in "Protective Groups in Organic Synthesis", 3rd ed., T.W.Green, P.G.M.Wuts, Wiley-Interscience, New York (1999). Also you have to understand that the transformation of the group, or substituent to another group, or Vice chemical manipulation can be performed at any intermediate connection or the final product a synthetic route to the final product, with the possible type of transformation is limited only by the internal incompatibility with other functional groups, which carries the molecule at this stage, conditions or reagents used in the transformation. Such internal incompatibility and how they might be overcome by the implementation of appropriate transformations and stages of synthesis in appropriate order will be easily understood by a person skilled in the field of organic synthesis. Examples of transformations are given below, and should be understood that the described transformation is not limited only to common groups or substituents, which are examples of transformations. Links and descriptions regarding other suitable transformations are given in "Comprehnsive Organic Transformations - A Guide to Functional Group Preparations", 2nd ed., R.C.Larock, Wiley-VCH, New York (1999). Links and descriptions regarding other suitable interactions described in textbooks of organic chemistry, for example "March''s Advanced Organic Chemistry", 5th ed., M.B.Smith, J.March, John Wiley & Sons (2001) or "Organic Synthesis", 2nd ed., M.B.Smith, McGraw-Hill, (2002). Methods purification of intermediates and final products include, for example, direct and ortofoto chromatography on a column or rotating plate, recrystallization, distillation and extraction from the liquid in the liquid or solid substance into a liquid, which will be easily understood by the specialist. Definitions of the substituents and groups are as in formula Ia and Ib, unless otherwise specified. The terms "room temperature" and "ambient temperature" shall mean, unless otherwise specified, the temperature between 16 and 25°C. the Term "temperature reflux distilled" shall mean, unless otherwise specified, relative to the solvent used application temperature at or slightly above the boiling point of the specified solvent. You have to understand that for heating the reaction mixtures can be used in the microwave. The terms "flash chromatography" or "column flash chromatography" should mean preparative chromatography on silica using an organic solvent or mixtures as the mobile phase.

The juice is stop

AUacetate;
ATMatmosphere;
aq.water;
BoC2Odi-tert-BUTYLCARBAMATE;
DBU1,8-diazabicyclo[5.4.0]undec-7-EN
DME1,2-dimethoxyethane;
DMAN,N-dimethylacetamide;
DMFN,N-dimethylformamide;
DMSOdimethyl sulfoxide;
dppf1,1'-bis(diphenylphosphino)ferrocene;
EtOActhe ethyl acetate;
EtOHethanol;
Et2Odiethyl ether;
hhour(s);
hepheptane;
hexHuck is an(s);
HPLChigh-performance liquid chromatography;
MeCNacetonitrile;
MeOHmethanol;
'ev O.N.during the night;
NBSN-bromosuccinimide
Pd(dppf)Cl21,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (II);
Pd(dba)2bis(dibenzylideneacetone)palladium (0);
Pd(PPh3)2Cl2dichlorobis(triphenylphosphine)palladium;
Rev. HPLCpreparative HPLC;
PTSApair-toluensulfonate acid;
K.T.room temperature;
p.c.the reaction mixture;
us.saturated;
TBAFfluoride tetrabutylammonium;
TFAtriperoxonane acid;
THFtetrahydrofuran;
Tostoilet;
OTftriftorbyenzola.

The intermediate compounds

The compounds of formula II-VI are useful intermediate compounds in obtaining the compounds of formula Ia and Ib. The compounds of formula II-VI are either commercially available or can be obtained from compounds that are either commercially available or described in the literature. For example, compounds in which one or more than one of Y1-Y3, R1 or R2 does not complies(comply) with the definitions of formula II-VI, can be used to obtain compounds of formula II-VI through transformations or the introduction of substituents or groups. Such examples are given below:

Y1=(OH)2In(Alkyl)2, Sn(n-Bu)3, Br, Cl, I, OTf
is a Q1-10 according to claim 1
Y2=Br, Cl, I, OTf, IN(OH)2In(Alkyl)2, Sn(n-Bu)3With the CH 2, CLOS
Y3= I, Br, CH2COCl

1) Obtaining compounds of formula II in which Y1represents a(Alkyl)2or IN(OH)2:

Processing corresponding benzofuran BuLi and the damping of trialkylborane followed by acid hydrolysis.

From the corresponding chlorides, bromides, iodides or triflates catalyzed by palladium-bilirubin when using, for example, bis(pinacolato)DIBORANE or dialkoxybenzene as reagents in terms of palladium catalysis using, for example, PdCl2(dppf) or Pd(dba)2with the addition of tricyclohexylphosphine as catalysts together with stoichiometric amounts of a base, such as Koas and NEt3in solvents such as DMSO, DMF, DMA or dioxane, at a temperature of from K.T. 80°C, or during subsequent acid hydrolysis (Ishiyama et al. Tetrahedron 2001, 57, 9813; Murata et al. J. Org. Chem. 2000, 65, 164).

2) Obtaining compounds of formula II in which Y1represents a halogen:

a) Halogenoalkane position 2 derived benzofuran can be done tert-butyllithium in post-processing I2for introduction of halogen (Zhang et l. J. Org. Chem. 2002, 67, 7048).

b) From the corresponding nitro-derivatives processing PBr3at 175°C (Lin, S.-Y. et al. J. Org. Chem. 2003, 68, 2968).

the Interaction catalyzed by palladium and copper compounds of the formula IV with trimethylsilylacetamide.

(i) Pd(Ph3P)2Cl2/CuI, Et3N/CH3CN; (ii) TBAF; (iii) NBS

Then removing the protective group TMS and halogenoalkane, for example, N-bromosuccinimide (Aquila, B.M., Tetrahedron Lett. 1997, 38, 2795).

3) Obtaining compounds of formula II in which Y1represents Sn(n-Bu)3, Sn(Me)3or SnPh3:

a) Introduction olomoucine group can be accomplished by the exchange of the halogen and metal when the corresponding halides, for example, BuLi as a source of lithium for the treatment of the respective halogen-substituted benzofurans, that is, where Y1= halogen. Followed by quenching reagent Sn(alkyl)3Cl (Li, J.J. et al., Bioorg. Med. Chem., 2003, 11, 3777).

b) Metallating alkyllithium reagent on the substrate, where Y1=H, and then transmetallation when using reagent Sn(alkyl)3Cl provides an introduction tin (Einhorn et al. Synthesis 1984, 11, 978).

4) obtaining the compounds of formula IV with Y3=CH2COCl:

Chloranhydride derivatives of compounds of formula IV can be obtained chetyrehstvolnym way from the corresponding benzyl alcohols.

(i) SOCl2, THF; (ii) NaCN, DMF; (iii) H2SO4, AcOH, H2O; (iv) SOCl2CH2Cl2.

Chlorination using, for example, SOCl2and then the introduction of a nitrile group. The hydrolysis of the nitrile group to a carboxylic acid and subsequent processing using SOCl2gives chloranhydride derivative of formula IV (.D.Collini et al., Bioorg. Med. Chem. Lett, 2004, 14, 4925).

5) obtaining the compounds of the formula V:

Catalyzed by palladium combination of arylacetylenes formula III with 2-itfinally formula IV in accordance with the standard Sonogashira conditions (Yin, Y.; Liebscher, J.; Chem. Rev. 2007, 107, 133).

Methods of obtaining its compounds of formula Ia and Ib

Non-limiting examples of methods of preparing compounds of formula Ia and Ib are given below:

1) Getting catalyzed by palladium cross-combination of intermediate compounds (IV) and (III) with Y2=SNSN2:

Catalyzed by palladium combination of styrene and 2-hydroxyalkylated generates stilinovic product. Or, stilinovic product can be obtained by Wittig reaction between the corresponding phosphonoamidate and aldehyde.

(i) a Palladium catalyst, a base; (ii) epoxidation; (iii) a weak acid.

Epoxidation intermediate stilbene and further cyclization in mild acidic conditions gives the derivative benzop the wound (Aslam et al., Tetrahedron, 2006, 62, 4214).

2) Obtaining catalyzed by palladium cross-combination of intermediate compounds (IV) and (III) with Y2=CLO:

While the cross-mix etileno requires additional processing to bring up benzofuranol product, cross combination hydroxyhalide and more reactive acetylenes in the Sonogashira conditions leads directly to the derived benzofuran (Aslam et al., Tetrahedron, 2006, 62, 4214).

(i) a Palladium catalyst, CuI, a base, DMF

(i) HAuCl4

If necessary, the cyclization can be induced by the use of gold as a catalyst in K.T. in such a solvent as Et2O or EtOH. Metals form with Alcina π-complex, which is then transformed into a σ-complex with nucleophilic attack of oxygen, and prototypecellvalue gives benzofuranyl product (V.Belting et al. Org. Lett., 2006, 8, 4489).

3) Receiving from the intermediate compound (III):

The reaction of the Friedel-craft between the respective Q and acetylchloride derivatives of the formula III and then removing the protection, for example, pyridine hydrobromide, at high temperature leads to cyclization and gives the compounds of formula I (M.D.Collini et al., Bioorg. Med. Chem. Lett., 2004, 14, 4925).

(i) AlCl3, Q; (i) pyridine hydrobromide, increasing the military temperature.

4) catalyzed by palladium cross the mixture of intermediate compounds (II) and (III):

Catalyzed by palladium combination Suzuki or Stille aryl halides or pseudohalogen intermediate compounds of formula III (e.g., Y2=Cl, Br, I or triflate) baronowie acids or esters of formula II (for example, Y1=(OH)2or(Alkyl)2or stannane formula II (for example, Y1=Sn(n-Bu)3). Palladium catalyst such as Pd(dppf)Cl2or Pd(PPh3)Cl2can be used in solvent such as DMF or EtOH, at a temperature, for example 80°C (Kotha et al. Tetrahedron 2002, 58, 9633-9695; J. Suzuki were obtained. Chem. 1999, 576, 147-168; Fugami et al. Top. Curr. Chem. 2002, 219, 87-130).

Methods of obtaining labeled compounds of the formula Ia

In General, the same synthesis reaction used to obtain its compounds of formula Ia of its reagents or intermediates, can be used for a similar introduction of the detected isotope appropriate labeled reagents or intermediates.

It is preferable to introduce the label at a later stage of the synthesis of compounds of formula Ia, especially if the label is an isotope with a relatively short half-life, such as11C. it is Most preferable to make this introduction as the last stage of the Intesa.

Some useful reagents synthons or intermediate compounds, labeled long-lived or non-radioactive isotopes, including, for example

[2/3N]H2, [2/3H]CH3I, [13/14C]CH3I, [13/14C]CN-, [13/14C]CO2there are commercially available and can, if necessary, be further transformed by conventional methods of synthesis. The reagents labelled with a relatively short-lived isotopes, such as11C and18F, get on the cyclotron, then appropriately capture and may expose additional synthetic manipulations to obtain the desired reagent. Getting labeled reagents and intermediates and synthetic manipulation and application and chemical properties of these precursors for the synthesis of more complex labeled molecules are well known to the specialist in the field of synthesis of radioactive compounds and the introduction of labels and reviewed in the literature (Långström et al. Acta Chem. Scand. 1999, 53, 651). Additional references see, for example, in: Ali et al. Synthesis 1996, 423 about the marking Halogens; Antoni G., T. Kihlberg, and Långström C. (2003) Handbook of Nuclear Chemistry, edited by A. Vertes, S. Nagy, and Klenscar Z., Vol. 4, 119-165 about tagging for use in PET; Saljoughian et al. Synthesis 2002, 1781 on the introduction of labels3H; McCarthy et al. Curr. Pharm. Des. 2000, 6, 1057 on the introduction of labels14C.

Detected isotopes that are useful for IU is possible compounds of formula Ia, as defined here, include11C,18F,75Br,76Br and120I for use in PET,123I and131I for use in SPECT,19F and13For use in MRI,3H,14C and125I for the detection in vitro and in post-mortem samples. The most useful isotopes for labeling are11C,18F,123I19F,3H and14C.

The following are non-limiting descriptions of the methods of obtaining labeled compounds of the formula Ia:

The compounds of formula Ia and Ib, which are hydroxy-, amino - or aminoalkyl group, are useful precursors for O - and N-alkylation, respectively, labeled alkylating agent, such as [11C]methyliodide or triplet, as described, for example, Solbach et al. Applied Radiation and Isotopes 2005, 62, 591 and Mathis et al. J. Med. Chem. 2003, 46, 2740, or [3H]-methyliodide, or [14S]-methyliodide.

For example, the compounds of formula Ia, in which one of R1 and R2 represents hydroxy (other represents hydrogen), or the compounds of formula Ib, in which one of R8 and R11 is a hydroxy (other represents hydrogen), or are precursors for labelling. When such precursors treated with [11With]methyliodide under alkaline conditions, for example, in the presence of potassium carbonate, in a solvent such as DMSO, selective O-alkilirovanie what happens in the presence of N-nucleophiles, such as amino or aminomethyl, due to the relatively higher reactivity of an atom of oxygen after deprotonation, and thus the formation of compounds of formula Ia and Ib, in which the group HE was transformed into a group Of[11C]CH3. The compounds of formula Ib, in which R8 or R11 represents a protected (e.g. TBDMS) group, hydroxy, X8represents N, and R10 represents hydroxy are useful precursors for labelling via O-alkylation of the use of11C-under the conditions in the presence of Ag2CO3as the base (Shinzo K. Synth Comm 2006, 36, 1235).

The most preferred precursors for labelling selective introduction11C-methyl group of the N-alkylation are compounds, in which the reactivity with respect to alkylation at present competing nucleophilic functional groups such as hydroxy or aromatic functional group N-H, is reduced or blocked by a suitable protecting group. The function of the protective group represents, in this context, the protection of nucleophilic functional groups from alkylation, and it should preferably be stable in non-aqueous alkaline conditions, which facilitated the desired N-alkylation, but can easily be removed in other ways the AMI after performing its function. Such protective groups and methods for their introduction and removal are well known to the specialist. Examples of protective groups useful for the protection of the aromatic hydroxyl groups from competitive alkylation include, without limiting them, methyl, 2-(trimethylsilyl)ethoxymethyl, alkoxymethyl and tert-butyldimethylsilyl. The removal of such protective groups after the alkylation is well known to the specialist and includes, in the case based on simile protective groups such as tert-butyldimethylsilyl, for example, the processing of a source of fluoride ions, such as TBAF, or treatment with water under alkaline conditions in a suitable solvent, such as DMSO, in the presence of KOH at K.T. Examples of protective groups useful for protecting aromatic functional groups N-H from competitive alkylation include, without limiting them, SO2N(CH3)2, SO2(para-methyl)phenyl, CO2CH2CCl3, CO2(CH2)2Si(CH3)2, tert-butyldimethylsilyl and P(=S)phenyl2. When the aromatic functional group and aromatic hydroxy functional group N-H at the same time protected from alkylation, it is preferable to use one protective group such as tert-butyldimethylsilyl, or two different protective groups, which make possible the simultaneous removal of protection from both functional is s groups in one laboratory stage one reagent to remove the protection.

The compounds of formula Ia or Ib, bearing an aromatic amino group, are useful precursors for labelling the initial diazotization (i.e., the transformation of the amino group in the grouping of N2+)when it's convenient, with subsequent conversion into the corresponding triazine derivative before subsequent processing labeled nucleophilic reagents in accordance with the standard reactions. Detected isotopes that can be entered in this way include, without limitation, their,18F,75Br,123I125I and131I, as described, for example, in Zhu et al. J. Org. Chem. 2002, 67, 943; Maeda et al. J. Label Compd Radiopharm 1985, 22, 487; Berridge et al. J. Label Compd Radiopharm 1985, 22, 687; Suehiro et al. J. Label Compd Radiopharm 1987, 24, 1143; Strouphauer et al. Int. J. Appl. Radial Isot. 1984, 35, 787; Kortylevicz et al. J. Lavel Compd Radiopharm 1994, 34, 1129; Khalaj et al. J. Label Compd Radiopharm 2001, 44, 235 and Rzeczotarski et al. J. Med. Chem. 1984, 27, 156.

With compounds of the formula Ib, bearing aromatic group triamcinolone, halogenoalkane labeled reagents leads to the displacement of the group triamcinolone, as described, for example, Staelens et al. J. Label Compd Radiopharm 2005, 48, 101; Hocke et al. Bioorg. Med. Chem. Lett. 2004, 14, 3963; Zhuang et al. J. Med. Chem. 2003, 46, 237; Füchtner et al. Appl. Rad. Isot. 2003, 58, 575 and Kao et al. J. Label Compd Radiopharm 2001, 44, 889. The same precursors are also useful for catalyzed by palladium transformations in the corresponding11C-labeled ketones and methyl-derivatives, as described in the example, in Lidström et al. J. Chem. Soc. Perkin TRANS. 1 1997, 2701 and Tarkiainen et al. J. Label Compd Radiopharm 2001, 44, 1013. Compounds substituted triamcinolonum, in turn, preferably obtained from the corresponding halides or pseudohalogen, such as triflate, well-known methods of using palladium as catalyst in the reaction with the corresponding distancem. Using this methodology, the group triamcinolone represents preferably trimethylol or tributylamine.

The compounds of formula Ib, which are aromatic group trialkylamine, preferably nBu3Sn, where X6 is a carbon, X7 or X8 is a nitrogen (the other is the carbon), and R10 represents methylamino, dimethylamino or methoxy, are suitable precursors for the introduction of the tags123I or125I jadesteinliege in oxidative conditions in the presence of labeled iodide in accordance with the method described, for example, in Zhuang et al. Nucl. Med. Biol. 2001, 28, 887.

When any of the heterocyclic substituent in the precursor is a leaving group suitable for nucleophilic aromatic substitution, such a displacement can be entered labeled nucleophile, such as a halide or cyanide, obtaining labeled compounds of formula Ia, as described, for example, in Zhang et al. Appl. Rad. Isot. 002, 57, 145. Aromatic ring, which is the displacement, preferably is relatively depleted in electrons for easy ongoing interaction and, therefore, it is necessary to replace dilatory electrons activating group, such as cyano, carbaldehyde, or nitro. Useful reaction, closely related nucleophilic aromatic substitution and well-known specialist, include the use of stoichiometric quantities of copper salts for the introduction of labeled atoms of iodine and application of catalysis with the use of palladium for the introduction of11C-labeled cyano group, as described, for example, in Musacio et al. J. Label Compd Radiopharm 1997, 34, 39, and Andersson et al. J. Label Compd Radiopharm 1998, 41, 567, respectively. Also the atom18F you can enter, for example, the use of K[18F]-K222in DMSO under microwave radiation, as described in Karramkam, M. et al. J. Labelled Compd. Rad. 2003, 46, 979. If the aromatic ring, which have a leaving group, is compared with benzene, more depleted in electrons, such as 2-halogenopyrimidines and-pyrimidines, for electrophilic aromatic substitution the use of activating groups is usually not necessary.

The compounds of formula Ia, where Q is a Q2, and Ib, where R3 and R10, respectively, are leaving groups, representing the fluorescent, chloro, bromo, iodo or sulfonate the ester, and either or both of x2 and X4, X6 and X8 is(are) a nitrogen, are suitable precursors for labelling nucleophilic aromatic substitution. Moreover, it is preferable to use a leaving group, which is chemically different from the group, entered by the interaction with tagged nucleophile, to facilitate chromatographic separation of the labeled product of the interaction from unspent predecessor.

The compounds of formula Ib, in which R8 or R11 represents a protected (e.g., TBDMS) group, hydroxy (other represents hydrogen, and R10 represents O(CH2)2OToS or NH(CH2)2OTos are useful precursors for labelling fluoride application or kryptofix complex 2,2,2-[18F]fluoride (Schirrmacher et al. J. Labelled Compd. Rad. 2001, 44, 627)or [18F]tetrabutylammonium fluoride in CH3CN when heated (run bed and Breakfast et al. Appl. Radiat. Isotopes 2002, 57, 853) as sources of nucleophilic18F for nucleophilic formal replacement of the leaving group OTos-. Other suitable leaving groups that can be used are well known to the expert and shall include, without limiting them, bromo, iodo, OSO2CF3, OSO2CH3and OSO2phenyl.

The compounds of formula 1b, in which R8 represents H, R11 represents an OSi(G3)3or OH 2G4, R10 represents N(CH3)SNO, N(CH3Of PINES3N(CH3)CO2tert-butyl or CONH2and R9 represents a nitro, N(CH3)3+, bromo, iodo, chloro, are useful precursors for labelling fluoride complex of kryptofix 2,2,2-[18F]fluoride as a source of nucleophilic18F for nucleophilic substitution leaving formal groups R9 (F.Dolle, Curr. Pharm. Design 2005, 11, 3221-3235).

For more useful ways, well known to the specialist, to obtain the labeled compounds of the formula Ia transformations of functional groups suitable precursors include N-acylation of amines [11S]-, [14S]- or [3H]-acylchlorides catalyzed by palladium [11S]- or [14S]-cyanide aromatic chlorides, bromides or iodides catalyzed by transition metal substitution of suitable halides on3H in the presence of [3N]H2and catalyzed by palladium carbonylation with [11/14C] (Perry et al. Organometallics 1994, 13, 3346).

Examples of connections

Below are some non-limiting examples of compounds according to this invention. All of the following as examples of compounds or their respective its analogues, which are not only precursors and thus the seat is s as such, show IC50less than 20 microns in described here, the analysis of competitive binding.

General methods

All used solvents were of quality for analysis, and usually for interactions used commercially available anhydrous solvents. Interaction is typically conducted in an inert atmosphere of nitrogen or argon.

1H-spectra were recorded on a NMR spectrometer Bruker av400, operating at 400 MHz for proton, equipped with a 3-mm protocolization the measuring head of SEI1H/D13C with Z-gradients, using liquid manipulator BEST 215 for input samples, or on the NMR spectrometer Bruker DPX400, operating at 400 MHz for proton, equipped with a 5-mm 4-nucleus probe head with Z-gradients.

If this is not specified in the examples, particularly,1H-spectra were recorded at 400 MHz in DMSO-d6as a solvent. The residual signal of the solvent was used as a reference. Used the following control signals: the middle line DMSO-d6δ 2.50 each; the middle line CD3OD δ 3,31; CDCl3δ 7,26. In cases where the spectra were taken in a mixture of CDCl3and CD3OD, the reference signal was set at 3.31 mln-1. All chemical shifts are given in million-1on the Delta scale (δ), and the fine splitting of the signals of records designated as s (singlet), d (doublet), t (triplet), q (Quartet), m (a mule is tiplet), br (broad signal); or

Spectra1The h and13C-NMR were recorded at 400 MHz for proton and 100 MHz for carbon-13 NMR spectrometer Varian Mercury Plus 400, which is equipped with a probe of a Varian 400 ATV PFG. All deuterated solvents contained in typical cases from 0.03 to 0.05%.about. tetramethylsilane, which was used as the reference signal (set at δ 0,00 how to1H and13C).

3H-spectra were recorded on a NMR spectrometer Bruker DRX600 operating at 640 MHz for tritium and at 600 MHz for proton, equipped with a 5 mm probe head3N/a1H SEX with Z-gradients.1H-decondensation3H-spectra were recorded on samples dissolved in CD3OD. For binding spectra3H-NMR was used virtual frequency calculated by multiplying the frequency of the internal TMS in1H-spectrum on the ratio Lavrovsky frequencies for3H and1H (1,06663975) in accordance with the description in Al-Rawi et al. J. Chem. Soc. Perkin Trans. II 1974, 1635.

Mass spectra were recorded on a liquid chromatograph/mass spectrometer (LC/MS) Waters, consisting of a system of Alliance 2795 or Acquity (LC), photodiode matrix detector Waters 2996 PDA and ELS detector (Sedex 75) and a single quadrupole mass spectrometer ZMD or ZQ. The mass spectrometer was equipped with electrospray ion source (ES)operating in the positive mode or negative it is. The voltage on the capillary was 3 kV and the cone 30 C. the Mass spectrometer was scanned at m/z 100-600 with preview time 0.7 sec. The column temperature was set at 40°C (Alliance) or 65°C (Acquity). The linear gradient started with 100% A (A: 10 mm NH4OAc in 5% MeCN) and ending at 100% B (B: MeCN). Used column X-Terra MS C8, a 3.0×50; 3.5 µm (Waters) at a flow rate of 1.0 ml/min (Alliance) or Acquity UPLCTMVEINS81.7 mm, and 2.1×50 mm, flow rate 1.2 ml/min

Mass spectra with electrospray ionization (ESMS) were recorded on a mass spectrometer Waters, consisting of an Alliance 2795 (LC) and detector (Waters Micromass ZQ at 120°C. the Mass spectrometer was equipped with electrospray ion source (ES)operating in the positive mode or negative ions. The mass spectrometer was scanned at m/z 100-1000 with a preview time of 0.3 sec.

Preparative chromatography (prep. HPLC) was performed on one of the two automated HPLC Waters: (1) equipped with a detector diode matrix and a column XTerra MS C8, 19×300 mm, 10 μm; (2) consists of a mass spectrometric detector ZQ working when using ESI in positive mode when the voltage on the capillary 3 kV and the cone 30 In, under mixed control UV and MS signal for determination of the collected fractions. Column: XBridgeTMPrep C8 5 μm OBDTM19×100 mm, Gradient MeCN/(95:5 with 0.1 M NH4OAc:MeCN) used when IC is grow thread 20 or 25 ml/min

Microwave heating was carried out in a single mode microwave chamber Creator, Initiator or a Smith Synthesizer, giving a continuous radiation at 2450 MHz, or in the CEM Discover LabMate, or Biotage Initiator at the same temperature in the recommended microwave tubes.

Predecessors

The following examples are useful as precursors to obtain the radiolabelled compounds of formula Ia and show the IC50more than 20 μm in the here described analysis of competitive binding.

5-Methoxybenzeneboronic acid

n-Utility 2.5 M in hexano (5.6 ml) was slowly added to a solution of 5-methoxybenzophenone (13.5 mmol) in dry THF (30 ml) at -78°C. After stirring for 1 hour at -78°C was added dropwise triisopropylsilyl (27,0 mmol) and the mixture was stirred for another 20 min at -78°C. bath was Removed with dry ice, was added 2 N. HCl (aq. 40 ml) and the mixture was left to warm to K.T. and then poured in water (50 ml). The resulting aqueous solution was extracted with diethyl ether, the organic layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum to obtain the connection specified in the header, in the form of a beige powder (2,40 g).1H-NMR δ mn-18.49 (s, 2H) 7.45 (d, 1H) 7.38 (s, 1H) 7.18 (d, 1H) 6.93 (dd, 1H) 3.78 (s, 3H).

5-(5-Methoxy-benzofuran-2-yl)-p is ridin-2-ol

5-Methoxybenzeneboronic acid (230 mg, 1.2 mmol), 5-iodine-2-pyridone (221 mg, 1.0 mmol), Pd(PPh3)2Cl2(17 mg, 0,024 mmol) and NEt3(317 μl, 2.4 mmol) were mixed in EtOH (10 ml) in a 20 ml microwave vial. The mixture was stirred at 140°C for 10 min in a microwave reactor. The solvent was removed under vacuum, was added water and the solution was extracted with EtOAc. The organic layer was dried over Na2SO4was filtered and the solvent was removed under vacuum. The crude substance was purified preparative HPLC to obtain the connection specified in the header, in the form of a white solid (20 mg).1H-NMR δ mn-111.95 (br.s., 1H) 7.94 (dd, 1H) 7.88 (s, 1H) 7.44 (d, 1H) 7.00-7.20 (m, 2H) 6.84 (dd, 1H) 6.48 (d, 1H) 3.78 (s, 3H); mass spectrometry m/z 242 (M+H).

Connection

Below are a few non-limiting examples of compounds according to this invention. All connections below as examples of its or their respective analogues, which are not only precursors and thus marked as such, are IC50less than 20 microns in described here, the analysis of competitive binding.

Example 1

Amide 5-(5-methoxy-benzofuran-2-yl)-pyridine-2-carboxylic acid

5-Methoxybenzeneboronic acid (1.2 mmol), 5-bromopyridin-2-carboxamide (1.0 mmol who), Pd(PPh3)2Cl2(0,024 mmol) and NEt3(317 μl) were mixed in EtOH (10 ml) in a 20 ml microwave vial. The mixture was stirred at 140°C for 10 min in a microwave reactor, filtered and the precipitate washed with water and EtOAc and dried under vacuum to obtain the compound indicated in heading (75 mg).1H-NMR δ mn-19.10 (d, 1H) 8.34 (dd, 1H) 8.21 (br.s., 1H) 8.00 (d, 1H) 7.52-7.72 (m, 3H) 7.25 (d, 1H) 7.00 (dd, 1H) 3.82 (s, 3H); mass spectrometry (MS) m/z 269 (M+H).

Example 2

Amide 5-(5-hydroxy-benzofuran-2-yl)-pyridine-2-carboxylic acid

Amide 5-(5-methoxy-benzofuran-2-yl)-pyridine-2-carboxylic acid (0.21 mmol) was mixed with CH2Cl2(3 ml) at 0°C under argon atmosphere. Added drops BBr3(1 M in CH2Cl2) (1.0 ml) and the mixture was stirred for 2 hours at K.T. Mixture is hydrolyzed in H2O and next NaHCO3(saturated, aqueous). The resulting mixture was filtered and the precipitate washed with H2O and EtOAc. The solid was dried at 40°C for 15 h under vacuum to obtain the connection specified in the header (20 mg).1H-NMR δ mn-19.08 (d, 1H) 8.33 (dd, 1H) 8.20 (br.s., 1H) 7.97 (d, 1H) 7.61 (br.s., 1H) 7.54 (s, 1H) 7.47 (d, 1H) 7.02 (d, 1H) 6.85 (none, 1H); MC m/z 255 (M+H).

Example 3

6-(5-Methoxy-benzofuran-2-yl)-nicotinamide

5-Methoxybenzeneboronic acid (1.2 mmol), 6-bromonicotinate (1.0 mmol), Pd(PPhsub> 3)2Cl2(0,024 mmol) and NEt3(317 μl) were mixed in EtOH (10 ml) in a 20 ml microwave vial. The mixture was stirred at 140°C for 10 min in a microwave reactor. The mixture was filtered, the precipitate washed with water and EtOAc and dried under vacuum to obtain the connection specified in the header (85 mg).1H-NMR δ mn-19.14 (d, 1H) 8.42 (dd, 1H) 7.97-8.25 (m, 2H) 7.63-7.80 (m, 2H) 7.58 (d, 1H) 7.22 (d, 1H) 6.98 (dd, 1H) 3.81 (s, 3H); MC m/z 269 (M+H).

Example 4

6-(5-Hydroxy-benzofuran-2-yl)-nicotinamide

6-(5-Methoxy-benzofuran-2-yl)-nicotinamide (0.25 mmol) was mixed with CH2Cl2(3 ml) at 0°C under argon atmosphere. Added drops BBr3(1 M in CH2Cl2) (1.0 ml) and the mixture was stirred for 2 h at K.T. Mixture is hydrolyzed in H2O and then NaHCO3(saturated, aqueous). The resulting mixture was filtered and the precipitate washed with H2O and EtOAc. The solid was dried at 40°C for 15 h under vacuum (12 mg).1H-NMR δ mn-19.11 (d, 1H) 8.38 (dd, 1H) 8.01-8.23 (m, 2H) 7.63-7.76 (m, 1H) 7.59 (s, 1H) 7.46 (d, 1H) 7.00 (d, 1H) 6.83 (dd, 1H); MC m/z 256 (M+H).

Example 5

[5-(5-Methoxy-benzofuran-2-yl)-pyridine-2-yl]-methylamine

5-Methoxybenzeneboronic acid (1.2 mmol), 5-bromopyridin-2-methylamine (1.0 mmol), Pd(PPh3)2Cl2(0,024 mmol) and NEt3(317 μl) were mixed in EtOH (10 ml) in a 20 ml microwave vial the horse. The mixture was stirred at 140°C for 10 min in a microwave reactor. The solvent was removed under vacuum, was added water and the solution was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude substance was purified preparative HPLC to obtain the connection specified in the header, in the form of a white solid (100 mg).1H-NMR δ mn-18.53 (d, 1H) 7.84 (dd, 1H) 7.44 (d, 1H) 7.08 (d, 1H) 7.04 (s, 1H) 6.91 (d, 1H) 6.81 (dd, 1H) 6.55 (d, 1H) 3.78 (s, 3H) 2.83 (d, 3H); MC m/z 255 (M+H).

Example 6

2-(6-Methylamino-pyridine-3-yl)-benzofuran-5-ol

[5-(5-Methoxy-benzofuran-2-yl)-pyridine-2-yl]-methylamine (0.24 mmol) was mixed with CH2Cl2(3 ml) at 0°C under argon atmosphere. Added drops BBr3(1 M in CH2Cl2) (1.0 ml, 1.0 mmol) and the mixture was stirred for 2 h at K.T. Mixture is hydrolyzed in N2Oh and then the solution of NaHCO3(saturated, aqueous). The resulting mixture was extracted with EtOAc, and the organic extracts were dried over Na2SO4. After filtration and evaporation of the solvent the crude substance was purified preparative HPLC to obtain the connection specified in the header, in the form of a white solid (21 mg).1H-NMR δ mn-19.10 (s, 1H) 8.50 (d, 1H) 7.81 (dd, 1H) 7.32 (d, 1H) 6.96 (s, 1H) 6.81-6.94 (m, 2H) 6.66 (dd, 1H) 6.54 (d, 1H) 2.82 (d, 3H); MC m/z 241 (M+H).

Example 7

6-(5-Methoxy-b is souran-2-yl)-pyridazin-3-ylamine

5-Methoxybenzeneboronic acid (1.2 mmol), 6-bromo-3-pyridazinone (1.0 mmol), Pd(PPh3)2Cl2(0,024 mmol) and NEt3(317 μl) were mixed in EtOH (10 ml) in a 20 ml microwave vial. The mixture was stirred at 140°C for 10 min in a microwave reactor. The solvent was removed under vacuum, was added water and the solution was extracted with EtOAc. The organic layer was dried over Na2SO4, was filtered, and the solvent was removed under vacuum. The crude substance was purified preparative HPLC to obtain the connection specified in the header, in the form of a white solid (51 mg).1H-NMR δ mn-17.77 (d, 1H) 7.52 (d, 1H) 7.35 (s, 1H) 7.19 (d, 1H) 6.79-6.98 (m, 2H) 6.72 (s, 2H) 3.80 (s, 3H); MC m/z 242 (M+H).

Example 8

2-(6-Amino-pyridazin-3-yl)-benzofuran-5-ol

6-(5-Methoxy-benzofuran-2-yl)-pyridazin-3-ylamine (0.14 mmol) was mixed with CH2Cl2(3 ml) at 0°C under argon atmosphere. Added drops BBr3(1 M in CH2Cl2, 1.0 ml) and the mixture was stirred for 2 h at K.T. Mixture is hydrolyzed in H2O and then NaHCO3(saturated, aqueous). The resulting mixture was extracted with EtOAc, and the organic extracts were dried over Na2SO4. After filtration and evaporation of the solvent the crude substance was purified preparative HPLC to obtain compound indicated in the title the information, in the form of a yellow solid (8 mg).1H-NMR δ mn-19.21 (s, 1H) 7.74 (d, 1H) 7.40 (d, 1H) 7.27 (s, 1H) 6.96 (d, 1H) 6.86 (d, 1H) 6.76 (dd, 1H) 6.69 (s, 2H); MC m/z 228 (M+H).

Example 9

5-(1-Benzothieno-2-yl)pyridine-2-carboxamide

2-Benzothiazolinone acid (1.8 mmol), 5-bromopyridin-2-carboxamide (1.2 mmol), 2 M2CO3(2.4 ml), Pd(dppf)Cl2(0.12 mmol) were mixed and stirred at 80°C in DMF for 3 h, the Reaction mixture was filtered and to the filtrate was added EtOAc and H2O. the Layers were separated and the aqueous phase was extracted with EtOAc twice. The organic extracts were dried over Na2SO4. The solvent is evaporated in vacuum to obtain a brown solid. The crude substance was subjected obetovannoi HPLC with getting the connection specified in the header, in the form of a light brown solid (11 mg).1H-NMR δ mn-19.07 (d, 1H) 8.34 (dd, 1H) 8.24-8.02 (m, 5H) 7.73 (br s, 1H) 7.54-7.37 (m, 2H); MC m/z 255 (M+H).

Example 10

5-(1-Benzofuran-2-yl)pyridine-2-carboxamide

2-Benzofuranol acid (3.1 mmol), 5-bromopyridin-2-carboxamide (3.7 mmol), 2 M2CO3(water, 6 ml) and Pd(dppf)Cl2(0.31 mmol) were mixed and stirred at 80°C in DMF for 2 h, the Reaction mixture was filtered and washed with H2O and EtOAc. To the remnants of the solids was added DMSO and filtered. The filtrate was collected and purified obetovannoi HPLC to obtain compound, specified in the header, in the form of a white solid (2.5 mg).1H-NMR δ mn-19.18 (d, 1H) 8.46 (dd, 1H) 8.13-8.19 (m, 2H) 7.68-7.78 (m, 4H) 7.43-7.30 (m, 2H); MC m/z 239 (M+H).

Example 11

2-(1-Benzofuran-2-yl)-6-methoxyimino[1,2-a]pyridine

Benzofuranol acid (0,289 mmol), 2-bromo-6-methoxyimino[1,2-a]pyridine (to 0.263 mmol), Pd(dppf)Cl2(of 0.013 mmol) and K2CO3(water) was stirred in DMF at 80°C under argon for 1 h, the Reaction mixture was left to cool to K.T. and added it to the brine. The reaction mixture was extracted with CH2Cl2and the organic phase was filtered. The solvents were removed under reduced pressure, and the residue was purified obetovannoi HPLC with getting the connection specified in the header (0.5 mg).1H-NMR δ mn-17.95 (s, 1H) 7.67 (d, 1H) 7.65-7.60 (m, 1H) 7.58-7.51 (m, 2H) 7.33-7.20 (m, 3H) 7.03 (dd, 1H) 3.86 (s, 3H); MC m/z 265 (M+H).

Example 12

2-(6-Fluoro-5-methylamino-pyridine-2-yl)-benzofuran-5-ol

a) 6-Bromo-2-fluoro-pyridine-3-ylamine

To a stirred solution of 2-fluoro-pyridine-3-ylamine (3.0 g, 26,79 mmol) in acetic acid (24 ml) was added sodium acetate (2.17 g, 26,46 mmol). The reaction mixture was cooled to 0-5°C. and added thereto in drops a solution of bromine (1,37 ml, 26,74 mmol) in acetic acid (8 ml). After 1 hour the reaction mixture was cooled to 0°C, was added to it 10%of the initial aqueous solution of sodium hydroxide to reach pH ~5 and the product was extracted with ethyl acetate (200 ml). The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified column flash chromatography using 20%ethyl acetate in hexane to obtain 6-bromo-2-fluoro-pyridine-3-ylamine (3,9 g) as a brown solid.1H-NMR (400 MHz, CDCl3) δ: 7.15 (d, J=7.8 Hz, 1H), 7.00 (dd, J=10.1, 7.8 Hz, 1H), 3.80 (s, 2H). ESMS (mass spectrometry with elektrorazpredelenie): m/z 191,32, 193,34 [M+1]+

b) 2-Fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridine-3-ylamine

5-Methoxybenzeneboronic acid (345 mg, of 1.80 mmol), 6-bromo-2-fluoro-pyridine-3-ylamine (286,5 mg, 1.50 mmol), Pd(PPh3)2Cl2of 25.2 mg, being 0.036 mmol) and Et3N (475,5 ál, to 3.41 mmol) were mixed in EtOH (10 ml) in a microwave vial. The reaction mixture was stirred at 140°C for 10 minutes in a microwave reactor. Then remove volatiles under reduced pressure and added water (20 ml). The product was extracted with ethyl acetate (30 ml). The organic layer was dried over Na2SO4and concentrated in vacuum. Purification of the crude product column flash chromatography using 25%ethyl acetate in hexane gave 2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridine-3-ylamine (268 mg) as a cream solid.1H-NMR (400 MHz, CDCl3) δ: 7.58 (d, J=7.6 Hz, 1H), 7.39 (d, J=Hz, 1H), 7.15 (m, 1H), 7.14 (s, 1H), 7.04 (d, J=2.6 Hz, 1H), 6.88 (m, 1H), 3.95 (s, 2H), 3.85 (s, 3H). ESMS: m/z 259,47 [M+1]+

C) [2-Fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridin-3-yl]-methyl-amine

To a stirred solution of 2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridine-3-ylamine (97 mg, 0,376 mmol) in a mixture of Meon (2 ml) and dichloroethane (1 ml) was added formaldehyde (37%solution in water, 0,167 ml of 2.23 mmol) and acetic acid (50 μl, 0.87 mmol). The reaction mixture was stirred for 2 hours at room temperature, then added to it in one piece NaCNBH3(94 mg, 1.50 mmol) and continued stirring for 45 minutes. This reaction mixture is then extinguished by the addition of water (2 ml). Volatiles were removed under reduced pressure, and the residue was extracted with dichloromethane (50 ml). The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The product was purified column flash chromatography using 20%ethyl acetate in hexane to obtain [2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridin-3-yl]-methyl-amine (35,7 mg) as a cream solid.1H-NMR (400 MHz, CDCl3) δ: 7.64 (d, J=8.2 Hz, 1H), 7.38 (d, J=8.98 Hz, 1H), 7.09 (s, 1H), 7.03 (d, J=2.34 Hz, 1H), 6.99 (dd, J=10.15, 8.20 Hz, 1H), 6.87 (dd, J=8.78, 2.54 Hz, 1H), 4.21 (br. s, 1H), 3.85 (s, 3H), 2.94 (d, J=5.07 Hz, 3H)

g) 2-(6-Fluoro-5-methylamino-pyridine-2-yl)-benzofuran-5-ol

To the mix is the solution of [2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridin-3-yl]-methyl-amine (31 mg, 0,114 mmol) in dichloromethane (3 ml) at 0°C under nitrogen atmosphere was added drops BBr3(1 M solution in CH2Cl2, 0,568 ml, 0,568 mmol). The reaction mixture was stirred for 1.5 hours at room temperature. Then the mixture was cooled to 0°C, was added a saturated solution of sodium bicarbonate (5 ml) and the resulting mixture extracted with dichloromethane (50 ml). The organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. Purification of the crude product flash chromatography using 30%ethyl acetate in hexane gave the connection specified in the header, 2-(6-fluoro-5-methylamino-pyridine-2-yl)-benzofuran-5-ol (22 mg) as a cream solid.1H-NMR (400 MHz, METHANOL-d4) δ: 7.62 (d, J=7.90 Hz, 1H), 7.28 (d, J=8.78 Hz, 1H), 7.08 (dd, J=10.54, 8.20 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=2.34 Hz, 1H), 6.74 (dd, J=8.78, 2.34 Hz, 1H), 2.87 (s, 3H). ESMS: m/z 259,47 [M+1]+

Example 13

2-(2-Fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol

a) 5-Bromo-6-fluoro-pyridin-2-ylamine

To a stirred solution of 6-fluoro-pyridine-2-ylamine (1.0 g, 8,93 mmol) in acetonitrile (50 ml), protected from light, under an atmosphere of nitrogen was added N-bromosuccinimide (0,79 g of 4.46 mmol). After 1 hour, was added an additional portion of N-bromosuccinimide (0,79 g of 4.46 mmol) and continued stirring at those who tell 3 hours. Volatiles were removed under reduced pressure, and the crude substance was purified column flash chromatography using a gradient from 25% to 30% ethyl acetate in hexane to obtain 5-bromo-6-fluoro-pyridine-2-ylamine (1.45 g) as a white solid.1H-NMR (400 MHz, CHLOROFORM-d) δ: 7,60 (t, J=8.59 Hz, 1 H), 6.15-6.36 (m, 1H) 4.58 (br.s., 2H). ESMS: m/z 193,34 [M+1]+for isotope81Br.

b) 6-Fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridine-2-ylamine

5-Methoxybenzeneboronic acid (230 mg, 1.20 mmol), 5-bromo-6-fluoro-pyridin-2-ylamine (191 mg, 1.00 mmol), Pd(PPh3)2Cl2(16,8 mg, 0,024 mmol) and Et3N (317 μl, of 2.27 mmol) were mixed in EtOH (10 ml) in a microwave vial. The reaction mixture was stirred at 140°C for 15 minutes in a microwave reactor. Then remove volatiles under reduced pressure, the residue suspended in water and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuum. Purification of the crude product column flash chromatography using 25%ethyl acetate in hexane gave 6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridine-2-ylamine (130 mg) as a cream solid.1H-NMR (400 MHz, CHLOROFORM-d) δ: 8.05-8.21 (m, 1H) 7.36 (d, J=8.59 Hz, 1H) 7.03 (d, J=1.95 Hz, 1H) 6.97 (d, J=3.12 Hz, 1H) 6.86 (dd, J=8.78, 2.54 Hz, 1H) 6.45 (d, J=6.63 Hz, 1H) 4.66 (br.s., H) 3.86 (s, 3H).

C) tert-Butyl ether [6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridine-2-yl]-carbamino acid

To a stirred solution of 6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridine-2-ylamine (220 mg, 0,853 mmol) in THF (10 ml) at 0°C was added NaHMDS (1,02 ml of 1.02 mmol, 1 M solution in THF) and stirred for 15 minutes. That was followed by the addition of di-tert-BUTYLCARBAMATE (262 mg, 1.2 mmol) in THF (5 ml) for 5 minutes. The reaction mixture was stirred for 2 hours at room temperature. Added EtOAc and saturated aqueous NaHCO3and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified column flash chromatography using 10%ethyl acetate in hexane to obtain the connection specified in the header (81 mg), in the form of a cream solid.1H-NMR (400 MHz, CHLOROFORM-d) δ: 8.31-8.38 (m, 1H) 7.93 (dd, J=8.60, 1.56 Hz, 1H) 7.41 (d, J=8.99 Hz, 1H) 7.16 (s, 1H) 7.10 (d, J=3.52 Hz, 1H) 7.06 (d, J=2.74 Hz, 1H) 6.92 (dd, J=8.99, 2.74 Hz, 1H) 3.87 (s, 3H) 1.55 (s, 9H).

g) tert-Butyl ether [6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridine-2-yl]-methyl-carbamino acid

To a stirred solution of tert-butyl methyl ether [6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridine-2-yl]-carbamino acid (78 mg, 0,218 mmol) in DMF (5 ml) at 0°Dobavlyali NaH (11 mg, 0.26 mmol, 57%dispersion in oil) and stirred the mixture for 10 minutes. Then add methyliodide (15 μl, 0.24 mmol) and continued stirring for 30 minutes at room temperature. Added additional portions of NaH (11 mg, 0.26 mmol, 57%dispersion in oil) and under the conditions (15 μl, 0.24 mmol) and the solution was stirred for 1 hour. The reaction mixture was extinguished with water (5 ml), and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Purification of the crude product column flash chromatography using 10%ethyl acetate in hexane gave compound indicated in heading (66 mg), in the form of a cream solid.1H-NMR (400 MHz, CHLOROFORM-d) δ: 8.25-8.33 (m, 1H) 7.87 (m, 1H) 7.41 (d, J=9.37 Hz, 1H) 7.14 (s, 1H) 7.06 (d, J=2.34 Hz, 1H) 6.92 (d, J=8.98 Hz, 1H) 3.86 (s, 3H) 3.43 (s, 3H) 1.56 (s, 9H).

d) 2-(2-Fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol

To a stirred solution of tert-butyl methyl ether [6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridine-2-yl]-methyl-carbamino acid (66 mg, 0,184 mmol) in dichloromethane (30 ml) at 0°C under nitrogen atmosphere was added drops BBr3(1 M solution in CH2Cl2, of 0.92 ml, of 0.92 mmol). The reaction mixture was stirred at room temperature overnight and then was cooled to 0°C. was Added saturated the initial sodium bicarbonate solution and then was extracted with the mixture of 5%methanol in dichloromethane and 5%methanol in ethyl acetate. The organic layers were separately washed with brine, dried over Na2SO4was filtered , concentrated and subjected to flash chromatography using 30%ethyl acetate in hexane to obtain 2-(2-fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol (19.9 mg) as a cream solid.1H-NMR (400 MHz, METHANOL-d4) δ: 8.02 (m, 1H), 7.27 (d, J=8.59 Hz, 1H), 6.90 (d, J=2.34 Hz, 1H), 6.77 (d, J=3.51 Hz, 1H), 6.70 (dd, J=8.59, 2.34 Hz, 1H), 6.43 (dd, J=8.59, 1.95 Hz, 1H), 2.89 (s, 3H). ESMS: m/z 259,47 [M+1]+

Example 14

2-(5-fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol

a) 5-Bromo-3-fluoro-pyridin-2-ylamine

To a solution of 3-fluoro-pyridine-2-ylamine (1.0 g, of 8.92 mmol) in 300 ml of acetonitrile was added NBS (794 mg, of 4.46 mmol) at 0°C. the Reaction mixture was intensively stirred for 15 minutes (protect from light) at 0°C and then at room temperature for 1 hour. Was added at 0°C. an additional portion of NBS (794 mg, of 4.46 mmol) and was stirred solution at room temperature for 2 hours. The reaction mixture was suppressed by the addition of Na2S2O3(saturated aqueous solution, 40 ml), and the product was extracted with EtOAc (3×40 ml). The combined organic extracts were washed with brine (2×50 ml), dried over MgSO4and concentrated in vacuum. The crude yellow solid was purified on Biotage when and the use of 3-20%EtOAc in hexane to obtain 5-bromo-3-fluoro-pyridine-2-ylamine (1.2 g). 1H-NMR (400 MHz, CHLOROFORM-d) δ million-17.93 (d, J=1.56 Hz, 1H) 7.37 (dd, J=9.76, 1.95 Hz, 1H) 4.63 (br.s., 2H).

b) tert-Butyl ether (5-bromo-3-fluoro-pyridine-2-yl)-carbamino acid

To a solution of 5-bromo-3-fluoro-pyridine-2-ylamine (1.2 g, 6,28 mmol) in THF (100 ml) was added NaHMDS (1 M in THF, 6.2 ml) at 0°C. the Solution was intensively stirred for 15 minutes (was green). To the reaction mixture slowly over 30 minutes at 0°C was added Boc2O (1.3 g, 5,95 mmol)dissolved in THF (5 ml). Then the reaction mixture was heated to room temperature, was stirred for 5 hours and extinguished NaHCO3(saturated aqueous solution, 40 ml). The product was extracted with EtOAc (3×40 ml). The organic extracts were dried over MgSO4and concentrated in vacuum. The residue was purified on Biotage using 3-10%EtOAc in hexane to obtain the connection specified in the header (600 mg)as a white solid.1H-NMR (400 MHz, CHLOROFORM-d) δ million-18.29 (br.s, 1H) 7.58 (dd, J=9.37, 1.95 Hz, 1H) 6.89 (br.s., 1H) 1.53 (s, N).

C) tert-Butyl ether (5-bromo-3-fluoro-pyridine-2-yl)-methyl-carbamino acid

To a solution of tert-butyl methyl ether (5-bromo-3-fluoro-pyridine-2-yl)-carbamino acid (600 mg, of 2.06 mmol) in dry DMF (20 ml) was added NaH (130 mg, is 3.08 mmol) at 0°C. the Solution was intensively stirred for 10 minutes at 0°C was added the to him MeI (180 μl, is 2.88 mmol). After 30 minutes the reaction mixture was extinguished NH4Cl (saturated aqueous solution), and the product was extracted with EtOAc (3×40 ml). The combined organic extracts were washed with water, dried over MgSO4and concentrated in vacuum. The residue was purified on Biotage using 3-15%EtOAc in hexane to obtain the connection specified in the header (470 mg)as a white solid.1H-NMR (400 MHz, CHLOROFORM-d) δ million-18.23 (d, J=1.95 Hz, 1H) 7.52 (dd, J=8.59, 1.95 Hz, 1H) 3.22 (s, 3H) 1.37 (s, 9H).

g) tert-Butyl ether [3-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridine-2-yl]-methyl-carbamino acid

To a degassed solution of tert-butyl methyl ether (5-bromo-3-fluoro-pyridine-2-yl)-methyl-carbamino acid (310 mg, 1.01 mmol) in EtOH (10 ml) was added Pd(PPh3)2Cl2(142 mg, 0.20 mmol), benzofurazanyl acid (291 mg, of 1.52 mmol) and Et3N (283 μl, 2.03 mmol). This reaction mixture was stirred in a microwave reactor for 30 minutes at 100°C. Volatiles were removed under reduced pressure, and the residue was purified column flash chromatography using 10%EtOAc in hexane to obtain the connection specified in the header (130 mg)as a white solid.1H-NMR (400 MHz, CHLOROFORM-d) δ million-18.68 (br.s, 1 H) 7.80 (d, J=11.71 Hz, 1H) 7.42 (d, J=8.98 Hz, 1H) 7.04 (s, 2H) 6,93 (dd, J=8.98, 2.34 Hz, 1H) 3.85 (s, 3H) 3.35 (s, 3H) 1.46 (s,9H). ESMS: m/z 359,41 (M+1)

d) 2-(5-fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol

To a solution of tert-butyl methyl ether [3-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridine-2-yl]-methyl-carbamino acid (130 mg, 0.35 mmol) in dry CH2Cl2(400 ml) was added BBr3(2.1 ml, 2.10 mmol) at -78°C. the Reaction mixture was left to warm to room temperature and stirring was continued for 14 hours. This reaction mixture is then extinguished by the addition of saturated aqueous NaHCO3and the product was extracted with EtOAc (3×30 ml). The combined extracts were dried over MgSO4and concentrated in vacuum. The crude residue was purified preparative thin-layer chromatography (TLC) using 30%EtOAc in CH2Cl2obtaining 2-(5-fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol (37 mg) as a white solid.1H-NMR (400 MHz, METHANOL-d4) δ million-18.31 (br.s, 1H) 7.68 (dd, J=12.10, 1.95 Hz, 1H) 7.29 (d, J=8.59 Hz, 1H) 6.86-6.94 (m, 2H) 6.72 (dd, J=8.78, 2.54 Hz, 1H) 2.99 (s, 3H). ESMS: m/z 259,41 (M+1)

Biological examples

The following compounds were used as compounds comparison and indicated below in the text by their respective specified names:

PIB
[3H]PIB

Compounds of the present invention were tested in one or more of the following tests/experiments/research.

Analysis of competitive binding

Competitive binding was carried out in 384-well filter tablets FB when using synthetic β1-40 2.7 nm [3H]PIB (or other3H-labeled radioligand where indicated) in phosphate buffer at pH 7.5 by the addition of various concentrations of non-radioactive compounds, the initial dissolved in DMSO. Mixture for binding were incubated for 30 min at room temperature followed by vacuum filtration and then double rinsed in 1%Triton-X100. After that, scintillation fluid was added to collected on the filter plate β1-40, and the activity remaining linked radioligand ([3H]PIB or other3H-labeled radioligand) was measured when using a 1450 Microbeta from PerkinElmer.

Experiments on the dissociation

Experiments on the dissociation was carried out in 96-well polypropylene tablets with deep holes. Fibrils of synthetic β1-40 people (2 μm in phosphate buffer pH 7.5) or buffer alone as control were incubated with 9 nm3H-labeled radioligand of the present invention for 4 hours at room t is mperature. Dissociation was started at different time points by addition of an equal volume of its compounds according to the present invention or a control compound (10 μm) in 4%DMSO in phosphate buffer at pH 7.5. The radioactivity was still associated with fibrils β1-40, at the end of incubation were detected on the filters FB after filtration apparatus Brandel when using wash buffer containing 0.1%Triton-X100.

Research revenues in the brain of rats in vivo

Effects on the brain after intravenous administration was determined in the rat brain. when using cassette dosing. Introduced four different compounds and then taking samples of plasma and brain in terms 2 and 30 minutes after injection. To calculate the ratio of concentrations in the brain at time 2 and 30 min and the percentage of the total injected dose was detected in the brain after 2 minutes. The concentration of the compounds was determined in plasma samples after deposition of protein analysis obetovannoi liquid chromatography coupled with tandem mass spectrometer with elektrorazpredelenie.

Binding to amyloid plaques in postmortem brain samples of a person with Alzheimer's disease (ad) and in the brain of transgenic mice

Placed on a glass slide brain slices (10 μm) mice, transgenic for AP/PS1, collected at the level of the lateral septum (bregma + 0,98 mm; see Paxinos and Franklin, 2001). Cortical slices person (7 μm) from two patients with BA and 1 control subject received from the Dutch tissue Bank.

Slices pre-incubated for 30 minutes at room temperature in 50 mm Tris-HCl (pH 7.4) in the presence or absence of 1 μm PIB. The slices are transferred to a buffer containing tritium-labeled compound (1 nm) with or without PIB PIB (1 μm) and incubated for 30 minutes at room temperature. The incubation was completed 3 consecutive 10-minute washes in buffer (1°C) and then a quick rinse in distilled water (1°C). Sections were air-dried in front of a fan. Dry the slices and plastic tritium standards (Amersham microscales-3H) were placed on the plates for phospho-imaging (Fuji) in the cassette was subjected to during the night. The next morning visualization tablets processed through phospho-Visualizer Fuji BAS 2500) when using software BAS Reader. The resulting images were transferred to the TIF format using the software Aida, optimized using Adobe Photoshop (v 8.0) and quantitatively determined using Image-J (NIH). Data were subjected to statistical analysis using Excel.

Binding in the brain of mice, APP/PS1 after the call is placed connections in-vivo

Not subjected to the effects of awake mice were fixed and intravenous infusion via tail vein injected or tritium-labeled compound of the present invention, or tritium-labeled control connection. In the experiment of the same type animals were quickly anestesiologi with isoflurane and were deceptional 20 minutes after administration of compound (1 MCI). In another type of experiment, the mice were given 1 MCI connection and anestesiology and deceptional at time 20, 40 or 80 minutes after injection. The brain was removed and frozen powdered dry ice. Of the brain were prepared sections (10 μm) in the frontal plane at the level of the striatum when using a cryostat, placed in a thawed state for sverhbystro freezing glass slides and air-dried.

Then used a methodology designed to optimize visualization of the bound ligand after the introduction in vivo. For the selective reduction of the levels of unbound radioactivity one-half of the sections were washed (3×10 min) in cold (1°C) Tris-buffer (50 mm, pH 7.4) followed by rapid washing in cold (1°C) deionized water. Then the sections were air-dried in front of a fan. Washed and nepomechie slices and tritium standards were subjected to tablets for phospho-imaging (Fuji). The tablet is for phospho-imaging was treated by phospho-Visualizer Fujifilm BAS-2500 when using software BAS Reader.

Biological example 1

Characterization of specific binding of new 2-heteroaryl-substituted derivatives of benzothiophene and benzofuran with β-amyloid fibrils in vitro

Specific binding was determined in the manner we describe here the analysis of competitive binding. IC50defined in the analysis of competitive binding (with [3H]PIB as radioligand) compounds of the present invention, shown in the Table.

IC50obtained with the compounds of the examples according to the present invention when tested in the analysis of competitive binding.
NAMEIC50(nm)
2-[6-(methylamino)pyridine-3-yl]-1-benzofuran-5-ol46
5-(5-methoxy-1-benzofuran-2-yl)pyridine-2-carboxamide61
6-(5-hydroxy-1-benzofuran-2-yl)nicotinamide43
5-(5-hydroxy-1-benzofuran-2-yl)pyridine-2-carboxamide600
5-(5-methoxy-1-benzofuran-2-yl)-N-methylpyridin-2-amine66
6-(5-methoxy-1-benzofuran-2-yl)pyridazin-3-amine912
2-(1-benzofuran-2-yl)-6-methoxyimino[1,2-a]pyridine361
5-(1-benzothieno-2-yl)pyridine-2-carboxamide30
5-(1-benzofuran-2-yl)pyridine-2-carboxamide19
6-(5-methoxy-1-benzofuran-2-yl)nicotinamide33
2-(6-aminopyridin-3-yl)-1-benzofuran-5-ol2705
2-(6-fluoro-5-methylamino-pyridine-2-yl)-benzofuran-5-ol44
2-(2-fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol18
2-(5-fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol32

1. The compound of formula Ia

where R1 is selected from H, hydroxy, methoxy;
R2 is selected from H;
X9selected from Oh;
Q represents a nitrogen-containing aromatic heterocycle selected from Q2;

where Q2 represents a 6-membered aromatic heterocycle containing one N atom or two atoms , where X1, X2, X3and X4independently selected from N or S; and where one or two of X1, X2, X3and X4is(are) a N, and the rest are With, and where the atom X1represents s, and the specified substituted With R4; and where the atom X2represents s, and the specified substituted With R5;
R3 is selected from amino, NHC groups1-3alkyl, N(C1-3alkyl)2, NH(CO)C1-3alkyl, (CO)NH2;
R4 is selected from H, fluorescent, bromo and iodo;
R5 is selected from H, fluorescent, bromo and iodo;
one or more than one of its constituent atoms may represent the detected isotope;
in the form of free base or its pharmaceutically acceptable salt, MES or MES salt;
provided that the following compounds are excluded:
.

2. The compound according to claim 1, where R1 is selected from H, hydroxy and methoxy.

3. The compound according to claim 1, where Q2 represents a pyridine ring, where X3and X4independently selected from N or S; and where one of X3and X4represents N and the other X1, X2, X3and X4represent C.

4. The compound according to claim 1, where R3 is selected from amino, group NH and (CO)NH2.

5. The compound according to claim 1, where R4 is selected from H, fluorescent.

6. The compound according to claim 1, where R5 is selected from H, fluorescent.

2-(6-methylamino-pyridine-3-yl)-1-benzofuran-5-ol
2-(6-fluoro-5-methylamino-pyridine-2-yl)-benzofuran-5-ol
2-(5-fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol,

and one or more than one of its constituent atoms may represent the detected isotope;
in the form of free base or its pharmaceutically acceptable salt, MES or MES salt.

8. The compound according to claim 1, with the specified connection is:

2-(2-fluoro-6-methylamino-pyridine-3-yl)-benzofuran-5-ol,


and one or more than one of its constituent atoms may represent the detected isotope;
in the form of free base or its pharmaceutically acceptable salt, MES or MES salt.

9. The compound according to claim 1, where one of its constituent atoms represents the detected ISAT the p 18F.

10. Pharmaceutical composition for imaging amyloid deposits containing the compound according to any one of claims 1 to 9, together with a pharmaceutically acceptable carrier.

11. The method of determination of amyloid deposits in vivo in a subject, comprising the stage of: (a) the introduction of the detected amount of the pharmaceutical composition of claim 10, and (b) detecting binding of the compound to amyloid Deposit in the subject.

12. The method according to claim 11, where the specified detection carried out by the group of methods selected from gamma imaging, magnetic resonance imaging and magnetic resonance spectroscopy.

13. The method according to item 12, where the subject is suspected of having the disease or syndrome is selected from the group consisting of Alzheimer's disease.

14. The compound according to any one of p and 9 for use in the prevention and/or treatment of Alzheimer's disease.

15. The use of compounds according to any one of p and 9 in the manufacture of a medicine for the prevention and/or treatment of Alzheimer's disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel tricyclic derivative of chemical formula 1 or pharmaceutically acceptable salts thereof: formula 1, where Y1, Y2 and Y3 independently denote H, C1-C10 alkyl with a straight or branched chain, hydroxy, C1-C10 alkoxy, -CCOR1, -NR2R3 or -A-B; A denotes -O-, -CH2-, -CH(CH3)-, -CH-N- or -CONH-; B denotes -(CH2)n1-Z, -(CH2)n2-NR2R3 or -(CH2)n3-OR1; Z denotes C5-C20 aryl, unsubstituted or substituted with R5 and selectively R6, C3-C10 cycloalkyl, unsubstituted or substituted with R5 and selectively R6, C1-C20 heterocyclic compound, unsubstituted or substituted with R5 and selectively R6; R1 denotes H or C1-C10 alkyl with a straight or branched chain; R2 and R3 independently denote H, C1-C10 alkyl with a straight or branched chain or -(CH2)n4R7; R5 denotes H, C1-C10 alkyl with a straight or branched chain, C5-C20 aryl or C1-C20 heterocyclic compound; R6 denotes H or C1-C10 alkyl with a straight or branched chain; R7 denotes -NR8R9, -COOR1, -OR1, -CF3, -CN, halogen or Z; R8 and R9 independently denote H or C1-C10 alkyl with a straight or branched chain; n1-n4 respectively denote an integer from 0 to 15; Y denotes H or C1-C10 alkyl with a straight or branched chain. The invention also relates to methods of producing a compound of formula 1, compositions containing the described compound and with effective inhibiting activity on poly(ADP-ribose)polymerase (PARP).

EFFECT: obtaining and describing novel compounds which can be suitable for preventing or treating diseases caused by excess PARP activity, especially neuropathic pain, neurodegenerative diseases, cardiovascular diseases, diabetic neuropathy, inflammatory diseases, osteoporosis and cancer.

23 cl, 123 ex, 7 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, method for production thereof, use thereof to produce a medicinal agent which inhibits MR activity.

EFFECT: improved method.

11 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) where values of substituents are given in description, possessing inhibiting activity with respect to cathepsin K as well as to pharmaceutical compositions for treating diseases, associated with cysteine protease activity and to methods of inhibiting cathepsin K in mammals, requiring such treatment by introduction of efficient amount of compound to mammal.

EFFECT: claimed is application of formula (I) compound or its pharmaceutically acceptable salt in manufacturing medication for application in cathepsin K inhibition in a warm-blooded animal.

10 cl, 45 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazopyridine compounds of formula (I) and pharmaceutically acceptable salts thereof, which inhibit kinase activity, selected from IGF-1R, IR, EGFR and Erb2 and have cell proliferation inhibitor properties. In formula (I) halogeno denotes a halogen; X1 is H or halogen, R1 is H, halogen or halogen-C1-C4alkyl; R2 is H or O-C1-C4alkyl; each R3 is identical or different and is independently selected from H, halogen, C1-C4alkyl, halogen-C1-C4alkyl and O-C1-C4alkyl; one of R4 and R5 is selected from H, halogen, C1-C4alkyl and O-C1-C4alkyl; and the other is a group selected from: (i), (ii) and (iii) where:(1) each R7 is H; a equals 0, 1, 2 or 3; R8 is selected from NH2, N(H)C1-C4alkyl, N(C1-C4alkyl)2 and a group of formula (iv): (iv), where: ring D is a 5-6-member saturated N-heterocycle, possibly containing 1 or 2 additional heteroatoms selected from N and O. Other values of radicals are given in the claim.

EFFECT: compounds can be used in treating different types of cancer.

4 tbl, 250 ex

Chemical compounds // 2469034

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes compounds of formula (I) wherein: R1 means C1-6alkyl or C3-6cycloalkyl; wherein R1 may be optionally carbon-substituted by one or more R6; R2 means hydrogen; R3 and R4 are carbon substitutes, and each is independently specified in carboxy, carbamoyl, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkoxy)carbamoyl, phenyl-R9 - or heterocyclyl-R10-; wherein R3 and R4 may be independently carbon-substituted by one or more R11; and wherein provided said heterocyclyl contains -NH - residue, then nitrogen may be optionally substituted by a group specified in R12; m has the value of 0, 1 or 2; wherein the values R3 may be equal or different; p has the value of 0, 1 or 2; wherein the values R4 may be equal or different; the ring A means nitrogen-containing 5- or 6-member heterocyclic group; wherein drawn nitrogen represents = N- and is found in an ortho-position to R1R2NC(O)NH group in formula (I); the ring B means phenyl or heterocyclyl; wherein provided said heterocyclyl contains -NH- residue, then nitrogen may be optionally substituted by a group specified in R14; R5 is specified in hydroxy, C1-6alkoxy or -N(R15)(R16); R6 and R11 are carbon substitutes and each is independently specified in halo, C1-6alkyl or C1-6alkoxy; R15 and R16 are independently specified in hydrogen, C1-6alkyl, C1-6alkoxy, cyclopropyl or cyclopentyl; R12 and R14 mean C1-6alkyl; wherein R14 may be optionally carbon specified by one or more R23; R9 and R10 mean a direct link; and R23 means halo or methoxy; wherein said heterocyclyl means pyridine, imidazole, triazole, thiazole, benzothiazole, imodazolepyridine, dihydroquinoline or thiadiazole, or its pharmaceutically acceptable salt; provided said compound represents other than ethyl ester of 5-[2-[[(ethylamino)carbonyl]amino]pyridin-4-yl]-4-methyl-4H-1,2,4-triazole-3-carboxylic acid or their pharmaceutically acceptable salts. There are also described pharmaceutical compositions on the basis of said compounds, a method for bacterial DNA-hydrase and/or bacterial topoisomerase IV inhibition in a homoiothermal animal, as well as a method of treating an infection in a homoiothermal animal.

EFFECT: there are prepared and described new compounds showing antibacterial activity.

24 cl, 165 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to fluorinated compounds of formula , where: D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more halogen atoms; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: halogen, C1-C10 alkyl; E denotes aryl which can be substituted with one or more fluoro-substitutes or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more fluoro-substitutes, and where Q denotes O; m denotes a number from 1 to 2; under the condition that: R3 is a fluoro-substitute, or group E includes a fluoro-substitute, or group Z includes a fluoro-substitute, with the condition that E does not denote 4-fluorophenyl or a compound of formula , where D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more of the following substitutes: chlorine, bromine, iodine; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: chlorine, bromine, iodine, C1-C10 alkyl; E denotes aryl which can be substituted with one or more chlorine, bromine or iodine atoms, and/or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more substitutes selected from chlorine, bromine, iodine or hydroxy, where Q denotes O, wherein when E denotes phenyl, E does not contain, as a substitute, iodine which is directly bonded to it at position 4; m denotes a number from 1 to 2; wherein at least one of Z, E and R3 includes iodine; under the condition that E does not denote 4-iodophenyl and under the condition that said compound is not a compound of formula (Ia), defined in the following table:

The invention also relates to a pharmaceutical composition based on the compound of formula (I) or (Ia), a diagnosis method, a method of treating said disorders, based on use of the compound of formula (I) or (Ia), and use of the compound of formula (I) or (Ia).

EFFECT: obtaining novel compounds useful in treating disorders in mammals, characterised by anomalous density of peripheral benzodiazepine receptors.

24 cl, 13 dwg, 9 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel disubstituted phenylpyrrolidines of formula , any stereoisomers thereof or any mixtures of stereoisomers thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, where Ar denotes phenyl; R1 denotes F, Cl; R2 denotes F and Cl; R3 denotes H, Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu, tert-Bu, cyclopropylmethyl, CFH2CH2CH2-, CF2HCH2CH2-, CF3CH2CH2-, allyl and CH3OCH2CH2-; X denotes F, OH; under the condition that X denotes OH, R3 does not denote H.

EFFECT: compounds are capable of increasing levels of dopamine, norepinephrine and serotonin, which enables their use in treating central nervous system disorders.

16 cl, 21 dwg, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3-alkyl(aryl)-2,2'-bithiophene-5-carboxylic acids and esters thereof of general formula I where R = C1-C10-alkyl or aryl; R1 = hydrogen atom or C1-C4 alkyl, involving reaction of 2-acyl thiophenes of general formula II with dimethyl formamide and phosphoryl chloride, and the formed 2-alkyl(aryl)-3-chloro-3-(2-thienyl)acrylaldehyde of general formula III reacts with thioglycolic ester in the presence of a base, and by hydrolysis of the obtained esters of general formula I, where R assumes values given above and R1=C1-C4 alkyl, 3-alkyl-2,2'-bithiophene-5-carboxylic acids are obtained, where R1 = hydrogen atom.

EFFECT: simpler method of producing compounds of formula I, which can be used in synthesis of solvatochromic and thermochromic dendrimers, oligothiophenes with adjustable electrical and optical properties.

1 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

EFFECT: compounds have inhibiting activity on IKKβ, which enables their use as a preventive or therapeutic agent for treating IKKβ mediated diseases.

26 cl, 1 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2,3-disubstituted indoles of general formula (I): , where the method involves the following steps: a) reaction of bromine diol (i): with dialkoxyborane in the presence of a ligand, a palladium catalyst, preferably selected from Pd(OAc)2, PdCl2, PdBr2, Pd2(dba)3, Pd2(dba)3.CHCl3, [Pd(ally)Cl]2,- Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, Pd/C and encapsulated Pd and a base to obtain a compound of general formula or, alternatively, reaction of compound (i) with a magnesium compound containing 3 alkyl groups, with subsequent treatment with a borate to obtain a compound of general formula ii given above; b) reaction of the product from step (a) with R2-Hal to obtain a compound of general formula I; where: R denotes (C1-C6)alkyl; R2 denotes: , , , , ,

, , , , ;

R3 denotes cyclopentyl: X denotes carboxymethyl; Hal denotes Br or I; or pharmaceutically acceptable salt thereof.

EFFECT: higher efficiency.

12 cl, 4 dwg, 2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: described are novel 1,2,4-triazolones of general formula (I):

, where A denotes N and values of other radicals are given in the claim, which are vasopressin receptor inhibitors, synthesis method thereof and use thereof to prepare medicinal agents for treating and/or preventing diseases, particularly for treating and/or preventing cardiovascular diseases.

EFFECT: high efficiency of using said derivatives.

6 cl, 512 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (1) in free form or in form of a salt. In formula (1): X1 and X2 all independently denote halogen; A denotes a radical of formula where (R1)1-2 denotes 1-2 identical or different substitutes selected from a group comprising C1-C4-alkyl, halogen-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, R2R3N-C1-C4-alkyl, halogen, hydroxy group, C1-C4-alkoxy group, halogen-C1-C4-alkoxy group, C1-C4-alkylthio group, C1-C4-alkanoyl, C1-C4-alkanoylamino group, C1-C4-alkylsulphonylamino group, C1-C4-alkylsulphonyl, C1-C4-alkylthionyl, NR2R3 and morpholinyl; or A denotes a radical of formula where ring (a) denotes a 5-member heterocyclic ring containing 1 or 2 heteroatoms selected from a group comprising O and N, which can further be substituted with C1-C4-alkyl, and which is annelated in positions 3 and 4; and R2 and R3 all independently denote hydrogen or C1-C4-alkyl. The invention also relates to a parasite control composition containing said compounds, a parasite control method on warm-blooded animals and use of compounds of formula (1) to prepare a parasite control composition.

EFFECT: high efficiency of using said compounds.

11 cl, 7 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula A

the radicals R1, R2, R3, R4, R5, R25, R26, U, T, W, V, Y are those as specified in clause 1 of the patent claim. Also, the invention refers to a method for preparing the compound of formula A, the drug based on this compound applied for treating disorders or diseases which are at least partially mediated by vanilloid receptor VR1 /NRPV1, as well as use of this compound for preparing the drug.

EFFECT: there are prepared and described new compounds which can be effective in treating diseases which are at least partially mediated by vanilloid receptor VR1 /NRPV1.

43 cl, 367 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted methyl-amines of general formula 1, having serotonin 5-HT6 receptor antagonist properties. In formula 1 , W is naphthalene, indolysin or quinoline; R1 is hydrogen, fluorine, chlorine, methyl; R2 is hydrogen, fluorine, methyl, phenyl, thiophen-2-yl, furan-2-yl, pyridyl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is methyl; or W is benzene, R3 assumes the value given above; R1 is 3-Cl, R2 is 3-piperazin-1-yl or 3-(4-methylpiperazin-1-yl); or R1 is hydrogen, R2 is phenyl or pyridyl; or R1 is hydrogen, fluorine, chlorine, methyl; R2 is 4-piperazin-1-yl or 4-(4-methylpiperazin-1-yl); or W is oxazole, R3 is optionally substituted methyl; R1 is chlorine or fluorine, R2 is methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is piperazin-1-yl, 4-methylpiperazin-1-yl, or R1 is chlorine, fluorine or methyl; R2 is furan-2-yl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is furan-2-yl, R3 is (tetrahydrofuran-2-yl)methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is thiophen-2-yl, R3 is 2-methoxyethyl, or R1 is chlorine or fluorine, R2 is thiophen-2-yl, R3 is methyl.

EFFECT: compounds can be used to treat central nervous system (CNS) diseases, such as psychiatric disorders, schizophrenia, anxiety disorders, as well as for improving mental capacity, for treating obesity or for studying the molecular mechanism of inhibiting serotonin 5-HT6 receptors.

15 cl, 27 dwg, 2 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel antibacterial chinolin derivatives of formula (1a), their stereochemically isomeric forms, N-oxides and pharmaceutically acceptable salts and solvates , where p equals 1; q equals 0, 1, 2, 3 or 4; R1 represents hydrogen, halogen, aryl or Het; R2 represents hydrogen or alkyloxy; R3 represents arylalkyl; each R4 and R5 independently represent hydrogen or alkyl; R7 represents hydrogen, alkyl or aryl; where aryl is selected from phenyl or naphtyl and is optionally substituted with 1, 2 or 3 substituents selected from hydroxy, halogen, cyano, nitro, amino, mono- or dialkylamino, alkyl, C2-6alkenyl, optionally substituted with phenyl, halogenalkyl, alkyloxy, halogenalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl or mono- or dialkylaminocarbonyl; where Het is selected from furanyl, thienyl, pyridinyl, benzofuranyl, optionally substituted with 1, 2 or 3 substituents selected from halogen, hydroxyl, alkyl or alkyloxy.

EFFECT: compounds can be used for creation of preparations on their base for treatment of bacterial infection

21 cl, 4 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel disubstituted phenylpyrrolidines of formula , any stereoisomers thereof or any mixtures of stereoisomers thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, where Ar denotes phenyl; R1 denotes F, Cl; R2 denotes F and Cl; R3 denotes H, Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu, tert-Bu, cyclopropylmethyl, CFH2CH2CH2-, CF2HCH2CH2-, CF3CH2CH2-, allyl and CH3OCH2CH2-; X denotes F, OH; under the condition that X denotes OH, R3 does not denote H.

EFFECT: compounds are capable of increasing levels of dopamine, norepinephrine and serotonin, which enables their use in treating central nervous system disorders.

16 cl, 21 dwg, 69 ex

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